Clinical characteristics and treatment strategies for A20 haploinsufficiency in Japan: A national epidemiological survey

Hidenori Ohnishi^1*Mayuka Shiraki¹Saori Kadowaki²Yuki Miwa¹Kenichi Nishimura³Yuta Maruyama⁴Dai Kishida⁵Chie Kobayashi⁶Hidetoshi Takada⁶Kanako Mitsunaga⁷Yuzaburo Inoue⁸Ebato Takasuke⁹Takayuki Miyamoto¹⁰Eitaro Hiejima¹⁰Shuzo Sato¹¹Kiyoshi Migita¹¹Tadashi Matsubayashi¹²Daisuke Kobayashi¹³Eriko Hasegawa¹³Utako Kaneko¹⁴Takashi Ishikawa¹⁵MASAFUMI ONODERA¹⁵Kohei Matsushita¹⁶Yuhki Koike¹⁶Hiroaki Umebayashi¹⁷Fumihiko Kakuta¹⁸Daiki Abukawa¹⁸Yasutomo Funakoshi¹⁹Masataka Ishimura²⁰Yusuke Otani²¹Takuya Nishizawa²¹Takashi Ishige²¹Reiko Hatori²¹Seiji Tanaka²²Shouichirou Kusunoki²³Kimitoshi Nakamura²³Harumi Shirai²⁴Yoshiho Hatai²⁵Futaba Miyaoka²⁶Shuya Kaneko²⁷Asami Shimbo²⁷Masaki Shimizu²⁷Hirokazu Kanegane²⁸Motomu Hashimoto²⁹Nobuo Negoro²⁹Taro Yoshida³⁰Yasunori Wada³⁰Masaaki Usami³¹Taizo Wada³¹Kazushi Izawa¹⁰Takahiro Yasumi³²Ryuta Nishikomori²²

• ¹Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan
• ²Department of Early Diagnosis and Preventive Medicine for Rare Intractable Pediatric Diseases, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan
• ³Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
• ⁴Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan
• ⁵Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
• ⁶Department of Child Health, Institute of Medicine, University of Tsukuba, Tsukuba, Japan
• ⁷Department of Allergy and Rheumatology, Chiba Children's Hospital, Chiba, Chiba, Japan
• ⁸Department of General Medical Science, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
• ⁹Department of Pediatrics, Kitasato University, Sagamihara, Japan
• ¹⁰Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan
• ¹¹Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan
• ¹²Department of Pediatrics, Seirei Hamamatsu General Hospital, Hamamatsu City, Japan
• ¹³Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
• ¹⁴Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Niigata, Japan
• ¹⁵Division of Immunology, National Center for Child Health and Development (NCCHD), Tokyo, Japan
• ¹⁶Department of Gastrointestinal and Pediatric Surgery, Mie University Graduate School of Medicine, Tsu, Japan
• ¹⁷Department of Rheumatism, Infectious Disease, Miyagi Children's Hospital, Sendai, Japan
• ¹⁸Department of Gastroenterology and Hepatology, Miyagi Children's Hospital, Sendai, Japan
• ¹⁹Department of Pediatrics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Nagasaki, Japan
• ²⁰Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
• ²¹Department of Pediatrics, Gunma University Graduate School of Medicine, Maebashi, Japan
• ²²Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan
• ²³Department of Pediatrics, Faculty of Life Sciences, Kumamoto University, Kumamoto, Kumamoto, Japan
• ²⁴Department of Rheumatology and Allergology, Japanese Red Cross Medical Center, Tokyo, Japan
• ²⁵Department of Pediatrics, Tokyo Bay Urayasu Ichikawa Medical Center, Urayasu, Chiba, Japan
• ²⁶Kawaguchi Municipal Medical Center, Saitama, Japan
• ²⁷Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
• ²⁸Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
• ²⁹Department of Clinical Immunology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
• ³⁰Department of Pediatrics, School of Medicine, Iwate Medical University, Yahaba, Japan
• ³¹Department of Pediatrics, School of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
• ³²Kyoto, Kyoto University Graduate School of Medicine, Kyoto, Kyōto, Japan

The severity of A20 haploinsufficiency (HA20) varies, with no established clinical guidelines for treatment. This study aimed to elucidate the clinical characteristics of, and the efficacy of treatments attempted in, patients with HA20 in Japan.Methods: Clinical information on HA20 patients from medical records was retrospectively collected through the attending physicians.Results: Seventy-two HA20 patients were identified in Japan. And, 54 patients from 37 unrelated families were analyzed in detail. HA20 patients exhibited common features, including recurrent fever, gastrointestinal and musculoskeletal symptoms, and autoimmune disease; various organ disorders (e.g. neurological, liver, and pulmonary diseases) were less common complications. Molecular target drugs (MTDs) were administered in 44.4% of patients, among which anti-tumor necrosis factor (TNF)-α agents showed efficacy in 59.5% of patients. Eleven patients did not experience control of inflammation with initial MTDs, most commonly because of relapse due to secondary failure of MTDs. Anti-drug antibodies were related to the secondary failure of adalimumab in one patient and infusion reactions to infliximab in two patients. In such refractory cases, other treatments (e.g. switching the first MTD to an alternative agent or adding a Janus kinase inhibitor or immunomodulators, or allogeneic hematopoietic cell transplantation [HCT]) were attempted. Conclusions: Our survey revealed that anti-TNF-α agents showed high efficacy. However, secondary failure of MTDs was a significant refractory-related factor in HA20 patients in Japan. Although antiinterferon therapies, thalidomide, and HCT might be potential treatment options, the results of this study suggest that further research is necessary to establish suitable treatments for HA20, especially for those with refractory disease.