Drug-Induced Autoimmune Hepatitis by Varenicline and Infliximab as a Continuous Disease Spectrum with Two Different Flares: Acute Liver Injury Followed by Hepatic Autoimmunity.

Drug-induced autoimmune hepatitis (DIAIH) is a rare and complex disorder caused by drugs that are commonly metabolized by hepatic microsomal cytochrome P450 (CYP) pathways. Whereas DIAIH presents generally with a single clinical flare, in rare cases its clinical course shows two different, consecutively emerging flares. The aim of this report was to analyze details of this rare but interesting phenomenon and to help improve appropriate causality evaluation in patients with suspected iDILI or DIAIH to provide better insight into the pathomechanistic steps leading the diseases. A clinical course with two flares was found in a DIAIH patient treated with varenicline, a smoking cessation drug, and in another patient experiencing DIAIH following intravenous application of infliximab used to treat ankylosing spondylitis. In both patients, the first flare was determined as a typical liver injury with increased serum activities of alanine aminotransferase (ALT) and normal titers of serum autoimmune parameters, classified as an acute liver injury analogous to idiosyncratic DILI (iDILI), with verified causality using a modified version of RUCAM (Roussel Uclaf Causality Assessment Method). After an interval of around two months from the cessation of varenicline use, the second flare emerged, as evidenced by increased serum ALT values now associated with newly increased serum autoimmune titers of antinuclear antibodies (ANAs), classifying this flare as hepatic autoimmune injury with verified causality for varenicline using the simplified autoimmune hepatitis (AIH) score. A similar clinical DIAIH course of a continuous disease with two flares was described for the second patient, who received infliximab and experienced an interval of one month between the first and second flare. Interestingly to note, neither varenicline nor infliximab is degraded via a CYP pathway, and the metabolic disposition of both drugs is low. In sum, DIAIH can develop with two consecutive flares caused by two drugs not metabolized by CYPs and with slow drug disposition, raising the question of whether this phenomenon of two flares can occur in additional cases of DIAIH due to other drugs metabolized by CYPs or non-CYPs, a question to be resolved by DILI experts in future cases of iDILI and DIAIH.