The case for measuring antibodies to specific citrullinated antigens

Abstract

Anti-citrullinated protein/peptide antibodies (ACPA) are the principal autoantibody system associated with rheumatoid arthritis (RA), with diagnostic sensitivity of 70% and specificity of 95%. Current testing for ACPA uses the anti-cyclic citrullinated peptide assay (anti-CCP) which measures a generalized reactivity with citrulline-containing peptides, thus giving no insight into reactivity to specific RA antigens. Of these, the best characterized are, α-enolase, fibrinogen/fibrin, vimentin, Type 2 collagen and filaggrin, antibodies to each of which are found in approximately 30–60% of RA cases. Given reports of cross-reactivity between citrullinated antigens, we discuss whether or not measuring these specific antibodies could aid: clinical diagnosis, identification of clinical subsets and drug responses, or provide insight into pathogenic mechanisms or etiology of RA.

Keywords::

• ACPA
• anti-CCP
• auto-antibody
• citrullination
• rheumatoid arthritis

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Anti-citrullinated protein/peptide antibodies (ACPA⁺) rheumatoid arthritis (RA) patients make up 70% of RA cases, with ACPA positivity being defined by generic tests such as anti-cyclic citrullinated peptide assay (anti-CCP).

• • A number of specific, well-defined citrullinated autoantigens have been described.

• • Cross-reactivity is observed to some degree between specific ACPA, however distinct patterns of reactivity and non-cross-reactive antibodies are also seen.

• • Measurement of specific ACPA adds little benefit over generic ACPA tests in the diagnosis of RA or prediction of disease severity, but higher numbers of specific ACPA may predict RA in those at risk.

• • No conclusive evidence yet links individual specific ACPA with any particular extra-articular manifestation.

• • ACPA may be involved in unique pathogenic mechanisms; citrullination of fibrinogen induces increased TNF-α production from macrophage/monocytes and antibodies to citrullinated vimentin increase osteoclast differentiation.

• • Immunodominant citrullinate enolase peptide and immunodominant citrullinated vimentin peptide ACPA are most strongly associated with the combination of HLA-DRB1 SE allele, PTPN22 gene and smoking.

• • Non-citrullinated variants of citrullinated autoantigens may be involved in breach of tolerance mechanisms.

Notes