SOX‐5 Transcription Factor: a Novel Psoriatic Autoantigen Preferentially Found in Women

Objective Adaptive immunity mediates psoriatic disease pathogenesis. We aimed to identify novel psoriatic autoantigens and their phenotypic associations in deeply characterized patient cohorts. Methods Sera from psoriatic arthritis (PsA) patients were used for autoantibody discovery. Immunoprecipitations performed with cell lysates were on‐bead digested, and autoantigens were identified by mass spectrometry. Prevalence and clinical features associated with anti–SRY‐Box transcription factor‐D (SOX‐D) antibodies were determined by screening discovery cohorts of patients with PsA (n = 135), patients with psoriasis without PsA (n = 24), and healthy controls (n = 41). A PsA validation cohort (n = 325) and disease control samples of individuals with rheumatoid arthritis (RA; n = 66) and systemic lupus erythematosus (SLE, n = 66) were assayed for anti‐SOX5 antibodies. Disease characteristics were compared by antibody status. Longitudinal data were analyzed using linear mixed‐effects models with patient‐specific intercept to ascertain associations. We also tested PsA sera for the recently described anti–ADAMTS‐L5 autoantibody in PsA. Results The novel autoantigens identified were SOX‐D transcription factors, with SOX‐5 being the focus of this analysis. Anti‐SOX5 antibodies were present in 8.9% (12 of 135) and 4.3% (14 of 323) of patients in the PsA discovery and validation cohorts, respectively, 12.5% of patients (3 of 24) in the psoriasis group, 2.4% (1 of 41) of healthy controls, and 7.6% (5 of 66) each of patients in the RA and SLE groups. Anti‐SOX5 were associated with female sex in both PsA cohorts (discovery: 15.7% women, 2.6% men, P = 0.006; validation: 6.3% women, 1.4% men, P = 0.049). In a longitudinal analysis adjusted for sex, anti‐SOX5 associated with biologic disease‐modifying antirheumatic drug treatment (95% vs 61%; P = 0.001; n = 96) and with differences in estimated treatment effects by mechanism of action. Anti–ADAMTS‐L5 autoantibodies were identified in 8 of 124 patients (6.5%) in the PsA group. Conclusion SOX‐D transcription factors are novel psoriatic autoantigens. Anti‐SOX5 antibodies were preferentially found in women with PsA and associated with specific clinical and treatment characteristics, suggesting that anti‐SOX5 antibodies may identify mechanistic subgroups. We independently validated anti–ADAMTS‐L5 autoantibodies in PsA.