A European study of patients with rheumatoid arthritis (RA) who were in remission evaluated the effect of reducing their stable dose of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) by half. The study evaluated how this reduction affected the risk of flare and compared the half-dose strategy with continuing csDMARDs without reduction.
Siri Lillegraven, MD, MPH, a senior researcher at Diakonhjemet Hospital, Oslo, Norway, and colleagues documented fewer flares in the stable-dose group, a finding that does not support treatment with half-dose therapy. They published their results online May 4, 2021, in JAMA.1
ACR vs. EULAR Guideline
Alireza Meysami, MD, a rheumatologist in the Henry Ford Health System, Detroit, who is not affiliated with the study, thinks this study answers an important question about reducing the dose of csDMARDs from the dose used to obtain RA remission. He explains that the 2021 ACR Duideline for the Treatment of RA recommends the starting doses of DMARDs, but does not suggest a tapering strategy.2 In contrast, EULAR recommendations suggest rheumatologists consider tapering csDMARDs in patients with RA who are in persistent remission with the treatment.3 Not only are the two recommendations inconsistent, but they leave rheumatologists with the concern that tapering the dose may result in the patient experiencing a flare. Indeed, the Tapering Strategy in Rheumatoid Arthritis (TARA) trial found a 33% flare rate over one year when tapering csDMARDs in patients who previously had controlled disease.4
“We do have a great plan to start patients on treatment,” says Dr. Meysami. “In RA, the cornerstone of the treatment is regulating or even suppressing the immune system. … A lot of patients express concerns, however. They ask, ‘How long are we going to continue the medications? Could I get by with a lower dose?’”
This study addresses when and how to stop these medications.
Study Design
The randomized, open-label study included 160 patients with RA who had been in remission for 12 months. These patients had no swollen joints and fulfilled a set of remission criteria that included an extensive joint examination. They were receiving stable csDMARD therapy: most of the patients (82%) were on monotherapy with methotrexate; 10% were on methotrexate, sulfasalazine and hydroxychloroquine; and 8% were on other monotherapies or duo therapies. None of the patients were on biologic treatments. The investigators randomly assigned patients to receive a half-dose of csDMARDs or continue their stable dose of csDMARDS.
At baseline, patients in the half-dose group on methotrexate monotherapy received a median of 19.5 mg of methotrexate per week, and patients in the stable-dose group received a median of 19.0 mg of methotrexate per week. In the half-dose group, the csDMARD treatment was reduced to a half dose at the baseline visit (e.g., 25 mg of methotrexate taken once per week was changed to 12.5 mg of methotrexate taken once per week). If a patient in the half-dose group used a combination of csDMARDs, each csDMARD was reduced by half.
The investigators defined flares as a combination of Disease Activity Score (DAS) greater than 1.6, which is the threshold for RA remission; an increase in DAS score of 0.6 units or more; and at least two swollen joints. The researchers also recorded a disease flare if the patient and investigator agreed a clinically significant flare had occurred. Dr. Meysami notes, this latter approach to diagnosing flares is more common in Europe than in the U.S.
Gradual Tapering an Option
During the 12 months of the study, 19 patients (25%) in the half-dose group experienced a disease flare, as did five (6%) in the stable-dose group (risk difference: 18%; 95% confidence interval, 7–29%]). However, Dr. Meysami notes that because the study was open label, physicians may have been more likely to worry about patients taking a half dose than those taking a full dose. Thus, they may have been more likely to document a flare in those patients. In the paper, the authors acknowledge this limitation, but emphasize that study investigators and nurses were repeatedly instructed about the importance of capturing flare outcomes in both groups.
Dr. Meysami also notes the study called for an abrupt switch from the full to half dose. In his practice, he is more likely to taper the medication dose gradually, monitoring to see if the patient tolerates the lower dose. According to Dr. Meysami, this paper suggests a gradual taper may be more beneficial than an abrupt reduction of the csDMARD dose.
Lara C. Pullen, PhD, is a medical writer based in the Chicago area.
References
- Lillegraven S, Sundlisæter NP, Aga AB, et al. 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. JAMA. 2021 May 4:325(17):1755–1764.
- Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. 2021. Arthritis Rheumatol. 2021 Jul;73(7):1108–1123.
- Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020 Jun;79(6):685–699.
- van Mulligen E, de Jong PHP, Kuijper TM, et al. Gradual tapering TNF inhibitors versus conventional synthetic DMARDs after achieving controlled disease in patients with rheumatoid arthritis: First-year results of the randomised controlled TARA study. Ann Rheum Dis. 2019 Jun;78(6):746–753.
