Baseline IgG-Fc N-glycosylation profile is associated with long-term outcome in a cohort of early inflammatory arthritis patients

Abstract

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease for which prediction of long-term prognosis from disease’s outset is not clinically feasible. The importance of immunoglobulin G (IgG) and its Fc N-glycosylation in inflammation is well-known and studies described its relevance for several autoimmune diseases, including RA. Herein we assessed the association between IgG N-glycoforms and disease prognosis at 2 years in an early inflammatory arthritis cohort. Methods Sera from 118 patients with early inflammatory arthritis naïve to treatment sampled at baseline were used to obtain IgG Fc glycopeptides, which were then analyzed in a subclass-specific manner by liquid chromatography coupled to mass spectrometry (LC-MS). Patients were prospectively followed and a favorable prognosis at 2 years was assessed by a combined index as remission or low disease activity (DAS28 < 3.2) and normal functionality (HAQ ≤ 0.25) while on treatment with conventional synthetic DMARDs and never used biologic DMARDs. Results We observed a significant association between high levels of IgG2/3 Fc galactosylation (effect 0.627 and adjusted p value 0.036 for the fully galactosylated glycoform H5N4F1; effect −0.551 and adjusted p value 0.04963 for the agalactosylated H3N4F1) and favorable outcome after 2 years of treatment. The inclusion of IgG glycoprofiling in a multivariate analysis to predict the outcome (with HAQ, DAS28, RF, and ACPA included in the model) did not improve the prognostic performance of the model. Conclusion Pending confirmation of these findings in larger cohorts, IgG glycosylation levels could be used as a prognostic marker in early arthritis, to overcome the limitations of the current prognostic tools.

Neutrophil Depletion Changes the N-Glycosylation Pattern of IgG in Experimental Murine Sepsis

“…The unique N-glycosylation pattern in the Fc region has been demonstrated to associate with inflammatory autoimmune conditions [ 50 , 51 ]. In addition, aging [ 52 , 53 ] and several pathological processes including coronavirus infection [ 54 , 55 ], inflammatory arthritis [ 56 ], type 1 diabetes [ 57 ], inflammatory bowel disease [ 58 ], and active tuberculosis infections [ 59 ] have been linked to changes in the N-glycosylation profile of the IgG Fc-region [ 60 ]. Finally, the altered Fc-glycosylation pattern in total plasma IgG was demonstrated to associate with pediatric meningococcal sepsis for the first time in 2018 [ 28 ].…”

IgG subclass and Fc glycosylation shifts are linked to the transition from pre- to inflammatory autoimmune conditions

“…Autoantigen-specific agalactosylated (non-galactosylated and non-sialylated; G0) IgG Abs are linked to pro-inflammatory conditions in inflammatory (auto-) immune diseases, whereas attachment of galactose and sialic acid is related to fewer inflammatory or even anti-inflammatory conditions ( Figure 1 ) ( 3 , 8 , 11 – 13 , 28 – 39 ). In most studies, IgG Fc bisection also correlates with pro-inflammatory conditions ( 28 ).…”