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Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: a multicentre, prospective, observational study in Japan
  1. Wataru Fukuda1,
  2. Tadamasa Hanyu2,
  3. Masaki Katayama3,
  4. Shinichi Mizuki4,
  5. Akitomo Okada5,
  6. Masayuki Miyata6,
  7. Yuichi Handa7,
  8. Masatoshi Hayashi8,
  9. Yoshinobu Koyama9,
  10. Kaoru Arii10,
  11. Toshiyuki Kitaori11,
  12. Hiroyuki Hagiyama12,
  13. Yoshinori Urushidani13,
  14. Takahito Yamasaki14,
  15. Yoshihiko Ikeno15,
  16. Tsuyoshi Suzuki16,
  17. Atsushi Omoto1,
  18. Toshifumi Sugitani17,
  19. Satoshi Morita17,
  20. Shigeko Inokuma18
  1. 1Center for Rheumatic Disease, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan
  2. 2Department of Rheumatology, Nagaoka Red Cross Hospital, Niigata, Japan
  3. 3Department of Rheumatology, Osaka Red Cross Hospital, Osaka, Japan
  4. 4Department of Rheumatology, Matsuyama Red Cross Hospital, Ehime, Japan
  5. 5Department of Rheumatology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan
  6. 6Department of Internal Medicine, Japanese Red Cross Fukushima Hospital, Fukushima, Japan
  7. 7Department of Rheumatology, Saitama Red Cross Hospital, Saitama, Japan
  8. 8Department of Orthopedic Surgery and Rheumatology, Nagano Red Cross Hospital, Nagano, Japan
  9. 9Department of Rheumatology, Japanese Red Cross Okayama Hospital, Okayama, Japan
  10. 10Department of Internal Medicine, Japanese Red Cross Kochi Hospital, Kochi, Japan
  11. 11Department of Orthopedics, Japanese Red Cross Fukui Hospital, Fukui, Japan
  12. 12Yokohama City Minato Red Cross Hospital, Kanagawa, Japan
  13. 13Department of Rheumatology, Matsue Red Cross Hospital, Shimane, Japan
  14. 14Department of Rehabilitation, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
  15. 15Department of Rheumatology, Nasu Red Cross Hospital, Tochigi, Japan
  16. 16Division of Allergy and Rheumatology, Japanese Red Cross Medical Center, Tokyo, Japan
  17. 17Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
  18. 18Department of Allergy and Rheumatology, Chiba Central Medical Center, Chiba, Japan
  1. Correspondence to Dr Wataru Fukuda, Center for Rheumatic Disease, Japanese Red Cross Kyoto Daiichi Hospital, 15-749 Honmachi, Higashiyama-ku, Kyoto City, Kyoto 605-0981, Japan; wataru-fukuda{at}


Background Although the reactivation of hepatitis B virus (HBV) is recognised as a serious complication in patients with rheumatic disease (RD) receiving immunosuppressive drugs (ISDs), the incidence and risk factors for reactivation remain controversial.

Objectives To investigate the incidence and risk factors for HBV reactivation in patients with RD.

Methods We performed a multicentre, observational, prospective study over 2 years in patients with resolved HBV infection. Patients with RD treated with a dose of ≥5 mg/day prednisolone and/or synthetic or biological ISDs with negative HB virus surface antigen and positive anti-HB virus surface antibody (HBsAb) and/or anti-HB virus core antibody (HBcAb) were enrolled. Quantitative HBV DNA results and related data were regularly recorded.

Results Among 1042 patients, including 959 with rheumatoid arthritis, HBV DNA was detected in 35 (1.93/100 person-years), with >2.1 log copies/mL observed in 10 patients (0.55/100 person-years). None of the reactivated patients, including seven treated with a nucleic acid analogue, showed overt hepatitis. Low HBsAb titres and advanced age seemed to be risk factors for HBV reactivation; however, reactivation was observed in three patients with positive HBsAb and negative HBcAb test results. The risk of reactivation was lower with methotrexate but higher with prednisolone among the different types of ISDs. The intervals from the start of ISD to reactivation were relatively long (3–182 months; median, 66 months).

Conclusions The incidence of HBV reactivation with ISD use was 1.93/100 person-years in patients with RD with resolved HBV infection. No overt hepatitis was observed in the reactivated patients.

  • Infections
  • Rheumatoid Arthritis
  • Treatment
  • Epidemiology

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  • Handling editor Tore K Kvien

  • Contributors Munetoshi Nakashima, Toshihisa Kanamono, Rika Okada, Ryo Takahashi, Masahito Sato, Kosaku Murakami, Akiko Yoshida, Aki Sakashita and Masatoshi Kadoya contributed for enrolment of patients and Ms Tamaki Ota contributed for data processing in this work.

  • Funding Ministry of Health Labour and Welfare in Japan (15ek0410004h0003).

  • Competing interests None declared.

  • Ethic approvals Japanese Red Cross Kyoto Daiichi Hospital. The hospital ethics committees of all contributing institutions approved the protocol for this study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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