title: Disease activity guided dose reduction and withdrawal of adalimumab or etanercept compared with usual care in rheumatoid arthritis: open label, randomised controlled, non-inferiority trial.
abstract: OBJECTIVE
  To evaluate whether a disease activity guided strategy of dose reduction of two tumour necrosis factor (TNF) inhibitors, adalimumab or etanercept, is non-inferior in maintaining disease control in patients with rheumatoid arthritis compared with usual care.
  
  
  METHODS
  Randomised controlled, open label, non-inferiority strategy trial.
  
  
  METHODS
  Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014.
  
  
  METHODS
  180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care.
  
  
  METHODS
  Disease activity guided dose reduction (advice to stepwise increase the injection interval every three months, until flare of disease activity or discontinuation) or usual care (no dose reduction advice). Flare was defined as increase in DAS28-CRP (a composite score measuring disease activity) greater than 1.2, or increase greater than 0.6 and current score of at least 3.2. In the case of flare, TNF inhibitor use was restarted or escalated.
  
  
  METHODS
  Difference in proportions of patients with major flare (DAS28-CRP based flare longer than three months) between the two groups at 18 months, compared against a non-inferiority margin of 20%. Secondary outcomes included TNF inhibitor use at study end, functioning, quality of life, radiographic progression, and adverse events.
  
  
  RESULTS
  Dose reduction of adalimumab or etanercept was non-inferior to usual care (proportion of patients with major flare at 18 months, 12% v 10%; difference 2%, 95% confidence interval -12% to 12%). In the dose reduction group, TNF inhibitor use could successfully be stopped in 20% (95% confidence interval 13% to 28%), the injection interval successfully increased in 43% (34% to 53%), but no dose reduction was possible in 37% (28% to 46%). Functional status, quality of life, relevant radiographic progression, and adverse events did not differ between the groups, although short lived flares (73% v 27%) and minimal radiographic progression (32% v 15%) were more frequent in dose reduction than usual care.
  
  
  CONCLUSIONS
  A disease activity guided, dose reduction strategy of adalimumab or etanercept to treat rheumatoid arthritis is non-inferior to usual care with regard to major flaring, while resulting in the successful dose reduction or stopping in two thirds of patients.Trial registration Dutch trial register (www.trialregister.nl), NTR 3216.
authors: Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands n.vanherwaarden@maartenskliniek.nl.
authors: Noortje
authors: N
authors: van Herwaarden
authors: Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands.
authors: Aatke
authors: A
authors: van der Maas
authors: Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands.
authors: Michiel J M
authors: MJ
authors: Minten
authors: Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands Department of Rheumatology, Radboud University Medical Centre (UMC), Nijmegen.
authors: Frank H J
authors: FH
authors: van den Hoogen
authors: Department for Health Evidence, Radboud UMC, Nijmegen.
authors: Wietske
authors: W
authors: Kievit
authors: ClinTRID, Karolinska Institute, Stockholm, Sweden.
authors: Ronald F
authors: RF
authors: van Vollenhoven
authors: Department of Rheumatology and Immunology, Utrecht UMC, Utrecht, Netherlands.
authors: Johannes W J
authors: JW
authors: Bijlsma
authors: Department of Pharmacy, Sint Maartenskliniek Department of Pharmacy, Radboud UMC, Nijmegen.
authors: Bart J F
authors: BJ
authors: van den Bemt
authors: Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands.
authors: Alfons A
authors: AA
authors: den Broeder
mesh_terms: D000068879:Adalimumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D018501:Antirheumatic Agents / Q000008:administration & dosage*; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000503:physiopathology; D003362:Cost-Benefit Analysis; D018450:Disease Progression; D004334:Drug Administration Schedule; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D005528:Foot / Q000000981:diagnostic imaging*; D006225:Hand / Q000000981:diagnostic imaging*; D006801:Humans; D007074:Immunoglobulin G / Q000008:administration & dosage*; D008297:Male; D009426:Netherlands / Q000453:epidemiology; D011788:Quality of Life; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage*; D012008:Recurrence; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab; D000068800:Etanercept