Predictive value of anti-CarP and anti-PAD3 antibodies alone or in combination with RF and ACPA for the severity of rheumatoid arthritis

Abstract

Objectives To analyse the predictive value of anti-carbamylated protein (anti-CarP) and anti-peptidyl-arginine deiminase type-3 (anti-PAD3) antibodies, alone or in combination with rheumatoid factors (RFs) and anti-citrullinated protein antibodies (ACPA), to identify patients at high risk of developing severe rheumatoid arthritis (RA) outcomes. Methods Patients within the « Swiss Clinical Quality Management » registry with a biobank sample were tested for RFs, ACPA, anti-CarP, and anti-PAD3 antibodies. We examined the association of each autoantibody with DAS28, HAQ and radiographic damage (Ratingen) at baseline and longitudinally. Results Analyses included 851 established RA patients and 516 disease controls [axial spondyloarthritis (axSpA = 320) and psoriatic arthritis (PsA = 196)]. Anti-CarP and anti-PAD3 antibodies were respectively present in 22.4% and 10.7% of the whole RA population, and in 13.2% and 3.8% of the RF and ACPA double seronegative patients. At baseline, RA patients with anti-PAD3 had higher DAS28 (4.2 vs 3.7; p = 0.005) and significantly more radiographic damage (14.9 vs 8.8; p = 0.02) than anti-PAD3 negative patients. In ACPA negative subgroup, baseline Ratingen scores were significantly higher in anti-PAD3 positive patients (p = 0.01). The combination of anti-PAD3, RF IgM, and ACPA was associated with significantly higher baseline radiographic scores than the double seropositive group (p = 0.04). The presence of any two of the previous autoantibodies was associated with significantly greater radiographic progression over 10 years than if all were absent (p = 0.02). There were no differences on RA outcome measures with regards to anti-CarP. Conclusions Anti-PAD3 antibodies are associated with higher disease activity and joint damage scores in RA patients.

Autoantibodies in Rheumatoid Arthritis: Historical Background and Novel Findings

“…Collectively, studies show that seropositivity for various autoantibodies in RA is associated with a more severe disease course, radiographic damage and bone loss, even prior to the disease onset [90,139,140]. In a recent observational study, various AMPA (to citrullinated, carbamylated, and acetylated peptides) were shown to contribute to the risk of radiographic progression only if present as a combination but not separately [95].…”

B Cell Involvement in the Pathogenesis of Ankylosing Spondylitis

“…In marked contrast with RA, the prevalence of these antibodies in the serum of AS patients is very low (2-4% for ACPAs and 10-20% for anti-CarP antibodies). Therefore, the diagnostic/prognostic value of ACPAs and anti-CarP antibodies is also rather limited in AS, compared to RA [99][100][101]144].…”

The Genetic, Environmental, and Immunopathological Complexity of Autoantibody-Negative Rheumatoid Arthritis

“…This is the case, for instance, of autoantibodies against carbamylated proteins (anti-CarP), reported to be present in 10-15% of RF and ACPA double-negative patients [102,103]. In contrast with the wellestablished clinical and pathogenetic role of ACPA [104,105], the significance of anti-CarP in the context of ACPA negativity remains controversial [106][107][108]. Still, the strong and specific association of HLA-B*08 carrying aspartate at position 9 with anti-CarP but not ACPA [109] reinforces the concept that the spectrum of autoimmunity in RA is broader than that traditionally recognized.…”