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.

Keywords: Fragment crystallizable; Immunoglobulin G; Inflammation; N-glycosylation; Rheumatoid arthritis.

Fig. 1

Relative abundances of subclass-specific IgG Fc N-glycoforms (H3N4F1, H4N4F1, H5N4F1, H5N4F1S1) in two diagnosis groups: 1 – rheumatoid arthritis; 2 – undifferentiated arthritis. No statistically significant differences between the groups using a general linear model as specified in the Methods section. Glycan compositions are given in terms of Hexose (H), N-acetylglucosamine (N), fucose (F), and sialic acid residues (S). The data were presented as a box plot where the lower and upper hinges correspond to the first and third quartiles. The upper whisker extends from the hinge to the largest value no further than 1.5 times the inter-quartile range (IQR) from the hinge while the lower one extends to the smallest value at most 1.5 times IQR. Data beyond the end of the whiskers are outliers and are plotted individually. The value represents the relative abundance of each presented glycoform within the sum of all glycoforms on a single subclass

Fig. 2

Relative abundances of subclass-specific IgG Fc N-glycoforms (H3N4F1, H4N4F1, H5N4F1, H5N4F1S1) in patients without (0) or with (1) “Favorable outcome” after 2 years of treatment. “Favorable outcome” was defined as DAS28 < 3.2, HAQ ≤ 0.25, and no biological disease-modifying antirheumatic drug was received during treatment. *Statistically significant associations (adjusted p value < 0.05) following the general linear model described in the Methods section. Glycan compositions and box plot description as in Fig. 1