Those with auto-immune features had serum ANA titers ranging from 1:80 to 1 1:2560, and 17 subjects underwent liver biopsy that revealed autoimmune histopathologic features in 15

Those with auto-immune features had serum ANA titers ranging from 1:80 to 1 1:2560, and 17 subjects underwent liver biopsy that revealed autoimmune histopathologic features in 15. underwent serologic analysis (67%) tested positive for anti-nuclear and/or smooth muscle antibodies. Of these 22, 17 underwent liver biopsy; 15 subjects had clear features of autoimmunity. The 22 subjects with autoimmune features had longer median latency (16 vs 10 weeks) and higher peak levels of alanine aminotransferase (784 vs 528 U/L) than the 12 without such Mouse monoclonal to HDAC3 features. There was 1 case of severe cholestasis. All but one subject improved after discontinuation of the implicated drug; 12 subjects received corticosteroid therapy. PQM130 No deaths were attributed to liver injury, although one patient with preexistent cirrhosis required liver transplantation. CONCLUSIONS Acute liver injury caused by TNF-antagonists may be a class effect because multiple agents in this category have been implicated. The most common presentation is an autoimmune phenotype with marked hepatocellular injury, but a mixed non-autoimmune pattern or predominant cholestasis also occurs. The prognosis is usually good after drug discontinuation, although some patients may benefit from a course of corticosteroids. Number, “type”:”clinical-trial”,”attrs”:”text”:”NCT00345930″,”term_id”:”NCT00345930″NCT00345930 Antagonists, Hepatotoxicity, Autoimmunity Biological response modifiers are prescribed to modify the bodys response to inflammation, infection, and PQM130 neoplasia. These compounds include interferons, interleukins, bone marrow colony-stimulating factors, and tumor necrosis factor (TNF)Cantagonists. All of the TNF-antagonists have been associated with drug-induced liver injury (DILI).1,2 In addition, these agents carry specific warnings about the risk of reactivation of chronic hepatitis B.3 A Food and Drug Administration postmarketing surveillance program received more than 130 reports of liver injury resulting from either infliximab or etanercept treatment.4 The results were reported in Food and Drug Administration minutes, and although in many of these cases competing causes were identified, including viral reactivation, 7 of the reported cases were notable for their strong association with the TNF-antagonist in question.4 Two cases of successful treatment with etanercept after a prior DILI episode attributed to infliximab have recently been reported, suggesting that cross-toxicity is not universal among the different TNF-antagonists.5,6 However, it has been shown that several TNF-antagonists have a similar ability to elicit the development of serologic markers of autoimmunity. These compounds have also been associated with reactivation of latent tuberculosis, hepatitis B, the PQM130 development of lymphoma, demyelinating disease, seizures, aplastic anemia, and skin rash.3 Accordingly, some reported cases of TNF-antagonistCinduced liver injury exhibited autoimmune features on liver histology.6 This suggests the possibility that genetically susceptible individuals may generate an idiosyncratic immune response after inhibition of the TNF-pathway.1 In this report, we describe cases that are deemed to be 50% likely to represent bona fide TNF-antagonistCassociated hepatotoxicity. Six were enrolled in the ongoing U.S. Drug-Induced Liver PQM130 Injury Network (DILIN) Prospective Registry Study.7 We also performed a detailed literature search and critically reviewed 34 additional published cases. Of those, 28 met criteria for inclusion. Herein we summarize the clinical and laboratory presentation as well as clinical outcome of these 34 subjects. Methods We searched the U.S. DILIN database (between 2003 and 2011) for instances of DILI associated with TNF-antagonists that were scored probable (score 3) or higher likelihood on the following scale developed by the DILIN group: 1 = definite ( 95% likelihood), 2 = highly likely (76%C95%), 3 = probable (51%C75%), 4 = possible (25%C50%), and 5 = unlikely ( 25%).7 This means that we did not include cases of elevated liver test results associated with a TNF-alpha antagonist, which by consensus evaluation were found to be only possible or unlikely (ie, 50% likelihood of DILI). The Roussel-Uclaf Causality Assessment Method (RUCAM)8 score was calculated according to published guidelines, and the mean score (from 3 reviewers) was calculated. Causality assessment by RUCAM scores is as follows: 0 or lower, relationship PQM130 with the drug excluded; 1C2, unlikely; 3C5, possible; 6C8, probable; and 8, highly probable. A DILIN severity score was assigned according to a previously published scale from 1 (mild with bilirubin 2.5.