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The majority of patients suffering from Crohn's disease will undergo at least one surgical resection of the bowel in the course of their disease. Surgery greatly improves the quality of life in these patients but the beneficial effect is only temporary.
After ileal or ileocolonic resection there is a 20–30% symptomatic recurrence rate in the first year after surgery, with a 10% increase in each subsequent year. Most patients will eventually suffer recurrence, and a reoperation rate of 50–60% is generally reported. The need for simple and effective prophylactic therapy after bowel resection for Crohn's disease is great.
The natural evolution of postoperative Crohn's recurrence has been well studied. After curative resection of the inflamed bowel (that is, removal of all macroscopically involved gut) the disease recurs within weeks to months proximal to the ileocolonic anastomosis.1 The tissue events can readily be visualised by ileocolonoscopy with biopsy in the months after surgery.
The presence of extensive lesions in the bowel, as visualised at endoscopy in the months after surgery, predicts rapid evolution to recurrent symptoms and eventually complications.
The behaviour of the disease (fibrostenotic versus perforating) tends to remain unchanged throughout the disease course and risk factors for early clinical recurrence are perforating behaviour, ileal or ileocolonic resection with ileocolonic anastomosis, and smoking.2,3
True prophylactic therapy implies that the formation of new lesions, from early aphthous ulcers to full blown Crohn's disease, can be prevented using drug therapy. In that respect postsurgical prophylaxis is different from maintenance of medically induced remission of Crohn's disease as in the latter situation active lesions are still present in the bowel even though the patient does not experience the typical symptoms of the disease. Recently it has also become possible to heal the bowel medically using anti-tumour necrosis factor antibodies, but relapse after this therapy is accompanied by immediate (almost overnight) relapse of typical Crohn's lesions.
There are currently two strategies that seem to interrupt the natural history of Crohn's disease postoperatively—that is, treatment with nitroimidazol antibiotics and immunosuppression therapy using 6-mercaptopurine or azathioprine. Other current therapies of Crohn's disease have been rather disappointing.
Sulphasalazine or other 5-aminosalicylic acid (5-ASA) formulations have limited value in the prophylaxis of Crohn's disease recurrence. Meta-analysis of placebo controlled trials using 5-ASA formulations suggest a 20–30% reduction in the relative risk of recurrence (10% of the absolute risk) at 18–24 months with high doses of 5-ASA but demonstrate overlap with unity.4–7 Glucocorticosteroids, including the topically acting drug budesonide, are not effective.
Antibiotics are an attractive therapy as there is evidence that the commensal flora is involved in the perpetuation of inflammation in the bowel. In a placebo controlled trial8 it was shown that metronidazole 20 mg/kg for three months after resection with ileocolonic anastomosis significantly decreased the severity of recurrent lesions in the neoterminal ileum. This results in a delayed symptomatic recurrence. In a recent trial9 we confirmed the efficacy of nitroimidazol antibiotics as ornidazol 1 g/day for one year not only decreased the rate of endoscopic recurrences but this regimen also significantly diminished the clinical recurrence rate (9% v 33%). Again, however, the effect lasts only as long as the drug is maintained. The main drawback of this treatment is the poor tolerance of this antibiotic regimen with polyneuropathy on chronic use being the most disturbing side effect.
Another appealing therapy for postoperative recurrence prevention in Crohn's disease is immunosuppression with azathioprine. This drug has been shown to be effective in maintaining medically induced remission and can even heal severe postoperative recurrent disease.
There are only limited data on the use of immunosuppression for postoperative prophylaxis.
In a two year multicentre trial,10 6-mercaptopurine 50 mg/day, mesalamine 3 g/day, and placebo were compared for postoperative maintenance of Crohn's disease remission. In this study 6-mercaptopurine was more effective than placebo. Clinical recurrence rates at 24 months amounted to 50% for 6-mercaptopurine, 59% for mesalamine, and 69% for placebo. Endoscopic recurrence rates were 68%, 77%, and 87% respectively.
The results of the latter study are somewhat disappointing in the sense that 6-mercaptopurine was less effective than expected. This is probably the consequence of the rather low dose of 50 mg of 6-mercaptopurine used where 1–1.5 mg/kg is the effective dose.
How should we then focus our therapeutic strategy? It is clear that a number of patients will not need postoperative prophylaxis as they will not suffer symptomatic recurrence because they either develop no new lesions or only limited tissue recurrence. The problem is that clinical risk factors for the development of clinical recurrence have not clearly been identified.
Therefore, we should focus on those patients who are identified as having developed important new Crohn's lesions in the remaining bowel as they will eventually develop symptomatic recurrence. With this aim we always carry out an ileocolonoscopy or barium follow through x rays in our patients in the clinical setting at six months after resection to identify those patients with clearcut recurrent lesions. These patients are candidates to receive 6-mercaptopurine or azathioprine. Induction of healing using anti-tumour necrosis factor strategies should be considered. Studies addressing the issue of postoperative recurrence prevention in Crohn's disease are greatly needed.
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