Abstract
BackgroundInterstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). However, the relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints.MethodsWe used data from SENSCIS®, a phase III trial investigating the efficacy and safety of nintedanib in patients with SSc-ILD. Joint models for longitudinal and time-to-event data were used to assess the association between rate of decline in FVC% predicted and hospitalisation-related endpoints (including time to first all-cause hospitalisation or death; time to first SSc-related hospitalisation or death; and time to first admission to an emergency room [ER] or admission to hospital followed by admission to intensive care unit [ICU] or death) during the treatment period, over 52 weeks in patients with SSc-ILD.ResultsThere was a statistically significant association between FVC decline and the risk of all-cause (n = 78) and SSc-related (n = 42) hospitalisations or death (both P < 0.0001). A decrease of 3% in FVC corresponded to a 1.43-fold increase in risk of all-cause hospitalisation or death (95% confidence interval [CI] 1.24, 1.65) and a 1.48-fold increase in risk of SSc-related hospitalisation or death (95% CI 1.23, 1.77). No statistically significant association was observed between FVC decline and admission to ER or to hospital followed by admission to ICU or death (n = 75; P = 0.15). The estimated slope difference for nintedanib versus placebo in the longitudinal sub-model was consistent with the primary analysis in SENSCIS®.ConclusionsThe association of lung function decline with an increased risk of hospitalisation suggests that slowing FVC decline in patients with SSc-ILD may prevent hospitalisations. Our findings also provide evidence that FVC decline may serve as a surrogate endpoint for clinically relevant hospitalisation-associated endpoints.Trial registrationClinicalTrials.govNCT02597933. Registered on 8 October 2015.
Highlights
Interstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc
Various time to hospitalisation endpoints in the context of the SENSCIS® trial period were considered for inclusion in a joint model. These were (1) time to first all-cause hospitalisation or death, (2) time to first SSc-related hospitalisation or death, (3) time to first admission to the emergency room (ER) or admission to hospital followed by admission to an intensive care unit (ICU) or death, (4) time to first admission to hospital followed by admission to ICU or death, and (5) time to first admission to hospital followed by use of mechanical ventilation or death
There was no association found between forced vital capacity (FVC) decline and the time to first admission to ER or admission to hospital followed by admission to ICU or death at either 52 weeks or whole trial (P = 0.1549 and P = 0.3376, respectively)
Summary
Interstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). The relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints. Interstitial lung disease (ILD) is a common manifestation of SSc, in which parenchymal involvement can lead to pulmonary fibrosis and declining pulmonary function [2, 3]. An FVC absolute decline of 5–9% with a diffusing capacity of the lung for carbon monoxide (DLCO) absolute decline of ≥ 15% has been considered optimal for trial purposes [8], and an FVC decline or improvement of approximately 3% was considered a minimal clinically important difference based on data from Scleroderma Lung Study I and II [6]
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