Unresolved Clinical Research Questions in IBD

Transcription

1 Unresolved Clinical Research Questions in IBD Bruce E. Sands, MD, MS Acting Chief, Gastrointestinal Unit Massachusetts General Hospital Associate Professor of Medicine Harvard Medical School Areas of interest Disease susceptibility Diagnosis Prognosis Disease monitoring Disease activity / outcome measures 1

2 Areas of interest Disease susceptibility Diagnosis Prognosis Disease monitoring Disease activity / outcome measures Disease Susceptibility What are the environmental factors that contribute to susceptibility to IBD? How does diet shape the gut flora? Methodologic question: how to record and measure diet accurately? What are the factors associated with industrialization that contribute to disease occurence? 2

3 Disease Susceptibility What are the triggers of IBD? Why is smoking a risk factor for Crohn s disease but protective for ulcerative colitis? Why is appendectomy for appendicitis protective for ulcerative colitis, but not for Crohn s disease? Disease Susceptibility What studies? Large prospective cohorts for case-control studies of environment, environment x gene risk association Validation studies to link diet to microbiome characteristics Physiologic studies of smoking Physologic studies related to appendicitis/appendectomy? RCT of appendecomty? 3

4 Areas of interest Disease susceptibility Diagnosis Prognosis Disease monitoring Disease activity / outcome measures Diagnosis The IBDs are complex multigenic disorders, yet we recognize 2 major phenotypic forms Are there other forms with common genetics? Is IBDU a distinct clinical entity? How can we arrive at more accurate diagnosis? (Laboratory diagnosis) 4

5 Diagnosis What studies? Unbiased studies of diagnosis using high throughput technologies (gene arrays, proteomics, metabolomics, others) Genetic and physiologic studies of indeterminate colitis ( seronegative colitis ) Areas of interest Disease susceptibility Diagnosis Prognosis Disease monitoring Disease activity / outcome measures 5

6 Prognosis Definition: how should we define aggressive disease phenotypes? Can we develop clinically useful prognostic models? If such models can developed, can they be married with early aggressive treatment strategies to Improve the natural history? Improve risk/benefit? Optimize cost/benefit? Prognosis What studies? Studies and consensus on the definition of aggressive disease phenotypes Develop new surrgogates for prognosis Genetic? Serologic? Imaging? Immunobiologic? Validation studies linking surrogates to ultimate outcome 6

7 Areas of interest Disease susceptibility Diagnosis Prognosis Disease monitoring Disease activity / outcome measures Disease monitoring Symptoms are not sufficiently accurate to monitor disease activity and progression In CD, difficulty in differentiating inflammatory vs. fibrotic stricture: a diagnostic dilemma that leads to a therapeutic conundrum What new modalities can be created / validated to monitor disease in a way that is Noninvasive? Inexpensive? Convenient? Non-ionizing? 7

8 Disease Monitoring Predictors of Relapse Can tests be developed to differentiate between patients on an effective maintenance therapy vs. those who are in a clinically quiescent phase of disease but who will flare within a year? (That is, can we develop reliable predictors of relapse?) Disease Monitoring Types of studies Validation of modalities of frequent home monitoring and application in therapeutic strategies Validation of newer laboratory assays and imaging modalities to assess activity / burden of inflammation complications such as stricture 8

9 Areas of interest Disease susceptibility Diagnosis Prognosis Disease monitoring Disease activity / outcome measures Outcomes Surrogate Endpoints of Remission What are the optimal endpoints for medical therapy in UC and CD? Specifically, are surrogate endpoints (such as endoscopic healing, absence of inflammatory markers in the stool, and histologic quiescence) more predictive of superior long-term outcome than clinical remission? Do the benefits associated with achieving these outcomes outweigh the costs and risks (i.e., is this approach cost-effective?) 9

10 Outcomes Disease activity indices in IBD are not optimized, particularly in CD Can we finally agree on a replacement for the CDAI? Need to measure symptoms/disease impact Need to accurately measure effect of therapy on inflammation Areas of interest Disease susceptibility Diagnosis Prognosis Disease monitoring Disease activity / outcome measures 10

11 Adverse Effects of Medical Therapy and Risk Communication What are the risks of medical therapy, particularly immunomodulators and biologic therapy? To what extent do IBD patients understand the risks of potent medical therapies, and how do they weigh the risks and benefits of medical therapies? Top-Down Strategy Strategies: Are top-down strategies (vs. standard stepup strategies) more effective in inducing remission? more effective in maintaining remission? able to change long-term outcomes (surgery, disability, quality of life)? more cost-effective? safer? 11

12 What medical therapies can prevent or delay recurrence after segmental resection for Crohn s disease: AZA/6MP? MTX? Low dose metronidazole? Other antibiotics? TNF antagonists? Which strategy is most optimal for postoperative prophylaxis after ileocolonic resection for Crohn s disease? Observe (interval ileocolonoscopy) and treat for recurrence? Treat all comers from the time of surgery? 12

13 Disease Modification Can early aggressive intervention soon after diagnosis change the course of disease, with withdrawal of very potent therapy and maintenance of long-term benefit off of medication? (That is, can disease modification be achieved?) Combination of Immunomodulators and Biologic Therapy What is the appropriate role of immunomodulators as combination therapy with biological therapies? Combination for induction and long-term maintenance? For induction but monotherapy (IMM or biologic) for maintenance? How do the trade-offs between the potential for additional efficacy and safety concerns of combination therapy balance out? 13

14 Immunogenicity of Biologic Therapy How can the immunogenicity of biologic therapy which limits safety and long-term efficacy best be mitigated? Can novel methods be developed to induce long-term immunologic tolerance to biologics? Prebiotic/Probiotic Therapy What is the efficacy of prebiotic or probiotic therapies in UC and CD? Animal models suggest that no single probiotic agent will be effective for all individuals Subgroups of individuals most likely to respond may need to be identified 14

15 Chemoprevention of Colorectal Cancer in IBD Are medical therapies able to decrease the risk of colon cancer in colonic IBD, including folate, ursodiol, 5-ASAs, statins? Adherence What are the causes of non-adherence to medical therapy? What strategies can improve adherence with medical therapy? 15

16 Quality of Care What are the indicators of high quality of care with regard to medical therapy? What broad-based interventions can be implemented to improve practice? (For example, less use of systemic steroids and narcotics, uniform screening for tuberculosis before biologic therapy) Surgery What is the effect of medical therapy on post-surgical complications in UC and CD? 16

17 Old medications, new uses? MERIT-UC (Methotrexate Response in the of UC) Hans Herfarth, PI CCFA Clinical Research Alliance study Conclusions Much opportunity to advance the field Opportunities for collaborative research exist, and in fact are needed Opportunities for translational research are unprecedented We need all the talent we can get! 17