Short-Term Changes In The Radiographic Extent Of Interstitial Lung Disease Predict Long-Term Mortality In Systemic Sclerosis

Background: The forced vital capacity (FVC) is often used as the primary endpoint in treatment trials for systemic sclerosis-interstitial lung disease (SSc-ILD), and while trends in FVC have been found to predict mortality in SSc-ILD,1,2 FVC measurements are also influenced by extra-pulmonary factors, such as cutaneous sclerosis, myopathy, and patient/technician effort. Change in the quantitative extent of ILD (QILD) on HRCT is an emerging endpoint in clinical trials; however, no studies have evaluated whether changes in radiographic extent ILD predict mortality in SSc-ILD. Objectives: To evaluate the relationship between changes QILD in the whole lung (WL) and long-term survival in patients who participated in the Scleroderma Lung Study (SLS) I3 and II.4 Methods: SLS I randomized 158 SSc-ILD patients to 12 months of cyclophosphamide (CYC) vs. placebo. SLS II randomized 142 SSc-ILD patients to 12 months of CYC, followed by 12 months of placebo vs. 24 months of mycophenolate (MMF). QILD-WL scores were calculated at baseline and 12 months (SLS I) and 24 months (SLS II). Participants were followed for up to 12 (SLS I) and 8 years (SLS II). Using landmark survival analysis, Kaplan Meier curves were generated to compare survival between participants who had worse QILD-WL scores (≥2% increase) and those who had stable/improved QILD-WL scores ( Results: Among all the SLS I and II participants, 82 and 90 had follow up HRCT scans, respectively, and were included in these analyses. SLS I participants with an increase in QILD-WL scores of ≥2% at 12 months had significantly worse long-term survival (P= 0.01; Figure). Similarly, SLS II participants with an increase in QILD-WL scores of ≥2% at 24 months had significantly worse long-term survival (P= 0.019; Figure). After adjusting for baseline FVC, age, and modified Rodnan skin score (mRSS), an increase in QILD-WL scores of ≥2% remained associated with worse long-term survival in SLS I (trend: P=0.089) and SLS II (P=0.014). Conclusion: Progression of the radiographic extent of ILD of ≥2% was associated with worse long-term survival in two independent SSc cohorts with extensive long-term follow up. The findings provide compelling evidence that short-term changes in the radiographic extent of ILD may serve as a surrogate endpoint for mortality in patients with SSc. References: [1]Goh NS, et al. Arthritis Rheum 2017. [2]Volkmann ER, et al. Ann Rheum Dis 2019. [3]Tashkin DP, et al. NEJM 2006. [4]Tashkin DP, et al. Lancet Resp Med 2016. Disclosure of Interests: Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Forbius, Corbus, Donald Tashkin: None declared, Michael Roth Grant/research support from: Genentech/Roche, Jonathan Goldin: None declared, Grace Kim: None declared