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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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DescriptionAetiologyPathophysiologyPredisposing factorsSymptomsSigns
InvestigationsComplicationsAlternativesManagement
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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DescriptionAetiologyPathophysiologyPredisposing factorsSymptomsSigns
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
InvestigationsComplicationsAlternativesManagement
Prognosis
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Prognosis
Average life expectancy = 10 years less thangeneral population
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