Association of smoking with the constitution of the anti–cyclic citrullinated peptide response in the absence of HLA–DRB1 shared epitope alleles

Abstract

Objective. Smoking is a risk factor for anti-cyclic citrullinated peptide (anti-CCP) antibody-positive rheumatoid arthritis (RA) in patients with HLA-DRB1 shared epitope (SE) alleles. It is unknown whether smoking influences not only the presence of these antibodies, but also other characteristics of the anti-CCP response, such as isotype usage. The aim of this study was to determine the influence of smoking on anti-CCP isotypes in RA patients, and to determine whether this influence is observed in the presence and/or absence of SE alleles.Methods. IgA, IgM, and IgG subclasses of anti-CCP antibodies were measured by enzyme-linked immunosorbent assay in serum obtained at the first visit to the Leiden Early Arthritis Clinic from 216 patients with anti-CCP-positive RA whose smoking habits were also assessed. HLA genotyping data were available for 202 of these patients.Results. IgA and IgM anti-CCP were more frequent in RA patients who were smokers than in those who were nonsmokers (odds ratio 2.8 and 1.8, respectively). In addition, levels of all isotypes of anti-CCP, except IgG3, were significantly higher (P < 0.05) in smokers. The number of anti-CCP isotypes was higher in smokers compared with nonsmokers, both in SEnegative RA (P ‫؍‬ 0.04) and in SE-positive RA (P ‫؍‬ 0.07).Conclusion. Patients with anti-CCP-positive RA who have a current or former tobacco exposure display a more extensive anti-CCP isotype usage in general, and IgA and IgM in particular, compared with patients with anti-CCP-positive RA who have never smoked. In contrast to its influence on the incidence of anti-CCP positivity, the influence of tobacco exposure on the constitution of the anti-CCP response is significant in SE-negative RA. These findings suggest a differential effect of tobacco exposure on the induction as compared with the propagation of the anti-CCP antibody response.

Circulating and Mucosal Antibodies to Citrullinated Antigens in Rheumatoid Arthritis

“…The numbers were however not large enough to draw any firm conclusions, although the findings are in line with data from Verpoort [82]. Further, Kokkonen and colleagues showed that smoking pre-RA patients developed circulating IgA-CCP earlier than their non-smoking counterparts [97].…”

“…Smoking has also been found to induce inflammation [78], and to associate with a number of autoimmune diseases [79][80][81][82][83]. However, components of cigarette smoke, e. g. nicotine, have also been shown to have immunosuppressive/anti-inflammatory effects [84,85].…”

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).…”

“…So far, the best documented ACPA test for clinical routine is IgG antibodies against the 'second generation' of cyclic citrullinated peptides (CCP). In a subset of IgG-ACPA positive patients circulating IgA-ACPA have been described, but the low sensitivity limits its diagnostic value (Verpoort et al 2006;Verpoort et al 2007;Svärd et al 2008;Svärd et al 2010). The prognostic value of serum IgA-ACPA has not been firmly established, but similar to rheumatoid factor (RF) of IgA-class (Houssien et al 1997;Lindqvist et al 2005;Berglin et al 2006), a more severe disease has been described in IgA-ACPA positive patients (Verpoort et al 2006;Verpoort et al 2007;Svärd et al 2008;Svärd et al 2010).…”

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

“…Accordingly, a geneenvironment interaction between the shared epitope and smoking in ACPAϩ, but not ACPA-, RA has been reported in northern European RA patient cohorts (8,9). On the other hand, however, the association of the specific HLA-DRB1 alleles with ACPAϩ RA appears to vary between different populations (10)(11)(12), and the specific gene-environment interaction in ACPAϩ RA could not be confirmed in all studies (13,14).…”