crohns disease (2)

7/31/2019 Crohns Disease (2)

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Dr Bernard Stacey


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DAPPSSICAMPDescriptionAetiologyPathophysiologyPredisposing factors

SymptomsSignsInvestigationsComplicationsAlternativesManagementPrognosis


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Areas of InterestCauses (Genetics and others)

Treatments (Drugs and surgery)

Assessment


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DescriptionAetiologyPathophysiologyPredisposing factorsSymptomsSignsInvestigationsComplicationsAlternativesManagement

Prognosis


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Crohns diseaseChronic inflammatory

condition

Can affect anypart of

the gutCommonly:large bowelterminal ileum

small bowel- localised, diffuse

perianal


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Description

AetiologyPathophysiologyPredisposing factorsSymptomsSignsInvestigationsComplicationsAlternativesManagement

Prognosis


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Crohns diseasePrevalence: 40 per 100,000

Incidence: approx 0.7 - 1 per 1000 peopleWestern world

Clusters

Affecting all agesPeaks in 20s and 60s


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DescriptionAetiology

PathophysiologyPredisposing factorsSymptomsSignsInvestigationsComplicationsAlternativesManagement

Prognosis


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Macroscopic featuresBowel thickened and narrowed

Deep fissuring ulcerscobblestoning

Fistulae and abcesses


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Microscopic features

(histology)

Inflammation extends throughout all layers

of bowelChronic inflammatory cells

Granulomas

60-75% only

Lymphoid hyperplasia


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DescriptionAetiologyPathophysiology

Predisposing factorsSymptomsSignsInvestigationsComplicationsAlternativesManagement

Prognosis


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SMOKING !Increased risk of:

Getting it in the first place

Aggressive diseaseRelapse

Hospital admissions

Surgery

Cancer


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GeneticsLong known that Crohns / UC is commoner in

families / twins

Not simple inheritanceSibling with CD/UC means 15-30x the risk

1 in 7 patients have a relative with the illness


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Genetics (2)THE HUMAN GENOME PROJECT

1996: Oxford group

Showed Crohns and UC share somesusceptibilty genes

Chromosomes 3, 7 and 12


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An Infective Cause for

Crohns?M. Paratuberculosis

E. Coli

Viruses eg: measles

Post-infectivebacteria

Clostridium

Bacteroides

Toothpaste

Cornflakes

Hygiene

Allergy

Refined sugars

Trauma

Pollutants


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DescriptionAetiologyPathophysiologyPredisposing factors

SymptomsSignsInvestigationsComplicationsAlternativesManagement

Prognosis


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Symptoms-depend on site of diseaseAbdominal pain

Weight loss

Diarrhoea +/- blood

Obstructive symptoms

Complications of fistulae

Complications of malabsorption

B12, Ca/Vit D, Zn, etc


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DescriptionAetiologyPathophysiologyPredisposing factorsSymptoms

SignsInvestigationsComplicationsAlternativesManagement

Prognosis


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Oral apthous ulceration


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Episcleritis


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Erythema NodosumIBD

TB/ SarcoidOCP, sulphonamidesStreptococcal infections

Yersinia, psitticosisLymphogranuloma

venereumConnective tissue

disordersTuleraemia


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Pyoderma

Gangrenosum


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Arthropathy with effusion

(supra-patellar)


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Sacro-ileitis


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DescriptionAetiologyPathophysiologyPredisposing factorsSymptomsSigns

InvestigationsComplicationsAlternativesManagement

Prognosis


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InvestigationsBlood tests and markers of nutritionHb, ESR/CRP, Albumin, LFTs

EndoscopyOGD, enteroscopy, colonoscopy HISTOLOGY

X-ray / ultrasoundSB meal/enema, Ba enema, fistulogram, CT

Nuclear medicineLabelled leucocyte scan

Laparoscopy


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Fissuring rose

thorn ulceration

in terminal ileum


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Skip lesions in thesmall bowel


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Non-invasive imagingVirtual colonoscopy

Fast CT scan after usual bowel prepLarge memory computer

Accompanying software


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Prognosis


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ComplicationsSocial / financial days off workPsychosexual surgery, stomas

Nutritional osteoporosis, B12Multiple resections short bowel

syndrome

Fistulae

Toxic megacolonPrimary sclerosing cholangitis

Cancerrisk after 10 years in total colitis


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0 2 4 6 8 10 15 20 25 30

Increasing risk of colorectal cancer in colitis years after diagnosis


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Differential diagnosisInitially often IBS

Ulcerative colitisInfective diarrhoeaespecially amoebic

Differential diagnosis of malabsorption and

malnutritionIleal TB / lymphoma

Behets disease


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InvestigationsComplicationsAlternatives

Management

Prognosis


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Current treatments5-ASA drugsSteroid enemasBudesonideSteroids(Elemental diets)AzathioprineMethotrexateInfliximab,

adalimumabSurgeryDiversionResection


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5-ASA drugsRole in prevention of colorectal cancer

Sulphasalazine

3% compliant patients

31% non-compliant patients

Mesalazine

Reduces risk by 81% at >1.2g/day


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SurveillanceTotal colitisEvery 3 yrs after 8 years

Every 2 years from 20-30 yearsAnnually thereafter

Left sided colitisAfter 15 years

Proctitisnil


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Remission rates:

Crohns UC

Overall 45% 58%

>6/12 Rx 64% 87%

IBD and azathioprine

Fraser et al: Gut. 2002;50(4):485-9


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Up to 1/3 of patients with IBD discontinue

azathioprine because of side-effects or lackof a clinical response

Life-threatening haematotoxicityNeutropenia

ThrombocytopeniaPancytopenia

IBD patients on azathioprine


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IBD patients on

azathioprine15% suffer early toxicityMost of these (77%) are within 12 weeks of

starting therapyNausea within 2 weeksDeranged LFTs within 8 weeksBone marrow toxicity within up to 12 weeks

Step up dosing???


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Human RBC TPMT

11

1

1

1 1 11 11 11

TPMT Activity, Units/ml RBC

Unrelated Adults111

TPMT H/TPMTH

TPMT L/TPMTH

TPMT L/TPMTL

%

OfSubje

ctsPer

.

UnitsofActivity

11

TPMTH/TPMTH

TPMTL/TPMTH

TPMTL/TPMTL


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1

1

11

11

11

11

11

1 11 11 11 11 >11

10%

5%


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Pharmacogenetic based

prescribingTailored azathioprine doses

Case reports of successful treatment ofhomozygous TPMTL patients with low doseazathioprine:

0.1 0.3 mg/kg

(eg: 70kg 7mg od)

Kaskas BA et al. Gut 2003; 52: 140-2


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Non-respondersInverse correlation between TPMT and 6-TGN6-TGN levels > 235 correlate with remission

Increasing AZA dose:1/3 will achieve remission

2/3 will not

6-TGN levels

No change in 6-TGN levels

BUT in mercaptopurine

metabolitesHepatotoxicity in 1/4


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AllopurinolUsed at 200mg with reduction of azathioprine

dose to 25%

Drives pathway towards 6TG by blocking XOarm

Needs careful monitoring


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MCV and 6-TGN levels166 patients with IBD starting AZA / 6-MPMean rise in MCV on treatment of 8

Good correlation between change in MCVand 6-TGN concentrations (p=0.001)

MCV is a simple and inexpensive alternative to

measurement of 6-TGN in patients treated withazathioprine or 6-mercaptopurine.


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TPMT - summary

1 : 300 absent activity; 10% relative deficiency

Measure it before you start therapy?Identify those prone to early leucopenic episodes

Identify those who may need supra-normal doses

Not a substitute for regular FBCs


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Azathioprine duration

of treatmentrisk of relapse if stopped after 2 years

Efficacy sustained over 5 years

What if a patient has been on azathioprine for10 years and is clinically well???


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Smoking and CrohnsF > M

4 x more likely to require surgery2 x the recurrence rate after surgery

4 x more likely to require steroids

5 x less likely to respond to infliximab

Heavy = >15 cigarettes/day


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Crohns patients and

smoking90% recognise dangers with respect toOverall health

Lung cancerCardiovascular disease

9% recognise an association with Crohns12% aware ofrisk of reoperation


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Crohns patients and

smoking42% patients smoke (general population =26%)

60% increase risk of relapse

10 year post surgical requirement forimmunosuppressants54% for smokers

24% for non-smokers

Benefits of stopping apparent within 1

year


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Methotrexate in

CrohnsWeekly 25mg IM for 4-6 months then

Weekly 15mg IM for up to a year65% maintain remission

Remission for up to 3 years but early relapse

when stopped


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Methotrexate in Crohns:

Side effectsBone marrow suppression

Muscle / joint achesIntercurrent infections

Liver fibrosis

Pneumonitis


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InfliximabAnti-TNFmonoclonal antibodyInfusion

Single / multiple doses (5mg/kg)

Resistant and fistulating Crohns disease

Potential for anaphylaxis

70% remission at 1 year


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Infliximab Licensed by NICE for those with: Severe active Crohns with or without fistulae

Crohns refractory to other immunemodulating drugs or who have toxicity fromthem

Those for whom surgery is inappropriate

Given either as single infusion or at weeks0, 2 and 6


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What is Infliximab ?The first licensed therapeutic anti-TNF

antibody

Chimaeric antibody

variable regions mouse anti-human TNF Ab A2

attached to human IgG 1 with kappa light chains

Wh t d I fli i b


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What does Infliximab

do?Binds to Soluble and Transmembrane TNF

Activates Complement

Ab-dependent cytotoxicity of activated CD4 cellsand macrophages

Decreases mucosal inflammatory cytokineproduction

Induces apoptosis in stimulated T cells

H i I fli i b


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How is Infliximab

givenAs a single infusion (Day Case)

Repeat infusions at approximately 2 monthintervals for maintenance


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Does Infliximab work?In non-fistulating disease: ~65% clinical response at 4 weeks (15%

placebo)

~50% of responding patients maintained inremission at 1 year (repeated infusions)

In fistulating disease:

50% of perianal fistula disease patients showclosure (13% placebo)

Wh t th


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What are the

problems?Rapid healing may lead to Gut obstruction Fistula blockage and abscess formation

Antibody formation (HACA)* Reactions to ~ 6% of infusions

?Failure of immune surveillance* ? Risk of malignancy (lymphoma)

Cost


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Summary There is no such thing as simplyCrohns disease.

Proctitis

Colitis

Small bowel focal, diffuse

Peri-anal

Stricturing

Fistulating


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SummaryDear Dr.

Diagnosis:

1. Stricturing distal ileal Crohns disease: 1995

2. On azathioprine Sept 2002 (MCV 84 93)

3. TPMT 36.5

4. Normal DEXA scan Oct 2002

5. Last steroid course ended July 2001


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SummaryCrohns5-ASA

Osteoporosis Rx

Methotrexate

Infliximab

Stop smoking

UC

5-ASA

Osteoporosis Rx

Ciclosporin

Azathioprine


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DescriptionAetiology

PathophysiologyPredisposing factorsSymptomsSigns


Prognosis


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Prognosis

Average life expectancy = 10 years less thangeneral population


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crohns disease (2)

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