Autoantibodies in Rheumatoid Arthritis - Laboratory and Clinical Perspectives.

Johan Rönnelid,Alf Kastbom,Carl Turesson

doi:10.3389/fimmu.2021.685312

Abstract

Measurement of two groups of autoantibodies, rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) have gained increasing significance in the diagnosis and classification of rheumatoid arthritis (RA) over the last 65 years. Despite this rising importance of autoimmune serology in RA, there is a palpable lack of harmonization between different commercial RF and ACPA tests. While a minimal diagnostic specificity has been defined for RF tests, which almost always are related to an international reference preparation, neither of this applies to ACPA. Especially assays with low diagnostic specificity are associated with very low positive predictive values or post-test probabilities in real world settings. In this review we focus on issues of practical bearing for the clinical physician diagnosing patients who potentially have RA, or treating patients diagnosed with RA. We advocate that all clinically used assays for RF and ACPA should be aligned to a common diagnostic specificity of 98-99% compared to healthy controls. This high and rather narrow interval corresponds to the diagnostic specificity seen for many commercial ACPA tests, and represents a specificity that is higher than what is customary for most RF assays. Data on antibody occurrence harmonized in this way should be accompanied by test result-specific likelihood ratios for the target diagnosis RA on an ordinal or interval scale, which will provide the clinical physician with more granular and richer information than merely relating numerical values to a single cut-off point. As many physicians today are used to evaluate autoantibodies as positive or negative on a nominal scale, the introduction of test result-specific likelihood ratios will require a change in clinical mindset. We also discuss the use of autoantibodies to prognosticate future arthritis development in at-risk patients as well as predict severe disease course and outcome of pharmacological treatment.

Highlights

Autoantibody measurements have been long-term companions to physicians involved in the management of rheumatoid arthritis (RA) patients, with increasing importance during the last decades
We suggest that diagnostic specificities should be harmonized for rheumatoid factor (RF) and anticitrullinated protein/peptide antibodies (ACPA) tests, and that both groups of assays should be aligned with comparable diagnostic specificities within a defined interval between 98-99% in comparison with healthy controls
Complementing these harmonized cutoffs with information about test result-specific likelihood ratios with substantially increase the richness and information value of autoantibody data delivered from the laboratories to the clinicians

Summary

Introduction

Autoantibody measurements have been long-term companions to physicians involved in the management of rheumatoid arthritis (RA) patients, with increasing importance during the last decades. Already in the diagnostic criteria for RA proposed in 1956 [1], a positive sheep cell agglutination test or a positive streptococcal agglutination test [2] was included among the criteria for definite or probable RA. The 1956 criteria [1] did not define what laboratory finding should constitute a positive reaction for RF, but the 1958 revised criteria [3], stated that any method to measure RF could be employed if “positive in not over 5% of normal controls” in two different laboratories, alternatively by a positive streptococcal agglutination test [3]. A specificity more than, but not including, 95% was employed

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Conclusion