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

Michael Kreuter, Francesco Del Galdo, Corinna Miede, Dinesh Khanna, Wim A Wuyts, Laura K Hummers, Margarida Alves, Nils Schoof, Christian Stock, Yannick Allanore, Michael Kreuter, Francesco Del Galdo, Corinna Miede, Dinesh Khanna, Wim A Wuyts, Laura K Hummers, Margarida Alves, Nils Schoof, Christian Stock, Yannick Allanore

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.gov NCT02597933 . Registered on 8 October 2015.

Keywords: Forced vital capacity; Hospitalisation; Joint model; SENSCIS; Surrogate endpoint; Systemic sclerosis-associated interstitial lung disease.

Conflict of interest statement

MK reports consultancy fees from Boehringer Ingelheim (BI), Roche and Galapagos, outside the submitted work. FDG reports research grants from Capella Biosciences, Mitsubishi-Tanabe, Chemomab and Kymab; and consultancy fees from Actelion, BI, AstraZeneca, Mitsubishi-Tanabe, Capella and Chemomab, outside the current work. DK reports research grants from Immune Tolerance Network, Bayer, Horizon and Pfizer; consultancy fees from Acceleron, Actelion, Abbvie, Amgen, Bayer, BI, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GlaxoSmithKline, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis and United Therapeutics; and employment at Eicos Science/CiviBioPharma, outside the submitted work. WW has nothing to disclose. LKH reports research grants from BI, Corbus, Cumberland, CSL Behring, Kadmon and Medpace; and advisory board fees from BI, outside the submitted work. YA reports consultancy fees from BI, during the conduct of the study. MA is an employee of Boehringer Ingelheim International GmbH. NS was an employee of Boehringer Ingelheim International GmbH at the time of this study. CS is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. CM is an employee of mainanalytics GmbH, which is a service provider contracted by BI.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Change in risk of first hospitalisation endpoints by decline in FVC% predicted a all-cause hospitalisation or death, b SSc-related hospitalisation or death and c ER or hospital admission followed by ICU or death. Data collected during the treatment period over 52 weeks. CI, confidence interval; ER, emergency room; FVC, forced vital capacity; HR, hazard ratio; ICU, intensive care unit; SSc, systemic sclerosis

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