Inflammatory Inflammatory Bowel DiseaseBowel Disease

Kevin Luey, FRACPKevin Luey, FRACPGastroenterologistGastroenterologist

Inflammatory Bowel DiseasesInflammatory Bowel Diseases

Infective colitisInfective colitis Ulcerative colitisUlcerative colitis Crohn’s colitisCrohn’s colitis Ischaemic colitisIschaemic colitis NSAID-colitisNSAID-colitis Radiation colitisRadiation colitis

CROHN’S DISEASECROHN’S DISEASE

ULCERATIVE COLITISULCERATIVE COLITIS

IBDIBD

Chronic inflammatory Chronic inflammatory disorders of the disorders of the

gastrointestinal tract of gastrointestinal tract of unknown aetiology but unknown aetiology but with an autoimmune with an autoimmune

basis, characterised by basis, characterised by ulceration and ulceration and

inflammation of the gut inflammation of the gut wall, causing abdominal wall, causing abdominal

pain, diarrhoea and rectal pain, diarrhoea and rectal bleeding.bleeding.

PrevalencePrevalencePrevalence varies world wide being more Prevalence varies world wide being more

common in developed countries. 100-200 common in developed countries. 100-200 per 100,000 in western countries. ? per 100,000 in western countries. ? Underestimate.Underestimate.

Higher prevalence in white races and Jews.Higher prevalence in white races and Jews.

More common in close relatives.More common in close relatives.

The prevalence of Crohn’s in the NZ The prevalence of Crohn’s in the NZ population is approximately 100 per population is approximately 100 per 100,000100,000

IncidenceIncidence

Was doubling every 10 years since Was doubling every 10 years since 19401940

Improved recognitionImproved recognition

Appears to be increasing slowly now.Appears to be increasing slowly now.

Real increaseReal increase

Currently 10-20/100,000Currently 10-20/100,000

PathogenesisPathogenesis

Still unknown nearly 100 years after first Still unknown nearly 100 years after first descriptiondescription

A combination of environmental factors A combination of environmental factors triggering chronic inflammation in a triggering chronic inflammation in a genetically predisposed hosts.genetically predisposed hosts.

Pathogenesis of IBDPathogenesis of IBD

genes

mucosal immunity

mucosal inflammation

IBD

foodmicroflora

drugs

smoking

Differences between Differences between Crohn’s and UCCrohn’s and UC

Differences in disease phenotypeDifferences in disease phenotype Differences in genetic associations Differences in genetic associations

(e.g. IBD1 on chromosome 16 coding (e.g. IBD1 on chromosome 16 coding for NOD2 important in CD but not UC)for NOD2 important in CD but not UC)

Both diseases long thought of as Both diseases long thought of as centering on upregulated immune centering on upregulated immune reactivity, but reactivity, but increasing evidence of disordered innate increasing evidence of disordered innate

immunity in CD immunity in CD

Phenotype Differences Phenotype Differences between Crohn’s disease between Crohn’s disease

and UCand UCCrohn’s DiseaseCrohn’s Disease

TransmuralTransmural Small and large Small and large

bowelbowel Skip lesionsSkip lesions Rectal SparingRectal Sparing Granulomata Granulomata

commoncommon

Ulcerative ColitisUlcerative Colitis MucosalMucosal Large bowel onlyLarge bowel only Continuous diseaseContinuous disease Rectal involvement Rectal involvement

95%95% Granulomata Granulomata

uncommonuncommon

Clinical Clinical presentations presentations

and patterns of and patterns of diseasedisease

IBD: key clinical factors. IBD: key clinical factors.

PresentationPresentation

diarrhoea, often diarrhoea, often bloodybloody

abdominal painabdominal painweight lossweight lossmalaisemalaise

Natural HistoryNatural History

Onset any age, peaks Onset any age, peaks early adulthood and early adulthood and 40-6040-60

Relapse and Relapse and remissionsremissions

life-longlife-long

Ulcerative colitisUlcerative colitisClinical featuresClinical features

Unformed stools Unformed stools Blood and mucusBlood and mucus Abdominal crampsAbdominal cramps UrgencyUrgency TenesmusTenesmus

Disease distributionDisease distribution Begins in rectum and Begins in rectum and

extends continuously extends continuously proximallyproximally

UC Clinical courseUC Clinical course

Natural historyNatural history Fulminant (often Fulminant (often

first episode)first episode) Chronic relapsing Chronic relapsing

and remittingand remitting Chronic continuousChronic continuous Self limiting Self limiting

(<10%)(<10%)

Relapse rateRelapse rate 50% in first year 50% in first year

ColectomyColectomy Pancolitis 30-40% in 5 yrsPancolitis 30-40% in 5 yrs Distal colitis; 10% in 5 Distal colitis; 10% in 5

yrsyrs 1%/year thereafter for all1%/year thereafter for all These rates appear to be These rates appear to be

falling since Infliximab falling since Infliximab

has become availablehas become available

ASSESSING SEVERITY OF UC(Truelove & Witts BMJ 1954)

<5/d, trace blood >5/d, bloody

No fever >37.8

<90 >90

Normal <10.5

<30 >30

stools

temperature

pulse

Hb

ESR

mild severe

Crohn’s disease Crohn’s disease Clinical featuresClinical features

Systemic Systemic symptomssymptoms Due to chronic Due to chronic

inflammationinflammation LethargyLethargy Loss of appetiteLoss of appetite Weight lossWeight loss FeverFever

Intestinal Intestinal symptomssymptoms Depend on disease Depend on disease

distributiondistribution Abdominal painAbdominal pain DiarrhoeaDiarrhoea Weight lossWeight loss Rectal bleedingRectal bleeding NauseaNausea

Crohn’s diseaseCrohn’s diseaseSites of involvementSites of involvement

Small bowelSmall bowel 30%30% Terminal ileumTerminal ileum 80%80%

Small and large bowelSmall and large bowel 50%50%

Large bowelLarge bowel 20%20%

Diagnostic Diagnostic investigationsinvestigations

DiagnosisDiagnosis Stool cultureStool culture Blood testsBlood tests

Inflammatory markersInflammatory markers Nutritional markersNutritional markers

Endoscopy and histologyEndoscopy and histology RadiologyRadiology Nuclear med scansNuclear med scans

White cell scansWhite cell scans DEXADEXA

ASCA/ANCAASCA/ANCA Faecal calprotectinFaecal calprotectin

Blood testsBlood tests

Raised CRP/ESRRaised CRP/ESR Raised platelets: correlate well with IBD Raised platelets: correlate well with IBD

rather than infectious colitisrather than infectious colitis Hypoalbuminaemia: correlates with high Hypoalbuminaemia: correlates with high

CRPCRP Full blood count – anaemia, neutrophiliaFull blood count – anaemia, neutrophilia Iron, Vitamin B12, folateIron, Vitamin B12, folate Renal functionRenal function Liver functionLiver function

EndoscopyEndoscopy

Oesophogastroduodenoscopy Oesophogastroduodenoscopy (gastroscopy)(gastroscopy)

Ileo-colonoscopy (colonoscopy)Ileo-colonoscopy (colonoscopy)

Enteroscopy (small bowel)Enteroscopy (small bowel)

Capsule endoscopyCapsule endoscopy

Endoscopy (ILEO-Endoscopy (ILEO-colonoscopy)colonoscopy)

HistologyHistology

Crypt distortion (implies Crypt distortion (implies inflammation for more than 6 weeks)inflammation for more than 6 weeks)

Chronic inflammatory cellsChronic inflammatory cells Granuloma formationGranuloma formation Can help with diagnosing Can help with diagnosing

microscopic colitismicroscopic colitis

RadiologyRadiology Plain filmsPlain films Contrast studies ? outdatedContrast studies ? outdated

Ba follow through, enemaBa follow through, enema CTCT

Collections (e.g. abcesses)Collections (e.g. abcesses) ComplicationsComplications

USUS Bowel wall thickeningBowel wall thickening CollectionsCollections

MRIMRI Perianal diseasePerianal disease Small bowelSmall bowel

AXR IN ACUTE UCAXR IN ACUTE UC

Transverse Transverse colon dilation, colon dilation, mucosal islands mucosal islands and thumb-and thumb-printingprinting

Crohn’s diseaseCrohn’s disease

Ileal stricture: CT Ileal stricture: CT enteroclysisenteroclysis

Ileal stricture: MRIIleal stricture: MRI

Treatment Treatment strategiesstrategies

MANAGEMENT OF IBDMANAGEMENT OF IBD

GeneralGeneral Education - CCSGEducation - CCSG Psychological Psychological

supportsupport Nutritional supportNutritional support Avoid risk factorsAvoid risk factors

smoking, drugssmoking, drugs

‘‘MDT’MDT’ GP, physician, GP, physician,

surgeon, surgeon, counsellor, nurse, counsellor, nurse, pharmacist, pharmacist, dietitiandietitian

Specific therapySpecific therapy medical, surgicalmedical, surgical

Ulcerative colitisUlcerative colitis

Ulcerative colitis Ulcerative colitis goals of therapygoals of therapy

Induce remission Induce remission Maintain remissionMaintain remission Quality of life (IBDQ)Quality of life (IBDQ) Prevent complicationsPrevent complications

DiseaseDisease Therapy relatedTherapy related

Appropriate timing for surgeryAppropriate timing for surgery

Ulcerative colitisUlcerative colitisTherapeutic considerationsTherapeutic considerations

ExtentExtent SeveritySeverity Disease complicationsDisease complications Response to previous therapiesResponse to previous therapies Lifestyle considerationsLifestyle considerations

UC Treatment OptionsUC Treatment Options

5 ASA – topical / oral5 ASA – topical / oral Steroids – topical / oral / systemicSteroids – topical / oral / systemic Azathioprine/6-MP/MethotrexateAzathioprine/6-MP/Methotrexate Cyclosporine – oral / systemicCyclosporine – oral / systemic Immunological therapies - biologicsImmunological therapies - biologics SurgerySurgery Alternative therapies – e.g. ProbioticsAlternative therapies – e.g. Probiotics

No treatment entirely effective or safeNo treatment entirely effective or safe

Management of fulminant Management of fulminant colitiscolitis

mortality reduced from 50% - 1.5%mortality reduced from 50% - 1.5% Meticulous clinical careMeticulous clinical care Multidisciplinary approachMultidisciplinary approach IV hydrocortisone 100mg qds (60%)IV hydrocortisone 100mg qds (60%) Prophylaxis against DVT/PEProphylaxis against DVT/PE Cyclosporin 2mg/kg (levels 150-250)Cyclosporin 2mg/kg (levels 150-250)

60% initial response, 30% long term60% initial response, 30% long term ? Biologics? Biologics Azathioprine on dischargeAzathioprine on discharge

5 ASA for active UC5 ASA for active UC

60% remission 60% remission OR 2.0 cf placebo in OR 2.0 cf placebo in

meta-analysismeta-analysis Topical in left sided Topical in left sided

disease (70% response)disease (70% response) Dose dependantDose dependant Renal toxicityRenal toxicity

Dose dependant Dose dependant nephritisnephritis

Class effect Class effect

Which 5ASA? What doseWhich 5ASA? What dose

stomach jejunum ileum stomach jejunum ileum coloncolon

PentasaPentasa(slow-release mesal)(slow-release mesal)

Asacol, SalofalkAsacol, Salofalk(pH-dependent mesalazine)(pH-dependent mesalazine)

sulphasalazine, olsalazine, balsalazidesulphasalazine, olsalazine, balsalazide(azo-bonded)(azo-bonded)

CORTICOSTEROIDS IN IBDCORTICOSTEROIDS IN IBD

Restrict to active IBDRestrict to active IBD No prophylactic roleNo prophylactic role Co-prescribe bone protectionCo-prescribe bone protection Minimise long-term useMinimise long-term use

RESPONSE TO STEROIDS IN IBDRESPONSE TO STEROIDS IN IBD

65% remission/improvement in 65% remission/improvement in 4/124/12

50% Crohn’s patients relapse or are 50% Crohn’s patients relapse or are steroid-dependent at 1 yearsteroid-dependent at 1 year

`̀

PROBLEMS WITH PROBLEMS WITH STEROIDSSTEROIDS

Given inappropriatelyGiven inappropriatelyRecurrence after stoppingRecurrence after stoppingSide-effectsSide-effectsFailure to heal mucosaFailure to heal mucosa

SIDE-EFFECTS OF SIDE-EFFECTS OF STEROIDSSTEROIDS

osteoporosis - give calcium/vit Dosteoporosis - give calcium/vit Ddiabetesdiabetesinfectionsinfectionsosteonecrosis of hiposteonecrosis of hiphypertensionhypertensionglaucoma/cataractsglaucoma/cataractsskin changes……….skin changes……….

Maintenance therapy for Maintenance therapy for UCUC

5 ASA5 ASA Azathioprine Azathioprine BiologicsBiologics

Azathioprine Azathioprine

Long term maintenance strategyLong term maintenance strategy Slow onset 2-3 monthsSlow onset 2-3 months Mainly uncontrolled dataMainly uncontrolled data 36% 1 year relapse compared to 36% 1 year relapse compared to

59%59%

??duration of therapy??duration of therapy

Side effects of Side effects of AzathioprineAzathioprine

Allergic responsesAllergic responses LeucopeniaLeucopenia Nausea and vomitingNausea and vomiting PancreatitisPancreatitis DermatologicalDermatological ? Malignancy? Malignancy ? Effects in pregnancy? Effects in pregnancyMonitoring:Monitoring: regular FBC and LFT regular FBC and LFT

Surgery for UCSurgery for UC

Fulminant colitisFulminant colitis

Failed medical treatmentFailed medical treatment

ComplicationsComplications

Cancer riskCancer risk

Surgery for UCSurgery for UC

Panproctocolectomy

Ileostomy

Pouch formation

Close stoma

Crohn’s diseaseCrohn’s disease

Crohn’s diseaseCrohn’s disease Goals of therapyGoals of therapy

Similar to UCSimilar to UC Nutrition/growthNutrition/growth Surgery – Not curativeSurgery – Not curative

- High relapse rate- High relapse rate Fistula managementFistula management

5ASA INDICATIONS5ASA INDICATIONS

Crohn’sCrohn’s mild-moderately active disease – esp. mild-moderately active disease – esp.

coloncolon ? Effectiveness as maintenance? Effectiveness as maintenance prophylaxis only after small bowel prophylaxis only after small bowel

resectionresection

Steroids in Crohn’s disease

Gut, 1994; 35: 360

Antibiotics in Crohn’s Antibiotics in Crohn’s diseasedisease

Metronidazole

Perianal / colonic disease

?active disease

Some benefit post surgery 1yr

Neuropathy

Azathioprine as Azathioprine as maintenance in Crohn’s maintenance in Crohn’s

diseasedisease

Benefit at 2.5mg/kg but not much beyond

Methotrexate in Crohn’s Methotrexate in Crohn’s diseasedisease

Start 25mg s/c weekly MTX for 16 weeks

Then maintain with 15mg s/c or oral weekly

Side effects of Side effects of methotrexatemethotrexate

Allergic reactionAllergic reaction Folate deficiency Folate deficiency Oral ulcerationOral ulceration Bone marrow suppressionBone marrow suppression Pneumonitis/pulmonary fibrosisPneumonitis/pulmonary fibrosis Hepatic fibrosisHepatic fibrosis TeratogenicTeratogenic

Healing of Colonic UlcerationWith Infliximab

Reprinted with permission of van Dullemen HM et al. Gastroenterology. 1995;109:129.

Pretreatment 4 Weeks Post treatment

Van Dullemen Gastroenterology 1995

Healing of Colonic Ulceration with Anti-TNFAnti-TNF Antibodies Antibodies

BiologicsBiologics

Anti- TNF alpha antibodies.Anti- TNF alpha antibodies. TNF alpha important near the TNF alpha important near the

beginning of the inflammatory beginning of the inflammatory cascadecascade

Blocking this prevents inflammation Blocking this prevents inflammation and resultant ulceration etc.and resultant ulceration etc.

IgG

Binding Site for TNF

• Infliximab •Chimeric monoclonal antibody

•Given as iv infusions (approx every 2 months)

•Adalimumab•Fully humanised

•Given as subcut injection every 2 weeks

Anti-TNFAnti-TNF Antibodies Antibodies

Infliximab ResultsInfliximab Results

Chronic activeChronic active 30% remission30% remission 30% 30%

improvementimprovement

FistulationFistulation 60% closure60% closure

Concurrent immunosuppressives or maintenance therapy essential

Early recurrence on stopping

General ContraindicationsGeneral Contraindications

Intestinal sepsisIntestinal sepsis pregnancy, lactation pregnancy, lactation (experience (experience

reassuring)reassuring) Infection – check esp. for TBInfection – check esp. for TB heart failureheart failure malignancymalignancy

Side EffectsSide Effects

infusion reactionsinfusion reactions acute 20%acute 20% delayed delayed

hypersensitivity 2%hypersensitivity 2% ANA - 50% dsDNA ANA - 50% dsDNA

AbsAbs lymphoma?lymphoma?

aplastic aplastic anaemiaanaemia

heart failureheart failure demyelination, demyelination,

aseptic aseptic meningitismeningitis

infections infections !!Cost - $5000 per infusion!!

AdalimumabAdalimumab

Humanised alpha TNF antibodyHumanised alpha TNF antibody Therefore less immunogenicTherefore less immunogenic Given subcutaneously rather than ivGiven subcutaneously rather than iv Similar results to InfliximabSimilar results to Infliximab Same precautions and side effectsSame precautions and side effects Given 2 weeklyGiven 2 weekly

COMPLICATIONS OF COMPLICATIONS OF IBDIBD

LOCALLOCAL ulcerationulceration bleedingbleeding stricturestricture perforationperforation fistulafistula abscessabscess cancercancer

SYSTEMICSYSTEMIC eyeseyes jointsjoints skinskin liverliver thrombosisthrombosis

Extra-intestinal Extra-intestinal manifestations of IBDmanifestations of IBD

Erythema nodosum

Pyoderma gangrenosum

Colorectal Cancer in UCColorectal Cancer in UC

High risk in Ulcerative ColitisHigh risk in Ulcerative Colitis Very high risk if have sclerosing Very high risk if have sclerosing

cholangitischolangitis Risk increases with duration and Risk increases with duration and

extent of disease extent of disease 2% after 10 years2% after 10 years 9% after 20 years9% after 20 years 19% after 30 years19% after 30 years

Colonoscopic Colonoscopic Surveillance in UCSurveillance in UC

Recommended colonoscopic Recommended colonoscopic surveillance with multiple biopsiessurveillance with multiple biopsies Every 2 years from 8-10 years after Every 2 years from 8-10 years after

diagnosisdiagnosis Annually after 20 yearsAnnually after 20 years

High grade dysplasia – colectomyHigh grade dysplasia – colectomy Low grade dysplasiaLow grade dysplasia ? Colectomy ? Colectomy

? 6 monthly ? 6 monthly colonoscopiescolonoscopies

Colorectal Cancer in Colorectal Cancer in Crohn’s ColitisCrohn’s Colitis

Evidence less clear cut than in UCEvidence less clear cut than in UC Increasing evidence that the risk is Increasing evidence that the risk is

similar to UC in Crohn’s colitis.similar to UC in Crohn’s colitis. Most experts recommend same Most experts recommend same

surveillance programme as for UCsurveillance programme as for UC

PROGNOSIS OF IBDPROGNOSIS OF IBD

lifelong relapses and remissionslifelong relapses and remissions bowel resections bowel resections

» UC 20%UC 20%» Crohn’s 70%Crohn’s 70%

mortality increasing slightly in mortality increasing slightly in Crohn’sCrohn’s

mortality decreasing rapidly in mortality decreasing rapidly in UCUC

Time trends of death from ulcerative colitis (full line) and Crohn's disease (dashed lines).

Sonnenberg A Int. J. Epidemiol. 2007;36:890-899

Published by Oxford University Press on behalf of the International Epidemiological Association © The Author 2007; all rights reserved.

SummarySummary

IBD common and affects wide range of IBD common and affects wide range of age groups, often the youngage groups, often the young

Multidisciplinary and holistic care is Multidisciplinary and holistic care is essential in such a chronic conditionessential in such a chronic condition

Treatment relies on induction of remission Treatment relies on induction of remission then maintenance with anti-inflammatory then maintenance with anti-inflammatory and immunosuppressive treatmentsand immunosuppressive treatments Steroids are not useful for maintenanceSteroids are not useful for maintenance Immunosuppressive regimens are applied in a Immunosuppressive regimens are applied in a

step-wise approachstep-wise approach

UNDERWRITERS’ VIEWUNDERWRITERS’ VIEW

INCREASING PREVALENCEINCREASING PREVALENCE DECREASING MORTALITY – Life ratingsDECREASING MORTALITY – Life ratings MORE EFFECTIVE MEDICATIONS but MORE EFFECTIVE MEDICATIONS but

not without morbidity – probably not without morbidity – probably balancing out for TRB and Trauma balancing out for TRB and Trauma (critical illness) ? For IP(critical illness) ? For IP

BOWEL CANCER RISK LOWER THAN BOWEL CANCER RISK LOWER THAN PREVIOUSLY THOUGHT – Trauma and IPPREVIOUSLY THOUGHT – Trauma and IP

Future genetic tests ?Future genetic tests ?