Rationale of concomitant cyclophosphamide for remission-induction in patients with antineutrophil cytoplasmic antibody-associated vasculitis: A propensity score-matched analysis of two nationwide prospective cohort studies

Abstract

Objectives

We evaluated the effectiveness of cyclophosphamide for patients with microscopic polyangiitis and granulomatosis with polyangiitis.

Methods

Patients treated with cyclophosphamide and glucocorticoid (cyclophosphamide group) or glucocorticoid alone (non-cyclophosphamide group) for remission-induction were enrolled from two Japanese nationwide prospective inception cohort studies. The effectiveness and safety outcomes were compared before and after propensity score (PS)- matching.

Results

Proportion of patients achieving Birmingham Vasculitis Activity Score (BVAS)-remission and BVAS-remission plus a daily prednisolone dosage of ≤10 mg (GC-remission) by Month 6 were not significantly different between cyclophosphamide and non-cyclophosphamide groups before (n = 144 and 155) and after (n = 94 for each group) PS-matching. In myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-positive PS-matched patients, GC-remission by Month 6 was superior in CYC group (n = 82) than in non-CYC group (n = 91) (49 vs. 31%, p = .020). Overall, end-stage renal disease-free and relapse-free survival rates, Vasculitis Damage Index score, and proportions of serious infection were comparable between the two groups both in the unmatched and PS-matched patients. Prednisolone doses at any point after treatment initiation in the PS-matched patients were lower in the cyclophosphamide group than in a non-cyclophosphamide group.

Conclusions

Concomitant cyclophosphamide use may improve GC-remission by Month 6 in MPO-ANCA-positive patients and could exert glucocorticoid sparing effect.

Keywords:

• Antineutrophil cytoplasmic antibody
• cyclophosphamide
• granulomatosis with polyangiitis
• microscopic polyangiitis
• propensity score

Acknowledgements

The authors thank Keiko Hongo, Tomomi Maruyama, Eri Katsuyama, Takayuki Katsuyama, Mariko Narazaki, Noriko Toyota-Tatebe, and Kouichi Sugiyama for their significant assistance in data management as well as patients and physicians who attended RemIT-JAV and RemIT-JAV-RPGN (see Appendix).

Conflict of interest

KS has received speaker honoraria from Chugai Pharma. MH has received research grants and/or honoraria from Takeda Pharma and Ayumi Pharma, Bristol-Myers Squibb, Chugai Pharma, Eisai, Mitsubishi Tanabe Pharma, Teijin Pharma, Taisho Toyama Pharma and Nippon Kayaku.

Appendix

Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis (JPVAS) and Research Committee of Intractable Renal Disease of the Ministry of Health, Labour, and Welfare of Japan: In addition to the authors, the following investigators and institutions participated in this study: Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences (Hitoshi Sugiyama); Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine (Seiichi Matsuo); Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine (Yoshinari Takasaki); Faculty of Health Sciences, Hokkaido University (Akihiro Ishizu); Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University (Tatsuya Atsumi); Department of the Control for Rheumatic Diseases, Graduate School of Medicine, Kyoto University (Takao Fujii); Department of Pathology, Keio University School of Medicine (Yasunori Okada); Department of Respiratory Medicine, Toho University Omori Medical Center (Sakae Homma); Department of Nephrology, Internal Medicine, Nagoya University Graduate School of Medicine (Naotake Tsuboi); Department of Nephrology, Faculty of Medicine, University of Tsukuba (Joichi Usui); Department of Clinical Pathology and Immunology, Kobe University Graduate School of Medicine (Shunichi Kumagai); Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital (Takahiko Sugihara); Department of Rheumatology, Shimane University Faculty of Medicine (Yohko Murakawa); Division of Nephrology and Rheumatology, Department of Internal Medicine Aichi Medical University School of Medicine (Shogo Banno); Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine (Hitoshi Hasegawa); Division of Nephrology, Department of Internal Medicine, Jichi Medical University (Wako Yumura); Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine (Hiroaki Matsubara); Division of Nephrology, Tokyo Medical University Hachioji Medical Center (Masaharu Yoshida); Department of Dermatology, Kitasato University School of Medicine (Kensei Katsuoka); Division of Immunology and Rheumatology, Department of Internal Medicine 3, Hamamatsu University School of Medicine (Noriyoshi Ogawa); Department of Hematology, Oncology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine (Atsushi Komatsuda); Department of Rheumatology, Niigata Rheumatic Center (Satoshi Ito); Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences (Atsushi Kawakami); Department of Nephrology, Iwate Prefectural Central Hospital (Izaya Nakaya); Division of Nephrology and Rheumatology, Department of Internal Medicine, Fukuoka University School of Medicine (Takao Saito); Shimane University, Faculty of Medicine, Division of Nephrology (Takafumi Ito); Department of Hemodialysis and Apheresis, Yokohama City University Medical Center (Nobuhito Hirawa); Center for Rheumatology, Okayama Saiseikai General Hospital (Masahiro Yamamura); Department of Medical Technology, School of Health Sciences, Faculty of Medicine, Niigata University (Masaaki Nakano); Department of Medicine, Kidney Center, Tokyo Women’s Medical University (Kosaku Nitta); Division of Nephrology and Hypertension, Kashiwa Hospital, Jikei University (Makoto Ogura); Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of Medical Sciences (Taio Naniwa); Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine (Shoichi Ozaki); Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo (Junichi Hirahashi); Division of Kidney and Hypertension, Department of Internal Medicine, Jikei University School of Medicine (Tatsuo Hosoya); Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University (Takashi Wada); Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine (Satoshi Horikoshi); Institute of Rheumatology, Tokyo Women’s Medical University (Yasushi Kawaguchi); Division of Clinical Immunology, Graduate School of Comprehensive Human Sciences, University of Tsukuba (Taichi Hayashi); Department of Nephrology, Hypertension, Diabetology, Endocrinology and Metabolic, Fukushima Medical University (Tsuyoshi Watanabe); Department of Nephrology, Japanese Red Cross Nagoya Daini Hospital (Daijo Inaguma); Department of Integrated Therapy for Chronic Kidney Disease, Kyushu University (Kazuhiko Tsuruya); Niigata Prefectural Shibata Hospital (Noriyuki Homma); Division of Rheumatology, Department of Internal Medicine, Keio University School of Medicine (Tsutomu Takeuchi); Division of Cardiology, Nephrology, Pulmonology and Neurology, Department of Internal Medicine, Asahikawa Medical University (Naoki Nakagawa); Kurobe City Hospital (Shinichi Takeda); National Fukuoka Higashi Medical Center (Ritsuko Katafuchi); Division of Nephrology, Department of Medicine, Faculty of Medical Sciences, University of Fukui (Masayuki Iwano); Tokyo Medical University Ibaraki Medical Center (Masaki Kobayashi); Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine (Hidehiro Yamada).

Additional information

Funding

This work was supported by grants from the Ministry of Health, Labour and Welfare, Japan (nannti-ippann-004 and -018) and the Japan Agency for Medical Research and Development [JP17ek0109104, JP17ek0109121, and JP18ek0109360].