PD Dr. med. R. Wiest / Dr. med. P. Juillerat, MSc. Donnerstag 18 ten Oktober 2012 UPDATE PROKTOLOGIE: Konservative Behandlungsmöglichkeiten?

Transcription

1 PD Dr. med. R. Wiest / Dr. med. P. Juillerat, MSc Donnerstag 18 ten Oktober 2012 UPDATE PROKTOLOGIE: Fisteln bei M. Crohn : Konservative Behandlungsmöglichkeiten? INTERDISZIPLINÄRE VISZERALE CHIRURGIE & MEDIZIN Source: MGH Crohn s and colitis center

2 Crohn s disease Original paper Burrill B. Crohn Mt Sinai Hospital New York City Crohn s disease first description in 1932: 6 of 14 original patients with fistulas Crohn, B.B., B Ginzburg, I. & Oppenheimer, G.D. Regional ileitis: a pathological and clinical entity. JAMA 1932, 99:

3 Evolution of Crohn s Disease 100 Cumul ative Pr robabili ity (%) Inflammatory Penetrating Stricturing Months Patients at risk: N= Schwartz DA et al. Gastroenterology 2002; 122: Cosnes J, et al. Inflamm Bowel Dis. 2002;8:

4 Crohn s disease : Epidemiology Cumulative incidence of fistula in CD patients: 30 50% (70%) In population-based studies up to 26% 5 y1 y 10 y 20 y None Prevalence : one third 10 y None 20 y life Tang LY, et al. Clin Gastroenterol Hepatol 2006;4: Schwartz DA et al. Gastroenterology 2002; 122:

5 Crohn s disease :Type of fistulas Entero-enteric enteric 24% (Ileo-cecal, ileo-ileal, ileal, ileo-rectal rectal,) Recto-vaginal 9% Other: Enterocutaneous, enterovesical - 13% Perianal 54% Schwartz DA et al. Gastroenterology 2002; 122:

6 Sandborn W. AGA Technical Review on perianal Crohn s disease. Gastroenterology 2003; 125:

7 Simple Classification of perianal fistula superficial (intrasphincteric/transphincteric) p begins low in the canal single opening on the skin not associated with an abscess not connected to other structures (e.g. vagina) Complexe deep high in the canal associated with an abscess multiple openings, or connects to an adjacent structure + pain + anorectal stricture or active disease of the rectum Bell SJ, & Kamm MA. Aliment Pharmacol Ther 2003;17: Schwartz DA, et al. Ann Int Med 2001;17:

8 Diagnostic approach to fistula in M.Crohn Physical examination (under anaesthesia) MRI/CT-imaging Endosonographic ultrasound Combination of two modalities approaches 100 % diagnostic accuracy Schwartz et al. Gastroenterology 2001 Horsthuis et al. Clin Image

9 Medical Treatment of fistula: Drawbacks Limited data: primary endpoint? RCT? Most published studies: therapy of perianal fistula For internal fistula (e.g. enterovesical, or enterovaginal), data are scarce Scoring and definition of response: placebo rate is 10%, method to assess response poor : Index: Perianal Disease Activity it Index (PDAI) Finger-compression technique: Number of draining fistula by investigator (e.g. endpoint = 50% reduction) Irvine EJ J Clin Gastroenterol Present D, et al. N Engl J Med

10 5ASA Compounds and Steroids STOP!!! Not an appropriate therapy for fistulizing disease! with steroids : deleterious outcome more surgeries 1 Anticalcineurin Inhibitors (tacrolimus and cyclosporin) are also not recommended despite some good results in open label trials Malchow H et al. Gastroenterology Nielsen et al, Nat Clin Pract 2010; 6(2) :

11 Antibiotics Metronidazol / Ciprofloxacin First line treatment in simple fistula Most studied in open-label trials 1 Only 1 RCT 2 comparing both antibiotics at 1000 mg/day 2 Good response within 6-8 week, but treatment duration 3-4 months! CAVE : Adverse events (mostly metronidazol): nausea (disulfiram-like reaction), vomiting, dark urine, abdominal cramping, diarrhea, metallic taste in the mouth and coating of the tongue. with prolonged administration: peripheral p neuropathy, (distal paraesthesia). With Ciprofloxacin: Tendinitis e.g. But, no healing High recurrence rate! (up to 50%) Best results: combination with Azathioprin 3. 43% vs. 15% response rate (after 20 weeks) 1. Bernstein LH, et al. Gastroenterology 1980; 79: Thia KT, et al IBD2009; 15: Dejaco et al APT

12 Thiopurines : Azathioprine / 6 Mercaptopurine (6MP) 1Metaanalysis Meta-analysis including 5 trials, by Pearson et al: OR 3.09 for active Crohn s disease OR (CI ) 13 in favor of fistula healing Largest series is on 6MP by Korelitz et al: Azathioprin i / 6MP ~ 40% Pearson DC et al. (1995) Ann Intern Med 123: Korelitz BI and Present DH (1985).Dig Dis Sci 30:

13 Methotrexate t t for fistulizing i Crohn s disease Response rate: 22-56%, but no good data A retrospective chart review by Mahadevan, et al 1 (Mayo Clinic): N= 16 patients with fistula, 4 (25%) with COMPLETE closure 5 (31%) with partial closure Overall response: 9 (56%) in 4-8 weeks response time Better and sustained response with combined therapy with: Anti-TNF inhibitors 2 1. U. Mahadevan et al, Aliment Pharmacol Ther (APT) 2003; 18: Schröder et al, APT 2004; 19(3):

14 Infliximab in Patienten mit perianaler Erkrankung Morbus Crohn Present, et al. 1999, Mount Sinai, NYC Response : complete closure P=0.001 P= % - 50 % Response Comparison : AZA/6MP < 40% Korelitz BI, Present DH. Dig Dis Sci 1985; 30: * p= p=0.04 *Placebo=Conventional Therapy Present D, et al. N Engl J Med. 1999;340:

15 Infliximab: ACCENT II post hoc analysis Fistula Response at Week 54 Sands, et al. 1999, MGH, Boston N= 296 Initial response ~ 70% maintained (195/282) after 3 doses response ~ 50% of responders at 1 Year week 14 (= 42/91) P= % (= 23/98) Sands, et al. N Engl J Med. 2004; 350:

16 Infliximab: ACCENT II post hoc analysis Fistula Response : mean Duration Sands, et al. 1999, MGH, Boston 40 weeks 14 weeks Sands, et al. N Engl J Med. 2004; 350:

17 Adalimumab - CHARM Trial Endpoint : Healing = no draining of fistula at last 2 visits. Follow up at weeks 56 N= 854 Patients, among them: p = 0, (14%) Patients with fistula Patient ts (%) % 37 % 33 % 30 % Placebo Adalimumab ab 40 mg/eow Adalimumab 40 mg/week All Adalimumab 0 6/47 11/30 12/40 23/70 Colombel JF et al. Gastroenterology 2007; 132 :

18 Certolizumab PRECISE 2 study: 58 had draining fistulas at baseline (55/58 perianal) 43% vs 54% (p= 0.069) Endpoint = closure of their fistula : ( at 2 consecutive visits; 3 weeks appart, across week 4-28) FACTS Study (Switzerland): open label 11 patients (22%) with complexe fistulas Reduction of >50% draining fistula: 72% (8/11) at 6 weeks PRECISE 2 : Schreiber et al, NEJM 2007; 357: Substudy: Schreiber Aliment Pharm Ther 2010; 33: FACTS: Schoepfer et al Inflamm Bowel Dis 2010; 16:

19 The best efficacy for perianal fistula therapy : combined treatment Infliximab + surgical drainage = Seton! N=32 Regueiro and Mardini. Inflamm Bowel Dis 2003; 9(2):

20 Treatment with the best evidence available for Perianal Fistula : Infliximab + surgical drainage = Seton! N=32 p=0.001 Regueiro and Mardini. Inflamm Bowel Dis 2003; 9(2):

21 Potential other/future approaches in fistulizing M.Crohn Adsorptive Carbon (AST-120) 1 -Follow up at weeks 56 N= 854 Patients, among them: 117 (14%) Patients with fistula 1 Fukuda Y et al. AJG

22 Summary of medical treatment based on EPACT Appropriateness criteria and ECCO guidelines 1st line naive patients Antibiotics Failure +/- SIMPLE COMPLEXE Non-resective Surgery (seton) 2 nd line MTX Thiopurines Failure or +/- 3rd line Anti-TNF agents IFX > ADA (> CZP) Aggressive Surgery (flap) Dr med. P. Juillerat, Inselspital Bern,

23 Thank you for your attention! 23

24 Crohn s disease : Epidemiology Cumulative incidence of fistula in CD patients: 30 50% (70%) Half of them! Will have fistula in their life! 10 y None 20 y life Tang LY, et al. Clin Gastroenterol Hepatol 2006;4: Schwartz DA et al. Gastroenterology 2002; 122: