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Professor Jimmy Limdi – Consultant Gastroenterologist and Head of the Section for IBD, Deputy Director for Research and Innovation at the Northern Care Alliance NHS Foundation Trust and Professor of Gastroenterology at the University of Manchester and Manchester Metropolitan University.

The medical management of Inflammatory bowel disease (IBD) has advanced dramatically in the last decade to include biological agents, but not every patient responds to therapy in the same way. In this blog, Professor Jimmy Limdi – Consultant Gastroenterologist and Head of the Section for IBD, Deputy Director for Research and Innovation at the Northern Care Alliance NHS Foundation Trust and Professor of Gastroenterology at the University of Manchester and Manchester Metropolitan University – discusses the proactive use of therapeutic drug monitoring (TDM) to aid clinical decision making and optimise patient responses to therapy.

Digesting the facts

Gastrointestinal disorders are becoming a global healthcare issue with continually increasing incidence and wide-reaching implications.1 In the UK alone, approximately 300,000 people have a diagnosis of IBD, a prevalence equating to 1 in every 210 individuals. Symptoms can be relatively mild or completely debilitating but, despite the prevalence and potential severity of Crohn’s disease (CD) and ulcerative colitis (UC), researchers have not yet been able to pin down the exact cause of these conditions.2,3 What we do know about the aetiology of IBD is that it is multifaceted, and scientists recognise several predisposing and precipitating characteristics – including genetics, immunology, an imbalance of gut bacteria, and diet and lifestyle – that may contribute to the onset of gastrointestinal symptoms. However, the heterogeneity of IBD mechanisms means that no universal cure for these diseases exists. Instead, the aim of most IBD treatments is to tackle inflammation and reduce the unpleasant effects of long-term gastrointestinal conditions.3

A medical minefield

A common IBD treatment method involves administering a biotherapeutic, a type of drug synthesised specifically to bind a particular molecular target in the immune system. For example, infliximab (IFX) – the most widely used biologic for both CD and UC – inhibits the proinflammatory cytokine tumour necrosis factor alpha (TNF-alpha), while other biologics bind different inflammatory mediators like integrins and interleukins.4 Biologics and biosimilars – more affordable biological medicines with a highly similar structure, function and efficacy to originator biologics – offer a distinct advantage over systemic small-molecule anti-inflammatories due to their direct mode of action. 5,6 However, every patient is unique, and individual responses to biotherapeutics can range from relatively rapid remission to a complete lack of response (LOR).

A poor response to a biological medicine may be the result of administering a drug with the wrong therapeutic mechanism or prescribing a subtherapeutic dose. On the other hand, a patient may develop a humoral immune response, which can lead to the formation of antidrug antibodies (ADAs) and subsequent loss of drug efficacy. This is fairly common; up to 30 per cent of patients treated with anti-TNF drugs will fail to respond at all, while as many as half of the patients who do see an initial response will experience a reduction in therapeutic effectiveness over time.7 Steps can be taken to counteract treatment failure, such as combination therapy with an immunomodulator, but this often causes unpleasant side effects like nausea, as well as increased risk of infections and malignancies. Ongoing monitoring of treatment progress is a more reliable way to tailor treatment to the patient’s unique needs.

Food for thought

Truly personalised IBD treatment relies on the analysis of a patient’s bloodstream drug levels and ADAs, which informs clinicians about disease progression and drug responses. TDM is used by as many as 96.6 per cent of gastroenterologists to direct care when a patient fails to respond adequately to a biological agent.7 A reactive approach can help clinicians tailor therapy to the patient; low drug levels but no antibodies may indicate a need for a higher treatment dose, while low drug levels and high ADA levels may direct clinicians to administer a different biologic or add immunosuppressants to the treatment regime.8 However, preliminary data suggests that proactive TDM might be associated with better therapeutic outcomes than empirical dose optimisation and reactive TDM,9-16 promoting higher rates of mucosal healing, preventing IBD-related surgeries and reducing unfavourable outcomes, including IBD-related hospitalisation and treatment failure.8,17 Unfortunately, only 54 per cent of clinicians currently take advantage of proactive TDM, as it is a relatively recent addition to the standard of care of IBD, and knowledge about its use in the field is limited.7

Pre-empting the future

While many clinicians are hesitant to put proactive TDM into practice, gastroenterologists within the Northern Care Alliance NHS Foundation Trust have embraced its potential to optimise IBD management. The trust outsources analysis of serum and plasma samples to national reference laboratories, where enzyme linked immunosorbent assays (ELISAs) – such as BIOHIT IDKmonitor® assays – are used to assess circulating drug levels and total ADAs. Looking to the future, improved access to testing services and clinical decision aids will soon improve the efficiency of this process, enabling remote monitoring of IBD patients and optimisation of drug dosages in real time,17 and making proactive TDM more accessible to clinicians worldwide. Used together, reactive and proactive TDM are valuable tools to aid IBD therapy, offering clinicians a way to maximise the effectiveness of biologics and enhance patient outcomes.

Summary

The individuality of patient responses to biological IBD therapies indicates a clear need for TDM practices to gain a clear understanding of disease progression and drug responses. However, although many gastroenterologists have welcomed TDM in a reactive setting, its proactive use is limited. Gastroenterologists working within the Northern Care Alliance NHS Foundation Trust rely on IDKmonitor® assays from BIOHIT to regularly monitor serum drug levels and ADAs in patients undergoing treatment, and have found it invaluable in preventing flare-ups, prolonging remission and optimising patient outcomes.

Find out more about BIOHIT’s IDKmonitor® kits.

Read about the experience of Dr Christian Selinger in our next blog, Personalising IBD treatment for better patient outcomes, which strengthens the case for implementing proactive TDM during IBD management.

References

  1. Zhang, Y. and Li, Y. 2014. Inflammatory bowel disease: Pathogenesis. World Journal of Gastroenterology, 20(1):91. doi: 10.3748/wjg.v20.i1.91.
  2. 2020. St Marks Hospital Foundation. Available at: https://www.stmarkshospitalfoundation.org.uk/how-we-are-saving-lives-at-st-marks/statistics/.
  3. Graham, D.B. and Xavier, R.J. 2020. Pathway paradigms revealed from the genetics of inflammatory bowel disease. Nature, 578(7796):527–539. doi: 10.1038/s41586-020-2025-2.
  4. Carroll, M. 2021. Which biologics can help treat ulcerative colitis (UC)?. Healthline Media. Available at: https://www.healthline.com/health/ulcerative-colitis-take-control/beyond-the-biologic#integrin-receptor-antagonists.
  5. Buchner, A.M., Schneider, Y. and Lichtenstein, G.R. 2020. Biosimilars in inflammatory bowel disease. American Journal of Gastroenterology, 116(1):45–56. doi: 10.14309/ajg.0000000000000844.
  6. Ben-Horin, S. et al. Biosimilars in inflammatory bowel disease: Facts and fears of extrapolation. Clinical Gastroenterology and Hepatology, 14(12):1685–1696. doi: 10.1016/j.cgh.2016.05.023.
  7. Hendy, P., Hart, A. and Irving, P. 2015. Anti-TNF drug and antidrug antibody level monitoring in IBD: A practical guide. Frontline Gastroenterology, 7(2):122–128. doi: 10.1136/flgastro-2014-100527.
  8. Negoescu, D.M. et al. Proactive vs reactive therapeutic drug monitoring of infliximab in Crohn’s Disease: A cost-effectiveness analysis in a simulated cohort. Inflammatory Bowel Diseases, 26(1):103–111. doi: 10.1093/ibd/izz113.
  9. Syed, N. et al. Proactive drug monitoring is associated with higher persistence to infliximab and adalimumab treatment and lower healthcare utilization compared with reactive and clinical monitoring. Crohn’s Colitis 360, 2(3):otaa050. doi: 10.1093/crocol/otaa050.
  10. Papamichael, K. et al. Improved long-term outcomes of patients with inflammatory bowel disease receiving proactive compared with reactive monitoring of serum concentrations of infliximab. Clinical Gastroenterology and Hepatology, 15(10):1580-1588.e3. doi: 10.1016/j.cgh.2017.03.031.
  11. Vaughn, B.P. et al. Proactive therapeutic concentration monitoring of infliximab may improve outcomes for patients with inflammatory bowel disease. Inflammatory Bowel Diseases, 20(11):1996–2003. doi: 10.1097/mib.0000000000000156.
  12. Lyles, J.L. et al. Effect of a practice-wide anti-TNF proactive therapeutic drug monitoring program on outcomes in pediatric patients with inflammatory bowel disease. Inflammatory Bowel Diseases, 27(4):482–492. doi: 10.1093/ibd/izaa102.
  13. Assa, A. et al. Proactive monitoring of adalimumab trough concentration associated with increased clinical remission in children with Crohn’s disease compared with reactive monitoring. Gastroenterology, 157(4). doi: 10.1053/j.gastro.2019.06.003.
  14. Sánchez‐Hernández, J.G. et al. A 3‐year prospective study of a multidisciplinary early proactive therapeutic drug monitoring programme of infliximab treatments in inflammatory bowel disease. British Journal of Clinical Pharmacology, 86(6):1165–1175. doi: 10.1111/bcp.14229.
  15. Papamichael, K. et al. Proactive therapeutic drug monitoring of adalimumab is associated with better long-term outcomes compared with standard of care in patients with inflammatory bowel disease. Journal of Crohn’s and Colitis, 13(8):976–981. doi: 10.1093/ecco-jcc/jjz018.
  16. Papamichael, K. et al. Proactive infliximab monitoring following reactive testing is associated with better clinical outcomes than reactive testing alone in patients with inflammatory bowel disease. Journal of Crohn’s and Colitis, 12(7):804–810. doi: 10.1093/ecco-jcc/jjy039.
  17. Proactive TDM may lead to better outcomes in IBD compared with reactive TDM. Gastroenterology Advisor. Available at: https://www.gastroenterologyadvisor.com/inflammatory-bowel-diseases-ibd/proactive-tdm-may-lead-to-better-outcomes-in-ibd-compared-with-reactive-tdm/.