Peripheral manifestations are major determinants of disease phenotype and outcome in new onset spondyloarthritis

Objectives: To delineate the impact of peripheral musculoskeletal manifestations on stratification of disease phenotype and outcome in new-onset spondyloarthritis (SpA), using a prospective observational nationwide inception cohort, the BelGian Inflammatory Arthritis and spoNdylitis cohorT (Be-Giant). Methods: Newly diagnosed adult SpA patients, fulfilling the Assessment of SpondyloArthritis international Society (ASAS) criteria for axial or peripheral SpA, were included in Be-Giant and prospectively followed every six months. Peripheral involvement (defined as arthritis, enthesitis and/or dactylitis) was determined in relation to clinically similar patient subsets at baseline and disease activity patterns during two-year follow-up, identified through K-means cluster analysis and latent class growth analysis. Results: From November 2010 to March 2020, 367 patients were enrolled in Be-Giant, of whom 162 (44%) had peripheral manifestations. Two patient clusters (A, axial predominant [n = 248] and B, peripheral predominant [n = 119]) were identified at diagnosis. Longitudinal analysis (n = 115) revealed two trajectories of disease activity in each cluster: one with persistently high disease activity over time ("High"), the other rapidly evolving to low disease activity ("Low"). In cluster A patients, peripheral manifestations predisposed to the "High" trajectory (OR = 2.0, 95%CI 1.3-3.1, p= 0.001), despite more rapid initiation of biologics compared with patients without peripheral manifestations (HR = 2.1, 95%CI 1.0-4.4, p= 0.04 - Cox proportional-hazards model). Conclusion: Peripheral musculoskeletal manifestations are major determinants of phenotypical diversity in new-onset SpA. Intriguingly, stratification of axial SpA according to concomitant peripheral involvement identified an endotype with an unfavorable outcome despite more prompt therapeutic intensification with biologics. These observations justify an endotype-tailored approach beyond current ASAS/EULAR management recommendations. Keywords: clusters; peripheral manifestations; spondyloarthritis; trajectories.