Rheumatoid arthritis

Clinical information

Rheumatoid arthritis (RA) is characterised by painful, swollen joints, movement restriction and progressing joint destruction. 0.5% to 1% of the worldwide population is affected, women approximately twice as often as men. Most new cases are diagnosed in women between 55 and 64 years of age and in men between 65 and 75 years of age. A majority of RA patients (approx. 70%) produce autoantibodies against citrullinated peptides (ACPA). Consequently, immune complexes are formed and the inflammation of the joints proceeds.

Autoantibodies in RA appear on average 3 to 5 years before the first joint complaints, but sometimes even 15 years before. The most important autoantibodies in preclinical RA are rheumatoid factors (RF) and ACPA, which are detected using primarily cyclic citrullinated peptides (CCP) but also Sa (citrullinated vimentin) and citrullinated enolase peptide 1 (CEP-1) as target antigens. ACPA are specific for RA and indicators of a severe, erosive destructive course. During the transition from the undifferentiated arthritis phase to RA, ACPA levels increase and remain high. ACPA have a high predictive value for the development of RA. Their detection supports the early recognition of the disease.

Diagnostics

The determination of ACPA has been part of the RA classification criteria of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) since 2010. ACPA are determined in parallel to RF. According to the scoring system of the ACR/EULAR classification, a high ACPA or RF titer is more relevant for the diagnosis of RA than a lower titer. Laboratory findings such as increased erythrocyte sedimentation rate, increased C-reactive protein and the detection of RF and/or ACPA are indicative of RA Aletaha et al., Ann Rheum Dis (2010), 69:1580-1588).

Autoantibodies against CCP can be determined using ELISA and ChLIA. For the detection of ACPA, second-generation CCP antigen (CCP2) is considered the gold standard. Test systems based on this antigen provide the highest sensitivity (80%, with a specificity of 98%). Antibodies against CCP are mainly IgG class antibodies and are more specific than RF, with a similar sensitivity. Anti-CCP antibodies are found in up to 60% of RF-negative patients.

CEP-1 is another relevant autoantigen, which is present in approx. 60% of anti-CCP-positive RA patients. The detection of antibodies against CEP-1 is highly specific for RA (specificity: 97.6%) and therefore suited as a supplementary test for the confirmation of serological findings. Moreover, the detection of anti-CEP-1 supports risk stratification: Anti-CEP-1 antibodies are associated with an erosive disease course and with interstitial lung diseases (Alunno et al., Rheumatology (2018) 57:850-855). Furthermore, anti-CEP-1 antibodies occur in a subtype of RA for which smoking and the HLA-DRB1 “shared epitope” alleles are the main risk factors (Mahdi et al., Nat Genet (2009) 41:1319-1324). Since anti-CEP-1 antibodies are directed against a target antigen which actually occurs in RA, their detection can provide insight into the cause and the pathogenesis of the disease.