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Methotrexate-induced interstitial lung disease (MI-ILD) can occur in rheumatoid arthritis (RA) patients.1 It is believed that Japanese RA patients are more susceptible to MI-ILD than other ethnic groups,2 ,3 suggesting that genetic factors are involved in the pathogenesis of MI-ILD. To date, biomarkers to predict development of MI-ILD in RA have not been established. A striking association between human leukocyte antigen (HLA) class I and cutaneous adverse reactions has been reported for several drugs.4–6 Here, we investigated HLA class I associations with MI-ILD in Japanese RA patients.
A case-control association study was performed on 55 Japanese RA patients (mean age ± SD: 69.3±8.5 years; 15 men, mean dose of methotrexate±SD: 6.7±2.6 mg/week; mean duration of methotrexate treatment±SD: 3.0±4.4 years) with episodes of MI-ILD, and 709 control Japanese RA patients (63.6±11.5 years; 146 men) without any episodes of MI-ILD, based on the genotyping data obtained with WAKFlow HLA typing kits (Wakunaga, Hiroshima, Japan). A significant association was found for HLA-A*31:01 (p = 8.06×10−5, corrected p [Pc]=1.93×10−3, OR 2.97, 95% CI 1.80 to 4.88, table 1). The A19 serological group (A*29–*33, and *74 alleles) was also significantly associated with increased risk of MI-ILD (p = 6.47×10−5, OR 2.59, 95% CI 1.67 to 4.01, table 1). None of the other HLA-B or C alleles was associated with MI-ILD.
Several studies have shown that HLA class I polymorphism contributes to its susceptibility to cutaneous adverse drug reactions.4–9 In these reports, each drug was associated with specific HLA class I alleles; thus, HLA-A*31:01 and B*15:02 were associated with carbamazepine, B*58:01 with allopurinol, and B*57:01 with abacavir. Our findings suggest that A*31:01 might be a multidrug hypersensitivity risk marker, and might imply presence of common pathogenic mechanisms between MI-ILD and cutaneous adverse drug reactions.
The molecular mechanisms underlying drug hypersensitivity associated with certain HLA alleles remain unclear. One possibility is that the HLA molecules modified with drugs may directly activate T cells.10 Alternatively, drugs or their metabolites may act as haptens binding to peptides loaded on the HLA molecules. Furthermore, a differential cellular handling of a drug-induced stress-response associated with HLA-A*31:01 cannot be excluded.
HLA-A*31:01 could be a useful clinical marker to predict MI-ILD. A significant association was also found for HLA-A*31:01 under the dominant model (p = 2.35×10−4, Pc = 5.65×10−3, OR 3.18, 95% CI 1.77 to 5.72). The specificity of the marker is 84.8%, and the sensitivity is 36.4% on the condition. Although they seem insufficient, MI-ILD is a life-threatening complication, and its prevention has crucial significance in the clinical practice of RA. Further genome-wide association studies will identify additional genetic markers, which will provide sufficient predictive value for routine clinical use in combination with HLA-A*31:01. Thus, our present findings provide useful information for promoting personalised medicine for RA.
Because of the limited sample size in our study, the association of A*31:01 should be confirmed in future independent studies. Also, because the allelic distribution of HLA in other ethnic populations is different from what it is in the Japanese population, the role of HLA class I in MI-ILD in RA in other populations needs to be investigated. The frequency of A*31:01 allele (8.7%, http://hla.or.jp/haplo/haplonavi.php?type=aril&lang=en) in the Japanese is higher than that in the Caucasian population (3.9%).6 Furthermore, A*31:01 is in linkage disequilibrium (LD) with DRB1*04:05, which is the most frequent shared epitope (SE) allele among Japanese RA patients (1.0% of haplotype frequency, http://hla.or.jp/haplo/haplonavi.php?type=haplo&lang=en). By contrast, DRB1*04:01, which is the most frequent SE allele in the Caucasian RA, is in LD with A*02:01 (2.5%, http://www.allelefrequencies.net/). Such population differences might explain the higher prevalence of MI-ILD in Japanese RA patients.
The RA-ILD Study Consortium includes Yasuo Suenaga and Hayato Utsunomiya at Department of Rheumatology, Beppu Medical Center, National Hospital Organization, Beppu 874-0011, Japan; Norihiko Watanabe at Chibaken Saiseikai Narashino Hospital, Narashino 275-8580, Japan; Akira Okamoto at Department of Rheumatology, Himeji Medical Center, National Hospital Organization, Himeji 670-8520, Japan; Kenji Ichikawa at Department of Rheumatology, Hokkaido Medical Center, National Hospital Organization, Sapporo 063-0005, Japan; Takeo Sato at Japanese Red Cross Kitami Hospital, Kitami 090-8666, Japan; Kiminori Hasegawa at Department of Rheumatology, Kin-ikyo Chuo Hospital, Sapporo 007-8505, Japan; Shunsei Hirohata and Tatsuo Nagai at Department of Rheumatology and Infectious Disease, Kitasato University School of Medicine, Sagamihara 252-0375, Japan; Tadashi Nakamura (present affiliation: Center for Rheumatic Disease & Rheumatology, NTT West Kyushu Hospital, Kumamoto 862-8655, Japan) at Kumamoto Center for Arthritis and Rheumatology, Kumamoto 862-0976, Japan; Shunsuke Mori at Kumamoto Saishunso National Hospital, National Hospital Organization, Kumamoto 861-1196, Japan; Yasuhiko Yoshinaga at Rheumatic Disease Center, Kurashiki Medical Center, Kurashiki 710-8522, Japan; Taka-aki Fukuda and Seiyo Honda at Division of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan; Eiichi Suematsu at Department of Internal Medicine and Rheumatology, Clinical Research Institute, Kyushu Medical Center, National Hospital Organization, Fukuoka 810-8563, Japan; Kunio Matsuta at Matsuta Clinic, Tokyo 155-0032, Japan; Koichiro Saisho at Department of Orthopedics/Rheumatology, Miyakonojo Hospital, National Hospital Organization, Miyakonojo 885-0014, Japan; Noriyuki Chiba at Department of Rheumatology, Morioka Hospital, National Hospital Organization, Morioka 020-0133, Japan; Kiyoshi Migita and Taiichiro Miyashita at Department of Rheumatology and Clinical Research Center, Nagasaki Medical Center, National Hospital Organization, Omura 856-8562, Japan; Satoshi Ito at Department of Rheumatology, Niigata Rheumatic Center, Shibata 957-0054, Japan; Naoshi Fukui and Akiko Komiya at Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara 252-0392, Japan; Yoshiyuki Arinuma (present affiliation: Department of Rheumatology and Infectious Disease, Kitasato University School of Medicine, Sagamihara, Japan), Hidekazu Futami, Atsushi Hashimoto, Tatsuoh Ikenaka, Toshihiro Matsui, Shinichi Nogi, Yuko Okazaki, and Hirokazu Takaoka (present affiliation: Center for Rheumatic Disease & Rheumatology, NTT West Kyushu Hospital, Kumamoto 862-8655, Japan) at Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara 252-0392, Japan; Makoto Sueishi at Department of Rheumatology, Shimoshizu National Hospital, National Hospital Organization, Yotsukaido 284-0003, Japan; Mitsuru Motegi at Department of Respiratory Medicine, Takasaki General Medical Center, National Hospital Organization, Takasaki 370-0829, Japan; Hajime Kono at Department of Internal Medicine, Teikyo University, Tokyo 173-0003, Japan; Kazuhiro Hatta at Tenri Hospital, Tenri 632-8552, Japan; Keigo Setoguchi at Allergy and Immunological Diseases, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo 113-8677, Japan; Shoji Sugii at Department of Rheumatology, Tokyo Metropolitan Tama Medical Center, Fuchu 183-8524, Japan; Yojiro Kawabe at Division of Rheumatology, Ureshino Medical Center, National Hospital Organization, Ureshino 843-0393, Japan; Shigeru Ohno at Center for Rheumatic Diseases, Yokohama City University Medical Center, Yokohama 232-0024, Japan; Shouhei Nagaoka and Akiko Suda at Department of Rheumatology, Yokohama Minami Kyosai Hospital, Yokohama 236-0037, Japan. We thank Ms Mayumi Yokoyama at Sagamihara Hospital for secretarial assistance.
Correction notice The article has been corrected since it was published Online First. The author list has been amended.
Contributors HF designed the study, carried out genotyping and statistical analyses, and wrote the manuscript. SO carried out genotyping. HF, KS, ST and RA-ILD Study Consortium members recruited Japanese patients with RA and collected clinical information. NT and ST designed and coordinated the study and helped with manuscript preparation.
Funding The work was supported by Grant-in-Aid for Scientific Research (B, C) (22390199, 22591090) from the Japan Society for the Promotion of Science; Health and Labour Science Research Grants from the Ministry of Health, Labour, and Welfare of Japan; Grants-in-Aid for Clinical Research from National Hospital Organization; Research Grants from Daiwa Securities Health Foundation; Research Grants from Japan Research Foundation for Clinical Pharmacology; Research Grants from The Nakatomi Foundation; Research Grants from Takeda Science Foundation; and research grants from pharmaceutical companies: Abbott Japan Co, Ltd; Astellas Pharma Inc; AstraZeneca KK; Bristol-Myers Squibb Co Ltd; Chugai Pharmaceutical Co, Ltd; Eisai Co, Ltd; Medical & Biological Laboratories Co, Ltd; Mitsuibishi Tanabe Pharma Corporation; Merck Sharp and Dohme Inc; Pfizer Japan Inc; Takeda Pharmaceutical Company Limited; and Teijin Pharma Limited. The funders had no role in study design, data collection and analysis, decision to publish, or preparing the manuscript.
Competing interests HF has the following conflicts. The following funders are supported in whole or in part by the subsequent pharmaceutical companies. The Japan Research Foundation for Clinical Pharmacology is run by Daiichi Sankyo; the Takeda Science Foundation is supported by an endowment from Takeda Pharmaceutical Company; and the Nakatomi Foundation was established by Hisamitsu Pharmaceutical Co, Inc. The Daiwa Securities Health Foundation was established by Daiwa Securities Group Inc. ST was supported by research grants from pharmaceutical companies: Abbott Japan Co, Ltd, Astellas Pharma Inc, AstraZeneca KK, Bristol-Myers Squibb Co Ltd, Chugai Pharmaceutical Co, Ltd, Eisai Co, Ltd, Medical & Biological Laboratories Co, Ltd, Mitsuibishi Tanabe Pharma Corporation, Merck Sharp and Dohme Inc, Pfizer Japan Inc, Takeda Pharmaceutical Company Limited, and Teijin Pharma Limited. The other authors declare no financial or commercial conflict of interest.
Patient consent Obtained.
Ethics approval This study was reviewed and approved by the research ethics committees of each participating institute.
Provenance and peer review Not commissioned; externally peer reviewed
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