TNF Inhibitor Tapering Increases Flare Risk in Patients with RA in Sustained Remission

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Compared to patients on stable TNFi, patients tapering TNFi to withdrawal experienced significantly more flares and had lower Boolean 2.0 remission rates.

Tapering tumor necrosis factor inhibitors (TNFi) to withdrawal may lead to an increased risk of flares compared to stable TNFi treatment in patients with rheumatoid arthritis (RA) in sustained remission, according to findings from a recent study.1

Results from the randomized, multicenter, open-label, non-inferiority ARCTIC REWIND trial showed more patients receiving stable TNFi treatment remained flare-free through 3 years compared to patients tapering TNFi to withdrawal. Additionally, TNFi tapering was associated with significantly lower Boolean 2.0 remission rates throughout the study.1

“Tapering of tumor necrosis factor inhibitor treatment in patients who have reached sustained remission is debated in current guidelines, and further data are needed regarding the long-term consequences of such strategies,” Kaja Eriksrud Kjørholt, MD, of the department of rheumatology at Diakonhjemmet Hospital in Norway, and colleagues wrote.1

RA treatment seeks to reduce joint pain and swelling to maintain/improve joint function. Biologics are frequently used to treat RA, and TNFi are among the most commonly prescribed biologics for RA because they reduce inflammation relatively quickly and can help prevent long-term joint damage. However, TNFi use is associated with several notable risks, including potential long-term consequences of tapering to withdrawal after sustained remission.2

A randomized, multicenter, open-label, non-inferiority trial, ARCTIC REWIND included patients with RA who were in sustained remission for ≥12 months on stable TNFi therapy and with no swollen joints at inclusion. Investigators randomly assigned patients in a 1:1 ratio to tapering to withdrawal of TNFi (4 months of half-dose, thereafter withdrawal) or continued stable TNFi therapy, with scheduled visits every 4 months for 3 years. Full-dose TNFi therapy was reinstated if a flare occurred.1

The primary endpoint of the present study was flare in disease activity over 3 years, with a flare was defined as a combination of disease activity score (DAS) > 1.6 (loss of remission status), an increase in DAS ≥0.6 units (change above minimal detectable change), and ≥2 swollen joints, or if the physician and patient agreed that a clinically significant flare had occurred. Secondary endpoints included remission status (ACR/EULAR Boolean 2.0 and DAS), 3-year change in radiographic joint damage assessed by van der Heijde modified Sharp Score, medication use and adverse events.1

Data were analyzed in the per-protocol population adjusting for center as a stratification factor. Flare-free survival was evaluated by Kaplan-Meier and risk of flare by Cox regression, while remission status and radiographic change were assessed by logistic and linear regression.1

Of 99 randomized patients, 92 received the allocated therapy and 80 completed 3-year follow-up. Mean baseline DAS was 0.8 (Standard deviation [SD], 0.3) in the tapering TNFi group, and 0.9 (SD, 0.4) in the stable TNFi group. Conventional synthetic disease-modifying antirheumatic drug co-medication was used by 89% of patients in the tapering group and 91% in the stable group.1

After 3 years, 25% (95% CI, 13 to 38) of patients in the tapering TNFi group remained flare-free compared to 85% (95% CI, 70 to 93) in the stable TNFi group, with a corresponding hazard ratio for flare of 9.4 (95% CI, 3.9 to 22.8; P <.0001). Investigators noted most patients regained DAS remission within the next visit after a flare (84% in the tapering group, 67% in the stable group).1

Investigators also pointed out significantly lower Boolean 2.0 remission rates in the tapering TNFi group than the stable TNFi group throughout the study period (adjusted risk difference 0 to 36 months, -24%; 95% CI, -33 to -15; P <.0001). Analysis of Boolean 1.0 remission rates revealed similar results.1

The median radiographic changes after 3 years were minimal in both groups (tapering group, 0.5; 95% CI, 0.0 to 2.0 vs stable group, 0.5; 95% CI, 0.0 to 1.5) and not significantly different between the groups (P = .06). Systemic glucocorticoids were used by 23% of patients in the tapering TNFi group and 13% of patients in the stable TNFi group during the study. In the tapering group, 10% of patients switched to other types of TNFi or JAK inhibitor treatment and 11% in the stable group switched as well.1

Adverse events occurred in 81% and 87% of patients in the tapering and stable groups, respectively. Serious adverse events occurred in 21% of those in the tapering group and 11% of those in the stable group.1

“These findings do not support tapering of TNFi treatment among RA patients in sustained remission,” investigators concluded.1


  2. Rath, L. Biologics. Arthritis Foundation. September 3, 2022. Accessed June 26, 2024.