Anti-citrullinated protein antibody

Anti-citrullinated protein antibodies (ACPA) or anti-cyclic citrullinated protein antibodies (anti-CCP) are autoantibodies (antibodies directed against one or more of an individual’s own proteins) that are frequently detected in the blood of rheumatoid arthritis patients. The main epitope for these antibodies is filaggrin, and there is cross-reactivity between ACPA and anti-keratin and anti-perinuclear factor.

During inflammation, arginine residues in proteins such as vimentin can be enzymatically converted into citrulline ones (a process called citrullination), and, if their shapes are significantly altered, the proteins may be seen as antigens by the immune system, thereby generating an immune response. ACPAs have proved to be powerful biomarkers that allow the diagnosis of rheumatoid arthritis (RA) to be made at a very early stage.

In July 2010, the 2010 ACR/EULAR Rheumatoid Arthritis Classification Criteria were introduced. These new classification criteria include ACPA testing, and overruled the "old" ACR criteria of 1987 and are adapted for early RA diagnosis.

History
The presence of autoantibodies against citrullinated proteins in rheumatoid arthritis patients was first described in the mid-1970s when the biochemical basis of antibody reactivity against keratin and filaggrin was investigated. Subsequent studies demonstrated that autoantibodies from RA patients react with a series of different citrullinated antigens, including fibrinogen, deiminated Epstein-Barr Virus Nuclear Antigen 1 and vimentin, which is a member of the intermediate filament family of proteins. Several assays for detecting ACPAs were developed in the following years, employing mutated citrullinated Vimentin (MCV-assay), filaggrin-derived peptides (CCP-assay) and viral citrullinated peptides (VCP-assay).

In 2010, ACPA testing has become substantial part of The 2010 ACR-EULAR classification criteria for rheumatoid arthritis.

Clinical significance
In a comparative study (in 2007), various detection kits had a sensitivity between 69.6% and 77.5% and a specificity between 87.8% and 96.4%. Despite the excellent performance of these immunoassays, for example CCP-assays, they only provide a sensitivity comparable with that of rheumatoid factor (RF). Moreover, analysis of the correlation of anti-CCP antibody titre with RA disease activity yielded conflicting results. Unfortunately, these artificial antigens are not expressed in the affected tissue, and therefore are probably not directly involved in the pathogenesis of RA.

In the more recent time, novel test systems utilizing ACPA have been developed. Citrullinated vimentin is a very promising autoantigen in RA, and a very suitable tool for studying this systemic autoimmune disease. Vimentin is secreted and citrullinated by macrophages in response to apoptosis, or by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). A newly developed ELISA system utilises genetically modified citrullinated vimentin (MCV), a naturally occurring isoform of vimentin to optimize the performance of the test. Noteworthy are the findings of a recently published study that highly valuates anti-MCV test systems for diagnosing rheumatoid arthritis in anti-CCP-negative patients.

Given that ACPA are more specific than rheumatoid factor, they are used to distinguish various causes of arthritis. Novel assays may be useful for monitoring disease activity and effects of RA therapy.

The reference ranges for blood tests of anti-citrullinated protein antibodies are: