Is it possible to predict treatment failure in IBD?

July 5, 2023

The use of tumour necrosis factor-α antagonists (anti-TNFs) to treat inflammatory bowel disease (IBD) continues to be refined.1 Although popular biopharmaceuticals – such as infliximab and adalimumab – induce a clinical response in up to 85 per cent of IBD patients, the risk of primary unresponsiveness or secondary loss of response (LOR) to these therapies remains a prevalent issue.2 As a result, there is ongoing research to understand the complexities of the pharmacokinetics and pharmacodynamics of these biological medications.1

One of the main gaps in our knowledge when it comes to IBD management is the inability to predict which biologic will be most effective for which patient. Current therapeutic approaches involve exposing patients to multiple medicines, one by one, until an effective treatment regime is discovered.3 Unfortunately, this tactic is time consuming and costly, and puts patients at risk for harmful drug-related side effects. As a result, there is a call for biomarkers that can guide clinical decision-making for biologic selection, helping to predict disease course and response to therapy.1

In our previous blogs, titled Personalising IBD treatment for better patient outcomes and A proactive approach to take control of IBD, we highlighted the potential of therapeutic drug monitoring (TDM) for detecting drug responsiveness in real time and directing IBD management. In this blog, we go one step further, summarising novel findings about a new biomarker – oncostatin M (OSM) – that holds huge potential for predicting anti-TNF treatment failure in IBD and supporting clinicians in selecting an appropriate and effective treatment plan on a patient-specific basis.4

Identifying therapeutic targets in IBD

IBD is a complex inflammatory disorder with multifaceted aetiology; genetic predisposition, environmental triggers, disruption of the gut microbiome and a dysregulated immune response are all thought to be involved in its onset.5 Many proposed therapeutics for IBD aim to reduce the immune imbalances that can lead to gastrointestinal symptoms, and TNF inhibitors are now a firmly established treatment for the condition. Several additional pro-inflammatory cytokines involved in orchestrating intestinal inflammation during the disease – including interferon-γ (IFN-γ), interleukin-6 (IL-6) and IL-17A – have also been targeted in clinical trials, but inhibiting their effects has generally resulted in negligible efficacy or adverse side effects.6 Researchers have recently turned their attention to OSM, a cytokine with a role that – until recently – remained a mystery in IBD. While a single-nucleotide polymorphism in the human OSM locus has been strongly associated with an increased risk of developing IBD,6 early studies in mouse models and human subjects revealed varying effects of the cytokine in different IBD phenotypes and stages of disease progression.4

An enigmatic cytokine

OSM is a member of the IL-6 cytokine family, and is produced by cells of hematopoietic origin, particularly type 1 T-helper (Th1) cells.1,4 Although the cytokine was originally identified in the late 1980s7 – when it was found to inhibit the development of certain human melanoma cells and other tumour cells, but promote the growth of normal fibroblasts – there is still a considerable amount that is not clear about its biology, in vivo functions and role in IBD.8

In certain cases, OSM is known to have anti-inflammatory effects, supporting haemostatic processes such as haematopoiesis, bone remodelling, cardiac tissue remodelling and liver regeneration.1 On the other hand, its overexpression can promote a variety of pathogenic processes and inflammatory conditions, including rheumatoid arthritis and several forms of cancer.1,4 Fortunately, potentially groundbreaking research has been conducted in recent years to investigate the role and significance of the OSM cytokine in IBD.

The predictive power of OSM expression

In 2017, West et al. conducted an in-depth study to characterise differences in OSM expression in human IBD patients compared to healthy individuals, and to identify whether overexpression of the protein was responsible for heightened intestinal inflammation in mouse models.6 Their findings included:

  • OSM is the most transcriptionally upregulated cytokine in the inflamed intestinal mucosa of Crohn’s disease (CD) patients, and one of the most upregulated cytokines in the stromal cells of ulcerative colitis (UC) patients;
  • upregulation of OSM coincides with increased expression of the OSM receptor (OSMR);
  • cytokine-receptor interactions promote inflammatory activity in the intestinal stroma, and result in the production of various pro-inflammatory molecules, including chemokines, cytokines and adhesion factors;
  • high pre-treatment intestinal OSM expression is strongly associated with drug resistance, including anti-TNF therapy failure; and
  • genetic deletion or pharmacological blockade of OSM during anti-TNF resistant IBD significantly attenuates inflammation in mouse models.6

This initial research revealed the potential predictive power of mucosal OSM expression for determining disease severity, as well as candidacy for anti-TNF therapy.4,6 However, collecting and analysing intestinal biopsies may not always be possible in a clinical setting, and additional studies have therefore been conducted to investigate the relationship between serum OSM concentrations and treatment outcomes. While preliminary small-scale research revealed conflicting results,9,10,11 Guo et al. used a large retrospective cohort study design to demonstrate an association between high OSM plasma concentrations and a lack of clinical remission in both CD and UC.1 These findings have been reinforced by similar results of numerous other studies investigating serum biomarkers.

What does the future hold for OSM-guided IBD treatment?

A large body of research currently demonstrates the role of OSM in IBD onset and progression, and its use as a serum biomarker for predicting treatment responses. Additionally, more recent evidence points to the effectiveness of OSM when used as biomarker in stool samples – alongside faecal calprotectin – for the diagnosis, monitoring and prediction of anti-TNF treatment response.12 However, there is still a lot that we do not know about the specific functions and significance of OSM in managing IBD, and research in this field is ongoing. Further investigations are required to better understand OSM expression and use as a prognostic indicator in different patient demographics – such as among paediatric populations13 – and in different disease phenotypes and sample types.

The IDK® Oncostatin M ELISA can be used to determine the level of OSM in serum, plasma and stool, offering a tool to help clinicians plan and optimise therapy in a patient-centred manner.

To find out more, visit:

www.biohithealthcare.co.uk/biohit-product/oncostatin-m-elisa-idk/

References

  1. Guo, A. et al. 2022. High Oncostatin M predicts lack of clinical remission for patients with inflammatory bowel disease on tumor necrosis factor α antagonists. Scientific Reports, 12(1):1185. doi:10.1038/s41598-022-05208-9.
  2. Selinger, C.P. et al. 2017. Infliximab Therapeutic Drug Monitoring Changes Clinical Decisions in a Virtual Biologics Clinic for Inflammatory Bowel Disease. Inflamm Bowel Dis. 23(12):2083-2088. doi:10.1097/MIB.0000000000001258.
  3. Rubin, D.T. et al. 2014. Real-world assessment of therapy changes, suboptimal treatment and associated costs in patients with ulcerative colitis or Crohn’s disease. Aliment Pharmacol. Ther. 39(10):1143-1155.
  4. Kim, W.M. et al. 2017. A role for oncostatin M in inflammatory bowel disease. Nature Medicine, 23(5):535-536. doi:10.1038/nm.4338.
  5. 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.
  6. West, N.R. et al. 2017. Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease. Nature Medicine, 23(5):579-589. doi:10.1038/nm.4307.
  7. Zarling, J.M. et al. 1986. Oncostatin M: A growth regulator produced by differentiated histiocytic lymphoma cells. Proceedings of the National Academy of Sciences, 83(24):9739-9743. doi:10.1073/pnas.83.24.9739.
  8. Richards, C.D. 2013. The enigmatic cytokine oncostatin M and roles in disease. ISRN Inflammation, 1-23. doi:10.1155/2013/512103.
  9. Bertani, L. et al. 2020. Serum oncostatin M at baseline predicts mucosal healing in Crohn’s disease patients treated with infiximab. Aliment Pharmacol Ther, 52(2):284-291. doi:10.1111/apt.15870.
  10. Minar, P. et al. Elevated pretreatment plasma oncostatin M is associated with poor biochemical response to infiximab. Crohn’s Colitis 360, 1(3). doi:10.1093/crocol/otz026.
  11. Verstockt, S. et al. 2021. Oncostatin M is a biomarker of diagnosis, worse disease prognosis, and therapeutic nonresponse in inflammatory bowel disease. Bowel Dis. 27(10):1564-1575. doi:10.1093/ibd/izab032.
  12. Cao, Y. et al. Combined use of fecal biomarkers in inflammatory bowel diseases: Oncostatin M and Calprotectin. Journal of Inflammation Research, 14:6409-6419. doi:10.2147/jir.s342846.
  13. Ezirike Ladipo, J. et al. Oncostatin-M does not predict treatment response in inflammatory bowel disease in a pediatric cohort. Journal of Pediatric Gastroenterology & Nutrition, 73(3):352-357. doi:10.1097/mpg.0000000000003201.


About BIOHIT HealthCare

BIOHIT HealthCare is a Finnish biotech company, headquartered in Helsinki, that specialises in the development, manufacture and distribution of kits and assays for the screening, diagnosis and monitoring of digestive diseases. Its core disease focus areas include stomach health and dyspepsia, reflux and acid dysregulation, Inflammatory Bowel Disease (IBD), functional gastrointestinal disorders (FGID), Irritable bowel syndrome (IBS), and gut microbiota dysbiosis. Innovating for Health www.biohithealthcare.co.uk

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