DMARD Taper to Discontinuation with Conventional Synthetics or TNF Inhibitors Increases Flare Risk in RA

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Patients with rheumatoid arthritis (RA) in remission who tapered and then fully stopped either conventional synthetic disease-modifying antirheumatic drug (csDMARD) or tumor necrosis factor (TNF) inhibitor therapy experienced more disease flares than those who received stable dose treatment in an open-label, randomized trial.

In the 3-year trial, called ARCTIC REWIND, 80% of patients taking stable doses of only csMARDs remained flare-free compared with 38% in another treatment arm taking only csDMARDs who tapered to a half dose and then discontinued all after 1 year. In patients who continued to receive half-dose csDMARDs for the entire study period, 57% remained flare-free.

A separate two treatment arms of the study that assessed the effect of tapering TNF inhibitor treatment to withdrawal showed that only 25% of patients who tapered TNF inhibitor to withdrawal remained flare-free over 3 years compared with 85% who remained on a stable TNF inhibitor dose.

Though the risk for flare was higher in both the half-dose csDMARD and drug-free groups, the results also suggested that tapering medication "could be a realistic option for some patients with rheumatoid arthritis in sustained remission on csDMARDs," wrote Kaja Kjørholt, MD, of the Center for Treatment of Rheumatic and Musculoskeletal Diseases at Diakonhjemmet Hospital in Oslo, Norway, and colleagues.

The 3-year results for the csDMARD-only arms of the trial were published on April 4 in The Lancet Rheumatology. The 3-year results of the TNF inhibitor arms of the study were presented as an abstract at the American College of Rheumatology (ACR) 2023 Annual Meeting.

Don't Avoid Tapering But Take an Individualized Approach

Many rheumatologists will taper patients with RA in remission to lower doses of medication, but the protocols for this study do not reflect clinical practice, noted James R. O'Dell, MD, chief of the Division of Rheumatology at the University of Nebraska Medical Center in Omaha, Nebraska. He was not involved with the research.

James R. O'Dell, MD

"I don't know of any rheumatologist who would ever think that it was a good idea to taper somebody completely off of all DMARDs," he told Medscape Medical News. "The only surprise is that more of them didn't flare," he continued, though he suspected that more patients would flare if they were followed for more time. Rheumatologists also would take a much more individualized approach when tapering to lower doses, he added, and do so at a much slower rate than what was observed in this study.

Both the ACR and the European Alliance of Associations for Rheumatology recommendations for the management of RA stated that tapering DMARDs can be considered for patients who have sustained remission, but they do not mention discontinuing medication entirely.

In the TNF inhibitor arms of the trial, the tapering group received a half dose of a TNF inhibitor for 4 months before stopping therapy entirely, which O'Dell noted was a large dip in too short a period.

"Nobody should be surprised that these people flared a lot," he said. However, tapering to lower doses of a TNF inhibitor can be successful, he noted, adding that more than half of his patients taking a TNF inhibitor are on less than their original dose. Completely tapering off a TNF inhibitor is less common and depends on what other DMARDs a patient is taking, he said, and complete drug-free remission in this population is highly unlikely.

O'Dell emphasized that the takeaway from these results should not be to avoid tapering medication because of flare risk but instead a tailored approach — something that is not possible with a study protocol — is needed.

"We want our patients to have all the medicine they need and no more," he said. "That sweet spot is different for each individual patient for how much TNF inhibition or how much conventional therapy they need. If we're thoughtful about that in the clinic, we can find that sweet spot," he said.


The open-label ARCTIC REWIND trial enrolled patients with RA in sustained remission, determined via Disease Activity Score (DAS), from 10 different hospitals in Norway. Researchers enrolled 160 patients in the csDMARD-only arms and randomized them to receive stable dose csDMARDs for 3 years or half-dose csDMARDs for 1 year, followed by complete withdrawal for the next 2 years; withdrawal of csDMARDs was only done in patients who had not had a flare during the first year. Participants had scheduled clinic visits every 4 months, and full-dose csDMARD therapy was resumed in patients who experienced disease flares.

There was a total of 99 patients randomized in the TNF inhibitor arms to continue stable TNF inhibitor therapy or to taper to a half dose for 4 months before discontinuing therapy. Like the csDMARD study, clinic visits occurred every 4 months, and full-dose therapy was resumed if a flare occurred. Patients taking a TNF inhibitor could also take a csDMARD as needed.

Last year, 1-year results for the csDMARD arms were published in JAMA, and 1-year results for the TNF inhibitor arms were reported in Annals of the Rheumatic Diseases.

At baseline, most patients across the three csDMARD groups (81%) had received methotrexate monotherapy. Triple therapy (methotrexate, sulfasalazine, and hydroxychloroquine) was used in 13% of the stable-dose group, 7% of the half-dose group, and 8% of the half-dose tapering to withdrawal group. Seven individuals in the stable-dose group, three individuals in the half-dose group, and three individuals the half-dose tapering to withdrawal group used other mono/duo therapies.

A total of 139 participants in the csDMARD-only arms completed 3 years of follow-up, with 68 in the stable-dose group, 36 in the half-dose group, and 35 in the half-dose tapering to withdrawal group.

Compared with the stable-dose group, the risk for flare was more than four times higher in the half-dose tapering to withdrawal group (hazard ratio [HR], 4.2; 95% CI, 2.2-8.2) and about three times higher in the half-dose group (HR, 2.9; 95% CI, 1.5-5.9). The flare risk between the half dose and half-dose tapering to withdrawal group was not statistically significant.

Most patients regained DAS remission status in the next clinic visit following a flare, the authors reported. Comparing the last visit to baseline, 10 patients in the taper-to-withdrawal group (27%) had increased treatment — either by adding a biologic or increasing csDMARD dose — compared with one patient (3%) in the half-dose group and 11 patients (14%) in the stable-dose group. Adverse events were common across all three groups, though were highest in the tapering to withdrawal group.

In the TNF inhibitor arms, a total of 80 patients completed the 3-year follow-up. By the end of 3 years, 75% of the tapering group experienced a disease flare compared with 15% of the stable TNF inhibitor group. Most patients regained DAS remission status in the next clinic visit following a flare, the authors reported. During the study, 23% of the tapering group and 13% of the stable TNF inhibitor group used systemic glucocorticoids. Four patients in the tapering group and two patients in the stable TNF inhibitor group switched to another TNF inhibitor during the study. An additional two patients in the stable TNF inhibitor group switched to a Janus kinase inhibitor during the 3-year study.

Adverse events were similar in both treatment groups, but serious adverse events were more common in the tapering group (21%) than in the stable-dose group (11%).

The authors concluded that the findings did not support tapering a TNF inhibitor to withdrawal for patients in sustained remission, but they noted that additional research is needed to identify which patients would fare better or worse tapering csDMARDs.

ARCTIC REWIND was funded by grants from The Research Council of Norway and The South-Eastern Norway Regional Health Authorities. Many of the authors disclosed financial ties to pharmaceutical companies. O'Dell disclosed no relevant financial relationships.

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