Autoantibodies against carbamylated proteins (anti-CarP) are another important serum biomarker in preclinical disease. They have been identified in the serum of at-risk patients before RA developed, including in 39% of seropositive patients with arthralgia compared to only 6% of controls in one study.15
No matter where autoimmunity begins, ACPAs and rheumatoid factor may be found in blood serum years before an individual develops clinical RA, and autoantibodies will increase as disease approaches. So testing at-risk patients for those signs could be clinically useful, says Prof. Emery.
“In patients who have positive autoantibodies, we now have a list of risk factors which can help predict progression. Thus, patients with a positive ACPA test should be thoroughly assessed,” he says.
However, autoantibodies alone won’t effectively pinpoint who is most at risk for RA in the wider population, says Prof. Emery. Data from a Dutch cohort show that while 40% of RA patients test positive for anti-CCP antibodies before diagnosis, the same positive test result only has a five-year positive predictive value of RA in 5% of the general population.16 Testing a large group of people without other factors to identify elevated risk is expensive, so patients should have other risk factors before testing is conducted, says Prof. Emery.
“Screening for autoantibodies at the population level has not proven to be cost-effective mainly because, in isolation, the presence of a low-titer autoantibody does not predict progression” of RA, he says. “Thus, we use links with primary care physicians to identify patients with other risk factors, particularly new musculoskeletal symptoms, which identify an ACPA-positive group more likely to progress.”
Importance of Symptoms
Patients may only seek medical care when they have one or more of those musculoskeletal symptoms: pain, fatigue, morning joint stiffness, muscle weakness, burning sensations or skin warmth and redness.17 These signs can show up before clinical arthritis develops, and are the fourth phase on the RA progression spectrum. Could certain symptoms point to those at higher risk to move forward to disease?
There’s some evidence that symptoms can be early predictors of disease risk. In one study, 20% of seropositive patients with arthralgia went on to develop arthritis within about two years. Of these patients, 60% of those who had symmetric small joint pain and morning stiffness progressed.18 Another study showed that small joint tenderness and early morning stiffness of 30 minutes or longer were associated with higher risk of progression to arthritis.19