Dr Bernard Stacey

DAPPSSICAMP

Description Aetiology Pathophysiology Predisposing factors Symptoms Signs Investigations Complications Alternatives Management Prognosis

Areas of Interest
Causes (Genetics and others) Treatments (Drugs and surgery) Assessment

 Description

Aetiology Pathophysiology Predisposing factors Symptoms Signs Investigations Complications Alternatives Management Prognosis

Crohns disease
Chronic inflammatory

condition Can affect any part of the gut Commonly: large bowel terminal ileum small bowel
- localised, diffuse
perianal

 Description

Aetiology

Pathophysiology Predisposing factors Symptoms Signs Investigations Complications Alternatives Management Prognosis

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

 Description Aetiology

Pathophysiology

Predisposing factors Symptoms Signs Investigations Complications Alternatives Management Prognosis

Macroscopic features
Bowel thickened and narrowed Deep fissuring ulcers cobblestoning Fistulae and abcesses

Microscopic features (histology)

Inflammation extends throughout all layers of

bowel Chronic inflammatory cells Granulomas

60-75% only

Lymphoid hyperplasia

 Description Aetiology Pathophysiology

Predisposing factors

Symptoms Signs Investigations Complications Alternatives Management Prognosis

SMOKING !
Increased risk of: Getting it in the first place Aggressive disease Relapse Hospital admissions Surgery Cancer

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

Genetics (2)
THE HUMAN GENOME PROJECT
1996: Oxford group Showed Crohns and UC share some susceptibilty

genes Chromosomes 3, 7 and 12

An Infective Cause for Crohns?

M. Paratuberculosis
E. Coli Viruses eg: measles

Toothpaste
Cornflakes Hygiene

Post-infective bacteria
Clostridium Bacteroides

Allergy
Refined sugars Trauma

Pollutants

Description Aetiology Pathophysiology Predisposing factors Signs Investigations Complications Alternatives Management Prognosis

Symptoms

Symptoms
-depend on site of disease
Abdominal pain
Weight loss Diarrhoea +/- blood Obstructive symptoms Complications of fistulae Complications of malabsorption B12, Ca/Vit D, Zn, etc

Description Aetiology Pathophysiology Predisposing factors Symptoms Investigations Complications Alternatives Management Prognosis

Signs

Oral apthous ulceration

Episcleritis

Erythema Nodosum
IBD
TB/ Sarcoid OCP, sulphonamides Streptococcal infections

Yersinia, psitticosis Lymphogranuloma venereum Connective tissue disorders Tuleraemia

Pyoderma Gangrenosum

Arthropathy with effusion (supra-patellar)

Sacro-ileitis

Description Aetiology Pathophysiology Predisposing factors Symptoms Signs

Investigations

Complications Alternatives Management Prognosis

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

Fissuring rose thorn ulceration in terminal ileum

Skip lesions in the small bowel

Non-invasive imaging
Virtual colonoscopy Fast CT scan after usual bowel prep Large memory computer Accompanying software

Description Aetiology Pathophysiology Predisposing factors Symptoms Signs Investigations

Complications
Alternatives Management Prognosis

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

0 2 4 6 8 10

15

20

25

30

Increasing risk of colorectal cancer in colitis years after diagnosis

Description Aetiology Pathophysiology Predisposing factors Symptoms Signs Investigations Complications

Alternatives
Management Prognosis

Differential diagnosis
Initially often IBS
Ulcerative colitis Infective diarrhoea
especially amoebic

Differential diagnosis of malabsorption and malnutrition Ileal TB / lymphoma Behets disease

Description Aetiology Pathophysiology Predisposing factors Symptoms Signs Investigations Complications Alternatives

Management
Prognosis

Current treatments

5-ASA drugs Steroid enemas Budesonide Steroids (Elemental diets) Azathioprine Methotrexate Infliximab, adalimumab Surgery
Diversion Resection

Whats new in IBD treatment?

DEXA scanning

Steroids

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

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

IBD and azathioprine

Remission rates:

Crohns Overall >6/12 Rx 45% 64%

UC 58% 87%

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

IBD patients on azathioprine

Up to 1/3 of patients with IBD discontinue

azathioprine because of side-effects or lack of a clinical response

Life-threatening haematotoxicity Neutropenia Thrombocytopenia Pancytopenia

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???

Azathioprine metabolism

Human RBC TPMT

% Of Subjects Per 0.5 Units of Activity
298 Unrelated Adults
10
TPMTH/TPMTH TPMTH/TPMTH

TPMT L /TPMTH TPMTL/TPMTH TPMTL/TPMTL TPMTL/TPMT L

0 0 5 10 15 20

TPMT Activity, Units/ml RBC

TPMT levels in Southampton 2002-3

30 25 20 15 10 5 0 0 10 20 30 40 >50

10%

5%

Pharmacogenetic based prescribing

Tailored azathioprine doses Case reports of successful treatment of homozygous

TPMTL patients with low dose azathioprine:

0.1 0.3 mg/kg (eg: 70kg 7mg od)

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

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 metabolites

Hepatotoxicity in 1/4

Allopurinol
Used at 200mg with reduction of azathioprine dose to

25% Drives pathway towards 6TG by blocking XO arm Needs careful monitoring

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 with azathioprine or 6-mercaptopurine.

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

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 years

and is clinically well???

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

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

Crohns patients and smoking

42% patients smoke (general population = 26%)
60% increase risk of relapse

10 year post surgical requirement for immunosuppressants

54% for smokers 24% for non-smokers

Benefits of stopping apparent within 1 year

Methotrexate in Crohns
Weekly 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

Methotrexate in Crohns: Side effects

Bone marrow suppression Muscle / joint aches Intercurrent infections Liver fibrosis Pneumonitis

Infliximab
Anti-TNF monoclonal antibody
Infusion Single / multiple doses (5mg/kg) Resistant and fistulating Crohns disease Potential for anaphylaxis 70% remission at 1 year

Infliximab

Licensed by NICE for those with:

Severe active Crohns with or without fistulae Crohns refractory to other immune modulating drugs or who have toxicity from them Those for whom surgery is inappropriate

Given either as single infusion or at weeks 0, 2 and 6

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

What does Infliximab do?

Binds to Soluble and Transmembrane TNF Activates Complement Ab-dependent cytotoxicity of activated CD4 cells and macrophages Decreases mucosal inflammatory cytokine production Induces apoptosis in stimulated T cells

How is Infliximab given

As a single infusion (Day Case) Repeat infusions at approximately 2 month intervals

for maintenance

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)

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

Summary

There is no such thing as simply Crohns disease.

Proctitis Colitis Small bowel focal, diffuse Peri-anal Stricturing Fistulating

Summary
Dear 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

Summary
Crohns
5-ASA Osteoporosis Rx 5-ASA Osteoporosis Rx

UC

Methotrexate
Infliximab Stop smoking

Ciclosporin

Azathioprine

Description Aetiology Pathophysiology Predisposing factors Symptoms Signs Investigations Complications Alternatives Management

Prognosis

Prognosis
Average life expectancy = 10 years less than general

population