Medicine (St Vincent's) - Theses
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ItemPost-operative Crohn's disease recurrence: clinical and microbiological studies( 2012)Crohn’s disease is a chronic inflammatory bowel disease that causes major morbidity. The cause is unknown but thought to relate to an exaggerated immune response to gut microbiota in genetically susceptible individuals. There is currently no known cure. The majority of patients with Crohn’s disease undergo surgery during their life, and 70 percent of these require a second operation due to disease recurrence. Surgery involves removing the diseased segment and joining the unaffected bowel. Even if all macroscopically involved bowel is removed disease usually recurs at, and proximal to, the anastomosis. Recurrent Crohn’s disease can be identified endoscopically before symptoms develop. However, it is unknown whether intervention based on endoscopic findings of recurrence influences the disease course. Immunosuppressive and antitumour necrosis factor therapy have emerged as effective treatments in the treatment of Crohn’s disease but their optimal usage for the prevention of post-operative recurrence of Crohn’s disease remains to be determined. This thesis encompasses the design and conduct of a clinical study which aimed to determine whether prospective endoscopic monitoring of post-operative patients, with treatment intensification for mucosal recurrence, is superior to the current standard of care based on treatment of symptoms. This thesis also includes a laboratory study, allied to the clinical study, in which the microbiota has been characterised and followed over time, from a starting point of absent mucosal disease at a site of known recurrence. This latter study aimed to establish whether specific changes in gut mucosal microbiota at the anastomosis are associated with disease recurrence. We initially demonstrated in a retrospective cohort study that the rates of endoscopic, clinical, and surgical recurrence are high after surgery and that that approaches to the management of postoperative recurrence have been variable in the past. Although there was no clinical benefit from colonoscopy or step-up therapy in this cohort we concluded that that this lack of benefit related to inconsistent timing of post-operative colonoscopy and a lack of standardised drug intervention in response to the endoscopic findings. We then devised a prospective randomized controlled trial to compare endoscopic monitoring of post-operative patients with treatment step-up for endoscopic recurrence, with standard care. In an analysis of the six month endoscopic outcome of patients with a high risk of recurrence we found that adalimumab was significantly superior to thiopurines in preventing endoscopic recurrence. In the laboratory we simultaneously characterised the mucosa associated microbiota in a sub-group of patients enrolled in the clinical study at the time of surgical resection and at the anastomosis six months post-operatively. We found that patients who developed recurrence or remained in remission could be differentiated on the basis of specific microbiota profiles, both at the time of surgery and six months later. In summary, postoperative recurrence remains an important issue despite the availability of immunosuppressive and anti-TNF drug therapy, when managing Crohn’s disease. This thesis comprises clinical studies focussing on the prevention of disease recurrence, and laboratory studies aimed at determining which bacteria may be implicated in recurrent disease.