Association of HLA Class II Alleles with Relapse and Interstitial Lung Disease in Myeloperoxidsae (MPO) -ANCA Positive Vasculitis in a Japanese Population

Aya Kawasaki¹, Ken-ei Sada², Fumio Hirano^3,4, Shigeto Kobayashi⁵, Hidehiro Yamada⁶, Hiroshi Furukawa^1,7, Kenji Nagasaka⁸, Takahiko Sugihara⁹, Kunihiro Yamagata¹⁰, Takayuki Sumida¹¹, Shigeto Tohma^12,13, Shoichi Ozaki⁶, Hiroshi Hashimoto¹⁴, Hirofumi Makino¹⁵, Yoshihiro Arimura¹⁶, Masayoshi Harigai¹⁷ and Naoyuki Tsuchiya¹, ¹University of Tsukuba, Faculty of Medicine, Molecular and Genetic Epidemiology Laboratory, Tsukuba, Japan, ²Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, ³Tokyo Medical and Dental University, Graduate School of Medical and Dental Sciences, Department of Rheumatology, Tokyo, Japan, ⁴Tokyo Medical and Dental UniversityGraduate School of Medical and Dental Sciences, Department of Lifetime Clinical Immunology, Tokyo, Japan, ⁵Department of Internal Medicine, Juntendo University Koshigaya Hospital, Koshigaya, Japan, ⁶St. Marianna University, School of Medicine, Department of Internal Medicine, Kawasaki, Japan, ⁷National Hospital Organization Sagamihara l Hospital, Clinical Research Center for Allergy and Rheumatology, Sagamihara, Japan, ⁸Department of Rheumatology, Ome Municipal General Hospital, Ome, Japan, ⁹Department of Medicine and Rheumatology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan, ¹⁰University of Tsukuba, Faculty of Medicine, Department of Nephrology, Tsukuba, Japan, ¹¹Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan, ¹²National Hospital Organization Tokyo Hospital, Sagamihara, Japan, ¹³National Hospital Organization Tokyo National Hospital, Kiyose, Japan, ¹⁴Juntendo University School of Medicine, Tokyo, Japan, ¹⁵Okayama University Hospital, Okayama, Japan, ¹⁶Kyorin University School of Medicine, First Department of Internal Medicine, Tokyo, Japan, ¹⁷Tokyo Women's Medical University, Division of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases, Institute of Rheumatology, Tokyo, Japan

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: ANCA, genetics, human leukocyte antigens (HLA) and interstitial lung disease

Session Information

Date: Tuesday, October 23, 2018

Title: Genetics, Genomics and Proteomics Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose: The high prevalence of microscopic polyangiitis (MPA) and myeloperoxidase (MPO)-ANCA positive patients as well as frequent occurrence of interstitial lung disease (ILD) constitute unique epidemiological features of ANCA-associated vasculitis (AAV) in the Japanese population. Recent genome-wide association studies in European populations indicated that HLA-class II region was most strongly associated with AAV. In the Japanese population, we reported that HLA-DRB1*09:01 was associated with susceptibility to, and DRB1*13:02 with protection against, MPA and MPO-ANCA positive AAV (MPO-AAV) in Japan. In this study, we examined whether HLA-class II are associated with relapse of MPO-AAV, as well as occurrence of ILD in MPO-AAV, in a Japanese population.

Methods: Relapse rate and time to first relapse were analyzed in 206 MPO-AAV patients, who entered prospective cohort studies of remission maintenance therapy (RemIT-JAV and RemIT-JAV-RPGN) and achieved remission during the observation period. Association of HLA-DRB1 alleles with relapse rate was tested by chi-square analysis or Fisher exact test, and relapse-free interval was analyzed by log-rank test. Association study with ILD was performed in 297 MPO-AAV patients (126 with ILD and 171 without ILD) and 596 healthy controls. Statistical analyses were conducted using logistic regression analysis under the additive model.

Results: Relapse occurred more frequently in the patients with DRB1*09:01 (DRB1*09:01 positive: 22/85, 25.9% vs DRB1*09:01 negative 18/121, 14.9%) (P=0.049, odds ratio [OR] 2.00), and time to relapse was significantly shorter in the patients with DRB1*09:01 than those without (P=0.048) (Figure 1). Although patients with DRB1*13:02 showed a tendency towards decreased relapse rate (DRB1*13:02 positive: 1/16 6.3% vs DRB1*13:02 negative: 39/190, 20.5%), the difference did not reach statistical significance (P=0.32, OR 0.26), nor did the time to first relapse (P=0.19). When the association of HLA alleles was tested between MPO-AAV with ILD and healthy individuals, DPB1*05:01 and DRB1*04:05 alleles were significantly decreased in MPO-AAV with ILD (Table 1). Case-case analysis between MPO-AAV patients with and without ILD also showed significant decrease of DPB1*05:01 in MPO-AAV with ILD (Table 1).

Conclusion: Association of DRB1*09:01 with relapse in MPO-AAV was observed in a Japanese population. In addition, HLA-DPB1*05:01 was significantly decreased in MPO-AAV with ILD.

Table 1. Association of HLA-class II alleles with interstitial lung disease in MPO-ANCA positive vasculitis
	allele frequency			vs HC		vs MPO-AAV without ILD
	MPO-AAV with ILD	MPO-AAV without ILD	HC	P	OR	P	OR
DRB1*01:01	0.099	0.070	0.059	0.020	1.77	0.20	1.49
DRB1*04:05	0.079	0.126	0.127	0.036	0.59	0.071	0.59
DRB1*08:02	0.060	0.038	0.028	0.013	2.21	0.23	1.59
DRB1*09:01	0.210	0.249	0.153	0.027	1.47	0.26	0.79
DPB1*04:02	0.147	0.126	0.093	0.0089	1.75	0.45	1.20
DPB1*05:01	0.290	0.386	0.381	0.0072	0.67	0.020	0.67
HC: healthy controls, OR: odds ratio, MPO-AAV: MPO-ANCA positive vasculitis, ILD: interstitial lung disease.

Disclosure: A. Kawasaki, None; K. E. Sada, None; F. Hirano, Chugai Pharmaceutical Co., Ltd.; Ono Pharmaceuticals; Mitsubishi Tanabe Pharma Co.; UCB Japan; CSL Behring; Towa Pharmaceutical Co., Ltd.; Abbvie Japan Co., Ltd.; Japan Blood Products Organization; Ayumi Pharmaceutical Co.; and Nippon Kayaku Co., Ltd.., 5,Sumitomo Dainippon Pharma Chugai Pharmaceutical Co., Ltd., 8; S. Kobayashi, None; H. Yamada, None; H. Furukawa, None; K. Nagasaka, None; T. Sugihara, Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. Ltd., Mitsubishi-Tanabe Pharma Co., Astellas Pharma Inc., Bristol Myers Squibb K.K. and Abbvie Japan Co., Ltd., 5; K. Yamagata, None; T. Sumida, None; S. Tohma, None; S. Ozaki, None; H. Hashimoto, None; H. Makino, None; Y. Arimura, None; M. Harigai, None; N. Tsuchiya, Japan Rheumatism Foundation, 2.

To cite this abstract in AMA style:

Kawasaki A, Sada KE, Hirano F, Kobayashi S, Yamada H, Furukawa H, Nagasaka K, Sugihara T, Yamagata K, Sumida T, Tohma S, Ozaki S, Hashimoto H, Makino H, Arimura Y, Harigai M, Tsuchiya N. Association of HLA Class II Alleles with Relapse and Interstitial Lung Disease in Myeloperoxidsae (MPO) -ANCA Positive Vasculitis in a Japanese Population [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/association-of-hla-class-ii-alleles-with-relapse-and-interstitial-lung-disease-in-myeloperoxidsae-mpo-anca-positive-vasculitis-in-a-japanese-population/. Accessed .

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