Long-term use of methotrexate does not result in hepatitis B reactivation in rheumatologic patients

Hepatitis B virus (HBV) infection is still prevalent in Asia, including Thailand. HBV can archive in hepatocytes for life and can reactivate after immunosuppression and chemotherapy administration. Use of immunosuppressive agents is recommended in many rheumatologic diseases and reactivation of HBV can occur. Data regarding the effect of methotrexate (MTX) on HBV reactivation is scanty. MTX is a well known cause of hepatic fibrosis but its effect on HBV reactivation is not clearly understood. There is no specific recommendation for HBV prophylaxis for patients using MTX. This study aimed to determine the prevalence of HBV seromarkers in rheumatologic patients who were treated with long-term MTX and to evaluate the hepatitis outcome in the patients with positive HBV markers.

This was a cross-sectional study at the Rheumatology Clinic, Siriraj Hospital, Bangkok, Thailand. Patients aged 15 years or older treated with MTX more than 24 weeks were invited in the study. Review of medical history, MTX prescription and dosage during the last 52 weeks, blood tests for liver function tests, HBV serology, and HBV DNA viral load were performed. The exclusion criteria included patients who were treated with biological DMARDs, drugs active against HBV, known co-infection with HCV or HIV and previous diagnosis of cirrhosis from any causes or presence of hepatocellular carcinoma.

A total of 173 patients were enrolled (153 females, 20 males, mean age of 52.6 ± 13.6 years). The majority of patients were diagnosed with rheumatoid arthritis (67.0%), SLE (13.9%), spondyloarthopathies (8.7%) and others (10.4%). Thirty percent of them (55/173) had no previous data for HBV seromarkers. Among 118 patients who had baseline data, only one patient (0.8%) had HBsAg positive. Average duration of treatment was 9.9 years and MTX dose prescribed was 571.6 ± 240.4 mg during the last 52 weeks. Out of 173 patients, only two had clinically significant hepatitis (1.16%) and one was HBsAg positive (0.58%). Ninety-six patients (55.5%) were negative for all HBV seromarkers, 67/173 (38.7%) positive for anti-HBs antibody and 65/173 (37.6%) positive for anti-HBc IgG. Only one in 65 patients (1.5%) who had any positive HBV seromarkers had HBV DNA detectable.

Prevalence of HBsAg positive rheumatologic patients treated with MTX in Thailand was only 0.58%, which was lower than the general Thai population. About one-third of the patients had exposure to HBV as demonstrated by presence of anti-HBc IgG (37.6%), but none of them had hepatitis B reactivation during 9.9 years of MTX treatment. Moreover, one case with HBsAg positive had been receiving MTX without HBV prophylaxis for 5 years but had no evidence of HBV flare and evidence of fibrosis. From our study, long-term MTX in patients exposed to HBV was safe and not associated with hepatitis flare. However, more study is needed as to whether HBV prophylaxis is required.