EVIDENCE BASED TREATMENT OF CROHN S DISEASE. Dr E Ndabaneze

Transcription

1 EVIDENCE BASED TREATMENT OF CROHN S DISEASE Dr E Ndabaneze

2 PLAN 1. Case presentation 2. Topic on Evidence based Treatment of Crohn s disease - Introduction pathology aetiology - Treatment - concept of evidence basedmedicine: levels of scientific evidence as a base for recommendations of treatment - Available drugs - Up to date evidence based treatment of Crohn s disease - References

3 CASE PRESENTATION Mrs G. P, 28 years old, Indian woman. -March, 13 th 1999, referred from Northdale hospital to SOP and then to G I clinic for further investigations and management of a suspected inflammatory bowel disease Symptoms : chronic abdominal pain, diarrhea, intermittent rectal bleeding, loss of weight: 6 months Family medical history: her brother has a Crohn s disease Physical examination: abdomen very tender in the right lower quadrant with a mass

4 Barium meal small bowel F/T review: granular stenosis of the last ileum Colonoscopy: caecum is edematous/ infiltrated, the last ileum not entered Biopsies : aspecific inflammation Diagnosis: Crohn s disease involving the last ileum and caecum Treatment: prednisolone 40 mg/day, mesalazine 800mg tds

5 Follow-up: - rapid improvement. Tapering prednisolone on 3 months - November, 1999: relapse: abdominal pain, inflammatory syndrome: 40 mg prednisone+ azathioprine100mg - July 2000: relapse on azathioprine alone. Resumption of prednisolone 40 mg and tapering doses more slowly - March 2001:incomplete clinical improvement. Small bowel barium follow through: strictures of 6 cm of the last ileum, sinus tracts and? abscesses. Ciprofloxacin and metronidazole added (15days). Improvement - October 2001: relapse of abdominal cramps. Barium meal- small bowel F/T: extension of the disease on caecum and ascending colon. Surgical resection considered, but patient very reluctant.. Methotrexate 25 mg / week started -November 29 th, 2001, methotrexate stopped : intolerance( nausea and vomiting). Azathioprine 100mg resumed + prednisone 20mg -January 17 th, 2002 patient very well. Only on azathioprine 100mg

6 WHAT NEXT IF SHE RELAPSES AGAIN? Alternatives: - Last new immunosuppressive drugs: anti TNF antibodies? - Surgery

7 EVIDENCE BASED TREATMENT OF CROHN S DISEASE 1) INTRODUCTION Pathology; - Crohn s disease is a chronic transmural inflammation of the gastrointestinal tract. Evolution characterized by alternating of flare-up and remissions - Anatomic distribution: Small and large bowel: 40-50% Small bowel alone: 30-40% Large bowel alone: 15-25% Peri-anal disease: 3-36% 3 36% Mouth: 6-8% 6 Stomach and duodenum: %.

8 Etiology: unknown, but predisposing factors: - Genetic susceptibility Higher incidence in certain ethnic groups. 20% of patients have a relative affected. Monozygotic twins concordant in more than 90%. - Environmental factors: : diet? infectious agents?. - Defects in immune system: : inability to down regulate the inflammatory process triggered by microbial flora of the gut with an overexpression of cytokins: : IL2, IL7, IL10, TNFA, Interleukin10 recepteur,, interleukin 2 recepteur, autoantibodies.leading to an autoimmune disease damaging the gastrointestinal wall.

9 THE TREATMENT OF CROHN S DISEASE. 1) Concept of levels of scientific evidence as a base for grading recommendations. GradeA: - Evidence from large randomized clinical trials or meta Evidence from large randomized clinical trials or meta-analysis analysis of multiples randomized trial which collectively have at least as much data as one single well w defined trial. -Evidence from at least one All or None high quality cohort study -Evidence from at least one moderate sized RCT or a meta-analysis analysis of small randomized trials. Grade B: - Evidence from at least one high quality study of non randomized Evidence from at least one high quality study of non randomized cohorts who did and did not receive the new therapy Grade C: - opinions from experts without reference to any of physiology or bench research.

10 2) Drugs available 1) - 5 aminosalicylates Sulfasalazine Mesalamine 2) - Glucocorticoids Prednisone Budesonide 3) - Immunosuppressive drugs Azathioprine. Methotrexate. Cyclosporin 4) - Antibiotics 5) - Anti-TNF antibodies

11 3) Up to date evidence based recommendations for the treatment of Crohn s disease Induction of remission: 1) Aminosalicylates - sulfasalazine: : marginally superior to placebo in active C D : GRADE A - mesalamine: : not more effective than sulfasalazine: : : GRADE A Conclusion: 5aminosalicylates for induction of remission ion only in mild C.D 2) Glucocorticoids : - Prednisone: 40 mg/day, 10-16weeks 16weeks : highly effective: GRADE A - Budesonide: : 9mg/day, weeks: attractive alternative to prednisone for active C.D of ileum and right colon: GRADE A 3) Antibiotics: Ciprofloxacin,and metronidazole: : no evidence of efficacy.

12 4) Immunosuppressive drugs - Purines antimetabolites: azathioprine 2,5 mg/kg/ 6mercaptopurine: effective for induction of remission (steroids resistance or steroids dependence ): GRADE A - Methotrexate: effective at doses of 25 mg/kg : GRADE A indication: steroid resistance/dependence - Cyclosporin uncontrolled studies have suggested that short duration high doses intravenous therapy may be beneficial in patients with refractory ry CD: controlled trials required before any definite recommendation.

13 5) Anti Tumor Necrosis Factor alfa antibodies: Infliximab: Highly effective: >80% respond : GRADE A Indication: failure of conventional therapies: very COSTLY

14 Maintenance of remission 1) Aminosalicylate : reduction of 10 20% of rate of relapse : modest effect of treatment: GRADE A 2) Glucocorticoids : - Prednisone: failure to maintain remission at low doses: GRADE A - Budesonide: : prolongs remission at a dose of 6mg/day but relapse occur 3) Azathioprine : effective at maintaining remission after induction of remission r : GRADE A 4) Methotrexate effective at 15 mg /day for maintaining remission: : GRADE A 5) Anti-TNF antibodies Effective at maintaining remission, but consequences of long term suppression of TNF: pulmonary TB, induction of anti- nuclear antibodies and even SLE.

15 Algorithm for the treatment of crohn s disease

16 Reference: EVIDENCE BASED GASTOENTEROLOGY AND HEPATOLOGY, EDITED by John McDonald, Andrew Burroughs, Brian Feagan BMJ Books, BMA House, London.