• A new piece of the IBD puzzle: a new tool to predict response to anti-TNFs

    “Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor–neutralizing therapy in patients with inflammatory bowel disease”. West NR et al. Nature Medicine 2017; 23(5): 579–89.

    Summary

    In Inflammatory Bowel Disease (IBD), the immune system is dysregulated and a number of pro-inflammatory molecules (cytokines) drive intestinal inflammation. These cytokines constitute attractive targets for the development of new treatments, and several of them have been targeted in clinical trials (including interferon (IFN)-γ, IL-6, and IL-17A), unfortunately with limited efficacy, or significant side effects in subgroups of patients.

    The most successful result so far has been obtained by blocking TNF using monoclonal antibodies (anti-TNF therapy), which is now firmly established as an effective therapeutic approach for IBD. However, up to 40% of patients do not respond to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. More recently, the IL-12–IL-23 neutralising antibody ustekinumab has also shown clinical efficacy for CD.

    The Authors of this scientific study sought to identify other cytokines that could potentially serve as alternative therapeutic targets to TNF. They investigated Oncostatin M (OSM), which is part of the IL-6 cytokine family.

    OSM is involved in many important processes in the human body, like liver repair, remodelling of cardiac-tissue, bone formation and bone marrow function. However, overproduction of OSM is thought to promote a variety of diseases, including skin and lung inflammation, atherosclerosis, and several forms of cancer. Moreover, a specific mutation in the human OSM gene is strongly associated with risk of IBD development.

    The Authors of this paper looked into previously published data from 162 patients with clinically active Crohn’s and 74 with ulcerative colitis, and examined which cytokines were most activated (i.e. higher gene expression) in the intestinal biopsies of these patients with IBD compared to healthy controls. Four cytokines were identified as the most significantly expressed both in CD and UC, in respect to controls: IL6, IL1A, IL1B, and OSM. As OSM is the least well-characterised in the gut, they chose to investigate it further.

    First, they found that OSM was the most highly expressed cytokine in the intestinal tissue from a group of untreated pediatric patients with newly diagnosed CD, in respect to healthy controls. Furthermore, OSM and its receptor were particularly activated in patients with deep mucosal ulcerations and their expression correlated closely with the severity of the histological findings. These initial results were validated by quantitative real-time PCR (RT–qPCR) in an independent group of patients with IBD and healthy controls from a different centre.

    The Authors also observed that OSM activity is consistently associated with a few more cytokines, that are also activated alongside. They called this group of cytokines “OSM-associated inflammatory module” and went on to check whether its activation is associated with responsiveness to anti-TNF therapy. They found that complete mucosal healing (endoscopic and histological disease remission) following treatment with anti-TNF was achieved by 69–85% of patients with low OSM module expression, but was observed in only 10% of those with high OSM module expression. In fact, OSM was found to be one of the 20 most strongly activated molecules in patients with anti-TNF-resistance, compared to those patients who responded to anti-TNF.

    As a final step of their study, they used an IBD mouse model and found that the number of cells expressing Osmr was markedly increased in the gut of mice with colitis. To determine whether OSM can influence the response to anti-TNF, the Authors used mice with a lack of OSM (Osm−/−). When IBD was induced in these Osm -/- mice, at peak disease severity their histology pattern looked significantly less severe compared to mice with IBD and able to produce OSM. Based on these experiments, the Authors conclude that high OSM expression in intestinal mucosa is reproducibly associated with a high risk of resistance to anti-TNF therapy.

    This study suggests the potential for developing a robust assay—based on measuring the expression of OSM or similar inflammatory factors—that could help clinicians determine whether to prescribe anti-TNF antibodies or to explore alternative therapeutic options.

    Dr Marco Gasparetto
    IBD CICRA Fellow
    Cambridge University Hospitals (CUH)
    Department of Paediatric Gastroenterology