The autoimmune response in rheumatoid arthritis (RA) is marked by anti-citrullinated protein antibodies (ACPA). A remarkable feature of ACPA-IgG is the abundant expression of N-linked glycans in the variable domain. Nonetheless, the presence of ACPA variable domain glycosylation (VDG) across disease stages and its’ response to therapy is poorly described. To understand its dynamics, we investigated the abundance of ACPA-IgG VDG in 1498 samples from individuals in different clinical disease stages.
Using liquid chromatography, we analyzed ACPA-IgG VDG profiles of 7 different cohorts from Japan, Canada, the Netherlands and Sweden. We assessed 106 healthy, 228 pre-symptomatic, 277 arthralgia, 307 patients at RA-onset/ early RA and 117 RA-patients after specific treatment decisions. Additionally, we measured VDG of 234 samples from RA-patients that did or did not achieve long-term drug-free remission (DFR) during up to 16 years follow-up.
Our data show that ACPA-IgG VDG significantly increases (p<0.0001) towards disease-onset and associates with ACPA-levels and epitope spreading pre-diagnosis. A slight increase in VDG was observed in established RA and a moderate influence of treatment (p=0.007). Individuals who later achieved DFR displayed reduced ACPA-IgG VDG already at RA-onset.
The abundance of ACPA-IgG VDG rises towards RA-onset and correlates with the maturation of the ACPA-response. While, ACPA-IgG VDG levels are rather stable in established disease, a lower degree at RA-onset correlates with DFR. Although the underlying biological mechanisms are still elusive, our data support the concept that VDG relates to an expansion of the ACPA-response pre-disease and contributes to disease-development.