Background. Disease relapse remains a major problem in the management of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). In the European populations, HLA-DPB1*04:01 is associated with both susceptibility and risk of relapse of proteinase 3 (PR3)-ANCA positive ANCA-associated vasculitis (AAV). In the Japanese population, we previously reported association of HLA-DRB1*09:01 and DQB1*03:03 with susceptibility to, and DRB1*13:02 with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, association of DQA1*03:02, which is in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, with susceptibility to MPO-AAV was reported in the Chinese population. However, association of these alleles with risk of relapse has not been reported. Here we examined whether HLA-class II is associated with risk of relapse in MPO-AAV. Methods. Firstly, association of HLA-DQA1*03:02 with susceptibility to MPO-AAV and MPA, and its relationship with previously reported DRB1*9:01 and DQB1*03:03 was examined in 440 Japanese patients and 779 healthy controls. Next, association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies of remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using false discovery rate (FDR) method. Results. Association of DQA1*03:02 with susceptibility to MPO-AAV and MPA was confirmed in the Japanese population (MPO-AAV: Puncorr=5.8x10-7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: Puncorr=1.1x10-5, OR 1.71, 95%CI 1.34-2.17). DQA1*03:02 was in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of DRB1*09:01 (Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87), DQA1*03:02 (Puncorr=0.020, Q=0.22, HR:2.11) or DQB1*03:03 (Puncorr=0.043, Q=0.48, HR:1.91) when compared with non-carriers in log-rank test. On the other hand, carriers of serine at position 13 of HLA-DRβ1 (HLA-DRβ1_13S), including carriers of DRB1*13:02, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). When the presence/absence of DQA1*03:02 and HLA-DRβ1_13S are combined, significant difference was detected between the groups with highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02). Conclusion. HLA-class II is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.

Dr. Kawasaki has received research grants from Ichiro Kanehara Foundation, Takeda Science Foundation, and Japan College of Rheumatology, and honoraria for lectures from Chugai Pharmaceutical Co. Ltd. Dr. Sada has received a research grant from Pfizer Inc., and honoraria for lectures from Glaxo SmithKline K.K. Dr. Hirano has received honoraria for lectures from Janssen Pharmaceuticals, Ono Pharmaceuticals, and Mitsubishi Tanabe Pharma. Dr, Kobayashi has received honoraria for the lectures from Novartis Pharma K.K, Eli Lilly Japan K.K., Chugai Pharma, Asahi Kasei Pharma, Gilead Sciences and Janssen Pharma K.K. Dr. Nagasaka has received speaking fee from Chugai Pharmaceutical Co. Ltd. Dr. Sugihara has received grants from AsahiKASEI Co., Ltd., Daiichi Sankyo, Chugai Pharmaceutical Co. and Ono Pharmaceutical, consulting fees from AsahiKASEI Co., Ltd., and honoraria for the lectures from Abbvie Japan Co., Ltd. AsahiKASEI Co., Ltd. Astellas Pharma Inc., Ayumi Pharmaceutical, Bristol Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd, Eli Lilly Japan K.K., Mitsubishi-Tanabe Pharma Co., Ono Pharmaceutical, Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., and UCB Japan Co. Ltd. Dr. Tamura has received grants from Astellas, Ayumi, Asahi Kasei Pharma, Asahi Kasei Medical, AbbVie, Eisai, Nippon Boehringer Ingelheim, Novartis Pharma, Bayer Yakuhin, Tanabe Mitsubishi, Taisho, and Chugai. Dr. Tamura has received speaker fees and/or consulting fees from AbbVie, Eli Lilly Japan, Eisai, GlaxoSmithKline, Novartis, Bristol Myers Squibb, TanabeMitsubishi, Chugai and Janssen. Dr. Itoh and Dr. Kusanagi have received grants from Asahi Kasei Pharma, Eizai, Teijin Pharma, and Chugai Pharmaceutical. Dr. Itoh has received honoraria for lectures from Asahi Kasei Pharma and Abbvie. Dr. Makino has served on advisory boards for Boehringer Ingelheim and Travere Therapeutics. Dr. Harigai has received grants from AbbVie Japan GK, Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., and Teijin Pharma Ltd. Dr. Harigai has received consulting fee from Kissei Pharmaceutical Co., Ltd., honoraria for lectures from AbbVie Japan GK, Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Kissei Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Co., and Teijin Pharma Ltd., participation for Advisory Board for Kissei Pharmaceutical Co., Ltd. Dr. Tsuchiya has received grants from Bristol-Myers Squibb K.K., the Naito Foundation, the Uehara Memorial Foundation, and collaborative research fund from H.U. Group Research Institute G.K.. Dr. Tsuchiya has received award grants from Japan College of Rheumatology and Japan Rheumatism Foundation, and honoraria for lectures from Teijin Ltd. Other authors have no competing interest to disclose.

This work was supported by the grants from the Japan Agency for Medical Research and Development "The Study Group for Strategic Exploration of Drug Seeds for ANCA Associated Vasculitis and Construction of Clinical Evidence [grant number 17ek0109104h0003]","The Strategic Study Group to Establish the Evidence for Intractable Vasculitis Guideline [grant number 17ek0109121h0003]", and "Multitiered study to address clinical questions for management of intractable vasculitides [grant number 20ek0109360h003]", Ministry of Health, Labour and Welfare [grant number JP20FC1044], Japan Society for the Promotion of Science KAKENHI [grant number JP17K09967, JP21K08435], research grants from Bristol-Myers Squibb K.K., Ichiro Kanehara Foundation, Takeda Science Foundation, the Uehara Memorial Foundation and award grants from Japan College of Rheumatology and Japan Rheumatism Foundation. The funders had no role in the design, analysis, interpretation and paper writing of this study.

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This study was reviewed and approved by the Faculty of Medicine Ethics Committee, University of Tsukuba (approval ID: 122, 123, 180, 227, 268). In addition, this study was also approved by Ethics Committees of the following institutes which participated in collaboration and/or recruitment of the subjects: Aichi Medical University, Asahikawa Medical University, Ehime University, Fukuoka University, Hamamatsu University, Hokkaido University, Iwate Prefectural Central Hospital, Juntendo University, Kagawa University. Kanazawa University, Kitano Hospital, Kyorin University, Kyoto University, Kyushu University, Nagasaki University, Nagoya City University, Nagoya University, Nara Medical University, National Defense Medical College, Okayama University, Okayama Saiseikai General Hospital, Saga University, Saitama Medical Center Hospital, Shimane University, The University of Miyazaki, The University of Tokyo, Toho University, Tokyo Medical and Dental University, Tokyo Medical University Hachioji Medical Center, Tokyo Metropolitan Geriatric Hospital, and Institute of Gerontology, and Tokyo Women's Medical University. This study was conducted in accordance with the principles of the Declaration of Helsinki and Ethical Guidelines for Human Genome/Gene Analysis Research implemented by Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labour and Welfare, and Ministry of Economy, Trade and Industry, of Japan. This study was performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from each participant.

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The datasets supporting the conclusions of this article are included within the article, Supplementary Table S1-S4, Supplementary Data 1 and 2 files. Further inquiries can be directed to the corresponding authors.