Impact of autoimmune serology test results on RA classification and diagnosis

Abstract

Rheumatoid arthritis (RA) is the most common systemic autoimmune disease and also the most severe arthritic disorder. The measurement of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) in serum supports the diagnosis of RA, which gained increasing significance over the last 65 years. However, a high variability between RF and ACPA methods has been described, impacting the diagnostic performance of the current ACR/EULAR RA classification criteria. The great number of commercially available assays, often lacking traceability to an international standard, is a major factor attributing to this in-between assay variability. The adoption of an international standard for ACPA, as is since long available for rheumatoid factor, is therefore highly desirable. Further harmonization in clinical interpretation of RF/ACPA assays could be obtained by harmonization of the cut-offs, for both the low and high antibody levels, based on predefined specificity in disease controls. Reporting test result specific likelihood ratios (LR) adds value in the interpretation of autoantibody tests. However, a good understanding of the control population used to define antibody test result interval-associated LRs is crucial in defining the diagnostic performance characteristics of antibody serology. Finally, specificity in RA classification can be improved by refining serological weight scoring taking into account the nature of the antibody, the antibody level and double RF + ACPA positivity.

Multicentre study to improve clinical interpretation of rheumatoid factor and anti-citrullinated protein/peptide antibodies test results

“…This is mainly related to differences in the way companies define cut-off values and to the differences in the patient and control populations used to establish the cut-off values. Importantly, the variability among RF and ACPA assays affects patient RA classification according to 2010 ACR/EULAR criteria13 33 and jeopardises RA diagnosis in routine rheumatological practice 11…”

“…Cut-off values for RF and ACPA are not aligned across manufacturers. Relatedly, cut-offs defining ‘high antibody positivity’ based on three times the manufacturer’s cut-off (as applied in the 2010 classification criteria11) are arbitrarily chosen and not aligned as well 13. In RA diagnosis, serology plays a crucial role in the diagnostic assessment of patients with less typical symptoms, that is, with a lower pre-test probability 11.…”

“…Relatedly, cut-offs defining ‘high antibody positivity’ based on three times the manufacturer’s cut-off (as applied in the 2010 classification criteria11) are arbitrarily chosen and not aligned as well 13. In RA diagnosis, serology plays a crucial role in the diagnostic assessment of patients with less typical symptoms, that is, with a lower pre-test probability 11. Using test result-specific LRs on a nomogram, one can calculate the post-test probability of disease 11 32 34.…”

“…In RA diagnosis, serology plays a crucial role in the diagnostic assessment of patients with less typical symptoms, that is, with a lower pre-test probability 11. Using test result-specific LRs on a nomogram, one can calculate the post-test probability of disease 11 32 34. Consequently, the use of harmonised LRs directly impacts clinical decision-making.…”

“…Clinical signs and symptoms alone are usually insufficient to diagnose RA. The presence of rheumatoid factor (RF) and anti-cyclic citrullinated protein/peptide antibodies (ACPA) in serum supports the diagnosis of RA 11. However, there is poor agreement among the currently available RF and ACPA assays, which may have an impact on RA diagnosis and classification of a patient 12–14.…”