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Therapeutic drug monitoring of adalimumab in RA: no predictive value of adalimumab serum levels and anti-adalimumab antibodies for prediction of response to the next bDMARD
  1. Evy Ulijn1,
  2. Nathan den Broeder1,
  3. Maike Wientjes1,
  4. Noortje van Herwaarden1,2,
  5. Inger Meek2,
  6. Lieke Tweehuysen1,
  7. Aatke van der Maas1,
  8. Bart JF van den Bemt3,4,
  9. Alfons A den Broeder1
  1. 1 Rheumatology, Sint Maartenskliniek, Nijmegen, Gelderland, Netherlands
  2. 2 Rheumatology, Radboud University Medical Center, Nijmegen, Netherlands
  3. 3 Pharmacy, Sint Maartenskliniek, Nijmegen, Netherlands
  4. 4 Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands
  1. Correspondence to Nathan den Broeder, Rheumatology, Sint Maartenskliniek, 6574 NA Ubbergen, Netherlands; n.denbroeder{at}


Background After adalimumab treatment failure, tumour necrosis factor inhibition (TNFi) and non-TNFi biological disease-modifying anti-rheumatic drugs (bDMARDs) are equally viable options on a group level as subsequent treatment in rheumatoid arthritis (RA) based on the current best evidence synthesis. However, preliminary data suggest that anti-adalimumab antibodies (anti-drug antibodies, ADA) and adalimumab serum levels (ADL) during treatment predict response to a TNFi as subsequent treatment.

Objective To validate the association of presence of ADA and/or low ADL with response to a subsequent TNFi bDMARD or non-TNFi bDMARD. Sub-analyses were performed for primary and secondary non-responders.

Methods A diagnostic test accuracy retrospective cohort study was done in consenting RA patients who discontinued adalimumab after >3 months of treatment due to inefficacy and started another bDMARD. Inclusion criteria included the availability of (random timed) serum samples between ≥8 weeks after start and ≤2 weeks after discontinuation of adalimumab, and clinical outcome measurements Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) between 3 to 6 months after treatment switch. Test characteristics for EULAR (European League Against Rheumatism) good response (DAS28-CRP based) after treatment with the next (non-)TNFi bDMARD were assessed using area under the receiver operating characteristic and sensitivity/specificity.

Results 137 patients were included. ADA presence was not predictive for response in switchers to a TNFi (sensitivity/specificity 18%/75%) or a non-TNFi (sensitivity/specificity 33%/70%). The same was true for ADL levels in patients that switched to a TNFi (sensitivity/specificity 50%/52%) and patients that switched to a non-TNFi (sensitivity/specificity 32%/69%). Predictive value of ADA and ADL were similar for both primary and secondary non-responders to adalimumab.

Conclusions In contrast to earlier research, we could not find predictive value for response to a second TNFi or non-TNFi for either ADA or random timed ADL.

  • rheumatoid arthritis
  • anti-TNF
  • DMARDs (biologic)
  • DAS28
  • disease activity

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  • Handling editor Josef S Smolen

  • Contributors EU, NdB, AdB, NvH and BvdB were involved in the conception and design of the study. EU, NdB, AB, LT and IM were involved in the data collection. EU, NdB and AdB contributed to the data analysis. EU, NdB, MW and AdB drafted the manuscript and all co-authors reviewed the manuscript critically and gave final approval for its submission.

  • Funding This study was not supported by any external funding. The laboratory analyses of adalimumab and antibodies and serum levels (ADA and ADL) were performed in the laboratory of Sanquin, Amsterdam.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Ethics approval Approval from the local ethics committee (Commissie Mensgebonden Onderzoek (CMO) region Arnhem-Nijmegen) was obtained (CMO: 2019–5443). Patients had either previously consented to inclusion in several biobanking studies, including the Nijmegen RA protocollaire follow-up23 (CMO-number: 2016–2281) and the BIOTOP study24 (CMO region Arnhem-Nijmegen, NL47946.091.14) or were sent opt-out informed consent letters with information about the aims and methods of the study. Patients were given 4 weeks to read the information and respond in case they are not willing to participate (according to Dutch law: WGBO art 458 sub 2). This study received no external funding. The laboratory analyses of adalimumab and ADA levels and personnel costs were funded by the Sint Maartenskliniek.

    The study was conducted according to the principles of the Declaration of Helsinki and in accordance to Dutch law: WMO, AVG, WGBO, code Goed Gedrag and NFU ‘richtlijn kwaliteitsborging mensgebonden onderzoek’.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. Additional unpublished data can be obtained from the corresponding author upon reasonable request.