Background and objectives Early diagnosis and treat-to-target strategies in rheumatoid arthritis (RA) have allowed the achievement of remission in a significant percentage of cases. Despite the possibility of remission maintenance even after treatment suspension, three critical issues remain unsolved: 1) to what extent suppression of inflammation can coincide with reversal of the pathogenic process, 2) the parameters able to predict in which patients treatments can be suspended, 3) the dynamics of relapse. In this study we investigated the outcome and predictors of relapse in a cohort of RA patients during drug-free follow-up after remission achievement with conventional DMARDs.
Materials and methods 62 RA patients achieving stable remission and candidate to DMARD suspension were recruited from our early arthritis clinic (EAC) according to the following criteria: 1) introduction of MTX within 12 months from symptoms’ onset, 2) at least 24 months of MTX treatment with a DAS28-driven protocol, 3) DAS28 < 2.6 for ≥6 months in the absence of corticosteroids. Following treatment suspension, patients were monitored at three months’ intervals through clinical-ultrasonographic (hands-feet)-radiographic and immunologic screenings (serological analyses and multicolour FACS profiles). The primary outcome was the maintenance of DAS28 < 3.2 in all visits (EAC target).
Results Baseline stratification showed SDAI remission in 77.4% of the patients, SDAI remission with hands power Doppler (PD) = 0 in 50%, while the absence of detectable clinical-subclinical synovitis (SJC44 = 0, PD hands-feet = 0) in 35.5%. At 12 months from recruitment, clinical relapse was observed in 42.5% of the patients with maintenance of clinical, functional and radiographic stability in 40.7%. As inferred by cumulative survival analyses through 24 months, in patients achieving SDAI remission, high titers of ACPA (with a strengthening effect of ACPA-RF double positivity) were the strongest predictor of relapse, independent of remission duration, further baseline remission depth and ultrasonographic status (HR [95% CI] = 4.19 [1.23–14.28], p = 0.02). In ACPA(high) patients, despite the achievement of stringent clinical-ultrasonographic remission at the time of drug withdrawal, isotype switched IgG ACPA serum levels were on average unchanged compared to paired values at disease diagnosis, with recognition of active spontaneous secretion by isolated PBMC ex-vivo and a specific association with systemic increased rates of proliferation within switched memory B cells (Ki67+IgD-CD27+) (p < 0.05).
Conclusions DMARD suspension/drug-holiday are possible options in a proportion of RA patients achieving stable remission. Ongoing immune activation (ACPA production with a possible cooperative function of RF) is the strongest predictor of disease reactivation in patients achieving DMARDs-induced clinical-ultrasonographic control of the inflammatory process.