Background In rheumatoid arthritis (RA), anti-citrullinated protein antibodies (ACPA) of the IgG isotype exhibit a specific, pro-inflammatory Fc glycosylation profile characterized by a low content of galactose and sialic acid residues (1). The absence of these sugars from the Fc-linked core glycan could influence the biological activity of ACPA during disease. As ACPA can be detected in sera several years before disease development, we hypothesized that a change in ACPA Fc-glycosylation might precede the onset of arthritis.

Objectives To study glycosylation patterns of the ACPA IgG Fc-fragment in patients with ACPA positive arthralgia.

Methods Serum samples (n=300) of patients with ACPA positive arthralgia (n=184) were collected at baseline and at various time points of follow-up. At the time of arthritis development, patients were classified as having either rheumatoid arthritis (RA) or undifferentiated arthritis (UA) based on the 1987 ACR criteria. ACPA of the IgG isotype were isolated from sera by affinity purification and digested with trypsin. Fc-glycopeptides were subsequently analyzed by nano-liquid chromatography mass spectrometry. ACPA-specific Fc glycosylation profiles were compared to those of non-specific IgG isolated from the same sera. ACPA isolated from a cohort of ACPA positive healthy blood-bank donors served as additional comparators.

Results At baseline, ACPA-IgG molecules displayed Fc-glycosylation patterns comparable to those of non-specific IgG. In contrast, ACPA lacked galactose residues at the onset of arthritis in patients presenting with RA, but not in patients presenting with UA. This decrease of ACPA Fc-galactosylation in RA patients occurred around 3 months prior to diagnosis and was paralleled by an increase in systemic inflammation (ESR). In addition, we noted a high degree of ACPA Fc core-fucosylation at baseline, which further increased prior to diagnosis.

Conclusions ACPA exhibit significant changes in Fc glycosylation that occur shortly before the clinical onset of RA. These changes towards a more pro-inflammatory Fc-glycan profile could be involved in driving the inflammatory immune response.

References

1. Scherer HU, van der Woude D, Ioan-Facsinay A, et al. Glycan profiling of anti-citrullinated protein antibodies isolated from human serum and synovial fluid. Arthritis Rheum. 2010;62:1620-9.

Disclosure of Interest None Declared