Prediction of long-term drug-free outcomes in ACPA-positive and -negative rheumatoid arthritis by combined clinical and ultrasound assessment of residual disease: a 5-year prospective study

Objective: To delineate, within the framework of current clinical practice and criteria, the sustainability of first-line immuno-suppressive treatment discontinuation in rheumatoid arthritis (RA) and the impact of residual disease in remission on long-term drug-free (DF) outcomes. Methods: RA patients, referring to the Pavia Early Arthritis Clinic (EAC) between 2009 and 2021 and achieving remission after DAS-driven methotrexate (MTX) monotherapy, were recruited. Eligible patients underwent DF follow-up at 3-month intervals over five years after MTX discontinuation. Pre-selected clinical, serological, and ultrasound (US) exposure variables at MTX withdrawal were analyzed using multivariable Cox-regression to predict time-to-flare. Results: Of 761 EAC patients with RA, 132 started DF follow-up (person-months: 3678). Sixty-two experienced a flare after a median (range) of 9 (3-60) months, resulting in a progressive decline in flare-free survival throughout the observation period. Whole-cohort multivariate Cox-regression identified anti-citrullinated protein antibody (ACPA) positivity (HR 4.20, 95% CI 2.37–7.44) and hands’ joints with grey scale (US-GS) alterations (GS>1; HR 2.18, 95% CI 1.20–3.93) as independent predictors. ACPA-positive patients in SDAI remission displayed a flare-free survival estimate at 5 years of 6.4% (95% CI 1.2-35.7) versus 78.2% (95% CI 67.4-90.8) for ACPA-negative patients in SDAI remission without residual US-GS alteration in hands’ joints (n=59); the latter group showing no evidence of radiographic progression and functional deterioration. Conclusions: Long-term DF remission is attainable in a niche subset of ACPA-negative RA. The examination of clinical and subclinical residual synovial abnormalities during remission allows for effective preemptive identification of this subset in real life.