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Incidence of Hepatitis B Virus Reactivation in Patients With Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209973 on 1 December 2016. Downloaded from Clinical and epidemiological research EXTENDED REPORT Incidence of hepatitis B virus reactivation in patients with resolved infection on immunosuppressive therapy for rheumatic disease: a multicentre, prospective, observational study in Japan Wataru Fukuda,1 Tadamasa Hanyu,2 Masaki Katayama,3 Shinichi Mizuki,4 Akitomo Okada,5 Masayuki Miyata,6 Yuichi Handa,7 Masatoshi Hayashi,8 Yoshinobu Koyama,9 Kaoru Arii,10 Toshiyuki Kitaori,11 Hiroyuki Hagiyama,12 Yoshinori Urushidani,13 Takahito Yamasaki,14 Yoshihiko Ikeno,15 Tsuyoshi Suzuki,16 Atsushi Omoto,1 Toshifumi Sugitani,17 Satoshi Morita,17 Shigeko Inokuma18 Handling editor Tore K Kvien ABSTRACT HBV infection is responsible for 40.2%, and HBV Background Although the reactivation of hepatitis B reactivation due to immunosuppressive drugs (ISDs) Additional material is ► virus (HBV) is recognised as a serious complication in has been observed in 6.8%, of fulminant hepatitis published online only. To view 2 please visit the journal online patients with rheumatic disease (RD) receiving cases in Japan. Because HBV reactivation could be (http://dx.doi.org/10.1136/ immunosuppressive drugs (ISDs), the incidence and risk caused by biological or non-biological disease- annrheumdis-2016-209973). factors for reactivation remain controversial. modifying antirheumatic drugs (DMARDs),3 HBV Objectives To investigate the incidence and risk infection is a serious problem for rheumatologists. For numbered affiliations see end of article. factors for HBV reactivation in patients with RD. HBV reactivation occurs in two forms: one involves Methods We performed a multicentre, observational, the harmful proliferation of virus seen in HB virus Correspondence to prospective study over 2 years in patients with resolved surface antigen (HBsAg)-positive people, healthy Dr Wataru Fukuda, Center for HBV infection. Patients with RD treated with a dose of carriers or patients with chronic HBV hepatitis and Rheumatic Disease, Japanese ≥5 mg/day prednisolone and/or synthetic or biological the other is seen in people with occult HBV infec- Red Cross Kyoto Daiichi ISDs with negative HB virus surface antigen and positive tion who are HBsAg-negative and anti-HB virus Hospital, 15-749 Honmachi, Higashiyama-ku, Kyoto City, anti-HB virus surface antibody (HBsAb) and/or anti-HB core antibody (HBcAb)-positive and/or anti-HB Kyoto 605-0981, Japan; wataru- virus core antibody (HBcAb) were enrolled. Quantitative virus surface antibody (HBsAb)-positive. Even [email protected] HBV DNA results and related data were regularly though the latter is less frequently seen than the recorded. former, strict monitoring and preventive treatment Received 27 May 2016 Results Among 1042 patients, including 959 with are recommended by guidelines in the USA,4 Revised 7 November 2016 1 5 6–8 Accepted 8 November 2016 rheumatoid arthritis, HBV DNA was detected in 35 Europe, Asia-Pacific and Japan. Published Online First (1.93/100 person-years), with >2.1 log copies/mL Because the prevalence of resolved HBV infection http://ard.bmj.com/ 1 December 2016 observed in 10 patients (0.55/100 person-years). None in Japan (23.2%) is much higher than that in of the reactivated patients, including seven treated with Western countries,9 all patients with rheumatoid a nucleic acid analogue, showed overt hepatitis. Low arthritis (RA) and other rheumatic diseases (RDs) in HBsAb titres and advanced age seemed to be risk Japan who receive immunosuppressive DMARDs, factors for HBV reactivation; however, reactivation was including methotrexate (MTX), leflunomide (LEF), observed in three patients with positive HBsAb and tacrolimus (TAC), mizoribine (MZB), corticoster- negative HBcAb test results. The risk of reactivation was oids and biological DMARDs, are recommended to on September 27, 2021 by guest. Protected copyright. lower with methotrexate but higher with prednisolone be screened and managed according to the guideline among the different types of ISDs. The intervals from the developed by the Drafting Committee for Hepatitis start of ISD to reactivation were relatively long Management Guidelines and the Japan Society of (3–182 months; median, 66 months). Hepatology.7 Patients with negative HBsAg results Conclusions The incidence of HBV reactivation with should be screened for HBsAb and HBcAb. If the ISD use was 1.93/100 person-years in patients with RD result for either of these antibodies is positive, the with resolved HBV infection. No overt hepatitis was patient needs to be monitored for HBV DNA (using observed in the reactivated patients. reverse transcription (RT)-PCR) every 1–3 months. Because the guideline has been strictly followed in Japan, the costs for HBV DNA monitoring and INTRODUCTION preventive treatment with nucleic acid analogues It is estimated that approximately 350 million (NAAs) have been increasing. However, there is people are infected with the hepatitis B virus insufficient clinical evidence to support the con- (HBV) worldwide and that one-third of the world’s cepts of the guideline currently, and its effectiveness To cite: Fukuda W, population is presently infected or has a history of for preventing fatal hepatic damage is unknown. Hanyu T, Katayama M, past HBV infection. End-stage liver disease related Our objective was to elucidate the frequency and et al. Ann Rheum Dis to HBV is responsible for over 0.5–1 million deaths risk factors for HBV reactivation in patients with 2017;76:1051–1056. per year.1 resolved HBV infection and RD. Fukuda W, et al. Ann Rheum Dis 2017;76:1051–1056. doi:10.1136/annrheumdis-2016-209973 1051 Ann Rheum Dis: first published as 10.1136/annrheumdis-2016-209973 on 1 December 2016. Downloaded from Clinical and epidemiological research METHODS regression analysis to evaluate risk factors for HBV reactivation This multicentre, observational, prospective study was con- and calculate risk ratios and its 95% CIs. We did not use multi- ducted by a study group consisting of rheumatologists in variate analysis because the number of events was too small for Japanese Red Cross hospitals beginning in 2013 and spanning analysis in a multivariate fashion. 2 years. Ethics Subjects In this study, we evaluated only information that is collected in Patients eligible for enrolment were those with RA or other usual medical practice, and we substituted the agreement acqui- RDs, over 18 years of age and attending a clinic for RDs in one sition in the document with posting based on ‘Ethical of the 16 Japanese Red Cross hospitals in Japan. Patients being Guidelines for Epidemiological Research’.12 treated with corticosteroids (≥5 mg of prednisolone or its equivalent dose); immunosuppressive synthetic DMARDs, RESULTS namely MTX, LEF, TAC, MZB or its equivalent and/or bio- Characteristics of enrolled patients fl logical DMARDs, namely in iximab, etanercept, adalimumab, Of 1330 patients, 1193 patients with RA and 137 other patients tocilizumab, abatacept, golimumab and certolizumab pegol with RD, initially enrolled, 75 patients who were were tested for HBsAg, HBsAb and HBcAb using chemilumin- HBsAg-positive or who received NAA were excluded. We then escent immunoassays. Patients with negative HBsAg (<0.05 IU/ excluded 213 other patients who dropped out for various ≥ mL) and positive HBsAb ( 10.0 mIU/mL) and/or positive reasons, including non-attendance, unrelated death or inad- ≥ HBcAb ( 1.0 S/CO (sample/cut-off)) results were tested for equate HBV DNA monitoring. Finally, we analysed 805 cases HBV DNA with RT-PCR, and those with negative results were observed for 24 months and 237 patients observed for enrolled. Patients positive for HBsAb alone need HBV DNA 12 months (figure 1). The characteristics of the enrolled patients monitoring except those with a history of HBV vaccination at the initial registration are shown in table 1. The average dose according to the Japanese Society of Hepatology guideline for of prednisolone in other patients with RD was more than twice 7 the management of HBV infection, as HBV reactivation is the dose in patients with RA. In the RA group, the majority of 10 11 reported in such patients. We excluded patients with posi- patients were treated with MTX, and almost one-third used bio- tive HBsAb and negative HBcAb with a history of vaccination logics, most (73.7%) of which were tumour necrosis factor from this study. (TNF) inhibitors. Other than MTX, TAC and MZB were used as ISDs in patients with RA. Registration The results regarding the presence of HBsAb and HBcAb are All data of the enrolled patients were recorded anonymously shown in table 2. The majority of patients were positive for and sent to the Japanese Red Cross Kyoto Daiichi Hospital both antibodies. Centre for Rheumatic Disease as password-protected digital information. The initial data collection was conducted from Incidence of HBV reactivation February 2013 to October 2014 and included the following HBV reactivation, as defined by positivity of HBV DNA, was information: basic patient characteristics, such as age, sex and found in 32 patients with RA and 3 with other RDs (in 1815 disease duration; data related to hepatitis, such as HBsAg, person-years) (table 3), and positivity ≥2.1 log copies/mL was HBsAb and HBcAb titres and aspartate transaminase and seen in 8 patients with RA and 2 with other RDs (in 1831 alanine transaminase levels within the last 3 months; immuno- person-years). Therefore, the frequency of HBV reactivation http://ard.bmj.com/ logical data, such as blood lymphocyte count and serum IgG was calculated to be 1.93/100 person-years, and the frequency levels; parameters related to disease activity, such as tender and of quantitative positivity (≥2.1 log copies/mL) was 0.55/100 swollen joints, Global Visual Analogue Scale score, Disease person-years. Seven of these patients were started on NAA Activity Score 28, C reactive protein level and erythrocyte sedi- mentation rate and information about medications, such as dose of steroids and MTX and use or no use of a biologic or other ISDs.
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