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Randomized Controlled Trial
. 2015 Apr 9:350:h1389.
doi: 10.1136/bmj.h1389.

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

Noortje van Herwaarden  1 , Aatke van der Maas  2 , Michiel J M Minten  2 , Frank H J van den Hoogen  3 , Wietske Kievit  4 , Ronald F van Vollenhoven  5 , Johannes W J Bijlsma  6 , Bart J F van den Bemt  7 , Alfons A den Broeder  2
Affiliations
Randomized Controlled Trial

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

Noortje van Herwaarden et al. BMJ. .

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.

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 (www.trialregister.nl), NTR 3216.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf 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.

Figures

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Fig 1 Flowchart of patient recruitment and dropout. TNFI=TNF inhibitor
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Fig 2 Primary outcome analyses
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Fig 3 Numbers of flares per patient during the study
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Fig 4 Mean scores for (A) disease activity, (B) functioning, and (C) quality of life during planned study visits for the dose reduction and usual care groups
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Fig 5 Numbers of glucocorticoid injections received per patient in each study group
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Fig 6 Probability plot for radiological progression in dose reduction and usual care groups
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