Presence of anti-acetylated peptide antibodies (AAPA) in inflammatory arthritis and other rheumatic diseases suggests discriminative diagnostic capacity towards early rheumatoid arthritis

Abstract

Aims: To determine the diagnostic value of anti-acetylated peptide antibodies (AAPA) in patients with rheumatoid arthritis (RA). Methods: Three acetylated peptides (ac-lysine, ac-lysine.inv and ac-ornithine) derived from vimentin were employed to measure AAPA by enzyme-linked immunosorbent assay (ELISA) in sera of 120 patients with early RA (eRA), 195 patients with established RA (est RA), 99 healthy controls (HC), and 216 patients with other inflammatory rheumatic diseases. A carbamylated and a citrullinated version of the vimentin peptide were used additionally. Receiver operating characteristics and logistic regression analyses were used to assess the discriminative capacity of AAPA. Results: AAPA were detected in 60% of eRA and 68.7% of estRA patients, 22.2% of HC, and 7.1– 30.6% of patients with other rheumatic diseases. Importantly, AAPA were also present in 40% of seronegative RA patients, while antibodies to the carbamylated peptide were detected less frequently. Diagnostic sensitivity of individual peptides for eRA was 28.3%, 35.8%, and 34% for ac-lysine, ac-ornithine, and ac-lysine.inv, respectively. Positive likelihood ratios (LR+) for eRA versus HC were 14.0, 7.1, and 2.1. While the presence of a single AAPA showed varying specificity (range: 84–98%), the presence of two AAPA increased specificity considerably since 26.7% of eRA, as compared with 6% of disease controls, were double positive. Thus, double positivity discriminated eRA from axial spondyloarthritis with a LR+ of 18.3. Remarkably, triple positivity was 100% specific for RA, being observed in 10% of eRA and 21.5% of estRA patients, even in the absence of RF and ACPA. Conclusion: AAPA are highly prevalent in early RA and occur also independently of RF and ACPA, thereby reducing the gap of seronegativity. Furthermore, multiple AAPA reactivity increased the specificity for RA, suggesting high diagnostic value of AAPA testing.

Disease mechanisms in preclinical rheumatoid arthritis: A narrative review

“…These findings suggest that anti-CarP is involved in the pathogenesis of RA, including of ACPA/RF-negative disease. Anti-acetylated peptide antibodies (AAPA) are another important class of non-ACPA autoantibodies that was recently described in 30-40% of patients with early or established seronegative RA (262,263). Further, diagnostic accuracy was greatly increased when positivity against more than one acetylated peptide was observed, with AAPAs against three acetylated peptides being 100% specific for RA (262).…”

“…Anti-acetylated peptide antibodies (AAPA) are another important class of non-ACPA autoantibodies that was recently described in 30-40% of patients with early or established seronegative RA (262,263). Further, diagnostic accuracy was greatly increased when positivity against more than one acetylated peptide was observed, with AAPAs against three acetylated peptides being 100% specific for RA (262). Together, ACPAs, anti-CarP and AAPAs may be classified as anti-modified-protein antibodies (AMPAs) (264).…”

Prospective Studies on the Risk of Rheumatoid Arthritis: The European Risk RA Registry

“…ACPA fine-specificities, IgG/IgA RF or anti-carbamylated, as well as other AMPAs can be found in some individuals negative for routine anti-CCP and/or RF tests. It seems that the HLA-DRB1 SE is associated with the formation of ACPAs, whereas smoking has its major role in individuals positive for both RF and ACPA, some indications highlight smoking with the occurrence of RF in seronegative disease ( 41 , 42 ).…”

“…Currently two thirds of patients fulfilling RA disease classification criteria are characterized by the presence of autoantibodies that have been post-translationally modified. As more disease-relevant post-translational modifications are discovered, the proportion of seropositive RA patients will likely increase ( 42 ). This means that in the future more autoantibody-positive at-risk individuals could be eligible for intervention studies.…”

Preventing rheumatoid arthritis: Lessons from that of type 1 diabetes

“…10 Furthermore, anti-acetylated protein antibodies (AAPAs) have been discovered as a group of autoantibodies specific to RA, adding value in distinguishing early RA from other undifferentiated inflammatory arthritis. [11][12][13] Although it has not yet been investigated, it is expected that AAPAs will be present in the preclinical phase of patients with RA.…”