Effect of Half-Dose vs Stable-Dose csDMARDs on Disease Flares in Patients With Rheumatoid Arthritis in Remission | Rheumatoid Arthritis | JN Learning | AMA Ed Hub [Skip to Content]
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Effect of Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Disease Flares in Patients With Rheumatoid Arthritis in RemissionThe ARCTIC REWIND Randomized Clinical Trial

Educational Objective
To understand the risk of tapering therapy in patients with rheumatoid arthritis who are in remission.
1 Credit CME
Key Points

Question  In patients with rheumatoid arthritis in remission taking conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), is reducing the csDMARDs to half dose noninferior to stable csDMARD dosage for the outcome of rheumatoid arthritis flares?

Findings  In this randomized clinical trial that included 160 patients with rheumatoid arthritis in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs resulted in disease flares in 25% vs 6% over 12 months; this did not meet the noninferiority criterion of a 20% difference. There were significantly fewer patients with flares in the stable-dose group.

Meaning  These findings do not support the use of half-dose treatment in patients with rheumatoid arthritis in remission taking csDMARDs.

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

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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Siri Lillegraven, MD, MPH, PhD, Division of Rheumatology and Research, Diakonhjemmet Hospital, PO Box 23 Vinderen, N-0319 Oslo, Norway (siri.lillegraven@gmail.com).

Accepted for Publication: March 11, 2021.

Author Contributions: Drs Lillegraven and Sexton had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Lillegraven, Paulshus Sundlisæter, and Aga share first authorship.

Concept and design: Lillegraven, Aga, Olsen, Lexberg, Uhlig, Solomon, van der Heijde, Kvien, Haavardsholm.

Acquisition, analysis, or interpretation of data: Lillegraven, Paulshus Sundlisæter, Aga, Sexton, Olsen, Fremstad, Spada, Madland, Høili, Bakland, I. J. W. Hansen, I. M. Hansen, Haukeland, Ljoså, Moholt, Uhlig, Kvien, Haavardsholm.

Drafting of the manuscript: Lillegraven, Paulshus Sundlisæter, Aga, Sexton, Lexberg, Uhlig.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Lillegraven, Aga, Sexton, Olsen, Kvien, Haavardsholm.

Obtained funding: Lillegraven, Høili, Haavardsholm.

Administrative, technical, or material support: Lillegraven, Paulshus Sundlisæter, Aga, Sexton, Spada, Madland, Høili, Bakland, Lexberg, I. J. W. Hansen, I. M. Hansen, Haukeland, Ljoså, Moholt, Kvien, Haavardsholm.

Supervision: Lillegraven, Aga, Lexberg, Uhlig, Kvien, Haavardsholm.

Other—delivery of patient data from our center: Fremstad.

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.

Funding/Support: The study was funded by the Research Council of Norway and South-Eastern Norway Regional Health Authority.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We thank the patients who have participated in the study, and we are grateful for the time and effort they have invested in the project. We thank the investigators, study nurses, and medical staff at the study centers for the invaluable contribution to the study. We are grateful to Camilla Fongen (PT, MSc, Diakonhjemmet Hospital, who received compensation for her role as project coordinator) for the contribution to the organization of the study and the data collection; the Department for Immunology and Transfusion Medicine at Oslo University Hospital for analyses of serological markers; our patient partners Ola-Jacob Sønsthagen and Eli Ormerod (BSc) (they did not receive compensation); and the funding sources.

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