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Purpose Pirfenidone and nintedanib unequivocally inhibit FVC decline, but have been inconsistently linked to reduced mortality in phase III studies. On the contrary, real-world data show a survival benefit of antifibrotic drugs. However, it is unknown what this benefit is across different Gender, Age, and Physiology (GAP) stages. Research Questions Is there a difference in transplant-free (TPF) survival of IPF patients receiving antifibrotic drugs (IPF.sup.AF) compared with an untreated cohort (IPF.sup.non-AF)? Is this different for patients with GAP stage I, II, or III. Methods This is a single-center observational cohort study using prospectively included patients diagnosed with IPF between 2008-2018. Primary outcomes were TPF survival difference and 1-, 2-, and 3-year cumulative mortality for IPF.sup.AF and IPF.sup.non-AF. This was repeated after stratification for GAP stage. Results In total, 457 patients were included. The median transplant-free survival was 3.4 years in IPF.sup.AF (n = 313) and 2.2 years in IPF.sup.non-AF (n = 144, p = 0.005). For GAP stage II, a median survival of 3.1 and 1.7 years was noted for IPF.sup.AF (n = 143) and IPF.sup.non-AF (n = 59, p < 0.001), respectively. A significantly lower 1-, 2-, and 3- year cumulative mortality was found for IPF.sup.AF with GAP stage II (1 yr: 7.0% vs 35.6%, 2 yr: 26.6% vs 55.9%, and 3 yr: 46.9% vs 69.5%). The 1-year cumulative mortality of IPF.sup.AF with GAP III was also significantly lower (19.0% vs 65.0%). Conclusion This large real-world study showed a survival benefit in IPF.sup.AF compared with IPF.sup.non-AF. This especially holds true for patients with GAP stage II and III., Author(s): Mark G. J. P. Platenburg [sup.1], Coline H. M. van Moorsel [sup.1] [sup.2], Ivo A. Wiertz [sup.1], Joanne J. van der Vis [sup.1] [sup.3], Adriane D. M. Vorselaars [sup.1] [...]

BackgroundThe major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD.MethodsThrough an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline.ResultsOut of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern.ConclusionIn this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

Purpose Connective tissue growth factor (CTGF) is an important mediator in fibrotic disease. Single nucleotide polymorphisms (SNPs) in CTGF have been found to be associated with different fibrotic diseases and CTGF protein was found to be upregulated in lung tissue, bronchoalveolar lavage cells, and plasma of idiopathic pulmonary fibrosis (IPF) patients. We investigated whether genetic variants predispose to sporadic IPF (spIPF), familial pulmonary fibrosis (FPF), and connective tissue disease associated ILD (CTD-ILD). Methods In total, 294 patients with spIPF and 294 healthy individuals were genotyped for CTGF rs12526196, rs9402373, rs6918698, and rs9399005. For replication of CTGF rs6918698 findings in pulmonary fibrosis, 128 patients with FPF, 125 with CTD-ILD, and an independent control cohort of 130 individuals were included. Lung tissue of 6 IPF patients was stained for CTGF to assess pulmonary localization. Results Of the four SNPs, only the minor allele frequency (MAF) of CTGF rs6918698 deviated between spIPF (MAF 0.41) and controls (MAF 0.47; OR 0.774 (0.615-0.975); p = 0.030). Further comparison of CTGF rs6918698G showed a difference between FPF (MAF 0.33) and controls (MAF 0.48; OR 0.545 (0.382-0.778); p = 0.001), but not with CTD-ILD. CTGF was localized in alveolar and bronchiolar epithelium, alveolar macrophages, myofibroblasts and endothelium and highly expressed in the basal cell layer of sandwich foci. Conclusion CTGF rs6918698G associates with spIPF and with FPF, but not with CTD-ILD in a Dutch cohort. CTGF is localized in lung tissue involved in IPF pathogenesis. Further research into the role of this SNP on CTGF expression and fibrogenesis is warranted., Author(s): Dymph Klay [sup.1], Joanne J. van der Vis [sup.1] [sup.2], Suzan M. Roothaan [sup.3], Tri Q. Nguyen [sup.3], Jan C. Grutters [sup.1] [sup.4], Roel Goldschmeding [sup.3], Coline H. M. [...]

Background and Objective: The minor T‐allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real‐world population of European IPF patients. Methods: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed. Results: In a multi‐variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42–49]) compared to non‐carriers (29 months [CI: 26–33]; p = 4 × 10−12). Conclusion: MUC5B minor allele carriage associates with a better median transplant‐free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients. In idiopathic pulmonary fibrosis (IPF), the proportion of MUC5B rs35705950 minor allele carriers increases significantly with age. In IPF patients diagnosed at ≥56 years, transplant free survival is significantly better for MUC5B minor allele carriers compared to non‐carriers. These findings support implementation of MUC5B genotyping for clinical prognostication in IPF. [ABSTRACT FROM AUTHOR]

Background: In some patients with progressive fibrosing interstitial lung disease (ILD), disease is caused by carriage of a mutation in a surfactant related gene (SRG) such as, SFTPC, SFTPA2 (SFTP) or ABCA3. However, no aggregated data on disease evolution and treatment outcome has ever been presented for these patients.Research Question: In adult ILD patients with an SRG mutation, what is the course of lung function after diagnosis and under treatment and the survival in comparison with sporadic idiopathic pulmonary fibrosis (sIPF) and familial pulmonary fibrosis (FPF)?Study Design and Methods: We retrospectively examined the clinical course of a cohort of adults SRG patients by screening 48 subjects from 20 families with an SRG mutation for availability of clinical follow-up data. For comparison, 248 FPF and 575 sIPF patients were included.Results: Twenty-three ILD patients (median age: 45, 11 male) with an SRG mutation fulfilled criteria. At diagnosis, SRG patients were younger and less often male, but had lower FVC (72 %predicted) and DLCO (46 %predicted) compared to FPF and sIPF. In SRG, median FVC decline 6 months after diagnosis was -40ml and median transplant-free survival in SRG was 44 months and not different from FPF and sIPF. FVC course was not different between the three cohorts, however, significant larger decrease in FVC was found while patients received immunomodulatory (IMD) or antifibrotic (AF) treatment compared to no treatment. Subsequent analysis in SRG showed that SFTP patients (n=7) treated 6 months with AF drugs had stable lung function with a median change in FVC of +40ml (IQR 130), while SRG patients treated with IMD drugs showed a variable response dependent on the gene involved.Interpretation: This study shows that ILD patients with an SRG mutation have progressive loss of lung function with severely reduced survival despite possible beneficial effects of treatment. [ABSTRACT FROM AUTHOR]