Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden

Abstract

BackgroundRheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years.ObjectiveTo evaluate serological risk markers in first-degree relatives from multicase families in relation to genetic and environmental risk factors.Methods51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 first-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls.ResultsThe concentrations and frequencies of all anti-CCP and RF isotypes were significantly increased in first-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigen-shared epitope (HLA-SE) significantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was significantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the first-degree relatives.ConclusionsAll anti-CCP and RF isotypes analysed occurred more commonly in unaffected first-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.

Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins

“…The ACPA prevalence was 2.8% in the entire group of twins, and 1.8% when excluding individuals with established RA. The latter is in the higher range of previously reported prevalences in smaller population-based studies13 41 of healthy individuals, but lower than the previously reported prevalence for non-diseased family members of RA patients 12 14 16. In ACPA-positive individuals without RA, specific reactivities against citrullinated antigens were sparse, whereas the frequency of these reactivities in twins with RA was similar to previously reported frequencies in other cohorts of established RA 9 33 43…”

A new window of opportunity in rheumatoid arthritis

“…Instead, studies of RA autoantibody isotypes in at risk populations indicate that preclinical autoimmune events may begin at mucosal surfaces. The observation that IgA ACPA is relatively enriched in first degree relatives (FDRs) of RA patients compared to the IgG isotype [11,12] supports the concept that localised mucosal immunity to citrullinated epitopes precedes, and indeed may trigger, systemic autoimmunity. Such mucosal autoimmune events may occur at the oral mucosa (specifically the periodontium), lung and/or the gastrointestinal tract [13].…”

Genética da artrite reumatoide: é necessário um novo impulso em populações latino‐americanas

“…16 Os alelos HLA-DRB1 com EC estão presentes em 64 a 70% dos pacientes com AR e em 55% dos seus parentes de primeiro grau; essa frequência é significativamente superior à observada em populaç ões-controle (35,8%). 26,27 Em pacientes com AR ACPA-positivos, 80% têm pelo menos um EC, enquanto 49% dos pacientes com AR ACPA-negativos têm EC. Essa interação entre os fatores de risco genéticos e a presença de autoanticorpos aumenta o risco de parentes de primeiro grau de pacientes com AR desenvolverem AR.…”