Therapeutic Drug Monitoring in Infliximab Induction and Remission of Immune-Mediated Inflammatory Diseases | Dermatology | JN Learning | AMA Ed Hub [Skip to Content]
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Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory DiseasesA Randomized Clinical Trial

Educational Objective
To learn the effect of therapeutic drug monitoring (TDM) during infliximab induction on clinical outcomes in patients with chronic immune-mediated inflammatory diseases.
1 Credit CME
Key Points

Question  Among patients with chronic immune-mediated inflammatory diseases initiating treatment with infliximab, does proactive therapeutic drug monitoring (TDM) improve clinical remission rates compared with standard therapy?

Findings  In this randomized clinical trial that included 411 patients, the proportion of patients who experienced disease remission after 30 weeks was 50.5% in the TDM group and 53.0% in the standard therapy group, a difference that was not statistically significant.

Meaning  These findings do not support routine use of proactive TDM during infliximab induction for improving disease remission rates.

Abstract

Importance  Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear.

Objective  To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM.

Design, Setting, and Participants  Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019.

Interventions  Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204).

Main Outcomes and Measures  The primary end point was clinical remission at week 30.

Results  Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, −8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively.

Conclusions and Relevance  Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates.

Trial Registration  ClinicalTrials.gov Identifier: NCT03074656

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Article Information

Corresponding Author: Silje Watterdal Syversen, MD, PhD, Division of Rheumatology and Research, Diakonhjemmet Hospital, PO Box 23 Vinderen, N-0319 Oslo, Norway (s.w.syversen@gmail.com).

Accepted for Publication: March 4, 2021.

Author Contributions: Drs Syversen and Sexton had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Syversen, Goll, and Jørgensen contributed equally and are co–first authors. Drs Jahnsen, Bolstad, and Haavardsholm contributed equally and are co–last authors.

Concept and design: Syversen, Goll, Jørgensen, Olsen, Torp, Mørk, Kvien, Jahnsen, Bolstad, Haavardsholm.

Acquisition, analysis, or interpretation of data: Syversen, Goll, Sandanger, Sexton, Olsen, Gehin, Warren, Brun, Klaasen, Karlsen, Noraberg, Zettel, Ljoså, Haugen, Njålla, Bruun, Seeberg, Michelsen, Strand, Skorpe, Blomgren, Bragnes, Dotterud, Thune, Ystrøm, Torp, Mielnik, Kvien, Jahnsen, Bolstad, Haavardsholm.

Drafting of the manuscript: Syversen, Goll, Jørgensen, Sexton, Warren, Blomgren, Torp, Kvien, Bolstad.

Critical revision of the manuscript for important intellectual content: Syversen, Goll, Jørgensen, Sandanger, Sexton, Olsen, Gehin, Warren, Brun, Klaasen, Karlsen, Noraberg, Zettel, Ljoså, Haugen, Njålla, Bruun, Seeberg, Michelsen, Strand, Skorpe, Bragnes, Dotterud, Thune, Ystrøm, Torp, Mielnik, Mørk, Kvien, Jahnsen, Bolstad, Haavardsholm.

Statistical analysis: Syversen, Sexton, Olsen, Brun, Torp, Kvien, Haavardsholm.

Obtained funding: Syversen, Goll, Jørgensen, Torp, Kvien, Bolstad, Haavardsholm.

Administrative, technical, or material support: Syversen, Goll, Sandanger, Sexton, Gehin, Warren, Brun, Klaasen, Noraberg, Zettel, Ljoså, Haugen, Njålla, Bruun, Seeberg, Michelsen, Strand, Skorpe, Bragnes, Dotterud, Thune, Torp, Jahnsen, Bolstad, Haavardsholm.

Supervision: Syversen, Goll, Jørgensen, Michelsen, Ystrøm, Torp, Mørk, Kvien, Jahnsen, Haavardsholm.

Conflict of Interest Disclosures: Dr Syversen reported receipt of personal fees from Thermo Fisher. Dr Goll reported receipt of personal fees from Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion Pharma, Sandoz, and Novartis. Dr Jørgensen reported receipt of personal fees from Celltrion, AOP Orphan Pharmaceuticals, and Norgine. Dr Gehin reported receipt of personal fees from Roche. Dr Michelsen reported receipt of personal fees from Novartis and grants from Novartis (paid to employer). Dr Dotterud reported receipt of personal fees from LEO Pharma. Dr Mørk reported receipt of personal fees from Novartis Norge, LEO Pharma, ACO Hud Norge, Celgene, AbbVie, Galderma Nordic, and UCB. Dr Kvien reported receipt of grants from AbbVie, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, and UCB and personal fees from AbbVie, Merck Sharp & Dohme, Hospira/Pfizer, Roche, UCB, Lilly, Hikma, Orion, Sanofi, Celltrion, Sandoz, Biogen, Amgen, Egis, Ewopharma, Mylan, EVA Pharma, and Gilead. Dr Bolstad reported receipt of personal fees from Roche, Janssen, and Novartis. Dr Haavardsholm reported receipt of personal fees from Pfizer, AbbVie, Celgene, Novartis, Janssen, Gilead, Lilly, and UCB. No other disclosures were reported.

Funding/Support: The study was funded by grants from the Norwegian Regional Health Authorities (interregional KLINBEFORSK grants) and the South-Eastern Norway Regional Health Authorities. The sponsor of the study was Diakonhjemmet Hospital.

Role of the Funder/Sponsor: Neither the funder of the study (the Regional Health Authorities) nor the sponsor (Diakonhjemmet Hospital) had any role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication. Neither the funder nor the sponsor had any right to veto publication or to control the decision regarding to which journal the manuscript was submitted. All drafts of the manuscript were prepared by the authors. All authors approved the final submitted version.

Data Sharing Statement: See Supplement 3.

Additional Contributions: We acknowledge the patient representatives, Jon Hagfors (Norwegian Rheumatism Association), Bjørn Gulbrandsen (Norwegian IBD Patient Organization), and Hilde Mellum (Psoriasis and Eczema Association of Norway), for their contributions during planning and conduct of the study. We acknowledge the members of the scientific advisory board, Josef Smolen, MD, PhD (University of Vienna), Alejandro C. Balsa, MD, PhD (University Hospital La Paz, Madrid), Geert D’Haens, MD, PhD (Amsterdam Academic Medical Center), Jørn Brynskov, MD, PhD (University of Copenhagen Herlev Hospital), Knut E. A. Lundin, MD, PhD (University of Oslo), and Diamant Thaci, MD, PhD (University of Lubeck). No compensation was received for their contributions to the protocol. We acknowledge Cecilie Moe, Bjørn Solvang, Nina Flatner, Trond Smedsrud, and Marius Eid, Department of Research Support for Clinical Trials at Oslo University Hospital, and Anja Bye, Clinical Research Unit Central Norway, for research support and data management (received compensation for their work).

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