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Reactivation of hepatitis B virus infection in patients with rheumatoid arthritis receiving tofacitinib: a real-world study
  1. Yi-Ming Chen1,2,3,4,
  2. Wen-Nan Huang1,2,
  3. Yi-Da Wu1,
  4. Ching-Tsai Lin1,
  5. Yi-Hsing Chen1,2,
  6. Der-Yuan Chen1,2,3,4,5,
  7. Tsu-Yi Hsieh1,6
  1. 1 Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, Taichung, Taiwan
  2. 2 Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
  3. 3 Institute of Biomedical Science, National Chung Hsing University, Taichung, Taiwan
  4. 4 Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan
  5. 5 Institute of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan
  6. 6 Ph D Program of Business, College of Business, Feng Chia University, Taichung, Taiwan
  1. Correspondence to Dr Tsu-Yi Hsieh, Division of Allergy, Immunology and Rheumatology, Taichung Veterans General Hospital, No. 1650, Sec. 4, Taiwan Boulevard, Taichung 40705, Taiwan; zuyihsieh{at}

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A recent study reported long-term safety outcomes of tofacitinib for rheumatoid arthritis (RA) in global clinical trials1; the safety profile of tofacitinib exposure through 8.5 years appeared stable over time, with no new detectable safety signals. However, since most tofacitinib studies excluded patients with chronic hepatitis B (HBV) infection,1 2 the risk of HBV reactivation among tofacitinib-treated patients remains unknown.

More than two billion people globally have been infected by HBV,3 and a substantial number of patients with RA outside North America and Western Europe have coexisting HBV infection.4 HBV reactivation is a critical challenge in patients with RA receiving biological therapy5; consequently, HBV screening is recommended before initiating biologics.3 Janus kinase inhibition may counteract the suppressive effects of interferon α on viral replication6; therefore, we assessed the risk of HBV reactivation in patients receiving tofacitinib.

We established a retrospective cohort of 116 Taiwanese patients with RA who received tofacitinib at a single medical centre between April 2015 and February 2017 (figure 1A). Eighty-one (69.8%) had HBV infection, based on positive screening results for IgG antibody to anti-HBV core antigen with/without anti-HBV surface antibody (anti-HBsAb) — commensurate with 68.5% HBV core antibody positivity in a recent population-based survey in Taiwan.7 Among patients with prior HBV infection, six were defined as HBV carriers by HBV surface antigen (HBsAg) positivity and a normal alanine aminotransferase (ALT) level (table 1). Follow-up HBV DNA and ALT was done 3–6 months after tofacitinib treatment; the other 75 had resolved HBV infections, defined as prior HBV infection with normal ALT levels, but without detectable serum HBV DNA or HBsAg.8 Patients 1 and 2 in table 1, who had low viral loads and did not receive pre-emptive nucleotide analogues (NUCs), developed HBV reactivation, defined by a 10-fold rise in HBV DNA.5 Patient 1 had an elevated ALT level; rescue NUCs with entecavir diminished the HBV viral load and ALT level, and this patient continued conventional disease-modifying antirheumatic drugs and tofacitinib (figure 1B). Among four HBV carriers who did not develop HBV reactivation, two had received pre-emptive NUCs treatment. Conversely, none of the 75 patients with prior HBV infection received antiviral therapy. HBsAbs were detectable in 54 (72.0%) patients. Fifty-three (70.7%) had repeated HBV DNA after tofacitinib therapy; no HBV reactivation was observed.

Figure 1

(A) Flow diagram of patients with RA and HBV infection during tofacitinib therapy. (B) Liver function tests and HBV viral loads following tofacitinib treatment in patient 1 of table 1 with HBV carrier. *Repeated HBV DNA available in 13 patients, #Repeated HBV DNA available in 40 patients. ALT, alanine aminotransferase; anti-HBc IgG, IgG antibody to antihepatitis B core antigen; HBsAg, HBV surface antigen; HBsAb, HBV surface antibody; HBV, hepatitis B virus; NUCs, nucleotide analogues; RA, rheumatoid arthritis.

Table 1

Clinical characteristics of six tofacitinib-treated HBV carriers with rheumatoid arthritis

This retrospective observational study is the first to report HBV reactivation in HBV carriers with RA who did not receive pre-emptive antiviral treatment during tofacitinib therapy, despite having low levels of HBV DNA. Furthermore, no patients with RA who received prophylactic therapy developed HBV reactivation, indicating the efficacy of antiviral prophylaxis in preventing HBV reactivation.8 Although half of the HBV carrier patients without pre-emptive NUCs did not experience HBV reactivation, more evidence is needed to demonstrate whether stringent HBV DNA monitoring followed by rescue treatment could be a safe alternative to antiviral prophylaxis.9 A recent report demonstrated HBV reactivation in rheumatic patients with resolved HBV infection,10 whereas none of our HBsAg-negative patients with resolved HBV infection developed HBV reactivation. The presence of HBsAb may provide additional protection against viral reactivation.9 Further studies are warranted to infer protection of HBsAb in patients with RA with tofacitinib treatment. Repeated viral load measurements may be necessary if overt hepatitis occurs.

In conclusion, prophylactic antiviral treatment and periodic HBV DNA follow-up are critical for chronic HBV carriers with RA receiving tofacitinib treatment. Tofacitinib therapy appears safe in patients with resolved HBV infection. It is clinically important for physicians to beware of the risk of HBV reactivation in HBV carriers with RA who do not receive pre-emptive NUCs treatment before tofacitinib therapy.


The authors would like to thank Ms Tzu-Yin Yen for her assistance with case management of patients with RA. Dr David Neil (PhD) of Content Ed Net (Taiwan) provided medical editing services on behalf of Taichung Veterans General Hospital.



  • Contributors All authors made substantial intellectual contributions to conception of the work, the interpretation of data and approval of the final manuscript. T-YH and Y-MC conceived of the study, generated the original hypothesis, designed the study, and drafted and revised the manuscript. W-NH, Y-DW, C-TL and Y-HC acquired clinical data and analysed data. D-YC conceived of the study, analysed data and revised the manuscript.

  • Funding This study was supported by a grant from Taichung Veterans General Hospital, Taiwan (TCVGH-1057309C).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval Institution Review Board of Taichung Veterans General Hospital.

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