Clustering reveals diagnostic overlap between Still’s disease and a hyperinflammatory subset of seronegative rheumatoid arthritis

Still’s disease (SD) and rheumatoid arthritis (RA), particularly seronegative RA, may overlap clinically and biologically, complicating diagnosis. We explored data-driven overlaps between SD, seronegative RA, and seropositive RA using unsupervised clustering. We retrospectively included 312 adults: 98 SD from the multicentric AURAL Still cohort and 214 RA (93 seropositive, 121 seronegative). Baseline clinical and laboratory data were analysed using factor analysis of mixed data followed by k-means clustering. SD patients were younger than RA patients and more frequently presented with fever and systemic features. Inflammatory markers (notably CRP and ferritin) were higher in SD than in both RA subsets. Three clusters were identified: Cluster 1 (n = 196) mainly comprised seropositive (45%) and seronegative RA (50%), with mild systemic inflammation and symmetrical polyarthritis; Cluster 2 (n = 73) was predominantly SD (92%), with systemic features, high inflammation and polyarthritis, and more frequent spontaneous remission without treatment; Cluster 3 (n = 43) mixed SD (49%) and seronegative RA (42%), characterised by moderate inflammation and asymmetrical oligoarthritis with low autoantibody rates. Most seronegative RA clustered with classical RA, but ~ 20% overlapped with SD-like phenotypes, suggesting a hyper-inflammatory subset which could be conceptualized as Systemic Inflammatory RA (SIRA). This proposal is hypothesis-generating and warrants prospective validation.