Infliximab Therapy in a Patient with Crohn’s Disease and Chronic Hepatitis B Virus Infection

To the Editors: We report on a 40-year-old man, diagnosed 25 years earlier with ileocolonic Crohn’s disease (CD), who had repeated inflammatory flaring episodes that failed to respond to corticosteroids and azathioprine and required multiple surgical interventions: ileocecal resection (1985), right hemicolectomy (1993), extended colectomy with anastomosis to descending colon at the splenic colon angle due to fistula and peritonitis (1998), fistulectomy (1998), and finally a terminal ileostomy through an opening in the abdominal wall in July 1999, after another 4 surgical procedures due to symptomatic fistulae were needed. The patient was diagnosed 20 years earlier of an inactive hepatitis B virus (HBV) infection (HBsAg, HBeAb, and HBcAb positives, with normal alanine amino-transferase [ALT] levels and HBV-DNA negative). A HBV reactivation (HBV-DNA of 3.9 × 105 copies/mm3, aspartate aminotransferase [AST] 127 IU/L, and ALT 122 IU/L) was detected in April 1999, and a liver biopsy—performed during one of his surgical procedures for the management of his CD—detected a cirrhotic chronic hepatitis. In August 1999, upon reappearance of 3 fistula tracts through abdominal wall, he began treatment with infliximab (5 mg/kg at weeks 0, 2, and 6 followed by infusions every 8 weeks). A total of 6 infliximab infusions were given, and serum AST and ALT levels decreased gradually with no worsening of HBV replication. Lamivudine at a daily dose of 100 mg was started, but HBV-DNA levels failed to decrease. The patient has been followed up for a 3-year period since the last infliximab infusion was administered. Despite the absence of any CD therapy, the patient has not experienced further CD inflammatory flares and has maintained fistula closure. He has a persistent HBV replication. CD patients have a higher risk of HBV and hepatitis C virus (HCV) infection due to the frequent need of surgical and endoscopic procedures. 1 Serum tumor necrosis factor-α (TNF-α) levels are increased in patients with HBV and HCV chronic infection. TNF-α is a pro-inflammatory cytokine with important biological functions, including cytotoxicity against virus-infected cells, several immunomodulatory activities, as well as a direct antiviral activity and inflammatory response initiation. 2 Inhibition of TNF-α by specific antibodies (infliximab) might then have a detrimental effect on HBV- and HCV-infected patients, leading to an increase in viral replication and worsening of their liver function. The safety of infliximab in chronic HCV infection has been demonstrated in a retrospective study of 12 rheumatoid arthritis patients 3 as well as in 4 isolated cases. 1,4,–6 Nevertheless, we do not have enough data on the use of infliximab in patients with HBV chronic infection. The case of a young woman with a positive HBsAg who developed a fulminant hepatitis, 2 weeks after receiving a second infliximab infusion for a refractory adult Still’s disease, has recently been published. 7 The authors speculated about the possibility of a sudden and massive intrahepatic release of TNF-α leading to liver destruction. Another case of a young patient with rheumatoid arthritis and chronic HBV infection who suffered an acute hepatitis, after infliximab and low-dose methotrexate therapy, was also recently communicated. 8 Though in this case infliximab may have predisposed the development of this complication, we should consider the well-known hepatotoxic effect of methotrexate and its role in the depletion of antiviral-specific cytotoxic cells, decreasing the viral clearance rate. In our patient, the infliximab infusion was accompanied by a continuous decrease in AST and ALT, though the viral replication was kept active. Furthermore, therapy with lamivudine was initiated but the replication activity could not be stopped. In conclusion, these results as well as others previously reported cannot exclude the role of infliximab in a possible viral reactivation, but other relevant factors, such as the concomitant use of immunosuppressants, could be responsible for the hepatic imbalance observed in some patients. We believe there is a need to perform a HBV and HCV serology in every CD patient, particularly before steroid, immunosuppressant, or infliximab treatment is initiated, and to monitor the viral replication during therapy. It may also be beneficial to prescribe antiviral therapy before infliximab in those patients where the use of this agent is not yet required.