今日の臨床サポート 今日の臨床サポート

著者: 狩野俊和 国立国際医療研究センター国府台病院 リウマチ膠原病科

監修: 金子礼志 国立健康危機管理研究機構(JIHS)国立国際医療センター 膠原病科

著者校正済:2022/09/14
現在監修レビュー中
参考ガイドライン:
  1. 日本リウマチ学会:関節リウマチ診療ガイドライン2020(2021年4月26日)
  1. 日本リウマチ学会関節リウマチ診療ガイドラインJCR2014に基づく一般医向け診療ガイドライン(2017年7月10日)
  1. 日本リウマチ学会:リウマチ診療のための関節エコー撮像法ガイドライン
  1. 日本リウマチ学会関節リウマチ(RA)に対するTNF阻害薬使用の手引き(2020年2月1日改訂版)
  1. 日本リウマチ学会関節リウマチ(RA)に対するIL-6阻害薬使用の手引き(2020年2月1日改訂版)
  1. 日本リウマチ学会関節リウマチ(RA)に対するアバタセプト使用の手引き(2020年2月1日改訂版)
  1. 日本リウマチ学会関節リウマチに対するデノスマブ使用の手引き
  1. 日本リウマチ学会:全例市販後調査のためのフィルゴチニブ使用ガイド(2020年12月4日)
  1. 日本リウマチ学会:全例市販後調査のためのウパダシチニブ適正使用ガイド(2020年6月14日)
  1. 日本リウマチ学会全例市販後調査のためのトファシチニブ適正使用ガイド(2020年2月1日改訂版)
  1. 日本リウマチ学会全例市販後調査のためのバリシチニブ適正使用ガイド(2020年2月1日改訂版)
  1. 日本リウマチ学会全例市販後調査のためのペフィシチニブ適正使用ガイド(2020年2月1日)
  1. 日本骨代謝学会ステロイド性骨粗鬆症の管理と治療ガイドライン2014年改訂版
  1. 日本リウマチ学会関節リウマチ治療におけるメトトレキサート(MTX)診療ガイドライン2016年改訂版
  1. 日本骨粗鬆症学会骨粗鬆症の予防と治療ガイドライン2015年版
患者向け説明資料

改訂のポイント:
  1. 関節リウマチ診療ガイドライン2020に基づいて記載を変更した。新薬については日本リウマチ学会ホームページのガイドラインに記載されている適正使用ガイドをもとに記載した。

概要・推奨   

  1. 関節リウマチは早期に十分な治療を開始できると寛解導入が容易である。そのために診断は迅速に行い、速やかに適切な治療を開始することが重要である(推奨度1)
  1. 必ずしも容易ではない早期関節炎の診断と治療方針の決定や、生物学的製剤を含む専門的知識を要する薬物治療、合併病態を有する患者の治療、関節リウマチに起因する関節手術などは主としてリウマチ専門医が行うべき医療である薬物治療が奏して安定的な経過をたどっている患者の日常診療や、基本的な薬剤の投与、非薬物治療などは一般医に推奨できる医療である(推奨度2)
  1. 1つ以上の関節炎を持つ患者で、他の疾患を除外でき、2010ACR/EULAR分類基準を満たせば関節リウマチと判断して治療を開始することは推奨されるが、専門家の意見も加味して慎重に判断する必要がある(推奨度1)
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  1. リウマトイド因子は感度・特異度ともに高くない。分類基準に該当する項目であるので測定する意義はあるが、陽性の場合でも他疾患の鑑別を幅広く考える必要がある(推奨度1)
  1. 関節炎患者に抗CCP抗体測定は特にリウマトイド因子陰性の場合に推奨される(推奨度2)
  1. MRIはX線で検出できない軽度の骨びらん、骨髄浮腫、滑膜肥厚の検出には有用であるため、リウマチが疑われる患者で単純X線上の変化が認められないときには考慮してよい(推奨度3)
  1. リウマチ診療は最善のケアを目指すものであり、患者とリウマチ専門医の共同作業であるため、患者自身が病気を知ることは重要である(推奨度1)
  1. リウマチの関節痛に対して非選択性非ステロイド系抗炎症薬(NSAIDs)は臨床症状改善には有効であり、疾患活動性がコントロールされるまで、または関節破壊に伴う痛みに対しては有用である。ただし、長期の関節破壊抑制効果は乏しい(推奨度2)
  1. 疾患活動性を有する早期リウマチ患者に、抗リウマチ薬に併用して、副腎皮質ステロイドを必要最小量(プレドニゾロン10mg以下)、短期間(数月以内)投与行ってよい。再燃時に使用する場合も同様である(推奨度2)
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  1. MTXは6~8mg/週から開始し、開始後4週間経過しても効果が不十分な場合は増量する。なお、16mg/週まで漸増することにより用量依存的に効果が増加することが期待できるため、忍容性に注意を払いつつ有効量まで増量することが推奨される(推奨度2)ただし、高齢者、低体重、腎機能低下、肺疾患、アルコール常飲、NSAIDs複数内服例では2~4mg/週で開始する。
  1. MTXの口内炎や消化管障害を減らす目的で、葉酸製剤を投与することは推奨される(推奨度1)
  1. MTXで効果不十分な関節リウマチ患者にMTXに加えて、サラゾスルファピリジン(SASP)、イグラチモド(IGU)、ブシラミン(BUC)、タクロリムス(TAC)の併用療法が推奨される(推奨度2)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧
  1. 関節リウマチ治療に経口ステロイドを3月以上使用また使用を予定する患者で危険因子をスコアで評価[1](J)し、スコアが3点以上の場合は、アレンドロネート、リセドロネートなどのビスホスホネート製剤の使用は強く推奨される(推奨度1)
  1. 関節リウマチ治療にステロイドを使用してない場合も、関節リウマチは骨粗鬆症を起こしやすい疾患であるため、原発性骨粗鬆症の評価と治療を行う[2](J)(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
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  1. デノスマブ(denosumab)は骨密度増加と関節破壊抑制が期待できるため、投与を考慮してよい(推奨度2)
  1. 生物学的製剤の選択方法は、投与方法、投与間隔、MTX併用可能か否か、合併症を考慮して選択する。ただし、MTXは併用可能なら併用するのが望ましい(推奨度1)
  1. MTX、生物学的製剤、JAK阻害薬開始前にはB型肝炎、C型肝炎、胸部X線検査、結核検査、β-Dグルカン測定を行い、リスクに応じた予防を行う(推奨度1)
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病態・疫学・診察 

疾患情報  
  1. 関節リウマチは、関節の滑膜細胞増殖・破骨細胞活性化を生じ、これにより関節痛、関節腫脹、関節の変形が生じる膠原病である。血管、心臓、肺、皮膚などの全身臓器にも障害が及ぶこともある。
  1. 関節リウマチは手指や手、足趾などの末梢関節を中心として全身の関節に炎症が起きることが特徴である。
  1. わが国では約200人に1人に発生し、20~50歳が好発年齢で男女比はおよそ1:4である。
  1. 診断は2010米国/欧州リウマチ学会(ACR/EULAR)分類基準(図<図表>)に従って行う。ACR1987分類基準(図<図表>)は、早期診断には不向きであったが除外基準がないため、非専門医にも使いやすい分類基準である。2010ACR/EULAR分類基準は“ほかに症状を説明し得る疾患がない”ことを前提に、より早期診断できるように変更された。しかし、非専門医にとって、“ほかに症状を説明し得る疾患がない”ことを的確に評価することは難しく、改訂される余地も残している。
  1. メトトレキサートや生物学的製剤、ヤヌスキナーゼ阻害薬(JAK阻害薬)の登場で早期の治療介入により関節炎を抑制し、多くの患者で関節破壊の予防ができるようになったが、これらの治療を行っている患者ではニューモシスチス肺炎などの日和見感染に注意する必要がある。
問診・診察のポイント  
ポイント:
  1. 持続する手関節、中手指節関節(MCP関節)、近位指節間関節(PIP関節)を中心とした多発関節痛をみたら、関節リウマチを疑い、関節症状と鑑別疾患の評価を行う。

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文献 

骨粗鬆症の予防と治療ガイドライン作成委員会. 骨粗鬆症の予防と治療ガイドライン2015年版. 2015; Available from: http://www.josteo.com/ja/guideline/doc/15_1.pdf
Daniel Aletaha, Tuhina Neogi, Alan J Silman, Julia Funovits, David T Felson, Clifton O Bingham, Neal S Birnbaum, Gerd R Burmester, Vivian P Bykerk, Marc D Cohen, Bernard Combe, Karen H Costenbader, Maxime Dougados, Paul Emery, Gianfranco Ferraccioli, Johanna M W Hazes, Kathryn Hobbs, Tom W J Huizinga, Arthur Kavanaugh, Jonathan Kay, Tore K Kvien, Timothy Laing, Philip Mease, Henri A Ménard, Larry W Moreland, Raymond L Naden, Theodore Pincus, Josef S Smolen, Ewa Stanislawska-Biernat, Deborah Symmons, Paul P Tak, Katherine S Upchurch, Jirí Vencovsky, Frederick Wolfe, Gillian Hawker
2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative.
Ann Rheum Dis. 2010 Sep;69(9):1580-8. doi: 10.1136/ard.2010.138461.
Abstract/Text OBJECTIVE: The 1987 American College of Rheumatology (ACR; formerly the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticised for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA.
METHODS: A joint working group from the ACR and the European League Against Rheumatism developed, in three phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct 'RA'.
RESULTS: In the new criteria set, classification as 'definite RA' is based on the confirmed presence of synovitis in at least one joint, absence of an alternative diagnosis better explaining the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in four domains: number and site of involved joints (range 0-5), serological abnormality (range 0-3), elevated acute-phase response (range 0-1) and symptom duration (two levels; range 0-1).
CONCLUSION: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimise the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct 'RA'.

PMID 20699241
Helga Radner, Tuhina Neogi, Josef S Smolen, Daniel Aletaha
Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: a systematic literature review.
Ann Rheum Dis. 2014 Jan;73(1):114-23. doi: 10.1136/annrheumdis-2013-203284. Epub 2013 Apr 16.
Abstract/Text BACKGROUND: The 2010 ACR/EULAR classification criteria for rheumatoid arthritis (RA) were developed to improve the identification of individuals for studies of RA. We aimed to summarise the performance of the criteria based on the published literature.
METHODS: We performed a systematic literature search to identify all studies investigating the 2010 criteria and reporting data allowing to calculate sensitivity (SENS), specificity (SPEC), and positive and negative predictive values. Where possible, meta-analysis was performed.
RESULTS: Seventeen full articles (total 6816 patients) and 17 meeting abstracts (total 4004 patients) fulfilled the inclusion criteria. Pooled sensitivity and specificity for RA (defined by different reference standards) were 0.82 (95% CI 0.79-0.84) and 0.61 (0.59-0.64). Results were comparable for different reference standards: for initiation of methotrexate pooled sensitivity was 0.85 (0.83-0.86) and specificity was 0.52 (0.49-0.54); for initiation of any disease modifying antirheumatic drug they were 0.80 (0.79-0.82) and 0.65 (0.61-0.68), respectively; and for expert opinion 0.88 (0.86-0.90) and 0.48 (0.35-0.52). No differences were observed for use of different types of joint counts. Eight studies and five meeting abstracts directly compared 1987 and 2010 criteria using different reference standards within different target populations showing higher overall sensitivity (+0.11 compared with 1987 criteria) at the cost of lower overall specificity (-0.04).
CONCLUSIONS: Two years after their publication, the 2010 ACR/EULAR criteria have been widely tested in the community. They are sensitive to detect cases of RA among various target populations, independent of how the latter is referenced.

PMID 23592710
F C Arnett, S M Edworthy, D A Bloch, D J McShane, J F Fries, N S Cooper, L A Healey, S R Kaplan, M H Liang, H S Luthra
The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.
Arthritis Rheum. 1988 Mar;31(3):315-24.
Abstract/Text The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.

PMID 3358796
日本リウマチ学会 関節リウマチ超音波標準化委員会編:リウマチ診療のための関節エコー撮像法ガイドライン、羊土社、2011年.
M Backhaus, T Kamradt, D Sandrock, D Loreck, J Fritz, K J Wolf, H Raber, B Hamm, G R Burmester, M Bollow
Arthritis of the finger joints: a comprehensive approach comparing conventional radiography, scintigraphy, ultrasound, and contrast-enhanced magnetic resonance imaging.
Arthritis Rheum. 1999 Jun;42(6):1232-45. doi: 10.1002/1529-0131(199906)42:6<1232::AID-ANR21>3.0.CO;2-3.
Abstract/Text OBJECTIVE: A prospective study was performed comparing conventional radiography, 3-phase bone scintigraphy, ultrasound, and magnetic resonance imaging (MRI) with precontrast and dynamic postcontrast examinations in 60 patients with various forms of arthritis including rheumatoid arthritis (RA), spondyl-arthropathy, and arthritis associated with connective tissue disease.
METHODS: A total of 840 finger joints were examined clinically and by all 4 imaging methods. Experienced investigators blinded to the clinical findings and diagnoses analyzed all methods independently of each other. The patients were divided into 2 groups. Group 1 included 32 patients (448 finger joints) without radiologic signs of destructive arthritis (Larsen grades 0-1) of the evaluated hand and wrist and group 2 included 28 patients (392 finger joints) with radiographs revealing erosions (Larsen grade 2) of the evaluated hand and/or wrist.
RESULTS: Clinical evaluation, scintigraphy, MRI, and ultrasound were each more sensitive than conventional radiography in detecting inflammatory soft tissue lesions as well as destructive joint processes in arthritis patients in group 1. All differences were statistically significant. We found ultrasound to be even more sensitive than MRI in the detection of synovitis. MRI detected erosions in 92 finger joints (20%; 26 patients) in group 1 that had not been detected by conventional radiography.
CONCLUSION: Our data indicate that MRI and ultrasound are valuable diagnostic methods in patients with arthritis who have normal findings on radiologic evaluation.

PMID 10366117
日本臨床検査標準化協議会・RF標準化検討委員会編:リウマトイド因子標準化のガイドライン(日本臨床検査標準化協議会認証)、2011年.
Kunihiro Nishimura, Daisuke Sugiyama, Yoshinori Kogata, Goh Tsuji, Takashi Nakazawa, Seiji Kawano, Katsuyasu Saigo, Akio Morinobu, Masahiro Koshiba, Karen M Kuntz, Isao Kamae, Shunichi Kumagai
Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis.
Ann Intern Med. 2007 Jun 5;146(11):797-808.
Abstract/Text BACKGROUND: Rheumatoid factor (RF) and autoantibodies against cyclic citrullinated peptide (CCP) are markers that might help physicians diagnose rheumatoid arthritis.
PURPOSE: To determine whether anti-CCP antibody more accurately identifies patients with rheumatoid arthritis and better predicts radiographic progression than does RF.
DATA SOURCES: MEDLINE through September 2006 and reference lists of retrieved studies and review articles.
STUDY SELECTION: Studies in any language that enrolled at least 10 participants and that examined the role of anti-CCP antibody and RF in the diagnosis or prognosis of known or suspected rheumatoid arthritis.
DATA EXTRACTION: Two authors independently evaluated studies for inclusion, rated methodological quality, and abstracted relevant data.
DATA SYNTHESIS: The DerSimonian-Laird random-effects method was used to summarize sensitivities, specificities, and positive and negative likelihood ratios from 37 studies of anti-CCP antibody and 50 studies of RF. The pooled sensitivity, specificity, and positive and negative likelihood ratios for anti-CCP antibody were 67% (95% CI, 62% to 72%), 95% (CI, 94% to 97%), 12.46 (CI, 9.72 to 15.98), and 0.36 (CI, 0.31 to 0.42), respectively. For IgM RF, the values were 69% (CI, 65% to 73%), 85% (CI, 82% to 88%), 4.86 (CI, 3.95 to 5.97), and 0.38 (CI, 0.33 to 0.44). Likelihood ratios among IgM RF, IgG RF, and IgA RF seemed to be similar. Results from studies of patients with early rheumatoid arthritis were similar to those from all studies. Three of 4 studies found that risk for radiographic progression was greater with anti-CCP antibody positivity than with IgM RF positivity.
LIMITATIONS: Many studies had methodological limitations. Studies of RF were heterogeneous and had wide ranges of sensitivity and specificity.
CONCLUSIONS: Anti-CCP antibodies are more specific than RF for diagnosing rheumatoid arthritis and may better predict erosivedisease.

PMID 17548411
Rohit Aggarwal, Katherine Liao, Raj Nair, Sarah Ringold, Karen H Costenbader
Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis.
Arthritis Rheum. 2009 Nov 15;61(11):1472-83. doi: 10.1002/art.24827.
Abstract/Text
PMID 19877103
Ori Elkayam, Refael Segal, Daniele Bendayan, Robert van Uitert, Carla Onnekink, Ger Jm Pruijn
The anti-cyclic citrullinated peptide response in tuberculosis patients is not citrulline-dependent and sensitive to treatment.
Arthritis Res Ther. 2010;12(1):R12. doi: 10.1186/ar2913. Epub 2010 Jan 25.
Abstract/Text INTRODUCTION: Patients with tuberculosis (TB) frequently produce anti-citrullinated protein antibodies (ACPA). The objective of this study is to characterize the citrulline-dependence of the ACPA reactivity in sera of patients with mycobacterium infections.
METHODS: Serum samples of 134 patients with untreated mycobacterium infections (122 TB, 12 nontuberculous mycobacterium) were tested for antibodies against both the citrullinated (Cit) and the non-citrullinated (Arg) form of 2 cyclic synthetic peptides. In 33 patients, a follow-up sample was tested six months after starting anti-mycobacterial drugs.
RESULTS: A substantial proportion of patients with mycobacterial infections demonstrated antibodies against 0401Cit, 0401Arg, 0722Cit and 0722Arg. Fourteen patients demonstrated anti-0401Cit, 83 anti-0401Arg, 22 anti-0722Cit and 61 anti-0722Arg, while none of these antibodies were detected in the 20 healthy controls. All the patients but one, who were anti-0401Cit and anti-0722Cit positive, demonstrated reactivity against the respective Arg peptide. In the subset of 33 patients with a follow-up test six months after starting treatment, the mean levels of antibodies to 0401Cit, 0401Arg, 0722Cit and 0722Arg significantly decreased after treatment. All the patients who were anti-0401Cit and anti-0722Cit positive turned negative after treatment. The presence of anti-0401Cit/Arg and anti-0722Cit/Arg was found to be significantly correlated with the presence of HIV.
CONCLUSIONS: ACPA may be found in patients with TB. In most of the cases, the reactivity is citrulline independent. A positive cyclic citrullinated peptide (CCP) test in these patients should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.

PMID 20100318
Zhichao Jin, Chun Xiang, Qing Cai, Xin Wei, Jia He
Alcohol consumption as a preventive factor for developing rheumatoid arthritis: a dose-response meta-analysis of prospective studies.
Ann Rheum Dis. 2014 Nov;73(11):1962-7. doi: 10.1136/annrheumdis-2013-203323. Epub 2013 Jul 29.
Abstract/Text OBJECTIVE: To summarise the evidence regarding the dose-response association between alcohol consumption and risk of rheumatoid arthritis (RA).
METHOD: Studies were identified from search of MEDLINE, Embase and Web of Science databases between 1 January 1946 and 10 April 2013, and from review of the conference abstracts and the reference lists of retrieved articles. Prospective studies that reported relative risks (RRs) with 95% CIs for the association between alcohol consumption and the risk of RA were included. Results from individual studies were pooled using a dose-response meta-analysis.
RESULTS: Up to 10 April 2013, 8 prospective studies contained 195 029 participants and 1878 RA cases were included. The results indicated that low to moderate alcohol consumption yielded a preventive effect on RA development (RR: 0.86; 95% CI 0.78 to 0.94), and provided some evidence of a non-linear relationship between alcohol consumption and risk of RA. Dose-response meta-analysis of the study data revealed that compared with that for no alcohol consumption, the adjusted RR was 0.93 (95% CI 0.88 to 0.98) for 3 g/day of alcohol consumption, 0.86 (95% CI 0.76 to 0.97) for 9 g/day, 0.88 (95% CI 0.78 to 0.99) for 12 g/day, 0.91 (95% CI 0.81 to 1.03) for 15 g/day, and 1.28 (95% CI 0.94 to 1.73) for 30 g/day. Subgroup analysis indicated that women who had low to moderate alcohol consumption had a 19% reduction in RA risk. Regardless of sex, a consistent low to moderate alcohol consumption for a period of at least 10 years was found to have a 17% reduction in RA risk.
CONCLUSIONS: Low to moderate alcohol consumption inversely associated with the development of RA in a manner that appears to be dose-dependent, time-dependent and sex-dependent. Large prospective studies that investigate gene-environment interactions are required to further clarify the aetiology of RA.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PMID 23897767
C A Smith, A D Woolf, M Lenci
Parvoviruses: infections and arthropathies.
Rheum Dis Clin North Am. 1987 Aug;13(2):249-63.
Abstract/Text Parvoviruses (PVs) are unique in that they are the only single-stranded DNA viruses of vertebrates. Two human PVs have now been described and characterized, and genomes sequenced: B19 and RA-1. The B19 PV is known to be associated with arthritis in humans, and RA-1 was recovered from the synovial cells of a patient with rheumatoid arthritis. This article will discuss the nature of these two viruses, their possible relationships to chronic joint disease of humans, and the clinical illnesses of B19 infection.

PMID 2827245
C A Smith, R E Petty, A J Tingle
Rubella virus and arthritis.
Rheum Dis Clin North Am. 1987 Aug;13(2):265-74.
Abstract/Text Rubella virus and the rubella virus vaccine are relatively common causes of acute arthralgias and occasionally objective arthritis. Rarely, chronic or relapsing joint syndromes may follow exposure to this virus or vaccine. This article will focus on the virus and its clinical illness. Major emphasis then will be given to the resulting arthritis syndromes and to consideration of the possible pathogenetic mechanisms of the joint manifestations.

PMID 3321211
Hiroyuki Yamashita, Kazuo Kubota, Yuko Takahashi, Ryogo Minamimoto, Miyako Morooka, Hiroshi Kaneko, Toshikazu Kano, Akio Mimori
Similarities and differences in fluorodeoxyglucose positron emission tomography/computed tomography findings in spondyloarthropathy, polymyalgia rheumatica and rheumatoid arthritis.
Joint Bone Spine. 2013 Mar;80(2):171-7. doi: 10.1016/j.jbspin.2012.04.006. Epub 2012 Jun 29.
Abstract/Text OBJECTIVES: We assessed fluorine-18 ((18)F)-labelled fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) findings in patients with seronegative spondyloarthritis (SpA), polymyalgia rheumatica (PMR), and rheumatoid arthritis (RA).
METHODS: We studied 53 patients with SpA (n=21), PMR (n=16), or RA (n=16) admitted to our hospital between 2006 and 2011. Disease activity in the ischial tuberosities, greater trochanters, spinous processes, vertebral bodies, and sacroiliac joints (SIJ) were evaluated by determining FDG accumulation using maximum standardized uptake values (SUV(max)) and FDG scores.
RESULTS: SUV(max) for ischial tuberosities was significantly higher in PMR than SpA or RA. SUV(max) for greater trochanters and spinous processes was significantly higher in PMR than RA (P<0.001) and significantly higher in SpA than in PMR or RA for SIJ (P=0.01). No significant difference in vertebral scores was observed among groups (P=0.488). FDG scores yielded similar results. X-ray findings were consistent with PET/CT findings in 3/15 (20%) patients with sacroiliitis, whereas magnetic resonance imaging findings were consistent with PET/CT findings in 4/7 (57.1%) patients.
CONCLUSIONS: PET/CT detection of inflammation in the ischial tuberosities, greater trochanters, and spinous processes discriminated between PMR and RA, but not between SpA and PMR. PET/CT findings can distinguish SpA from RA and PMR and are useful for the early diagnosis of sacroiliitis.

Copyright © 2012 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.
PMID 22749663
Walter P Maksymowych, Maria E Suarez-Almazor, Heidi Buenviaje, Bobbi-Lynn Cooper, Caroline Degeus, Michael Thompson, Anthony S Russell
HLA and cytokine gene polymorphisms in relation to occurrence of palindromic rheumatism and its progression to rheumatoid arthritis.
J Rheumatol. 2002 Nov;29(11):2319-26.
Abstract/Text OBJECTIVE: Palindromic rheumatism (PR) is an episodic arthropathy that may precede typical rheumatoid arthritis (RA), although pathogenetic relationships between these disorders remain unclear. The predictive value for those immunogenetic risk factors implicated in RA for disease progression in PR remains to be established. A previous retrospective analysis from our group has implicated rheumatoid factor in disease progression. Our objective was to determine the contribution of HLA and cytokine gene polymorphisms implicated in RA to predisposition to PR and to progression of PR to chronic joint inflammation.
METHODS: We studied 147 patients with PR seen in a tertiary referral center; 87 were selected retrospectively from the period 1986-96 using a structured selection process and 60 were selected prospectively in the period 1997-2001. Comparison groups included 149 patients with RA and 149 ethnically matched controls. Typing for HLA-DRB1 alleles and HLA-DRB1-04 subtypes was performed following polymerase chain reaction (PCR) amplification using sequence-specific primers (SSP). Cytokine genotypes were ascertained following PCR-SSP with and without digestion with restriction enzymes. Time-adjusted survival analysis (Kaplan-Meier) and multivariate logistic regression were used to assess the independent contribution of immunogenetic markers in assessing progression of PR to chronic joint inflammation.
RESULTS: Thirty-one percent of patients progressed to connective tissue disease after a mean of 10.6 (retrospective group) and 3.9 (prospective group) years. A significantly increased prevalence of the shared epitope (SE) allele was noted in patients with PR (65%) versus controls (39%) (OR 2.9, 95% CI 1.8-4.6, p < 0.001). This primarily reflected increased prevalence of the DRB1-0401 and 0404 and not DRB1-01 alleles. A weak contribution to disease susceptibility was also noted with carriage of the IL4 promoter -590T (OR 1.8, 95% CI 1.1-3.0, p = 0.02) and IL4 intron 3 RP1 (OR 1.7, 95% CI 1.1-2.9, p = 0.03) alleles. The TNFa +489A allele was associated with RA (OR = 2.7, 95% CI 1.5-5.1, p = 0.001) in both SE+ and SE- patients, but not with PR. Time-adjusted and multivariate Cox regression analysis revealed that only homozygosity for SE alleles was a significant independent risk factor for disease progression to chronicity in PR (hazard ratio 2.9, 95% CI 1.2-6.9, p = 0.02). However, none of 8 patients homozygous for SE- DRB1 XP4n alleles developed chronic disease after 10 years of followup (p = 0.07).
CONCLUSION: The immunogenetic risk profile for PR resembles that for RA, indicating that PR is likely not an independent entity. A significant gene dose effect for SE alleles is operative in determining risk for progression from PR to RA.

PMID 12415587
Essi Koskinen, Pekka Hannonen, Tuulikki Sokka
Palindromic rheumatism: longterm outcomes of 60 patients diagnosed in 1967-84.
J Rheumatol. 2009 Sep;36(9):1873-5. doi: 10.3899/jrheum.090025. Epub 2009 Jul 31.
Abstract/Text OBJECTIVE: To study longterm outcomes of 60 patients with palindromic rheumatism (PR) diagnosed in 1967-1984.
METHODS: A cohort of patients with PR was identified in Jyväskylä Central Hospital in 1967-84, and reexamined in 1984-86. In 2006, medical records of the patients were reviewed to analyze the proportion of patients who had developed chronic rheumatoid arthritis (RA), had joint replacement surgery, or had died. Patients' health status was reviewed by mail questionnaires including functional status on the Health Assessment Questionnaire (HAQ), pain, and the number of painful joints.
RESULTS: Forty patients developed chronic RA over the observation period of over 20 years, among whom 38 patients within 10 years and 2 patients after 10 years. Twenty-four patients had died by 2006, 17 (42%) in the RA group and 7 (35%) in the non-RA group. Nine patients, all in the RA group (23%), had received 1 or more joint replacements. The mean HAQ score was 0.57 in the non-RA survivors (mean age 70 yrs), compared to 0.89 in the RA group (mean age 66 yrs) (p = 0.020, adjusted for age). Pain scores and the number of painful joints were similar between the groups.
CONCLUSION: Two-thirds of the patients with PR developed chronic arthritis. The risk to develop chronic arthritis remained over 10 years. The RA group was characterized with functional declines and having joint replacements as longterm outcomes of the disease.

PMID 19648311
G Salvador, A Gomez, O Vinas, G Ercilla, J D Canete, J Munoz-Gomez, R Sanmarti
Prevalence and clinical significance of anti-cyclic citrullinated peptide and antikeratin antibodies in palindromic rheumatism. An abortive form of rheumatoid arthritis?
Rheumatology (Oxford). 2003 Aug;42(8):972-5. doi: 10.1093/rheumatology/keg268. Epub 2003 Apr 16.
Abstract/Text OBJECTIVE: To analyse the prevalence and clinical significance of anti-cyclic citrullinated peptide antibodies (anti-CCP) and antikeratin antibodies (AKA) in patients with palindromic rheumatism (PR).
METHOD: Sixty-three patients with PR were included: 33 were defined as pure or persistent PR at the time of serum test measurement, and 30 as associated PR, defined as patients with past history of PR who had developed persistent arthritis at the time of serum test: [21 with rheumatoid arthritis (RA)]. Sixty patients with early RA, and 80 with seronegative spondyloarthropathy were included as control groups. Anti-CCP were determined by a standardized ELISA test and AKA by indirect immunofluorescence in rat oesophagus. Clinical characteristics of these pure PR patients were compared according to the presence or absence of anti-CCP antibodies. A follow-up study was also performed.
RESULTS: Anti-CCP were detected in 18 out of 32 (56.3%) patients with pure PR and 10 out of 30 (33.3%) with associated PR (38.1% in RA-associated PR patients). AKA were detected in 12 patients out of 33, with pure PR (36.4%), and in 9 out of 30 with associated PR (30%) (33.3% in RA-associated PR patients). The prevalence of anti-CCP and AKA in the RA control group was 55% (not significantly different from the pure PR group) and 61.7% (with respect to pure PR patients, P=0.02), respectively. In the spondyloarthropathy group, the prevalence of anti-CCP and AKA was 2.5 and 3.8%, respectively (P<0.001 compared with pure PR patients). No significant clinical differences were observed between pure PR patients with and without CCP antibodies.
CONCLUSIONS: Anti-CCP and, to a lesser extent, AKA, were found in a high proportion of patients with PR, suggesting that this syndrome is an abortive form of RA. The predictive value of these antibodies in PR, as markers of progression to an established RA, remains uncertain.

PMID 12730510
Anthony S Russell, Al Devani, Walter P Maksymowych
The role of anti-cyclic citrullinated peptide antibodies in predicting progression of palindromic rheumatism to rheumatoid arthritis.
J Rheumatol. 2006 Jul;33(7):1240-2. Epub 2006 May 15.
Abstract/Text OBJECTIVE: To determine whether the presence of anti-cyclic citrullinated peptide (anti-CCP) antibodies at presentation is of prognostic value in patients with palindromic arthritis.
METHODS: Stored sera, taken around the time of presentation from patients with palindromic arthritis, where available, were assessed for anti-CCP antibodies, and results were correlated with subsequent clinical outcome.
RESULTS: Twenty-nine of 61 patients had progressed to rheumatoid arthritis after a mean followup of 5.4 years; 83% of these had had anti-CCP antibodies in their baseline sera.
CONCLUSION: The sensitivity/specificity and likelihood ratios for CCP antibodies were better than rheumatoid factor in predicting outcome.

PMID 16724377
Qingping Yao, Xiangqian Su, Roy D Altman
Is remitting seronegative symmetrical synovitis with pitting edema (RS3PE) a subset of rheumatoid arthritis?
Semin Arthritis Rheum. 2010 Aug;40(1):89-94. doi: 10.1016/j.semarthrit.2008.11.006. Epub 2009 Feb 13.
Abstract/Text OBJECTIVES: To contrast and compare the spectrum of remitting seronegative symmetrical synovitis with pitting edema (RS3PE) with rheumatoid arthritis (RA) using an illustrative case.
METHODS: The relevant English literature of RS3PE was searched using the keywords "RS3PE" alone and in combination with terms such as neoplasia and rheumatic disease. Original and review articles were reviewed and the clinical setting was exemplified with a case report.
RESULTS: RS3PE initially was reported to represent a form of RA. However, RS3PE has clinical features that are different from both early- and late-onset RA, such as lack of bony erosions and rheumatoid factor. RS3PE is thought to involve vascular endothelial growth factor, suggesting an infectious etiology, generally has an excellent prognosis, and is associated with neoplasia not commonly seen in RA, and the RA associated human leukocyte antigen (HLA) DRB1 genotype is absent.
CONCLUSIONS: Based on the clinical, laboratory, suspected infectious etiology, genetic differences, and types of associated malignancies, RS3PE appears to be a distinct entity rather than a subset of RA.

Copyright 2010 Elsevier Inc. All rights reserved.
PMID 19217650
David T Felson, Josef S Smolen, George Wells, Bin Zhang, Lilian H D van Tuyl, Julia Funovits, Daniel Aletaha, Cornelia F Allaart, Joan Bathon, Stefano Bombardieri, Peter Brooks, Andrew Brown, Marco Matucci-Cerinic, Hyon Choi, Bernard Combe, Maarten de Wit, Maxime Dougados, Paul Emery, Daniel Furst, Juan Gomez-Reino, Gillian Hawker, Edward Keystone, Dinesh Khanna, John Kirwan, Tore K Kvien, Robert Landewé, Joachim Listing, Kaleb Michaud, Emilio Martin-Mola, Pamela Montie, Theodore Pincus, Pamela Richards, Jeffrey N Siegel, Lee S Simon, Tuulikki Sokka, Vibeke Strand, Peter Tugwell, Alan Tyndall, Desirée van der Heijde, Suzan Verstappen, Barbara White, Frederick Wolfe, Angela Zink, Maarten Boers, American College of Rheumatology, European League Against Rheumatism
American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials.
Arthritis Rheum. 2011 Mar;63(3):573-86. doi: 10.1002/art.30129.
Abstract/Text OBJECTIVE: Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition.
METHODS: A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analyzed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes.
RESULTS: Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (e.g., tender and swollen joint counts, C-reactive protein [CRP] level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year followup data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (a) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤ 1, or (b) when the score on the Simplified Disease Activity Index is ≤ 3.3.
CONCLUSION: We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. We recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

Copyright © 2011 by the American College of Rheumatology.
PMID 21294106
David T Felson, Josef S Smolen, George Wells, Bin Zhang, Lilian H D van Tuyl, Julia Funovits, Daniel Aletaha, Cornelia F Allaart, Joan Bathon, Stefano Bombardieri, Peter Brooks, Andrew Brown, Marco Matucci-Cerinic, Hyon Choi, Bernard Combe, Maarten de Wit, Maxime Dougados, Paul Emery, Daniel Furst, Juan Gomez-Reino, Gillian Hawker, Edward Keystone, Dinesh Khanna, John Kirwan, Tore K Kvien, Robert Landewé, Joachim Listing, Kaleb Michaud, Emilio Martin-Mola, Pamela Montie, Theodore Pincus, Pamela Richards, Jeffrey N Siegel, Lee S Simon, Tuulikki Sokka, Vibeke Strand, Peter Tugwell, Alan Tyndall, Desirée van der Heijde, Suzan Verstappen, Barbara White, Frederick Wolfe, Angela Zink, Maarten Boers
American College of Rheumatology/European League against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials.
Ann Rheum Dis. 2011 Mar;70(3):404-13. doi: 10.1136/ard.2011.149765.
Abstract/Text OBJECTIVE: Remission in rheumatoid arthritis (RA) is an increasingly attainable goal, but there is no widely used definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials. This work was undertaken to develop such a definition.
METHODS: A committee consisting of members of the American College of Rheumatology, the European League Against Rheumatism, and the Outcome Measures in Rheumatology Initiative met to guide the process and review prespecified analyses from RA clinical trials. The committee requested a stringent definition (little, if any, active disease) and decided to use core set measures including, as a minimum, joint counts and levels of an acute-phase reactant to define remission. Members were surveyed to select the level of each core set measure that would be consistent with remission. Candidate definitions of remission were tested, including those that constituted a number of individual measures of remission (Boolean approach) as well as definitions using disease activity indexes. To select a definition of remission, trial data were analysed to examine the added contribution of patient-reported outcomes and the ability of candidate measures to predict later good radiographic and functional outcomes.
RESULTS: Survey results for the definition of remission suggested indexes at published thresholds and a count of core set measures, with each measure scored as 1 or less (eg, tender and swollen joint counts, C reactive protein (CRP) level, and global assessments on a 0-10 scale). Analyses suggested the need to include a patient-reported measure. Examination of 2-year follow-up data suggested that many candidate definitions performed comparably in terms of predicting later good radiographic and functional outcomes, although 28-joint Disease Activity Score-based measures of remission did not predict good radiographic outcomes as well as the other candidate definitions did. Given these and other considerations, we propose that a patient's RA can be defined as being in remission based on one of two definitions: (1) when scores on the tender joint count, swollen joint count, CRP (in mg/dl), and patient global assessment (0-10 scale) are all ≤1, or (2) when the score on the Simplified Disease Activity Index is ≤3.3.
CONCLUSION: We propose two new definitions of remission, both of which can be uniformly applied and widely used in RA clinical trials. The authors recommend that one of these be selected as an outcome measure in each trial and that the results on both be reported for each trial.

PMID 21292833
D T Felson, J J Anderson, M Boers, C Bombardier, D Furst, C Goldsmith, L M Katz, R Lightfoot, H Paulus, V Strand
American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis.
Arthritis Rheum. 1995 Jun;38(6):727-35.
Abstract/Text OBJECTIVE: Trials of rheumatoid arthritis (RA) treatments report the average response in multiple outcome measures for treated patients. It is more clinically relevant to test whether individual patients improve with treatment, and this identifies a single primary efficacy measure. Multiple definitions of improvement are currently in use in different trials. The goal of this study was to promulgate a single definition for use in RA trials.
METHODS: Using the American College of Rheumatology (ACR) core set of outcome measures for RA trials, we tested 40 different definitions of improvement, using a 3-step process. First, we performed a survey of rheumatologists, using actual patient cases from trials, to evaluate which definitions corresponded best to rheumatologists' impressions of improvement, eliminating most candidate definitions of improvement. Second, we tested 20 remaining definitions to determine which maximally discriminated effective treatment from placebo treatment and also minimized placebo response rates. With 8 candidate definitions of improvement remaining, we tested to see which were easiest to use and were best in accord with rheumatologists' impressions of improvement.
RESULTS: The following definition of improvement was selected: 20% improvement in tender and swollen joint counts and 20% improvement in 3 of the 5 remaining ACR core set measures: patient and physician global assessments, pain, disability, and an acute-phase reactant. Additional validation of this definition was carried out in a comparative trial, and the results suggest that the definition is statistically powerful and does not identify a large percentage of placebo-treated patients as being improved.
CONCLUSION: We present a definition of improvement which we hope will be used widely in RA trials.

PMID 7779114
D L Scott, D P Symmons, B L Coulton, A J Popert
Long-term outcome of treating rheumatoid arthritis: results after 20 years.
Lancet. 1987 May 16;1(8542):1108-11.
Abstract/Text Outcome of therapy, in terms of functional capacity, radiological measures of joint damage, erythrocyte sedimentation rate (ESR), rheumatoid factor, and mortality, was determined prospectively in 112 consecutive rheumatoid arthritis (RA) patients treated for 20 years at one centre, where a policy of active treatment was pursued with the use of gold, chloroquine, steroids, and, in resistant cases, penicillamine or cytotoxic drugs. By 20 years 35% were dead. Mortality was often attributable to RA. Function improved in the early years of treatment but declined considerably between 10 and 20 years. At 20 years 19% were severely disabled. Radiographs showed related evidence of increasing joint destruction. The ESR and rheumatoid factor levels changed little. Age, late presentation, and rheumatoid factor seropositivity at presentation were poor prognostic factors. The concept of "remission-inducing" drugs is fallacious. Early treatment may be advantageous, but the prognosis of RA is not good.

PMID 2883443
E Lindqvist, T Saxne, P Geborek, K Eberhardt
Ten year outcome in a cohort of patients with early rheumatoid arthritis: health status, disease process, and damage.
Ann Rheum Dis. 2002 Dec;61(12):1055-9.
Abstract/Text OBJECTIVE: To investigate outcome as measured by health status, disease process, and damage in an unselected group of patients with early rheumatoid arthritis (RA) monitored prospectively for 10 years and to search for prognostic factors.
PATIENTS AND METHODS: 183 patients with RA with disease duration <2 years were assessed annually at a team care unit. Health status was measured by the Health Assessment Questionnaire (HAQ) and functional class. Disease process was assessed by clinical and laboratory measures of disease activity and evaluation of disease course. Damage was quantified as occurrence of major extra-articular manifestations and need for large joint replacements. Possible predictive factors were evaluated by logistic regression analyses.
RESULTS: 168/183 patients completed the entire follow up period. Of all 183 patients, 137 (75%) had been treated with disease modifying antirheumatic drugs and 84 (46%) with low dose oral glucocorticoids. After 10 years 158 patients (94%) managed daily life activities independently (functional class I-II). As measured by the HAQ 20% had almost no disability, 28% were mildly disabled, and 10% were seriously disabled. Median HAQ score had increased from 0.8 to 1.1 (p<0.001). Disease activity was significantly reduced. 133 patients (79%) had a relapsing remitting disease course and 30 patients (18%) were in remission as defined by the American College of Rheumatology criteria. Thirty patients (17%) had undergone large joint replacements. Fifteen patients (8%) had developed major extra-articular complications. The HAQ score during the first three months predicted disability at 10 years with an odds ratio of 13.4.
CONCLUSIONS: Prospective studies such as this give important knowledge of the variable long term prognosis of RA and provide necessary background information for clinical trials of new treatment modalities.

PMID 12429534
D M van der Heijde, M A van Leeuwen, P L van Riel, A M Koster, M A van 't Hof, M H van Rijswijk, L B van de Putte
Biannual radiographic assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis.
Arthritis Rheum. 1992 Jan;35(1):26-34.
Abstract/Text In a prospective followup study of 147 patients with rheumatoid arthritis of recent onset, we assessed the progression of radiographic evidence of joint damage on films of the patients' hands and feet obtained biannually. Patients were receiving first-line and second-line treatment. Ninety patients were followed up for 3 years, and 57 were followed up for only 2 years. Radiographic damage was determined by a modification of the method described by Sharp, and to ensure comparability of findings, we determined the percentage of damage per joint group (actual score divided by the maximum possible score). After 3 years, radiographic damage was present in 70% of the patients, all of whom could be identified after 1 year of study. Overall, 18-20% of the joints of the hands and feet were affected after 3 years, with relatively little abnormality per joint (approximately 8% of maximum possible score). During the entire followup, more foot joints than hand joints were affected. The rate of progression in the first year was significantly higher than in the second and third years of study, indicating a flattening of the curve of radiographic progression of joint damage.

PMID 1731813
R Knevel, M Schoels, T W J Huizinga, D Aletaha, G R Burmester, B Combe, R B Landewé, J S Smolen, T Sokka, D M F M van der Heijde
Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying antirheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis.
Ann Rheum Dis. 2010 Jun;69(6):987-94. doi: 10.1136/ard.2009.126748. Epub 2010 May 6.
Abstract/Text OBJECTIVES: To perform a systematic literature review of effective strategies for the treatment of rheumatoid arthritis (RA).
METHODS: As part of a European League Against Rheumatism (EULAR) Task Force investigation, a literature search was carried out from January 1962 until February 2009 in PubMed/Ovid Embase/Cochrane and EULAR/American College of Rheumatism (ACR)) abstracts (2007/2008) for studies with a treatment strategy adjusted to target a predefined outcome. Articles were systematically reviewed and clinical outcome, physical function and structural damage were compared between intensive and less intensive strategies. The results were evaluated by an expert panel to consolidate evidence on treatment strategies in RA.
RESULTS: The search identified two different kinds of treatment strategies: strategies in which the reason for treatment adjustment differed between the study arms ('steering strategies', n=13) and strategies in which all trial arms used the same clinical outcome to adjust treatment with different pharmacological treatments ('medication strategies', n=7). Both intensive steering strategies and intensive medication strategies resulted in better outcome than less intensive strategies in patients with early active RA.
CONCLUSION: Intensive steering strategies and intensive medication strategies produce a better clinical outcome, improved physical function and less structural damage than conventional steering or treatment. Proof in favour of any steering method is lacking and the best medication sequence is still not known.

PMID 20448280
Monika Schoels, Rachel Knevel, Daniel Aletaha, Johannes W J Bijlsma, Ferdinand C Breedveld, Dimitrios T Boumpas, Gerd Burmester, Bernard Combe, Maurizio Cutolo, Maxime Dougados, Paul Emery, Desirée van der Heijde, Tom W J Huizinga, Joachim Kalden, Edward C Keystone, Tore K Kvien, Emilio Martin-Mola, Carlomaurizio Montecucco, Maarten de Wit, Josef S Smolen
Evidence for treating rheumatoid arthritis to target: results of a systematic literature search.
Ann Rheum Dis. 2010 Apr;69(4):638-43. doi: 10.1136/ard.2009.123976.
Abstract/Text OBJECTIVES: To summarise existing evidence on a target oriented approach for rheumatoid arthritis (RA) treatment.
METHODS: We conducted a systematic literature search including all clinical trials testing clinical, functional, or structural values of a targeted treatment approach. Our search covered Medline, Embase and Cochrane databases until December 2008 and also conference abstracts (2007, 2008).
RESULTS: The primary search yielded 5881 citations; after the selection process, 76 papers underwent detailed review. Of these, only seven strategic clinical trials were extracted: four studies randomised patients to routine or targeted treatment, two compared two different randomised targets and one compared targeted treatment to a historical control group. Five trials dealt with early RA patients. All identified studies showed significantly better clinical outcomes of targeted approaches than routine approaches. Disability was reported in two studies with no difference between groups. Four studies compared radiographic outcomes, two showing significant benefit of the targeted approach.
CONCLUSION: Only few studies employed randomised controlled settings to test the value of treatment to a specific target. However, they provided unanimous evidence for benefits of targeted approaches. Nevertheless, more data on radiographic and functional outcomes and on patients with established RA are needed.

PMID 20237123
Iain B McInnes, James R O'Dell
State-of-the-art: rheumatoid arthritis.
Ann Rheum Dis. 2010 Nov;69(11):1898-906. doi: 10.1136/ard.2010.134684.
Abstract/Text The understanding of the pathogenesis and optimal therapeutics for rheumatoid arthritis (RA) has advanced remarkably over the last decade. This review highlights these key advances, particularly the outcomes of genome-wide scans which have provided an increasingly robust appraisal of the complex genetics that underpin RA. Such observations are placed in pathogenetic context, particularly concerning the breach of tolerance that presages synovitis and the mechanisms that subserve chronicity. The key therapeutic strategies and treatment agents, both conventional and biological, now available to effectively manage the disease are described. Throughout the review, emphasis is placed on unanswered questions and challenges in this exciting field.

PMID 20959326
M M Ward, J P Leigh, J F Fries
Progression of functional disability in patients with rheumatoid arthritis. Associations with rheumatology subspecialty care.
Arch Intern Med. 1993 Oct 11;153(19):2229-37.
Abstract/Text BACKGROUND: To determine whether patients with rheumatoid arthritis and their physicians make appropriate decisions regarding referral to rheumatologists and the need for continuing rheumatology care, we examined the relationship between the progression of functional disability in these patients and their use of rheumatology subspecialty care over time.
METHODS: A cohort of 282 patients with rheumatoid arthritis was followed prospectively for up to 10 years. Participants were categorized into three subgroups based on the pattern of care received from rheumatologists over the study period: patients who were never treated by a rheumatologist; patients treated by a rheumatologist only intermittently; and patients treated by a rheumatologist at least once during each 6-month study period. The outcome was the rate of progression of functional disability, measured using the Health Assessment Questionnaire Disability Index.
RESULTS: Among the 52 patients who had not been referred to a rheumatologist, 30 (58%) had rates of progression of functional disability that were stable or improving over time (rate < 0.01 Disability Index units per year), while 22 (42%) had rates that were worsening (rate > or = 0.01 Disability Index units per year). Among patients treated by rheumatologists, the average rate of progression was substantially lower among the 69 patients who were treated regularly by a rheumatologist than among 161 patients treated by rheumatologists intermittently (0.008 Disability Index units per year vs 0.020 Disability Index units per year). This difference was associated with more intensive use of second-line antirheumatic medications, and more frequent joint surgeries, among patients treated by rheumatologists on a regular basis.
CONCLUSIONS: Most patients with rheumatoid arthritis in this community cohort were treated by a rheumatologist, but 42% of those not referred had progressively increasing functional disability. Among patients treated by rheumatologists, those who had continuing care from rheumatologists experienced lower rates of progression of functional disability than those who had only intermittent care. These results suggest that use of rheumatology subspecialty care is associated with better health outcomes in rheumatoid arthritis.

PMID 8215726
D H Solomon, D W Bates, R S Panush, J N Katz
Costs, outcomes, and patient satisfaction by provider type for patients with rheumatic and musculoskeletal conditions: a critical review of the literature and proposed methodologic standards.
Ann Intern Med. 1997 Jul 1;127(1):52-60.
Abstract/Text PURPOSE: To compare the outcomes of care provided by generalists with that provided by specialists for patients with musculoskeletal and rheumatic conditions.
DATA SOURCES: English-language studies published between 1986 and April 1996 were identified through a MEDLINE search.
STUDY SELECTION: Studies that compared generalists' and specialists' treatment preferences, appropriateness of care, or outcomes with regard to musculoskeletal and rheumatic conditions were examined.
DATA EXTRACTION: Studies were reviewed for methodologic rigor and outcomes.
DATA SYNTHESIS: Low back pain is treated by many types of providers, without consistent differences in outcomes across provider types. In one study, however, patients were more satisfied with chiropractic care than with care provided by primary care physicians, although the former cost twice as much as the latter. For osteoarthritis of the hip, rheumatologists and primary care providers reported using different therapeutic regimens. For acute mono- and oligoarthritis, rheumatologists performed arthrocentesis more appropriately than nonrheumatologists and produced shorter durations of hospitalization. In the management of gout, rheumatologists used colchicine during the introduction of urate-lowering therapy more appropriately than other providers. In two population-based cohorts of patients with rheumatoid arthritis, patients cared for by rheumatologists were prescribed significantly more disease-modifying agents and had less disability than patients cared for by generalists.
CONCLUSIONS: Although empirical data are scant, there seem to be differences between generalists and specialists for a range of outcomes in various musculoskeletal and rheumatic conditions. Studies to data have important methodologic limitations that need to be addressed in future research.

PMID 9214253
L A Criswell, C L Such, E H Yelin
Differences in the use of second-line agents and prednisone for treatment of rheumatoid arthritis by rheumatologists and non-rheumatologists.
J Rheumatol. 1997 Dec;24(12):2283-90.
Abstract/Text OBJECTIVE: To compare the use of methotrexate (MTX), intramuscular (i.m.) gold, hydroxychloroquine, and prednisone for rheumatoid arthritis (RA) treatment among patients managed by rheumatologists and nonrheumatologists.
METHODS: Multiple regression analysis to estimate the likelihood of starting treatment and response to treatment for patients managed by rheumatologists and nonrheumatologists. All regression analyses were adjusted for patient demographic and clinical characteristics.
RESULTS: Therapy with all agents studied was initiated more frequently for patients with RA with at least some contact with rheumatologists during the year than for those managed strictly by nonrheumatologists. The adjusted odds ratios for starts on these medications ranged from 1.14 for im gold to 15.11 for MTX for patients managed by rheumatologists compared to those managed by nonrheumatologists. However, due to the low frequency of initiation of treatment with most of these drugs for patients managed strictly by nonrheumatologists, only the odds ratio for prednisone reached statistical significance (OR = 2.94, p = 0.0082). In the year after initiation of therapy with these agents, patients managed by rheumatologists experienced better response to treatment than those managed by nonrheumatologists. These differences were statistically significant for MTX (p = 0.0447) and nearly significant for im gold (p = 0.0597).
CONCLUSION: These results provide evidence of systematic differences in the propensity of rheumatologists and nonrheumatologists to initiate therapy with these antirheumatic drugs. If the observed differences in initial response to treatment translate into substantial differences in longterm outcomes, then these results suggest that the welfare of patients with RA may be jeopardized by the current trend toward primary care and restricted access to rheumatologists.

PMID 9415629
Anne-Christine Rat, Viviana Henegariu, Marie-Christophe Boissier
Do primary care physicians have a place in the management of rheumatoid arthritis?
Joint Bone Spine. 2004 May;71(3):190-7. doi: 10.1016/j.jbspin.2003.09.003.
Abstract/Text OBJECTIVE: Few recommendations have been issued about the management of rheumatoid arthritis (RA), which varies widely across physicians. The primary care physician (PCP) plays a unique role as the first physician to evaluate the patient. The objective of this study was to evaluate the place of PCPs in the management of RA.
METHODS: Medline was searched for articles reporting management of rheumatoid arthritis in primary care practice.
RESULTS: Currently, the goal of initiating a disease modifying anti-rheumatic drug (DMARD) early is unrealistic for numerous patients. Agreement between PCPs and rheumatologists about the diagnosis of RA is only passable, but PCPs tend to overdiagnose RA. Median time from symptom onset to second-line treatment was 19 months and the best predictive factor for a longer lag time before DMARD prescription was the time from symptom onset to the first rheumatologist visit. Moreover, DMARDs are only rarely prescribed by PCPs. Some data suggest that the impact of rheumatologists care is positive on outcomes but it has to be confirmed by longitudinal, randomized studies, with valid outcomes and diagnosis criteria. Recognition of the need for timely referral is an important goal in the teaching of students and generalists. Moreover, the nature of management differences between rheumatologists and PCPs has to be explored. We should also think how to create a better coordination. This starts by knowing what are the needs of the PCP (e.g. education, access to phone advice or rapid consultation) and by defining common plan if the care should be shared.
CONCLUSION: Several healthcare professionals, among whom the PCP plays a pivotal role, should share the management of RA. PCPs and rheumatologists should be encouraged to work together on optimizing the management of patients with RA.

Copyright 2003 Elsevier SAS
PMID 15182789
Diane Lacaille, Aslam H Anis, Daphne P Guh, John M Esdaile
Gaps in care for rheumatoid arthritis: a population study.
Arthritis Rheum. 2005 Apr 15;53(2):241-8. doi: 10.1002/art.21077.
Abstract/Text OBJECTIVE: Treatment guidelines for rheumatoid arthritis (RA) now recommend early, aggressive, and persistent use of disease-modifying antirheumatic drugs (DMARDs) to prevent joint damage in all people with active inflammation, and evaluation by a rheumatologist, when possible. This research assesses whether care for RA, at a population level, is consistent with current treatment guidelines.
METHODS: Using administrative billing data from the Ministry of Health in 1996-2000, all prevalent RA cases in British Columbia, Canada were identified. Data were obtained on all medications and all provincially-funded health care services.
RESULTS: We identified 27,710 RA cases, yielding a prevalence rate of 0.76%, consistent with epidemiologic studies. DMARD use was inappropriately low. Only 43% of the entire RA cohort received a DMARD at least once over 5 years, and 35% over 2 years. When used, DMARDs were started in a timely fashion, but were not used consistently. Care by a rheumatologist increased DMARD use 31-fold. Yet, only 48% and 34% saw a rheumatologist over 5 and 2 years, respectively. DMARD use was significantly more frequent, persistent, and more often used as combination therapy with continuous rheumatologist care. DMARDs were used by 84% and 73%, 40%, and 10% of people followed by rheumatologists continuously and intermittently, internists, and family physicians, respectively (P < 0.001). NSAID use, physiotherapy, and orthopedic surgeries were similar across these 4 care groups.
CONCLUSION: RA care in the British Columbia population was not consistent with current treatment guidelines. Efforts to educate family physicians and consumers about the shift in RA treatment paradigms and to improve access to rheumatologists are needed.

PMID 15818655
Michael P M van der Linden, Saskia le Cessie, Karim Raza, Diane van der Woude, Rachel Knevel, Tom W J Huizinga, Annette H M van der Helm-van Mil
Long-term impact of delay in assessment of patients with early arthritis.
Arthritis Rheum. 2010 Dec;62(12):3537-46. doi: 10.1002/art.27692.
Abstract/Text OBJECTIVE: During the last decade, rheumatologists have learned to initiate disease-modifying antirheumatic drugs (DMARDs) early to improve the outcome of rheumatoid arthritis (RA). However, the effect of delay in assessment by a rheumatologist on the outcome of RA has scarcely been explored. The purpose of this study was to examine the association between delay in assessment by a rheumatologist, rates of joint destruction, and probability of achieving DMARD-free remission in patients with RA. Patient characteristics associated with components of delay (by the patient, by the general practitioner [GP], and overall) were assessed.
METHODS: A total of 1,674 early arthritis patients from the Leiden Early Arthritis Clinic cohort were evaluated for patient delay, GP delay, and total delay in assessment by a rheumatologist. Among 598 RA patients, associations between total delay, achievement of sustained DMARD-free remission, and the rate of joint destruction over 6 years followup were determined.
RESULTS: The median patient, GP, and total delays in seeing a rheumatologist among patients with early arthritis were 2.4 weeks, 8.0 weeks, and 13.7 weeks, respectively. Among all diagnoses, those diagnosed as having RA or spondylarthritis had the longest total delay (18 weeks). Among the RA patients, 69% were assessed in ≥12 weeks; this was associated with a hazard ratio of 1.87 for not achieving DMARD-free remission and a 1.3 times higher rate of joint destruction over 6 years, as compared with assessment in <12 weeks. Older age, female sex, gradual symptom onset, involvement of the small joints, lower levels of C-reactive protein, and the presence of autoantibodies were associated with longer total delay.
CONCLUSION: Only 31% of the RA patients were assessed in <12 weeks of symptom onset. Assessment in <12 weeks is associated with less joint destruction and a higher chance of achieving DMARD-free remission as compared with a longer delay in assessment. These results imply that attempts to diminish the delay in seeing a rheumatologist will improve disease outcome in patients with RA.

Copyright © 2010 by the American College of Rheumatology.
PMID 20722031
Lydia G Schipper, Laura T C van Hulst, Richard Grol, Piet L C M van Riel, Marlies E J L Hulscher, Jaap Fransen
Meta-analysis of tight control strategies in rheumatoid arthritis: protocolized treatment has additional value with respect to the clinical outcome.
Rheumatology (Oxford). 2010 Nov;49(11):2154-64. doi: 10.1093/rheumatology/keq195. Epub 2010 Jul 29.
Abstract/Text OBJECTIVES: Tight control studies including regular assessments of disease activity have shown that this approach has beneficial effects on disease activity, disability and joint damage in treating RA patients. Some of these studies included tight control with protocolized treatment, while others applied tight control without protocolized treatment. The aim of this study was to compare the effects of tight control with usual care and to compare the effects of tight control studies with and without protocolized treatment adjustments.
METHODS: A systematic literature search was performed to identify clinical trials in RA that evaluated tight control strategies in comparison with usual care. Two types of study were compared: (i) those using disease activity monitoring with protocolized treatment adjustments, and (ii) those using disease activity monitoring without protocolized treatment adjustments. The databases PubMed and Cochrane were searched from 1995 up to 2009. Primary outcome measure was the mean change in the 28-joint DAS (DAS-28), which was used in a random-effects meta-analysis.
RESULTS: Six controlled trials regarding tight control in RA patients were included in the meta-analysis. In all trials, patients treated in the tight control arms had significantly higher DAS-28 responses than patients treated according to usual care [weighted mean difference (WMD) = 0.59, P < 0.001]. Moreover, tight control was significantly more effective (P < 0.001) by means of protocolized treatment adjustments (WMD = 0.97) compared with non-protocolized monitoring of disease activity (WMD = 0.25).
CONCLUSION: Tight control in RA resulted in significantly better clinical outcomes than usual care. It is suggested but not proved that tight control with protocolized treatment adjustments is more beneficial than if no such protocol is used.

PMID 20671022
Y P M Goekoop-Ruiterman, J K de Vries-Bouwstra, C F Allaart, D van Zeben, P J S M Kerstens, J M W Hazes, A H Zwinderman, H K Ronday, K H Han, M L Westedt, A H Gerards, J H L M van Groenendael, W F Lems, M V van Krugten, F C Breedveld, B A C Dijkmans
Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial.
Arthritis Rheum. 2005 Nov;52(11):3381-90. doi: 10.1002/art.21405.
Abstract/Text OBJECTIVE: Several treatment strategies have proven value in the amelioration of rheumatoid arthritis (RA), but the optimal strategy for preventing long-term joint damage and functional decline is unclear. We undertook this study to compare clinical and radiographic outcomes of 4 different treatment strategies, with intense monitoring in all patients.
METHODS: In a multicenter, randomized clinical trial, 508 patients were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), and initial combination therapy with the tumor necrosis factor antagonist infliximab (group 4). Treatment adjustments were made every 3 months in an effort to obtain low disease activity (a Disease Activity Score in 44 joints of < or =2.4).
RESULTS: Initial combination therapy including either prednisone (group 3) or infliximab (group 4) resulted in earlier functional improvement than did sequential monotherapy (group 1) and step-up combination therapy (group 2), with mean scores at 3 months on the Dutch version of the Health Assessment Questionnaire (D-HAQ) of 1.0 in groups 1 and 2 and 0.6 in groups 3 and 4 (P < 0.001). After 1 year, mean D-HAQ scores were 0.7 in groups 1 and 2 and 0.5 in groups 3 and 4 (P = 0.009). The median increases in total Sharp/Van der Heijde radiographic joint score were 2.0, 2.5, 1.0, and 0.5 in groups 1-4, respectively (P < 0.001). There were no significant differences in the number of adverse events and withdrawals between the groups.
CONCLUSION: In patients with early RA, initial combination therapy including either prednisone or infliximab resulted in earlier functional improvement and less radiographic damage after 1 year than did sequential monotherapy or step-up combination therapy.

PMID 16258899
Yvonne P M Goekoop-Ruiterman, Jeska K de Vries-Bouwstra, Cornelia F Allaart, Derkjen van Zeben, Pit J S M Kerstens, J Mieke W Hazes, Aelko H Zwinderman, André J Peeters, Johanna M de Jonge-Bok, Constant Mallée, Wim M de Beus, Peter B J de Sonnaville, Jacques A P M Ewals, Ferdinand C Breedveld, Ben A C Dijkmans
Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial.
Ann Intern Med. 2007 Mar 20;146(6):406-15.
Abstract/Text BACKGROUND: In patients with early rheumatoid arthritis, initial combination therapies provide earlier clinical improvement and less progression of joint damage after 1 year compared with initial monotherapies (as demonstrated in the BeSt study).
OBJECTIVE: To evaluate whether the initial clinical and radiographic efficacy of combination therapies could be maintained during the second year of follow-up in patients with early rheumatoid arthritis.
DESIGN: Randomized, controlled clinical trial with blinded assessors.
SETTING: 18 peripheral and 2 university medical centers in the Netherlands.
PATIENTS: 508 patients with early active rheumatoid arthritis.
INTERVENTION: Sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), or initial combination therapy with infliximab (group 4). Trimonthly treatment adjustments were made to achieve low disease activity.
MEASUREMENTS: Primary end points were functional ability (Health Assessment Questionnaire) and Sharp-van der Heijde score for radiographic joint damage.
RESULTS: Groups 3 and 4 had more rapid clinical improvement during the first year; all groups improved further to a mean functional ability score of 0.6 (overall, P = 0.257) and 42% were in remission (overall, P = 0.690) during the second year. Progression of joint damage remained better suppressed in groups 3 and 4 (median scores of 2.0, 2.0, 1.0, and 1.0 in groups 1, 2, 3, and 4, respectively [P = 0.004]). After 2 years, 33%, 31%, 36%, and 53% of patients in groups 1 through 4, respectively, were receiving single-drug therapy for initial treatment. There were no significant differences in toxicity.
LIMITATIONS: Patients and physicians were aware of the allocated group, and the assessors were blinded.
CONCLUSIONS: Currently available antirheumatic drugs can be highly effective in patients with early rheumatoid arthritis in a setting of tight disease control. Initial combination therapies seem to provide earlier clinical improvement and less progression of joint damage, but all treatment strategies eventually showed similar clinical improvements. In addition, combination therapy can be withdrawn successfully and less treatment adjustments are needed than with initial monotherapies.

PMID 17371885
J K de Vries-Bouwstra, Y P M Goekoop-Ruiterman, K N Verpoort, G M T Schreuder, J A P M Ewals, J P Terwiel, H K Ronday, P J S M Kerstens, R E M Toes, R R P de Vries, F C Breedveld, B A C Dijkmans, T W J Huizinga, C F Allaart
Progression of joint damage in early rheumatoid arthritis: association with HLA-DRB1, rheumatoid factor, and anti-citrullinated protein antibodies in relation to different treatment strategies.
Arthritis Rheum. 2008 May;58(5):1293-8. doi: 10.1002/art.23439.
Abstract/Text OBJECTIVE: To determine the association of HLA-DRB1, rheumatoid factor (RF), and anti-citrullinated protein antibody (ACPA) status with progression of joint damage in early rheumatoid arthritis (RA) treated according to different treatment strategies.
METHODS: The present study was conducted using data from the BeSt study (Behandelstrategieën voor Reumatoide Artritis [treatment strategies for rheumatoid arthritis]), a randomized trial comparing 4 targeted (toward achievement of a Disease Activity Score [DAS] of < or =2.4) treatment strategies: sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with methotrexate, sulfasalazine, and prednisone (group 3), and initial combination therapy with methotrexate and infliximab (group 4), in 508 patients with early RA. Multivariate logistic regression analysis was used to predict progressive disease (increase of Sharp/van der Heijde score over 2 years beyond the smallest detectable change [4.6]) according to the presence or absence of the shared epitope (SE), DERAA, RF, and ACPA, with correction for other baseline characteristics.
RESULTS: Progressive disease could not be predicted by presence of the SE: the odds ratio in groups 1, 2, 3, and 4, respectively, was 1.4, 2.6, 1.9, and 3.0. DERAA carriership did not protect against progressive disease (odds ratio 0.4, 1.4, 0.9, and 0.9 in groups 1, 2, 3, and 4, respectively). RF positivity and ACPA positivity predicted progressive disease in group 1 (odds ratio 4.7 [95% confidence interval 1.5-14.5] for RF and 12.6 [95% confidence interval 3.0-51.9] for ACPA), but not in groups 2-4 (for RF, odds ratio [95% confidence interval] 1.5 [0.5-4.9], 1.0 [0.3-3.3], and 1.4 [0.4-4.8] in group 2, group 3, and group 4, respectively; for ACPA, odds ratio [95% confidence interval] 3.4 [0.8-14.2], 1.7 [0.5-5.4], and 1.8 [0.5-6.8] in group 2, group 3, and group 4).
CONCLUSION: In patients with early RA treated with the goal of tight control of the DAS, no significant association between HLA-DRB1 status and radiographic progression was found. RF and ACPA were predictive of progressive disease only in patients treated with sequential monotherapy. These observations suggest that effective treatment can prevent radiographic progression, even in patients with risk factors for severe damage.

PMID 18438829
T Möttönen, P Hannonen, M Leirisalo-Repo, M Nissilä, H Kautiainen, M Korpela, L Laasonen, H Julkunen, R Luukkainen, K Vuori, L Paimela, H Blåfield, M Hakala, K Ilva, U Yli-Kerttula, K Puolakka, P Järvinen, M Hakola, H Piirainen, J Ahonen, I Pälvimäki, S Forsberg, K Koota, C Friman
Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group.
Lancet. 1999 May 8;353(9164):1568-73.
Abstract/Text BACKGROUND: The treatment of rheumatoid arthritis should aim at clinical remission. This multicentre, randomised trial with 2-year follow-up sought evidence on the efficacy and tolerability of combination therapy (sulphasalazine, methotrexate, hydroxychloroquine, and prednisolone) compared with treatment with a single disease-modifying antirheumatic drug, with or without prednisolone, in the treatment of early rheumatoid arthritis.
METHODS: 199 patients were randomly assigned to two treatment groups. 195 started the treatment (97 received combination and 98 single drug therapy). Single-drug therapy in all patients started with sulphasalazine; in 51 patients methotrexate was later substituted. Oral prednisolone was required by 63 patients. The primary outcome measure was induction of remission. Analyses were intention to treat.
FINDINGS: 87 patients in the combination group and 91 in the single-therapy group completed the trial. After a year, remission was achieved in 24 of 97 patients with combination therapy, and 11 of 98 with single-drug therapy (p=0.011). The remission frequencies at 2 years were 36 of 97 and 18 of 98 (p=0.003). Clinical improvement (American College of Rheumatology criteria of 50% clinical response) was achieved after 1 year in 68 (75%) patients with combination therapy, and in 56 (60%) using single-drug therapy (p=0.028), while at the 2-year visit 69 and 57 respectively (71% vs 58%, p=0.058) had clinically improved. The frequencies of adverse events were similar in both treatment groups.
INTERPRETATION: Combination therapy was better and not more hazardous than single treatment in induction of remission in early rheumatoid arthritis. The combination strategy as an initial therapy seems to increase the efficacy of the treatment in at least a proportion of patients with early rheumatoid arthritis.

PMID 10334255
Kari Puolakka, Hannu Kautiainen, Timo Möttönen, Pekka Hannonen, Markku Korpela, Heikki Julkunen, Reijo Luukkainen, Kaisa Vuori, Leena Paimela, Harri Blåfield, Markku Hakala, Marjatta Leirisalo-Repo
Impact of initial aggressive drug treatment with a combination of disease-modifying antirheumatic drugs on the development of work disability in early rheumatoid arthritis: a five-year randomized followup trial.
Arthritis Rheum. 2004 Jan;50(1):55-62. doi: 10.1002/art.11436.
Abstract/Text OBJECTIVE: To compare the efficacy of therapy with a combination of disease-modifying antirheumatic drugs (DMARDs) versus therapy with a single DMARD in the prevention of work disability in patients with early rheumatoid arthritis (RA).
METHODS: In the Finnish Rheumatoid Arthritis Combination Therapy trial, 195 patients with recent-onset RA were randomly assigned to receive either combination therapy with DMARDs (sulfasalazine, methotrexate, hydroxychloroquine) plus prednisolone or single therapy with a DMARD with or without prednisolone. After 2 years, the drug treatment strategy was no longer restricted. At baseline, 162 patients (80 in the combination-treatment group and 82 in the single-treatment group) were still working or at least available for work. After 5 years of followup, data on all sick leave and retirement were obtained from social insurance registers or case records. The main outcome for each patient was the cumulative duration of all sick leaves and RA-related disability pensions, divided by the observation period during which the patient was not retired because of another disease or because of age.
RESULTS: The cumulative duration of work disability per patient-observation year was significantly lower in those randomized to combination therapy than in those randomized to single therapy: median 12.4 days (interquartile range [IQR] 0-54) versus 32.2 days (IQR 6-293) (P = 0.008, sex- and age-adjusted P = 0.009). This was mainly due to the difference in sick leaves (i.e., work disability periods CONCLUSION: Aggressive initial treatment of RA with a combination of DMARDs improves 5-year outcome in terms of lost productivity in patients with RA of recent onset.

PMID 14730599
Vappu Rantalaiho, Markku Korpela, Pekka Hannonen, Hannu Kautiainen, Salme Järvenpää, Marjatta Leirisalo-Repo, Markku Hakala, Kari Puolakka, Heikki Julkunen, Riitta Luosujärvi, Timo Möttönen, FIN-RACo Trial Group
The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial.
Arthritis Rheum. 2009 May;60(5):1222-31. doi: 10.1002/art.24447.
Abstract/Text OBJECTIVE: To evaluate the evolution of functional and clinical outcomes over 11 years in patients with early rheumatoid arthritis (RA) initially treated with a combination of 3 disease-modifying antirheumatic drugs (DMARDs) or with a single DMARD.
METHODS: A cohort of 199 patients with early active RA were initially randomized to receive treatment with a combination of methotrexate, sulfasalazine, and hydroxychloroquine with prednisolone or treatment with a single DMARD (initially, sulfasalazine) with or without prednisolone. After 2 years, the drug treatment strategy became unrestricted, but still targeted remission. At 11 years, function was assessed with the Health Assessment Questionnaire (HAQ), and clinical outcomes were assessed with the modified Minimal Disease Activity (MDA) measure and the American College of Rheumatology (ACR) criteria for remission.
RESULTS: At 11 years, 138 patients were assessed (68 in the combination-DMARD group and 70 in the single-DMARD group). The mean+/-SD HAQ scores were 0.34+/-0.54 in the combination-DMARD group and 0.38+/-0.58 in the single-DMARD group (P=0.88). Modified MDA was achieved by 63% (95% confidence interval [95% CI] 51, 77) and by 43% (95% CI 32, 55) (P=0.016) of the combination-DMARD group and the single-DMARD group, respectively, and ACR remission by 37% (95% CI 26, 49) and by 19% (95% CI 11, 29) (P=0.017), respectively.
CONCLUSION: Initial therapy with a combination of DMARDs in early RA results in higher rates of patients achieving modified MDA and strict ACR remission even over the long term than initial single-DMARD therapy. Targeting remission with tight clinical controls results in good functional and clinical outcomes in most RA patients.

PMID 19404945
Catriona Grigor, Hilary Capell, Anne Stirling, Alex D McMahon, Peter Lock, Ramsay Vallance, Wilma Kincaid, Duncan Porter
Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial.
Lancet. 2004 Jul 17-23;364(9430):263-9. doi: 10.1016/S0140-6736(04)16676-2.
Abstract/Text BACKGROUND: Present treatment strategies for rheumatoid arthritis include use of disease-modifying antirheumatic drugs, but a minority of patients achieve a good response. We aimed to test the hypothesis that an improved outcome can be achieved by employing a strategy of intensive outpatient management of patients with rheumatoid arthritis--for sustained, tight control of disease activity--compared with routine outpatient care.
METHODS: We designed a single-blind, randomised controlled trial in two teaching hospitals. We screened 183 patients for inclusion. 111 were randomly allocated either intensive management or routine care. Primary outcome measures were mean fall in disease activity score and proportion of patients with a good response (defined as a disease activity score <2.4 and a fall in this score from baseline by >1.2). Analysis was by intention-to-treat.
FINDINGS: One patient withdrew after randomisation and seven dropped out during the study. Mean fall in disease activity score was greater in the intensive group than in the routine group (-3.5 vs -1.9, difference 1.6 [95% CI 1.1-2.1], p<0.0001). Compared with routine care, patients treated intensively were more likely to have a good response (definition, 45/55 [82%] vs 24/55 [44%], odds ratio 5.8 [95% CI 2.4-13.9], p<0.0001) or be in remission (disease activity score <1.6; 36/55 [65%] vs 9/55 [16%], 9.7 [3.9-23.9], p<0.0001). Three patients assigned routine care and one allocated intensive management died during the study; none was judged attributable to treatment.
INTERPRETATION: A strategy of intensive outpatient management of rheumatoid arthritis substantially improves disease activity, radiographic disease progression, physical function, and quality of life at no additional cost.

PMID 15262104
S M van der Kooij, Y P M Goekoop-Ruiterman, J K de Vries-Bouwstra, M Güler-Yüksel, A H Zwinderman, P J S M Kerstens, P A H M van der Lubbe, W M de Beus, B A M Grillet, H K Ronday, T W J Huizinga, F C Breedveld, B A C Dijkmans, C F Allaart
Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis.
Ann Rheum Dis. 2009 Jun;68(6):914-21. doi: 10.1136/ard.2008.092254. Epub 2008 Jul 28.
Abstract/Text OBJECTIVES: To compare the occurrence of drug-free remission, functional ability and radiological damage after 4 years of response-driven treatment according to four different treatment strategies for rheumatoid arthritis (RA).
METHODS: Patients with recent-onset, active RA (n = 508) were randomly assigned to four different treatment strategies: (1) sequential monotherapy; (2) step-up combination therapy; (3) initial combination therapy with prednisone and (4) initial combination therapy with infliximab. Treatment was adjusted based on 3-monthly disease activity score (DAS) assessments, aiming at a DAS < or =2.4. From the third year, patients with a sustained DAS <1.6 discontinued treatment.
RESULTS: In total, 43% of patients were in remission (DAS <1.6) at 4 years and 13% were in drug-free remission: 14%, 12%, 8% and 18% of patients in groups 1-4, respectively. The absence of anti-cyclic citrullinated peptide antibodies, male gender and short symptom duration were independently associated with drug-free remission. Functional ability and remission were maintained in all four groups with the continuation of DAS-driven treatment, without significant differences between the groups. Significant progression of joint damage was observed in 38% and 31% of patients in groups 3 and 4 versus 51% and 54% of patients in groups 1 and 2 (p<0.05, group 4 versus groups 1 and 2, group 3 versus group 2).
CONCLUSIONS: In patients with recent-onset active RA, drug-free remission was achieved in up to 18% of patients. DAS-driven treatment maintained clinical and functional improvement, independent of the treatment strategy. Joint damage progression remained significantly lower after initial combination therapy compared with initial monotherapy.

PMID 18662933
Axel Finckh, Nick Bansback, Carlo A Marra, Aslam H Anis, Kaleb Michaud, Stanley Lubin, Marc White, Sonia Sizto, Matthew H Liang
Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis.
Ann Intern Med. 2009 Nov 3;151(9):612-21. doi: 10.7326/0003-4819-151-9-200911030-00006.
Abstract/Text BACKGROUND: Long-term control or remission of rheumatoid arthritis (RA) may be possible with very early treatment. However, no optimal first therapeutic strategy has been determined.
OBJECTIVE: To assess the potential cost-effectiveness of major therapeutic strategies for very early RA.
DESIGN: Decision analytic model with probabilistic sensitivity analyses.
DATA SOURCES: Published data, the National Data Bank for Rheumatic Diseases, and actual 2007 hospital costs.
TARGET POPULATION: U.S. adults with very early RA (symptom duration TIME HORIZON: Lifetime.
PERSPECTIVE: Health care provider and societal.
INTERVENTION: 3 management strategies were compared: a symptomatic or "pyramid" strategy with initial nonsteroidal anti-inflammatory drugs, patient education, pain management, and low-dose glucocorticoids, and disease-modifying antirheumatic drugs (DMARDs) at 1 year for nonresponders; early DMARD therapy with methotrexate; and early therapy with biologics and methotrexate.
OUTCOME MEASURES: Cost per quality-adjusted life-year (QALY) gained.
RESULTS OF BASE-CASE ANALYSIS: By reducing the progression of joint erosions and subsequent functional disability, both early intervention strategies increase quality-adjusted life more than the pyramid strategy and save long-term costs. When the cost of very early intervention is factored in, the cost-effectiveness ratio of the early DMARD strategy is $4849 per QALY (95% CI, $0 to $16 354 per QALY) compared with the pyramid strategy, whereas the benefits gained through the early biologic strategy come at a substantial incremental cost. The early DMARD strategy maximizes the effectiveness of early DMARDs and reserves the use of biologics for patients with more treatment-resistant disease of longer duration, for which the incremental benefit of biologics is greater.
RESULTS OF SENSITIVITY ANALYSIS: The early biologic strategy becomes more cost-effective if drug prices are reduced, risk for death is permanently lowered through biologic therapy, patients experience drug-free remission, responders can be selected before therapy initiation, or effective alternative antirheumatic agents are available for patients for whom several biologics have failed.
LIMITATIONS: Data on the long-term effect of very early therapeutic interventions on the natural progression in disability and joint erosions are limited. The study considered only tumor necrosis factor inhibitors and not the newer biologics.
CONCLUSION: According to the most objective measures of RA progression, very early intervention with conventional DMARDs is cost-effective. The cost-effectiveness of very early intervention with biologics remains uncertain.

PMID 19884622
Michaela A Stoffer, Monika M Schoels, Josef S Smolen, Daniel Aletaha, Ferdinand C Breedveld, Gerd Burmester, Vivian Bykerk, Maxime Dougados, Paul Emery, Boulos Haraoui, Juan Gomez-Reino, Tore K Kvien, Peter Nash, Victoria Navarro-Compán, Marieke Scholte-Voshaar, Ronald van Vollenhoven, Désirée van der Heijde, Tanja A Stamm
Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update.
Ann Rheum Dis. 2015 May 19;. doi: 10.1136/annrheumdis-2015-207526. Epub 2015 May 19.
Abstract/Text OBJECTIVE: A systematic literature review (SLR; 2009-2014) to compare a target-oriented approach with routine management in the treatment of rheumatoid arthritis (RA) to allow an update of the treat-to-target recommendations.
METHODS: Two SLRs focused on clinical trials employing a treatment approach targeting a specific clinical outcome were performed. In addition to testing clinical, functional and/or structural changes as endpoints, comorbidities, cardiovascular risk, work productivity and education as well as patient self-assessment were investigated. The searches covered MEDLINE, EMBASE, Cochrane databases and Clinicaltrial.gov for the period between 2009 and 2012 and separately for the period of 2012 to May of 2014.
RESULTS: Of 8442 citations retrieved in the two SLRs, 176 articles underwent full-text review. According to predefined inclusion/exclusion criteria, six articles were included of which five showed superiority of a targeted treatment approach aiming at least at low-disease activity versus routine care; in addition, publications providing supportive evidence were also incorporated that aside from expanding the evidence provided by the above six publications allowed concluding that a target-oriented approach leads to less comorbidities and cardiovascular risk and better work productivity than conventional care.
CONCLUSIONS: The current study expands the evidence that targeting low-disease activity or remission in the management of RA conveys better outcomes than routine care.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PMID 25990290
S M M Verstappen, J W G Jacobs, M J van der Veen, A H M Heurkens, Y Schenk, E J ter Borg, A A M Blaauw, J W J Bijlsma, Utrecht Rheumatoid Arthritis Cohort study group
Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial).
Ann Rheum Dis. 2007 Nov;66(11):1443-9. doi: 10.1136/ard.2007.071092. Epub 2007 May 22.
Abstract/Text BACKGROUND: To investigate whether intensive treatment with methotrexate (MTX) according to a strict protocol and a computerised decision program is more beneficial compared to conventional treatment with MTX in early rheumatoid arthritis.
METHODS: In a two-year multicentre open label strategy trial, 299 patients with early rheumatoid arthritis were randomly assigned to the intensive strategy group or the conventional strategy group. Patients in both groups received MTX, the aim of treatment being remission. Patients in the intensive treatment group came to the outpatient clinic once every month; adjustment of the MTX dosage was tailored to the individual patient on the basis of predefined response criteria, using a computerised decision program. Patients of the conventional strategy group came to the outpatient clinic once every three months; they were treated according to common practice. Cyclosporine was added if patients had an inadequate response to maximal tolerated MTX doses.
RESULTS: Seventy six (50%) patients in the intensive strategy group achieved at least one period of remission during the two year trial, versus 55 patients (37%) in the conventional strategy group (p = 0.03). Areas under the curve for nearly all clinical variables were significantly lower-that is, there was a better clinical effect for the intensive treatment group compared with the conventional treatment group.
CONCLUSION: The results of this study show that it is possible to substantially enhance the clinical efficacy early in the course of the disease by intensifying treatment with MTX, aiming for remission, tailored to the individual patient. Furthermore, participating rheumatologists indicated that the computerised decision program could be a helpful tool in their daily clinical practice.

PMID 17519278
Josef S Smolen, Daniel Aletaha, Johannes W J Bijlsma, Ferdinand C Breedveld, Dimitrios Boumpas, Gerd Burmester, Bernard Combe, Maurizio Cutolo, Maarten de Wit, Maxime Dougados, Paul Emery, Alan Gibofsky, Juan Jesus Gomez-Reino, Boulos Haraoui, Joachim Kalden, Edward C Keystone, Tore K Kvien, Iain McInnes, Emilio Martin-Mola, Carlomaurizio Montecucco, Monika Schoels, Désirée van der Heijde, Desirée van der Heijde, T2T Expert Committee
Treating rheumatoid arthritis to target: recommendations of an international task force.
Ann Rheum Dis. 2010 Apr;69(4):631-7. doi: 10.1136/ard.2009.123919. Epub 2010 Mar 9.
Abstract/Text BACKGROUND: Aiming at therapeutic targets has reduced the risk of organ failure in many diseases such as diabetes or hypertension. Such targets have not been defined for rheumatoid arthritis (RA).
OBJECTIVE: /st> To develop recommendations for achieving optimal therapeutic outcomes in RA.
METHODS: A task force of rheumatologists and a patient developed a set of recommendations on the basis of evidence derived from a systematic literature review and expert opinion; these were subsequently discussed, amended and voted upon by >60 experts from various regions of the world in a Delphi-like procedure. Levels of evidence, strength of recommendations and levels of agreement were derived.
RESULTS: The treat-to-target activity resulted in 10 recommendations. The treatment aim was defined as remission with low disease activity being an alternative goal in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with appropriate therapeutic adaptation to reach the desired state within 3 to a maximum of 6 months was recommended. Follow-up examinations ought to employ composite measures of disease activity which include joint counts. Additional items provide further details for particular aspects of the disease. Levels of agreement were very high for many of these recommendations (> or =9/10).
CONCLUSION: The 10 recommendations are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA based on evidence and expert opinion.

PMID 20215140
日本リウマチ学会MTX診療ガイドライン策定小委員会編. 関節リウマチにおけるメトトレキサート(MTX)診療ガイドライン2016年改訂版.
Karin Niedermann, Jaap Fransen, Ruud Knols, Daniel Uebelhart
Gap between short- and long-term effects of patient education in rheumatoid arthritis patients: a systematic review.
Arthritis Rheum. 2004 Jun 15;51(3):388-98. doi: 10.1002/art.20399.
Abstract/Text OBJECTIVE: To systematically review educational or psychoeducational interventions for patients with rheumatoid arthritis focusing on long-term effects, especially health status.
METHODS: Two independent reviewers appraised the methodologic quality of the included randomized controlled trials, published between 1980 and July 2002.
RESULTS: Validity scores of studies ranged from 3 to 9 (of 11). The 7 educational programs mainly improved knowledge and compliance in the short and long term, but there was no improvement in health status. All 4 psychoeducational programs improved coping behavior in the short term, 2 of them showing a positive long-term effect on physical or psychological health variables.
CONCLUSION: Methodologically better-designed studies had more difficulties demonstrating positive outcome results. Short-term effects in program targets are generally observed, whereas long-term changes in health status are not convincingly demonstrated. There is a need to find better strategies to enhance the transfer of short-term effects into gains in health status.

PMID 15188324
R P Riemsma, J R Kirwan, E Taal, J J Rasker
Patient education for adults with rheumatoid arthritis.
Cochrane Database Syst Rev. 2003;(2):CD003688. doi: 10.1002/14651858.CD003688.
Abstract/Text BACKGROUND: Because of the unpredictability people with arthritis face on a daily basis, patient education programmes have become an effective complement to traditional medical treatment giving people with arthritis the strategies and the tools necessary to make daily decisions to cope with the disease.
OBJECTIVES: To assess the effectiveness of patient education interventions on health status in patients with rheumatoid arthritis.
SEARCH STRATEGY: We searched MEDLINE, EMBASE and PsycINFO and the Cochrane Controlled Trials Register. A selection of review articles (see references) were examined to identify further relevant publications. There was no language restriction.
SELECTION CRITERIA: Randomised controlled trials (RCT's) evaluating patient education interventions that included an instructional component and a non-intervention control group; pre- and post-test results available separately for RA, either in the publication or from the studies' authors; and study results presented in full, end-of-study report.
MAIN RESULTS: Thirty-one studies with relevant data were included. We found significant effects of patient education at first follow-up for scores on disability, joint counts, patient global assessment, psychological status, and depression. A trend favouring patient education was found for scores on pain. Physician global assessment was not assessed in any of the included studies. The dimensions of anxiety and disease activity showed no significant effects. At final follow up no significant effects of patient education were found, although there was a trend favouring patient education for scores on disability.
REVIEWER'S CONCLUSIONS: Patient education as provided in the studies reviewed here had small short-term effects on disability, joint counts, patient global assessment, psychological status and depression. There was no evidence of long-term benefits in adults with rheumatoid arthritis.

PMID 12804484
Emalie Hurkmans, Florus J van der Giesen, Thea Pm Vliet Vlieland, Jan Schoones, E C H M Van den Ende
Dynamic exercise programs (aerobic capacity and/or muscle strength training) in patients with rheumatoid arthritis.
Cochrane Database Syst Rev. 2009 Oct 7;(4):CD006853. doi: 10.1002/14651858.CD006853.pub2. Epub 2009 Oct 7.
Abstract/Text BACKGROUND: An up-to-date overview of the effectiveness and safety of dynamic exercise therapy (exercise therapy with a sufficient intensity, duration, and frequency to establish improvement in aerobic capacity and/or muscle strength) is lacking.
OBJECTIVES: To assess the effectiveness and safety of short-term (< three months) and long-term (> three months) dynamic exercise therapy programs (aerobic capacity and/or muscle strength training), either land or water-based, for people with RA. To do this we updated a previous Cochrane review (van den Ende 1998) and made categories for the different forms of dynamic exercise programs.
SEARCH STRATEGY: A literature search (to December 2008) within various databases was performed in order to identify randomised controlled trials (RCTs).
SELECTION CRITERIA: RCTs that included an exercise program fulfilling the following criteria were selected: a) frequency at least twice weekly for > 20 minutes; b) duration > 6 weeks; c) aerobic exercise intensity > 55% of the maximum heart rate and/or muscle strengthening exercises starting at 30% to 50% of one repetition maximum; and d) performed under supervision. Moreover, the RCT included one or more of the following outcome measures: functional ability, aerobic capacity, muscle strength, pain, disease activity or radiological damage.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible studies, rated the methodological quality, and extracted data. A qualitative analysis (best-evidence synthesis) was performed and, where appropriate, a quantitative data analysis (pooled effect sizes).
MAIN RESULTS: In total, eight studies were included in this updated review (two additional studies). Four of the eight studies fulfilled at least 8/10 methodological criteria. In this updated review four different dynamic exercise programs were found: (1) short-term, land-based aerobic capacity training, which results show moderate evidence for a positive effect on aerobic capacity (pooled effect size 0.99 (95% CI 0.29 to 1.68). (2) short-term, land-based aerobic capacity and muscle strength training, which results show moderate evidence for a positive effect on aerobic capacity and muscle strength (pooled effect size 0.47 (95% CI 0.01 to 0.93). (3) short-term, water-based aerobic capacity training, which results show limited evidence for a positive effect on functional ability and aerobic capacity. (4) long-term, land-based aerobic capacity and muscle strength training, which results show moderate evidence for a positive effect on aerobic capacity and muscle strength. With respect to safety, no deleterious effects were found in any of the included studies.
AUTHORS' CONCLUSIONS: Based on the evidence, aerobic capacity training combined with muscle strength training is recommended as routine practice in patients with RA.

PMID 19821388
Kelson Ng Silva, Aline Mizusaki Imoto, Gustavo Jm Almeida, Alvaro N Atallah, Maria Stella Peccin, Virginia Fernandes Moça Trevisani
Balance training (proprioceptive training) for patients with rheumatoid arthritis.
Cochrane Database Syst Rev. 2010 May 12;(5):CD007648. doi: 10.1002/14651858.CD007648.pub2. Epub 2010 May 12.
Abstract/Text BACKGROUND: Patients with rheumatoid arthritis may have an increased risk of falls due to impairments in lower-extremity joints, which may result in either mobility, or postural stability problems. There is evidence in the literature suggesting that balance, agility and coordination training techniques can induce changes in lower-extremity muscle activity patterns that result in improvement in dynamic joint stability.The mechanoreceptors present in and around the joints are responsible for maintaining postural control and joint position sense. These receptors are integrated to compose the somatosensorial system. In combination with visual and auditory inputs, which improve our spatial perception even further, the systems are able to maintain a stable body posture.However, there is a lack of information on the efficacy of balance training alone in patients with rheumatoid arthritis.
OBJECTIVES: To assess the effectiveness and safety of balance training (proprioceptive training) to improve functional capacity in patients with rheumatoid arthritis.
SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 4), MEDLINE via PubMed (January 1966 to December 2008), EMBASE (January 1980 to December 2008), LILACS (January 1982 to December 2008), CINAHL (January 1982 to December 2008), PEDro and Scirus (inception to 2008). We also handsearched conference abstracts.
SELECTION CRITERIA: All eligible randomised controlled trials (RCT) or controlled clinical trials (CCT) comparing balance training (proprioceptive training) with any other intervention or with no intervention.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed titles or abstracts, or both, for inclusion criteria.
MAIN RESULTS: The electronic search identified 864 studies. From this search, 17 studies described general exercises in rheumatoid arthritis patients as the main topic. After analysing them, we observed that the main interventions were exercises to improve muscle strength, endurance, and dynamic exercises (swimming, walking, etc). As we did not find any studies investigating the effects of balance training alone or in combination with other therapies in patients with rheumatoid arthritis, it was not possible to include any data regarding the chosen topic in this systematic review.
AUTHORS' CONCLUSIONS: There is no research available examining the efficacy of balance training alone in patients with rheumatoid arthritis. The effectiveness and safety of balance training to improve functional capacity of these patients remains unclear. We suggest that future research should give more importance to balance training by either increasing the number and duration of sessions or investigating its efficacy alone.

PMID 20464755
Ineke Breedland, Corinne van Scheppingen, Martha Leijsma, Nienke P Verheij-Jansen, Ellen van Weert
Effects of a group-based exercise and educational program on physical performance and disease self-management in rheumatoid arthritis: a randomized controlled study.
Phys Ther. 2011 Jun;91(6):879-93. doi: 10.2522/ptj.20090010. Epub 2011 Apr 7.
Abstract/Text BACKGROUND: Evidence supports the use of educational and physical training programs for people with rheumatoid arthritis (RA).
OBJECTIVE: The purpose of this study was to evaluate the effects of a group-based exercise and educational program on the physical performance and disease self-management of people with RA.
DESIGN: This was a randomized controlled trial.
SETTING: The study was conducted at a rehabilitation center in the Netherlands.
PARTICIPANTS: Thirty-four people diagnosed with RA participated in the study. Participants were randomly assigned to either an intervention group (n=19) or a waiting list control group (n=15).
INTERVENTION: The intervention in this study was an 8-week, multidisciplinary, group therapy program for people with RA, consisting of physical exercise designed to increase aerobic capacity and muscle strength (force-generating capacity) together with an educational program to improve health status and self-efficacy for disease-self-management.
MEASUREMENTS: The main outcome measures were maximum oxygen uptake (Vo(2)max), muscle strength of the elbow and knee flexors and extensors, health status, and perceived self-efficacy. All data were recorded before intervention in week 1, after intervention in week 9, and at follow-up in week 22.
RESULTS: The intervention group showed significant improvement (12.1%) in Vo(2)max at week 9 compared with the control group (-1.7%). Although significant within-group changes were found over time for muscle strength of the upper and lower extremities and health status that favored the intervention group, no between-group changes were found regarding these outcomes.
LIMITATIONS: An important limitation was the small number of participants included in our study, which may have resulted in a lack of power.
CONCLUSIONS: The present group-based exercise and educational program for people with RA had a beneficial effect on aerobic capacity but not on muscle strength, health status, or self-efficacy.

PMID 21474637
Barbara Strasser, Gunther Leeb, Christoph Strehblow, Wolfgang Schobersberger, Paul Haber, Edmund Cauza
The effects of strength and endurance training in patients with rheumatoid arthritis.
Clin Rheumatol. 2011 May;30(5):623-32. doi: 10.1007/s10067-010-1584-2. Epub 2010 Oct 8.
Abstract/Text Patients with rheumatoid arthritis (RA) suffer from muscle loss, causing reduced muscle strength and endurance. The current study aimed to: (1) evaluate the effects of combined strength and endurance training (CT) on disease activity and functional ability in patients with RA and (2) investigate the benefits of a 6-month supervised CT program on muscle strength, cardio-respiratory fitness, and body composition of RA patients. Forty patients with RA, aged 41-73 years, were recruited for the current study. Twenty of these patients (19 females, one male) were randomly assigned to a 6-month supervised CT program; 20 patients (17 females, three males) served as controls. Within the CT program, strength training consisted of sets of weight bearing exercises for all major muscle groups. In addition to strength training, systematic endurance training was performed on a cycle ergometer two times per week. For RA patients involved in CT, disease activity (p = 0.06) and pain (p = 0.05) were reduced after the 6-month training period while general health (p = 0.04) and functional ability (p = 0.06) improved. Cardio-respiratory endurance was found to have improved significantly (by 10%) after 6 months of CT (p < 0.001). The overall strength of patients undertaking CT increased by an average of 14%. Lean body mass increased, and the percentage of body fat was found to decrease significantly (p < 0.05). A combination of strength and endurance training resulted in considerable improvements in RA patients' muscle strength and cardio-respiratory endurance, accompanied by positive changes in body composition and functional ability. Long-term training appears to be effective in reducing disease activity and associated pain and was found to have no deleterious effects.

PMID 20931346
E M J Steultjens, J Dekker, L M Bouter, D van Schaardenburg, M A H van Kuyk, C H M van den Ende
Occupational therapy for rheumatoid arthritis.
Cochrane Database Syst Rev. 2004;(1):CD003114. doi: 10.1002/14651858.CD003114.pub2.
Abstract/Text BACKGROUND: For persons with rheumatoid arthritis (RA) the physical, personal, familial, social and vocational consequences are extensive. Occupational therapy (OT), with the aim to facilitate task performance and to decrease the consequences of rheumatoid arthritis for daily life activities, is considered to be a cornerstone in the management of rheumatoid arthritis. Till now the efficacy of occupational therapy for patients with rheumatoid arthritis on functional performance and social participation has not been systematically reviewed.
OBJECTIVES: To determine whether OT interventions (classified as comprehensive therapy, training of motor function, training of skills, instruction on joint protection and energy conservation, counseling, instruction about assistive devices and provision of splints) for rheumatoid arthritis patients improve outcome on functional ability, social participation and/or health related quality of life.
SEARCH STRATEGY: Relevant full length articles were identified by electronic searches in Medline, Cinahl, Embase, Amed, Scisearch and the Cochrane Musculoskeletal group Specialised Register. The reference list of identified studies and reviews were examined for additional references. Date of last search: December 2002.
SELECTION CRITERIA: Controlled (randomized and non-randomized) and other than controlled studies (OD) addressing OT for RA patients were eligible for inclusion.
DATA COLLECTION AND ANALYSIS: The methodological quality of the included trials was independently assessed by two reviewers. Disagreements were resolved by discussion. A list proposed by Van Tulder et al. (Van Tulder 1997) was used to assess the methodological quality. For outcome measures, standardized mean differences were calculated. The results were analysed using a best evidence synthesis based on type of design, methodological quality and the significant findings of outcome and/or process measures.
MAIN RESULTS: Thirty-eight out of 58 identified occupational therapy studies fulfilled all inclusion criteria. Six controlled studies had a high methodological quality. Given the methodological constraints of uncontrolled studies, nine of these studies were judged to be of sufficient methodological quality. The results of the best evidence synthesis shows that there is strong evidence for the efficacy of "instruction on joint protection" (an absolute benefit of 17.5 to 22.5, relative benefit of 100%) and that limited evidence exists for comprehensive occupational therapy in improving functional ability (an absolute benefit of 8.7, relative benefit of 20%). Indicative findings for evidence that "provision of splints" decreases pain are found (absolute benefit of 1.0, relative benefit of 19%).
REVIEWER'S CONCLUSIONS: There is evidence that occupational therapy has a positive effect on functional ability in patients with rheumatoid arthritis.

PMID 14974005
Wanruchada Katchamart, Judith Trudeau, Veerapong Phumethum, Claire Bombardier
Methotrexate monotherapy versus methotrexate combination therapy with non-biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis.
Cochrane Database Syst Rev. 2010 Apr 14;(4):CD008495. doi: 10.1002/14651858.CD008495. Epub 2010 Apr 14.
Abstract/Text BACKGROUND: Methotrexate (MTX) is among the most effective disease modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) with less toxicity and better tolerability.
OBJECTIVES: To evaluate the efficacy and toxicity of MTX monotherapy compared to MTX combination with non-biologic DMARDs in adult with RA.
SEARCH STRATEGY: Trials were identified in MEDLINE (1950 to 2009), EMBASE (1980 to 2009), the Cochrane Controlled trials Registry (CENTRAL) (up to 2009), the American and European scientific meeting abstracts 2005-9, the reference lists of all relevant studies, letters, and review articles.
SELECTION CRITERIA: Randomized controlled trials comparing MTX monotherapy versus MTX combined with other non-biologic DMARDs of at least 12 weeks of trial duration in adult RA patients.
DATA COLLECTION AND ANALYSIS: Two reviewers independently identified eligible studies,extracted the data, and assessed the risk of bias of relevant studies.The efficacy analysis was stratified into 3 groups based on previous DMARDs use: DMARD naive, MTX inadequate response, and non-MTX DMARDs inadequate response. The toxicity analysis was stratified by DMARD combination and pooled across trials for each combination. Our prespecified primary analysis was based on total withdrawal rates for efficacy or toxicity.
MAIN RESULTS: A total of 19 trials (2,025 patients) from 6,938 citations were grouped by the type of patients randomised. Trials in DMARD naive patients showed no significant advantage of the MTX combination versus monotherapy; withdrawals for lack of efficacy or toxicity were similar in both groups (risk ratio (RR) 1.16, 95% CI.0.70 to 1.93, absolute risk difference(ARD) 5%, 95%CI-3% to 13%). Trials in MTX or non-MTX DMARDs inadequate responder patients also showed no difference in withdrawal rates between the MTX combo versus mono groups with RR 0.86 95% CI 0.49 to1.51, ARD -2 %, 95% CI-13 % to 8 % and RR 0.75 95% CI 0.41 to 1.35, ARD -10%, 95% CI -31% to 11%, respectively. Significant reductions of pain and improvement in physical function (measured by Health Assessment Questionnaire or HAQ) were found in the MTX combination group, but only in MTX-inadequate responders (absolute risk difference -9.72%, 95%CI -14.7% to -4.75% for pain and mean difference (MD) -0.28, 95%CI -0.36 to -0.21 (0-3) for HAQ).
AUTHORS' CONCLUSIONS: When the balance of efficacy and toxicity is taken into account, the moderate level of evidence from our systematic review showed no statistically significant advantage of the MTX combination versus monotherapy. Trials are needed that compare currently used MTX doses and combination therapies.

PMID 20393970
James R O'Dell, Ted R Mikuls, Thomas H Taylor, Vandana Ahluwalia, Mary Brophy, Stuart R Warren, Robert A Lew, Amy C Cannella, Gary Kunkel, Ciaran S Phibbs, Aslam H Anis, Sarah Leatherman, Edward Keystone, CSP 551 RACAT Investigators
Therapies for active rheumatoid arthritis after methotrexate failure.
N Engl J Med. 2013 Jul 25;369(4):307-18. doi: 10.1056/NEJMoa1303006. Epub 2013 Jun 11.
Abstract/Text BACKGROUND: Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate--a common scenario in the management of rheumatoid arthritis.
METHODS: We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48.
RESULTS: Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications.
CONCLUSIONS: With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT ClinicalTrials.gov number, NCT00405275.)

PMID 23755969
Masako Hara, Tohru Abe, Sachiko Sugawara, Yutaka Mizushima, Keiko Hoshi, Shoichiro Irimajiri, Hiroshi Hashimoto, Shinichi Yoshino, Nobuo Matsui, Masashi Nobunaga, Shigeyuki Nakano
Efficacy and safety of iguratimod compared with placebo and salazosulfapyridine in active rheumatoid arthritis: a controlled, multicenter, double-blind, parallel-group study.
Mod Rheumatol. 2007;17(1):1-9. doi: 10.1007/s10165-006-0542-y. Epub 2007 Feb 20.
Abstract/Text We conducted a 28-week, randomized, double-blind, parallel-group study of iguratimod in 376 Japanese patients with active rheumatoid arthritis to compare the efficacy and safety of the drug with those of placebo and salazosulfapyridine. In the American College of Rheumatology (ACR) 20 response rate, iguratimod was superior to placebo (53.8% versus 17.2%; Fisher's exact test, P < 0.001) and was not inferior to salazosulfapyridine (63.1% versus 57.7%, 95% confidence interval for the rate difference, -7.9% to 18.7%). Iguratimod began exhibiting its therapeutic effect within 8 weeks after the initiation of treatment and was effective even in patients who had a poor response to previous treatment with disease-modifying antirheumatic drugs. No statistically significant difference was noted in the incidence of adverse reactions between iguratimod and salazosulfapyridine. The study results suggest that iguratimod could become a new option for the treatment of rheumatoid arthritis.

PMID 17278015
Naoki Ishiguro, Kazuhiko Yamamoto, Kou Katayama, Masakazu Kondo, Takayuki Sumida, Tsuneyo Mimori, Satoshi Soen, Kota Nagai, Tomonobu Yamaguchi, Masako Hara, Iguratimod-Clinical Study Group
Concomitant iguratimod therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: a randomized, double-blind, placebo-controlled trial.
Mod Rheumatol. 2013 May;23(3):430-9. doi: 10.1007/s10165-012-0724-8. Epub 2012 Jul 26.
Abstract/Text OBJECTIVES: To investigate the efficacy and safety of iguratimod (T-614) in Japanese patients with active rheumatoid arthritis who had inadequate response to stable background methotrexate (MTX) alone.
METHODS: In this multicenter, double-blind, controlled trial, a total of 253 patients were randomized at 2:1 ratio to either the iguratimod group or the placebo group. Iguratimod was orally administered at dosages of 25 mg/day for the first 4 weeks (25 mg once daily) and 50 mg/day for the subsequent 20 weeks (25 mg twice daily). MTX at dosage of 6 or 8 mg/week was administered to patients in both groups.
RESULTS: The rate of 20 % improvement in American College of Rheumatology criteria (ACR20) at week 24 was 69.5 % in the iguratimod group compared with 30.7 % in the placebo group (P < 0.001). Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index, Disease Activity Score 28 <3.2, and rheumatoid factor were also observed. The most commonly reported adverse events (AEs) were blood iron decrease, nasopharyngitis, and lymphocyte decrease. These AEs were mild or moderate in severity. No deaths occurred.
CONCLUSION: The study results suggest that iguratimod in combination with MTX was efficacious and had a manageable safety profile.

PMID 22833377
Masako Hara, Tohru Abe, Sachiko Sugawara, Yutaka Mizushima, Keiko Hoshi, Shoichiro Irimajiri, Hiroshi Hashimoto, Shinichi Yoshino, Nobuo Matsui, Masashi Nobunaga
Long-term safety study of iguratimod in patients with rheumatoid arthritis.
Mod Rheumatol. 2007;17(1):10-6. doi: 10.1007/s10165-006-0543-x. Epub 2007 Feb 20.
Abstract/Text We conducted a 52-week clinical study of iguratimod in 394 Japanese patients with rheumatoid arthritis to evaluate the long-term safety of the drug. Iguratimod was administered orally at a daily dose of 25 mg for the first 4 weeks and 50 mg for the subsequent 48 weeks. Some of the patients continued the treatment for 100 weeks for their benefit. The cumulative incidence of adverse events for 100 weeks was 97.6%. The cumulative incidence of adverse reactions was 65.3%; unfavorable symptoms and signs (excluding abnormal laboratory data changes) accounted for 33.2% of the reactions, and abnormal laboratory data changes accounted for 50.4%. The continued treatment rate was 66.8% at week 28 and 53.6% at week 52. For reference, the American College of Rheumatology (ACR) 20 response rate was calculated for the patients who had assessable disease activity, who did not violate the study protocol, and who continued the study treatment at weeks 28 and 52. The rate was 46.9% at week 28 and 41.0% at week 52. To use iguratimod safely for a long time, patients should be observed closely for adverse reactions such as increased hepatic enzymes.

PMID 17278016
Jasvinder A Singh, Daniel E Furst, Aseem Bharat, Jeffrey R Curtis, Arthur F Kavanaugh, Joel M Kremer, Larry W Moreland, James O'Dell, Kevin L Winthrop, Timothy Beukelman, S Louis Bridges, W Winn Chatham, Harold E Paulus, Maria Suarez-Almazor, Claire Bombardier, Maxime Dougados, Dinesh Khanna, Charles M King, Amye L Leong, Eric L Matteson, John T Schousboe, Eileen Moynihan, Karen S Kolba, Archana Jain, Elizabeth R Volkmann, Harsh Agrawal, Sangmee Bae, Amy S Mudano, Nivedita M Patkar, Kenneth G Saag
2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis.
Arthritis Care Res (Hoboken). 2012 May;64(5):625-39. doi: 10.1002/acr.21641.
Abstract/Text
PMID 22473917
Kenneth G Saag, Gim Gee Teng, Nivedita M Patkar, Jeremy Anuntiyo, Catherine Finney, Jeffrey R Curtis, Harold E Paulus, Amy Mudano, Maria Pisu, Mary Elkins-Melton, Ryan Outman, Jeroan J Allison, Maria Suarez Almazor, S Louis Bridges, W Winn Chatham, Marc Hochberg, Catherine MacLean, Ted Mikuls, Larry W Moreland, James O'Dell, Anthony M Turkiewicz, Daniel E Furst, American College of Rheumatology
American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis.
Arthritis Rheum. 2008 Jun 15;59(6):762-84. doi: 10.1002/art.23721.
Abstract/Text
PMID 18512708
Josef S Smolen, Robert Landewé, Ferdinand C Breedveld, Maxime Dougados, Paul Emery, Cecile Gaujoux-Viala, Simone Gorter, Rachel Knevel, Jackie Nam, Monika Schoels, Daniel Aletaha, Maya Buch, Laure Gossec, Tom Huizinga, Johannes W J W Bijlsma, Gerd Burmester, Bernard Combe, Maurizio Cutolo, Cem Gabay, Juan Gomez-Reino, Marios Kouloumas, Tore K Kvien, Emilio Martin-Mola, Iain McInnes, Karel Pavelka, Piet van Riel, Marieke Scholte, David L Scott, Tuulikki Sokka, Guido Valesini, Ronald van Vollenhoven, Kevin L Winthrop, John Wong, Angela Zink, Désirée van der Heijde
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs.
Ann Rheum Dis. 2010 Jun;69(6):964-75. doi: 10.1136/ard.2009.126532. Epub 2010 May 5.
Abstract/Text Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.

PMID 20444750
Josef S Smolen, Robert Landewé, Ferdinand C Breedveld, Maya Buch, Gerd Burmester, Maxime Dougados, Paul Emery, Cécile Gaujoux-Viala, Laure Gossec, Jackie Nam, Sofia Ramiro, Kevin Winthrop, Maarten de Wit, Daniel Aletaha, Neil Betteridge, Johannes W J Bijlsma, Maarten Boers, Frank Buttgereit, Bernard Combe, Maurizio Cutolo, Nemanja Damjanov, Johanna M W Hazes, Marios Kouloumas, Tore K Kvien, Xavier Mariette, Karel Pavelka, Piet L C M van Riel, Andrea Rubbert-Roth, Marieke Scholte-Voshaar, David L Scott, Tuulikki Sokka-Isler, John B Wong, Désirée van der Heijde
EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update.
Ann Rheum Dis. 2014 Mar;73(3):492-509. doi: 10.1136/annrheumdis-2013-204573. Epub 2013 Oct 25.
Abstract/Text In this article, the 2010 European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA) with synthetic and biological disease-modifying antirheumatic drugs (sDMARDs and bDMARDs, respectively) have been updated. The 2013 update has been developed by an international task force, which based its decisions mostly on evidence from three systematic literature reviews (one each on sDMARDs, including glucocorticoids, bDMARDs and safety aspects of DMARD therapy); treatment strategies were also covered by the searches. The evidence presented was discussed and summarised by the experts in the course of a consensus finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) were determined. Fourteen recommendations were developed (instead of 15 in 2010). Some of the 2010 recommendations were deleted, and others were amended or split. The recommendations cover general aspects, such as attainment of remission or low disease activity using a treat-to-target approach, and the need for shared decision-making between rheumatologists and patients. The more specific items relate to starting DMARD therapy using a conventional sDMARD (csDMARD) strategy in combination with glucocorticoids, followed by the addition of a bDMARD or another csDMARD strategy (after stratification by presence or absence of adverse risk factors) if the treatment target is not reached within 6 months (or improvement not seen at 3 months). Tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars), abatacept, tocilizumab and, under certain circumstances, rituximab are essentially considered to have similar efficacy and safety. If the first bDMARD strategy fails, any other bDMARD may be used. The recommendations also address tofacitinib as a targeted sDMARD (tsDMARD), which is recommended, where licensed, after use of at least one bDMARD. Biosimilars are also addressed. These recommendations are intended to inform rheumatologists, patients, national rheumatology societies and other stakeholders about EULAR's most recent consensus on the management of RA with sDMARDs, glucocorticoids and bDMARDs. They are based on evidence and expert opinion and intended to improve outcome in patients with RA.

PMID 24161836
柏崎禎夫ほか:慢性関節リウマチに対するL-377(メトトレキサートカプセル)の至適投与量検討試験.炎症 16:437-458,1996.
H J Williams, R F Willkens, C O Samuelson, G S Alarcón, M Guttadauria, C Yarboro, R P Polisson, S R Weiner, M E Luggen, L M Billingsley
Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis. A controlled clinical trial.
Arthritis Rheum. 1985 Jul;28(7):721-30.
Abstract/Text One hundred eighty-nine patients with rheumatoid arthritis were entered into a prospective, controlled, double-blind multicenter trial comparing placebo and methotrexate (MTX). One hundred ten patients completed 18 weeks of therapy. No remissions were seen, but patients able to tolerate low-dose pulse MTX therapy were significantly improved, compared with patients receiving placebo therapy, for all clinical variables measured, including joint pain/tenderness and swelling counts, rheumatoid nodules, and patient and physician assessment of disease activity. MTX treatment demonstrated statistically significant improvement over placebo in patients with anemia, elevated erythrocyte sedimentation rate, and rheumatoid factor. However, nearly one-third of the patients receiving MTX were withdrawn for adverse drug reactions, of which elevated levels of liver enzymes was the most common. Pancytopenia occurred in 2 patients taking MTX. All adverse drug effects resolved without sequelae. MTX appears to be effective in the treatment of active rheumatoid arthritis but requires close monitoring for toxicity.

PMID 3893441
M E Weinblatt, J S Coblyn, D A Fox, P A Fraser, D E Holdsworth, D N Glass, D E Trentham
Efficacy of low-dose methotrexate in rheumatoid arthritis.
N Engl J Med. 1985 Mar 28;312(13):818-22. doi: 10.1056/NEJM198503283121303.
Abstract/Text Twenty-eight patients with refractory rheumatoid arthritis completed a randomized 24-week double-blind crossover trial comparing oral methotrexate (2.5 to 5 mg every 12 hours for three doses weekly) with placebo. The methotrexate group had significant reductions (P less than 0.01 as compared with the placebo group) in the number of tender or painful joints, the duration of morning stiffness, and disease activity according to physician and patient assessments at the 12-week crossover visit; reductions in the number of swollen joints (P less than 0.05) and 15-m walking time (P less than 0.03) also occurred. These variables, as well as the grip strength and erythrocyte sedimentation rate, showed significant (P less than 0.01) improvement at 24 weeks in the population crossed over to methotrexate. A significantly increased frequency (P less than 0.03) of the HLA-DR2 haplotype occurred in the eight patients with the most substantial response to methotrexate. Adverse reactions during methotrexate therapy included transaminase elevation (21 per cent), nausea (18 per cent), and diarrhea (12 per cent); one patient was withdrawn from the trial because of diarrhea. One patient died while receiving the placebo. Methotrexate did not affect measures of humoral or cellular immunity. We conclude that this trial provides evidence of the short-term efficacy of methotrexate in rheumatoid arthritis, but the mechanism of action is unknown. Longer trials will be required to determine the ultimate safety and effectiveness of this drug.

PMID 3883172
K Visser, W Katchamart, E Loza, J A Martinez-Lopez, C Salliot, J Trudeau, C Bombardier, L Carmona, D van der Heijde, J W J Bijlsma, D T Boumpas, H Canhao, C J Edwards, V Hamuryudan, T K Kvien, B F Leeb, E M Martín-Mola, H Mielants, U Müller-Ladner, G Murphy, M Østergaard, I A Pereira, C Ramos-Remus, G Valentini, J Zochling, M Dougados
Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative.
Ann Rheum Dis. 2009 Jul;68(7):1086-93. doi: 10.1136/ard.2008.094474. Epub 2008 Nov 25.
Abstract/Text OBJECTIVES: To develop evidence-based recommendations for the use of methotrexate in daily clinical practice in rheumatic disorders.
METHODS: 751 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise, Exchange) Initiative of 2007-8 consisting of three separate rounds of discussions and Delphi votes. Ten clinical questions concerning the use of methotrexate in rheumatic disorders were formulated. A systematic literature search in Medline, Embase, Cochrane Library and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts was conducted. Selected articles were systematically reviewed and the evidence was appraised according to the Oxford levels of evidence. Each country elaborated a set of national recommendations. Finally, multinational recommendations were formulated and agreement among the participants and the potential impact on their clinical practice was assessed.
RESULTS: A total of 16 979 references was identified, of which 304 articles were included in the systematic reviews. Ten multinational key recommendations on the use of methotrexate were formulated. Nine recommendations were specific for rheumatoid arthritis (RA), including the work-up before initiating methotrexate, optimal dosage and route, use of folic acid, monitoring, management of hepatotoxicity, long-term safety, mono versus combination therapy and management in the perioperative period and before/during pregnancy. One recommendation concerned methotrexate as a steroid-sparing agent in other rheumatic diseases.
CONCLUSIONS: Ten recommendations for the use of methotrexate in daily clinical practice focussed on RA were developed, which are evidence based and supported by a large panel of rheumatologists, enhancing their validity and practical use.

PMID 19033291
三森明夫:RAの血管炎(悪性関節リウマチ).膠原病診療ノート.第3版,p.485,日本医事新報社,2013年.
Z Ortiz, B Shea, M E Suarez-Almazor, D Moher, G A Wells, P Tugwell
The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials.
J Rheumatol. 1998 Jan;25(1):36-43.
Abstract/Text OBJECTIVE: To assess the efficacy of folic acid and folinic acid in reducing the mucosal and gastrointestinal (GI) side effects of low dose methotrexate (MTX) in patients with rheumatoid arthritis (RA).
METHODS: A systematic review was carried out using the methods recommended by the Cochrane Collaboration. We used MEDLINE and performed hand searches that included bibliographic references, Current Contents, abstracts of rheumatology meetings, and 4 rheumatology journals to select double blind randomized controlled trials (RCT) in which adult patients with RA were treated with low doses of MTX (< 20 mg/week), concurrently with folic or folinic acid. The quality of the RCT was assessed. The overall treatment effect across trials (reduction in toxicity) was estimated using a fixed effects model. Disease activity was evaluated using standardized mean differences to ensure comparability across outcome measures. Sensitivity analyses were conducted evaluating different doses and the quality of the trials. Costs per month in different countries were compared.
RESULTS: Of 11 trials retrieved, 7 met inclusion criteria. The total sample included 307 patients, of which 147 were treated with folate supplementation, 67 patients with folic, and 80 with folinic acid. A 79% reduction in mucosal and GI side effects was observed for folic acid [OR = 0.21 (95% CI 0.10 to 0.44)]. For folinic acid, a clinically but nonstatistically significant reduction of 42% was found [OR = 0.58 (95% CI 0.29 to 1.16)]. No major differences were observed between low and high doses of folic or folinic acid. Hematologic side effects could not be analyzed, since details by patients of each event were not provided. No consistent differences in disease activity variables were observed when comparing placebo and folic acid or folinic acid at low doses; patients receiving high dose folinic acid had increased tender and swollen joint counts. Substantial differences in costs across countries were found; folinic acid was more expensive.
CONCLUSION: Our results support the protective effect of folate supplementation in reducing MTX side effects related to the oral and GI systems.

PMID 9458200
S L Morgan, J E Baggott, W H Vaughn, J S Austin, T A Veitch, J Y Lee, W J Koopman, C L Krumdieck, G S Alarcón
Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial.
Ann Intern Med. 1994 Dec 1;121(11):833-41.
Abstract/Text OBJECTIVE: To determine the effect of two different weekly doses of folic acid on the toxicity and efficacy of low-dose methotrexate therapy for rheumatoid arthritis.
DESIGN: Randomized, double-blind, placebo-controlled study.
PATIENTS: 79 persons between 19 and 78 years of age who fulfilled the American Rheumatism Association's criteria for rheumatoid arthritis.
INTERVENTION: Participants were randomly assigned to visually identical placebo or to 5 mg or 27.5 mg of folic acid each week.
MEASUREMENTS: Duration, intensity, and clinical severity of toxic events; efficacy (indices of joint tenderness and swelling and grip strength); plasma and erythrocyte folate levels; and other laboratory variables.
RESULTS: Folic acid supplementation at either dose did not affect the efficacy of methotrexate therapy as judged by joint indices and patient and physician assessments of disease. Patients given folic acid supplements had lower toxicity scores than did participants given placebo (P < or = 0.001). Low blood folate levels and increased mean corpuscular volumes were associated with substantial methotrexate toxicity, whereas daily dietary intakes of more than 900 nmol (400 micrograms) of folic acid were associated with little methotrexate toxicity.
CONCLUSIONS: Folic acid, an inexpensive vitamin, is safe in a broad range of doses and protects patients with rheumatoid arthritis who are taking methotrexate from toxicity while preserving the efficacy of methotrexate.

PMID 7978695
S L Morgan, J E Baggott, W H Vaughn, P K Young, J V Austin, C L Krumdieck, G S Alarcón
The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis.
Arthritis Rheum. 1990 Jan;33(1):9-18.
Abstract/Text Thirty-two patients with rheumatoid arthritis completed a 24-week, placebo-controlled, double-blind trial of folic acid (FA) supplementation during low-dose methotrexate (MTX) therapy. Administration of the daily FA supplement significantly lowered toxicity scores without affecting efficacy, as measured by joint counts, joint indices, and patient and physician evaluation of disease activity. Fifteen patients experienced some sort of toxicity; 67% were in the placebo group, and 33% were in the FA supplement group. Four patients in the placebo group had toxicity levels serious enough to require discontinuation of the MTX, while no patients in the FA supplement group discontinued MTX because of toxicity. Low-normal initial plasma and red blood cell folate levels were predictive of future toxicity with MTX therapy. We conclude that a daily supplement of 1 mg of FA during low-dose MTX therapy (median dose 7.5 mg/week [16.4 mumoles]) is usefull in lessening toxicity without altering efficacy during the first 6 months of treatment.

PMID 2405864
日本リウマチ学会 MTX診療ガイドライン策定小委員会編:関節リウマチ治療におけるメトトレキサート(MTX)治療ガイドライン2016年改訂版.羊土社、2016、P45-51.
Corinna Weber-Schoendorfer, Christina Chambers, Evelin Wacker, Delphine Beghin, Nathalie Bernard, Network of French Pharmacovigilance Centers, Svetlana Shechtman, Diana Johnson, Benedikte Cuppers-Maarschalkerweerd, Alessandra Pistelli, Maurizio Clementi, Ursula Winterfeld, Georgios Eleftheriou, Anna Pupco, Kelly Kao, Heli Malm, Elisabeth Elefant, Gideon Koren, Thierry Vial, Asher Ornoy, Reinhard Meister, Christof Schaefer
Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicenter cohort study.
Arthritis Rheumatol. 2014 May;66(5):1101-10. doi: 10.1002/art.38368.
Abstract/Text OBJECTIVE: High-dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX.
METHODS: Pregnancy outcome in women taking MTX (≤30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease-matched women and a group of women without autoimmune diseases (neither group was exposed to MTX).
RESULTS: The study sample included 324 MTX-exposed pregnancies (188 exposed post-conception, 136 exposed pre-conception), 459 disease-matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post-conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 [6.6%]) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 [2.9%]) (adjusted odds ratio [OR] 3.1 [95% CI 1.03-9.5]) and the disease-matched cohort (14 of 393 [3.6%]) (adjusted OR 1.8 [95% CI 0.6-5.7]). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% [95% CI 8.0-25.3]) nor the risk of major birth defects (4 of 114 [3.5%]) was increased in the pre-conception cohort. Elective termination rates were increased in both of the MTX-exposed cohorts. There were no other significant differences among groups in other study end points.
CONCLUSION: Post-conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre-conception cohort.

Copyright © 2014 by the American College of Rheumatology.
PMID 24470106
ファイザー「リウマトレックス適正使用情報」vol.22(重篤な副作用及び死亡症例の発現状況)2016年6月.
E Loza, J A Martinez-Lopez, L Carmona
A systematic review on the optimum management of the use of methotrexate in rheumatoid arthritis patients in the perioperative period to minimize perioperative morbidity and maintain disease control.
Clin Exp Rheumatol. 2009 Sep-Oct;27(5):856-62.
Abstract/Text OBJECTIVE: To examine the use of metho-trexate (MTX) in rheumatoid arthritis (RA) patients during the perioperative period.
METHODS: Systematic review of studies retrieved by a sensitive search strategy in Medline (1961-July 2007), Embase (1961-July 2007), Cochrane Library (up to July 2007), and from the abstracts of the ACR (2005, 2006) and EULAR (2005-2007) annual scientific meetings.
SELECTION CRITERIA: (population) studies had to include patients with RA undergoing surgery; (intervention and control) studies had to test continuing MTX versus stopping MTX; and (outcomes), studies had to report complications within a year after the surgery including infections, wound morbidity, surgery complications, and RA flares. Only randomized controlled trials (RCT) or high quality cohort studies with a control group were included.
RESULTS: Patients from the four included studies were mostly women with mean ages around 60. All of them underwent elective orthopaedic surgery and were taking MTX doses mainly from 5 mg/week to 10 mg/week. By order of level of evidence, we found two RCTs, in which continuing on MTX was not associated with increasing risk of surgery complications, but it was statistically associated with less RA flares. In a prospective cohort study, four infections were observed in the MTX group while none were observed in the control group. No disease flare was reported in any group. A retrospective study showed that patients on MTX reported fewer cases of wound morbitity (p=0.038), RA flares (p=0.050), and no differences related to infections compared to those who stopped MTX.
CONCLUSIONS: Continuing with low doses of MTX seems to be a safe option during the perioperative period in RA patients without relevant comorbidities and/or risk factors of infections, undergoing elective orthopaedic surgery, while maintaining disease control.

PMID 19917174
Koichi Murata, Tadashi Yasuda, Hiromu Ito, Makoto Yoshida, Makoto Shimizu, Takashi Nakamura
Lack of increase in postoperative complications with low-dose methotrexate therapy in patients with rheumatoid arthritis undergoing elective orthopedic surgery.
Mod Rheumatol. 2006;16(1):14-9. doi: 10.1007/s10165-005-0444-4.
Abstract/Text To determine the potential contribution of intermittent low-dose methotrexate (MTX) treatment (2-8 mg/week) to postoperative complications, we studied 122 patients with rheumatoid arthritis (RA) who had 201 surgical procedures. The patients with treatment with MTX were allocated to two groups: those who continued MTX (group A, 77 procedures) and those who discontinued MTX more than 1 week (group B, 21 procedures). The patients who had no treatment with MTX were allocated to group C (103 procedures). The incidence of postoperative infection, poor wound healing, and flare-up of RA was compared between the three groups. Postoperative infection occurred in 3.9%, 4.8%, and 3.9% in groups A, B, and C, respectively. Poor wound healing was experienced in 1.3%, 9.5%, and 7.8% in groups A, B, and C, respectively. At 4 weeks postoperatively, 3.9%, 14.3%, and 6.8% of flares were seen in groups A, B, and C, respectively. No significant difference was found in the patients with or without perioperative use of MTX. From these results, it is unlikely that continuation of intermittent low-dose MTX treatment increases the risk of postoperative complications in patients with RA. Continued treatment with MTX during perioperative period could suppress disease flares, especially in severe RA patients.

PMID 16622718
D M Grennan, J Gray, J Loudon, S Fear
Methotrexate and early postoperative complications in patients with rheumatoid arthritis undergoing elective orthopaedic surgery.
Ann Rheum Dis. 2001 Mar;60(3):214-7.
Abstract/Text OBJECTIVES: To determine whether continued methotrexate treatment increases the risk of postoperative infections or of surgical complications in patients with rheumatoid arthritis (RA) within one year of elective orthopaedic surgery.
DESIGN: A prospective randomised study of postoperative infection or surgical complications occurring within one year of surgery in patients with RA who underwent elective orthopaedic surgery.
SUBJECTS: 388 patients with RA who were to undergo elective orthopaedic surgery. Patients who were receiving methotrexate were randomly allocated to groups who either continued methotrexate (group A) or who discontinued methotrexate from two weeks before surgery until two weeks after surgery (group B). Their complication rates were compared with complications occurring in 228 patients with RA (group C) who were not receiving methotrexate and who also underwent elective orthopaedic surgery.
MAIN OUTCOME MEASURES: Signs of postoperative infection were recorded, including rubor, discharge, systemic infection, and frequency of wound dehiscence as well as the incidence of any surgical complication requiring a secondary revision procedure that occurred within one year of surgery. The frequencies of flare up activity of RA at six weeks and six months after surgery were also recorded. A flare of rheumatoid disease was defined as an increase in joint pain in two or more joints notified by the patient as well as by an increase in articular index of at least 25% after surgery.
RESULTS: Signs of infection or surgical complications occurred in two of 88 procedures in group A (2%), 11 of 72 procedures in group B (15%), and 24 of 228 (10.5%) procedures in group C. The surgical complication or infection frequency in group A was less than that in either group B (p<0.003) or group C (p=0.026). At six weeks after surgery there were no flares in group A, six flares in group B (8%), and six flares in group C (2.6%). Logistic regression analysis of the overall surgical complication rate in all the patients with RA studied showed that methotrexate, whether continued or discontinued before surgery, did not increase the early complication rate in the patients with RA who underwent elective orthopaedic surgery. Other drugs-penicillamine, indometacin, cyclosporin, hydroxychloroquine, chloroquine, and prednisolone-all did significantly increase the risk of infection or surgical complication after elective orthopaedic surgery. The risk of surgery was also increased in the presence of intercurrent chronic diseases-diabetes, hypertension, bronchiectasis, psoriasis, asthma, and ischaemic heart disease.
CONCLUSION: Continuation of methotrexate treatment does not increase the risk of either infections or of surgical complications occurring in patients with RA within one year of elective orthopaedic surgery. Thus methotrexate treatment should not be stopped in patients whose disease is controlled by the drug before elective orthopaedic surgery.

PMID 11171680
M T Carpenter, S G West, S A Vogelgesang, D E Casey Jones
Postoperative joint infections in rheumatoid arthritis patients on methotrexate therapy.
Orthopedics. 1996 Mar;19(3):207-10.
Abstract/Text The effect of low dose methotrexate (MTX) on postoperative complications in rheumatoid arthritis patients undergoing elective total joint arthroplasty was observed prospectively in 32 patients. Patients were assigned to discontinue MTX the week prior to and during the week of surgery (Group 1, n = 19) or to continue MTX throughout the perioperative period (Group 2, n = 13). Nineteen patients in Group 1 had 26 procedures, with no postoperative infections. Thirteen patients in Group 2 had 16 procedures, with 4 postoperative infections: 2 infected prostheses, 1 infected joint fusion, and 1 deep wound infection (P = .03). No patient had a postoperative flare of rheumatoid arthritis. Temporary discontinuation of MTX prior to joint arthroplasty appears to decrease the risk of postoperative infection.

PMID 8867548
J Sany, J M Anaya, F Canovas, B Combe, C Jorgensen, S Saker, M N Thaury, J P Gavroy
Influence of methotrexate on the frequency of postoperative infectious complications in patients with rheumatoid arthritis.
J Rheumatol. 1993 Jul;20(7):1129-32.
Abstract/Text OBJECTIVE: To evaluate the influence of methotrexate (MTX) on the frequency of postoperative complications in patients with rheumatoid arthritis (RA).
METHODS: We conducted a randomized unblinded prospective study in 64 patients with RA treated with MTX and who underwent orthopedic surgery. Two groups of patients were constituted: in Group A (32 patients), MTX was interrupted 7 days before the surgery; in Group B (32 patients), MTX was not discontinued.
RESULTS: Fifty surgical procedures were performed in Group A and 39 procedures in Group B. No postoperative infection was observed in any group. A prolonged wound healing was noticed in 6 cases in Group A and in 4 cases in Group B (not significant).
CONCLUSION: We suggest that the interruption of MTX is not required in patients with RA when an orthopedic surgical treatment is planned. However a large prospective study is needed to make a definitive conclusion.

PMID 8371204
M E Weinblatt, D Reda, W Henderson, A Giobbie-Hurder, D Williams, A Diani, S Docsa
Sulfasalazine treatment for rheumatoid arthritis: a metaanalysis of 15 randomized trials.
J Rheumatol. 1999 Oct;26(10):2123-30.
Abstract/Text OBJECTIVE: To assess the efficacy and safety of sulfasalazine (SSZ) compared to placebo and other disease modifying drugs.
METHODS: A metaanalysis was performed on 15 randomized clinical trials of rheumatoid arthritis (RA) that included SSZ (2 g/day average dose, 36 weeks average followup) as a treatment. Eight trials included a placebo group (PL), 2 hydroxychloroquine (HCQ) (350 mg/day average dose), 3 D-penicillamine (D-Pen) (667 mg/day average dose), and 4 gold sodium thiomalate or aurothioglucose (GST) (25 mg, 1 g/wk).
RESULTS: Compared to PL, SSZ was superior for improvement in erythrocyte sedimentation rate (ESR) (SSZ 37%, PL 14%; p < 0.0001), morning stiffness duration (SSZ 61%, PL 33%; p = 0.008), pain visual analog scale (SSZ 42%, PL 15%; p < 0.0001), articular index (SSZ 46%, PL 20%; p < 0.0001), number of swollen joints (SSZ 51%, PL 26%; p < 0.0001), number of painful joints (SSZ 59%, PL 33%; p = 0.004), and patient global assessment (SSZ 26%, PL 14%; p = 0.02). Withdrawals from study because of adverse drug reactions were increased (SSZ 24%, PL 7%; p < 0.0001), but lack of efficacy dropouts were decreased (SSZ 8%, PL 21%; p < 0.0001). Compared to HCQ, SSZ tended to have fewer lack of efficacy dropouts (SSZ 5%, HCQ 15%; p = 0.055) and improved ESR (SSZ 43%, HCQ 26%; p = 0.10) and morning stiffness duration (SSZ 59%, HCQ 40%; p = 0.09). Compared to GST, adverse drug reaction dropouts were significantly fewer (SSZ 12%, GST 29%; p < 0.0001), while withdrawals due to lack of efficacy were greater (SSZ 13%, GST 4%; p = 0.006). More patients tended to complete treatment taking SSZ (SSZ 69%, GST 61%; p = 0.09).
CONCLUSION: Over all, the metaanalysis provides data that support the effectiveness of SSZ as a treatment for RA.

PMID 10529127
慢性関節リウマチに対するサラゾスルファピリジン腸溶錠(PJ-306)の二重盲検比較試験.リウマチ 31:327, 1991.
Tetsuji Sawada, Shigeko Inokuma, Takeo Sato, Takeshi Otsuka, Yukihiko Saeki, Tsutomu Takeuchi, Takemasa Matsuda, Tamiko Takemura, Akira Sagawa, Study Committee for Leflunomide-induced Lung Injury, Japan College of Rheumatology
Leflunomide-induced interstitial lung disease: prevalence and risk factors in Japanese patients with rheumatoid arthritis.
Rheumatology (Oxford). 2009 Sep;48(9):1069-72. doi: 10.1093/rheumatology/kep052. Epub 2009 Mar 25.
Abstract/Text OBJECTIVES: The possible link between LEF and interstitial lung disease (ILD) has evoked increasing concern. The aim of the present study was to elucidate the prevalence and risk factors for newly developed and/or exacerbated ILD, based on post-marketing surveillance data, in which all RA patients receiving LEF were pre-registered and monitored for 24 weeks in Japan.
METHODS: We analysed data from a cohort of 5054 RA patients who were prescribed LEF since its launch in September 2003 in Japan. Multivariable logistic analysis was performed to identify the risk factors for newly developed and/or exacerbation of ILD.
RESULTS: Sixty-one (1.2%) of 5054 RA patients who received LEF were reported to have development and/or exacerbation of ILD as an adverse drug reaction to LEF, judged by the attending physicians. Multivariable logistic regression analysis identified pre-existing ILD [odds ratio (OR) 8.17; 95% CI 4.63, 14.4], cigarette smoking (3.12; 95% CI 1.73, 5.60), a low body weight (<40 kg vs >50 kg) (2.91; 95% CI 1.15, 7.37) and the use of a loading dose (3.97; 95% CI 1.22, 12.9) as independent risk factors for LEF-induced ILD.
CONCLUSIONS: Pre-existing ILD was the most important risk factor for LEF-induced ILD. We suggest that LEF should not be prescribed for RA patients complicated with ILD.

PMID 19321513
Takeo Sato, Shigeko Inokuma, Akira Sagawa, Takemasa Matsuda, Tamiko Takemura, Takeshi Otsuka, Yukihiko Saeki, Tsutomu Takeuchi, Tetsuji Sawada, Study Committee for Leflunomide-induced Lung Injury, Japan College of Rheumatology
Factors associated with fatal outcome of leflunomide-induced lung injury in Japanese patients with rheumatoid arthritis.
Rheumatology (Oxford). 2009 Oct;48(10):1265-8. doi: 10.1093/rheumatology/kep227. Epub 2009 Aug 3.
Abstract/Text OBJECTIVE: To elucidate the factors associated with poor prognosis of LEF-induced lung injury in patients with RA.
METHODS: The background and clinical and laboratory features of LEF-induced lung injury were examined and compared between patients who died of and who recovered from it.
RESULTS: Among 22 patients who developed LEF-induced lung injury, 9 died of and 13 recovered from it. The patients who died tended to have pre-existing interstitial pneumonia (8/9 vs 6/13, P = 0.07). The loading and maintenance doses, serum concentration of the LEF metabolite A771726 and administration period did not differ between the groups. Patients who died had more frequently hypoxaemia of <60 Torr and mechanical ventilation, and had a high serum CRP level (19.3 +/- 9.4 vs 10.1 +/- 8.1 mg/dl, P = 0.03) and a low albumin level (2.7 +/- 0.6 vs 3.3 +/- 0.5 g/dl, P = 0.03) at the lung injury onset. The peripheral blood lymphocyte count decreased in both groups at the lung injury onset, and it remained low until fatal outcome, in contrast to a re-increase upon recovery (406 +/- 394 vs 1203 +/- 399/microl, P = 0.006). The main histopathological finding in two autopsied patients was diffuse alveolar damage, in contrast to the alveolitis observed in a biopsied patient who recovered.
CONCLUSIONS: Pre-existing interstitial pneumonia, extremely high serum CRP and low albumin levels, severe hypoxaemia and mechanical ventilation indicated poor prognosis. Peripheral blood lymphocytopenia developed in association with lung injury, and a sustained low lymphocyte count indicated a fatal outcome.

PMID 19651883
L A Criswell, K G Saag, K M Sems, V Welch, B Shea, G Wells, M E Suarez-Almazor
Moderate-term, low-dose corticosteroids for rheumatoid arthritis.
Cochrane Database Syst Rev. 2000;(2):CD001158. doi: 10.1002/14651858.CD001158.
Abstract/Text OBJECTIVES: To perform a systematic review of low-dose corticosteroid efficacy in the moderate term for the treatment of rheumatoid arthritis (RA).
SEARCH STRATEGY: We conducted a search in MEDLINE from 1966 to 1998, using the keywords "corticosteroids" and "rheumatoid arthritis". We also handsearched all issues of Arthritis and Rheumatism and the Scandinavian Journal of Rheumatology from their dates of first publication to 1994. Furthermore, we examined all Arthritis and Rheumatism abstracts over the 15 year period preceding 1994. References of all identified studies were searched for relevant trials. Authors of unpublished manuscripts were contacted.
SELECTION CRITERIA: Studies were selected by two independent reviewers (LC, KS) using a set of predetermined criteria. Specifically, we required that trials be randomized or cross-over and report at least one of the following outcome measures in a quantitative manner: joint tenderness, joint swelling, grip strength, or erythrocyte sedimentation rate (ESR). We also required that trials be of at least three months duration and use prednisone (or a comparable corticosteroid preparation) at a mean dosage of less than or equal to 15 mg/day. We included studies that used either placebo or active drug controls (i.e., comparative studies).
DATA COLLECTION AND ANALYSIS: We compared the effectiveness of prednisone to placebo and/or active controls using a fixed effects model for continuous data. A chi square test for homogeneity was performed, and where heterogeneity existed a random effects model was used. We reported results for all available outcomes recommended by the Outcome Measures for Rheumatology Trials (OMERACT) group. These included the number of tender and swollen joints, pain, functional status and ESR. Grip strength was also evaluated. Standardized mean differences (SMD) were used for outcomes assessing the same concept with different scales (eg. swollen joint counts).
MAIN RESULTS: Very few studies directly assessed the effectiveness of corticosteroids for RA treatment and many were of poor methodologic quality. Only seven of 34 studies identified by our search met criteria for inclusion. Our results indicated that corticosteroids were significantly more effective than placebo controls for four of six outcomes assessed [standardized mean difference for tender joints = -0.37 (95%CI: -0. 59, -0.14), swollen joints = -0.41 (-0.67, -0.16), pain = -0.43 (-0. 74, -0.12), and functional status = -0.57 (-0.92, -0.22)]. The results for grip strength and ESR were not significant [GS = +0.30 (-0.19, +0.80), weighted mean difference (WMD) for ESR = -7.03 (-18. 06, +4.01)]. The single trial that compared prednisone to aspirin indicated no statistically significant difference between these groups for joint tenderness (0.10 (-0.35, +0.55) and for ESR [0.00 (-11.09, +11.09]. Overall, the four outcomes assessed in the single trial that compared prednisone to chloroquine suggested that the effectiveness of these two agents is similar [SMD for joint tenderness = +0.23 (-0.30, +0.75), swollen joints = +0.43 (-0.11, +0. 96), functional status = -0.27 (-0.80, +0.26), and WMD for ESR = -16. 00 (-30.58, -1.42)].
REVIEWER'S CONCLUSIONS: Based on the limited data available, moderate-term prednisone treatment of RA appears to be superior to placebo and comparable to treatment with aspirin or chloroquine in improving several common rheumatoid arthritis disease activity measures.

PMID 10796420
V Strand, S Cohen, M Schiff, A Weaver, R Fleischmann, G Cannon, R Fox, L Moreland, N Olsen, D Furst, J Caldwell, J Kaine, J Sharp, F Hurley, I Loew-Friedrich
Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group.
Arch Intern Med. 1999 Nov 22;159(21):2542-50.
Abstract/Text CONTEXT: Leflunomide is a reversible inhibitor of de novo pyrimidine synthesis shown to be effective in a phase 2 trial in 402 patients with active rheumatoid arthritis (RA).
OBJECTIVE: To compare the efficacy and safety of leflunomide treatment with placebo and methotrexate treatment in patients with active RA.
DESIGN: Randomized, double-blind, placebo, and active-controlled 12-month study.
SETTING: Forty-seven university and private rheumatology practices in the United States and Canada.
PATIENTS: Diagnosis of RA by the American College of Rheumatology (ACR) criteria for duration of 6 months or longer and no previous methotrexate treatment.
INTERVENTION: Leflunomide treatment (20 mg/d), placebo, or methotrexate treatment (7.5-15 mg/wk).
MAIN OUTCOME MEASURES: American College of Rheumatology success rate (completed 52 weeks of treatment and met the ACR > or = 20% response criteria), disease progression as assessed by x-ray films, and improvement in function and health-related quality of life using the intent-to-treat population.
RESULTS: The 482 patients studied were predominantly women (mean age, 54 years; mean disease duration, 6.7 years) for whom a mean of 0.8 disease-modifying antirheumatic drugs had failed. The ACR response and success rates for patients receiving leflunomide treatment (52% and 41%, respectively) and methotrexate treatment (46% and 35%, respectively) were significantly higher than those for patients receiving placebo (26% and 19%, respectively) (P<.001), and they were statistically equivalent, with mean time to initial response at 8.4 weeks for patients receiving leflunomide vs 9.5 weeks for patients receiving methotrexate therapy. X-ray analyses demonstrated less disease progression with leflunomide (P=.001) and methotrexate (P = .02) therapy than with placebo. Leflunomide and methotrexate treatment improved measures of physical function and health-related quality of life significantly more than placebo (P<.001 and P<.05, respectively). Common adverse events for patients receiving leflunomide treatment included gastrointestinal complaints, skin rash, and reversible alopecia. Asymptomatic transaminase elevations resulted in treatment discontinuations for 7.1% of patients receiving leflunomide therapy, 1.7% of patients receiving placebo, and 3.3% of patients receiving methotrexate therapy.
CONCLUSIONS: Clinical responses following administration of leflunomide, a new therapeutic agent for the treatment of RA, were statistically superior to those with placebo and equivalent to those with methotrexate treatment. Both active treatments improved signs and symptoms of active RA, delayed disease progression as demonstrated by x-ray films, and improved function and health-related quality of life.

PMID 10573044
Ji Hyeon Ju, Sung-Il Kim, Jun-Hee Lee, Sang-Il Lee, Wan-Hee Yoo, Jung-Yoon Choe, Seung-Hie Chung, Jisoo Lee, You-Hyun Lee, Shin-Seok Lee, Hyun-Jung Yoon, Chong-Hyeon Yoon, Ho-Youn Kim, Sung-Hwan Park
Risk of interstitial lung disease associated with leflunomide treatment in Korean patients with rheumatoid arthritis.
Arthritis Rheum. 2007 Jun;56(6):2094-6. doi: 10.1002/art.22666.
Abstract/Text
PMID 17530652
Satoshi Ito, Takayuki Sumida
Interstitial lung disease associated with leflunomide.
Intern Med. 2004 Dec;43(12):1103-4.
Abstract/Text
PMID 15645640
S P Y Wong, C M Chu, C H Kan, H S Tsui, W L Ng
Successful treatment of leflunomide-induced acute pneumonitis with cholestyramine wash-out therapy.
J Clin Rheumatol. 2009 Dec;15(8):389-92. doi: 10.1097/RHU.0b013e3181c3f87e.
Abstract/Text Drug-induced acute pneumonitis is a rare but potentially fatal adverse drug reaction. A high index of suspicion is needed for early diagnosis as it mimics community acquired pneumonia and interstitial lung disease that can occur in rheumatoid arthritis. We report a 32-year-old Chinese lady who suffered from leflunomide-induced pneumonitis and improved dramatically after receiving cholestyramine wash-out therapy. This case illustrates the need for clinical alertness to this potentially fatal complication. When in doubt, discontinuation of leflunomide and empirical wash-out therapy should be administered without delay.

PMID 19955995
Fumikazu Sakai, Satoshi Noma, Yasuyuki Kurihara, Hidehiro Yamada, Arata Azuma, Shoji Kudoh, Youichi Ichikawa
Leflunomide-related lung injury in patients with rheumatoid arthritis: imaging features.
Mod Rheumatol. 2005;15(3):173-9. doi: 10.1007/s10165-005-0387-9.
Abstract/Text Imaging findings of 26 cases of leflunomide (Arava)-related acute lung injury were analyzed. Thirteen cases had pre-existing interstitial pulmonary disease on chest X-ray or computed tomography. The main features of clinically determined leflunomide-induced acute lung injury were similar to those caused by other drugs: diffuse or widespread patchy ground-glass opacities and/or consolidation, frequently accompanied by septal thickening and intralobular reticular opacities. We categorized these findings into four patterns: diffuse alveolar damage (DAD), acute eosinophilic pneumonia, hyperreaction, and cryptogenic organizing pneumonia. The DAD group had a higher mortality rate, but statistically not a significant one. It is impossible to exclude infectious disease such as pneumocystis carinii pneumonia based on imaging findings, and detailed correlation of imaging findings with clinical and laboratory findings is essential in order to make a correct diagnosis.

PMID 17029058
Joel M Kremer, Joseph S Habros, Karen S Kolba, Jeffrey L Kaine, Mary Ann Borton, Laurel J Mengle-Gaw, Benjamin D Schwartz, Wayne Wisemandle, Qais A Mekki, Tacrolimus-Methotrexate Rheumatoid Arthritis Study Group
Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate: a six-month, open-label study.
Arthritis Rheum. 2003 Oct;48(10):2763-8. doi: 10.1002/art.11257.
Abstract/Text OBJECTIVE: To assess the safety of tacrolimus used in combination with oral methotrexate (MTX) to control the signs and symptoms of rheumatoid arthritis (RA) in patients whose disease remains active despite treatment with MTX.
METHODS: This was a multicenter open-label study conducted at 13 US sites. Eighty patients who at baseline had active RA (mean tender/painful joint count 29.4, mean swollen joint count 17.4, mean erythrocyte sedimentation rate 25.1 mm/hour) despite treatment for >/=1 month with a stable, maximally tolerated dosage of oral MTX (RESULTS: Seven patients (12.5%) withdrew from the study because of adverse events possibly or probably related to treatment with tacrolimus, and 4 (5.0%) withdrew due to lack of efficacy. One serious adverse event (pancreatitis) was possibly related to tacrolimus treatment. The mean (+/-SD) creatinine (Cr) level increased from 0.74 +/- 0.16 mg/dl at baseline to 0.81 +/- 0.22 mg/dl (P < 0.001) at the end of treatment. Twenty-three patients (28.8%) had a >/=30% maximum increase in the Cr level from baseline during the study, with the Cr level in 3 patients (3.8%) exceeding the range considered normal for their age and sex. The maximum Cr level during the study was 1.8 mg/dl. The ACR20 clinical response rate at the end of treatment was 52.5% (95% confidence interval 41.6-63.4%).
CONCLUSION: In patients whose active RA persists despite treatment with MTX, tacrolimus in combination with MTX is safe and well-tolerated and provides clinical benefit.

PMID 14558080
David E Yocum, Daniel E Furst, Jeffrey L Kaine, Andrew R Baldassare, Jon T Stevenson, Mary Ann Borton, Laurel J Mengle-Gaw, Benjamin D Schwartz, Wayne Wisemandle, Qais A Mekki, Tcrolimus Rheumatoid Arthritis Study Group
Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial.
Arthritis Rheum. 2003 Dec;48(12):3328-37. doi: 10.1002/art.11363.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of tacrolimus as monotherapy in controlling the signs and symptoms of patients with rheumatoid arthritis (RA).
METHODS: This was a 6-month, phase III, double-blind, multicenter study. Patients with active RA who had discontinued all disease-modifying antirheumatic drugs (DMARDs) for an appropriate washout period (at least 1 month) and who, after the washout period, had a stable joint count (at least 10 tender/painful joints and 7 swollen joints) were stratified according to DMARD intolerance or DMARD resistance, and randomized to receive a single daily oral dose of placebo, tacrolimus 2 mg, or tacrolimus 3 mg.
RESULTS: A total of 464 patients received at least 1 dose of study drug. Baseline characteristics were similar among the 3 treatment groups. American College of Rheumatology 20% improvement (ACR20) success (defined as completion of 6 months of treatment and an ACR20 response at the month 6 visit) for the placebo, tacrolimus 2 mg, and tacrolimus 3 mg groups was 10.2%, 18.8% (P < 0.05 versus placebo), and 26.8% (P < 0.0005 versus placebo), respectively. At the end of treatment, the ACR20 and ACR50 response rates in the 3-mg group were 32.0% (P < 0.005 versus placebo) and 11.8% (P < 0.05 versus placebo), respectively. DMARD-intolerant patients had better ACR response rates than did DMARD-resistant patients. Although serum creatinine levels increased by >/=40% from baseline at some time during the trial in 20% and 29% of patients receiving tacrolimus 2 mg/day and 3 mg/day, respectively, the serum creatinine level remained within the normal range throughout the trial in approximately 90% of patients.
CONCLUSION: Tacrolimus, at dosages of both 2 mg/day and 3 mg/day, is efficacious and safe as monotherapy for patients with active RA, but treatment with the 3-mg dose of tacrolimus resulted in generally better ACR response rates.

PMID 14673984
D E Yocum, D E Furst, W G Bensen, F X Burch, M A Borton, L J Mengle-Gaw, B D Schwartz, W Wisememandle, Q A Mekki, Tacrolimus RA Study Group
Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience.
Rheumatology (Oxford). 2004 Aug;43(8):992-9. doi: 10.1093/rheumatology/keh155. Epub 2004 Mar 10.
Abstract/Text OBJECTIVE: To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA).
METHODS: Patients with active RA who had discontinued all DMARDs for at least 2 weeks and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids.
RESULTS: 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67+/-19 micromol/l (0.76+/-0.22 mg/dl) at baseline to 75+/-26 micromol/l (0.85+/-0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had > or =30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a > or =30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints.
CONCLUSION: This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.

PMID 15014199
Hirobumi Kondo, Toru Abe, Hiroshi Hashimoto, Shoji Uchida, Shoichiro Irimajiri, Masako Hara, Sachiko Sugawara
Efficacy and safety of tacrolimus (FK506) in treatment of rheumatoid arthritis: a randomized, double blind, placebo controlled dose-finding study.
J Rheumatol. 2004 Feb;31(2):243-51.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of tacrolimus (FK506) in patients with active rheumatoid arthritis (RA) exhibiting resistance to disease modifying antirheumatic drug (DMARD) therapy, and to determine the optimal dosage.
METHODS: A total of 212 patients with DMARD-resistant RA were enrolled in this double blind, multicenter, randomized, placebo controlled study and allocated to 3 groups. Patients were administered tacrolimus at a dosage of 1.5 mg/day (68 patients) or 3 mg/day (70 patients), or placebo (74 patients), for 16 weeks. They were allowed to continue taking prednisolone (< or = 5 mg/day) and/or one nonsteroidal antiinflammatory drug (NSAID) during the study. Clinical assessment was based on the American College of Rheumatology (ACR) 20% criteria.
RESULTS: ACR 20% response rates were higher in both tacrolimus groups (3 mg: 48.3%; 1.5 mg: 24.6%) than in the placebo group (14.1%), with the rate in the 3 mg group significantly higher. There were no significant differences between the tacrolimus groups and placebo group in the incidence of adverse events. The main adverse events in the tacrolimus groups, especially in the 3 mg group, were renal function abnormalities and gastrointestinal symptoms. However, no significant differences were observed among the 3 groups in the incidence of any adverse event except decrease in serum Mg level.
CONCLUSION: Our findings demonstrate excellent dose-dependent efficacy of tacrolimus in patients with DMARD-resistant RA and strongly suggest the usefulness of tacrolimus for treatment of RA. The optimal dosage appears to be 3 mg/day in terms of efficacy and safety.

PMID 14760792
Yoichi Ichikawa, Terunobu Saito, Hisashi Yamanaka, Masashi Akizuki, Hirobumi Kondo, Shigeto Kobayashi, Hisaji Oshima, Shinichi Kawai, Nobuaki Hama, Hidehiro Yamada, Tsuneyo Mimori, Koichi Amano, Yasushi Tanaka, Yasuo Matsuoka, Sumiki Yamamoto, Tsukasa Matsubara, Norikazu Murata, Tomiaki Asai, Yasuo Suzuki, MTX-BUC Combination Study Group, Japanese Ministry of Health, Labour and Welfare's "Research for Establishment of Therapeutic Guidelines in Early Rheumatoid Arthritis"
Therapeutic effects of the combination of methotrexate and bucillamine in early rheumatoid arthritis: a multicenter, double-blind, randomized controlled study.
Mod Rheumatol. 2005;15(5):323-8. doi: 10.1007/s10165-005-0420-z.
Abstract/Text Disease-modifying antirheumatic drug (DMARD) combination therapies are used widely, but there have been few reports clearly demonstrating that combination therapy is more effective than DMARD monotherapy. We conducted a multicenter, double-blind controlled trial in order to clarify that the combination of methotrexate and bucillamine is more effective than either alone. The subjects of this study were 71 patients with active rheumatoid arthritis within 2 years of onset. Dosages were 8 mg methotrexate with 5 mg folic acid per week (MTX group), 200 mg bucillamine per day (BUC group), or both MTX and BUC (combination group). Clinical effects and adverse reactions were observed for 96 weeks. The ACR 20 response rate was 79.2% in the combination group, significantly higher than the rates of 43.5% for the MTX group (P = 0.008) and 45.8% for the BUC group (P = 0.0178). The cumulative survival curve of maintaining the ACR 20 response was significantly higher in the combination group than in the MTX and BUC groups (P = 0.0123 and P = 0.0088, respectively). The mean increase in the total Sharp score over 96 weeks was 12.6 +/- 9.0 in the combination group, significantly lower (P = 0.0468) than the value of 28.0 +/- 28.3 for the single DMARD (combined MTX and BUC) group. The incidence of adverse reactions did not differ significantly between the three groups. It was concluded that the combination therapy with MTX and BUC showed significantly higher clinical efficacy than either of the single DMARD therapies.

PMID 17029087
Tsuyoshi Kasama, Kuninobu Wakabayashi, Tsuyoshi Odai, Takeo Isozaki, Mizuho Matsunawa, Nobuyuki Yajima, Yusuke Miwa, Masao Negishi, Hirotsugu Ide
Effects of low-dose mizoribine pulse therapy in combination with methotrexate in rheumatoid arthritis patients with an insufficient response to methotrexate.
Mod Rheumatol. 2009;19(4):395-400. doi: 10.1007/s10165-009-0179-8. Epub 2009 May 14.
Abstract/Text The aim was to determine the efficacy of low-dose intermittent pulse administration of mizoribine (MZR), a purine synthesis inhibitor, in combination with methotrexate (MTX) to control the symptoms of rheumatoid arthritis (RA) in patients with an insufficient clinical response to MTX alone. Twenty-seven patients with active RA, despite treatment with MTX, were enrolled and given MZR in combination with MTX and continued for 24 weeks. The primary endpoint was assessment of clinical improvements using the European League against Rheumatism (EULAR) criteria. Administering MZR to RA patients with an insufficient response to MTX produced significant improvements in the Disease Activity Score 28 (DAS28) after 8-24 weeks. In addition, after 24 weeks, 60.0% and 8.0% of patients had achieved moderate and good responses, respectively, and there were significant reductions in Modified Health Assessment Questionnaire and serum matrix metalloproteinase-3 levels. The present preliminary study suggests that low-dose MZR in combination with MTX is well tolerated and provides both clinical and economic benefits.

PMID 19440813
Shinichi Kawai, Hiroshi Hashimoto, Hirobumi Kondo, Takashi Murayama, Takahiro Kiuchi, Toru Abe
Comparison of tacrolimus and mizoribine in a randomized, double-blind controlled study in patients with rheumatoid arthritis.
J Rheumatol. 2006 Nov;33(11):2153-61. Epub 2006 Sep 1.
Abstract/Text OBJECTIVE: To compare the efficacy and safety of tacrolimus and mizoribine in patients with rheumatoid arthritis (RA).
METHODS: Adult patients with RA with an insufficient response to at least one disease modifying antirheumatic drug (DMARD) were randomized to receive 28 weeks of double-blind treatment with tacrolimus 3 mg once daily or mizoribine 50 mg three times daily. The primary efficacy endpoint was the American College of Rheumatology 20% (ACR20) response. Safety was evaluated by adverse events.
RESULTS: A total of 204 patients were enrolled for study (103 in the tacrolimus group, 101 in the mizoribine group). Significantly more patients receiving tacrolimus achieved an ACR20 response compared with mizoribine (48.5 vs 10.0%, respectively; p = 0.001). Tacrolimus was also superior to mizoribine in ACR50 and ACR70 response rate, tender and painful joint counts, swollen joint counts and patient and physician assessments of pain, disease activity, and patient's physical function assessment based on the Modified Health Assessment Questionnaire (p < 0.001). Adverse events were more frequent in the tacrolimus group than the mizoribine group (65.0 vs 59.4%); however, there were no statistically significant differences between treatment groups.
CONCLUSION: Tacrolimus improves RA symptoms to a significantly greater extent than mizoribine in patients with RA inadequately controlled with at least one prior DMARD. Tacrolimus has the potential to be a useful and highly effective treatment for RA.

PMID 16960930
Keita Nishimura, Jinju Nishino, Akira Kouchi, Naotsugu Nakamura, Shin Nakajima, Isamu Yokoe, Hitomi Haraoka, Takashi Matsushita
Efficacy and safety of single-dose mizoribine for patients with rheumatoid arthritis: results at 6 months after switching from a multiple-dose regimen without a change in total daily dose.
Mod Rheumatol. 2011 Apr;21(2):158-63. doi: 10.1007/s10165-010-0373-8. Epub 2010 Nov 25.
Abstract/Text To determine the efficacy and safety of single-dose mizoribine (MZR) for patients with rheumatoid arthritis (RA), a 6-month, single-arm, open-label, prospective observation study was performed. In patients who had been taking MZR at 100-150 mg/day in 2-3 divided portions continuously for at least 3 months, and who had shown a lack of clinical response, or escape (defined as a lack of response at the time of switching, even if some form of response had been shown before that), multiple-dose administration was switched to single-dose administration without changing the total daily dose. Efficacy was assessed in terms of the disease activity score, using the 28-joint count and erythrocyte sedimentation rate (DAS 28-ESR). Of the 34 enrolled patients, 28 met all the eligibility criteria and were assessed for efficacy, and finally 26 patients were able to receive the single-dose regimen throughout the full 6 months. The DAS28-ESR showed a significant decrease from 2 months after switching, and 46.4% of the 28 patients finally achieved a good or moderate response (3 and 10 patients, respectively). With regard to safety, no serious adverse events were observed. In conclusion, the administration of MZR at 100 or 150 mg in a single dose is thought to be a useful alternative form of MZR therapy.

PMID 21107634
Masanobu Horikoshi, Satoshi Ito, Mizue Ishikawa, Naoto Umeda, Yuya Kondo, Hiroto Tsuboi, Taichi Hayashi, Daisuke Goto, Isao Matsumoto, Takayuki Sumida
Efficacy of mizoribine pulse therapy in patients with rheumatoid arthritis who show a reduced or insufficient response to infliximab.
Mod Rheumatol. 2009;19(3):229-34. doi: 10.1007/s10165-009-0162-4. Epub 2009 Mar 27.
Abstract/Text The efficacy of infliximab, a chimeric antibody against tumor necrosis factor-alpha used to treat patients with rheumatoid arthritis (RA), tends to decrease as patients develop human antichimeric antibody against infliximab (HACA). The clinical study reported here was designed to evaluate the efficacy of mizoribine (MZR) pulse therapy in patients who show a reduced or insufficient response to infliximab. Ten RA patients who had active arthritis despite infliximab therapy were treated with MZR pulse therapy at a dose of 100 mg MZR and methotrexate (MTX) and the disease activity assessed at baseline and at weeks 4-8, 12-16, and 20-24. The dose was increased to 150 mg in those patients who showed an insufficient response to MZR. The mean 28-joint disease activity score (DAS28) at weeks 12-16 and 20-24 of therapy was significantly lower than that at baseline. A moderate or good European League against Rheumatism (EULAR) response was achieved in seven patients (70%) at weeks 12-16 and in five patients (50%) at weeks 20-24. The dose of 150 mg MZR was effective in one of the three patients who showed an insufficient response to pulse therapy with 100 mg MZR. Based on these results, we propose that MZR pulse therapy should be attempted before the patient is switched to other biologics.

PMID 19326186
日本リウマチ学会. 関節リウマチ(RA)に対するTNF阻害薬使用ガイドライン(2018年11月4日改訂版). 2018; Available from: https://www.ryumachi-jp.com/publish/guide/guideline_tnf/
日本リウマチ学会. 関節リウマチ(RA)に対するIL-6阻害薬使用ガイドライン(2018年8月14日改訂版). 2018; Available from: https://www.ryumachi-jp.com/publish/guide/guideline_il-6/
B Blumenauer, M Judd, G Wells, A Burls, A Cranney, M Hochberg, P Tugwell
Infliximab for the treatment of rheumatoid arthritis.
Cochrane Database Syst Rev. 2002;(3):CD003785. doi: 10.1002/14651858.CD003785.
Abstract/Text BACKGROUND: Infliximab is a human murine chimeric anti-tumour necrosis factor alpha monoclonal antibody recently approved for the treatment of refractory RA.
OBJECTIVES: To assess the efficacy and safety of infliximab for the treatment of rheumatoid arthritis.
SEARCH STRATEGY: Electronic databases including Biological Abstracts, CINAHL, Current Contents, Dissertation Abstracts, EBM Reviews, HealthSTAR and MEDLINE were searched from 1966 to March 2002. Rheumatoid arthritis was searched as an exploded MESH heading. Infliximab was searched as a text word as it is not currently indexed. The search was not limited by language, year of publication or type of publication. The specific search strategy is shown below.
SELECTION CRITERIA: All randomized controlled trials comparing infliximab 1, 3, 5 or 10 mg/kg with methotrexate(MTX) to MTX alone, or without MTX to placebo, with a minimum duration of 6 months and at least 2 infusions were eligible.
DATA COLLECTION AND ANALYSIS: Data was extracted by 2 independent reviewers and the methodological quality of the trials was assessed using a validated assessment tool scale. Outcome variables included the ACR core set of disease activity measures for RA clinical trials and radiographic outcome data. Withdrawals and toxicity were also included. End of trial results were pooled. Continuous data were pooled using weighted mean differences and dichotomous data using relative risks.
MAIN RESULTS: Two trials with a total of 529 patients met the inclusion criteria. Patients fulfilling the American Rheumatism Association 1987 RA diagnostic criteria were randomized to receive either infliximab 1mg/kg (with and without MTX), 3mg/kg(with and without MTX), 10mg/kg of infliximab (with and without MTX) or placebo infusion plus MTX. Infusions were given every 4 or 8 weeks. After 6 months ACR 20, ACR 50 and ACR 70 response rates were significantly improved in all infliximab doses compared to control. The number needed to treat with infliximab to achieve an ACR 20, 50 or 70 response in patients with refractory RA under specialist care ranged from 2.9 to 3.3 for ACR 20, 3.6 to 4.8 for ACR 50 and 5.9 to 12.5 for ACR 70 depending on the dose (3mg/kg or 10mg/kg given either every 4 or 8 weeks). Total withdrawals and withdrawals due to lack of efficacy were lower for all doses of infliximab versus controls. Withdrawals for adverse events and withdrawals for other reasons were not statistically significantly different for those receiving infliximab from control.
REVIEWER'S CONCLUSIONS: Treatment with infliximab for 6 and 12 months significantly reduces RA disease activity and appeared to have an acceptable safety profile in these trials. Total radiographic scores improved, fewer patients showed radiographic progression, and more patients showed radiographic improvement with infliximab treatment at 12 months compared to controls. However, only 2 trials met the inclusion criteria, and these results are largely driven by the largest trial. The available efficacy and toxicity data is relatively short-term (6-12 months). In order to detect rare events that may be associated with infliximab, larger and longer term studies are required.

PMID 12137712
P E Lipsky, D M van der Heijde, E W St Clair, D E Furst, F C Breedveld, J R Kalden, J S Smolen, M Weisman, P Emery, M Feldmann, G R Harriman, R N Maini, Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group
Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group.
N Engl J Med. 2000 Nov 30;343(22):1594-602. doi: 10.1056/NEJM200011303432202.
Abstract/Text BACKGROUND: Neutralization of tumor necrosis factor a (TNF-alpha) for three to six months reduces the symptoms and signs of rheumatoid arthritis. However, the capacity of this approach to effect a more sustained benefit and its effect on joint damage are not known.
METHODS: We treated 428 patients who had active rheumatoid arthritis despite methotrexate therapy with placebo or infliximab, a chimeric monoclonal antibody against TNF-alpha, in intravenous doses of 3 or 10 mg per kilogram of body weight every 4 or 8 weeks in combination with oral methotrexate for 54 weeks. We assessed clinical responses with use of the criteria of the American College of Rheumatology, the quality of life with a health-status questionnaire, and the effect on joint damage radiographically.
RESULTS: The combination of infliximab and methotrexate was well tolerated and resulted in a sustained reduction in the symptoms and signs of rheumatoid arthritis that was significantly greater than the reduction associated with methotrexate therapy alone (clinical response, 51.8 percent vs. 17.0 percent; P<0.001). The quality of life was also significantly better with infliximab plus methotrexate than with methotrexate alone. Radiographic evidence of joint damage increased in the group given methotrexate, but not in the groups given infliximab and methotrexate (mean change in radiographic score, 7.0 vs. 0.6, P<0.001). Radiographic evidence of progression of joint damage was absent in infliximab-treated patients whether or not they had a clinical response.
CONCLUSIONS: In patients with persistently active rheumatoid arthritis despite methotrexate therapy, repeated doses of infliximab in combination with methotrexate provided clinical benefit and halted the progression of joint damage.

PMID 11096166
E William St Clair, Désirée M F M van der Heijde, Josef S Smolen, Ravinder N Maini, Joan M Bathon, Paul Emery, Edward Keystone, Michael Schiff, Joachim R Kalden, Ben Wang, Kimberly Dewoody, Roberta Weiss, Daniel Baker, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset Study Group
Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial.
Arthritis Rheum. 2004 Nov;50(11):3432-43. doi: 10.1002/art.20568.
Abstract/Text OBJECTIVE: To compare the benefits of initiating treatment with methotrexate (MTX) and infliximab (anti-tumor necrosis factor alpha [anti-TNFalpha] monoclonal antibody) with those of MTX treatment alone in patients with rheumatoid arthritis (RA) of < or =3 years' duration.
METHODS: RA patients were eligible if they had active disease and no prior treatment with MTX or a TNFalpha inhibitor. One thousand forty-nine patients were randomly assigned in a 4:5:5 ratio to 3 treatment groups: MTX-placebo, MTX-3 mg/kg infliximab, and MTX-6 mg/kg infliximab. MTX dosages were rapidly escalated to 20 mg/week, and infliximab or placebo infusions were given at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46.
RESULTS: At week 54, the median percentage of American College of Rheumatology improvement (ACR-N) was higher for the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than for the MTX-placebo group (38.9% and 46.7% versus 26.4%, respectively; P < 0.001 for both comparisons). Patients in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups also showed less radiographic progression than those receiving MTX alone (mean +/- SD changes in van der Heijde modification of the total Sharp score at week 54: 0.4 +/- 5.8 and 0.5 +/- 5.6 versus 3.7 +/- 9.6, respectively; P < 0.001 for each comparison). In addition, physical function improved significantly more in the MTX-3 mg/kg infliximab and MTX-6 mg/kg infliximab groups than in the MTX-placebo group. Infliximab therapy was associated with a significantly higher incidence of serious infections, especially pneumonia.
CONCLUSION: For patients with active RA in its early stages, combination therapy with MTX and infliximab provides greater clinical, radiographic, and functional benefits than treatment with MTX alone.

PMID 15529377
J S Smolen, C Han, D M F M van der Heijde, P Emery, J M Bathon, E Keystone, R N Maini, J R Kalden, D Aletaha, D Baker, J Han, M Bala, E W St Clair, Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group
Radiographic changes in rheumatoid arthritis patients attaining different disease activity states with methotrexate monotherapy and infliximab plus methotrexate: the impacts of remission and tumour necrosis factor blockade.
Ann Rheum Dis. 2009 Jun;68(6):823-7. doi: 10.1136/ard.2008.090019. Epub 2008 Jul 1.
Abstract/Text OBJECTIVE: To examine the association of radiographic progression and disease activity states in patients with rheumatoid arthritis (RA) treated with methotrexate with or without infliximab.
METHODS: Patients (n = 1049) with active RA for 3 years or less and no previous methotrexate treatment were randomly assigned (4 : 5 : 5) to receive methotrexate plus placebo or methotrexate plus infliximab 3 or 6 mg/kg at weeks 0, 2 and 6, and every 8 weeks thereafter to week 46. Disease activity was classified by the simplified disease activity index as remission (< or =3.3), low (>3.3 to < or =11), moderate (>11 to < or =26), high (>26). Radiographic progression was measured as a change from baseline to week 54 in total Sharp score.
RESULTS: At weeks 14 and 54, more patients receiving methotrexate plus infliximab than methotrexate plus placebo were in remission (10.7% versus 2.8% week 14; 21.3% versus 12.3% week 54; p<0.001 for both). Methotrexate plus placebo halted radiographic progression only if patients achieved remission within 3 months, whereas methotrexate plus infliximab also halted or minimised progression in patients with low or moderate activity, respectively. Patients with persistently high disease activity levels had much less progression of joint damage if treated with methotrexate plus infliximab versus methotrexate monotherapy. Even with infliximab plus methotrexate there was a direct relationship between disease activity and radiographic changes, although the slope was deflected when compared with methotrexate monotherapy.
CONCLUSION: With methotrexate, joint damage progresses even at low and moderate disease activity levels, whereas methotrexate plus infliximab inhibits radiographic progression across all disease activity states.

PMID 18593759
Tsutomu Takeuchi, Nobuyuki Miyasaka, Kazuhiko Inoue, Tohru Abe, Takao Koike, RISING study
Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study.
Mod Rheumatol. 2009;19(5):478-87. doi: 10.1007/s10165-009-0195-8. Epub 2009 Jul 22.
Abstract/Text This study is a prospective, randomized, double-blind study to compare the efficacy and safety of 10 mg/kg infliximab with those of 3 mg/kg infliximab treatment in methotrexate-refractory rheumatoid arthritis patients. After the patients received 3 mg/kg infliximab infusion at weeks 0, 2, and 6, they were randomly assigned to be administered 3, 6 or 10 mg/kg infliximab every 8 weeks from week 14 to 46. Mean American College of Rheumatology improvement (ACR-N) at week 54, the primary endpoint, was 51.3% and 58.3% for the 3 mg/kg and 10 mg/kg groups, respectively, with a statistically significant difference. Treatment with 10 mg/kg was found to be remarkably beneficial in patients who had not responded to three infusions with 3 mg/kg at week 10. The median changes in the modified Sharp score were 0.0 in the two groups. There were no significant differences in the incidences of adverse events between the groups. In patients who achieved better clinical response or greater inhibition of progression of joint damage, trough serum infliximab level was significantly higher than in patients who did not. The magnitudes of both efficacies were correlated with the trough serum infliximab level (ClinicalTrials.gov number: NCT00691028).

PMID 19626391
B Blumenauer, M Judd, A Cranney, A Burls, D Coyle, M Hochberg, P Tugwell, G Wells
Etanercept for the treatment of rheumatoid arthritis.
Cochrane Database Syst Rev. 2003;(4):CD004525. doi: 10.1002/14651858.CD004525.
Abstract/Text BACKGROUND: Etanercept is a soluble tumour necrosis factor alpha-receptor DMARD for the treatment of rheumatoid arthritis (RA).
OBJECTIVES: To assess the efficacy and safety of etanercept for the treatment of RA.
SEARCH STRATEGY: Five electronic databases were searched from 1966 to February 2003 with no language restriction.
SELECTION CRITERIA: All randomized controlled trials (minimum 6 month duration) comparing three possible combinations 1) etanercept (10 mg or 25 mg twice weekly) with methotrexate (MTX) to MTX alone 2) etanercept to MTX, or 3) etanercept to placebo were eligible.
DATA COLLECTION AND ANALYSIS: Two reviewers extracted data and assessed the methodological quality of the trails. The American College of Rheumatology (ACR) core set of disease activity measures for RA clinical trials, radiographic, withdrawals and toxicity outcomes were analyzed.
MAIN RESULTS: Three trials were included in this review. Two trials compared an experimental group who were started on etanercept compared to a control group; both groups had the same ongoing background therapy of nonsteroidals in both trials plus in one trial one group was on stable methotrexate. In these two trials the ACR 20, ACR 50 and ACR 70 response rates at 6 months were statistically significantly and clinically important with etanercept 25 mg subcutaneous injections (SC) twice weekly. Sixty-four percent of people receiving etanercept ache vied an ACR 20 response compared to 15% of controls and the number needed to treat (NNT) with etanercept is 2 people. Thirty-nine percent of those receiving etanercept achieved an ACR 50 response compared to 4% of taking control treatment and the NNT is three. Fifteen percent of people taking etanercept achieved an ACR 70 compared to 1% of controls with a NNT of 7 people. In the third trial of starting etanercept compared to starting methotrexate the number of participants who achieved an ACR 20, 50 or response at 6 and 12 months were not statistically significant for either etanercept dose. Etanercept treatment showed a statistically significantly and clinically important affect on joint damage as measured by the Sharp erosion score. Among participants who received etanercept 72% had no increase in their erosion score compared to 60% of participants in the methotrexate group. Withdrawal and toxicity results were acceptable.
REVIEWER'S CONCLUSIONS: Etanercept 25 mg SC twice weekly was more efficacious than control treatment for ACR 20, 50 and 70 at 6 months, and over 12 months it slowed joint damage.

PMID 14584021
Jasvinder A Singh, George A Wells, Robin Christensen, Elizabeth Tanjong Ghogomu, Lara Maxwell, John K Macdonald, Graziella Filippini, Nicole Skoetz, Damian Francis, Luciane C Lopes, Gordon H Guyatt, Jochen Schmitt, Loredana La Mantia, Tobias Weberschock, Juliana F Roos, Hendrik Siebert, Sarah Hershan, Michael Pt Lunn, Peter Tugwell, Rachelle Buchbinder
Adverse effects of biologics: a network meta-analysis and Cochrane overview.
Cochrane Database Syst Rev. 2011 Feb 16;(2):CD008794. doi: 10.1002/14651858.CD008794.pub2. Epub 2011 Feb 16.
Abstract/Text BACKGROUND: Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates.
OBJECTIVES: To compare the adverse effects of tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS).
METHODS: Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework.
MAIN RESULTS: We included 163 RCTs with 50,010 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for tuberculosis (TB) reactivation, lymphoma, and congestive heart failure. Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events (odds ratio (OR) 1.19, 95% CI 1.09 to 1.30; number needed to treat to harm (NNTH) = 30, 95% CI 21 to 60) and withdrawals due to adverse events (OR 1.32, 95% CI 1.06 to 1.64; NNTH = 37, 95% CI 19 to 190) and an increased risk of TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706) compared to control.The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment. Certolizumab pegol was associated with significantly higher risk of serious infections compared to control treatment (OR 3.51, 95% CI 1.59 to 7.79; NNTH = 17, 95% CI 7 to 68). Infliximab was associated with significantly higher risk of withdrawals due to adverse events compared to control (OR 2.04, 95% CI 1.43 to 2.91; NNTH = 12, 95% CI 8 to 28). Indirect comparisons revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events compared to most other biologics.  Although the overall numbers are relatively small, certolizumab pegol was associated with significantly higher odds of serious infections compared to etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab; abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections.  Abatacept, adalimumab, etanercept and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events.
AUTHORS' CONCLUSIONS: Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results.There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics. 

PMID 21328309
L W Moreland, S W Baumgartner, M H Schiff, E A Tindall, R M Fleischmann, A L Weaver, R E Ettlinger, S Cohen, W J Koopman, K Mohler, M B Widmer, C M Blosch
Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein.
N Engl J Med. 1997 Jul 17;337(3):141-7. doi: 10.1056/NEJM199707173370301.
Abstract/Text BACKGROUND: Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist - a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc).
METHODS: In this multicenter, double-blind trial, we randomly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR:Fc (0.25, 2, or 16 mg per square meter of body-surface area) twice weekly for three months. The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria.
RESULTS: Treatment with TNFR:Fc led to significant reductions in disease activity, and the therapeutic effects of TNFR:Fc were dose-related. At three months, 75 percent of the patients in the group assigned to 16 mg of TNFR:Fc per square meter had improvement of 20 percent or more in symptoms, as compared with 14 percent in the placebo group (P<0.001). In the group assigned to 16 mg per square meter, the mean percent reduction in the number of tender or swollen joints at three months was 61 percent, as compared with 25 percent in the placebo group (P<0.001). The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms. There were no dose-limiting toxic effects, and no antibodies to TNFR:Fc were detected in serum samples.
CONCLUSIONS: In this three-month trial TNFR:Fc was safe, well tolerated, and associated with improvement in the inflammatory symptoms of rheumatoid arthritis.

PMID 9219699
L W Moreland, M H Schiff, S W Baumgartner, E A Tindall, R M Fleischmann, K J Bulpitt, A L Weaver, E C Keystone, D E Furst, P J Mease, E M Ruderman, D A Horwitz, D G Arkfeld, L Garrison, D J Burge, C M Blosch, M L Lange, N D McDonnell, M E Weinblatt
Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial.
Ann Intern Med. 1999 Mar 16;130(6):478-86.
Abstract/Text BACKGROUND: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months.
OBJECTIVE: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis.
DESIGN: Randomized, double-blind, placebo-controlled trial with blinded joint assessors.
SETTING: 13 North American centers.
PATIENTS: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs.
INTERVENTION: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months.
MEASUREMENTS: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months.
RESULTS: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects.
CONCLUSIONS: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.

PMID 10075615
M E Weinblatt, J M Kremer, A D Bankhurst, K J Bulpitt, R M Fleischmann, R I Fox, C G Jackson, M Lange, D J Burge
A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.
N Engl J Med. 1999 Jan 28;340(4):253-9. doi: 10.1056/NEJM199901283400401.
Abstract/Text BACKGROUND: Patients treated with methotrexate for rheumatoid arthritis often improve but continue to have active disease. This study was undertaken to determine whether the addition of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein (TNFR:Fc), to methotrexate therapy would provide additional benefit to patients who had persistent rheumatoid arthritis despite receiving methotrexate.
METHODS: In a 24-week, double-blind trial, we randomly assigned 89 patients with persistently active rheumatoid arthritis despite at least 6 months of methotrexate therapy at a stable dose of 15 to 25 mg per week (or as low as 10 mg per week for patients unable to tolerate higher doses) to receive either etanercept (25 mg) or placebo subcutaneously twice weekly while continuing to receive methotrexate. The primary measure of clinical response was the American College of Rheumatology criteria for a 20 percent improvement in measures of disease activity (ACR 20) at 24 weeks.
RESULTS: The addition of etanercept to methotrexate therapy resulted in rapid and sustained improvement. At 24 weeks, 71 percent of the patients receiving etanercept plus methotrexate and 27 percent of those receiving placebo plus methotrexate met the ACR 20 criteria (P<0.001); 39 percent of the patients receiving etanercept plus methotrexate and 3 percent of those receiving placebo plus methotrexate met the ACR 50 criteria (for a 50 percent improvement) (P<0.001). Patients receiving etanercept plus methotrexate had significantly better outcomes according to all measures of disease activity. The only adverse events associated with etanercept were mild injection-site reactions, and no patient withdrew from the study because of adverse events associated with etanercept.
CONCLUSIONS: In patients with persistently active rheumatoid arthritis, the combination of etanercept and methotrexate was safe and well tolerated and provided significantly greater clinical benefit than methotrexate alone.

PMID 9920948
F Navarro-Sarabia, R Ariza-Ariza, B Hernandez-Cruz, I Villanueva
Adalimumab for treating rheumatoid arthritis.
Cochrane Database Syst Rev. 2005 Jul 20;(3):CD005113. doi: 10.1002/14651858.CD005113.pub2. Epub 2005 Jul 20.
Abstract/Text BACKGROUND: Adalimumab is a fully human anti-TNFalpha monoclonal antibody. Published studies indicate that its use in patients with RA can be effective and safe.
OBJECTIVES: The aim of this review was to assess the efficacy and safety of adalimumab in the treatment of RA.
SEARCH STRATEGY: Electronic databases were searched up to August, 2004: MEDLINE, CINAHL, EBM Reviews (CDSR, ACP Journal Club, DARE and CENTRAL) and Health STAR. Conference proceedings were hand searched and pharmaceutical companies were contacted to obtain additional unpublished data from published trials. Adalimumab was searched as a text word as it is not currently indexed. The search was not limited by language, year of publication or type of publication.
SELECTION CRITERIA: All randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing adalimumab alone or in combination with DMARDs to placebo or other DMARDs.
DATA COLLECTION AND ANALYSIS: Two reviewers independently collected the data in a standardized form and assessed the methodological quality of the trial using validated criteria. Outcome measures included ACR and EULAR responses, DAS 28 and components of ACR response and radiographic data. Safety data were also included. Continuous data were reported as weighted mean difference (WMD) with 95% confidence interval (95%CI), absolute benefit (AB) and relative difference (RD). Dichotomous outcomes were reported as relative risk (RR) with 95% CI, absolute risk difference (ARD) or risk difference (RDiff) with 95%CI and number needed to treat (NNT) or to harm (NNH). When significant heterogeneity was not found, data were pooled.
MAIN RESULTS: Six studies with 2381 patients were included in this review. Two comparisons were done: A. adalimumab subcutaneously (sc) + methotrexate (or DMARDs) versus placebo sc + methotrexate (or DMARDs). B. adalimumab sc in monotherapy versus placebo sc. In the comparison A, with adalimumab 40 mg every other week (e.o.w.), the RR to achieve an ACR 20 response at 24 weeks ranged in the included studies from 1.52 to 4.63, and the NNT ranged from 1.9 to 5.4. The RR (95%CI) to achieve an ACR 50 response was 4.63 (3.04-7.05), and the NNT was 3.0 (95%CI 2.0-6.0). The RR (95%CI) to achieve an ACR 70 response was 5.14 (3.14-8.41) and the number needed to treat was 7.0 (95%CI 5.0-13.0). At 52 weeks, the RRs (95%CI) to achieve an ACR 20, 50, and 70 response were 2.46 (1.87-3.22), 4.37 (2.77-6.91), and 5.15 (2.60-10.22), with NNTs of 2.9, 3.1, and 5.3, respectively. At 52 weeks, adalimumab 40 mg e.o.w. and 20 mg every week (e.w.) significantly slowed the radiological progression including Sharp modified index, erosion score, and joint space score (only with 40 mg e.o.w.). In the comparison B, with adalimumab 40 mg e.o w. , the RRs to achieve an ACR 20, 50, and 70 response at 24/26 weeks were 1.91 (1.17-3.10), 2.84 (1.58-5.12), and 7.33 (2.25-33.90) with NNTs of 5.0 (95%CI 3.0-9.0), 7.0 (4.0-20.0), and 9.0 (3.0-38.0), respectively. In most of the analysed studies and comparisons, there were not significant differences in safety outcomes between adalimumab and control groups. The development of positive antinuclear antibodies was significantly more frequent in adalimumab patients than in placebo patients. Serious infections were significantly more frequent in adalimumab patients in only one study (Keystone 2004) with a RR (95%CI) of 7.64(1.02-57.18) and a NNH of 30.2.
AUTHORS' CONCLUSIONS: On the basis of the studies reviewed here, adalimumab in combination with methotrexate is efficacious and safe in the treatment of the rheumatoid arthritis. Adalimumab 40 mg sc e.o.w. and 20 mg e.w. slows the radiographic progression at 52 weeks. Adalimumab in combination with DMARDs other than methotrexate is also efficacious and safe, even though data from one only study are available and the number of patients in each group is low. Adalimumab in monotherapy is efficacious and safe in the treatment of the rheumatoid arthritis but the effect size is lower than with combined therapy.

PMID 16034967
Michael E Weinblatt, Edward C Keystone, Daniel E Furst, Larry W Moreland, Michael H Weisman, Charles A Birbara, Leah A Teoh, Steven A Fischkoff, Elliot K Chartash
Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial.
Arthritis Rheum. 2003 Jan;48(1):35-45. doi: 10.1002/art.10697.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX.
METHODS: In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks.
RESULTS: An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events.
CONCLUSION: The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.

PMID 12528101
Edward C Keystone, Arthur F Kavanaugh, John T Sharp, Hyman Tannenbaum, Ye Hua, Leah S Teoh, Steven A Fischkoff, Elliot K Chartash
Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.
Arthritis Rheum. 2004 May;50(5):1400-11. doi: 10.1002/art.20217.
Abstract/Text OBJECTIVE: Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX).
METHODS: In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]).
RESULTS: At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week.
CONCLUSION: In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.

PMID 15146409
Ferdinand C Breedveld, Michael H Weisman, Arthur F Kavanaugh, Stanley B Cohen, Karel Pavelka, Ronald van Vollenhoven, John Sharp, John L Perez, George T Spencer-Green
The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment.
Arthritis Rheum. 2006 Jan;54(1):26-37. doi: 10.1002/art.21519.
Abstract/Text OBJECTIVE: To compare the efficacy and safety of adalimumab plus methotrexate (MTX) versus MTX monotherapy or adalimumab monotherapy in patients with early, aggressive rheumatoid arthritis (RA) who had not previously received MTX treatment.
METHODS: This was a 2-year, multicenter, double-blind, active comparator-controlled study of 799 RA patients with active disease of < 3 years' duration who had never been treated with MTX. Treatments included adalimumab 40 mg subcutaneously every other week plus oral MTX, adalimumab 40 mg subcutaneously every other week, or weekly oral MTX. Co-primary end points at year 1 were American College of Rheumatology 50% improvement (ACR50) and mean change from baseline in the modified total Sharp score.
RESULTS: Combination therapy was superior to both MTX and adalimumab monotherapy in all outcomes measured. At year 1, more patients receiving combination therapy exhibited an ACR50 response (62%) than did patients who received MTX or adalimumab monotherapy (46% and 41%, respectively; both P < 0.001). Similar superiority of combination therapy was seen in ACR20, ACR70, and ACR90 response rates at 1 and 2 years. There was significantly less radiographic progression (P < or = 0.002) among patients in the combination treatment arm at both year 1 and year 2 (1.3 and 1.9 Sharp units, respectively) than in patients in the MTX arm (5.7 and 10.4 Sharp units) or the adalimumab arm (3.0 and 5.5 Sharp units). After 2 years of treatment, 49% of patients receiving combination therapy exhibited disease remission (28-joint Disease Activity Score <2.6), and 49% exhibited a major clinical response (ACR70 response for at least 6 continuous months), rates approximately twice those found among patients receiving either monotherapy. The adverse event profiles were comparable in all 3 groups.
CONCLUSION: In this population of patients with early, aggressive RA, combination therapy with adalimumab plus MTX was significantly superior to either MTX alone or adalimumab alone in improving signs and symptoms of disease, inhibiting radiographic progression, and effecting clinical remission.

PMID 16385520
Jasvinder A Singh, Shahrzad Noorbaloochi, Gurkirpal Singh
Golimumab for rheumatoid arthritis.
Cochrane Database Syst Rev. 2010 Jan 20;(1):CD008341. doi: 10.1002/14651858.CD008341. Epub 2010 Jan 20.
Abstract/Text BACKGROUND: Golimumab is a humanized inhibitor of Tumor necrosis factor-alpha, recently approved by the Food and Drug Administration (FDA) for the treatment of Rheumatoid arthritis (RA).
OBJECTIVES: The objective of this systematic review was to compare the efficacy and safety of golimumab (alone or in combination with DMARDs or biologics) to placebo (alone or in combination with DMARDs or biologics) in randomized or quasi-randomized clinical trials in adults with RA.
SEARCH STRATEGY: An expert librarian searched six databases for any clinical trials of golimumab in RA, including the Cochrane Central Register of Controlled Trials (CENTRAL), OVID MEDLINE, CINAHL, EMBASE, Science Citation Index (Web of Science) and Current Controlled Trials databases.
SELECTION CRITERIA: Studies were included if they used golimumab in adults with RA, were randomized or quasi-randomized and provided clinical outcomes.
DATA COLLECTION AND ANALYSIS: Two review authors (JS, SN) independently reviewed all titles and abstracts, selected appropriate studies for full review and reviewed the full-text articles for the final selection of included studies. For each study, they independently abstracted study characteristics, safety and efficacy data and performed risk of bias assessment. Disagreements were resolved by consensus. For continuous measures, we calculated mean differences or standardized mean differences and for categorical measures, relative risks. 95% confidence intervals were calculated.
MAIN RESULTS: Four RCTs with 1,231 patients treated with golimumab and 483 patients treated with placebo were included. Of these, 436 were treated with the FDA-approved dose of golimumab 50 mg every four weeks. Compared to patients treated with placebo+methotrexate, patients treated with the FDA-approved dose of golimumab+methotrexate were 2.6 times more likely to reach ACR50 (95% confidence interval (CI) 1.3 to 4.9; P=0.005 and NNT= 5, 95% confidence interval 2 to 20), no more likely to have any adverse event (relative risk 1.1, 95% Cl 0.9 to 1.2; P=0.44), and 0.5 times as likely to have overall withdrawals (95% Cl 0.3 to 0.8; P=0.005). Golimumab-treated patients were significantly more likely to achieve remission, low disease activity and improvement in functional ability compared to placebo (all statistically significant). No significant differences were noted between golimumab and placebo regarding serious adverse events, infections, serious infections, lung infections, tuberculosis, cancer, withdrawals due to adverse events and inefficacy and deaths. No radiographic data were reported.
AUTHORS' CONCLUSIONS: With an overall high grade of evidence, at the FDA-approved dose, golimumab is significantly more efficacious than placebo in treatment of patients with active RA , when used in combination with methotrexate. The short-term safety profile, based on short-term RCTs, is reasonable with no differences in total adverse events, serious infections, cancer, tuberculosis or deaths. Long-term surveillance studies are needed for safety assessment.

PMID 20091667
E C Keystone, M C Genovese, L Klareskog, E C Hsia, S T Hall, P C Miranda, J Pazdur, S-C Bae, W Palmer, J Zrubek, M Wiekowski, S Visvanathan, Z Wu, M U Rahman, GO-FORWARD Study
Golimumab, a human antibody to tumour necrosis factor {alpha} given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study.
Ann Rheum Dis. 2009 Jun;68(6):789-96. doi: 10.1136/ard.2008.099010. Epub 2008 Dec 9.
Abstract/Text OBJECTIVE: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy.
METHODS: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24.
RESULTS: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively.
CONCLUSION: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.

PMID 19066176
Josef S Smolen, Jonathan Kay, Mittie K Doyle, Robert Landewé, Eric L Matteson, Jürgen Wollenhaupt, Norman Gaylis, Frederick T Murphy, Jeffrey S Neal, Yiying Zhou, Sudha Visvanathan, Elizabeth C Hsia, Mahboob U Rahman, GO-AFTER study investigators
Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial.
Lancet. 2009 Jul 18;374(9685):210-21. doi: 10.1016/S0140-6736(09)60506-7. Epub 2009 Jun 26.
Abstract/Text BACKGROUND: Tumour necrosis factor alpha (TNFalpha) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFalpha inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors.
METHODS: 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimumab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov, number NCT00299546.
FINDINGS: Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14.0 (IQR 9.0-22.0) swollen and 26.0 (16.0-41.0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2.5 [95% CI 1.5-4.2], p=0.0006), and 58 (38%) patients on 100 mg golimumab (2.8 [1.6-4.7], p=0.0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1-16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1-24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab.
INTERPRETATION: Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors.
FUNDING: Centocor Research and Development and Schering-Plough Research Institute.

PMID 19560810
Paul Emery, Roy M Fleischmann, Larry W Moreland, Elizabeth C Hsia, Ingrid Strusberg, Patrick Durez, Peter Nash, Eric Jason B Amante, Melvin Churchill, Won Park, Bernardo Antonio Pons-Estel, Mittie K Doyle, Sudha Visvanathan, Weichun Xu, Mahboob U Rahman
Golimumab, a human anti-tumor necrosis factor alpha monoclonal antibody, injected subcutaneously every four weeks in methotrexate-naive patients with active rheumatoid arthritis: twenty-four-week results of a phase III, multicenter, randomized, double-blind, placebo-controlled study of golimumab before methotrexate as first-line therapy for early-onset rheumatoid arthritis.
Arthritis Rheum. 2009 Aug;60(8):2272-83. doi: 10.1002/art.24638.
Abstract/Text OBJECTIVE: To assess the safety and efficacy of golimumab in methotrexate (MTX)-naive patients with active rheumatoid arthritis (RA).
METHODS: MTX-naive patients with RA (n = 637) were randomized to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Subcutaneous injections of golimumab or placebo were administered every 4 weeks. The dosage of MTX/placebo capsules started at 10 mg/week and escalated to 20 mg/week. The primary end point, the proportion of patients meeting the American College of Rheumatology 50% improvement criteria (achieving an ACR50 response) at week 24, required significant differences between groups 3 and 4 combined (combined group) versus group 1 and significant differences in a pairwise comparison (group 3 or group 4 versus group 1).
RESULTS: An intent-to-treat (ITT) analysis of the ACR50 response at week 24 did not show a significant difference between the combined group and group 1 (38.4% and 29.4%, respectively; P=0.053), while a post hoc modified ITT analysis (excluding 3 untreated patients) of the ACR50 response showed statistically significant differences between the combined group and group 1 (38.5% versus 29.4%; P=0.049) and between group 3 (40.5%; P=0.038) but not group 4 (36.5%; P=0.177) and group 1. Group 2 was noninferior to group 1 for the ACR50 response at week 24 (33.1%; 95% confidence interval lower bound -5.2%; predefined delta value for noninferiority -10%). The combination of golimumab plus MTX demonstrated a significantly better response compared with placebo plus MTX in most other efficacy parameters, including response/remission according to the Disease Activity Score in 28 joints. Serious adverse events occurred in 7%, 3%, 6%, and 6% of patients in groups 1, 2, 3, and 4, respectively.
CONCLUSION: Although the primary end point was not met, the modified ITT analysis of the primary end point and other prespecified efficacy measures demonstrated that the efficacy of golimumab plus MTX is better than, and the efficacy of golimumab alone is similar to, the efficacy of MTX alone in reducing RA signs and symptoms in MTX-naive patients, with no unexpected safety concerns.

PMID 19644849
Takeuchi T, Harigai M, Tanaka Y, Yamanaka H, Ishiguro N, Yamamoto K, Miyasaka N, Koike T, Kanazawa M, Oba T, Yoshinari T, Baker D. Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: results of the phase 2/3, multicentre, randomised, double-blind, placebo-controlled GO-MONO study through 24 weeks. Ann Rheum Dis [Internet]. 2013 Sep [cited 2018 Nov 8];72(9):1488–1495. Available from: http://ard.bmj.com/lookup/doi/10.1136/annrheumdis-2012-201796
Edward Keystone, Désireé van der Heijde, David Mason, Robert Landewé, Ronald Van Vollenhoven, Bernard Combe, Paul Emery, Vibeke Strand, Philip Mease, Chintu Desai, Karel Pavelka
Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Arthritis Rheum. 2008 Nov;58(11):3319-29. doi: 10.1002/art.23964.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of 2 dosage regimens of lyophilized certolizumab pegol (a novel PEGylated anti-tumor necrosis factor agent) as adjunctive therapy to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) with an inadequate response to MTX therapy alone.
METHODS: In this 52-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 982 patients were randomized 2:2:1 to receive treatment with subcutaneous certolizumab pegol at an initial dosage of 400 mg given at weeks 0, 2, and 4, with a subsequent dosage of 200 mg or 400 mg given every 2 weeks, plus MTX, or placebo plus MTX. Co-primary end points were the response rate at week 24 according to the American College of Rheumatology 20% criteria for improvement (ACR20) and the mean change from baseline in the modified total Sharp score at week 52.
RESULTS: At week 24, ACR20 response rates using nonresponder imputation for the certolizumab pegol 200-mg and 400-mg groups were 58.8% and 60.8%, respectively, as compared with 13.6% for the placebo group. Differences in ACR20 response rates versus placebo were significant at week 1 and were sustained to week 52 (P < 0.001). At week 52, mean radiographic progression from baseline was reduced in patients treated with certolizumab pegol 200 mg (0.4 Sharp units) or 400 mg (0.2 Sharp units) as compared with that in placebo-treated patients (2.8 Sharp units) (P < 0.001 by rank analysis). Improvements in all ACR core set of disease activity measures, including physical function, were observed by week 1 with both certolizumab pegol dosage regimens. Most adverse events were mild or moderate.
CONCLUSION: Treatment with certolizumab pegol 200 or 400 mg plus MTX resulted in a rapid and sustained reduction in RA signs and symptoms, inhibited the progression of structural joint damage, and improved physical function as compared with placebo plus MTX treatment in RA patients with an incomplete response to MTX.

PMID 18975346
J Smolen, R B Landewé, P Mease, J Brzezicki, D Mason, K Luijtens, R F van Vollenhoven, A Kavanaugh, M Schiff, G R Burmester, V Strand, J Vencovsky, D van der Heijde
Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial.
Ann Rheum Dis. 2009 Jun;68(6):797-804. doi: 10.1136/ard.2008.101659. Epub 2008 Nov 17.
Abstract/Text BACKGROUND: Certolizumab pegol is a PEGylated tumour necrosis factor inhibitor.
OBJECTIVE: To evaluate the efficacy and safety of certolizumab pegol versus placebo, plus methotrexate (MTX), in patients with active rheumatoid arthritis (RA).
METHODS: An international, multicentre, phase 3, randomised, double-blind, placebo-controlled study in active adult-onset RA. Patients (n = 619) were randomised 2:2:1 to subcutaneous certolizumab pegol (liquid formulation) 400 mg at weeks 0, 2 and 4 followed by 200 mg or 400 mg plus MTX, or placebo plus MTX, every 2 weeks for 24 weeks. The primary end point was ACR20 response at week 24. Secondary end points included ACR50 and ACR70 responses, change from baseline in modified Total Sharp Score, ACR core set variables and physical function.
RESULTS: Significantly more patients in the certolizumab pegol 200 mg and 400 mg groups achieved an ACR20 response versus placebo (p< or =0.001); rates were 57.3%, 57.6% and 8.7%, respectively. Certolizumab pegol 200 and 400 mg also significantly inhibited radiographic progression; mean changes from baseline in mTSS at week 24 were 0.2 and -0.4, respectively, versus 1.2 for placebo (rank analysis p< or =0.01). Certolizumab pegol-treated patients reported rapid and significant improvements in physical function versus placebo; mean changes from baseline in HAQ-DI at week 24 were -0.50 and -0.50, respectively, versus -0.14 for placebo (p< or =0.001). Most adverse events were mild or moderate, with low incidence of withdrawals due to adverse events. Five patients developed tuberculosis.
CONCLUSION: Certolizumab pegol plus MTX was more efficacious than placebo plus MTX, rapidly and significantly improving signs and symptoms of RA and physical function and inhibiting radiographic progression.
TRIAL REGISTRATION NUMBER: NCT00175877.

PMID 19015207
R Fleischmann, J Vencovsky, R F van Vollenhoven, D Borenstein, J Box, G Coteur, N Goel, H-P Brezinschek, A Innes, V Strand
Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study.
Ann Rheum Dis. 2009 Jun;68(6):805-11. doi: 10.1136/ard.2008.099291. Epub 2008 Nov 17.
Abstract/Text BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis (RA). Treatment with TNFalpha inhibitors reduces disease activity and improves outcomes for patients with RA. This study evaluated the efficacy and safety of certolizumab pegol 400 mg, a novel, poly-(ethylene glycol) (PEG)ylated, Fc-free TNFalpha inhibitor, as monotherapy in patients with active RA.
METHODS: In this 24-week, multicentre, randomised, double-blind, placebo-controlled study, 220 patients previously failing > or =1 disease-modifying antirheumatic drug (DMARD) were randomised 1:1 to receive subcutaneous certolizumab pegol 400 mg (n = 111) or placebo (n = 109) every 4 weeks. The primary endpoint was 20% improvement according to the American College of Rheumatology criteria (ACR20) at week 24. Secondary endpoints included ACR50/70 response, ACR component scores, 28-joint Disease Activity Score Erythrocyte Sedimentation Rate 3 (DAS28(ESR)3), patient-reported outcomes (including physical function, health-related quality of life (HRQoL), pain and fatigue) and safety.
RESULTS: At week 24, the ACR20 response rates were 45.5% for certolizumab pegol 400 mg every 4 weeks vs 9.3% for placebo (p<0.001). Differences for certolizumab pegol vs placebo in the ACR20 response were statistically significant as early as week 1 through to week 24 (p<0.001). Significant improvements in ACR50, ACR components, DAS28(ESR)3 and all patient-reported outcomes were also observed early with certolizumab pegol and were sustained throughout the study. Most adverse events were mild or moderate and no deaths or cases of tuberculosis were reported.
CONCLUSIONS: Treatment with certolizumab pegol 400 mg monotherapy every 4 weeks effectively reduced the signs and symptoms of active RA in patients previously failing > or =1 DMARD compared with placebo, and demonstrated an acceptable safety profile.
TRIAL REGISTRATION NUMBER: NCT00548834.

PMID 19015206
Michael E Weinblatt, Roy Fleischmann, Tom W J Huizinga, Paul Emery, Janet Pope, Elena M Massarotti, Ronald F van Vollenhoven, Jürgen Wollenhaupt, Clifton O Bingham, Ben Duncan, Niti Goel, Owen R Davies, Maxime Dougados
Efficacy and safety of certolizumab pegol in a broad population of patients with active rheumatoid arthritis: results from the REALISTIC phase IIIb study.
Rheumatology (Oxford). 2012 Dec;51(12):2204-14. doi: 10.1093/rheumatology/kes150. Epub 2012 Aug 25.
Abstract/Text OBJECTIVE: To investigate the efficacy and safety of certolizumab pegol (CZP) in a broad population of patients with active RA.
METHODS: In this 12-week, double-blind period of the phase IIIb trial, RA patients with inadequate response to at least one DMARD were randomized 4:1 to CZP (400 mg at weeks 0, 2 and 4, followed by 200 mg every 2 weeks) or placebo (every 2 weeks) plus current therapy stratified by previous TNF inhibitor use, concomitant methotrexate use and disease duration (<2 vs ≥2 years). The primary outcome was ACR20 response rate at week 12.
RESULTS: Of 1063 patients (CZP = 851; placebo = 212), 37.6% had previous TNF inhibitor use. Baseline mean HAQ Disability Index (HAQ-DI) and DAS 28-joint assessment-ESR [DAS28(ESR)] values were 1.5 and 6.4 in the CZP group, and 1.6 and 6.4 in the placebo group, respectively. The primary endpoint was significant (week 12 ACR20, CZP vs placebo: 51.1 vs 25.9%; P < 0.001); differences were noted at week 2 (31.8 vs 8.5%; P < 0.001). HAQ-DI and DAS28(ESR) change from baseline and ACR50 were significant from week 2. Week 12 ACR20 responses were similar across CZP patient subgroups regardless of concomitant DMARD use at baseline. Adverse and serious adverse events were comparable between CZP and placebo, with no new safety signals.
CONCLUSION: CZP was associated with rapid and consistent clinical responses and improved physical function in a diverse group of RA patients, irrespective of concomitant or previous therapy.
TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov/, NCT00717236.

PMID 22923753
T Takeuchi, Y Tatsuki, Y Nogami, N Ishiguro, Y Tanaka, H Yamanaka, N Kamatani, M Harigai, J Ryu, K Inoue, H Kondo, S Inokuma, T Ochi, T Koike
Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis.
Ann Rheum Dis. 2008 Feb;67(2):189-94. doi: 10.1136/ard.2007.072967. Epub 2007 Jul 20.
Abstract/Text OBJECTIVES: A large-scale postmarketing surveillance (PMS) study was carried out to determine the safety profile of infliximab in Japanese patients with rheumatoid arthritis (RA).
METHODS: The PMS study was performed for all patients with RA who were treated with infliximab. They were consecutively registered in the PMS study at the initiation of infliximab treatment and were prospectively monitored with all adverse events noted for a period of 6 months. All case reports, which include safety-related events, were collected monthly.
RESULTS: Adverse drug reactions (ADRs) were assessed for 6 months in 5000 patients who were consecutively enrolled in the PMS study. The incidence rates of total and serious ADRs were 28.0% and 6.2%, respectively. "Infections" or "respiratory disorders" were most commonly observed among serious ADRs. Bacterial pneumonia developed in 2.2%, tuberculosis in 0.3%, suspected Pneumocystis jiroveci pneumonia (PCP) in 0.4% and interstitial pneumonitis in 0.5%. Bacterial pneumonia (for which individuals of male gender, of older age and those with advanced rheumatoid arthritis and comorbid respiratory disease were most at risk) began to develop immediately after the start of treatment, while tuberculosis, PCP and interstitial pneumonitis developed about 1 month later. Serious infusion reactions were observed in 0.5% and were more likely to occur in patients who had participated in previous clinical trials of infliximab.
CONCLUSION: This postmarketing surveillance study of patients treated with infliximab showed that infliximab in combination with low-dose MTX was well tolerated in Japanese patients with active RA.

PMID 17644554
Takao Koike, Masayoshi Harigai, Naoki Ishiguro, Shigeko Inokuma, Shuji Takei, Tsutomu Takeuchi, Hisashi Yamanaka, Yoshiya Tanaka
Safety and effectiveness of adalimumab in Japanese rheumatoid arthritis patients: postmarketing surveillance report of the first 3,000 patients.
Mod Rheumatol. 2012 Aug;22(4):498-508. doi: 10.1007/s10165-011-0541-5. Epub 2011 Oct 13.
Abstract/Text This interim analysis of postmarketing surveillance data for adalimumab-treated rheumatoid arthritis (RA) patients summarizes safety and effectiveness during the first 24 weeks of therapy for the first 3,000 patients treated in Japan (June 2008-December 2009). Patient eligibility for antitumor necrosis factor therapy was based on the Japanese College of Rheumatology treatment guidelines and Japanese labeling. All patients were screened for tuberculosis. Approximately 50% of the population was biologic naïve, 66% received concomitant methotrexate (MTX), and 72% received concomitant glucocorticoids. The overall incidence rate of adverse events was 31% (5.5% serious) and that of adverse drug reactions (ADRs) was 27% (4.1% serious). Incidence rates of ADRs and serious ADRs were similar regardless of prior biologic therapy or concomitant MTX use but were significantly higher in patients receiving glucocorticoids compared with those not receiving glucocorticoids. Bacterial/bronchial pneumonia occurred in 1.2% of patients; interstitial pneumonia, 0.6%; Pneumocystis jirovecii pneumonia, 0.3%; tuberculosis, 0.13%; and administration-site reactions, 6.1%. Mean 28-joint Disease Activity Scores decreased significantly after 24 weeks from 5.29 to 3.91. All subgroups showed significant improvement, particularly the biologic-naïve patients receiving concomitant MTX. No new safety concerns were identified. ADR Incidence rates were similar to those of other biologic agents approved for RA.

PMID 21993918
Masayoshi Harigai, Ryuji Koike, Nobuyuki Miyasaka, Pneumocystis Pneumonia under Anti-Tumor Necrosis Factor Therapy (PAT) Study Group
Pneumocystis pneumonia associated with infliximab in Japan.
N Engl J Med. 2007 Nov 1;357(18):1874-6. doi: 10.1056/NEJMc070728.
Abstract/Text
PMID 17978303
Frederick Wolfe, Liron Caplan, Kaleb Michaud
Treatment for rheumatoid arthritis and the risk of hospitalization for pneumonia: associations with prednisone, disease-modifying antirheumatic drugs, and anti-tumor necrosis factor therapy.
Arthritis Rheum. 2006 Feb;54(2):628-34. doi: 10.1002/art.21568.
Abstract/Text OBJECTIVE: Pneumonia is a major cause of mortality and morbidity in rheumatoid arthritis (RA). This study was undertaken to determine the rate and predictors of hospitalization for pneumonia and the extent to which specific RA treatments increase pneumonia risk.
METHODS: RA patients (n = 16,788) were assessed semiannually for 3.5 years. Pneumonia was confirmed by medical records or detailed patient interview. Covariates included RA severity measures, diabetes, pulmonary disease, and myocardial infarction. Cox proportional hazards regression was used to determine the multivariable risk associated with RA treatments.
RESULTS: After adjustment for covariates, prednisone use increased the risk of pneumonia hospitalization (hazard ratio [HR] 1.7 [95% confidence interval 1.5-2.0]), including a dose-related increase in risk (< or = 5 mg/day HR 1.4 [95% confidence interval 1.1-1.6], > 5-10 mg/day HR 2.1 [95% confidence interval 1.7-2.7], > 10 mg/day HR 2.3 [95% confidence interval 1.6-3.2]). Leflunomide also increased the risk (HR 1.2 [95% confidence interval 1.0-1.5]). HRs for etanercept (0.8 [95% confidence interval 0.6-110]) and sulfasalazine (0.7 [95% confidence interval 0.5-1.0]) did not reflect an increased risk of pneumonia. HRs for infliximab, adalimumab, and methotrexate were not significantly different from zero.
CONCLUSION: There is a dose-related relationship between prednisone use and pneumonia risk in RA. No increase in risk was found for anti-tumor necrosis factor therapy or methotrexate. These data call into question the belief that low-dose prednisone is safe. Because corticosteroid use is common in RA, the results of this study suggest that prednisone exposure may have important public health consequences.

PMID 16447241
R N Maini, P C Taylor, J Szechinski, K Pavelka, J Bröll, G Balint, P Emery, F Raemen, J Petersen, J Smolen, D Thomson, T Kishimoto, CHARISMA Study Group
Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate.
Arthritis Rheum. 2006 Sep;54(9):2817-29. doi: 10.1002/art.22033.
Abstract/Text OBJECTIVE: To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti-interleukin-6 (IL-6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).
METHODS: The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.
RESULTS: A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose-related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C-reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high-density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.
CONCLUSION: These results indicate that targeted blockade of IL-6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

PMID 16947782
P Emery, E Keystone, H P Tony, A Cantagrel, R van Vollenhoven, A Sanchez, E Alecock, J Lee, J Kremer
IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial.
Ann Rheum Dis. 2008 Nov;67(11):1516-23. doi: 10.1136/ard.2008.092932. Epub 2008 Jul 14.
Abstract/Text OBJECTIVES: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy.
METHODS: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed.
RESULTS: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups.
CONCLUSION: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile.
TRIAL REGISTRATION NUMBER: NCT00106522.

PMID 18625622
Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, Woodworth T, Gomez-Reino JJ. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: The tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum [Internet]. 2008 Oct [cited 2018 Nov 8];58(10):2968–2980. Available from: http://doi.wiley.com/10.1002/art.23940
Norihiro Nishimoto, Jun Hashimoto, Nobuyuki Miyasaka, Kazuhiko Yamamoto, Shinichi Kawai, Tsutomu Takeuchi, Norikazu Murata, Désirée van der Heijde, Tadamitsu Kishimoto
Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab.
Ann Rheum Dis. 2007 Sep;66(9):1162-7. doi: 10.1136/ard.2006.068064. Epub 2007 May 7.
Abstract/Text OBJECTIVE: To evaluate the ability of tocilizumab (a humanised anti-IL-6 receptor antibody) monotherapy to inhibit progression of structural joint damage in patients with RA.
METHODS: In a multi-centre, x ray reader-blinded, randomised, controlled trial, 306 patients with active RA of <5 years' duration were allocated to receive either tocilizumab monotherapy at 8 mg/kg intravenously every 4 weeks or conventional disease-modifying antirheumatic drugs (DMARDs) for 52 weeks. Radiographs of hands and forefeet were scored by the van der Heijde modified Sharp method.
RESULTS: Patients had a mean disease duration of 2.3 years and a disease activity score in 28 joints of 6.5 at baseline. Mean total modified Sharp score (TSS) was 29.4, which was very high despite the relatively short disease duration. At week 52, the tocilizumab group showed statistically significantly less radiographic change in TSS (mean 2.3; 95% CI 1.5 to 3.2) than the DMARD group (mean 6.1; 95% CI 4.2 to 8.0; p<0.01). Tocilizumab monotherapy also improved signs and symptoms. The overall incidences of AEs were 89% and 82% (serious AEs: 18% and 13%; serious infections: 7.6% and 4.1%) in the tocilizumab and DMARD groups, respectively.
CONCLUSION: Tocilizumab monotherapy was generally well tolerated and provided radiographic benefit in patients with RA.

PMID 17485422
Jasvinder A Singh, Saba Beg, Maria Angeles Lopez-Olivo
Tocilizumab for rheumatoid arthritis: a Cochrane systematic review.
J Rheumatol. 2011 Jan;38(1):10-20. doi: 10.3899/jrheum.100717. Epub 2010 Oct 15.
Abstract/Text OBJECTIVE: to compare the benefit and safety of tocilizumab to placebo in patients with rheumatoid arthritis (RA).
METHODS: we searched multiple databases for published randomized or controlled clinical trials comparing benefit and safety of tocilizumab to placebo, disease-modifying antirheumatic drugs (DMARD), or other biologics. For dichotomous outcomes, we calculated the relative risk, and for continuous outcomes, the mean difference.
RESULTS: eight randomized controlled trials were included in this systematic review, with 3334 participants, 2233 treated with tocilizumab and 1101 controls. The US and Canadian approved dose of tocilizumab, 8 mg/kg every 4 weeks, was given to 1561 participants. In patients taking concomitant methotrexate, compared to placebo, patients treated with approved dose of tocilizumab were substantially and statistically significantly more likely than placebo to achieve the American College of Rheumatology 50 (absolute percentage, 38.8% vs 9.6%, respectively; RR 3.2, 95% CI 2.7, 3.7); Disease Activity Score remission (30.5% vs 2.7%; RR 8.7, 95% CI 6.3, 11.8); and a clinically meaningful decrease in Health Assessment Questionnaire (HAQ)/Modified HAQ scores (60.5% vs 34%; RR 1.8, 95% CI 1.6, 1.9). There were no substantive statistically significant differences in serious adverse effects (0.8% vs 0.7%; RR 1.2, 95% CI 0.8, 1.6) or withdrawals due to adverse events (4.9% vs 3.7%; RR 1.4, 95% CI 0.9, 2.1); however, tocilizumab-treated patients were significantly more likely to have any adverse event (74% vs 65%; RR 1.05, 95% CI 1.03, 1.07); elevation in the ratio of low-density lipoprotein to high-density lipoprotein cholesterol (HDL; 20% vs 12%; RR 1.7, 95% CI 1.2, 2.2); and increase in the ratio of total to HDL cholesterol (12% vs 7%; RR 1.7, 95% CI 1.2, 2.6); and they were less likely to withdraw from treatment for any reason (8.1% vs 14.9%; RR 0.6, 95% CI 0.5, 0.8).
CONCLUSION: at the approved dose of 8 mg/kg every 4 weeks, tocilizumab in combination with methotrexate/DMARD is beneficial in decreasing RA disease activity and improving function. Tocilizumab treatment was associated with a significant increase in cholesterol levels and occurrence of any adverse event, but not serious adverse events. Larger safety studies are needed to address these safety concerns.

PMID 20952462
Norihiro Nishimoto, Kazuyuki Yoshizaki, Nobuyuki Miyasaka, Kazuhiko Yamamoto, Shinichi Kawai, Tsutomu Takeuchi, Jun Hashimoto, Junichi Azuma, Tadamitsu Kishimoto
Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial.
Arthritis Rheum. 2004 Jun;50(6):1761-9. doi: 10.1002/art.20303.
Abstract/Text OBJECTIVE: Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA.
METHODS: In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria.
RESULTS: Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients.
CONCLUSION: Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

PMID 15188351
Gerd R Burmester, William F Rigby, Ronald F van Vollenhoven, Jonathan Kay, Andrea Rubbert-Roth, Ariella Kelman, Sophie Dimonaco, Nina Mitchell
Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial.
Ann Rheum Dis. 2016 Jun;75(6):1081-91. doi: 10.1136/annrheumdis-2015-207628. Epub 2015 Oct 28.
Abstract/Text OBJECTIVES: The efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, has not previously been evaluated in a population consisting exclusively of patients with early rheumatoid arthritis (RA).
METHODS: In a double-blind randomised controlled trial (FUNCTION), 1162 methotrexate (MTX)-naive patients with early progressive RA were randomly assigned (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and placebo+MTX (comparator group). The primary outcome was remission according to Disease Activity Score using 28 joints (DAS28-erythrocyte sedimentation rate (ESR) <2.6) at week 24. Radiographic and physical function outcomes were also evaluated. We report results through week 52.
RESULTS: The intent-to-treat population included 1157 patients. Significantly more patients receiving 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo than receiving placebo+MTX achieved DAS28-ESR remission at week 24 (45% and 39% vs 15%; p<0.0001). The 8 mg/kg TCZ+MTX group also achieved significantly greater improvement in radiographic disease progression and physical function at week 52 than did patients treated with placebo+MTX (mean change from baseline in van der Heijde-modified total Sharp score, 0.08 vs 1.14 (p=0.0001); mean reduction in Health Assessment Disability Index, -0.81 vs -0.64 (p=0.0024)). In addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX groups demonstrated clinical efficacy that was at least as effective as MTX for these key secondary endpoints. Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group.
CONCLUSIONS: TCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA.
TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT01007435.

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PMID 26511996
中外製薬. アクテムラ最終報告. アクテムラ点滴静注用 全例調査最終報告「関節リウマチ」「多関節に活動性を有する若年性特発性関節炎」. 2019;
Norihiro Nishimoto, Kyoko Ito, Nobuhiro Takagi
Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions.
Mod Rheumatol. 2010 Jun;20(3):222-32. doi: 10.1007/s10165-010-0279-5. Epub 2010 Mar 11.
Abstract/Text We present safety and efficacy data from Japanese clinical studies on monotherapy with tocilizumab (TCZ), a humanized anti-interleukin 6 receptor monoclonal antibody, in which 601 patients with moderate to severe rheumatoid arthritis, with a total of 2188 patient-years (pt-yr) exposure, were enrolled. The median treatment duration was 3.8 years. The incidence of adverse events (AEs), including abnormal laboratory test results, was calculated as 465.1 per 100 pt-yr. The most common serious adverse events (SAEs) were infections (6.22 per 100 pt-yr). There was no increase in the frequency of AEs or SAEs with long-term treatment. Abnormalities in the laboratory test results, such as increases in lipid parameters or abnormal liver function parameters, were common, but most were mild and there were no SAEs related to them. At baseline, 546 patients (90.8%) were taking corticosteroids; of these, 77.8% were able to decrease their corticosteroid dose during the study period, while 35.2% discontinued corticosteroids altogether. In the patients treated longer than 5 years, 91.3, 73.0, and 51.3% met the ACR20, ACR50, and ACR70 response criteria, respectively, and 59.7% met the DAS remission criterion (DAS28 <2.6) at 5 years. In conclusion, based on these results, TCZ has shown good tolerability and high efficacy during long-term treatment.

PMID 20221663
中外製薬. アクテムラ点滴静注用長期フォローアップ調査の最終報告. 2014;
Joel M Kremer, Rene Westhovens, Marc Leon, Eduardo Di Giorgio, Rieke Alten, Serge Steinfeld, Anthony Russell, Maxime Dougados, Paul Emery, Isaac F Nuamah, G Rhys Williams, Jean-Claude Becker, David T Hagerty, Larry W Moreland
Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig.
N Engl J Med. 2003 Nov 13;349(20):1907-15. doi: 10.1056/NEJMoa035075.
Abstract/Text BACKGROUND: Effective new therapies are needed for rheumatoid arthritis. Current therapies target the products of activated macrophages; however, T cells also have an important role in rheumatoid arthritis. A fusion protein--cytotoxic T-lymphocyte-associated antigen 4-IgG1 (CTLA4Ig)--is the first in a new class of drugs known as costimulation blockers being evaluated for the treatment of rheumatoid arthritis. CTLA4Ig binds to CD80 and CD86 on antigen-presenting cells, blocking the engagement of CD28 on T cells and preventing T-cell activation. A preliminary study showed that CTLA4Ig may be effective for the treatment of rheumatoid arthritis.
METHODS: We randomly assigned patients with active rheumatoid arthritis despite methotrexate therapy to receive 2 mg of CTLA4Ig per kilogram of body weight (105 patients), 10 mg of CTLA4Ig per kilogram (115 patients), or placebo (119 patients) for six months. All patients also received methotrexate therapy during the study. The clinical response was assessed at six months with use of the criteria of the American College of Rheumatology (ACR), which define the response according to its extent: 20 percent (ACR 20), 50 percent (ACR 50), or 70 percent (ACR 70). Additional end points included measures of the health-related quality of life.
RESULTS: Patients treated with 10 mg of CTLA4Ig per kilogram were more likely to have an ACR 20 than were patients who received placebo (60 percent vs. 35 percent, P<0.001). Significantly higher rates of ACR 50 and ACR 70 responses were seen in both CTLA4Ig groups than in the placebo group. The group given 10 mg of CTLA4Ig per kilogram had clinically meaningful and statistically significant improvements in all eight subscales of the Medical Outcomes 36-Item Short-Form General Health Survey. CTLA4Ig was well tolerated, with an overall safety profile similar to that of placebo.
CONCLUSIONS: In patients with active rheumatoid arthritis who were receiving methotrexate, treatment with CTLA4Ig significantly improved the signs and symptoms of rheumatoid arthritis and the health-related quality of life. CTLA4Ig is a promising new therapy for rheumatoid arthritis.

Copyright 2003 Massachusetts Medical Society
PMID 14614165
Mark C Genovese, Jean-Claude Becker, Michael Schiff, Michael Luggen, Yvonne Sherrer, Joel Kremer, Charles Birbara, Jane Box, Kannan Natarajan, Isaac Nuamah, Tracy Li, Richard Aranda, David T Hagerty, Maxime Dougados
Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition.
N Engl J Med. 2005 Sep 15;353(11):1114-23. doi: 10.1056/NEJMoa050524.
Abstract/Text BACKGROUND: A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy.
METHODS: Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed.
RESULTS: After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group.
CONCLUSIONS: Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.

Copyright 2005 Massachusetts Medical Society.
PMID 16162882
Lara J Maxwell, Jasvinder A Singh
Abatacept for rheumatoid arthritis: a Cochrane systematic review.
J Rheumatol. 2010 Feb;37(2):234-45. doi: 10.3899/jrheum.091066. Epub 2010 Jan 15.
Abstract/Text OBJECTIVE: To perform a systematic review of efficacy and safety of abatacept in patients with rheumatoid arthritis (RA).
METHODS: We searched the Cochrane Library, MEDLINE, EMBASE, ACP Journal Club, and Biosis Previews for randomized controlled trials (RCT) comparing abatacept alone or in combination with disease modifying antirheumatic drugs (DMARD)/biologics to placebo or other DMARD/biologics in patients with RA. Two reviewers independently assessed search results, risk of bias, and extracted data.
RESULTS: Seven trials with 2908 patients were included. Compared with placebo, patients with RA treated with abatacept were 2.2 times more likely to achieve an American College of Rheumatology 50% response (ACR50) at one year (relative risk 2.21, 95% CI 1.73, 2.82) with a 21% (95% CI 16%, 27%) absolute risk difference between groups. The number needed to treat to achieve an ACR50 response was 5 (95% CI 4, 7). Significantly greater improvements in physical function, disease activity, pain, and radiographic progression were noted in abatacept-treated patients compared to placebo. Total adverse events (AE) were greater in the abatacept group (RR 1.05, 95% CI 1.01, 1.08). Other harm outcomes were not significant, with the exception of serious infections at 12 months, which were more common in the abatacept group versus control group (Peto odds ratio 1.91, 95% CI 1.07, 3.42). Serious AE were more numerous in the abatacept + etanercept group versus the placebo + etanercept group (RR 2.30, 95% CI 1.15, 4.62).
CONCLUSION: Abatacept seems to be efficacious and safe in the treatment of RA. Abatacept should not be used in combination with other biologics to treat RA. Further longterm studies and postmarketing surveillance are required to assess for longer-term harms and sustained efficacy.

PMID 20080922
Paul Emery, Gerd R Burmester, Vivian P Bykerk, Bernard G Combe, Daniel E Furst, Emilie Barré, Chetan S Karyekar, Dennis A Wong, Tom W J Huizinga
Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b, multicentre, randomised, active-controlled AVERT study of 24 months, with a 12-month, double-blind treatment period.
Ann Rheum Dis. 2015 Jan;74(1):19-26. doi: 10.1136/annrheumdis-2014-206106. Epub 2014 Nov 3.
Abstract/Text OBJECTIVES: To evaluate clinical remission with subcutaneous abatacept plus methotrexate (MTX) and abatacept monotherapy at 12 months in patients with early rheumatoid arthritis (RA), and maintenance of remission following the rapid withdrawal of all RA treatment.
METHODS: In the Assessing Very Early Rheumatoid arthritis Treatment phase 3b trial, patients with early active RA were randomised to double-blind, weekly, subcutaneous abatacept 125 mg plus MTX, abatacept 125 mg monotherapy, or MTX for 12 months. Patients with low disease activity (Disease Activity Score (DAS)28 (C reactive protein (CRP)) <3.2) at month 12 entered a 12-month period of withdrawal of all RA therapy. The coprimary endpoints were the proportion of patients with DAS28 (CRP) <2.6 at month 12 and both months 12 and 18, for abatacept plus MTX versus MTX.
RESULTS: Patients had <2 years of RA symptoms, DAS28 (CRP) ≥3.2, anticitrullinated peptide-2 antibody positivity and 95.2% were rheumatoid factor positive. For abatacept plus MTX versus MTX, DAS28 (CRP) <2.6 was achieved in 60.9% versus 45.2% (p=0.010) at 12 months, and following treatment withdrawal, in 14.8% versus 7.8% (p=0.045) at both 12 and 18 months. DAS28 (CRP) <2.6 was achieved for abatacept monotherapy in 42.5% (month 12) and 12.4% (both months 12 and 18). Both abatacept arms had a safety profile comparable with MTX alone.
CONCLUSIONS: Abatacept plus MTX demonstrated robust efficacy compared with MTX alone in early RA, with a good safety profile. The achievement of sustained remission following withdrawal of all RA therapy suggests an effect of abatacept's mechanism on autoimmune processes.
TRIAL REGISTRATION NUMBER: NCT01142726.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PMID 25367713
生物学的製剤使用ガイドライン策定小委員会:全例市販後調査のためのトファシチニブ使用ガイドライン(2014年6月29日改訂版)、日本リウマチ学会.
Meliha Crnkic Kapetanovic, Carmen Roseman, Göran Jönsson, Lennart Truedsson
Heptavalent pneumococcal conjugate vaccine elicits similar antibody response as standard 23-valent polysaccharide vaccine in adult patients with RA treated with immunomodulating drugs.
Clin Rheumatol. 2011 Dec;30(12):1555-61. doi: 10.1007/s10067-011-1856-5. Epub 2011 Sep 29.
Abstract/Text The objectives of the study were to compare antibody response in immunosuppressed patients with rheumatoid arthritis (RA) after vaccination with heptavalent pneumococcal conjugate vaccine (PCV7) to that of RA patients and healthy controls vaccinated with 23-valent polysaccharide vaccine (PPV23) and to study the impact of disease and/or treatment characteristics and type of vaccine on antibody response following pneumococcal vaccination in patients with RA. In total, 253 RA patients treated with methotrexate (MTX), anti-TNF blockers as monotherapy or anti-TNF + MTX were vaccinated with a single dose (0.5 ml) of PCV7. In addition, 149 RA patients receiving corresponding treatments and 47 healthy controls were vaccinated with a single dose (0.5 ml) of PPV23. Serotype-specific IgG to 23F and 6B were measured at vaccination and 4-6 weeks after vaccination using ELISA. Antibody response ratio (ARR), i.e. ratio between post-/prevaccination antibody levels, was compared between corresponding treatment groups. Differences in ARR were analysed using analysis of variance. Positive antibody response (posAR) was defined as equal to or greater than twofold increase in prevaccination antibody levels. Possible predictors of posAR were analysed using logistic regression model. Corresponding RA treatment groups showed similar ARR and posAR for both serotypes regardless of vaccine type. Higher age at vaccination and concomitant MTX were identified as predictors of impaired posAR for both serotypes tested, whereas type of vaccine did not influence posAR significantly. PCV7 elicits similar antibody response as PPV23 in patients with RA receiving immunosuppressive treatment. In RA patients, higher age and MTX treatment but not type of vaccine predicted impaired posAR.

PMID 21956234
Kiyoshi Migita, Yukihiro Akeda, Manabu Akazawa, Shigeto Tohma, Fuminori Hirano, Haruko Ideguchi, Ryutaro Matsumura, Eiichi Suematsu, Tomoya Miyamura, Shunsuke Mori, Takahiro Fukui, Yasumori Izumi, Nozomi Iwanaga, Hiroshi Tsutani, Kouichirou Saisyo, Takao Yamanaka, Shiro Ohshima, Takao Sugiyama, Yojiro Kawabe, Masao Katayama, Yasuo Suenaga, Akira Okamoto, Hisaji Ohshima, Yasumasa Okada, Kenji Ichikawa, Shigeru Yoshizawa, Kenji Kawakami, Toshihiro Matsui, Hiroshi Furukawa, Kazunori Oishi
Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tacrolimus.
Arthritis Res Ther. 2015 Jun 3;17:149. doi: 10.1186/s13075-015-0662-x. Epub 2015 Jun 3.
Abstract/Text INTRODUCTION: In rheumatoid arthritis (RA) patients receiving immunosuppressive treatments, vaccination against Streptococcus pneumoniae is recommended. The objective of the study was to evaluate the effects of tacrolimus (TAC) on immune response following administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) in patients with established RA.
METHODS: Patients with RA (n = 133) were vaccinated with PPSV23. Patients were classified into TAC (n = 29), methotrexate (MTX) (n = 55), control (n = 35), and TAC/MTX (n = 14) treatment groups. We measured the concentrations of pneumococcal serotypes 6B and 23F by using an enzyme-linked immunosorbent assay and determined antibody functionality by using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI), before and 4 to 6 weeks after vaccination. A positive antibody response was defined as at least a twofold increase in the IgG concentration or as at least a 10-fold increase in the OI.
RESULTS: IgG concentrations and OIs were significantly increased in all treatment groups after PPSV23 vaccination. The TAC treatment group appears to respond in a manner similar to that of the RA control group in terms of 6B and 23F serotype concentration and function. In contrast, the MTX group had the lowest immune response. Patients who received a combination of TAC and MTX (TAC/MTX) also had a diminished immune response compared with those who received TAC alone.
CONCLUSIONS: TAC monotherapy does not appear to impair PPSV23 immunogenicity in patients with RA, whereas antibody production and function may be reduced when TAC is used with MTX. Thus, PPSV23 administration during ongoing TAC treatment should be encouraged for infection-prone TAC-treated patients with rheumatic diseases.
TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.

PMID 26036592
Jeffrey R Curtis, Eun Bong Lee, Irina V Kaplan, Kenneth Kwok, Jamie Geier, Birgitta Benda, Koshika Soma, Lisy Wang, Richard Riese
Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme.
Ann Rheum Dis. 2015 Apr 22;. doi: 10.1136/annrheumdis-2014-205847. Epub 2015 Apr 22.
Abstract/Text OBJECTIVES: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme.
METHODS: Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies.
RESULTS: Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA.
CONCLUSIONS: The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
PMID 25902789
Roy Fleischmann, Joel Kremer, John Cush, Hendrik Schulze-Koops, Carol A Connell, John D Bradley, David Gruben, Gene V Wallenstein, Samuel H Zwillich, Keith S Kanik, ORAL Solo Investigators
Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.
N Engl J Med. 2012 Aug 9;367(6):495-507. doi: 10.1056/NEJMoa1109071.
Abstract/Text BACKGROUND: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis.
METHODS: In this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity).
RESULTS: At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, vs. -0.19 points; P<0.001). The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P=0.62 and P=0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts.
CONCLUSIONS: In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.).

PMID 22873530
Désirée van der Heijde, Yoshiya Tanaka, Roy Fleischmann, Edward Keystone, Joel Kremer, Cristiano Zerbini, Mario H Cardiel, Stanley Cohen, Peter Nash, Yeong-Wook Song, Dana Tegzová, Bradley T Wyman, David Gruben, Birgitta Benda, Gene Wallenstein, Sriram Krishnaswami, Samuel H Zwillich, John D Bradley, Carol A Connell, ORAL Scan Investigators
Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study.
Arthritis Rheum. 2013 Mar;65(3):559-70. doi: 10.1002/art.37816.
Abstract/Text OBJECTIVE: The purpose of this 24-month phase III study was to examine structural preservation with tofacitinib in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Data from a planned 12-month interim analysis are reported.
METHODS: In this double-blind, parallel-group, placebo-controlled study, patients receiving background MTX were randomized 4:4:1:1 to tofacitinib at 5 mg twice daily, tofacitinib at 10 mg twice daily, placebo to tofacitinib at 5 mg twice daily, and placebo to tofacitinib at 10 mg twice daily. At month 3, nonresponder placebo-treated patients were advanced in a blinded manner to receive tofacitinib as indicated above; remaining placebo-treated patients were advanced at 6 months. Four primary efficacy end points were all analyzed in a step-down procedure.
RESULTS: At month 6, response rates according to the American College of Rheumatology 20% improvement criteria for tofacitinib at 5 mg and 10 mg twice daily were higher than those for placebo (51.5% and 61.8%, respectively, versus 25.3%; both P < 0.0001). At month 6, least squares mean (LSM) changes in total modified Sharp/van der Heijde score for tofacitinib at 5 mg and 10 mg twice daily were 0.12 and 0.06, respectively, versus 0.47 for placebo (P = 0.0792 and P ≤ 0.05, respectively). At month 3, LSM changes in the Health Assessment Questionnaire disability index score for tofacitinib at 5 mg and 10 mg twice daily were -0.40 (significance not declared due to step-down procedure) and -0.54 (P < 0.0001), respectively, versus -0.15 for placebo. At month 6, rates of remission (defined as a value <2.6 for the 4-variable Disease Activity Score in 28 joints using the erythrocyte sedimentation rate) for tofacitinib at 5 mg and 10 mg twice daily were 7.2% (significance not declared due to step-down procedure) and 16.0% (P < 0.0001), respectively, versus 1.6% for placebo. The safety profile was consistent with findings in previous studies.
CONCLUSION: Data from this 12-month interim analysis demonstrate that tofacitinib inhibits progression of structural damage and improves disease activity in patients with RA who are receiving MTX.

Copyright © 2013 by the American College of Rheumatology.
PMID 23348607
Ronald F van Vollenhoven, Roy Fleischmann, Stanley Cohen, Eun Bong Lee, Juan A García Meijide, Sylke Wagner, Sarka Forejtova, Samuel H Zwillich, David Gruben, Tamas Koncz, Gene V Wallenstein, Sriram Krishnaswami, John D Bradley, Bethanie Wilkinson, ORAL Standard Investigators
Tofacitinib or adalimumab versus placebo in rheumatoid arthritis.
N Engl J Med. 2012 Aug 9;367(6):508-19. doi: 10.1056/NEJMoa1112072.
Abstract/Text BACKGROUND: Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis.
METHODS: In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion. The three primary outcome measures were a 20% improvement at month 6 in the American College of Rheumatology scale (ACR 20); the change from baseline to month 3 in the score on the Health Assessment Questionnaire-Disability Index (HAQ-DI) (which ranges from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity).
RESULTS: At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5% and 52.6%, respectively) and among those receiving adalimumab (47.2%) than among those receiving placebo (28.3%) (P<0.001 for all comparisons). There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group. Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in two patients in the 10-mg tofacitinib group. Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts.
CONCLUSIONS: In patients with rheumatoid arthritis receiving background methotrexate, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy. (Funded by Pfizer; ORAL Standard ClinicalTrials.gov number, NCT00853385.).

PMID 22873531
Gerd R Burmester, Ricardo Blanco, Christina Charles-Schoeman, Jürgen Wollenhaupt, Cristiano Zerbini, Birgitta Benda, David Gruben, Gene Wallenstein, Sriram Krishnaswami, Samuel H Zwillich, Tamas Koncz, Koshika Soma, John Bradley, Charles Mebus, ORAL Step investigators
Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial.
Lancet. 2013 Feb 9;381(9865):451-60. doi: 10.1016/S0140-6736(12)61424-X. Epub 2013 Jan 5.
Abstract/Text BACKGROUND: Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis.
METHODS: We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Europe, and Latin America. 399 patients aged 18 years or older with moderate-to-severe rheumatoid arthritis and inadequate response to tumour necrosis factor inhibitors (TNFi) were randomly assigned in a 2:2:1:1 ratio with an automated internet or telephone system to receive twice a day treatment with: tofacitinib 5 mg (n=133); tofacitinib 10 mg (n=134); or placebo (n=132), all with methotrexate. At month 3, patients given placebo advanced to either tofacitinib 5 mg twice a day (n=66) or 10 mg twice a day (n=66). Primary endpoints included American College of Rheumatology (ACR)20 response rate, mean change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI), and rates of disease activity score (DAS)28-4(ESR) less than 2·6 (referred to as DAS28<2·6), all at month 3. The full analysis set for the primary analysis included all randomised patients who received at least one dose of study medication and had at least one post-baseline assessment. This trial is registered with www.ClinicalTrials.gov, number NCT00960440.
FINDINGS: At month 3, ACR20 response rates were 41·7% (55 of 132 [95% CI vs placebo 6·06-28·41]; p=0·0024) for tofacitinib 5 mg twice a day and 48·1% (64 of 133; [12·45-34·92]; p<0·0001) for tofacitinib 10 mg twice a day versus 24·4% (32 of 131) for placebo. Improvements from baseline in HAQ-DI were -0·43 ([-0·36 to -0·15]; p<0·0001) for 5 mg twice a day and -0·46 ([-0·38 to -0·17]; p<0·0001) for 10 mg twice a day tofacitinib versus -0·18 for placebo; DAS28<2·6 rates were 6·7% (eight of 119; [0-10·10]; p=0·0496) for 5 mg twice a day tofacitinib and 8·8% (11 of 125 [1·66-12·60]; p=0·0105) for 10 mg twice a day tofacitinib versus 1·7% (two of 120) for placebo. Safety was consistent with phase 2 and 3 studies. The most common adverse events in months 0-3 were diarrhoea (13 of 267; 4·9%), nasopharyngitis (11 of 267; 4·1%), headache (11 of 267; 4·1%), and urinary tract infection (eight of 267; 3·0%) across tofacitinib groups, and nausea (nine of 132; 6·8%) in the placebo group.
INTERPRETATION: In this treatment-refractory population, tofacitinib with methotrexate had rapid and clinically meaningful improvements in signs and symptoms of rheumatoid arthritis and physical function over 6 months with manageable safety. Tofacitinib could provide an effective treatment option in patients with an inadequate response to TNFi.
FUNDING: Pfizer.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23294500
Joel Kremer, Zhan-Guo Li, Stephen Hall, Roy Fleischmann, Mark Genovese, Emilio Martin-Mola, John D Isaacs, David Gruben, Gene Wallenstein, Sriram Krishnaswami, Samuel H Zwillich, Tamas Koncz, Richard Riese, John Bradley
Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial.
Ann Intern Med. 2013 Aug 20;159(4):253-61. doi: 10.7326/0003-4819-159-4-201308200-00006.
Abstract/Text BACKGROUND: Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA.
OBJECTIVE: To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs.
DESIGN: 1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544).
SETTING: 114 centers in 19 countries.
PATIENTS: 792 patients with active RA despite nonbiologic DMARD therapy.
INTERVENTION: Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily.
MEASUREMENTS: Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments.
RESULTS: Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups.
LIMITATIONS: Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited.
CONCLUSION: Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate.
PRIMARY FUNDING SOURCE: Pfizer.

PMID 24026258
医薬品インタビューフォーム:スマイラフ錠. アステラス製薬株式会社 2019.
Tsutomu Takeuchi, Yoshiya Tanaka, Satoshi Soen, Hisashi Yamanaka, Toshiyuki Yoneda, Sakae Tanaka, Takaya Nitta, Naoki Okubo, Harry K Genant, Désirée van der Heijde
Effects of the anti-RANKL antibody denosumab on joint structural damage in patients with rheumatoid arthritis treated with conventional synthetic disease-modifying antirheumatic drugs (DESIRABLE study): a randomised, double-blind, placebo-controlled phase 3 trial.
Ann Rheum Dis. 2019 Apr 29;. doi: 10.1136/annrheumdis-2018-214827. Epub 2019 Apr 29.
Abstract/Text OBJECTIVE: To evaluate the efficacy of denosumab in suppressing joint destruction when added to conventional synthetic disease-modifying antirheumatic drug (csDMARD) therapy in patients with rheumatoid arthritis (RA).
METHODS: This was a multi-centre, randomised, double-blind, parallel-group, placebo-controlled phase 3 study in Japan. Patients with RA aged ≥20 years receiving csDMARDs were randomly assigned (1:1:1) to denosumab 60 mg every 3 months (Q3M), denosumab 60 mg every 6 months (Q6M) or placebo. The change in the modified total Sharp score (mTSS) and effect on bone mineral density (BMD) at 12 months was evaluated.
RESULTS: In total, 654 patients received the trial drugs. Denosumab groups showed significantly less progression of joint destruction. The mean changes in the mTSS at 12 months were 1.49 (95% CI 0.99 to 1.99) in the placebo group, 0.99 (95% CI 0.49 to 1.49) in the Q6M group (p=0.0235) and 0.72 (95% CI 0.41 to 1.03) in the Q3M group (p=0.0055). The mean changes in bone erosion score were 0.98 (95% CI 0.65 to 1.31) in the placebo group, 0.51 (95% CI 0.22 to 0.80) in the Q6M group (p=0.0104) and 0.22 (95% CI 0.09 to 0.34) in the Q3M group (p=0.0001). No significant between-group difference was observed in the joint space narrowing score. The per cent change in lumbar spine (L1-L4) BMD in the placebo, Q6M and Q3M groups were -1.03%, 3.99% (p<0.0001) and 4.88% (p<0.0001). No major differences were observed among safety profiles.
CONCLUSIONS: Denosumab inhibits the progression of joint destruction, increases BMD and is well tolerated in patients with RA taking csDMARD.

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PMID 31036625
Takeshi Mochizuki, Koichiro Yano, Katsunori Ikari, Kosei Kawakami, Ryo Hiroshima, Naoko Koenuma, Mina Ishibashi, Shigeki Momohara
Effects of denosumab treatment on bone mineral density and joint destruction in patients with rheumatoid arthritis.
J Bone Miner Metab. 2018 Jul;36(4):431-438. doi: 10.1007/s00774-017-0848-1. Epub 2017 Jul 5.
Abstract/Text We aimed to investigate the efficacy of denosumab for rheumatoid arthritis (RA). This study enrolled 70 RA patients who received denosumab 60 mg subcutaneous injection at baseline and at 6 months. Bone mineral densities (BMD) of the lumbar spine, total hip, femoral neck, and hand were measured by dual energy X-ray absorptiometry. Changes in total modified Sharp score (mTSS), erosion (EN) score, and joint space narrowing score at baseline from 12 months before and at 12 months from baseline. The mean values of BMD of the lumbar spine, total hip, femoral neck, and hand significantly increased by 7.3, 4.7, 3.9, and 5.4%, respectively, at 12 months. At 12 months from baseline, there were significant decreases in the values of mTSS (1.13 vs. 0.59; p = 0.002) and EN score (0.40 vs. 0.07; p < 0.001), compared with the values at baseline from 12 months before. The existing combined modality therapy with denosumab might be effective for osteoporosis and joint destruction in patients with RA.

PMID 28681148
J R Kirwan
The effect of glucocorticoids on joint destruction in rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose Glucocorticoid Study Group.
N Engl J Med. 1995 Jul 20;333(3):142-6. doi: 10.1056/NEJM199507203330302.
Abstract/Text BACKGROUND: Oral glucocorticoids are widely used to treat patients with rheumatoid arthritis, but their effect on joint destruction, as assessed radiologically, is uncertain.
METHODS: We conducted a randomized, double-blind trial comparing oral prednisolone (7.5 mg daily for two years) with placebo in 128 adults with active rheumatoid arthritis of less than two years' duration. Except for systemic corticosteroids, other treatments could be prescribed. The primary outcome variables were the progression of damage as seen on radiographs of the hand after one and two years, as measured by the Larsen index, and the appearance of erosions in hands that had no erosions at base line. The radiographs were viewed jointly by a radiologist and a rheumatologist who were unaware of the treatment assignment and the time point at which the films were obtained.
RESULTS: The statistical analysis of radiologically detected changes was based on 106 patients for whom there were films obtained at base line and two years later. After two years, the Larsen scores increased by a mean of 0.72 unit in the prednisolone group, indicating very little change, and by 5.37 units in the placebo group, indicating substantial joint destruction (P = 0.004). Of the 212 hands of these patients, 147 (69.3 percent) had no erosions at the start of the study. At two years, 15 of the 68 such hands in the prednisolone group (22.1 percent) and 36 of the 79 such hands in the placebo group (45.6 percent) had acquired erosions (difference, 23.5 percentage points; 95 percent confidence interval, 5.9 to 40.7; P = 0.007). The patients in the prednisolone group had greater reductions than the patients in the placebo group in scores on an articular index and for pain and disability at 3 months; for pain at 6 months; and for disability at 6, 12, and 15 months (all P < 0.05). There was no difference between groups in standardized scores for the acute-phase response. The adverse events were typical of those encountered with antirheumatoid drugs.
CONCLUSIONS: In patients with early, active rheumatoid arthritis, prednisolone (7.5 mg daily) given for two years in addition to other treatments substantially reduced the rate of radiologically detected progression of disease.

PMID 7791815
Amalia A van Everdingen, Johannes W G Jacobs, Dirk R Siewertsz Van Reesema, Johannes W J Bijlsma
Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial.
Ann Intern Med. 2002 Jan 1;136(1):1-12.
Abstract/Text BACKGROUND: Oral glucocorticoids combined with disease-modifying antirheumatic drugs are beneficial and retard radiologic joint damage in rheumatoid arthritis.
OBJECTIVE: To investigate the clinical efficacy, disease-modifying properties, and side effects of low-dose glucocorticoids as monotherapy for previously untreated patients with early active rheumatoid arthritis.
DESIGN: 2-year randomized, double-blind, placebo-controlled clinical trial.
SETTING: 2 outpatient rheumatology clinics.
PATIENTS: 81 patients with early active rheumatoid arthritis who had not been treated with disease-modifying antirheumatic drugs.
INTERVENTION: 41 patients were assigned to 10 mg of oral prednisone per day, and 40 were assigned to placebo. Nonsteroidal anti-inflammatory drugs were allowed in both groups. After 6 months, sulfasalazine (2 g/d) could be prescribed as rescue medication.
MEASUREMENTS: Clinical variables were assessed at baseline and every 3 months; radiologic studies were performed every 6 months. Adverse effects were documented every 3 months.
RESULTS: In the first 6 months, the prednisone group showed more clinical improvement than the placebo group. This effect was not seen after 6 months except in grip strength and the 28-joint score for tenderness. Use of additional therapies was significantly less common in the prednisone group, particularly in the first 6 months. More than 65% of those who completed the study were not taking sulfasalazine. After month 6, radiologic scores showed significantly less progression in the prednisone group than in the placebo group. No clinically relevant adverse effects were observed, except for a higher incidence of osteoporotic fractures in the prednisone group.
CONCLUSIONS: Prednisone, 10 mg/d, provides clinical benefit, particularly in the first 6 months, and substantially inhibits progression of radiologic joint damage in patients with early active rheumatoid arthritis and no previous treatment with disease-modifying antirheumatic drugs. Because of their limited disease-modifying effects, glucocorticoids should be combined with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

PMID 11777359
T Pincus, C J Swearingen, G Luta, T Sokka
Efficacy of prednisone 1-4 mg/day in patients with rheumatoid arthritis: a randomised, double-blind, placebo controlled withdrawal clinical trial.
Ann Rheum Dis. 2009 Nov;68(11):1715-20. doi: 10.1136/ard.2008.095539. Epub 2008 Dec 15.
Abstract/Text OBJECTIVE: A randomised double-blind placebo controlled withdrawal clinical trial of prednisone versus placebo in patients with rheumatoid arthritis (RA), treated in usual clinical care with 1-4 mg/day prednisone, withdrawn to the same dose of 1 mg prednisone or identical placebo tablets.
METHODS: All patients were from one academic setting and all trial visits were conducted in usual clinical care. Patients were taking stable doses of 1-4 mg prednisone with stable clinical status, documented quantitatively by patient questionnaire scores. The protocol included three phases: (1) equivalence: 1-4 study prednisone 1 mg tablets taken for 12 weeks to ascertain their efficacy compared with the patient's usual tablets before randomisation; (2) transfer: substitution of a 1 mg prednisone or identical placebo tablet every 4 weeks (over 0-12 weeks) to the same number as baseline prednisone; (3) comparison: observation over 24 subsequent weeks taking the same number of either placebo or prednisone tablets as at baseline. The primary outcome was withdrawal due to patient-reported lack of efficacy versus continuation in the trial for 24 weeks.
RESULTS: Thirty-one patients were randomised, 15 to prednisone and 16 to placebo, with three administrative discontinuations. In "intent-to-treat" analyses, 3/15 prednisone and 11/16 placebo participants withdrew (p = 0.03). Among participants eligible for the primary outcome, 3/13 prednisone and 11/15 placebo participants withdrew for lack of efficacy (p = 0.02). No meaningful adverse events were reported, as anticipated.
CONCLUSION: Efficacy of 1-4 mg prednisone was documented. Evidence of statistically significant differences with only 31 patients may suggest a robust treatment effect.

PMID 19074913
K G Saag, R Koehnke, J R Caldwell, R Brasington, L F Burmeister, B Zimmerman, J A Kohler, D E Furst
Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events.
Am J Med. 1994 Feb;96(2):115-23.
Abstract/Text PURPOSE: The purpose of this study was to better define the toxicity of low dose (less than or equal to 15 mg/d prednisone or equivalent) long-term (greater than 1 year) corticosteroids in the treatment of rheumatoid arthritis (RA).
PATIENTS AND METHODS: We examined an historical cohort of 112 RA patients on low dose (6.1 +/- 3.1 mg/d, mean +/- SD) long-term (6.2 +/- 4.6 years) prednisone (CS) and compared them to 112 matched RA patients not using prednisone (CO). CS were matched one-to-one with CO for sex (75% women), age (+/- 5 yrs), race (98% white), and duration of disease (+/- 5 yrs). Subjects were determined by review of unselected medical records from three distinct rheumatology practice settings. For CS, charts were abstracted from the date of prednisone start for predefined adverse events (AEs).
RESULTS: Ninety-two (92) AEs were noted in CS versus 31 in CO and included: fracture (CS:21 versus CO:8), serious infections (CS:14 versus CO:4), gastrointestinal (GI) bleed or ulcer (CS:11 versus CO:4), and cataracts (CS:17 versus CO:5). At time of first AE, CS prednisone average dose was 7.0 +/- 2.6 mg with a duration of 4.9 +/- 3.9 years. Stepwise multiple logistic regression analysis was used to create a model which included all clinically relevant variables and all parameters significantly different at the cohort inception. Prednisone average dose of greater than 10 to less than or equal to 15 mg/d correlated most strongly with the development of an AE (Odds Ratio (OR) = 32.3, 95% Confidence Interval (CI) 4.6, 220). Average prednisone 5 to 10 mg (OR = 4.5, 95% CI 2.1, 9.6), RA nodules (OR = 3.9, 95% CI 1.9, 8.0), and bony erosions (OR = 2.4, 95% CI 1.2, 4.7) also entered the final model. Kaplan Meier survival curves for the development of the first AE showed a dose-response relationship between prednisone and AE occurrence, independent of rheumatoid nodules. Subset analyses utilized a nested case control design for the development of three serious AEs: fractures, serious infections, and GI events. These analyses revealed possible relationships between prednisone use and the development of each specific AE (prednisone use OR: fracture 3.9, 95% CI 0.8, 18.1; infection 8.0, 95% CI 1.0, 64.0; and GI event 3.3, 95% CI 0.9, 12.1).
CONCLUSIONS: Although disease severity is an important confounding factor, low dose long-term prednisone use equal to or greater than 5 mg/d is correlated with the development of specific adverse events in a dose-dependent fashion.

PMID 8109596
L M Buckley, E S Leib, K S Cartularo, P M Vacek, S M Cooper
Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. A randomized, double-blind, placebo-controlled trial.
Ann Intern Med. 1996 Dec 15;125(12):961-8.
Abstract/Text BACKGROUND: Therapy with low-dose corticosteroids is commonly used to treat allergic and autoimmune diseases. Long-term use of corticosteroids can lead to loss of bone mineral density and higher risk for vertebral fractures. Calcium and vitamin D3 supplementation is rational therapy for minimizing bone loss, but little evidence for its effectiveness exists.
OBJECTIVE: To assess 1) the effects of supplemental calcium and vitamin D3 on bone mineral density of patients with rheumatoid arthritis and 2) the relation between the effects of this supplementation and corticosteroid use.
DESIGN: 2-year randomized, double-blind, placebo-controlled trial.
SETTING: University outpatient-care facility.
PATIENTS: 96 patients with rheumatoid arthritis, 65 of whom were receiving treatment with corticosteroids (mean dosage, 5.6 mg/d).
INTERVENTION: Calcium carbonate (1000 mg/d) and vitamin D3 (500 IU/d) or placebo.
MEASUREMENTS: Bone mineral densities of the lumbar spine and femur were determined annually.
RESULTS: Patients receiving prednisone therapy who were given placebo lost bone mineral density in the lumbar spine and trochanter at a rate of 2.0% and 0.9% per year, respectively. Patients receiving prednisone therapy who were given calcium and vitamin D3 gained bone mineral density in the lumbar spine and trochanter at a rate of 0.72% (P = 0.005) and 0.85% (P = 0.024) per year, respectively. In patients receiving prednisone therapy, bone mineral densities of the femoral neck and the Ward triangle did not increase significantly with calcium and vitamin D3. Calcium and vitamin D3 did not improve bone mineral density at any site in patients who were not receiving corticosteroids.
CONCLUSION: Calcium and vitamin D3 prevented loss of bone mineral density in the lumbar spine and trochanter in patients with rheumatoid arthritis who were treated with low-dose corticosteroids.

PMID 8967706
T P van Staa, H G Leufkens, L Abenhaim, B Zhang, C Cooper
Oral corticosteroids and fracture risk: relationship to daily and cumulative doses.
Rheumatology (Oxford). 2000 Dec;39(12):1383-9.
Abstract/Text OBJECTIVE: This study examined the effects of daily and cumulative oral corticosteroid doses on the risk of fractures.
METHODS: Information was obtained from the General Practice Research Database, which contains medical records of general practitioners in England and Wales. The study included 244 235 oral corticosteroid users and 244 235 controls.
RESULTS: Patients taking higher doses (at least 7. 5 mg daily of prednisolone or equivalent) had significantly increased risks of non-vertebral fracture [relative rate (RR)=1.44, 95% confidence interval (CI) 1.34-1.54], hip fracture (RR=2.21, 95% CI 1.85-2.64) and vertebral fracture (RR=2.83, 95% CI 2.35-2.40) relative to patients using oral corticosteroids at lower doses (less than 2.5 mg per day). Fracture risk was also elevated among people with higher cumulative exposure to oral corticosteroids over the study period, but this effect was almost wholly removed by adjustment for daily dose, age, gender and other confounding variables.
CONCLUSIONS: These findings suggest that the adverse skeletal effects of oral corticosteroids manifest rapidly and are related to daily dose. The level of previous exposure to oral corticosteroids was not a strong determinant of the risk of fracture. Preventive measures against corticosteroid-induced osteoporosis should therefore be instituted as soon after the commencement of glucocorticoid therapy as possible.

PMID 11136882
P C Gotzsche, H K Johansen
Short-term low-dose corticosteroids vs placebo and nonsteroidal antiinflammatory drugs in rheumatoid arthritis.
Cochrane Database Syst Rev. 2004;(3):CD000189. doi: 10.1002/14651858.CD000189.pub2.
Abstract/Text BACKGROUND: The effect of low dose corticosteroids, equivalent to 15 mg prednisolone daily or less, in patients with rheumatoid arthritis has been questioned. We performed a systematic review of trials which compared corticosteroids with placebo or non-steroidal, anti-inflammatory drugs.
OBJECTIVES: To determine whether short-term (i.e. as recorded within the first month of therapy), oral low-dose corticosteroids (corresponding to a maximum of 15 mg prednisolone daily) is superior to placebo and non-steroidal, anti-inflammatory drugs in patients with rheumatoid arthritis.
SEARCH STRATEGY: PubMed, The Cochrane Central Register of Controlled Trials (CENTRAL ), reference lists were searched until February 2004.
SELECTION CRITERIA: All randomised studies comparing an oral corticosteroid (not exceeding an equivalent of 15 mg prednisolone daily) with placebo or a non-steroidal, anti-inflammatory drug were eligible if they reported clinical outcomes within one month after start of therapy. For adverse effects, long-term trials and matched cohort studies were also selected.
DATA COLLECTION AND ANALYSIS: Decisions on which trials to include were made independently by two observers based on the methods sections of the trials. Standardised mean difference (random effects model) was used for the statistical analyses.
MAIN RESULTS: Ten studies, involving 320 patients, were included. Prednisolone had a marked effect over placebo on joint tenderness (standardised mean difference 1.30, 95% confidence interval 0.78 to 1.83), pain (1.75, 0.87 to 2.64) and grip strength (0.41, 0.13 to 0.69). Measured in the original units, the differences were 12 tender joints (6 to 18) and 22 mm Hg (5 to 40) for grip strength. Prednisolone also had a greater effect than non-steroidal, anti-inflammatory drugs on joint tenderness (0.63, 0.11 to 1.16) and pain (1.25, 0.26 to 2.24), whereas the difference in grip strength was not significant (0.31, -0.02 to 0.64). Measured in the original units, the differences were 9 tender joints (5 to 12) and 12 mm Hg (-6 to 31). The risk of adverse effects, also during moderate- and long-term use, seemed acceptable.
REVIEWERS' CONCLUSIONS: Prednisolone in low doses (not exceeding 15 mg daily) may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means. Since prednisolone is highly effective, short-term placebo controlled trials studying the clinical effect of low-dose prednisolone or other oral corticosteroids are no longer necessary.

PMID 15266426
市川陽一: 全身性エリテマトーデスの予後因子と治療. 日本医事新報1987; 3322: 3-11 .
K G Saag, R Emkey, T J Schnitzer, J P Brown, F Hawkins, S Goemaere, G Thamsborg, U A Liberman, P D Delmas, M P Malice, M Czachur, A G Daifotis
Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group.
N Engl J Med. 1998 Jul 30;339(5):292-9. doi: 10.1056/NEJM199807303390502.
Abstract/Text BACKGROUND: Osteoporosis is a common complication of long-term glucocorticoid therapy for which there is no well-proved preventive or restorative treatment.
METHODS: We carried out two 48-week, randomized, placebo-controlled studies of two doses of alendronate in 477 men and women, 17 to 83 years of age, who were receiving glucocorticoid therapy. The primary end point was the difference in the mean percent change in lumbar-spine bone density from base line to week 48 between the groups. Secondary outcomes included changes in bone density of the hip, biochemical markers of bone turnover, and the incidence of new vertebral fractures.
RESULTS: The mean (+/-SE) bone density of the lumbar spine increased by 2.1+/-0.3 percent and 2.9+/-0.3 percent, respectively, in the groups that received 5 and 10 mg of alendronate per day (P<0.001) and decreased by 0.4+/-0.3 percent in the placebo group. The femoral-neck bone density increased by 1.2+/-0.4 percent and 1.0+/-0.4 percent in the respective alendronate groups (P<0.01) and decreased by 1.2+/-0.4 percent in the placebo group (P<0.01). The bone density of the trochanter and total body also increased significantly in the patients treated with alendronate. There were proportionally fewer new vertebral fractures in the alendronate groups (overall incidence, 2.3 percent) than in the placebo group (3.7 percent) (relative risk, 0.6; 95 percent confidence interval, 0.1 to 4.4). Markers of bone turnover decreased significantly in the alendronate groups (P<0.001). There were no differences in serious adverse effects among the three groups, but there was a small increase in nonserious upper gastrointestinal effects in the group receiving 10 mg of alendronate.
CONCLUSIONS: Alendronate increases bone density in patients receiving glucocorticoid therapy.

PMID 9682041
J D Adachi, K G Saag, P D Delmas, U A Liberman, R D Emkey, E Seeman, N E Lane, J M Kaufman, P E Poubelle, F Hawkins, R Correa-Rotter, C J Menkes, J A Rodriguez-Portales, T J Schnitzer, J A Block, J Wing, H H McIlwain, R Westhovens, J Brown, J A Melo-Gomes, B L Gruber, M J Yanover, M O Leite, K G Siminoski, M C Nevitt, J T Sharp, M P Malice, T Dumortier, M Czachur, W Carofano, A Daifotis
Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, double-blind, placebo-controlled extension trial.
Arthritis Rheum. 2001 Jan;44(1):202-11. doi: 10.1002/1529-0131(200101)44:1<202::AID-ANR27>3.0.CO;2-W.
Abstract/Text OBJECTIVE: To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids.
METHODS: This is a 12-month extension of a previously completed 1-year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence.
RESULTS: The mean (+/-SEM) lumbar spine BMD increased by 2.8 +/- 0.6%, 3.9 +/- 0.7%, and 3.7 +/- 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P < or = 0.001) and decreased by -0.8 +/- 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P < or = 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P < or = 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P < or = 0.05). Bone turnover markers (N-telopeptides of type I collagen and bone-specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P < or = 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups.
CONCLUSION: Alendronate is an effective, well-tolerated therapy for the prevention and treatment of glucocorticoid-induced osteoporosis, with sustained treatment advantages for up to 2 years.

PMID 11212161
S Cohen, R M Levy, M Keller, E Boling, R D Emkey, M Greenwald, T M Zizic, S Wallach, K L Sewell, B P Lukert, D W Axelrod, A A Chines
Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.
Arthritis Rheum. 1999 Nov;42(11):2309-18. doi: 10.1002/1529-0131(199911)42:11<2309::AID-ANR8>3.0.CO;2-K.
Abstract/Text OBJECTIVE: Risedronate, a new pyridinyl bisphosphonate, is a potent antiresorptive bone agent. This study examines the safety and efficacy of daily, oral risedronate therapy for the prevention of corticosteroid-induced bone loss.
METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 224 men and women who were initiating long-term corticosteroid treatment. Patients received either risedronate (2.5 mg or 5 mg) or placebo daily for 12 months. Each patient also received 500 mg of elemental calcium daily. The primary outcome measure was the percentage of change in lumbar spine bone mineral density (BMD). Secondary measures included proximal femur BMD and incidence of vertebral fractures.
RESULTS: After 12 months, the lumbar spine BMD (mean +/- SEM) did not change significantly compared with baseline in the 5-mg (0.6 +/- 0.5%) or the 2.5-mg (-0.1 +/- 0.7%) risedronate groups, while it decreased in the placebo group (-2.8 +/- 0.5%; P < 0.05). The mean differences in BMD between the 5-mg risedronate and the placebo groups were 3.8 +/- 0.8% at the lumbar spine (P < 0.001), 4.1 +/- 1.0% at the femoral neck (P < 0.001), and 4.6 +/- 0.8% at the femoral trochanter (P < 0.001). A trend toward a decrease in the incidence of vertebral fracture was observed in the 5-mg risedronate group compared with the placebo group (5.7% versus 17.3%; P = 0.072). Risedronate was well tolerated, and the incidence of upper gastrointestinal adverse events was comparable among the 3 groups.
CONCLUSION: Risedronate therapy prevents bone loss in patients initiating long-term corticosteroid treatment.

PMID 10555025
M Wallen, D Gillies
Intra-articular steroids and splints/rest for children with juvenile idiopathic arthritis and adults with rheumatoid arthritis.
Cochrane Database Syst Rev. 2006 Jan 25;(1):CD002824. doi: 10.1002/14651858.CD002824.pub2. Epub 2006 Jan 25.
Abstract/Text BACKGROUND: Resting or immobilizing a joint to enhance outcomes following intra-articular (IA) steroid injection is generally advocated. This systematic review aimed to determine the efficacy of IA steroid injections and the influence of post-injection rest.
OBJECTIVES: 1. Compare IA steroid injections versus no treatment or placebo. 2. Determine the effects of rest following IA steroid injection in rheumatoid or juvenile idiopathic arthritis.
SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL- Issue 4, 2003), Cochrane Database of Systematic Reviews (CDSR - Issue 4, 2003), Database of Abstracts of Reviews of Effectiveness (DARE - searched 8.1.04), MEDLINE (1966 to August Week 2 2004), EMBASE (1980 to August Week 2 2004) , CINAHL (1982 to December Week 2 2003), Clinical Trials site of the National Institute of Health, (USA - searched 8.1.04), OTseeker (Occupational Therapy Systematic Evaluation of Evidence - searched 8.1.04) and PEDro (Physiotherapy Evidence Database - searched 8.1.04) were searched. Journals and reference lists were hand searched.
SELECTION CRITERIA: Eligible were randomised controlled trials of IA steroid injections or of rest following IA steroid injections in rheumatoid or juvenile idiopathic arthritis.
DATA COLLECTION AND ANALYSIS: Potentially relevant references were evaluated and all data extracted by two independent reviewers.
MAIN RESULTS: Five trials (n=346) examining IA steroid injection in the knee joint were included. It was not possible to pool data as outcome measures, timing of follow up and the methods of data reporting differed between trials. There was inconclusive conflicting evidence from two trials that walking time was reduced. There was evidence from one moderate quality trial that pain was reduced at 1-day post-injection (0-100 VAS from 28.33 to 13.46; McGill Pain Scale from 8.89 to 3.96) but not at 1 week or 7-12 weeks post-injection. There is some evidence that IA injections improved knee flexion (by 14 degrees) and reduced knee extension lag (by 20 degrees), knee circumference (median reduction = 0.3 cm) and morning stiffness (reduced from 60 mins to 7.6 mins). One trial (n=91) examined the effects of rest following injection in the knee. The rested group achieved significant improvement in pain, stiffness, knee circumference, and walking time when compared with the non-rested group (no point estimates provided). One trial evaluated rest following injection of the wrist (n=117). Relapse rate was higher in the rested group (rest relapse rate = 24/58, no-rest group = 14/59); but there were no differences between the rested and non-rested groups on pain, joint circumference, wrist function, grip strength or ROM.
AUTHORS' CONCLUSIONS: There is some evidence to support the use of IA steroid injections and resting a knee following injections but that wrists should not be rested following injections. The included studies involved adult participants so any conclusions can only cautiously applied to children. Further research is required to examine the use and type of rest and the differential responses of different joints following injections.

PMID 16437446
Merete Lund Hetland, Kristian Stengaard-Pedersen, Peter Junker, Tine Lottenburger, Torkell Ellingsen, Lis Smedegaard Andersen, Ib Hansen, Henrik Skjødt, Jens Kristian Pedersen, Ulrik Birk Lauridsen, Anders Svendsen, Ulrik Tarp, Jan Pødenphant, Gert Hansen, Hanne Lindegaard, Anselmo de Carvalho, Mikkel Østergaard, Kim Hørslev-Petersen, CIMESTRA Study Group
Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: an investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study.
Arthritis Rheum. 2006 May;54(5):1401-9. doi: 10.1002/art.21796.
Abstract/Text OBJECTIVE: To investigate whether disease control can be achieved in early active rheumatoid arthritis (RA) by treatment with methotrexate and intraarticular betamethasone, and whether the addition of cyclosporine to the regimen has any additional effect.
METHODS: Patients (n = 160) were randomized to receive methotrexate 7.5 mg/week plus cyclosporine 2.5 mg/kg of body weight/day (combination therapy) or methotrexate plus placebo-cyclosporine (monotherapy). At weeks 0, 2, 4, 6, and 8 and every 4 weeks thereafter, betamethasone was injected into swollen joints (maximum 4 joints or 4 ml per visit). Beginning at week 8, if synovitis was present, the methotrexate dosage was increased stepwise up to 20 mg/week, with a subsequent stepwise increase in the cyclosporine or placebo-cyclosporine dosage up to 4 mg/kg.
RESULTS: At 52 weeks, 20% improvement according to the American College of Rheumatology criteria (ACR20) was achieved in 85% of the combination therapy group versus 68% of the monotherapy group (P = 0.02). The median individual overall ACR response (ACR-N) in the 2 groups was 80.0% (interquartile range 40.1-91.8%) and 54.5% (interquartile range 2.4-87.8%), respectively (P = 0.025). At 48 and 52 weeks, ACR remission criteria were met in 35% of the combination therapy group and 28% of the monotherapy group. Progression in the Larsen score at 52 weeks was -0.2 +/- 6.5 and 0.4 +/- 6.9 (mean +/- SD) in the combination therapy and monotherapy groups, respectively. Serum creatinine levels increased by 7%, and hypertrichosis was more prevalent, in the combination therapy group.
CONCLUSION: Combined treatment with methotrexate and intraarticular glucocorticoid showed excellent disease control and stopped the progression of erosions in patients with early active RA, who had a poor prognosis. Addition of cyclosporine improved the ACR20 and ACR-N responses, whereas the ACR50 and ACR70 responses, remission rates, and radiographic changes did not differ between the 2 study groups.

PMID 16645967
Kim Hørslev-Petersen, Merete Lund Hetland, Peter Junker, Jan Pødenphant, Torkell Ellingsen, Palle Ahlquist, Hanne Lindegaard, Asta Linauskas, Annette Schlemmer, Mette Yde Dam, Ib Hansen, Hans Christian Horn, Christian Gytz Ammitzbøll, Anette Jørgensen, Sophine B Krintel, Johnny Raun, Julia S Johansen, Mikkel Østergaard, Kristian Stengaard-Pedersen, OPERA Study-Group
Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial.
Ann Rheum Dis. 2014 Apr;73(4):654-61. doi: 10.1136/annrheumdis-2012-202735. Epub 2013 Feb 23.
Abstract/Text OBJECTIVES: An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP<3.2) at 12 months.
METHODS: In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (<6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6-9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP<3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward.
RESULTS: Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP<3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7-5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7-4.7) (p=0.009). Remission rates were: DAS28CRP<2.6: 74%/49%, Clinical Disease Activity Index≤2.8: 61%/41%, Simplified Disease Activity Index<3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008CONCLUSIONS: Adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment did not increase the proportion of patients who reached the DAS28CRP<3.2 treatment target, but improved DAS28CRP, remission rates, function and quality of life in DMARD-naïve ERA.

PMID 23434570
T Wienecke, P C Gøtzsche
Paracetamol versus nonsteroidal anti-inflammatory drugs for rheumatoid arthritis.
Cochrane Database Syst Rev. 2004;(1):CD003789. doi: 10.1002/14651858.CD003789.pub2.
Abstract/Text BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) are usually preferred for simple analgesics such as paracetamol for rheumatoid arthritis. It is not clear, however, whether the trade-offs between benefits and harms of NSAIDs are preferable to those of paracetamol (paracetamol is also called acetaminophen).
OBJECTIVES: To compare the benefits and harms of paracetamol with NSAIDs in patients with rheumatoid arthritis.
SEARCH STRATEGY: Medline Silverplatter, Embase databases were searched up until Sept 2002. Reference lists of identified articles were also searched.
SELECTION CRITERIA: Randomised double-blind studies comparing paracetamol with an NSAID.
DATA COLLECTION AND ANALYSIS: Decisions on inclusion of trials and data extraction were performed by the two authors independently.
MAIN RESULTS: Four cross-over studies, published between 1968 and 1982, involving 121 patients, and four different NSAIDs were included. The generation of the allocation sequence and the use of methods to conceal the allocation were not described in any of the studies. The studies were double-blind but it was not clear whether the blinding was effective. Methods for collecting adverse effects were not described. The NSAIDs were preferred more often than paracetamol by the patients or the investigator. In the largest trial, 20 out of 54 patients (37%) preferred ibuprofen and 7 out of 54 (13%) paracetamol. Investigators preference (as established by joint tenderness, grip strength and joint circumference) was 17 out of 35 for diclofenac versus 5 out of 35 for paracetamol in another trial. However, because of the weaknessess in the trials, no firm conclusion can be drawn.
REVIEWER'S CONCLUSIONS: When considering the trade off between the benefits and harms of non-steroidal anti-inflammatory drugs and paracetamol/acetaminophen, it is not known whether one is better than the other for rheumatoid arthritis. But people with rheumatoid arthritis and the researchers in the study did prefer non-steroidal anti-inflammatory drugs more than acetaminophen/paracetamol. There is a need for a large trial, with appropriate randomisation, double-blinding, test of the success of the blinding, and with explicit methods to measure and analyse pain and adverse effects.

PMID 14974037
Alexandra N Colebatch, Jonathan L Marks, Christopher J Edwards
Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis).
Cochrane Database Syst Rev. 2011 Nov 9;(11):CD008872. doi: 10.1002/14651858.CD008872.pub2. Epub 2011 Nov 9.
Abstract/Text BACKGROUND: Methotrexate is routinely used in the treatment of inflammatory arthritis. There have been concerns regarding the safety of using concurrent non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, or paracetamol (acetaminophen), or both, in these people.
OBJECTIVES: To systematically appraise and summarise the scientific evidence on the safety of using NSAIDs, including aspirin, or paracetamol, or both, with methotrexate in inflammatory arthritis; and to identify gaps in the current evidence, assess the implications of those gaps and to make recommendations for future research to address these deficiencies.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, second quarter 2010); MEDLINE (from 1950); EMBASE (from 1980); the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE). We also handsearched the conference proceedings for the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) (2008 to 2009) and checked the websites of regulatory agencies for reported adverse events, labels and warnings.
SELECTION CRITERIA: Randomised controlled trials and non-randomised studies comparing the safety of methotrexate alone to methotrexate with concurrent NSAIDs, including aspirin, or paracetamol, or both, in people with inflammatory arthritis.
DATA COLLECTION AND ANALYSIS: Two authors independently assessed the search results, extracted data and assessed the risk of bias of the included studies.
MAIN RESULTS: Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis using various NSAIDs, including aspirin. There were no identified studies for other forms of inflammatory arthritis.For NSAIDs, 13 studies were included that used concurrent NSAIDs, of which nine studies examined unspecified NSAIDs. The mean number of participants was 150.4 (range 19 to 315), mean duration 2182.9 (range 183 to 5490) days, although the study duration was not always clearly defined, and the studies were mainly of low to moderate quality. Two of these studies reported no evidence for increased risk of methotrexate-induced pulmonary disease; one study assessed the effect of concurrent NSAIDs on renal function and found no adverse effect; one study identified no adverse effect on liver function; three studies demonstrated no increase in methotrexate withdrawal; and one study showed no increase in all adverse events, including major toxic reactions. However, transient thrombocytopenia was demonstrated in one study, specifically when NSAIDs were taken on the same week day as methotrexate. This study was a retrospective review that involved small numbers only and was of moderate quality; these finding have not been replicated since.Four studies looked at specific NSAIDs (etodolac, piroxicam, celecoxib and etoricoxib), with a mean number of participants of 25.8 (range 14 to 50) and mean study duration of 16.8 (range 14 to 23) days. These studies were mainly of moderate quality. The studies were primarily pharmacokinetic studies but also reported adverse events as secondary outcomes. There were no clinically significant adverse effects with concomitant piroxicam or etodolac; and only mild adverse events with celecoxib or etoricoxib, such as nausea and vomiting, and headaches.For aspirin, seven studies provided data on adverse events with the use of aspirin and methotrexate. These studies included a mean number of participants of 100 (range 11 to 232), had a mean duration of 1325 (range 8 to 2928) days and were mainly of low to moderate quality. Two of the studies reported no evidence for increased risk of methotrexate-induced pulmonary disease and two studies showed no increase in all adverse events including major toxic reactions; however, none of these studies specified the dose of aspirin that was used. One study demonstrated that concurrent aspirin adversely affected liver function at a mean dose of 6.84 tablets of aspirin per day, which is a possible daily dose of 2.1 g presuming that 300 mg aspirin tablets were given. A further study described a partially reversible decline in renal function with 2 g daily of aspirin. One study reported no increase in adverse events with 975 g aspirin daily, however the study duration was only one week.For paracetamol, no studies were identified for inclusion.
AUTHORS' CONCLUSIONS: In the management of rheumatoid arthritis, the concurrent use of NSAIDs with methotrexate appears to be safe provided appropriate monitoring is performed. The use of anti-inflammatory doses of aspirin should be avoided.

PMID 22071858
Choitsu Sakamoto, Satoshi Soen
Efficacy and safety of the selective cyclooxygenase-2 inhibitor celecoxib in the treatment of rheumatoid arthritis and osteoarthritis in Japan.
Digestion. 2011;83(1-2):108-23. doi: 10.1159/000318746. Epub 2010 Nov 1.
Abstract/Text BACKGROUND/AIMS: Gastrointestinal (GI) disorders are common adverse reactions of nonsteroidal anti-inflammatory drugs (NSAIDs). Loxoprofen is a representative NSAID widely used in East Asia. A selective cyclooxygenase-2 inhibitor, celecoxib, was introduced in Japan in 2007. In this study, we aimed to compare the efficacy and safety of celecoxib with those of loxoprofen in Japanese patients.
METHODS: We analyzed the data from 12 clinical studies conducted in Japan. These data of Japanese patients were compared with those of the patients in the West that had been published after 2000.
RESULTS: The efficacy of celecoxib as an analgesic was comparable to that of loxoprofen, whereas serious GI events, including symptomatic ulcers, were significantly less frequent with celecoxib than with loxoprofen in Japanese patients with rheumatoid arthritis (RA) and osteoarthritis (OA) (p = 0.039). These results were consistent with the findings of the studies conducted in the West. The incidence of serious cardiovascular events was 0.1% in 2,398 subjects on celecoxib, which was not statistically different from the incidence in subjects on loxoprofen (0.3%; p = 0.3404) and those on placebo (0.2%); this result was also consistent with the data of the studies conducted in the West.
CONCLUSION: The analgesic activity of celecoxib, which was used for the treatment of RA, OA, and low back pain, was comparable to that of loxoprofen, and celecoxib was safer in terms of GI injury often caused by other nonselective NSAIDs.

Copyright © 2010 S. Karger AG, Basel.
PMID 21042022
Scott D Solomon, Marc A Pfeffer, John J V McMurray, Rob Fowler, Peter Finn, Bernard Levin, Craig Eagle, Ernest Hawk, Mariajosé Lechuga, Ann G Zauber, Monica M Bertagnolli, Nadir Arber, Janet Wittes, APC and PreSAP Trial Investigators
Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas.
Circulation. 2006 Sep 5;114(10):1028-35. doi: 10.1161/CIRCULATIONAHA.106.636746.
Abstract/Text BACKGROUND: Cyclooxygenase-2 (COX-2) inhibitors have been shown to reduce colorectal adenomas but have been associated with increased cardiovascular risk.
METHODS AND RESULTS: The Adenoma Prevention With Celecoxib (APC) trial studied celecoxib 200 mg twice daily and 400 mg twice daily and the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial used 400 mg once daily totest the efficacy and safety of celecoxib against placebo in reducing colorectal adenoma recurrence after polypectomy. An independent safety committee for both studies adjudicated and categorized serious cardiovascular events and then combined individual patient data from these long-term trials to improve the estimate of the cardiovascular risk and blood pressure changes associated with celecoxib compared with placebo. For adjudicated cardiovascular events, 77% and 54% in APC and PreSAP, respectively, had 37 months of follow-up. For APC and PreSAP combined, 83 patients experienced cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure. The hazard ratio for this prespecified composite end point was 2.6 (95% confidence interval [CI], 1.1 to 6.1) in patients taking 200 mg twice daily, 3.4 (95% CI, 1.5 to 7.9) in patients taking 400 mg twice daily in APC, and 1.3 (95% CI, 0.6 to 2.6) in patients taking 400 mg once daily in PreSAP (P for heterogeneity = 0.13 comparing the combined doses in APC with the dose in PreSAP). The overall hazard ratio for this composite end point was 1.9 (95% CI, 1.1 to 3.1). Both dose groups in APC showed significant systolic blood pressure elevations at 1 and 3 years (200 mg twice daily: 1 year, 2.0 mm Hg; 3 years,2.6 mm Hg; 400 mg twice daily: 1 year, 2.9 mm Hg; 3 years, 5.2 mm Hg); however, the 400 mg once daily group inPreSAP did not (P0.0001 between studies).
CONCLUSIONS: Celecoxib at 200 or 400 mg twice daily or 400 mg once daily showed a nearly 2-fold-increased cardiovascular risk. The trend for a dose-related increase in cardiovascular events and blood pressure raises the possibility that lower doses or other dose intervals may be associated with less cardiovascular risk.

PMID 16943394
L M March, A L Barcenilla, M J Cross, H M Lapsley, D Parker, P M Brooks
Costs and outcomes of total hip and knee joint replacement for rheumatoid arthritis.
Clin Rheumatol. 2008 Oct;27(10):1235-42. doi: 10.1007/s10067-008-0891-3. Epub 2008 May 24.
Abstract/Text The objective of the study was to ascertain costs and outcomes of total joint replacement surgery for rheumatoid arthritis (RA) in Australia from the patients' perspective and to explore whether costs were affected by health status pre- or postsurgery. RA patients, scheduled for primary unilateral total knee replacement (TKR) or total hip replacement (THR) surgery at five Sydney hospitals, were approached. Preoperatively, patients retrospectively recorded expenses incurred over the previous 3 months and the health assessment questionnaire (HAQ). Postoperatively, patients completed detailed prospective cost diaries, short form (SF) 36, and HAQ every 3 months during the first postoperative year. In addition, patients were asked to complete a visual analogue measure for pain at 12 months postsurgery. Arthritis-specific cost information included prescription and nonprescription medication, visits to health professionals, tests, special equipment, alterations to the house, and use of private or community services. Thirty-one TKR and 11 THR patients provided cost data for the first postoperative year. Out-of-pocket costs and service utilization decreased over the first postoperative year for both TKR and THR patients. In addition, there was an improvement in the health status as measured by SF-36 but not the HAQ at 3 and 12 months postoperatively. The small sample size of this analysis is reflective of the current national trends of RA joint replacement surgery. Despite the low incidence of RA joint replacement surgery, it was substantiated that patients consider the positive impact on health outcomes and costs important. The generic SF-36 detected improvements in the health status of these RA patients, while total HAQ scores failed to do so. HAQ was found to be insensitive in reflecting improvements following lower limb replacement surgery. Patient out-of-pocket costs significantly decreased postoperatively; however, these costs remain substantial compared to osteoarthritis total joint replacement patients.

PMID 18500442
H Osnes-Ringen, T K Kvien, J E Henriksen, P Mowinckel, H Dagfinrud
Orthopaedic surgery in 255 patients with inflammatory arthropathies: longitudinal effects on pain, physical function and health-related quality of life.
Ann Rheum Dis. 2009 Oct;68(10):1596-601. doi: 10.1136/ard.2008.096362. Epub 2008 Oct 24.
Abstract/Text OBJECTIVE: To examine the effectiveness of orthopaedic surgery in patients with inflammatory arthropathies with regard to longitudinal changes in pain, physical function and health-related quality of life and explore differences in effectiveness between replacement versus non-replacement surgery and surgery in the upper versus the lower limb.
METHODS: 255 patients (mean age 57.5 years (SD 13.1), 76.7% female) with inflammatory arthropathies underwent orthopaedic surgical treatment and responded to mail surveys at baseline and during follow-up (3, 6, 9 and 12 months). The booklet of questionnaires included the arthritis impact measurement scales 2 (AIMS2), health assessment questionnaire (HAQ), short form 36 (SF-36), EQ-5D and visual analogue scales (VAS) addressing patient global, fatigue, general pain and pain in the actual joint. Standardised response means (SRM) were calculated to estimate the magnitude of improvement.
RESULTS: Significant improvement was seen for most of the dimensions of health, the largest improvement for pain in the actual joint (SRM 1.17) at one year follow-up. SRM for AIMS-2 physical, SF-36 physical and HAQ were 0.1, 0.48 and 0.05, respectively. The overall numeric improvement (SRM) in utility was 0.10 (0.37) with EQ-5D and 0.03 (0.27) with SF-6D. Improvement overall was similar after surgery in the upper versus the lower limb, but was larger in patients undergoing replacement surgery than in patients undergoing other surgical procedures (SRM 1.54 vs 1.08 for pain in the actual joint).
CONCLUSIONS: Surgical procedures have a major positive impact on pain in the actual joint, but improvement is less in other dimensions of health. Health benefits were larger after replacement surgery than after other surgical procedures.

PMID 18952639
Koichiro Yano, Katsunori Ikari, Eisuke Inoue, Asami Tokita, Yu Sakuma, Ryo Hiroshima, Takuji Iwamoto, Kosei Kawakami, Atsuo Taniguchi, Hisashi Yamanaka, Shigeki Momohara
Effect of total knee arthroplasty on disease activity in patients with established rheumatoid arthritis: 3-year follow-up results of combined medical therapy and surgical intervention.
Mod Rheumatol. 2010 Oct;20(5):452-7. doi: 10.1007/s10165-010-0309-3. Epub 2010 May 19.
Abstract/Text Though excellent clinical results have been reported for total knee arthroplasty (TKA) in rheumatoid arthritis (RA) patients, the medium-term effect of TKA on RA disease activity remains unknown. This analysis aimed to assess changes in disease activity after TKA in patients with established RA. We analyzed the systemic effects of TKA on RA disease activity 3 years after intervention. Routine clinical and laboratory assessments were recorded at baseline, less than less than 0.5 years after TKA, and 3 years after TKA. Of the registered RA patients, 130 TKA patients were followed for 3 years after surgery. RA disease activity was measured using the Disease Activity Score 28 (DAS28). Patients were divided into three groups by preoperative baseline DAS28: low (DAS28 ≤ 3.2, n = 8), moderate (DAS28 > 3.2 but ≤5.1, n = 68), and high (DAS28 > 5.1, n = 54) disease activity. The postoperative DAS28 (<0.5 years [DAS1] and 3 years [DAS3] after surgery) scores of each patient were compared to their baseline (DAS0) scores using the paired t-test. The mean DAS28 decreased from 4.85 (DAS0) to 4.14 (DAS1; P = 1.07E-12), and this decrease was sustained at 3 years (DAS3 = 3.97; P = 4.73E-15). Subanalysis results revealed a systemic effect of TKA on disease activity in patients with moderate or high disease activity (DAS0 = 4.33; DAS1 = 3.72 [P = 5.94E-06]; DAS3 = 3.81 [P = 7.89E-06]; and DAS0 = 5.79; DAS1 = 4.86 [P = 1.14E-08]; DAS3 = 4.37 [P = 1.03E-11], respectively). While no significant changes in medication were noted, the average dose of prednisolone tended to decrease over time. We conclude that TKA, which is known to result in good clinical outcomes for damaged knees, has a secondary systemic effect on RA disease activity. Combination therapy consisting of medical treatment and surgical intervention is thought to effectively improve the condition of RA patients who have destructive arthritis in the knee joint, with the effect lasting for at least 3 years.

PMID 20490599
Shigeki Momohara, Eisuke Inoue, Katsunori Ikari, Koichiro Yano, Asami Tokita, Taku Suzuki, Yu Sakuma, Ryo Hiroshima, Kosei Kawakami, Ikuko Masuda, Takuji Iwamoto, Atsuo Taniguchi, Hisashi Yamanaka
Efficacy of total joint arthroplasty in patients with established rheumatoid arthritis: improved longitudinal effects on disease activity but not on health-related quality of life.
Mod Rheumatol. 2011 Oct;21(5):476-81. doi: 10.1007/s10165-011-0432-9. Epub 2011 Mar 4.
Abstract/Text Though excellent clinical results have been reported for total joint arthroplasty (TJA) in rheumatoid arthritis (RA) patients, the longitudinal effects of TJA on pain, physical function, and health-related quality of life in RA patients remain unknown. This study aimed to assess changes in disease activity and health-related quality of life after TJA in patients with established RA. We analyzed the effect of total knee arthroplasty (TKA) and total hip arthroplasty (THA) on RA disease activity in an observational cohort of RA patients. Of the registered RA patients, 333 TKA and 77 THA patients were followed for 5 years after surgery. RA disease activity and health-related quality of life were measured using the Disease Activity Score 28 (DAS28) and a Japanese version of the Stanford health assessment questionnaire (J-HAQ). The mean DAS28 in TKA patients decreased from 4.66 (preoperatively) to 4.02 (3 years postoperatively) and to 3.94 (5 years postoperatively); the mean DAS28 in THA patients decreased from 4.41 (preoperatively) to 3.99 (3 years postoperatively) and to 3.92 (5 years postoperatively). The mean J-HAQ for TKA remained essentially unchanged, ranging from 1.48 (preoperatively) to 1.45 (3 years postoperatively) and to 1.47 (5 years postoperatively); the mean J-HAQ for THA also remained unchanged, ranging from 1.74 (preoperatively) to 1.74 (3 years postoperatively) and to 1.73 (5 years postoperatively). Of the total J-HAQ score, the lower limb score improved while the upper limb score worsened. Although TKA and THA improve clinical outcomes in damaged knees and hips and have a positive secondary systemic effect on RA disease activity, they have not had a continuously good effect on the measures of health-related quality of life. We conclude that tight control of RA disease activity is indicated for those patients with TKA and/or THA.

PMID 21373798
Masatoshi Hayashi, Toshihisa Kojima, Koji Funahashi, Daizo Kato, Hiroyuki Matsubara, Tomone Shioura, Yasuhide Kanayama, Yuji Hirano, Naoki Ishiguro
Effect of total arthroplasty combined with anti-tumor necrosis factor agents in attenuating systemic disease activity in patients with rheumatoid arthritis.
Mod Rheumatol. 2012 Jun;22(3):363-9. doi: 10.1007/s10165-011-0527-3. Epub 2011 Oct 7.
Abstract/Text We assessed the effect of total large-joint arthroplasty combined with anti-tumor necrosis factor (TNF) therapy for rheumatoid arthritis (RA). We studied 45 RA patients (age 57.91 ± 12.74 years, RA duration 13.43 ± 8.28 years) who underwent total arthroplasty (35 knees, 19 hips, 3 elbows, and 1 ankle) between August 2002 and November 2009. All patients received anti-TNF agents (infliximab, 22; etanercept, 33; adalimumab, 3) during the period of the study (that is, they were being treated with the agents when operated on and postoperatively). The disease activity score 28 (DAS28)-erythrocyte sedimentation rate (mean ± standard deviation) in all patients improved significantly from baseline (just before the operation; 4.32 ± 0.99) to 1 year after the operation (3.35 ± 0.93) in contrast with the finding that the mean DAS28-ESR values had remained unchanged from 1 year before the operation to the baseline. Changes in clinical variables in the 58 cases were investigated at baseline, and at 4, 12, and 52 weeks after the operation. The patients were divided by a median split of baseline demographics into 2 groups for further evaluation. Compared with the high-value groups, those with low C-reactive protein and matrix metalloproteinase-3 values showed better results and had lower disease activity. Overall, the DAS28-ESR in both groups had improved 1 year after the operation. In RA patients who are being treated with anti-TNF agents, large-joint arthroplasty may be beneficial, not only for the relief of pain arising from joint destruction, but also for the systemic reduction of RA activity.

PMID 21979824
Anna Clara Benoni, Ann Bremander, Anna Nilsdotter
Patient-reported outcome after rheumatoid arthritis-related surgery in the lower extremities: a report from the Swedish National Register of Rheuma Surgery (RAKIR).
Acta Orthop. 2012 Apr;83(2):179-84. doi: 10.3109/17453674.2011.645193. Epub 2011 Dec 29.
Abstract/Text BACKGROUND AND PURPOSE: Although decreasing with the development of effective pharmacological regimes, joint surgery has improved the function and quality of life of patients with rheumatoid arthritis (RA). Few studies have assessed patient-reported outcomes after RA surgery to the lower extremities. Here we report patient-relevant outcome after RA-related surgery based on the first data from the Swedish National Register of Rheuma Surgery (RAKIR).
PATIENTS AND METHODS: 258 RA patients (212 women) who had joint surgery performed at the Department of Orthopaedics, Spenshult Hospital between September 2007 and June 2009 were included. Mean age at surgery was 64 (20-86) years. The patients completed the SF-36 and HAQ questionnaires preoperatively and 6 months postoperatively, and 165 patients completed them after 12 months.
RESULTS: Improvement was seen as early as at 6 months. At 12 months, 165 patients (141 women)-including hip (n = 15), knee (n = 27), foot (n = 102), and ankle (n = 21) patients-reported statistically significant improvements from preoperatively to 12 months postoperatively in HAQ (mean change: -0.11) and SF-36 subscales physical function (11), role physical (12), bodily pain (13), social functioning (6.4), and role emotional (9.4). Hip and knee patients reported the greatest improvements.
INTERPRETATION: Orthopedic RA-related surgery of the lower extremities has a strong effect on pain and physical function. Improvement is evident as early as 6 months postoperatively and remains after 12 months.

PMID 22206446
O Robertsson, K Knutson, S Lewold, S Goodman, L Lidgren
Knee arthroplasty in rheumatoid arthritis. A report from the Swedish Knee Arthroplasty Register on 4,381 primary operations 1985-1995.
Acta Orthop Scand. 1997 Dec;68(6):545-53.
Abstract/Text The Swedish Knee Arthroplasty Register has data on 4,381 primary operations performed 1985-1995 for rheumatoid arthritis. Of these, 192 were performed with unicompartmental prostheses and 4143 with tricompartmental. 77% were women and the mean age was 66 years. There were 126 first, 20 second, and 1 third revision in tricompartmental arthroplasties, mainly for loosening, infection and patellar problems. There were 38 first, 3 second, and 1 third revision in unicompartmental arthroplasties, mainly for progression of RA and loosening. Cumulative revision rates (Kaplan-Meier) were calculated. Tricompartmental knees had a 10-year cumulative revision rate of 5% and uni-knees 25%. Patients treated before 1990, men and patients younger than 55 had higher revision rates than patients treated after 1990, women and older patients, respectively. Cemented tibial components resulted in lower revision rates than uncemented ones. There was no significant difference in revision rates between patellar replaced and unreplaced knees or between the 9 commonest implant types.

PMID 9462354
H Shiga, S Yoshino, H Nakamura, M Nagashima
Long-term results of Yoshino total knee arthroplasties in rheumatoid arthritis.
Arch Orthop Trauma Surg. 1998;117(1-2):15-7.
Abstract/Text A review was made of 267 Yoshino total knee arthroplasties performed on 184 patients with rheumatoid arthritis between June 1978 and December 1983. The average duration of follow-up was 14.3 years. Of these patients 46.7% died during the follow-up period. The main causes of death were cardiac disease, respiratory disease and renal disease. According to the Japanese Orthopaedic Association (JOA) knee rating system, JOA scores decreased significantly with time after surgery, but remained significantly higher than the preoperative scores. The flexion angle after surgery had decreased compared with the preoperative flexion angle and decreased further 3 years after surgery and later. The cumulative survival rate was 88.6%. This rate was mainly affected by postoperative infection and aseptic loosening of the tibial components.

PMID 9457329
P A Schai, R D Scott, T S Thornhill
Total knee arthroplasty with posterior cruciate retention in patients with rheumatoid arthritis.
Clin Orthop Relat Res. 1999 Oct;(367):96-106.
Abstract/Text The objective of the present study was to evaluate posterior cruciate ligament retention in total knee arthroplasty for patients with rheumatoid arthritis to determine long term ligamentuous stability. The study concerns an average 11-year followup (range, 10-13 years) of 52 patients (81 knees) with rheumatoid arthritis who had a total knee arthroplasty using a contemporary posterior cruciate retaining prosthesis. Particular attention was given to component survivorship and clinical stability. Fourteen patients (20 knees) died; none of these patients required revision surgery. No patients were lost to followup. Sixty-one knees in 38 patients were examined. In this group, the Knee Society knee score averaged 95 points (range, 63-100 points) and function score averaged 74 points (range, 0-100 points). Postoperative flexion averaged 112 degrees and extension averaged 0 degree. Four knees had 3 degrees asymptomatic hyperextension; one knee with 5 degrees hyperextension occasionally gave way. Five well aligned knees had between 6 degrees and 9 degrees varus or valgus laxity in extension, but no patient reported subjective instability. Two patients underwent revision surgery. One patient had a worn metal backed patella component replaced and the other patient had an open synovectomy for recurrent active rheumatoid synovitis. Thirteen-year survivorship based on need for revision surgery was 97% with the 95% confidence limits between 88% and 100%. There was no radiographic loosening or subsidence of prosthetic components. At 11-year followup, patients with rheumatoid arthritis whose knees were replaced with posterior cruciate retention prostheses experienced results equivalent to or better than those reported for patients with osteoarthritis at a similar followup. Late hyperextension and subsequent instability may be a concern in the second decade of followup.

PMID 10546603
M J Archibeck, R A Berger, R M Barden, J J Jacobs, M B Sheinkop, A G Rosenberg, J O Galante
Posterior cruciate ligament-retaining total knee arthroplasty in patients with rheumatoid arthritis.
J Bone Joint Surg Am. 2001 Aug;83-A(8):1231-6.
Abstract/Text BACKGROUND: Although initial reports on posterior cruciate ligament-retaining total knee arthroplasty in patients with rheumatoid arthritis have been encouraging, a high rate of late instability necessitating revision has been reported recently. The purpose of the present prospective study was to analyze the results of posterior cruciate ligament-retaining total knee arthroplasty in patients with rheumatoid arthritis.
METHODS: Seventy-two posterior cruciate ligament-retaining total knee arthroplasties in fifty-one patients with rheumatoid arthritis were studied prospectively. All procedures were performed with the Miller-Galante I prosthesis. Eighteen patients (twenty-four knees) died before the eight-year follow-up and one patient (two knees) was lost to follow-up, leaving forty-six knees (thirty-two patients) for review. These forty-six knees were evaluated clinically (with particular attention to posterior instability) and radiographically at annual intervals for a mean of 10.5 years (range, eight to fourteen years).
RESULTS: Forty-four (95%) of forty-six knees had a good or excellent result at a mean of 10.5 years. However, nine (13%) of the original seventy-two knees had revision of the implant, with six of the revisions performed because of failure of a metal-backed patellar component. The rate of survival at ten years was 93% 4% with femoral or tibial revision for any reason as the end point and 81% 5% with any reoperation as the end point. There was no aseptic loosening in any knee. Posterior instability was identified clinically and/or radiographically in two (2.8%) of the original seventy-two knees; both unstable knees were in the same patient.
CONCLUSION: Posterior cruciate ligament-retaining total knee arthroplasty yielded satisfactory clinical and radiographic results in patients with rheumatoid arthritis at intermediate-term follow-up (mean, 10.5 years). Therefore, we believe that it remains an excellent treatment option for these patients.

PMID 11507132
G S Gill, A B Joshi
Long-term results of retention of the posterior cruciate ligament in total knee replacement in rheumatoid arthritis.
J Bone Joint Surg Br. 2001 May;83(4):510-2.
Abstract/Text We analysed the long-term results with a mean follow-up of 10.2 years, of 66 total knee replacements in 42 patients with rheumatoid arthritis. In all cases the posterior cruciate ligament was retained. There were only three complications (4.5%). Revision surgery was necessary in five knees (7.6%), including one (1.5%) with infection. At the final follow-up, 75.8% of knees were rated excellent clinically. Only 15% had an excellent function score. The survival rate of the implant was 90.7% at 19 years. The clinical, radiological and survivorship analysis shows that the posterior-cruciate-retaining knee arthroplasty performs well in rheumatoid arthritis.

PMID 11380120
J A Rodriguez, H Bhende, C S Ranawat
Total condylar knee replacement: a 20-year followup study.
Clin Orthop Relat Res. 2001 Jul;(388):10-7.
Abstract/Text Between 1976 and 1979, 220 total knee replacements were done on 164 patients using the Total Condylar Knee replacement. The diagnosis was rheumatoid arthritis in 111 knees and osteoarthritis in 109 knees. Patients with 157 knees are known to have died as of December 1998, leaving 63 knees in patients who are still alive. Twelve patients with 18 knees were lost to followup. The average 20-year followup data (range, 18-22 years) are presented for 45 knees in 30 patients using Knee Society evaluations. The average Knee Society clinical score for the surviving patients was 88 points, and the average functional score was 58 points. The radiographic followup averaged 19 years. The average overall alignment was 3 degrees valgus. Femoral lucencies were present in 17 of 40 adequate lateral views, most commonly about the anterior and posterior surfaces. Two femoral components were loose. Twenty-two tibial components had radiolucencies; four radiolucencies were circumferential. The remaining 41 knees retained a well-fixed cemented central peg despite proximal interface lucencies. From the group of 220 knees, 14 revisions have been done at an average of 11.4 years postoperative. Two knee replacements were revised for isolated tibial loosening, whereas one knee replacement had isolated femoral loosening. Three knee replacements were revised for loosening of both components, and one was revised for isolated patellar loosening. Four patients had sepsis develop; three of these four patients were treated with two-stage revision, and one underwent fusion. Three patients were treated for supracondylar fractures. The Total Condylar Knee replacement maintains excellent durability at 20-years followup.

PMID 11451106
C J van Loon, C Pluk, M C de Waal Malefijt, M de Kock, R P Veth
The GSB total knee arthroplasty. A medium- and long-term follow-up and survival analysis.
Arch Orthop Trauma Surg. 2001;121(1-2):26-30.
Abstract/Text From 1981 to 1987, 77 GSB-II total knee arthroplasties were implanted in 65 patients. There were 23 men and 42 women aged on average 60 years old (range 30-85 years). The diagnosis was osteoarthritis (OA) in 21 knees, rheumatoid arthritis (RA) in 44 knees, and other in 12 knees. A clinical and radiological follow-up was performed in two stages after a mean of 6.7 years (61 knees) and 14.8 years (22 knees) to assess the medium- and long-term results and to determine if deterioration had occurred after mid-term follow-up. A survival analysis was done with two endpoints: (1) revision, and (2) revision, moderate or severe pain and lost to follow-up (worst-case scenario). At the last follow-up 36 patients (44 knees) had died, 2 patients (2 knees) refused examination, and 3 patients (3 knees) were lost to follow-up. Six knees had been revised for malposition (1.3%), septic (3.9%) and aseptic (2.6%) loosening. The mean Knee Society score after 6.7 and 14.8 years was 85 points (OA 82 points, RA 87 points). Lateralisation, subluxation or dislocation of the patella was present in 8 of 17 knees at the last follow-up. The 6- and 15-year survival rates with revision as the endpoint were 95% (CI 89%-100%) and 87% (CI 65%-100%), respectively. For the worst-case scenario, the 6- and 15-year survival rates were 95% (CI 89%-100%) and 56% (CI 0%-100%), respectively. The medium- and long-term results of the GSB-II total knee arthroplasty were good, and a decline in the knee score did not occur beyond the mid-term follow-up. Patella complications were abundant, and a marked decrease in implant survival was noted when moderate or severe pain and lost to follow-up were included as endpoints.

PMID 11195114
Amy R Crowder, Gavan P Duffy, Robert T Trousdale
Long-term results of total knee arthroplasty in young patients with rheumatoid arthritis.
J Arthroplasty. 2005 Oct;20(7 Suppl 3):12-6. doi: 10.1016/j.arth.2005.05.020.
Abstract/Text Forty-seven cemented total knee arthroplasties in 32 patients with rheumatoid arthritis who were 55 years or younger (average, 43) were followed until death or a minimum of 15 years. The average follow-up was 18 years. There were 6 revisions; 5 of 6 revisions had severe polyethylene wear and osteolysis. All revisions occurred after 17 years (range, 17-23). Three of these had fracture of the tibial component associated with polyethylene wear through; the remaining 2 had loose tibial and femoral components. One patient sustained a distal femoral periprosthetic fracture requiring revision of the total knee. Cemented total knee arthroplasty in the young patient with rheumatoid arthritis is reliable and durable at an average 18 years of follow-up with an estimated survivorship of 100% at 15 years and 93.7% at 20 years.

PMID 16213997
Klemmens Trieb, Maximillian Schmid, Thomas Stulnig, Wolfgang Huber, Axel Wanivenhaus
Long-term outcome of total knee replacement in patients with rheumatoid arthritis.
Joint Bone Spine. 2008 Mar;75(2):163-6. doi: 10.1016/j.jbspin.2007.06.008. Epub 2007 Sep 24.
Abstract/Text OBJECTIVES: We analysed the long-term clinical and radiological results of 68 consecutive total knee replacements in 50 patients with rheumatoid arthritis.
METHODS: At a mean follow-up of 11.2+/-1.2 years (range, 9.7-13.7) all revisions were included. Thirty-seven knees in 28 patients still alive were followed retrospectively clinically and radiologically, all other patients who died without revision were censored at time of the last clinical follow-up and no patient was lost to follow-up. Revision was necessary in 13 knees (19%, one revised twice), including an overall deep infection rate of 1.47%.
RESULTS: The survival rate was 81.6+/-0.05% at 12 years with any revision or removal of the prosthesis as an end point. There was no significant difference in survival between cemented, uncemented or hybrid fixation (log rank, 0.2544). The average Knee Society Scores were 77.2 points clinical (range, 40-95 points) and 75.3 points functional (range, 30-100 points), respectively, at final follow-up. The body mass index (BMI) was 25.9 at surgery and 25.3 at follow-up (n.s.). There was no correlation between BMI, age, side, gender and revision frequency. No arthroplasty was at risk for removal or revision at follow-up.
CONCLUSIONS: The study shows good 10-12-year clinical and radiological results for the PCA knee replacement in patients with rheumatoid arthritis without preference for the method of fixation or patient weight.

PMID 18165132
Matthew D Miller, Nicholas M Brown, Craig J Della Valle, Aaron G Rosenberg, Jorge O Galante
Posterior cruciate ligament-retaining total knee arthroplasty in patients with rheumatoid arthritis: a concise follow-up of a previous report.
J Bone Joint Surg Am. 2011 Nov 16;93(22):e130(1-6). doi: 10.2106/JBJS.J.01695.
Abstract/Text 7We previously reported the minimum eight-year follow-up results of cruciate-retaining total knee arthroplasty in a consecutive series of seventy-two knees in patients with rheumatoid arthritis. In the present study, we evaluated the longer-term outcomes after twenty to twenty-five years of follow-up. Since the publication of our original study, ten knees have been revised: three because of periprosthetic fracture, three because of infection, two because of patellofemoral failure, and two because of posterior instability. The rate of implant survival at twenty years after surgery was 69% (95% confidence interval [CI], 56% to 79%) with revision for any reason as the end point, 81% (95% CI, 69% to 89%) with femoral or tibial component revision for any reason as the end point, and 93% (95% CI, 83% to 97%) with posterior instability as the end point. These long-term results demonstrate that posterior cruciate ligament insufficiency with instability was rarely the cause of failure following cruciate-retaining total knee arthroplasty in patients with rheumatoid arthritis.

PMID 22262390
Young Kyun Woo, Ki Won Kim, Jin Wha Chung, Hwa Sung Lee
Average 10.1-year follow-up of cementless total knee arthroplasty in patients with rheumatoid arthritis.
Can J Surg. 2011 Jun;54(3):179-84. doi: 10.1503/cjs.000910.
Abstract/Text BACKGROUND: Total knee arthroplasty (TKA) using a cemented technique has been recommended in patients with rheumatoid arthritis owing to the initial stability of the fixation and long-term durability of the components; however, similar long-term follow-up results have been reported in patients who have undergone cementless TKA. The purpose of this study was to evaluate the radiologic and clinical outcomes of cementless TKA in patients with rheumatoid arthritis.
METHODS: We enrolled patients undergoing cementless TKA from March 1990 to February 2000. Clinical and radiologic evaluations were performed using the Knee Society clinical rating system and radiographic evaluation and scoring system.
RESULTS: We included the cases of 112 patients who underwent 179 cementless TKA procedures in our analysis. Their mean age was 62.3 years, and the mean follow-up period was 10.1 years. The final survival rate was 0.968 at the 15.5-year follow-up. Regarding radiologic results after surgery, the mean total valgus angle was 6.7°, the mean femoral flexion angle was 97.5° and the mean tibial angle was 89.2° on the anteroposterior radiographs. On the lateral films, the mean femoral flexion angle was 1.6° and the mean tibial angle was 89.2°. At the last follow-up, the mean total valgus angle was 6.5°, the mean femoral flexion angle was 97.4° and the mean tibial angle was 89.1°, as seen on the anteroposterior view. On the lateral views, the mean femoral flexion angle was 1.4° and the mean tibial angle was 89.0°. Regarding the clinical outcome, the mean knee score and function score on the Knee Society clinical rating system were also enhanced from 47.5 and 43.6, respectively, before the operation to 91.2 and 82.3, respectively, at the last follow-up.
CONCLUSION: On radiologic and clinical follow-up of cementless TKA for patients with rheumatoid arthritis, there were no serious complications, and the results of the operation were satisfactory with improvement in range of motion and clinical symptoms.

PMID 21609517
M J Chmell, R D Scott
Total knee arthroplasty in patients with rheumatoid arthritis. An overview.
Clin Orthop Relat Res. 1999 Sep;(366):54-60.
Abstract/Text Total knee arthroplasty in patients with rheumatoid arthritis presents several unique challenges. Patients with rheumatoid arthritis often have additional medical, anesthetic, and global musculoskeletal problems that are not present in the patient with osteoarthritis. In terms of the knee, these patients usually have osteopenia and may present with an array of bone and soft tissue deformities, each of which can impact the initial success and long term durability of a total knee replacement. Despite these potential difficulties, the early and long term results of total knee arthroplasty in patients with rheumatoid arthritis have proven to be excellent.

PMID 10627718
P A Schai, T S Thornhill, R D Scott
Total knee arthroplasty with the PFC system. Results at a minimum of ten years and survivorship analysis.
J Bone Joint Surg Br. 1998 Sep;80(5):850-8.
Abstract/Text A consecutive series of 235 total knee arthroplasties using the PFC system was followed prospectively for at least ten years in 186 patients. The operation was for osteoarthritis in 150 knees, for rheumatoid arthritis in 83, and for Paget's disease and femoral osteonecrosis in one knee each. At the latest review 56 patients had died, five were too ill to assess and three could not be traced. The PFC knee replacement utilised was a non-conforming posterior-cruciate-retaining prosthesis with a polyethylene insert which is flat in the sagittal plane. The patella was resurfaced using a metal-backed component in 170 cases, but later in the series we used an all-polyethylene component in 22 knees; 43 patellae were not resurfaced. The survival without need for reoperation for any reason was 90% at ten years. Nineteen revisions were component-related due to failure of nine metal-backed patellae, nine polyethylene inserts, and one unresurfaced patella; two reoperations were for synovectomy (one for recurrent haemarthrosis and one for recurrent rheumatoid synovitis) and three were for metastatic joint infection. There were no revisions for aseptic loosening of femoral or tibial components, or the all-polyethylene patellar replacement. The PFC system provides good and predictable results in tricompartmental arthritis of the knee. Loosening appeared to be negligible, but there were wear-related problems in 8%. The change from a metal-backed patella and an increase in the contact area of the tibial insert should provide further improvement by minimising wear.

PMID 9768897
Eiko Seki, Isao Matsushita, Eiji Sugiyama, Hirohumi Taki, Koichiro Shinoda, Hiroyuki Hounoki, Hiraku Motomura, Tomoatsu Kimura
Radiographic progression in weight-bearing joints of patients with rheumatoid arthritis after TNF-blocking therapies.
Clin Rheumatol. 2009 Apr;28(4):453-60. doi: 10.1007/s10067-008-1076-9. Epub 2008 Dec 23.
Abstract/Text The aim of the present study was to assess the influence of tumor necrosis factor (TNF)-blocking therapies on weight-bearing joints in patients with rheumatoid arthritis. Changes in clinical variables and radiological findings in 213 weight-bearing joints (69 hip joints, 63 knee joints, and 81 ankle joints) of 42 consecutive patients were investigated at baseline and at 1 year of TNF-blocking therapies. Structural damage to the weight-bearing joints was assessed using the Larsen scoring method. Detailed comparisons of the sizes and locations of erosions were performed for each set of radiographs of the respective joints. Assessment of radiographs of the 213 weight-bearing joints indicated progression of the Larsen grade in eight joints. Another five joints without Larsen grade progression showed apparent radiographic progression of joint damage based on increases in bony erosions. Overall, 13 joints (6%) of eight patients (19%) showed progression of joint damage after 1 year of TNF-blocking therapies. Analysis of each baseline grade indicated that radiographic progression of joint damage was inhibited in most grade 0-II joints. On the other hand, all hip and knee joints with pre-existing damage of grade III/IV showed apparent progression even in patients with good response. The results further suggested that radiographic progression may occur in less damaged joints when the patients were non-responders to the therapy. Among the weight-bearing joints, ankle joints showed different radiographic behavior and four ankle joints displayed improvement of radiographic damage. Early initiation of anti-TNF therapy should be necessary especially when the patients are starting to show early structural damage in weight-bearing joints.

PMID 19104753
W M Tang, K Y Chiu
Primary total hip arthroplasty in patients with rheumatoid arthritis.
Int Orthop. 2001;25(1):13-6.
Abstract/Text Twenty-eight (11 cemented and 17 noncemented) total hip arthroplasties (THA) were performed in 20 patients with rheumatoid arthritis (RA). The average age at operation was 42.1 years and the average follow-up was 10.8 years. There were two deep infections requiring removal of the prosthesis. Three cemented acetabular cups and one cemented femoral component were revised due to aseptic loosening. One cemented cup was loosened radiologically. One PCA polyethylene liner was revised because of significant wear. Both cemented and noncemented femoral components are capable of providing respectable results in RA patients. The relatively inferior results of THA among RA patients is due not only to the fixation method, but also to the poorer bone quality.

PMID 11374260
A K Jana, C A Engh, P J Lewandowski, R H Hopper, C A Engh
Total hip arthroplasty using porous-coated femoral components in patients with rheumatoid arthritis.
J Bone Joint Surg Br. 2001 Jul;83(5):686-90.
Abstract/Text We studied the results of total hip arthroplasty (THA) using AML porous-coated femoral components at a mean follow-up of 11 years in a non-selected, consecutive series of patients with rheumatoid arthritis. We reviewed 64 patients with 82 primary THAs using these components. There were seven men (8 hips) and 57 women (74 hips) with a mean age of 55.1 years (24 to 80) at the time of surgery. Nine patients (11 hips) died before the two-year follow-up. Of the remaining 71 hips, only one stem was revised for aseptic loosening. Survivorship for the stems was 98.1% (95% confidence interval (CI) 94.5 to 100.0) at ten years, using a life-table analysis, with revision for any reason as an endpoint. Of the 70 unrevised stems, 66 (94%) had bony ingrowth, while four (6%) were radiologically loose at the most recent follow-up (mean 11.4 years). Our study shows the excellent long-term results which can be achieved with porous-coated femoral components in patients with rheumatoid arthritis.

PMID 11476306
Rob Zwartele, Anil Peters, Johannes Brouwers, Paul Olsthoorn, Ronald Brand, Cornelis Doets
Long-term results of cementless primary total hip arthroplasty with a threaded cup and a tapered, rectangular titanium stem in rheumatoid arthritis and osteoarthritis.
Int Orthop. 2008 Oct;32(5):581-7. doi: 10.1007/s00264-007-0383-0. Epub 2007 Jul 3.
Abstract/Text The aim of this study was to assess the outcome of primary cementless total hip arthroplasty in rheumatoid arthritis patients and to compare the results with osteoarthritis patients. Sixty-four patients (77 hips) with rheumatoid arthritis and 120 patients (135 hips) with osteoarthritis had a conical-shaped Zweymueller threaded cup and a tapered, rectangular Zweymueller stem implanted and were assessed after an average of 12.5 years. The endpoints for survival analysis were failure of one or both components due to radiographic loosening or revision. Revision was defined as exchange of cup, stem or both. When the PE-insert or the ceramic ball head were exchanged leaving cup and stem in place, e.g. for PE-wear or dislocation, this was not considered a revision but a re-intervention. No differences were found in survival rates; however, in the rheumatoid arthritis group there was an increased rate of malposition of the cup, avulsions of the greater trochanter, and increased bone resorption in the trochanteric region. This study shows that despite altered biomechanical properties of rheumatoid bone, mechanical stability and osseous integration of cementless prosthesis are not compromised and, although a higher complication rate did occur, long-term survival is excellent.

PMID 17609955
Antti Eskelinen, Pekka Paavolainen, Ilkka Helenius, Pekka Pulkkinen, Ville Remes
Total hip arthroplasty for rheumatoid arthritis in younger patients: 2,557 replacements in the Finnish Arthroplasty Register followed for 0-24 years.
Acta Orthop. 2006 Dec;77(6):853-65. doi: 10.1080/17453670610013132.
Abstract/Text BACKGROUND: The results of total hip arthroplasty (THA) in young patients with rheumatoid arthritis (RA) have been reported in only a few studies. On a nationwide level, the outcome of THA in these patients is unknown. We evaluated the population-based survival of THA in patients under 55 years of age with RA and factors affecting the survival.
PATIENTS: Between 1980 and 2003, 2,557 primary THAs performed for RA in patients less than 55 years of age were reported to the Finnish Arthroplasty Register.
RESULTS: Proximally circumferentially porous-coated uncemented stems had a 15-year survival rate of 89% (95% CI 83-94) with aseptic loosening as endpoint. The risk of stem revision due to aseptic loosening was higher with cemented stems than with proximally porouscoated uncemented stems implanted during the same period (RR 2.4; p < 0.001). In contrast, Cox regression analysis showed that the risk of cup revision was significantly higher for all uncemented cup concepts than for all-polyethylene cemented cups with any cup revision as endpoint. There were no significant differences in survival between the THR concepts.
INTERPRETATIONS: Uncemented proximally circumferentially porous-coated stems and cemented all-poly-ethylene cups are currently the implants of choice for young patients with RA.

PMID 17260192
Keijo T Mäkelä, Antti Eskelinen, Pekka Pulkkinen, Petri Virolainen, Pekka Paavolainen, Ville Remes
Cemented versus cementless total hip replacements in patients fifty-five years of age or older with rheumatoid arthritis.
J Bone Joint Surg Am. 2011 Jan 19;93(2):178-86. doi: 10.2106/JBJS.I.01283.
Abstract/Text BACKGROUND: results obtained from single-center studies indicate that a cemented total hip replacement is the treatment of choice for the management of patients over fifty-five years of age with rheumatoid arthritis. The aim of this study was to analyze population-based survival rates for cemented and cementless total hip replacements in patients aged fifty-five years or over with rheumatoid arthritis in Finland.
METHODS: between 1980 and 2006, a total of 6000 primary total hip replacements performed for the management of rheumatoid arthritis in patients who were fifty-five years of age or older were entered in the Finnish Arthroplasty Registry. 4019 of them fulfilled our inclusion criteria and were subjected to analysis. The implants were classified into one of three possible groups: (1) a cementless group (a noncemented proximally porous-coated stem and a noncemented porous-coated press-fit cup), (2) a cemented group 1 (a cemented, loaded-taper stem combined with a cemented, all-polyethylene cup), or (3) a cemented group 2 (a cemented, composite-beam stem with a cemented, all-polyethylene cup).
RESULTS: cementless stems and cups, analyzed separately, had a significantly lower risk of revision for aseptic loosening than cemented implants in patients who were fifty-five years of age or older with rheumatoid arthritis. The fifteen-year survival rate of cementless total hip replacements (80%) was comparable with the rates of the cemented groups (86% in cemented group 1 and 79% in cemented group 2) when revisions for any reason were used as the end point.
CONCLUSIONS: cementless and cemented total hip replacements produced comparable long-term results in patients who were fifty-five years of age or older with rheumatoid arthritis.
LEVEL OF EVIDENCE: therapeutic Level III. See Instructions to Authors for a complete description of levels of evidence.

PMID 21248215
Hans D Carl, Jan Ploetzner, Bernd Swoboda, Gerd Weseloh, Lutz Arne Mueller
Cementless total hip arthroplasty in patients with rheumatoid arthritis using a tapered designed titanium hip stem minimum: 10-year results.
Rheumatol Int. 2011 Mar;31(3):353-9. doi: 10.1007/s00296-009-1300-1. Epub 2009 Dec 18.
Abstract/Text The results of cementless tapered designed femoral stem were studied at a minimum 10-year follow-up in a non-selected, consecutive group of 27 patients (39 hips) with rheumatoid arthritis. Clinical and radiological analyses were performed in 27 hips, 17 patients (mean age at surgery 45 years) after a mean of 12 years. The postoperative Harris hip score was excellent for 14 hips, 9 hips were rated as good and 4 hips were fair or poor. No stem had to be revised for aseptic loosening. Proximal stress shielding was observed in 26 hips (96%); heterotopic ossification was present in 11 hips (41%). Six hips required revision of the acetabular component. With uncemented tapered femoral fixation excellent 12-year results are achieved in patients with rheumatoid arthritis.

PMID 20020135
Christoffer Rud-Sørensen, Alma B Pedersen, Søren Paaske Johnsen, Anders Hammerich Riis, Søren Overgaard
Survival of primary total hip arthroplasty in rheumatoid arthritis patients.
Acta Orthop. 2010 Feb;81(1):60-5. doi: 10.3109/17453671003685418.
Abstract/Text BACKGROUND AND PURPOSE: There has been a limited amount of research on survival of total hip arthroplasties (THAs) in rheumatoid arthritis (RA). We therefore performed a population-based, nationwide study to compare the survival of primary THAs in RA patients and in osteoarthritis (OA) patients. We also wanted to identify predictors of THA failure in RA patients.
METHODS: Using the Danish Hip Arthroplasty Registry, we identified 1,661 primary THAs in RA patients and 64,858 in OA patients, all of which were inserted between 1995 and 2008. The follow-up period was up to 14 years for both groups.
RESULTS: Regarding overall THA survival, the adjusted RR for RA patients compared to OA patients was 0.81 (95% CI: 0.65-1.01). We found no difference in survival of cups between primary THAs in RA and OA patients. In contrast, there was better overall survival of stems in RA patients than in OA patients, both regarding revision due to aseptic loosening (adjusted RR = 0.58; 95% CI: 0.34-0.99) and for any reason (adjusted RR = 0.63; 95% CI: 0.45-0.88). In RA patients, males had a higher risk of revision than females concerning aseptic loosening of the stem, any revision of the stem, and any revision of both components.
INTERPRETATION: The overall survival of primary THAs in RA patients is similar to THA survival in OA patients. Stem survival appeared to be better in RA patients, while survival of the total THA concept did not show any statistically significant differences between the two groups. In RA patients, males appear to have a greater risk of revision than females.

PMID 20180721
B Michael Wroblewski, Paul D Siney, Patricia A Fleming
Charnley low-frictional torque arthroplasty in young rheumatoid and juvenile rheumatoid arthritis: 292 hips followed for an average of 15 years.
Acta Orthop. 2007 Apr;78(2):206-10. doi: 10.1080/17453670710013690.
Abstract/Text INTRODUCTION: In the early 1960s, Charnley was cautious with his patient selection for total hip replacement. As follow-up increased and confidence in the operation grew, younger patients were selected. We present our results of the Charnley LFA in young patients with rheumatoid and juvenile rheumatoid arthritis with a followup of up to 36 years.
PATIENTS: We studied 292 Charnley low-friction arthroplasties in 195 young patients with an established diagnosis of rheumatoid arthritis. Their mean age at operation was 38 (12-50) years; 168 (58%) were receiving steroids and 79 (27%) were on non-steroidal antiinflammatory medication. The mean follow-up for the whole group was 15 (1-36) years. 24 patients could not be traced (33 hips), and 61 patients died (88 hips).
RESULTS: 25 patients (41 hips) had had a revision. The main indication for revision was cup loosening. In the 85 patients (130 hips) attending follow-up, their mean age at surgery was 36 (17-50) years and the mean follow-up was 20 (10-36) years. 98% were pain-free or had no more than occasional discomfort, 44% claimed to have normal or near-normal function, while 62% had full or almost full range of movement of the replaced hip. Radiographically, 29 cups (22%) were considered to be loose. 1 stem (1%) was definitely loose and 2 stems (2%) were probably loose. With revision for any indication as the endpoint, the survival was 74% at 25 years follow-up.
INTERPRETATION: The Charnley LFA continues to be an excellent hip replacement, even for very young rheumatoid arthritis patients. Wear and aseptic cup loosening are the main long-term problems.

PMID 17464608
M G Creighton, J J Callaghan, J P Olejniczak, R C Johnston
Total hip arthroplasty with cement in patients who have rheumatoid arthritis. A minimum ten-year follow-up study.
J Bone Joint Surg Am. 1998 Oct;80(10):1439-46.
Abstract/Text One hundred and six consecutive total hip arthroplasties with cement were performed by one surgeon, at least ten years before the time of the present clinical and radiographic review, in seventy-five patients who had adult-onset rheumatoid arthritis. Two patients (three hips) were lost to follow-up. Seven (7 per cent) of the remaining 103 hips were revised. The revisions were performed because of infection (three hips), dislocation (two hips), or aseptic loosening (two hips). Of the ninety-eight hips that were not lost to follow-up or revised because of infection or dislocation, eight (8 per cent) had radiographic loosening of the acetabular component and two (2 per cent) had radiographic loosening of the femoral component. Although the prevalence of radiographic loosening of the acetabular component was four times greater than the prevalence of radiographic loosening of the femoral component, the prevalence of revision because of aseptic loosening of the acetabular component was identical to that for the femoral component (one component each). These results compared favorably with those of total hip arthroplasty with cement, performed by the same surgeon, for the treatment of other diagnoses. Loosening of the acetabular component was significantly associated with a younger age at the time of the index operation (p = 0.03) and with acetabular osteolysis (p = 0.0006). Of forty-eight hips in thirty-two patients who survived for at least ten years, 96 per cent (forty-six hips) were considered by the patients to have a satisfactory result. At the time of the latest follow-up, twenty-four (75 per cent) of the patients had no pain in the hip. Although eighteen patients (56 per cent) could walk without support at a minimum of ten years after the operation, we found that the functional results for patients who had rheumatoid arthritis were inferior to those observed for patients who had had a total hip arthroplasty with cement, performed by the same surgeon, for the treatment of other diagnoses.

PMID 9801212
松下功,森田裕司,伊藤芳章:関節リウマチに対するセメントレス人工股関節設置換術の長期成績.Hip Jt 2008;34:22-25.
上田祐輔,徳永裕彦,松矢浩暉,市川宜弘,井上豪:関節リウマチによる股関節障害に対するセメントレス人工股関節置換術の長期成績.日本関節病学会誌 2011;30(4):495-501.
H C Thomason, P F Lachiewicz
The influence of technique on fixation of primary total hip arthroplasty in patients with rheumatoid arthritis.
J Arthroplasty. 2001 Aug;16(5):628-34. doi: 10.1054/arth.2001.23720.
Abstract/Text This is a prospective, consecutive study of 98 total hip arthroplasties implanted by 1 surgeon in 66 patients with rheumatoid arthritis. The mean follow-up time was 7.4 years (range, 2-13 years). All 98 acetabular components were uncemented titanium fiber metal-coated components fixed with multiple screws. Sixty-five hips had bulk or cancellous allograft for protrusio acetabuli. Following a prospective protocol based on patient age, 51 hips had an uncemented femoral component, and 47 hips had a cemented femoral component. Using the Harris Hip Score, 30 hips were rated as excellent; 44, good; 15, fair; and 9, poor. There were no early deep infections. One hybrid hip was removed for late metastatic infection at 7 years. Radiographic evaluation of 98 acetabular components showed 1 case of septic loosening, 2 cases of aseptic loosening (1 patient asymptomatic), and 1 case with severe wear and ischial osteolysis. None of the 47 cemented femoral components subsided, and osteolysis was seen in only 3 femora (7%). Of the 51 uncemented femoral components, subsidence occurred in 7 hips (14%), and osteolysis occurred in 15 hips (30%). Uncemented acetabular components have a high rate of success in patients with rheumatoid arthritis who have a total hip arthroplasty. There is a high rate of subsidence and osteolysis, however, with first-generation cementless femoral components.

PMID 11503123
Robert Pivec, Aaron J Johnson, Simon C Mears, Michael A Mont
Hip arthroplasty.
Lancet. 2012 Nov 17;380(9855):1768-77. doi: 10.1016/S0140-6736(12)60607-2. Epub 2012 Sep 26.
Abstract/Text Total hip arthroplasty is a cost-effective surgical procedure undertaken to relieve pain and restore function to the arthritic hip joint. More than 1 million arthroplasties are done every year worldwide, and this number is projected to double within the next two decades. Symptomatic osteoarthritis is the indication for surgery in more than 90% of patients, and its incidence is increasing because of an ageing population and the obesity epidemic. Excellent functional outcomes are reported; however, careful patient selection is needed to achieve best possible results. The present economic situation in many developed countries will place increased pressure on containment of costs. Future demand for hip arthroplasty, especially in patients younger than 65 years, emphasises the need for objective outcome measures and joint registries that can track lifetime implant survivorship. New generations of bearing surfaces such as metal-on-metal, ceramic-on-ceramic, and metal-on-ceramic, and techniques such as resurfacing arthroplasty have the potential to improve outcomes and survivorship, but findings from prospective trials are needed to show efficacy. With the recall of some metal-on-metal bearings, new bearing surfaces have to be monitored carefully before they can be assumed to be better than traditional bearings.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 23021846
C P Little, A J Graham, A J Carr
Total elbow arthroplasty: a systematic review of the literature in the English language until the end of 2003.
J Bone Joint Surg Br. 2005 Apr;87(4):437-44. doi: 10.1302/0301-620X.87B4.15692.
Abstract/Text
PMID 15795188
J C T van der Lugt, P M Rozing
Systematic review of primary total elbow prostheses used for the rheumatoid elbow.
Clin Rheumatol. 2004 Aug;23(4):291-8. doi: 10.1007/s10067-004-0884-9. Epub 2004 Apr 16.
Abstract/Text Total elbow prosthesis (TEP) has been shown to be a viable option for treatment of the rheumatoid elbow. Many types of TEP have been studied, but the heterogeneity of the studies makes most conclusions subject to discussion. The aim of this systematic review is to show the differences between the most commonly used TEP for the destroyed rheumatoid elbow. After a search in Pubmed (NLM, Bethesda, USA) the senior author selected eight frequently used TEP: the Capitellocondylar, Coonrad-Morrey, GSB III, Kudo, Liverpool, Norway, Roper-Tuke and Souter-Strathclyde. For inclusion studies we arbitrarily formulated nine criteria, after which clearly adverse events were defined for comparison purposes. The Capitellocondylar and Souter-Strathclyde prostheses are the most-studied treatments for replacing the rheumatoid elbow. In contrast to the Capitellocondylar, the Souter-Strathclyde prosthesis showed higher loosening rates but implemented modifications of the design have reduced these rates in recent studies. Nevertheless, in relation to most other joint replacements in rheumatoid patients, all TEP still have higher complication rates. For this reason an elbow prosthesis may just be warranted in seriously disabled patients.

PMID 15293088
N Tanaka, H Kudo, K Iwano, H Sakahashi, E Sato, S Ishii
Kudo total elbow arthroplasty in patients with rheumatoid arthritis: a long-term follow-up study.
J Bone Joint Surg Am. 2001 Oct;83-A(10):1506-13.
Abstract/Text BACKGROUND: Improvements in the design of total elbow prostheses over the last two decades have led to better and more consistent results. The type-3 Kudo total elbow prosthesis was developed in 1980. The long-term results of use of this implant have not been reported. Because it is an unlinked prosthesis, it is not known whether preservation of the anterior oblique component of the ulnar collateral ligament at the time of implantation is important.
METHODS: A type-3 Kudo total elbow arthroplasty with cement was performed in forty-seven patients (fifty elbows) with rheumatoid arthritis. Revision rates, clinical symptoms, postoperative complications, and radiographic changes were assessed eleven to sixteen years (mean, thirteen years) postoperatively.
RESULTS: The overall survival rate of the prosthesis was 90% at sixteen years. The mean Mayo elbow performance scores were all poor (mean overall score, 43 points) initially. The overall score was substantially improved at both the intermediate follow-up examination (four to six years after the operation) and the late follow-up examination (eleven to sixteen years after the operation), to 81 and 77 points, respectively. The overall rate of radiolucency about the humeral component was 45% at the intermediate follow-up examination and 100% at the long-term follow-up examination. The rate of radiolucency about the ulnar component at the intermediate and late follow-up examinations was 4.3% and 8.9%, respectively. No great differences in results were found with preservation of the anterior oblique component of the ulnar collateral ligament.
CONCLUSIONS: This long-term follow-up study showed acceptable results of the type-3 Kudo total elbow arthroplasty in patients with rheumatoid arthritis. Preservation of the ulnar collateral ligament does not seem to be necessary when performing this procedure.

PMID 11679601
H Gellman, R J Caputo, V Carter, A Aboulafia, M McKay
Comparison of short and long thumb-spica casts for non-displaced fractures of the carpal scaphoid.
J Bone Joint Surg Am. 1989 Mar;71(3):354-7.
Abstract/Text A prospective study was undertaken of fifty-one patients who were randomly assigned to treatment with either a long or a short thumb-spica cast for a non-displaced fracture of the carpal scaphoid. The duration of follow-up was at least until union; the average follow-up was twelve months. Twenty-eight fractures were treated with a long thumb-spica cast and twenty-three, with a short thumb-spica cast. The hands that initially were treated with a long thumb-spica cast were placed in a short thumb-spica cast after six weeks. Fractures that initially were treated with a long thumb-spica cast united at an average of 9.5 weeks and those that were maintained in a short thumb-spica cast, at an average of 12.7 weeks. There were no non-unions and two delayed unions in the fractures that initially were treated with a long thumb-spica cast, compared with two non-unions and six delayed unions in those that had only a short thumb-spica cast. Fractures of the proximal or middle third of the carpal scaphoid had a significantly shorter time to union when they were treated initially in a long thumb-spica cast. Fractures of the distal third did well regardless of the type of immobilization.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 2925707
Edward W Kelly, Jennifer Coghlan, Simon Bell
Five- to thirteen-year follow-up of the GSB III total elbow arthroplasty.
J Shoulder Elbow Surg. 2004 Jul-Aug;13(4):434-40. doi: 10.1016/S105827460400045X.
Abstract/Text Between 1988 and 1995, the senior author performed total elbow arthroplasty in 28 elbows (23 patients) with the GSB III prosthesis. At the most recent follow-up, 7 patients had died (9 elbows) and 1 had the implant removed because of a deep infection. The remaining 18 elbows (15 patients) were available for clinical and radiographic review at a mean period of 7.6 years (range, 5.5-11.9 years). All 15 patients were satisfied with the results of their elbow replacement, with a mean Mayo elbow performance score of 91 (range, 75-100). The mean flexion/extension and supination/pronation arcs improved by 33 degrees and 67 degrees, respectively. Radiographic follow-up demonstrated progressive loosening in only 1 patient and no progressive loosening in those with an adequate cement technique. Mild or moderate lysis of the distal humeral or proximal ulnar components was noted in 10 elbows, and severe lysis of the distal humerus was seen in 1. Of the patients, 6 (21%) had mild complications: triceps avulsions in 3, superficial wound infections in 2, and an undisplaced fracture of the distal humeral medial condyle in 1. In 4 patients (14%) complications developed requiring reoperation, including exchange of the polyethylene bushing because of wear, debridement of synovitis, resection arthroplasty for deep infection, and exploration of an ulnar nerve palsy. In 2 additional patients (7%), persistent ulnar nerve paresthesias developed postoperatively. Of the 28 elbow replacements performed with the GSB III prosthesis, only 1 required revision because of loosening at a mean follow-up of 7.6 years. The results of this series of GSB III elbow replacements in patients with rheumatoid arthritis demonstrate reasonable survivorship of this prosthesis.

PMID 15220885
C A Mancuso, T P Sculco, T L Wickiewicz, E C Jones, L Robbins, R F Warren, P Williams-Russo
Patients' expectations of knee surgery.
J Bone Joint Surg Am. 2001 Jul;83-A(7):1005-12.
Abstract/Text BACKGROUND: Patients' expectations of medical care are linked to their requests for treatment and to their assessments of outcome and satisfaction. Our goals were to measure patients" preoperative expectations of knee surgery and to develop and test patient-derived knee expectations surveys.
METHODS: An initial sample of 377 patients (mean age, 54.6 18.2 years; 52% women) was enrolled in the survey-development phase. One hundred and sixty-one (43%) of these patients subsequently underwent total knee arthroplasty; seventy-five (20%), cruciate ligament repair; eighty-five (23%), meniscal surgery; and fifty-six (15%), surgery for another knee condition. Preoperatively, these patients were asked open-ended questions about their expectations of knee surgery. Their responses were grouped with use of qualitative research techniques to generate categories of expectations. Categories were transformed into specific questions and were formatted into two draft surveys, one for patients undergoing total knee arthroplasty and one for patients undergoing other surgical procedures on the knee. A second sample of 163 patients (mean age, 55.1 17.5 years; 49% women) was enrolled in the survey-testing phase, and they completed the draft surveys on two separate occasions to establish test-retest reliability. Items were selected for the final surveys if they were cited by 5% of the patients, if they represented important functional changes resulting from surgery, or if they represented potentially unrealistic expectations. All selected items fulfilled reliability criteria, defined as a kappa (or weighted kappa) value of 0.4, or were deemed to be clinically relevant by a panel of orthopaedic surgeons.
RESULTS: From the survey-development phase, a total of fifty-two categories of expectations were discerned; they included both anticipated items such as pain relief and improvement in walking ability and unanticipated items such as improving psychological well-being. Expectations varied by diagnosis and patient characteristics, including functional status. Two final surveys were generated: the seventeen-item Hospital for Special Surgery Knee Replacement Expectations Survey and the twenty-item Hospital for Special Surgery Knee Surgery Expectations Survey. Each required less than five minutes to complete.
CONCLUSIONS: Patients have multiple expectations of knee surgery in the areas of symptom relief and improvement of physical and psychosocial function, and these expectations vary according to the diagnosis. We developed two valid and reliable surveys that can be used preoperatively to direct patient education and shared decision-making and to provide a framework for setting reasonable goals. Reexamining patients' responses postoperatively could provide a way to assess fulfillment of expectations, which is a crucial patient-derived measure of outcome and satisfaction.

PMID 11451969
D R Gill, B F Morrey
The Coonrad-Morrey total elbow arthroplasty in patients who have rheumatoid arthritis. A ten to fifteen-year follow-up study.
J Bone Joint Surg Am. 1998 Sep;80(9):1327-35.
Abstract/Text Sixty-nine patients (seventy-eight elbows) who had rheumatoid arthritis were managed with a Coonrad-Morrey total elbow arthroplasty between 1981 and 1986. At the time of the present review, forty-one patients (forty-six elbows) were alive and had been followed for at least ten years after the procedure (Group 1). The remaining twenty-eight patients (thirty-two elbows) had died or had had a revision less than ten years after the procedure or had been followed for less than ten years (Group 2). The patients in Group 1 had a younger mean age at the time of the procedure, but all other preoperative parameters were similar for both groups. At the latest follow-up evaluation, 97 per cent of the elbows (forty-five of the forty-six in Group 1 and thirty-one of the thirty-two in Group 2) were not painful or were only mildly painful. The mean arc of flexion-extension was 28 to 131 degrees; this represents an increase of 13 degrees (15 degrees in Group 1 and 7 degrees in Group 2) compared with the preoperative value. The mean arc of pronation was 68 degrees, and the mean arc of supination was 62 degrees; this represents an increase of 21 degrees. The results for seventy-four of the seventy-eight elbows (all forty-six in Group 1 and twenty-eight of the thirty-two in Group 2) were considered satisfactory by the patients. One patient thought that the status of the elbow was unchanged compared with preoperatively, and three thought that it was worse. Seventy-six of the seventy-eight elbows had long-term radiographic evaluation; the two remaining elbows were excluded because a resection arthroplasty had been performed. There were two loose ulnar components; one was associated with an infection, and the other had been causing no symptoms at the time of the patient's death. In addition, both components were radiographically loose in an elbow that had had a revision without cement after a previous total elbow arthroplasty. Five bushings (7 per cent) were completely worn, and six (8 per cent) were partially worn. Complications occurred in eleven elbows (14 per cent) and were serious, necessitating reoperation, in ten (13 per cent). Delayed complications included three avulsions of the triceps, two deep infections, two ulnar fractures, and one fracture of an ulnar component. In addition, two elbows were revised because of aseptic loosening. No patient had persistent ulnar neuritis or serious skin complications. At the latest clinical follow-up evaluation, according to the Mayo elbow performance score, forty-three of the seventy-eight elbows had an excellent result; twenty-six, a good result; seven, a fair result; and two (both in Group 2), a poor result. The rate of survival of the prosthesis was 92.4 per cent, with 86 per cent good or excellent and 14 per cent fair or poor results.

PMID 9759818
Brent Graham, Andrew Green, Michelle James, Jeffrey Katz, Marc Swiontkowski
Measuring patient satisfaction in orthopaedic surgery.
J Bone Joint Surg Am. 2015 Jan 7;97(1):80-4. doi: 10.2106/JBJS.N.00811.
Abstract/Text In addition to their wish to understand the clinical results of orthopaedic interventions, clinicians, patients, and payers are increasingly interested in patient satisfaction, both with the process of care and with outcomes. The construct of satisfaction is complex and depends on the context in which care takes place, including the nature of treatment, its setting, and most importantly the expectation of patients prior to treatment. The characteristics of scales that are effective measures of satisfaction are the same as those of all effective measurement instruments--i.e., reliability, validity, and responsiveness. Measurement of patient satisfaction may be especially important in evaluations of established procedures and processes so that the value of those procedures and processes to patients can be more completely understood.

Copyright © 2015 by The Journal of Bone and Joint Surgery, Incorporated.
PMID 25568398
J C T van der Lugt, R B Geskus, P M Rozing
Primary Souter-Strathclyde total elbow prosthesis in rheumatoid arthritis.
J Bone Joint Surg Am. 2004 Mar;86-A(3):465-73.
Abstract/Text BACKGROUND: Total elbow arthroplasty is a well-established treatment for the painful elbow joint in patients with rheumatoid arthritis. We present the results of what we believe to be the first prospective study of the Souter-Strathclyde total elbow prosthesis.
METHODS: Between June 1982 and December 2000, 204 primary total elbow prostheses were inserted in 166 patients who had rheumatoid arthritis. No patient was lost to follow-up. The mean duration of follow-up was 6.4 years. All patients were examined preoperatively, at one and two years postoperatively, and at regular intervals thereafter.
RESULTS: Six of the 204 elbows had pain at rest at the time of the latest follow-up. Ten patients (ten elbows) without previous neurological symptoms had development of paresthesias in the distribution of the ulnar nerve postoperatively. Patients who had pain at rest or at night and those who had ulnar nerve symptoms preoperatively were found to have a significant chance of having the same complaints postoperatively. Pain at rest or at night and a decrease in function during the follow-up period were associated with humeral loosening. Twenty-four elbows had revision of the total elbow prosthesis because of loosening of the humeral component (ten), loosening after fracture (six), dislocation (four), infection (two), restricted range of motion (one), or fracture of the middle part of the humeral shaft, proximal to the prosthesis (one). One prosthesis was removed because of humeral loosening, and eight were removed because of deep infection. Another five prostheses were radiographically loose at the time of the latest follow-up. The rate of implant survival, according to the method of Kaplan-Meier, was 77.4% after ten years and 65.2% after eighteen years.
CONCLUSIONS: Total elbow replacement is associated with a high complication rate and therefore may be warranted only for seriously disabled patients. Currently, the results associated with the Souter-Strathclyde total elbow prosthesis are comparable with the results associated with other prostheses, but loosening of the humeral component remains a concern.
LEVEL OF EVIDENCE: Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence.

PMID 14996870
Christopher P Little, Alastair J Graham, Georgios Karatzas, David A Woods, Andrew J Carr
Outcomes of total elbow arthroplasty for rheumatoid arthritis: comparative study of three implants.
J Bone Joint Surg Am. 2005 Nov;87(11):2439-48. doi: 10.2106/JBJS.D.02927.
Abstract/Text BACKGROUND: As the English-language literature on prosthetic elbow arthroplasty contains only two comparative studies of implants in contemporary use, to our knowledge, comparisons of prosthetic performance is difficult. An improved knowledge of comparative outcomes would be valuable in guiding implant selection.
METHODS: We identified three groups of consecutive patients who had undergone prosthetic elbow arthroplasty with the Souter-Strathclyde, Kudo, or Coonrad-Morrey implant for the treatment of rheumatoid arthritis. There were thirty-three elbows in each group. All procedures were done by or under the supervision of one surgeon. Surviving patients in whom the elbow had not been revised were followed for a mean of sixty-one months after treatment with the Souter-Strathclyde implant, sixty-seven months after treatment with the Kudo implant, and sixty-eight months after treatment with the Coonrad-Morrey implant. Clinical function was assessed on the basis of pain relief and the range of flexion. Survivorship was assessed with use of a life-table method, with revision surgery and radiographic signs of loosening as the end points.
RESULTS: The groups were comparable in terms of age, sex, and mean duration of follow-up. All three implant procedures relieved pain. Sustained improvement in the range of flexion was comparable among the three groups, with no implant procedure dramatically changing the fixed flexion deformity and all three improving maximum flexion. Revision surgery was needed because of infection, dislocation, and aseptic loosening. Survival of the Coonrad-Morrey implant was better than that of the other two implants. The five-year survival rates, with revision and radiographic signs of loosening as the end points, were 85% and 81% for the Souter-Strathclyde implant, 93% and 82% for the Kudo implant, and 90% and 86% for the Coonrad-Morrey implant. While radiographic evidence of loosening of the Coonrad-Morrey implants was less common, we noted focal osteolysis adjacent to 16% of these ulnar components and half of these cases progressed to frank loosening.
CONCLUSIONS: The clinical function of these implants was similar in terms of pain relief and range of motion. We believe that component linkage with the Coonrad-Morrey implant prevents dislocation without increasing the risk of loosening.

PMID 16264119
Anne Christie, Hanne Dagfinrud, Kari Engen Matre, Hilde Iren Flaatten, Hanne Ringen Osnes, Kåre Birger Hagen
Surgical interventions for the rheumatoid shoulder.
Cochrane Database Syst Rev. 2010 Jan 20;(1):CD006188. doi: 10.1002/14651858.CD006188.pub2. Epub 2010 Jan 20.
Abstract/Text BACKGROUND: Involvment of the shoulder joint in patients with rheumatoid arthritis (RA) leads to severe destruction of the glenohumeral joint. When conservative treatment does not result in sufficient improvement, surgical procedures may be considered as the only beneficial treatment option.
OBJECTIVES: To assess beneficial and harmful effects of all forms of surgical treatment in the management of the shoulder in people with rheumatoid arthritis.
SEARCH STRATEGY: Articles were identified by searches in The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, SCISEARCH and reference lists of relevant articles (January 1995 to May 2008).
SELECTION CRITERIA: Randomised Controlled Trials, and Controlled Clinical Trials reporting on effects of shoulder surgery. In addition case-series were included for the assessment of complications.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial quality and extracted the data.
MAIN RESULTS: One RCT, one CCT and 21 case-series were included. The RCT compared cemented versus uncemented humeral stem fixation in arthroplasty and found no significant differences between the two groups after two years (low quality evidence). The CCT compared rotator cuff repair with augmented subscapularis transposition versus subscapularis transposition alone and reported significant differences in favour of the augmented subscapularis transposition after 2 years in function, mean difference (MD) 4.00 on a 0 to 30 scale (95% CI 1.11 to 6.89) and pain, MD 4.00 on a 0 to 20 scale (95% CI 0.84 to 7.16) (low quality evidence). Based on 11 case series (mean follow up 4.5 to 12 years) complications were reported in 11% (95% CI: 9.9% to 12.1%) of the total shoulder arthroplasties, while 10 case-series (mean follow-up 2.7 to 11.3 years) reported complications in 9.9% (95% CI: 8.4% to 11.4%) of the hemiarthroplasties (very low quality evidence).
AUTHORS' CONCLUSIONS: The effects of surgical treatment in the management of the shoulder in people with rheumatoid arthritis are largely unknown due to the paucity of randomised controlled trials.

PMID 20091587
John W Sperling, Robert H Cofield, Cathy D Schleck, W Scott Harmsen
Total shoulder arthroplasty versus hemiarthroplasty for rheumatoid arthritis of the shoulder: results of 303 consecutive cases.
J Shoulder Elbow Surg. 2007 Nov-Dec;16(6):683-90. doi: 10.1016/j.jse.2007.02.135. Epub 2007 Oct 29.
Abstract/Text Between January 1, 1976 and December 31, 1991, 195 total shoulder arthroplasties and 108 hemiarthroplasties were performed in 247 patients in patients with rheumatoid arthritis. One hundred and eighty-seven total shoulder arthroplasties and 95 hemiarthroplasties with complete preoperative evaluation, operative records, and minimum 2-year follow-up (mean, 11.6 years) or follow-up until revision were included in the clinical analysis. Twenty patients had died and 1 was lost to follow-up. All 303 shoulders were included in the survival analysis. There was significant long term pain relief (P < .0001), improvement in active abduction (P < .0001), and external rotation (P < .0001) with both hemiarthroplasty and total shoulder arthroplasty (TSA). There was not a significant difference in improvement in pain and motion comparing hemiarthroplasty and TSA for patients with a thin or torn rotator cuff. However, among patients with an intact rotator cuff, improvement in pain and abduction were significantly greater with TSA. Additionally, among patients with an intact rotator cuff, the risk for revision was significantly lower for TSA (P = .04). Radiographs were available for 152 total shoulder arthroplasties and 63 hemiarthroplasties with a minimum 2-year follow-up. Glenoid erosion was present in 62 of 63 hemiarthroplasties (98%). Glenoid periprosthetic lucency was present in 110 of 152 total shoulder arthroplasties (72%). The data from this study indicate that there is marked long-term pain relief and improvement in motion with shoulder arthroplasty. Among patients with an intact rotator cuff, TSA appears to be the preferred procedure for pain relief, improvement in abduction, and lower risk of revision surgery.

PMID 18029202
O Sneppen, S Fruensgaard, H V Johannsen, B S Olsen, J O Sojbjerg, N H Andersen
Total shoulder replacement in rheumatoid arthritis: proximal migration and loosening.
J Shoulder Elbow Surg. 1996 Jan-Feb;5(1):47-52.
Abstract/Text A prospective study of 62 Neer mark II total shoulder arthroplasties performed during the period from 1981 to 1990 on 51 patients with rheumatoid arthritis was undertaken to evaluate factors associated with component loosening and proximal humeral migration. Thirty-two (51%) showed proximal migration of the humerus before surgery was performed. The mean follow-up time was 92 months (range 52 to 139 months). The results revealed proximal migration in 55% of the patients (34 shoulders), and 40% (25 shoulders) showed progressive radiographic loosening of the glenoid component. Five of 12 press-fit humeral components demonstrated progressive radiographic loosening, whereas no signs of loosening were found in 50 cemented humeral components. In spite of progressive component loosening and progressive migration, this study demonstrated good pain relief in 89% of the patients (55 shoulders) and also a significant improvement in range of movement and function. The presence of proximal humeral migration did not significantly influence the average results-neither pain relief, range of movement, abduction force, nor function. Also, component loosening did not significantly influence the average pain relief, range of movement, abduction force, or function. The risk of clinical asymptomatic loosening is a relatively late complication that is eventually followed by pronounced bone destruction related to the loose component. Long-term radiographic control of total shoulders with rheumatoid arthritis is recommended. Hemiarthroplasty with a cemented humeral prosthesis may be a better treatment in the end stage of rheumatoid arthritis of the shoulder.

PMID 8919442
T Torisu
Isolated avulsion fracture of the tibial attachment of the posterior cruciate ligament.
J Bone Joint Surg Am. 1977 Jan;59(1):68-72.
Abstract/Text Twenty-one patients with isolated avulsion fracture of the tibial attachment of the posterior cruciate ligament were treated in our hospital during the period 1965 to 1976. Twelve of the patients had fresh injuries and nine, injuries with delayed union or non-union. Twelve of the twenty-one patients were treated conservatively and nine, by surgical repair by means of staple fixation. Detachment of the posterior horn of the meniscus with an avulsed and displaced bone fragment was found in five of the nine patients operated on. All the patients were followed for an average of four years and eight months. Satisfactory results were obtained in every instance.

PMID 833178
M E Torchia, R H Cofield, C R Settergren
Total shoulder arthroplasty with the Neer prosthesis: long-term results.
J Shoulder Elbow Surg. 1997 Nov-Dec;6(6):495-505.
Abstract/Text We determined the outcome of 113 total shoulder replacement arthroplasties performed with a Neer prosthesis between 1975 and 1981. The operations were performed for the treatment of osteoarthritis, rheumatoid arthritis, and old fractures or dislocations with traumatic arthritis. The probability of implant survival was 93% after 10 years and 87% after 15 years. Complications requiring reoperation developed in 14 shoulders. Seventy-nine patients with 89 replacements were available for follow-up a minimum of 5 years after the operation (mean 12.2 years, range 5 to 17 years). Relief from moderate or severe pain was achieved in 83% of shoulders. Active abduction improved by an average of 40 degrees to an average of 117 degrees. The amount of elevation that was regained was related to the amount of rotator cuff disease. Seventy-five glenoid components developed bone-cement radiolucencies, and 39 (44%) glenoid components had radiographic evidence of definite loosening. Glenoid loosening was associated with pain. A shift in position of the humeral component occurred in 49% of the press-fit stems and in none of the cemented stems. Humeral component loosening was not associated with pain.

PMID 9437598
Ashwin V Deshmukh, Mark Koris, David Zurakowski, Thomas S Thornhill
Total shoulder arthroplasty: long-term survivorship, functional outcome, and quality of life.
J Shoulder Elbow Surg. 2005 Sep-Oct;14(5):471-9. doi: 10.1016/j.jse.2005.02.009.
Abstract/Text This study examines long-term outcomes of total shoulder arthroplasty (TSA) via survivorship analysis, patient questionnaires, and minimum 10-year physical examinations. The study group consisted of 320 consecutive TSAs performed in 267 patients between 1974 and 1988. Diagnoses included rheumatoid arthritis (69%), osteoarthritis (22%), and juvenile rheumatoid arthritis (4.7%). Minimum 10-year physical examination follow-up was obtained on a subset of 72 TSAs at a mean (+/- SD) of 14.0 +/- 2.7 years. A Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire was obtained from 80 patients with 103 TSAs at a mean of 15.4 +/- 3.4 years after the index procedure (range, 10.4-23.2 years). Kaplan-Meier survivorship rates with revision as the endpoint at 5, 10, 15, and 20 years were 98%, 93%, 88%, and 85%, respectively. Of the shoulders, 22 (6.9%) required a revision, most commonly for loosening of one or both components (15 shoulders). Dislocation occurred earlier than other causes of revision or complication (P < .05, analysis of variance). Minimum 10-year physical examination follow-up revealed lasting, significant improvements in range of motion and strength. The patients' subjective assessments of TSA were favorable in that 92% felt that their shoulder was "much better" or "better" after TSA. The mean DASH score was 49 +/- 25; no significant differences were found among diagnoses. Long-term analysis of the Neer-type TSA revealed survivorship rates comparable to other joint replacements. The significant improvements in relief of pain, shoulder range of motion, and strength are associated with a high degree of patient satisfaction.

PMID 16194737
Nahum Rosenberg, Lars Neumann, Amit Modi, Istvan J Mersich, Angus W Wallace
Improvements in survival of the uncemented Nottingham Total Shoulder prosthesis: a prospective comparative study.
BMC Musculoskelet Disord. 2007 Aug 4;8:76. doi: 10.1186/1471-2474-8-76. Epub 2007 Aug 4.
Abstract/Text BACKGROUND: The uncemented Nottingham Total Shoulder Replacement prosthesis system (Nottingham TSR) was developed from the previous BioModular shoulder prosthesis taking into consideration the causes of the initial implant's failure. We investigated the impact of changes in the design of Nottingham TSR prosthesis on its survivorship rate.
METHODS: Survivorship analyses of three types of uncemented total shoulder arthroplasty prostheses (BioModular, initial Nottingham TSR and current Nottingham TSR systems with 11, 8 and 4 year survivorship data respectively) were compared. All these prostheses were implanted for the treatment of disabling pain in the shoulder due to primary and secondary osteoarthritis or rheumatoid arthritis. Each type of the prosthesis studied was implanted in consecutive group of patients--90 patients with BioModular system, 103 with the initial Nottingham TSR and 34 patients with the current Nottingham TSR system. The comparison of the annual cumulative survivorship values in the compatible time range between the three groups was done according to the paired t test.
RESULTS: The 8-year and 11-year survivorship rates for the initially used modified BioModular uncemented prosthesis were relatively low (75.6% and 71.7% respectively) comparing to the reported survivorship of the conventional cemented implants. The 8-year survivorship for the uncemented Nottingham TSR prosthesis was significantly higher (81.8%), but still not in the desired range of above 90%, that is found in other cemented designs. Glenoid component loosening was the main factor of prosthesis failure in both prostheses and mainly occurred in the first 4 postoperative years. The 4-year survivorship of the currently re-designed Nottingham TSR prosthesis, with hydroxylapatite coating of the glenoid baseplate, was significantly higher, 93.1% as compared to 85.1% of the previous Nottingham TSR.
CONCLUSION: The initial Nottingham shoulder prosthesis showed significantly higher survivorship than the BioModular uncemented prosthesis, but lower than expected. Subsequently re-designed Nottingham TSR system presented a high short term survivorship rate that encourages its ongoing use.

PMID 17683577
S Wakitani, K Imoto, M Saito, N Murata, A Hirooka, M Yoneda, T Ochi
Evaluation of surgeries for rheumatoid shoulder based on the destruction pattern.
J Rheumatol. 1999 Jan;26(1):41-6.
Abstract/Text OBJECTIVE: To identify the optimal treatment of rheumatoid shoulder, we analyzed the clinical results of shoulder surgeries according to each type of shoulder destruction pattern.
METHODS: Forty-seven shoulder surgeries for rheumatoid arthritis (18 arthroscopic synovectomies, 10 total shoulder replacements, 19 humeral head replacements) were assessed clinically and compared in regard to 5 different destruction patterns of rheumatoid shoulder (nonprogressive, arthrosis-like, erosive, collapse, and mutilating patterns).
RESULTS: For nonprogressive-type shoulders, we were able to obtain both pain relief and range of motion (ROM) improvement with arthroscopic synovectomy. For erosive-type shoulders, we could obtain pain relief but no ROM improvement with synovectomy; and we obtained both pain relief and ROM improvement with prosthetic replacement. For the collapse-type shoulders, we could not obtain pain relief or ROM improvement with arthroscopic synovectomy, but did obtain pain relief with prosthetic replacement. For mutilating-type shoulders, we could obtain only pain relief with prosthetic replacement. The results of the various surgeries for rheumatoid shoulder were distinctly different depending on the shoulder destruction patterns.
CONCLUSION: These findings could be of value for the selection of treatment, including a surgical procedure, for rheumatoid shoulders. For the nonprogressive-type and for erosive-type shoulders before bone destruction progresses, arthroscopic synovectomy should be selected. For erosive-type shoulders after bone destruction, for the collapse-type, and for mutilating-type shoulders, prosthetic replacement should be selected. In regard to the prosthetic replacement, the humeral component should be cemented because the incidence of migration in noncemented humeral component procedures was high.

PMID 9918238
松田雅彦,浜崎充,高木理彰,後藤康夫:関節リウマチ肩に対する人工関節置換術の長期成績.整形外科 2005;56(11):1413-1416.
I A Trail, D Nuttall
The results of shoulder arthroplasty in patients with rheumatoid arthritis.
J Bone Joint Surg Br. 2002 Nov;84(8):1121-5.
Abstract/Text We have performed a clinical and radiological analysis of 105 shoulder arthroplasties in patients with rheumatoid arthritis. The clinical results showed improvements in the Constant-Murley and Association of Shoulder and Elbow Surgeons score of 21 and 35, respectively. Both were statistically significant (p < 0.001). This improvement was maintained over a period of 8.8 years. There was no statistically significant difference in the scores after hemiarthroplasty and those after total arthroplasty. The presence of an intact rotator cuff was associated with improved function in both groups. In spite of the use of an uncemented humeral stem, no implant was radiologically loose or at risk. There was lucency in a single zone in 14 implants. One glenoid component was at risk and 16 had lucency in a single zone. There was, however, a significant difference in the amount of lucency which was associated with pegged and keeled glenoid components (p = 0.005). In the group with hemiarthroplasty, two or more years after surgery there was superior migration of the humeral component by more than 5 mm in 18 shoulders (28%) and medial migration by more than 2 mm in eight (16%). Both superior and medial migration had an effect on the outcome. Revision was undertaken in four patients for persistent pain relating to medial migration. With revision taken as the endpoint for survival after eight years, 92% were found to be still in situ.

PMID 12463655
M J Woodruff, A P Cohen, J G Bradley
Arthroplasty of the shoulder in rheumatoid arthritis with rotator cuff dysfunction.
Int Orthop. 2003;27(1):7-10. doi: 10.1007/s00264-002-0406-9. Epub 2002 Oct 23.
Abstract/Text We carried out a retrospective analysis of 17 total shoulder replacements using the reversed Delta III prosthesis in patients with rheumatoid arthritis of the glenohumeral joint complicated by rotator cuff dysfunction. Outcome was assessed using the Constant-Murley scoring system. In addition, general health status was assessed with the Short Form Health Survey and radiographical analysis of the prostheses undertaken. Mean age at the time of surgery was 64 years. Thirteen shoulders were followed up for more than 5 years (mean 87 months). Median Constant-Murley score was 59.0; median scores for general health were 33.40 and 49.36 for the physical and mental components respectively. Radiographical analysis revealed evidence of lucencies about the humeral component in all cases and about the glenoid component in five cases. Despite the good clinical results, the high incidence of radiographical lucencies is of concern.

PMID 12582801
宮本隆司,菅本一臣:当科における人工肩関節置換術の成績―関節リウマチ肩の機能評価を中心に.臨整外 2003;38(9):1137-1142.
P L R Wood, H Prem, C Sutton
Total ankle replacement: medium-term results in 200 Scandinavian total ankle replacements.
J Bone Joint Surg Br. 2008 May;90(5):605-9. doi: 10.1302/0301-620X.90B5.19677.
Abstract/Text We describe the medium-term results of a prospective study of 200 total ankle replacements at a single-centre using the Scandinavian Total Ankle Replacement. A total of 24 ankles (12%) have been revised, 20 by fusion and four by further replacement and 27 patients (33 ankles) have died. All the surviving patients were seen at a minimum of five years after operation. The five-year survival was 93.3% (95% confidence interval (CI) 89.8 to 96.8) and the ten-year survival 80.3% (95% CI 71.0 to 89.6). Anterior subluxation of the talus, often seen on the lateral radiograph in osteoarthritic ankles, was corrected and, in most instances, the anatomical alignment was restored by total ankle replacement. The orientation of the tibial component, as seen on the lateral radiograph, also affects the position of the talus and if not correct can hold the talus in an abnormal anterior position. Subtalar arthritis may continue to progress after total ankle replacement. Our results are similar to those published previously.

PMID 18450626
Masataka Nishikawa, Tetsuya Tomita, Masakazu Fujii, Tetsu Watanabe, Jun Hashimoto, Kazuomi Sugamoto, Takahiro Ochi, Hideki Yoshikawa
Total ankle replacement in rheumatoid arthritis.
Int Orthop. 2004 Apr;28(2):123-6. doi: 10.1007/s00264-003-0512-3. Epub 2003 Oct 7.
Abstract/Text We reviewed 21 patients with rheumatoid arthritis who had a total ankle replacement between 1984 and 2000. The average follow-up was 72 (15-169) months. Clinical results were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) score. At the latest review, three ankles had been revised. Two ankles were excellent, seven good, three fair, and 12 poor. Eleven patients with 13 ankles had residual pain, with radiographs showing a high incidence of radiolucent lines. Migration of the tibial component was seen in 13 ankles and collapse of talus in nine. Although clinical results were poor, patient satisfaction was not.

PMID 15224171
G A Primiano, T C Reef
Disruption of the proximal carpal arch of the hand.
J Bone Joint Surg Am. 1974 Mar;56(2):328-32.
Abstract/Text
PMID 4452693
Eerik T Skyttä, Helka Koivu, Antti Eskelinen, Mikko Ikävalko, Pekka Paavolainen, Ville Remes
Total ankle replacement: a population-based study of 515 cases from the Finnish Arthroplasty Register.
Acta Orthop. 2010 Feb;81(1):114-8. doi: 10.3109/17453671003685459.
Abstract/Text BACKGROUND AND PURPOSE: Although total ankle replacement (TAR) is a recognized procedure for treatment of the painful arthritic ankle, the best choice of implant and the long-term results are still unknown. We evaluated the survival of two TAR designs and factors associated with survival using data from the nationwide arthroplasty registry in Finland.
METHODS: 573 primary TARs were performed during the period 1982-2006 because of rheumatic, arthritic, or posttraumatic ankle degeneration. We selected contemporary TAR designs that were each used in more than 40 operations, including the S.T.A.R. (n = 217) and AES (n = 298), to assess their respective survival rates. The mean age of the patients was 55 (17-86) years and 63% of operations were performed in women. Kaplan-Meier analysis and the Cox regression model were used for survival analysis. The effects of age, sex, diagnosis, and hospital volume were also studied.
RESULTS: The annual incidence of TAR was 1.5 per 10(5) inhabitants. The 5-year overall survivorship for the whole TAR cohort was 83% (95% CI: 81-86), which agrees with earlier reports. The most frequent reasons for revision were aseptic loosening of one or both of the prosthesis components (39%) and instability (39%). We found no difference in survival rate between the S.T.A.R. and AES designs. Furthermore, age, sex, diagnosis, and hospital volume (< 10 and > 100 replacements in each of 17 hospitals) did not affect the TAR survival.
INTERPRETATION: Based on our findings, we cannot conclude that any prosthesis was superior to any other. A high number of technical errors in primary TARs suggests that this low-volume field of implant arthroplasty should be centralized to fewer units.

PMID 20180720
Nikolaos Gougoulias, Anil Khanna, Nicola Maffulli
How successful are current ankle replacements?: a systematic review of the literature.
Clin Orthop Relat Res. 2010 Jan;468(1):199-208. doi: 10.1007/s11999-009-0987-3. Epub 2009 Jul 18.
Abstract/Text UNLABELLED: Total ankle arthroplasty provides an alternative to arthrodesis for management of ankle arthritis. What is the outcome of total ankle arthroplasty implants currently in use? We conducted a systematic literature search of studies reporting on the outcome of total ankle arthroplasty. We included peer-reviewed studies reporting on at least 20 total ankle arthroplasties with currently used implants, with a minimum followup of 2 years. The Coleman Methodology Score was used to evaluate the quality of the studies. Thirteen Level IV studies of overall good quality reporting on 1105 total ankle arthroplasties (234 Agility, 344 STAR, 153 Buechel-Pappas, 152 HINTEGRA, 98 Salto, 70 TNK, 54 Mobility) were included. Residual pain was common (range, 27%-60%), superficial wound complications occurred in 0% to 14.7%, deep infections occurred in 0% to 4.6% of ankles, and ankle function improved after total ankle arthroplasty. The overall failure rate was approximately 10% at 5 years with a wide range (range, 0%-32%) between different centers. Superiority of an implant design over another cannot be supported by the available data.
LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

PMID 19618248
Niels C Jensen, Frank Linde
Long-term follow-up on 33 TPR ankle joint replacements in 26 patients with rheumatoid arthritis.
Foot Ankle Surg. 2009;15(3):123-6. doi: 10.1016/j.fas.2008.08.009. Epub 2008 Oct 26.
Abstract/Text BACKGROUND: There exist very few long-term follow-up studies, on total ankle replacement (TAR). In the present study a cohort of rheumatoid arthritic (RA) were followed for up to 23 years.
METHODS: Thirty-three TAR were performed in 26 RA patients from 1980 to 1993. Removal of the prostheses and radiolucency was considered endpoints. All patients were followed to prosthesis failure or until death of the patients or until January 2008.
RESULTS: Two patients with 3 prostheses were still alive with their prosthesis in place. Eighteen patients with 23 prostheses had died with their prosthesis in place. Two patients had their ipsilateral leg amputated 12 and 14 years after operation of unrelated causes. Five prostheses in 4 patients had been removed. The 10 years prosthesis survival was 85%, when removal is the endpoint.
CONCLUSIONS: The long-term survival of this first generation type of TAR adds some optimism to the development of TAR.

PMID 19635418
Bjørg-Tilde S Fevang, Stein A Lie, Leif I Havelin, Johan G Brun, Arne Skredderstuen, Ove Furnes
257 ankle arthroplasties performed in Norway between 1994 and 2005.
Acta Orthop. 2007 Oct;78(5):575-83. doi: 10.1080/17453670710014257.
Abstract/Text BACKGROUND AND PURPOSE: There have been few reports on the long-term outcome of ankle replacements. The Norwegian Arthroplasty Register has been registering ankle replacements since 1994, but no analysis of these data has been published to date. Here we report data on the use of total ankle replacements and the revision rate in the Norwegian population over a 12-year period.
METHODS: We used the Norwegian Arthroplasty Register to find ankle arthroplasties performed between 1994 and 2005. Patient demographics, diagnoses, brands of prosthesis, revisions, and time trends were investigated.
RESULTS: There were 257 primary ankle replacements, 32 of which were cemented TPR prostheses and 212 of which were cementless STAR prostheses. The overall 5- year and 10-year survival was 89% and 76%, respectively. Prosthesis survival was the same for the cementless STAR prosthesis and the cemented TPR prosthesis. There was no significant influence of age, sex, type of prosthesis, diagnosis, or year of operation on the risk of revision. The incidence of ankle replacements due to osteoarthritis, but not due to inflammatory arthritis, increased over the years.
INTERPRETATION: The revision rate was acceptable compared to other studies of ankle arthroplasties, but high compared to total knee and hip arthroplasties. The overall incidence of ankle replacements increased during the study period.

PMID 17966015
Anders Henricson, Jan-Åke Nilsson, Ake Carlsson
10-year survival of total ankle arthroplasties: a report on 780 cases from the Swedish Ankle Register.
Acta Orthop. 2011 Dec;82(6):655-9. doi: 10.3109/17453674.2011.636678. Epub 2011 Nov 9.
Abstract/Text BACKGROUND AND PURPOSE: There is an ongoing need to review large series of total ankle replacements (TARs) for monitoring of changes in practice and their outcome. 4 national registries, including the Swedish Ankle Register, have previously reported their 5-year results. We now present an extended series with a longer follow-up, and with a 10-year survival analysis.
PATIENTS AND METHODS: Records of uncemented 3-component TARs were retrospectively reviewed, determining risk factors such as age, sex, and diagnosis. Prosthetic survival rates were calculated with exchange or removal of components as endpoint-excluding incidental exchange of the polyethylene meniscus.
RESULTS: Of the 780 prostheses implanted since 1993, 168 (22%) had been revised by June 15, 2010. The overall survival rate fell from 0.81 (95% CI: 0.79-0.83) at 5 years to 0.69 (95% CI: 0.67-0.71) at 10 years. The survival rate was higher, although not statistically significantly so, during the latter part of the period investigated. Excluding the STAR prosthesis, the survival rate for all the remaining designs was 0.78 at 10 years. Women below the age of 60 with osteoarthritis were at a higher risk of revision, but age did not influence the outcome in men or women with rheumatoid arthritis. Revisions due to technical mistakes at the index surgery and instability were undertaken earlier than revisions for other reasons.
INTERPRETATION: The results have slowly improved during the 18-year period investigated. However, we do not believe that the survival rates of ankle replacements in the near future will approach those of hip and knee replacements-even though improved instrumentation and design of the prostheses, together with better patient selection, will presumably give better results.

PMID 22066551
Hongmou Zhao, Yunfeng Yang, Guangrong Yu, Jiaqian Zhou
A systematic review of outcome and failure rate of uncemented Scandinavian total ankle replacement.
Int Orthop. 2011 Dec;35(12):1751-8. doi: 10.1007/s00264-011-1339-y. Epub 2011 Sep 1.
Abstract/Text PURPOSE: The purpose of this study was to provide cumulative data about the intermediate to long-term outcome of Scandinavian total ankle replacement (STAR) in the literature and to provide a summary of survival rate, implant failure rate and reasons.
METHODS: A comprehensive search for all relevant articles published in English and German from January 1995 to May 2011 was conducted. Two reviewers evaluated each study to determine whether it was eligible for inclusion and, if so, collected data of interest. The intermediate to long-term outcomes were determined. Evidence-based meta-analytic pooling of results across studies was performed to determine survival and failure rates.
RESULTS: Sixteen primary studies with 2,088 implants were identified. The mean American Orthopaedic Foot and Ankle Society (AOFAS) score was 77.8 points, and the mean Kofoed ankle score was 76.4 points. The pooled mean five year survival rate was 85.9% [95% confidence interval (CI) 80.9-90.3], and the pooled mean ten year survival rate was 71.1% (95% CI 60.9-81.5). Pooled failure rate was 11.1% (95% CI 7.6 -14.9), with a mean follow-up time of 52 months; 41% failed within one year of initial operation. The first three reasons associated with implant failure were aseptic loosening (5.2%), malalignment (1.7%) and deep infection (1.0%).
CONCLUSIONS: We found that STAR prosthesis achieved encouraging results in terms of intermediate to long-term outcome. The five and ten year survival rates were acceptable. However, the failure rate was still high. The major reasons for implant failure were aseptic loosening and malalignment. Maybe the increase of surgeons' experience and patient selection could improve outcomes and decrease failure rate.

PMID 21881886
Xan F Courville, Paul J Hecht, Anna N A Tosteson
Is total ankle arthroplasty a cost-effective alternative to ankle fusion?
Clin Orthop Relat Res. 2011 Jun;469(6):1721-7. doi: 10.1007/s11999-011-1848-4. Epub 2011 Mar 11.
Abstract/Text BACKGROUND: Total ankle arthroplasty (TAA) implantation is increasing, as the potential for pain relief and restoration of function and risks are compared with those for ankle fusion. A previous analysis with a simple decision tree suggested TAA was cost-effective compared with ankle fusion. However, reevaluation is warranted with the availability of newer, more costly implants and longer-term patient followup data.
QUESTIONS/PURPOSES: Considering all direct medical costs regardless of the payer, we determined if TAA remains a cost-effective alternative to ankle fusion when updated evidence is considered.
PATIENTS AND METHODS: Using a Markov model, we evaluated expected costs and quality-adjusted life years (QALY) for a 60-year-old hypothetical cohort with end-stage ankle arthritis treated with either TAA or ankle fusion. Costs were estimated from 2007 diagnosis-related group (DRG) and current procedural terminology (CPT) codes for each procedure. Rates were extracted from the literature. The incremental cost-effectiveness ratio (ICER), a measure of added cost divided by QALY gained for TAA relative to ankle fusion, was estimated. To identify factors affecting the value of TAA, sensitivity analyses were performed on all variables.
RESULTS: TAA costs $20,200 more than ankle fusion and resulted in 1.7 additional QALY, with an ICER of $11,800/QALY gained. Few variables in the sensitivity analyses resulted in TAA no longer being cost-effective.
CONCLUSION: Despite more costly implants and longer followup, TAA remains a cost-effective alternative to ankle fusion in a 60-year-old cohort with end-stage ankle arthritis.

PMID 21394559
Charles L Saltzman, Robert G Kadoko, Jin Soo Suh
Treatment of isolated ankle osteoarthritis with arthrodesis or the total ankle replacement: a comparison of early outcomes.
Clin Orthop Surg. 2010 Mar;2(1):1-7. doi: 10.4055/cios.2010.2.1.1. Epub 2010 Feb 4.
Abstract/Text BACKGROUND: Ankle arthrodesis and replacement are two common surgical treatment options for end-stage ankle osteoarthritis. However, the relative value of these alternative procedures is not well defined. This study compared the clinical and radiographic outcomes as well as the early perioperative complications of the two procedures.
METHODS: Between January 2, 1998 and May 31, 2002, 138 patients were treated with ankle fusion or replacements. Seventy one patients had isolated posttraumatic or primary ankle arthritis. However, patients with inflammatory arthritis, neuropathic arthritis, concomitant hind foot fusion, revision procedures and two component system ankle replacement were excluded. Among them, one group of 42 patients had a total ankle replacement (TAR), whereas the other group of 29 patients underwent ankle fusion. A complete follow-up could be performed on 89% (37/42) and 73% (23/29) of the TAR and ankle fusion group, respectively. The mean follow-up period was 4.2 years (range, 2.2 to 5.9 years).
RESULTS: The outcomes of both groups were compared using a student's t-test. Only the short form heath survery mental component summary score and Ankle Osteoarthritis Scale pain scale showed significantly better outcomes in the TAR group (p < 0.05). In the radiographic evaluation, there was no significant difference in preoperative and postoperative osteoarthritis between the TAR and fusion groups.
CONCLUSIONS: The clinical results of TAR are similar to those of fusion at an average follow-up of 4 years. However, the arthroplasty group showed better pain relief and more postoperative complications that required surgery.

PMID 20190994
Gerard P Slobogean, Alastair Younger, Kelly L Apostle, Carlo A Marra, Kevin Wing, Murray Penner, Tim Daniels, Mark Glazebrook
Preference-based quality of life of end-stage ankle arthritis treated with arthroplasty or arthrodesis.
Foot Ankle Int. 2010 Jul;31(7):563-6. doi: 10.3113/FAI.2010.0563.
Abstract/Text BACKGROUND: Health state values, or "utilities,'' are an important preference-based measure of quality of life used by health economists. This study describes the utilities reported by a multicenter cohort of subjects with end-stage ankle arthritis treated with ankle arthrodesis or total ankle arthroplasty.
MATERIALS AND METHODS: Subjects with end-stage ankle arthritis were enrolled in a multicenter prospective cohort study. All subjects received either ankle arthrodesis or total ankle arthroplasty. Participants completed baseline SF-36 outcome evaluations preoperatively and at 1-year followup. Preference-based quality of life was assessed using health state values (HSVs) derived from the SF-36 (SF-6D transformation).
RESULTS: 107 subjects were included. The mean baseline SF-6D health state value for the TAA group was 0.67 (95% CI 0.64 to 0.69) and 0.66 (95% CI 0.63 to 0.68) for the arthrodesis group. At 1-year followup, the mean reported health state value was 0.73 (95% CI 0.71 to 0.76) for the total ankle arthroplasty group and 0.73 (95% CI 0.70 to 0.76) for the ankle arthrodesis group. The 1-year followup results approach age- and gender-matched US population norms. Health state values poorly correlated with age, however, significant differences between genders were detected.
CONCLUSION: These data demonstrate an improvement in preference-based quality of life following ankle arthroplasty or arthrodesis. The results also provide necessary data that can be used in future cost-effectiveness analyses.

PMID 20663421
Luis Esparragoza, Carlos Vidal, Javier Vaquero
Comparative study of the quality of life between arthrodesis and total arthroplasty substitution of the ankle.
J Foot Ankle Surg. 2011 Jul-Aug;50(4):383-7. doi: 10.1053/j.jfas.2011.03.004. Epub 2011 May 4.
Abstract/Text Our goal was to compare the health status of patients with primary and secondary arthrosis of the ankle before and after arthrodesis or total substitution arthroplasty, and to determine the improvement in quality of life and whether there is any difference between these techniques. A prospective comparative study of clinical-functional evaluation was performed using the American Orthopaedic Foot & Ankle Society (AOFAS) scale and quality of life with the short form (SF)-36 questionnaire in patients who underwent arthrodesis (16 cases) or total substitution arthroplasty of the ankle (14 cases) after 2 years (mean, 25.2 months) of follow-up after surgery, in comparison with the baseline preoperative status. In this series of comparable patients, both techniques showed a statistically significant improvement with regard to the clinical evaluation and quality of life after 2 years of follow-up; the arthrodesis group increased from mean AOFAS values of 37.12 to 45.62 (P = .055) and mean SF-36 values of 32.96 to 46.25 (P = .008), whereas in the arthroplasty group the mean values of AOFAS increased from 33 to 62 (P = .024) and SF-36 from 33.62 to 59.84 (P = .001). Nevertheless, in all cases the improvement was statistically greater in patients who underwent arthroplasty than in those who underwent arthrodesis (P = .048 for AOFAS, and P = .026 for SF-36). In conclusion, arthrodesis and arthroplasty represent good options in the surgical treatment of ankle arthrosis, providing both a significant improvement in function and in the health perception and quality of life of the patient. New-generation total ankle substitution arthroplasty provides an improvement in the quality of life and perception of general health of the patient with arthrosis of this joint, when this technique is compared with surgical fusion.

Copyright © 2011 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.
PMID 21536459
Fabian G Krause, Markus Windolf, Biraj Bora, Murray J Penner, Kevin J Wing, Alastair S E Younger
Impact of complications in total ankle replacement and ankle arthrodesis analyzed with a validated outcome measurement.
J Bone Joint Surg Am. 2011 May 4;93(9):830-9. doi: 10.2106/JBJS.J.00103. Epub 2011 Apr 15.
Abstract/Text BACKGROUND: Major modifications in the design and techniques of total ankle replacement have challenged the perception that ankle arthrodesis is the treatment of choice for end-stage ankle arthritis. High complication and revision rates have been reported after both procedures.
METHODS: We performed radiographic evaluations at a mean of thirty-nine months following 114 total ankle replacements done with use of commonly used implants and at a mean of thirty-seven months following forty-seven ankle arthrodeses. The mean age was sixty-four years for the patients (fifty-one female and sixty-three male) who underwent total ankle replacement and fifty-nine years in the patients (fifteen female and thirty-two male) who underwent ankle arthrodesis. The impact of complications was analyzed with use of the Ankle Osteoarthritis Scale (AOS), a validated outcome instrument.
RESULTS: Both groups had significant improvement in the mean AOS score (p < 0.001). There was no significant difference in the mean improvement between the two groups (p = 0.96). The complication rate was 54% following total ankle replacement and 26% following ankle arthrodesis, which was a significant difference (p = 0.003). The impact of major complications on the AOS outcome score was significant in both the total ankle replacement group (p = 0.031) and the ankle arthrodesis group (p = 0.02).
CONCLUSIONS: At the time of follow-up, at a minimum of two years postoperatively, the outcomes of total ankle replacement and ankle arthrodesis, with regard to pain relief and function, were comparable. While the rate of complications was significantly higher following total ankle replacement, the impact of complications on outcome was clinically relevant in both groups.

PMID 21498491
Dae Gyu Kwon, Chin Youb Chung, Moon Seok Park, Ki Hyuk Sung, Tae Won Kim, Kyoung Min Lee
Arthroplasty versus arthrodesis for end-stage ankle arthritis: decision analysis using Markov model.
Int Orthop. 2011 Nov;35(11):1647-53. doi: 10.1007/s00264-011-1336-1. Epub 2011 Aug 20.
Abstract/Text BACKGROUND: Total ankle arthroplasty and arthrodesis are the two mainstreams of treatment for end-stage ankle arthritis. This study was performed to determine which is a better choice for ankle arthritis, using a decision analysis and Markov model to reflect the repetitive nature of revision arthroplasty.
METHODS: Based on current published evidence, a decision tree was constructed to compare the clinical outcomes of total ankle arthroplasty and arthrodesis, which contained the possible clinical events and the probabilities. Total ankle arthroplasty was subject to revision arthroplasty, and a Markov model was adopted for this branch to reflect this repetitive trait of the procedure. Arthrodesis could cause adjacent arthritis, and a conventional decision analysis model was adopted for this branch. Quality well-being index score was used for clinical outcome assessment, which was the utility in the decision tree. Sensitivity analysis was performed to test the stability of the decision tree and the threshold values.
RESULTS: The model favoured total ankle arthroplasty over arthrodesis in terms of quality well-being index score. Sensitivity analysis showed that the model was considerably stable, unaffected by the changes in probabilities of failure after total ankle arthroplasty and adjacent arthritis after arthrodesis.
CONCLUSIONS: Based on current evidence, total ankle arthroplasty was found to be a better treatment than arthrodesis for ankle arthritis. Future development in the implant materials, improved understanding of ankle biomechanics, and surgical techniques will further enhance the clinical outcome of total ankle arthroplasty.

PMID 21858503
Reinhard Schuh, Jochen Hofstaetter, Martin Krismer, Roberto Bevoni, Reinhard Windhager, Hans-Joerg Trnka
Total ankle arthroplasty versus ankle arthrodesis. Comparison of sports, recreational activities and functional outcome.
Int Orthop. 2012 Jun;36(6):1207-14. doi: 10.1007/s00264-011-1455-8. Epub 2011 Dec 16.
Abstract/Text PURPOSE: Ankle arthrodesis (AAD) and total ankle replacement (TAR) are the major surgical treatment options for severe ankle arthritis. There is an ongoing discussion in the orthopaedic community whether ankle arthrodesis or ankle fusion should be the treatment of choice for end stage osteoarthritis. The purpose of this study was to compare the participation in sports and recreational activities in patients who underwent either AAD or TAR for end-stage osteoarthritis of the ankle.
METHODS: A total of 41 patients (21 ankle arthrodesis /20 TAR) were examined at 34.5 (SD18.0) months after surgery. At follow-up, pre- and postoperative participation in sports and recreational activities has been assessed. Activity levels were determined using the ankle activity score according to Halasi et al. and the University of California at Los Angeles (UCLA) activity scale. Clinical and functional outcome was assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) hindfoot score. The percentage of patients participating in sports and recreational activities, UCLA score and AOFAS score were compared between both treatment groups.
RESULTS: In the AAD group 86% were active in sports preoperatively and in the TAR group this number was 76%. Postoperatively in both groups 76% were active in sports (AAD, p = 0.08). The UCLA score was 7.0 (± 1.9) in the AAD group and 6.8 (± 1.8) in the TAR group (p = 0.78). The AOFAS score reached 75.6 (± 14) in the AAD group and 75.6 (± 16) in the TAR group (p = 0.97). The ankle activity score decrease was statistically significant for both groups (p = 0.047).
CONCLUSIONS: Our study revealed no significant difference between the groups concerning activity levels, participation in sports activities, UCLA and AOFAS score. After AAD the number of patients participating in sports decreased. However, this change was not statistically significant.

PMID 22173565
S L Haddad, J C Coetzee, R Estok, K Fahrbach, D Banel, L Nalysnyk
Intermediate and long-term outcomes of total ankle arthroplasty and ankle arthrodesis. A systematic review of the literature.
J Bone Joint Surg Am. 2007 Sep;89(9):1899-905. doi: 10.2106/JBJS.F.01149.
Abstract/Text BACKGROUND: The efficacy of total ankle replacement compared with that of ankle fusion continues to be one of the most debated topics in foot and ankle surgery. The purpose of this study was to determine whether there are sufficient objective cumulative data in the literature to compare the two procedures. A systematic review of the literature addressing the intermediate and long-term outcomes of interest in total ankle arthroplasty and ankle arthrodesis was performed.
METHODS: A comprehensive search of MEDLINE for all relevant articles published in English from January 1, 1990, to March 2005 was conducted. Additionally, relevant abstracts from the 2003 and 2004 annual proceedings of major orthopaedic meetings were eligible. Two reviewers evaluated each study to determine whether it was eligible for inclusion and collected the data of interest. Meta-analytic pooling of group results across studies was performed for the two procedures. The analysis of the outcomes focused on second-generation ankle implants.
RESULTS: The systematic review identified forty-nine primary studies, ten of which evaluated total ankle arthroplasty in a total of 852 patients and thirty-nine of which evaluated ankle arthrodesis in a total of 1262 patients. The mean AOFAS (American Orthopaedic Foot and Ankle Society) Ankle-Hindfoot Scale score was 78.2 points (95% confidence interval, 71.9 to 84.5) for the patients treated with total ankle arthroplasty and 75.6 points (95% confidence interval, 71.6 to 79.6) for those treated with arthrodesis. Meta-analytic mean results showed 38% of the patients treated with total ankle arthroplasty had an excellent result, 30.5% had a good result, 5.5% had a fair result, and 24% had a poor result. In the arthrodesis group, the corresponding values were 31%, 37%, 13%, and 13%. The five-year implant survival rate was 78% (95% confidence interval, 69.0% to 87.6%) and the ten-year survival rate was 77% (95% confidence interval, 63.3% to 90.8%). The revision rate following total ankle arthroplasty was 7% (95% confidence interval, 3.5% to 10.9%) with the primary reason for the revisions being loosening and/or subsidence (28%). The revision rate following ankle arthrodesis was 9% (95% confidence interval, 5.5% to 11.6%), with the main reason for the revisions being nonunion (65%). One percent of the patients who had undergone total ankle arthroplasty required a below-the-knee amputation compared with 5% in the ankle arthrodesis group.
CONCLUSIONS: On the basis of these findings, the intermediate outcome of total ankle arthroplasty appears to be similar to that of ankle arthrodesis; however, data were sparse. Comparative studies are needed to strengthen this conclusion.

PMID 17768184
Nelson F SooHoo, David S Zingmond, Clifford Y Ko
Comparison of reoperation rates following ankle arthrodesis and total ankle arthroplasty.
J Bone Joint Surg Am. 2007 Oct;89(10):2143-9. doi: 10.2106/JBJS.F.01611.
Abstract/Text BACKGROUND: The role of ankle arthroplasty in the treatment of ankle arthritis is controversial. Ankle fusion is commonly performed, but there is ongoing concern about functional limitations and arthritis in the adjacent subtalar joint following ankle arthrodesis. The use of ankle arthroplasty as an alternative to ankle fusion is expanding, but reported results have been limited to those in case series. The purpose of this study was to compare the reoperation rates following ankle arthrodesis and ankle replacement on the basis of observational, population-based data from all inpatient admissions in California over a ten-year period. Our hypothesis was that patients treated with ankle replacement would have a lower risk of undergoing subtalar fusion but a higher overall risk of undergoing major revision surgery.
METHODS: We used California's hospital discharge database to identify patients who had undergone ankle replacement or ankle arthrodesis as inpatients in the years 1995 through 2004. Short-term outcomes, including rates of major revision surgery, pulmonary embolism, amputation, and infection, were examined. Long-term outcomes that were analyzed included the rates of major revision surgery and subtalar joint fusion. Logistic and proportional hazard regression models were used to estimate the impact of the choice of ankle replacement or ankle fusion on the rates of adverse outcomes, with adjustment for patient factors including age and comorbidity.
RESULTS: A total of 4705 ankle fusions and 480 ankle replacements were performed during the ten-year study period. Patients who had undergone ankle replacement had an increased risk of device-related infection and of having a major revision procedure. The rates of major revision surgery after ankle replacement were 9% at one year and 23% at five years compared with 5% and 11% following ankle arthrodesis. Patients treated with ankle arthrodesis had a higher rate of subtalar fusion at five years postoperatively (2.8%) than did those treated with ankle replacement (0.7%). Regression analysis confirmed a significant increase in the risk of major revision surgery (hazard ratio, 1.93 [95% confidence interval, 1.50 to 2.49]; p < 0.001) but a decreased risk of subtalar fusion (hazard ratio, 0.28 [95% confidence interval, 0.09 to 0.87]; p = 0.03) in patients treated with ankle replacement compared with those treated with ankle fusion.
CONCLUSIONS: This study confirms that, compared with ankle fusion, ankle replacement is associated with a higher risk of complications but also potential advantages in terms of a decreased risk of the patient requiring subtalar joint fusion. Additional controlled trials are needed to clarify the appropriate indications for ankle arthrodesis and ankle replacement.

PMID 17908889
Kenji Takenouchi, Minoru Morishita, Kimihisa Saitoh, Kouichi Wauke, Hiroshi Takahashi, Masakazu Nagashima
Long-term results of ankle arthrodesis using an intramedullary nail with fins in patients with rheumatoid arthritis hindfoot deformity.
J Nippon Med Sch. 2009 Oct;76(5):240-6.
Abstract/Text We report herein the results of a retrospective study of 30 ankle arthrodesis procedures performed in 27 patients with rheumatoid arthritis from 1994 through 2001 using a novel design of intramedullary nail with fins. The surgical treatment, post-operative management and clinical evaluation are described. The clinical evaluation, at an average follow-up period of more than 10 years, was based on foot disease scores from the Japanese Orthopaedic Association and scores obtained preoperatively, postoperatively, and during follow-ups 1 (November 2001) and 2 (November 2007) were compared. These variables showed significant improvement between before surgery and at follow-up evaluations. Non-union was not observed and no marked changes of the Chopart joint were seen between before surgery and at follow-up evaluations. Delayed wound healing was seen in 9 of 30 joints. However, infection neuropathy or other complications were not found. We conclude that arthrodesis using an intramedullary nail with fins is an effective treatment for severe hindfoot deformities in patients with rheumatoid arthritis because no cases of non-union were observed and because clinical results over the mean 10-year follow-up period were good or satisfactory.

PMID 19915307
N Voutilainen, H Pätiälä, T Juutilainen, E K Partio, P Rokkanen
Long-term results of ankle and triple arthrodeses fixed with self-reinforced polylevolactic acid implants in patients with rheumatoid arthritis.
Rheumatol Int. 2001 Aug;20(6):229-34.
Abstract/Text Self-reinforcing polylevolactic acid (SR-PLLA) implants have been used in arthrodeses of patients with rheumatoid arthritis. No long-term evaluation has been published so far. Two patients (three ankles) with destruction of the ankle joint and seven with destruction of the subtalar joint received ten arthrodeses. One out of three ankle arthrodeses healed and nonunion developed in two. Five out of seven triple arthrodeses attained bony union. Two patients with malunion of the subtalar and talonavicular joints are free of symptoms and need no reoperation. One superficial wound infection healed by oral antibiotics. In one patient, an ankle arthrodesis was performed 6 years after the triple arthrodesis of the left foot. SR-PLLA implants can be used in triple arthrodesis in rheumatoid arthritic patients with good results comparable to those of other studies. The problems with nonunion of ankle arthrodeses noticed in former studies are also attributable to this fixation method.

PMID 11563581
E A Belt, H Mäenpää, M U Lehto
Outcome of ankle arthrodesis performed by dowel technique in patients with rheumatic disease.
Foot Ankle Int. 2001 Aug;22(8):666-9.
Abstract/Text Between the years 1988 and 1994, 19 ankle arthrodeses were performed on 18 patients (nine men) using the dowel technique. Patients were followed until a fusion had occurred, a non-union was successfully rearthrodesed, or a pseudoarthrosis was stabilized with orthosis treatment. Patients' radiographs and documents were analyzed both preoperatively and during the healing period. Subtalar fusion had been performed previously in eight ankles and rheumatoid destruction of subtalar complex was observed in seven other hindfeet. The original dowel method was used in 13 ankles and a modified procedure was performed in six. Local bone grafts were utilized. Solid fusion was achieved in 13 ankles (68%), but with delayed union in two cases. Non-union was present in six ankles, and two re-arthrodeses were performed with successful fusion in the other. Orthosis treatment was necessary in three of five ankles with permanent non-union. One chronic infection leading to non-union was detected. Only two of the six ankles (33%) with the modified technique using additional exposures healed without complications. In the dowel technique, the preoperative position of the ankle and location of the guiding Kirschner wire are of crucial importance and the original technique with a large cutter should be used. In patients with rheumatic disease, this fusion method did not yield acceptable results.

PMID 11527029
Charlotte Mabille, Yannick Degboe, Arnaud Constantin, Thomas Barnetche, Alain Cantagrel, Adeline Ruyssen-Witrand
Infectious risk associated to orthopaedic surgery for rheumatoid arthritis patients treated by anti-TNFalpha.
Joint Bone Spine. 2017 Jul;84(4):441-445. doi: 10.1016/j.jbspin.2016.06.011. Epub 2016 Sep 20.
Abstract/Text INTRODUCTION: Although biotherapy has greatly improved the prognosis of RA many patients have still recourse to an orthopaedic surgery. The current recommendation for scheduled surgery is to discontinue administration of the biological agent two to six weeks before surgery. Reinitiating anti-TNF therapy is proposed when the patient has healed. We wanted to know whether patients treated with anti-TNFα were exposed to an infectious risk undergoing a surgical procedure and if discontinuation of anti-TNFα therapy altered the risk of surgical infection.
METHODS: We conducted a systematic review of the literature in PubMed, Embase and Cochrane until March 2014. We selected studies that reported post-operative infections by comparing patients treated with anti-TNFα to patients treated with csDMARD without biological treatment, or patients who continued anti-TNFα therapy to the patients who discontinued treatment prior to surgery.
RESULTS: A first meta-analysis of 12 studies evaluating postoperative infection risk in patients treated with anti-TNFα showed that the postoperative infection risk doubled (RR=1.81 [1.31-2.50]). Seven studies were grouped into a second meta-analysis to evaluate the benefit of the preventive discontinuation of anti-TNFα. Discontinuation of treatment did not alter the post-operative infection risk significantly: RR=0.69 [0.39-1.21].
CONCLUSION: This study showed that patients treated with anti-TNFα were more at risk of post-operative infection undergoing orthopaedic surgery. Preventive discontinuation of anti-TNFα does not seem to change this risk.

Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.
PMID 27663754
Marine Clay, Arnaud Mazouyes, Melanie Gilson, Philippe Gaudin, Athan Baillet
Risk of postoperative infections and the discontinuation of TNF inhibitors in patients with rheumatoid arthritis: A meta-analysis.
Joint Bone Spine. 2016 Dec;83(6):701-705. doi: 10.1016/j.jbspin.2015.10.019. Epub 2016 Apr 23.
Abstract/Text OBJECTIVE: To determine whether continuation of tumor necrosis factor inhibitors (TNFi) before surgery increases the risk of surgical site infection (SSI) in rheumatoid arthritis (RA) patients.
METHODS: A systematic review of the literature was conducted from January 2000 to May first 2014, using the databases of PubMed, Cochrane review, Embase, and manual research of abstracts presented in scientific congresses. Most included studies were retrospective. We compared the risk of SSI in the case of discontinuation of TNFi versus continuing TNFi treatment before a surgery.
RESULTS: Six studies, with a total of 2743 patients (1360 in the group continuing TNFi agent and 1383 in the group discontinuing TNFi) were included. There was a decreased risk of SSI in patients stopping TNFi (relative risk [RR]=0.62 [95% confidence interval [CI] 0.43-0.89], P=0.99, I2=0%). Concerning overall complications, there was also a decreased risk in patients discontinuing TNFi treatment (RR=0.60 [95% CI 0.42-0.87], P=0.26, I2=25%).
CONCLUSION: This meta-analysis showed an increased risk of SSI in patients under TNF inhibitor, and a decreased risk of SSI in case of interruption of treatment during the perioperative time.

Copyright © 2016 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.
PMID 27118016
Eunice J Kim, Harold R Collard, Talmadge E King
Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern.
Chest. 2009 Nov;136(5):1397-405. doi: 10.1378/chest.09-0444.
Abstract/Text Interstitial lung disease (ILD) is a frequent extraarticular manifestation of rheumatoid arthritis (RA). While the nonspecific interstitial pneumonia pattern predominates in most forms of connective tissue-associated ILD, studies in patients with RA-associated ILD (RA-ILD) suggest that the usual interstitial pneumonia (UIP) pattern is more common in this patient population. High-resolution CT (HRCT) scans appear accurate in identifying UIP pattern in many patients with RA-ILD. Although the data are limited, UIP pattern appears to predict worse survival in RA-ILD patients. Larger, prospective, multicenter studies are needed to confirm this finding. We propose that the evaluation of patients with RA-ILD should focus on identifying those with UIP pattern on HRCT scans, as these patients are likely to carry a worse prognosis. In patients in whom the underlying pattern cannot be determined by HRCT scanning, surgical lung biopsy should be considered.

PMID 19892679
奥田恭章ほか:高分解能CTによる慢性関節リウマチにおける間質性肺炎/肺線維症の検討.リウマチ 1993;33:12-19.
Yutaro Nakamura, Takafumi Suda, Yusuke Kaida, Masato Kono, Hironao Hozumi, Dai Hashimoto, Noriyuki Enomoto, Tomoyuki Fujisawa, Naoki Inui, Shiro Imokawa, Kazumasa Yasuda, Toshihiro Shirai, Hideki Suganuma, Satoru Morita, Hiroshi Hayakawa, Yasuo Takehara, Thomas V Colby, Kingo Chida
Rheumatoid lung disease: prognostic analysis of 54 biopsy-proven cases.
Respir Med. 2012 Aug;106(8):1164-9. doi: 10.1016/j.rmed.2012.04.004. Epub 2012 May 3.
Abstract/Text OBJECTIVE: To investigate the prognostic significance of histopathological characteristics in patients with biopsy-proven rheumatoid lung disease (RLD).
MATERIALS AND METHODS: Retrospective analysis was conducted on samples from 54 RLD patients who underwent surgical lung biopsies (SLBs) at Hamamatsu University Hospital and affiliated hospitals between 1980 and 2009. The overall survival rate, the spectrum of histopathological diagnosis and their associated prognostic significance were investigated.
RESULTS: The study group consisted of 30 men and 24 women with a median age of 60.3 years. Histopathological analysis revealed the following: usual interstitial pneumonia (UIP), 15 cases; nonspecific interstitial pneumonia/fibrosis, 16 cases; organizing pneumonia, 4 cases; unclassifiable, 2 cases; desquamative interstitial pneumonia, 1 case; and bronchiolar disease, 16 cases. In survival outcome, 10 yr survival rate was 76.6%. Patients with UIP had significantly worse prognosis than those with non-UIP (RLD cases except those with UIP) (p = 0.0452).
CONCLUSION: RLD includes several histopathological groups. Patients with UIP have worse survival than those with other types of RLD. Histopathological diagnosis may have a major impact on prognostication in patients with RLD.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22560113
Ganesh Raghu, Harold R Collard, Jim J Egan, Fernando J Martinez, Juergen Behr, Kevin K Brown, Thomas V Colby, Jean-François Cordier, Kevin R Flaherty, Joseph A Lasky, David A Lynch, Jay H Ryu, Jeffrey J Swigris, Athol U Wells, Julio Ancochea, Demosthenes Bouros, Carlos Carvalho, Ulrich Costabel, Masahito Ebina, David M Hansell, Takeshi Johkoh, Dong Soon Kim, Talmadge E King, Yasuhiro Kondoh, Jeffrey Myers, Nestor L Müller, Andrew G Nicholson, Luca Richeldi, Moisés Selman, Rosalind F Dudden, Barbara S Griss, Shandra L Protzko, Holger J Schünemann, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis
An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.
Am J Respir Crit Care Med. 2011 Mar 15;183(6):788-824. doi: 10.1164/rccm.2009-040GL.
Abstract/Text This document is an international evidence-based guideline on the diagnosis and management of idiopathic pulmonary fibrosis, and is a collaborative effort of the American Thoracic Society, the European Respiratory Society, the Japanese Respiratory Society, and the Latin American Thoracic Association. It represents the current state of knowledge regarding idiopathic pulmonary fibrosis (IPF), and contains sections on definition and epidemiology, risk factors, diagnosis, natural history, staging and prognosis, treatment, and monitoring disease course. For the diagnosis and treatment sections, pragmatic GRADE evidence-based methodology was applied in a question-based format. For each diagnosis and treatment question, the committee graded the quality of the evidence available (high, moderate, low, or very low), and made a recommendation (yes or no, strong or weak). Recommendations were based on majority vote. It is emphasized that clinicians must spend adequate time with patients to discuss patients' values and preferences and decide on the appropriate course of action.

PMID 21471066
Angelo de Lauretis, Srihari Veeraraghavan, Elisabetta Renzoni
Review series: Aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ?
Chron Respir Dis. 2011;8(1):53-82. doi: 10.1177/1479972310393758.
Abstract/Text The lung is frequently involved in connective tissue diseases (CTDs), although the frequency of lung manifestations varies according to the type of CTD. Interstitial lung diseases (ILD) are frequently seen in CTDs, particularly systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA), accounting for a significant proportion of deaths. A large percentage of patients with CTD-associated ILD has limited and stable disease, not requiring treatment. However, a significant minority has severe and/or progressive disease, necessitating prompt initiation of treatment. CTD-ILD histological patterns include non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP). NSIP is the most common pattern in all CTDs, except for RA, characterized by a higher frequency of UIP. ILD can present acutely or chronically, with acute presentations being more common in systemic lupus erythematosus and PM/DM. Idiopathic pulmonary fibrosis (IPF) is a progressively worsening ILD characterized by inflammation and fibrosis. The characteristic histological pattern of IPF is UIP. Interestingly, a UIP pattern is associated with a significantly better survival in CTD-related disease compared to the idiopathic variety. Prognosis in IPF is dismal, with a median survival since diagnosis of 2-3 years. No treatment regimen has been shown to improve survival in IPF. By contrast, although there have been only two randomized placebo-controlled trials investigating the effect of immunosuppressive treatment in SSc-associated ILD, clinical experience suggests that immunosuppressive drugs in CTD-related ILDs are capable of benefiting a significant proportion of patients, particularly those with certain histological patterns of disease. This review will essentially focus on CTD-associated ILD and will compare aspects of clinical presentation and management to those of IPF.

PMID 21339375
Y Tsuchiya, N Takayanagi, H Sugiura, Y Miyahara, D Tokunaga, Y Kawabata, Y Sugita
Lung diseases directly associated with rheumatoid arthritis and their relationship to outcome.
Eur Respir J. 2011 Jun;37(6):1411-7. doi: 10.1183/09031936.00019210. Epub 2010 Sep 30.
Abstract/Text The outcome and cause of death of each lung disease directly associated with rheumatoid arthritis (RA-LD) have been poorly investigated. A retrospective study was conducted of 144 patients with RA-LD, in whom the median follow-up period after the initial visit for a respiratory examination was 4.5 yrs. A total of 57 patients were identified with usual interstitial pneumonia (UIP), 31 with bronchiectasis, 16 with nonspecific interstitial pneumonia (NSIP), 11 with bronchiolitis, five with organising pneumonia (OP), five with diffuse alveolar damage (DAD) and 19 with combined disease. The 5-yr survival rates were 36.6% in the UIP group, 87.1% in the bronchiectasis group, 93.8% in the NSIP group, 88.9% in the bronchiolitis group, 60.0% in the OP group and 20.0% in the DAD group. Survival of patients with DAD was worse than that of patients with UIP. Overall, survival of patients with UIP was worse than that of patients with bronchiectasis, NSIP or bronchiolitis. Of the 144 patients, 71 (49.3%) died, of whom 58 (81.7%) died due to respiratory lesions. Of patients with RA-LD, patients with DAD experienced the highest mortality, and the survival of patients with UIP was worse than that of patients with NSIP.

PMID 20884744
I-Nae Park, Dong Soon Kim, Tae Sun Shim, Chae-Man Lim, Sang Do Lee, Younsuck Koh, Woo Sung Kim, Won Dong Kim, Se Jin Jang, Thomas V Colby
Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary fibrosis.
Chest. 2007 Jul;132(1):214-20. doi: 10.1378/chest.07-0323. Epub 2007 Mar 30.
Abstract/Text BACKGROUND: Acute exacerbation (AE) in idiopathic pulmonary fibrosis (IPF) is increasingly recognized as a relatively common and highly morbid clinical event. However, clinical data on AE in non-IPF interstitial pneumonia are sparse. This study was performed to find the frequency, clinical features, and outcome of AE in non-IPF interstitial pneumonia.
METHODS: Retrospective analysis of 10 patients who satisfied the modified Akira criteria for AE during follow-up of 74 patients with surgical lung biopsy-confirmed idiopathic nonspecific interstitial pneumonia (I-NSIP) and 93 patients with biopsy-confirmed interstitial pneumonia associated with collagen vascular disease (CVD-IP).
RESULTS: AE occurred in six patients with I-NSIP (1-year frequency, 4.2%) and in four patients with CVD-IP (rheumatoid arthritis [RA], n = 3; scleroderma, n = 1), with 1-year frequency of 3.3%. Median age was 58 years (range, 47 to 75); six patients were female. AE occurred in two patients immediately after surgical biopsy. Median duration of acute symptom before hospital admission was 10 days (range, 1 to 30). Median ratio of Pao(2) to the fraction of inspired oxygen (Fio(2)) was 172 (range, 107 to 273), and Pao(2)/Fio(2) ratio was < 200 in six patients. Surgical lung biopsy performed at the time of AE in two patients revealed diffuse alveolar damage superimposed on nonspecific interstitial pneumonia pattern. Four patients with I-NSIP survived to discharge and were followed up for 24 months (range, 6 to 121).
CONCLUSION: AE occurred in the patients with I-NSIP with apparently better prognosis. In patients with CVD-IP, AE occurred mostly with RA-usual interstitial pneumonia in our small series with poor outcome.

PMID 17400667
千葉茂樹,蛯名雅仁:剥離性間質性肺炎,呼吸細気管支炎関連性間質性肺炎,気腫合併肺線維症.間質性肺炎を究める(滝澤始編).メジカルビュー社,2012;190-195.
Y Suzuki, R Uehara, C Tajima, A Noguchi, M Ide, Y Ichikawa, Y Mizushima
Elevation of serum hepatic aminotransferases during treatment of rheumatoid arthritis with low-dose methotrexate. Risk factors and response to folic acid.
Scand J Rheumatol. 1999;28(5):273-81.
Abstract/Text Sixty-six rheumatoid arthritis (RA) patients were analyzed retrospectively to assess the incidence and risk factors for elevation of serum hepatic aminotransferases during methotrexate (MTX) therapy. The effect of folate supplementation on serum ALT and RA activity was evaluated prospectively in 14 patients who showed a sustained high serum level of ALT. The frequency of elevation of serum AST or ALT was 4-5 times greater than in patients taking other DMARDs. Multivariate linear regression analysis demonstrated that elevation of ALT was independently associated with sex (female), obesity, baseline ALT, MTX dose, and gastrointestinal side effects. Folate supplementation caused ALT levels to decrease in all patients within 3 months. Eleven patients showed no change of RA activity, but 3 patients dropped out of the study because of the exacerbation of RA. These results suggest that careful monitoring of serum hepatic aminotransferases is necessary in patients with predisposing factors, especially those receiving more than 0.15 mg/kg of MTX weekly. Folate supplementation can reverse the sustained elevation of ALT, but might cause exacerbation of RA in some patients.

PMID 10568423
D M van der Heijde, P L van Riel, M A van Leeuwen, M A van 't Hof, M H van Rijswijk, L B van de Putte
Prognostic factors for radiographic damage and physical disability in early rheumatoid arthritis. A prospective follow-up study of 147 patients.
Br J Rheumatol. 1992 Aug;31(8):519-25.
Abstract/Text We studied the influence of demographic, clinical, laboratory and genetic features and radiographic damage at onset on the outcome after 2 years in a prospective study of 147 patients with classical or definite RA with disease duration shorter than 1 year at entry. Outcome was determined by physical disability and by radiographic damage of hands and feet. By means of multiple regression analysis and discriminant analysis outcome was explained from variables at the start and during the first 6 months. No clinically relevant conclusions could be made for physical disability due to the low explained variance and small number of patients with bad physical disability. Radiographic damage after 2 years was predicted by high disease activity at the start (measured as erythrocyte sedimentation rate, C-reactive protein or Disease Activity Score) combined with DR4 or DR2 (as a prognostically favourable factor) and rheumatoid factor positivity. Radiographic damage could be better predicted if disease activity during the first 6 months was included. Absence or presence of progression of radiographic damage could be correctly predicted in 83% of the patients.

PMID 1386548
J Allain, A Saraux, C Guedes, I Valls, V Devauchelle, P Le Goff
Prevalence of symptomatic bronchiectasis in patients with rheumatoid arthritis.
Rev Rhum Engl Ed. 1997 Oct;64(10):531-7.
Abstract/Text OBJECTIVE: To evaluate the prevalence of symptomatic bronchiectasis in patients with rheumatoid arthritis.
METHODS: Cross-sectional retrospective study of 453 rheumatoid arthritis patients. All patients completed a questionnaire designed to detect manifestations of bronchiectasis and had a chest film taken. Computed tomography of the chest was performed in those patients whose chest film was normal.
RESULTS: Thirteen patients (2.9%), all female, had symptoms that met Walker's criteria for definite (n = 7) or probable (n = 6) bronchiectasis. Symptom onset was during childhood or adolescence in 69% of cases and antedated the first symptoms of rheumatoid arthritis in all patients but one. Six of the 13 patients (46%) had chest film abnormalities suggestive of bronchiectasis, and three of the remaining seven patients had abnormal computed tomography findings, yielding a total of nine cases of bronchiectasis confirmed by imaging studies among the 13 patients with suggestive symptoms (69%). This proportion rose to 90% when the three patients who failed to come to their computed tomography appointment were excluded.
CONCLUSION: Using a methodological approach similar to that previously used by pneumologists, we found a 2.9% prevalence of symptomatic bronchiectasis in a population of hospitalized rheumatoid arthritis patients, which is higher than the 0.03% prevalence previously reported in the population at large.

PMID 9385689
中島洋:関節リウマチの呼吸器病変.呼吸器科 2005;8:432-436.
T Perez, M Remy-Jardin, B Cortet
Airways involvement in rheumatoid arthritis: clinical, functional, and HRCT findings.
Am J Respir Crit Care Med. 1998 May;157(5 Pt 1):1658-65. doi: 10.1164/ajrccm.157.5.9710018.
Abstract/Text The aim of the present study was to assess the prevalence and characteristics of airways involvement in rheumatoid arthritis (RA) patients in the absence of interstitial lung disease. We prospectively evaluated, with high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs), 50 patients with RA (nine males and 41 females; mean age: 57.8 yr), including 39 nonsmokers and 11 smokers (mean cigarette consumption: 15.3 pack-yr) without radiographic evidence of RA-related lung changes. PFTs demonstrated airway obstruction (i.e., reduced FEV1/VC) in nine patients (18%) and small airways disease (SAD) (i.e., decreased FEF(25-75), defined as exceeding the predicted value by 1.64 residual SD [RSD] or more, and/or an increased phase III slope > 2 SD by single breath nitrogen washout) in four patients (8%). HRCT demonstrated bronchial and/or lung abnormalities in 35 cases (70%), consisting of air trapping (n = 16; 32%), cylindral bronchiectasis (n = 15; 30%), mild heterogeneity in lung attenuation (n = 10; 20%), and/or centrilobular areas of high attenuation (n = 3; 6%). Airway obstruction and SAD were correlated with the presence of bronchiectasis and bronchial-wall thickening (p = 0.003), and with bronchial infection (p = 0.01), but were unrelated to rheumatologic data. FEF(25-75) was reduced and the slope of phase III was increased in patients with airway changes on HRCT scans, whereas no PFT abnormalities were found in 13 of 15 patients with normal HRCT scans. HRCT depicted features of SAD in 20 of the 33 patients with normal PFTs. HRCT findings were unrelated to rheumatologic data. A high prevalence of airway abnormalities as assessed with HRCT and/or PFTs was observed in our RA population. HRCT appears to be more sensitive than PFTs for detecting small airways disease.

PMID 9603152
D M Geddes, B Corrin, D A Brewerton, R J Davies, M Turner-Warwick
Progressive airway obliteration in adults and its association with rheumatoid disease.
Q J Med. 1977 Oct;46(184):427-44.
Abstract/Text Six patients with rapidly progressive airway obliteration in the absence of chronic bronchitis or emphysema are reported. Because this pattern of lung disease is very uncommon and five of the six patients had classical rheumatoid arthritis an association between the two diseases is suggested. The patients presented with rapidly developing breathlessness, and râles and a high-pitched mid-inspiratory squeak were heard over the lung fields. Chest radiographs showed distended lungs but were otherwise normal. Tests of lung fuction showed airflow obstruction, most marked at low lung volumes, with air trapping. The carbon monoxide gas transfer coefficient, maximum static recoil pressure and static compliance were normal. In spite of treatment with antibiotics, bronchodilators and corticosteroids, five died in respiratory failure five to 18 months after first becoming breathless. Post-mortem examination in four patients showed an obliterative bronchiolitis but no mucous gland hypertrophy or significant emphysema.

PMID 594297
S A Yousem, T V Colby, C B Carrington
Follicular bronchitis/bronchiolitis.
Hum Pathol. 1985 Jul;16(7):700-6.
Abstract/Text Nineteen open lung biopsies demonstrating follicular bronchitis/bronchiolitis were reviewed with special attention to clinical manifestations. Morphologically, follicular bronchitis/bronchiolitis was represented by coalescent reactive germinal centers adjacent to airways in the absence of clinical or pathologic evidence of chronic obstructive pulmonary disease or bronchiectasis. Three clinicopathologic groups were identified: 1) patients with collagen vascular diseases, especially rheumatoid arthritis and Sjögren's syndrome; 2) patients with a familial form of the disease or with immunodeficiency syndromes; and 3) a heterogeneous group of patients with frequent peripheral blood eosinophilia, suggesting a hypersensitivity reaction. Prognosis was related to age at the time of biopsy and, to some extent, to the clinical group. Steroid therapy had inconsistent effects in all groups identified. The differential diagnosis of lymphoid lesions in the lung is also discussed.

PMID 4007845
杉山幸比古:膠原病に関連した細気管支病変.呼吸 2008;27:289-293.
Sakae Homma, Susumu Sakamoto, Masateru Kawabata, Kazuma Kishi, Eiyasu Tsuboi, Noriko Motoi, Akira Hebisawa, Kunihiko Yoshimura
Comparative clinicopathology of obliterative bronchiolitis and diffuse panbronchiolitis.
Respiration. 2006;73(4):481-7. doi: 10.1159/000088684. Epub 2005 Sep 29.
Abstract/Text BACKGROUND: The progressive airway obliteration caused by obliterative bronchiolitis (OB) has been widely noted in the world. In contrast, the obstructive respiratory disorder caused by diffuse panbronchiolitis (DPB) has been reported mainly from Japan. Therefore, there might be a considerable overlap between OB and DPB in Japan.
OBJECTIVES AND METHODS: To clarify the clinicopathological similarities as well as the differences between OB and DPB, 15 patients with OB and 6 patients with DPB were evaluated clinicopathologically.
RESULTS: The underlying disorders in OB were graft-versus-host disease (GVHD) in 7, rheumatoid arthritis in 3, Kartagener's syndrome in 2, and polymyositis/dermatomyositis, non-tuberculous mycobacterial disease and mycoplasmal pneumonia in one each. The lung pathology demonstrated that the primary obstructive lesions were in the membranous bronchioli in OB. In contrast, they were confined to the respiratory bronchioli in DPB. In addition, OB was classified into two major morphologic types, namely, constrictive and cellular. Clinical manifestations included cough and/or dyspnea in 13 with OB and in 6 with DPB, chronic parasinusitis in 3 with cellular OB and in 6 with DPB. The pulmonary function tests revealed obstructive impairments in all patients with OB and DPB. The chest CT images showed small centrilobular nodules in 64% of those with OB and in all with DPB. The prognosis of constrictive OB was worse than that of cellular OB and DPB.
CONCLUSIONS: This study demonstrated that histopathologically marked differences existed between OB and DPB, although striking similarities in clinical manifestations were also noted in both diseases.

PMID 16195663
松尾清一:間質性腎炎.日本臨牀 2002;60(増刊号1):486-492.
H Kobayashi, S Tada, T Fuchigami, Y Okuda, K Takasugi, T Matsumoto, M Iida, K Aoyagi, A Iwashita, Y Daimaru, M Fujishima
Secondary amyloidosis in patients with rheumatoid arthritis: diagnostic and prognostic value of gastroduodenal biopsy.
Br J Rheumatol. 1996 Jan;35(1):44-9.
Abstract/Text Upper gastrointestinal endoscopy was performed in patients with rheumatoid arthritis (RA) during the period 1989-1991, and biopsy specimens were obtained from the stomach and from the duodenum for examining amyloid deposits. Among 407 patients, gastrointestinal amyloidosis was confirmed in 54 (13.3%). Twenty-two patients were regarded as having slight amyloid deposits, while 32 patients were categorized as having marked amyloid deposits. The incidence of clinical manifestations suggestive of systemic amyloidosis was more frequent in the marked deposits group than in the slight deposits group (47% vs 14%, P<0.05). Among the patients who died of manifestations associated with amyloidosis, the survival period following endoscopy was shorter in the marked deposits group than in the slight deposits group. These findings suggest that gastroduodenal biopsies may be useful for diagnosing secondary amyloidosis and that the degree of amyloid deposits seems to be correlated with the clinical manifestations of RA.

PMID 8624622
Thirusha Lane, Julian D Gillmore, Ashutosh D Wechalekar, Philip N Hawkins, Helen J Lachmann
Therapeutic blockade of interleukin-6 by tocilizumab in the management of AA amyloidosis and chronic inflammatory disorders: a case series and review of the literature.
Clin Exp Rheumatol. 2015 Nov-Dec;33(6 Suppl 94):S46-53. Epub 2015 Jun 29.
Abstract/Text OBJECTIVES: AA amyloidosis is the most serious potential complication of chronic inflammatory disorders. The main aim of treatment is to suppress inflammation thereby inhibiting serum amyloid A protein (SAA), which is the precursor of AA amyloid fibrils, to prevent or halt amyloid deposition. Interleukin (IL)-6 blockade is frequently effective in inflammatory conditions, however, there are few published data on its use in AA amyloidosis or the systemic autoinflammatory diseases (SAIDs) or chronic inflammatory conditions. We assessed clinical and serological responses and adverse events associated with tocilizumab (TCZ) use in 20 adult patients with inflammatory disorders refractory to other treatments, including 70% with AA amyloidosis and four with renal transplants.
METHODS: In addition to routine haematology and biochemistry (including SAA) blood panels, patients with AA amyloidosis underwent SAP scintigraphy to quantify amyloid load. Those with SAIDs underwent genetic analysis to identify mutations/variants in known associated genes. Quality of life (QoL) was surveyed using SF-36v2®.
RESULTS: Whole-cohort median pre-treatment SAA fell from 70 to 4 mg/L within 10 days of the first dose; this response has been maintained over an on-treatment follow-up period of 23 months (p<0.0001). AA amyloid deposits either regressed or remained stable. QoL improved in several domains. Infections were the predominant adverse effect experienced, but none resulted in permanent discontinuation of therapy.
CONCLUSIONS: This small series shows that in patients with treatment-refractory chronic inflammatory conditions TCZ can be effective in suppressing inflammation, and in those with AA amyloidosis, can lead to regression of amyloid deposits. Longer follow-up is required to determined long-term safety and efficacy in these conditions.

PMID 26120866
Juan Antonio Avina-Zubieta, Jamie Thomas, Mohsen Sadatsafavi, Allen J Lehman, Diane Lacaille
Risk of incident cardiovascular events in patients with rheumatoid arthritis: a meta-analysis of observational studies.
Ann Rheum Dis. 2012 Sep;71(9):1524-9. doi: 10.1136/annrheumdis-2011-200726. Epub 2012 Mar 16.
Abstract/Text OBJECTIVE: To determine the magnitude of the risk of incident cardiovascular disease (CVD; fatal and non-fatal), including acute myocardial infarction (MI), cerebrovascular accidents (CVA) and congestive heart failure (CHF), in patients with rheumatoid arthritis (RA) compared to the general population through a meta-analysis of controlled observational studies.
METHODS: The authors searched the Medline, Embase, LILACS and Cochrane databases from their inception to June 2011. Observational studies meeting the following criteria were included: (1) prespecified RA criteria; (2) predefined CVD criteria for incident CVD (MI, CVA or CHF); (3) a comparison group; and (4) RR estimates, 95% CI or data for calculating them. The authors calculated the pooled RR using the random-effects model and tested for heterogeneity using the bootstrap version of the Q statistic.
RESULTS: Fourteen studies comprising 41 490 patients met the inclusion criteria. Overall, there was a 48% increased risk of incident CVD in patients with RA (pooled RR 1.48 (95% CI 1.36 to 1.62)). The risks of MI and CVA were increased by 68% (pooled RR 1.68 (95% CI 1.40 to 2.03)) and 41% (pooled RR 1.41 (95% CI 1.14 to 1.74)). The risk of CHF was assessed in only one study (RR 1.87 (95% CI 1.47 to 2.39)). Significant heterogeneity existed in all main analyses. Subgroup analyses showed that inception cohort studies were the only group that did not show a significantly increased risk of CVD (pooled RR 1.12 (95% CI 0.97 to 1.65)).
CONCLUSIONS: Published data indicate that the risk of incident CVD is increased by 48% in patients with RA compared to the general population. Sample and cohort type influenced the estimates of RR.

PMID 22425941
Felty AR:Chronic arthritis in adult associated with splenomegaly and leukopenia:A report of five cases of an unusual clinical syndrome. Johns Hopkins Hosp Bull 35:16, 1924.
Geza P Balint, Peter V Balint
Felty's syndrome.
Best Pract Res Clin Rheumatol. 2004 Oct;18(5):631-45. doi: 10.1016/j.berh.2004.05.002.
Abstract/Text Felty's syndrome (FS) comprises a triad of rheumatoid arthritis (RA), neutropenia and splenomegaly, occurring in less than 1% of RA patients. Clinically it is characterized by severe joint destruction contrasting with moderate or absent joint inflammation and severe extra-articular disease, including a high frequency of rheumatoid nodules, lymphadenopathy, hepatopathy, vasculitis, leg ulcers, skin pigmentation etc. Recurrent bacterial infections are mostly due to the severe, otherwise unexplained neutropenia. The cause of neutropenia lies in both decreased granulopoiesis and increased peripheral destruction of granulocytes. Recurrent infections may lead to increased mortality. Spontaneous remission of the syndrome also occurs. Over 95% of FS patients are positive for rheumatoid factor (RF), 47-100% are positive for antinuclear antibody (ANA), and 78% of patients have the HLA-DR4*0401 antigen. Some 30% of FS patients have large granular lymphocyte (LGL) expansion. LGL expansion associated with uncomplicated RA is immunogenetically and phenotypically very similar to but clinically different from FS. Neutropenia of FS can be effectively treated with disease-modifying anti-rheumatic drugs (DMARDs), the widest experience being with methotrexate (MTX). Results of treatment with granulocyte colony-stimulating factor (G-CSF) are encouraging, but there is no experience with other biological agents. Splenectomy results in immediate improvement of neutropenia in 80% of the patients, but the rate of infection decreases to a lesser degree.

PMID 15454123
G Campion, P J Maddison, N Goulding, I James, M J Ahern, I Watt, D Sansom
The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations.
Medicine (Baltimore). 1990 Mar;69(2):69-80.
Abstract/Text Thirty-two patients with the Felty syndrome, defined by the presence of rheumatoid arthritis, splenomegaly, and neutropenia, have been studied in comparison with 32 patients with rheumatoid arthritis matched for age, sex, and disease duration, and 9 patients with rheumatoid arthritis and idiopathic neutropenia. Patients with the Felty syndrome had severe destructive arthritis, which progressed during follow-up despite little evidence of objective synovitis, and a higher frequency of extra-articular manifestations, including vasculitis. Bacterial infection tended to occur in patients with the lowest neutrophil count but continued to occur in some despite normalization of the WBC. Prognosis was poor and 8 deaths occurred, predominantly from sepsis. Serologic features were prominent. High titers of IgG rheumatoid factor and circulating immune complexes characterized patients with persistent neutropenia. A family history of rheumatoid arthritis was more common in patients with the Felty syndrome. The association with HLA DR4 was very strong; in addition there was an increased frequency of the DQw3 variant, 3b, suggesting that HLA Class II genes in linkage with DR4 may contribute to disease expression.

PMID 1969604
Kam A Newman, Mojtaba Akhtari
Management of autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus.
Autoimmun Rev. 2011 May;10(7):432-7. doi: 10.1016/j.autrev.2011.01.006. Epub 2011 Jan 18.
Abstract/Text Autoimmune neutropenia, caused by neutrophil-specific autoantibodies is a common phenomenon in autoimmune disorders such as Felty's syndrome and systemic lupus erythematosus. Felty's syndrome is associated with neutropenia and splenomegaly in seropositive rheumatoid arthritis which can be severe and with recurrent bacterial infections. Neutropenia is also common in systemic lupus erythematosus and it is included in the current systemic lupus classification criteria. The pathobiology of the autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus is complex, and it could be a major cause of morbidity and mortality due to increased risk of sepsis. Treatment should be individualized on the basis of patient's clinical situation, and prevention or treatment of the infection. Recombinant human granulocyte colony-stimulating factor is a safe and effective therapeutic modality in management of autoimmune neutropenia associated with Felty's syndrome and systemic lupus erythematosus, which stimulates neutrophil production. There is a slight increased risk of exacerbation of the underlying autoimmune disorder, and recombinant human granulocyte colony-stimulating factor dose and frequency should be adjusted at the lowest effective dose.

Copyright © 2010 Elsevier B.V. All rights reserved.
PMID 21255689
S Wassenberg, G Herborn, R Rau
Methotrexate treatment in Felty's syndrome.
Br J Rheumatol. 1998 Aug;37(8):908-11.
Abstract/Text Felty's syndrome is a rare disorder characterized as a systemic manifestation of severe rheumatoid arthritis associated with granulocytopenia and splenomegaly. We report a retrospective analysis of a series of seven patients treated successfully with low-dose methotrexate. leading to sustained clinical improvement (number of swollen joints) and normalization of the granulocyte count for an observation period of 1 yr. Our cohort is the largest ever published with methotrexate treatment of this rare condition. Our results confirm earlier single case reports suggesting methotrexate to be the first-choice treatment nowadays in Felty's syndrome.

PMID 9734684
J Ravindran, N Shenker, A K Bhalla, H Lachmann, P Hawkins
Case report: Response in proteinuria due to AA amyloidosis but not Felty's syndrome in a patient with rheumatoid arthritis treated with TNF-alpha blockade.
Rheumatology (Oxford). 2004 May;43(5):669-72. doi: 10.1093/rheumatology/keh128.
Abstract/Text
PMID 15103032
S J Stanworth, M Bhavnani, C Chattopadhya, H Miller, D R Swinson
Treatment of Felty's syndrome with the haemopoietic growth factor granulocyte colony-stimulating factor (G-CSF).
QJM. 1998 Jan;91(1):49-56.
Abstract/Text Felty's syndrome (FS) (rheumatoid arthritis with neutropenia and splenomegaly) has a poor prognosis, largely because of the high risk of severe infection. Granulocyte colony-stimulating factor (G-CSF) is an emerging treatment for chronic neutropenia. We prospectively monitored its use in eight patients with recurrent infections or who required joint surgery. Significant side-effects were documented in five, including nausea, malaise, generalized joint pains, and in one patient, a vasculitic skin rash. In two patients treatment had to be stopped, and in these cases G-CSF had been started at full vial dosage (300 micrograms/ml filgrastim or 263 micrograms/ml lenograstim) alternate days or daily. G-CSF treatment was continued in three patients by restarting at reduced dose, and changing the proprietary formulation. G-CSF raised the neutrophil count, reduced severe infection, and allowed surgery to be performed. A combined clinical and laboratory index suggested that long-term treatment (up to 3.5 years) did not exacerbate the arthritis. Once on established treatment, it may be possible to use smaller weekly doses of G-CSF to maintain the same clinical benefit. One of the three patients whose FS was associated with a large granular T-cell lymphocytosis showed a reduction in this subset of lymphocytes during G-CSF treatment.

PMID 9519212
C G Barnes, A L Turnbull, B Vernon-Roberts
Felty's syndrome. A clinical and pathological survey of 21 patients and their response to treatment.
Ann Rheum Dis. 1971 Jul;30(4):359-74.
Abstract/Text
PMID 4104268
橋本博史:厚生省特定疾患難治性血管炎調査研究班1995年度研究報告書 p.9 1996.
三森明夫:RAの血管炎(悪性関節リウマチ).膠原病診療ノート.第3版,p.513-515,日本医事新報社,2013年.
Ross E Petty, Taunton R Southwood, Prudence Manners, John Baum, David N Glass, Jose Goldenberg, Xiaohu He, Jose Maldonado-Cocco, Javier Orozco-Alcala, Anne-Marie Prieur, Maria E Suarez-Almazor, Patricia Woo, International League of Associations for Rheumatology
International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001.
J Rheumatol. 2004 Feb;31(2):390-2.
Abstract/Text
PMID 14760812
武井修治ほか:小慢データを利用した若年性特発性関節炎JLAの二次調査.小児慢性特定疾患治療研究事業の登録・管理・評価・情報提供に関する研究.平成19年度総括・分担研究報告書,p102-113,2008.
Hench JJ, Rosenburg EF: Palindromic rheumatism. Arch Intern Med 1944;73:293-321.
van de Laar M, et al: Miscellaneous inflammatory arthritis. In: Eular Compendium on Rheumatic Disease(ed by Bijlsma JWJ), BMJ Publishing Group and European League Against Rheumatism, London, 2009.
P Hannonen, T Möttönen, M Oka
Palindromic rheumatism. A clinical survey of sixty patients.
Scand J Rheumatol. 1987;16(6):413-20.
Abstract/Text Sixty patients with palindromic rheumatism (PR) with a total follow-up time of 598 years and 295 years prospectively are presented. The study shows that PR is not a rare condition, but the syndrome is often ignored or misdiagnosed by the physician. Most cases of PR appear to evolve into chronic arthritis. PR may precede other kinds of systemic diseases, such as SLE, Wegener's granulomatosis, and multiple myeloma. The presence of PR in patients with fibromyalgia is reported in this paper. Gold appears to be the best drug for the treatment of PR. Cases of fibromyalgia and PR are treated successfully with antimalarial drugs. Our proposed diagnostic criteria for PR are as follows: 1) recurrent attacks of sudden-onset mono or polyarthritis or of periarticular tissue inflammation, lasting from a few hours to one week; 2) verification of at least one attack by a physician; 3) subsequent attacks in at least three different joints; 4) exclusion of other forms of arthritides.

PMID 3423751
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、渡邉裕次、井ノ口岳洋、梅田将光および日本医科大学多摩永山病院 副薬剤部長 林太祐による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
狩野俊和 : 特に申告事項無し[2024年]
監修:金子礼志 : 特に申告事項無し[2025年]

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