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

Abstract

ObjectivesAlthough 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.MethodsA 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.ResultsFrom 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.ConclusionsDFR 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.

Tapering towards DMARD-free remission in established rheumatoid arthritis: 2-year results of the TARA trial

“… 6 In particular, the duration of DFR is an important measure of sustainability, and inversely related to the frequency of disease flares. 22 …”

“…6 In particular, the duration of DFR is an important measure of sustainability, and inversely related to the frequency of disease flares. 22 In both tapering groups, all patients who reached DFR, reached it after 18 months of follow-up. Interestingly, none of those patients experienced a flare in the 6 months after DMARD stop, whereas other studies reported flare rates between 5% and 25% in the first 6 months after achieving DFR.…”

Correspondence on ‘Tapering towards DMARD-free remission in rheumatoid arthritis‘

“…3. The low percentage of patients who achieved sustained remission, 31% in the group that first decreased csDMARD and 21% in the TNFi group, is replicated in various systematic reviews such as those by Verstappen et al 4 that reported DFR in 5% and 24.3% less than 12 months after DMARD withdrawal, and between 11.6% to 19.4% after more than 12 months. Exacerbations developed frequently during the DMARD taper (41.8%-75%), and in the first year after achieving DFR (10.4%-11.8%).…”

Early DAS response after DMARD-start increases probability of achieving sustained DMARD-free remission in rheumatoid arthritis

“…Several patient characteristics at time of diagnosis have been studied [ 2 , 7 – 10 ], but these poorly explained SDFR development. Only the presence of auto-antibodies was repeatedly found to be unfavorable for SDFR development [ 2 , 7 , 8 , 11 – 13 ]. This relates to the existence of two subsets of RA patients, in which those with auto-antibodies have a lower capability of achieving SDFR [ 3 , 12 ].…”

“…Measures of inflammation (joint counts, acute phase reactants, MRI-detected joint inflammation) at the time of diagnosis appeared non-informative in distinguishing which RA patients are likely to achieve SDFR [ 2 , 7 – 10 , 13 , 14 ]. Potentially, differences in biological pathways leading towards disease resolution, i.e., SDFR, are not detectable at baseline, but might unfold later on.…”