After analyzing past studies and classification criteria, authors found multiple factors that could be implemented into the current rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) tests for a more specific rheumatoid arthritis (RA) classification.
This refinement includes factoring in the nature and level of the antibody as well as the double rheumatoid factor (RF) and positivity.
Past research on RF/ACPA measurement in serum to diagnose RA has increased in significance. However, past studies have noted the high variability between measurement methods and how that impacts the diagnostic performance of the current 2010 American College of Rheumatology/European League Against Rheumatism (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 authors explained. “The adoption of an international standard for ACPA, as is since long available for rheumatoid factor, is therefore highly desirable.”
Sensitivities of RF and ACPA for RA are comparable (±60%), although ACPA are more specific (±95%) for RA and are associated with poorer outcomes. Despite these differences, the 2010 ACR/EULAR criteria gave RF and ACPA similar weights in scoring.
The authors found that establishing a universal cut-off for low and high antibody levels based on predefined specificity in disease controls and reporting likelihood ratios (LR) based on test results helps interpret autoantibody tests like RF/ACPA and therefore make a more specific diagnosis. According to the authors, a vital factor in defining the diagnostic characteristics is having a strong understanding of control populations used to define antibody test result interval-associated LRs.
The 2010 classification criteria scores between 0 and 10, with a score of 6 or higher allowing the classification of RA. A low positive RA or ACPA contributes 2 points and a high positive contributes 3 points. However, arbitrary cut-off values have led to major variations between RF and ACPA evaluations, and therefore different percentages of patients receiving a RA diagnosis.
“There is a general trend that cut-off values of RF tests are set at a lower specificity than for ACPA, due to the inherent lower diagnostic performance of RF assays,” the authors explained. “Using a single cut-off value only provides the clinician with dichotomous information.”
The nature and level of each antibody should not be treated equally, they said. While past research has come to the understanding that higher RF or ACPA leads to a higher LR for RA, this does not take into account that ACPA has a higher specificity and LR compared with RF, or that combined RF and ACPA positivity is associated with even higher LRs.
“By adapting serological weight factors based on inherent diagnostic performance characteristics of RF and ACPA, antibody level and combined positivity, a gain in diagnostic specificity in RA classification is to be expected,” they said.
While it does not nearly solve every other issue or develop a definitive specificity, the adoption of an ACPA international standard and the standardization of RF among companies is the next step in the harmonization of these tests.
“There is now increasing awareness that efforts should be undertaken to harmonize interpretation of RF and ACPA test results in order to further improve classification and diagnosis of RA,” the authors concluded.
Van Hoovels L, Studenic P, Sieghart D, Steiner G, Bossuyt X, Rönnelid J. Impact of autoimmune serology test results on RA classification and diagnosis. J Transl Autoimmun. Published online January 6, 2022. doi:10.1016/j.jtauto.2022.100142