Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis

Abstract

Objective - To examine the safety of the use of disease modifying anti- rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) patients with chronic vital hepatitis (CVH). Methods - Records of 600 Chinese patients satisfying the ARA criteria for RA in two rheumatology centers were reviewed. Patients with CVH were studied. Liver enzymes were checked before (baseline) and during DMARD use at 3-month intervals or more frequently if necessary. Drug- episodes (D-Ep), defined as the continuous use of DMARD, singly or in combination, for more than 6 months in a patient, were analysed. Changes in serum liver alanine transaminase (ALT) levels as multiples of the upper range of normal were taken to reflect the severity of hepatotoxicity. Changes of ALT to ≥ 1.5 times the upper range of normal if they were measured at baseline or ≥ 2 times the upper range of normal if they were measured during and after the use of DMARD were considered as abnormal. Control patients included those with CVH alone (n = 623) or RA without CVH (n = 62) matched for age, sex and D-Ep. Results - 30 RA patients were found to have concomitant CVH. One patient was excluded because of use of NSAID alone (n = 1). Among the 29 patients, 23 were HBsAg +ve and 6 were anti-HCVAb +ve. A total of 47 D-Ep were analysed. 20/47 (42.6%) of D-Ep in 16/29 (55.2%) RA +CVH patients developed abnormal ALT levels after a mean 1.9-year duration of DMARD use. This was statistically significant when compared with 13/94 (13.8%) of D-Ep which ended with abnormal ALT levels in 13/62 (21%) patients with RA alone (p < 0.0001 for D-Ep which ended up with abnormal ALT, and p < 0.02 for the number of patients who developed abnormal ALT) and 128/623 (20.5%) patients with CVH alone (p < 0.005). 53% (9/17) of hydroxychloroquine (HCQ) D-Ep were associated with an abnormal outcome. Corresponding figures for sulphasalazine (SAZP) and oral or intramuscular gold preparations were 55.6% (5/9) and 0% (0/3) respectively. Two patients on methotrexate, used either singly or in combination, had normal ALT levels throughout the study period. One patient on azathioprine developed reactivation of hepatitis B infection. When D-Ep of the RA +CVH group were further analysed, 16/43 (37.2%) and 4/4 (100%) D-Ep which started with normal and abnormal baseline ALT respectively developed further liver enzyme derangement. Conclusion - The use of DMARD in RA +CVH patients is associated with a high incidence of hepatotoxicity. The effect is likely to be synergistic. This includes drugs such as HCQ, which is generally believed to be less hepatotoxic.