Infliximab Induced Hepatitis with Autoimmune Features

Abstract

Purpose: 37-year-old man with Ulcerative Colitis since 11 years, on infliximab for last 8 months, presented with increasing fatigue, myalgia and fever. Laboratory evaluation revealed elevated liver enzymes (Table 1). Patient had extensive work up including viral serologies, fungal etiologies, iron studies, alpha-1 antitrypsin and ceruloplasmin levels which were non diagnostic. Antinuclear antibody (ANA) Titers were 1:640 (homogenous pattern). Antidouble stranded DNA (Ds DNA) was positive and complement levels were low. Anti-smith antibody, smooth muscle antibody, F-actin antibody, anti-neutrophilic cytoplasmic antibodies(ANCA), SS-A and SS-B were all negative. Colonoscopy showed severe inflammation in descending colon, sigmoid colon and rectum with multiple ulcerations and inflammatory exudate. Biopsies showed active colitis with no dysplasia. MRCP showed periportal inflammatory changes and pericholecystic edema. Liver biopsy showed predominantly portal hepatitis with bridging necrosis, neutrophilic cholangitis and increased eosinophils suggestive of drug induced Hepatitis most likely secondary to infliximab. After discontinuation of infliximab, liver enzymes trended down by 10 weeks and were normal after 5 months. ANA and Ds-DNA remained elevated. Although generally safe and well tolerated, tumor necrosis factor-α (TNF-α) inhibitors are associated with the induction of autoantibodies in a dose and duration dependent manner. Autoimmune hepatitis (AIH) is a very rare adverse side effect of infliximab. To date only 6 cases of AIH have been reported. Pathogenesis of infliximab induced hepatitis is unclear. One hypothesis could be an increase of apoptotic particles which represent a reservoir of autoantigens. Nucleosomes which represent core chromatin are major auto antigens released during cell death. One group has shown higher levels of circulating nucleosomes following infliximab infusions. The accumulation of nucleosomes could possibly enhance development of auto antibodies in subjects with appropriate genetic backgrounds. Another theory is that TNF-α blockade interferes with the normal cytotoxic T-lymphocyte suppression of auto (self)-reactive B cell production. Genetic predisposition is also thought to be important, with HLA DR3 and DR4 alleles being associated with Type 1 AIH. Withdrawal of infliximab is the standard therapy for TNF-α induced hepatitis. Average clinical recovery after removal of offending agent is 10 months. As TNF-a inhibitors are being used more frequently for management of inflammatory bowel disease, we need to remember AIH as a potential consequence of TNF inhibitor therapy.Table 1