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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Certolizumab

Last Update: February 10, 2017.

OVERVIEW

Introduction

Certolizumab is a Fab fragment of a monoclonal antibody to human tumor necrosis factor alpha (TNFα) which has potent antiinflammatory activity and is used in the therapy of severe rheumatoid arthritis and inflammatory bowel disease. Certolizumab has had limited use and has yet to be specifically linked to instances of idiosyncratic acute liver injury or reactivation of hepatitis B, but is likely to cause similar hepatic injury to what has been described for other TNFα antagonists such as infliximab and adalimumab.

Background

Certolizumab (ser" toe liz' ue mab) is a Fab fragment of a humanized recombinant monoclonal antibody to TNFα linked to polyethylene glycol. The monoclonal antibody fragment binds avidly to serum and tissue bound TNFα causing its inactivation and degradation. Inhibition of TNFα activity leads to modulation of the inflammatory and pain pathways activated by this cytokine. The polyethylene glycol alters its pharmacokinetics, prolonging its half-life, and allowing for every 4 week administration. Certolizumab was approved in the United States in 2007 for use in Crohn disease and its indications were subsequently extended to rheumatoid and psoriatic arthritis and ankylosing spondylitis. Certolizumab is considered a disease modifying antirheumatic drug (DMARD) and has been shown to improve symptoms as well as joint and cartilage damage in the inflammatory arthritides. Certolizumab is available as lyophilized powder for reconstitution or in prefilled syringes as 200 mg/1.0 mL under the brand name of Cimzia. The typical dose of certolizumab for Crohn disease is 200 to 400 mg subcutaneously initially and at weeks 2 and 4, followed by 400 mg every 4 weeks. Recommendations vary slightly by indicationCommon side effects include injection site reactions, headache, nausea, abdominal discomfort, diarrhea, skin rash and fever. Severe side effects include bone marrow suppression and hypersensitivity reactions. TNFα antagonists are also capable of causing immune suppression, which can result in reactivation of microbial infections including tuberculosis and hepatitis B.

Hepatotoxicity

Certolizumab has been associated with a low rate of serum aminotransferase elevations during therapy, similar to the rate found with placebo therapy. The ALT elevations have been transient, mild and asymptomatic, and have rarely required dose modification. Certolizumab has been available for a relatively short period of time, and case reports of clinically apparent hepatic injury due to its use have not been published. Nevertheless, it is likely that certolizumab, like infliximab and adalimumab, is capable of inducing clinically apparent liver injury that resembles autoimmune hepatitis, which generally arises after at least 3 months of use and is associated with a hepatocellular pattern of serum enzyme elevation and autoantibody formation. Autoimmune hepatitis induced by anti-TNFα blocking agents can be severe and self-sustained and require corticosteroid therapy.

Certolizumab, like other TNFα antagonists, can also be expected to cause reactivation of chronic hepatitis B. Reactivation typically occurs in patients who are inactive HBsAg carriers, with normal serum aminotransferase levels and no or only low levels of HBV DNA in serum. The immune suppression caused by the immunomodulatory agent leads to an increase in HBV replication and rise in serum HBV DNA levels. With stopping the immunosuppression (or between cycles of therapy), restoration of immune function leads to an acute immunological response to the heightened viral replication and a flare of hepatitis, that can be severe and can result in hepatic failure and death. Reactivation in patients with anti-HBc without HBsAg (serologic pattern of previous HBV infection) has been reported only rarely in patients treated with anti-TNF antagonists, and is more common after therapy with rituximab and bone marrow transplantation. The anti-TNF inhibitors have little or no effect on hepatitis C virus levels and have been used safely in patients with chronic hepatitis C.

Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism of liver injury due to certolizumab and other TNFα antagonists is not known, but is likely caused by immune modulation and induction of autoimmunity.

Outcome and Management

Most published cases of hepatotoxicity due to anti-TNFα agents have been mild and self-limited. Patients who are to start certolizumab therapy should be screened for evidence of hepatitis B, and those with preexisting HBsAg should be offered prophylaxis with an oral antiviral agent such as lamivudine, tenofovir or entecavir. Patients who develop an autoimmune hepatitis-like syndrome during certolizumab therapy may not recover promptly with stopping the TNFα antagonist and may require corticosteroid therapy. In this event, the corticosteroid dose should be kept to a minimum to control the disease and, ultimately, attempts should be made to withdraw immunosuppression (or decrease to levels used before administration of certolizumab). Rechallenge with another monoclonal antibody based TNFα antagonist after hepatotoxicity from certolizumab has not been reported, but there does not appear to be cross reactivity in hepatic injury between either adalimumab or infliximab and etanercept, which is not a monoclonal antibody, but rather an altered form of the TNFα receptor.

References on the hepatotoxicity and safety of the anti-TNF necrosis factor agents are given together at the end of the Overview section on the Tumor Necrosis Factor Antagonists.

Drug Class: Antirheumatic Agents; Gastrointestinal Agents, Inflammatory Bowel Disease Agents

Other Drugs in the Subclass, Tumor Necrosis Factor Antagonists: Adalimumab, Etanercept, Golimumab, Infliximab

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Certolizumab – Cimzia®

DRUG CLASS

Antirheumatic Agents; Gastrointestinal Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Certolizumab Pegol 428863-50-7 Monoclonal antibodyNot available

ANNOTATED BIBLIOGRAPHY

References updated: 10 February 2017

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    (Expert review of hepatotoxicity published in 1999; no mention of tumor necrosis factor antagonists such as infliximab or certolizumab).
  • Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.
    (Review of hepatotoxicity of immunosuppressive agents; "the biological immuno-suppressants are largely free from hepatototxicity, with the exception of the TNF alpha antagonists").
  • Wallace JL, Sharkey KA. Pharmacotherpay of inflammatory bowel disesae. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1350-62.
    (Textbook of pharmacology and therapeutics).
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    (Controlled trial of methotrexate with or without certolizumab in 619 patients with rheumatoid arthritis; ALT elevations occurred in 5% of patients on methotrexate alone vs 2% on the combination; 5 cases of tuberculosis on certolizumab, but no mention of clinically apparent liver injury).
  • Shale MJ, Seow CH, Coffin CS, Kaplan GG, Panaccione R, Ghosh S. Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease. Aliment Pharmacol Ther 2010; 31: 20-34. [PubMed: 19681818]
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    (Systematic review of literature identified 257 patients with preexisting HBV markers who received anti-TNF therapy, reactivation occurred in 39% of 89 patients with HBsAg [5 had acute liver failure, 4 died], but only 5% of 168 with anti-HBc without HBsAg [1 died]; lamivudine prophylaxis decreased, but did not eliminate reactivation [62% vs 23% in HBsAg carriers).
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    (Description of 6 cases of acute liver injury due to anti-TNF agents from the US included 5 women [83%], ages 28 to 54 years, onset after 2-52 weeks of treatment with infliximab [n=3], etanercept [n=2] or adalumimab [n=1], ANA present in 3, [peak bilirubin 1.5-34.2 mg/dL, ALT 384-1687 U/L, Alk P 83-1311 U/L], 5 treated with corticosteroids, but all ultimately recovered).
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    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, the most common implicated agents being nimesulide [n=53: 30%], cyproterone [n=18], nitrofurantoin [n=17], antituberculosis drugs [n=13] and flutamide [n=12: 7%]; but none were attributed to a TNF antagonist).
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    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 6 cases were attributed to TNF antagonists: 1 to adalimumab, 2 etanercept and 3 infliximab, but none to certolizumab or golimumab).
  • Petríková J, Jarčuška P, Svajdler M, Pella D, Macejová Z. Autoimmune hepatitis triggered by adalimumab and allergic reactions after various anti-TNFα therapy agents in a patient with rheumatoid arthritis. Isr Med Assoc J 2015; 17: 256-8. [PubMed: 26040057]
    (33 year old woman with rheumatoid arthritis developed fatigue after 3 doses of adalimumab [bilirubin not given, ALT 888 U/L, Alk P 348 U/L, ANA positive], biopsy showing interface hepatitis, resolving with prednisolone; later having allergic reactions to etanercept and certolizumab, but responding to anakinra).

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