Chronic Refractory Pouch Dysfunction

Transcription

1 Chronic Refractory Pouch Dysfunction Anatomy of Pelvic Pouches Afferent limb (neo-ti) Tip of J J S W Inlet Efferent limb Bo Shen, MD The Ed and Joey Story Endowed Chair Professor of Medicine The Cleveland Clinic Foundation Cleveland, Ohio Indications for Colectomy in UC Outlet/cuff/ anal transitional Efferent limb zone Frequency of Chronic with Different Pouch Configurations 00% 80% 60% 40% 20% 3.0% 8.3% 0.0% 0% J pouch S pouch K pouch N = 25 N = 45 N = 36 Mukewar S, Shen B, DDW 202 J, K Pouches vs. Ileostomy Brooke Ileostomy Kock Pouch Pelvic J Pouch Disorders of the Ileal Pouch Surgical/ Mechanical Inflammatory/ Infectious Functional Neoplastic Systemic/ Metabolic - Irritable - Pouch/ATZ - Anemia -Anastomotic leak - pouch syn. Neoplasia - Bone loss - Pelvic sepsis - Cuffitis -Anismus - Lymphoma - Vit D def. - Sinus - Crohn s dis. Poor Squamous - Renal stone - Fistula - Small cell cancer - Vit B2 def. - Strictures bowel bacterial compliance - Pseudo- Celiac dis. -Afferent limb syn. overgrowth obstruction/ - Efferent limb syn. - Inflammatory megapouch - Infecundity polyps - Hypersensitive - Sexual suture lines dysfunction - Pouchalgia - Portal vein thrombi - Prolapse - Twist/volvulus Updated from Shen B, et al. AJG 2005;00; Foreign body

2 Afferent Limb Syndrome Owl s Eyes and Pouch Dysfunction Shen B, Remzi FH, Fazio VW. CGH 2008;6:45-58 Endoscopic Predictors of Pouch Failure Factor HR (95% CI) p Crohn s pouch 2.7 (.2, 6.3) 0.08 Surgical complications 4.4 (.7,.2) Post-operative biologics 5.3 (2.5,.2) < abnormalities of Owls beak 3.6 (.5, 8.7) Cuff endoscopy score.5 (.3,.7) <0.00 Efferent Limb Syndrome 7 cm N = 426 Shen B, Remzi FH, Fazio VW. CGH 2008;6: cm Alder K, Shen B. IBDJ 203 S pouch (no owls eyes) Twisted Pouch 2

3 Endoscopic Clues for Etiology of? Kock Pouch Hemorrhagic Fever-CMV Tight Nipple Valve Stricture C. Diff NSAID Ischemia Chronic Natural History of Ischemia Surgery-associated anatomic comp Refractory Relapsing Disease Activity Episodic Nl pouch or FAP pouch Months Metronidazole Pathogenetic Model of Why not in FAP Pouches? Abnormal Immune Response Therapeutic Target Genetic Susceptibility Mechanical factors (e.g. ischemia) Alteration commensal bacteria (dysbiosis) Pathogens Therapeutic Target Therapeutic Target Luminal factors (e.g.nsaids) Navaneethan U & Shen B. AJG 200;05:5-64 Cipro Rifaximin Tinidazole Antifungals FMT? Risk Factors for Extensive UC Backwash ileitis Primary sclerosing cholangitis P-ANCA IL-ra, NOD2 polymorphisms NOD2 gene polymorphisms Precolectomy thrombocytosis Fazio VW, et al. Ann Surg995 Schmidt CM, et al. Ann Surg 998 Non-smoker Lohmuller JL, et al. Ann Surg 990 Fleshner P, et al. Gut2003 NSAIDs Achkar JP, et al. CGH 2005 Arthralgia Shen B, et al AJG 2005 Meier CB, et al. IBDJ 2005 Surgical techniques?? Shen B, et al, CGH 2006 Fleshner P, et al. CGH2007 Koltun W, et al. DCR 20 Tyler A, et al. Gut 202 3

4 Management of Conventional RCT of Antibiotic Therapy in Cipro or Metronidazole x 2 wks Median in PDAI score N Type of pouchitis Agent Madden994 3 Chronic pouchitis Metro 400 mg TID vs. placebo 7 N/A Shen Acute pouchitis Cipro g/d vs.n Metro. 20 mg/kg/d 4 Cipro -6.7 Metro -5.9 Isaacs Acute or Chronic pouchitis Rifaximin.2 g/ d vs. placebo in study group Authors Days Responded Not Responded Metronidazole or Cipro x 2 more wks Infrequent Relapse Frequent Relapse Antx -responsive Antibiotics prn Responded Antx -dependent Probiotic or Antibiotic Carbon Microsphere? Lactulose? Not Responded Antx-refractory Cipro + Metronidazole or Rifaximin or Tinidazole x 4 wks Not Responded 5-ASA/steroids/ Immunomodulators/Biologics? Open-labeled Trials of Antibiotics in N Type of pouchitis Drugs Duration (days) Med ian in PDAI Madiba acute p. antx dependent p. chr antx refractory p, Metro 200 mg TID 30 Clin response in 77% acute p. Shen Antibiotic dependent p. Rifaximin 200 mg/day 90-3 Shen Chronic antx refractory p. Cipro g/day + Tinidazole 5/mg/kg/d 28-7 Gionchetti Chronic antx refractory p. Cipro g/d +Rifaximin 2 g/ d 5-7 Abdelrazaq Chronic antx refractory p. Cipro gm/d + Rifaximin 2g/d 4-2 Kornbluth Chronic antx refractory p. Rifaximin g/d 2 Clin response in 8% Mimura Refractory acute p. Metro mg/d + Cipro gm/d 28-9 Hurst Acute antx responsive p. Metro. 750 mg/d or Cipro g/d 7 Clin response in 94% Study Probiotics in Primary or Secondary Prophylaxis of Authors Year N Design Gionchetti/Gastro RCT Relapse 9 mo : 5% vs 00% Gionchetti /Gastro RCT 2 (0%) in study group; 8 (40%) in placebo group had pouchitis at 2 mo Mimura/Gut RCT Relapse 9 mo: 6% vs 85% Shen/APT Openlabeled McLaughlin/DDW Openlabeled Outcome On VSL3 at 8 mo: 9% Idiopathic (dysbiosis-associated) Rationale for Antibiotic/Probiotic Therapy in Idiopathic Shoot blindly Target: dysbiosis alteration in quality/quanlity of commensal bacteria Consequences Bacterial resistance Opportunistic infection (C. difficile) Remission 3% 4

5 Fecal Coliform Culture in Number Patients Resistant Sensitive + Treat E. Coli 6 Klebsiella Ciprofloxacin (00%) Co-amoxiclav (40%) Cefixime (60%) Trimethoprim (73%) Co-amoxiclav (53%) Trimethoprim (3%) Colistin (33%) Coliform, not classified 2 Pseudomonas Morganella Range of C. difficile 4-wk treatment with sensitive antibiotics (N =5): - Median 24-hr st ool f requency: Median PDAI symptom score: 4 0 McLaughlin SD. CGH 2009;7:545 Secondary (with identifiable etiology/triggering factors) Innocent? superimposed infectant? or original culprit? Campylobacter Pathogen-associated pouchitis NSAID-induced pouchitis Ischemic pouchitis Immune-mediated pouchitis Fever, malaise, dehydration Rx: Erythromycin Shen B, et al. AJG 200;05:472-3 Clostridium difficile Infection in Pouch Authors Year N Prevalence Outcome Mann/ DCR Recovered Shen/ DDS Recovered Shen/ CGH % Risk factors: Male (OR=5.0) Shen/NRGH Fatal 96 % (PCR for toxin B) Refractory/Recurrence to vancomycin Li/IBDJ 203 C. diff pouchitis CMV He XS, Shen B. IBDJ 200 C. diff enteritis 5

6 Candida: Part of Mucosal Associated Bacteria/Fungi Navaneethan U & Shen B. AJG 200;05:5-64 Imaging Features of Ischemic Ischemic Ischemic Clues: Male Difficult pouch in operative note (the issue of reach ) Obese or excessive weight gain (>5% of baseline) Abdominal surgery (hernia repair, mesh) Portal vein thrombi Antibiotic refractory Crohn s Disease Shen B, et al. IBDJ 200 Implication of the Identification of Ischemic Different from ischemic colitis or mesenteric ischemia Necrosis/bowel infarction hardly occurs Doppler or angiogram often negative Potential surgical treatment Lysis of adhesion Pouch revision or redo pouch (J J; J K) Shen B, et al, Inflamm Bowel Dis 200;6: Ischemic Lysis of Adhesion in Treatment of Ischemic Shen B, et al, Inflamm Bowel Dis 200;6:

7 Clinical Clues for Immune-mediated + enteritis Chronic antibiotic-refractory pouchitis Concurrent autoimmune disorders Serum autoantibodies -Year Budesonide in PSC-associated /Enteritis Pre- Post- P Afferent limb Endoscopy Score 2.3 ± ± Pouch Endoscopy Score 2.5 ± ± N = 8 Induction: 9mg/day 3 months Maintenance: 3mg/day No impact on LFTs Navaneethan U, et al. JCC 202;6: Enteritis in PSC + UC with or without Colectomy and Ileal Pouch Neo-Terminal Ileum Pouch Inlet Terminal Ileum Ileal Cecal Valve IgG4-associated 29% in refractory pouchitis Serum IgG4 may be normal Current autoimmune disorders are common Budesonide-st line therapy Pouch Colon Navaneethan U, et al. JCC 20;5:570-6 PSC-associated /Enteritis Long segment of distal small bowel disease in addition to diffuse pouchitis Concurrent autoimmune disorders are common (3% vs. 6% in control) Budesonide-st line therapy Autoimmune (GVHD-like) Chronic antibiotic-refractory pouchitis Concurrent autoimmune diseases Serum auto-antibodies Budesonide, small dose immunomodulator Apoptosis Normal Pouch Shen B. IBDJ 20;7: Autoimmune Jiang W, et al. DCR 202;55:

8 Cuffitis: A Residual UC? Ischemic/Collagenous Cuffitis B 2 cm D Shen B, et al. IBDJ 200 Cuffitis Diagnosis at the st Visit* N = 20 5ASA/steroidresponsive Cuffitis 5ASA/steroidrefractory Cuffitis 5ASA/steroiddependent Cuffitis N = 40 N = 58 N = 22 Crohn s Disease Refractory Cuffitis Surgical Complications (Fistula, Sinus) N = 9 N = 25 N = 4 Pouch Excision/Revision/ Diversion Pouch Excision/Revision /Diversion Pouch Excision/Revision / Diversion N=7 N=5 N=4 Lysis Adhesion in Treatment of Refractory Cuffitis *Mean duration of IBD before colectomy = 7.4 ± 7.2 yrs Wu B, et al. IBDJ 203 Mean duration of the pouch = 7. ± 5.3 yrs Refractory Cuffitis-A Sign of CD? Chronic Inflammation Low-grade Dysplasia High-grade Dysplasia Invasive Cancer 3 Years 8

9 Pouch Cancer/Dysplasia: Is Surveillance Endoscopy Indicated & Adequate? Cox Model for Risk Factors for Pouch Neoplasia 7 months Adjusted HR (95%CI) P Male gender.6 ( ) Age at pouch.0 ( ) Duration of UC.0 ( ) PSC 0.4 ( ) Chronic pouchitis 0.69 ( ) Extensive colitis.53 ( ) ( ) < ( ) ( ) Colectomy for cancer Colectomy for dysplasia Mucosectomy Kariv R, et al. Gastroenterology 200;39: Classification of Crohn s Disease of Pouch Inflammatory Pouch Neoplasia: Cleveland Clinic Experience N=3203 Fibrostenotic Fistulizing Crohn s Disease in Patients with IPAA Cumulative Frequency % Yu 2000 Duetsch N = 59 N = 272 Fazio 2003 Neilly 999 N = 86 N = 7 Gemlo 992 N = 96 Keighley 2000 N = 222 Peyregne 999 N = 54 adenocarcinoma ; lymphoma ; SCC 3; dysplasia 23 Kariv R, et al. Gastroenterology 200;39:

10 Pouch Failure in Patients with Crohn s Disease 00 C umulat iv e Frequenc y % Diagnostic Algorithm for Crohn s Pouch Pouch Endoscopy & Biopsy Iatrogenic Complications, (fistula, leaks) / Ileitis 5-ASA Failure Cuffitis Diagnostic/ Therapeutic EUA 0 N = 67 Peyregne 999 Duetsch 99 Sagar 996 Gemlo 992 Tulchinsky 2003 Keighley 2000 Neilly 999 N = 79 N = 9 N = 37 N = 3 N = 3 N = 23 N=8 Trial of Biologics Shen B. IBDJ 2009;5: Open-Labeled Trial Infliximab in Fistulizing Crohn s Disease of the Pouch 00 Diagnosis/Management of Pouch Disorders Clinical Presentations Consistent with Antibiotic-refractory Chronic Median f/u = 22 months N = 26 Pouchoscopy + Biopsy 80 % of Cases Crohn s Disease Confirmed Review Colectomy Specimen, Contrasted Enema CTE MRI, EGD, serology? Fazio 995 Crohn s Disease Suspected Antibiotic Failure Diffuse /Enteritis 62% Segmental /Ileitis or Distal ± Cuffitis Stricture/ Fistula Sinus/Obstruction/ Structural Disease % 23% Labs (microbiology, ANA, LFTs, IgG4, celiac/anti- microsomal abs) Histology (apoptosis, IgG4, hematoidin) Histology, Abdominal Imaging ± Exam under Anesthesia 5% 20 Pathogen-induced 0 Complete Response Partial Response No Response Pouch Failure Induction Therapy Colombel JF, et al. AJG 2005 Adalimumab for Crohn s Disease of Pouch Factor Short term Long term Clinical response (N=48) None (%) 4(29.2) 22(45.8) Partial (%) Complete (%) 0(20.8) 24(50.0) 0(20.8) 6(33.3) Clinical response inflammatory fibrostenotic disease (N=23) or None (%) Partial (%) 7(30.4) 6(26.) 2(52.2) 4(7.4) 0(43.5) 7(30.4) None (%) 7(28.0) 0(40.0) Partial (%) 4(6.0) 6(24.0) Complete (%) Clinical response in fistulizing disease (N=25) Complete (%) Mucosal healing (%) Pouch failure (%) 4(56.0) 9(36.0) 20(4.7) NA 3(27.) 9(8.8) C.difficile CMV Immune-mediated PSC associated IgG4associated Ischemic Crohn s Disease Surgical Complications Autoimmune Pouchopathy Shen B. CGH 203 Summary A number of patients with chronic refractory pouch dysfunction in fact have surgery-associated mechanical or structural disorders is disease spectrum with ranging etiopathogenetic pathways, disease course, and prognosis De novo Crohn s disease can occur in pouch patients with a preoperative diagnosis of UC Emerging C. diffificle infection is challenging Cuffitis can in patients with restorative colectomy with ileal pouches Cancer risk persists after colectomy Most pouch cancer occurs at the cuff area Li Y, et al. IBDJ 202;8:

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