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.

Figure 1

A, Dendrogram of the 6,927 patients with systemic sclerosis (SSc) included in the cluster analysis. The length of the vertical lines represents the degree of similarity between patients. Patients were divided into 2 clusters (cluster A and B) and into 6 clusters (clusters 1–6). B, Heatmap showing the clinical characteristics in each cluster. dcSSc = diffuse cutaneous SSc; CK = creatine kinase; PH = pulmonary hypertension; CRP = C‐reactive protein; ACA = anticentromere antibody; anti–topo I = anti–topoisomerase I.

Figure 2

A, Main characteristics of the 2 clusters (cluster A and cluster B) of patients with systemic sclerosis (SSc). B, Left, Proportions of each cluster with the main clinical characteristics of diffuse cutaneous SSc (dcSSc), restrictive defect, and suspected pulmonary hypertension (PH) on echocardiography (echo). Right, Peak modified Rodnan skin thickness score (MRSS), mortality (per 1,000 patient‐years [py]), and percentages of patients with anticentromere antibodies (ACAs) and anti–topoisomerase I (anti–topo I) antibodies in each cluster. C, Kaplan‐Meier survival curves for the 2 clusters. D, Forest plot showing mortality hazard ratios and 95% confidence intervals for the 2 clusters. Broken line shows the hazard ratio for the reference group. Green symbols represent cluster A; orange symbols represent cluster B. DU = digital ulcer; ILD = interstitial lung disease.

Figure 3

A, Main characteristics of the 6 clusters (clusters 1–6) of patients with systemic sclerosis (SSc). B, Left, Proportions of each cluster with the main clinical characteristics of diffuse cutaneous SSc (dcSSc), restrictive defect, and suspected pulmonary hypertension (PH) on echocardiography (echo). Right, Peak modified Rodnan skin thickness score (MRSS), mortality (per 1,000 patient‐years [py]), and percentages of patients with anticentromere antibodies (ACAs) and anti–topoisomerase I (anti–topo I) antibodies in each cluster. C, Kaplan‐Meier survival curves for the 6 clusters. D, Forest plot showing mortality hazard ratios and 95% confidence intervals for the 6 clusters. Broken line shows the hazard ratio for the reference group. Colors represent the different clusters as indicated in C. GI = gastrointestinal; ILD = interstitial lung disease; DL co = diffusing capacity for carbon monoxide; DU = digital ulcer.