Research Letter
March 28, 2023
Discontinuation of Conventional Synthetic Disease-Modifying Antirheumatic Drugs in Patients With Rheumatoid Arthritis and Excellent Disease Control
Siri Lillegraven, Nina Paulshus Sundlisæter, Anna-Birgitte Aga, et al
JAMA. 2023;329(12):1024-1026. doi:10.1001/jama.2023.0492
With advances in rheumatoid arthritis (RA) therapy, more patients achieve sustained remission. Treatment recommendations suggest considering dosage tapering of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in these patients.1 Although flares appear more frequently when tapering csDMARDs vs full-dose therapy,2,3 tapering could be successful in some patients.4 However, it is uncertain whether discontinuation of csDMARDs is realistic and sustainable.
We assessed the 12-month risk of disease activity flares when discontinuing csDMARDs compared with continuing half-dose csDMARDs in patients with RA and excellent disease control.
Methods
This randomized, open-label trial is part of the ARCTIC REWIND project, which included adults (aged 18-80 years) with RA (American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 criteria) in sustained remission according to Disease Activity Score (DAS; range, 0-10, with higher scores indicating greater disease activity) based on assessment of 28 (DAS28) or 44 (DAS) joints for 12 months or longer with stable csDMARD therapy, and with no swollen joints (of 44 assessed) and DAS remission at inclusion. Patients enrolled at 10 Norwegian hospitals were randomized 1:1 by computer-based center-stratified block randomization. In study period 1 (inclusion from June 17, 2013, to June 18, 2018), patients were allocated to half-dose or stable csDMARDs.2 Those who tapered medication to half-dose and remained flare-free for 1 year were eligible for the second (current) study period (last visit June 26, 2020), with randomization to csDMARD discontinuation or continued half-dose. Visits occurred every 4 months and additionally if disease activity increased. Full-dose csDMARD was reinstated in the event of a flare. The South-Eastern Norway Regional Ethics Committee approved the study; patients provided written informed consent.
The primary analysis tested superiority of discontinuing csDMARDs or maintaining a stable half-dose regarding disease flare during 12 months of follow-up, using a center-stratified risk difference estimator. Flare was defined as a combination of DAS greater than 1.6, change in DAS of 0.6 units or greater, and 2 or more swollen joints. Additionally, flare could be registered if the physician and patient agreed that a clinically significant flare occurred. Secondary end points, including reachievement of remission after flare, radiographic progression (change in the van der Heijde modified Sharp score ≥1 unit per year), and adverse events, were analyzed using logistic or linear mixed-effects models as appropriate. Sample size was determined with respect to the initial comparison in study period 1.2 Primary and secondary efficacy analyses were performed in randomized patients attending 1 or more efficacy evaluation, with robustness analyses for the primary end point in patients without major protocol deviations and in those using methotrexate monotherapy. Stata version 16.0 (StataCorp) and R version 4.0.3 (R Foundation) were used for analyses; 95% CIs around the risk difference that did not include 0 defined statistical significance.
Results
Of 78 patients randomized to half-dose therapy in study period 1, 56 were eligible for the current study. Baseline characteristics were mostly well balanced (Table). A flare within 12 months was experienced by 10 of 26 patients (38.5%) discontinuing csDMARD, compared with 5 of 30 (16.7%) continuing a half-dose (risk difference, 21.5% [95% CI, −3.4% to 49.7%]) (Figure). Comparable results were found in the per-protocol population and methotrexate monotherapy users. Median time to flare among those with flare was 179 (IQR, 99-245) days in the discontinuation group and 133 (IQR, 126-217) days in the half-dose group.
At the first visit after flare, 8 of 10 patients (80.0% [95% CI, 44.4%-97.5%]) in the discontinuation group and 2 of 3 (66.7% [95% CI, 9.5%-99.2%]) in the half-dose group regained DAS remission. Radiographic joint damage progression was absent in 84.0% of patients who discontinued therapy and 69.0% of those who continued half-dose therapy (risk difference, 13.9% [95% CI, −10.6% to 38.3%]). Total adverse events numbered 22 in the discontinuation group and 26 in the half-dose group, including 1 serious adverse event (infection).
Discussion
For patients with RA in sustained remission while receiving half-dose csDMARD treatment, continuation of a csDMARD half-dose was not found to be superior to withdrawal regarding disease flare risk. Although a numerically higher number of flares was observed in the discontinuation group, most patients achieved drug-free remission for 1 year or longer. The data suggest that csDMARD withdrawal might be viable in some patients and that structured follow-up of DMARD treatment–free patients is advisable, because most patients with flare regained remission by restarting full-dose csDMARDs.5 Study limitations include the open-label design and limited sample size. The results provide a basis for shared decision-making in treatment of patients with RA achieving remission.
