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.

• Authors: Siri Lillegraven, Nina Paulshus Sundlisæter, Anna-Birgitte Aga, Joseph Sexton, Inge C Olsen, Hallvard Fremstad, Cristina Spada, Tor Magne Madland, Christian A Høili, Gunnstein Bakland, Åse Lexberg, Inger Johanne Widding Hansen, Inger Myrnes Hansen, Hilde Haukeland, Maud-Kristine Aga Ljoså, Ellen Moholt, Till Uhlig, Daniel H Solomon, Désirée van der Heijde, Tore K Kvien, Espen A Haavardsholm
• Journal: JAMA (JAMA) Vol. 325 Issue 17 Pg. 1755-1764 (05 04 2021) ISSN: 1538-3598 [Electronic] United States
• PMID: 33944875 (Publication Type: Equivalence Trial, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antirheumatic Agents
• Sulfasalazine
• Hydroxychloroquine
• Leflunomide
• Methotrexate

Topics

• Adult
• Aged
• Antirheumatic Agents (administration & dosage, adverse effects)
• Arthritis, Rheumatoid (diagnostic imaging, drug therapy, pathology)
• Dose-Response Relationship, Drug
• Drug Therapy, Combination
• Female
• Humans
• Hydroxychloroquine (administration & dosage)
• Leflunomide (administration & dosage)
• Male
• Methotrexate (administration & dosage, adverse effects)
• Middle Aged
• Radiography
• Sulfasalazine (administration & dosage)
• Symptom Flare Up
• Ultrasonography