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.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies.