Steven D. Nathan, MD
Medical Director, Lung Transplant Program
Advanced Lung Disease Program
Inova Fairfax Hospital
Falls Church, Virginia

Oldham JM, Ma S-F, Martinez FJ, Anstrom KJ, Raghu G, Schwartz DA, Valenzi E, Witt L, Lee C, Vij R, Huang Y, Strek ME, Noth I, and for the IPFnet Investigators. TOLLIP, MUC5B and the Response to N-acetylcysteine Among Individuals with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. First published online 02 Sep 2015 as DOI: 10.1164/rccm.201505-1010OC

This study is a post-hoc exploratory analysis of patients from the PANTHER trial. The study question is whether polymorphisms in TOLLIP or MUC5B modify the effect of therapeutic interventions. Single nucleotide polymorphisms (SNPs) within TOLLIP and MUC5B have recently been shown to be associated with IPF susceptibility and survival, and five SNPs were chosen for this analysis – rs5743890, rs5743894,m rs5743854, rs3750920 (all from TOLLIP) and rs35705950 (from MUC5B). The number of available samples ranged from 13 to 30 in the rs3750920 groups.

No significant interaction was detected between triple therapy and any of the SNPs of interest. Interaction modeling showed significant interaction between N-acetylcysteine (NAC) therapy and the T allele of rs3750920 within TOLLIP (Pinteraction = 0.001). Survival analysis stratified by rs3750920 (TOLLIP) genotype is shown in the figure. Among patients with a CC genotype (left panel), NAC therapy was associated with significantly worse survival than placebo in unadjusted analysis (P = 0.01), but not after multivariable adjustment (HR 3.23; 95% CI 0.79-13.16; P = 0.10). There was no difference in survival between NAC and placebo groups in patients with a CT genotype in unadjusted analysis (P = 0.82), or after multivariable adjustment (HR 0.76; 95% CI 0.27-2.19; P = 0.62). Among patients with a TT genotype, NAC therapy was associated with borderline improved survival compared to placebo in unadjusted analysis (P = 0.06), and with significantly reduced endpoint risk after multivariable adjustment (HR 0.14; 95% CI 0.02-0.83; P = 0.03).

Expert Commentary
If the findings of this study are reproduced in larger cohorts the discovery of differential responses of patients to NAC based on DNA polymorphisms may lead to individualization of therapy of patients with IPF. Patients with the rs3750920 TT genotype may benefit from NAC treatment; the same treatment may not be of benefit for CT patients and may be harmful for CC patients. This paper lays the foundation for future clinical trials and precision therapy in IPF through SNP analysis of individual patients. Studies assessing interactions with the currently approved IPF drugs nintedanib and pirfenidone might be revealing and are encouraged.