Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis

Abstract

IntroductionWe and others have previously shown that antibodies against cyclic citrullinated proteins (anti-CCP) precede the development of rheumatoid arthritis (RA) and in a more recent study we reported that individuals who subsequently developed RA had increased concentrations of several cytokines and chemokines years before the onset of symptoms of joint disease. Here we aimed to evaluate the prevalence and predictive values of anti-CCP antibodies of IgG, IgM and IgA isotype in individuals who subsequently developed RA and also to relate these to cytokines and chemokines, smoking, genetic factors and radiographic score.MethodsA case-control study (1:4 ratio) was nested within the Medical Biobank and the Maternity cohorts of Northern Sweden. Patients with RA were identified from blood donors predating the onset of disease by years. Matched controls were selected randomly from the same registers. IgG, IgA and IgM anti-CCP2 antibodies were determined using EliA anti-CCP assay on ImmunoCAP 250 (Phadia AB, Uppsala, Sweden).ResultsOf 86 patients with RA identified as blood donors prior to the onset of symptoms, samples were available from 71 for analyses. The median (Q1 to Q3) predating time was 2.5 years (1.1 to 5.9 years). The sensitivity of anti-CCP antibodies in the pre-patient samples was 35.2% for IgG, 23.9% for IgA, and 11.8% for IgM. The presence of IgG and IgA anti-CCP antibodies was highly significant compared with controls. IgG and IgA anti-CCP2 predicted RA significantly in conditional logistic regression models odds ratio (OR) = 94.1, 95% confidence interval (CI) 12.7 to 695.4 and OR = 11.1, 95% CI 4.4 to 28.1, respectively, the IgM anti-CCP showed borderline significance OR = 2.5 95% CI 0.9 to 6.3. Concentrations of all anti-CCP isotypes increased the closer to the onset of symptoms the samples were collected with an earlier and higher increase for IgG and IgA compared with IgM anti-CCP. IgA and IgG anti-CCP positive individuals had different patterns of up-regulated chemokines and also, smoking brought forward the appearance of IgA anti-CCP antibodies in pre-RA individuals.ConclusionsAnti-CCP2 antibodies of both the IgG and IgA isotypes pre-dated the onset of RA by years; also, both IgG and IgA anti-CCP2 antibodies predicted the development of RA, with the highest predictive value for IgG anti-CCP2 antibodies.

Circulating and Mucosal Antibodies to Citrullinated Antigens in Rheumatoid Arthritis

“…This strengthens the hypothesis that smoking is of etiological importance in the very early stages of RA development [96]. Among pre-RA patients who are smokers, IgA anti-CCP antibodies appear significantly earlier than in non-smokers [97]. However, the mechanism by which cigarette smoking contributes to the development of RA is not known.…”

Salivary IgA antibodies to cyclic citrullinated peptides (CCP) in rheumatoid arthritis

“…For instance, it is well established that a combination of cigarette smoking and genetic carriage of HLA-DRB1/SE is a strong risk of developing IgG-ACPA positive, but not IgG-ACPA negative, RA (Morgan et al 2009;Padyukov et al 2011). Although derived from studies of much smaller format, there are indications of serum IgA-ACPA being even more strongly related to smoking but not to SE (Verpoort et al 2007;Svärd et al 2010) and Kokkonen et al showed that smoking pre-RA patients developed circulating IgA-CCP earlier than did their non-smoking counterparts (Kokkonen et al 2011).…”

Cross‐reactivity of a human IgG1 anticitrullinated fibrinogen monoclonal antibody to a citrullinated profilaggrin peptide

“…[11][12][13][14][15] These ACPA responses, primarily characterized by IgG 1 and IgG 4 subtypes (99 and 98% of ACPA-positive RA patient sera, respectively), have been found to be present up to years before disease onset and to be highly specific (98%) and sensitive (up to 80%) for RA. [16][17][18][19][20][21] Thus, APCA are used as a supplement to clinical diagnosis of RA. 20 The most frequently used peptide-based immunoassay for ACPA detection is based on cyclic citrullinated peptides (CCP).…”