Dr. Matt. JohnsonDr. Matt. JohnsonProf R.J.NichollsProf R.J.Nicholls

Dr. A.ForbesDr. A.ForbesProf P.CiclitiraProf P.Ciclitira

The Management The Management ofof

Pouchitis and Pouchitis and CuffitisCuffitis

ProctocolectomyProctocolectomy

UCUC 10-20% all UC patients10-20% all UC patients For medical refractory disease or For medical refractory disease or

dysplasiadysplasia FAPFAP

Mean age at diagnosis of cancer = 39yMean age at diagnosis of cancer = 39y

A PouchA Pouch

Pathological changes Pathological changes within a normal Healthy within a normal Healthy

PouchPouch 6/526/52

plasma cell infiltrationplasma cell infiltration raised eosinophilsraised eosinophils Later = lymphocyte infiltrationLater = lymphocyte infiltration

6/126/12 Villous atrophyVillous atrophy

>6/12>6/12 ““Normal adaptation” with cell influx stabilizingNormal adaptation” with cell influx stabilizing Tendency to colonic metaplasia “colonic type mucosa”Tendency to colonic metaplasia “colonic type mucosa”

Pouch FloraPouch Flora

Prox jejunum Prox jejunum 10103 3 (cfu/g of dry (cfu/g of dry stool)stool)

Ileum Ileum 10105-85-8

Pouch Pouch 10107-107-10

Caecum Caecum 101011-12 11-12

{Nicholls RJ, 1981}{Tabaquhali S, 1970}{Nicholls RJ, 1981}{Tabaquhali S, 1970}

Pouch FloraPouch Flora

The proportion of anaerobes increases distally The proportion of anaerobes increases distally

Ileum = Ileum = 1:1 1:1 (Anaerobe : aerobe)(Anaerobe : aerobe)

Caecum = Caecum = 1000:11000:1{Philipsin, 1975}{Philipsin, 1975}

Ileal Pouch = Ileal Pouch = 100:1100:1

Colonic type flora (bacterioides, Colonic type flora (bacterioides, bifidobacteria)bifidobacteria)

{Shepherd NA, 1989}{Shepherd NA, 1989}

Bowel FloraBowel Flora

10x as many bacteria as cells in the body10x as many bacteria as cells in the body 1kg of our weight 1kg of our weight {Farrell {Farrell

RJ,2002}RJ,2002} 55% of stool55% of stool ““the neglected organ” the neglected organ” {Bocci {Bocci

V,1992}V,1992} Bacterial profiles are genetically Bacterial profiles are genetically

determined and remain stable lifelongdetermined and remain stable lifelong{van de Merwe JP, 1988}{van de Merwe JP, 1988}

PouchitisPouchitis

Endoscopic Findings in Endoscopic Findings in PouchitisPouchitis

OedemaOedema GranularityGranularity FriableFriable Loss of vascularLoss of vascular Mucosal exudatesMucosal exudates UlcerationUlceration

These changes can be patchyThese changes can be patchy Inflammation is often worse in the Inflammation is often worse in the

posterior/dependent segment of the pouch)posterior/dependent segment of the pouch)

Histological Pouchitis Histological Pouchitis DefinitionsDefinitions

1986 Moskowitz Histopathological Scoring System 1986 Moskowitz Histopathological Scoring System > 4 = > 4 = PouchitisPouchitis

AcuteAcute Acute PMNC infiltration into the crypts and surface Acute PMNC infiltration into the crypts and surface

epithelium (3/3)epithelium (3/3)1.1. MildMild2.2. Moderate + Crypt AbscessesModerate + Crypt Abscesses3.3. Severe + Crypt AbscessesSevere + Crypt Abscesses

Superficial ulceration (3/3)Superficial ulceration (3/3)1.1. <25% of field<25% of field2.2. 25-50%25-50%3.3. >50%>50%

ChronicChronic Chronic (lymphocytic) infiltration (3/3)Chronic (lymphocytic) infiltration (3/3) Degree of villous atrophy (3/3)Degree of villous atrophy (3/3)

Pouchitis SymptomsPouchitis Symptoms A) Post Op Stool FrequencyA) Post Op Stool Frequency B) Rectal BleedingB) Rectal Bleeding C) Faecal Urgency* +/- CrampsC) Faecal Urgency* +/- Cramps D) Fever (unusual)D) Fever (unusual)

* usually due to inflammation at the * usually due to inflammation at the distal/efferent limb of the pouchdistal/efferent limb of the pouch

There is often poor correlation between There is often poor correlation between symptoms and either the endoscopic or histology symptoms and either the endoscopic or histology appearance appearance

Pouchitis Disease Activity Index,Pouchitis Disease Activity Index,Sandborn 1994 Sandborn 1994

>7 = Acute Pouchitis>7 = Acute Pouchitis

Clinical PatternClinical Pattern

After 6/12 patients fall into 3 After 6/12 patients fall into 3 catagories;catagories;

1.1. No pouchitis (45%)No pouchitis (45%)

2.2. Episodic Pouchitis (42%)Episodic Pouchitis (42%)

3.3. Chronic Pouchitis (13%) Chronic Pouchitis (13%) = > 4/52= > 4/52 Relapsing / Remitting (>3-4 a year)Relapsing / Remitting (>3-4 a year) Antibiotic DependentAntibiotic Dependent Persistent / Refractory PouchitisPersistent / Refractory Pouchitis

Causes of PouchitisCauses of Pouchitis

Known Causes of Pouch InflammationKnown Causes of Pouch Inflammation

Crohn’sCrohn’s IschaemiaIschaemia RadiationRadiation 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 Dysbiosis (alteration in the balance of the normal bowel flora)bowel flora)

Bacterial Aetiology for Bacterial Aetiology for IBD - UCIBD - 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 Rx= Antibiotics and an enema of “normal” faecal

bacteriabacteria Benefits were maintained for 6 monthsBenefits were maintained for 6 months

{Bennet JD, 1989}{Bennet JD, 1989}

AntibioticsAntibiotics

Reduce severity and duration of UCReduce severity and duration of UC{Dickinson RJ, 1985}{Mantzaris GJ, 1994}{Turunen UM, 1998}{Present DH, 1998}{Cummings {Dickinson RJ, 1985}{Mantzaris GJ, 1994}{Turunen UM, 1998}{Present DH, 1998}{Cummings

JH, 2001}JH, 2001}

Improve Pouchitis - endoscopy and histologyImprove Pouchitis - endoscopy and histology{Madden MV, 1994}{Kmiot WA, 1993}{Hurst RD, 1996/8}{Shen B, 2001}{Scott AD, 1989}{Madden MV, 1994}{Kmiot WA, 1993}{Hurst RD, 1996/8}{Shen B, 2001}{Scott AD, 1989}

{Gionchetti P, 1999}{Mimura T, 2002}{Gionchetti P, 1999}{Mimura T, 2002}

Treatment of Acute Treatment of Acute PouchitisPouchitis

1.1. Metronidazole 1-2g PO for 7/7Metronidazole 1-2g PO for 7/7{MaddenMV,1994}{MaddenMV,1994}

55% SEs = N+V, abdo discomfort,headache, 55% SEs = N+V, abdo discomfort,headache, skin rash, metallic taste, disulfiram like skin rash, metallic taste, disulfiram like reaction with Xol, peripheral neuropathyreaction with Xol, peripheral neuropathy

2.2. Metronidazole suppositories (40-Metronidazole suppositories (40-160mg/d) 160mg/d) {Isaacs 1997}{Isaacs 1997}

3.3. Ciprofloxacin 500mg bd PO 7/7 Ciprofloxacin 500mg bd PO 7/7 {Shen 2001}{Shen 2001}

7/7 course < 14/7 course < combination7/7 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)

Other Treatments to Other Treatments to ConsiderConsider

1.1. Pentasa 2g bd PO Pentasa 2g bd PO {Tytgat GN,1988}{Shepherd {Tytgat GN,1988}{Shepherd NA, 1989}NA, 1989}

2.2. Budesonide 9mg PO Budesonide 9mg PO {Shepherd NA, 1989}{Shepherd NA, 1989}

3.3. Budesonide suppositories Budesonide suppositories {Boschi, 1992}{Boschi, 1992}

60% relapse60% relapse

4.4. Azathioprine Azathioprine {MacMillan 1999}{MacMillan 1999}

5.5. Bismuth Subsalicylate Bismuth Subsalicylate {Tremaine 1998}{Tremaine 1998}

6.6. Glutamine / Butyrate (SCFA) Glutamine / Butyrate (SCFA) enemas/suppos enemas/suppos {de Silva HJ, 1989}{de Silva HJ, 1989}

7.7. Allopurinol 300mg bd PO Allopurinol 300mg bd PO {Levin KE, 1992}{Levin KE, 1992}

Probiotic Therapy for Probiotic Therapy for PouchitisPouchitis

VSL 3 (Gionchetti 1994)VSL 3 (Gionchetti 1994) 4x lactobacilli4x lactobacilli 3x bifidobacteria3x bifidobacteria 1x Strep Salivarius1x Strep Salivarius 1x S. thermaphiles1x S. thermaphiles

Remission can be maintained in Remission can be maintained in 92.5% at 9/12 Vs 0% in the placebo 92.5% at 9/12 Vs 0% in the placebo groupgroup

Probiotic Trials in Acute Probiotic Trials in Acute PouchitisPouchitis

High dose of probiotics is effective in the treatment of mild pouchitis. A pilot High dose of probiotics is effective in the treatment of mild pouchitis. A pilot study.study.

Amanidini C, Gionchetti P et al. Digestive and Liver Disease 2002; 34 (Suppl. Amanidini C, Gionchetti P et al. Digestive and Liver Disease 2002; 34 (Suppl. 1):A961):A96 Abstract Abstract

Positive resultsPositive results NB = Not written up into a paper ?NB = Not written up into a paper ?

whywhy

Probiotic Trials in Chronic Probiotic Trials in Chronic PouchitisPouchitis

Oral bacteriotherapy as maintainance therapy in patients wih chronic pouchitis: Oral bacteriotherapy as maintainance therapy in patients wih chronic pouchitis: a double blind placebo controlled trial. Giochetti P, et al. Gastroenterology a double blind placebo controlled trial. Giochetti P, et al. Gastroenterology

2000; 119:305-309 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

Trials of Probiotics as Trials of Probiotics as ProphylaxisProphylaxis

Prophylaxis of pouchitis onset with probiotic therapy: a double blind placebo Prophylaxis of pouchitis onset with probiotic therapy: a double blind placebo controlled trial. controlled trial.

Giochetti P, et al. Gastroenterology 2000; 124: 1202-1209 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

Probiotics as od Probiotics as od MaintainanceMaintainance

Once daily high high dose probiotic therapy maintaining remission in Once daily high high dose probiotic therapy maintaining remission in recurrent/refractory pouchitis. recurrent/refractory pouchitis.

Mimura T, et al. GUT 2004; 124: 108-114 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

Probiotic Therapeutic Probiotic Therapeutic MechanismsMechanisms

Increasing the acidity (increases SCFAs)Increasing the acidity (increases SCFAs) Altering the hosts immune response at the GI Altering the hosts immune response at the GI

mucosamucosa 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-Induces T cell shift towards Th2 (anti-

inflammatory)inflammatory) May competitively inhibit adherence of May competitively inhibit adherence of

potentially pathogenic bacteriapotentially pathogenic bacteria Increase intestinal mucus productionIncrease intestinal mucus production Produce SCFAs and vitamins Produce SCFAs and vitamins

What’s on OfferWhat’s on OfferNameName StrainStrain ImplanImplan

ttUsesUses

Saccaromyces Saccaromyces boulardiiboulardii

YesYes DiarrhoeaDiarrhoea

Prevention + Prevention + RxRx

ActimelActimel L.casei strainL.casei strain DN-114001DN-114001

YesYes

Stoneyfield Stoneyfield YogurtYogurt

L.reiteriL.reiteri YesYes Diarrhoea RxDiarrhoea Rx

ArlaArla L.acidophilusL.acidophilus NCFB 1748NCFB 1748

YesYes

L.rhamnosusL.rhamnosus VTT E-97800VTT E-97800

YesYes

PrimaLivPrimaLiv L.rhamnosusL.rhamnosus 271271

YesYes

YakultYakult L.caseiL.casei strain strain Shirota Shirota

YesYes

CulturelleCulturelle L.caseiL.casei GG GG YesYes CDTCDT

Pro VivaPro Viva L.plantarumL.plantarum 299v299v

YesYes IBSIBS

VSL#3 Trial in Chronic VSL#3 Trial in Chronic PouchitisPouchitis

Recently managed to acquire funding for 10 local Recently managed to acquire funding for 10 local patients to receive 1 year of VSL#3patients to receive 1 year of VSL#3

May be able to import for GPs who are prepared May be able to import for GPs who are prepared to payto pay

The group will be closely monitored to assessThe group will be closely monitored to assess Cost / Benefit ratioCost / Benefit ratio Primary Culture Assays and PDAI before and Primary Culture Assays and PDAI before and

3/123/12 Assess long term outcomeAssess long term outcome If successful we will assess the effects of If successful we will assess the effects of

terminating after 3-6/12terminating after 3-6/12

Where’s the Future Where’s the Future HeadingHeading

Pre-bioticsPre-biotics ““Non-Digestible Food (NDF) ingredients that Non-Digestible Food (NDF) ingredients that

beneficially effect he host by selectively stimulating beneficially effect he host by selectively stimulating the growth and/or activity of one or a limited the growth and/or activity of one or a limited number of bacteria in the colon, that can improve number of bacteria in the colon, that can improve host health” host health” 11 {Gibson G. 1995} {Gibson G. 1995}

Such CHO – soluble fibreSuch CHO – soluble fibre A) Encourages growth of beneficial (saccharolytic) A) Encourages growth of beneficial (saccharolytic)

bacteriabacteria B) Attract harmful (proteolytic) bacteria away from B) Attract harmful (proteolytic) bacteria away from

mucosa (gut wall) by saturating the adhesin-CHO mucosa (gut wall) by saturating the adhesin-CHO binding sitesbinding sites

Prebiotics Side EffectsPrebiotics Side Effects

Flatulence + BloatingFlatulence + Bloating Rx = Gradually increase fibre with Rx = Gradually increase fibre with

time time Gradual increase in Bifidobacterium Gradual increase in Bifidobacterium Decrease freely available NDFDecrease freely available NDF Decreases gas formed by other bacteria Decreases gas formed by other bacteria

Prebiotics and the PouchPrebiotics and the Pouch

Inulin 24g a day for 21/7 Inulin 24g a day for 21/7 (crossover trial)(crossover trial)11

Decreased inflammation in Decreased inflammation in 19/19 pouches19/19 pouches

1.1. Welters C. et al. Effect of dietary inulin Welters C. et al. Effect of dietary inulin supplementation on inflammation of pouch supplementation on inflammation of pouch mucosa in patients with ileal pouch anal mucosa in patients with ileal pouch anal anastamosis. Diseases of the colon and rectum anastamosis. Diseases of the colon and rectum 45: 621-627 45: 621-627

Natural PrebioticsNatural Prebiotics Nutraceuticals = “functional foods” Nutraceuticals = “functional foods” Inulin / Fructo-oligosaccharides / Inulin / Fructo-oligosaccharides /

Lactulose Transgalacto-oilgosaccharidesLactulose Transgalacto-oilgosaccharides

Chicory (boiled root = 90% inulin)Chicory (boiled root = 90% inulin) Jerusalem artichokeJerusalem artichoke Onion Onion LeekLeek GarlicGarlic AsparagusAsparagus BananaBanana (cereals eg. Oatmeal)(cereals eg. Oatmeal)

33%26%

8%15% 14%

0

10

20

30

40

50

60

70

Number of patients

Hb Iron Folate B12 Vit D

Proportion of pouch patients with nutritional deficiencies

Normal

Deficient

ConclusionConclusion

Pouch histology can help guide the Pouch histology can help guide the medical management medical management Acute pouch inflammation associated withAcute pouch inflammation associated with

AnaemiaAnaemia Iron deficiency Iron deficiency

Chronic pouch inflammation associated withChronic pouch inflammation associated with Folate, Vitamin D and B12 deficiencies Folate, Vitamin D and B12 deficiencies

Benefits of correcting deficienciesBenefits of correcting deficiencies Prevent potential long term complications Prevent potential long term complications Anecdotal considerable improvement in the Anecdotal considerable improvement in the

QOLQOL

FAP PouchesFAP Pouches

Healthy Inflamed

Chart 1Percentage of FAP Pouches with Histological Evidence of

Significant Acute, and Mixed Inflammatory Changes

Acute Chronic Mixed0

5

10

15

20

25

30

35

Histological Inflammation

Chart 2Percentage of FAP Pouch Patients with PDAI Scores

Diagnostic of Active Pouchitis

Histology Endoscopy Clinical PDAI0

10

20

30

40

50

PDAI Score and its Individual Components

%

55 of 190 had evidence of endoscopic

inflammationOf those 55, 14% had a PDAI of >7

suggestive of active pouchitis

This gave an overall prevalence of

pouchitis in FAP pouches as 4%

CuffitisCuffitis

Almost exclusive to those with a Almost exclusive to those with a stapled anastamosisstapled anastamosis

There is a 60% risk of leaving There is a 60% risk of leaving residual rectal mucosa behind when residual rectal mucosa behind when stapling a pouch with a 1-2cm anal stapling a pouch with a 1-2cm anal transition zone transition zone

Even after mucosectomy there is a Even after mucosectomy there is a 20% of residual islands of rectal 20% of residual islands of rectal mucosa left on the rectal cuff mucosa left on the rectal cuff

Cuffitis SymptomsCuffitis Symptoms

1.1. UrgencyUrgency

2.2. Diarrhoea (Frequency)Diarrhoea (Frequency)

3.3. Burning Pain (pre/post-Burning Pain (pre/post-defecation)defecation)

4.4. TenesmusTenesmus

Treatment of Cuffitis Treatment of Cuffitis

Is similar to the treatment of proctitisIs similar to the treatment of proctitis

1.1. Mesalazine suppositories / enemasMesalazine suppositories / enemas2.2. Predsol suppositories / enemasPredsol suppositories / enemas3.3. ? Lignocaine gel? Lignocaine gel

ConsiderConsider Metronidazole suppositoriesMetronidazole suppositories

Pre – Pouch IleitisPre – Pouch Ileitis

1.1. Pentasa granules / POPentasa granules / PO

2.2. AzathioprineAzathioprine

3.3. Other Immuno-modulatorsOther Immuno-modulators