Three-quarters of patients in RA remission flare within 3 years of TNF inhibitor taper
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SAN DIEGO — Approximately 75% of patients in rheumatoid arthritis remission who taper TNF inhibitors to withdrawal experience a flare within 3 years, according to data presented at ACR Convergence 2023.
Meanwhile, just 15% of patients in RA remission who remained on stable TNF inhibition demonstrated flare during the same time period, the researchers wrote.
“During the last few decades, patients with rheumatoid arthritis have gained a lot of new opportunities for treatment,” Siri Lillegraven, MD, PhD, MPH, of Diakonhjemmet Hospital, in Oslo, Norway, said at a press conference during the meeting. “This has led to an increasing number of patients with very excellent disease control, also known as remission. A contributing factor to this development has been the introduction of TNF inhibitors, which target the specific components of the immune system.
“However, with this development, many clinicians and patients have raised questions about whether patients actually need to maintain the same level of treatment when they have achieved disease control as was necessary for them to gain that control,” she added.
To examine the 3-year impact of tapering TNF inhibitors to withdrawal, compared with remaining on stable treatment, Lillegraven and colleagues conducted the ARCTIC REWIND trial, a randomized, multicenter, open-label, non-inferiority study of 99 patients in sustained RA remission for 12 months. All participants had been on stable TNF inhibition with no swollen joints at enrollment, according to the researchers.
Participants were randomized 1:1 to either taper TNF inhibitors, according to a regimen of 4 months of half doses followed by withdrawal, or continue with stable therapy, with visits every 4 months across 3 years. Full TNF inhibitor doses were reinstated in the event of a flare.
The primary endpoint was disease flare during the 3-year study period. Flare was defined as a combination of a Disease Activity Score (DAS) greater than 1.6, an increase in DAS of 0.6 units or greater, and the appearance of at least two swollen joints; or if the physician and patient together agreed that a flare had occurred. Secondary endpoints included remission status, medication use and adverse events.
Among the randomized participants, 80 completed the full 3 years of follow-up. The mean baseline DAS was 0.8 in the taper group and 0.9 in the stable therapy group. In addition, co-medication with conventional synthetic disease-modifying antirheumatic drugs was used by 89% in the tapering group and 91% in the stable group.
According to the researchers, 25% of patients (95% CI, 13% to 38%) in the taper group remained flare free after 3 years, compared with 85% of patients (95% CI, 70% to 93%) in the stable treatment group, representing an HR of 9.4 (95% CI, 3.9-22.8). Most patients — 81% in the taper group and 67% in stable group — regained remission within the next visit following a flare.
The researchers additionally reported significantly lower Boolean 2.0 remission rates throughout the study period among patients who tapered vs. those in the stable group (adjusted risk difference from 0 to 36 months = –25%; 95% CI, –33% to –16%).
Approximately 23% of patients in the taper group used at least one systemic glucocorticoid during the study, compared with 13% in the stable group. Meanwhile, 10% in the taper group switched to other types of TNF inhibitors or JAK inhibition, compared with 11% in the stable group. Adverse events occurred in 81% of those in the tapering group, with 21% experienced serious adverse events. In the stable group, these rates were 89% and 11%, respectively.
“We think these results have important implications for clinical decision making,” Lillegraven said. “Based on our data, we think that the practice of tapering TNF inhibitor treatment in this particular patient group should not be supported. However, it is important to take into account that patients have different other factors that might warrant tapering. In addition, we think that patients who want to taper treatment should be informed about the potential risks and benefits of tapering medication, in order to inform a good shared decision-making process.
“As clinicians, we naturally would like to be able to identify those patients who can taper safely to withdrawal,” she added. “Although most patients had flare, we saw that there was a 25% group that had no flares even though they tapered their medication.”
Perspective
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Rheumatologists have wrestled for years with the vexing and important question of whether we should taper and/or withdraw targeted therapies in patients with rheumatoid arthritis who are at low disease activity, especially those who are in “remission.” The arguments in favor of tapering and withdrawal are obvious — reducing both cost and the risk for adverse effects or harm from the medication. The argument against tapering or withdrawal is the risk for flare and harm from the disease. Because TNF inhibitors have been used in RA longer than any other targeted therapies, there is now a large amount of data on this issue.
This trial, named “ARCTIC REWIND” confirms the prevailing evidence that many more patients with RA flare after withdrawal of TNF inhibitors than those maintained on therapy. This well-designed study demonstrated quite a large difference — only 25% in the tapering group remained flare-free over 3 years, compared with 85% in the group that remained on stable TNF inhibitors.
The magnitude of the difference in this study was quite large even compared with other similar RCTs, likely largely due to the longer, 3-year duration of this trial. Other similar trials have generally been limited to approximately 12 months of follow-up. Unsurprisingly, glucocorticoid use was higher in the taper group. Meanwhile, adverse effects were similar between groups, but serious adverse effects were higher in the taper group.
In ARCTIC REWIND, remission was tightly defined as a DAS less than or equal to 1.6. Flares were defined as an increase of at least 0.6 DAS units, with certain other reasonable clinical criteria — either two or more swollen joints or patient and physician agreement that a flare had occurred. Virtually no practicing rheumatologists use DAS in practice. However, while most do not precisely know what a “DAS 1.6” looks like, they know swollen joints and a clinical flare when they see it.
The take home lesson is that it is a bad idea to taper and withdraw TNF-inhibitor therapy in patients with RA whose disease is well controlled. Thanks to Dr. Lillegraven and colleagues for most conclusively proving this.
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Lillegraven S. Abstract L07. Presented at: ACR Convergence 2023; Nov. 10-15, 2023; San Diego.
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