In patients with rheumatoid arthritis who have evidence of hepatitis B or C infection, can TNF-a antagonists or IL-1 antagonists be safely used?

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Dee Dee Wu, MD
Rheumatology Fellow
Hospital for Special Surgery

This challenging clinical question arises because of the dual function of tumor necrosis factor alpha (TNF-a), a cytokine produced primarily by activated macrophages, which serves as a principal mediator of inflammation and cellular immune responses. On the one hand, TNF-a has been shown to be an important pathogenic mediator in patients with viral hepatitis, particularly in hepatitis B (HBV) infection, with liver injury related primarily to the elicited immune response, rather than to the viral infection itself. On the other hand, TNF-a plays a major role in the host's defense against viral infections. TNF-a achieves its anti-viral effects through direct cytotoxicity, activation of cytotoxic T-cells against infected cells, and inhibition of HBV gene expression and replication. Clinically, the role of TNF-a in HBV clearance is supported by studies demonstrating a significant increase in TNF-a production by peripheral mononuclear cells at the time of successful conversion of HBe antigen to HBe antibody in interferon alpha (IFN-a)-treated patients. Thus, the concern about using TNF-a antagonists in patients with HBV exists because of the potential to exacerbate the underlying hepatitis. This fear is substantiated by the fact that HBV reactivation is a well-known adverse event in patients with chronic infection receiving cytotoxic or immunosuppressive treatment.

Because the pathogenesis of hepatocellular damage in hepatitis C (HCV) infection is less understood, it is more difficult to predict the risk involved in using TNF-a antagonists in these patients. However, similar to HBV infection, high serum TNF levels have been shown to play a role in the pathogenesis of liver necrosis, and successful treatment of HCV infection reduces TNF-a levels to normal and clears the virus.

Interleukin-1 (IL-1) is a prominent pro-inflammatory cytokine produced by monocytes and macrophages that promotes T-cell proliferation. It has been suggested that IL-1 plays a role in viral clearance through regulation of the antigen presentation process. Molecular analysis has shown that IL-1 can enhance IFN-stimulated target gene expression and affect HBV gene transcription in hepatocytes. In HCV infection, the precise biological role of IL-1 is less well-defined, although one study demonstrated that IL-1 inhibited HCV subgenomic RNA replication in human hepatoma cells.

Only a few case reports involving the use of TNF-a antagonists in patients with known HBV and HCV infection have been published in the gastroenterology and rheumatology literature. Nearly all of these involved the use of infliximab (Remicade), a chimeric monoclonal antibody against TNF-a. There were no reports involving adalimumab (Humira), the newest TNF-a antagonist, or anakinra (Kineret), the recombinant IL-1 receptor antagonist.

There have been two case reports implicating infliximab, with severe liver injury occurring in patients with chronic HBV infection. The first involved a patient with rheumatoid arthritis (RA) and chronic HbsAg receiving Infliximab (6mg/kg) q8 weeks and low dose methotrexate (10mg/wk), who subsequently developed acute hepatitis one and a half years after initiation of therapy[1]. The authors attributed the acute hepatitis to HBV reactivation from infliximab treatment, rather than methotrexate, because methotrexate-associated fulminant hepatitis B has been rare despite its widespread use in HBV prevalent countries. The second involved a patient with adult onset Still's disease and chronic HbsAg who developed fulminant hepatitis, requiring orthotopic liver transplant, after his second dose of infliximab (3mg/kg)[2]. Although HBV reactivation was initially suspected, tests were negative for HBV DNA. However, the authors felt that infliximab was strongly implicated based on the temporal relationship between onset of hepatitis and infliximab infusion.

In contrast, the experience with TNF-a antagonists in HCV infection has been more favorable. Campell et al reported the use of infliximab in a patient with Crohn's disease and HCV, with no worsening of liver function or viral load[3]. Holtmann reported a similar experience with an additional two patients who received a single dose of Infliximab (5mg/kg). Both patients had no increase in liver enzymes, measured at 3 months post-infusion in the first patient and 12 months in the second, or in viral load, measured at 9 months and 12 months respectively[4]. Most recently, a small retrospective study involving 12 patients with RA and chronic HCV infection concluded that use of etanercept (Enbrel) and infliximab did not affect liver function tests or viral load within a one-year period[5].

In summary, the few reported experiences with TNF-a antagonists in HBV and HCV infection suggest that TNF-a antagonists should be avoided in patients with HBV infection, and used with caution in patients with HCV. There have been no reported data on the use or safety of adalimumab or anakinra. More studies involving larger numbers of patients and longer follow-up are needed to better assess the safety of these agents in this patient population.

[1] Ostuni P, Botsios C, et al. Hepatitis B reactivation in a chronic hepatitis B surface antigen carrier with rheumatoid arthritis treated with infliximab and low dose methotrexate. Ann Rheum Dis 2003;62:686-87.

[2] Michel M, Duvoux C, et al. Fulminant hepatitis after infliximab in a pt with hepatitis B virus treated for an Adult Onset Still's disease. J Rheum 2003;30:7.

[3] Campbell S, Ghosh S. Infliximab therapy for Crohn's disease in the presence of chronic hepatitis C infection. Eur J Gastroenterol Hepatol 2001 Feb; 13(2):191-2.

[4] Holtmann, MH. Treatment of Patients with Crohn's disease and Concomitant Chronic Hepatitis C with a Chimeric Monoclonal Antibody to TNF. AJG 2003;98 (2):504-5.

[5] Peterson JR, Wener MH, et al. Safety of TNF-a antagonists in patients with Rheumatoid Arthritis and Chronic Hepatitis C [abstract]. Arthritis Rheum 2001;44 Suppl 9:156.

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