[Skip to Content]
[Skip to Content Landing]

Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory DiseasesA Randomized Clinical Trial

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

Question  Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, is proactive therapeutic drug monitoring (TDM) more effective than standard therapy to sustain disease control without disease worsening?

Findings  In this randomized clinical trial that included 458 patients, the proportion of patients with sustained disease control without disease worsening during 52 weeks of follow-up was 74% in the TDM group and 56% in the standard therapy group, a statistically significant difference.

Meaning  Proactive TDM compared with treatment without TDM during maintenance infliximab therapy was more likely to lead to sustained disease control over 52 weeks for patients with immune-mediated inflammatory diseases.

Abstract

Importance  Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy.

Objective  To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM.

Design, Setting, and Participants  Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020.

Interventions  Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230).

Main Outcome and Measures  The primary outcome was sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period.

Results  Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6% (95% CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively.

Conclusions and Relevance  Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach.

Trial Registration  ClinicalTrials.gov Identifier: NCT03074656

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 Credit(s)™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

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: November 9, 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, Jørgensen, and Goll contributed equally. Drs Jahnsen, Bolstad, and Haavardsholm contributed equally.

Concept and design: Syversen, Jørgensen, Goll, Sandanger, Sexton, Olsen, Gehin, Mørk, Kvien, Jahnsen, Bolstad, Haavardsholm.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Syversen, Jørgensen, Goll, Brun, Bjørlykke, Sexton, Gehin, Mørk, Kvien, Jahnsen, Bolstad.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Syversen, Brun, Bjørlykke, Sexton, Olsen, Haavardsholm.

Obtained funding: Syversen, Kvien, Bolstad, Haavardsholm.

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

Supervision: Syversen, Jørgensen, Goll, Brun, Sandanger, Bjørlykke, Sexton, Gehin, Noraberg, Bruun, Dotterud, Ljoså, Haugen, Njålla, Zettel, Ystrøm, Bragnes, Skorpe, Thune, Seeberg, Michelsen, Blomgren, Strand, Mielnik, Torp, Mørk, Kvien, Jahnsen, Bolstad, Haavardsholm.

Conflict of Interest Disclosures: Dr Syversen reported receipt of personal fees from Thermo Fisher. Dr Jørgensen reported receipt of personal fees from Bristol Myers Squibb, Roche, Celltrion, and Norgine. Dr Goll reported receipt of personal fees from AbbVie, Pfizer, Sandoz, Celltrion, Lilly, UCB, and Boehringer Ingelheim. Dr Dotterud reported receipt of personal fees from LEO Pharma. Dr Michelsen reported receipt of personal fees from Novartis and grants from Novartis paid to her employer. Dr Mørk reported receipt of personal fees from Novartis Norge, LEO Pharma, ACO Hud Norge, Cellgene, AbbVie, and Galderma Nordic. Dr Kvien reported receipt of grants from AbbVie, Amgen, Bristol Myers Squibb, Novartis, Pfizer, and UCB and personal fees from Amgen, Celltrion, Egis, Evapharma, Ewopharma, Gilead, Hikma, Mylan, Oktal, Pfizer, Sandoz, Sanofi, and UCB. 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: This 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 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.

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), 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).

Data Sharing Statement: See Supplement 3.

References
1.
Roda  G , Jharap  B , Neeraj  N , Colombel  JF .  Loss of response to anti-TNFs: definition, epidemiology, and management.   Clin Transl Gastroenterol. 2016;7(1):e135. doi:10.1038/ctg.2015.63PubMedGoogle Scholar
2.
Mourad  AI , Gniadecki  R .  Biologic drug survival in psoriasis: a systematic review and comparative meta-analysis.   Front Med (Lausanne). 2021;7:625755. doi:10.3389/fmed.2020.625755PubMedGoogle Scholar
3.
Movahedi  M , Hepworth  E , Mirza  R , Cesta  A , Larche  M , Bombardier  C .  Discontinuation of biologic therapy due to lack/loss of response and adverse events is similar between TNFi and non-TNFi class: results from a real-world rheumatoid arthritis cohort.   Semin Arthritis Rheum. 2020;50(5):915-922. doi:10.1016/j.semarthrit.2020.06.020PubMedGoogle ScholarCrossref
4.
Flurey  CA , Morris  M , Richards  P , Hughes  R , Hewlett  S .  It’s like a juggling act: rheumatoid arthritis patient perspectives on daily life and flare while on current treatment regimes.   Rheumatology (Oxford). 2014;53(4):696-703. doi:10.1093/rheumatology/ket416PubMedGoogle ScholarCrossref
5.
Markusse  IM , Dirven  L , Gerards  AH ,  et al.  Disease flares in rheumatoid arthritis are associated with joint damage progression and disability: 10-year results from the BEST study.   Arthritis Res Ther. 2015;17(1):232. doi:10.1186/s13075-015-0730-2PubMedGoogle ScholarCrossref
6.
Berg  DR , Colombel  JF , Ungaro  R .  The role of early biologic therapy in inflammatory bowel disease.   Inflamm Bowel Dis. 2019;25(12):1896-1905. doi:10.1093/ibd/izz059PubMedGoogle ScholarCrossref
7.
Adedokun  OJ , Sandborn  WJ , Feagan  BG ,  et al.  Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis.   Gastroenterology. 2014;147(6):1296-1307. doi:10.1053/j.gastro.2014.08.035PubMedGoogle ScholarCrossref
8.
Vande Casteele  N , Khanna  R , Levesque  BG ,  et al.  The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn’s disease.   Gut. 2015;64(10):1539-1545. doi:10.1136/gutjnl-2014-307883PubMedGoogle ScholarCrossref
9.
St Clair  EW , Wagner  CL , Fasanmade  AA ,  et al.  The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multicenter, randomized, double-blind, placebo-controlled trial.   Arthritis Rheum. 2002;46(6):1451-1459. doi:10.1002/art.10302PubMedGoogle ScholarCrossref
10.
Maneiro  JR , Salgado  E , Gomez-Reino  JJ .  Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated inflammatory conditions: systematic review and meta-analysis.   JAMA Intern Med. 2013;173(15):1416-1428. doi:10.1001/jamainternmed.2013.7430PubMedGoogle ScholarCrossref
11.
Papamichael  K , Cheifetz  AS , Melmed  GY ,  et al.  Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases.   Clin Gastroenterol Hepatol. 2019;17(9):1655-1668. doi:10.1016/j.cgh.2019.03.037PubMedGoogle ScholarCrossref
12.
Torres  J , Bonovas  S , Doherty  G ,  et al.  ECCO guidelines on therapeutics in Crohn’s disease: medical treatment.   J Crohns Colitis. 2020;14(1):4-22. doi:10.1093/ecco-jcc/jjz180PubMedGoogle ScholarCrossref
13.
Smolen  JS , Landewé  RBM , Bijlsma  JWJ ,  et al.  EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.   Ann Rheum Dis. 2020;79(6):685-699. doi:10.1136/annrheumdis-2019-216655PubMedGoogle ScholarCrossref
14.
Syversen  SW , Goll  GL , Jørgensen  KK ,  et al.  Therapeutic drug monitoring of infliximab compared to standard clinical treatment with infliximab: study protocol for a randomised, controlled, open, parallel-group, phase IV study (the NOR-DRUM study).   Trials. 2020;21(1):13. doi:10.1186/s13063-019-3734-4PubMedGoogle ScholarCrossref
15.
Syversen  SW , Goll  GL , Jørgensen  KK ,  et al.  Effect of therapeutic drug monitoring vs standard therapy during infliximab induction on disease remission in patients with chronic immune-mediated inflammatory diseases: a randomized clinical trial.   JAMA. 2021;325(17):1744-1754. doi:10.1001/jama.2021.4172PubMedGoogle ScholarCrossref
16.
World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053PubMedGoogle ScholarCrossref
17.
Jørgensen  KK , Olsen  IC , Goll  GL ,  et al; NOR-SWITCH Study Group.  Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial.   Lancet. 2017;389(10086):2304-2316. doi:10.1016/S0140-6736(17)30068-5PubMedGoogle ScholarCrossref
18.
Prevoo  ML , van ’t Hof  MA , Kuper  HH , van Leeuwen  MA , van de Putte  LB , van Riel  PL .  Modified disease activity scores that include twenty-eight-joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis.   Arthritis Rheum. 1995;38(1):44-48. doi:10.1002/art.1780380107PubMedGoogle ScholarCrossref
19.
England  BR , Tiong  BK , Bergman  MJ ,  et al.  2019 Update of the American College of Rheumatology recommended rheumatoid arthritis disease activity measures.   Arthritis Care Res (Hoboken). 2019;71(12):1540-1555. doi:10.1002/acr.24042PubMedGoogle ScholarCrossref
20.
Lukas  C , Landewé  R , Sieper  J ,  et al; Assessment of Spondyloarthritis International Society.  Development of an ASAS-endorsed disease activity score (ASDAS) in patients with ankylosing spondylitis.   Ann Rheum Dis. 2009;68(1):18-24. doi:10.1136/ard.2008.094870PubMedGoogle ScholarCrossref
21.
Machado  P , Landewé  R , Lie  E ,  et al; Assessment of Spondyloarthritis International Society.  Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores.   Ann Rheum Dis. 2011;70(1):47-53. doi:10.1136/ard.2010.138594PubMedGoogle ScholarCrossref
22.
Lewis  JD , Chuai  S , Nessel  L , Lichtenstein  GR , Aberra  FN , Ellenberg  JH .  Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis.   Inflamm Bowel Dis. 2008;14(12):1660-1666. doi:10.1002/ibd.20520PubMedGoogle ScholarCrossref
23.
Harvey  RF , Bradshaw  JM .  A simple index of Crohn’s-disease activity.   Lancet. 1980;1(8167):514. doi:10.1016/s0140-6736(80)92767-1PubMedGoogle ScholarCrossref
24.
Vermeire  S , Schreiber  S , Sandborn  WJ , Dubois  C , Rutgeerts  P .  Correlation between the Crohn’s disease activity and Harvey-Bradshaw indices in assessing Crohn’s disease severity.   Clin Gastroenterol Hepatol. 2010;8(4):357-363. doi:10.1016/j.cgh.2010.01.001PubMedGoogle ScholarCrossref
25.
Fredriksson  T , Pettersson  U .  Severe psoriasis—oral therapy with a new retinoid.   Dermatologica. 1978;157(4):238-244. doi:10.1159/000250839PubMedGoogle ScholarCrossref
26.
Turner  D , Ricciuto  A , Lewis  A ,  et al; International Organization for the Study of IBD.  STRIDE-II: an update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of IBD (IOIBD): determining therapeutic goals for treat-to-target strategies in IBD.   Gastroenterology. 2021;160(5):1570-1583. doi:10.1053/j.gastro.2020.12.031PubMedGoogle ScholarCrossref
27.
Papamichael  K , Van Stappen  T , Vande Casteele  N ,  et al.  Infliximab concentration thresholds during induction therapy are associated with short-term mucosal healing in patients with ulcerative colitis.   Clin Gastroenterol Hepatol. 2016;14(4):543-549. doi:10.1016/j.cgh.2015.11.014PubMedGoogle ScholarCrossref
28.
Vande Casteele  N , Ferrante  M , Van Assche  G ,  et al.  Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease.   Gastroenterology. 2015;148(7):1320-1329. doi:10.1053/j.gastro.2015.02.031PubMedGoogle ScholarCrossref
29.
Kleinman  LC , Norton  EC .  What’s the risk? a simple approach for estimating adjusted risk measures from nonlinear models including logistic regression.   Health Serv Res. 2009;44(1):288-302. doi:10.1111/j.1475-6773.2008.00900.xPubMedGoogle ScholarCrossref
30.
Fernandes  SR , Bernardo  S , Simões  C ,  et al.  Proactive infliximab drug monitoring is superior to conventional management in inflammatory bowel disease.   Inflamm Bowel Dis. 2020;26(2):263-270. doi:10.1093/ibd/izz131PubMedGoogle ScholarCrossref
31.
Papamichael  K , Chachu  KA , Vajravelu  RK ,  et al.  Improved long-term outcomes of patients with inflammatory bowel disease receiving proactive compared with reactive monitoring of serum concentrations of infliximab.   Clin Gastroenterol Hepatol. 2017;15(10):1580-1588. doi:10.1016/j.cgh.2017.03.031PubMedGoogle ScholarCrossref
32.
D’Haens  G , Vermeire  S , Lambrecht  G ,  et al; GETAID.  Increasing infliximab dose based on symptoms, biomarkers, and serum drug concentrations does not increase clinical, endoscopic, and corticosteroid-free remission in patients with active luminal Crohn’s disease.   Gastroenterology. 2018;154(5):1343-1351. doi:10.1053/j.gastro.2018.01.004PubMedGoogle ScholarCrossref
33.
Curtis  JR , Ogdie  A , George  MD .  Treatment strategies for patients with immune-mediated inflammatory diseases.   JAMA. 2021;325(17):1726-1728. doi:10.1001/jama.2021.2740PubMedGoogle ScholarCrossref
34.
Feuerstein  JD , Nguyen  GC , Kupfer  SS , Falck-Ytter  Y , Singh  S ; American Gastroenterological Association Institute Clinical Guidelines Committee.  American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease.   Gastroenterology. 2017;153(3):827-834. doi:10.1053/j.gastro.2017.07.032PubMedGoogle ScholarCrossref
35.
Mrowietz  U , Kragballe  K , Reich  K ,  et al.  Definition of treatment goals for moderate to severe psoriasis: a European consensus.   Arch Dermatol Res. 2011;303(1):1-10. doi:10.1007/s00403-010-1080-1PubMedGoogle ScholarCrossref
36.
Berth-Jones  J , Grotzinger  K , Rainville  C ,  et al.  A study examining inter- and intrarater reliability of three scales for measuring severity of psoriasis: Psoriasis Area and Severity Index, Physician’s Global Assessment and Lattice System Physician’s Global Assessment.   Br J Dermatol. 2006;155(4):707-713. doi:10.1111/j.1365-2133.2006.07389.xPubMedGoogle ScholarCrossref
37.
D’Haens  G , Sandborn  WJ , Feagan  BG ,  et al.  A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis.   Gastroenterology. 2007;132(2):763-786. doi:10.1053/j.gastro.2006.12.038PubMedGoogle ScholarCrossref
38.
Lamb  CA , Kennedy  NA , Raine  T ,  et al; IBD Guidelines eDelphi Consensus Group.  British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults.   Gut. 2019;68(suppl 3):s1-s106. doi:10.1136/gutjnl-2019-318484PubMedGoogle ScholarCrossref
39.
Mitrev  N , Vande Casteele  N , Seow  CH ,  et al; IBD Sydney Organisation and Australian Inflammatory Bowel Diseases Consensus Working Group.  Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases.   Aliment Pharmacol Ther. 2017;46(11-12):1037-1053. doi:10.1111/apt.14368PubMedGoogle ScholarCrossref
40.
Takeuchi  T , Miyasaka  N , Inoue  K , Abe  T , Koike  T ; RISING Study.  Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING Study.   Mod Rheumatol. 2009;19(5):478-487. doi:10.3109/s10165-009-0195-8PubMedGoogle ScholarCrossref
AMA CME Accreditation Information

Credit Designation Statement: The American Medical Association designates this Journal-based CME activity activity for a maximum of 1.00  AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to:

  • 1.00 Medical Knowledge MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program;;
  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
Want full access to the AMA Ed Hub?
After you sign up for AMA Membership, make sure you sign in or create a Physician account with the AMA in order to access all learning activities on the AMA Ed Hub
Buy this activity
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Close
Close

Lookup An Activity

or

My Saved Searches

You currently have no searches saved.

Close

My Saved Courses

You currently have no courses saved.

Close