Crohns Disease (1)

7/30/2019 Crohns Disease (1)

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Dr Bernard Stacey


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DAPPSSICAMP DescriptionAetiology Pathophysiology Predisposing factors

Symptoms Signs Investigations ComplicationsAlternatives Management Prognosis


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Areas of Interest

Causes (Genetics and others)

Treatments (Drugs and surgery)

Assessment


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Description

Aetiology Pathophysiology Predisposing factors Symptoms Signs Investigations ComplicationsAlternatives Management

Prognosis


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Crohns disease Chronic inflammatory

condition

Can affect any part of the

gut Commonly:

large bowel

terminal ileum

small bowel- localised, diffuse

perianal


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Description

Aetiology Pathophysiology Predisposing factors Symptoms Signs Investigations ComplicationsAlternatives Management

Prognosis


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Crohns disease Prevalence: 40 per 100,000

Incidence: approx 0.7 - 1 per 1000 people Western world

Clusters

Affecting all ages

Peaks in 20s and 60s


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DescriptionAetiology

Pathophysiology Predisposing factors Symptoms Signs Investigations ComplicationsAlternatives Management

Prognosis


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Macroscopic features

Bowel thickened and narrowed

Deep fissuring ulcers cobblestoning

Fistulae and abcesses


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Microscopic features

(histology)

Inflammation extends throughout all layers of

bowel Chronic inflammatory cells

Granulomas

60-75% only

Lymphoid hyperplasia


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DescriptionAetiology Pathophysiology

Predisposing factors Symptoms Signs Investigations ComplicationsAlternatives Management

Prognosis


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SMOKING ! Increased risk of:

Getting it in the first place

Aggressive disease Relapse

Hospital admissions

Surgery

Cancer


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Genetics Long known that Crohns / UC is commoner in

families / twins

Not simple inheritance Sibling 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 some susceptibilty

genes

Chromosomes 3, 7 and 12


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An Infective Cause for Crohns? M. Paratuberculosis

E. Coli

Viruses eg: measles Post-infective bacteria

Clostridium

Bacteroides

Toothpaste

Cornflakes

Hygiene Allergy

Refined sugars

Trauma

Pollutants


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DescriptionAetiology Pathophysiology Predisposing factors

Symptoms Signs Investigations ComplicationsAlternatives Management

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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DescriptionAetiology Pathophysiology Predisposing factors Symptoms

Signs Investigations ComplicationsAlternatives Management

Prognosis


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Oral apthous ulceration


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Episcleritis


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Erythema Nodosum IBD

TB/ Sarcoid OCP, sulphonamides Streptococcal infections

Yersinia, psitticosis Lymphogranuloma venereum Connective tissue disorders Tuleraemia


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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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DescriptionAetiology Pathophysiology Predisposing factors Symptoms Signs

Investigations ComplicationsAlternatives Management

Prognosis


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Investigations Blood tests and markers of nutrition

Hb, ESR/CRP, Albumin, LFTs

Endoscopy OGD, enteroscopy, colonoscopy HISTOLOGY

X-ray / ultrasound SB meal/enema, Ba enema, fistulogram, CT

Nuclear medicine Labelled leucocyte scan

Laparoscopy


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Fissuring rosethorn ulceration in

terminal ileum


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Skip lesions in the smallbowel


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Non-invasive imagingVirtual colonoscopy

Fast CT scan after usual bowel prep Large memory computer

Accompanying software


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InvestigationsComplicationsAlternatives Management

Prognosis


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Complications Social / financial days off work

Psychosexual surgery, stomas

Nutritional osteoporosis, B12 Multiple resections short bowel syndrome

Fistulae

Toxic megacolon

Primary sclerosing cholangitis Cancer

risk 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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Investigations Complications

Alternatives Management

Prognosis


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Differential diagnosis Initially often IBS

Ulcerative colitis Infective diarrhoea

especially amoebic

Differential diagnosis of malabsorption and

malnutrition Ileal TB / lymphoma

Behets disease


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Investigations ComplicationsAlternatives

Management

Prognosis


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Current treatments 5-ASA drugs Steroid enemas Budesonide Steroids (Elemental diets) Azathioprine Methotrexate Infliximab, adalimumab

Surgery Diversion Resection


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Whats new in IBD treatment?


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DEXA scanning


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Steroids


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5-ASA drugs Role 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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Surveillance Total colitis

Every 3 yrs after 8 years

Every 2 years from 20-30 years Annually thereafter

Left sided colitis After 15 years

Proctitis nil


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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 lack of aclinical response

Life-threatening haematotoxicity Neutropenia

Thrombocytopenia Pancytopenia

IBD patients on azathioprine


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IBD patients on azathioprine 15% suffer early toxicity

Most of these (77%) are within 12 weeks of starting

therapy Nausea within 2 weeks

Deranged LFTs within 8 weeks

Bone marrow toxicity within up to 12 weeks

Step up dosing???


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Azathioprine metabolism


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Human RBC TPMT

10

5

00 5 10 15 20

TPMT Activity, Units/ml RBC

298 Unrelated Adults

TPMTH/TPMTH

TPMTL/TPMTH

TPMTL/TPMTL

%O

fSubje

ctsPer

0.5UnitsofActivity

TPMTH/TPMTH

TPMTL/TPMTHTPMTL/TPMTL


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TPMT levels in Southampton 2002-3

0

5

10

15

20

25

30

0 10 20 30 40 >50

10% 5%


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Pharmacogenetic based

prescribing

Tailored azathioprine doses

Case reports of successful treatment of homozygousTPMTL patients with low dose azathioprine:

0.1 0.3 mg/kg

(eg: 70kg 7mg od)

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


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Non-responders Inverse correlation between TPMT and 6-TGN

6-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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Allopurinol Used at 200mg with reduction of azathioprine dose to

25%

Drives pathway towards 6TG by blocking XO arm

Needs careful monitoring


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MCV and 6-TGN levels 166 patients with IBD starting AZA / 6-MP

Mean rise in MCV on treatment of 8

Good correlation between change in MCV and 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

treatment

risk of relapse if stopped after 2 years

Efficacy sustained over 5 years

What if a patient has been on azathioprine for 10 yearsand is clinically well???


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Smoking and Crohns F > M

4 x more likely to require surgery 2 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 smoking 90% recognise dangers with respect to

Overall health

Lung cancer Cardiovascular disease

9%recognise an association with Crohns

12% aware of risk of reoperation


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Crohns patients and smoking 42% patients smoke (general population = 26%)

60% increase risk of relapse

10 year post surgical requirement forimmunosuppressants

54% 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 year 65% maintain remission

Remission for up to 3 years but early relapse when

stopped


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Methotrexate in Crohns:

Side effects

Bone marrow suppression

Muscle / joint aches

Intercurrent infections

Liver fibrosis

Pneumonitis


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InfliximabAnti-TNF monoclonal antibody

Infusion

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 immune modulating drugsor who have toxicity from them

Those for whom surgery is inappropriate

Given either as single infusion or at weeks 0, 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


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What does Infliximab do? Binds to Soluble and Transmembrane TNF

Activates Complement

Ab-dependent cytotoxicity of activated CD4 cells andmacrophages

Decreases mucosal inf lammatory cytokine production

Induces apoptosis in stimulated T cells


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How is Infliximab givenAs a single infusion (Day Case)

Repeat infusions at approximately 2 month intervalsfor 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 in remission at

1 year (repeated infusions)

In fistulating disease:

50% of perianal fistula disease patients show closure(13% placebo)


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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 simply Crohns

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 20025. Last steroid course ended July 2001


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SummaryCrohns 5-ASA

Osteoporosis Rx

Methotrexate

Infliximab

Stop smoking

UC

5-ASA

Osteoporosis Rx

Ciclosporin

Azathioprine


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Investigations ComplicationsAlternatives Management

Prognosis


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Prognosis

Average life expectancy = 10 years less than generalpopulation


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Documents

Crohns Disease (1)