Use of subclinical synovitis to classify RA yields high false-positive rate
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Using subclinical synovitis, rather than clinical arthritis, to identify rheumatoid arthritis produces a high false-positive rate, with 44% to 89% never developing the disease, according to data published in Rheumatology.
“Early start with [disease-modifying antirheumatic drugs] has become key in the treatment of RA because of its association with improved disease outcomes,” Cleo Rogier, MD, MSc, of Erasmus University Medical Center, in the Netherlands, and colleagues wrote. “It has also fueled research that aims to identify patients at risk for RA in the symptomatic phase preceding clinically apparent arthritis in the hope that even earlier treatment may prevent the development of RA. At present, clinically apparent arthritis is mandatory for diagnosing RA and according to current guidelines is the regular starting point for DMARD treatment.”
“However, this basic notion seems to be shifting in some places,” they added. “A recent Dutch study showed that rheumatologists are increasingly willing to initiate ‘preventive’ treatment in the absence of clinical arthritis. Subclinical synovitis has indeed been consistently reported as a predictor for RA development; however, not all patients with this feature will develop RA. Therefore, the question remains how often DMARD treatment in such patients would be correct and how frequently patients will be overtreated, as they would not have developed RA in the absence of DMARD treatment.”
To determine the rate patients with subclinical synovitis who never progress to inflammatory arthritis, both with and without anti-citrullinated protein antibodies (ACPA), and whether using the 2010 classification criteria for RA in those with subclinical synovitis but without clinical arthritis reduced the false-positive rate, Rogier and colleagues studied three longitudinal cohorts.
The first cohort, from the multicenter, observational SONAR study, included 166 patients with arthralgia. These participants underwent baseline bilateral ultrasound of the MCP joints 2-5, MTP joints 2-5 and the wrists. Subclinical synovitis was defined as a greyscale score of at least 2 and/or a power Doppler score of at least 1.
The second cohort included 473 patients who were clinically suspected of arthralgia. Participants underwent contrast-enhanced 1.5T MRI of the wrists, MCP joints 2-5 and MTP joints 2-5. The resulting scans were then scored for subclinical synovitis according to the Rheumatoid Arthritis MRI Score, with a synovitis score of 1 or higher used as the cut-off.
The last cohort included 162 patients who were positive for ACPA and/or rheumatoid factor. Bilateral ultrasound of the wrists, MCP joints 2-3, and MTP joints 2, 3 and 5 were performed at baseline. Subclinical synovitis was defined using the same criteria as the SONAR study.
In all three cohorts, the primary outcome was the development of inflammatory arthritis after 1 year, assessed through physical examination by the treating rheumatologist. This outcome was also assessed at 3 years in the second and third cohorts. Analyses were stratified for ACPA.
According to the researchers, subclinical synovitis was present at baseline in 36%, 41% and 31% of participants in cohorts one, two and three, respectively. Among those who were ACPA-positive and demonstrated subclinical synovitis, 54%, 44% and 68%, respectively, never developed inflammatory arthritis. In those who were ACPA-negative, these percentages were even higher — 66%, 85% and 89%, respectively. Similar results were recorded after 3years in cohorts two and three.
“Our results showed that the presence of subclinical synovitis and ACPA positivity is not equal to RA development,” Rogier and colleagues wrote. “Therefore, in our view, further observational studies on the natural disease course are necessary to derive accurate and validated risk stratification for patients presenting with arthralgia. Thus, when randomized clinical trials show that treatment of arthralgia patients prevents progression to IA, we can apply this treatment to the right patients and avoid significant overtreatment.”
Perspective
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Today, some rheumatologists initiate DMARD therapy in patients with arthralgias at times based on a musculoskeletal ultrasound or MRI demonstrating evidence of subclinical synovitis despite negative serologies or, in some cases, with a positive ACPA. Rogier and colleagues evaluated the data from three longitudinal cohorts that followed the course of patients with arthralgia over a 1-year period of time to determine those who developed clinical arthritis with or without a positive ACPA. In all three cohorts, neither DMARD therapy nor glucocorticoid injections were initiated unless a patient developed clinically-apparent arthritis.
In the ACPA-positive patients, 54%, 44% and 68% of patients did not develop inflammatory arthritis. In the ACPA-negative patients, 66%, 85% and 89% of patients did not develop inflammatory arthritis. This suggests that if patients with arthralgias and musculoskeletal ultrasound or MRI evidence of subclinical arthritis are treated with DMARD therapy, that many patients will be exposed to DMARDs, and their associated potential toxicities, without clinical benefit or need.
Hopefully, further research will demonstrate the risk factors that better predict those patients with arthralgias who will develop inflammatory arthritis so that we can treat the appropriate patients without exposing other patients unnecessarily to DMARD therapy.
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