今日の臨床サポート

全身性エリテマトーデス腎障害

著者: 久保かなえ 東京都健康長寿医療センター膠原病・リウマチ科/東京大学医学部附属病院 アレルギー・リウマチ内科

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:2020/07/03
参考ガイドライン:
  1. 全身性エリテマトーデス(SLE)の診療ガイドライン2019
編集: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班、日本リウマチ学会
  1. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus.
Ann Rheum Dis. 2019 Jun;78(6):736-745. PMID: 30926722
  1. American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis. Arthritis Care Res (Hoboken). 2012 Jun;64(6):797-808. PMID:22556106
  1. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis. 2012 Nov;71(11):1771-82. PMID: 22851469
  1. KDIGO clinical practice guideline for glomerulonephritis. Chapter 12: Lupus nephritis.
Kidney Int Supplements 2012 June;2(2):221-32.
  1. EULAR recommendations for women's health and the management of family planning, assisted reproduction, pregnancy and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome.
Ann Rheum Dis. 2017 Mar;76(3):476-485. PMID: 27457513
  1. 日本リウマチ学会、日本皮膚科学会による皮膚エリテマトーデスおよび全身性エリテマトーデスに対するヒドロキシクロロキン使用のための簡易ガイドライン(2015.10.20版)
  1. 日本眼科学会によるヒドロキシクロロキン適正使用のための手引き(2016.6.10版)
患者向け説明資料

概要・推奨   

  1. SLEで尿所見異常や進行性腎機能障害を認めた場合にはループス腎炎を疑い、禁忌がない限り積極的に腎生検施行を考慮する(推奨度1
  1. III型、IV型ループス腎炎に対する寛解導入療法では、高用量ステロイド薬に加えシクロホスファミド(CPA)またはミコフェノール酸モフェチル(MMF)を併用する(推奨度1)
  1. 全身性エリテマトーデスの診療ガイドラインおよびACR、EULAR/ERA-EDTA、KDIGOのループス腎炎ガイドラインを参考に、検査や治療方針を検討する(推奨度1)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必
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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:
久保かなえ : 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. ガイドラインに基づき確認を行った。
  1. SLE分類基準およびループス腎炎の腎生検分類の改訂について追加記載した。

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(SLE)は自己免疫疾患の1つで、細胞核成分に対する抗体により多臓器に障害を及ぼし、慢性の経過で多彩な症状を呈する。
  1. 難病法による平成30年度末のわが国のSLEの医療受給者証保持者数は61,060人で、平成26年度末統計では、男女比は約1:8と女性に多い。15~55歳程度の比較的若年で発症することが多い[1]
  1. SLEにおいてループス腎炎を発症する頻度には人種差があるが、アジア人では約半数であったという報告がある[2]
  1. ループス腎炎は2本鎖DNA(dsDNA)-抗DNA抗体などの自己抗原と自己抗体の免疫複合体が糸球体に沈着し補体を活性化して炎症が生じる免疫複合体型の腎炎である。
  1. ループス腎炎は病理組織所見からInternational Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003分類および2018年改訂によって6型に分類され(表<図表>,表<図表>,表<図表>)、組織型により治療方針や予後が異なる。
  1. ループス腎炎による腎生存率は10年で80~90%程度である[3][4][5]
  1. 抗リン脂質抗体が関与した血栓や微小血管障害の合併を認めることがある。
  1. SLEに、高血圧性腎硬化症や、糖尿病性腎症、薬剤性腎障害などの非ループス腎炎による腎障害が合併することがある[6]
 
ループス腎炎の活動性病変と免疫沈着

ループス腎炎でみられる全節性管内細胞増多、ヒアリン血栓とワイヤーループ病変、壊死性病変、蛍光抗体法による免疫グロブリンの沈着。
a:全節性管内細胞増多
b:ヒアリン血栓とワイヤーループ
c:分節性壊死性病変
d:蛍光抗体法でみたIgG沈着

出典

img1:  著者提供
 
 
 
  1. 全身性エリテマトーデスの診療ガイドラインおよびACR、EULAR/ERA-EDTA、KDIGOのループス腎炎ガイドラインを参考に、検査や治療方針を検討する(推奨度1)
  1. まとめ:2012年にAmerican College of Rheumatology (ACR)、European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA)、Kidney Disease Improving Global Outcomes (KDIGO)の各グループからループス腎炎のガイドラインが発表され、2019年に日本から全身性エリテマトーデスの診療ガイドラインが発表された[7][8][9]
  1. 代表事例の説明:ループス腎炎の評価方法、組織型で分けられた治療方法、モニタリング、末期腎不全の対応、妊娠への対応などが述べられている。ACRのガイドラインではIII型、IV型、V型、妊娠例の治療について図のようなアルゴリズムが提示されている[7]
  1. 結論:疾患活動性の抑制効果、再燃の予防効果、ステロイド薬の減量効果、治療に伴う副作用の軽減、長期的な腎予後・生命予後の改善効果を考慮し、寛解導入療法または寛解維持療法に適した治療を選択する必要があり、ガイドラインを参考にすることを推奨するが、個々の症例に適した治療の検討を十分に行うことが重要である。
  1. 追記:寛解導入治療および寛解維持治療のエビデンスはRCTが蓄積されているが、ステロイドの減量・中止や免疫抑制薬の継続期間についてのエビデンスに課題が残る。寛解導入療法不応例での免疫抑制薬変更の有効性についてのデータは乏しい。難治例に対する治療は確立されていない。リツキシマブのように日本で保険適用外となっている薬剤がある。
 
ACRのガイドラインにおけるIII/IV型、V型、妊娠合併ループス腎炎に対する治療アルゴリズム

①III/IV型ループス腎炎に対する寛解導入療法 ② 増殖性病変のない、ネフローゼ域の蛋白尿を伴うV型ループス腎炎の治療 ③ III, IV, V型ループス腎炎の妊娠時の治療
PSL; プレドニゾロン
CPA;シクロホスファミド
MMF; ミコフェノール酸モフェチル
AZA; アザチオプリン

出典

img1:  American College of Rheumatology guidelines for screening, treatment, and management of lupus nephritis.
 
 Arthritis Care Res (Hoboken). 2012 Jun;6・・・
問診・診察のポイント  
SLEに伴う臓器病変の評価:
  1. SLEに伴う臓器病変の評価を行う。

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文献 

著者: S P Ballou, M A Khan, I Kushner
雑誌名: Arthritis Rheum. 1982 Jan;25(1):55-60.
Abstract/Text We compared the frequency of clinical features of systemic lupus erythematosus (SLE) and determined survival in 113 patients with younger-onset lupus (age less than 55 at clinical diagnosis) and 25 patients with older-onset disease (age greater than or equal to 55 at diagnosis). The most striking difference was in the racial distribution; 59% of the younger patients were black, compared with only 20% of the older-onset patients (P less than 0.001). Major manifestation of lupus (including clinically evident renal disease, central nervous system involvement, cutaneous involvement, and hemocytopenia) occurred with similar frequency in both age groups. Antibodies to DNA were detectable equally often in both groups, but hypocomplementemia was more common in the younger patients. Five-year survival in the younger-onset group (79%) was similar to that of the older-onset group (72%); there was a tendency toward relatively improved survival in patients survival of appropriately matched control populations. Major significant differences in racial distribution included 1) a higher incidence of serositis in older whites and in blacks regardless of age, and 2) more frequent hypocomplementemia in younger patients within both racial groups.

PMID 6978135  Arthritis Rheum. 1982 Jan;25(1):55-60.
著者: Victoria A Seligman, Raymond F Lum, Jean L Olson, Hongzhe Li, Lindsey A Criswell
雑誌名: Am J Med. 2002 Jun 15;112(9):726-9.
Abstract/Text
PMID 12079714  Am J Med. 2002 Jun 15;112(9):726-9.
著者: Hitoshi Yokoyama, Takashi Wada, Akinori Hara, Junya Yamahana, Izaya Nakaya, Motoo Kobayashi, Kiyoki Kitagawa, Satoshi Kokubo, Yasunori Iwata, Keiichi Yoshimoto, Kazuaki Shimizu, Norihiko Sakai, Kengo Furuichi, Kanazawa Study Group for Renal Diseases and Hypertension
雑誌名: Kidney Int. 2004 Dec;66(6):2382-8. doi: 10.1111/j.1523-1755.2004.66027.x.
Abstract/Text BACKGROUND: A considerable diversity in prognosis is seen with lupus glomerulonephritis (LGN). Hence, the clinical usefulness of a recent International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification to judge the long-term outcome of human LGN has been investigated.
METHODS: We studied retrospectively 60 subjects with LGN (7 males, 53 females, mean age of 33 years old) who underwent renal biopsies and were followed from 1 to 366 months, with a mean of 187 months. We diagnosed renal pathology as classes, active and sclerosing lesions, according to the new and WHO1995 classification of LGN, and analyzed the clinicopathologic factors affecting to the prognosis of LGN.
RESULTS: New classification got much higher consensus in the judgment of classes (98% vs. 83%, P = 0.0084). The group of Class IV-S (N = 6) or IV-G (N = 17) at initial biopsies showed higher rate of end-stage renal failure (ESRF) compared with that of Class I, II, III or V (40.9% vs. 2.6%, P < 0.001). The mean 50% renal survival time of Class IV was 189 +/- 29 months, and patients with Class IV-S tended to have a poorer prognosis (95 +/- 22 months for IV-S vs. 214 +/- 35 months for IV-G, P = 0.1495). Class IV was also selected as the most significant risk factor for ESRF by stepwise model (P = 0.002). In subanalysis for ESRF in Class IV (-S or -G), treatment including methylprednisolone pulse therapy was only selected as a significant improving factor for primary outcome (P = 0.034). In addition, activity index was the significant risk factor of death and/or ESRF after initial renal biopsies (P = 0.043). As for actuarial patient death during all follow-up periods, complications with anti-phospholipid syndrome or nephrotic syndrome were significant risk factors (P = 0.013, P = 0.041, respectively).
CONCLUSION: New ISN/RPS 2003 classification provided beneficial pathologic information relevant to the long-term renal outcome and the optimal therapy preventing ESRF and/or death in patients with LGN.

PMID 15569330  Kidney Int. 2004 Dec;66(6):2382-8. doi: 10.1111/j.1523-・・・
著者: Maria G Tektonidou, Abhijit Dasgupta, Michael M Ward
雑誌名: Arthritis Rheumatol. 2016 Jun;68(6):1432-41. doi: 10.1002/art.39594.
Abstract/Text OBJECTIVE: End-stage renal disease (ESRD) is a major consequence of lupus nephritis, but how this risk has changed over time is unknown. We conducted this systematic review to examine changes in ESRD among adults with lupus nephritis from 1971 to 2015 and to estimate risks of ESRD among contemporary patients.
METHODS: We searched PubMed, Embase, and the Cochrane Database of Systematic Reviews for cohort studies and clinical trials on ESRD in adults with lupus nephritis. We analyzed studies from developed and developing countries separately. The outcome was probability of ESRD at 5, 10, and 15 years of lupus nephritis.
RESULTS: We included 187 articles that reported on 18,309 patients. In developed countries, the 5-year risk of ESRD decreased from 16% (95% confidence interval [95% CI] 14-17%) in 1970-1979 to 11% (95% CI 10-12%) in the mid-1990s and then plateaued. ESRD risks at 10 years and 15 years showed steeper declines in the 1970s and 1980s but also plateaued in 1993-1997, with a notable increase in the late 2000s. The decrease in risk after 1980 coincided with increased use of cyclophosphamide. The 15-year ESRD risk was higher in developing countries than in developed countries. Patients with class IV lupus nephritis had the greatest risk of ESRD, with a 15-year risk of 44% during the 2000s.
CONCLUSION: Risks of ESRD in lupus nephritis improved between the 1970s and the mid-1990s and then plateaued, with an increase in the late 2000s. This pattern suggests limitations in the effectiveness of, or access to, current treatments.

© 2016, American College of Rheumatology.
PMID 26815601  Arthritis Rheumatol. 2016 Jun;68(6):1432-41. doi: 10.10・・・
著者: J Yang, D Liang, H Zhang, Z Liu, W Le, M Zhou, W Hu, C Zeng, Z Liu
雑誌名: Lupus. 2015 Dec;24(14):1468-78. doi: 10.1177/0961203315593166. Epub 2015 Jul 2.
Abstract/Text In the present study, we observed the renal outcomes in a cohort of 1814 Chinese patients with biopsy-proven lupus nephritis (LN) and evaluated the risk factors associated with poor renal prognosis. The 5 -, 10 -, 15 - and 20-year renal survival rates were 93.1%, 87.9%, 81.0% and 68.3%, respectively. Gender, LN duration, mean arterial pressure (MAP), proteinuria, serum creatinine, haemoglobin and pathological classification at the time of biopsy were independent risk factors for end-stage renal disease (ESRD). The long-term renal outcomes of patients with class II LN were unfavorable as opposed to those with class V. Additionally, the time-average proteinuria (TA-Pro) and the time-average mean arterial pressure (TA-MAP) during the follow-up were important risk factors for ESRD, with better predictive values than the baseline proteinuria and MAP. The results underscore the need for proteinuria and blood pressure control during follow-up in patients with LN; proteinuria levels should be controlled at least to < 1.0 g/24 h, and optimally to < 0.5 g/24 h; MAP should not exceed 96.5 mmHg. More attention should be paid to class II LN and emphasis should be placed on recurrence prevention of class II LN.

© The Author(s) 2015.
PMID 26139236  Lupus. 2015 Dec;24(14):1468-78. doi: 10.1177/0961203315・・・
著者: E Baranowska-Daca, Y J Choi, R Barrios, G Nassar, W N Suki, L D Truong
雑誌名: Hum Pathol. 2001 Oct;32(10):1125-35. doi: 10.1053/hupa.2001.28227.
Abstract/Text Renal biopsy specimens from patients with systemic lupus erythematosus (SLE) rarely show changes that are pathogenetically and morphologically unrelated to SLE. The morphology and behavior of these nonlupus nephritides are not well known. Two hundred fifty-two renal biopsies performed on 224 patients with SLE collected from 3,036 native kidney biopsies performed between 1975 and 1998 were reviewed, and those that showed nonlupus nephritides (index biopsies) were selected for studies. Thirteen biopsy specimens with nonlupus nephritides were identified in 13 patients, who belonged to 3 clinically distinct groups. Group I included 6 patients in whom SLE was diagnosed at the time of index biopsies. The index biopsies in these patients showed focal segmental glomerusclerosis (FSGS; 3 cases), Immunoglobulin (Ig) M nephropathy (1 case), and thin basement membrane disease (1 case). The diagnostic features for FSGS included segmental sclerosis involving at least 1 glomerulus, absence of lupus nephritis or other conditions that may cause nonspecific segmental sclerosis of glomeruli such as ischemia or nephrosclerosis, and nephrotic-range proteinuria. There was uniform, global, diffuse and marked thinning of the glomerular basement membrane in the case of thin basement membrane disease. Group II included 3 patients in whom SLE was diagnosed 2 to 9 years before the time of index biopsies and SLE was active at the time of biopsy. The index biopsies in these patients showed FSGS (2 cases) and hypertensive nephrosclerosis (1 case). Group III included 4 patients in whom SLE was diagnosed 5 to 36 years before the time of index biopsies and SLE was inactive at the time of biopsy. The index biopsies in these patients showed 1 case each of amyloidosis, FSGS, hypertensive nephrosclerosis, and allergic acute tubulointerstitial nephritis. Previous renal biopsies, performed in 5 patients, showed IgM nephropathy (1 case), diffuse proliferative lupus GN (1 case), focal proliferative lupus GN (1 case), and mesangial proliferative lupus GN (2 cases). Follow-up biopsies, performed in 3 patients, confirmed the diagnosis of FSGS (2 cases) and hypertensive nephrosclerosis (1 case) noted in the index biopsies. Nonlupus nephritides may occasionally be encountered in SLE patients, regardless of clinical or serologic disease activity. These renal lesions display a broad morphologic spectrum in which FSGS seems most frequent. Renal biopsy plays a crucial role in identifying these lesions, which may have prognostic and therapeutic implications distinct from those of lupus nephritis.

Copyright 2001 by W.B. Saunders Company
PMID 11679948  Hum Pathol. 2001 Oct;32(10):1125-35. doi: 10.1053/hupa.・・・
著者: Bevra H Hahn, Maureen A McMahon, Alan Wilkinson, W Dean Wallace, David I Daikh, John D Fitzgerald, George A Karpouzas, Joan T Merrill, Daniel J Wallace, Jinoos Yazdany, Rosalind Ramsey-Goldman, Karandeep Singh, Mazdak Khalighi, Soo-In Choi, Maneesh Gogia, Suzanne Kafaja, Mohammad Kamgar, Christine Lau, William J Martin, Sefali Parikh, Justin Peng, Anjay Rastogi, Weiling Chen, Jennifer M Grossman, American College of Rheumatology
雑誌名: Arthritis Care Res (Hoboken). 2012 Jun;64(6):797-808. doi: 10.1002/acr.21664.
Abstract/Text
PMID 22556106  Arthritis Care Res (Hoboken). 2012 Jun;64(6):797-808. d・・・
著者: George K Bertsias, Maria Tektonidou, Zahir Amoura, Martin Aringer, Ingeborg Bajema, Jo H M Berden, John Boletis, Ricard Cervera, Thomas Dörner, Andrea Doria, Franco Ferrario, Jürgen Floege, Frederic A Houssiau, John P A Ioannidis, David A Isenberg, Cees G M Kallenberg, Liz Lightstone, Stephen D Marks, Alberto Martini, Gabriela Moroni, Irmgard Neumann, Manuel Praga, Matthias Schneider, Argyre Starra, Vladimir Tesar, Carlos Vasconcelos, Ronald F van Vollenhoven, Helena Zakharova, Marion Haubitz, Caroline Gordon, David Jayne, Dimitrios T Boumpas, European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association
雑誌名: Ann Rheum Dis. 2012 Nov;71(11):1771-82. doi: 10.1136/annrheumdis-2012-201940. Epub 2012 Jul 31.
Abstract/Text OBJECTIVES: To develop recommendations for the management of adult and paediatric lupus nephritis (LN).
METHODS: The available evidence was systematically reviewed using the PubMed database. A modified Delphi method was used to compile questions, elicit expert opinions and reach consensus.
RESULTS: Immunosuppressive treatment should be guided by renal biopsy, and aiming for complete renal response (proteinuria <0.5 g/24 h with normal or near-normal renal function). Hydroxychloroquine is recommended for all patients with LN. Because of a more favourable efficacy/toxicity ratio, as initial treatment for patients with class III-IV(A) or (A/C) (±V) LN according to the International Society of Nephrology/Renal Pathology Society 2003 classification, mycophenolic acid (MPA) or low-dose intravenous cyclophosphamide (CY) in combination with glucocorticoids is recommended. In patients with adverse clinical or histological features, CY can be prescribed at higher doses, while azathioprine is an alternative for milder cases. For pure class V LN with nephrotic-range proteinuria, MPA in combination with oral glucocorticoids is recommended as initial treatment. In patients improving after initial treatment, subsequent immunosuppression with MPA or azathioprine is recommended for at least 3 years; in such cases, initial treatment with MPA should be followed by MPA. For MPA or CY failures, switching to the other agent, or to rituximab, is the suggested course of action. In anticipation of pregnancy, patients should be switched to appropriate medications without reducing the intensity of treatment. There is no evidence to suggest that management of LN should differ in children versus adults.
CONCLUSIONS: Recommendations for the management of LN were developed using an evidence-based approach followed by expert consensus.

PMID 22851469  Ann Rheum Dis. 2012 Nov;71(11):1771-82. doi: 10.1136/an・・・
著者:
雑誌名: Kidney Int Suppl (2011). 2012 Jun;2(2):221-232. doi: 10.1038/kisup.2012.25.
Abstract/Text
PMID 25018937  Kidney Int Suppl (2011). 2012 Jun;2(2):221-232. doi: 10・・・
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: Ann Rheum Dis. 2019 Sep;78(9):1151-1159. doi: 10.1136/annrheumdis-2018-214819. Epub 2019 Aug 5.
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 1001 subjects and validation compared with previous criteria in a new validation cohort of 1270 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 seven clinical (constitutional, haematological, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunological (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 reflect current thinking about SLE and provide an improved foundation for SLE research.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.
PMID 31383717  Ann Rheum Dis. 2019 Sep;78(9):1151-1159. doi: 10.1136/a・・・
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: G S Markowitz, V D D'Agati
雑誌名: Kidney Int. 2007 Mar;71(6):491-5. doi: 10.1038/sj.ki.5002118. Epub 2007 Jan 31.
Abstract/Text The 2003 International Society of Nephrology (ISN)/Renal Pathology Society (RPS) Classification of lupus nephritis (LN) was designed to eliminate ambiguities and standardize definitions. Major changes from the 1982 Modified WHO Classification include the elimination of the normal biopsy category and the subcategories of membranous Class V, the introduction of sharper distinctions between the classes, and the addition of subcategories within diffuse LN (class IV) for predominantly segmental (LN IV-S) and global (LN IV-G) lesions. It stipulates that sclerotic glomeruli owing to scarred LN should be taken into account when assessing the percentage of glomeruli affected by LN. Since its publication, the ISN/RPS classification has been used successfully in a number of clinical-pathologic studies. Several studies addressing the relationship between LN IV-S and LN IV-G have failed to identify a significantly worse outcome in IV-S than IV-G, although there were some differences in presenting clinical and pathologic features. Importantly, the ISN/RPS classification has achieved its goal of improved interobserver reproducibility. Its use has increased the percentage of LN biopsies meeting criteria for class IV. As it gains widespread acceptance, the ISN/RPS classification is already providing a standardized approach to renal biopsy interpretation needed to compare outcome data across centers.

PMID 17264872  Kidney Int. 2007 Mar;71(6):491-5. doi: 10.1038/sj.ki.50・・・
著者: N Hiramatsu, T Kuroiwa, H Ikeuchi, A Maeshima, Y Kaneko, K Hiromura, K Ueki, Y Nojima
雑誌名: Rheumatology (Oxford). 2008 May;47(5):702-7. doi: 10.1093/rheumatology/ken019. Epub 2008 Apr 4.
Abstract/Text OBJECTIVES: To determine if the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 classification of lupus nephritis (LN) is helpful in predicting renal outcome.
METHODS: A total of 92 patients with LN who underwent renal biopsy in our hospital were re-classified according to the ISN/RPS 2003 criteria.
RESULTS: The mean patient age was 36.8 yrs and the median observation period was 65 months. The relative frequency for each class was as follows: Class I (minimal mesangial LN) 0%, Class II (mesangial proliferative LN) 13%, Class III (focal LN) 17%, Class IV (diffuse LN) 60% and Class V (membranous LN) 10%. Within Class IV, diffuse segmental (Class IV-S) was 25% and diffuse global (Class IV-G) 75%. During the observation period, renal function was more likely to deteriorate in Class IV-G cases than in Class IV-S cases. Importantly, when Class IV-G was subdivided into cases involving active lesion alone [IV-G (A)] or chronic lesion [IV-G (A/C)], the majority of cases in IV-G (A) was nephrotic, but responded well to therapy. In contrast, renal function declined only in IV-G (A/C) cases. Patients with Class IV-G (A/C) had persistent proteinuria in spite of intensified therapies. Moreover, the higher proportion of chronic lesions was related with the deterioration of renal function.
CONCLUSIONS: This study showed that in Class IV-G cases, renal outcome differed in the presence of chronicity. Chronicity could be a critical factor in predicting outcome. Thus, the revised classification of LN is clinically valuable in identifying different renal outcomes among patients with diffuse LN.

PMID 18390590  Rheumatology (Oxford). 2008 May;47(5):702-7. doi: 10.10・・・
著者: Emilie C Rijnink, Y K Onno Teng, Suzanne Wilhelmus, Mathilde Almekinders, Ron Wolterbeek, Karlien Cransberg, Jan A Bruijn, Ingeborg M Bajema
雑誌名: Clin J Am Soc Nephrol. 2017 May 8;12(5):734-743. doi: 10.2215/CJN.10601016. Epub 2017 May 4.
Abstract/Text BACKGROUND AND OBJECTIVES: The prognostic significance of histopathologic (sub)classes in the current classification of lupus nephritis (LN) is controversial. We analyzed clinical and histopathologic predictors of renal outcome in LN outside the framework of the classification.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Variables (50 histopathologic and ten clinical) were tested in mixed, linear, and Cox regression models for their association with renal flare, ESRD, and eGFR during follow-up (1, 5, and 10 years) in 105 patients with LN who underwent biopsy from 1987 to 2011. The Cockcroft-Gault (normalized to a body surface area of 1.73 m2) and Schwartz formulas were used to calculate eGFR for adults and children, respectively.
RESULTS: During median follow-up of 9.9 years (25th-75th percentile, 5.9-13.8), 47 patients experienced a renal flare and 21 progressed to ESRD. Renal flare was predicted by fibrinoid necrosis (hazard ratio [HR], 1.04 per %; 95% confidence interval [95% CI], 1.00 to 1.07) and nonwhite race (HR, 2.23; 95% CI, 1.23 to 4.04). ESRD was predicted by fibrinoid necrosis (HR, 1.08 per %; 95% CI, 1.02 to 1.13), fibrous crescents (HR, 1.09 per %; 95% CI, 1.02 to 1.17), interstitial fibrosis/tubular atrophy (IF/TA) ≥25% (HR, 3.89; 95% CI, 1.25 to 12.14), eGFR at baseline (HR, 0.98 per ml/min per 1.73 m2; 95% CI, 0.97 to 1.00), and nonwhite race (HR, 7.16; 95% CI, 2.34 to 21.91). A higher mean eGFR during follow-up was associated with normal glomeruli (+0.2 ml/min per 1.73 m2 per %; 95% CI, 0.1 to 0.4). Like ESRD, a lower eGFR during follow-up was associated with fibrous crescents, IF/TA≥25%, and nonwhite race, as well as with cellular/fibrocellular crescents (-0.4 ml/min per 1.73 m2 per %; 95% CI, -0.6 to -0.2) and age (-0.8 ml/min per 1.73 m2 per year; 95% CI, -1.2 to -0.4).
CONCLUSION: The LN classification should include an index of evidence-based prognosticators. Awaiting validation of a formal index, we suggest that at least fibrinoid necrosis, fibrous crescents, and IF/TA warrant explicit independent scoring to assess the risk of progressive renal dysfunction in conjunction with clinical findings.

Copyright © 2017 by the American Society of Nephrology.
PMID 28473317  Clin J Am Soc Nephrol. 2017 May 8;12(5):734-743. doi: 1・・・
著者: H A Austin, D T Boumpas, E M Vaughan, J E Balow
雑誌名: Kidney Int. 1994 Feb;45(2):544-50.
Abstract/Text Despite several years of intense investigation, there continues to be controversy about the value of clinical, demographic and histologic features in prediction of outcomes of lupus nephritis. In addition, contemporary treatments have reduced the risk of progressive renal injury and thus may have altered the prognostic significance of some of these factors. We have therefore re-examined the predictive value of variables previously associated with an increased risk of renal insufficiency by studying 65 patients with severe lupus nephritis treated with intensive regimens of intravenous pulse cyclophosphamide or methylprednisolone. Five clinical features at study entry were each associated with an increased probability of doubling the serum creatinine: age greater than 30 years, Black race, hematocrit less than 26%, serum creatinine greater than 2.4 mg/dl, and C3 complement less than 76 mg/dl. By multivariate survival analysis, serum creatinine, hematocrit and race emerged as the strongest set of independent clinical predictors; the other clinical and demographic factors, including age and C3 complement did not contribute significantly to outcome predictions in the context of these three variables. Renal biopsy evaluation offered additional prognostic information and showed that patients with severe active and chronic histologic changes were at increased risk for developing renal insufficiency. The combination of cellular crescents and interstitial fibrosis was particularly ominous. Outcome predictions based on the strongest clinical model (serum creatinine, hematocrit and race) were significantly enhanced by the addition of renal pathology data. Consideration of these prognostic factors may contribute to decisions regarding the type and intensity of immunosuppressive therapy for patients with lupus nephritis.

PMID 8164443  Kidney Int. 1994 Feb;45(2):544-50.
著者: G Contreras, V Pardo, C Cely, E Borja, A Hurtado, C De La Cuesta, K Iqbal, O Lenz, A Asif, N Nahar, B Leclerq, C Leon, I Schulman, F Ramirez-Seijas, A Paredes, A Cepero, T Khan, F Pachon, E Tozman, G Barreto, D Hoffman, M Almeida Suarez, J C Busse, M Esquenazi, A Esquenazi, L Garcia Mayol, H Garcia Estrada
雑誌名: Lupus. 2005;14(11):890-5.
Abstract/Text The objective of this study was to identify the factors associated with important clinical outcomes in a case-control study of 213 patients with lupus nephritis. Included were 47% Hispanics, 44% African Americans and 9% Caucasians with a mean age of 28 years. Fifty-four (25%) patients reached the primary composite outcome of doubling serum creatinine, end-stage renal disease or death during a mean follow-up of 37 months. Thirty-four percent African Americans, 20% Hispanics and 10% Caucasians reached the primary composite outcome (P < 0.05). Patients reaching the composite outcome had predominantly proliferative lupus nephritis (WHO classes: 30% III, 32% IV, 18% V and 5% II, P < 0.025) with higher activity index score (7 +/- 6 versus 5 +/- 5, P < 0.05), chronicity index (CI) score (4 +/- 3 versus 2 +/- 2 unit, P < 0.025), higher baseline mean arterial pressure (MAP) (111 +/- 21 versus 102 +/- 14 mmHg, P < 0.025) and serum creatinine (1.9 +/- 1.3 versus 1.3 +/- 1.0 mg/dL, P < 0.025), but lower baseline hematocrit (29 +/- 6 versus 31 + 5%, P < 0.025) and complement C3 (54 +/- 26 versus 65 + 33 mg/dL, P < 0.025) compared to controls. More patients reaching the composite outcome had nephrotic range proteinuria compared to controls (74% versus 56%, P < 0.025). By multivariate analysis, CI (hazard ratio [95% CI] 1.18 [1.07-1.30] per point), MAP (HR 1.02 [1.00-1.03] per mmHg), and baseline serum creatinine (HR 1.26 [1.04-1.54] per mg/dL) were independently associated with the composite outcome. We concluded that hypertension and elevated serum creatinine at the time of the kidney biopsy as well as a high CI are associated with an increased the risk for chronic renal failure or death in patients with lupus nephritis.

PMID 16335581  Lupus. 2005;14(11):890-5.
著者: Feng Yu, Ying Tan, Gang Liu, Su-xia Wang, Wan-zhong Zou, Ming-hui Zhao
雑誌名: Kidney Int. 2009 Aug;76(3):307-17. doi: 10.1038/ki.2009.136. Epub 2009 Apr 29.
Abstract/Text There are few clinicopathologic and outcome data on patients with crescentic lupus nephritis, therefore, we determined factors of the disease by retrospectively reviewing the records of 327 patients diagnosed with lupus nephritis. Of these, 152 cases were regrouped as class IV-G, including 33 patients with crescentic glomerulonephritis. Significantly, all patients with crescentic glomerulonephritis had acute kidney injury as compared with only about a quarter of the patients without the disease. On pathological evaluation, activity scores, chronicity indexes, relapse rates, and the frequency of positive serum anti-neutrophil cytoplasmic antibody (ANCA) were each significantly higher, whereas complete remission rates and renal outcomes, over a mean follow-up of 4 years, were significantly poorer in patients with crescentic glomerulonephritis. Our study shows that crescentic glomerulonephritis was not rare in patients with lupus nephritis and that their long-term outcome was poor. The precise role of ANCA in the pathologic course of crescentic lupus nephritis remains to be determined.

PMID 19404274  Kidney Int. 2009 Aug;76(3):307-17. doi: 10.1038/ki.2009・・・
著者: Christine Hsieh, Anthony Chang, Daniel Brandt, Riteesha Guttikonda, Tammy O Utset, Marcus R Clark
雑誌名: Arthritis Care Res (Hoboken). 2011 Jun;63(6):865-74. doi: 10.1002/acr.20441.
Abstract/Text OBJECTIVE: In lupus nephritis, glomerular injury correlates poorly with progression to renal failure. While the tubulointerstitium is also commonly involved, the importance of such involvement is not well defined. Therefore, we developed a simple method to assess the prognostic utility of measuring tubulointerstitial inflammation (TI).
METHODS: Sixty-eight systemic lupus erythematosus patients with lupus nephritis were enrolled. Tubulointerstitial lymphocytic infiltrates were quantitated both by anti-CD45 antibody staining and standard histochemical staining. Followup data were obtained and survival analysis was carried out to determine which histologic features were predictive of subsequent renal failure.
RESULTS: By CD45 staining, TI was a common pathologic finding, with 72% of biopsies having moderate or severe involvement. The extent of TI correlated with serum creatinine, but not with double-stranded DNA antibodies, serum C3, or glomerular inflammation. TI severity, but not glomerular injury, identified patients at greater risk for renal failure (P = 0.02). A high National Institutes of Health (NIH) chronicity index also identified patients at risk for renal failure. However, when the glomerular and tubulointerstitial subcomponents of the NIH chronicity index were separated in a bivariate model, only tubulointerstitial chronicity provided prognostic information (hazard ratio [HR] 2.2, 95% confidence interval [95% CI] 1.3-3.6; P = 0.002 versus HR 1.0, 95% CI 0.7-1.5; P = 0.97 for glomerular chronicity).
CONCLUSION: TI identifies lupus nephritis patients at greatest risk for progression to renal failure. The immunologic mechanisms underlying TI may provide novel targets for therapeutic intervention.

Copyright © 2011 by the American College of Rheumatology.
PMID 21309006  Arthritis Care Res (Hoboken). 2011 Jun;63(6):865-74. do・・・
著者: Samih H Nasr, Vivette D D'Agati, Hye-Ran Park, Paul L Sterman, Juan D Goyzueta, Robert M Dressler, Shawn M Hazlett, Robert N Pursell, Christopher Caputo, Glen S Markowitz
雑誌名: Clin J Am Soc Nephrol. 2008 May;3(3):682-90. doi: 10.2215/CJN.04391007. Epub 2008 Feb 20.
Abstract/Text BACKGROUND AND OBJECTIVES: Lupus nephritis is a classic immune complex glomerulonephritis. In contrast, antineutrophil cytoplasmic antibodies are associated with necrotizing and crescentic glomerulonephritis, in the absence of significant immune deposits. Antineutrophil cytoplasmic antibodies are detected by indirect immunofluorescence in 20% of patients with systemic lupus erythematosus. We report 10 cases of necrotizing and crescentic lupus nephritis with antineutrophil cytoplasmic antibody seropositivity.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Ten patients with systemic lupus erythematosus, antineutrophil cytoplasmic antibody positivity, and renal biopsy findings of lupus nephritis and antineutrophil cytoplasmic antibody-associated glomerulonephritis were identified. The clinical features, pathologic findings, and outcomes are described.
RESULTS: The cohort consisted of eight women and two men with a mean age of 48.4 yr. Perinuclear antineutrophil cytoplasmic antibody was detected by indirect immunofluorescence in nine patients. Four of the nine patients and the single remaining patient were found to have myeloperoxidase-antineutrophil cytoplasmic antibodies by enzyme-linked immunosorbent assay. Clinical presentation included proteinuria, hematuria, and acute renal insufficiency, with mean creatinine of 7.1 mg/dl. All biopsies exhibited prominent necrosis and crescents with absent or rare subendothelial deposits and were interpreted as lupus nephritis and antineutrophil cytoplasmic antibody-associated glomerulonephritis. All patients received cyclophosphamide and prednisone. Three patients died of infectious complications. Among the remaining seven patients, five achieved a complete or near-complete remission, one had a remission with subsequent relapse, and one had no response to therapy.
CONCLUSION: Antineutrophil cytoplasmic antibody-associated necrotizing and crescentic glomerulonephritis may occur superimposed on lupus nephritis. In patients with lupus nephritis and biopsy findings of prominent necrosis and crescent formation in the absence of significant endocapillary proliferation or subendothelial deposits, antineutrophil cytoplasmic antibody testing by enzyme-linked immunosorbent assay is recommended.

PMID 18287252  Clin J Am Soc Nephrol. 2008 May;3(3):682-90. doi: 10.22・・・
著者: C-H Li, Y-C Li, P-S Xu, X Hu, C-Y Wang, G-L Zou
雑誌名: Scand J Rheumatol. 2006 May-Jun;35(3):201-8. doi: 10.1080/03009740500303181.
Abstract/Text OBJECTIVES: To evaluate the clinical and laboratory features of patients with lupus nephritis (LN) in the presence and absence of anti-glomerular basement membrane antibodies (anti-GBM) and to establish whether the characteristics of the disease correlate with anti-GBM.
METHODS: We performed a retrospective study of 157 hospitalised patients with systemic lupus erythematosus (SLE), 91 of whom had LN. The test for anti-GBM used an enzyme-linked immunosorbent assay (ELISA). Clinical and laboratory data were collected and assessed in LN patients with and without anti-GBM.
RESULTS: Anti-GBM was detected in 14 (8.9%) of 157 patients with SLE. All of the 14 patients developed LN; of these, 10 reached the criteria for crescentic glomerulonephritis (CGN) and five were diagnosed as Goodpasture's disease. Serum anti-GBM levels were correlated with the presence of both anti-double-stranded DNA antibodies (anti-dsDNA) and anti-nucleosome antibodies (anti-NuA). Significant differences in extrarenal clinical manifestations were found between anti-GBM-positive and -negative LN patients, with regard to pleuritis, pulmonary haemorrhage, sinusitis, and anaemia in particular.
CONCLUSIONS: LN with anti-GBM is not rare in Chinese patients. Anti-GBM, together with the additional nephritogenic potential of anti-dsDNA and anti-NuA, may play an essential role in the pathogenesis of the anti-GBM disease in LN. Therefore, in addition to routine anti-GBM assay, anti-dsDNA and anti-NuA measurements should be performed early to ensure a prompt diagnosis and immediate treatment in patients with anti-GBM-mediated disease.

PMID 16766367  Scand J Rheumatol. 2006 May-Jun;35(3):201-8. doi: 10.10・・・
著者:
雑誌名: N Engl J Med. 1991 Jan 17;324(3):150-4. doi: 10.1056/NEJM199101173240303.
Abstract/Text BACKGROUND: The antimalarial drug hydroxychloroquine is thought to be effective in controlling some of the manifestations of systemic lupus erythematosus, but its effectiveness has not been demonstrated conclusively.
METHODS: We conducted a six-month, randomized, double-blind, placebo-controlled study of the effect of discontinuing hydroxychloroquine sulfate treatment in 47 patients with clinically stable systemic lupus erythematosus. The patients were randomly assigned to continue their same dose of hydroxychloroquine (n = 25) or to receive placebo (n = 22) for 24 weeks. Ten patients in each group were also taking prednisone.
RESULTS: The relative risk of a clinical flare-up, defined as the development of specific clinical manifestations of systemic lupus erythematosus or an increase in their severity, was 2.5 times higher (95 percent confidence interval, 1.08 to 5.58) in the patients taking placebo than in those continuing to take hydroxychloroquine (16 of 22 patients vs. 9 of 25 had flare-ups), and the time to a flare-up was shorter (P = 0.02). The relative risk of a severe exacerbation of disease that required withdrawal from the study was 6.1 times higher (95 percent confidence interval, 0.72 to 52.44) for the patients taking placebo (5 of 22 patients vs. 1 of 25 had severe exacerbations of disease). Changes in the dose of prednisone were not different in the two groups.
CONCLUSIONS: Patients with quiescent systemic lupus erythematosus who are taking hydroxychloroquine are less likely to have a clinical flare-up if they are maintained on the drug.

PMID 1984192  N Engl J Med. 1991 Jan 17;324(3):150-4. doi: 10.1056/NE・・・
著者: Barri J Fessler, Graciela S Alarcón, Gerald McGwin, Jeffrey Roseman, Holly M Bastian, Alan W Friedman, Bruce A Baethge, Luis Vilá, John D Reveille, LUMINA Study Group
雑誌名: Arthritis Rheum. 2005 May;52(5):1473-80. doi: 10.1002/art.21039.
Abstract/Text OBJECTIVE: To examine whether hydroxychloroquine (HCQ) usage is associated with a reduced risk of damage accrual in patients with systemic lupus erythematosus (SLE).
METHODS: Patients (n = 518) meeting the American College of Rheumatology criteria for diagnosis of SLE and with RESULTS: Fifty-six percent of the patients were treated with HCQ at the time of study enrollment. Patients who were not treated with HCQ on enrollment had higher SLAM and SDI scores than patients who were treated. Untreated patients were significantly more likely to have major organ involvement such as renal disease (P < 0.0001) or central nervous system disease (P < 0.0025). Results of unadjusted analysis suggested that treated patients were less likely to accrue damage (hazard ratio [HR] 0.68). With adjustment for differences in treatment assignment, HCQ usage was still associated with a reduced risk of developing new damage, with an HR of 0.68 (95% confidence interval [95% CI] 0.53-0.93) (P = 0.014). With adjustment for differences in treatment assignment, HCQ usage was still associated with a reduced risk of developing new damage (HR 0.73 [95% CI 0.52-1.00]) (P = 0.05). However, patients receiving HCQ who had no damage at study entry had a statistically significant decrease in the risk of damage accrual (HR 0.55 [95% CI 0.34-0.87]) (P = 0.0111), whereas those receiving HCQ who had damage at study entry did not (HR 1.106 [95% CI 0.70-1.74]) (P = 0.6630).
CONCLUSION: These findings indicate that, after adjustment for propensity to receive HCQ, HCQ usage is independently associated with a reduced risk of damage accrual in SLE patients who had not yet accrued damage at the time of treatment initiation.

PMID 15880829  Arthritis Rheum. 2005 May;52(5):1473-80. doi: 10.1002/a・・・
著者: Guillermo J Pons-Estel, Graciela S Alarcón, Gerald McGwin, Maria I Danila, Jie Zhang, Holly M Bastian, John D Reveille, Luis M Vilá, Lumina Study Group
雑誌名: Arthritis Rheum. 2009 Jun 15;61(6):830-9. doi: 10.1002/art.24538.
Abstract/Text OBJECTIVE: To assess whether hydroxychloroquine can delay renal damage development in lupus nephritis patients.
METHODS: Lupus nephritis patients (n = 256) from the LUpus in MInorities, NAture versus nurture study (n = 635), a multiethnic cohort of African Americans, Hispanics, and Caucasians, age > or =16 years with disease duration < or =5 years at baseline (T0) were studied. Renal damage was defined using the Systemic Lupus International Collaborating Clinics Damage Index (> or =1 of the following lasting at least 6 months: estimated/measured glomerular filtration rate <50%, 24-hour proteinuria > or =3.5 gm and/or end-stage renal disease, regardless of dialysis or transplantation). Patients with renal damage before T0 were excluded (n = 53). The association between hydroxychloroquine use and renal damage (as defined, or omitting proteinuria) was estimated using Cox proportional regression analyses adjusting for potential confounders. Kaplan-Meier survival curves based on hydroxychloroquine intake or the World Health Organization (WHO) class glomerulonephritis were also derived.
RESULTS: Sixty-three (31.0%) of the 203 patients included developed renal damage over a mean +/- SD disease duration of 5.2 +/- 3.5 years. The most frequent renal damage domain item was proteinuria. Patients who received hydroxychloroquine (79.3%) exhibited a lower frequency of WHO class IV glomerulonephritis, had lower disease activity, and received lower glucocorticoid doses than those who did not take hydroxychloroquine. After adjusting for confounders, hydroxychloroquine was protective of renal damage occurrence in full (hazard ratio [HR] 0.12, 95% confidence interval [95% CI] 0.02-0.97, P = 0.0464) and reduced (HR 0.29, 95% CI 0.13-0.68, P = 0.0043) models. Omitting proteinuria provided comparable results. The cumulative probability of renal damage occurrence was higher in those who did not take hydroxychloroquine and those classified as WHO class IV glomerulonephritis (P < 0.0001).
CONCLUSION: After adjusting for possible confounding factors, the protective effect of hydroxychloroquine in retarding renal damage occurrence in systemic lupus erythematosus is still evident.

PMID 19479701  Arthritis Rheum. 2009 Jun 15;61(6):830-9. doi: 10.1002/・・・
著者: Samuel K Shinjo, Eloísa Bonfá, Daniel Wojdyla, Eduardo F Borba, Luis A Ramirez, Hugo R Scherbarth, João C Tavares Brenol, Rosa Chacón-Diaz, Oscar J Neira, Guillermo A Berbotto, Ignacio Garcia De La Torre, Eduardo M Acevedo-Vázquez, Loreto Massardo, Leonor A Barile-Fabris, Francisco Caeiro, Luis H Silveira, Emilia I Sato, Sandra Buliubasich, Graciela S Alarcón, Bernardo A Pons-Estel, Grupo Latino Americano de Estudio del Lupus Eritematoso (Gladel)
雑誌名: Arthritis Rheum. 2010 Mar;62(3):855-62. doi: 10.1002/art.27300.
Abstract/Text OBJECTIVE: To evaluate the beneficial effect of antimalarial treatment on lupus survival in a large, multiethnic, international longitudinal inception cohort.
METHODS: Socioeconomic and demographic characteristics, clinical manifestations, classification criteria, laboratory findings, and treatment variables were examined in patients with systemic lupus erythematosus (SLE) from the Grupo Latino Americano de Estudio del Lupus Eritematoso (GLADEL) cohort. The diagnosis of SLE, according to the American College of Rheumatology criteria, was assessed within 2 years of cohort entry. Cause of death was classified as active disease, infection, cardiovascular complications, thrombosis, malignancy, or other cause. Patients were subdivided by antimalarial use, grouped according to those who had received antimalarial drugs for at least 6 consecutive months (user) and those who had received antimalarial drugs for <6 consecutive months or who had never received antimalarial drugs (nonuser).
RESULTS: Of the 1,480 patients included in the GLADEL cohort, 1,141 (77%) were considered antimalarial users, with a mean duration of drug exposure of 48.5 months (range 6-98 months). Death occurred in 89 patients (6.0%). A lower mortality rate was observed in antimalarial users compared with nonusers (4.4% versus 11.5%; P< 0.001). Seventy patients (6.1%) had received antimalarial drugs for 6-11 months, 146 (12.8%) for 1-2 years, and 925 (81.1%) for >2 years. Mortality rates among users by duration of antimalarial treatment (per 1,000 person-months of followup) were 3.85 (95% confidence interval [95% CI] 1.41-8.37), 2.7 (95% CI 1.41-4.76), and 0.54 (95% CI 0.37-0.77), respectively, while for nonusers, the mortality rate was 3.07 (95% CI 2.18-4.20) (P for trend < 0.001). After adjustment for potential confounders in a Cox regression model, antimalarial use was associated with a 38% reduction in the mortality rate (hazard ratio 0.62, 95% CI 0.39-0.99).
CONCLUSION: Antimalarial drugs were shown to have a protective effect, possibly in a time-dependent manner, on SLE survival. These results suggest that the use of antimalarial treatment should be recommended for patients with lupus.

PMID 20131238  Arthritis Rheum. 2010 Mar;62(3):855-62. doi: 10.1002/ar・・・
著者: G Ruiz-Irastorza, M V Egurbide, J I Pijoan, M Garmendia, I Villar, A Martinez-Berriotxoa, J G Erdozain, C Aguirre
雑誌名: Lupus. 2006;15(9):577-83.
Abstract/Text Antimalarials have shown beneficial effects on systemic lupus erythematosus (SLE) activity. Our aim was to investigate whether antimalarials protect against thrombosis and influence survival in SLE patients. A prospective cohort including 232 patients with SLE were included in the study at the time of lupus diagnosis. End points were documented thrombosis and death due to any cause. A Cox regression-multiple-failure time survival analysis model was fitted to establish the effect of antimalarials on the development of thrombosis. Kaplan-Meier survival curves and propensity score adjusted-Cox regression analysis were performed to investigate the effect of antimalarials use on survival. Of our subjects, 204 patients (88%) were women. 230 patients (99%) were white. 150 patients (64%) had ever received antimalarials. Median time on antimalarials was 52 months (range three to 228 months). The Cox multiple-failure time survival analysis showed that taking antimalarials was protective against thrombosis (HR 0.28, 95% CI 0.08-0.90), while aPL-positivity (HR 3.16, 95% CI 1.45-6.88) and previous thrombosis (HR 3.85, 95% CI 1.50-9.91) increased the risk of thrombotic events. Twenty-three patients died, 19 of whom (83%) had never received antimalarials. No patient treated with antimalarials died of cardiovascular complications. Cumulative 15-year survival rates were 0.68 for never versus 0.95 for ever treated patients (P < 0.001). Age at diagnosis and propensity score-adjusted HR for antimalarials ever versus never users was 0.14 (95% CI 0.04-0.48). Our study shows a protective effect of antimalarials against thrombosis and an increased survival of SLE patients taking these drugs. These data support the routine use of antimalarials in all patients with SLE.

PMID 17080912  Lupus. 2006;15(9):577-83.
著者: Hyejung Jung, Raja Bobba, Jiandong Su, Zhaleh Shariati-Sarabi, Dafna D Gladman, Murray Urowitz, Wendy Lou, Paul R Fortin
雑誌名: Arthritis Rheum. 2010 Mar;62(3):863-8. doi: 10.1002/art.27289.
Abstract/Text OBJECTIVE: The antimalarial medication hydroxychloroquine has been proposed as a thromboprotective agent in systemic lupus erythematosus (SLE), but studies thus far have been limited by the possibility of confounding by indication. This study was conducted to assess whether exposure to antimalarial drugs is associated with a decrease in thrombovascular events (TEs) in patients with SLE.
METHODS: The study was designed as a nested case-control study embedded in an inception cohort of patients with SLE, which allowed adjustments for possible confounding by calendar year, duration of disease, duration of observation, and severity of lupus. After controlling for the possible confounding variables in conditional logistic regression models, the use of antimalarial drugs was assessed for its effects on the development of TEs in lupus patients.
RESULTS: Fifty-four cases of TE were identified, and these were matched with 108 control subjects (lupus patients without TEs). Univariate analyses identified older age (odds ratio [OR] 1.04, 95% confidence interval [95%CI] 1.01-1.07) or being older than age 50 years (OR 3.5, 95% CI 1.4-8.6) and ever having hypertension (OR 2.5, 95% CI 1.0-5.8) as being associated with an increased risk of TEs, whereas use of antimalarial drugs (OR 0.31, 95% CI 0.13-0.71) was associated with a decreased risk of TEs. Separate analyses were done for arterial and venous TEs, which yielded similar results. In multivariate analyses, use of antimalarial drugs (OR 0.32, 95% CI 0.14-0.74) and older age (OR 1.04, 95% CI 1.01-1.07) were the only 2 variables that remained significant.
CONCLUSION: The results from this nested case-control study demonstrate that, after accounting for the effects of disease severity, disease duration, and calendar year, antimalarial drugs were found to be thromboprotective, being associated with a 68% reduction in the risk of all TEs, with a range of risk reduction of at least 26% up to as high as 86%.

PMID 20131232  Arthritis Rheum. 2010 Mar;62(3):863-8. doi: 10.1002/art・・・
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: Kate Franklyn, Chak Sing Lau, Sandra V Navarra, Worawit Louthrenoo, Aisha Lateef, Laniyati Hamijoyo, C Singgih Wahono, Shun Le Chen, Ou Jin, Susan Morton, Alberta Hoi, Molla Huq, Mandana Nikpour, Eric F Morand, Asia-Pacific Lupus Collaboration
雑誌名: Ann Rheum Dis. 2016 Sep;75(9):1615-21. doi: 10.1136/annrheumdis-2015-207726. Epub 2015 Oct 12.
Abstract/Text AIMS: Treating to low disease activity is routine in rheumatoid arthritis, but no comparable goal has been defined for systemic lupus erythematosus (SLE). We sought to define and validate a Lupus Low Disease Activity State (LLDAS).
METHODS: A consensus definition of LLDAS was generated using Delphi and nominal group techniques. Criterion validity was determined by measuring the ability of LLDAS attainment, in a single-centre SLE cohort, to predict non-accrual of irreversible organ damage, measured using the Systemic Lupus International Collaborating Clinics Damage Index (SDI).
RESULTS: Consensus methodology led to the following definition of LLDAS: (1) SLE Disease Activity Index (SLEDAI)-2K ≤4, with no activity in major organ systems (renal, central nervous system (CNS), cardiopulmonary, vasculitis, fever) and no haemolytic anaemia or gastrointestinal activity; (2) no new lupus disease activity compared with the previous assessment; (3) a Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI physician global assessment (scale 0-3) ≤1; (4) a current prednisolone (or equivalent) dose ≤7.5 mg daily; and (5) well tolerated standard maintenance doses of immunosuppressive drugs and approved biological agents. Achievement of LLDAS was determined in 191 patients followed for a mean of 3.9 years. Patients who spent greater than 50% of their observed time in LLDAS had significantly reduced organ damage accrual compared with patients who spent less than 50% of their time in LLDAS (p=0.0007) and were significantly less likely to have an increase in SDI of ≥1 (relative risk 0.47, 95% CI 0.28 to 0.79, p=0.005).
CONCLUSIONS: A definition of LLDAS has been generated, and preliminary validation demonstrates its attainment to be associated with improved outcomes in SLE.

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 26458737  Ann Rheum Dis. 2016 Sep;75(9):1615-21. doi: 10.1136/ann・・・
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: 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: 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: Tak-Mao Chan, Kai-Chung Tse, Colin Siu-On Tang, Mo-Yin Mok, Fu-Keung Li, Hong Kong Nephrology Study Group
雑誌名: J Am Soc Nephrol. 2005 Apr;16(4):1076-84. doi: 10.1681/ASN.2004080686. Epub 2005 Feb 23.
Abstract/Text Mycophenolate mofetil (MMF) and the sequential use of cyclophosphamide followed by azathioprine (CTX-AZA) demonstrate similar short-term efficacy in the treatment of diffuse proliferative lupus nephritis (DPLN), but MMF is associated with less drug toxicity. Results from an extended long-term study, with median follow-up of 63 mo, that investigated the role of MMF as continuous induction-maintenance treatment for DPLN are presented. Thirty-three patients were randomized to receive MMF, and 31 were randomized to the CTX-AZA treatment arm, both in combination with prednisolone. More than 90% in each group responded favorably (complete or partial remission) to induction treatment. Serum creatinine in both groups remained stable and comparable over time. Creatinine clearance increased significantly in the MMF group, but the between-group difference was insignificant. Improvements in serology and proteinuria were comparable between the two groups. A total of 6.3% in the MMF group and 10.0% of CTX-AZA-treated patients showed doubling of baseline creatinine during follow-up (P = 0.667). Both the relapse-free survival and the hazard ratio for relapse were similar between MMF- and CTX-AZA-treated patients (11 and nine patients relapsed, respectively) and between those with MMF treatment for 12 or >/=24 mo. MMF treatment was associated with fewer infections and infections that required hospitalization (P = 0.013 and 0.014, respectively). Four patients in the CTX-AZA group but none in the MMF group reached the composite end point of end-stage renal failure or death (P = 0.062 by survival analysis). It is concluded that MMF and prednisolone constitute an effective continuous induction-maintenance treatment for DPLN in Chinese patients.

PMID 15728784  J Am Soc Nephrol. 2005 Apr;16(4):1076-84. doi: 10.1681/・・・
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: Frédéric A Houssiau, Carlos Vasconcelos, David D'Cruz, Gian Domenico Sebastiani, Enrique de Ramon Garrido Ed, Maria Giovanna Danieli, Daniel Abramovicz, Daniel Blockmans, Alessandro Mathieu, Haner Direskeneli, Mauro Galeazzi, Ahmet Gül, Yair Levy, Peter Petera, Rajko Popovic, Radmila Petrovic, Renato Alberto Sinico, Roberto Cattaneo, Josep Font, Geneviève Depresseux, Jean-Pierre Cosyns, Ricard Cervera
雑誌名: Arthritis Rheum. 2002 Aug;46(8):2121-31. doi: 10.1002/art.10461.
Abstract/Text OBJECTIVE: Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment.
METHODS: In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed.
RESULTS: Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant.
CONCLUSION: The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen.

PMID 12209517  Arthritis Rheum. 2002 Aug;46(8):2121-31. doi: 10.1002/a・・・
著者: Meng-Yu Weng, Chia-Tse Weng, Ming-Fei Liu
雑誌名: Clin Rheumatol. 2010 Jul;29(7):771-5. doi: 10.1007/s10067-010-1403-9. Epub 2010 Mar 2.
Abstract/Text Mycophenolate mofetil (MMF) has recently been introduced as an immunosuppressive agent for the treatment of glomerulonephritis with systemic lupus erythematosus (SLE) and the data have been encouraging. However, response to MMF treatment appears to differ ethnically. Therefore, we determined efficacy and safety of low-dose MMF for Taiwanese patients with lupus nephritis. We studied 36 lupus nephritis patients who were treated with MMF. The dose started at 0.5 g/day and we collected the data from patients who received up to 1 g/day MMF. Outcome measures were 24 h for proteinuria, serum creatinine, C3/C4 levels, and anti-dsDNA titers collected at the baseline and at 3-month treatment intervals. Daily urinary protein significantly decreased from 6.15 +/- 4.28 g to 2.69 +/- 2.36 g at the last visit (P < 0.01) in spite of the significant absence of changes in serum creatinine levels. The response rate was 65.7% including five (14.3%) cases of complete remission and 18 (51.4%) cases of partial remission. The concomitant oral prednisolone dose decreased significantly from 20.07 +/- 11.78 mg/day to 13.93 +/- 6.79 mg/day at 6 months (P < 0.01). The level of C3 increased significantly from 59.46 +/- 32.73 to 71.99 +/- 25.81 (P < 0.01) and the anti-dsDNA antibody titer decreased from 161.71 +/- 221.42 to 46.57 +/- 117.47 (P < 0.01). No severe adverse effects were observed in the study. Low-dose MMF (0.5 to 1 g/day) combined with glucocorticoids appears to be a safe and effective therapy for lupus nephritis in Taiwanese patients. Our results suggest that lupus nephritis in Oriental patients might respond to lower doses of MMF than Caucasians.

PMID 20195879  Clin Rheumatol. 2010 Jul;29(7):771-5. doi: 10.1007/s100・・・
著者: Frédéric A Houssiau, Carlos Vasconcelos, David D'Cruz, Gian Domenico Sebastiani, Enrique de Ramon Garrido, Maria Giovanna Danieli, Daniel Abramovicz, Daniel Blockmans, Alessandro Mathieu, Haner Direskeneli, Mauro Galeazzi, Ahmet Gül, Yair Levy, Peter Petera, Rajko Popovic, Radmila Petrovic, Renato Alberto Sinico, Roberto Cattaneo, Josep Font, Geneviève Depresseux, Jean-Pierre Cosyns, Ricard Cervera
雑誌名: Arthritis Rheum. 2004 Dec;50(12):3934-40. doi: 10.1002/art.20666.
Abstract/Text OBJECTIVE: In the Euro-Lupus Nephritis Trial (ELNT), 90 patients with lupus nephritis were randomly assigned to a high-dose intravenous cyclophosphamide (IV CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or a low-dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks), each of which was followed by azathioprine (AZA). After a median followup of 41 months, a difference in efficacy between the 2 regimens was not observed. The present analysis was undertaken to extend the followup and to identify prognostic factors.
METHODS: Renal function was prospectively assessed quarterly in all 90 patients except 5 who were lost to followup. Survival curves were derived using the Kaplan-Meier method.
RESULTS: After a median followup of 73 months, there was no significant difference in the cumulative probability of end-stage renal disease or doubling of the serum creatinine level in patients who received the low-dose IV CYC regimen versus those who received the high-dose regimen. At long-term followup, 18 patients (8 receiving low-dose and 10 receiving high-dose treatment) had developed permanent renal impairment and were classified as having poor long-term renal outcome. We demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 g/24 hours) was the best predictor of good long-term renal outcome.
CONCLUSION: Long-term followup of patients from the ELNT confirms that, in lupus nephritis, a remission-inducing regimen of low-dose IV CYC followed by AZA achieves clinical results comparable with those obtained with a high-dose regimen. Early response to therapy is predictive of good long-term renal outcome.

PMID 15593207  Arthritis Rheum. 2004 Dec;50(12):3934-40. doi: 10.1002/・・・
著者: Farah Tamirou, David D'Cruz, Shirish Sangle, Philippe Remy, Carlos Vasconcelos, Christoph Fiehn, Maria del Mar Ayala Guttierez, Inge-Magrethe Gilboe, Maria Tektonidou, Daniel Blockmans, Isabelle Ravelingien, Véronique le Guern, Geneviève Depresseux, Loïc Guillevin, Ricard Cervera, Frédéric A Houssiau, MAINTAIN Nephritis Trial Group
雑誌名: Ann Rheum Dis. 2016 Mar;75(3):526-31. doi: 10.1136/annrheumdis-2014-206897. Epub 2015 Mar 10.
Abstract/Text OBJECTIVE: To report the 10-year follow-up of the MAINTAIN Nephritis Trial comparing azathioprine (AZA) and mycophenolate mofetil (MMF) as maintenance therapy of proliferative lupus nephritis, and to test different definitions of early response as predictors of long-term renal outcome.
METHODS: In 2014, data on survival, kidney function, 24 h proteinuria, renal flares and other outcomes were collected for the 105 patients randomised between 2002 and 2006, except in 13 lost to follow-up.
RESULTS: Death (2 and 3 in the AZA and MMF groups, respectively) and end-stage renal disease (1 and 3, respectively) were rare events. Time to renal flare (22 and 19 flares in AZA and MMF groups, respectively) did not differ between AZA and MMF patients. Patients with good long-term renal outcome had a much more stringent early decrease of 24 h proteinuria compared with patients with poor outcome. The positive predictive value of a 24 h proteinuria <0.5 g/day at 3 months, 6 months and 12 months for a good long-term renal outcome was excellent (between 89% and 92%). Inclusion of renal function and urinalysis in the early response criteria did not impact the value of early proteinuria decrease as long-term prognostic marker.
CONCLUSIONS: The long-term follow-up data of the MAINTAIN Nephritis Trial do not indicate that MMF is superior to AZA as maintenance therapy in a Caucasian population suffering from proliferative lupus nephritis. Moreover, we confirm the excellent positive predictive value of an early proteinuria decrease for long-term renal outcome.
TRIAL REGISTRATION NUMBER: NCT00204022.

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 25757867  Ann Rheum Dis. 2016 Mar;75(3):526-31. doi: 10.1136/annr・・・
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: Chi Chiu Mok, King Yee Ying, Cheuk Wan Yim, Yui Pong Siu, Ka Hang Tong, Chi Hung To, Woon Leung Ng
雑誌名: Ann Rheum Dis. 2016 Jan;75(1):30-6. doi: 10.1136/annrheumdis-2014-206456. Epub 2014 Dec 30.
Abstract/Text OBJECTIVE: To compare the efficacy of tacrolimus (TAC) and mycophenolate mofetil (MMF) for the initial therapy of lupus nephritis (LN).
STUDY DESIGN: This is an open randomised controlled parallel group study.
METHODS: Adult patients with biopsy-confirmed active LN (class III/IV/V) were randomised to receive prednisolone (0.6 mg/kg/day for 6 weeks and tapered) in combination with either TAC (0.06-0.1 mg/kg/day) or MMF (2-3 g/day) for 6 months. Good responders were shifted to azathioprine for maintenance. The primary outcome was the rate of complete renal response (CR) at 6 months and the secondary outcomes included partial renal response, renal flares and decline of renal function over time.
RESULTS: 150 patients (92% women; aged 35.5±12.8 years; 81% class III/IV) were randomised (76 MMF, 74 TAC). At month 6, the rate of CR was 59% in the MMF and 62% in the TAC group (treatment difference: 3.0% (-12%, 18%); p=0.71). Major infective episodes occurred in 9.2% patients treated with MMF and in 5.4% patients treated with TAC (p=0.53). Maintenance therapy with azathioprine was given to 79% patients. After 60.8±26 months, proteinuric and nephritic renal flares developed in 24% and 18% of patients in the MMF group and 35% (p=0.12) and 27% (p=0.21) in the TAC group, respectively. The cumulative incidence of a composite outcome of decline of creatinine clearance by ≥30%, development of chronic kidney disease stage 4/5 or death was 21% in the MMF and 22% in the TAC group of patients (p=0.35).
CONCLUSIONS: TAC is non-inferior to MMF, when combined with prednisolone, for induction therapy of active LN. With azathioprine maintenance for 5 years, a non-significant trend of higher incidence of renal flares and renal function decline is observed with the TAC regimen.
TRIAL REGISTRATION NUMBER: Hospital Authority Research Ethics Committee Clinical Trial Registry (HARECCTR0500018; Hong Kong) and US ClinicalTrials.gov (NCT00371319).

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 25550339  Ann Rheum Dis. 2016 Jan;75(1):30-6. doi: 10.1136/annrhe・・・
著者: Mary Anne Dooley, David Jayne, Ellen M Ginzler, David Isenberg, Nancy J Olsen, David Wofsy, Frank Eitner, Gerald B Appel, Gabriel Contreras, Laura Lisk, Neil Solomons, ALMS Group
雑誌名: N Engl J Med. 2011 Nov 17;365(20):1886-95. doi: 10.1056/NEJMoa1014460.
Abstract/Text BACKGROUND: Maintenance therapy, often with azathioprine or mycophenolate mofetil, is required to consolidate remission and prevent relapse after the initial control of lupus nephritis.
METHODS: We carried out a 36-month, randomized, double-blind, double-dummy, phase 3 study comparing oral mycophenolate mofetil (2 g per day) and oral azathioprine (2 mg per kilogram of body weight per day), plus placebo in each group, in patients who met response criteria during a 6-month induction trial. The study group underwent repeat randomization in a 1:1 ratio. Up to 10 mg of prednisone per day or its equivalent was permitted. The primary efficacy end point was the time to treatment failure, which was defined as death, end-stage renal disease, doubling of the serum creatinine level, renal flare, or rescue therapy for lupus nephritis. Secondary assessments included the time to the individual components of treatment failure and adverse events.
RESULTS: A total of 227 patients were randomly assigned to maintenance treatment (116 to mycophenolate mofetil and 111 to azathioprine). Mycophenolate mofetil was superior to azathioprine with respect to the primary end point, time to treatment failure (hazard ratio, 0.44; 95% confidence interval, 0.25 to 0.77; P = 0.003), and with respect to time to renal flare and time to rescue therapy (hazard ratio, <1.00; P < 0.05). Observed rates of treatment failure were 16.4% (19 of 116 patients) in the mycophenolate mofetil group and 32.4% (36 of 111) in the azathioprine group. Adverse events, most commonly minor infections and gastrointestinal disorders, occurred in more than 95% of the patients in both groups (P = 0.68). Serious adverse events occurred in 33.3% of patients in the azathioprine group and in 23.5% of those in the mycophenolate mofetil group (P = 0.11), and the rate of withdrawal due to adverse events was higher with azathioprine than with mycophenolate mofetil (39.6% vs. 25.2%, P = 0.02).
CONCLUSIONS: Mycophenolate mofetil was superior to azathioprine in maintaining a renal response to treatment and in preventing relapse in patients with lupus nephritis who had a response to induction therapy. (Funded by Vifor Pharma [formerly Aspreva]; ALMS ClinicalTrials.gov number, NCT00377637.).

PMID 22087680  N Engl J Med. 2011 Nov 17;365(20):1886-95. doi: 10.1056・・・
著者: Frédéric A Houssiau, David D'Cruz, Shirish Sangle, Philippe Remy, Carlos Vasconcelos, Radmila Petrovic, Christoph Fiehn, Enrique de Ramon Garrido, Inge-Magrethe Gilboe, Maria Tektonidou, Daniel Blockmans, Isabelle Ravelingien, Véronique le Guern, Geneviève Depresseux, Loïc Guillevin, Ricard Cervera, MAINTAIN Nephritis Trial Group
雑誌名: Ann Rheum Dis. 2010 Dec;69(12):2083-9. doi: 10.1136/ard.2010.131995. Epub 2010 Sep 10.
Abstract/Text BACKGROUND: Long-term immunosuppressive treatment does not efficiently prevent relapses of lupus nephritis (LN). This investigator-initiated randomised trial tested whether mycophenolate mofetil (MMF) was superior to azathioprine (AZA) as maintenance treatment.
METHODS: A total of 105 patients with lupus with proliferative LN were included. All received three daily intravenous pulses of 750 mg methylprednisolone, followed by oral glucocorticoids and six fortnightly cyclophosphamide intravenous pulses of 500 mg. Based on randomisation performed at baseline, AZA (target dose: 2 mg/kg/day) or MMF (target dose: 2 g/day) was given at week 12. Analyses were by intent to treat. Time to renal flare was the primary end point. Mean (SD) follow-up of the intent-to-treat population was 48 (14) months.
RESULTS: The baseline clinical, biological and pathological characteristics of patients allocated to AZA or MMF did not differ. Renal flares were observed in 13 (25%) AZA-treated and 10 (19%) MMF-treated patients. Time to renal flare, to severe systemic flare, to benign flare and to renal remission did not statistically differ. Over a 3-year period, 24 h proteinuria, serum creatinine, serum albumin, serum C3, haemoglobin and global disease activity scores improved similarly in both groups. Doubling of serum creatinine occurred in four AZA-treated and three MMF-treated patients. Adverse events did not differ between the groups except for haematological cytopenias, which were statistically more frequent in the AZA group (p=0.03) but led only one patient to drop out.
CONCLUSIONS: Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance.

PMID 20833738  Ann Rheum Dis. 2010 Dec;69(12):2083-9. doi: 10.1136/ard・・・
著者: Howard A Austin, Gabor G Illei, Michelle J Braun, James E Balow
雑誌名: J Am Soc Nephrol. 2009 Apr;20(4):901-11. doi: 10.1681/ASN.2008060665. Epub 2009 Mar 18.
Abstract/Text Patients with lupus membranous nephropathy (LMN) are at substantial long-term risk for morbidity and mortality associated with protracted nephrotic syndrome, including ESRD. The optimal treatment for this condition is controversial. Forty-two patients with LMN participated in a randomized, controlled trial to compare adjunctive immunosuppressive drugs with prednisone alone. Adjunctive regimens included either cyclosporine (CsA) for 11 mo or alternate-month intravenous pulse cyclophosphamide (IVCY) for six doses; the control group received alternate-day prednisone alone. Median proteinuria was 5.4 g/d (range 2.7 to 15.4 g/d). We assessed the primary outcome, time to remission of proteinuria during the 12-mo protocol, by univariate survival analysis. At 1 yr, the cumulative probability of remission was 27% with prednisone, 60% with IVCY, and 83% with CsA. Although both IVCY and CsA were more effective than prednisone in inducing remissions of proteinuria, relapse of nephrotic syndrome occurred significantly more often after completion of CsA than after IVCY. By multivariate survival analysis, treatment with prednisone and high-grade proteinuria (>5 g/d) but not race or ethnicity were independently associated with a decreased probability of remission. Adverse effects during the 12-mo protocol included insulin-requiring diabetes (one with prednisone and two with CsA), pneumonia (one with prednisone and two with CsA), and localized herpes zoster (two with IVCY). In conclusion, regimens containing CsA or IVCY are each more effective than prednisone alone in inducing remission of proteinuria among patients with LMN.

PMID 19297556  J Am Soc Nephrol. 2009 Apr;20(4):901-11. doi: 10.1681/A・・・
著者: Jai Radhakrishnan, Dimitrios-Anestis Moutzouris, Ellen M Ginzler, Neil Solomons, Ilias I Siempos, Gerald B Appel
雑誌名: Kidney Int. 2010 Jan;77(2):152-60. doi: 10.1038/ki.2009.412. Epub 2009 Nov 4.
Abstract/Text Class V lupus nephritis (LN) occurs in one-fifth of biopsy-proven cases of systemic lupus erythematosus. To study the effectiveness of treatments in this group of patients, we pooled analysis of two large randomized controlled multicenter trials of patients with diverse ethnic and racial background who had pure class V disease. These patients received mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) as induction therapy for 24 weeks, with percentage change in proteinuria and serum creatinine as end points. Weighted mean differences, pooled odds ratios, and confidence intervals were calculated by using a random-effects model. A total of 84 patients with class V disease were divided into equal groups, each group had comparable entry variables but one received MMF and one received IVC. Within these groups, 33 patients on MMF and 32 patients on IVC completed 24 weeks of treatment. There were no differences between the groups in mean values for the measured end points. Similarly, no difference was found regarding the number of patients who did not complete the study or who died. In patients with nephrotic syndrome, no difference was noted between those treated with MMF and IVC regarding partial remission or change in urine protein. Hence we found that the response to MMF as induction treatment of patients with class V LN appears to be no different from that to IVC.

PMID 19890271  Kidney Int. 2010 Jan;77(2):152-60. doi: 10.1038/ki.2009・・・
著者: Desmond Y H Yap, Xueqing Yu, Xiang-Mei Chen, Fuming Lu, Nan Chen, Xue-Wang Li, Colin So Tang, Tak Mao Chan
雑誌名: Nephrology (Carlton). 2012 May;17(4):352-7. doi: 10.1111/j.1440-1797.2012.01574.x.
Abstract/Text AIM: This pilot study compared mycophenolate mofetil (MMF) and tacrolimus (Tac) in the treatment of severe membranous lupus nephritis (MLN).
METHOD: This was a 24 month prospective, randomized, open-label multi-centre exploratory study on Chinese patients with biopsy-proven pure Class V MLN with nephrotic syndrome. Patients were randomized to treatment with either MMF or Tac, both in combination with prednisolone and the efficacy and tolerability outcomes were examined.
RESULTS: Sixteen patients were included, seven in the MMF and nine in the Tac treatment arm. At 24 months the complete response, partial response and overall response rates were 57.1% vs. 11.1% (P = 0.049), 14.3% vs. 44.4% (P = 0.197) and 71.4% vs. 55.6% (P = 0.515) in the MMF and Tac groups, respectively. The two groups had similar reduction of proteinuria and longitudinal profiles of serum albumin and creatinine levels. Serum creatinine remained stable in both groups, except in two patients who had a transient increase associated with high Tac blood levels. Adverse events in the MMF group included herpes zoster in one patient and reversible leucopenia in another, while in the Tac group four patients had severe infections and one developed new onset diabetes. No relapse occurred during the study period.
CONCLUSION: Both MMF and Tac when combined with corticosteroids are effective treatment options for severe MLN.

© 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.
PMID 22295934  Nephrology (Carlton). 2012 May;17(4):352-7. doi: 10.111・・・
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: H Kanda, K Kubo, S Tateishi, K Sato, A Yonezumi, K Yamamoto, T Mimura
雑誌名: Lupus. 2005;14(4):288-92.
Abstract/Text Recent immunosuppressive treatments for lupus nephritis have improved renal survival rate, however, there still exists lupus nephritis refractory to these treatments. Angiotensin receptor blockers (ARBs) are known not only to decrease blood pressure but also to have an independent renoprotecting effect by interrupting renin-angiotensin system. The aim of this study was to evaluate whether ARBs have an additive effect on refractory lupus nephritis. Enrolled in this trial were twelve patients with lupus nephritis who were diagnosed by renal biopsy and remained proteinuria despite corticosteroids and/or immunosuppressive treatments. ARB, losartan or candesartan, was administered for six months. Various clinical parameters were compared before and after ARB administration. Proteinuria decreased after ARB treatment in 83% of the patients and the median amount of proteinuria significantly decreased from 2530 mg/g Cr to 459 mg/g Cr (P = 0.03). In addition, serum albumin and cholesterol levels were significantly improved. Systolic blood pressure significantly decreased, but none had symptoms of hypotension. The antiproteinuric effect of ARB did not correlate with the reduction of blood pressure. Interestingly, higher total complement activity levels before ARB treatment were associated with a greater reduction of proteinuria. The addition of ARB would be a safe and effective treatment for lupus nephritis with persistent proteinuria despite corticosteroids and/or immunosuppressive treatments.

PMID 15864915  Lupus. 2005;14(4):288-92.
著者: K C Tse, F K Li, S Tang, C S-O Tang, K N Lai, T M Chan
雑誌名: Lupus. 2005;14(12):947-52.
Abstract/Text Angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) reduces proteinuria and the rate of renal function deterioration in diabetic nephropathy and other glomerular diseases, but its role in quiescent lupus nephritis has not been established. We conducted a retrospective study to investigate the effects of ACEI/ARB on proteinuria and renal function in patients with persistent proteinuria (>1 g/day) despite resolution of acute lupus nephritis following immunosuppressive treatment. Fourteen out of 92 patients were included. The duration of treatment with ACEI/ARB was 52.1 +/- 35.7 months. The levels of proteinuria, serum albumin, serum creatinine, systolic and diastolic blood pressure were 1.10 to 6.90 g/day, 35.8 +/- 3.6 g/L, 102.54 +/- 34.48 micromol/L, 137.6 +/- 10.9 and 81.9 +/- 9.2 mmHg at baseline. Proteinuria and serum albumin showed significant sustained improvements after 6 and 24 months of treatment. Comparison of slopes for serial proteinuria, albumin and reciprocal of serum creatinine before and after treatment showed significant improvements in six (43%), eight (57%) and two patients, respectively. At last follow-up proteinuria remained significantly lower (0.36 g/day, P = 0.043) and albumin higher (41.3 +/- 2.2 g/L, P = 0.023). Eleven (78.6%) patients had proteinuria improved by >50%, and five had insignificant proteinuria at last follow-up. Systolic blood pressure was significantly reduced from 6 months onwards, but this did not correlate with proteinuria reduction. Diastolic blood pressure, serum creatinine, creatinine clearance, anti-dsDNA, C3 and haemoglobin were not altered. We conclude that ACEI/ARB effectively reduces proteinuria and improves serum albumin in patients with persistent proteinuria despite quiescent lupus nephritis.

PMID 16425574  Lupus. 2005;14(12):947-52.
著者: S Durán-Barragán, G McGwin, L M Vilá, J D Reveille, G S Alarcón, LUMINA (LIX): a multiethnic US cohort
雑誌名: Rheumatology (Oxford). 2008 Jul;47(7):1093-6. doi: 10.1093/rheumatology/ken208. Epub 2008 May 29.
Abstract/Text OBJECTIVE: To examine if angiotensin-converting enzyme (ACE) inhibitor use delays the occurrence of renal involvement and decreases the risk of disease activity in SLE patients.
METHODS: SLE patients (Hispanics, African Americans and Caucasians) from the lupus in minorities: nature vs nurture (LUMINA) cohort were studied. Renal involvement was defined as ACR criterion and/or biopsy-proven lupus nephritis. Time-to-renal involvement was examined by univariable and multivariable Cox proportional hazards regression analyses. Disease activity was examined with a case-crossover design and a conditional logistic regression model; in the case intervals, a decrease in the SLAM-R score >or=4 points occurred but not in the control intervals.
RESULTS: Eighty of 378 patients (21%) were ACE inhibitor users; 298 (79%) were not. The probability of renal involvement free-survival at 10 yrs was 88.1% for users and 75.4% for non-users (P = 0.0099, log rank test). Users developed persistent proteinuria and/or biopsy-proven lupus nephritis (7.1%) less frequently than non-users (22.9%), P = 0.016. By multivariable Cox proportional hazards regression analyses, ACE inhibitors use [hazard ratio (HR) 0.27; 95% CI 0.09, 0.78] was associated with a longer time-to-renal involvement occurrence whereas African American ethnicity (HR 3.31; 95% CI 1.44, 7.61) was with a shorter time. ACE inhibitor use (54/288 case and 254/1148 control intervals) was also associated with a decreased risk of disease activity (HR 0.56; 95% CI 0.34, 0.94).
CONCLUSIONS: ACE inhibitor use delays the development of renal involvement and associates with a decreased risk of disease activity in SLE; corroboration of these findings in other lupus cohorts is desirable before practice recommendations are formulated.

PMID 18511474  Rheumatology (Oxford). 2008 Jul;47(7):1093-6. doi: 10.1・・・
著者: Maria G Tektonidou, Flora Sotsiou, Lidia Nakopoulou, Panayiotis G Vlachoyiannopoulos, Haralampos M Moutsopoulos
雑誌名: Arthritis Rheum. 2004 Aug;50(8):2569-79. doi: 10.1002/art.20433.
Abstract/Text OBJECTIVE: To evaluate the prevalence, clinical associations, and outcome of antiphospholipid syndrome (APS) nephropathy in patients with systemic lupus erythematosus (SLE) and antiphospholipid antibodies (aPL) and in SLE patients without aPL.
METHODS: Kidney biopsy specimens obtained from 81 patients with aPL (18 of whom had APS) and 70 patients without aPL were retrospectively examined for the presence of APS nephropathy. Clinical and serologic data obtained at the time of kidney biopsy and during a mean followup of 7 years were recorded. In cases for which serial kidney biopsy specimens were available, the evolution of APS nephropathy was examined.
RESULTS: APS nephropathy existed in 39.5% of patients with aPL, compared with only 4.3% of patients without aPL. APS nephropathy was associated with both lupus anticoagulant and anticardiolipin antibodies. Among aPL-positive SLE patients, APS nephropathy was found in two-thirds of those with APS and in one-third of those without APS. A strong association between APS nephropathy and the presence of arterial thrombosis and livedo reticularis was noted. Patients with APS nephropathy had a higher frequency of hypertension and elevated serum creatinine levels at the time of kidney biopsy but did not have a higher frequency of renal insufficiency, end-stage renal disease, or death at the end of followup. Serial kidney biopsy specimens were available from 11 patients and showed progression of APS nephropathy lesions. During followup, manifestations of APS (especially arterial thromboses) developed more frequently in the SLE/non-APS patients with APS nephropathy than in those without APS nephropathy.
CONCLUSION: Among patients with SLE, APS nephropathy occurs almost exclusively in those with aPL, suggesting an important role of aPL in the pathogenesis of APS nephropathy. Patients with APS nephropathy develop hypertension, raised serum creatinine levels, and progression of histologic lesions, all of which are associated with a poor renal outcome. Manifestations of APS also tend to develop in these patients. APS nephropathy should be included in the APS classification criteria, and the use of appropriate anticoagulant therapy should be tested.

PMID 15334471  Arthritis Rheum. 2004 Aug;50(8):2569-79. doi: 10.1002/a・・・
著者: Hui Zheng, Yi Chen, Wen Ao, Yan Shen, Xiao-wei Chen, Min Dai, Xiao-dong Wang, Yu-cheng Yan, Cheng-de Yang
雑誌名: Arthritis Res Ther. 2009;11(3):R93. doi: 10.1186/ar2736. Epub 2009 Jun 22.
Abstract/Text INTRODUCTION: Glomerular microthrombosis (GMT) is a common vascular change in patients with lupus nephritis (LN). The mechanism underlying GMT is largely unknown. Although several studies have reported the association of antiphospholipid antibodies (aPL) with GMT, the relation between GMT and aPL remains controversial. Previous studies have demonstrated that some aPL could bind to several hemostatic and fibrinolytic proteases that share homologous enzymatic domains. Of the protease-reactive aPL, some can inhibit the anticoagulant activity of activated protein C and the fibrinolytic function of plasmin, and hinder the antithrombin inactivation of thrombin. The purpose of this study was to investigate the prevalence of GMT in LN patients and examine the relation between the aPL profiles (including some protease-reactive aPL) and GMT.
METHODS: Renal biopsy specimens were examined for the presence of glomerular microthrombi. Plasma samples from 25 LN patients with GMT (LN-GMT group) and 99 LN patients without GMT (LN-non-GMT group) were tested for lupus anticoagulant and antibodies against cardiolipin, beta2 glycoprotein I, plasmin, thrombin, tissue plasminogen activator, and annexin II.
RESULTS: The prevalence of GMT in LN patients was 20.2%. Compared with the LN-non-GMT group, the LN-GMT group had an elevated systemic lupus erythematosus disease activity index; elevated renal tissue injury activity and chronicity indices; elevated serum creatinine, blood urea nitrogen, and proteinuria levels; a lower serum C3 level and much intense glomerular C3, C1q staining; and a higher frequency of hypertension (P < 0.05 for all). Additionally, the detection rate of lupus anticoagulant, immunoglobulin G (IgG) anti-beta2 glycoprotein I and anti-thrombin antibodies were higher in the LN-GMT group than in the LN-non-GMT group (P < 0.05 for all). No statistical differences were found in the detection rates of IgG anti-cardiolipin, plasmin, tissue plasminogen activator, or annexin II antibodies (P > 0.05 for all). No detectable difference in IgM autoantibodies to the above antigens was observed between the two groups.
CONCLUSIONS: GMT occurs in approximately 20.2% of LN patients. Patients with GMT have severer renal tissue injuries and poorer renal functions than patients without GMT. The lupus anticoagulant and antibodies against beta2 glycoprotein I and thrombin may play a role in GMT.

PMID 19545416  Arthritis Res Ther. 2009;11(3):R93. doi: 10.1186/ar2736・・・
著者: J M Esdaile, M Abrahamowicz, T Grodzicky, Y Li, C Panaritis, R du Berger, R Côte, S A Grover, P R Fortin, A E Clarke, J L Senécal
雑誌名: Arthritis Rheum. 2001 Oct;44(10):2331-7. doi: 10.1002/1529-0131(200110)44:10<2331::aid-art395>3.0.co;2-i.
Abstract/Text OBJECTIVE: The frequency of coronary heart disease (CHD) and stroke are increased in systemic lupus erythematosus (SLE), but the extent of the increase is uncertain. We sought to determine to what extent the increase could not be explained by common risk factors.
METHODS: The participants at two SLE registries were assessed retrospectively for the baseline level of the Framingham study risk factors and for the presence of vascular outcomes: nonfatal myocardial infarction (MI), death due to CHD, overall CHD (nonfatal MI, death due to CHD, angina pectoris, and congestive heart failure due to CHD), and stroke. For each patient, the probability of the given outcome was estimated based on the individual's risk profile and the Framingham multiple logistic regression model, corrected for observed followup. Ninety-five percent confidence intervals (95% CIs) were estimated by bootstrap techniques.
RESULTS: Of 296 SLE patients, 33 with a vascular event prior to baseline were excluded. Of the 263 remaining patients, 34 had CHD events (17 nonfatal MIs, 12 CHD deaths) and 16 had strokes over a mean followup period of 8.6 years. After controlling for common risk factors at baseline, the increase in relative risk for these outcomes was 10.1 for nonfatal MI (95% CI 5.8-15.6), 17.0 for death due to CHD (95% CI 8.1-29.7), 7.5 for overall CHD (95% CI 5.1-10.4), and 7.9 for stroke (95% CI 4.0-13.6).
CONCLUSION: There is a substantial and statistically significant increase in CHD and stroke in SLE that cannot be fully explained by traditional Framingham risk factors alone.

PMID 11665973  Arthritis Rheum. 2001 Oct;44(10):2331-7. doi: 10.1002/1・・・
著者:
雑誌名: Kidney Int Suppl (2011). 2012 Jun;2(2):156-162. doi: 10.1038/kisup.2012.15.
Abstract/Text
PMID 25018928  Kidney Int Suppl (2011). 2012 Jun;2(2):156-162. doi: 10・・・
著者: Dafna D Gladman, Anu Tandon, Dominique Ibañez, Murray B Urowitz
雑誌名: J Rheumatol. 2010 Apr;37(4):754-8. doi: 10.3899/jrheum.090872. Epub 2010 Mar 15.
Abstract/Text OBJECTIVE: To evaluate the effect of lupus nephritis on pregnancy with respect to fetal outcome, maternal complications, and lupus activity.
METHODS: All pregnancies seen between 1970 and 2003 in the Lupus Clinic were evaluated for the 3 outcomes. Renal disease was defined as the presence of nephrotic syndrome, dialysis, renal transplant, serum creatinine > 120 mmol/l, proteinuria, sterile hematuria and pyuria, or the presence of casts. Fetal complications were evaluated in pregnancies resulting in either live births or stillbirths. Generalized estimating equations were used to test for differences in outcomes between pregnancies with and without the presence of active renal disease. Repeated measures adjustments were made in the model for multiple pregnancies in the same mother.
RESULTS: There were 193 pregnancies in 104 women. Of these, 81 occurred in the presence of active renal disease during the study period, defined as 6 months prior to conception until the date of pregnancy outcome. One hundred twelve pregnancies were defined as nonrenal. No statistical difference was found in pregnancy outcome. Fetal complications were not different between the 2 groups with the exception of low birth weight and congenital malformations, which were observed more frequently in the renal group. Pregnancy-induced hypertension was more frequent in pregnancies with renal disease. Lupus flares were also more likely to occur in pregnancies with renal disease compared to those without.
CONCLUSION: Lupus nephritis in pregnancy does not lead to worsened pregnancy or fetal outcomes. Active renal disease, however, is associated with pregnancy-induced hypertension, as well as a flare of lupus activity during pregnancy.

PMID 20231194  J Rheumatol. 2010 Apr;37(4):754-8. doi: 10.3899/jrheum.・・・
著者: S J Wagner, I Craici, D Reed, S Norby, K Bailey, H J Wiste, C M Wood, K G Moder, K P Liang, K V Liang, C Rose, T Rozkos, M Sitina, J P Grande, V D Garovic
雑誌名: Lupus. 2009 Apr;18(4):342-7. doi: 10.1177/0961203308097575.
Abstract/Text The objective of this study was to determine the impact of lupus nephritis disease activity on maternal and foetal outcomes in pregnant patients with systemic lupus erythematosus (SLE). Medical records of all pregnant patients with SLE treated at our institution between 1976 and 2007 were reviewed. All patients met American College of Rheumatology classification criteria for SLE. Demographic data, history of lupus nephritis, nephritis disease activity and maternal and foetal outcomes of pregnancy were abstracted. Active lupus nephritis was defined as the presence of proteinuria >0.5 g/day and/or active urinary sediment with or without an elevation in serum creatinine (Cr). Quiescent lupus nephritis was confirmed in the presence of proteinuria <0.5 mg/day and inactive urinary sediment. We identified 58 patients with 90 pregnancies. Compared with pregnancies in SLE patients without renal involvement (n = 47), pregnancies in patients with active lupus nephritis (n = 23) were associated with a higher incidence of maternal complications (57% vs 11%, P < 0.001), whereas those with quiescent lupus nephritis (n = 20) were not (35% vs 11%, P = 0.10). Women with active lupus nephritis were more likely to deliver preterm than women without lupus nephritis, median of 34 weeks vs 40 gestational weeks, respectively (P = 0.002) and were more likely to suffer foetal loss (35% vs 9%, P = 0.031). Active, but not quiescent, lupus nephritis during pregnancy is associated with a higher incidence of maternal and foetal complications compared with pregnancies in SLE patients without renal involvement.

PMID 19276302  Lupus. 2009 Apr;18(4):342-7. doi: 10.1177/0961203308097・・・
著者: Enrico Imbasciati, Angela Tincani, Gina Gregorini, Andrea Doria, Gabriella Moroni, Gianfranca Cabiddu, Daniele Marcelli
雑誌名: Nephrol Dial Transplant. 2009 Feb;24(2):519-25. doi: 10.1093/ndt/gfn348. Epub 2008 Jun 18.
Abstract/Text BACKGROUND: Only few data are available on pregnancy in patients with lupus nephritis (LN) diagnosed before conception. The aim of this study was to identify the risk factors for complicated pregnancy in women with pre-existing LN.
METHODS: In a multicentre study, we collected data on 113 pregnancies occurring in 81 women with pre-existing biopsy-proven LN. Primary outcomes were fetal loss including perinatal death and renal flares during and 12 months after pregnancy. Univariate and logistic regression analyses were used to identify predictors of outcomes.
RESULTS: Renal biopsy performed 7.2 +/- 4.9 years before pregnancy showed the following WHO classes: 6 patients in II, 8 in III, 48 in IV and 19 in V. At conception, most patients were in complete (49%) or partial (27%) remission. There were nine spontaneous abortions, one stillbirth and five neonatal deaths. Thirty-one deliveries were preterm. Birth weight was <2500 g in 34 newborns. During pregnancy or after delivery, there were 34 renal flares, most of which (20) were reversible. Three patients had a progressive decline of glomerular filtration rate (one on dialysis). At logistic regression analysis, the pregnancy outcome was predicted by hypocomplementaemia at conception (RR 19.02; 90% CI 4.58-78.96) and aspirin during pregnancy (RR 0.11; 90% CI 0.03-0.38). Renal flare was predicted by renal status (partial remission RR 3.0; 90% CI 1.23-7.34, nonremission RR 9.0; 90% CI 3.59-22.57).
CONCLUSIONS: Pregnancy can be successful in most women with pre-existing LN, even for those with a severe renal involvement at onset. Renal flares during and after pregnancy are not uncommon and can be predicted by renal status assessed before pregnancy. Normocomplementaemia and low-dose aspirin therapy during pregnancy are independent predictors of a favourable fetal outcome.

PMID 18565977  Nephrol Dial Transplant. 2009 Feb;24(2):519-25. doi: 10・・・
著者: L Andreoli, G K Bertsias, N Agmon-Levin, S Brown, R Cervera, N Costedoat-Chalumeau, A Doria, R Fischer-Betz, F Forger, M F Moraes-Fontes, M Khamashta, J King, A Lojacono, F Marchiori, P L Meroni, M Mosca, M Motta, M Ostensen, C Pamfil, L Raio, M Schneider, E Svenungsson, M Tektonidou, S Yavuz, D Boumpas, A Tincani
雑誌名: Ann Rheum Dis. 2017 Mar;76(3):476-485. doi: 10.1136/annrheumdis-2016-209770. Epub 2016 Jul 25.
Abstract/Text OBJECTIVES: Develop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS).
METHODS: Systematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus.
RESULTS: Family planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease.
CONCLUSIONS: Recommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

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 27457513  Ann Rheum Dis. 2017 Mar;76(3):476-485. doi: 10.1136/ann・・・
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: E J Lewis, L G Hunsicker, S P Lan, R D Rohde, J M Lachin
雑誌名: N Engl J Med. 1992 May 21;326(21):1373-9. doi: 10.1056/NEJM199205213262101.
Abstract/Text BACKGROUND: The prognosis of patients with systemic lupus erythematosus who have glomerulonephritis is poor, despite treatment with immunosuppressive therapy. Plasmapheresis therapy has been used, but there have been few controlled clinical observations of its efficacy.
METHODS: We carried out a randomized, controlled trial comparing a standard-therapy regimen of prednisone and cyclophosphamide (standard therapy) with a regimen of standard therapy plus plasmapheresis in 86 patients with severe lupus nephritis in 14 medical centers. The patients underwent plasmapheresis three times weekly for four weeks. Drug therapy was standardized, with strict adherence to nine detailed medical-management protocols.
RESULTS: Forty-six patients received standard therapy, and 40 patients received standard therapy plus plasmapheresis. The mean follow-up was 136 weeks. Six patients (13 percent) in the standard-therapy group and eight patients (20 percent) in the plasmapheresis group died. Renal failure developed in 8 patients (17 percent) in the standard-therapy group, as compared with 10 (25 percent) in the plasmapheresis group. Thirty patients (35 percent) reached stopping points--14 (30 percent) in the standard-therapy group and 16 (40 percent) in the plasmapheresis group. A similar number of patients in each group had a decrease in both the serum creatinine concentration and urinary protein excretion to approximately normal values. Patients treated with plasmapheresis had a significantly more rapid reduction of serum concentrations of antibodies against double-stranded DNA and cryoglobulins.
CONCLUSIONS: Treatment with plasmapheresis plus a standard regimen of prednisone and cyclophosphamide therapy does not improve the clinical outcome in patients with systemic lupus erythematosus and severe nephritis, as compared with the standard regimen alone.

PMID 1569973  N Engl J Med. 1992 May 21;326(21):1373-9. doi: 10.1056/・・・

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