Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate: An open-label extension of a randomized, double-blind, placebo-controlled trial

Abstract

Objective. To obtain safety and efficacy data on combination treatment with iguratimod and methotrexate (MTX) in an open-label extension study in patients with active rheumatoid arthritis (RA).

Methods. Following a 28-week, randomized, double-blind trial of adding iguratimod or placebo to stable MTX therapy, patients entered a 24-week extension. Patients randomized to the iguratimod + MTX group continued treatment. Patients treated with placebo + MTX switched to iguratimod + MTX [the (placebo/iguratimod) + MTX group].

Results. In the iguratimod + MTX group, the rate of 20% improvement in American College of Rheumatology criteria (ACR20) at week 52 (71.3%) was similar to that at week 24 (69.5%). ACR50, ACR70 and Health Assessment Questionnaire Disability Index at week 52 significantly improved compared with the values at week 24. In the (placebo/iguratimod + MTX) group, the switch to iguratimod treatment significantly improved ACR20 from 30.7% at week 24 to 72.1% at week 52. Frequent adverse events for 52 weeks in the iguratimod + MTX group were nasopharyngitis, upper respiratory tract inflammation, stomatitis, lymphocyte decrease, AST increase, ALT increase and blood iron decrease. These adverse events were predominantly mild or moderate in severity. No deaths occurred.

Conclusion. Efficacy and tolerance of iguratimod + MTX therapy was maintained to 52 weeks in patients with active RA with inadequate response to MTX.

Keywords:

• Disease-modifying antirheumatic drug
• Iguratimod
• Methotrexate
• Rheumatoid arthritis
• T-614

Acknowledgements

This study was funded by Toyama Chemical Co., Ltd., Tokyo, Japan and Eisai Co., Ltd., Tokyo, Japan.

The authors wish to thank all the collaborating members of the Iguratimod-Clinical Study Group. Principal investigators and institutions were as follows: Kou Katayama (Katayama Orthopedic Rheumatology Clinic), Naoichiro Yukawa (Kyoto University Hospital), Satoshi Soen (Nara Hospital, Kinki University School of Medicine), Katsumi Eguchi, Atsushi Kawakami (Nagasaki University Hospital), Shuji Ohno (Ohno Clinic), Tomohiko Yoshida (Setagaya Rheumatology Center, Internal Medicine Department Yoshida Clinic), Takaaki Fukuda (Kurume University Medical Center), Keisuke Hashimoto (Hashimoto Clinic for Orthopedic or Rheumatic Diseases), Takashi Sato (Association of Medical Corporation Dainohara Orthopedic Surgery), Yuichi Takahashi (Yu Family Clinic), Eiji Sugiyama (Hiroshima University Hospital), Kenji Kohriyama (Shinsuma Hospital), Yasuhiko Munakata (Medical Corporation Biei Taihaku Sakura Hospital), Koichi Kitamura (Hakodate Goryokaku Hospital), Kanzo Amano (Hiroshima Clinic), Shigeo Miyashima (Miyashima RA and Orthopaedic Clinic), Akira Sagawa (Sagawa Akira Rheumatology Clinic), Takeo Sakurai (Inoue Hospital), Hiroo Yamane (Toyooka-daiichi Hospital), Wataru Hirose (Hirose Clinic), Hiroshi Nakashima (Nakajima Orthopaedic Surgery), Tamami Yoshitama (Yoshitama Clinic Rheumatology and Internal Medicine), Koichi Hirota (Hirota Medical Clinic), Motohide Kaneko (Kaneko Internal Medicine Rheumatology Clinic), Kunio Matsuta (Matsuta Clinic), Atsushi Fujisaku (Tomakomai City Hospital), Masanobu Mine (Suga Orthopedic Hospital), Shintaro Yano (Sanyakai Medical Corporation Maebashi Hirosegawa Clinic), Ichiro Oki (Oki Medical Clinic), Tatsumi Chijiwa (Medical Corporation Takatakai Kochi-Kinen Hospital), Masaya Mukai (Sapporo City General Hospital), Kazutoshi Aoki (Saitama Social Insurance Hospital), Munetoshi Nakashima (The Japanese Red Cross Nagasaki Genbaku Hospital), Jun Kishi (Tokushima University Hospital), Toshihisa Kanamono (Nagano Red Cross Hospital), Shuji Ohta (Taga General Hospital), Toshiaki Tsukada (Isahaya Health Insurance General Hospital), Yukitaka Ueki (Sasebo Chuo Hospital), Seiji Tsuboi (Shizuoka Kousei Hospital), Hirobumi Takahashi (Takahashi Medical Clinic), Hiroki Tsuchiya (Nagoya Kyoritsu Clinic), Tomomasa Izumiyama (Higashisendai Rheumatology Medical Clinic), Yukiyoshi Oishi, Yuji Hirano (Toyohashi Municipal Hospital), Takefumi Kato (Medical Corporation Kato Orthopedic Surgery), Shinichi Yamaguchi (Yamaguchi Clinic), Takanori Nagamine (Nagamine Orthopedic Clinic), Isao Furugo (JR Kyushu Hospital), Yasutaka Takagi (Tonami General Hospital), Takayuki Sumida (Tsukuba University Hospital), Ryosuke Kanda (Kitasenzoku Orthopedic Clinic), Keiji Maeda (NTT West Osaka Hospital), Tomomi Tsuru (Medical Co.LTA PS Clinic), Masakazu Kondo (Kondo Clinic of Rheumatology and Orthopaedic Surgery), Masatoshi Naito (Fukuoka University Hospital), Makoto Nishinarita (Nishinarita Clinic Office), Masakazu Nagashima (Tokyo Metropolitan Bokutoh Hospital), Hiroyuki Miyake (Ichinomiya Municipal Hospital), Takehiko Ayabe (Ayabe Clinic), Hideki Amma (Social Insurance Chukyo Hospital), Takeshi Oguchi (Anjo Kosei Hospital), Mitsugu Takahashi (Takahashi Orthopedics Clinic), Hiroshi Morio, Masaki Hiraguri (Japanese Red Cross Narita Hospital), Minoru Kurihara (Funaboriekimaeseikeigekanaika), Haruhiko Matsumoto (Munehiro Hospital), Juhro Fujimori (The Hofu Clinic for Orthopaedics and Rheumatology), Hiroshi Tsurukami (Tsurukami Clinic of Orthopedic and Rheumatology), Hiroshi Nakamura (Nakamura Orthopedic Clinic), Akio Suda (Suda Memorial Orthopedic Clinic), Hiroyuki Hagiyama (Yokohama City Minato Red Cross Hospital), Akikatsu Nakashima (Ishikawa-ken Saiseikai Kanazawa Hospital), Teiji Kontani (Komatsu Municipal Hospital), Shigeru Kamei (Kamei Orthopaedics), Takashi Maruyama (Yaenosato Hospital), Fumio Shinomiya (Centre for Rheumatic Disease, Mima Hospital in Yoshinogawa City), Seiji Yoshizawa (Hamanomachi Hospital), Kazuhide Tanimura (Hokkaido Medical Center for Rheumatic Diseases), Koji Hashimoto (Yamauchi Hospital), Hajime Kawamura (Kawamura Medical Clinic), Hiroyuki Nara (Kokubunji Sakura Clinic), Hidetomo Sato (Nasu Kogen Clinic), Shigeki Hidaka (Hidaka Orthopedic Hospital), Kenichi Murase (Nishikasai South Gate Department of Orthopedic Surgery and Rheumatology CL), Minoru Irahara (Irahara Clinic), Sadamu Suzuki (Suzuki Clinic), Makoto Kawakami (Tamatsukuri Kosei-Nenkin Hospital), Eisuke Shono (Shono Rheumatology Clinic), Junichi Obata (Hikarichuo Clinic), Motohiro Oribe (Oribe Clinic of Rheumatism and Medicine), Shoji Uchida (Uchida Clinic), Masao Nakajima (Kasumigaseki Urban Clinic), Takuya Sawabe (Hiroshima Red Cross Hospital and Atomic-bomb Survivors Hospital), Koichiro Ishikawa (Ishikawa Orthopaedic and Rheumatism Hospital), Shin Munesada (Asunaro Orthopedic Clinic), Takashi Ohira (Ohira Orthopedic Hospital), Masaaki Yoshida (Yoshida Orthopedic Rheumatology Clinic), Tsukasa Matsubara (Matsubara Mayflower Hospital, Association of the Medical Corporation of Matsubara Clinic), Shigeru Honjo (Honjo Rheumatism Clinic), and Yuji Yamanishi (Hiroshima Rheumatology Clinic).

Conflict of interest

N.I. has received speakers bureau from AbbVie GK, Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Otsuka Pharmaceutical Co., Ltd., Pfizer Japan Inc., Taisho Toyama Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. M.K. has received speakers bureau from Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Pfizer Japan Inc. T.S. has received grant and research support from Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Pfizer Japan Inc.; speakers bureau from AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Santen Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. T.M. has received grant and research support from Asahi Kasei Pharma Corporation, Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd.; speakers bureau from Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Santen Pharmaceutical Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., and Takeda Pharmaceutical Co., Ltd. S.S. has received grant and research support from Asahi Kasei Pharma Corporation, Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Sanofi Aventis K.K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Limited; speakers bureau from Astellas Pharma Inc., Bristol-Myers Squibb K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Santen Pharmaceutical Co., Ltd., Toyama Chemical Co., Ltd. K.Y. has received grant and research support from Astellas Pharma Inc., Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., and Santen Pharmaceutical Co., Ltd.; speakers bureau from AbbVie GK, Bristol-Myers Squibb K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Santen Pharmaceutical Co., Ltd. K.N. is an employee of Eisai Co., Ltd. T.Y. is an employee of Toyama Chemical Co., Ltd. M.H., N.I., K.K., M.K., T.S., T.M., S.S., and K.Y. served for consultancy to Eisai Co., Ltd. and Toyama Chemical Co., Ltd.