Crohn's disease (CD) is a chronic inflammatory condition affecting the gastrointestinal tract of nearly 800,000 children and adults in the United States, and it is characterized by recurrent bouts of acute bowel wall inflammation that frequently lead to intestinal scarring, perforations, and blockages. Currently, effective treatment is limited, with many CD patients undergoing surgical removal of intestine within 10 years of diagnosis. Recent advances in aggressive medical approaches (including biologic therapies, immunomodulators, or combinations thereof) may lead to improved outcomes, including longer remissions with greater mucosal healing and fewer disease-related complications. Radiologic evaluation of CD is typically accomplished by contrast-enhanced CT or MRI. However, both have safety concerns, and our preliminary data suggest it may require months to detect response to biologic therapies. Hence, there is a critical unmet need for safe, objective radiologic measures of intestinal inflammation that can be used for early prediction of durable responses to medical therapy. The long- term objective of this research program is to optimize and test the accuracy of novel nonionizing, noninvasive methods for detecting, measuring, and serially monitoring intestinal inflammation and for predicting ultimate response to medical therapy in small bowel CD. We propose to evaluate the accuracy of several noncontrast, quantitative MRI techniques, including both novel and current standard of care approaches. The central hypothesis of this proposal is that novel functional objective MRI measures can detect and quantify intestinal inflammation as well as provide accurate, early prediction of eventual response to treatment, including endoscopic mucosal healing, particularly when compared to conventional CT and MRI morphologic measurements. Novel MRI techniques to be evaluated in our studies will measure: 1) mesenteric flow (ml/min) and velocity (cm/sec), 2) intestinal peristalsis frequency and pattern, and 3) bowel wall perfusion and molecular water diffusion using an intravoxel incoherent motion (IVIM) approach. Preliminary work by our group has shown that these novel MRI methods can be used to successfully image the bowel of children and adults, including neonates. This application aims to: 1) refine and test novel noncontrast MRI techniques for bowel assessment in healthy control subjects in order to acquire normative data; 2) test novel noncontrast MRI techniques in newly diagnosed small bowel CD patients in order to determine how these markers change in the setting of active intestinal inflammation; and 3) assess the abilities of novel MRI techniques for early prediction of clinical, laboratory, and endoscopic responses to medical therapy in newly diagnosed small bowel CD patients. Data acquired in this pilot study will be used to plan subsequent larger prospective investigations to evaluate if these MRI techniques can guide more personalized patient management strategies, contribute to improved health-related quality of life, lower healthcare costs, and provide new opportunities to test candidate anti-inflammatory medications using noninvasive MRI as a surrogate endpoint.
Public Health Relevance This project addresses the challenge of developing imaging markers to noninvasively measure intestinal inflammation in children and adults with Crohn's disease without exposing them to radiation. The proposed study also will assess multiple novel MRI methods that may allow early prediction of response to medical therapy. Such markers could potentially enable more personalized medical therapies, improve clinical outcomes (including health-related quality of life), and decrease healthcare costs as well as aid in the future development and testing of anti-inflammatory therapies in Crohn's disease.
