New research has identified three distinct clinical clusters of patients with systemic lupus erythematosus who had different disease trajectories and outcomes, potentially advancing classification and personalized treatment approaches.

In the study, published in RMD Open, researchers from CHU de Rennes in France analyzed 278 patients with systemic lupus erythematosus (SLE) who met the 2019 EULAR/American College of Rheumatology (ACR) classification criteria. They performed hierarchical clustering analyses at both diagnosis and the last available visit to define distinct patient subgroups, with clusters labeled as 1, 2, and 3 at diagnosis and 1', 2', and 3' at the final visit.

"We identified a distinct MCTD phenotype within [patients with] SLE, a severe SLE phenotype with poor prognosis, and a third group of [patients with] SLE with lower visceral involvement," the study authors reported. "Clusters remained stable over time, providing insights into disease progression," they added.

Cluster 1: Milder Disease With Better Outcomes (67% of Patients at Diagnosis)

This largest subgroup exhibited early articular (95%) and mucocutaneous (59%) symptoms with the greatest survival rate. These patients showed less organ involvement and required fewer immunosuppressive treatments. This pattern remained largely stable throughout follow-up.

Cluster 2: Severe Disease With Poor Prognosis (26% of Patients at Diagnosis)

This group displayed the most severe phenotype, including renal involvement (62%), positivity for anti-DNA (90%) and anti-Sm (34%) autoantibodies, and poorer overall prognosis. These patients required more aggressive immunosuppressive therapy and had higher rates of intensive care unit admission. Further, this cluster expanded during follow-up to include 32% of patients.

Cluster 3: Mixed Connective Tissue Disease-Like Features (7% of Patients at Diagnosis)

This smaller cluster showed characteristics overlapping with mixed connective tissue disease (MCTD), a condition that shares features of lupus, scleroderma, and polymyositis. It was characterized by Raynaud's phenomenon (100%), puffy fingers (81%), and scleroderma-like features including interstitial lung disease (56%). Nearly 90% of these patients had anti-U1-RNP 70 kDa autoantibodies. Notably, over 50% of them transitioned to a different cluster during follow-up, suggesting this phenotype may evolve into more typical SLE over time.

Clinical Significance

The study was among the first to compare clinical subgroups of SLE from diagnosis to final follow-up since the adoption of the 2019 EULAR/ACR classification criteria. With a substantial mean follow-up period of 13.1 years, the research could provide valuable longitudinal data on disease progression.

"The clinical phenotype is shaped by the immunologic characteristics," the study authors stated. "MCTD clinical phenotype could be classified as systemic lupus, suggesting a specific subgroup of systemic lupus patients with anti-U1-RNP 70 kDa autoantibodies exhibiting scleroderma-like features," they continued.

For clinicians, these findings may help explain the heterogeneity of treatment responses among patients and could lead to more targeted therapeutic approaches based on which cluster a patient falls into at diagnosis. Early identification of patients likely to have a more severe disease course (cluster 2) might prompt more aggressive initial treatment.

The researchers noted that limitations included the retrospective nature of the study and its focus on a single medical center, suggesting that multicenter studies would be needed to further validate these clusters.

The authors declared having no competing interests.