Anti-carbamylated protein antibodies in the pre-symptomatic phase of rheumatoid arthritis, their relationship with multiple anti-citrulline peptide antibodies and association with radiological damage

Abstract

IntroductionThe presence of a new autoantibody system, anti-carbamylated protein (anti-CarP) antibodies, has been identified in rheumatoid arthritis (RA). The presence of anti-CarP antibodies was evaluated in samples taken from individuals who subsequently developed RA before and after onset of symptoms and related to previously analysed antibodies against citrullinated peptides (ACPA specificities) and anti-CCP2.MethodsA total of 252 individuals, with 423 samples from before onset of symptoms of RA, and 197 population controls were identified as donors to the Medical Biobank of Northern Sweden; 192 of them were also sampled at the time of diagnosis. All samples were analysed for anti-CarP IgG and anti-CCP2 antibodies using ELISAs. Ten different antibody reactivities against citrullinated antigens (ACPA specificities) were analysed using a custom-made microarray based on the ImmunoCAP ISAC system (Phadia).ResultsThe concentration of anti-CarP antibodies was significantly increased in the pre-symptomatic individuals compared with controls (P <0.001) and also increased significantly after disease onset (P <0.001). The sensitivity for anti-CarP antibodies in the pre-symptomatic individuals was 13.9% (95% CI: 11 to 17.6) and 42.2% (95% CI: 35.4 to 49.3) following development of RA. Anti-CarP antibody positivity was found in 5.1% to 13.3% of individuals negative for anti-CCP2 or ACPA specificities. Presence of anti-CarP antibodies was significantly related to radiological destruction at baseline, at 24 months and also to radiological change (P <0.05, all).ConclusionsThe results indicate that anti-CarP antibodies are associated with disease development, even after adjusting for the presence of different ACPA fine specificities, and in anti-CCP2 negative individuals and contribute to the identification of a subset of patients with worse radiological progression of the disease independent of ACPA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-015-0536-2) contains supplementary material, which is available to authorized users.

The role for neutrophil extracellular traps in cystic fibrosis autoimmunity

“…In contrast to anti-BPI responses, the lack of association between ACarPa and anti-Cif IgG levels suggests that ACarPA arise independently of infection and are most likely a marker of neutrophil-driven bronchial inflammation reported in other chronic diseases (24,68,69). Alternatively, it may be that ACarPA influence clinical phenotype by impairing the antibacterial activity on NETs.…”

The association between anti-carbamylated protein (anti-CarP) antibodies and radiographic progression in early rheumatoid arthritis: a study exploring replication and the added value to ACPA and rheumatoid factor

“…Anti-CarP antibodies are predominantly present in RA with the reported sensitivity and specificity for RA of 44% and 89%, respectively 26. Intriguingly, already in the presymptomatic individuals the presence of anti-CarP antibodies is associated with RA development in ACPA-negative individuals and also with worse radiological progression independent of ACPA 15. In a small cohort of patients with RA, the presence of anti-CarP antibodies and anti-CarP combined with ACPA has been reported to correlate with joint erosion score 17…”

“…First, the association of anti-CarP with radiographic progression has to be replicated in a large cohort with longitudinal radiographic follow-up. At present, there is some evidence suggestion replication, but these studies were considerably smaller than the identification cohort;15 17 hence, compelling replication is still lacking. Second, in clinical practice, ACPA and RF are generally determined and both autoantibodies associate with more severe radiographic progression.…”

Association between anti-citrullinated alpha enolase antibodies and clinical features in a cohort of patients with rheumatoid arthritis: a pilot study

“…In addition, it is known that ACPA may occur years before the diagnosis of RA and that some patients already display erosions at the time of diagnosis. These observations may further strengthen the role of ACPA in the development of bone erosions (19)(20)(21)(22). With regard to the association between anti-CEP1 and ILD, it is interesting to note that 70% of patients with ILD display either anti-CEP1 alone or in association with anti-CCP, while only a small proportion of anti-CCP+ anti-CEP1-patients display ILD.…”