Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial

Abstract

Objectives: Many patients with rheumatoid arthritis (RA) require treatment with tumour necrosis factor inhibitor (TNFi) to reach remission. It is debated whether tapering of TNFi to discontinuation should be considered in sustained remission. The aim of ARCTIC REWIND TNFi was to assess the effect of tapering TNFi to withdrawal compared with stable treatment on the risk of disease activity flares in patients with RA in remission ≥1 year.

Methods: This randomised, open-label, non-inferiority trial was undertaken at nine Norwegian rheumatology departments. Patients with RA in remission ≥12 months on stable TNFi therapy were allocated by computer-based block-randomisation to tapering to discontinuation of TNFi or stable TNFi. Conventional synthetic disease-modifying antirheumatic co-medication was unchanged. The primary endpoint was disease flare during the 12-month study period (non-inferiority margin 20%), assessed in the per-protocol population.

Results: Between June 2013 and January 2019, 99 patients were enrolled and 92 received the allocated treatment strategy. Eighty-four patients were included in the per-protocol population. In the tapering TNFi group, 27/43 (63%) experienced a flare during 12 months, compared with 2/41 (5%) in the stable TNFi group; risk difference (95% CI) 58% (42% to 74%). The tapering strategy was not non-inferior to continued stable treatment. The number of total/serious adverse events was 49/3 in the tapering group, 57/2 in the stable group.

Conclusion: In patients with RA in remission for more than 1 year while using TNFi, an increase in flare rate was reported in those who tapered TNFi to discontinuation. However, most regained remission after reinstatement of full-dose treatment.

Trial registration numbers: EudraCT: 2012-005275-14 and clinicaltrials.gov: NCT01881308.

Keywords: arthritis, rheumatoid; treatment; tumor necrosis factor inhibitors.

Figure 1

Flow of patients in the ARCTIC REWIND TNFi Study. ^aRemission according to established criteria should be documented for at least 12 months. ^bDAS is a composite measure of disease activity with scores ranging from 0 to 10, higher scores indicate more disease activity, remission defined as <1.6. ^cStratified by study site. DAS, Disease Activity Score. TNFi, tumour necrosis factor inhibitor.

Figure 2

Flare rate (primary outcome) in tapered versus stable TNFi treatment flare was defined as a combination of Disease Activity Score (DAS) above the cut-off for remission (1.6), a change in DAS of at least 0.6, and at least two swollen joints or that both the treating physician and the patient agreed that a clinically significant flare had occurred. The dotted, vertical line represents the non-inferiority margin. ^aThe primary analysis was performed in all randomised patients meeting the study entry criteria and with no protocol deviations affecting the treatment efficacy (defined as failure to follow the treatment regimen or withdrawal from the study). ^bSeven patients who were randomised but did not have verified initiation of treatment are excluded (five from the tapering group and two from the stable group). ^cAnalysis performed in patients within the primary analysis population who used methotrexate co-medication. csDMARD, conventional synthetic disease-modifying antirheumatic drug; TNFi, tumour necrosis factor inhibitor.

Figure 3

Secondary endpoints. Analysed in the primary analysis population, defined as all randomised patients meeting the study entry criteria and with no protocol deviations affecting the treatment efficacy. Patients were followed up for a median (IQR) of 364 days (358–378 days) in the tapered group and 366 days (357–378 days) in the stable group. Variables are displayed based on clinical relevance. Boxes mark first and third quartiles, the band inside the box is the second quartile (the median), while the whiskers indicate the highest and lowest values within 1.5 × the IQR. Dots denote individual patients (outliers).^a Disease Activity Score (DAS, range 0–10) includes a 44 swollen joint count assessment of tender joints by the Ritchie Articular Index, the erythrocyte sedimentation rate (ESR) and patient’s global assessment of disease activity on a VAS 0–100 mm. Remission is defined as any value below 1.6, low disease activity 1.6–2.4, moderate disease activity >2.4–3.7 and high disease activity >3.7, thus higher scores indicating more disease activity. ^bPROMIS assesses the ability to perform basic and instrumental activities of daily living. The total score is translated into a T score with a mean (SD) of 50 (10). A score of 50 equals the average for the general US population. ^cThe van der Heijde–modified Sharp scoring method assesses erosions in 16 joints of each hand and 6 joints of each foot, and the erosions are given a score of 1 to 5. Joint space narrowing is assessed in 15 joints for each hand and 6 joints for each foot. This gives scores for erosions on a scale of 0–280 and joint space narrowing on a scale of 0–168, thus the total van der Heijde–modified Sharp score ranges from 0 to 448, with higher scores indicating greater joint damage. A good radiographic outcome is commonly defined as no progression. ^dDisease Activity Score at the visit before a flare occurred, at the flare visit, and at visits after flare in the half-dose arm in those with all components available to calculate DAS. A flare could be recorded both at regular visits and at additional visits. PROMIS, Patient-Reported Outcomes Measurement Information 20-item Short Form Physical Function; TNFi, tumour necrosis factor inhibitor; VAS Visual Analogue Scale.