Impact of lung function decline on time to hospitalisation events in systemic sclerosis-associated interstitial lung disease (SSc-ILD): a joint model analysis

Abstract

Background 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). 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. Methods We 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. Results There 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®. Conclusions The 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 registration ClinicalTrials.govNCT02597933. Registered on 8 October 2015.

Decline in forced vital capacity as a surrogate for mortality in patients with pulmonary fibrosis

“…In our analyses, an increase in the rate of decline in FVC % predicted of 1 percentage point over 52 weeks increased the risk of acute exacerbation or death by 12%, and the risk of hospitalization or death by 9%. An analysis of the SENSCIS trial using similar methodology found a similar association between decline in FVC % predicted and risk of hospitalization or death over 52 weeks 38 …”

“…An analysis of the SENSCIS trial using similar methodology found a similar association between decline in FVC % predicted and risk of hospitalization or death over 52 weeks. 38 Strengths of our analyses include the large and heterogeneous population of subjects, the standardized procedure for measuring FVC and the use of a joint modelling approach that allows for estimation of time-dependent effects that considers temporality (i.e., FVC changes precede events at the individual level). Our analyses were limited by the time frame over which FVC decline and mortality were assessed (52 weeks), the use of different definitions for an acute exacerbation across the trials, and the lack of collection of data on acute exacerbations in the SENSCIS trial.…”

Efficacy and Safety of Nintedanib in Patients with Connective Tissue Disease-Interstitial Lung Disease (CTD-ILD): A Real-World Single Center Experience

“…Nintedanib was started on patients with progressive fibrosing ILD as previously defined [ 17 , 30 , 32 ]. PFTs in routine examination and in clinical trials mainly focus on FVC, DLco, and forced expiratory volume in 1 s (FEV1) measurements [ 33 , 34 , 35 ]. The % of the predicted values of the FVC, Dlco, and FEV1 was preferred as it is considered a primary outcome value and provides an adjusted, reliable, and simple prognostic factor [ 36 , 37 ].…”

State-of-the-art evidence in the treatment of systemic sclerosis

“…Data from the SENSCIS trial found that a decline in FVC increased hospitalizations and death, and a decrease in FVC of 3% was associated with 43% higher hospitalization and mortality 91 . Thus, although remaining an important complication and cause of death in SSc, lung fibrosis is now better understood and more manageable, with evidence-based treatment including medications to slow progression of fibrosis (nintedanib and possibly pirfenidone) and to potentially prevent ILD changes in early dcSSc (tocilizumab).…”