今日の臨床サポート

全身性エリテマトーデス

著者: 三森経世 医療法人 医仁会武田総合病院

監修: 上阪等 千葉西総合病院 膠原病リウマチセンター

著者校正/監修レビュー済:2021/02/24
参考ガイドライン:
  1. 厚生労働科学研究費補助金難治性疾患等政策研究事業自己免疫疾患に関する調査研究(自己免疫班)、日本リウマチ学会編集:全身性エリテマトーデス診療ガイドライン2019.南山堂、東京、2019年10月.
患者向け説明資料

概要・推奨   

  1. SLEの診断は1997年改訂ACR改訂分類基準に準拠する(推奨度1)。
  1. 腎症状が認められれば可能な限り腎生検を行って病型を診断する(推奨度1)。
  1. SLEにおける中枢神経症状は、ACRのNPSLE分類に従って病型分類を行う(推奨度1)。
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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。
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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
  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
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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:
三森経世 : 特に申告事項無し[2021年]
監修:上阪等 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 欧州リウマチ学会・米国リウマチ学会によるSLEの新分類基準(2019)を記載した。
  1. わが国におけるSLEの診療ガイドライン(2019)が作成され、病態別治療アルゴリズムを記載した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 全身性エリテマトーデス(systemic lupus erythematosus、SLE)は免疫異常を基盤として多彩な自己免疫現象を特徴とし、多臓器を障害する全身性炎症性疾患、自己免疫疾患である。
  1. 全身性エリテマトーデス腎障害については別項目を参照にする。
  1. 全身性エリテマトーデスは、指定難病であり、SLEDAI スコア 4 点以上の場合などは、申請し認定されると医療費の自己負担分の一部が公費負担として助成される。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
 
わが国のSLE診療ガイドライン(2019):
  1. わが国において、厚生労働省自己免疫疾患研究班SLE分科会により、2019年に「SLEの診療ガイドライン」が刊行された。このガイドラインではQ&A形式で構成され、33項目の治療に関する質問(CQ)に対する推奨および解説が記載され、推奨度とその根拠となるエビデンスレベルが明示されている[1]
  1. 本ガイドラインの各推奨文を元にして、SLEの診療アルゴリズムがまとめられている。
 
SLEの病態別治療アルゴリズム(わが国のSLE診療ガイドライン2019より)

まずSLEを診断し、さらに疾患活動性を評価して治療を選択する。ヒドロキシクロロキンは臓器病変、病態を問わず全例で投与を考慮する。さらに臓器病変に応じて治療を選択し、寛解導入を目指す。ループス腎炎では生検病理所見に応じてステロイド大量投与に加えてミコフェノール酸モフェチル(MMF)またはシクロホスファミド大量静注(IVCY)併用を考慮する。精神神経ループス(NPSLE)ではステロイド大量投与にIVCYを併用し、難治例ではリツキシマブを考慮する。その他の臓器病変については、主体となる病態に応じた治療法を考慮する。寛解導入が得られればステロイドを減量し、適切な免疫抑制薬併用により、寛解維持療法に移行する。初期療法で寛解が得られない場合は、3rd line治療法として血漿交換療法、リツキシマブ、既存の免疫抑制薬の併用や変更などを考慮するが、これらには十分なエビデンスがない。

問診・診察のポイント  
  1. 発熱などの全身症状、関節痛、皮疹、光線過敏症、蛋白尿、精神症状などを含む多彩な症状を認めたら、SLEを疑う。

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文献 

著者: M C Hochberg
雑誌名: Arthritis Rheum. 1997 Sep;40(9):1725. doi: 10.1002/1529-0131(199709)40:9<1725::AID-ART29>3.0.CO;2-Y.
Abstract/Text
PMID 9324032  Arthritis Rheum. 1997 Sep;40(9):1725. doi: 10.1002/1529・・・
著者: Michelle Petri, Ana-Maria Orbai, Graciela S Alarcón, Caroline Gordon, Joan T Merrill, Paul R Fortin, Ian N Bruce, David Isenberg, Daniel J Wallace, Ola Nived, Gunnar Sturfelt, Rosalind Ramsey-Goldman, Sang-Cheol Bae, John G Hanly, Jorge Sánchez-Guerrero, Ann Clarke, Cynthia Aranow, Susan Manzi, Murray Urowitz, Dafna Gladman, Kenneth Kalunian, Melissa Costner, Victoria P Werth, Asad Zoma, Sasha Bernatsky, Guillermo Ruiz-Irastorza, Munther A Khamashta, Soren Jacobsen, Jill P Buyon, Peter Maddison, Mary Anne Dooley, Ronald F van Vollenhoven, Ellen Ginzler, Thomas Stoll, Christine Peschken, Joseph L Jorizzo, Jeffrey P Callen, S Sam Lim, Barri J Fessler, Murat Inanc, Diane L Kamen, Anisur Rahman, Kristjan Steinsson, Andrew G Franks, Lisa Sigler, Suhail Hameed, Hong Fang, Ngoc Pham, Robin Brey, Michael H Weisman, Gerald McGwin, Laurence S Magder
雑誌名: Arthritis Rheum. 2012 Aug;64(8):2677-86. doi: 10.1002/art.34473.
Abstract/Text OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the American College of Rheumatology (ACR) systemic lupus erythematosus (SLE) classification criteria in order to improve clinical relevance, meet stringent methodology requirements, and incorporate new knowledge regarding the immunology of SLE.
METHODS: The classification criteria were derived from a set of 702 expert-rated patient scenarios. Recursive partitioning was used to derive an initial rule that was simplified and refined based on SLICC physician consensus. The SLICC group validated the classification criteria in a new validation sample of 690 new expert-rated patient scenarios.
RESULTS: Seventeen criteria were identified. In the derivation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (49 versus 70; P = 0.0082) and had greater sensitivity (94% versus 86%; P < 0.0001) and equal specificity (92% versus 93%; P = 0.39). In the validation set, the SLICC classification criteria resulted in fewer misclassifications compared with the current ACR classification criteria (62 versus 74; P = 0.24) and had greater sensitivity (97% versus 83%; P < 0.0001) but lower specificity (84% versus 96%; P < 0.0001).
CONCLUSION: The new SLICC classification criteria performed well in a large set of patient scenarios rated by experts. According to the SLICC rule for the classification of SLE, the patient must satisfy at least 4 criteria, including at least one clinical criterion and one immunologic criterion OR the patient must have biopsy-proven lupus nephritis in the presence of antinuclear antibodies or anti-double-stranded DNA antibodies.

Copyright © 2012 by the American College of Rheumatology.
PMID 22553077  Arthritis Rheum. 2012 Aug;64(8):2677-86. doi: 10.1002/a・・・
著者: Martin Aringer, Karen Costenbader, David Daikh, Ralph Brinks, Marta Mosca, Rosalind Ramsey-Goldman, Josef S Smolen, David Wofsy, Dimitrios T Boumpas, Diane L Kamen, David Jayne, Ricard Cervera, Nathalie Costedoat-Chalumeau, Betty Diamond, Dafna D Gladman, Bevra Hahn, Falk Hiepe, Søren Jacobsen, Dinesh Khanna, Kirsten Lerstrøm, Elena Massarotti, Joseph McCune, Guillermo Ruiz-Irastorza, Jorge Sanchez-Guerrero, Matthias Schneider, Murray Urowitz, George Bertsias, Bimba F Hoyer, Nicolai Leuchten, Chiara Tani, Sara K Tedeschi, Zahi Touma, Gabriela Schmajuk, Branimir Anic, Florence Assan, Tak Mao Chan, Ann Elaine Clarke, Mary K Crow, László Czirják, Andrea Doria, Winfried Graninger, Bernadett Halda-Kiss, Sarfaraz Hasni, Peter M Izmirly, Michelle Jung, Gábor Kumánovics, Xavier Mariette, Ivan Padjen, José M Pego-Reigosa, Juanita Romero-Diaz, Íñigo Rúa-Figueroa Fernández, Raphaèle Seror, Georg H Stummvoll, Yoshiya Tanaka, Maria G Tektonidou, Carlos Vasconcelos, Edward M Vital, Daniel J Wallace, Sule Yavuz, Pier Luigi Meroni, Marvin J Fritzler, Ray Naden, Thomas Dörner, Sindhu R Johnson
雑誌名: Arthritis Rheumatol. 2019 Sep;71(9):1400-1412. doi: 10.1002/art.40930. Epub 2019 Aug 6.
Abstract/Text OBJECTIVE: To develop new classification criteria for systemic lupus erythematosus (SLE) jointly supported by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR).
METHODS: This international initiative had four phases. 1) Evaluation of antinuclear antibody (ANA) as an entry criterion through systematic review and meta-regression of the literature and criteria generation through an international Delphi exercise, an early patient cohort, and a patient survey. 2) Criteria reduction by Delphi and nominal group technique exercises. 3) Criteria definition and weighting based on criterion performance and on results of a multi-criteria decision analysis. 4) Refinement of weights and threshold scores in a new derivation cohort of 1,001 subjects and validation compared with previous criteria in a new validation cohort of 1,270 subjects.
RESULTS: The 2019 EULAR/ACR classification criteria for SLE include positive ANA at least once as obligatory entry criterion; followed by additive weighted criteria grouped in 7 clinical (constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and 3 immunologic (antiphospholipid antibodies, complement proteins, SLE-specific antibodies) domains, and weighted from 2 to 10. Patients accumulating ≥10 points are classified. In the validation cohort, the new criteria had a sensitivity of 96.1% and specificity of 93.4%, compared with 82.8% sensitivity and 93.4% specificity of the ACR 1997 and 96.7% sensitivity and 83.7% specificity of the Systemic Lupus International Collaborating Clinics 2012 criteria.
CONCLUSION: These new classification criteria were developed using rigorous methodology with multidisciplinary and international input, and have excellent sensitivity and specificity. Use of ANA entry criterion, hierarchically clustered, and weighted criteria reflects current thinking about SLE and provides an improved foundation for SLE research.

© 2019, American College of Rheumatology.
PMID 31385462  Arthritis Rheumatol. 2019 Sep;71(9):1400-1412. doi: 10.・・・
著者: Jan J Weening, Vivette D D'Agati, Melvin M Schwartz, Surya V Seshan, Charles E Alpers, Gerald B Appel, James E Balow, Jan A Bruijn, Terence Cook, Franco Ferrario, Agnes B Fogo, Ellen M Ginzler, Lee Hebert, Gary Hill, Prue Hill, J Charles Jennette, Norella C Kong, Philippe Lesavre, Michael Lockshin, Lai-Meng Looi, Hirofumi Makino, Luiz A Moura, Michio Nagata
雑誌名: J Am Soc Nephrol. 2004 Feb;15(2):241-50.
Abstract/Text The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or = 50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions]. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

PMID 14747370  J Am Soc Nephrol. 2004 Feb;15(2):241-50.
著者:
雑誌名: Arthritis Rheum. 1999 Apr;42(4):599-608. doi: 10.1002/1529-0131(199904)42:4<599::AID-ANR2>3.0.CO;2-F.
Abstract/Text OBJECTIVE: To develop a standardized nomenclature system for the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE).
METHODS: An international, multidisciplinary committee representing rheumatology, neurology, psychiatry, neuropsychology, and hematology developed case definitions, reporting standards, and diagnostic testing recommendations. Before and after the meeting, clinician committee members assigned diagnoses to sets of vignettes randomly generated from a pool of 108 NPSLE patients. To assess whether the nomenclature system improved diagnostic agreement, a consensus index was developed and pre- and postmeeting scores were compared by t-tests.
RESULTS: Case definitions including diagnostic criteria, important exclusions, and methods of ascertainment were developed for 19 NPSLE syndromes. Recommendations for standard reporting requirements, minimum laboratory evaluation, and imaging techniques were formulated. A short neuropsychological test battery for the diagnosis of cognitive deficits was proposed. In the postmeeting exercise, a statistically significant improvement in diagnostic agreement was observed.
CONCLUSION: The American College of Rheumatology (ACR) Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests. It is intended to facilitate and enhance clinical research, particularly multicenter studies, and reporting. In clinical settings, consultation with other specialists may be required. It should be useful for didactic purposes but should not be used uncritically or as a substitute for a clinical diagnosis. The complete case definitions are available on the ACR World Wide Web site: http://www.rheumatology .org/ar/ar.html.

PMID 10211873  Arthritis Rheum. 1999 Apr;42(4):599-608. doi: 10.1002/1・・・
著者: Jan J Weening, Vivette D D'Agati, Melvin M Schwartz, Surya V Seshan, Charles E Alpers, Gerald B Appel, James E Balow, Jan A Bruijn, Terence Cook, Franco Ferrario, Agnes B Fogo, Ellen M Ginzler, Lee Hebert, Gary Hill, Prue Hill, J Charles Jennette, Norella C Kong, Philippe Lesavre, Michael Lockshin, Lai-Meng Looi, Hirofumi Makino, Luiz A Moura, Michio Nagata, International Society of Nephrology Working Group on the Classification of Lupus Nephritis, Renal Pathology Society Working Group on the Classification of Lupus Nephritis
雑誌名: Kidney Int. 2004 Feb;65(2):521-30. doi: 10.1111/j.1523-1755.2004.00443.x.
Abstract/Text The currently used classification reflects our understanding of the pathogenesis of the various forms of lupus nephritis, but clinicopathologic studies have revealed the need for improved categorization and terminology. Based on the 1982 classification published under the auspices of the World Health Organization (WHO) and subsequent clinicopathologic data, we propose that class I and II be used for purely mesangial involvement (I, mesangial immune deposits without mesangial hypercellularity; II, mesangial immune deposits with mesangial hypercellularity); class III for focal glomerulonephritis (involving <50% of total number of glomeruli) with subdivisions for active and sclerotic lesions; class IV for diffuse glomerulonephritis (involving > or =50% of total number of glomeruli) either with segmental (class IV-S) or global (class IV-G) involvement, and also with subdivisions for active and sclerotic lesions; class V for membranous lupus nephritis; and class VI for advanced sclerosing lesions. Combinations of membranous and proliferative glomerulonephritis (i.e., class III and V or class IV and V) should be reported individually in the diagnostic line. The diagnosis should also include entries for any concomitant vascular or tubulointerstitial lesions. One of the main advantages of the current revised classification is that it provides a clear and unequivocal description of the various lesions and classes of lupus nephritis, allowing a better standardization and lending a basis for further clinicopathologic studies. We hope that this revision, which evolved under the auspices of the International Society of Nephrology and the Renal Pathology Society, will contribute to further advancement of the WHO classification.

PMID 14717922  Kidney Int. 2004 Feb;65(2):521-30. doi: 10.1111/j.1523-・・・
著者: T Mimori
雑誌名: Intern Med. 1999 Jul;38(7):523-32.
Abstract/Text Systemic connective tissue diseases are characterized by the production of a number of autoantibodies directed against various cellular constituents. These autoantibodies are closely associated with certain diseases and clinical manifestations, and are therefore useful for clinical practice such as to diagnose diseases and to predict clinical subsets, disease activity and prognosis. To understand the etiology and pathogenic mechanisms of connective tissue diseases; it is particularly important to elucidate the structure and function of target autoantigens recognized by these disease-specific autoantibodies. In recent years, the nature of many target autoantigens have been identified using molecular biology approaches. Most of them are intracellular enzymes and regulatory factors necessary for important biological function involved in gene replication, transcription, RNA processing and protein translation. Thus, the studies of autoantibodies are useful not only in clinical medicine but also in basic cellular and molecular biology.

PMID 10435356  Intern Med. 1999 Jul;38(7):523-32.
著者: W W Chatham, R P Kimberly
雑誌名: Lupus. 2001;10(3):140-7.
Abstract/Text Through direct signals to the nucleus mediated by the glucocorticoid receptor, exogenous glucocorticoids impact a broad array of cellular functions. DNA binding of the glucocorticoid receptor, depending upon the specific promoter to which the receptor binds, affects gene expression by recruiting transcription factors to the promoter or by interfering with the function of co-factors required for gene transcription. Steroid effects on the adhesion functions and release of products by phagocytic cells are prompt, occurring within hours of administration. Administration of corticosteroids results in rapid depletion of circulating T-cells due to a combination of effects including enhanced circulatory emigration, induction of apoptosis, inhibition of T-cell growth factors, and impaired release of cells from lymphoid tissues. Corticosteroid effects on B-cell function and immunoglobulin production are more delayed. The broad, generally suppressive effects of corticosteroids on the immune response render them useful for the management of most organ system manifestations of lupus. Corticosteroid toxicity in lupus is notable for greater susceptibility to infections, osteoporosis, osteonecrosis and accelerated atherogenesis. Although use of corticosteroids for patients with severe disease manifestations is associated with higher numbers of deaths from infections, overall survival appears to be improved.

PMID 11315342  Lupus. 2001;10(3):140-7.
著者: E S Cathcart, B A Idelson, M A Scheinberg, W G Couser
雑誌名: Lancet. 1976 Jan 24;1(7952):163-6.
Abstract/Text Seven patients with diffuse proliferative lupus nephritis were subjected to highdose intravenous methylprednisolone (pulse) therapy. Following the pulse, five patients with rapidly deteriorating ranal function improved within three days and their serum-creatinine levels returned to baseline by one month. All seven patients demonstrated reversal of severe immunological abnormalities including increased serum D.N.A binding, decreased serum C3 levels, and reduced number of T lymphocytes in the peripheral blood. This form of therapy may make it possible to maintain patients with lupus nephritis on lower doses of steroids than is normally feasible.

PMID 54681  Lancet. 1976 Jan 24;1(7952):163-6.
著者: C G Mackworth-Young, J David, S H Morgan, G R Hughes
雑誌名: Ann Rheum Dis. 1988 Jun;47(6):496-502.
Abstract/Text A double blind, placebo controlled trial was performed in 25 patients to study the use of intravenous methylprednisolone (IVMP) in the treatment of active systemic lupus erythematosus (SLE). The trial examined the additive effect of IVMP on a background of conventional oral steroid treatment. Patients were followed up for six months. The results showed a trend towards more consistent overall improvement in the first two weeks after IVMP administration compared with placebo, but this difference was not maintained at one month or subsequently. They also suggested a quicker resolution of hypocomplementaemia in the treatment group. Other parameters of disease activity showed no difference. Side effects were generally mild and were similar in incidence between the two groups. Thus it is concluded that IVMP may improve initial suppression of active lupus in some patients when added to conventional oral steroid treatment, but that this additional benefit is not maintained; IVMP is, however, a relatively safe treatment when used in this way.

PMID 3289511  Ann Rheum Dis. 1988 Jun;47(6):496-502.
著者: R S Flanc, M A Roberts, G F M Strippoli, S J Chadban, P G Kerr, R C Atkins
雑誌名: Cochrane Database Syst Rev. 2004;(1):CD002922. doi: 10.1002/14651858.CD002922.pub2.
Abstract/Text BACKGROUND: Lupus nephritis is the renal manifestation of systemic lupus erythematosus (SLE) - a disease mainly affecting young women with substantial morbidity and mortality. It is classified by the World Health Organization (WHO) criteria I - VI based on histology. WHO Class IV is a diffuse proliferative glomerulonephritis which has the worst prognosis without treatment, with a reported 17% five year survival in the era 1953-1969. This survival was 82% in the early 1990's and continues to improve. An important factor behind this has been the use of cytotoxics such as cyclophosphamide in addition to steroids.
OBJECTIVES: To assess the benefits and harms of different treatments in biopsy-proven proliferative lupus nephritis (LN).
SEARCH STRATEGY: We searched the Cochrane Renal Group's specialised register (January 2003), the Cochrane Central Register of Randomised Controlled Trials (CENTRAL - The Cochrane Library issue 1, 2003), MEDLINE (1966 - 31 January 2003), EMBASE (1980 - 31 January 2003) and handsearched reference lists of retrieved articles.
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing treatments for PLN in both adult and paediatric patients with Class III, IV, Vc, Vd lupus nephritis were included. All treatments were considered.
DATA COLLECTION AND ANALYSIS: Data was extracted and quality assessed independently by two reviewers, with differences resolved by discussion. Dichotomous outcomes are reported as relative risk (RR) and measurements on continuous scales are reported as weighted mean differences (WMD) with 95% confidence intervals. Subgroup analysis by study quality, drug type and drug route have been performed where possible to explore reasons for heterogeneity.
MAIN RESULTS: Of 920 articles identified, 25 were RCTs suitable for inclusion, which enrolled 915 patients. The majority compared cyclophosphamide or azathioprine plus steroids versus steroids alone. Cyclophosphamide plus steroids reduced the risk of doubling of serum creatinine (RR 0.59, 95% CI 0.40 to 0.88) compared to steroids alone but had no impact on mortality (RR 0.98, 95% CI 0.53 to 1.82). The risk of ovarian failure was significantly increased (RR 2.18, 95% CI 1.10 to 4.34). Azathioprine plus steroids reduced the risk of all cause mortality compared to steroids alone (RR 0.60, 95% CI 0.36 to 0.99), but did not alter renal outcomes. Neither therapy was associated with increased risk of major infection. No benefit was found with addition of plasma exchange to cyclophosphamide or azathioprine plus steroids for mortality ( RR 0.71, 95% CI 0.50 to 1.02), doubling of serum creatinine (RR 0.17, 95% CI 0.02 to 1.26) or end-stage renal failure (RR 1.24, 95% CI 0.60 to 2.57). There was also no increased risk of major infection (RR 0.69, 95% CI 0.35 to 1.37).
REVIEWER'S CONCLUSIONS: Until future RCTs of newer agents are completed, the current use of cyclophosphamide combined with steroids remains the best option to preserve renal function in proliferative LN. The smallest effective dose and shortest duration of treatment should be used to minimise gonadal toxicity, without compromising efficacy.

PMID 14973998  Cochrane Database Syst Rev. 2004;(1):CD002922. doi: 10.・・・
著者: Lorna Henderson, Philip Masson, Jonathan C Craig, Robert S Flanc, Matthew A Roberts, Giovanni F M Strippoli, Angela C Webster
雑誌名: Cochrane Database Syst Rev. 2012 Dec 12;12:CD002922. doi: 10.1002/14651858.CD002922.pub3. Epub 2012 Dec 12.
Abstract/Text BACKGROUND: Cyclophosphamide, in combination with corticosteroids has been used to induce remission in proliferative lupus nephritis, the most common kidney manifestation of the multisystem disease, systemic lupus erythematosus. Cyclophosphamide therapy has reduced mortality from over 70% in the 1950s and 1960s to less than 10% in recent years. Cyclophosphamide combined with corticosteroids preserves kidney function but is only partially effective and may cause ovarian failure, infection and bladder toxicity. Several new agents, including mycophenolate mofetil (MMF), suggest reduced toxicity with equivalent rates of remission. This is an update of a Cochrane review first published in 2004.
OBJECTIVES: To assess the benefits and harms of different immunosuppressive treatments in biopsy-proven proliferative lupus nephritis.
SEARCH METHODS: For this update, we searched the Cochrane Renal Group's Specialised Register (up to 15 April 2012) through contact with the Trials' Search Coordinator using search terms relevant to this review.
SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any treatments for biopsy-proven lupus nephritis in both adult and paediatric patients with class III, IV, V +III and V +IV lupus nephritis were included. All immunosuppressive treatments were considered.
DATA COLLECTION AND ANALYSIS: Data were abstracted and quality assessed independently by two authors, with differences resolved by discussion. Dichotomous outcomes were reported as risk ratio (RR) and measurements on continuous scales reported as mean differences (MD) with 95% confidence intervals (CI).
MAIN RESULTS: We identified 50 RCTs involving 2846 participants. Of these, 45 studies (2559 participants) investigated induction therapy, and six studies (514 participants), considered maintenance therapy.Compared with intravenous (IV) cyclophosphamide, MMF was as effective in achieving stable kidney function (5 studies, 523 participants: RR 1.05, 95% CI 0.94 to 1.18) and complete remission of proteinuria (6 studies, 686 participants: RR 1.16, 95% CI 0.85 to 1.58). No differences in mortality (7 studies, 710 participants: RR 1.02, 95% CI 0.52 to 1.98) or major infection (6 studies, 683 participants: RR 1.11, 95% CI 0.74 to 1.68) were observed. A significant reduction in ovarian failure (2 studies, 498 participants: RR 0.15, 95% CI 0.03 to 0.80) and alopecia (2 studies, 522 participants: RR 0.22, 95% CI 0.06 to 0.86) was observed with MMF. In maintenance therapy, the risk of renal relapse (3 studies, 371 participants: RR 1.83, 95% CI 1.24 to 2.71) was significantly higher with azathioprine compared with MMF. Multiple other interventions were compared but outcome data were relatively sparse. Overall study quality was variable. The internal validity of the design, conduct and analysis of the included RCTs was difficult to assess in some studies because of the omission of important methodological details. No study adequately reported all domains of the risk of bias assessment so that elements of internal bias may be present.
AUTHORS' CONCLUSIONS: MMF is as effective as cyclophosphamide in inducing remission in lupus nephritis, but is safer with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse with no increase in clinically important side effects. Adequately powered trials with long term follow-up are required to more accurately define the risks and eventual harms of specific treatment regimens.

PMID 23235592  Cochrane Database Syst Rev. 2012 Dec 12;12:CD002922. do・・・
著者: H A Austin, J H Klippel, J E Balow, N G le Riche, A D Steinberg, P H Plotz, J L Decker
雑誌名: N Engl J Med. 1986 Mar 6;314(10):614-9. doi: 10.1056/NEJM198603063141004.
Abstract/Text We evaluated renal function in 107 patients with active lupus nephritis who participated in long-term randomized therapeutic trials (median follow-up, seven years). For patients taking oral prednisone alone, the probability of renal failure began to increase substantially after five years of observation. Renal function was better preserved in patients who received various cytotoxic-drug therapies, but the difference was statistically significant only for intravenous cyclophosphamide plus low-dose prednisone as compared with high-dose prednisone alone (P = 0.027). The advantage of treatment with intravenous cyclophosphamide over oral prednisone alone was particularly apparent in the high-risk subgroup of patients who had chronic histologic changes on renal biopsy at study entry. Patients treated with intravenous cyclophosphamide have not experienced hemorrhagic cystitis, cancer, or a disproportionate number of major infections. We conclude that, as compared with high-dose oral prednisone alone, treatment of lupus glomerulonephritis with intravenous cyclophosphamide reduces the risk of end-stage renal failure with few serious complications.

PMID 3511372  N Engl J Med. 1986 Mar 6;314(10):614-9. doi: 10.1056/NE・・・
著者: D T Boumpas, H A Austin, E M Vaughn, J H Klippel, A D Steinberg, C H Yarboro, J E Balow
雑誌名: Lancet. 1992 Sep 26;340(8822):741-5.
Abstract/Text Pulse cyclophosphamide is more effective than prednisone alone in preventing renal failure in lupus nephritis. We undertook a randomised, controlled trial to find out whether pulse methylprednisolone could equal pulse cyclophosphamide in preserving renal function in patients with lupus nephritis, and whether there was a difference between long and short courses of pulse cyclophosphamide in preventing exacerbations. 65 patients (60 female, 5 male; median [range] age 29 [10-48] years) with severe lupus nephritis were assigned randomly to monthly pulse methylprednisolone for 6 months (25 patients), monthly pulse cyclophosphamide for 6 months (20), or monthly cyclophosphamide for 6 months followed by quarterly pulse cyclophosphamide for 2 additional years (20). Patients treated with pulse methylprednisolone had a higher probability of doubling serum creatinine than those treated with long-course cyclophosphamide (p less than 0.04). Risk of doubling creatinine was not significantly different between short and long course cyclophosphamide. However, patients treated with short-course cyclophosphamide had a higher probability of exacerbations than those treated with long-course cyclophosphamide (p less than 0.01). An extended course of pulse cyclophosphamide is more effective than 6 months of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. Addition of a quarterly maintenance regimen to monthly pulse cyclophosphamide reduces the rate of exacerbations.

PMID 1356175  Lancet. 1992 Sep 26;340(8822):741-5.
著者: M F Gourley, H A Austin, D Scott, C H Yarboro, E M Vaughan, J Muir, D T Boumpas, J H Klippel, J E Balow, A D Steinberg
雑誌名: Ann Intern Med. 1996 Oct 1;125(7):549-57.
Abstract/Text BACKGROUND: Uncertainty exists about the efficacy and toxicity of bolus therapy with methylprednisolone or of the combination of methylprednisolone and cyclophosphamide in the treatment of lupus nephritis.
OBJECTIVE: To determine 1) whether intensive bolus therapy with methylprednisolone is an adequate substitute for bolus therapy with cyclophosphamide and 2) whether the combination of methylprednisolone and cyclophosphamide is superior to bolus therapy with methylprednisolone or cyclophosphamide alone.
DESIGN: Randomized, controlled trial with at least 5 years of follow-up.
SETTING: Government referral-based research hospital.
PATIENTS: 82 patients with lupus nephritis who had 10 or more erythrocytes per high-power field, cellular casts, proteinuria (> 1 g of protein per day), and a renal biopsy specimen that showed proliferative nephritis.
INTERVENTIONS: Bolus therapy with methylprednisolone (1 g/m2 body surface area), given monthly for at least 1 year; bolus therapy with cyclophosphamide (0.5 to 1.0 g/m2 body surface area), given monthly for 6 months and then quarterly; or bolus therapy with both methylprednisolone and cyclophosphamide.
MEASUREMENTS: 1) Renal remission (defined as < 10 dysmorphic erythrocytes per high-power field, the absence of cellular casts, and excretion of < 1 g of protein per day without doubling of the serum creatinine level), 2) prevention of doubling of the serum creatinine level, and 3) prevention of renal failure requiring dialysis.
RESULTS: Renal remission occurred in 17 of 20 patients in the combination therapy group (85%), 13 of 21 patients in the cyclophosphamide group (62%), and 7 of 24 patients in the methylprednisolone group (29%) (P < 0.001). Twenty-eight patients (43%) did not achieve renal remission. By life-table analysis, the likelihood of remission during the study period was greater in the combination therapy group than in the methylprednisolone group (P = 0.028). Combination therapy and cyclophosphamide therapy were not statistically different. Adverse events were amenorrhea (seen in 41% of the cyclophosphamide group, 43% of the combination therapy group, and 7.4% of the methylprednisolone group), cervical dysplasia (seen in 11% of the cyclophosphamide group. 7.1% of the combination therapy group, and 0% of the methylprednisolone group), avascular necrosis (seen in 11% of the cyclophosphamide group, 18% of the combination therapy group, and 22% of the methylprednisolone group), herpes zoster (seen in 15% of the cyclophosphamide group, 21% of the combination therapy group, and 3.7% of the methylprednisolone group) and at least one infection (seen in 26% of the cyclophosphamide group. 32% of the combination therapy group, and 7.4% of the methylprednisolone group).
CONCLUSIONS: Monthly bolus therapy with methylprednisolone was less effective than monthly bolus therapy with cyclophosphamide. A trend toward greater efficacy with combination therapy was seen.

PMID 8815753  Ann Intern Med. 1996 Oct 1;125(7):549-57.
著者: D T Boumpas, H Yamada, N J Patronas, D Scott, J H Klippel, J E Balow
雑誌名: Q J Med. 1991 Dec;81(296):975-84.
Abstract/Text We studied the effect of parenteral pulse cyclophosphamide therapy in nine patients with active systemic lupus erythematosus and severe central nervous system involvement. Seven patients had focal neurological deficits and/or seizures associated with abnormalities on cerebrospinal fluid analysis and/or magnetic resonance imaging. Two patients had organic brain syndrome with psychosis and normal cerebrospinal fluid and/or magnetic resonance imaging analysis. Six patients were unresponsive to treatment with high dose corticosteroid. Cyclophosphamide, 0.75-1.0 g/m2 body surface area, was administered intravenously every month for at least 2 months. Eight patients had a complete recovery or recovered with minor residuals. Cyclophosphamide was well tolerated with few side effects. We conclude that parenteral pulse cyclophosphamide is an effective adjunctive therapy for the management of patients with active systemic lupus erythematosus and central nervous system symptoms.

PMID 1808642  Q J Med. 1991 Dec;81(296):975-84.
著者: P C Ramos, M J Mendez, P R Ames, M A Khamashta, G R Hughes
雑誌名: Clin Exp Rheumatol. 1996 May-Jun;14(3):295-9.
Abstract/Text OBJECTIVE: The effect of pulse cyclophosphamide treatment was retrospectively assessed in 25 systemic lupus erythematosus (SLE) patients with central nervous system involvement. All patients who tested positive for anti-phospholipid antibodies and/or lupus anticoagulant were excluded.
RESULTS: Low-dose intravenous cyclophosphamide pulses (500 mg) were administered weekly in all patients. Twenty-four out of 25 patients attained a good response (after a mean of 11 days). Cyclophosphamide was well tolerated in all patients with only minor side effects. None of the patients experienced ovarian failure, cystitis or herpes zoster.
CONCLUSIONS: Weekly low-dose cyclophosphamide pulses appear to be safe and effective for the management of neuropsychiatric manifestations in SLE patients without antiphospholipid antibodies.

PMID 8809444  Clin Exp Rheumatol. 1996 May-Jun;14(3):295-9.
著者: L Barile-Fabris, R Ariza-Andraca, L Olguín-Ortega, L J Jara, A Fraga-Mouret, J M Miranda-Limón, J Fuentes de la Mata, P Clark, F Vargas, J Alocer-Varela
雑誌名: Ann Rheum Dis. 2005 Apr;64(4):620-5. doi: 10.1136/ard.2004.025528.
Abstract/Text BACKGROUND: Severe neurological involvement in systemic lupus erythematosus (NPSLE) is one of the most dreadful complications of the disease.
OBJECTIVE: To identify the best drug, dose, and treatment.
PATIENTS AND METHODS: The study was a controlled clinical trial at two tertiary care centres of patients with SLE according to the ACR criteria, with incident (no more than 15 days) onset of severe NP manifestations such as seizures, optic neuritis, peripheral or cranial neuropathy, coma, brainstem disease, or transverse myelitis. Induction treatment with 3 g of IV methylprednisolone (MP) followed by either IV monthly cyclophosphamide (Cy) versus IV MP bimonthly every 4 months for 1 year and then IV Cy or IV MP every 3 months for another year. The primary end point was response to treatment: at least 20% improvement from basal conditions on clinical, laboratory, or specific neurological testing variables.
RESULTS: Overall, a response rate of 75% was observed. Of the 32 patients studied, 18/19 receiving Cy and 7/13 receiving MP responded to treatment (p<0.03).
CONCLUSIONS: Cy seems to be more effective than MP in the treatment of acute, severe NPSLE.

PMID 15769918  Ann Rheum Dis. 2005 Apr;64(4):620-5. doi: 10.1136/ard.2・・・
著者: V F M Trevisani, A A Castro, J F Neves Neto, A N Atallah
雑誌名: Cochrane Database Syst Rev. 2006 Apr 19;(2):CD002265. doi: 10.1002/14651858.CD002265.pub2. Epub 2006 Apr 19.
Abstract/Text BACKGROUND: Neuropsychiatric involvement in systemic lupus erythematosus is complex and several clinical presentations are related to this disease such as: convulsions, chronic headache, transverse myelitis, vascular brain disease, psychosis and neural cognitive dysfunction. This systematic review is an update of a review performed in 2000.
OBJECTIVES: To assess the efficacy and safety of cyclophosphamide and methylprednisolone in the treatment of neuropsychiatric manifestations of systemic lupus erythematosus.
SEARCH STRATEGY: We searched EMBASE, LILACS, Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE up to and including May 2005. Additional articles were sought through handsearching in relevant journals. There were no language restrictions.
SELECTION CRITERIA: All randomised controlled trials that compared cyclophosphamide to methylprednisolone were included. Patients of any age and gender were included as long as they fulfilled the criterion of the American College of Rheumatology for the diagnosis of systemic lupus erythematosus and presented with any one of the following neuropsychiatric events: convulsions, organic brain syndrome and cranial neuropathy. Outcome measures included the following: a) overall mortality (primary event); b) motor and psychiatric deficit (primary event); c) clinical improvement (secondary event).
DATA COLLECTION AND ANALYSIS: Data was independently extracted by two reviewers and cross-checked. The methodological quality of each trial was assessed by the same two reviewers. Details of the randomisation (generation and concealment), blinding, and the number of patients lost to follow-up were recorded. Dichotomous data was presented as relative risks with corresponding 95% confidence intervals and a clinical relevance table was produced.
MAIN RESULTS: We found one randomised controlled trial of 32 patients comparing cyclophosphamide versus methylprednisolone for the treatment of neuropsychiatric involvement in the systemic lupus erythematosus. A significantly greater number of people responded to treatment in the cyclophosphamide group. Treatment response was found in 94.7% (18/19) of patients using cyclophosphamide compared with 46.2% (6/13) in the methylprednisolone group at 24 months (RR 2.05, 95% CI 1.13, 3.73) The NNT for response to treatment is 2. Cyclophosphamide use was associated with a reduction in prednisone requirements. A significant decrease in the number seizures per month was observed in the cyclophosphamide group. All the patients in the cyclophosphamide group had electroencephalographic improvement. No significant differences in adverse effects between the groups were found. It was not possible to extract more data from the study because there was a small number of patients in the others clinical subgroups of neurological manifestations and the authors did not provide sufficient information for data extraction.
AUTHORS' CONCLUSIONS: This systematic review found one randomised controlled trial with a small number of patients in the different clinical subgroups of neurological manifestation. It seems that cyclophosphamide is more effective in the treatment of neuropsychiatric involvement in systemic erythematosus lupus compared with methylprednisolone. However, properly designed randomised controlled trials that involve large, representative numbers of individuals, with explicit clinical and laboratory diagnosis criteria, sufficient duration of follow-up and description of all relevant outcome measures are necessary to guide practice.

PMID 16625558  Cochrane Database Syst Rev. 2006 Apr 19;(2):CD002265. d・・・
著者: Gabriel Contreras, Victoriano Pardo, Baudouin Leclercq, Oliver Lenz, Elaine Tozman, Patricia O'Nan, David Roth
雑誌名: N Engl J Med. 2004 Mar 4;350(10):971-80. doi: 10.1056/NEJMoa031855.
Abstract/Text BACKGROUND: Long-term therapy with cyclophosphamide enhances renal survival in patients with proliferative lupus nephritis; however, the beneficial effect of cyclophosphamide must be weighed against its considerable toxic effects.
METHODS: Fifty-nine patients with lupus nephritis (12 in World Health Organization class III, 46 in class IV, and 1 in class Vb) received induction therapy consisting of a maximum of seven monthly boluses of intravenous cyclophosphamide (0.5 to 1.0 g per square meter of body-surface area) plus corticosteroids. Subsequently, the patients were randomly assigned to one of three maintenance therapies: quarterly intravenous injections of cyclophosphamide, oral azathioprine (1 to 3 mg per kilogram of body weight per day), or oral mycophenolate mofetil (500 to 3000 mg per day) for one to three years. The base-line characteristics of the three groups were similar, with the exception that the chronicity index was 1.9 points lower in the cyclophosphamide group than in the mycophenolate mofetil group (P=0.009).
RESULTS: During maintenance therapy, five patients died (four in the cyclophosphamide group and one in the mycophenolate mofetil group), and chronic renal failure developed in five (three in the cyclophosphamide group and one each in the azathioprine and mycophenolate mofetil groups). The 72-month event-free survival rate for the composite end point of death or chronic renal failure was higher in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group (P=0.05 and P=0.009, respectively). The rate of relapse-free survival was higher in the mycophenolate mofetil group than in the cyclophosphamide group (P=0.02). The incidence of hospitalization, amenorrhea, infections, nausea, and vomiting was significantly lower in the mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group.
CONCLUSIONS: For patients with proliferative lupus nephritis, short-term therapy with intravenous cyclophosphamide followed by maintenance therapy with mycophenolate mofetil or azathioprine appears to be more efficacious and safer than long-term therapy with intravenous cyclophosphamide.

Copyright 2004 Massachusetts Medical Society
PMID 14999109  N Engl J Med. 2004 Mar 4;350(10):971-80. doi: 10.1056/N・・・
著者: T M Chan, F K Li, C S Tang, R W Wong, G X Fang, Y L Ji, C S Lau, A K Wong, M K Tong, K W Chan, K N Lai
雑誌名: N Engl J Med. 2000 Oct 19;343(16):1156-62. doi: 10.1056/NEJM200010193431604.
Abstract/Text BACKGROUND: The combination of cyclophosphamide and prednisolone is effective for the treatment of severe lupus nephritis but has serious adverse effects. Whether mycophenolate mofetil can be substituted for cyclophosphamide is not known.
METHODS: In 42 patients with diffuse proliferative lupus nephritis we compared the efficacy and side effects of a regimen of prednisolone and mycophenolate mofetil given for 12 months with those of a regimen of prednisolone and cyclophosphamide given for 6 months, followed by prednisolone and azathioprine for 6 months. Complete remission was defined as a value for urinary protein excretion that was less than 0.3 g per 24 hours, with normal urinary sediment, a normal serum albumin concentration, and values for serum creatinine and creatinine clearance that were no more than 15 percent above the base-line values. Partial remission was defined as a value for urinary protein excretion that was between 0.3 and 2.9 g per 24 hours, with a serum albumin concentration of at least 30 g per liter.
RESULTS: Eighty-one percent of the 21 patients treated with mycophenolate mofetil and prednisolone (group 1) had a complete remission, and 14 percent had a partial remission, as compared with 76 percent and 14 percent, respectively, of the 21 patients treated with cyclophosphamide and prednisolone followed by azathioprine and prednisolone (group 2). The improvements in the degree of proteinuria and the serum albumin and creatinine concentrations were similar in the two groups. One patient in each group discontinued treatment because of side effects. Infections were noted in 19 percent of the patients in group 1 and in 33 percent of those in group 2 (P = 0.29). Other adverse effects occurred only in group 2; they included amenorrhea (in 23 percent of the patients), hair loss (19 percent), leukopenia (10 percent), and death (10 percent). The rates of relapse were 15 percent and 11 percent, respectively.
CONCLUSIONS: For the treatment of diffuse proliferative lupus nephritis, the combination of mycophenolate mofetil and prednisolone is as effective as a regimen of cyclophosphamide and prednisolone followed by azathioprine and prednisolone but is less toxic.

PMID 11036121  N Engl J Med. 2000 Oct 19;343(16):1156-62. doi: 10.1056・・・
著者: Ellen M Ginzler, Mary Anne Dooley, Cynthia Aranow, Mimi Y Kim, Jill Buyon, Joan T Merrill, Michelle Petri, Gary S Gilkeson, Daniel J Wallace, Michael H Weisman, Gerald B Appel
雑誌名: N Engl J Med. 2005 Nov 24;353(21):2219-28. doi: 10.1056/NEJMoa043731.
Abstract/Text BACKGROUND: Since anecdotal series and small, prospective, controlled trials suggest that mycophenolate mofetil may be effective for treating lupus nephritis, larger trials are desirable.
METHODS: We conducted a 24-week randomized, open-label, noninferiority trial comparing oral mycophenolate mofetil (initial dose, 1000 mg per day, increased to 3000 mg per day) with monthly intravenous cyclophosphamide (0.5 g per square meter of body-surface area, increased to 1.0 g per square meter) as induction therapy for active lupus nephritis. A change to the alternative regimen was allowed at 12 weeks in patients who did not have an early response. The study protocol specified adjunctive care and the use and tapering of corticosteroids. The primary end point was complete remission at 24 weeks (normalization of abnormal renal measurements and maintenance of baseline normal measurements). A secondary end point was partial remission at 24 weeks.
RESULTS: Of 140 patients recruited, 71 were randomly assigned to receive mycophenolate mofetil and 69 were randomly assigned to receive cyclophosphamide. At 12 weeks, 56 patients receiving mycophenolate mofetil and 42 receiving cyclophosphamide had satisfactory early responses. In the intention-to-treat analysis, 16 of the 71 patients (22.5 percent) receiving mycophenolate mofetil and 4 of the 69 patients receiving cyclophosphamide (5.8 percent) had complete remission, for an absolute difference of 16.7 percentage points (95 percent confidence interval, 5.6 to 27.9 percentage points; P=0.005), meeting the prespecified criteria for noninferiority and demonstrating the superiority of mycophenolate mofetil to cyclophosphamide. Partial remission occurred in 21 of the 71 patients (29.6 percent) and 17 of the 69 patients (24.6 percent), respectively (P=0.51). Three patients assigned to cyclophosphamide died, two during protocol therapy. Fewer severe infections and hospitalizations but more diarrhea occurred among those receiving mycophenolate.
CONCLUSIONS: In this 24-week trial, mycophenolate mofetil was more effective than intravenous cyclophosphamide in inducing remission of lupus nephritis and had a more favorable safety profile.

Copyright 2005 Massachusetts Medical Society.
PMID 16306519  N Engl J Med. 2005 Nov 24;353(21):2219-28. doi: 10.1056・・・
著者: Gerald B Appel, Gabriel Contreras, Mary Anne Dooley, Ellen M Ginzler, David Isenberg, David Jayne, Lei-Shi Li, Eduardo Mysler, Jorge Sánchez-Guerrero, Neil Solomons, David Wofsy, Aspreva Lupus Management Study Group
雑誌名: J Am Soc Nephrol. 2009 May;20(5):1103-12. doi: 10.1681/ASN.2008101028. Epub 2009 Apr 15.
Abstract/Text Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.

PMID 19369404  J Am Soc Nephrol. 2009 May;20(5):1103-12. doi: 10.1681/・・・
著者: Nobuyuki Miyasaka, Shinichi Kawai, Hiroshi Hashimoto
雑誌名: Mod Rheumatol. 2009;19(6):606-15. doi: 10.1007/s10165-009-0218-5. Epub 2009 Aug 18.
Abstract/Text We evaluated the efficacy and safety of tacrolimus in patients receiving glucocorticoid therapy for lupus nephritis. Patients with persistent nephritis were randomized to receive 28 weeks of double-blind treatment with tacrolimus (3 mg/day) or placebo. The primary endpoint was the change in the lupus nephritis disease activity index (LNDAI) calculated from scores for daily urinary protein excretion, urinary red cells, serum creatinine, anti-double-stranded DNA antibody, and serum complement. Statistical analysis was performed using the full analysis set. The LNDAI was decreased by 32.9 +/- 31.0% (mean +/- SD) in the tacrolimus group (n = 28) and was increased by 2.3 +/- 38.2% in the placebo group (n = 35) at final evaluation. There was significant improvement in the tacrolimus group. Daily urinary protein excretion showed a significant decrease in the tacrolimus group (p < 0.001). The complement (C3) level showed a significant increase in the tacrolimus group (p = 0.001). Treatment-related adverse events occurred in 92.9% of the tacrolimus group and 80.0% of the placebo group, but the difference was not significant. In patients on glucocorticoid therapy for lupus nephritis, addition of tacrolimus to basal therapy achieved significant improvement compared with placebo. Tacrolimus may therefore be a useful alternative treatment for lupus nephritis.

PMID 19688181  Mod Rheumatol. 2009;19(6):606-15. doi: 10.1007/s10165-0・・・
著者: Hao Bao, Zhi-Hong Liu, Hong-Lang Xie, Wei-Xin Hu, Hai-Tao Zhang, Lei-Shi Li
雑誌名: J Am Soc Nephrol. 2008 Oct;19(10):2001-10. doi: 10.1681/ASN.2007121272. Epub 2008 Jul 2.
Abstract/Text Treatment of class V+IV lupus nephritis remains unsatisfactory despite the progress made in the treatment of diffuse proliferative lupus nephritis. In this prospective study, 40 patients with class V+IV lupus nephritis were randomly assigned to induction therapy with mycophenolate mofetil, tacrolimus, and steroids (multitarget therapy) or intravenous cyclophosphamide (IVCY). Patients were treated for 6 mo unless complete remission was not achieved, in which case treatment was extended to 9 mo. An intention-to-treat analysis revealed a higher rate of complete remission with multitarget therapy at both 6 and 9 mo (50 and 65%, respectively) than with IVCY (5 and 15%, respectively). At 6 mo, eight (40%) patients in each group experienced partial remission, and at 9 mo, six (30%) patients receiving multitarget therapy and eight (40%) patients receiving IVCY experienced partial remission. There were no deaths during this study. Most adverse events were less frequent in the multitarget therapy group. Calcineurin inhibitor nephrotoxicity was not observed, but three patients developed new-onset hypertension with multitarget therapy. In conclusion, multitarget therapy is superior to IVCY for inducing complete remission of class V+IV lupus nephritis and is well tolerated.

PMID 18596121  J Am Soc Nephrol. 2008 Oct;19(10):2001-10. doi: 10.1681・・・
著者: R John Looney, Jennifer H Anolik, Debbie Campbell, Raymond E Felgar, Faith Young, Lois J Arend, James A Sloand, Joseph Rosenblatt, Iñaki Sanz
雑誌名: Arthritis Rheum. 2004 Aug;50(8):2580-9. doi: 10.1002/art.20430.
Abstract/Text OBJECTIVE: Safer and more effective therapies are needed for the treatment of systemic lupus erythematosus (SLE). B lymphocytes have been shown to play fundamental pathogenic roles in SLE, and therefore, elimination of B cells with the use of rituximab may represent a new therapy for SLE.
METHODS: A phase I/II dose-escalation trial of rituximab added to ongoing therapy in SLE was conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (1 week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to determine the effectiveness of B cell depletion. The Systemic Lupus Activity Measure (SLAM) score was used as the primary outcome for clinical efficacy.
RESULTS: Rituximab was well tolerated in this patient population, with most experiencing no significant adverse effects. Only 3 serious adverse events, which were thought to be unrelated to rituximab administration, were noted. A majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B cells/microl). In these patients, the SLAM score was significantly improved at 2 and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by paired t-test). This improvement persisted for 12 months, despite the absence of a significant change in anti-double-stranded DNA antibody and complement levels. Six patients developed human antichimeric antibodies (HACAs) at a level > or =100 ng/ml. These HACA titers were associated with African American ancestry, higher baseline SLAM scores, reduced B cell depletion, and lower levels of rituximab at 2 months after initial infusion.
CONCLUSION: Rituximab therapy appears to be safe for the treatment of SLE and holds significant therapeutic promise, at least for the majority of patients experiencing profound B cell depletion. Based on these results, controlled trials of rituximab appear to be warranted.

PMID 15334472  Arthritis Rheum. 2004 Aug;50(8):2580-9. doi: 10.1002/ar・・・
著者: Mikiko Tokunaga, Kazuyoshi Saito, Daisuke Kawabata, Yoshitaka Imura, Takao Fujii, Shingo Nakayamada, Shizuyo Tsujimura, Masao Nawata, Shigeru Iwata, Taeko Azuma, Tsuneyo Mimori, Yoshiya Tanaka
雑誌名: Ann Rheum Dis. 2007 Apr;66(4):470-5. doi: 10.1136/ard.2006.057885. Epub 2006 Nov 15.
Abstract/Text AIM: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious treatment-resistant phenotype of systemic lupus erythematosus. A standard treatment for NPSLE is not available. This report describes the clinical and laboratory tests of 10 patients with NPSLE before and after rituximab treatment, including changes in lymphocyte phenotypes.
METHODS: Rituximab was administered at different doses in 10 patients with refractory NPSLE, despite intensive treatment.
RESULTS: Treatment with rituximab resulted in rapid improvement of central nervous system-related manifestations, particularly acute confusional state. Rituximab also improved cognitive dysfunction, psychosis and seizure, and reduced the SLE Disease Activity Index Score at day 28 in all 10 patients. These effects lasted for >1 year in five patients. Flow cytometric analysis showed that rituximab down regulated CD40 and CD80 on B cells and CD40L, CD69 and inducible costimulator on CD4+ T cells.
CONCLUSIONS: Rituximab rapidly improved refractory NPSLE, as evident by resolution of various clinical signs and symptoms and improvement of radiographic findings. The down regulation of functional molecules on B and T cells suggests that rituximab modulates the interaction of activated B and T cells through costimulatory molecules. These results warrant further analysis of rituximab as treatment for NPSLE.

PMID 17107983  Ann Rheum Dis. 2007 Apr;66(4):470-5. doi: 10.1136/ard.2・・・
著者: Yoshiya Tanaka, Kazuhiko Yamamoto, Tsutomu Takeuchi, Norihiro Nishimoto, Nobuyuki Miyasaka, Takayuki Sumida, Yoshihito Shima, Kazuki Takada, Isao Matsumoto, Kazuyoshi Saito, Takao Koike
雑誌名: Mod Rheumatol. 2007;17(3):191-7. doi: 10.1007/s10165-007-0565-z. Epub 2007 Jun 20.
Abstract/Text Although corticosteroids and immunosuppressants are widely used for the treatments of systemic lupus erythematosus (SLE), safer and more effective therapies are prerequisite. We and others have reported that anti-CD20 antibody rituximab targeting B cells are effective for refractory SLE and, therefore, safety and clinical efficacy of rituximab in SLE was evaluated by a multicenter phase I/II clinical trial. An open-label, multicenter study of 15 patients with active and refractory SLE (total British Isles Lupus Assessment Group [BILAG] score 8 to 17) was conducted. Rituximab was administered to 5 SLE patients as 4 infusions of 500 mg/body every week and to 10 SLE patients as 2 infusions of 1000 mg/body every other week. Assessment of safety, infusion reactions and adverse effects was used as the primary outcome for clinical tolerability and was evaluated by 28 weeks. Rituximab was well tolerated, with most experiencing no significant adverse effects. B cells rapidly reduced in all patients and remained low until 6 months post-treatment. Four patients developed human antichimeric antibodies without affecting efficacy of rituximab. Changes in routine safety laboratory tests clearly related to rituximab were not observed. Nine among 14 evaluable patients achieved the major or partial clinical response of BILAG score and prednisolone dose significantly decreased at the 28 weeks. Rituximab therapy appears to be safe for the treatment of active SLE patients and holds significant therapeutic promise, at least for the majority of patients experiencing profound B-cell depletion.

PMID 17564773  Mod Rheumatol. 2007;17(3):191-7. doi: 10.1007/s10165-00・・・
著者: Joan T Merrill, C Michael Neuwelt, Daniel J Wallace, Joseph C Shanahan, Kevin M Latinis, James C Oates, Tammy O Utset, Caroline Gordon, David A Isenberg, Hsin-Ju Hsieh, David Zhang, Paul G Brunetta
雑誌名: Arthritis Rheum. 2010 Jan;62(1):222-33. doi: 10.1002/art.27233.
Abstract/Text OBJECTIVE: B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE.
METHODS: Patients entered with >or=1 British Isles Lupus Assessment Group (BILAG) A score or >or=2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182.
RESULTS: In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had >or=1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab.
CONCLUSION: The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials.

PMID 20039413  Arthritis Rheum. 2010 Jan;62(1):222-33. doi: 10.1002/ar・・・
著者: Brad H Rovin, Richard Furie, Kevin Latinis, R John Looney, Fernando C Fervenza, Jorge Sanchez-Guerrero, Romeo Maciuca, David Zhang, Jay P Garg, Paul Brunetta, Gerald Appel, LUNAR Investigator Group
雑誌名: Arthritis Rheum. 2012 Apr;64(4):1215-26. doi: 10.1002/art.34359. Epub 2012 Jan 9.
Abstract/Text OBJECTIVE: To evaluate the efficacy and safety of rituximab in a randomized, double-blind, placebo-controlled phase III trial in patients with lupus nephritis treated concomitantly with mycophenolate mofetil (MMF) and corticosteroids.
METHODS: Patients (n = 144) with class III or class IV lupus nephritis were randomized 1:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. The primary end point was renal response status at week 52.
RESULTS: Rituximab depleted peripheral CD19+ B cells in 71 of 72 patients. The overall (complete and partial) renal response rates were 45.8% among the 72 patients receiving placebo and 56.9% among the 72 patients receiving rituximab (P = 0.18); partial responses accounted for most of the difference. The primary end point (superior response rate with rituximab) was not achieved. Eight placebo-treated patients and no rituximab-treated patients required cyclophosphamide rescue therapy through week 52. Statistically significant improvements in serum complement C3, C4, and anti-double-stranded DNA (anti-dsDNA) levels were observed among patients treated with rituximab. In both treatment groups, a reduction in anti-dsDNA levels greater than the median reduction was associated with reduced proteinuria. The rates of serious adverse events, including infections, were similar in both groups. Neutropenia, leukopenia, and hypotension occurred more frequently in the rituximab group.
CONCLUSION: Although rituximab therapy led to more responders and greater reductions in anti-dsDNA and C3/C4 levels, it did not improve clinical outcomes after 1 year of treatment. The combination of rituximab with MMF and corticosteroids did not result in any new or unexpected safety signals.

Copyright © 2012 by the American College of Rheumatology.
PMID 22231479  Arthritis Rheum. 2012 Apr;64(4):1215-26. doi: 10.1002/a・・・
著者: Zhihong Liu, Haitao Zhang, Zhangsuo Liu, Changying Xing, Ping Fu, Zhaohui Ni, Jianghua Chen, Hongli Lin, Fuyou Liu, Yongcheng He, Yani He, Lining Miao, Nan Chen, Ying Li, Yong Gu, Wei Shi, Weixin Hu, Zhengzhao Liu, Hao Bao, Caihong Zeng, Minlin Zhou
雑誌名: Ann Intern Med. 2015 Jan 6;162(1):18-26. doi: 10.7326/M14-1030.
Abstract/Text BACKGROUND: Treatment of lupus nephritis (LN) remains challenging.
OBJECTIVE: To assess the efficacy and safety of a multitarget therapy consisting of tacrolimus, mycophenolate mofetil, and steroid compared with intravenous cyclophosphamide and steroid as induction therapy for LN.
DESIGN: 24-week randomized, open-label, multicenter study. (ClinicalTrials.gov: NCT00876616).
SETTING: 26 renal centers in China.
PATIENTS: Adults (aged 18 to 65 years) with biopsy-proven LN.
INTERVENTION: Tacrolimus, 4 mg/d, and mycophenolate mofetil, 1.0 g/d, versus intravenous cyclophosphamide with a starting dose of 0.75 (adjusted to 0.5 to 1.0) g/m2 of body surface area every 4 weeks for 6 months. Both groups received 3 days of pulse methylprednisolone followed by a tapering course of oral prednisone therapy.
MEASUREMENTS: The primary end point was complete remission at 24 weeks. Secondary end points included overall response (complete and partial remission), time to overall response, and adverse events.
RESULTS: After 24 weeks of therapy, more patients in the multitarget group (45.9%) than in the intravenous cyclophosphamide group (25.6%) showed complete remission (difference, 20.3 percentage points [95% CI, 10.0 to 30.6 percentage points]; P < 0.001). The overall response incidence was higher in the multitarget group than in the intravenous cyclophosphamide group (83.5% vs. 63.0%; difference, 20.4 percentage points [CI, 10.3 to 30.6 percentage points]; P < 0.001), and the median time to overall response was shorter in the multitarget group (difference, -4.1 weeks [CI, -7.9 to -2.1 weeks]). Incidence of adverse events did not differ between the multitarget and intravenous cyclophosphamide groups (50.3% [91 of 181] vs. 52.5% [95 of 181]).
LIMITATION: The study was limited to 24 weeks of follow-up.
CONCLUSION: Multitarget therapy provides superior efficacy compared with intravenous cyclophosphamide as induction therapy for LN.
PRIMARY FUNDING SOURCE: National Basic Research Program of China, National Key Technology R&D Program.

PMID 25383558  Ann Intern Med. 2015 Jan 6;162(1):18-26. doi: 10.7326/M・・・
著者: Hidetoshi Kagawa, Tsutomu Hiromasa, Takayuki Hara, Ayako Takaki, Ryutaro Yamanaka, Ken-ei Sada, Hirofumi Makino
雑誌名: Clin Exp Nephrol. 2012 Oct;16(5):760-6. doi: 10.1007/s10157-012-0632-4. Epub 2012 Apr 11.
Abstract/Text BACKGROUND: Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.
METHODS: We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.
RESULTS: All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine.
CONCLUSIONS: This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.

PMID 22492013  Clin Exp Nephrol. 2012 Oct;16(5):760-6. doi: 10.1007/s1・・・
著者: A Nomura, H Shimizu, M Kishimoto, Y Suyama, R Rokutanda, Y Ohara, K Yamaguchi, M Okada
雑誌名: Lupus. 2012 Nov;21(13):1444-9. doi: 10.1177/0961203312458468. Epub 2012 Aug 23.
Abstract/Text The prognosis of lupus nephritis (LN) has improved since the introduction of immunosuppressant therapies, but the safety and effectiveness of treatments can also be improved. We retrospectively assessed the treatment courses of 12 patients with systemic lupus erythematosus who were treated with glucocorticoid, mizoribine (MZR) and tacrolimus. This regimen was used as initial therapy for active LN in six patients (mean glucocorticoid dose, 66.6 mg); four of these six patients also received pulse methylprednisolone therapy. The starting doses of MZR and tacrolimus were 150 and 3 mg, respectively, and they were titrated as required. Five of six patients achieved complete remission and one achieved partial remission at 6 months. Five patients who completed 12-month analysis achieved complete remission. Another six patients were given the combination regimen for treating minor flares or for steroid sparing. The mean prednisolone doses were reduced from 11.0 mg at baseline to 6.6 mg at 12 months. Six patients experienced minor adverse events, including three minor infections. One patient stopped tacrolimus because of suspected toxicity. All 12 patients were successfully treated, and none experienced severe adverse events. Multitarget therapy combining glucocorticoid, MZR and tacrolimus may have the potential to become a treatment option which is effective and safe.

PMID 22917589  Lupus. 2012 Nov;21(13):1444-9. doi: 10.1177/09612033124・・・
著者: H Tanaka, T Aizawa, S Watanabe, E Oki, K Tsuruga, T Imaizumi
雑誌名: Lupus. 2014 Jul;23(8):813-8. doi: 10.1177/0961203314528553. Epub 2014 Mar 20.
Abstract/Text BACKGROUND: Recent advances in the management of lupus nephritis (LN) have also contributed to a favorable outcome in patients with pediatric-onset LN. Nevertheless, we believe that a more effective and less toxic treatment is needed to attain optimal control of pediatric-onset LN.
METHODS: Seven consecutive children with biopsy-proven LN (four with class III/IV and three with class V) received multitarget induction therapy consisting of mizoribine (MZR), tacrolimus (Tac), and prednisolone (PDN). They were prospectively evaluated at three, six, and 12 months, and at the latest observation point after a mean period of 32 months. Post-treatment renal biopsy was performed in two patients with class III/IV.
RESULTS: Despite gradually tapering the dose of concomitantly administered PDN, a significant improvement compared with baseline values was observed in the urinary, serological, and clinical assessment measures even at three months of treatment, and the favorable changes persisted throughout the treatment period in most of the study participants except for one. In two patients who underwent post-treatment renal biopsy, a marked histologic improvement was confirmed. No serious adverse events were observed.
CONCLUSIONS: Multitarget therapy may be an attractive option for the treatment of pediatric-onset LN. Further studies involving a larger number of patients are needed.

© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.
PMID 24651669  Lupus. 2014 Jul;23(8):813-8. doi: 10.1177/0961203314528・・・
著者: G Ruiz-Irastorza, M Ramos-Casals, P Brito-Zeron, M A Khamashta
雑誌名: Ann Rheum Dis. 2010 Jan;69(1):20-8. doi: 10.1136/ard.2008.101766.
Abstract/Text BACKGROUND: Antimalarial drugs (AMs), chloroquine (CQ) and hydroxychloroquine (HCQ), are frequently withdrawn in patients with lupus with either severe or remitting disease. However, additional effects beyond immunomodulation have been recently described. The aim of the present work was to analyse all the published evidence of the beneficial and adverse effects of AM therapy in systemic lupus erythematosus (SLE).
METHODS: A systematic review of the English literature between 1982 and 2007 was conducted using the MEDLINE and EMBASE databases. Randomised controlled trials (RCTs) and observational studies were selected. Case reports were excluded except for toxicity reports. The GRADE system was used to analyse the quality of the evidence.
RESULTS: A total of 95 articles were included in the systematic review. High levels of evidence were found that AMs prevent lupus flares and increase long-term survival of patients with SLE; moderate evidence of protection against irreversible organ damage, thrombosis and bone mass loss. Toxicity related to AMs is infrequent, mild and usually reversible, with HCQ having a safer profile. In pregnant women, high levels of evidence were found that AMs, particularly HCQ, decrease lupus activity without harming the baby. By contrast, evidence supporting an effect on severe lupus activity, lipid levels and subclinical atherosclerosis was weak. Individual papers suggest effects in preventing the evolution from SLE-like to full-blown SLE, influencing vitamin D levels and protecting patients with lupus against cancer.
CONCLUSIONS: Given the broad spectrum of beneficial effects and the safety profile, HCQ should be given to most patients with SLE during the whole course of the disease, irrespective of its severity, and be continued during pregnancy.

PMID 19103632  Ann Rheum Dis. 2010 Jan;69(1):20-8. doi: 10.1136/ard.20・・・
著者: Daniel J Wallace, Vineet S Gudsoorkar, Michael H Weisman, Swamy R Venuturupalli
雑誌名: Nat Rev Rheumatol. 2012 Sep;8(9):522-33. doi: 10.1038/nrrheum.2012.106. Epub 2012 Jul 17.
Abstract/Text Antimalarial agents have routinely been used for the treatment of systemic lupus erythematosus (SLE) for over 50 years. These agents continue to enjoy success as the initial pharmacotherapy for SLE even in the era of targeted therapies. Antimalarial agents have numerous biological effects that are responsible for their immunomodulatory actions in SLE. Their inhibitory effect on Toll-like receptor-mediated activation of the innate immune response is perhaps the most important discovery regarding their putative mechanism of action, but some other, previously known properties, such as antithrombotic and antilipidaemic effects, are now explained by new research. In the 1980s and 1990s, these antihyperlipidaemic and antithrombotic effects were demonstrated in retrospective clinical studies, and over the past few years prospective studies have confirmed those findings. Knowledge about the risk-benefit profile of antimalarial agents during pregnancy and lactation has evolved, as has the concept of retinal toxicity. Antimalarial agents have unique disease-modifying properties in SLE and newer iterations of this class of anti-inflammatory agents will have a profound effect upon the treatment of autoimmune disease.

PMID 22801982  Nat Rev Rheumatol. 2012 Sep;8(9):522-33. doi: 10.1038/n・・・
著者: N Yokogawa, H Eto, A Tanikawa, T Ikeda, K Yamamoto, T Takahashi, H Mizukami, T Sato, N Yokota, F Furukawa
雑誌名: Arthritis Rheumatol. 2017 Apr;69(4):791-799. doi: 10.1002/art.40018.
Abstract/Text OBJECTIVE: To assess the efficacy and tolerability of hydroxychloroquine (HCQ) in patients with cutaneous lupus erythematosus (CLE), in a phase III clinical trial conducted in Japan.
METHODS: We conducted a double-blind, randomized, parallel-group clinical trial. This was a baseline-controlled study, and the group differences were evaluated in an exploratory analysis. A total of 103 patients with active CLE (according to a Cutaneous Lupus Erythematosus Disease Area and Severity Index [CLASI] activity score of ≥4) were included. Patients were randomized 3:1 to receive HCQ or placebo during the 16-week double-blind period, and all patients were given HCQ during the following 36-week single-blind period. The primary efficacy end point was a reduction in the CLASI activity score at week 16. The secondary end points included the central photo evaluation (5-point scale), patient's global assessment (7-point scale), the Skindex-29 score, and investigator's global assessment (7-point scale, based on the other 3 secondary end points). In patients with systemic lupus erythematosus, fatigue and musculoskeletal pain were assessed. Safety was assessed up to week 55.
RESULTS: The mean CLASI score at week 16 was significantly improved from baseline in both the HCQ group and the placebo group: mean change -4.6 (95% confidence interval [95% CI] -6.1, -3.1) (P < 0.0001), and mean change -3.2 (95% CI -5.1, -1.3) (P = 0.002), respectively, without between-group difference (P = 0.197). The investigator's global assessment demonstrated a greater proportion of "improved" and "remarkably improved" patients in the HCQ group (51.4% versus 8.7% in the placebo group [P = 0.0002 between groups]). The other secondary end points supported the efficacy of HCQ. Cellulitis, drug eruption, hepatic dysfunction, and Stevens-Johnson syndrome were shown to be serious adverse events related to HCQ use.
CONCLUSION: The results of this randomized clinical trial support the efficacy and tolerability of HCQ in patients with CLE.

© 2016, American College of Rheumatology.
PMID 27992698  Arthritis Rheumatol. 2017 Apr;69(4):791-799. doi: 10.10・・・
著者: William Stohl, Andreas Schwarting, Masato Okada, Morton Scheinberg, Andrea Doria, Anne E Hammer, Christi Kleoudis, James Groark, Damon Bass, Norma Lynn Fox, David Roth, David Gordon
雑誌名: Arthritis Rheumatol. 2017 May;69(5):1016-1027. doi: 10.1002/art.40049. Epub 2017 Apr 7.
Abstract/Text OBJECTIVE: To assess the efficacy and safety of subcutaneous (SC) belimumab in patients with systemic lupus erythematosus (SLE).
METHODS: Patients with moderate-to-severe SLE (score of ≥8 on the Safety of Estrogens in Lupus Erythematosus National Assessment [SELENA] version of the SLE Disease Activity Index [SLEDAI]) were randomized 2:1 to receive weekly SC belimumab 200 mg or placebo by prefilled syringe in addition to standard SLE therapy for 52 weeks. The primary end point was the SLE Responder Index (SRI4) at week 52. Secondary end points were reduction in the corticosteroid dosage and time to severe flare. Safety was assessed according to the adverse events (AEs) reported and the laboratory test results.
RESULTS: Of 839 patients randomized, 836 (556 in the belimumab group and 280 in the placebo group) received treatment. A total of 159 patients withdrew before the end of the study. At entry, mean SELENA-SLEDAI scores were 10.5 in the belimumab group and 10.3 in the placebo group. More patients who received belimumab were SRI4 responders than those who received placebo (61.4% versus 48.4%; odds ratio [OR] 1.68 [95% confidence interval (95% CI) 1.25-2.25]; P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171.0 days versus 118.0 days; hazard ratio 0.51 [95% CI 0.35-0.74]; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% versus 11.9%; OR 1.65 [95% CI 0.95-2.84]; P = 0.0732), compared with placebo. AE incidence was comparable between treatment groups; serious AEs were reported by 10.8% of patients taking belimumab and 15.7% of those taking placebo. A worsening of IgG hypoglobulinemia by ≥2 grades occurred in 0.9% of patients taking belimumab and 1.4% of those taking placebo.
CONCLUSION: In patients with moderate-to-severe SLE, weekly SC doses of belimumab 200 mg plus standard SLE therapy significantly improved their SRI4 response, decreased severe disease flares as compared with placebo, and had a safety profile similar to placebo plus standard SLE therapy.

© 2017 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.
PMID 28118533  Arthritis Rheumatol. 2017 May;69(5):1016-1027. doi: 10.・・・
著者: Yoshiya Tanaka, Damon Bass, Myron Chu, Sally Egginton, Beulah Ji, Herbert Struemper, David Roth
雑誌名: Mod Rheumatol. 2019 May;29(3):452-460. doi: 10.1080/14397595.2018.1480915. Epub 2018 Jul 20.
Abstract/Text OBJECTIVES: To assess the efficacy and safety of intravenous (IV) belimumab plus standard systemic lupus erythematosus (SLE) therapy standard of care (SoC) in Japanese patients with SLE.
METHODS: A Phase 3, multicenter, double-blind, placebo-controlled, 52-week study (BEL 113750; NCT01345253) in patients with SLE, randomized 2:1 to belimumab 10 mg/kg plus SoC or placebo plus SoC to Week 48.
RESULTS: Sixty of 707 randomized patients were enrolled from study centers in Japan (belimumab, n = 39; placebo, n = 21). In this cohort, more patients achieved SLE Responder Index 4 response at Week 52 in the belimumab group compared with placebo (46.2% [18/39] vs. 25.0% [5/20]; odds ratio, 2.57 [95% confidence interval: 0.78, 8.47]; p=.1204). Fewer patients receiving belimumab experienced a severe flare through Week 52, with longer median time to flare compared with placebo. More patients with baseline prednisone dose >7.5 mg/d receiving belimumab had a dose reduction of ≥25% from baseline to ≤7.5 mg/d during Weeks 40-52, compared with placebo. No new safety issues were identified within the Japanese cohort.
CONCLUSION: In Japanese patients with SLE, belimumab improved disease activity, with efficacy and safety results similar and consistent to the pivotal Phase 3 trials, suggesting that belimumab is a potential treatment option in this population.

PMID 29792370  Mod Rheumatol. 2019 May;29(3):452-460. doi: 10.1080/143・・・

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