Location and amount of joint involvement differentiates rheumatoid arthritis into different clinical subsets

Background Rheumatoid arthritis (RA) is a heterogeneous disease. Patients vary in symptoms, prognosis and treatment response, demonstrating the need for a more refined taxonomy. Objective To identify distinct phenotypic subsets of RA patients based on baseline clinical data, in order to advance understanding of disease etiology and treatment strategies. Methods We collected hematological, serological, and clinical data from RA-patients in the Leiden Rheumatology clinic(n = 1,387), and combined multimodal deep learning techniques with clustering to identify phenotypically distinct RA subsets. These clusters were tested for associations in clinical outcomes. Findings were replicated in clinical trial data (n = 307) and independent secondary care (9 clinics, n = 515), and further explored for histological differences in synovial tissue (n = 194). Results Four distinct RA subsets with different Joint Involvement Patterns (JIP), emerged: 1) foot-predominant arthritis, 2) seropositive oligoarticular disease, 3) seronegative hand arthritis, and 4) polyarthritis. We found high cluster stability, no physician influence, significant difference in remission rates (P = 0.007) and methotrexate failure (P < 0.001) in initial and replication sets. The JIP-hand subgroup had significantly better outcomes. This was largest in the ACPA-positive stratum (JIP-hand versus JIP-foot (HR:0.37 (95%CI: 0.15–0.60) P < 0.001), JIP-hand versus JIP-poly HR:0.33 (95%CI: 0.15–0.72) P = 0.005). This was independent of baseline disease activity, clinical markers (RF, ACPA, Sex, Age), and symptom duration. Synovial histology showed both JIP-poly and JIP-hand had increased synovial lining and inflammatory infiltrate, with JIP-hand showing notably high stromal density. JIP-feet scored evenly across categories without standing out, while JIP-oligo had lower synovitis degree. Conclusions We identified and validated four distinct RA phenotypes characterized by joint involvement patterns, which associate with treatment outcomes and synovial histology. These findings may allow for targeted research into RA mechanisms and therapies.