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We appreciate the comments by Bluett et al1 on our report of an association of HLA-A*31:01 with methotrexate-induced interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA).2 They have tried to reveal the genetic factors associated with methotrexate-induced ILD, but found no significant association except three suggestive loci in chromosome 1, 9 and 14. This study did not show the association of A*31:01 with methotrexate-induced ILD, though the p value of the analysis was still 0.21 in spite of the small sample size with 62 cases and 175 controls. The meta-analysis with our previous study2 or other forthcoming HLA association studies on methotrexate-induced ILD may reveal more conclusive results in the future.
Genetic factors would be involved in the pathogenesis of methotrexate-induced ILD, because the susceptibility of methotrexate-induced ILD in Japanese patients with RA are thought to be higher than other ethnic groups or patients with other autoimmune diseases.3 4 However, there are few reports of genome-wide association study of drug-induced ILD.5 Since the prevalence of drug-induced ILD is low and the clinical conditions of the patients with drug-induced ILD are various,6 genetic analyses …
Funding This study was supported by Grants-in-Aid for Scientific Research (B, C) (26293123, 15K09543), for Young Scientists (B) (24791018) 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 Practical Research Project for Allergic Diseases and Immunology (Research on Allergic Diseases and Immunology) from Japan Agency for Medical Research and Development, Grants-in-Aid for Clinical Research from National Hospital Organization, Research Grants from Japan Research Foundation for Clinical Pharmacology, Research Grants from Takeda Science Foundation, Research Grants from Daiwa Securities Health Foundation, Research Grants from Mitsui Sumitomo Insurance Welfare Foundation, Research Grants from The Nakatomi Foundation, Bristol-Myers K.K. RA Clinical Investigation Grant from Bristol-Myers Squibb and research grants from the following pharmaceutical companies: Teijin Pharma, Takeda Pharmaceutical Company Limited, Pfizer Japan, Merck Sharp and Dohme, Mitsuibishi Tanabe Pharma, Eisai, Chugai Pharmaceutical, Astellas Pharma, Abbott Japan. 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, and the following funders are supported wholly or in part by the indicated pharmaceutical companies; Mitsui Sumitomo Insurance Welfare Foundation was established by Mitsui Sumitomo Insurance, the Daiwa Securities Health Foundation was established by Daiwa Securities Group, the Takeda Science Foundation is supported by an endowment from Takeda Pharmaceutical Company, the Nakatomi Foundation was established by Hisamitsu Pharmaceutical and the Japan Research Foundation for Clinical Pharmacology is run by Daiichi Sankyo. HF received honoraria from Ajinomoto, Ayumi Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Pfizer Japan, Luminex and Takeda Pharmaceutical Company. NT is supported by SENSHIN Medical Research Foundation, which is supported by an endowment from Mitsubishi Tanabe Pharma and received honoraria from Asahi Kasei, Eisai, Daiichi Sankyo. ST was supported by research grants from pharmaceutical companies: Abbott Japan, Astellas Pharma, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma Merck Sharp and Dohme, Pfizer Japan, Takeda Pharmaceutical Company, Teijin Pharma. ST received honoraria from Pfizer Japan, Mitsubishi Tanabe Pharma, Ono Pharmaceutical, Chugai Pharmaceutical, AbbVie GK, Astellas Pharma, Asahi Kasei Pharma. The other authors declare no financial or commercial conflict of interest.
Provenance and peer review Commissioned; internally peer reviewed.
Collaborators The RA-ILD Study Consortium includes Norihiko Watanabe (Chibaken Saiseikai Narashino Hospita), Kiyoshi Migita (Fukushima Medical University), Takeo Sato (Jichi Medical University), Shunsei Hirohata, Tatsuo Nagai, and Yoshiyuki Arinuma (Kitasato University), Tadashi Nakamura and Hirokazu Takaoka (Kumamoto Shinto General Hospital), Yasuhiko Yoshinaga (Kurashiki Medical Center), Kunio Matsuta (Matsuta Clinic), Yasuo Suenaga and Hayato Utsunomiya (NHO Beppu Medical Center), Akira Okamoto (NHO Himeji Medical Center), Kenji Ichikawa (NHO Hokkaido Medical Center), Shunsuke Mori (NHO Kumamoto Saishunso National Hospita), Eiichi Suematsu (NHO Kyushu Medical Center), Koichiro Saisho (NHO Miyakonojo Medical Center), Noriyuki Chiba (NHO Morioka Hospital), Naoshi Fukui, Akiko Komiya, Atsushi Hashimoto, Tatsuoh Ikenaka, and Yuko Okazaki (NHO Sagamihara Hospital), Makoto Sueishi (NHO Shimoshizu National Hospital), Mitsuru Motegi (NHO Takasaki General Medical Center), Yojiro Kawabe (NHO Ureshinoo Medical Center), Satoshi Ito (Niigata Rheumatic Center), Kiminori Hasegawa (Sapporo Yamanoue Hospital), Hajime Kono (Teikyo University), Kazuhiro Hatta (Tenri Hospital), Keigo Setoguchi (Tokyo Metropolitan Komagome Hospital), Shoji Sugii (Tokyo Metropolitan Tama Medical Center), Shigeru Ohno (Yokohama City University Medical Center), Shouhei Nagaoka and Akiko Suda (Yokohama Minami Kyosai Hospital).