Cluster Analysis Identifies Rheumatoid Arthritis Phenotypes with Distinct Features of Pulmonary Involvement

Rheumatoid Arthritis (RA) is a heterogeneous disease with variable articular and extra-articular manifestations. Interstitial Lung Disease (ILD) is a serious complication contributing to morbidity and mortality. The study aims to identify distinct clinical phenotypes using a clustering approach and to determine the prevalence of RA-associated ILD (RA-ILD) in a Vietnamese cohort.

This prospective study included 306 patients fulfilling the 2010 ACR/EULAR RA criteria. ILD was diagnosed by high-resolution computed tomography according to ATS/ERS/JRS/ALAT standards. Demographic, clinical, serologic, and radiologic data were collected. Partitioning around medoids clustering with Gower’s distance was applied to identify phenotypic subgroups.

Among 306 patients (median age 59 years; 87.6% female), 101 (33.0%) had ILD. Cluster analysis identified four phenotypes. Clusters 1 and 2 were articular-dominant with minimal pulmonary involvement, whereas Clusters 3 and 4 were pulmonary-dominant with higher ILD prevalence and greater fibrosis severity, demonstrating a reciprocal pattern between joint and lung manifestations. Cluster 2 emerged as a unique clinical phenotype, marked by later onset of disease, minimal pulmonary lesions, and male predominance. Patients with RA-ILD had longer disease duration, higher CRP levels, and higher RF titers compared with those without ILD. Respiratory symptoms were significantly more frequent in the ILD group, whereas swollen joint counts and DAS28-CRP scores were lower. The usual interstitial pneumonia pattern predominated (69.3%).

The study comprehensively characterized RA phenotypes in a Vietnamese cohort of 306 patients and identified divergent articular and pulmonary patterns, including a prevalence of RA-associated interstitial lung disease (RA-ILD) of 33%, consistent with previously reported estimates (10–50%). Cluster analysis revealed reciprocal phenotypes: two clusters were characterized by more severe articular involvement with limited pulmonary fibrosis, whereas two others showed greater pulmonary manifestations. Notably, patients with RA-ILD exhibited fewer swollen joints and lower pain scores than those without ILD, suggesting that lung involvement does not necessarily parallel joint disease severity at a single time point. Instead, systemic inflammatory burden may be more closely associated with pulmonary pathology, as clusters with greater lung involvement demonstrated higher ESR levels. RA-ILD predominantly occurred in older individuals, supporting the role of aging-related mechanisms in fibrotic susceptibility. A distinct cluster with male predominance, later disease onset, and minimal pulmonary lesions was also observed.

Vietnamese RA exhibits substantial clinical heterogeneity with divergent articular- and pulmonary-dominant phenotypes.