Decoding sarcoidosis chronicity through phenotypic profiling

Sarcoidosis is a heterogeneous granulomatous disease of unknown aetiology, characterised by a highly variable clinical behaviour. While some patients experience a self‑limited course, others develop chronic and relapsing disease. At present, no precise phenotyping strategy exists in clinical practice to reliably predict which patients will progress to chronicity.

The aim of this study was to identify distinct phenotypic clusters sharing common clinical characteristics and to evaluate the predictive value of these clusters for disease outcomes.

This is a retrospective, single-center study. Histologically confirmed sarcoidosis patients (N = 68), diagnosed between January 2022 and December 2023 at the 5th Pulmonary Medicine Department of SOTIRIA Chest Diseases Hospital of Athens, were included. All patients had >2 years of follow-up.

Multiple correspondence analysis (MCA) followed by hierarchical clustering on principal components (HCPC) was performed to identify phenotypic clusters. Logistic regression was performed to identify the prognostic factors of chronicity.

A total of 68 consecutive patients with sarcoidosis were included in the study. The mean age at diagnosis was 57.6 ± 11.1 years, with the majority being females (61.8%). Thoracic involvement, including either intrathoracic lymph nodes and/or the lungs, was the most frequently detected. Overall, fatigue, cough, and arthralgia were among the most frequently reported symptoms. Two phenotypic clusters were identified, including 63 (92.6%) and 5 (7.4%) patients. Cluster 1 was characterised by minimal extrapulmonary involvement, whereas Cluster 2 showed a higher frequency of multi-organ disease, including liver (80%), musculoskeletal (75%), spleen (67%), cardiac (50%) and skin (43%) involvement. Cluster stability was moderate to weak. The clustering phenotype was not associated with chronicity. However, involvement of lymph nodes only was associated with reduced odds of chronicity (OR 0.17, 95% CI 0.02-0.69), while arthritis was strongly associated with increased chronicity risk (OR 17.02, 95% CI 2.04-471.07). Exploratory 3-cluster analysis suggested a potential arthritis-predominant phenotype, although of low stability.

Two distinct phenotypes in sarcoidosis are identified by using cluster analysis. In a sensitivity analysis that allowed for three clusters, a third cluster, characterised by the presence of arthritis and predominant eye and skin involvement, emerged. Interestingly, the presence of lone intrathoracic or extrathoracic lymphadenopathy appears to be significantly protective against chronicity.