Clinical Information

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by interactions between the environment, specific genetic risk factors, and the human immune system. It affects about 0.6% of the United States population with a global prevalence of 0.24%.(1) Clinically, RA is typified by progressive damage of synovial joints, inflammation, production of diverse autoantibodies, and variable extra-articular manifestations.(2-4) To facilitate early diagnosis, the American College of Rheumatology/European League Against Rheumatism 2010 RA classification criteria recommend testing for rheumatoid factors (RF) and anticitrullinated protein antibodies (ACPA).(2) RF are autoantibodies directed against the Fc portion of immunoglobulin, while ACPA are directed against peptides and proteins containing citrulline, a modified form of the amino acid arginine.(5,6)

Rheumatoid factor is a heterogeneous group of autoantibodies and can be found in other inflammatory rheumatic and nonrheumatic conditions with increased prevalence in healthy individuals 60 years and older. More than 75% of patients with RA have an IgM antibody to RF. The titer of RF correlates poorly with disease activity, but those patients with high titers tend to have more severe disease and, thus, a poorer prognosis than seronegative patients. Compared to early serologic tests for RA, including RF, several studies have demonstrated that ACPA have much improved specificity for RA.(4,5,7) A systemic review and meta-analysis of 33 studies, including patients with RA and healthy or disease controls, demonstrated the sensitivity of anti-mutated citrullinated vimentin, anticyclic citrullinated peptide, and RF of 71%, 71%, 77%, with the specificity of 89%, 95%, 73%, and the area under the curve of the summary receiver operating characteristic of 89%, 95%, 82%, respectively.(7) Based on these studies, there exist a subset of patients with RA who are negative for RF and ACPA IgG (seronegative) who must be diagnosed clinically or with use of emerging diagnostic tests.(4,6,8)

In addition to the use of RF and ACPA IgG to diagnose RA, RF and ACPA isotype antibodies and other serologic biomarkers have been used to predict if, and when, an individual who has inflammatory arthritis (IA) may develop future clinically apparent IA and assess genetic and environmental risks.(3,4,8,9)  Furthermore, patients with RA may be categorized based on the phase of disease (early versus established), presence or absence of antibodies (seropositive versus seronegative), clinical manifestations (joint erosion, interstitial lung disease, or cardiovascular), or specific risks (genes, sex, or smoking).(2-4) Delayed diagnosis of RA is associated with joint erosion, destruction or deformities, poor response to treatment with ultimate increase in morbidity, and mortality.(3,4) Although late RA prognosis may be linked to adverse consequences, early diagnosis has been reported to improve outcomes; notably reduced joint destruction or deformity, delayed radiologic progression, and decreased functional disability.(3,4,10)

For more information see Connective Tissue Disease Cascade.