1. Dr. Matt. Johnson Prof R.J.Nicholls Dr. A.Forbes Prof P.Ciclitira The Management of Pouchitis and Cuffitis

2. Proctocolectomy UC UC 10-20% all UC patients 10-20% all UC patients For medical refractory disease or dysplasia For medical refractory disease or dysplasia FAP FAP Mean age at diagnosis of cancer = 39y Mean age at diagnosis of cancer = 39y

5. A Pouch

6. Pathological changes within a normal Healthy Pouch 6/52 6/52 plasma cell infiltration plasma cell infiltration raised eosinophils raised eosinophils Later = lymphocyte infiltration Later = lymphocyte infiltration 6/12 6/12 Villous atrophy Villous atrophy >6/12 >6/12 “Normal adaptation” with cell influx stabilizing “Normal adaptation” with cell influx stabilizing Tendency to colonic metaplasia “colonic type mucosa” Tendency to colonic metaplasia “colonic type mucosa”

7. Pouch Flora Prox jejunum 10 3 (cfu/g of dry stool) Prox jejunum 10 3 (cfu/g of dry stool) Ileum 10 5-8 Ileum 10 5-8 Pouch 10 7-10 Pouch 10 7-10 Caecum 10 11-12 Caecum 10 11-12 {Nicholls RJ, 1981}{Tabaquhali S, 1970}

8. Pouch Flora The proportion of anaerobes increases distally The proportion of anaerobes increases distally Ileum = 1:1 (Anaerobe : aerobe) Ileum = 1:1 (Anaerobe : aerobe) Caecum = 1000:1 Caecum = 1000:1 {Philipsin, 1975} Ileal Pouch = 100:1 Ileal Pouch = 100:1 Colonic type flora (bacterioides, bifidobacteria) Colonic type flora (bacterioides, bifidobacteria) {Shepherd NA, 1989}

9. Bowel Flora 10x as many bacteria as cells in the body 10x as many bacteria as cells in the body 1kg of our weight {Farrell RJ,2002} 1kg of our weight {Farrell RJ,2002} 55% of stool 55% of stool “the neglected organ” {Bocci V,1992} “the neglected organ” {Bocci V,1992} Bacterial profiles are genetically determined and remain stable lifelong Bacterial profiles are genetically determined and remain stable lifelong {van de Merwe JP, 1988}

10. Pouchitis

11. Endoscopic Findings in Pouchitis Oedema Oedema Granularity Granularity Friable Friable Loss of vascular Loss of vascular Mucosal exudates Mucosal exudates Ulceration Ulceration These changes can be patchy These changes can be patchy Inflammation is often worse in the posterior/dependent segment of the pouch) Inflammation is often worse in the posterior/dependent segment of the pouch)

12. Histological Pouchitis Definitions 1986 Moskowitz Histopathological Scoring System > 4 = Pouchitis Acute Acute Acute PMNC infiltration into the crypts and surface epithelium (3/3) Acute PMNC infiltration into the crypts and surface epithelium (3/3) 1. Mild 2. Moderate + Crypt Abscesses 3. Severe + Crypt Abscesses Superficial ulceration (3/3) Superficial ulceration (3/3) 1. <25% of field 2. 25-50% 3. >50% Chronic Chronic Chronic (lymphocytic) infiltration (3/3) Chronic (lymphocytic) infiltration (3/3) Degree of villous atrophy (3/3) Degree of villous atrophy (3/3)

13. Pouchitis Symptoms A) Post Op Stool Frequency A) Post Op Stool Frequency B) Rectal Bleeding B) Rectal Bleeding C) Faecal Urgency* +/- Cramps C) Faecal Urgency* +/- Cramps D) Fever (unusual) D) Fever (unusual) * usually due to inflammation at the distal/efferent limb of the pouch * usually due to inflammation at the distal/efferent limb of the pouch There is often poor correlation between symptoms and either the endoscopic or histology appearance There is often poor correlation between symptoms and either the endoscopic or histology appearance

14. Pouchitis Disease Activity Index, Sandborn 1994 >7 = Acute Pouchitis

15. Clinical Pattern After 6/12 patients fall into 3 catagories; After 6/12 patients fall into 3 catagories; 1. No pouchitis (45%) 2. Episodic Pouchitis (42%) 3. Chronic Pouchitis (13%) = > 4/52 Relapsing / Remitting (>3-4 a year) Relapsing / Remitting (>3-4 a year) Antibiotic Dependent Antibiotic Dependent Persistent / Refractory Pouchitis Persistent / Refractory Pouchitis

16. Causes of Pouchitis Known Causes of Pouch Inflammation Crohn’s Crohn’s Ischaemia Ischaemia Radiation Radiation Specific pathogenic infections (CDT, CMV) Specific pathogenic infections (CDT, CMV) Localised infection (pelivic abscess) Localised infection (pelivic abscess) ?Reaction to secondary bile acids ?Reaction to secondary bile acids ?Stasis (no association found) ?Stasis (no association found) Dysbiosis (alteration in the balance of the normal bowel flora) Dysbiosis (alteration in the balance of the normal bowel flora)

17. Bacterial Aetiology for IBD - UC In 1989 a case report with active refractory UC In 1989 a case report with active refractory UC Rx= Antibiotics and an enema of “normal” faecal bacteria Rx= Antibiotics and an enema of “normal” faecal bacteria Benefits were maintained for 6 months Benefits were maintained for 6 months {Bennet JD, 1989} Antibiotics Antibiotics Reduce severity and duration of UC Reduce severity and duration of UC {Dickinson RJ, 1985}{Mantzaris GJ, 1994}{Turunen UM, 1998}{Present DH, 1998}{Cummings JH, 2001} Improve Pouchitis - endoscopy and histology Improve Pouchitis - endoscopy and histology {Madden MV, 1994}{Kmiot WA, 1993}{Hurst RD, 1996/8}{Shen B, 2001}{Scott AD, 1989}{Gionchetti P, 1999}{Mimura T, 2002}

18. Treatment of Acute Pouchitis 1. Metronidazole 1-2g PO for 7/7 {MaddenMV,1994} 55% SEs = N+V, abdo discomfort,headache, skin rash, metallic taste, disulfiram like reaction with Xol, peripheral neuropathy 55% SEs = N+V, abdo discomfort,headache, skin rash, metallic taste, disulfiram like reaction with Xol, peripheral neuropathy 2. Metronidazole suppositories (40-160mg/d) {Isaacs 1997} 3. Ciprofloxacin 500mg bd PO 7/7 {Shen 2001} 7/7 course < 14/7 course < combination 7/7 course < 14/7 course < combination Cipro + Metro {Mimura T, 2002} Cipro + Metro {Mimura T, 2002} Cipro + Rifampicin {Gionchetti P, 1999} Cipro + Rifampicin {Gionchetti P, 1999} Prophylactic doses (increased resistance) Prophylactic doses (increased resistance)

19. Other Treatments to Consider 1. Pentasa 2g bd PO {Tytgat GN,1988}{Shepherd NA, 1989} 2. Budesonide 9mg PO {Shepherd NA, 1989} 3. Budesonide suppositories {Boschi, 1992} 60% relapse 60% relapse 4. Azathioprine {MacMillan 1999} 5. Bismuth Subsalicylate {Tremaine 1998} 6. Glutamine / Butyrate (SCFA) enemas/suppos {de Silva HJ, 1989} 7. Allopurinol 300mg bd PO {Levin KE, 1992}

20. Probiotic Therapy for Pouchitis VSL 3 (Gionchetti 1994) VSL 3 (Gionchetti 1994) 4x lactobacilli 4x lactobacilli 3x bifidobacteria 3x bifidobacteria 1x Strep Salivarius 1x Strep Salivarius 1x S. thermaphiles 1x S. thermaphiles Remission can be maintained in 92.5% at 9/12 Vs 0% in the placebo group Remission can be maintained in 92.5% at 9/12 Vs 0% in the placebo group

21. Probiotic Trials in Acute Pouchitis High dose of probiotics is effective in the treatment of mild pouchitis. A pilot study. Amanidini C, Gionchetti P et al. Digestive and Liver Disease 2002; 34 (Suppl. 1):A96 Abstract Abstract Positive results Positive results NB = Not written up into a paper ?why NB = Not written up into a paper ?why

22. Probiotic Trials in Chronic Pouchitis Oral bacteriotherapy as maintainance therapy in patients wih chronic pouchitis: a double blind placebo controlled trial. Giochetti P, et al. Gastroenterology 2000; 119:305-309 Placebo n = 20 6g VSL 3 n = 20 40 Patients n = 20 n = 0 n = 3 n = 17 Relapse Remission after 9/12

23. Trials of Probiotics as Prophylaxis Prophylaxis of pouchitis onset with probiotic therapy: a double blind placebo controlled trial. Giochetti P, et al. Gastroenterology 2000; 124: 1202-1209 Placebo n = 20 6g VSL 3 n = 20 40 Patients n = 8 40% n = 12 60% n = 2 10% n = 18 90% Pouchitis Remission after 12/12

24. Probiotics as od Maintainance Once daily high high dose probiotic therapy maintaining remission in recurrent/refractory pouchitis. Mimura T, et al. GUT 2004; 124: 108-114 Placebo n = 16 6g VSL 3 n = 20 36 Patients n = 15 93% n = 1 7% n = 2, +1 15% n = 17 85% Pouchitis Remission after 12/12

25. Probiotic Therapeutic Mechanisms Increasing the acidity (increases SCFAs) Increasing the acidity (increases SCFAs) Altering the hosts immune response at the GI mucosa Altering the hosts immune response at the GI mucosa Produce antibiotic like substances (bacteriocins) Produce antibiotic like substances (bacteriocins) Increased IgA + IL 10 (anti-inflammatory) Increased IgA + IL 10 (anti-inflammatory) Decreases IFNg and TNFa (pro-inflammatory) Decreases IFNg and TNFa (pro-inflammatory) Induces T cell shift towards Th2 (anti-inflammatory) Induces T cell shift towards Th2 (anti-inflammatory) May competitively inhibit adherence of potentially pathogenic bacteria May competitively inhibit adherence of potentially pathogenic bacteria Increase intestinal mucus production Increase intestinal mucus production Produce SCFAs and vitamins Produce SCFAs and vitamins

26. What’s on Offer NameStrainImplantUses Saccaromyces boulardii YesDiarrhoea Prevention + Rx Actimel L.casei strain DN- 114001 Yes Stoneyfield Yogurt L.reiteriYes Diarrhoea Rx Arla L.acidophilus NCFB 1748 Yes L.rhamnosus VTT E-97800 Yes PrimaLiv L.rhamnosus 271 Yes Yakult L.casei strain Shirota Yes Culturelle L.casei GG YesCDT Pro Viva L.plantarum 299v YesIBS

27. VSL#3 Trial in Chronic Pouchitis Recently managed to acquire funding for 10 local patients to receive 1 year of VSL#3 Recently managed to acquire funding for 10 local patients to receive 1 year of VSL#3 May be able to import for GPs who are prepared to pay May be able to import for GPs who are prepared to pay The group will be closely monitored to assess The group will be closely monitored to assess Cost / Benefit ratio Cost / Benefit ratio Primary Culture Assays and PDAI before and 3/12 Primary Culture Assays and PDAI before and 3/12 Assess long term outcome Assess long term outcome If successful we will assess the effects of terminating after 3-6/12 If successful we will assess the effects of terminating after 3-6/12

28. Where’s the Future Heading Pre-biotics Pre-biotics “Non-Digestible Food (NDF) ingredients that beneficially effect he host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, that can improve host health” 1 {Gibson G. 1995} “Non-Digestible Food (NDF) ingredients that beneficially effect he host by selectively stimulating the growth and/or activity of one or a limited number of bacteria in the colon, that can improve host health” 1 {Gibson G. 1995} Such CHO – soluble fibre Such CHO – soluble fibre A) Encourages growth of beneficial (saccharolytic) bacteria A) Encourages growth of beneficial (saccharolytic) bacteria B) Attract harmful (proteolytic) bacteria away from mucosa (gut wall) by saturating the adhesin-CHO binding sites B) Attract harmful (proteolytic) bacteria away from mucosa (gut wall) by saturating the adhesin-CHO binding sites

29. Prebiotics Side Effects Flatulence + Bloating Flatulence + Bloating Rx = Gradually increase fibre with time Rx = Gradually increase fibre with time Gradual increase in Bifidobacterium Gradual increase in Bifidobacterium Decrease freely available NDF Decrease freely available NDF Decreases gas formed by other bacteria Decreases gas formed by other bacteria

30. Prebiotics and the Pouch Inulin 24g a day for 21/7 (crossover trial) 1 Inulin 24g a day for 21/7 (crossover trial) 1 Decreased inflammation in 19/19 pouches Decreased inflammation in 19/19 pouches 1. Welters C. et al. Effect of dietary inulin supplementation on inflammation of pouch mucosa in patients with ileal pouch anal anastamosis. Diseases of the colon and rectum 45: 621- 627

31. Natural Prebiotics Nutraceuticals = “functional foods” Nutraceuticals = “functional foods” Inulin / Fructo-oligosaccharides / Lactulose Transgalacto-oilgosaccharides Inulin / Fructo-oligosaccharides / Lactulose Transgalacto-oilgosaccharides Chicory (boiled root = 90% inulin) Chicory (boiled root = 90% inulin) Jerusalem artichoke Jerusalem artichoke Onion Onion Leek Leek Garlic Garlic Asparagus Asparagus Banana Banana (cereals eg. Oatmeal) (cereals eg. Oatmeal)

33. Conclusion Pouch histology can help guide the medical management Pouch histology can help guide the medical management Acute pouch inflammation associated with Acute pouch inflammation associated with Anaemia Anaemia Iron deficiency Iron deficiency Chronic pouch inflammation associated with Chronic pouch inflammation associated with Folate, Vitamin D and B12 deficiencies Folate, Vitamin D and B12 deficiencies Benefits of correcting deficiencies Benefits of correcting deficiencies Prevent potential long term complications Prevent potential long term complications Anecdotal considerable improvement in the QOL Anecdotal considerable improvement in the QOL

34. FAP Pouches HealthyInflamed

35. Chart 1 Percentage of FAP Pouches with Histological Evidence of Significant Acute, and Mixed Inflammatory Changes AcuteChronicMixed 0 5 10 15 20 25 30 35 Histological Inflammation Chart 2 Percentage of FAP Pouch Patients with PDAI Scores Diagnostic of Active Pouchitis HistologyEndoscopyClinicalPDAI 0 10 20 30 40 50 PDAI Score and its Individual Components % 55 of 190 had evidence of endoscopic inflammation Of those 55, 14% had a PDAI of >7 suggestive of active pouchitis This gave an overall prevalence of pouchitis in FAP pouches as 4%

36. Cuffitis Almost exclusive to those with a stapled anastamosis Almost exclusive to those with a stapled anastamosis There is a 60% risk of leaving residual rectal mucosa behind when stapling a pouch with a 1-2cm anal transition zone There is a 60% risk of leaving residual rectal mucosa behind when stapling a pouch with a 1-2cm anal transition zone Even after mucosectomy there is a 20% of residual islands of rectal mucosa left on the rectal cuff Even after mucosectomy there is a 20% of residual islands of rectal mucosa left on the rectal cuff

37. Cuffitis Symptoms 1. Urgency 2. Diarrhoea (Frequency) 3. Burning Pain (pre/post-defecation) 4. Tenesmus

38. Treatment of Cuffitis Is similar to the treatment of proctitis 1. Mesalazine suppositories / enemas 2. Predsol suppositories / enemas 3. ? Lignocaine gel Consider Metronidazole suppositories Metronidazole suppositories

39. Pre – Pouch Ileitis 1. Pentasa granules / PO 2. Azathioprine 3. Other Immuno-modulators