REmission in rheumatoid arthritis - assessing WIthdrawal of disease-modifying antirheumatic drugs in a Non-Inferiority Design

The treatment of rheumatoid arthritis (RA) has changed drastically during the last two decades following the introduction of biologic drugs and the improvement of treatment strategies using established disease-modifying drugs. The treatment target in early RA has become remission (no or very little signs or symptoms of disease activity) and no development of joint damage. The aim of the ARCTIC REWIND study is to assess if and how disease-modifying antirheumatic drugs (DMARDs) can be withdrawn in patients with early RA who have been in remission for at least one year. ARCTIC REWIND is a Norwegian multicenter study, randomizing early RA patients who have been in remission for at least a year to different treatment strategies. The study has two parts, one study assessing patients using synthetic DMARDs, the second including patients on biologic DMARDs. Patients are followed for three years with disease activity measures, imaging modalities, and measures of physical function and health related quality of life. The last patient in the synthetic DMARD study was included in June 2018, and the last patient in the biologic DMARD study was included in January 2019. Within the last year, the main results from both studies have been presented at international congresses, and the process to publicize the results is ongoing. One of two main publications from the study has been accepted for publication, with results showing an increase in disease activity flares in patients who reduce synthetic disease-modifying antirheumatic drugs to half-dose. The other main publication is expected to be accepted for publication within 2021. A large number of other publications are expected within the next years. The results will improve treatment of this patient group.

The ARCTIC REWIND study provides results that can help physicians make better treatment choices for patients with rheumatoid arthritis (RA) in remission. The study results show a significant increase in disease activity flares in patients tapering their treatment, both for csDMARD medication and the tumor necrosis inhibitors. Additionally, we observed more joint damage in patients tapering their csDMARD treatment. Very few disease activity flares occurred if patients in sustained remission received stable treatment, illustrating that the RA disease course can have a favorable outcome, even with the cheapest and globally most available DMARDs. The results from the project have gained international interest, and are expected to influence both international and national treatment recommendations. The results will inform shared decision making.

-Background and objectives- Remission is the treatment target in rheumatoid arthritis (RA), but knowledge about the best way to treat RA patients who achieve sustained remission is limited. Disease-modifying antirheumatic drugs (DMARDs) have potential ser ious adverse events, and biologic DMARDs are costly to the society, with TNF inhibitors as the three most costly prescription-only drugs in Norway in 2011. The objectives for ARCTIC REWIND are to assess the effect of tapering and withdrawal of DMARDs on d isease activity in RA patients in sustained remission, to study predictors for successful tapering and withdrawal of DMARDs in this patient group, and to study cost-effectiveness of different treatment options in RA remission. -Methods- ARCTIC REWIND is a randomized, open, controlled, parallel-group, multicenter, phase IV, non-inferiority strategy study. Patients with less than five years of disease duration and stable remission for at least 12 months are randomized to either continued stable treatment or tapering and withdrawal of DMARDs. Patients are assessed by clinical examination, patient reported outcome measures, ultrasonography, MRI and X-ray, and monitored for adverse events. The primary endpoint of the study is the proportion of patients who a re non-failures (have not experienced a flare) at 12 months. Secondary endpoints include composite disease activity scores and remission criteria, joint damage and inflammation assessed by various imaging modalities, work participation, health care resour ce use and health related quality of life. -Relevance and benefit to society- The results from ARCTIC REWIND will lead to better treatment decisions in RA remission and might allow more patients to step down their treatment. If tapering and withdrawal of TNF inhibitors is non-inferior to full-dose in RA remission, the potential savings to the society will be significant and can fund other important health care measures.