Inflammatory bowel disease (IBD) means ulcerative colitis and Crohn’s disease. These are inflammatory conditions that affect the gut, usually starting between the ages of 15 and 35, affecting 0.5-1.0% of the Western world. The epidemic is global, with an exponential increase in India, East Asia and Latin America. Over 230 susceptibility genes have been identified, but the causes (for there must be several, although all unknown) must be environmental. Blame food, refrigeration, or hygiene: the critical area of study is the interaction between the microbiota (the bugs in the gut) and the immune system. This is the focus of research at the Translational Gastroenterology Unit in Oxford.
Sadly, treatment for such a common immunoinflammatory disorder affecting young people at such a productive time in their lives, is only modestly effective. The treatments of 50 years ago remain the mainstay today. In the past 20 years, just three new classes of treatment have been introduced (anti-TNF, anti-integrin and anti-IL23 therapy). A fourth (JAK inhibitor therapy) will become available for ulcerative colitis, but not Crohn’s, in 2019. All took 15 or more years to reach the current stage where just a third of patients treated with these agents reach steroid-free remission. Even more remarkably, less than a third of patients affected by IBD in the UK are treated with these effective, ‘biological’ agents. How poor is that? There is a large, unmet clinical need for a condition that affects the entire family in its consequences. Fortunately there are more than 30 novel agents and approaches under trial. Some agents (such as secukinumab, an anti-IL17A inhibitor) work for ankylosing spondylitis, but make Crohn’s disease worse: we in Oxford were the first to show this in 2012 (doi: 10.1136/gutjnl-2011-301668).
That means that we have to understand why patients respond to one treatment and not another, why one immunoinflammatory disease gets better on one treatment and worse on another and how to accelerate the transition from science to clinical care. Our work has identified the first biomarker that predicts non-response to the most commonly used biological therapy, anti-TNF therapy (Oncostatin M, doi: 10.1038/nm.4307). This may seem an odd way to advance, but since two thirds of people with IBD treated with these agents do not respond, this matters – especially when they cost more that £10k per patient per year.
We wish to understand what predicts response or non-response to treatment across different diseases and to develop novel treatments for IBD such as anti-Oncostatin M targeted therapy.
Our preclinical characterisation of the immuno-biology in IBD suggests that OSM-mediated inflammation may be important. There is therefore a strong rationale not only for exploring OSM blockade as a novel therapeutic pathway in IBD, but also for investigating whether OSM is a biomarker that can personalise treatment to responders to anti-TNF therapy.
We hypothesize that there is a distinct OSM signature in the blood of some patients with IBD, that this signature will correlate with clinical non-response to anti-TNF therapy and that anti-OSM therapy will be effective in these patients.
We will study immune and bacterial signatures in blood and stool of patients before and after biologic treatments including anti-TNF therapy and anti-OSM therapy. We will investigate OSM as a biomarker to select patients for anti-TNF therapy. We hope to detect a “signature” that will predict response to therapy in some (or all) individuals. This will pave the way for personalised therapy and accelerate the introduction of novel therapy for patients with IBD.