Objective: To investigate levels and possible extramucosal formation of secretory immunoglobulins, including anti-citrullinated protein antibodies (ACPA), in rheumatoid arthritis (RA).

Methods: Three patient groups were studied: i) ACPA-positive patients with musculoskeletal pain without clinical arthritis, ii) recent-onset RA, and iii) established RA. In baseline serum (i and ii) and paired synovial fluid samples (iii), we analyzed total secretory IgA (TSIgA), total secretory IgM (TSIgM), free secretory component (SC), and SC ACPA. Extramucosal formation of SC ACPA was investigated by pre-incubating RA sera and affinity-purified ACPA with recombinant free SC.

Results: Compared to healthy controls, serum levels of TSIgA and TSIgM were increased both in early RA and at-risk patients (p<0.05). Early RA patients with elevated total secretory immunoglobulins had significantly higher disease activity during 3-year follow-up compared to those without increased levels. At-risk patients developing arthritis during follow-up (39/82) had higher baseline TSIgA levels compared to those who did not (p=0.041). In established RA, TSIgA and TSIgM levels were higher in serum than in synovial fluid (p<0.001), but SC ACPA adjusted for total secretory immunoglobulin concentration were higher in synovial fluid (p<0.001). Pre-incubation with recombinant free SC yielded increased SC ACPA reactivity in sera as well as in affinity-purified IgA and IgM ACPA preparations.

Conclusion: Circulating secretory immunoglobulins are elevated before and at RA onset. In the presence of free SC, secretory immunoglobulins may form outside the mucosa, and SC ACPA are enriched in RA joints. These findings shed important new light on the mucosal connection in RA development.