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.
Highlights
We and others have previously shown that antibodies against cyclic citrullinated proteins 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
The factors analysed were; Interleukin (IL)1b, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, IL-1 receptor antagonist (Ra), IL-2 receptor(R)alpha, basic fibroblast growth factor (FGF-basic), granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF), interferon (IFN)-g, interferon-inducible protein (IP-10)/(CXCL10), monocyte chemo-attractant protein (MCP)-1/(CCL2), macrophage inflammatory protein (MIP)-1a/(CCL3), MIP-1b/(CCL4), platelet-derived growth factor-BB (PDGF-BB), tumor necrosis factor (TNF)-a, vascular endothelial growth factor (VEGF), monokine induced by interferon-g (MIG/CXCL9), and macrophage-migration inhibitory factor (MIF)
Samples from the 71 individuals before they presented with any symptoms of joint disease and 276 matched controls analysed for the presence of anti-CCP2 antibodies of the IgG, IgA and IgM isotypes showed significantly increased levels, and the concentrations were further increased when these individuals were diagnosed with RA (Table 2)
Summary
We 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. In a more recent study we reported that individuals who subsequently developed RA had significantly increased levels of several cytokines and chemokines years before the onset of RA [5]. Patients with recent onset RA and positive for IgA anti-CCP2 antibodies were reported to suffer a more severe disease course over the first three years compared with patients negative for IgA anti-CCP2 antibodies [10] and the number of different isotypes has recently been related to the long-term radiographic progression in anti-CCP2 antibody positive RA patients [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
