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Response to: Comment on l’Ami et al titled ‘Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial’ by den Broeder et al
  1. Merel J l’Ami1,
  2. Charlotte L M Krieckaert1,2,
  3. Michael T Nurmohamed2,
  4. Ronald F van Vollenhoven3,
  5. Theo Rispens4,
  6. Maarten Boers5,
  7. Gerrit Jan Wolbink1
  1. 1Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam, The Netherlands
  2. 2Department of Reumatology, Amsterdam Rheumatology and immunology Center, Location VU University Medical Center, Amsterdam, The Netherlands
  3. 3Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Location Amsterdam Medical Center, Amsterdam, The Netherlands
  4. 4Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands
  5. 5Department of Immunopathology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
  1. Correspondence to Merel J l’Ami, Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, Amsterdam 1056 AB, The Netherlands ; m.lami{at}

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We thank den Broeder et al for their interest in our study and for their suggestions concerning further research.1 Our study did not target the broad issue of dose tapering, but focused on the population of patients with rheumatoid arthritis with high adalimumab concentrations (>8 µg/mL).2 We hypothesised that given the wide variation in serum concentrations on standard dosing and the established plateau in the concentration–response relationship—even in active disease3—there would be a role for individualised dosing to optimise adalimumab therapy. Unlike den Broeder et al, we find nothing peculiar about our research question or design to investigate whether overexposure could be reduced without an increase in disease activity. This study gives a clear positive answer.

We share with den Broeder et al a belief in the importance of research concerning optimal use of biological treatments. den Broeder et al highlight a stepwise dose reduction based on disease activity, where the dose is downtitrated to zero or until the occurrence of a flare4; we believe this may also be a valuable strategy in optimising adalimumab therapy. We note in passing that our study was designed in 2012, when discontinuation of biologics was still very contentious.

den Broeder et al claim that our non-inferiority analysis strategy was defined post hoc based on the record in the trial register, but we stated there as primary outcome ‘Similar deltaDAS28 in patients with high serum adalimumab concentrations who are randomly assigned to continuation of the regular dose or to dose interval prolongation’. We think we adequately explained our problems with recruitment and our ways to handle this in the analysis. In addition, given the actual results, statistically favouring the dose reduction group, we think this point is moot.

In sum, we showed that patients with high adalimumab concentrations can safely reduce the dose. We think that this study highlights an important topic in biological treatment. Overexposure should be avoided regardless of treatment targets, in light of high drug costs and a possibly increased risk of adverse events.


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  • Handling editor Josef S Smolen

  • Contributors All authors have made substantial contributions to the conception, drafting and revising of the work, and all approved the final version and are accountable for all aspects of the work.

  • Funding GJW has received research funding from Pfizer and honoraria for lectures and in advisory boards of Pfizer, UCB, BMS, AbbVie, Novartis and Biogen.

  • Competing interests CLK has received honoraria for lectures from Pfizer and MTN has received research funding or speaking/consultancy honoraria from AbbVie, Pfizer, Merck, Roche, BMS, UCB, Eli Lilly, Celgene and Janssen. RvV has received research support and grants from AbbVie, Amgen, BMS, GSK, Pfizer, Roche, UCB and honoraria for consultancy from AbbVie, Biotest, BMS, Celgene, Crescendo, GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB and Vertex. TR has received honoraria for lectures from Pfizer, AbbVie and Regeneron and a research grant from Genmab. MB has received consultancy for Pfizer, BMS, UCB and Teva.

  • Provenance and peer review Commissioned; internally peer reviewed.

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