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

Abstract

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 MUC5B (mucin 5B, rs35705950) and DSP (desmoplakin, rs2076295) on antifibrotic treatment outcomes in IPF.

Methods: MUC5B rs35705950 and DSP rs2076295 were assessed in IPF patients (n = 210, 139 men/71 women) from the Czech EMPIRE registry and age- or sex-matched healthy individuals (n = 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 MUC5B rs35705950*T allele (55.2% versus 20.9%, p < 0.001) and the DSP rs2076295*G allele (80.4% versus 68.3%, p < 0.001) in IPF compared with controls. On antifibrotic drugs, lower mortability was observed in IPF patients with DSP G* allele (p = 0.016) and MUC5B T* allele (p = 0.079). Carriers of the DSP 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; p = 0.013] and a slower decline in lung function (HR = 8.51; 95% CI = 1.68-43.14; p = 0.010). Patients with a TT genotype (rs2076295) benefitted from treatment with pirfenidone by prolonged OS (p = 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 MUC5B rs35705950*T allele carriage, no difference in treatment outcome was observed for nintedanib or pirfenidone (p = 0.784). In the multivariate model, smoking, age, forced vital capacity (FVC) and DL_CO (diffuse lung capacity) at the IPF diagnosis were associated with survival.

Conclusion: Our real-world study showed that IPF patients with MUC5B T* allele or DSP G* allele profit from antifibrotic treatment by lower mortability. Moreover, carriers of the DSP rs2076295*G allele benefit from treatment with nintedanib, and TT genotype from treatment with pirfenidone. MUC5B 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.

Keywords: IPF; antifibrotic treatment; desmoplakin; mucin 5; single nucleotide polymorphisms.

Figure 1.

Mortality in IPF patients subdivided according to the carriage of MUC5B*T allele treated with (a) nintedanib or pirfenidone or (b) without antifibrotic treatment and comparison between nintedanib or pirfenidone treatments versus without antifibrotic treatment for (c) *T allele carriers and (d) GG genotypes.

Figure 2.

Mortality in IPF patients subdivided according to the carriage of MUC5B*T allele treated with (a) nintedanib or (b) pirfenidone and comparison between nintedanib and pirfenidone treatments for (c) *T allele carriers and (d) GG genotypes.

Figure 3.

Hazard risk for all-cause death and a lung function decline in IPF patients with respect to the MUC5B rs35705950. Hazard risks (HRs) are presented with 95% confidence intervals noted in parentheses.

Figure 4.

Mortality in IPF patients subdivided according to the carriage of DSP rs2076295*G allele treated with (a) nintedanib or pirfenidone or (b) without antifibrotic treatment and comparison between nintedanib or pirfenidone treatments versus without antifibrotic treatment for (c) *T allele carriers and (d) GG genotypes.

Figure 5.

Mortality in IPF patients subdivided according to the carriage of DSP rs2076295*G allele treated with (a) nintedanib and (b) pirfenidone and comparison between nintedanib and pirfenidone treatments for (c) *G allele carriers and (d) TT genotypes.

Figure 6.

Hazard risk for all-cause death and a lung function decline in IPF patients with respect to the DSP rs2076295 variants. Hazard risks (HRs) are presented with 95% confidence intervals noted in parentheses.