Drug‐induced liver injury (DILI) sometimes presents with an autoimmune hepatitis‐like phenotype (AI‐DILI), and it is challenging to distinguish it from de novo autoimmune hepatitis (AIH). We conducted a study to identify autoantibodies unique to AI‐DILI by profiling serum autoantibodies. Autoantibodies were quantified using an autoantigen array containing 94 autoantigens from four groups: AI‐DILI (n = 65), DILI controls (n = 67), de novo AIH (n = 17), and healthy controls (HCs; n = 30). In 37 patients with AI‐DILI, samples were also collected 6 months after presentation. AI‐DILI and de novo AIH had similar anti‐neutrophil antibody and anti‐smooth muscle antibody prevalence. Compared to HCs, de novo AIH had an increase in many immunoglobulin G (IgG; 35 [46.1%]) and IgM (51 [70%]) autoantibodies, whereas AI‐DILI had an increase of IgM (40 [54.8%]) but not IgG autoantibodies. DILI controls had a similar IgG and IgM profile compared to HCs. Comparing de novo AIH to AI‐DILI identified 18 (23.7%) elevated IgG but only one (1.4%) IgM autoantibodies, indicating the unique IgG autoantibody profile in de novo AIH. Compared to DILI and HCs, increased IgM autoantibodies in AI‐DILI and de novo AIH were common; however, AI‐DILI induced by different drugs showed different frequencies of IgM autoantibodies, with nitrofurantoin‐related AI‐DILI showing a higher number of increased IgM autoantibodies. AI‐DILI autoantibody levels at diagnosis and at 6 months showed a significant decline in 37 IgM autoantibodies. A model with highly correlated IgG and IgM was fitted into multivariate logistic regression and revealed an area under the curve of 0.87 (95% confidence interval, 0.79‐0.95) to distinguish de novo AIH from AI‐DILI. Conclusion: The unique IgG and IgM autoantibody signature appears to be a promising biomarker for distinguishing AI‐DILI from de novo AIH.
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