Can DMARD Doses Be Safely Reduced for RA Patients? Korean Trial Says Yes.

Close to 90% of patients with rheumatoid arthritis (RA) well controlled on targeted therapies were able to take 50% dosage reductions without experiencing worsened disease activity in a randomized trial, South Korean researchers said.

Patients in low disease activity (LDA) status maintained it on half-doses of biologic or targeted oral medications at a rate of 88.2%, compared with 89.6% for those assigned to continue their usual dosing in the multicenter, 6-month study, according to Shin-Seok Lee, MD, PhD, of Chonnam National University Medical School and Hospital in Gwangju, South Korea, and colleagues.

With this difference of -1.43 percentage points (95% CI -8.09 to 5.23) in the 348-patient trial, prespecified criteria for noninferiority were easily met, the researchers reported in Arthritis & Rheumatology.

The structured tapering strategy used in the dose-reduction arm “appears to be a feasible treatment approach in patients with RA who have achieved sustained low disease activity,” they wrote. “With careful patient selection, close monitoring, and timely treatment re-escalation when needed, dose tapering may reduce treatment burden while maintaining disease control and health-related quality of life.”

But questions still remain, not least because other tapering or withdrawal studies on disease-modifying antirheumatic drugs (DMARDs) have yielded mixed results. Furthermore, some secondary measures in the new trial leaned in favor of usual dosing, and the 6-month study period may not be long enough for firm conclusions on efficacy.

The desire to reduce targeted DMARD dosing is certainly admirable. These products are expensive and come with side effects. But the benefits from dose reductions must be weighed against the risks for disease worsening and flares, and the attendant secondary risks such as cardiovascular disease.

Withdrawal strategies aiming at a full stop have appeared less successful than those just seeking to reduce the dosages, so Lee and colleagues developed a protocol of the latter type. Their specific approach varied with the targeted DMARD type — tumor necrosis factor (TNF) inhibitors, biologics with non-TNF targets, or Janus kinase (JAK) inhibitors — with either the dose per administration cut by half or the dosing interval doubled. Either way, the goal was a 50% reduction in drug exposure.

They recruited 348 RA patients in South Korea who had maintained LDA status for at least 6 months on one of these DMARDs, randomizing them 1:1 to either dosage reduction or usual dosing. Mean patient age was 56, and 82.5% were women; disease duration averaged more than 11 years.

Forty-two percent of patients were taking a TNF inhibitor, either adalimumab (Humira) or etanercept (Enbrel); 37% were on a JAK inhibitor, either tofacitinib (Xeljanz) or baricitinib (Olumiant); and the rest were evenly divided between the interleukin-6 inhibitor tocilizumab (Actemra) or the T-cell deactivator abatacept (Orencia).

In the dose-reduction arm, patients using biologic drugs had the dosing intervals extended in two steps, the first taken immediately and the second at week 12 to achieve 50% less exposure. Those using tofacitinib had the daily dosage cut in half immediately, with one 5-mg pill given daily instead of two. Baricitinib users, instead of taking 4 mg once daily, either took the drug every other day or switched to a 2-mg pill daily, depending on availability. For both JAK inhibitors, these doses were then kept through week 24. In the control arm, of course, patients stayed on their original dosing.

Disease Activity Index Score in 28 joints as modified by erythrocyte sedimentation rate (DAS28-ESR) was the primary outcome measure, with LDA defined as a score ≤3.2. Patients with values rising above 3.2 were considered to have worsened disease and no longer in LDA. A host of other disease activity, global health, and quality-of-life measures were also tracked. Primary results were taken at week 24, i.e., when patients on biologics in the reduction arm had used their new dosing scheme for 12 weeks, or 24 weeks among those on JAK inhibitors.

Some secondary outcomes numerically favored the continuation approach. In particular, mean scores for DAS28-ESR, Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI), which were nearly identical between study arms at baseline, crept up slightly in the tapering group (e.g., by 1 SDAI point, from 4 at baseline) while remaining unchanged with continuation.

Lee and colleagues also looked at predictors of successful tapering, examining 13 different factors. Only one showed statistical significance: patients on JAK inhibitors were less likely to maintain LDA at week 24 than those using TNF blockers (adjusted OR 0.278, P=0.048).

Chief among the study’s limitations was the 6-month duration, and the fact that most participants in the tapering group were on their 50% doses for only half that time; longer follow-up is needed to adequately assess “radiographic progression, the long-term durability of the tapering strategy, or cumulative safety outcomes,” the researchers acknowledged.

The relatively short half-life of JAK inhibitors might account for its apparent inferiority to anti-TNF agents for LDA maintenance, but this requires further confirmation. Also, the trial was unblinded, and patients’ medication adherence prior to enrollment was not checked.