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

Abstract

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.

Keywords: ACPA; anti-CCP3; at-risk; inflammatory arthritis; prediction; rheumatoid arthritis; subclinical synovitis; third-generation anti-CCP antibodies; ultrasound.

Fig. 1

Categories along the RA ‘continuum' defined by the EULAR Standing Committee on Investigative Rheumatology UA: undifferentiated arthritis.

Fig. 2

Kaplan–Meier analysis shows US subclinical synovitis-free survival time in CCP2⁺ at-risk individuals Percentages refer to the individuals who developed US subclinical synovitis at 12 and 24 months follow-up (black lines). HL: high level.

Fig. 3

The ‘disease continuum' of CCP2⁺ at-risk individuals Anti-CCP⁺ at-risk individuals with MSK symptoms but without any joint involvement (clinical or subclinical) may represent the critical time point for timing interventions to prevent the onset of joint disease. UA: undifferentiated arthritis.