Distinct symptom profiles in rheumatoid arthritis identified using data-driven clustering of inflammation and patient-reported measures

Symptom burden in rheumatoid arthritis (RA) is heterogenous and not fully explained by inflammatory activity alone. This study aimed to identify clinically distinct subgroups based on patient-reported symptom burden and inflammatory measures in patients with established, active RA initiating treatment changes. Data were analyzed from 283 participants in the Central Pain in Rheumatoid Arthritis Study at baseline and 12-weeks. Participants completed patient-reported measures on pain, fatigue, sleep, and psychosocial factors. Clinical measures of inflammation included the 28-swollen joint count (SJC28) and serum high-sensitivity C-reactive protein (hsCRP) to assess peripheral and systemic inflammatory activity, respectively. Unsupervised clustering using a partitioning algorithm (K-means) was performed on standardized symptom scores to identify clusters using baseline data. Cluster differences in baseline demographic and clinical characteristics were examined. Four distinct clusters were identified that differed in inflammatory activity and patient-reported symptom burden. Cluster 1 ( n = 117) had low-to-moderate inflammatory activity with low-to-moderate symptoms across domains. Cluster 2 ( n = 77) exhibited moderate inflammatory activity with minimal symptom burden. Cluster 3 ( n = 68) demonstrated the highest symptom burden (pain, fatigue, sleep disturbances and psychological distress) with moderate inflammation. Cluster 4 ( n = 21) was characterized by the highest inflammatory activity with low-to-moderate symptom burden. Significant overall heterogeneity across the four clusters was observed for hsCRP, SJC28, and all patient-reported measures ( p < 0.001). In exploratory analyses, all clusters improved in inflammation and across symptom domains at 12 weeks, but cluster 3 remained most symptomatic. We identified four clinically distinct subgroups characterized by patterns of inflammatory activity and patient-reported symptom burden in active RA. Differences in symptom burden were only partly related to inflammation, revealing a subgroup with features consistent with centralized pain.