Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Viewpoint
  • Published:

Biologic agents and liver toxicity: an added concern or therapeutic opportunity?

Nature Clinical Practice Rheumatology volume 3, pages 422–423 (2007)Cite this article

Biologic agents have transformed the armamentarium of available treatments for chronic inflammatory conditions. Tumor necrosis factor (TNF) inhibitors have proven to be highly effective, but are also associated with a variety of uncommon but serious toxic effects. These toxicities are well established and include risk of infection, malignancy and a number of other disorders,1 many of which seem to have autoimmune mechanisms. Surprisingly, therefore, the effects of biologic agents (including TNF inhibitors, rituximab and tocilizumab) on the liver have only recently come to light as both a problem because of potential toxicity, and as an opportunity for further indications of clinical efficacy. The issues that surround the potential effects of biologic agents on the liver can be more conveniently viewed as infectious and non-infectious.

In terms of non-infectious complications, TNF inhibitors have proven to be generally quite safe in terms of liver toxicity; only infliximab has shown a small and non-clinically significant effect on liver enzymes (but not on more important markers of liver function such as bilirubin or synthetic function).2 This effect seems to be disease specific, as it is more commonly seen in patients with psoriatic arthritis and spondyloarthropathy than in patients with rheumatoid arthritis or Crohn's disease.2,3 As well as these enzymatic signals, rare cases of serious liver toxicity have been observed in patients who receive treatment with all three of the FDA-approved TNF inhibitors, with the majority of toxicities being reported in patients exposed to infliximab. As these agents, including infliximab, have generated several million patient-years of exposure, these adverse events (n <40, FDA unpublished data courtesy of Jeffrey Segal) must be considered distinctly rare. Relatively few cases of such serious liver toxicity have been described in the peer-reviewed literature, but all have been associated with infliximab and each has demonstrated features consistent with an autoimmune type of hepatitis.4 Physician awareness of these toxicities is crucial, as the prompt discontinuation of the drug leads to improvement in most patients. Tocilizumab, an inhibitor of the receptor for IL-6, has demonstrated a clear but small signal of liver toxicity in early clinical trials with a dose-related effect demonstrated on aspartate transaminase, alanine transaminase and bilirubin; no patients experienced significant elevations of both alanine transaminase and bilirubin.5 The pattern of liver injury is quite different from that observed with other biologic agents and might be a direct effect of removing IL-6. Animal models of IL-6 knockouts have provided conflicting data on the role of IL-6 in reducing liver injury or impairing healing, depending on the nature of toxic injury.6

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Desai SB and Furst DE (2006) Problems encountered during anti-tumour necrosis factor therapy. Best Pract Res Clin Rheumatol 20: 757–790

    Article  CAS  Google Scholar 

  2. Remicade® (Centocor, Inc. Horsham, PA) website [http://www.remicade.com]

  3. Feletar M et al. (2004) Treatment of refractory psoriatic arthritis with infliximab: a 12 month observational study of 16 patients. Ann Rheum Dis 63: 156–161

    Article  CAS  Google Scholar 

  4. Germano V et al. (2005) Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis 64: 1519–1520

    Article  CAS  Google Scholar 

  5. Maini RN et al. (2006) Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 54: 2817–2829

    Article  CAS  Google Scholar 

  6. Gao B (2005) Cytokines, STATs and liver disease. Cell Mol Immunol 2: 92–100

    CAS  PubMed  Google Scholar 

  7. Calabrese LH et al. (2006) Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies. Ann Rheum Dis 65: 983–989

    Article  CAS  Google Scholar 

  8. Beyaert R and Fiers W (1998) Tumor necrosis factor and lymphotoxin. In Cytokines, 335–361 (Eds Mire-Sluis AR and Thorpe R) San Diego, CA: Academic Press

    Chapter  Google Scholar 

  9. Zein NN, Etanercept Study Group (2005) Etanercept as an adjuvant to interferon and ribavirin in treatment-naive patients with chronic hepatitis C virus infection: a phase 2 randomized, double-blind, placebo-controlled study. J Hepatol 42: 315–322

    Article  CAS  Google Scholar 

  10. Peterson JR et al. (2003) Effect of tumour necrosis factor alpha antagonists on serum transaminases and viraemia in patients with rheumatoid arthritis and chronic hepatitis C infection. Ann Rheum Dis 62: 1078–1082

    Article  CAS  Google Scholar 

  11. Ferri C and Mascia MT (2006) Cryoglobulinemic vasculitis. Curr Opin Rheumatol 18: 54–63

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. LH Calabrese is a Rheumatologist and N Zein is a Hepatologist, both at the Cleveland Clinic Foundation, OH, USA.,

    Leonard H Calabrese & Nizar Zein

Authors
  1. Leonard H Calabrese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nizar Zein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leonard H Calabrese.

Ethics declarations

Competing interests

Dr Zein has received research support from Centercore.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Calabrese, L., Zein, N. Biologic agents and liver toxicity: an added concern or therapeutic opportunity?. Nat Rev Rheumatol 3, 422–423 (2007). https://doi.org/10.1038/ncprheum0537

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncprheum0537

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing