Intended for healthcare professionals

CCBYNC Open access

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

BMJ 2015; 350 doi: (Published 09 April 2015) Cite this as: BMJ 2015;350:h1389
  1. Noortje van Herwaarden, trainee in rheumatology1,
  2. Aatke van der Maas, rheumatologist and clinical epidemiologist1,
  3. Michiel J M Minten, research assistant1,
  4. Frank H J van den Hoogen, professor of rheumatology, head of department of rheumatology 12,
  5. Wietske Kievit, assistant professor of health technology assessment 3,
  6. Ronald F van Vollenhoven, professor of rheumatology and epidemiologist4,
  7. Johannes W J Bijlsma, professor of rheumatology, current head of department of rheumatology at UvA-AMC and VU UMC5,
  8. Bart J F van den Bemt, pharmacist and assistant professor in clinical pharmacology at Radboud UMC 67,
  9. Alfons A den Broeder, rheumatologist and clinical epidemiologist, head of staff rheumatology department 1
  1. 1Department of Rheumatology, Sint Maartenskliniek, Nijmegen, PO Box 9011, 6500 GM, Netherlands
  2. 2Department of Rheumatology, Radboud University Medical Centre (UMC), Nijmegen
  3. 3Department for Health Evidence, Radboud UMC, Nijmegen
  4. 4ClinTRID, Karolinska Institute, Stockholm, Sweden
  5. 5Department of Rheumatology and Immunology, Utrecht UMC, Utrecht, Netherlands
  6. 6Department of Pharmacy, Sint Maartenskliniek
  7. 7 Department of Pharmacy, Radboud UMC, Nijmegen
  1. Correspondence to: N van Herwaarden n.vanherwaarden{at}
  • Accepted 15 February 2015


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.

Design Randomised controlled, open label, non-inferiority strategy trial.

Setting Two rheumatology outpatient clinics in the Netherlands, from December 2011 to May 2014.

Participants 180 patients with rheumatoid arthritis and low disease activity using adalimumab or etanercept; 121 allocated to the dose reduction strategy, 59 to usual care.

Interventions 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.

Main outcome measures 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 (, NTR 3216.


  • We thank all the patients who were willing to participate in this study; the rheumatologists and other healthcare professionals in the Sint Maartenskliniek Nijmegen and Woerden for participation in patient recruitment and data collection; Chantal Bouman and Nienke Lesuis for help during study inclusion, participating in data collection, and scoring radiographs (CB); Els van den Ende and Alexander Rennings for their roles on the data safety monitoring board; Nienke Cuperus for her role as monitor of this study; and Thasia Woodworth for valuable advice and corrections of the manuscript.

  • Contributors: NvH, AdB, AvdM, BvdB, FvdH, RvV, and JB were involved in the study design. NvH, AdB, MM, AvdM, and FvdH were involved in the data collection. NvH, AdB, AvdM, MM, and WK performed the data analyses. All authors were involved in writing, revision, and final approval of the manuscript. NvH is the study guarantor.

  • Funding: The study received no external funding.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: JB received grants and personal fees from Pfizer and AbbVie, during the conduct of the study; and grants and personal fees from Roche, Bristol Myers Squibb, Union Chimique Belge, outside the submitted work. RvV received grants from AbbVie, BMS, GlaxoSmithKline (GSK), Pfizer, Roche, and UCB, and personal fees from AbbVie, Biotest, BMS, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, and Vertex, outside the submitted work. The other authors declare no conflicts of interest.

  • Ethical approval: This study was approved by the local ethics committee (Commissie Mensgebonden Onderzoek region Arnhem-Nijmegen, NL37704.091.11).

  • Data sharing: The authors commit to making the relevant anonymised patient level data available on reasonable request.

  • Transparency: The lead author affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:

View Full Text