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. 2025 Jun 12:16:1548042.
doi: 10.3389/fimmu.2025.1548042. eCollection 2025.

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

Mayuka Shiraki  1 , Saori Kadowaki  2 , Yuki Miwa  1 , Kenichi Nishimura  3 , Yuta Maruyama  4 , Dai Kishida  5 , Kazuo Imagawa  6 , Chie Kobayashi  6 , Hidetoshi Takada  6 , Kanako Mitsunaga  7 , Yuzaburo Inoue  7   8 , Takasuke Ebato  9 , Takayuki Miyamoto  10 , Eitaro Hiejima  10 , Shuzo Sato  11 , Kiyoshi Migita  11 , Tadashi Matsubayashi  12 , Daisuke Kobayashi  13 , Eriko Hasegawa  13 , Utako Kaneko  14 , Takashi Ishikawa  15 , Masafumi Onodera  15 , Kohei Matsushita  16 , Yuhki Koike  16 , Hiroaki Umebayashi  17 , Fumihiko Kakuta  18 , Daiki Abukawa  18 , Yasutomo Funakoshi  19 , Masataka Ishimura  20 , Yusuke Otani  21 , Takuya Nishizawa  21 , Takashi Ishige  21 , Reiko Hatori  21 , Seiji Tanaka  22 , Shouichirou Kusunoki  23 , Kimitoshi Nakamura  23 , Harumi Shirai  24 , Yoshiho Hatai  25 , Futaba Miyaoka  26 , Shuya Kaneko  27 , Asami Shimbo  27 , Masaki Shimizu  27 , Hirokazu Kanegane  28 , Motomu Hashimoto  29 , Nobuo Negoro  29 , Taro Yoshida  30 , Yasunori Wada  30 , Masaaki Usami  31 , Taizo Wada  31 , Kazushi Izawa  10 , Takahiro Yasumi  10   32 , Ryuta Nishikomori  22 , Hidenori Ohnishi  1   33   34   35
Affiliations

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

Mayuka Shiraki et al. Front Immunol. .

Abstract

Background: 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 anti-interferon 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.

Keywords: A20 haploinsufficiency; TNFAIP3; autoinflammatory disease; molecular target drugs; secondary failure.

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Conflict of interest statement

The Department of Early Diagnosis and Preventive Medicine for Rare Intractable Pediatric Diseases, Graduate School of Medicine, Gifu University is an endowed department supported by an unrestricted grant from the Gifu Research Center for Public Health. KNi received honoraria for lectures from Novartis Pharma, Abbvie and AstraZeneca, and his department received corporate scholarship grants from Chugai Pharmaceutical and Mitsubishi-Tanabe. DKi received honoraria for lectures from Novartis Pharma, Abbvie, Mitsubishi-Tanabe, Chugai Pharmaceutical, AstraZeneca, Pfizer, Eli Lilly, Asahi KASEI, GSK, Eisai, Taisho Pharmaceutical, UCB Japan and Amgen. YI received grants from Pfizer Japan Inc. and honoraria for lectures from Abbvie Japan GK and AstraZeneca K.K. TE received honoraria for lectures from Abbvie and Novartis Pharma. SS received grants from Chugai Pharmaceutical and Asahi Kasei. DKo received honoraria for lectures from Novartis Pharma, Abbvie, Janssen, Mitsubishi-Tanabe, Chugai Pharmaceutical, AstraZeneca, Pfizer and Eli Lilly. EHa received honoraria for lectures from Abbvie. UK received honoraria for lectures from Novartis Pharma and Abbvie. MO received honoraria for lectures from Chugai Pharmaceutical, Teijin Pharma, Astellas Pharma Inc., Novartis Pharma, Takeda pharmaceuticals and BioMarin Pharmaceutical Japan. HU received honoraria for lectures from Novartis Pharma, Chugai Pharmaceutical, GlaxoSmithKline, Abbvie and Pfizer. DA received honoraria for lectures from Abbvie and Mitsubishi-Tanabe. MI received honoraria for lectures from Mitsubishi-Tanabe and Chugai Pharmaceutical and participated in a clinical trial conducted by Novartis Pharma. TakuI received payment or honoraria for lectures and presentations from Mitsubishi Tanabe Pharma Corporation, EA Pharma, Abbvie GK, Janssen Pharma, Nihon Kayaku, Alfressa Pharma, Takeda Pharmaceuticals, JIMRO, Eisai, Sandoz, and Miyarisan. HS received honoraria for presentations from Novartis Pharma. MasS received honoraria for lectures from Novartis Pharma, Abbvie, Chugai, AstraZeneca, Pfizer and Eli Lilly. HK received honoraria for lectures from Takeda pharmaceuticals. MH received research grants and/or speaker fees from Abbvie, Asahi Kasei, Astellas, Bristol Meyers, Chugai, EA Pharma, Eisai, Daiichi Sankyo, Eli Lilly, Novartis Pharma, Taisho Toyama, and Mitsubishi Tanabe Pharma Corporation. NN received honoraria for educational events from Abbvie. YW received honoraria for lectures from Chugai Pharmaceutical, Pfizer and Eli Lilly. KI received honoraria for lectures and presentations from Novartis and consulting fees from SOBI. TYa received honoraria for lectures and presentations from Novartis Pharma. HO received honoraria for lectures and presentations from Novartis and Abbvie, and participated in a clinical trial conducted by SOBI, and his department received scholarship grants from Chugai, Asahi Kasei, Abbott Japan, Kyowa Kirin, Otsuka Pharmaceutical, Sumitomo Pharma, maruho, JCR, Japan Blood Products Organization, Mitsubishi-Tanabe and Shionogi. The remaining author declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Domain structure of TNFAIP3 (A20) and sites of variation identified in 54 patients with A20 haploinsufficiency in Japan. OTU, operational taxonomic unit; ZnF, zinc finger domain.
Figure 2
Figure 2
Reporter gene activity of truncating TNFAIP3 variants. The inhibitory effects of the wild-type gene and each variant on nuclear factor (NF)-κB reporter gene activity were compared. The pathogenicity of the truncating variants was examined using an NF-κB-driven luciferase reporter gene activity assay in A20-deficient HEK293 cells stimulated with tumor necrosis factor (TNF)-α (20 ng/mL). The wild-type gene had an inhibitory effect on NF-κB reporter gene activity, while the pathological variants had a disrupted inhibitory effect. Activities of frameshift and nonsense variants (A) and splice variants (B) of TNFAIP3 (A20). *P < 0.05, ***P < 0.001, ****P < 0.0001, as determined by one-way analysis of variance with Tukey’s multiple comparison test. RLU, relative light unit.
Figure 3
Figure 3
Treatments used for 54 patients with A20 haploinsufficiency in Japan. (A) Effects of each drug. (B) Continuity rate of each drug. NSAIDs, non-steroidal anti-inflammatory drugs.
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