今日の臨床サポート

多発血管炎性肉芽腫症(旧名Wegener肉芽腫症):(膠原病科)

著者: 金子駿太 JCHO 東京山手メディカルセンター

監修: 金子礼志 国立国際医療研究センター 膠原病科

著者校正/監修レビュー済:2021/09/29
参考ガイドライン:
  1. 厚生労働科学研究費補助金 難治性疾患等政策研究事業(難治性疾患政策研究事業):ANCA関連血管炎診療ガイドライン2017
  1. 欧州リウマチ学会・欧州腎臓学会・欧州腎臓透析学会議:EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis 2015
患者向け説明資料

概要・推奨   

  1. 多発血管炎性肉芽腫症(granulomatosis with polyangiitis、GPA)患者ではANCAの陽性率は高い。腎症を伴う全身型の場合は80~90%で陽性である。また、頭頚部または肺のみに病変を認める限局型の場合は約60%で陽性である。したがって、GPAを疑う患者でのPR3-ANCA(c-ANCA)、MPO-ANCA(p-ANCA)測定は推奨される(推奨度1)。
  1. ANCA値の治療中のモニタリングは推奨される。ANCA上昇は血管炎再燃に先行することが多い。ただし、ANCA上昇を認めても血管炎が再燃しない症例も存在することから、ANCA上昇のみでは治療強化は行わない(推奨度1)。
  1. 初期治療のステロイドは1mg/kgで開始する。急速進行性糸球体腎炎や広範な肺病変を伴う場合は、導入時にステロイドパルス併用が推奨される。シクロホスファミドなどの免疫抑制薬の併用はほぼ必須である(推奨度1)。
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
  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
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:
金子駿太 : 未申告[2021年]
監修:金子礼志 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 上記ガイドラインを元に定期レビューを行い、主に治療について加筆修正した。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 多発血管炎性肉芽腫症とは、全身の血管炎と鼻と肺の肉芽腫、および壊死性半月体糸球体腎炎を示す疾患である。1939年にドイツの病理学者Wegenerが、全身の血管炎と鼻と肺の肉芽腫、および壊死性半月体糸球体腎炎を示した3剖検例を報告したためにウェゲナー肉芽腫症と呼ばれていたが、2011年granulomatosis with polyangiitis(GPA)と国際的には改称された。
  1. 発熱、体重減少などの全身症状とともに、①頭頚部の症状:膿性鼻漏、鼻出血、鞍鼻、中耳炎、視力低下、咽喉頭潰瘍など、②肺症状:血痰、呼吸困難など、③急速進行性腎炎、④その他:紫斑、多発関節痛、多発神経炎など――が生じる疾患である。通常、①→②→③の順序で起こることが多い。
  1. ①②③のすべての症状が揃っているときを全身型、いずれか2つの症状のみのときを限局型という。
  1. シクロホスファミド治療が導入されてから、血管炎のくすぶりと病巣の感染併発を繰り返し治癒は困難であるものの、予後は劇的に改善している。
  1. またGPAに難治性の中耳炎が合併することはよく知られているが、GPAを含めた顕微鏡的多発血管炎(microscopic polyangiitis、MPA)、好酸球性多発血管炎性肉芽腫症(eosinophilic granulomatosis with polyangiitis、EGPA)の診断基準に合致しないような、ANCA陽性を伴う難治性中耳炎が近年相次いで報告され、2012年の日本耳鼻科学会総会・学術講演会にて、ANCA関連血管炎性中耳炎(otitid media with ANCA associated vasculitis、OMAAV)という疾患概念が提唱された。
  1. GPAは、厚生労働省の難病に指定されており、2016年度は2,708人が登録されている。重症度分類3度以上を認める場合などでは、申請し認定されると保険料の自己負担分の一部が公費負担として助成される([平成27年1月施行])。
  1.  難病法に基づく医療費助成制度 
問診・診察のポイント  
  1. 上気道症状を確認する。

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文献 

著者: Javier D Finkielman, Augustine S Lee, Amber M Hummel, Margaret A Viss, Gregory L Jacob, Henry A Homburger, Tobias Peikert, Gary S Hoffman, Peter A Merkel, Robert Spiera, E William St Clair, John C Davis, W Joseph McCune, Andrea K Tibbs, Steven R Ytterberg, John H Stone, Ulrich Specks, WGET Research Group
雑誌名: Am J Med. 2007 Jul;120(7):643.e9-14. doi: 10.1016/j.amjmed.2006.08.016.
Abstract/Text BACKGROUND: The pathogenic significance of antineutrophilic cytoplasmic antibodies (ANCA) in Wegener's granulomatosis is controversial. Their presence is influenced by the extent, severity, and activity of the disease at the time of sampling. The objective of this study was to determine the frequency of ANCA in patients with active Wegener's granulomatosis and to assess the influence of disease severity on test results.
METHODS: Baseline serum samples from the 180 participants in a multicentric prospective trial were tested for ANCA by indirect immunofluorescence, direct enzyme-linked immunosorbent assay (ELISA), and capture ELISA. Disease activity was measured using the Birmingham Vasculitis Activity Score for Wegener's granulomatosis. All patients had active disease at enrollment. Patients were categorized as having severe (n=128) or limited (n=52) Wegener's granulomatosis.
RESULTS: When all ANCA detection methods were combined, 166 patients (92%) were ANCA positive, including 96% with severe disease and 83% with limited disease.
CONCLUSION: ANCA are detectable in nearly all patients with active severe Wegener's granulomatosis, but approximately 1 of 5 patients with active limited disease are ANCA negative. Immunofluorescence and both direct and capture ELISAs are required for optimal detection, suggesting that ANCA are not recognized equally well by all testing methods.

PMID 17602941  Am J Med. 2007 Jul;120(7):643.e9-14. doi: 10.1016/j.amj・・・
著者: G S Hoffman, U Specks
雑誌名: Arthritis Rheum. 1998 Sep;41(9):1521-37. doi: 10.1002/1529-0131(199809)41:9<1521::AID-ART2>3.0.CO;2-A.
Abstract/Text
PMID 9751084  Arthritis Rheum. 1998 Sep;41(9):1521-37. doi: 10.1002/1・・・
著者: Thomas F Hiemstra, Michael Walsh, Alfred Mahr, Caroline O Savage, Kirsten de Groot, Lorraine Harper, Thomas Hauser, Irmgard Neumann, Vladimir Tesar, Karl-Martin Wissing, Christian Pagnoux, Wilhelm Schmitt, David R W Jayne, European Vasculitis Study Group (EUVAS)
雑誌名: JAMA. 2010 Dec 1;304(21):2381-8. doi: 10.1001/jama.2010.1658. Epub 2010 Nov 8.
Abstract/Text CONTEXT: Current remission maintenance therapies for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are limited by partial efficacy and toxicity.
OBJECTIVE: To compare the effects of mycophenolate mofetil with azathioprine on the prevention of relapses in patients with AAV.
DESIGN, SETTING, AND PARTICIPANTS: Open-label randomized controlled trial, International Mycophenolate Mofetil Protocol to Reduce Outbreaks of Vasculitides (IMPROVE), to test the hypothesis that mycophenolate mofetil is more effective than azathioprine for preventing relapses in AAV. The trial was conducted at 42 centers in 11 European countries between April 2002 and January 2009 (42-month study). Eligible patients had newly diagnosed AAV (Wegener granulomatosis or microscopic polyangiitis) and were aged 18 to 75 years at diagnosis.
INTERVENTIONS: Patients were randomly assigned to azathioprine (starting at 2 mg/kg/d) or mycophenolate mofetil (starting at 2000 mg/d) after induction of remission with cyclophosphamide and prednisolone.
MAIN OUTCOME MEASURES: The primary end point was relapse-free survival, which was assessed using a Cox proportional hazards model. The secondary end points were Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria.
RESULTS: A total of 156 patients were assigned to azathioprine (n = 80) or mycophenolate mofetil (n = 76) and were followed up for a median of 39 months (interquartile range, 0.66-53.6 months). All patients were retained in the analysis by intention to treat. Relapses were more common in the mycophenolate mofetil group (42/76 patients) compared with the azathioprine group (30/80 patients), with an unadjusted hazard ratio (HR) for mycophenolate mofetil of 1.69 (95% confidence interval [CI], 1.06-2.70; P = .03). Severe adverse events did not differ significantly between groups. There were 22 severe adverse events in 13 patients (16%) in the azathioprine group and there were 8 severe adverse events in 8 patients (7.5%) in the mycophenolate mofetil group (HR, 0.53 [95% CI, 0.23-1.18]; P = .12). The secondary outcomes of Vasculitis Damage Index, estimated glomerular filtration rate, and proteinuria did not differ significantly between groups.
CONCLUSIONS: Among patients with AAV, mycophenolate mofetil was less effective than azathioprine for maintaining disease remission. Both treatments had similar adverse event rates.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00307645.

PMID 21060104  JAMA. 2010 Dec 1;304(21):2381-8. doi: 10.1001/jama.2010・・・
著者: C Mukhtyar, L Guillevin, M C Cid, B Dasgupta, K de Groot, W Gross, T Hauser, B Hellmich, D Jayne, C G M Kallenberg, P A Merkel, H Raspe, C Salvarani, D G I Scott, C Stegeman, R Watts, K Westman, J Witter, H Yazici, R Luqmani, European Vasculitis Study Group
雑誌名: Ann Rheum Dis. 2009 Mar;68(3):310-7. doi: 10.1136/ard.2008.088096. Epub 2008 Apr 15.
Abstract/Text OBJECTIVES: To develop European League Against Rheumatism (EULAR) recommendations for the management of small and medium vessel vasculitis.
METHODS: An expert group (consisting of 10 rheumatologists, 3 nephrologists, 2 immunologists, 2 internists representing 8 European countries and the USA, a clinical epidemiologist and a representative from a drug regulatory agency) identified 10 topics for a systematic literature search using a modified Delphi technique. In accordance with standardised EULAR operating procedures, recommendations were derived for the management of small and medium vessel vasculitis. In the absence of evidence, recommendations were formulated on the basis of a consensus opinion.
RESULTS: In all, 15 recommendations were made for the management of small and medium vessel vasculitis. The strength of recommendations was restricted by low quality of evidence and by EULAR standardised operating procedures.
CONCLUSIONS: On the basis of evidence and expert consensus, recommendations have been made for the evaluation, investigation, treatment and monitoring of patients with small and medium vessel vasculitis for use in everyday clinical practice.

PMID 18413444  Ann Rheum Dis. 2009 Mar;68(3):310-7. doi: 10.1136/ard.2・・・
著者: Michael Walsh, Peter A Merkel, Chen-Au Peh, Wladimir M Szpirt, Xavier Puéchal, Shouichi Fujimoto, Carmel M Hawley, Nader Khalidi, Oliver Floßmann, Ron Wald, Louis P Girard, Adeera Levin, Gina Gregorini, Lorraine Harper, William F Clark, Christian Pagnoux, Ulrich Specks, Lucy Smyth, Vladimir Tesar, Toshiko Ito-Ihara, Janak Rashme de Zoysa, Wojciech Szczeklik, Luis Felipe Flores-Suárez, Simon Carette, Loïc Guillevin, Charles D Pusey, Alina L Casian, Biljana Brezina, Andrea Mazzetti, Carol A McAlear, Elizabeth Broadhurst, Donna Reidlinger, Samir Mehta, Natalie Ives, David R W Jayne, PEXIVAS Investigators
雑誌名: N Engl J Med. 2020 Feb 13;382(7):622-631. doi: 10.1056/NEJMoa1803537.
Abstract/Text BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD).
RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups.
CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32053298  N Engl J Med. 2020 Feb 13;382(7):622-631. doi: 10.1056/・・・
著者: JulieAnne G McGregor, Susan L Hogan, Yichun Hu, Caroline E Jennette, Ronald J Falk, Patrick H Nachman
雑誌名: Clin J Am Soc Nephrol. 2012 Feb;7(2):240-7. doi: 10.2215/CJN.05610611. Epub 2011 Dec 1.
Abstract/Text BACKGROUND AND OBJECTIVES: The optimal course of glucocorticoid therapy in anti-neutrophil cytoplasmic autoantibody (ANCA) disease is unknown. This cohort study evaluates effects of glucocorticoid therapy duration on patient outcomes and adverse events.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study assessed 147 patients diagnosed between January 1, 2000 and January 1, 2009 who were treated with glucocorticoids and cyclophosphamide. Patients with end stage kidney disease at presentation, treatment resistance, or who had died within 6 months were excluded. Patients were divided into three groups: 0, 5, or >5 mg prednisone daily at 6 months after therapy initiation. The latter two groups were combined for assessment of adverse events. Wilcoxon rank sum, Kruskal-Wallis, or Fisher's exact tests were used for between-group comparisons. Time to relapse was evaluated by the Kaplan-Meier method with log-rank test for comparison.
RESULTS: There were no differences between groups in ANCA specificity, serum creatinine, frequency of risk factors for relapse, or length of therapy with immunosuppressants. Length of glucocorticoid therapy had no impact on time to relapse (hazard ratio, 0.69 [95% confidence interval (CI), 0.23-2.02]; 1.01, [95% CI, 0.57-1.81] for the 5-mg and >5-mg groups, respectively), relapse-free survival, end stage kidney disease, or death. Patients receiving glucocorticoids beyond 6 months had significantly higher incidence of infections (0.64 infections per person-year versus 0.39, P<0.0001) and a marginally significant higher frequency of new-onset diabetes mellitus (odds ratio, 2.03; 95% CI, 0.94-4.38).
CONCLUSIONS: Glucocorticoid therapy beyond 6 months is associated with a significantly greater risk of infections but not a significantly decreased risk of relapse.

PMID 22134625  Clin J Am Soc Nephrol. 2012 Feb;7(2):240-7. doi: 10.221・・・
著者: M Haubitz, U Frei, U Rother, R Brunkhorst, K M Koch
雑誌名: Nephrol Dial Transplant. 1991;6(8):531-5.
Abstract/Text Twenty-three patients with Wegener's granulomatosis, 15 with daily oral cyclophosphamide therapy and eight with intravenous cyclophosphamide pulse therapy, were studied retrospectively. All patients had involvement of the kidneys and systemic symptoms. Mean monthly cyclophosphamide dose was 1.0 g in the pulse group and 2.7 g in the daily treated group. In all patients remission could be achieved. During 207.5 months of daily oral therapy the following complications were observed: leukopenia, necessitating dose reduction in seven patients, severe infection in one patient, relapses in three patients. During 103 months of intravenous pulse therapy one patient developed leukopenia. No patient had a severe infection. Two relapses were seen. Our data suggest that cyclophosphamide pulse therapy is an effective treatment strategy in patients with Wegener's granulomatosis and kidney involvement. It offers the chance of bladder protection and marked total dose reduction, possibly decreasing the risk of malignancies.

PMID 1956550  Nephrol Dial Transplant. 1991;6(8):531-5.
著者: L Guillevin, J F Cordier, F Lhote, P Cohen, B Jarrousse, I Royer, P Lesavre, C Jacquot, P Bindi, P Bielefeld, J F Desson, F Détrée, A Dubois, E Hachulla, B Hoen, D Jacomy, C Seigneuric, D Lauque, M Stern, M Longy-Boursier
雑誌名: Arthritis Rheum. 1997 Dec;40(12):2187-98. doi: 10.1002/1529-0131(199712)40:12<2187::AID-ART12>3.0.CO;2-H.
Abstract/Text OBJECTIVE: To investigate the effectiveness and side effects of oral versus pulse cyclophosphamide (CYC) in combination with corticosteroids (CS) in the treatment of systemic Wegener's granulomatosis (WG).
METHODS: Patients with newly diagnosed systemic WG were enrolled in a prospective, randomized trial. At the time of diagnosis, prior to randomization, every patient received a daily injection of methylprednisolone for 3 days, followed by daily oral prednisone (1 mg/kg/day) and a 0.7-gm/m2 pulse of CYC. Patients were then randomly assigned to receive either prednisone plus intravenous pulse CYC (group A) or prednisone plus oral CYC (group B) as first-line treatment. CYC was given for at least 1 year and was then progressively tapered and discontinued.
RESULTS: Fifty patients were included in the study: 27 in group A and 23 in group B. At 6 months, 24 group A patients (88.9%) were in remission, versus 18 group B patients (78.3%). At the end of the trial, 18 group A patients (66.7%) and 13 group B patients (56.5%) were in remission. In group A, 66.7% of the patients experienced side effects, versus 69.6% in group B. Infectious side effects were significantly more frequent in group B (69.6%) than in group A (40.7%) (P < 0.05). The incidence of Pneumocystis carinii pneumonia was higher in oral CYC-treated patients (30.4%) than in pulse CYC-treated patients (11.1%). Nine group A patients (33.3%) and 10 group B patients (43.5%) died. Actuarial curves showed that relapses were significantly more frequent in group A (59.2%) than in group B (13%) (P = 0.02).
CONCLUSION: Our results indicate that pulse CYC is as effective as oral CYC in achieving initial remission of WG and is associated with fewer side effects and lower mortality. However, in the long term, treatment with pulse CYC does not maintain remission or prevent relapses as well as oral CYC.

PMID 9416856  Arthritis Rheum. 1997 Dec;40(12):2187-98. doi: 10.1002/・・・
著者: Christian Pagnoux, Alfred Mahr, Mohamed A Hamidou, Jean-Jacques Boffa, Marc Ruivard, Jean-Pierre Ducroix, Xavier Kyndt, François Lifermann, Thomas Papo, Marc Lambert, José Le Noach, Mehdi Khellaf, Dominique Merrien, Xavier Puéchal, Stéphane Vinzio, Pascal Cohen, Luc Mouthon, Jean-François Cordier, Loïc Guillevin, French Vasculitis Study Group
雑誌名: N Engl J Med. 2008 Dec 25;359(26):2790-803. doi: 10.1056/NEJMoa0802311.
Abstract/Text BACKGROUND: Current standard therapy for Wegener's granulomatosis and microscopic polyangiitis combines corticosteroids and cyclophosphamide to induce remission, followed by a less toxic immunosuppressant such as azathioprine or methotrexate for maintenance therapy. However, azathioprine and methotrexate have not been compared with regard to safety and efficacy.
METHODS: In this prospective, open-label, multicenter trial, we randomly assigned patients with Wegener's granulomatosis or microscopic polyangiitis who entered remission with intravenous cyclophosphamide and corticosteroids to receive oral azathioprine (at a dose of 2.0 mg per kilogram of body weight per day) or methotrexate (at a dose of 0.3 mg per kilogram per week, progressively increased to 25 mg per week) for 12 months. The primary end point was an adverse event requiring discontinuation of the study drug or causing death; the sample size was calculated on the basis of the primary hypothesis that methotrexate would be less toxic than azathioprine. The secondary end points were severe adverse events and relapse.
RESULTS: Among 159 eligible patients, 126 (79%) had a remission, were randomly assigned to receive a study drug in two groups of 63 patients each, and were followed for a mean (+/-SD) period of 29+/-13 months. Adverse events occurred in 29 azathioprine recipients and 35 methotrexate recipients (P=0.29); grade 3 or 4 events occurred in 5 patients in the azathioprine group and 11 patients in the methotrexate group (P=0.11). The primary end point was reached in 7 patients who received azathioprine as compared with 12 patients who received methotrexate (P=0.21), with a corresponding hazard ratio for methotrexate of 1.65 (95% confidence interval, 0.65 to 4.18; P=0.29). There was one death in the methotrexate group. Twenty-three patients who received azathioprine and 21 patients who received methotrexate had a relapse (P=0.71); 73% of these patients had a relapse after discontinuation of the study drug.
CONCLUSIONS: These results do not support the primary hypothesis that methotrexate is safer than azathioprine. The two agents appear to be similar alternatives for maintenance therapy in patients with Wegener's granulomatosis and microscopic polyangiitis after initial remission. (ClinicalTrials.gov number, NCT00349674.)

2008 Massachusetts Medical Society
PMID 19109574  N Engl J Med. 2008 Dec 25;359(26):2790-803. doi: 10.105・・・
著者: Rodrigo Cartin-Ceba, Fernando C Fervenza, Ulrich Specks
雑誌名: Curr Opin Rheumatol. 2012 Jan;24(1):15-23. doi: 10.1097/BOR.0b013e32834d5730.
Abstract/Text PURPOSE OF REVIEW: To review the present knowledge about the use of rituximab (RTX) in patients with granulomatosis with polyangiitis (Wegener's; GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (Churg-Strauss; EGPA), also collectively referred to as antineutrophil cytoplasmic antibody-associated vasculitis.
RECENT FINDINGS: More than 20 case series and cohort studies involving more than 200 patients focusing on RTX use for patients with refractory GPA and MPA have been reported. Two randomized controlled trials have shown that RTX is not inferior to cyclophosphamide (CYC) for induction of remission in severe GPA and MPA. The RAVE trial has further shown that RTX is superior to CYC for patients with severe disease relapses. In addition, reports are emerging on the use of RTX for remission maintenance in chronically relapsing patients. There are also preliminary reports on the beneficial use of RTX in eosinophilic granulomatosis with polyangiitis (Churg-Strauss).
SUMMARY: RTX is the first proven alternative to CYC for remission induction in severe GPA and MPA. RTX is the preferred agent for patients presenting with severe disease flares, and its use had become the de facto standard of care for patients with chronically relapsing refractory GPA. Its use in EGPA requires further investigation.

PMID 22089095  Curr Opin Rheumatol. 2012 Jan;24(1):15-23. doi: 10.1097・・・
著者: John H Stone, Peter A Merkel, Robert Spiera, Philip Seo, Carol A Langford, Gary S Hoffman, Cees G M Kallenberg, E William St Clair, Anthony Turkiewicz, Nadia K Tchao, Lisa Webber, Linna Ding, Lourdes P Sejismundo, Kathleen Mieras, David Weitzenkamp, David Ikle, Vicki Seyfert-Margolis, Mark Mueller, Paul Brunetta, Nancy B Allen, Fernando C Fervenza, Duvuru Geetha, Karina A Keogh, Eugene Y Kissin, Paul A Monach, Tobias Peikert, Coen Stegeman, Steven R Ytterberg, Ulrich Specks, RAVE-ITN Research Group
雑誌名: N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/NEJMoa0909905.
Abstract/Text BACKGROUND: Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen.
METHODS: We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months.
RESULTS: Nine centers enrolled 197 ANCA-positive patients with either Wegener's granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P=0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events.
CONCLUSIONS: Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; ClinicalTrials.gov number, NCT00104299.)

2010 Massachusetts Medical Society
PMID 20647199  N Engl J Med. 2010 Jul 15;363(3):221-32. doi: 10.1056/N・・・
著者: Michael Walsh, Alina Casian, Oliver Flossmann, Kerstin Westman, Peter Höglund, Charles Pusey, David R W Jayne, European Vasculitis Study Group (EUVAS)
雑誌名: Kidney Int. 2013 Aug;84(2):397-402. doi: 10.1038/ki.2013.131. Epub 2013 Apr 24.
Abstract/Text Patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500 μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53-1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40-1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.

PMID 23615499  Kidney Int. 2013 Aug;84(2):397-402. doi: 10.1038/ki.201・・・
著者: Marjan C Slot, Jan Willem Cohen Tervaert, Maarten M Boomsma, Coen A Stegeman
雑誌名: Arthritis Rheum. 2004 Apr 15;51(2):269-73. doi: 10.1002/art.20234.
Abstract/Text OBJECTIVE: To analyze disease-free survival in patients with antineutrophil cytoplasmic antibody (ANCA)-associated small-vessel vasculitis (AAV) treated with cyclophosphamide only or switched to azathioprine after 3 months of full remission while taking cyclophosphamide.
METHODS: We analyzed disease-free survival in all consecutive patients diagnosed with AAV between 1990 and 2000 at our center. Patients were treated with cyclophosphamide only (1990-1996) or switched to azathioprine after 3 months of remission while taking cyclophosphamide (1997-2000). All patients received at least 12 months of followup.
RESULTS: Of the total 128 patients, 53 (41%) relapsed. Forty-four of the 128 patients (34%) had been switched to azathioprine therapy. Disease-free survival at 2 and 4 years was 76% and 65% in the cyclophosphamide group compared with 76% and 51% in the azathioprine group. In patients with proteinase 3 (PR3) classic ANCA (C-ANCA)-associated vasculitis who were switched to azathioprine (n = 33), a positive C-ANCA titer at the moment of treatment switch (n = 13) was significantly associated with relapse (RR 2.6, 95% confidence interval 1.1-8.0; P = 0.04). In patients with a negative ANCA titer at the time of switch to azathioprine, disease-free survival at 2 and 4 years was 80% and 62%, which was identical to that for patients treated with cyclophosphamide only. In patients who were ANCA-positive at the time of treatment switch, disease-free survival at 2 and 4 years was only 58% and 17%.
CONCLUSION: Switching cyclophosphamide to azathioprine after induction of remission in patients with PR3-ANCA-associated vasculitis who are still ANCA-positive at the time of treatment switch is associated with a high risk of relapse.

PMID 15077271  Arthritis Rheum. 2004 Apr 15;51(2):269-73. doi: 10.1002・・・
著者: M M Boomsma, C A Stegeman, M J van der Leij, W Oost, J Hermans, C G Kallenberg, P C Limburg, J W Tervaert
雑誌名: Arthritis Rheum. 2000 Sep;43(9):2025-33. doi: 10.1002/1529-0131(200009)43:9<2025::AID-ANR13>3.0.CO;2-O.
Abstract/Text OBJECTIVE: Prediction of relapses in Wegener's granulomatosis (WG) by measuring levels of antineutrophil cytoplasmic antibodies (ANCA) directed against proteinase 3 (PR3) or myeloperoxidase (MPO) remains a controversial issue. To assess the value of serial quantification of ANCA by indirect immunofluorescence (IIF) and antigen-specific enzyme-linked immunosorbent assay (ELISA) for monitoring disease activity in patients with WG, a prospective observational study was conducted in patients with WG attending an outpatient clinic in the Netherlands.
METHODS: One hundred patients with WG (85 with PR3-ANCA, 15 with MPO-ANCA) were studied prospectively from 1996 to 1998. Serum samples were obtained and analyzed every 2 months for ANCA levels. Disease activity was prospectively assessed without knowledge of the ANCA levels.
RESULTS: Relapses occurred in 37 of 100 patients (37%). Thirty-four (92%) of the 37 patients showed a rise in the level of ANCA preceding their relapse, as detected by ELISA or IIF. The predictive value of an increase in ANCA titers for relapse was 57% (17 of 30) for cytoplasmic/classic ANCA (cANCA; by IIF), 71% (27 of 38) for PR3-ANCA (by ELISA), and 100% (3 of 3) for MPO-ANCA (by ELISA). The predictive value of a rise in ANCA as measured by ELISA or IIF did not substantially improve following concomitant measurement of the IgG3 subclass of PR3-ANCA. Forty-three percent of patients who showed a rise in cANCA (by IIF) and 29% with a rise in PR3-ANCA (by ELISA) did not subsequently experience a relapse.
CONCLUSION: Serial measurement of ANCA levels is valuable for the early prediction of relapses in patients with WG.

PMID 11014352  Arthritis Rheum. 2000 Sep;43(9):2025-33. doi: 10.1002/1・・・
著者: D R Jayne, G Gaskin, C D Pusey, C M Lockwood
雑誌名: QJM. 1995 Feb;88(2):127-33.
Abstract/Text We studied 60 patients with ANCA-positive systemic vasculitis (SV) to assess the prognostic significance of clinical and serological features at presentation, and the value of sequential monitoring of ANCA, C-reactive protein (CRP) and ESR levels as predictors of disease relapse. Patients were recruited at the time of diagnosis, treated with a standard protocol, and assessed monthly for one year. Clinical remission was achieved in 56/60 (93%), and ANCA became undetectable in 50/60 (83%) after treatment. During the one year follow-up period, disease relapses were seen in 23 (38%) patients. No specific associations were observed between initial disease presentation, initial ANCA level or ANCA antigenic specificity and relapse. However, 13/23 (57%) of relapses were preceded by a rise in ANCA a mean of 7.8 weeks earlier, while at the time of relapse 19/23 (83%) were ANCA-positive. Rises in CRP and ESR occurred in 23/60 (38%) and 14/43 (33%), respectively, but were less closely associated with relapse than ANCA. A sustained rise in ANCA was seen in six patients without relapse while clinical relapse occurred with a negative ANCA in four. Sequential ANCA monitoring at monthly intervals during disease remission is of value, at least during the first year, in the prediction and diagnosis of relapse in SV, and is superior to measurement of CRP or ESR.

PMID 7704563  QJM. 1995 Feb;88(2):127-33.
著者: C A Stegeman, J W Tervaert, P E de Jong, C G Kallenberg
雑誌名: N Engl J Med. 1996 Jul 4;335(1):16-20. doi: 10.1056/NEJM199607043350103.
Abstract/Text BACKGROUND: Respiratory tract infections may trigger relapses in patients with Wegener's granulomatosis in remission. Uncontrolled data have suggested that treatment with trimethoprim-sulfamethoxazole (co-trimoxazole) may be beneficial.
METHODS: We conducted a prospective, randomized, placebo-controlled study of the efficacy of co-trimoxazole (800 mg of sulfamethoxazole and 160 mg of trimethoprim) given twice daily for 24 months in preventing relapses in patients with Wegener's granulomatosis in remission during or after treatment with cyclophosphamide and prednisolone. Relapses and infections were assessed with predefined criteria based on clinical, laboratory, and histopathological findings. Patients were evaluated at least once every three months for signs of disease activity, compliance with the treatment regimen, side effects of the therapy, and evidence of infections. Titers of serum antineutrophil cytoplasmic antibodies were measured serially.
RESULTS: Forty-one patients were assigned to receive co-trimoxazole, and 40 to receive placebo. In 8 of the 41 patients in the co-trimoxazole group (20 percent), the drug had to be stopped because of side effects. According to life-table analysis, 82 percent of the patients remained in remission at 24 months, as compared with 60 percent of the patients in the placebo group (relative risk of relapse, 0.40; 95 percent confidence interval, 0.17 to 0.98). There were fewer respiratory tract infections (P = 0.005) and non-respiratory tract infections (P = 0.05) in the co-trimoxazole group than in the placebo group. There were no significant differences in antineutrophil cytoplasmic antibody titers at any time. Proportional-hazards regression analysis identified treatment with co-trimoxazole as an independent factor associated with prolonged disease-free survival and a positive antineutrophil cytoplasmic antibody test at the start of treatment as a risk factor for relapse.
CONCLUSIONS: Treatment with co-trimoxazole reduces the incidence of relapses in patients with Wegener's granulomatosis in remission.

PMID 8637536  N Engl J Med. 1996 Jul 4;335(1):16-20. doi: 10.1056/NEJ・・・

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