Background/Purpose: Studies have shown that anti-citrullinated protein antibodies (ACPA) are a risk factor for the development of arthritis. We aimed to investigate in a prospective setting whether ACPA and other biomarkers could predict the development of ultrasound detected arthritis

Methods: Subjects with positive ACPA-test referred from primary-care to the Rheumatology clinic, that lacked arthritis in the hands, feet and any other symptomatic joints by clinical and ultrasound examination (according to EULAR-OMERACT definition), were recruited into the Risk-RA research program during 2015-2016, and were followed-up to the end of January 2019. at inclusion, a detailed clinical examination was performed and blood samples were analyzed for 13 specific ACPA reactivities (using custom made peptide microarray) as well as 92 inflammation-associated protein biomarkers (using a multiplex immunoassay with Olink proximity extension technology). Presence of HLA-SE was analyzed using DR low-resolution kit. Univariate and multivariate analysis were used to investigate the association between clinical and laboratory parameters and development of ultrasound detected arthritis adjusting for the follow-up time.

Results: 46% (30 out of 65) of the Risk RA subjects developed ultrasound detectable arthritis during a median follow-up time of 11 months. The remaining 54% (35 out of 55) were followed for a median of 27 months (range 17-39) without any signs of ultrasound detectable arthritis. Those subjects that developed arthritis had a higher prevalence of HLA-SE (83% vs 55%) as well as an increased incidence of ultrasound detected tenosynovitis (40% vs 5%) as compared to those that did-not develop arthritis. ACPA reactivities to citrullinated vimentim peptides (cit vim 2-17: 20% vs 6%; and cit vim 60-75: 67% vs 44%) and citrullinated histone peptides (cit H4 31-50: 87% vs 47%; and cit H3 21-44: 47% vs 22%) were a more common occurrence in subjects developing ultrasound detectable arthritis.
Backward selection in Cox regression model showed that ultrasound detectable arthritis could be predicted in a model including HLA-SE, tenosynovitis and ACPA reactivity to cit H4 31-50. Hazard ratio (HR) for arthritis development were 2.2 (95% CI 0.8-6, p=0.13) for HLA-SE carriers and 2.9 (95% CI 1.3-6.5, p=0.01) for tenosynovitis, and 3.4 (95% CI 1.2-10, p=0.02) for Anti-citrullinated H4 31-50 positivity. Only modest differences were observed for few of the tested inflammatory markers in those developing as compared to those not developing ultrasound detectable arthritis: Interleukin- 6 (3.9 vs 3.3 AU/ML), Programmed death-ligand 1 (4.9 vs 5.2 AU/ML) and Chemokine (C-X-C motif) ligand 6 (9.2 vs 9.5 AU/ML).

Conclusion: Certain ACPA fine specificities, HLA-SE and tenosynovitis predicts the development of ultrasound detectable arthritis in seropositive individuals with musculoskeletal symptoms who are at risk for RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-ultrasound-detectable-arthritis-among-acpa-positive-subjects-with-musculoskeletal-symptoms-the-risk-ra-prospective-study/