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Predicting outcomes for Crohn's disease using a molecular biomarker: profile trial

Nurulamin Noor, Biljana Brezina, Juan De La Revilla Negro, Francis Dowling, Simon Bond, Lynne Whitehead, Jacinta Lee, Paul Lyons, Eoin McKinney, Kenneth Smith, James Lee and Miles Parkes
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DOI: https://doi.org/10.7861/clinmed.22-4-s22
Clin Med July 2022
Nurulamin Noor
ACambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Biljana Brezina
ACambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Juan De La Revilla Negro
ACambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Francis Dowling
BCambridge Clinical Trials Unit, Cambridge, UK
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Simon Bond
BCambridge Clinical Trials Unit, Cambridge, UK
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Lynne Whitehead
ACambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Jacinta Lee
CUniversity of Cambridge School of Clinical Medicine, Cambridge, UK
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Paul Lyons
CUniversity of Cambridge School of Clinical Medicine, Cambridge, UK
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Eoin McKinney
CUniversity of Cambridge School of Clinical Medicine, Cambridge, UK
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Kenneth Smith
CUniversity of Cambridge School of Clinical Medicine, Cambridge, UK
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James Lee
DThe Francis Crick Institute, London, UK
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Miles Parkes
ACambridge University Hospitals NHS Foundation Trust, Cambridge, UK
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Introduction

Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), collectively affect 0.8% of the population in the UK.1 IBD can have a profound health and socio-economic impact on patients, typically affecting educational achievement, relationships and employment.1 However, the course of IBD varies substantially between individuals and accurate prognostic markers have historically not been available to guide clinical practice.3 It has, therefore, become widely recognised that no single treatment strategy would be optimal for all patients.4 Accordingly, there has been an aspiration for a more personalised approach in IBD, being named one of the key research priorities by a research priority-setting partnership group, which included patients, clinicians and other key stakeholders.5,6

Previously, our group has described a transcriptional signature detectable within peripheral blood CD8 T-cells at diagnosis, identifying two subgroups of patients, correlating with subsequent disease course.7,8 We have sought to develop a biomarker that could re-capitulate the previously identified prognostic CD8 subgroups and then assess whether such a biomarker could improve clinical outcomes by appropriately matching therapy to disease course for individual patients.

Methods

From a training cohort of 69 newly diagnosed IBD patients, we simultaneously obtained a whole-blood PAXgene® RNA tube and peripheral-blood CD8 T-cell sample. Gene expression in both samples was measured by microarray. Statistical modelling was used to identify a transcriptional classifier in whole-blood gene expression data re-capitulating the CD8 findings and optimised into a multi-gene qPCR assay with independent validation in a second, independent cohort of 123 newly diagnosed patients.

The PROFILE trial has incorporated this classifier to compare relative efficacy of ‘top-down’ and ‘accelerated step-up’ therapy between biomarker-defined subgroups of 400 patients with newly diagnosed Crohn's disease.9 PROFILE is assessing outcomes that have consistently been reported as important to patients: clinical remission and avoidance/reduction of steroids and surgery, as well as quality of life. Alongside the trial, a formal health economic analysis is being conducted, as well as a national evaluation by the National Institute for Health and Care Excellence (NICE). If clinical utility is demonstrated, then it is anticipated that this biomarker-stratified approach could be implemented into routine clinical care.

Results

Following application of statistical learning methods described, a 17-gene qPCR assay was developed and optimised. In the validation cohort, 123 patients could be classified into two distinct subgroups: IBDhi (high risk) and IBDlo (lower risk). Irrespective of the underlying diagnosis, IBDhi patients experienced significantly more aggressive disease than IBDlo patients, with earlier need for treatment escalation (hazard ratio 2.65 (CD) and 3.12 (UC)).10 Subsequently, this biomarker has been used to stratify therapy in the PROFILE trial (395 enrolled), where recruitment has completed and follow-up due for completion in December 2022.

Conclusion

We have developed, optimised and validated a whole-blood qPCR classifier that predicts disease course from diagnosis in patients with IBD. This classifier is currently being assessed in the PROFILE trial, the first biomarker-stratified trial in gastroenterology and, if clinical utility of a stratified treatment approach is demonstrated, this would represent a major step towards personalised therapy in IBD.

Funding statement

This trial is funded by the Wellcome Trust via an investment in PredictImmune (200448/Z/16/Z).

  • © Royal College of Physicians 2022. All rights reserved.

References

  1. ↵
    1. Jones GR
    , Lyons M, Plevris N, et al. IBD prevalence in Lothian, Scotland, derived by capture-recapture methodology. Gut 2019;68:1953–60.
    OpenUrlAbstract/FREE Full Text
    1. Lamb CA
    , Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut 2019;68:S1–106.
    OpenUrlCrossRef
  2. ↵
    1. Noor NM
    , Verstockt B, Parkes M, Lee JC. Personalised medicine in Crohn's disease. Lancet Gastroenterol Hepatol 2020;5:80–92.
    OpenUrl
  3. ↵
    1. Verstockt B
    , Noor NM, Marigorta UM, et al. Results of the Seventh Scientific Workshop of ECCO: Precision medicine in IBD - disease outcome and response to therapy. J Crohn's Colitis 2021;15:1431–42.
    OpenUrl
  4. ↵
    1. Noor NM
    , Sousa P, Paul S, Roblin X. Early Diagnosis, Early Stratification, and Early Intervention to Deliver Precision Medicine in IBD. Inflamm Bowel Dis 2021;izab228. [Epub ahead of print].
  5. ↵
    1. Hart AL
    , Lomer M, Verjee A, et al. What are the top 10 research questions in the treatment of inflammatory bowel disease? J Crohn's Colitis 2017;11:204–11.
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    1. McKinney EF
    , Lyons PA, Carr EJ, et al. A CD8+T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 2010;16:586–91.
    OpenUrlCrossRefPubMed
  7. ↵
    1. Lee JC
    , Lyons PA, McKinney EF, et al. Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest 2011;121:4170–9.
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  8. ↵
    1. Parkes M
    , Noor NM, Dowling F, et al. PRedicting Outcomes for Crohn's dIsease using a moLecular biomarkEr (PROFILE): Protocol for a multicentre, randomised, biomarker-stratified trial. BMJ Open 2018;8:e026767.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Biasci D
    , Lee JC, Noor NM, et al. A blood-based prognostic biomarker in IBD. Gut 2019;68:1386–95.
    OpenUrlAbstract/FREE Full Text
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Predicting outcomes for Crohn's disease using a molecular biomarker: profile trial
Nurulamin Noor, Biljana Brezina, Juan De La Revilla Negro, Francis Dowling, Simon Bond, Lynne Whitehead, Jacinta Lee, Paul Lyons, Eoin McKinney, Kenneth Smith, James Lee, Miles Parkes
Clinical Medicine Jul 2022, 22 (Suppl 4) 22-23; DOI: 10.7861/clinmed.22-4-s22

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Predicting outcomes for Crohn's disease using a molecular biomarker: profile trial
Nurulamin Noor, Biljana Brezina, Juan De La Revilla Negro, Francis Dowling, Simon Bond, Lynne Whitehead, Jacinta Lee, Paul Lyons, Eoin McKinney, Kenneth Smith, James Lee, Miles Parkes
Clinical Medicine Jul 2022, 22 (Suppl 4) 22-23; DOI: 10.7861/clinmed.22-4-s22
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