Effect of Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Disease Flares in Patients With Rheumatoid Arthritis in Remission: The ARCTIC REWIND Randomized Clinical Trial

Abstract

Importance: Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear.

Objective: To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission.

Design, setting, and participants: ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019.

Interventions: Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80).

Main outcomes and measures: The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin.

Results: Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred.

Conclusions and relevance: Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy.

Trial registration: ClinicalTrials.gov Identifier: NCT01881308.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Lillegraven reported receiving grants from the Research Council of Norway and South-Eastern Norway Regional Health Authority during the conduct of the study. Dr Paulshus Sundlisæter reported receiving grants from the Research Council of Norway and South-Eastern Norway Regional Health Authority during the conduct of the study. Dr Aga reported receiving personal fees from AbbVie, Eli Lilly, Novartis, and Pfizer outside the submitted work. Dr Olsen reported his institution receiving reimbursement for data management services from Diakonhjemmet Hospital during the conduct of the study. Dr Madland reported receiving personal fees from Novartis for lectures outside the submitted work. Dr Bakland reported receiving personal fees from UCB, AbbVie, and Novartis outside the submitted work. Dr Haukeland reported receiving personal fees from Novartis outside the submitted work. Mrs Moholt reported receiving grants from the Research Council of Norway and South-Eastern Norway Regional Health Authority during the conduct of the study. Dr Uhlig reported receiving personal fees from Eli Lilly, Novartis, and Pfizer outside the submitted work. Dr Solomon reported receiving nonfinancial support from Amgen and grants from AbbVie, Corrona, Janssen, and Genentech during the conduct of the study. Dr van der Heijde reported receiving personal fees from AbbVie, Amgen, Astellas, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Celgene, Cyxone, Daiichi Sankyo, Eisai, Eli Lilly, Galapagos, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, and UCB Pharma outside the submitted work and serving as director of Imaging Rheumatology BV. Dr Kvien reported receiving grants from AbbVie, Merck Sharp & Dohme, Novartis, Pfizer, UCB, and Bristol Myers Squibb and personal fees from AbbVie, Biogen, Celltrion, Egis, Eli Lilly, Merck Sharp & Dohme, Mylan, Hikma, Novartis, Oktal, Orion Pharma, Pfizer, Roche, Sandoz, Sanofi, UCB, and Gilead outside the submitted work. Dr Haavardsholm reported receiving grants from the Research Council of Norway and South-Eastern Norway Regional Health Authority during the conduct of the study and personal fees from Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Eli Lilly, and UCB outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flow of Patients in the ARCTIC REWIND csDMARD Study

ACR indicates American College of Rheumatology; csDMARD, conventional synthetic disease-modifying antirheumatic drugs; DAS, Disease Activity Score; and EULAR, European Alliance of Associations for Rheumatology. aRemission according to established criteria should be documented for at least 12 months. bDAS is a composite measure of disease activity with scores ranging from 0 to 10, higher scores indicate more disease activity, remission defined as <1.6. cStratified by study site.

Figure 2.. Flare Rate Within 12 Months (Primary Outcome) in Half-Dose vs Stable-Dose Antirheumatic Drug Treatment

Flare was defined as a combination of Disease Activity Score (DAS) above the cutoff for remission (1.6), a change in DAS of at least 0.6, and at least 2 swollen joints or that both the treating physician and the patient agreed that a clinically significant flare had occurred. The blue, dotted, vertical line represents the noninferiority margin. csDMARD indicates conventional synthetic disease-modifying antirheumatic drug. aThe primary analysis was performed in all randomized patients meeting the study entry criteria and with no protocol deviations affecting the treatment efficacy (defined as failure to follow the treatment regimen or withdrawal from the study). bFour patients who were randomized but did not have verified initiation of treatment are excluded (2 from each group). cAnalysis performed in patients within the primary analysis population who used methotrexate monotherapy.

Figure 3.. Secondary End Points

Analyzed in the primary analysis population, defined as all randomized patients meeting the study entry criteria and with no protocol deviations affecting the treatment efficacy. Patients were followed up for a median (IQR) of 364 days (364-371) in the half-dose group and 364 days (360-377) in the stable-dose group. Variables displayed based on clinical relevance. PROMIS indicates Patient-Reported Outcomes Measurement Information 20-item Short Form Physical Function. Boxes mark first and third quartiles, the band inside the box is the second quartile (the median), while the whiskers indicate the highest and lowest values within 1.5 × the interquartile range (IQR). Dots denote individual patients (outliers). aSee footnote c under Table 1 for scale descriptions. bPROMIS assesses the ability to perform basic and instrumental activities of daily living. The total score is translated into a T score with a mean (SD) of 50 (10). A score of 50 equals the average for the general US population. cThe van der Heijde–modified Sharp scoring method assesses erosions in 16 joints of each hand and 6 joints of each foot, and the erosions are given a score of 1 to 5. Joint space narrowing is assessed in 15 joints for each hand and 6 joints for each foot. This gives scores for erosions on a scale from 0 to 280 and joint space narrowing on a scale from 0 to 168, thus the total van der Heijde–modified Sharp score ranges from 0 to 448, with higher scores indicating greater joint damage. A good radiographic outcome is commonly defined as no progression. dDisease Activity Score at the visit before a flare occurred, at the flare visit, and at visits after flare in the half-dose arm in those with all components available to calculate DAS.