DMARD-free remission as novel treatment target in rheumatoid arthritis: A systematic literature review of achievability and sustainability

Abstract

Objectives: Although current treatment guidelines for rheumatoid arthritis (RA) suggest tapering disease-modifying anti-rheumatic drugs (DMARDs), it is unclear whether DMARD-free remission (DFR) is an achievable and sustainable outcome. Therefore, we systematically reviewed the literature to determine the prevalence and sustainability of DFR and evaluated potential predictors for DFR.

Methods: A systematic literature search was performed in March 2019 in multiple databases. All clinical trials and observational studies reporting on discontinuation of DMARDs in RA patients in remission were included. Our quality assessment included a general assessment and assessment of the description of DFR. Prevalence of DFR and its sustainability and flares during tapering and after DMARD stop were summarised. Also, potential predictors for achieving DFR were reviewed.

Results: From 631 articles, 51 were included, comprising 14 clinical trials and 5 observational studies. DFR definition differed, especially for the duration of DMARD-free state. Considering only high- and moderate-quality studies, DFR was achieved in 5.0%-24.3% and sustained DFR (duration>12 months) in 11.6%-19.4% (both relative to the number of patients eligible for tapering). Flares occurred frequently during DMARD tapering (41.8%-75.0%) and in the first year after achieving DFR (10.4%-11.8%), while late flares, >1 year after DMARD-stop, were infrequent (0.3%-3.5%). Many patient characteristics lacked association with DFR. Absence of autoantibodies and shared epitope alleles increased the chance of achieving DFR.

Conclusions: DFR is achievable in RA and is sustainable in ~10%-20% of patients. DFR can become an important outcome measure for clinical trials and requires consistency in the definition. Considering the high rate of flares in the first year after DMARD stop, a DMARD-free follow-up of >12 months is advisable to evaluate sustainability.

Keywords: DMARD-free remission; disease flare; rheumatoid arthritis; tapering.

Figure 1

Flow diagram of study selection. DMARDs, disease-modifying antirheumatic drugs.

Figure 2

Summary of flare rate and DFR prevalence, all as percentage of the number of patients that were eligible for DMARD tapering, depicted on a timeline. DFR prevalence was grouped by the duration of DFR. Data are presented as DFR percentage (CI). Data were based on high-quality or moderate-quality studies. Prevalence and CIs were calculated using the number of DFR patients divided by the number of patients eligible for tapering. Results from observational studies are indicated in italic. *indicates that studies that allowed the use of i.a. or systemic corticosteroids in patients that were considered to be in DFR(absolute number of patients that used corticosteroids after DMARD stop was not reported) or use in DMARD-free status was not clearly reported. ^X indicates moderate-quality studies. DMARD, disease-modifying antirheumatic drugs; DFR, DMARD-free remission; SDFR, sustained DMARD-free remission.

Figure 3

Overview of studied predictors of achieving DMARD-free remission. Data are presented from variables that were reported in >1 study, based on statistical significance obtained in regression analysis. If both univariable and multivariable regression was applied, the result of the multivariable regression was used. Presented are the absence (left panel) and presence of an association with achieving DFR over time (right panel), the number of studies is indicated per predictor, the total number of patients in these studies is plotted on the x-axis. The directionality of the effect is indicated in colours, green indicates an increased risk of achieving DFR, red indicates a decreased risk of achieving DFR. For symptom duration, no differentiation was made for analyses using this as continuous or categorical variable. BMI, body mass index; CRP, C reactive protein; DAS, Disease Activity Score; ESR, estimated sedimentation rate; HAQ, Health Assessment Questionnaire; RF, rheumatoid factor; SJC, swollen joint count.