Skip to main content

Advertisement

SpringerLink
Log in

Ustekinumab Serum Trough Levels May Identify Suboptimal Responders to Ustekinumab in Crohn’s Disease

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Introduction

The aim of this study was to evaluate the association between serum ustekinumab (UST) trough levels and response to induction and maintenance UST treatment in refractory Crohn’s Disease (CD) patients.

Methods

We performed a prospective study including CD patients who received UST from September 2015 to January 2017. Patients received 90 mg of UST subcutaneously at weeks 0, 4, and 12, then every 8 weeks. Two cohorts of patients were analyzed: an induction cohort and a maintenance cohort. We evaluated clinical, biological, and imaging/endoscopic response to UST treatment. UST trough levels and anti-UST antibodies were dosed at weeks 12 and 28 in the induction cohort, and at a single time point in the maintenance cohort.

Results

Forty-nine patients were enrolled in the maintenance cohort. Mean concentrations of UST were 1.88 ± 1.40 µg/mL. UST trough levels were not significantly different in patients with or without clinical, biological, or imaging/endoscopic responses to UST treatment (p > 0.11). Twenty-three consecutive patients were included in the induction cohort. At week 12, mean UST concentrations were 1.45 ± 1.15 µg/mL. Patients with a biological response to UST treatment had significant higher serum UST trough concentration (median 1.72 µg/mL) than non-responders (median 0.56 µg/mL, p = 0.02). A UST trough level ≥ 1.10 µg/mL at week 12 was associated with a biological response to UST treatment at 6 months.

Conclusion

UST trough levels were associated with a biological response at the end of the induction phase. In patients with low levels of UST, optimization treatment may be necessary to obtain a sustained response.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

UST:

Ustekinumab

CD:

Crohn’s disease

IBD:

Inflammatory bowel disease

TNF:

Tumor necrosis factor

IFX:

Infliximab

ADA:

Adalimumab

HBI:

Harvey–Bradshaw index

PGA:

Physician global assessment

CRP:

C-reactive protein

MRI:

Magnetic resonance imaging

ELISA:

Enzyme-linked immunosorbent assay

ROC:

Receiver operating characteristic

IQR:

Interquartile range

References

  1. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet Lond Engl. 2012;380:1590–1605.

    Article  Google Scholar 

  2. Peyrin-Biroulet L, Loftus EV, Colombel J-F, Sandborn WJ. The natural history of adult Crohn’s disease in population-based cohorts. Am J Gastroenterol. 2010;105:289–297.

    Article  Google Scholar 

  3. Colombel J-F, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial. Gastroenterology. 2007;132:52–65.

    Article  CAS  Google Scholar 

  4. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet Lond Engl. 2002;359:1541–1549.

    Article  CAS  Google Scholar 

  5. Yanai H, Hanauer SB. Assessing response and loss of response to biological therapies in IBD. Am J Gastroenterol. 2011;106:685–698.

    Article  CAS  Google Scholar 

  6. Peluso I, Pallone F, Monteleone G. Interleukin-12 and Th1 immune response in Crohn’s disease: pathogenetic relevance and therapeutic implication. World J Gastroenterol. 2006;12:5606–5610.

    Article  CAS  Google Scholar 

  7. Neurath MF. IL-23: a master regulator in Crohn disease. Nat Med. 2007;13:26–28.

    Article  CAS  Google Scholar 

  8. Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2016;375:1946–1960.

    Article  CAS  Google Scholar 

  9. Wils P, Bouhnik Y, Michetti P, et al. Long-term efficacy and safety of ustekinumab in 122 refractory Crohn’s disease patients: a multicentre experience. Aliment Pharmacol Ther. 2018;47:588–595.

    Article  CAS  Google Scholar 

  10. Wils P, Bouhnik Y, Michetti P, et al. Subcutaneous ustekinumab provides clinical benefit for two-thirds of patients with Crohn’s disease refractory to anti-tumor necrosis factor agents. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2016;14:242–250.e1-2.

    CAS  Google Scholar 

  11. Ma C, Fedorak RN, Kaplan GG, et al. Clinical, endoscopic and radiographic outcomes with ustekinumab in medically-refractory Crohn’s disease: real world experience from a multicentre cohort. Aliment Pharmacol Ther. 2017;45:1232–1243.

    Article  CAS  Google Scholar 

  12. Kopylov U, Afif W, Cohen A, et al. Subcutaneous ustekinumab for the treatment of anti-TNF resistant Crohn’s disease—the McGill experience. J Crohns Colitis. 2014;8:1516–1522.

    Article  CAS  Google Scholar 

  13. Vande Casteele N, Herfarth H, Katz J, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases. Gastroenterology. 2017;153:835–857.e6.

    Article  Google Scholar 

  14. Verstockt B, Moors G, Bian S, et al. Influence of early adalimumab serum levels on immunogenicity and long-term outcome of anti-TNF naive Crohn’s disease patients: the usefulness of rapid testing. Aliment Pharmacol Ther. 2018;48:731–739.

    Article  CAS  Google Scholar 

  15. Roblin X, Rinaudo M, Sparrow MP, et al. Pharmacokinetics in IBD: ready for prime time? Curr Drug Targets. 2014;15:1049–1055.

    Article  CAS  Google Scholar 

  16. Mitrev N, Vande Casteele N, Seow CH, et al. Review article: consensus statements on therapeutic drug monitoring of anti-tumour necrosis factor therapy in inflammatory bowel diseases. Aliment Pharmacol Ther. 2017;46:1037–1053.

    Article  CAS  Google Scholar 

  17. Peyrin-Biroulet L, Bouhnik Y, Roblin X, et al. French national consensus clinical guidelines for the management of Crohn’s disease. Dig Liver Dis Off J Ital Soc Gastroenterol Ital Assoc Study Liver. 2017;49:368–377.

    Google Scholar 

  18. Roblin X, Rinaudo M, Del Tedesco E, et al. Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases. Am J Gastroenterol. 2014;109:1250–1256.

    Article  CAS  Google Scholar 

  19. Sandborn WJ, Feagan BG, Fedorak RN, et al. A randomized trial of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with moderate-to-severe Crohn’s disease. Gastroenterology. 2008;135:1130–1141.

    Article  CAS  Google Scholar 

  20. Sandborn WJ, Gasink C, Gao L-L, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J Med. 2012;367:1519–1528.

    Article  CAS  Google Scholar 

  21. Battat R, Kopylov U, Bessissow T, et al. Association between ustekinumab trough concentrations and clinical, biomarker, and endoscopic outcomes in patients with Crohn’s disease. Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2017;15:1427–1434.e2.

    CAS  Google Scholar 

  22. Adedokun OJ, Xu Z, Gasink C, et al. Pharmacokinetics and exposure response relationships of ustekinumab in patients with Crohn’s disease. Gastroenterology. 2018;154:1660–1671.

    Article  CAS  Google Scholar 

  23. Menting SP, van den Reek JMPA, Baerveldt EM, et al. The correlation of clinical efficacy, serum trough levels and antidrug antibodies in ustekinumab-treated patients with psoriasis in a clinical-practice setting. Br J Dermatol. 2015;173:855–857.

    Article  CAS  Google Scholar 

  24. Harris KA, Horst S, Gadani A, et al. Patients with refractory Crohn’s disease successfully treated with ustekinumab. Inflamm Bowel Dis. 2016;22:397–401.

    Article  Google Scholar 

  25. Menter A, Papp KA, Gooderham M, et al. Drug survival of biologic therapy in a large, disease-based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). J Eur Acad Dermatol Venereol JEADV. 2016;30:1148–1158.

    Article  CAS  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Gastroenterology Department, CHRU Lille, Université Lille, Lille, France

    Claire Painchart, Maria Nachury, Pierre Desreumaux, Julien Branche, Romain Gérard, Clémentine Lauriot Dit Prevost, Pauline Wils, Thomas Lambin & Benjamin Pariente

  2. Immunology Laboratory, CHRU Lille, Université Lille, Lille, France

    Séverine Brabant & Myriam Labalette

  3. Gastroenterology Department, CHR Roubaix, Roubaix, France

    Nicolas Duveau

  4. Inserm Unit 995, Lille, France

    Pierre Desreumaux & Benjamin Pariente

  5. Gastroenterology Department, CHR Valenciennes, Valenciennes, France

    Médina Boualit

Authors
  1. Claire Painchart
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Séverine Brabant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nicolas Duveau
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria Nachury
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pierre Desreumaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Julien Branche
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Romain Gérard
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Clémentine Lauriot Dit Prevost
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pauline Wils
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Thomas Lambin
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Médina Boualit
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Myriam Labalette
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Benjamin Pariente
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CP and BP conceived and designed the study, interpreted the data, drafted the manuscript, and supervised the study. CP, BP and ND gave administrative, technical, or material support. All authors took part in data acquisition, critical revision of the manuscript for important intellectual content, and approval of the final version.

Corresponding author

Correspondence to Benjamin Pariente.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Fig.

 1: Serum UST trough levels at the end of the induction phase (week 12) in the induction cohort according to the clinical response to UST treatment. Boxplot of serum UST trough levels in patients with (left box) or without (right box) clinical response to UST therapy at week 12. The box represents the 25th–75th percentiles, and the whiskers correspond to the 5th–95th percentiles. W. Abbreviations: UST, ustekinumab (TIFF 48 kb)

Supplementary material 2 (DOCX 16 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Painchart, C., Brabant, S., Duveau, N. et al. Ustekinumab Serum Trough Levels May Identify Suboptimal Responders to Ustekinumab in Crohn’s Disease. Dig Dis Sci 65, 1445–1452 (2020). https://doi.org/10.1007/s10620-019-05865-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-019-05865-3

Keywords

Search

Navigation