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Infliximab, a humanised, mouse derived, genetically engineered, monoclonal antibody to tumour necrosis factor α (TNFα), is successfully used in association with low dose methotrexate in the treatment of rheumatoid arthritis (RA).1 Serious infections have been reported to be associated with infliximab treatment.1,2 However, the safety of infliximab is unknown or has not been yet established in chronic viral infections, including human immunodeficiency virus, hepatitis B virus (HBV) or hepatitis C virus infections. We describe a case, from our cohort of 102 patients treated with infliximab plus methotrexate, who carried hepatitis B surface antigen (HBsAg) and subsequently developed acute hepatitis due to HBV reactivation after 16 months of treatment with infliximab.
A 49 year old man was diagnosed as having RA in January 1990. HBsAg, and HBe and HBc antibodies were positive, while HBe antigen and HBs antibodies were negative. From January 1990 to May 2000 he received several treatments consisting of different disease modifying antirheumatic drugs (DMARDs) (hydroxychloroquine, sulfasalazine, sodium aurothiomalate, and cyclosporin A) in addition to oral steroids (<10 mg/day of prednisone) and non-steroidal antiinflammatory drugs. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) remained persistently normal. However, response to these treatments was poor, and peripheral arthritis persisted. In June 2000 he began treatment with infliximab (6 mg/kg every eight weeks) associated with methotrexate (10 mg/week), with a good response of the joint signs and symptoms, as well as the inflammatory indices. In January 2002 he developed malaise, anorexia, fatigue, increased levels of AST (97 IU/l) and ALT (176 IU/l), and then he was admitted to our division.
Hepatomegaly was evident on the physical examination. Serum AST, ALT, and total bilirubin were further raised to 336 IU/l, 573 IU/l, and 22.6 μmol/l, respectively. Hypoalbuminaemia and prolongation of the prothrombin time were also found. Abdominal ultrasonography showed ascites. There was no evidence of hepatitis A and C virus, Epstein-Barr virus, cytomegalovirus, or herpes simplex virus infection. IgM HBc antibodies, and high serum HBV/DNA polymerase levels (1492 pg/ml) were detected, and acute hepatitis caused by HBV reactivation was diagnosed. Infliximab and methotrexate were stopped, while prednisone (8 mg/day) was continued. Lamivudine at a daily dose of 100 mg was started, and, after two months, serum AST and ALT returned to normal (30 and 40 IU/l, respectively) and HBV/DNA polymerase levels dropped (9 pg/ml).
Hepatitis B reactivation is a well known adverse event in patients with chronic HBV infection receiving cytotoxic or immunosuppressive treatment.3
Inhibition of TNFα might lead to additional advantages for viral replication owing to escape from host antiviral mechanisms. The antiviral activity of TNFα has long been recognised.4 Indeed, synergistic activity of interferon γ (INFγ) and TNFα has been shown to affect early steps in herpes simplex virus replication at the level of early gene transcription and translation,5 while these cytokines inhibit murine cytomegalovirus late gene transcription and DNA replication.6
Data from animal models indicate that INFγ and TNFα may also synergistically inhibit HBV gene expression and replication, leading to a reduction in the intracellular level of HBV transcripts.7,8 Moreover, TNFα, which is induced by HBV antigens, is supposed to be beneficial for viral clearance.9 On the other hand, methotrexate might reduce the clearance of intrahepatic HBV depleting specific cytotoxic cells.10
Despite the wide use of methotrexate in the treatment of RA and the high prevalence of HBV infections in some countries, to our knowledge, only two other cases11,12 with fulminant hepatitis B (precore variant mutant type) after two years’ treatment and concomitant discontinuation of methotrexate have been reported.
So far, no reports have described an association between HBV hepatitis and conventional DMARDs such as d-penicillamine or sulfasalazine. Instead, a case with both Crohn’s disease and ongoing active hepatitis C infection has been reported. The patient underwent infliximab treatment with no worsening of his liver function or polymerase chain reaction status during a 16 week follow up period.13
Our case suggests that serological assay for hepatitis B should be performed before treatment with infliximab. If immunosuppressant drugs must be used in patients with RA and chronic infection with HBV, then liver function and HBV/DNA polymerase levels should be closely monitored.