Short-term progression of interstitial lung disease in systemic sclerosis predicts long-term survival in two independent clinical trial cohorts

Abstract

Objective: To assess survival and identify predictors of survival in patients with systemic sclerosis-interstitial lung disease (SSc-ILD) who participated in the Scleroderma Lung Studies (SLS) I and II.

Methods: SLS I randomised 158 patients with SSc-ILD to 1 year of oral cyclophosphamide (CYC) vs placebo. SLS II randomised 142 patients to 1 year of oral CYC followed by 1 year of placebo vs 2 years of mycophenolate mofetil. Counting process Cox proportional hazard modelling identified variables associated with long-term mortality in SLS I and II. Internal validation was performed using joint modelling.

Results: After a median follow-up of 8 years, 42% of SLS I patients died, and when known the cause of death was most often attributable to SSc. There was no significant difference in the time to death between treatment arms in SLS I or II. Higher baseline skin score, older age, and a decline in the forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLCO) over 2 years were independently associated with an increased risk of mortality in SLS I. The Cox model identified the same mortality predictor variables using the SLS II data.

Conclusion: In addition to identifying traditional mortality risk factors in SSc (skin score, age), this study demonstrated that a decline in FVC and DLCO over 2 years was a better predictor of mortality than baseline FVC and DLCO. These findings suggest that short-term changes in surrogate measures of SSc-ILD progression may have important effects on long-term outcomes.

Keywords: interstitial lung disease; survival; systemic sclerosis; treatment.

Figure 1.

Time death (Figure 1a) and time to death or organ failure (Figure 1b) from randomization in SLS I. There was no significant difference in the time to death (p=0.335 by log-rank test; Figure 1a), nor the time to death or organ failure (p=0. 539 by log-rank test; Figure 1b) for patients randomized to CYC versus placebo in SLS I. The last known date they were known to be alive was used for the survival analysis.

Figure 2.

Time death (Figure 2a)and time to death or organ failure (Figure 2b) from randomization in SLS II. There was no significant difference in the time to death (p=0.627 by log-rank test; Figure 2a), nor the time to death or organ failure (p=0.343 by log-rank test; Figure 2b) for patients randomized to CYC versus MMF in SLS II. The last known date they were known to be alive was used for the survival analysis.