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Drug-induced liver injury linked to multiple TNF-alpha antagonists

Drug-induced liver injury, most often presenting as acute hepatocellular injury with autoimmune features, may be a class effect of tumor necrosis factor-alpha antagonists, according to a recent case and literature review.

Researchers evaluated six cases of drug-induced liver injury (DILI) associated with tumor necrosis factor-alpha (TNF-a) antagonists, all collected from the US DILI Network (DILIN) database between 2003 and 2011. An additional 28 cases were collected via literature review of the PubMed database for studies evaluating TNF-a antagonist-related hepatotoxicity.

Maurizio Bonacini

“The study was prompted by the fact that the DILIN consortium started accumulating well-defined cases of drug hepatotoxicity,” researcher Maurizio Bonacini, MD, associate clinical professor in the department of transplantation at the California Pacific Medical Center in San Francisco, told Healio.com. “It was decided that literature cases should also be included to try to establish the most common presentation of anti-TNF toxicity.”

Infliximab was involved in 26 cases, with four cases each considered related to adalimumab and etanercept. According to a DILIN probability scale, the drug was a “definite” cause of injury in one case, “very likely” in 21 cases and the “probable” cause of DILI in 12 cases. Median latency was 13 weeks across all cases.

Anti-nuclear (ANA) and/or smooth muscle antibodies were observed in 22 of 33 patients who received serologic analysis and had higher peak ALT levels (784 U/L compared with 528 U/L; P=.03). They also experienced longer latency periods (median 16 weeks vs. 10 weeks; P=.17) than those without autoimmune symptoms.

No patients died from their injuries, and only one did not experience improvement after drug discontinuation, excluding 12 patients who also received corticosteroids. One cirrhotic patient required liver transplantation. Bonacini said this was in keeping with typical DILI prognosis, in which approximately 5% of patients require transplantation or die, but urged caution when treating cirrhotic patients with anti-TNF medications.

“Acute liver injury caused by TNF-alpha antagonists may be a class effect because multiple agents in this category have been implicated,” the researchers concluded. “The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed nonautoimmune pattern or predominant cholestatis also occurs. … The prognosis is generally favorable, and corticosteroids may be helpful in accelerating resolution in subjects with autoimmune features.”