Nanna Makholm

Background: Randomised trials have shown that nintedanib slows decline in lung function in progressive pulmonary fibrosis (PPF), but real-world outcomes remain limited. We evaluated long-term lung function trajectories, survival, and predictors of survival in a nationwide cohort initiating nintedanib. Methods: This nationwide retrospective cohort study included all patients initiating nintedanib for PPF at the four tertiary Danish interstitial lung disease (ILD) centres between 2022 and 2024. Longitudinal changes in forced vital capacity (FVC) before and after treatment initiation were analysed using linear mixed-effects models. Survival was estimated using Kaplan-Meier analysis and Cox proportional hazards were used to identify predictors of mortality Results: We included 359 patients (median age 72 years; 58% male). Median baseline FVC was 2.31 L (69% predicted) and diffusing capacity for carbon monoxide (D _LCO ) 42% predicted. A usual interstitial pneumonia (UIP) pattern was present in 45%. The most frequent diagnoses were systemic autoimmune rheumatic disease-associated ILD (38%) and fibrotic hypersensitivity pneumonitis (28%). FVC decline decreased from 224 mL/year (95% CI 198–250) before treatment to 92 mL/year (95% CI 49–135) after initiation, a difference of 132 mL/year (95% CI 80–184; p<0.001). During a median follow-up of 25.2 months, 115 deaths occurred. Survival was 94.1% at 6 months, 84.8% at 12 months, and 70.7% at 24 months. Higher age and lower baseline FVC and DLCO were associated with increased mortality. Conclusion: In this nationwide real-world PPF cohort, nintedanib was associated with reduced lung function decline, but mortality remained substantial, highlighting the aggressive nature of PPF.

Background Progressive pulmonary fibrosis (PPF) is a common phenotype of fibrotic interstitial lung diseases (fILD) and is associated with substantial mortality. Antifibrotic therapy slows disease progression in clinical trials, but real-world data on survival remain limited. We aimed to evaluate survival and identify prognostic factors in patients with PPF managed at tertiary ILD centers. Methods In this nationwide, multicenter cohort study, we included all patients with PPF initiating antifibrotic therapy at all Danish ILD centers between 2022 and 2024. Survival and prognostic factors were analyzed using Kaplan–Meier methods and Cox proportional hazards regression models. Results A total 359 patients with PPF were included (median age 72 years, IQR 63–77; 42% female). Most patients were ILD–gender, age, physiology (ILD-GAP) stage I (74%). Median FVC was 69% predicted (IQR 57–84), and median DLCO 42% (IQR 34–51). The most common ILD diagnoses were autoimmune rheumatic ILD (38%, mainly rheumatoid arthritis-ILD) and hypersensitivity pneumonitis (28%), with usual interstitial pneumonia (UIP) pattern on HRCT in 45%. During follow-up, 117 patients died. Survival was 94.2%, 85.0%, and 70.4% at 6, 12, and 24 months, respectively. Survival did not differ by UIP pattern (log-rank p=1.00). High age and low baseline FVC % were independently associated with increased mortality. Differences in survival by sex, ILD-GAP stage, and ILD subtype were not statistically significant. Conclusion In this nationwide real-world cohort, one out of three patients with PPF died within two years. High age and low baseline FVC were key prognostic factors, while UIP pattern was not associated with survival. Our findings provide real-world benchmarks for survival in PPF and may support clinical risk assessment.

Background: Progressive pulmonary fibrosis (PPF) represents a common disease behaviour across fibrotic interstitial lung diseases (F-ILDs). PPF was defined in 2022, but data on extent and prognosis remain limited. The aim of this study was to determine the proportion of those with F-ILD who progress to PPF, investigate predictors of PPF and compare survival between PPF and non-PPF patients. Methods: This prospective longitudinal cohort study included all incident cases of F-ILD diagnosed at Danish tertiary interstitial lung disease (ILD) centres between 1 June 2016 and 31 May 2017. Patients with idiopathic pulmonary fibrosis or fewer than two pulmonary function tests were excluded. Data were obtained from the Danish ILD database (DANILDA) and national registries. PPF was defined according to the 2022 criteria. Survival was analysed using Kaplan–Meier estimates and Cox regression with PPF modelled as a time-dependent covariate and delayed entry handled by left truncation. Results: Of the 197 patients included, 57% developed PPF during 4 years of follow-up (median 13 months). No baseline variables predicted PPF development. The PPF group experienced a greater annual decline in forced vital capacity (FVC) (adjusted mean difference −140 mL·year ⁻¹ ; p=0.001) and diffusing capacity of the lung for carbon monoxide (−2.97 percentage points per year; p=0.009) than the non-PPF group. The 3-, 5- and 7-year survival rates were 73%, 58% and 48%, respectively, among those with PPF, and did not differ significantly between people with PPF and those with non-PPF. A higher baseline ILD–gender–age–physiology index (ILD-GAP) stage was independently associated with decreased survival (hazard ratio 2.64; p<0.001). Conclusion: In this nationwide real-world cohort, almost six out of 10 patients with F-ILD developed PPF within 4 years. Although patients with PPF exhibited a greater annual decline in FVC, survival rates did not differ between people with PPF and those with non-PPF.

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (F-ILD) are characterised by progressive loss of lung function, worsening symptoms, and poor prognosis. Current antifibrotic therapies slow disease progression but do not arrest or reverse fibrosis and are frequently associated with adverse effects. Senicapoc, a selective KCa3.1 channel inhibitor, has shown antifibrotic effects in preclinical models, human lung myofibroblasts, and ex vivo human lung tissue. This study aims to determine whether senicapoc reduces the rate of decline in forced vital capacity (FVC) over 26 weeks, compared with placebo, in patients with IPF or other progressive F-ILD, while also characterising safety and tolerability. Methods: This is an investigator-initiated, prospective, randomised, double-blind, placebo-controlled, multicentre phase II trial. Adults with IPF or other F-ILD with documented progression despite optimised antifibrotic management according to standard care and individual tolerability will be randomised 1:1 to receive senicapoc 30 mg once daily or a matching placebo for 26 weeks in addition to standard care. The primary outcome is the rate of decline in FVC over 26 weeks. Secondary outcomes include changes in diffusion capacity, 6 min walk distance, dyspnoea, health-related quality of life, adverse events, and senicapoc plasma concentrations, with mortality and exacerbations assessed as exploratory outcomes. The planned sample size is 140 participants. The primary analysis will be conducted in the intention-to-treat population using a linear mixed-effects model for repeated measurements. Results: No results are available, as this article describes the study protocol. Conclusions: This study will provide proof of concept for the efficacy, safety, and tolerability of senicapoc in progressive fibrotic interstitial lung disease. If successful, it will support further clinical development of KCa3.1 inhibition as a novel antifibrotic strategy.

Extract In fibrotic interstitial lung disease (F-ILD), characterized by progressive scarring, breathlessness is a defining symptom contributing to hospitalizations, mortality, and poor quality of life (QoL). [1, 2] Patients with F-ILD experience distress from breathlessness, while caregivers report feeling overwhelmed, anxious and depressed due to lack of support [3–5]. Without preparation to manage breathlessness at home, patients often seek emergency care, leading to respiratory hospitalizations and escalating costs [6]. Median survival post hospitalizations are 2.8 months, compared to 27.7 months for non-respiratory hospitalizations [7], highlighting need for dedicated dyspnoea care. Despite guidelines that recommend symptom management and quality of life measures with disease-modifying therapy [8, 9], breathlessness remains an unmet need. Shareable abstract Themes of invisibility and visibility; complexity of assessment; and prioritizing breathlessness in fibrotic interstitial lung disease revealed knowledge gaps, need for activity-based assessment, and experiential learning for clinicians.