Ultrasound subclinical synovitis in anti-CCP-positive at-risk individuals with musculoskeletal symptoms: an important and predictable stage in the rheumatoid arthritis continuum

OBJECTIVES: To investigate whether anti-CCP2-positive at-risk individuals with musculoskeletal (MSK) symptoms but without clinical synovitis (CCP2(+) at-risk) develop US subclinical synovitis before inflammatory arthritis and if US subclinical synovitis can be predicted. METHODS: First, US scans of CCP2(+) at-risk individuals who developed inflammatory arthritis (‘progressors’) were reviewed for subclinical synovitis prior to inflammatory arthritis development. Patients in whom the pre-progression US scan was negative but the scan was conducted >6 months before progression were excluded. Subsequently, regression analyses were performed to identify predictors of US synovitis in CCP2(+) at-risk individuals without baseline US abnormalities who had one or more longitudinal US scan and a complete dataset. RESULTS: US subclinical synovitis was detected in one or more scan in 75 of 97 progressors (77.3%) {median time to inflammatory arthritis development from first evidence of US synovitis 26.5 weeks [interquartile range (IQR) 7–60]}, in whom one or more scan was available, excluding those with a negative scan >6 months from inflammatory arthritis development (n = 38). In 220 CCP2(+) at-risk individuals with normal baseline US scans, who had one or more longitudinal US scan and a complete dataset, US synovitis was detected in 69/220 (31.4%) [median time to first developing US synovitis 56.4 weeks (IQR 33.0–112.0)]. In the multivariable analysis, only anti-CCP3 antibodies were predictive for the development of US synovitis [odds ratio 4.75 (95% CI 1.97, 11.46); P < 0.01]. CONCLUSIONS: In anti-CCP2(+) at-risk individuals, a stage of subclinical synovitis usually precedes the development of inflammatory arthritis. Anti-CCP2(+)/CCP3(+) individuals without clinical or US subclinical synovitis may represent the optimal window of opportunity for intervention to prevent joint disease.