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

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\ub13 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 trial

Cellular and molecular diversity in rheumatic autoimmune diseases

With the increasing armamentarium of high-throughput tools available at manageable cost, it is attractive and informative to determine the molecular underpinnings of patient heterogeneity in systemic sclerosis (SSc). Given the highly variable clinical outcomes of patients labelled with the same diagnosis, unravelling the cellular and molecular basis of disease heterogeneity will be crucial to predicting disease risk, stratifying management and ultimately informing a patient-centered precision medicine approach. Herein, we summarise the findings of the past several years in the fields of genomics, transcriptomics, and proteomics that contribute to unraveling the cellular and molecular heterogeneity of SSc. Expansion of these findings and their routine integration with quantitative analysis of histopathology and imaging studies into clinical care promise to inform a scientifically driven patient-centred personalized medicine approach to SSc in the near future