POS0464 IS IT POSSIBLE TO IDENTIFY INDIVIDUALS AT IMMINENT-RISK OF SUB-CLINICAL JOINT INVOLVEMENT?
Authors: A. Di Matteo, K. Mankia, L. Duquenne, E. Cipolletta, J. Nam, L. Garcia-Montoya, R. Wakefield, M. Mahler, P. Emery
Journal: Annals of the Rheumatic Diseases (2021)

Background: In anti-CCP antibody (Ab) positive at-risk individuals with MSK symptoms but without clinical synovitis, the detection of ultrasound (US) subclinical inflammation is associated with an increased risk of progression to inflammatory arthritis (IA) 1 . Studies suggest that in these at-risk individuals, MSK symptoms develop before subclinical joint inflammation occurs on US. As such, anti-CCP Ab positive individuals with MSK symptoms in the absence of clinical or sub-clinical inflammation may be at the critical time-point for preventive treatments, before joint inflammation occurs and eventually becomes established (i.e., before the ‘second-hit’ in RA pathogenesis); however, identifying these individuals is challenging. Objectives: To identify, in second generation anti-CCP Ab (CCP2+) at-risk individuals with MSK symptoms, but without clinical or sub-clinical synovitis, predictors of US sub-clinical synovitis. Methods: In 186 CCP2+ at-risk individuals with normal baseline US scan (i.e., no synovitis or bone erosions), and a complete dataset, US data were analyzed at 6, 12 months, then annually until occurrence of IA. US synovitis was identified according to the EULAR/OMERACT definitions 2 . Relevant demographic (age and gender), clinical [early morning stiffness (EMS), tenderness in the small joints of the hands] and serological [anti-CCP2 Ab level, third generation anti-CCP Ab (CCP3) and rheumatoid factor (RF)] data were collected at baseline. Regression analyses, Kaplan-Meier analysis and Log-Rank test were performed. Results: US synovitis was detected in ≥1 longitudinal US scan in 69/186 (37.1%) at-risk individuals (median time to first developing US synovitis: 53 weeks, IQR 27.0-105.8; median number of joints with US synovitis: 2.0, IQR 1.0-2.0). As shown in Table 1, only anti-CCP3 Ab were significantly associated with development of US sub-clinical synovitis in the multi-variable analysis while borderline results were observed with age. Table 1. Regression analyses for the development of US synovitis. Univariable analysis Multivariable analysis OR (95% CI) p-value OR (95% CI) p-value Gender (male) 1.02 (0.52-2.02) 0.95 / / Age 1.03 (1.01-1.06 ) &lt;0.01 1.03 (1.00-1.06 ) 0.03 Tenderness in the hands 0.86 (0.46-1.61) 0.64 / / EMS 1.60 (0.87-2.95) 0.13 / / Anti-CCP2 Ab (high titre) 2.79 (1.37-5.67 ) &lt;0.01 1.20 (0.50-2.89) 0.69 Anti-CCP3+ 4.44 (2.28-8.66 ) &lt;0.01 3.30 (1.39-7.89 ) &lt;0.01 RF+ 2.96 (0.46-1.61 ) 0.01 1.45 (0.68-3.11) 0.33 CCP2+ individuals with positive anti-CCP3 Ab show a significantly reduced sub-clinical synovitis-free survival rate compared with individuals with negative anti-CCP3 Ab (Figure 1). At 1- and 2-year follow-up, respectively 23.3% and 38.3% of individuals with dual CCP2/CCP3 positivity developed sub-clinical synovitis on longitudinal scans, compared with 8.4% and 13.3% of CCP2+ individuals with negative anti-CCP3 Ab (p=0.01) (Figure 1a). Similar results were observed in the subgroup of high level CCP2+ individuals. At 1- and 2-year follow-up, respectively 24.5% and 39.4% of high level CPP2/anti-CCP3+, but only 6.1% and 15.2% of CCP2+ individuals with negative anti-CCP3 developed sub-clinical synovitis on longitudinal scans (p&lt;0.01) (Figure 1b). Figure 1. Kaplan-Meier analysis shows US sub-clinical synovitis free survival time in CCP2+ at-risk individuals. Conclusion: In anti-CCP2+ at-risk individuals with MSK symptoms, anti-CCP3 antibodies improve prediction of imminent development of subclinical joint inflammation. This may represent the critical time-point for interventions to prevent the onset of joint disease. This is also a unique population for investigating the drivers of joint involvement in the development of RA. References: [1]Duquenne L, et al. The Role of Ultrasound Across the Inflammatory Arthritis Continuum: Focus on “At-Risk” Individuals. 2020. [2]D’Agostino MA, et al. Scoring ultrasound synovitis in rheumatoid arthritis: a EULAR-OMERACT ultrasound taskforce — Part 1: definition and development of a standardised, consensus-based scoring system. 2017. Disclosure of Interests: Andrea Di Matteo Grant/research support from: This study was conducted while Andrea Di Matteo was an ARTICULUM Fellow., Kulveer Mankia Speakers bureau: KM reports personal fees from Abbvie, UCB and Eli Lilly (all &lt;$10.000), outside the submitted work., Grant/research support from: Research grants from BMS, Eli Lilly (all &lt;$10.000), Laurence Duquenne: None declared, Edoardo Cipolletta: None declared, Jacqueline Nam: None declared, Leticia Garcia-Montoya: None declared, Richard Wakefield Speakers bureau: RJW has received honoraria from Abbvie, Novartis and GE for ultrasound related educational activities (all &lt;$10.000)., Michael Mahler Employee of: MM is employee of Inova Diagnostics, commercializing CCP3, Paul Emery Speakers bureau: PE reports consultant fees from BMS, AbbVie, Gilead, Galapagos, Lilly, MSD, Pfizer, Novartis, Roche, and Samsung outside the submitted work (all &lt;$10.000)., Grant/research support from: He also reports research grants from UCB, AbbVie, Lilly, Novartis, BMS, Pfizer, MSD and Roche, outside the submitted work. PE is National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) director and BRC funds supported this work. Leticia Garcia-Montoya and Laurence Duquenne are NIHR BRC fellows.