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 (<2% increase). Cox proportional hazards models were created to determine whether the change in QILD-WL scores predicted survival after controlling other variables found to affect survival in these cohorts.
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: Goh NS, et al. Arthritis Rheum 2017.
Volkmann ER, et al. Ann Rheum Dis 2019.
Tashkin DP, et al. NEJM 2006.
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
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