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HLA-A*31:01 and methotrexate-induced interstitial lung disease in Japanese rheumatoid arthritis patients: a multidrug hypersensitivity marker?
  1. Hiroshi Furukawa1,
  2. Shomi Oka1,
  3. Kota Shimada2,3,
  4. Rheumatoid Arthritis-Interstitial Lung Disease Study Consortium,
  5. Naoyuki Tsuchiya4,
  6. Shigeto Tohma1
  1. 1Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan
  2. 2Department of Rheumatology, Sagamihara Hospital, National Hospital Organization, Sagamihara, Japan
  3. 3Tokyo Metropolitan Tama Medical Center, Fuchu, Japan
  4. 4Molecular and Genetic Epidemiology Laboratory, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
  1. Correspondence to Dr Hiroshi Furukawa, Clinical Research Center for Allergy and Rheumatology, Sagamihara Hospital, National Hospital Organization, 18-1 Sakuradai, Minami-ku, Sagamihara, Kanagawa 252-0392, Japan; h-furukawa{at}

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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.

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Table 1

HLA-A allele frequency in the RA patients

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 …

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  • 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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