SNOWMASS, COLO. — Tocilizumab has a “liver signal” that's likely to cause headaches for rheumatologists.
The problem arises from the associated high frequency of elevated liver function tests when tocilizumab (Actemra) is prescribed with methotrexate, a combination that was specifically okayed under both Food and Drug Administration and European Medicines Agency indications, Dr. Leonard H. Calabrese said at a symposium sponsored by the American College of Rheumatology.
The existing guidelines for methotrexate are not going to work as well when the drug is used in combination with tocilizumab. Because of the high rate of elevated liver enzymes, the guidelines are going to need to be reworked, predicted Dr. Calabrese, professor of medicine at the Cleveland Clinic Foundation.
Dr. Calabrese stressed that to date, the liver toxicity data for tocilizumab are “reasonably reassuring”: The vast majority of cases of increased liver enzyme levels are mild, with elevations no more than three times the upper limit of normal. The elevations are transient, and levels return to normal without treatment discontinuation or even dose adjustment. No serious drug-induced hepatotoxicity has been observed in more than 4,100 patient-years of exposure, nor has direct hyperbilirubinemia been seen.
That said, it's important to recognize that drug-induced serious hepatotoxicity is a rare event that often goes unrecognized until after a drug reaches the broader market. In fact, despite its rarity, hepatotoxicity is the No. 1 cause for withdrawal of drugs from the marketplace, Dr. Calabrese continued.
The approved indication for tocilizumab is treatment of moderate to severe rheumatoid arthritis in patients with an inadequate response to one or more tumor necrosis factor blockers. Tocilizumab, a once-monthly intravenous agent, may be used alone or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs. The FDA has required Genentech Inc. to implement a REMS (Risk Evaluation and Mitigation Strategy) that includes a plan to inform physicians how to monitor for liver and other GI side effects.
The tocilizumab label advises patients to tell their physicians of any preexisting liver problems, and alerts them to the need for liver function tests before and during therapy. Information included on the label in January 2010 warns of the possibility of elevated ALT in patients on the drug.
Clinical trials demonstrate that tocilizumab as monotherapy has a rate of elevated liver function tests similar to that of methotrexate monotherapy. When the drugs are used in combination, however, mildly elevated liver enzymes have occurred in one-third to nearly one-half of patients in the various studies.
It's not surprising that tocilizumab—a humanized monoclonal antibody directed against the interleukin-6 receptor—has displayed an early liver signal, in Dr. Calabrese's view. Hepatocytes express IL-6, a pleiotropic cytokine with numerous effects that are important to homeostatic regulation of the liver. Tocilizumab inhibits the STAT3 (signal transducer and activator of transcription 3) pathway, which plays a key role in blocking apoptotic injury to the liver. In animal studies, impedance of the STAT3 pathway greatly reduced the liver's ability to buffer injury resulting from alcohol and various other stressors.
As for the hepatic side effects of the other biologic agents used in rheumatology, infliximab (Remicade) carries the strongest warning language from the FDA. “Infliximab is an exception to the anti-TNF class. It's the only one that has a small liver signal even within the confines of clinical trials,” Dr. Calabrese said.
All of the TNF blockers have been linked to rare postmarketing reports of autoimmune hepatitis or other forms of severe hepatotoxicity, but infliximab is the one that has come up most frequently.
Disclosures: Dr. Calabrese disclosed serving as a paid consultant to Genentech, Roche, Amgen Inc., Centocor Inc., UCB Pharma Inc., Sanofi-Aventis, and Wyeth.