Association of Combined Anti-Ro52/TRIM21 and Anti-Ro60/SSA Antibodies With Increased Sj?gren Disease Severity Through Interferon Pathway Activation

Objective. The biologic diagnosis of primary Sj & ouml;gren disease (SjD) mainly relies on anti-Ro60/SSA antibodies, whereas the significance of anti-Ro52/TRIM21 antibodies currently remains unclear. The aim of this study was to characterize the clinical, serological, biologic, transcriptomic, and interferon profiles of patients with SjD according to their anti-Ro52/TRIM21 antibody status. Methods. Patients with SjD from the European PRECISESADS (n = 376) and the Brittany Diagnostic Suspicion of primitive Sj & ouml;gren's Syndrome (DIApSS); (n = 146) cohorts were divided into four groups: double negative (Ro52(-)/Ro60(-)), isolated anti-Ro52/TRIM21 positive (Ro52(+)), isolated anti-Ro60/SSA positive (Ro60(+)), and double-positive (Ro52(+)/Ro60(+)) patients. Clinical information; EULAR Sj & ouml;gren Syndrome Disease Activity Index, a score representing systemic activity; and biologic markers associated with disease severity were evaluated. Transcriptome data obtained from whole blood by RNA sequencing and type I and II interferon signatures were analyzed for PRECISESADS patients. Results. In the DIApSS cohort, Ro52(+)/Ro60(+) patients showed significantly more parotidomegaly (33.3% vs 0%-11%) along with higher beta 2-microglobulin (P = 0.0002), total immunoglobulin (P < 0.0001), and erythrocyte sedimentation rate levels (P = 0.002) as well as rheumatoid factor (RF) positivity (66.2% vs 20.8%-25%) compared to other groups. The PRECISESADS cohort corroborated these observations, with increased arthritis (P = 0.046), inflammation (P = 0.005), hypergammaglobulinemia (P < 0.0001), positive RF (P < 0.0001), leukopenia (P = 0.004), and lymphopenia (P = 0.009) in Ro52(+)/Ro60(+) patients. Cumulative EULAR Sj & ouml;gren Syndrome Disease Activity Index results further confirmed these disparities (P = 0.002). Transcriptome analysis linked anti-Ro52/TRIM21 antibody positivity to interferon pathway activation as an underlying cause for these clinical correlations. Conclusion. These results suggest that the combination of anti-Ro52/TRIM21 and anti-Ro60/SSA antibodies is associated with a clinical, biologic, and transcriptional profile linked to greater disease severity in SjD through the potentiation of the interferon pathway activation by anti-Ro52/TRIM21 antibodies.