Op0019 stable Versus Tapered and Withdrawn Treatment With Tumor Necrosis Factor Inhibitor in Rheumatoid Arthritis Remission (Arctic Rewind): A Randomised, Open-Label, Phase 4, Non-Inferiority Trial

Abstract

Background:Remission is the preferred treatment target in rheumatoid arthritis (RA), and many patients require biologic DMARDs to reach this state. It is debated whether tapering of tumor necrosis factor inhibitor (TNFi) treatment to discontinuation should be considered in RA patients who sustain remission on treatment (1).Objectives:The primary study objective was to assess the effect of tapering and withdrawal of TNFi on the risk of flares in RA patients in clinical remission.Methods:In the non-inferiority ARCTIC REWIND trial, RA patients in remission for at least 12 months on stable TNFi therapy were randomly assigned to continued stable TNFi or tapering (half-dose TNFi for 4 months, thereafter withdrawal of TNFi), with visits every four months. csDMARD co-medication was kept stable in both arms. Patients had to be in DAS remission at inclusion with 0/44 swollen joints. The primary endpoint was the proportion of patients with disease flare during the 12-month study period (defined as DAS>1.6, change in DAS>0.6 and 2 or more swollen joints, or the physician and patient agreed that a clinically significant flare had occurred). Full-dose TNFi was reinstated in case of flares in the tapering arm. The non-inferiority margin was 20%, with a predefined superiority test if non-inferiority was not shown. The inferiority null-hypothesis was tested in the per-protocol population by mixed effect logistic regression. Radiographs were scored by van der Heijde modified Sharp score (0 and 12 months, average of two readers, progression: ≥1 unit change). ClinicaltrialsNCT01881308.Results:We randomised 99 patients, 92 received the allocated treatment strategy, 84 were included in the per-protocol population. Baseline characteristics, clinical and ultrasound disease activity were balanced (Table). csDMARD co-medication was used by 93% in the stable and 88% in the tapering arm. In the primary analysis, 5% of patients in the stable TNFi arm experienced a flare during 12 months, compared to 63% in the tapering TNFi arm. The risk difference (95% CI) was 58% (42% to 74%, Fig 1), with stable treatment being deemed superior to tapering. 90% in the stable and 81% in the tapering arm did not show progression of radiographic joint damage, difference (95% CI) -9% (-24%, 6%). At 12 months, DAS scores, DAS remission and function were similar between groups (Fig 2). The numbers of adverse events (AE)/serious AE in the stable and tapering arm were 57/2 and 50/3, respectively, with 26 and 15 infections.Conclusion:In a randomised clinical trial assessing patients in prolonged and deep RA remission, we observed a large increase in the flare rate in patients who tapered and discontinued TNFi. Patients responded well to reinstated treatment and remission rates in the two study arms were comparable at 12 months.References:[1]Smolen et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. ARD 2020Table 1.Baseline values – n (%), mean (SD), or median (IQR)Stable, n=45Tapering, n=47Age, yrs57 (11)58 (13)Female30 (67%)25 (53%)ACPA+35 (78%)36 (77%)Symptom duration, yrs10 (7)12 (7)DAS0.9 (0.4)0.8 (0.3)CRP mg/L1 (1 – 2)1 (1 – 3)No ulttrasound power Doppler signal in any of 32 joints42 (96%)44 (94%)Disclosure of Interests:Siri Lillegraven: None declared, Nina Paulshus Sundlisæter: None declared, Anna-Birgitte Aga: None declared, Joe Sexton: None declared, Inge Olsen: None declared, Åse Lexberg: None declared, Tor Magne Madland: None declared, Hallvard Fremstad: None declared, Christian A. Høili Consultant of: Novartis, Gunnstein Bakland Consultant of: Novartis, UCB, Cristina Spada: None declared, Hilde Haukeland Consultant of: Novartis, Inger M. Hansen: None declared, Ellen Moholt: None declared, Till Uhlig Consultant of: Lilly, Pfizer, Speakers bureau: Grünenthal, Novartis, Daniel Solomon Grant/research support from: Funding from Abbvie and Amgen unrelated to this work, Désirée van der Heijde Consultant of: AbbVie, Amgen, Astellas, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Cyxone, Daiichi, Eisai, Eli-Lilly, Galapagos, Gilead Sciences, Inc., Glaxo-Smith-Kline, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Takeda, UCB Pharma; Director of Imaging Rheumatology BV, Tore K. Kvien Grant/research support from: Received grants from Abbvie, Hospira/Pfizer, MSD and Roche (not relevant for this abstract)., Consultant of: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Paid instructor for: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Speakers bureau: Have received personal fees from Abbvie, Biogen, BMS, Celltrion, Eli Lily, Hospira/Pfizer, MSD, Novartis, Orion Pharma, Roche, Sandoz, UCB, Sanofi and Mylan (not relevant for this abstract)., Espen A Haavardsholm Grant/research support from: AbbVie, UCB Pharma, Pfizer Inc, MSD Norway, Roche Norway, Consultant of: Pfizer, AbbVie, Janssen-Cilag, Gilead, UCB Pharma, Celgene, Lilly, Paid instructor for: UCB Pharma, Speakers bureau: Pfizer, AbbVie, UCB Pharma, Celgene, Lilly, Roche, MSD

Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis

“…Non-inferiority was not demonstrated as 37.2% (tapering/stopping) vs 95.1% (continuation) maintained DAS44 remission (risk difference: 58% (95% CI 43% to 74%)) after 1 year. In the tapering arm 19% of patients experienced radiographic progression of joint damage, compared with 10% in the TNFi continuation arm 50…”

Towards the Lowest Efficacious Dose: Results From a Multicenter Noninferiority Randomized Open‐Label Controlled Trial Assessing Tocilizumab or Abatacept Injection Spacing in Rheumatoid Arthritis in Remission

“…Finally, regarding safety, to our knowledge, this is the first study showing potentially fewer severe adverse events in the spacing versus maintenance arms in terms of infectious events. [14][15][16][17][18][19][20][21][22] Actually, the common thinking for safety issues is a phenomenon called "depletion of the susceptible," whereby people at risk of the most common treatment side effects are likely to experience them in the first months after treatment initiation; consequently, patients with adequate and durable responses to the treatment are those with low risk profile. 34 Our findings indicate that, as shown in many other chronic diseases, drug tapering can lead to disease reactivation, including severe flares and progression.…”

“…Despite these limitations, our results agree with current knowledge on bDMARD discontinuation strategy. Trials assessing a disease activity–driven tapering strategy for TNFi treatment, such as STRASS or ARCTIC REWIND, did not demonstrate NI in terms of flare occurrence: flares occurred in 76.6% and 63% of patients tapering the TNFi, respectively, versus 46.5% and 5% of patients maintaining bDMARDs at a full dose 17,19 . Only the DRESS trial demonstrated NI of tapering compared to maintenance strategy for major flares but not short‐term flares 14 .…”

“…Most published studies have investigated TNFi tapering and discontinuation but provided contradictory results. Most failed to demonstrate noninferiority (NI) in terms of the incidence of flares 17–22 . Two studies demonstrated NI for the primary outcome but also found a significantly increased rate of flare or structural damage progression 16,23 …”

“…Most failed to demonstrate noninferiority (NI) in terms of the incidence of flares. [17][18][19][20][21][22] Two studies demonstrated NI for the primary outcome but also found a significantly increased rate of flare or structural damage progression. 16,23 The amount of evidence on the potential benefit of non-TNFi bDMARD tapering is more limited.…”