Predictors of disease worsening defined by progression of organ damage in diffuse systemic sclerosis: a European Scleroderma Trials and Research (EUSTAR) analysis

Abstract

Objectives: Mortality and worsening of organ function are desirable endpoints for clinical trials in systemic sclerosis (SSc). The aim of this study was to identify factors that allow enrichment of patients with these endpoints, in a population of patients from the European Scleroderma Trials and Research group database.

Methods: Inclusion criteria were diagnosis of diffuse SSc and follow-up over 12±3 months. Disease worsening/organ progression was fulfilled if any of the following events occurred: new renal crisis; decrease of lung or heart function; new echocardiography-suspected pulmonary hypertension or death. In total, 42 clinical parameters were chosen as predictors for the analysis by using (1) imputation of missing data on the basis of multivariate imputation and (2) least absolute shrinkage and selection operator regression.

Results: Of 1451 patients meeting the inclusion criteria, 706 had complete data on outcome parameters and were included in the analysis. Of the 42 outcome predictors, eight remained in the final regression model. There was substantial evidence for a strong association between disease progression and age, active digital ulcer (DU), lung fibrosis, muscle weakness and elevated C-reactive protein (CRP) level. Active DU, CRP elevation, lung fibrosis and muscle weakness were also associated with a significantly shorter time to disease progression. A bootstrap validation step with 10 000 repetitions successfully validated the model.

Conclusions: The use of the predictive factors presented here could enable cohort enrichment with patients at risk for overall disease worsening in SSc clinical trials.

Keywords: disease worsening; mortality; predictive factors; systemic sclerosis.

Figure 1

Average regression coefficients across 100 imputations plotted against the penalisation parameter, lambda. The vertical dashed line represents the selected model chosen as it had the smallest Bayesian information criterion. Traces in colour are those of the regression coefficients (and hence predictor variables) that remained in the final model. Traces for excluded regression coefficients are plotted in black and are not specified in the legend. CRP, C-reactive protein.

Figure 2

Event-free survival in patients with SSc depending on risk factors for progression of organ damage. (A) Event-free survival of patients with SSc fulfilling the inclusion criteria (diffuse SSc, death or at least one follow-up visit earliest at 12±3 months after baseline visit in 2009 or later) with risk factors (elevated CRP and presence of lung fibrosis) versus no risk factors (active DU, CRP elevation, significant dyspnoea, lung fibrosis, muscle weakness, pericardial effusion and proteinuria). The median survival time for patients with and without risk factors was 1.53 years (95% CI 1.13 to 1.99) and 4.48 years (95% CI 3.70 to 4.97), respectively. The log-rank test was significant (p<0.001). (B) Event-free survival of patients with SSc fulfilling the inclusion criteria with risk factors (elevated CRP and active DU) versus no risk factors. The median survival time for patients with and without risk factors was 1.82 years (95% CI 1.23 to 2.47) and 4.48 (95% CI 3.70 to 4.97) years, respectively. The log-rank test was significant (p<0.001). CRP, C-reactive protein; DU, digital ulcer; LF, lung fibrosis; SSc, systemic sclerosis.