Profiling of IgG N-glycosylation for axial spondyloarthritis and other rheumatic diseases

Axial spondyloarthritis (axSpA) is an inflammatory rheumatic disease with challenges in diagnosis and disease activity assessment. While alterations in immunoglobulin G (IgG) N-glycosylation have been observed in varied rheumatic diseases, those in axSpA remains unclear. This study aims to explore the role of IgG N-glycan profiles in diagnosis and disease activity of axSpA. A clinical case-control study was conducted involving patients with axSpA (n = 138), systemic lupus erythematosus (n = 102), rheumatoid arthritis (n = 106), osteoarthritis (n = 33), gout (n = 41) and healthy controls (n = 117). Ultra-performance liquid chromatography was employed to analyze the composition of the serum IgG N-glycome. Associations between IgG N-glycans and axSpA were investigated and compared to healthy controls and other four rheumatic diseases. The relationship among IgG N-glycosylation, disease activity, and inflammatory cytokines of axSpA patients were analyzed. The receiver operating characteristic (ROC) curve analysis was applied to evaluate the diagnostic/classification performance of IgG N-glycans to distinguish axSpA and its disease activity. In patients with axSpA, the abundances of IgG galactosylation and sialylation were significantly lower than healthy controls, while the abundance of fucosylation was higher than the other four studied rheumatic diseases. Additionally, two asialylated IgG N-glycans (FA2 and FA2 [3]G1) were associated with axSpA, with adjusted odds ratios (AORs) of 5.62 (95% CI: 3.41–9.24) and 0.33 (95% CI: 0.22–0.50), respectively. Notably, decreased FA2 [3]G1 emerged as a characteristic IgG N-glycan associated with all five studied rheumatic diseases, while decreased FA2BG2S2 was a unique IgG N-glycan differentiating axSpA from the other four rheumatic diseases. Furthermore, FA2 displayed positive association with disease activity indicators (ASDAS-CRP, SPARCC-SIJ and SPARCC-spine) in axSpA. IgG N-glycans, particularly FA2 [3]G1, FA2BG2S2 and FA2, demonstrated canonical correlation with inflammatory cytokines, including interleukin-23 and tumor necrosis factor α, in axSpA (r = 0.519, P = 0.017). Specific IgG N-glycans hold potential as novel biomarkers to enhance diagnosis and disease activity assessment in axSpA management.