Risk and Association of Specific HLA Alleles With Nintedanib‐Induced Gastrointestinal Adverse Reactions: A Discovery Study in an Italian Population

Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal lung disease with limited treatment options. Nintedanib and pirfenidone are the only antifibrotic drugs approved by both the USA and European medicinal agencies, but their efficacy and tolerability remain concerns. This exploratory study investigates the association between genetic variation in the Major Histocompatibility Complex (MHC) region and adverse effects (AEs) of these therapies. HLA genotyping has been previously performed in a discovery cohort of 124 IPF Italian patients, with recorded drug-related AEs. Logistic regression analysis using an additive model identified HLA-C*06:02 as a significant risk factor, increasing the likelihood of AEs sixfold in nintedanib-treated patients (p = 0.0043, OR = 6.54, 95% C.I. 1.80–23.75). Notably, gastrointestinal toxicity—the most common AE—was strongly associated with this allele (p = 0.0005, OR = 11.85, 95% C.I. 2.94–47.71). These findings suggest a potential immune-mediated mechanism involving IL-23-driven inflammation and underscore the importance of pharmacogenetic tools in tailoring antifibrotic therapy. Implementing genetic screening could help minimize AEs and improve patient outcomes. Larger studies are warranted to validate these associations and guide personalized treatment strategies.