今日の臨床サポート

ANCA関連血管炎の診断と初期治療(ミミック含む)

著者: 田巻弘道 聖路加国際病院 リウマチ膠原病センター

監修: 岸本暢将 杏林大学医学部 腎臓・リウマチ膠原病内科

著者校正/監修レビュー済:2021/03/03
参考ガイドライン:
  1. 難治性疾患等政策研究事業:ANCA関連血管炎診療ガイドライン2017
  1. ヨーロッパリウマチ学会(EULAR):EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis (2016)
  1. EGPA consensus task force: Eosinophilic Granulomatosis With Polyangiitis (Churg-Strauss)(EGPA) Consensus Task Force Recommendations for Evaluation and Management.
患者向け説明資料

概要・推奨   

  1. ANCA関連血管炎を診断する際には、全体的な臨床像、血清学的検査、必要で可能であれば生検などを組み合わせて行うと同時に、同様の症状をきたすような感染症や悪性腫瘍の除外を行うことも大切である。
  1. 重篤な臓器障害あるいは生命の危機にあるようなANCA関連血管炎の寛解導入療法ではステロイドに加えて、シクロフォスファミドあるいはリツキシマブを併用して治療する。
  1. シクロフォスファミドやリツキシマブを使用するような重篤なANCA関連血管炎で、血漿交換をルーチンで使用することは勧められない。
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  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
  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
  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。
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、林太祐、渡邉裕次、井ノ口岳洋、梅田将光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。
※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、実際の保険適用の査定において保険適用及び保険適用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用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:
田巻弘道 : 講演料(中外製薬)[2021年]
監修:岸本暢将 : 講演料(中外製薬,日本イーライリリー,ノバルティス,ヤンセンファーマ,ユーシービージャパン,田辺三菱製薬,アッヴィ合同会社,エーザイ(株),ブリストル・マイヤーズスクイブ(株),ギリアド・サイエンシズ(株))[2021年]

病態・疫学・診察

イントロダクション  
  1. ANCA(anti-neutrophil cytoplasmic antibody[抗好中球細胞質抗体])関連血管炎は、多発血管炎性肉芽腫症(GPA [granulomatosis with polyangiitis]、以前はウェゲナー肉芽腫症と呼ばれていた)、顕微鏡的多発血管炎(MPA [microscopic polyangiitis])、好酸球性多発血管炎性肉芽腫症(EGPA [eosinophilic granulomatosis with polyangiitis]、以前はチャーグ・ストラウス症候群と呼ばれていた)の3疾患を含み、これらの3疾患は2012年のチャペルヒルコンセンサス会議で小型血管炎に分類されている[1]
  1. GPA、MPA、EGPAは肺胞出血、免疫複合体の沈着のほとんどない半月体形成性急速進行性壊死性腎炎、肺胞出血、多発単神経炎、紫斑などの3疾患に共通する臨床症状をきたす一方で、GPAでは血管外の壊死性肉芽腫性病変、EGPAでは好酸球浸潤に伴う臓器障害並びに好酸球浸潤を伴う肉芽種性病変が出現するなどそれぞれの疾患ごとに異なる臨床症状も認める[2]
  1. ANCAは間接蛍光抗体法で核周囲が染色されるperinuclear-ANCA(P-ANCA)と細胞質が染色されるcytoplasmic ANCA(C-ANCA)との2種類がある。P-ANCAの対応抗原はミエロペルオキシダーゼ(MPO)であり、MPO-ANCAとも呼ばれる。C-ANCAの対応応現はプロテナーゼ3(PR3)であり、PR3-ANCAとも呼ばれる[3]。ANCAはGPA、MPA、EGPAに共通してみとめられるが、GPAではPR3-ANCAが、MPAではMPO-ANCAが陽性となることが多い。EGPAではMPO-ANCAが陽性となることが多いが、EGPAの中でもANCAが陽性となるのは多くとも半数程度とされている[2]
  1. GPA、MPA、EGPAの加療においては、臨床症状を抑える寛解導入期と、寛解に至った後に再燃を防ぐ目的で行う維持期との2期に渡る治療をおこなう。治療薬の選択としては、ステロイドによる治療が行われるとともに、免疫抑制剤や生物学的製剤による加療が追加されることが基本となる。GPAとMPAでは、2種の血管炎が同じ臨床試験で治療薬の評価が行われてきたということもあり、共通した治療戦略が取られるのに対して、EGPAでは好酸球性の症状が出ることもあり、GPAやMPAとは異なる治療戦略をとることが一般的である[4]
  1. 有効な治療薬が見出される以前、GPAは平均生存期間は5カ月、1年以内に82%、2年以内に90%以上が死ぬ病気であった。有効な治療薬の開発とともに現時点では5年生存率が80%程度の疾患となっている[5][6][7]
定義  
  1. 血管炎の医学的な記載の発端は1800年代後半の結節性多発動脈炎となる。その中から、1930年代に結節性多発動脈炎様の所見と壊死性肉芽腫を特徴とする現在でいうところのGPAがWegenerによってなされた。また、結節性多発動脈炎様の症状と喘息や好酸球増多が併発する、現在EGPAと分類されている疾患が1950年代にChurgとStrausによって記述された。このころ、GPAとEGPAの病理像が比較され、似通った所見があるのと同時に異なる所見があることが示されている。また、結節性多発動脈炎の中に、微小動脈瘤がなく肺や壊死性腎炎をきたす一群の記載も1940年代から1950年代に報告された。後々、1980年代に現在MPAとして定義されている疾患が確立していったが、最終的にMPAが正式に血管炎の中で定義づけされるのは1994年のチャペルヒル会議からである[8]
  1. 以前は、結節性多発動脈炎という疾患の中に含まれていたGPA、MPA、EGPAは、臨床症状や病理所見が共通する部分もあったが、臨床症状の違いや病理所見の違いがあるということもあり違う疾患へと分けられるという歴史を辿った。1982年にANCAの存在が最初に記述されたものの[9]当初は注目を浴びていなかったが、後々、GPA、MPA、EGPAの3疾患にANCAが共通してみられることもあり、再度、ANCA関連血管炎という疾患概念が提唱されることとなった。
  1. 現時点での最新の血管炎の定義は2012年にアメリカのノースカロライナ州チャペルヒルで行われた会議にて合意されたものである(<図表>)。ANCA関連血管炎はこの会議において小型血管炎として定義されている。チャペルヒルコンセンサス会議における小型血管炎、ANCA関連血管炎、MPA、GPA、EGPAの定義は以下のようになっている[1]
 
 
  1. 小型血管炎とは臓器実質の小型動脈、細動脈、毛細血管、小静脈に主として起きる血管炎である。

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文献 

著者: J C Jennette, R J Falk, P A Bacon, N Basu, M C Cid, F Ferrario, L F Flores-Suarez, W L Gross, L Guillevin, E C Hagen, G S Hoffman, D R Jayne, C G M Kallenberg, P Lamprecht, C A Langford, R A Luqmani, A D Mahr, E L Matteson, P A Merkel, S Ozen, C D Pusey, N Rasmussen, A J Rees, D G I Scott, U Specks, J H Stone, K Takahashi, R A Watts
雑誌名: Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.37715.
Abstract/Text
PMID 23045170  Arthritis Rheum. 2013 Jan;65(1):1-11. doi: 10.1002/art.・・・
著者: Christian Pagnoux
雑誌名: Eur J Rheumatol. 2016 Sep;3(3):122-133. doi: 10.5152/eurjrheum.2015.0043. Epub 2016 Jan 29.
Abstract/Text Antineutrophil cytoplasm antibody (ANCA)-associated vasculitides are small-vessel vasculitides that include granulomatosis with polyangiitis (formerly Wegener's granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome). Renal-limited ANCA-associated vasculitides can be considered the fourth entity. Despite their rarity and still unknown cause(s), research pertaining to ANCA-associated vasculitides has been very active over the past decades. The pathogenic role of antimyeloperoxidase ANCA (MPO-ANCA) has been supported using several animal models, but that of antiproteinase 3 ANCA (PR3-ANCA) has not been as strongly demonstrated. Moreover, some MPO-ANCA subsets, which are directed against a few specific MPO epitopes, have recently been found to be better associated with disease activity, but a different method than the one presently used in routine detection is required to detect them. B cells possibly play a major role in the pathogenesis because they produce ANCAs, as well as neutrophil abnormalities and imbalances in different T-cell subtypes [T helper (Th)1, Th2, Th17, regulatory cluster of differentiation (CD)4+ CD25+ forkhead box P3 (FoxP3)+ T cells] and/or cytokine-chemokine networks. The alternative complement pathway is also involved, and its blockade has been shown to prevent renal disease in an MPO-ANCA murine model. Other recent studies suggested strongest genetic associations by ANCA type rather than by clinical diagnosis. The induction treatment for severe granulomatosis with polyangiitis and microscopic polyangiitis is relatively well codified but does not (yet) really differ by precise diagnosis or ANCA type. It comprises glucocorticoids combined with another immunosuppressant, cyclophosphamide or rituximab. The choice between the two immunosuppressants must consider the comorbidities, past exposure to cyclophosphamide for relapsers, plans for pregnancy, and also the cost of rituximab. Once remission is achieved, maintenance strategy following cyclophosphamide-based induction relies on less toxic agents such as azathioprine or methotrexate. The optimal maintenance strategy following rituximab-based induction therapy remains to be determined. Preliminary results on rituximab for maintenance therapy appear promising. Efforts are still under way to determine the optimal duration of maintenance therapy, ideally tailored according to the characteristics of each patient and the previous treatment received.

PMID 27733943  Eur J Rheumatol. 2016 Sep;3(3):122-133. doi: 10.5152/eu・・・
著者: Elena Csernok, Frank Moosig
雑誌名: Nat Rev Rheumatol. 2014 Aug;10(8):494-501. doi: 10.1038/nrrheum.2014.78. Epub 2014 Jun 3.
Abstract/Text Detection of antineutrophil cytoplasmic antibodies (ANCAs) is a well-established diagnostic test used to evaluate suspected necrotizing vasculitis of small blood vessels. Conditions associated with these antibodies, collectively referred to as ANCA-associated vasculitides, include granulomatosis with polyangiitis (formerly known as Wegener granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome). The diagnostic utility of ANCA testing depends on the type of assay performed and on the clinical setting. Most laboratories worldwide use standard indirect immunofluorescence tests (IFT) to screen for ANCA and then confirm positive IFT results with antigen-specific tests for proteinase 3 (PR3) and myeloperoxidase (MPO). Developments such as automated image analysis of immunofluorescence patterns, so-called third-generation PR3-ANCA and MPO-ANCA ELISA, and multiplex technology have improved the detection of ANCAs. However, challenges in routine clinical practice remain, including methodological aspects of IFT performance, the diverse antigen-specific assays available, the diagnostic value of testing in clinical settings and the prognostic value of serial ANCA monitoring in the prediction of disease relapse. This Review summarizes the available data on ANCA testing, discusses the usefulness of the various ANCA assays and advises on the clinical indications for the use of ANCA testing.

PMID 24890776  Nat Rev Rheumatol. 2014 Aug;10(8):494-501. doi: 10.1038・・・
著者: Nkechinyere Emejuaiwe
雑誌名: Curr Rheumatol Rep. 2019 May 23;21(7):33. doi: 10.1007/s11926-019-0835-8. Epub 2019 May 23.
Abstract/Text PURPOSE OF REVIEW: The long-term survival of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV) has improved dramatically as a direct result of evolving therapy. This review summarizes evidence-based treatment strategies with currently approved immunosuppressive medications to serve as a guide for practitioners in the management of patients with AAV.
RECENT FINDINGS: Targeted therapy aimed at minimizing treatment-related adverse effects while optimizing effectiveness is a propagated approach. Such tailored therapy considers disease severity and is especially warranted in those at high risk for relapsing vasculitis. As treatment options for AAV become available, the need to tailor therapy has become increasingly relevant to optimize patient outcomes.

PMID 31123922  Curr Rheumatol Rep. 2019 May 23;21(7):33. doi: 10.1007/・・・
著者: E W WALTON
雑誌名: Br Med J. 1958 Aug 2;2(5091):265-70. doi: 10.1136/bmj.2.5091.265.
Abstract/Text
PMID 13560836  Br Med J. 1958 Aug 2;2(5091):265-70. doi: 10.1136/bmj.2・・・
著者: A S Fauci, B F Haynes, P Katz, S M Wolff
雑誌名: Ann Intern Med. 1983 Jan;98(1):76-85. doi: 10.7326/0003-4819-98-1-76.
Abstract/Text Eighty-five patients with Wegener's granulomatosis were studied for 21 years at the National Institutes of Health. Patients were treated with a protocol consisting of cyclophosphamide, 2 mg/kg body weight d, together with prednisone, 1 mg/kg body weight d, followed by conversion of the prednisone to an alternate-day regimen. Complete remissions were achieved in 79 of 85 patients (93%). The mean duration of remission for living patients was 48.2 (+/- 3.6) months. Twenty-three patients are off all therapy for a mean duration of 35.3 (+/- 6.3) months without therapy. This study provides a prospective experience with Wegener's granulomatosis and shows that long-term remissions can be induced and maintained in an extremely high number of patients by the combination of daily cyclophosphamide and alternate-day prednisone therapy.

PMID 6336643  Ann Intern Med. 1983 Jan;98(1):76-85. doi: 10.7326/0003・・・
著者: Oliver Flossmann, Annelies Berden, Kirsten de Groot, Chris Hagen, Lorraine Harper, Caroline Heijl, Peter Höglund, David Jayne, Raashid Luqmani, Alfred Mahr, Chetan Mukhtyar, Charles Pusey, Niels Rasmussen, Coen Stegeman, Michael Walsh, Kerstin Westman, European Vasculitis Study Group
雑誌名: Ann Rheum Dis. 2011 Mar;70(3):488-94. doi: 10.1136/ard.2010.137778. Epub 2010 Nov 24.
Abstract/Text BACKGROUND: Wegener's granulomatosis and microscopic polyangiitis are antineutrophil cytoplasm antibodies (ANCA)-associated vasculitides with significant morbidity and mortality. The long-term survival of patients with ANCA associated vasculitis treated with current regimens is uncertain.
OBJECTIVE: To describe the long-term patient survival and possible prognostic factors at presentation in an international, multicentre, prospectively recruited representative patient cohort who were treated according to strictly defined protocols at presentation and included the full spectrum of ANCA-associated vasculitis disease.
METHODS: Outcome data were collected for 535 patients who had been recruited at the time of diagnosis to four randomised controlled trials between 1995 and 2002. Trial eligibility was defined by disease severity and extent, covered the spectrum of severity of ANCA-associated vasculitis and used consistent diagnostic criteria. Demographic, clinical and laboratory parameters at trial entry were tested as potential prognostic factors in multivariable models.
RESULTS: The median duration of follow-up was 5.2 years and 133 (25%) deaths were recorded. Compared with an age- and sex-matched general population there was a mortality ratio of 2.6 (95% CI 2.2 to 3.1). Main causes of death within the first year were infection (48%) and active vasculitis (19%). After the first year the major causes of death were cardiovascular disease (26%), malignancy (22%) and infection (20%). Multivariable analysis showed an estimated glomerular filtration rate <15 ml/min, advancing age, higher Birmingham Vasculitis Activity Score, lower haemoglobin and higher white cell count were significant negative prognostic factors for patient survival.
CONCLUSION: Patients with ANCA-associated vasculitis treated with conventional regimens are at increased risk of death compared with an age- and sex-matched population.

PMID 21109517  Ann Rheum Dis. 2011 Mar;70(3):488-94. doi: 10.1136/ard.・・・
著者: Gene V Ball
雑誌名: Rheum Dis Clin North Am. 2010 Aug;36(3):439-46. doi: 10.1016/j.rdc.2010.05.004. Epub 2010 Jun 15.
Abstract/Text An essential early step toward understanding vasculitis was recognition in 1948 of the differences between the small artery disease of polyarteritis, essentially sparing the glomerulus and lungs, and disease of glomerular vessels and small veins, often involving the lungs. By 1951, Churg and Strauss drew on their knowledge of vasculitis literature and renal pathology to provide an authoritative description of the syndrome bearing their names. One year later a paper from Australia described a syndrome of febrile systemic illness with myalgias, arthralgias, microscopic hematuria, and a serum antibody reacting with neutrophil cytoplasm antigens. Within 30 years, nephrologists and immunologists in northern Europe linked antineutrophil cytoplasm antibodies to a specific vasculitis, Wegener's granulomatosis. Falk and Jennette later determined that pANCA reacted with cytoplasmic myeloperoxidase, and that cANCA did not; the antigen with which cANCA reacted was soon identified as a novel serine proteinase. New and better treatments of AAV will follow progress in understanding their pathogenesis.

Copyright 2010 Elsevier Inc. All rights reserved.
PMID 20688242  Rheum Dis Clin North Am. 2010 Aug;36(3):439-46. doi: 10・・・
著者: D J Davies, J E Moran, J F Niall, G B Ryan
雑誌名: Br Med J (Clin Res Ed). 1982 Aug 28-Sep 4;285(6342):606. doi: 10.1136/bmj.285.6342.606.
Abstract/Text
PMID 6297657  Br Med J (Clin Res Ed). 1982 Aug 28-Sep 4;285(6342):606・・・
著者: Shouichi Fujimoto, Richard A Watts, Shigeto Kobayashi, Kazuo Suzuki, David R W Jayne, David G I Scott, Hiroshi Hashimoto, Hiroyuki Nunoi
雑誌名: Rheumatology (Oxford). 2011 Oct;50(10):1916-20. doi: 10.1093/rheumatology/ker205. Epub 2011 Jul 28.
Abstract/Text OBJECTIVES: The epidemiological manifestations of ANCA-associated vasculitis (AAV) differ geographically. However, there have been no prospective studies comparing the incidence of AAV between Japan and Europe over the same time period using the same case definitions.
METHODS: The incidence of AAV was determined by a population-based method in Miyazaki prefecture, Japan, and Norfolk, U.K., between 2005 and 2009. Patients with AAV were defined and classified according to the European Medicines Agency (EMEA) algorithm.
RESULTS: The number of incident cases of AAV in Japan and the U.K. were 86 and 50, respectively, and the average annual incidence over the 5-year period was 22.6/million (95% CI 19.1, 26.2) and 21.8/million (95% CI 12.6, 30.9) in Japan and the U.K., respectively. The average age was higher in patients in Japan than in patients in the U.K. [mean (median), 69.7 (72) vs. 60.5 (61) years]. Microscopic polyangiitis (MPA) was the predominant subtype in Japan (83%), while granulomatosis with polyangiitis (Wegener's) was more frequent in the U.K. (66%). As for the pattern of ANCA positivity, >80% of Japanese patients were pANCA/MPO positive, whereas two-thirds of U.K. patients were cANCA/PR3 positive. Renal involvement in MPA was very common in both countries, but was much less common in granulomatosis with polyangiitis in Japan compared with the U.K.
CONCLUSION: There was no major difference in AAV incidence between Japan and the U.K., but this prospective study found MPA and MPO-ANCA to be more common in Japan and granulomatosis with polyangiitis and PR3-ANCA to be more common in the U.K., in line with earlier reports.

PMID 21798892  Rheumatology (Oxford). 2011 Oct;50(10):1916-20. doi: 10・・・
著者: Ken-ei Sada, Masahiro Yamamura, Masayoshi Harigai, Takao Fujii, Hiroaki Dobashi, Yoshinari Takasaki, Satoshi Ito, Hidehiro Yamada, Takashi Wada, Junichi Hirahashi, Yoshihiro Arimura, Hirofumi Makino, Research Committee on Intractable Vasculitides, the Ministry of Health, Labour and Welfare of Japan
雑誌名: Arthritis Res Ther. 2014 Apr 23;16(2):R101. doi: 10.1186/ar4550. Epub 2014 Apr 23.
Abstract/Text INTRODUCTION: We investigated the clinical and serological features of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in Japan using data from a nationwide, prospective, inception cohort study.
METHODS: In total, 156 Japanese patients with newly diagnosed AAV were classified according to the European Medicines Agency (EMEA) algorithm with exploratory surrogate markers for AAV-related non-granulomatous pulmonary lesions, predefined as alveolar haemorrhage and interstitial lung disease (ILD), and their clinical and serological features were evaluated.
RESULTS: Using the EMEA algorithm, we identified 14 patients (9.0%) with eosinophilic granulomatosis with polyangiitis (EGPA), 33 (21.2%) with granulomatosis with polyangiitis (GPA), 78 (50.0%) with microscopic polyangiitis and renal-limited vasculitis (MPA/RLV), and 31 (19.9%) with unclassifiable vasculitis. The average ages of patients with EGPA (male/female, 5/9), GPA (12/21), and MPA/RLV (35/43) and unclassifiable (9/22) were 58.0, 63.6, 71.1, and 70.6 years, respectively. Myeloperoxidase (MPO)-ANCA and proteinase-3 ANCA positivity was 50.0% and 0% for EGPA, 54.6% and 45.5% for GPA, 97.4% and 2.6% for MPA/RLV, and 93.5% and 3.2% for unclassifiable, respectively. According to the Birmingham Vasculitis Activity Score (BVAS), cutaneous (71.4%) and nervous system (92.9%) manifestations were prominent in EGPA and ear, nose, and throat manifestations (84.9%) and chest manifestations (66.7%) in GPA. Renal manifestations developed frequently in MPA/RLV (91.0%) and GPA (63.6%). The average serum creatinine levels were 0.71 mg/dL for EGPA, 1.51 mg/dL for GPA, 2.46 mg/dL for MPA/RLV, and 0.69 mg/dL for unclassifiable. The percentages of patients with ILD were 14.3% for EGPA, 9.0% for GPA, 47.4% for MPA/RLV, and 61.3% for unclassifiable. Patients with ILD (n = 61) had significantly lower BVAS (P = 0.019) with fewer ear, nose, and throat and cardiovascular manifestations than patients without ILD (n = 95).
CONCLUSIONS: MPO-ANCA-positive MPA/RLV is the most common form of AAV in Japanese patients, and one-half of patients with GPA were positive for MPO-ANCA. ILD is an important clinical manifestation in Japanese patients with AAV. Unclassifiable vasculitis with MPO-ANCA positivity and ILD may represent a novel variant of MPA.
TRIAL REGISTRATION: The University Hospital Medical Information Network Clinical Trials Registry: UMIN000001648. Registered 28 February 2009.

PMID 24758294  Arthritis Res Ther. 2014 Apr 23;16(2):R101. doi: 10.118・・・
著者: J Charles Jennette, Ronald J Falk
雑誌名: Nat Rev Rheumatol. 2014 Aug;10(8):463-73. doi: 10.1038/nrrheum.2014.103. Epub 2014 Jul 8.
Abstract/Text Antineutrophil cytoplasmic autoantibodies (ANCAs) are the probable cause of a distinct form of vasculitis that can be accompanied by necrotizing granulomatosis. Clinical and experimental evidence supports a pathogenesis that is driven by ANCA-induced activation of neutrophils and monocytes, producing destructive necrotizing vascular and extravascular inflammation. Pathogenic ANCAs can originate from precursor natural autoantibodies. Pathogenic transformation might be initiated by commensal or pathogenic microbes, legal or illegal drugs, exogenous or endogenous autoantigen complementary peptides, or dysregulated autoantigen expression. The ANCA autoimmune response is facilitated by insufficient T-cell and B-cell regulation. A putative pathogenic mechanism for vascular inflammation begins with ANCA-induced activation of primed neutrophils and monocytes leading to activation of the alternative complement pathway, which sets in motion an inflammatory amplification loop in the vessel wall that attracts and activates neutrophils with resultant respiratory burst, degranulation, extrusion of neutrophil extracellular traps, apoptosis and necrosis. The pathogenesis of extravascular granulomatosis is less clear, but a feasible scenario proposes that a prodromal infectious or allergic condition positions primed neutrophils in extravascular tissue in which they can be activated by ANCAs in interstitial fluid to produce extravascular necrotizing injury that would initiate an innate granulomatous inflammatory response to wall off the necrotic debris.

PMID 25003769  Nat Rev Rheumatol. 2014 Aug;10(8):463-73. doi: 10.1038/・・・
著者: Hong Xiao, Peter Heeringa, Peiqi Hu, Zhi Liu, Minglang Zhao, Yasuaki Aratani, Nobuyo Maeda, Ronald J Falk, J Charles Jennette
雑誌名: J Clin Invest. 2002 Oct;110(7):955-63. doi: 10.1172/JCI15918.
Abstract/Text Antineutrophil cytoplasmic autoantibodies (ANCAs) are identified in the circulation of approximately 80% of patients with pauci-immune necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis, such as microscopic polyangiitis and Wegener granulomatosis. The most common antigen target for ANCAs is myeloperoxidase (MPO), which is found in neutrophils and monocytes. We report definitive experimental animal evidence that ANCAs are pathogenic. MPO knockout (Mpo(-/-)) mice were immunized with mouse MPO. Splenocytes from these mice or from control mice were injected intravenously into recombinase-activating gene-2-deficient (Rag2(-/-)) mice, which lack functioning B lymphocytes and T lymphocytes. All mice that received splenocytes developed mild to moderate glomerular immune deposits, but only mice that received 1 x 10(8) or 5 x 10(7) anti-MPO splenocytes developed severe necrotizing and crescentic glomerulonephritis, granulomatous inflammation, and systemic necrotizing vasculitis, including necrotizing arteritis and hemorrhagic pulmonary capillaritis. To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2(-/-) mice and wild-type mice. Mice that received anti-MPO IgG but not mice that received control IgG developed focal necrotizing and crescentic glomerulonephritis with a paucity of glomerular Ig deposition. Thus, anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and crescent formation in the absence of functional T or B lymphocytes in Rag2(-/-) mice and in the presence of an intact immune system in wild-type C57BL/6J mice. This animal model offers strong support for a direct pathogenic role for ANCA IgG in human glomerulonephritis and vasculitis.

PMID 12370273  J Clin Invest. 2002 Oct;110(7):955-63. doi: 10.1172/JCI・・・
著者: Lani Shochet, Stephen Holdsworth, A Richard Kitching
雑誌名: Front Immunol. 2020;11:525. doi: 10.3389/fimmu.2020.00525. Epub 2020 Apr 9.
Abstract/Text Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a rare and severe autoimmune multisystemic disease. Its pathogenesis involves multiple arms of the immune system, as well as complex interactions between immune cells and target organs. Experimental animal models of disease can provide the crucial link from human disease to translational research into new therapies. This is particularly true in AAV, due to low disease incidence and substantial disease heterogeneity. Animal models allow for controlled environments in which disease mechanisms can be defined, without the clinical confounders of environmental and lifestyle factors. To date, multiple animal models have been developed, each of which shed light on different disease pathways. Results from animal studies of AAV have played a crucial role in enhancing our understanding of disease mechanisms, and have provided direction toward newer targeted therapies. This review will summarize our understanding of AAV pathogenesis as has been gleaned from currently available animal models, as well as address their strengths and limitations. We will also discuss the potential for current and new animal models to further our understanding of this important condition.

Copyright © 2020 Shochet, Holdsworth and Kitching.
PMID 32373109  Front Immunol. 2020;11:525. doi: 10.3389/fimmu.2020.005・・・
著者: Renate Kain, Markus Exner, Ricarda Brandes, Reinhard Ziebermayr, Dawn Cunningham, Carol A Alderson, Agnes Davidovits, Ingrid Raab, Renate Jahn, Oliver Ashour, Susanne Spitzauer, Gere Sunder-Plassmann, Minoru Fukuda, Per Klemm, Andrew J Rees, Dontscho Kerjaschki
雑誌名: Nat Med. 2008 Oct;14(10):1088-96. doi: 10.1038/nm.1874. Epub 2008 Oct 5.
Abstract/Text Pauci-immune focal necrotizing glomerulonephritis (FNGN) is a severe inflammatory disease associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA). Here we characterize autoantibodies to lysosomal membrane protein-2 (LAMP-2) and show that they are a new ANCA subtype present in almost all individuals with FNGN. Consequently, its prevalence is nearly twice that of the classical ANCAs that recognize myeloperoxidase or proteinase-3. Furthermore, antibodies to LAMP-2 cause pauci-immune FNGN when injected into rats, and a monoclonal antibody to human LAMP-2 (H4B4) induces apoptosis of human microvascular endothelium in vitro. The autoantibodies in individuals with pauci-immune FNGN commonly recognize a human LAMP-2 epitope (designated P(41-49)) with 100% homology to the bacterial adhesin FimH, with which they cross-react. Rats immunized with FimH develop pauci-immune FNGN and also develop antibodies to rat and human LAMP-2. Finally, we show that infections with fimbriated pathogens are common before the onset of FNGN. Thus, FimH-triggered autoimmunity to LAMP-2 provides a previously undescribed clinically relevant molecular mechanism for the development of pauci-immune FNGN.

PMID 18836458  Nat Med. 2008 Oct;14(10):1088-96. doi: 10.1038/nm.1874.・・・
著者: Aleeza J Roth, Joshua D Ooi, Jacob J Hess, Mirjan M van Timmeren, Elisabeth A Berg, Caroline E Poulton, JulieAnne McGregor, Madelyn Burkart, Susan L Hogan, Yichun Hu, Witold Winnik, Patrick H Nachman, Coen A Stegeman, John Niles, Peter Heeringa, A Richard Kitching, Stephen Holdsworth, J Charles Jennette, Gloria A Preston, Ronald J Falk
雑誌名: J Clin Invest. 2013 Apr;123(4):1773-83. doi: 10.1172/JCI65292. Epub 2013 Mar 15.
Abstract/Text Anti-neutrophil cytoplasmic antibody-associated (ANCA-associated) small vessel necrotizing vasculitis is caused by immune-mediated inflammation of the vessel wall and is diagnosed in some cases by the presence of myeloperoxidase-specific antibodies (MPO-ANCA). This multicenter study sought to determine whether differences in ANCA epitope specificity explain why, in some cases, conventional serologic assays do not correlate with disease activity, why naturally occurring anti-MPO autoantibodies can exist in disease-free individuals, and why ANCA are undetected in patients with ANCA-negative disease. Autoantibodies from human and murine samples were epitope mapped using a highly sensitive epitope excision/mass spectrometry approach. Data indicated that MPO autoantibodies from healthy individuals had epitope specificities different from those present in ANCA disease. Importantly, this methodology led to the discovery of MPO-ANCA in ANCA-negative disease that reacted against a sole linear sequence. Autoantibodies against this epitope had pathogenic properties, as demonstrated by their capacity to activate neutrophils in vitro and to induce nephritis in mice. The confounder for serological detection of these autoantibodies was the presence of a fragment of ceruloplasmin in serum, which was eliminated in purified IgG, allowing detection. These findings implicate immunodominant epitopes in the pathology of ANCA-associated vasculitis and suggest that autoantibody diversity may be common to other autoimmune diseases.

PMID 23549081  J Clin Invest. 2013 Apr;123(4):1773-83. doi: 10.1172/JC・・・
著者: Priya J Bansal, Mary C Tobin
雑誌名: Ann Allergy Asthma Immunol. 2004 Oct;93(4):398-401. doi: 10.1016/S1081-1206(10)61400-7.
Abstract/Text BACKGROUND: Microscopic polyangiitis is a systemic vasculitis characterized by small vessel involvement. Studies suggest myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) is involved in its pathogenesis, and the titer may reflect disease activity.
OBJECTIVE: To report a case of transplacental transfer of MPO-ANCA from a mother to a 33-week gestational age neonate that resulted in neonatal pulmonary hemorrhage and renal involvement that was successfully treated with high-dose steroid therapy and exchange transfusion.
METHODS: MPO-ANCA titers from the cord blood and the neonate on the 8th, 15th, and 25th days of life (DOLs) were obtained. Metabolic panels and chest x-ray examinations were performed for the neonate and mother and the following values were measured: ANCA, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody, serial urinalysis, and complete blood cell count. Anti-glomerular basement membrane, quantitative immunoglobulins, anticardiolipin antibody, and rheumatoid factor were also measured for the neonate.
RESULTS: The neonate had elevated MPO-ANCA titers at birth. Pulmonary hemorrhage and renal involvement were seen on DOL 2. High-dose steroid therapy decreased symptoms within 1.5 hours of initiation. Exchange transfusion performed on DOL 5 removed all of the remaining MPO-ANCA by DOL 25. The child remains asymptomatic to date.
CONCLUSIONS: To our knowledge, this is the first reported case of transplacental transfer of MPO-ANCA resulting in pulmonary-renal syndrome that was successfully treated with high-dose steroid therapy and exchange transfusion.

PMID 15521377  Ann Allergy Asthma Immunol. 2004 Oct;93(4):398-401. doi・・・
著者: Francisco Silva, Ulrich Specks, Sanjeev Sethi, Maria Valentina Irazabal, Fernando C Fervenza
雑誌名: Am J Kidney Dis. 2009 Sep;54(3):542-5. doi: 10.1053/j.ajkd.2009.02.016. Epub 2009 Apr 23.
Abstract/Text Myeloperoxidase (MPO)-specific antineutrophil cytoplasmic antibodies have been proposed as pathogenic for microscopic polyangiitis. Supporting this hypothesis, a case report of transplacental anti-MPO antibody transfer presumably causing a vasculitis-like syndrome in the newborn is cited frequently. Here, we report a case of transplacental transfer of high levels of anti-MPO antibodies not resulting in clinical compromise in the newborn. The mother developed microscopic polyangiitis 5 years before the pregnancy. After induction therapy, remission was maintained with low-dose prednisone and azathioprine for 4.5 years despite high levels of anti-MPO antibodies (>100 U/mL). The patient elected to become pregnant, immunosuppression was maintained during pregnancy, and a normal-term neonate was delivered. The newborn's venous blood anti-MPO antibody levels decreased gradually from greater than 100 U/mL at birth to undetectable by day 120. No clinical manifestation of vasculitis developed in the newborn. This case supports that anti-MPO antibodies alone are not pathogenic without additional cofactors.

PMID 19395136  Am J Kidney Dis. 2009 Sep;54(3):542-5. doi: 10.1053/j.a・・・
著者: Paul A Lyons, Tim F Rayner, Sapna Trivedi, Julia U Holle, Richard A Watts, David R W Jayne, Bo Baslund, Paul Brenchley, Annette Bruchfeld, Afzal N Chaudhry, Jan Willem Cohen Tervaert, Panos Deloukas, Conleth Feighery, Wolfgang L Gross, Loic Guillevin, Iva Gunnarsson, Lorraine Harper, Zdenka Hrušková, Mark A Little, Davide Martorana, Thomas Neumann, Sophie Ohlsson, Sandosh Padmanabhan, Charles D Pusey, Alan D Salama, Jan-Stephan F Sanders, Caroline O Savage, Mårten Segelmark, Coen A Stegeman, Vladimir Tesař, Augusto Vaglio, Stefan Wieczorek, Benjamin Wilde, Jochen Zwerina, Andrew J Rees, David G Clayton, Kenneth G C Smith
雑誌名: N Engl J Med. 2012 Jul 19;367(3):214-23. doi: 10.1056/NEJMoa1108735.
Abstract/Text BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a severe condition encompassing two major syndromes: granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) and microscopic polyangiitis. Its cause is unknown, and there is debate about whether it is a single disease entity and what role ANCA plays in its pathogenesis. We investigated its genetic basis.
METHODS: A genomewide association study was performed in a discovery cohort of 1233 U.K. patients with ANCA-associated vasculitis and 5884 controls and was replicated in 1454 Northern European case patients and 1666 controls. Quality control, population stratification, and statistical analyses were performed according to standard criteria.
RESULTS: We found both major-histocompatibility-complex (MHC) and non-MHC associations with ANCA-associated vasculitis and also that granulomatosis with polyangiitis and microscopic polyangiitis were genetically distinct. The strongest genetic associations were with the antigenic specificity of ANCA, not with the clinical syndrome. Anti-proteinase 3 ANCA was associated with HLA-DP and the genes encoding α(1)-antitrypsin (SERPINA1) and proteinase 3 (PRTN3) (P=6.2×10(-89), P=5.6×10(-12,) and P=2.6×10(-7), respectively). Anti-myeloperoxidase ANCA was associated with HLA-DQ (P=2.1×10(-8)).
CONCLUSIONS: This study confirms that the pathogenesis of ANCA-associated vasculitis has a genetic component, shows genetic distinctions between granulomatosis with polyangiitis and microscopic polyangiitis that are associated with ANCA specificity, and suggests that the response against the autoantigen proteinase 3 is a central pathogenic feature of proteinase 3 ANCA-associated vasculitis. These data provide preliminary support for the concept that proteinase 3 ANCA-associated vasculitis and myeloperoxidase ANCA-associated vasculitis are distinct autoimmune syndromes. (Funded by the British Heart Foundation and others.).

PMID 22808956  N Engl J Med. 2012 Jul 19;367(3):214-23. doi: 10.1056/N・・・
著者: Alfred D Mahr, Jeffrey C Edberg, John H Stone, Gary S Hoffman, E William St Clair, Ulrich Specks, Paul F Dellaripa, Philip Seo, Robert F Spiera, Farshid N Rouhani, Mark L Brantly, Peter A Merkel
雑誌名: Arthritis Rheum. 2010 Dec;62(12):3760-7. doi: 10.1002/art.27742.
Abstract/Text OBJECTIVE: Deficiency of α(1) -antitrypsin (α(1) AT) may be a determinant of susceptibility to Wegener's granulomatosis (WG). Several previous, mainly small, case-control studies have shown that 5-27% of patients with WG carried the α(1) AT deficiency Z allele. It is not clear whether the S allele, the other major α(1) AT deficiency variant, is associated with WG. This study investigated the relationship of the α(1) AT deficiency Z and S alleles with the risk of developing WG in a large cohort.
METHODS: We studied the distribution of the α(1) AT deficiency alleles Z and S in 433 unrelated Caucasian patients with WG and 421 ethnically matched controls. Genotyping was performed using an allele discrimination assay. Results were compared between cases and controls using exact statistical methods.
RESULTS: Among the patients with WG, the allele carriage frequencies of Z and S were 7.4% and 11.5%, respectively. The frequencies of the 6 possible genotypes differed in a statistically significant manner between cases and controls (P = 0.01). The general genetic 2-parameter codominant model provided the best fit to the data. Compared with the normal MM genotype, the odds ratio (OR) for MZ or MS genotypes was 1.47 (95% confidence interval [95% CI] 0.98-2.22), and the OR for ZZ, SS, or SZ genotypes was 14.58 (95% CI 2.33-∞). ORs of similar direction and magnitude were observed within the restricted cohorts that excluded cases and controls carrying ≥1 Z or ≥1 S allele.
CONCLUSION: Both Z and S alleles display associations with risk of WG in a codominant genetic pattern. These findings strengthen the evidence of a causal link between α(1) AT deficiency and susceptibility to WG.

Copyright © 2010 by the American College of Rheumatology.
PMID 20827781  Arthritis Rheum. 2010 Dec;62(12):3760-7. doi: 10.1002/a・・・
著者: Paul A Lyons, James E Peters, Federico Alberici, James Liley, Richard M R Coulson, William Astle, Chiara Baldini, Francesco Bonatti, Maria C Cid, Heather Elding, Giacomo Emmi, Jörg Epplen, Loïc Guillevin, David R W Jayne, Tao Jiang, Iva Gunnarsson, Peter Lamprecht, Stephen Leslie, Mark A Little, Davide Martorana, Frank Moosig, Thomas Neumann, Sophie Ohlsson, Stefanie Quickert, Giuseppe A Ramirez, Barbara Rewerska, Georg Schett, Renato A Sinico, Wojciech Szczeklik, Vladimir Tesar, Damjan Vukcevic, European Vasculitis Genetics Consortium, Benjamin Terrier, Richard A Watts, Augusto Vaglio, Julia U Holle, Chris Wallace, Kenneth G C Smith
雑誌名: Nat Commun. 2019 Nov 12;10(1):5120. doi: 10.1038/s41467-019-12515-9. Epub 2019 Nov 12.
Abstract/Text Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

PMID 31719529  Nat Commun. 2019 Nov 12;10(1):5120. doi: 10.1038/s41467・・・
著者: Augusto Vaglio, Ines Casazza, Chiara Grasselli, Domenico Corradi, Renato A Sinico, Carlo Buzio
雑誌名: Kidney Int. 2009 Nov;76(9):1006-11. doi: 10.1038/ki.2009.210. Epub 2009 Jun 10.
Abstract/Text
PMID 19516244  Kidney Int. 2009 Nov;76(9):1006-11. doi: 10.1038/ki.200・・・
著者: Ryoji Nishi, Haruki Koike, Ken Ohyama, Yuki Fukami, Shohei Ikeda, Yuichi Kawagashira, Masahiro Iijima, Masahisa Katsuno, Gen Sobue
雑誌名: Neurology. 2020 Apr 21;94(16):e1726-e1737. doi: 10.1212/WNL.0000000000009309. Epub 2020 Mar 26.
Abstract/Text OBJECTIVE: To investigate the clinicopathologic features of eosinophilic granulomatosis with polyangiitis (EGPA)-associated neuropathy with a focus on the presence or absence of anti-neutrophil cytoplasmic antibodies (ANCAs).
METHODS: We examined the clinical features and pathologic findings of sural nerve biopsy specimens from 82 patients with EGPA-associated neuropathy. Of these patients, 32.9% were myeloperoxidase (MPO)-ANCA positive, and 67.1% were MPO-ANCA negative. PR3-ANCA was negative in all of 78 examined patients.
RESULTS: Upper limb symptoms were more frequently reported as initial neuropathic manifestations in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (44.4% vs 14.6%, p < 0.01). The serum levels of C-reactive protein were significantly higher in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p < 0.05). Sural nerve biopsy specimens showed findings suggestive of vasculitis (i.e., destruction of vascular structures) in epineurial vessels; these results were seen more frequently in the MPO-ANCA-positive group than in the MPO-ANCA-negative group (p < 0.0001). Conversely, the numbers of eosinophils in the lumen of the epineurial vessels (p < 0.01) and epineurial vessels occluded by intraluminal eosinophils (p < 0.05) were higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group. Furthermore, the incidence of eosinophil infiltration in the endoneurium was higher in the MPO-ANCA-negative group than in the MPO-ANCA-positive group (p < 0.01).
CONCLUSIONS: This study suggests that the pathogenesis of EGPA comprises at least 2 distinct mechanisms: ANCA-associated vasculitis resulting in ischemic effects and inflammation, which is prominent in MPO-ANCA-positive patients, and eosinophil-associated vascular occlusion leading to ischemia and eosinophil-associated tissue damage, which is conspicuous in MPO-ANCA-negative patients.

© 2020 American Academy of Neurology.
PMID 32217776  Neurology. 2020 Apr 21;94(16):e1726-e1737. doi: 10.1212・・・
著者: Cloé Comarmond, Christian Pagnoux, Mehdi Khellaf, Jean-François Cordier, Mohamed Hamidou, Jean-François Viallard, François Maurier, Stéphane Jouneau, Boris Bienvenu, Xavier Puéchal, Olivier Aumaître, Guillaume Le Guenno, Alain Le Quellec, Ramiro Cevallos, Olivier Fain, Bertrand Godeau, Raphaèle Seror, Bertrand Dunogué, Alfred Mahr, Philippe Guilpain, Pascal Cohen, Achille Aouba, Luc Mouthon, Loïc Guillevin, French Vasculitis Study Group
雑誌名: Arthritis Rheum. 2013 Jan;65(1):270-81. doi: 10.1002/art.37721.
Abstract/Text OBJECTIVE: Earlier studies of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA), with limited patient numbers and followup durations, demonstrated that clinical presentation at diagnosis, but not outcome, differed according to antineutrophil cytoplasmic antibody (ANCA) status. This study was undertaken to describe the main characteristics of a larger patient cohort and their long-term outcomes.
METHODS: A retrospective study of EGPA patients in the French Vasculitis Study Group cohort who satisfied the American College of Rheumatology criteria and/or Chapel Hill definitions was conducted. Patient characteristics and outcomes were compared according to ANCA status and year of diagnosis.
RESULTS: We identified 383 patients diagnosed between 1957 and June 2009 (128 [33.4%] before 1997 or earlier) and followed up for a mean±SD of 66.8±62.5 months. At diagnosis, their mean±SD age was 50.3±15.7 years, and 91.1% had asthma (duration 9.3±10.8 years). Main manifestations included peripheral neuropathy (51.4%); ear, nose, and throat (ENT) signs (48.0%); skin lesions (39.7%); lung infiltrates (38.6%); and cardiomyopathy (16.4%). Among the 348 patients tested at diagnosis for ANCA, the 108 ANCA-positive patients (31.0%) had significantly more frequent ENT manifestations, peripheral neuropathy, and/or renal involvement, but less frequent cardiac manifestations, than the ANCA-negative patients. Vasculitis relapses occurred in 35.2% of the ANCA-positive versus 22.5% of the ANCA-negative patients (P=0.01), and 5.6% versus 12.5%, respectively, died (P<0.05). The 5-year relapse-free survival rate was 58.1% (95% confidence interval [95% CI] 45.6-68.6) for ANCA-positive and 67.8% (95% CI 59.8-74.5) for ANCA-negative patients (P=0.35). Multivariable analysis identified cardiomyopathy, older age, and diagnosis during or prior to 1996 as independent risk factors for death and lower eosinophil count at diagnosis as predictive of relapse.
CONCLUSION: The characteristics and long-term outcomes of EGPA patients differ according to their ANCA status. Although EGPA relapses remain frequent, mortality has declined, at least since 1996.

Copyright © 2013 by the American College of Rheumatology.
PMID 23044708  Arthritis Rheum. 2013 Jan;65(1):270-81. doi: 10.1002/ar・・・
著者: C A Langford
雑誌名: Cleve Clin J Med. 1998 Mar;65(3):135-40. doi: 10.3949/ccjm.65.3.135.
Abstract/Text Anti-neutrophil cytoplasmic antibodies with a cytoplasmic staining pattern (c-ANCA) have been found to have a high degree of sensitivity and specificity for Wegener's granulomatosis. Nevertheless, despite the attraction of using this autoantibody as a diagnostic test, in almost all instances it should not be used in place of a biopsy to diagnose Wegener's granulomatosis.

PMID 9540246  Cleve Clin J Med. 1998 Mar;65(3):135-40. doi: 10.3949/c・・・
著者: J C Jennette, A S Wilkman, R J Falk
雑誌名: Kidney Int. 1998 Mar;53(3):796-8. doi: 10.1038/ki.1998.36.
Abstract/Text
PMID 9507231  Kidney Int. 1998 Mar;53(3):796-8. doi: 10.1038/ki.1998.・・・
著者: Xavier Bossuyt, Niels Rasmussen, Pieter van Paassen, Bernard Hellmich, Bo Baslund, Pieter Vermeersch, Daniel Blockmans, Jan-Willem Cohen Tervaert, Elena Csernok, Jan Damoiseaux
雑誌名: Rheumatology (Oxford). 2017 Sep 1;56(9):1533-1541. doi: 10.1093/rheumatology/kex170.
Abstract/Text Objective: The objective of this multicentre study was to improve the clinical interpretation of PR3- and MPO-ANCAs as an adjunct for the diagnosis of ANCA-associated vasculitis (AAV) by defining thresholds and test result intervals based on predefined specificities and by calculating test result interval-specific likelihood ratios (LRs).
Methods: Eight different PR3- and MPO-ANCA immunoassays from seven companies were evaluated using 251 diagnostic samples from AAV patients and 924 diseased controls.
Results: Thresholds for antibody levels were determined based on predefined specificities (95, 97.5, 99 and 100%) and used to delimit test result intervals. Test result interval-specific LRs were determined. For all assays, the LR for AAV increased with increasing antibody level. For all but one immunoassay, high antibodies levels (associated with LR >55) were found in a substantial fraction (>65%) of patients. The area under the curve (AUC) of receiver operating characteristics analysis of a diagnostic approach in which positive results were confirmed by IIF or another immunoassay was not substantially higher than the AUC of performing immunoassay only. The highest AUC was found when immunoassay was combined with another immunoassay or with IIF.
Conclusion: To diagnose AAV based on PR3- and MPO-ANCA, it is useful to define thresholds for antibody levels and to assign test result interval-specific LRs. Higher antibody levels are associated with a higher likelihood for disease. Such information improves clinical interpretation.

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com
PMID 28541581  Rheumatology (Oxford). 2017 Sep 1;56(9):1533-1541. doi:・・・
著者: A Schnabel, K Holl-Ulrich, K Dalhoff, M Reuter, W L Gross
雑誌名: Eur Respir J. 1997 Dec;10(12):2738-43. doi: 10.1183/09031936.97.10122738.
Abstract/Text This study was performed to determine the value of transbronchial biopsy (TBB) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides and mild-to-moderate pulmonary involvement. Included in the study were 19 patients with Wegener's granulomatosis (WG) and six patients with Churg-Strauss syndrome (CSS) with evidence of active pulmonary disease but without gross parenchymal lesions accessible by radiologically guided biopsy. All of the patients had undergone staging examinations which included TBB taken from peripheral lung tissue and from any focal tracheobronchial lesions. Any suspicious lesion in the upper respiratory tract was biopsied by an otolaryngologist and the number of positive biopsies was compared with that of TBB. In the WG patients, only two out of 17 biopsies of alveolar tissue yielded histopathological findings supporting the diagnosis of WG. In five WG patients, ulcerative or exophytic airway lesions were found whose histopathologies were invariably positive. Otolaryngological examination revealed abnormal findings in 19 WG patients and biopsies from these sites yielded positive results in 13 instances. In CSS, TBB produced a diagnostically helpful histopathology in four of six cases and biopsies from the upper respiratory tract were positive in five out of six cases. We conclude that transbronchial biopsies of alveolar tissue are seldom positive in Wegener's granulomatosis patients with mild-to-moderate pulmonary disease unless they are taken from grossly abnormal lung areas. Conversely, ulcerative, exophytic or stenotic tracheobronchial lesions had a high rate of positive findings. These results further suggest that the upper rather than the lower respiratory tract should be the biopsy site of first choice in Wegener's granulomatosis. In Churg-Strauss syndrome, the upper and lower respiratory tract seem to yield a roughly equal number of positive biopsies.

PMID 9493653  Eur Respir J. 1997 Dec;10(12):2738-43. doi: 10.1183/090・・・
著者: W D Travis, G S Hoffman, R Y Leavitt, H I Pass, A S Fauci
雑誌名: Am J Surg Pathol. 1991 Apr;15(4):315-33. doi: 10.1097/00000478-199104000-00001.
Abstract/Text We report the pulmonary pathologic features in 87 open lung biopsies from 67 patients with Wegener's granulomatosis (WG) who were treated at a single institution from 1968 to 1990. At the time of open lung biopsy, 48 patients (72%) had classical WG with renal involvement; 19 (28%) had limited WG without renal involvement. The pathologic features were divided into major and minor manifestations. In the 82 specimens demonstrating no infectious organism, the three major pathologic manifestations of classical WG observed were also useful diagnostic criteria and included: (a) parenchymal necrosis, (b) vasculitis, and (c) granulomatous inflammation accompanied by an inflammatory infiltrate composed of a mixture of neutrophils, lymphocytes, plasma cells, histiocytes, and eosinophils. Parenchymal necrosis was found in 84% of biopsy specimens either as neutrophilic microabscesses (65% of specimens) or as large (67%) or small (69%) areas of geographic necrosis. Areas of geographic necrosis were usually surrounded by palisading histiocytes and giant cells. Additional granulomatous lesions consisted of microabscesses surrounded by giant cells (69%), poorly formed granulomas (59%), and scattered giant cells (79%). Sarcoid-like granulomas were uncommon (4%), and in only one specimen (1%) appeared within an inflammatory lesion of WG. Vascular changes were identified in 94% of biopsy specimens. Vascular inflammation was classified as chronic (37% arterial, 64% venous), acute (37% arterial, 29% venous), non-necrotizing granulomatous (22% arterial, 9% venous), and necrotizing granulomatous (22% arterial, 10% venous). Fibrinoid necrosis was relatively uncommon (11% arterial, 6% venous). Cicatricial changes were found in arteries in 41% of biopsy specimens and in veins in 16%. Capillaritis was present in 31% of specimens. Minor pathologic lesions were commonly observed in biopsy specimens associated with classical WG lesions, but they were usually inconspicuous and not useful diagnostic criteria. These included interstitial fibrosis (26%), alveolar hemorrhage (49%), tissue eosinophils (100%), organizing intraluminal fibrosis (70%), endogenous lipoid pneumonia (59%), lymphoid aggregates (37%), and a variety of bronchial/bronchiolar lesions including acute and chronic bronchiolitis (51% and 64%), follicular bronchiolitis (28%), and bronchiolitis obliterans (31%). These minor lesions were often found at the periphery of typical nodules of WG. However, in 15 specimens (18%) a minor pathologic feature represented the dominant or major finding: pulmonary fibrosis (six specimens, 7%), diffuse pulmonary hemorrhage (six specimens, 7%), lipoid pneumonia (one specimen, 1%), acute bronchopneumonia (one specimen, 1%), and chronic bronchiolitis, bronchiolitic obliterans with organizing pneumonia (BOOP), and bronchocentric granulomatosis (one specimen, 1%).(ABSTRACT TRUNCATED AT 400 WORDS)

PMID 2006712  Am J Surg Pathol. 1991 Apr;15(4):315-33. doi: 10.1097/0・・・
著者: K Aasarød, L Bostad, J Hammerstrøm, S Jørstad, B M Iversen
雑誌名: Nephrol Dial Transplant. 2001 May;16(5):953-60. doi: 10.1093/ndt/16.5.953.
Abstract/Text BACKGROUND: The main purpose of this study was to examine histopathological changes seen in renal biopsies from patients with Wegener's granulomatosis (WG) with varying degrees of renal involvement and to study possible correlations between the morphological variables and the severity of the disease.
METHODS: Ninety-four patients with WG and active renal disease were included in this retrospective study. All patients had a percutaneous renal biopsy taken on their first admission to the hospital and 14 patients had a second biopsy. The patients were followed for a median of 42.5 months (range 0.5-184).
RESULTS: Segmental necrotizing glomerulonephritis and extracapillary proliferation were present in 85.1 and 91.5% respectively. Of seven patients (7.4%) with normal serum creatinine and urinary protein excretion <0.5 g/day, all had crescents and six had segmental glomerular necrosis. Serum creatinine at biopsy correlated significantly with the percentage of glomeruli with crescents (rho=0.52, P=0.0004), with necrosis (rho=0.36, P=0.002) and with the percentage of normal glomeruli (rho=-0.55, P=0.0003). On a multivariate analysis, only the percentage of normal glomeruli was significantly associated with renal function and development of end-stage renal disease. In 14 second biopsies after a mean of 41.2 (+/-26) months, chronicity scores had increased significantly in 13 biopsies in spite of full immunosuppressive treatment.
CONCLUSION: Although renal biopsy is of value in defining renal involvement in WG, it is of limited help in the early stage of the disease in predicting renal outcome for the individual patient. A follow-up biopsy can be useful in revealing the degree of activity and chronicity and hence be of importance for the choice of further therapy.

PMID 11328900  Nephrol Dial Transplant. 2001 May;16(5):953-60. doi: 10・・・
著者: K O Devaney, W D Travis, G Hoffman, R Leavitt, R Lebovics, A S Fauci
雑誌名: Am J Surg Pathol. 1990 Jun;14(6):555-64. doi: 10.1097/00000478-199006000-00006.
Abstract/Text The majority of patients with classic Wegener's granulomatosis present with symptoms of head and neck disease; accordingly, accurate interpretation of biopsy specimens from these sites is essential. This report details the histologic findings in 126 head and neck biopsy specimens from 70 patients (36 male and 34 female). Tissues were obtained from the following sites: 60 nasal, 27 paranasal sinuses, 17 laryngeal, five periorbital, five oral, four middle ear, three mastoid, two external ear, and three salivary gland. Vasculitis, necrosis, and granulomatous inflammation together were seen in only 16% of all head and neck biopsy specimens. Both vasculitis and granulomatous inflammation were seen in 21% and vasculitis and necrosis in 23% of the biopsy specimens reviewed. We discuss the problems in differential diagnosis, particularly the importance of excluding granulomatous infectious processes, which can imitate the histopathologic features of Wegener's granulomatosis. Based on this study, we propose criteria for the diagnosis of Wegener's granulomatosis based on biopsy specimens from the head and neck region.

PMID 2337204  Am J Surg Pathol. 1990 Jun;14(6):555-64. doi: 10.1097/0・・・
著者: Xavier Bossuyt, Jan-Willem Cohen Tervaert, Yoshihiro Arimura, Daniel Blockmans, Luis Felipe Flores-Suárez, Loïc Guillevin, Bernhard Hellmich, David Jayne, J Charles Jennette, Cees G M Kallenberg, Sergey Moiseev, Pavel Novikov, Antonella Radice, Judith Anne Savige, Renato Alberto Sinico, Ulrich Specks, Pieter van Paassen, Ming-Hui Zhao, Niels Rasmussen, Jan Damoiseaux, Elena Csernok
雑誌名: Nat Rev Rheumatol. 2017 Nov;13(11):683-692. doi: 10.1038/nrrheum.2017.140. Epub 2017 Sep 14.
Abstract/Text Anti-neutrophil cytoplasmic antibodies (ANCAs) are valuable laboratory markers used for the diagnosis of well-defined types of small-vessel vasculitis, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). According to the 1999 international consensus on ANCA testing, indirect immunofluorescence (IIF) should be used to screen for ANCAs, and samples containing ANCAs should then be tested by immunoassays for proteinase 3 (PR3)-ANCAs and myeloperoxidase (MPO)-ANCAs. The distinction between PR3-ANCAs and MPO-ANCAs has important clinical and pathogenic implications. As dependable immunoassays for PR3-ANCAs and MPO-ANCAs have become broadly available, there is increasing international agreement that high-quality immunoassays are the preferred screening method for the diagnosis of ANCA-associated vasculitis. The present Consensus Statement proposes that high-quality immunoassays can be used as the primary screening method for patients suspected of having the ANCA-associated vaculitides GPA and MPA without the categorical need for IIF, and presents and discusses evidence to support this recommendation.

PMID 28905856  Nat Rev Rheumatol. 2017 Nov;13(11):683-692. doi: 10.103・・・
著者: Jean-François Augusto, Virginie Langs, Julien Demiselle, Christian Lavigne, Benoit Brilland, Agnès Duveau, Caroline Poli, Alain Chevailler, Anne Croue, Frederic Tollis, Johnny Sayegh, Jean-François Subra
雑誌名: PLoS One. 2016;11(7):e0158871. doi: 10.1371/journal.pone.0158871. Epub 2016 Jul 8.
Abstract/Text BACKGROUND: Recent studies have demonstrated the key role of the complement alternative pathway (cAP) in the pathophysiology of experimental ANCA-associated vasculitis (AAV). However, in human AAV the role of cAP has not been extensively explored. In the present work, we analysed circulating serum C3 levels measured at AAV onset and their relation to outcomes.
METHODS: We conducted a retrospective observational cohort study including 45 consecutive patients with AAV diagnosed between 2000 and 2014 with serum C3 measurement at diagnosis, before immunosuppressive treatment initiation. Two groups were defined according to the median serum C3 level value: the low C3 group (C3<120 mg/dL) and the high C3 level group (C3≥120 mg/dL). Patient and renal survivals, association between C3 level and renal pathology were analysed.
RESULTS: Serum complement C3 concentration remained in the normal range [78-184 mg/dL]. Compared with the high C3 level, the patients in the low C3 level group had lower complement C4 concentrations (P = 0.008) and lower eGFR (P = 0.002) at diagnosis. The low C3 level group had poorer patient and death-censored renal survivals, compared with the high C3 level group (P = 0.047 and P = 0.001, respectively). We observed a significant negative correlation between C3 levels and the percentage of glomeruli affected by cellular crescent (P = 0.017, r = -0.407). According to the Berden et al renal histologic classification, patients in the crescentic/mixed category had low C3 levels more frequently (P<0.01). Interestingly, we observed that when patients with the crescentic/mixed histologic form were analysed according to C3 level, long term renal survival was significantly greater in the high C3 level group than in the low C3 level group (100% vs 40.7% at 6 years, p = 0.046). No relationship between serum C4 and renal outcome was observed.
CONCLUSION: A Low C3 serum level in AAV patients at diagnosis is associated with worse long-term patient and renal survival.

PMID 27391243  PLoS One. 2016;11(7):e0158871. doi: 10.1371/journal.pon・・・
著者: Matija Crnogorac, Ivica Horvatic, Patricia Kacinari, Danica Galesic Ljubanovic, Kresimir Galesic
雑誌名: J Nephrol. 2018 Apr;31(2):257-262. doi: 10.1007/s40620-017-0445-3. Epub 2017 Oct 13.
Abstract/Text AIM: To determinate the prognostic significance of low serum C3 at the time of diagnosis of ANCA-associated vasculitis (AAV).
METHODS: Our cohort included 75 consecutive patients with AAV diagnosed from January 2005 to December 2015. C3 levels were measured at the time of diagnosis. Patients were divided into two groups, those with low serum C3 levels (< 0.9 g/l) and those with normal serum C3 levels (0.9-1.8 g/l). We analysed association between serum C3 levels and both combined and singularly patient and renal survival (ESRD). Small number of relapsed patients did not allow for the statistical analysis to be performed as to weather the low serum C3 is associated with relapse rate in AAV patients.
RESULTS: Low serum C3 levels were significantly associated with worse combined end-point patient and renal survival (HR 3.079; 95% CI 1.231-7.701; p = 0.016), and on multivariate adjusted analysis association remained significant (HR 2.831; 95% CI 1.093-7.338; p = 0.032). For both end-points individually low serum C3 levels were significantly associated with poorer patient survival (HR 6.378; 95% CI 2.252-18.065; p < 0.001; on multivariate adjusted analysis HR 4.315 95% CI 1.350-13.799; p = 0.014) and renal survival (HR 3.207; 95% CI 1.040-9.830; p = 0.043; on multivariate adjusted analysis HR 3.679; 95% CI 1.144-11.827; p = 0.029). In our study there was no significant association between serological and patohistological phenotypes and serum C3 levels.
CONCLUSION: Lower serum C3 levels at the diagnosis is associated with poorer patient and renal outcomes in AAV patients.

PMID 29027625  J Nephrol. 2018 Apr;31(2):257-262. doi: 10.1007/s40620-・・・
著者: G S Hoffman, G S Kerr, R Y Leavitt, C W Hallahan, R S Lebovics, W D Travis, M Rottem, A S Fauci
雑誌名: Ann Intern Med. 1992 Mar 15;116(6):488-98. doi: 10.7326/0003-4819-116-6-488.
Abstract/Text OBJECTIVE: To prospectively study the clinical features, pathophysiology, treatment and prognosis of Wegener granulomatosis.
DESIGN: Of the 180 patients with Wegener granulomatosis referred to the National Institute of Allergy and Infectious Diseases during the past 24 years, 158 have been followed for 6 months to 24 years (a total of 1229 patient-years).
MEASUREMENTS: Characteristics of clinical presentation, surgical pathology, course of illness, laboratory and radiographic findings, and the results of medical and surgical treatment have been recorded in a computer-based information retrieval system.
SETTING: The Warren Magnuson Clinical Center of the National Institutes of Health.
MAIN RESULTS: Men and women were equally represented; 97% of patients were white, and 85% were more than 19 years of age. The mean period of follow-up was 8 years. One hundred and thirty-three patients (84%) received "standard" therapy with daily low-dose cyclophosphamide and glucocorticoids. Eight (5.0%) received only low-dose cyclophosphamide. Six (4.0%) never received cyclophosphamide and were treated with other cytotoxic agents and glucocorticoids. Ten patients (6.0%) were treated with only glucocorticoids. Ninety-one percent of patients experienced marked improvement, and 75% achieved complete remission. Fifty percent of remissions were associated with one or more relapses. Of 99 patients followed for greater than 5 years, 44% had remissions of greater than 5 years duration. Thirteen percent of patients died of Wegener granulomatosis, treatment-related causes, or both. Almost all patients had serious morbidity from irreversible features of their disease (86%) or side effects of treatment (42%).
CONCLUSIONS: The course of Wegener granulomatosis has been dramatically improved by daily treatment with cyclophosphamide and glucocorticoids. Nonetheless, disease- and treatment-related morbidity is often profound. Alternative forms of therapy have not yet achieved the high rates of remission induction and successful maintenance that have been reported with daily cyclophosphamide treatment. Despite continued therapeutic success with cyclophosphamide, our long-term follow-up of patients with Wegener granulomatosis has led to increasing concerns about toxicity resulting from prolonged cyclophosphamide therapy and has encouraged investigation of other therapeutic regimens.

PMID 1739240  Ann Intern Med. 1992 Mar 15;116(6):488-98. doi: 10.7326・・・
著者: Frank Moosig, Jan Phillip Bremer, Bernhard Hellmich, Julia Ulrike Holle, Konstanze Holl-Ulrich, Martin Laudien, Christine Matthis, Claudia Metzler, Bernhard Nölle, Gert Richardt, Wolfgang L Gross
雑誌名: Ann Rheum Dis. 2013 Jun;72(6):1011-7. doi: 10.1136/annrheumdis-2012-201531. Epub 2012 Aug 11.
Abstract/Text OBJECTIVE: To evaluate a vasculitis centre based management strategy for eosinophilic granulomatosis and polyangiitis (Churg-Strauss, EGPA).
METHODS: A retrospective cohort study at a vasculitis referral centre was performed. All EGPA patients admitted from 1990 to 2009 were included. A structured interdisciplinary work-up for proof of diagnosis, Disease Extent Index and Birmingham Vasculitis Activity Score was performed. Immunosuppressive therapy was initiated and regularly adapted. Treatment targets were induction and maintenance of remission according to definitions given by the European League Against Rheumatism and the European Vasculitis Study Group. Outcomes were mortality, rate of remission, relapses, adverse events and prednisolone-dose.
RESULTS: Out of 269 patients with suspected EGPA 150 fulfilled the inclusion criteria. Of those, 104 had more than one follow-up visit resulting in a mean follow up of 53±4.9 months. By using additional data sources the follow-up concerning survival was extended to 92±5 month. Severe organ manifestations occurred at heart (46%), kidney (18%) and lungs (10%). Cyclophosphamide was used in 107 patients (71%). The prednisolone-doses of all patients were within the targeted range (i.e. ≤7.5 mg) in 69% of the total follow-up time; the median dose at end of follow-up was 5mg/d. The 10-year survival rate was 89% resulting in mortality comparable to the general population (SMR 1.29). Only patients with cardiac failure associated with EGPA had an increased mortality (SMR 3.06).
CONCLUSIONS: Regular re-evaluation and target-orientated adaption of therapy may lead to normalization of life expectancy and attenuation of disease progression. Continued centre based interdisciplinary treatment should be standard of care.

PMID 22887848  Ann Rheum Dis. 2013 Jun;72(6):1011-7. doi: 10.1136/annr・・・
著者: Bertrand Dunogué, Benjamin Terrier, Pascal Cohen, Julien Marmursztejn, Paul Legmann, Luc Mouthon, Denis Duboc, Olivier Vignaux, Loïc Guillevin, French Vasculitis Study Group
雑誌名: Autoimmun Rev. 2015 Sep;14(9):774-80. doi: 10.1016/j.autrev.2015.04.013. Epub 2015 May 8.
Abstract/Text OBJECTIVE: To determine the diagnostic and prognostic significance of cardiac magnetic resonance imaging (CMRI) in a cohort of patients with eosinophilic granulomatosis with polyangiitis (EGPA).
METHODS: We conducted a monocentric retrospective study including 42 EGPA patients who had consecutively undergone CMRI at diagnosis or during follow-up, independently of signs of cardiac involvement.
RESULTS: Forty-two patients (male 59.5%, mean age at diagnosis 46.5 years) were included. ANCA was positive in 26.2%, and median EGPA duration before the 1st CMRI screening was 5 months. Seventeen (40.5%) were diagnosed with cardiomyopathy, independently of CMRI findings. CMRI showed myocardial late gadolinium enhancement (LGE) in 82.4% patients with cardiomyopathy vs. 44% without cardiomyopathy (P=0.024). Using LGE as the sole criterion, CMRI sensitivity and specificity for diagnosing cardiomyopathy were 82.4% and 56%, respectively. Among the 15 patients with cardiomyopathy who underwent additional CMRI during follow-up, CMRI-detected cardiac lesions had improved in 7 patients, while those of 8 patients worsened or stabilized despite treatment. These latter patients presented with significantly more cardiac events during follow-up (P=0.026). No differences were found between non-cardiomyopathic patients with or without CMRI anomalies concerning EGPA cardiac manifestations and outcomes.
CONCLUSION: The diagnostic significance of myocardial LGE in EGPA patients remains uncertain and should not be the only criterion for cardiomyopathy diagnosis. For patients with no other signs of cardiomyopathy, CMRI-detected anomalies do not seem to adversely affect prognosis or outcome. For patients with cardiomyopathy, CMRI reassessment seems promising in detecting patients with a less favorable cardiac outcome.

Copyright © 2015 Elsevier B.V. All rights reserved.
PMID 25960167  Autoimmun Rev. 2015 Sep;14(9):774-80. doi: 10.1016/j.au・・・
著者: Julien Marmursztejn, Loic Guillevin, Regine Trebossen, Pascal Cohen, Philippe Guilpain, Christian Pagnoux, Luc Mouthon, Paul Legmann, Olivier Vignaux, Denis Duboc
雑誌名: Rheumatology (Oxford). 2013 Apr;52(4):642-50. doi: 10.1093/rheumatology/kes155. Epub 2012 Jul 5.
Abstract/Text OBJECTIVE: Churg-Strauss syndrome (CSS) cardiac involvement is associated with a poor prognosis. Recently cardiac MRI (CMRI) has emerged as a promising technique to detect early CSS cardiac involvement. However, CMRI-detected myocardial delayed enhancement (MDE) could correspond to fibrosis or inflammation. Fluoro-2-deoxyglucose PET (FDG-PET) was previously used in other systemic diseases to distinguish between them. To determine whether the CMRI-MDE detected in CSS patients reflected fibrosis or myocardial inflammation, patients in CSS remission underwent FDG-PET.
METHODS: Twenty consecutive CSS patients in remission (BVAS = 0) were recruited. Fourteen patients [eight men, six women; mean (S.D.) age 49 (9) years; mean disease duration 3.5 (2.9) years] with CMRI-detected MDE, and six patients [four men, two women; mean (S.D.) age 44 (15) years; mean disease duration 3.5 (5.3) years] with normal CMRI underwent FDG-PET. Segments with MDE on CMRI were analysed on FDG-PET images, with myocardial FDG hypofixation defining fibrosis and hyperfixation corresponding inflammation.
RESULTS: Among the 14 patients with MDE on CMRI, FDG-PET showed 10 had hypofixation, 2 had hyperfixation and 2 had normal scans. CSS duration at the time of CMRI was shorter for patients with myocardial inflammation than in those with fibrosis. The six patients with normal CMRI had normal FDG-PET images.
CONCLUSION: For CSS patients in remission, CMRI detected subclinical active myocardial lesions and could be recommended to assess cardiac involvement. However, because CMRI-detected MDE can reflect fibrosis or inflammation, FDG-PET might help to distinguish between the two.

PMID 22772324  Rheumatology (Oxford). 2013 Apr;52(4):642-50. doi: 10.1・・・
著者: Mohammad Reza Ardalan, Matias Trillini
雑誌名: Caspian J Intern Med. 2012 Summer;3(3):496-9.
Abstract/Text BACKGROUND: Sub-acute bacterial endocarditis (SBE) rarely presents with features of a small vessel vasculitis. Patients with SBE can also develop multiple serological abnormalities including ANCA. In this report, we present a case of infective endocarditis mimicked ANCA associated glomerulonephritis.
CASE PRESENTATION: A 57-year old male with a clinical picture of rapidly progressive renal failure (RPGN) and positive seology for PR3-ANCA (C-ANCA) was referred to our hospital. The renal histology findings were compatible with focal and segmental glomerular necrosis. After receiving corticosteroid therapy, the patient became febrile and his general condition worsened. Cardiac ultrasound echocardiographic study disclosed multiple large vegetations on the aortic valve. After appropriate antibiotic therapy and valvular surgery, the patient's condition improved and his serum creatinine reached 1.7 mg/d.
CONCLUSION: Misdiagnosis of SBE as ANCA-associated vasculitis and an inappropriate immunosuppressive therapy can have catastrophic consequences.

PMID 24009921  Caspian J Intern Med. 2012 Summer;3(3):496-9.
著者: Alfred Mahr, Frédéric Batteux, Sarah Tubiana, Claire Goulvestre, Michel Wolff, Thomas Papo, François Vrtovsnik, Isabelle Klein, Bernard Iung, Xavier Duval, IMAGE Study Group
雑誌名: Arthritis Rheumatol. 2014 Jun;66(6):1672-7. doi: 10.1002/art.38389.
Abstract/Text OBJECTIVE: Infective endocarditis (IE) mimics primary systemic vasculitis, and there are sporadic reports of positivity for antineutrophil cytoplasmic antibodies (ANCAs) among patients with IE. Because the frequency of ANCAs in IE is unknown, this study was undertaken to assess the seroprevalence of ANCAs in a large number of patients with IE.
METHODS: The study was conducted in the framework of a single-center prospective cohort study of incident IE cases. Demographic, clinical, laboratory, and microbiologic data were collected, and magnetic resonance imaging of the brain was performed at diagnosis. For those patients whose serum had been stored at diagnosis, ANCAs were assessed by indirect immunofluorescence assay in ethanol-, formalin-, and methanol-fixed neutrophils. In addition, ANCA specificity for proteinase 3 (PR3) and myeloperoxidase (MPO) was assessed by enzyme-linked immunosorbent assay. Rheumatoid factor (RF), antinuclear antibodies (ANAs), anticardiolipin antibodies (aCL), and serum Ig levels were also measured. Comparisons between groups were made using Wilcoxon's rank sum and chi-square or Fisher's exact tests.
RESULTS: Among 109 patients with IE, 18% had cytoplasmic ANCAs (cANCA) and/or perinuclear ANCAs (pANCA) and 8% had PR3-ANCAs or MPO-ANCAs, some with very high titers. Positivity for both cANCA or pANCA and PR3-ANCAs or MPO-ANCAs was found in 6% of patients, and RF, ANAs, and aCL were detected in 35%, 16%, and 23% of samples, respectively. No consistent clinical pattern of IE was observed in the anti-PR3/anti-MPO-positive IE patients, whereas positivity for cANCA/pANCA was associated with younger age (P = 0.022), more frequent occurrence of echocardiographic vegetations (P = 0.043), and above-normal serum IgG levels (P = 0.017).
CONCLUSION: ANCAs, including PR3- and MPO-ANCAs, occur in a substantial proportion of patients with IE. The link between cANCA/pANCA and specific features of IE requires further study.

Copyright © 2014 by the American College of Rheumatology.
PMID 24497495  Arthritis Rheumatol. 2014 Jun;66(6):1672-7. doi: 10.100・・・
著者: Zhao Cui, Ming-Hui Zhao
雑誌名: Nat Rev Nephrol. 2011 Jul 19;7(12):697-705. doi: 10.1038/nrneph.2011.89. Epub 2011 Jul 19.
Abstract/Text Antiglomerular basement membrane (anti-GBM) disease is an autoimmune disorder that mostly presents as raised titers of antibodies against the GBM, rapidly progressive glomerulonephritis and pulmonary hemorrhage. The disease is caused by antibodies against noncollagenous domain of α3 chain of type IV collagen, which contains the epitopes E(A) and E(B). The humoral and cellular immunity contributing to the initiation of anti-GBM disease has been extensively studied as a model for autoimmune diseases, although most of the data come from animal studies. The disease is rare, but diagnoses have been made in hundreds of patients. Substantial advances have been made in the understanding of human anti-GBM disease, and it can be treated successfully. In this Review we summarize the current knowledge on the prevalence, clinical manifestations, treatment and outcomes of human anti-GBM disease. We discuss findings on pathogenesis from human studies, with close attention to disease initiation and the immunological features of progression from quiescent autoimmune homeostasis in healthy individuals to fulminant anti-GBM disease. Further studies on autoreactive T cells are expected to clarify specific features of human anti-GBM disease and could lead to the development of new therapies.

PMID 21769105  Nat Rev Nephrol. 2011 Jul 19;7(12):697-705. doi: 10.103・・・
著者: T Hellmark, J L Niles, A B Collins, R T McCluskey, C Brunmark
雑誌名: J Am Soc Nephrol. 1997 Mar;8(3):376-85.
Abstract/Text An appreciable percentage of patients with serum anti-glomerular basement membrane (anti-GBM) antibodies also have antineutrophil cytoplasmic antibodies (ANCA), against either myeloperoxidase (MPO-ANCA), or proteinase 3 (PR3-ANCA). In sera without ANCA, the anti-GBM antibodies have been shown to react mainly with the noncollagenous domain (NC1) of Type IV collagen, and especially with its alpha 3 chain, alpha 3(IV)NC1. In most sera, the antibodies can be partially blocked by a monoclonal antibody (Mab17) against alpha 3(IV)NC1, suggesting that a limited region is recognized. Although there is evidence that some anti-GBM antibodies that coexist with ANCA react with alpha 3(IV)NC1, extensive analysis of the specificity of such anti-GBM antibodies has not been reported. In the study presented here, sera were analyzed from 332 patients tested both for anti-GBM antibodies and ANCA (MPO or PR3-ANCA) and found to have one or more positive tests. Of the 100 sera with anti-GBM antibodies, 38 also had ANCA-25 with MPO-ANCA (66%), 12 with PR3-ANCA (32%), and one with both (2%). Of the 232 sera with ANCA only, 153 had MPO-ANCA (66%), 75 had PR3-ANCA (32%), and four had both (2%). Sera was also analyzed from 259 other patients who had positive ANCA tests and were not tested for anti-GBM antibodies: 138 had MPO-ANCA (54%), and 121 had PR3-ANCA (46%). The relative frequencies of MPO or PR3-ANCA in patients with coexisting anti-GBM antibodies did not differ significantly from those in all patients with ANCA (P = 0.35). Seventeen sera with anti-GBM antibodies only and 16 sera with anti-GBM antibodies plus ANCA were selected for further studies to compare the specificity of anti-GBM antibodies in sera with or without ANCA. Using enzyme-linked immunosorbent assays (ELISA), all sera in both groups were found to react with the NC1 domain (as a hexamer) of bovine Type IV collagen and with alpha 3 (IV)NC1 monomers. Furthermore, all but six sera also reacted with one or more of the alpha 1, 2, and 4 (IV)NC1 monomers, generally with considerably lower titers. Reactivity to alpha 3(IV)NC1 was partially blocked by Mab17, with comparable degrees of inhibition in both groups. Western blot analysis with the human NC1 domains revealed no differences in reactivity between the two groups. Thus, differences in antigen specificities of anti-GBM antibodies in sera with or without ANCA were not detected. The anti-GBM response in both situations is hypothesized to be driven by the same immunogen, which is probably derived from NC1 domains of endogenous Type IV collagen.

PMID 9071706  J Am Soc Nephrol. 1997 Mar;8(3):376-85.
著者: Jeremy B Levy, Tarig Hammad, Anne Coulthart, Tammy Dougan, Charles D Pusey
雑誌名: Kidney Int. 2004 Oct;66(4):1535-40. doi: 10.1111/j.1523-1755.2004.00917.x.
Abstract/Text BACKGROUND: Patients have been described who have both anti-neutrophil cytoplasm antibodies (ANCA) and anti-glomerular basement membrane (GBM) antibodies. We have attempted to define the true prevalence of such "double positive" patients, and describe in detail their clinical features and outcome.
METHODS: We have reviewed all serologic assays performed between 1990 and 2000 in a single institution, and the case notes of patients having sera positive for both ANCA and anti-GBM antibodies. During this time 20,392 sera were initially tested for ANCA, and 4808 sera tested for anti-GBM antibodies.
RESULTS: Five percent of all ANCA-positive serum samples were also positive for anti-GBM antibodies, and 32% of all anti-GBM positive samples had detectable ANCA. Of 27 patients with both antibodies, 82% had anti-myeloperoxidase specific P-ANCA. Pulmonary hemorrhage occurred in 44%. Renal biopsy showed extensive glomerular cellular crescents in most patients. Patient and renal survival rates were 52% and 26%, respectively, at one year. Sixty-eight percent of patients were dialysis-dependent at presentation, and none of these recovered renal function, despite immunosuppression with or without plasma exchange.
CONCLUSION: Serologic evidence of double positivity for both ANCA and anti-GBM antibodies is common in patients with either antibody. In our study these patients have a poor prognosis when presenting with severe disease and initially behave more like anti-GBM disease than vasculitis. Recovery from severe renal failure is rare.

PMID 15458448  Kidney Int. 2004 Oct;66(4):1535-40. doi: 10.1111/j.1523・・・
著者: Abraham Rutgers, Marjan Slot, Pieter van Paassen, Peter van Breda Vriesman, Peter Heeringa, Jan Willem Cohen Tervaert
雑誌名: Am J Kidney Dis. 2005 Aug;46(2):253-62. doi: 10.1053/j.ajkd.2005.05.003.
Abstract/Text BACKGROUND: In a substantial proportion of patients with crescentic glomerulonephritis (CGN), both anti-glomerular basement membrane (GBM) antibodies and antineutrophil cytoplasmic antibodies (ANCAs) with specificity for myeloperoxidase (MPO-ANCA) are detected. In the present study, we questioned whether histological and clinical features of patients with both ANCA and anti-GBM antibodies differ from those of patients with either ANCA or anti-GBM alone.
METHODS: We reviewed the Limburg renal biopsy registry (1978 to 2003; n = 1,373) for cases of CGN. The presence of linear fluorescence on renal biopsy and the presence of ANCA and/or anti-GBM antibodies were measured. Subsequently, we assessed patient characteristics and follow-up and compared histological findings among the different groups.
RESULTS: We identified 46 MPO-ANCA-positive, 10 double-positive, and 13 anti-GBM-positive patients. Mean ages were 63, 64, and 52 years (P = 0.04), and serum creatinine levels were 5.0, 10.3, and 9.6 mg/dL (445, 910, and 850 micromol/L), respectively (P = 0.01). Granulomatous periglomerular inflammation was found in either MPO-ANCA- or double-positive patients, but not in anti-GBM-positive patients with CGN without MPO-ANCAs. Patient survival among the 3 groups was different, although not statistically significant (log rank P = 0.17, with 75%, 79%, and 100% alive at 1 year, respectively). Renal survival analysis showed significant differences among the 3 groups (P = 0.04, with 65%, 10%, and 15% off dialysis therapy at 1 year, respectively).
CONCLUSION: In patients with both anti-GBM antibodies and MPO-ANCAs, histological findings differ from those of patients with anti-GBM antibodies only. However, renal survival in these patients is not better than that in anti-GBM-positive patients and is worse compared with patients with MPO-ANCAs only.

PMID 16112043  Am J Kidney Dis. 2005 Aug;46(2):253-62. doi: 10.1053/j.・・・
著者: Konstantin N Konstantinov, Constance J Ulff-Møller, Antonios H Tzamaloukas
雑誌名: Autoimmun Rev. 2015 Mar;14(3):201-3. doi: 10.1016/j.autrev.2014.10.020. Epub 2014 Nov 4.
Abstract/Text The precise cause of the antineutrophil cytoplasmic antibodies (ANCA) autoimmunity is not known and is likely to be multifactorial. Infections may trigger formation of ANCA and a fraction of the patients with infection-triggered ANCA develop ANCA-associated vasculitis. Here we discuss some of the proposed mechanisms of ANCA formation during the course of infection. They include initiation of autoimmune response by microbial peptides that are complementary to autoantigens; epigenetic silencing and antigen complementarity leading to upregulation of autoantigen genes; molecular mimicry between bacterial and self-antigens; formation of neutrophil extracellular traps that stimulate immune processes including production of ANCA; and interaction of bacterial components with Toll-like receptors, which leads to formation of mediators affecting the immune responses to infections and can trigger ANCA production. Further work is needed to clarify these mechanisms and develop preventive measures and therapeutic interventions.

Published by Elsevier B.V.
PMID 25448042  Autoimmun Rev. 2015 Mar;14(3):201-3. doi: 10.1016/j.aut・・・
著者: M H Zhao, D R Jayne, L G Ardiles, F Culley, M E Hodson, C M Lockwood
雑誌名: QJM. 1996 Apr;89(4):259-65. doi: 10.1093/qjmed/89.4.259.
Abstract/Text Cystic fibrosis (CF), a genetic disorder, is characterized by chronic pulmonary infection/inflammation which leads to respiratory failure. The presence of anti-neutrophil cytoplasmic autoantibodies (ANCA) has previously been observed in the sera of patients with CF. In view of the known relationship of ANCA with primary vasculitis and of their putative pathogenetic role in these disorders, we studied the presence, specificity and isotype of ANCA and their clinical associations in 66 adult CF patients. None of the 66 CF samples had autoantibodies to the major ANCA antigens, proteinase 3 or myeloperoxidase. However, 60/66 (91%) CF samples contained IgG, and 55/66 (83%) IgA, autoantibodies to bactericidal/permeability-increasing protein (BPI), a recently-characterized ANCA specificity. All the IgA anti-BPI-positive samples were also IgG anti-BPI-positive. The autoantibody specificity was confirmed by inhibition assay and immunoblotting of CF sera against a neutrophil granule preparation. Furthermore, in this cross-sectional study, anti-BPI levels were inversely correlated with the observed reductions in FEV1 and FVC (IgA anti-BPI & FEV1: r = -0.508, p < 0.0001), and both IgG and IgA anti-BPI levels were higher in CF patients with secondary vasculitis (n = 6) than in those without (p < 0.05). ANCA with specificity for BPI were present in the majority of CF sera in this study and autoimmune processes may be associated with the development of pulmonary injury in CF.

PMID 8733512  QJM. 1996 Apr;89(4):259-65. doi: 10.1093/qjmed/89.4.259・・・
著者: P A Merkel, R P Polisson, Y Chang, S J Skates, J L Niles
雑誌名: Ann Intern Med. 1997 Jun 1;126(11):866-73. doi: 10.7326/0003-4819-126-11-199706010-00003.
Abstract/Text BACKGROUND: Two types of antineutrophil cytoplasmic antibodies (ANCA), antiproteinase 3 antibodies (anti-PR3) and antimyeloperoxidase antibodies (anti-MPO), are useful in the diagnosis of such types of vasculitis as Wegener granulomatosis and microscopic polyangiitis. Connective tissue diseases frequently appear in the differential diagnosis of this spectrum of vasculitis.
OBJECTIVE: To determine the prevalence of ANCA in patients with connective tissue disease.
DESIGN: Blinded, controlled study of a 5-year inception cohort.
SETTING: Tertiary-care university teaching hospitals.
PATIENTS: 70 patients with rheumatoid arthritis, 70 patients with systemic lupus erythematosus, 45 patients with scleroderma, 36 patients with inflammatory myositis, 44 patients with the sjögren syndrome, 33 patients with the antiphospholipid syndrome, and 165 patients with early undifferentiated connective tissue disease (EUCTD). Serum was taken from 200 blood donors and 52 patients who had known vasculitis and positive results on tests for anti-PR3 or anti-MPO; these patients served as controls.
MEASUREMENTS: The presence of anti-PR3 and anti-MPO was determined by combining the results of indirect immunofluorescence tests for cytoplasmic (C-ANCA) and perinuclear (P-ANCA) patterns with the results of enzymelinked immunosorbent assays (ELISAs) directed to measure antigen.
RESULTS: Cytoplasmic ANCA was not detected in any study or control patient. Perinuclear ANCA was commonly detected among patients with lupus (31%) but was uncommon among patients in other groups (0% to 5%). In all cases, P-ANCA was associated with the presence of antinuclear antibodies. Atypical ANCA immunofluorescence patterns were fairly common in all groups (11% to 39%). Antiproteinase 3 was detected by ELISA in study patients (1 patient with rheumatoid arthritis, 1 with lupus, 1 with polymyositis, and 6 with EUCTD). Antimyeloperoxidase was detected by ELISA in 2 study patients (1 with rheumatoid arthritis and 1 with lupus). None of the patients with positive ELISA results had evidence of renal vasculitis during follow-up. When an ANCA scoring system that combines immunofluorescence and ELISA was used, the test specificity for vasculitis was 99.5% among patients with connective tissue disease.
CONCLUSIONS: Patients with connective tissue disease are known to develop multiple autoantibodies; positivity for anti-PR3 and anti-MPO ANCA in such patients is highly specific for anti-PR3. However, P-ANCA immunofluorescence, which may have positive results because of the presence of antinuclear antibodies, is not a specific marker of anti-MPO. A rigorous ANCA testing system that combines the results of immunofluorescence with those of ELISA is highly specific for Wegener granulomatosis and related vasculitides even in patients with connective tissue disease.

PMID 9163287  Ann Intern Med. 1997 Jun 1;126(11):866-73. doi: 10.7326・・・
著者: C Roozendaal, M A de Jong, A P van den Berg, R T van Wijk, P C Limburg, C G Kallenberg
雑誌名: J Hepatol. 2000 May;32(5):734-41. doi: 10.1016/s0168-8278(00)80241-x.
Abstract/Text BACKGROUND/AIMS: The clinical relevance of anti-neutrophil cytoplasmic antibodies (ANCA) in autoimmune liver disease is unclear. Defining the antigenic specificities of ANCA in these diseases may improve their clinical significance.
METHODS: We studied the target antigens of ANCA in 88 patients with autoimmune hepatitis, 53 patients with primary biliary cirrhosis, and 55 patients with primary sclerosing cholangitis by indirect immunofluorescence, antigen-specific enzyme-linked immunosorbent assays, and immunodetection on Western blot, using an extract of whole neutrophils as a substrate. We related the data to clinical symptoms of autoimmune liver disease.
RESULTS: By indirect immunofluorescence, ANCA were present in 74% of patients with autoimmune hepatitis, 26% of patients with primary biliary cirrhosis, and 60% of patients with primary sclerosing cholangitis. Major antigens were catalase, alpha-enolase, and lactoferrin. The presence of ANCA as detected by indirect immunofluorescence was associated with the occurrence of relapses in autoimmune hepatitis, with decreased liver synthesis function in primary biliary cirrhosis and in primary sclerosing cholangitis, and with increased cholestasis in primary sclerosing cholangitis. ANCA of defined specificities had only limited clinical relevance.
CONCLUSIONS: ANCA as detected by indirect immunofluorescence seem associated with a more severe course of autoimmune liver disease. The target antigens for ANCA in these diseases include catalase, alpha-enolase, and lactoferrin. Assessment of the antigenic specificities of ANCA in autoimmune liver disease does not significantly contribute to their clinical significance.

PMID 10845659  J Hepatol. 2000 May;32(5):734-41. doi: 10.1016/s0168-82・・・
著者: S Lindgren, S Nilsson, L Nässberger, H Verbaan, J Wieslander
雑誌名: J Gastroenterol Hepatol. 2000 Apr;15(4):437-42. doi: 10.1046/j.1440-1746.2000.02078.x.
Abstract/Text BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA) against proteinase 3 are diagnostic of Wegener's granulomatosis, but ANCA occur also in patients with other inflammatory disorders, such as ulcerative colitis, primary sclerosing cholangitis (PSC) and autoimmune hepatitis. As their predictive value for autoimmune liver disease remains unknown, we analysed the prevalence and antigen specificity of ANCA in patients with various chronic liver diseases (CLD).
METHODS: We studied sera from 100 patients with primary biliary cirrhosis (PBC), from 76 with PSC and from 279 with various CLD, consecutively drawn during a 5-year period at the time of liver biopsy. The ANCA were detected by indirect immunofluorescence (IIF) while the antigen specificity was characterized by ELISA by using lactoferrin, neutrophil elastase, cathepsin G and BPI (bactericidal/permeability increasing protein) as antigens.
RESULTS: In PBC, ANCA were detected by IIF in 39 patients (39%). The antigen reactivity by ELISA was lactoferrin in seven, elastase in 15, BPI in 20 and cathepsin G in four patients. Four patients had reactivity against more than one antigen. In PSC, IIF demonstrated ANCA in 49 patients (65%). The antigen reactivity was lactoferrin in 17, elastase in 14, BPI in 20 and cathepsin G in four patients. Twelve patients showed reactivity against more than one antigen. In CLD, ANCA were observed in sera from 55 patients (20%). Nineteen of 45 patients (42%) with autoimmune liver disease were ANCA positive versus 36/234 (15%) with non-autoimmune liver disease (P = 0.0002). Among IIF-positive patients, antibody reactivity against lactoferrin was noted in 14, elastase in 28, BPI in 25 and cathepsin G in five patients. Twenty-one patients had reactivity against more than one antigen. Elastase and BPI antibodies occurred more frequently in patients with autoimmune compared to non-autoimmune liver disease (P < 0.01).
CONCLUSIONS: Anti-neutrophil cytoplasmic antibodies are prevalent in patients with chronic liver diseases, but although they occur more frequently in patients with autoimmune liver disease their specificity and sensitivity for autoimmune liver disease is low. The predominant antigens are lactoferrin, elastase and BPI, but the correlation between IIF findings and ELISA reactivity against these antigens is weak.

PMID 10824890  J Gastroenterol Hepatol. 2000 Apr;15(4):437-42. doi: 10・・・
著者: C Roozendaal, C G Kallenberg
雑誌名: Clin Exp Immunol. 1999 May;116(2):206-13. doi: 10.1046/j.1365-2249.1999.00905.x.
Abstract/Text Since the first detection of ANCA in IBD, numerous studies have dealt with their prevalence, antigenic specificities, clinical significance, pathophysiological role, and their induction. This review summarizes the information obtained from those studies and shows that ANCA are not directly useful as diagnostic and prognostic factors in IBD. ANCA were detected in 50-85% of patients with ulcerative colitis (UC) and 10-20% of patients with Crohn's disease (CD). Multiple target antigens are recognized by these autoantibodies, including both cytoplasmic and nuclear proteins. A pathophysiological role for ANCA in IBD is far from clear. On the one hand, it is suggested that ANCA are genetic markers of susceptibility for IBD, and on the other hand, the induction of ANCA in those diseases may just be an epiphenomenon of chronic inflammation. We discuss recent evidence that ANCA may be induced by a break-through of tolerance towards bacterial antigens.

PMID 10337008  Clin Exp Immunol. 1999 May;116(2):206-13. doi: 10.1046/・・・
著者: William F Pendergraft, John L Niles
雑誌名: Curr Opin Rheumatol. 2014 Jan;26(1):42-9. doi: 10.1097/BOR.0000000000000014.
Abstract/Text PURPOSE OF REVIEW: Antineutrophil cytoplasmic autoantibody (ANCA) vasculitis is a systemic autoimmune disease resulting in small-vessel inflammation caused by pathogenic autoantibodies directed against proteinase 3 or myeloperoxidase. Legal drug culprits have been implicated as causative agents in secondary forms of disease, and a recent burst of reports also implicate levamisole-adulterated cocaine as a culprit.
RECENT FINDINGS: Here, we briefly discuss all drug culprits associated with ANCA vasculitis and then focus on clinical, serologic, therapeutic and mechanistic aspects of four main drug culprits receiving attention of late, namely hydralazine, minocycline, propylthiouracil (PTU) and levamisole-adulterated cocaine.
SUMMARY: Hydralazine, minocycline, propylthiouracil and levamisole-adulterated cocaine use should be closely considered in any patient where ANCA vasculitis is entertained given the wide use of these drugs in the community. Furthermore, medical practitioners should test urine for the presence of cocaine in any patient with presumed ANCA vasculitis, and if positive, then urine should also be tested for levamisole. Clinical features can be severe requiring not only drug cessation and supportive care, but also immunosuppression, plasma exchange in severe cases and dialysis as needed. Clinical trial investigators should strongly consider excluding patients with drug-induced forms of disease and mechanistic inroads are greatly needed in these secondary forms of disease to help elucidate the underlying cause and pathogenesis of ANCA vasculitis.

PMID 24276086  Curr Opin Rheumatol. 2014 Jan;26(1):42-9. doi: 10.1097/・・・
著者: Martina M McGrath, Tamara Isakova, Helmut G Rennke, Ann M Mottola, Karen A Laliberte, John L Niles
雑誌名: Clin J Am Soc Nephrol. 2011 Dec;6(12):2799-805. doi: 10.2215/CJN.03440411. Epub 2011 Oct 6.
Abstract/Text BACKGROUND AND OBJECTIVES: Approximately 70% of illicit cocaine consumed in the United States is contaminated with levamisole. Most commonly used as a veterinary antihelminthic agent, levamisole is a known immunomodulating agent. Prolonged use in humans has been associated with cutaneous vasculitis and agranulocytosis. We describe the development of a systemic autoimmune disease associated with antineutrophil cytoplasmic antibodies (ANCA) in cocaine users. This complication appears to be linked to combined cocaine and levamisole exposure.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Cases were identified between March 2009 and November 2010 at Massachusetts General Hospital's ANCA laboratory. Cocaine exposure was identified from patient history in all cases. Medical records were reviewed for clinical presentation and for laboratory and diagnostic evaluation.
RESULTS: Thirty cases of ANCA positivity associated with cocaine ingestion were identified. All had antimyeloperoxidase antibodies and 50% also had antiproteinase 3 antibodies. Complete clinical and laboratory data were available for 18 patients. Arthralgia (83%) and skin lesions (61%) were the most frequent complaints at presentation. Seventy-two percent of patients reported constitutional symptoms, including fever, night sweats, weight loss, or malaise. Four patients had biopsy-proven vasculitis. Two cases of acute kidney injury and three cases of pulmonary hemorrhage occurred. From the entire cohort of 30, two cases were identified during the first 3 months of our study period and nine cases presented during the last 3 months.
CONCLUSIONS: We describe an association between the ingestion of levamisole-contaminated cocaine and ANCA-associated systemic autoimmune disease. Our data suggest that this is a potentially life-threatening complication of cocaine use.

PMID 21980179  Clin J Am Soc Nephrol. 2011 Dec;6(12):2799-805. doi: 10・・・
著者: L A Anderson, R M Pfeiffer, O Landgren, S Gadalla, S I Berndt, E A Engels
雑誌名: Br J Cancer. 2009 Mar 10;100(5):822-8. doi: 10.1038/sj.bjc.6604935.
Abstract/Text Autoimmune conditions are associated with an elevated risk of lymphoproliferative malignancies, but few studies have investigated the risk of myeloid malignancies. From the US Surveillance Epidemiology and End Results (SEER)-Medicare database, 13 486 myeloid malignancy patients (aged 67+ years) and 160 086 population-based controls were selected. Logistic regression models adjusted for gender, age, race, calendar year and number of physician claims were used to estimate odds ratios (ORs) for myeloid malignancies in relation to autoimmune conditions. Multiple comparisons were controlled for using the Bonferroni correction (P<0.0005). Autoimmune conditions, overall, were associated with an increased risk of acute myeloid leukaemia (AML) (OR 1.29) and myelodysplastic syndrome (MDS, OR 1.50). Specifically, AML was associated with rheumatoid arthritis (OR 1.28), systemic lupus erythematosus (OR 1.92), polymyalgia rheumatica (OR 1.73), autoimmune haemolytic anaemia (OR 3.74), systemic vasculitis (OR 6.23), ulcerative colitis (OR 1.72) and pernicious anaemia (OR 1.57). Myelodysplastic syndrome was associated with rheumatoid arthritis (OR1.52) and pernicious anaemia (OR 2.38). Overall, autoimmune conditions were not associated with chronic myeloid leukaemia (OR 1.09) or chronic myeloproliferative disorders (OR 1.15). Medications used to treat autoimmune conditions, shared genetic predisposition and/or direct infiltration of bone marrow by autoimmune conditions, could explain these excess risks of myeloid malignancies.

PMID 19259097  Br J Cancer. 2009 Mar 10;100(5):822-8. doi: 10.1038/sj.・・・
著者: Amir Agha, Helen Bateman, Ashley Sterrett, Joanne Valeriano-Marcet
雑誌名: Curr Rheumatol Rep. 2012 Dec;14(6):526-31. doi: 10.1007/s11926-012-0281-3.
Abstract/Text While the link between malignancy and vasculitis has been known for some time, the association of vasculitis and myelodysplastic syndrome (MDS) has only recently been reported. This article reviews the most current and landmark publications regarding MDS, as well as malignancy-associated vasculitis. We include theories of paraneoplastic associations, immune pathogenesis including an associated cytokine transcriptional factor (interferon regulatory factor-1 [IFN-1]), and the relationship to treatment. Key clinical features that suggest underlying malignancy in patients with vasculitis are highlighted. Although the association between vasculitis and malignancy is rare, leukocytoclastic vasculitis is the most common vasculitis associated with MDS, hematologic malignancies as well as solid tumors. We review several articles that demonstrate a paraneoplastic association between vasculitis and various malignancies, but overall, the connection is still unclear and not well defined. Certain features that suggest a true paraneoplastic association are outlined. Further studies are needed to advance our understanding of this complex topic.

PMID 22821200  Curr Rheumatol Rep. 2012 Dec;14(6):526-31. doi: 10.1007・・・
著者: M A Hamidou, S Derenne, M A Audrain, J M Berthelot, A Boumalassa, J Y Grolleau
雑誌名: Rheumatology (Oxford). 2000 Apr;39(4):417-20. doi: 10.1093/rheumatology/39.4.417.
Abstract/Text OBJECTIVE: To evaluate the prevalence of antineutrophil cytoplasmic antibodies (ANCA) and rheumatic manifestations associated with chronic haematological malignancies.
METHODS: Two groups of patients were prospectively studied (group I: 60 patients with myelodysplastic syndromes and group II: 140 patients with lymphoid malignancies) for clinical 'immune' manifestations and ANCA.
RESULTS: In the myelodysplastic group, six patients had ANCA-negative systemic medium-size vasculitis, one had systemic vasculitis with cytoplasmic ANCA, one relapsing polychondritis, one giant cell arteritis, one polymyalgia rheumatica, one polyarthritis and two fasciitis. In group II, two patients had ANCA-negative systemic vasculitis, two had leucocytoclastic vasculitis associated with tuberculosis, two had polyarthritis, one polymyalgia rheumatica and one giant cell arteritis. Six sera were ANCA-positive with perinuclear pattern in four cases, atypical pattern in one and cytoplasmic pattern in one. Two sera had anti-myeloperoxidase (MPO) specificity, and others had no known specificity; none had anti-proteinase 3 (PR3) specificity. Global prevalence of ANCA in our cohort was 3%, similar to the French general population.
CONCLUSION: Polyarteritis nodosa-type systemic vasculitis and polymyalgia rheumatica were the most frequent findings (18%) in myelodysplastic syndromes and particularly in chronic myelomonocytic leukaemia. ANCA were not helpful for the diagnosis of vasculitis. Vasculitis associated with infection, in particular tuberculosis, must be ruled out.

PMID 10817775  Rheumatology (Oxford). 2000 Apr;39(4):417-20. doi: 10.1・・・
著者: Hiromichi Tamaki, Soumya Chatterjee, Carol A Langford
雑誌名: Immunol Allergy Clin North Am. 2015 Aug;35(3):453-76. doi: 10.1016/j.iac.2015.05.001. Epub 2015 Jun 17.
Abstract/Text Peripheral and tissue eosinophilia can be a prominent feature of several unique rheumatologic and vascular diseases. These diseases span a wide range of clinical features, histologic findings, therapeutic approaches, and outcomes. Despite the rare nature of these entities--which makes large-scale studies challenging--knowledge has continued to grow regarding their epidemiology, pathophysiology, and management. This review compares and contrasts 5 rheumatologic and vascular conditions in which eosinophilia can be seen: eosinophilic granulomatosis with polyangiitis (Churg-Strauss), immunoglobulin G4-related disease, diffuse fasciitis with eosinophilia, eosinophilia-myalgia syndrome, and eosinophilic myositis.

Copyright © 2015 Elsevier Inc. All rights reserved.
PMID 26209895  Immunol Allergy Clin North Am. 2015 Aug;35(3):453-76. d・・・
著者: Princess U Ogbogu, Bruce S Bochner, Joseph H Butterfield, Gerald J Gleich, Johannes Huss-Marp, Jean Emmanuel Kahn, Kristin M Leiferman, Thomas B Nutman, Florian Pfab, Johannes Ring, Marc E Rothenberg, Florence Roufosse, Marie-Helene Sajous, Javed Sheikh, Dagmar Simon, Hans-Uwe Simon, Miguel L Stein, Andrew Wardlaw, Peter F Weller, Amy D Klion
雑誌名: J Allergy Clin Immunol. 2009 Dec;124(6):1319-25.e3. doi: 10.1016/j.jaci.2009.09.022.
Abstract/Text BACKGROUND: Hypereosinophilic syndrome (HES) is a heterogeneous group of rare disorders defined by persistent blood eosinophilia > or =1.5 x 10(9)/L, absence of a secondary cause, and evidence of eosinophil-associated pathology. With the exception of a recent multicenter trial of mepolizumab (anti-IL-5 mAb), published therapeutic experience has been restricted to case reports and small case series.
OBJECTIVE: The purpose of the study was to collect and summarize baseline demographic, clinical, and laboratory characteristics in a large, diverse cohort of patients with HES and to review responses to treatment with conventional and novel therapies.
METHODS: Clinical and laboratory data from 188 patients with HES, seen between January 2001 and December 2006 at 11 institutions in the United States and Europe, were collected retrospectively by chart review.
RESULTS: Eighteen of 161 patients (11%) tested were Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) mutation-positive, and 29 of 168 patients tested (17%) had a demonstrable aberrant or clonal T-cell population. Corticosteroid monotherapy induced complete or partial responses at 1 month in 85% (120/141) of patients with most remaining on maintenance doses (median, 10 mg prednisone equivalent daily for 2 months to 20 years). Hydroxyurea and IFN-alpha (used in 64 and 46 patients, respectively) were also effective, but their use was limited by toxicity. Imatinib (used in 68 patients) was more effective in patients with the FIP1L1-PDGFRA mutation (88%) than in those without (23%; P < .001).
CONCLUSION: This study, the largest clinical analysis of patients with HES to date, not only provides useful information for clinicians but also should stimulate prospective trials to optimize treatment of HES.

PMID 19910029  J Allergy Clin Immunol. 2009 Dec;124(6):1319-25.e3. doi・・・
著者: Ulrich Specks, Peter A Merkel, Philip Seo, Robert Spiera, Carol A Langford, Gary S Hoffman, Cees G M Kallenberg, E William St Clair, Barri J Fessler, Linna Ding, Lisa Viviano, Nadia K Tchao, Deborah J Phippard, Adam L Asare, Noha Lim, David Ikle, Brett Jepson, Paul Brunetta, Nancy B Allen, Fernando C Fervenza, Duvuru Geetha, Karina Keogh, Eugene Y Kissin, Paul A Monach, Tobias Peikert, Coen Stegeman, Steven R Ytterberg, Mark Mueller, Lourdes P Sejismundo, Kathleen Mieras, John H Stone, RAVE-ITN Research Group
雑誌名: N Engl J Med. 2013 Aug 1;369(5):417-27. doi: 10.1056/NEJMoa1213277.
Abstract/Text BACKGROUND: The 18-month efficacy of a single course of rituximab as compared with conventional immunosuppression with cyclophosphamide followed by azathioprine in patients with severe (organ-threatening) antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is unknown.
METHODS: In a multicenter, randomized, double-blind, double-dummy, noninferiority trial, we compared rituximab (375 mg per square meter of body-surface area administered once a week for 4 weeks) followed by placebo with cyclophosphamide administered for 3 to 6 months followed by azathioprine for 12 to 15 months. The primary outcome measure was complete remission of disease by 6 months, with the remission maintained through 18 months.
RESULTS: A total of 197 patients were enrolled. As reported previously, 64% of the patients in the rituximab group, as compared with 53% of the patients in the cyclophosphamide-azathioprine group, had a complete remission by 6 months. At 12 and 18 months, 48% and 39%, respectively, of the patients in the rituximab group had maintained the complete remissions, as compared with 39% and 33%, respectively, in the comparison group. Rituximab met the prespecified criteria for noninferiority (P<0.001, with a noninferiority margin of 20%). There was no significant difference between the groups in any efficacy measure, including the duration of complete remission and the frequency or severity of relapses. Among the 101 patients who had relapsing disease at baseline, rituximab was superior to conventional immunosuppression at 6 months (P=0.01) and at 12 months (P=0.009) but not at 18 months (P=0.06), at which time most patients in the rituximab group had reconstituted B cells. There was no significant between-group difference in adverse events.
CONCLUSIONS: In patients with severe ANCA-associated vasculitis, a single course of rituximab was as effective as continuous conventional immunosuppressive therapy for the induction and maintenance of remissions over the course of 18 months. (Funded by the National Institute of Allergy and Infectious Diseases and others; RAVE ClinicalTrials.gov number, NCT00104299.)

PMID 23902481  N Engl J Med. 2013 Aug 1;369(5):417-27. doi: 10.1056/NE・・・
著者: Susan L Hogan, Ronald J Falk, Hyunsook Chin, Jianwen Cai, Caroline E Jennette, J Charles Jennette, Patrick H Nachman
雑誌名: Ann Intern Med. 2005 Nov 1;143(9):621-31. doi: 10.7326/0003-4819-143-9-200511010-00005.
Abstract/Text BACKGROUND: Predictors of treatment resistance and relapse have not been well described in antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis.
OBJECTIVE: To identify clinical, pathologic, and serologic predictors of treatment resistance and relapse in a community-based cohort of patients with ANCA-associated vasculitis.
DESIGN: Cohort of patients identified at or near the time of biopsy diagnosis and followed as clinically indicated.
SETTING: The Glomerular Disease Collaborative Network.
PATIENTS: 350 patients who received a new diagnosis of ANCA-associated vasculitis between 1985 and 2003 and were followed for a median of 49 months.
MEASUREMENTS: Patients were categorized according to whether they had antiproteinase-3 (anti-PR3) antibodies or antimyeloperoxidase (anti-MPO) antibodies. Organ involvement was determined by biopsy or by well-defined clinical criteria. Treatment resistance was defined as progressive decline in kidney function with active urine sediment or the persistence or appearance of extrarenal manifestations. Relapse was defined as the time to the resurgence of vasculitic symptoms.
RESULTS: Treatment resistance affected 23% of 334 treated patients and was associated with female sex, black ethnicity, and presentation with severe kidney disease (odds ratio per serum creatinine elevation of 100 micromol/L [1.13 mg/dL], 1.28 [95% CI, 1.16 to 1.39]). The following factors were associated with relapse in 258 (77%) patients who attained remission: seropositivity for anti-PR3 antibodies (hazard ratio, 1.87 [CI, 1.11 to 3.14]) and disease of the lung (hazard ratio, 1.71 [CI, 1.04 to 2.81]) or upper respiratory tract (hazard ratio, 1.73 [CI, 1.04 to 2.88]). Relapses occurred in 26% of patients with no risk factors versus 73% of patients with all 3 risk factors (hazard ratio, 3.7 [CI, 1.4 to 9.7]). Among 143 patients attaining remission who subsequently stopped all immunosuppressant therapy, relapse rates were similar for those who had received cyclophosphamide therapy for 6 months or less (34%) compared with those treated for a longer duration (35%), even after adjusting for risk factors for relapse (hazard ratio, 1.41 [CI, 0.80 to 2.50]).
LIMITATIONS: The cohort mostly included patients with biopsy-proven kidney disease. Patients were not followed with uniform treatment protocols, and only limited information about their clinical course before diagnosis was available.
CONCLUSIONS: Female or black patients, or those with severe kidney disease, may be resistant to initial treatment more often than other patients with ANCA-associated small-vessel vasculitis. Increased risk for relapse appears to be related to the presence of lung or upper airway disease and anti-PR3 antibody seropositivity.

PMID 16263884  Ann Intern Med. 2005 Nov 1;143(9):621-31. doi: 10.7326/・・・
著者: Gunnar Tomasson, Peter C Grayson, Alfred D Mahr, Michael Lavalley, Peter A Merkel
雑誌名: Rheumatology (Oxford). 2012 Jan;51(1):100-9. doi: 10.1093/rheumatology/ker280. Epub 2011 Oct 29.
Abstract/Text OBJECTIVE: The value of repeated ANCA measurements among patients with an established diagnosis of ANCA-associated vasculitis (AAV) remains controversial. The aim of this study was to explore whether either of the two distinct patterns of ANCA values during remission, a rise in ANCA or persistently positive ANCA, predicted future relapse.
METHODS: MEDLINE and EMBASE searches were performed. Studies with at least 10 subjects with AAV from which both sensitivity and specificity of a rise in ANCA and/or persistent ANCA for future disease relapse could be calculated were included. Likelihood ratios were calculated for each study and pooled to arrive at summary estimates. I(2)-values were calculated as a measure of heterogeneity and meta-regression was used to explore sources of heterogeneity.
RESULTS: Nine articles on a rise in ANCA and nine articles on persistent ANCA were included. The summary estimates for positive likelihood ratio (LR(+)) and negative likelihood ratio (LR(-)) of a rise in ANCA during remission on subsequent relapse of disease were 2.84 (95% CI 1.65, 4.90) and 0.49 (95% CI 0.27, 0.87), respectively. The summary estimates for LR(+) and LR(-) of persistent ANCA during remission for subsequent disease relapse were 1.97 (95% CI 1.43, 2.70) and 0.73 (95% CI 0.50, 1.06), respectively. There was substantial between-study heterogeneity, which was partially explained by the frequency of ANCA measurements.
CONCLUSION: Among patients with AAV, a rise in or persistence of ANCA during remission is only modestly predictive of future disease relapse. There is limited use to serial ANCA measurements during disease remission to guide treatment decisions for individual patients with AAV.

PMID 22039267  Rheumatology (Oxford). 2012 Jan;51(1):100-9. doi: 10.10・・・
著者: Weifeng Shang, Yong Ning, Xiu Xu, Menglan Li, Shuiming Guo, Min Han, Rui Zeng, Shuwang Ge, Gang Xu
雑誌名: PLoS One. 2015;10(5):e0126016. doi: 10.1371/journal.pone.0126016. Epub 2015 May 14.
Abstract/Text OBJECTIVE: The purpose of this paper is to examine cancer incidence in patients with ANCA-associated vasculitis (AASV) derived from population-based cohort studies by means of meta-analysis.
METHODS: Relevant electronic databases were searched for studies characterizing the associated risk of overall malignancy in patients with AASV. Standardized incidence rates (SIRs) with 95% confidence intervals (CIs) were used to evaluate the strength of association. We tested for publication bias and heterogeneity and stratified for site-specific cancers.
RESULTS: Six studies (n = 2,578) were eventually identified, of which six provided the SIR for overall malignancy, five reported the SIR for non-melanoma skin cancer (NMSC), four for leukemia, five for bladder cancer, three for lymphoma, three for liver cancer, four for lung cancer, three for kidney cancer, four for prostate cancer, four for colon cancer and four for breast cancer. Overall, the pooled SIR of cancer in AASV patients was 1.74 (95%CI = 1.37-2.21), with moderate heterogeneity among these studies (I(2) = 65.8%, P = 0.012). In sub-analyses for site-specific cancers, NMSC, leukemia and bladder cancer were more frequently observed in patients with AASV with SIR of 5.18 (95%CI = 3.47-7.73), 4.89 (95%CI = 2.93-8.16) and 3.84 (95%CI = 2.72-5.42) respectively. There was no significant increase in the risk of kidney cancer (SIR = 2.12, 95%CI = 0.66-6.85), prostate cancer (SIR = 1.45, 95%CI = 0.87-2.42), colon cancer (SIR = 1.26, 95%CI = 0.70-2.27), and breast cancer (SIR = 0.95, 95%CI = 0.50-1.79). Among these site-specific cancers, only NMSC showed moderate heterogeneity (I2 = 55.8%, P = 0.06). No publication bias was found by using the Begg's test and Egger's test.
CONCLUSIONS: This meta-analysis shows that AASV patients treatment with cyclophosphamide (CYC) are at increased risk of late-occurring malignancies, particularly of the NMSC, leukemia and bladder cancer. However, there is no significant association between AASV and kidney cancer, prostate cancer, colon cancer and breast cancer. These findings emphasize monitoring and preventative management in AASV patients after cessation of CYC therapy is momentous.

PMID 25973882  PLoS One. 2015;10(5):e0126016. doi: 10.1371/journal.pon・・・
著者: M Yates, R A Watts, I M Bajema, M C Cid, B Crestani, T Hauser, B Hellmich, J U Holle, M Laudien, M A Little, R A Luqmani, A Mahr, P A Merkel, J Mills, J Mooney, M Segelmark, V Tesar, K Westman, A Vaglio, N Yalçındağ, D R Jayne, C Mukhtyar
雑誌名: Ann Rheum Dis. 2016 Sep;75(9):1583-94. doi: 10.1136/annrheumdis-2016-209133. Epub 2016 Jun 23.
Abstract/Text In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. 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) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
PMID 27338776  Ann Rheum Dis. 2016 Sep;75(9):1583-94. doi: 10.1136/ann・・・
著者: Kirsten de Groot, Lorraine Harper, David R W Jayne, Luis Felipe Flores Suarez, Gina Gregorini, Wolfgang L Gross, Rashid Luqmani, Charles D Pusey, Niels Rasmussen, Renato A Sinico, Vladimir Tesar, Philippe Vanhille, Kerstin Westman, Caroline O S Savage, EUVAS (European Vasculitis Study Group)
雑誌名: Ann Intern Med. 2009 May 19;150(10):670-80.
Abstract/Text BACKGROUND: Current therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis are limited by toxicity.
OBJECTIVE: To compare pulse cyclophosphamide with daily oral cyclophosphamide for induction of remission.
DESIGN: Randomized, controlled trial. Random assignments were computer-generated; allocation was concealed by faxing centralized treatment assignment to providers at the time of enrollment. Patients, investigators, and assessors of outcomes were not blinded to assignment.
SETTING: 42 centers in 12 European countries.
PATIENTS: 149 patients who had newly diagnosed generalized ANCA-associated vasculitis with renal involvement but not immediately life-threatening disease.
INTERVENTION: Pulse cyclophosphamide, 15 mg/kg every 2 to 3 weeks (76 patients), or daily oral cyclophosphamide, 2 mg/kg per day (73 patients), plus prednisolone.
MEASUREMENT: Time to remission (primary outcome); change in renal function, adverse events, and cumulative dose of cyclophosphamide (secondary outcomes).
RESULTS: Groups did not differ in time to remission (hazard ratio, 1.098 [95% CI, 0.78 to 1.55]; P = 0.59) or proportion of patients who achieved remission at 9 months (88.1% vs. 87.7%). Thirteen patients in the pulse group and 6 in the daily oral group achieved remission by 9 months and subsequently had relapse. Absolute cumulative cyclophosphamide dose in the daily oral group was greater than that in the pulse group (15.9 g [interquartile range, 11 to 22.5 g] vs. 8.2 g [interquartile range, 5.95 to 10.55 g]; P < 0.001). The pulse group had a lower rate of leukopenia (hazard ratio, 0.41 [CI, 0.23 to 0.71]).
LIMITATIONS: The study was not powered to detect a difference in relapse rates between the 2 groups. Duration of follow-up was limited.
CONCLUSION: The pulse cyclophosphamide regimen induced remission of ANCA-associated vasculitis as well as the daily oral regimen at a reduced cumulative cyclophosphamide dose and caused fewer cases of leukopenia.
PRIMARY FUNDING SOURCE: The European Union.

PMID 19451574  Ann Intern Med. 2009 May 19;150(10):670-80.
著者: Lorraine Harper, Matthew D Morgan, Michael Walsh, Peter Hoglund, Kerstin Westman, Oliver Flossmann, Vladimir Tesar, Phillipe Vanhille, Kirsten de Groot, Raashid Luqmani, Luis Felipe Flores-Suarez, Richard Watts, Charles Pusey, Annette Bruchfeld, Niels Rasmussen, Daniel Blockmans, Caroline O Savage, David Jayne, EUVAS investigators
雑誌名: Ann Rheum Dis. 2012 Jun;71(6):955-60. doi: 10.1136/annrheumdis-2011-200477. Epub 2011 Nov 29.
Abstract/Text INTRODUCTION: The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study.
METHODS: Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised.
RESULTS: Median duration of follow-up was 4.3 years (IQR, 2.95-5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs.
DISCUSSION: Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.

PMID 22128076  Ann Rheum Dis. 2012 Jun;71(6):955-60. doi: 10.1136/annr・・・
著者: John H Stone, Peter A Merkel, Robert Spiera, Philip Seo, Carol A Langford, Gary S Hoffman, Cees G M Kallenberg, E William St Clair, Anthony Turkiewicz, Nadia K Tchao, Lisa Webber, Linna Ding, Lourdes P Sejismundo, Kathleen Mieras, David Weitzenkamp, David Ikle, Vicki Seyfert-Margolis, Mark Mueller, Paul Brunetta, Nancy B Allen, Fernando C Fervenza, Duvuru Geetha, Karina A Keogh, Eugene Y Kissin, Paul A Monach, Tobias Peikert, Coen Stegeman, Steven R Ytterberg, Ulrich Specks, RAVE-ITN Research Group
雑誌名: N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905.
Abstract/Text BACKGROUND: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen.
METHODS: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months.
RESULTS: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.
CONCLUSIONS: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

2010 Massachusetts Medical Society
PMID 20647199  N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/N・・・
著者: David R W Jayne, Gill Gaskin, Niels Rasmussen, Daniel Abramowicz, Franco Ferrario, Loic Guillevin, Eduardo Mirapeix, Caroline O S Savage, Renato A Sinico, Coen A Stegeman, Kerstin W Westman, Fokko J van der Woude, Robert A F de Lind van Wijngaarden, Charles D Pusey, European Vasculitis Study Group
雑誌名: J Am Soc Nephrol. 2007 Jul;18(7):2180-8. doi: 10.1681/ASN.2007010090. Epub 2007 Jun 20.
Abstract/Text Systemic vasculitis associated with autoantibodies to neutrophil cytoplasmic antigens (ANCA) is the most frequent cause of rapidly progressive glomerulonephritis. Renal failure at presentation carries an increased risk for ESRD and death despite immunosuppressive therapy. This study investigated whether the addition of plasma exchange was more effective than intravenous methylprednisolone in the achievement of renal recovery in those who presented with a serum creatinine >500 micromol/L (5.8 mg/dl). A total of 137 patients with a new diagnosis of ANCA-associated systemic vasculitis confirmed by renal biopsy and serum creatinine >500 micromol/L (5.8 mg/dl) were randomly assigned to receive seven plasma exchanges (n = 70) or 3000 mg of intravenous methylprednisolone (n = 67). Both groups received oral cyclophosphamide and oral prednisolone. The primary end point was dialysis independence at 3 mo. Secondary end points included renal and patient survival at 1 yr and severe adverse event rates. At 3 mo, 33 (49%) of 67 after intravenous methylprednisolone compared with 48 (69%) or 70 after plasma exchange were alive and independent of dialysis (95% confidence interval for the difference 18 to 35%; P = 0.02). As compared with intravenous methylprednisolone, plasma exchange was associated with a reduction in risk for progression to ESRD of 24% (95% confidence interval 6.1 to 41%), from 43 to 19%, at 12 mo. Patient survival and severe adverse event rates at 1 yr were 51 (76%) of 67 and 32 of 67 (48%) in the intravenous methylprednisolone group and 51 (73%) of 70 and 35 of (50%) 70 in the plasma exchange group, respectively. Plasma exchange increased the rate of renal recovery in ANCA-associated systemic vasculitis that presented with renal failure when compared with intravenous methylprednisolone. Patient survival and severe adverse event rates were similar in both groups.

PMID 17582159  J Am Soc Nephrol. 2007 Jul;18(7):2180-8. doi: 10.1681/A・・・
著者: Michael Walsh, Peter A Merkel, Chen-Au Peh, Wladimir M Szpirt, Xavier Puéchal, Shouichi Fujimoto, Carmel M Hawley, Nader Khalidi, Oliver Floßmann, Ron Wald, Louis P Girard, Adeera Levin, Gina Gregorini, Lorraine Harper, William F Clark, Christian Pagnoux, Ulrich Specks, Lucy Smyth, Vladimir Tesar, Toshiko Ito-Ihara, Janak Rashme de Zoysa, Wojciech Szczeklik, Luis Felipe Flores-Suárez, Simon Carette, Loïc Guillevin, Charles D Pusey, Alina L Casian, Biljana Brezina, Andrea Mazzetti, Carol A McAlear, Elizabeth Broadhurst, Donna Reidlinger, Samir Mehta, Natalie Ives, David R W Jayne, PEXIVAS Investigators
雑誌名: N Engl J Med. 2020 Feb 13;382(7):622-631. doi: 10.1056/NEJMoa1803537.
Abstract/Text BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD).
RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups.
CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32053298  N Engl J Med. 2020 Feb 13;382(7):622-631. doi: 10.1056/・・・
著者: G G Hunder, S G Sheps, G L Allen, J W Joyce
雑誌名: Ann Intern Med. 1975 May;82(5):613-8.
Abstract/Text Alternate-day corticosteroid therapy was compared with two daily corticosteroid regimens for the treatment of giant cell arteritis. In a prospective study 60 patients with this disease were randomly assigned to three treatment groups: group A, 15 mg of prednisone every 8 hours; group B, 45 mg of prednisone every morning; and group C, 90 mgof prednisone every other morning. After 1 month of treatment, the arteritis seemed to be completely suppressed in 18 patients in group A and 16 in group B but in only 6 in group C. In the 14 other patients in group C, the continuing symptoms were cyclic and developed during the day steroids were not given. By changing to a daily regimen, the arteritis was controlled in most patients in group C. Adverse reactions to prednisone were noted frequently in groups A and B but rarely in group C.

PMID 1137255  Ann Intern Med. 1975 May;82(5):613-8.
著者: Kirsten De Groot, Niels Rasmussen, Paul A Bacon, Jan Willem Cohen Tervaert, Conleth Feighery, Gina Gregorini, Wolfgang L Gross, Raashid Luqmani, David R W Jayne
雑誌名: Arthritis Rheum. 2005 Aug;52(8):2461-9. doi: 10.1002/art.21142.
Abstract/Text OBJECTIVE: Standard therapy for antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) with cyclophosphamide (CYC) and prednisolone is limited by toxicity. This unblinded, prospective, randomized, controlled trial was undertaken to determine whether methotrexate (MTX) could replace CYC in the early treatment of AASV.
METHODS: Patients with newly diagnosed AASV, with serum creatinine levels <150 mumoles/liter, and without critical organ manifestations of disease were randomized to receive either standard oral CYC, 2 mg/kg/day or oral MTX, 20-25 mg/week; both groups received the same prednisolone regimen. All drug treatments were gradually tapered and withdrawn by 12 months. Followup continued to 18 months. The primary end point was the remission rate at 6 months (noninferiority testing).
RESULTS: One hundred patients were recruited from 26 European centers; 51 patients were randomized to the MTX group and 49 to the CYC group. At 6 months, the remission rate in patients treated with MTX (89.8%) was not inferior to that in patients treated with CYC (93.5%) (P = 0.041). In the MTX group, remission was delayed among patients with more extensive disease (P = 0.04) or pulmonary involvement (P = 0.03). Relapse rates at 18 months were 69.5% in the MTX group and 46.5% in the CYC group; the median time from remission to relapse was 13 months and 15 months, respectively (P = 0.023, log rank test). Two patients from each group died. Adverse events (mean 0.87 episodes/patient) included leukopenia, which was less frequent in the MTX versus the CYC group (P = 0.012), and liver dysfunction, which was more frequent in the MTX group (P = 0.036).
CONCLUSION: MTX can replace CYC for initial treatment of early AASV. The MTX regimen used in the present study was less effective for induction of remission in patients with extensive disease and pulmonary involvement and was associated with more relapses than the CYC regimen after termination of treatment. The high relapse rates in both treatment arms support the practice of continuation of immunosuppressive treatment beyond 12 months.

PMID 16052573  Arthritis Rheum. 2005 Aug;52(8):2461-9. doi: 10.1002/ar・・・
著者: Rachel B Jones, Thomas F Hiemstra, Jose Ballarin, Daniel Engelbert Blockmans, Paul Brogan, Annette Bruchfeld, Maria C Cid, Karen Dahlsveen, Janak de Zoysa, Georgína Espigol-Frigolé, Peter Lanyon, Chen Au Peh, Vladimir Tesar, Augusto Vaglio, Michael Walsh, Dorothy Walsh, Giles Walters, Lorraine Harper, David Jayne, European Vasculitis Study Group (EUVAS)
雑誌名: Ann Rheum Dis. 2019 Mar;78(3):399-405. doi: 10.1136/annrheumdis-2018-214245. Epub 2019 Jan 5.
Abstract/Text OBJECTIVES: Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV.
METHODS: We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study.
RESULTS: At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3).
CONCLUSION: MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate.
TRIAL REGISTRATION NUMBER: NCT00414128.

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PMID 30612116  Ann Rheum Dis. 2019 Mar;78(3):399-405. doi: 10.1136/ann・・・
著者: David Jayne, Niels Rasmussen, Konrad Andrassy, Paul Bacon, Jan Willem Cohen Tervaert, Jolanta Dadoniené, Agneta Ekstrand, Gill Gaskin, Gina Gregorini, Kirsten de Groot, Wolfgang Gross, E Christiaan Hagen, Eduardo Mirapeix, Erna Pettersson, Carl Siegert, Alberto Sinico, Vladimir Tesar, Kerstin Westman, Charles Pusey, European Vasculitis Study Group
雑誌名: N Engl J Med. 2003 Jul 3;349(1):36-44. doi: 10.1056/NEJMoa020286.
Abstract/Text BACKGROUND: The primary systemic vasculitides usually associated with autoantibodies to neutrophil cytoplasmic antigens include Wegener's granulomatosis and microscopic polyangiitis. We investigated whether exposure to cyclophosphamide in patients with generalized vasculitis could be reduced by substitution of azathioprine at remission.
METHODS: We studied patients with a new diagnosis of generalized vasculitis and a serum creatinine concentration of 5.7 mg per deciliter (500 micromol per liter) or less. All patients received at least three months of therapy with oral cyclophosphamide and prednisolone. After remission, patients were randomly assigned to continued cyclophosphamide therapy (1.5 mg per kilogram of body weight per day) or a substitute regimen of azathioprine (2 mg per kilogram per day). Both groups continued to receive prednisolone and were followed for 18 months from study entry. Relapse was the primary end point.
RESULTS: Of 155 patients studied, 144 (93 percent) entered remission and were randomly assigned to azathioprine (71 patients) or continued cyclophosphamide (73 patients). There were eight deaths (5 percent), seven of them during the first three months. Eleven relapses occurred in the azathioprine group (15.5 percent), and 10 occurred in the cyclophosphamide group (13.7 percent, P=0.65). Severe adverse events occurred in 15 patients during the induction phase (10 percent), in 8 patients in the azathioprine group during the remission phase (11 percent), and in 7 patients in the cyclophosphamide group during the remission phase (10 percent, P=0.94 for the comparison between groups during the remission phase). The relapse rate was lower among the patients with microscopic polyangiitis than among those with Wegener's granulomatosis (P=0.03).
CONCLUSIONS: In patients with generalized vasculitis, the withdrawal of cyclophosphamide and the substitution of azathioprine after remission did not increase the rate of relapse. Thus, the duration of exposure to cyclophosphamide may be safely reduced.

Copyright 2003 Massachusetts Medical Society
PMID 12840090  N Engl J Med. 2003 Jul 3;349(1):36-44. doi: 10.1056/NEJ・・・
著者: Christian Pagnoux, Alfred Mahr, Mohamed A Hamidou, Jean-Jacques Boffa, Marc Ruivard, Jean-Pierre Ducroix, Xavier Kyndt, François Lifermann, Thomas Papo, Marc Lambert, José Le Noach, Mehdi Khellaf, Dominique Merrien, Xavier Puéchal, Stéphane Vinzio, Pascal Cohen, Luc Mouthon, Jean-François Cordier, Loïc Guillevin, French Vasculitis Study Group
雑誌名: N Engl J Med. 2008 Dec 25;359(26):2790-803. doi: 10.1056/NEJMoa0802311.
Abstract/Text BACKGROUND: Current standard therapy for Wegener's granulomatosis and microscopic polyangiitis combines corticosteroids and cyclophosphamide to induce remission, followed by a less toxic immunosuppressant such as azathioprine or methotrexate for maintenance therapy. However, azathioprine and methotrexate have not been compared with regard to safety and efficacy.
METHODS: In this prospective, open-label, multicenter trial, we randomly assigned patients with Wegener's granulomatosis or microscopic polyangiitis who entered remission with intravenous cyclophosphamide and corticosteroids to receive oral azathioprine (at a dose of 2.0 mg per kilogram of body weight per day) or methotrexate (at a dose of 0.3 mg per kilogram per week, progressively increased to 25 mg per week) for 12 months. The primary end point was an adverse event requiring discontinuation of the study drug or causing death; the sample size was calculated on the basis of the primary hypothesis that methotrexate would be less toxic than azathioprine. The secondary end points were severe adverse events and relapse.
RESULTS: Among 159 eligible patients, 126 (79%) had a remission, were randomly assigned to receive a study drug in two groups of 63 patients each, and were followed for a mean (+/-SD) period of 29+/-13 months. Adverse events occurred in 29 azathioprine recipients and 35 methotrexate recipients (P=0.29); grade 3 or 4 events occurred in 5 patients in the azathioprine group and 11 patients in the methotrexate group (P=0.11). The primary end point was reached in 7 patients who received azathioprine as compared with 12 patients who received methotrexate (P=0.21), with a corresponding hazard ratio for methotrexate of 1.65 (95% confidence interval, 0.65 to 4.18; P=0.29). There was one death in the methotrexate group. Twenty-three patients who received azathioprine and 21 patients who received methotrexate had a relapse (P=0.71); 73% of these patients had a relapse after discontinuation of the study drug.
CONCLUSIONS: These results do not support the primary hypothesis that methotrexate is safer than azathioprine. The two agents appear to be similar alternatives for maintenance therapy in patients with Wegener's granulomatosis and microscopic polyangiitis after initial remission. (ClinicalTrials.gov number, NCT00349674.)

2008 Massachusetts Medical Society
PMID 19109574  N Engl J Med. 2008 Dec 25;359(26):2790-803. doi: 10.105・・・
著者: Thomas F Hiemstra, Michael Walsh, Alfred Mahr, Caroline O Savage, Kirsten de Groot, Lorraine Harper, Thomas Hauser, Irmgard Neumann, Vladimir Tesar, Karl-Martin Wissing, Christian Pagnoux, Wilhelm Schmitt, David R W Jayne, European Vasculitis Study Group (EUVAS)
雑誌名: JAMA. 2010 Dec 1;304(21):2381-8. doi: 10.1001/jama.2010.1658. Epub 2010 Nov 8.
Abstract/Text CONTEXT: Current remission maintenance therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are limited by partial efficacy and toxicity.
OBJECTIVE: To compare the effects of mycophenolate mofetil with azathioprine on the prevention of relapses in patients with AAV.
DESIGN, SETTING, AND PARTICIPANTS: Open-label randomized controlled trial, International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE), to test the hypothesis that mycophenolate mofetil is more effective than azathioprine for preventing relapses in AAV. The trial was conducted at 42 centers in 11 European countries between April 2002 and January 2009 (42-month study). Eligible patients had newly diagnosed AAV (Wegener granulomatosis or microscopic polyangiitis) and were aged 18 to 75 years at diagnosis.
INTERVENTIONS: Patients were randomly assigned to azathioprine (starting at 2 mg/kg/d) or mycophenolate mofetil (starting at 2000 mg/d) after induction of remission with cyclophosphamide and prednisolone.
MAIN OUTCOME MEASURES: The primary end point was relapse-free survival, which was assessed using a Cox proportional hazards model. The secondary end points were Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria.
RESULTS: A total of 156 patients were assigned to azathioprine (n = 80) or mycophenolate mofetil (n = 76) and were followed up for a median of 39 months (interquartile range, 0.66-53.6 months). All patients were retained in the analysis by intention to treat. Relapses were more common in the mycophenolate mofetil group (42/76 patients) compared with the azathioprine group (30/80 patients), with an unadjusted hazard ratio (HR) for mycophenolate mofetil of 1.69 (95% confidence interval [CI], 1.06-2.70; P = .03). Severe adverse events did not differ significantly between groups. There were 22 severe adverse events in 13 patients (16%) in the azathioprine group and there were 8 severe adverse events in 8 patients (7.5%) in the mycophenolate mofetil group (HR, 0.53 [95% CI, 0.23-1.18]; P = .12). The secondary outcomes of Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria did not differ significantly between groups.
CONCLUSIONS: Among patients with AAV, mycophenolate mofetil was less effective than azathioprine for maintaining disease remission. Both treatments had similar adverse event rates.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00307645.

PMID 21060104  JAMA. 2010 Dec 1;304(21):2381-8. doi: 10.1001/jama.2010・・・
著者: Loïc Guillevin, Christian Pagnoux, Alexandre Karras, Chahera Khouatra, Olivier Aumaître, Pascal Cohen, François Maurier, Olivier Decaux, Jacques Ninet, Pierre Gobert, Thomas Quémeneur, Claire Blanchard-Delaunay, Pascal Godmer, Xavier Puéchal, Pierre-Louis Carron, Pierre-Yves Hatron, Nicolas Limal, Mohamed Hamidou, Maize Ducret, Eric Daugas, Thomas Papo, Bernard Bonnotte, Alfred Mahr, Philippe Ravaud, Luc Mouthon, French Vasculitis Study Group
雑誌名: N Engl J Med. 2014 Nov 6;371(19):1771-80. doi: 10.1056/NEJMoa1404231.
Abstract/Text BACKGROUND: The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission.
METHODS: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both).
RESULTS: The 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer).
CONCLUSIONS: More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. (Funded by the French Ministry of Health; MAINRITSAN ClinicalTrials.gov number, NCT00748644; EudraCT number, 2008-002846-51.).

PMID 25372085  N Engl J Med. 2014 Nov 6;371(19):1771-80. doi: 10.1056/・・・
著者: Pierre Charles, Benjamin Terrier, Élodie Perrodeau, Pascal Cohen, Stanislas Faguer, Antoine Huart, Mohamed Hamidou, Christian Agard, Bernard Bonnotte, Maxime Samson, Alexandre Karras, Noémie Jourde-Chiche, François Lifermann, Pierre Gobert, Catherine Hanrotel-Saliou, Pascal Godmer, Nicolas Martin-Silva, Grégory Pugnet, Marie Matignon, Olivier Aumaitre, Jean-François Viallard, François Maurier, Nadine Meaux-Ruault, Sophie Rivière, Jean Sibilia, Xavier Puéchal, Philippe Ravaud, Luc Mouthon, Loïc Guillevin, French Vasculitis Study Group
雑誌名: Ann Rheum Dis. 2018 Aug;77(8):1143-1149. doi: 10.1136/annrheumdis-2017-212878. Epub 2018 Apr 25.
Abstract/Text OBJECTIVE: To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs).
METHODS: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group.
RESULTS: Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2-4) vs 5 (5-5) administrations.
CONCLUSION: AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions.
TRIAL REGISTRATION NUMBER: NCT01731561; Results.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 29695500  Ann Rheum Dis. 2018 Aug;77(8):1143-1149. doi: 10.1136/a・・・
著者: Pierre Charles, Élodie Perrodeau, Maxime Samson, Bernard Bonnotte, Antoine Néel, Christian Agard, Antoine Huart, Alexandre Karras, François Lifermann, Pascal Godmer, Pascal Cohen, Catherine Hanrotel-Saliou, Nicolas Martin-Silva, Grégory Pugnet, François Maurier, Jean Sibilia, Pierre-Louis Carron, Pierre Gobert, Nadine Meaux-Ruault, Thomas Le Gallou, Stéphane Vinzio, Jean-François Viallard, Eric Hachulla, Christine Vinter, Xavier Puéchal, Benjamin Terrier, Philippe Ravaud, Luc Mouthon, Loïc Guillevin
雑誌名: Ann Intern Med. 2020 Jun 2;. doi: 10.7326/M19-3827. Epub 2020 Jun 2.
Abstract/Text BACKGROUND: Biannual rituximab infusions over 18 months effectively maintain remission after a "standard" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).
OBJECTIVE: To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen.
DESIGN: Randomized controlled trial. (ClinicalTrials.gov: NCT02433522).
SETTING: 39 clinical centers in France.
PATIENTS: 68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy.
INTERVENTION: Rituximab or placebo infusion every 6 months for 18 months (4 infusions).
MEASUREMENTS: The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0.
RESULTS: From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) (P = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) (P = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group.
LIMITATION: Potential selection bias based on previous rituximab response and tolerance.
CONCLUSION: Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy.
PRIMARY FUNDING SOURCE: French Ministry of Health and Hoffmann-La Roche.

PMID 32479166  Ann Intern Med. 2020 Jun 2;. doi: 10.7326/M19-3827. Epu・・・
著者: Gary S Hoffman, Colleen K Thomas-Golbanov, James Chan, Lee M Akst, Isaac Eliachar
雑誌名: J Rheumatol. 2003 May;30(5):1017-21.
Abstract/Text OBJECTIVE: To determine the longterm efficacy of intralesional long-acting corticosteroid injection plus dilatation (ILCD) for subglottic stenosis (SGS) in Wegener's granulomatosis (WG).
METHODS: Since November 1994, all patients with WG who presented with SGS of more than 50% or symptoms of airway compromise were treated with intralesional injection of methylprednisolone acetate, injected directly into the stenotic segment, followed by microsurgical lysis of the stenotic ring and serial dilatation with Maloney bougies or Fogarty catheter balloon. The procedure was repeated at a later date if re-stenosis occurred. Patient outcome was evaluated over a period of 7 years.
RESULTS: Twenty-one patients underwent 64 procedures. Mean followup was 40.6 months. Patients who did not have scarring from prior procedures required a mean of 2.4 procedures at mean intervals of 11.6 months to maintain subglottic patency. Patients with established laryngotracheal scarring required a mean of 4.1 procedures at mean intervals of 6.8 months to maintain patency. None of the 21 patients required a new tracheostomy. Only 2 significant complications occurred, both pneumothoraces. There were no adverse longterm sequelae.
CONCLUSION: ILCD is effective therapy for SGS due to WG. Best results are obtained when these endoscopic techniques are performed prior to other forms of surgery, which may produce extensive scar formation. Based on this experience, the authors recommend ILCD as the preferred therapy in WG-SGS.

PMID 12734898  J Rheumatol. 2003 May;30(5):1017-21.
著者: Giorgio Trivioli, Benjamin Terrier, Augusto Vaglio
雑誌名: Rheumatology (Oxford). 2020 May 1;59(Supplement_3):iii84-iii94. doi: 10.1093/rheumatology/kez570.
Abstract/Text Eosinophilic granulomatosis with polyangiitis is characterized by asthma, blood and tissue eosinophilia and small-vessel vasculitis. The clinical presentation is variable, but two main clinic-pathologic subsets can be distinguished: one hallmarked by positive ANCA and predominant 'vasculitic' manifestations (e.g. glomerulonephritis, purpura and mononeuritis multiplex) and the other by negative ANCA and prominent 'eosinophilic' manifestations (e.g. lung infiltrates and cardiomyopathy). The pathogenesis is not fully understood but probably results from the interplay between T and B cells and eosinophils. Eosinophilic granulomatosis with polyangiitis must be differentiated from several conditions, including hypereosinophilic syndromes and other small-vessel vasculitides. The overall survival is good; however, patients frequently relapse and have persistent symptoms. The recently developed monoclonal antibodies targeting B cells and eosinophilopoietic cytokines such as IL-5 are emerging as valid alternatives to conventional immunosuppressive therapies. In this review, we discuss the essential features of eosinophilic granulomatosis with polyangiitis, with particular respect to the most relevant issues concerning clinical presentation and management.

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PMID 32348510  Rheumatology (Oxford). 2020 May 1;59(Supplement_3):iii8・・・
著者: M Gayraud, L Guillevin, P Cohen, F Lhote, P Cacoub, P Deblois, B Godeau, M Ruel, E Vidal, M Piontud, J P Ducroix, S Lassoued, B Christoforov, P Babinet
雑誌名: Br J Rheumatol. 1997 Dec;36(12):1290-7. doi: 10.1093/rheumatology/36.12.1290.
Abstract/Text Twenty-five patients with good-prognosis polyarteritis nodosa or Churg-Strauss syndrome entered a prospective, randomized, multicentre study comparing two treatments: either oral corticosteroids and oral cyclophosphamide (CY; 2 mg/kg/day) for 1 yr (group A), or oral corticosteroids and monthly i.v. CY pulses (0.6 g/m2) (group B) for 1 yr. The objective was to determine the optimal CY regimen. Judgement criteria were the efficacy of the treatment in controlling the disease and the development of side-effects. Among the 25 patients who could be analysed, complete recovery was achieved with the experimental treatment in 9/12 patients in group A and 10/13 patients in group B. Two patients in each group relapsed after the end of therapy and were well controlled by corticosteroids or other drugs. One failure occurred in each group. The mean follow-up was 60.8 +/- 14.5 months after the beginning of the treatment. Side-effects associated with the administration of CY and steroids were noted 27 times in group A vs 14 times in group B (not significant). The oldest patient in these series (group B) died of pneumonia. No superiority in terms of efficacy could be established between the two regimens; however, the number of patients included was too small to conclude definitively. Toxic side-effects were significantly more frequent in women (P < 0.02). The high number of adverse effects leads us to recommend pulse over oral CY and an overall lowering of the doses of immunosuppression.

PMID 9448590  Br J Rheumatol. 1997 Dec;36(12):1290-7. doi: 10.1093/rh・・・
著者: A J Mohammad, A Hot, F Arndt, F Moosig, M-J Guerry, N Amudala, R Smith, P Sivasothy, L Guillevin, P A Merkel, D R W Jayne
雑誌名: Ann Rheum Dis. 2016 Feb;75(2):396-401. doi: 10.1136/annrheumdis-2014-206095. Epub 2014 Dec 2.
Abstract/Text BACKGROUND: Conventional treatment of eosinophilic granulomatosis with polyangiitis (EGPA) (Churg-Strauss) with glucocorticoids, with or without additional immunosuppressive drugs, is limited by partial efficacy, frequent toxicity and a high relapse rate. Rituximab is a licensed treatment for granulomatosis with polyangiitis and microscopic polyangiitis and is of potential benefit to patients with EGPA.
METHODS: Patients with EGPA who received rituximab as single or repeated courses were identified from four vasculitis centres. Standardised data collection was performed, including disease activity status and adverse events, at the time of initial treatment and after 6 and 12 months. Remission was defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 and partial response as a ≥50% reduction in BVAS compared with baseline.
RESULTS: 41 patients (21 women) with EGPA treated with rituximab between 2003 and 2013 were identified. 15 (37%) had refractory, 21 (51%) relapsing and 5 (12%) new onset disease. 19 received a single course and 22 received repeat-dose rituximab to prevent relapse. By 6 months, 83% improved with remission in 34% and partial response in 49%, and by 12 months 49% were in remission and 39% had a partial response. Prednisolone doses decreased in all patients by 6 and 12 months. Antineutrophil cytoplasmic antibody positivity at baseline was associated with a higher remission rate at 12 months. Adverse events included 15 infections (6 were severe).
CONCLUSIONS: The treatment of EGPA with rituximab resulted in high rates of improvement and reduced requirement of prednisolone. Rituximab may be considered for the treatment of EGPA.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
PMID 25467294  Ann Rheum Dis. 2016 Feb;75(2):396-401. doi: 10.1136/ann・・・
著者: Jens Thiel, Fabian Hässler, Ulrich Salzer, Reinhard E Voll, Nils Venhoff
雑誌名: Arthritis Res Ther. 2013 Sep 24;15(5):R133. doi: 10.1186/ar4313. Epub 2013 Sep 24.
Abstract/Text INTRODUCTION: Eosinophilic granulomatosis with polyangiitis (EGPA) is part of antineutrophil cytoplasmic antibodies (ANCAs)-associated vasculitides. In EGPA small-vessel vasculitis is associated with eosinophilia and asthma. About 40% of EGPA patients are ANCA-positive, suggesting a role for B cells in the pathogenesis of EGPA. B cell-depleting therapy with rituximab (RTX) can be effective in ANCA-positive EGPA, but very few patients have been published to date. The role of RTX in the treatment of ANCA-negative EGPA is unclear.
METHODS: We report a single-center cohort of patients with eosinophilic granulomatosis with polyangiitis. Of these patients, nine (six ANCA-positive, three ANCA-negative) had been treated with RTX for relapsing or refractory disease on standard immunosuppressive treatment. In a retrospective analysis, data on treatment response, frequency of relapses, adverse events, and peripheral B-cell reconstitution were evaluated. Furthermore, serum immunoglobulin concentrations, ANCA status, and peripheral B cell subpopulations were assessed after RTX treatment.
RESULTS: All patients had high disease activity before RTX treatment. At presentation 3 months after RTX therapy, all ANCA-positive and ANCA-negative patients had responded to RTX, with one patient being in complete remission, and eight patients being in partial remission. After a mean follow-up of 9 months, C-reactive protein concentrations had normalized, eosinophils had significantly decreased, and prednisone had been tapered in all patients. In all patients, RTX therapy was combined with a standard immunosuppressive therapy. Within the 9-month observation period, no relapse was recorded. Three patients were preemptively retreated with RTX, and during the median follow-up time of 3 years, no relapse occurred in these patients. During the follow-up of 13 patient-years, five minor but no major infections were recorded.
CONCLUSIONS: In our analysis on nine patients with EGPA resistant to standard therapy, rituximab proved to be an efficient and safe treatment for ANCA-positive and ANCA-negative patients. Preemptive retreatment with RTX, combined with standard maintenance immunosuppressants, resulted in a sustained treatment response. Prospective, randomized trials evaluating the use of RTX in EGPA are warranted.

PMID 24286362  Arthritis Res Ther. 2013 Sep 24;15(5):R133. doi: 10.118・・・
著者: Matthieu Groh, Christian Pagnoux, Chiara Baldini, Elisabeth Bel, Paolo Bottero, Vincent Cottin, Klaus Dalhoff, Bertrand Dunogué, Wolfgang Gross, Julia Holle, Marc Humbert, David Jayne, J Charles Jennette, Romain Lazor, Alfred Mahr, Peter A Merkel, Luc Mouthon, Renato Alberto Sinico, Ulrich Specks, Augusto Vaglio, Michael E Wechsler, Jean-François Cordier, Loïc Guillevin
雑誌名: Eur J Intern Med. 2015 Sep;26(7):545-53. doi: 10.1016/j.ejim.2015.04.022. Epub 2015 May 9.
Abstract/Text OBJECTIVE: To develop disease-specific recommendations for the diagnosis and management of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA).
METHODS: The EGPA Consensus Task Force experts comprised 8 pulmonologists, 6 internists, 4 rheumatologists, 3 nephrologists, 1 pathologist and 1 allergist from 5 European countries and the USA. Using a modified Delphi process, a list of 40 questions was elaborated by 2 members and sent to all participants prior to the meeting. Concurrently, an extensive literature search was undertaken with publications assigned with a level of evidence according to accepted criteria. Drafts of the recommendations were circulated for review to all members until final consensus was reached.
RESULTS: Twenty-two recommendations concerning the diagnosis, initial evaluation, treatment and monitoring of EGPA patients were established. The relevant published information on EGPA, antineutrophil-cytoplasm antibody-associated vasculitides, hypereosinophilic syndromes and eosinophilic asthma supporting these recommendations was also reviewed.
DISCUSSION: These recommendations aim to give physicians tools for effective and individual management of EGPA patients, and to provide guidance for further targeted research.

Copyright © 2015 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
PMID 25971154  Eur J Intern Med. 2015 Sep;26(7):545-53. doi: 10.1016/j・・・
著者: Michael E Wechsler, Praveen Akuthota, David Jayne, Paneez Khoury, Amy Klion, Carol A Langford, Peter A Merkel, Frank Moosig, Ulrich Specks, Maria C Cid, Raashid Luqmani, Judith Brown, Stephen Mallett, Richard Philipson, Steve W Yancey, Jonathan Steinfeld, Peter F Weller, Gerald J Gleich, EGPA Mepolizumab Study Team
雑誌名: N Engl J Med. 2017 May 18;376(20):1921-1932. doi: 10.1056/NEJMoa1702079.
Abstract/Text BACKGROUND: Eosinophilic granulomatosis with polyangiitis is an eosinophilic vasculitis. Mepolizumab, an anti-interleukin-5 monoclonal antibody, reduces blood eosinophil counts and may have value in the treatment of eosinophilic granulomatosis with polyangiitis.
METHODS: In this multicenter, double-blind, parallel-group, phase 3 trial, we randomly assigned participants with relapsing or refractory eosinophilic granulomatosis with polyangiitis who had received treatment for at least 4 weeks and were taking a stable prednisolone or prednisone dose to receive 300 mg of mepolizumab or placebo, administered subcutaneously every 4 weeks, plus standard care, for 52 weeks. The two primary end points were the accrued weeks of remission over a 52-week period, according to categorical quantification, and the proportion of participants in remission at both week 36 and week 48. Secondary end points included the time to first relapse and the average daily glucocorticoid dose (during weeks 48 through 52). The annualized relapse rate and safety were assessed.
RESULTS: A total of 136 participants underwent randomization, with 68 participants assigned to receive mepolizumab and 68 to receive placebo. Mepolizumab treatment led to significantly more accrued weeks of remission than placebo (28% vs. 3% of the participants had ≥24 weeks of accrued remission; odds ratio, 5.91; 95% confidence interval [CI], 2.68 to 13.03; P<0.001) and a higher percentage of participants in remission at both week 36 and week 48 (32% vs. 3%; odds ratio, 16.74; 95% CI, 3.61 to 77.56; P<0.001). Remission did not occur in 47% of the participants in the mepolizumab group versus 81% of those in the placebo group. The annualized relapse rate was 1.14 in the mepolizumab group, as compared with 2.27 in the placebo group (rate ratio, 0.50; 95% CI, 0.36 to 0.70; P<0.001). A total of 44% of the participants in the mepolizumab group, as compared with 7% of those in the placebo group, had an average daily dose of prednisolone or prednisone of 4.0 mg or less per day during weeks 48 through 52 (odds ratio, 0.20; 95% CI, 0.09 to 0.41; P<0.001). The safety profile of mepolizumab was similar to that observed in previous studies.
CONCLUSIONS: In participants with eosinophilic granulomatosis with polyangiitis, mepolizumab resulted in significantly more weeks in remission and a higher proportion of participants in remission than did placebo, thus allowing for reduced glucocorticoid use. Even so, only approximately half the participants treated with mepolizumab had protocol-defined remission. (Funded by GlaxoSmithKline and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT02020889 .).

PMID 28514601  N Engl J Med. 2017 May 18;376(20):1921-1932. doi: 10.10・・・
著者: Karina A Keogh
雑誌名: Drug Saf. 2007;30(10):837-43. doi: 10.2165/00002018-200730100-00003.
Abstract/Text Concern has been raised in the medical literature that the use of leukotriene receptor antagonists for the treatment of asthma may be associated with an increased incidence of Churg-Strauss syndrome, a rare small-vessel vasculitic syndrome. This review provides a critical appraisal of the literature to address this question. The incidence of Churg-Strauss syndrome in the general population is one to four cases per million. In patients with asthma it is 20-60 cases per million patient-years, which is similar to that seen in a population receiving leukotriene receptor antagonists. There is no evidence for a direct causative role of leukotriene receptor antagonists in the development of Churg-Strauss syndrome. There may be multiple other non-causative reasons for an association, including the fact that these agents may be initiated in patients who are already in the process of developing Churg-Strauss syndrome, or that the use of leukotriene receptor antagonists leads to a reduction in corticosteroid use, which in turn allows the Churg-Strauss syndrome to be 'unmasked'.

PMID 17867722  Drug Saf. 2007;30(10):837-43. doi: 10.2165/00002018-200・・・
著者: F P Ognibene, J H Shelhamer, G S Hoffman, G S Kerr, D Reda, A S Fauci, R Y Leavitt
雑誌名: Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):795-9. doi: 10.1164/ajrccm/151.3_Pt_1.795.
Abstract/Text The risk factors and clinical and laboratory parameters in Pneumocystis carinii pneumonia in patients with Wegener's granulomatosis have not been well characterized. We undertook a retrospective chart review of all patients with a diagnosis of Wegener's granulomatosis and P. carinii pneumonia who were followed at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. The chart review focused on clinical, laboratory, and roentgenologic evidence of P. carinii pneumonia. Eleven cases of P. carinii pneumonia were diagnosed in some 180 patients with Wegener's granulomatosis, for an overall incidence of approximately 6%. All patients developed P. carinii pneumonia either during the initial course of treatment or during therapy for recurrent Wegener's granulomatosis. All patients were receiving daily glucocorticoids and a second immunosuppressive therapy. Lymphocytopenia was noted in all patients, with a mean +/- SEM total lymphocyte count of 303 +/- 69 cells/microL. All patients tested (10 of 11) were seronegative for human immunodeficiency virus (HIV) infection. Eight presented with worsening chest roentgenograms compared with baseline, whereas three presented with normal chest roentgenograms. We conclude that P. carinii is a common opportunistic pathogen in patients with Wegener's granulomatosis receiving immunosuppressive therapy. Therapeutic immunosuppression (daily glucocorticoids and immunosuppressive agents) and the resultant lymphocytopenia, as well as the lymphocyte and monocyte functional abnormalities caused by glucocorticoids, may be the most likely factors predisposing to P. carinii pneumonia in patients with Wegener's granulomatosis. Based on our data, all patients with Wegener's granulomatosis should be given chemoprophylaxis against P. carinii while they are receiving daily glucocorticoids.(ABSTRACT TRUNCATED AT 250 WORDS)

PMID 7881673  Am J Respir Crit Care Med. 1995 Mar;151(3 Pt 1):795-9. ・・・
著者: Hefziba Green, Mical Paul, Liat Vidal, Leonard Leibovici
雑誌名: Mayo Clin Proc. 2007 Sep;82(9):1052-9. doi: 10.4065/82.9.1052.
Abstract/Text OBJECTIVE: To assess the efficacy of prophylaxis for Pneumocystis pneumonia (PCP), caused by Pneumocystis jirovecii (formerly Pneumocystis carinii), for immunocompromised non-HIV-infected patients by conducting a systematic review and meta-analysis.
METHODS: We searched for randomized controlled trials that compared prophylaxis using antibiotics effective against P jirovecii, given orally or intravenously, vs placebo, no intervention, or antibiotics with no activity against P jirovecii. In addition, we included trials that compared different PCP prophylactic regimens or administration schedules. The search included the Cochrane Central Register of Controlled Trials, PubMed, Latin American and Caribbean Health Sciences Literature, and conference proceedings. No language, year, or publication restrictions were applied. Two reviewers (H.G. and M.P.) independently searched, selected trials, extracted data, and performed methodological quality assessment. Relative risks (RRs) with 95% confidence intervals (CIs) are reported. Meta-analysis was performed using the random-effects model.
RESULTS: Twelve randomized trials were identified, including 1245 patients (50% children) who had undergone autologous bone marrow or solid organ transplant or who had hematologic cancer. When trimethoprim-sulfamethoxazole was administered, a 91% reduction was observed in the occurrence of PCP (RR, 0.09; 95% CI, 0.02-0.32); the number needed to treat was 15 (95% CI, 13-20) patients, with no heterogeneity. Pneumocystis pneumonia-related mortality was significantly reduced (RR, 0.17; 95% CI, 0.03-0.94), whereas all-cause mortality did not differ significantly (RR, 0.79; 95% CI, 0.18-3.46). Adverse events that required discontinuation occurred in 3.1% of adults and none of the children, and all were reversible. No differences between once-daily and thrice-weekly administration schedules were found.
CONCLUSION: Balanced against severe adverse events, PCP prophylaxis is warranted when the risk for PCP is higher than 3.5% for adults. Adverse events are less frequent in children, for whom prophylaxis might be warranted at lower PCP incidence rates.

PMID 17803871  Mayo Clin Proc. 2007 Sep;82(9):1052-9. doi: 10.4065/82.・・・
著者: Anat Stern, Hefziba Green, Mical Paul, Liat Vidal, Leonard Leibovici
雑誌名: Cochrane Database Syst Rev. 2014 Oct 1;(10):CD005590. doi: 10.1002/14651858.CD005590.pub3. Epub 2014 Oct 1.
Abstract/Text BACKGROUND: Pneumocystis pneumonia (PCP) is a disease affecting immunocompromised patients. PCP among these patients is associated with significant morbidity and mortality.
OBJECTIVES: To assess the effectiveness of PCP prophylaxis among non-HIV immunocompromised patients; and to define the type of immunocompromised patient for whom evidence suggests a benefit for PCP prophylaxis.
SEARCH METHODS: Electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2014, Issue 1), MEDLINE and EMBASE (to March 2014), LILACS (to March 2014), relevant conference proceedings; and references of identified trials.
SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing prophylaxis with an antibiotic effective against PCP versus placebo, no intervention, or antibiotic(s) with no activity against PCP; and trials comparing different antibiotics effective against PCP among immunocompromised non-HIV patients. We only included trials in which Pneumocystis infections were available as an outcome.
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias in each trial and extracted data from the included trials. We contacted authors of the included trials to obtain missing data. The primary outcome was documented PCP infections. Risk ratios (RR) with 95% confidence intervals (CI) were estimated and pooled using the random-effects model.
MAIN RESULTS: Thirteen trials performed between the years 1974 and 2008 were included, involving 1412 patients. Four trials included 520 children with acute lymphoblastic leukemia and the remaining trials included adults with acute leukemia, solid organ transplantation or autologous bone marrow transplantation. Compared to no treatment or treatment with fluoroquinolones (inactive against Pneumocystis), there was an 85% reduction in the occurrence of PCP in patients receiving prophylaxis with trimethoprim/sulfamethoxazole, RR of 0.15 (95% CI 0.04 to 0.62; 10 trials, 1000 patients). The evidence was graded as moderate due to possible risk of bias. PCP-related mortality was also significantly reduced, RR of 0.17 (95% CI 0.03 to 0.94; nine trials, 886 patients) (low quality of evidence due to possible risk of bias and imprecision), but in trials comparing PCP prophylaxis against placebo or no treatment there was no significant effect on all-cause mortality (low quality of evidence due to imprecision). Occurrence of leukopenia or neutropenia and their duration were not reported consistently. No significant differences in overall adverse events or events requiring discontinuation were seen comparing trimethoprim/sulfamethoxazole to no treatment or placebo (four trials, 470 patients, moderate quality evidence). No differences between once daily versus thrice weekly trimethoprim/sulfamethoxazole were seen (two trials, 207 patients).
AUTHORS' CONCLUSIONS: Given an event rate of 6.2% in the control groups of the included trials, prophylaxis for PCP using trimethoprim/sulfamethoxazole is highly effective among non-HIV immunocompromised patients, with a number needed to treat to prevent PCP of 19 patients (95% CI 17 to 42). Prophylaxis should be considered for patients with a similar baseline risk of PCP.

PMID 25269391  Cochrane Database Syst Rev. 2014 Oct 1;(10):CD005590. d・・・
著者: Alexandre Karras, Christian Pagnoux, Marion Haubitz, Kirsten de Groot, Xavier Puechal, Jan Willem Cohen Tervaert, Mårten Segelmark, Loic Guillevin, David Jayne, European Vasculitis Society
雑誌名: Ann Rheum Dis. 2017 Oct;76(10):1662-1668. doi: 10.1136/annrheumdis-2017-211123. Epub 2017 May 25.
Abstract/Text OBJECTIVES: A prospective randomised trial to compare two different durations of maintenance immunosuppressive therapy for the prevention of relapse in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV).
METHODS: Patients with AAV were recruited 18-24 months after diagnosis if they were in stable remission after cyclophosphamide/prednisolone-based induction followed by azathioprine/prednisolone maintenance therapy. They were randomised (1:1) to receive continued azathioprine/prednisolone to 48 months from diagnosis (continuation group) or to withdraw azathioprine/prednisolone by 24 months (withdrawal group). The primary endpoint was the relapse risk, from randomisation to 48 months from diagnosis.
RESULTS: One hundred and seventeen patients were randomised and 110 remained to the trial end. At entry, median serum creatinine was 116 μmol/L (range 58-372), 53% were ANCA positive. The percentage of patients presenting with relapse was higher in the withdrawal than in the continuation treatment group (63% vs 22%, p<0.0001, OR 5.96, 95% CI 2.58 to 13.77). ANCA positivity at randomisation was associated with relapse risk (51% vs 29%, p=0.017, OR 2.57, 95% CI 1.16 to 5.68). Renal function, ANCA specificity, vasculitis type and age were not predictive of relapse. Severe adverse events were more frequent in the continuation than withdrawal groups (nine vs three events), but the continuation group had better renal outcome (0 vs 4 cases of end-stage renal disease), with no difference in patient survival.
CONCLUSIONS: Prolonged remission maintenance therapy with azathioprine/prednisolone, beyond 24 months after diagnosis reduces relapse risk out to 48 months and improves renal survival in AAV.
TRIAL REGISTRATION NUMBER: ISRCTN13739474.

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
PMID 28546260  Ann Rheum Dis. 2017 Oct;76(10):1662-1668. doi: 10.1136/・・・

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