Background and objectives ACPA have been detected in individuals predating onset of rheumatoid arthritis (RA), with an initially limited spectrum of reactivities that gradually broadens to the wide recognition of different citrullinated substrates typical of established RA. Among the targets of ACPA, viral deiminated (citrullinated) proteins and antigens derived from neutrophil extracellular traps like histone H4 have been described. The aim of this study is to analyse the evolution of antibody response in pre-RA using citrullinated exogenous (viral peptides) and self (H4 peptides) antigens as substrates to detect ACPA.
Patients and methods 521 individuals sampled before any symptoms of RA and 272 population controls were identified as donors to the Medical Biobank of Northern Sweden; 241 plasma of early RA-patients were also collected. ACPA were detected by ELISA on viral citrullinated peptides derived from EBNA 1 and EBNA2 (VCP1 and VCP2) and on histones 4 (H4) derived peptides (HCP1 and HCP2).
Results Anti-VCP1 antibodies were detected in 10.4% of the pre-symptomatic individuals as compared with 36.1% in early RA; anti-VCP2 in 17.1% vs. 52.3%; anti-HCP1 in 10.2% vs. 37.3%; anti-HCP216.3% vs. 48.5%. Anti-VCP and anti-HCP concentrations were significantly increased in pre-symptomatic individuals as compared with controls (p < 0.001). Mean antibody concentration and frequency of positivityincreased steadily approaching symptom onset. ACPA specific for HCP or VCP appeared at the same time (median (Q1-Q3) 5.3 (2.9–8.9) years before symptom onset); positivity for anti-VCP2, HCP1 and HCP2 was associated with disease development. Combination of anti-VCP1, anti-VCP2 and anti–HCP2 and negativity for anti-HCP1 yielded a highrisk ratio (OR=18.70; 95% CI 2.53–138.47; p < 0.004). Anti-VCP2 and anti-HCP2 antibodies were associated in presymptomatic individuals with HLA-SE but not with PTPN22 T-allele.
Conclusions Anti-VCP and anti-HCP antibodies start to appear long before disease onset and predict disease development, butno hierarchy of citrullinated epitopes can be drawn in the building up of the ACPA response. Taken together with previous findings, these results suggest that no inciting citrullinated antigen so far described is common to all RA patients; data are rather compatible with a stochastic mechanism in ACPA production.
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