Prophylaxis in Crohn’s disease after surgical intervention

Dr. ALI KHALIL

Surgical indications

> 50 % of Patients with ileal or ileocolonic crohn’s disease undergo

resection of the diseased bowel because of complications

including:

• Stenosis

• Abcess

• Fistula

• Intractable disease

Complications of Crohn’s Disease

Crohn’s Strictures

Complications of Crohn’s Disease

Crohn’s Fistulae

Recurrence of the disease

• Recurrence can be demonstrated endoscopically in 73% - 93% of patients at 1 year

• at the site of resection

• Approximately 50% of patients requierd repeat surgery within 10 years

• Risk factors: - age > 30 years

- duration of disease > 5 years

- use of corticosteroids > 6 months

- smoking habits

- chronic activity

Crohn’s diseaseTreatment Goals

• Diagnosis and prompt therapeutic response

• Induction of complete remission

• Maintenance of clinical remission

• Prevent recurrence of disesase in disease-free segments of the

bowel after surgery

• Low side-effect profile to enhance compliance

Crohn’s Disease - Treatment

Conventional therapies:

• Aminosalicylates

• Corticosteroids/Budesonide

• Immunomodulators

• Antibiotics

• Anti-metabolites

• Biologic Modifiers

AminosalicylatesMesalamine (1)

• A meta-analysis of 15 randomised controlled trials

• 2097 patients

• The mesalamine significantly reduced the risk of symptomatic

relapse

• The benefits are mainly observed in the post surgical setting

« confidence interval (–21,8% to 4,5% )

Camma C et al, gastroenterology 2001

AminosalicylatesMesalamine (2)

• Randomisad controled trial

• 163 patients

• 1,5 g of (Rowasa and salofalk) twice a day for 8 weeks

• Mesalamine is effective in decreasing the risk of reccurent

crohn’s disease after surgical resection

• The symptomatic reccurence rate in the treatment group was

31 % compared with 41 % in the placebo group ( p=0,031)

Mcleod et al, gastroenterology 1995

AminosalicylatesMesalamine (3)

• Double-blind multicenter clinical trial

• 3g/day of Pentasa , 12 months of treatment

• 67 patients

• The overall rate of severe endoscopic reccurence was 24%

in the mesalamine group and 56% int the placebo group after 1

year

Brignola et al, gastroenterology 1995

AminosalicylatesMesalamine (4)

• Prospective, double-blind, multicenter study

• 4g/day Pentasa vs placebo continued for 18 months

• 318 patients

• 10 days after resection

• Relapse after 18 months: 24,5% in group mesalamine

31,4% in placebo group

• Some relapse-preventing effect was found in patients was isolated small bowel disease

Lochts et al, gastroenterology 2000

AminosalicylatesMesalazine

• A multicenter randomized control trial

• 110 patients

• 2,4 g Asacol/day vs no treatment at all

• Colonoscopy and ileoscopy at 6 months and yearly therafter

• Over 2 year period: prevent 39 % of all reccurences and 55%

of the severe reccurences

Caprilli et al, aliment pharmacol ther 1995

AminosalicylatesConclusion

3 studies showed that mesalamine is effective in decreasing the risk of reccurence

One study showed that mesalamine did not significantly affect the postoperative course of crohn’s disease

CorticoïdesBudesonide

• A double-blind randomized trial

• 129 patients

• 6 mg/day or placebo within two weeks from surgery

• The frequency of endoscopic reccurrence did not differ between the groups

at 3 and 12 months

• In patients with disease activity as indication for surgery, the endoscopic

reccurrence rate at the anastomosis was lower in the budesonide group

• But not in patients with fibrostenosis as indication for surgery

Hellers et al, gastroenterology 1999

percentage of patients with macroscopic recurrence of inflammation in the neoterminal ileum

BudesonidePlacebo

Patients with recurence

Patients with recurence

percentage of patients with macroscopic recurrence

of inflammation of anastomosis

PlaceboBudesonide

Endoscopy score

BudesonidePlacebo

Endoscopy score in the neoterminal ileum

Endoscopy score

Endoscopy score at anastomosis

BudesonidePlacebo

ImmunomodulatorsImmunomodulators6-Mercaptopurine (6-MP)6-Mercaptopurine (6-MP)

• Randomized study, double-blind• 131 patients• 6-MP (50mg), mesalamine (3g) or placebo daily

6-MP Mesalamine Placebo

Clinical recurrence

50% 58% 77%

Endoscopic recurrence

43% 63% 64%

Radiographic recurrence

33% 46% 49%

Stephen et al, gastroenterology 2004

Clinical recurrenceClinical recurrence

Endoscopic recurrenceEndoscopic recurrence

Radiographic recurrenceRadiographic recurrence

ImmunomodulatorsImmunomodulatorsAzathioprineAzathioprine

• Comparative trial

• 142 patients

• Azathioprine (2 mg/kg/day) and mesalamine (3 g/day) for 24

months

• Relapse was experienced in 17 patients (34%) receiving

azathioprine and 28 (46%) receiving mesalamine but the

difference was not significant

Ardizzone et al, gastroenterology 2004

ImmunomodulatorsImmunomodulatorsConclusionConclusion

6-MP, 50mg daily was more effective than placebo at preventing post-operative recurrence of crohn’s disease and should be considered as a maintenance therapy after ileocolic resection

The difference was not significant between azathioprine and mesalamine

More placebo-controlled studies of recurrence prevention with immunosuppressives are necessary

Higher risk of toxicity

AntibioticsAntibioticsMetronidazoleMetronidazole

• A double-blind controlled trial

• 60 patients

• Metrornidazole 20mg/kg/day or placebo continued for 3months

• At 12 weeks, 75 % of patients in the placebo group had recurrent lesions in

the neoterminal ileum as compared with 52% in the metronidazole group

• The incidence of endoscopic recurrence was significantly reduced by

metronidazole as compared with placebo

Rutilements et al, gastroenterology 2005

AntibioticsAntibioticsOrnidazoleOrnidazole

• A double-blind randomized trial

• 80 patients

• Ornidazole 1 g/day or placebo continued for 1 year within 1week

of resection

• Clinical recurrence rate at 1 year from 37.5% in placebo group to

7.9% in the ornidazole group

• Endoscopic recurrence was reduced from 79% in Placebo to 53.6% in the ornidazole group

Rutgeerts et al, gastroenterology 2005

AntibioticsAntibioticsConclusionsConclusions

Metronidazole therapy for 3 months decreased the severity of early recurrence of crohn’s disease after resection and seems to delay symptomatic recurrence

Ornidazole 1g/day is effective for the prevention of recurrence of Crohn’s disease after ileocolonic resection

Ornidazole have a better safety profile

Summary

• Mesalamine 3g/day, 12 months of treatment within two weeks from surgery is considered as first choice treatment

• Immunomodulators should be considered as a maintenance therapy after ileocolic resection

• Ornidazole 1g/day, 3-6 months of treatment, is effective to prevent posoperative recurrence of crohn’s disease

• Budesonide 6mg/ day, may be more effective in patients with high disease activity as a primary indication for surgery