Effects of tapering conventional synthetic disease-modifying antirheumatic drugs to drug-free remission versus stable treatment in rheumatoid arthritis (ARCTIC REWIND): 3-year results from an open-label, randomised controlled, non-inferiority trial.

BACKGROUND

Tapering of disease-modifying antirheumatic drugs (DMARDs) to drug-free remission is an attractive treatment goal for patients with rheumatoid arthritis, although long-term effects of tapering and withdrawal remain unclear. We compared 3-year risks of flare between three conventional synthetic DMARD treatment strategies in patients with rheumatoid arthritis in sustained remission.

METHODS

In this open-label, randomised controlled, non-inferiority trial, we enrolled patients aged 18-80 years with rheumatoid arthritis who had been in sustained remission for at least 1 year on stable conventional synthetic DMARD therapy. Patients from ten hospitals in Norway were randomly assigned (2:1:1) with centre stratification to receive stable conventional synthetic DMARDs, half-dose conventional synthetic DMARDs, or half-dose conventional synthetic DMARDs for 1 year followed by withdrawal of all conventional synthetic DMARDs. The primary endpoint of this part of the study was disease flare over 3 years, analysed as flare-free survival and risk difference in the per-protocol population with a non-inferiority margin of 20%. This trial is registered with ClinicalTrials.gov (NCT01881308) and is completed.

FINDINGS

Between June 17, 2013, and June 18, 2018, 160 patients were enrolled and randomly assigned to receive stable-dose conventional synthetic DMARDs (n=80), half-dose conventional synthetic DMARDs (n=42), or half-dose conventional synthetic DMARDs tapering to withdrawal (n=38). Four patients did not receive the intervention and 156 patients received the allocated treatment strategy. One patient was excluded due to major protocol violation and 155 patients were included in the per-protocol analysis. 104 (67%) of 156 patients were women and 52 (33%) were men. 139 patients completed 3-years follow-up without major protocol violation; 68 (87%) of 78 patients in the stable-dose group, 36 (88%) of 41 patients in the half-dose group and 35 (95%) of 37 patients in the half-dose tapering to withdrawal group. During the 3-year study period, 80% (95% CI 69-88%) were flare-free in the stable-dose group, compared with 57% (41-71%) in the half-dose group and 38% (22-53%) in the half-dose tapering to withdrawal group. Compared with stable-dose conventional synthetic DMARDs, the risk difference of flare was 23% (95% CI 6-41%, p=0·010) in the half-dose group and 40% (22-58%, p<0·0001) in the half-dose tapering to withdrawal group, non-inferiority was therefore not shown. Adverse events were reported in 65 (83%) of 78 patients in the stable-dose group, 36 (90%) of 40 patients in the half-dose group, and 36 (97%) of 37 patients in the half-dose tapering to withdrawal group. One death occurred in the stable-dose conventional synthetic DMARD group (sudden death considered unlikely related to the study medication).

INTERPRETATION

Two conventional synthetic DMARD tapering strategies were associated with significantly lower rates of flare-free survival compared with stable conventional synthetic DMARD treatment, and the data do not support non-inferiority. However, drug-free remission was achiveable for a significant subgroup of patients. This trial provides information on risk and benefits of different treatment strategies important for shared decision making.

FUNDING

Research Council of Norway and South-Eastern Norway Regional Health Authority.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests KEK and NPS report grants from The Research Council of Norway and from The South-Eastern Norway Regional Health Authority during the conduct of the study. A-BA reports personal fees from AbbVie, Eli Lilly, Novartis, and Pfizer, outside the submitted work. ICO reports grants from EU commission, personal fees from Dilafor AB, the European Medicines Agency, and the European Clinical Research Infrastructure Network, outside the submitted work and serves on a data safety monitoring board for Oslo University Hospital. CS reports personal fees from UCB outside the submitted work. TMM reports personal fees from Boehringer outside the submitted work. GB reports personal fees from UCB outside the submitted work and is a board member of Norwegian Society of Rheumatology. HH reports personal fees from UCB outside the submitted work. M-KAL reports personal fees from AbbVie outside the submitted work. TU reports personal fees from Eli Lilly, Galapagos, Pfizer, and UCB, outside the submitted work. TKK reports grants and personal fees from AbbVie, Novartis, Pfizer, and UCB; grants from Bristol Myers Squibb, Galapagos; and personal fees from Gilead, Janssen, Sandoz, and Grünenthal, outside the submitted work. DHS reports grants from CorEvitas, Horizon, Janssen, and Moderna and personal royalties on several UpToDate chapters, outside the submitted work; and is an unpaid board member of CARRA. DvdH reports personal fees from AbbVie, ArgenX, Bayer, BMS, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Pfizer, Takeda, and UCB, outside the submitted work; is an associate editor for Annals Rheumatic Diseases; is a director for Imaging Rheumatology BV; is an editorial board member Journal of Rheumatology and RMD Open; and is an advisor assessment for Axial Spondyloarthritis international Society. EAH reports grants from The Research Council of Norway and The South-Eastern Norway Regional Health Authority during the conduct of the study; personal fees from Pfizer, AbbVie, UCB, Boehringer Ingelheim, Eli Lilly, Galapagos, Gilead, and Novartis, outside the submitted work. SL reports grants from The Research Council of Norway and The South-Eastern Norway Regional Health Authority during the conduct of the study. JS, HF, CAH, ÅL, IJWH, IMH and EM declare no competing interests.