Circulating secretory IgA antibodies against cyclic citrullinated peptides in early rheumatoid arthritis associate with inflammatory activity and smoking

Abstract

Background: A possible association between mucosal immunization and inflammation, as well as the initiation and propagation of rheumatoid arthritis (RA), is attracting renewed interest. The aim of this study was to evaluate the possible occurrence and clinical correlations of circulating secretory immunoglobulin A (SIgA) antibodies against the second-generation cyclic citrullinated peptides (CCP) among patients with recent-onset RA followed prospectively over 3 years.

Methods: Baseline serum samples from 636 patients with recent-onset RA were analyzed for SIgA anti-CCP antibodies by using an enzyme-linked immunosorbent assay with a secondary antibody directed against secretory component. SIgA anti-CCP status at baseline was analyzed in relation to smoking, HLA-DRB1/shared epitope (SE), and the disease course over 3 years. Significant findings were evaluated in regression analysis that included age, sex, smoking, and SE.

Results: Seventeen percent of the patients tested positive for circulating SIgA anti-CCP, and the occurrence was confirmed by detection of secretory component in an affinity-purified IgA anti-CCP fraction. SIgA anti-CCP positivity at baseline was associated with slightly higher baseline erythrocyte sedimentation rate (ESR) (mean 38 vs. 31 mm/first hour, p = 0.004) and C-reactive protein (CRP) (mean 30 vs. 23 mg/L, p = 0.047). During follow-up, SIgA anti-CCP-positive patients had a higher mean AUC regarding ESR (adjusted p = 0.003), although there were no significant differences regarding CRP, tender and swollen joint counts, or radiological joint damage (median Larsen progression 1.0 vs. 1.0, p = 0.22). SIgA anti-CCP was associated significantly with smoking (79 % ever smokers among SIgA anti-CCP-positive patients vs. 59 % in SIgA anti-CCP-negative patients, adjusted OR 2.19, 95 % CI 1.01-4.37, p = 0.027) but not with carriage of the SE (80 % vs. 73 %, p = 0.62).

Conclusions: Circulating SIgA anti-CCP, which is present in a subgroup of patients with early RA, is not related to SE, but it is environmentally linked to cigarette smoking. This finding strengthens the hypothesis that immunization against citrullinated peptides and/or proteins may occur at mucosal surfaces of the airways. Analysis of SIgA antibodies in serum may be a convenient and more versatile means to investigate the "mucosal connection" in RA compared with analyses in mucosal fluid samples.

Keywords: Anticitrullinated protein antibodies; Mucosal immunity; Rheumatoid arthritis; Secretory immunoglobulin A.

Fig. 1

Occurrence of immunoglobulin A (IgA) and secretory IgA (SIgA) anti-cyclic citrullinated protein (anti-CCP) antibodies in patients with early rheumatoid arthritis (RA) testing positive (a) or negative (b) for IgG anti-CCP. SIgA reactivity to CCP and cyclic arginine peptide (CAP) in ten patients with RA (c), and SIgA anti-CCP levels in patients with RA and control subjects (d). AU arbitrary units

Fig. 2

Western blotting for the detection of secretory component in an (A) immunoglobulin G (IgG) anti-cyclic citrullinated protein (anti-CCP) antibody fraction and (B) an IgA anti-CCP fraction. An 80 kDa band corresponding to the secretory component is visible in the IgA anti-CCP fraction

Fig. 3

Three-year disease course of early rheumatoid arthritis in relation to secretory immunoglobulin A (SIgA) anti-cyclic citrullinated peptide (anti-CCP) antibody status as mirrored by (a) erythrocyte sedimentation rate (ESR), (b) C-reactive protein (CRP), (c) 28-joint Disease Activity Score (DAS28), (d) swollen joint count, and (e) tender joint count. Mean values are shown, and p values refer to differences in AUC

Fig. 4

Secretory immunoglobulin A (SIgA) and immunoglobulin G (IgG) anticyclic citrullinated protein antibodies in relation to (a) shared epitope (SE) and (b) smoking in patients with early rheumatoid arthritis