Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis

Abstract

Objective Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. Methods A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty‐four clinical and serologic variables were used for clustering. Results Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. Conclusion Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis.

Early trajectories of skin thickening are associated with severity and mortality in systemic sclerosis

“…In our study, patients with ATA were present in all five trajectory classes while we noted that lcSSc patients were predominantly in class 1 and those with dcSSc were mainly in classes 2 to 5. This heterogeneity is well known and has been confirmed by several recent works highlighting the importance of autoantibodies, cutaneous subset, and disease duration to predict organ complications and survival [7,23,28]. In particular, it appears relevant to distinguish especially ATA-associated lcSSc from ATAassociated dcSSc [33,34].…”

“…Most patients with ACA (95%) were assigned to class 1. However, 42% of patients in class 1 had ATA, which is a higher proportion than that usually observed in lcSSc [24,27,28]. In addition to lcSSc, there were 20 patients (17%) with dcSSc associated with ATA and whose median baseline mRSS was 9 (IQR 6.5; 9.5).…”

“…In addition to lcSSc, there were 20 patients (17%) with dcSSc associated with ATA and whose median baseline mRSS was 9 (IQR 6.5; 9.5). Low mRSS values have already been reported in dcSSc [29][30][31] and some limitations on the current classification have been identified [28,32], especially when the forearms are involved. Their assignation to class 1 was probably related to the modeled trajectory shape of class 1 that was fitter to their individual trajectories than the other modeled trajectories classes.…”

Recent advances steer the future of systemic sclerosis toward precision medicine

“…Furthermore, Gemma Lepri and Michael Hughes contributed equally to this work. recent work which included 11,318 patients from the EUSTAR database using cluster analysis found that restricting subsets to only skin involvement did not capture the heterogeneity of SSc and that organ damage/autoantibody status identified homogenous groups of patients with different prognosis [17].…”

“…To date, a total of four subsets have been recognized and validated by multiple studies [20][21][22]: the fibroproliferative, the inflammatory, the limited, and the normal-like subset. The fibroproliferative subset is characterized by a significant proliferative signature (mitotic cell cycle, chromosome segregation, cell division, and microtubule cytoskeleton) and the plateletderived growth factor (PDGF) pathway has been suggested to have a relationship with this subset [17]. In the inflammatory intrinsic subset, the gene expression signature is addressing the immune system process, the inflammatory and defense response, and the vascular response.…”