Joint pain is a frequent presenting complaint. Many physicians order a panel of antibodies in patients with musculoskeletal complaints screening for a rheumatic disorder. Traditionally this includes testing for presence of Rheumatoid factors (RF), antibodies against Citrullinated Cyclic Peptides (ACPA or anti-CCP) and antinuclear Antibodies (ANA) and sometime HLA-B27 and ANCA tests.
This strategy is expensive (approx. $150 to the taxpayers) and inappropriate when there is no clinical evidence of joint inflammation. Arthritis is a clinical diagnosis with typical examination findings of synovial inflammation (i.e., swollen, tender, sometimes red and warm joint(s) having reduced range of motion). Most patients with arthralgia will not have arthritis/synovitis and following examination will not require further investigations for arthritis (Figure1).
Rheumatoid Arthritis (RA) is defined and diagnosed by the presence of chronic, usually symmetric synovitis involving wrist, MCP, PIP and MTP joints. These clinical findings are sufficient to diagnose RA, as there is no specific laboratory test for diagnosis
Natural autoantibodies circulate in healthy persons where they contribute to the maintenance of immune tolerance. The isolated finding of increased levels of autoantibodies in the circulation thus does not suggest the (impending) presence of autoimmune disease. As illustrated (Figure 2), healthy people with findings of an autoantibody are considered to be in a state of (? increased natural) autoimmunity but only a minority will progress to a state of autoimmune disease.
This progression, through a complex and poorly understood processes of antibody maturation by somatic mutations, is impossible to predict or even prevent. Thus, positive autoAb results in patients without clinical evidence of synovitis do not indicate a current or future inflammatory joint disease.
Autoantibodies and RA Rheumatoid factors (RF) are polyclonal antibodies directed mainly against modified sites of the Fc portion of IgG. The origin of this antibody-against-antibody response is not well understood, but most likely results from a durable or strong stimulus (e.g., smoking, infections) leading to alterations (glycosylation, phosphorylation) in the molecular structure of IgG, which then provokes a humoral immune response with activation of RF producing B cells.
The possible useful functions of RF include clearance of the resulting Ig-IgG immune complexes. RF activity can be mediated by antibodies of all Ig subclasses, but most clinical laboratories traditionally only measure IgM-RF, with RF from IgA, IgG, IgD and IgE subclasses mainly used in research projects.
There are multiple assays in use for the detection of IgM-RF (agglutination test of sensitised sheep red blood cells, latex fixation test (LFT), turbidimetry, radioimmunoassay, enzyme-linked immune-absorbent assays (ELISA) and as RF testing is unfortunately not standardised, results are not per se comparable from one WA laboratory to the other.
In addition to these technical issues, multiple population-based studies have found that the presence of RF often is part of the natural autoAb repertoire with less than 10% specificity for RA (Table 1). Taken together it comes as no surprise that the high rate of false positive results makes IgM-RF useless as a screening method for RA. In short, RF testing cannot replace joint examination.
Antibodies against artificially produced cyclic citrullinated peptides (anti-CCP Ab) arise when citrullination of proteins occurs during a post-translational conversion of arginine to citrulline residues by peptidylarginine deiminase enzymes (PAD). Such citrullination can occur during inflammation of multiple tissues and a range of citrullinated proteins (e.g., vimentin, fibrinogen) can trigger an antigen-driven maturation of B-cells to produce anti-CCP Ab. This immunological process is essentially similar to what underlies RF formation.
Anti-CCP Ab can be detected in up to 5-10% of healthy individuals and is thus not recommended as a screening method for RA. In patients with evidence of synovitis, anti-CCP Ab are as sensitive as RF and more specific (around 70%) for confirming RA. Anti-CCP Ab also associate with genetic risk factors for RA and delineate a subset of RA patients with more severe disease. Importantly, ELISA based anti-CCP Ab testing is largely standardised.
Most patients presenting with joint pain will not have synovitis on joint examination and, in this setting of low pre-test probability, there is a high risk of false positive results (especially with RF) and unnecessary spending of health dollars. These patients are better served by allied health assistance with their underlying degenerative joint problems (osteoarthrosis) or soft tissue pains than a referral to a specialist based on the incidental finding of RF or ACPA.
Key messages
- RA is a clinical diagnosis
- RF and ACPA testing are not needed to diagnose RA and there is a high risk of false positive
- These autoantibodies have only a limited role in delineating disease severity in patients with a clinical diagnosis of RA.
– References available on request