rs2076295 variants influence nintedanib and pirfenidone outcomes in idiopathic pulmonary fibrosis: a pilot study.

Background: The antifibrotic drugs nintedanib and pirfenidone are used for the treatment of idiopathic pulmonary fibrosis (IPF). We analysed the association of common profibrotic polymorphisms in (mucin 5B, rs35705950) and (desmoplakin, rs2076295) on antifibrotic treatment outcomes in IPF.

Methods: rs35705950 and rs2076295 were assessed in IPF patients ( = 210, 139 men/71 women) from the Czech EMPIRE registry and age- or sex-matched healthy individuals ( = 205, 125 men/80 women). Genetic data were collated with overall survival (OS), acute exacerbation episodes, worsening lung function and antifibrotic treatment.

Results: We confirmed overexpression of the rs35705950*T allele (55.2% 20.9%,  < 0.001) and the rs2076295*G allele (80.4% 68.3%,  < 0.001) in IPF compared with controls. On antifibrotic drugs, lower mortability was observed in IPF patients with G* allele ( = 0.016) and T* allele ( = 0.079). Carriers of the rs2076295*G allele benefitted from nintedanib treatment compared with TT genotype by a longer OS [hazard ratio (HR) = 7.99; 95% confidence interval (CI) = 1.56-40.90;  = 0.013] and a slower decline in lung function (HR = 8.51; 95% CI = 1.68-43.14;  = 0.010). Patients with a TT genotype (rs2076295) benefitted from treatment with pirfenidone by prolonged OS ( = 0.040; HR = 0.35; 95% CI = 0.13-0.95) compared with nintedanib treatment. Both associations were confirmed by cross-validation analysis. After stratifying by rs35705950*T allele carriage, no difference in treatment outcome was observed for nintedanib or pirfenidone ( = 0.784). In the multivariate model, smoking, age, forced vital capacity (FVC) and DL (diffuse lung capacity) at the IPF diagnosis were associated with survival.

Conclusion: Our real-world study showed that IPF patients with T* allele or G* allele profit from antifibrotic treatment by lower mortability. Moreover, carriers of the rs2076295*G allele benefit from treatment with nintedanib, and TT genotype from treatment with pirfenidone. rs35705950 did not impact the outcome of treatment with either nintedanib or pirfenidone. Our single-registry pilot study should be confirmed with an independent patient cohort.