The Impact of IgG Fc‐Glycosylation on Disease Dynamics in Primary Sjögren's Disease‐ Insights from the Belgian Sjögren's Syndrome Transition Trial

Objectives Glycans attached to the fragment crystallizable region (Fc) of IgG antibodies influence their pro‐ or anti‐inflammatory effector function. We aimed to explore the interrelation between the Fc‐glycosylation profile and disease transition, disease activity and outcome in patients with suspected and confirmed primary Sjögren's Disease (SjD). Methods IgG Fc‐sialylation and IgG Fc‐galactosylation serum levels were determined in 300 patients from the Belgian Sjögren's Syndrome Transition Trial (BeSSTT). This cohort includes both suspected and confirmed SjD patients meeting the 2016 ACR/EULAR criteria. Salivary gland involvement was evaluated through ultrasonography (Hocevar score 0‐48) and histopathology (focus score). The relative amount of sialylated and galactosylated IgG was determined by capillary electrophoresis after using the endoS endoglycosidase based assay. Results SjD patients exhibited significantly lower sialylation and galactosylation levels versus asymptomatic anti‐SSA carriers and sicca patients. Lower sialylation and galactosylation levels were significantly associated with an increase in B‐cell activation markers and distinct autoantibody profiles, particularly with multiple autoantibody reactivities. They were also linked to histopathological salivary gland alterations, higher Hocevar scores and importantly with risk factors for non Hodgkin lymphoma (NHL) development. In contrast, mono‐anti‐Ro60 positive and anti‐SSA negative SjD patients had normal IgG Fc‐glycosylation. Conclusions This study points to a novel role of IgG Fc‐glycosylation in SjD in predicting disease transition, monitoring disease activity, and risk stratification for NHL development . image