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Crohn’s disease. 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)

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crohn s disease

Crohn’s disease

Dr Bernard Stacey

dappssicamp
“DAPPSSICAMP”
  • Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
areas of interest
Areas of Interest
  • “Causes” (Genetics and others)
  • Treatments (Drugs and surgery)
  • Assessment
slide4
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
crohn s disease1
Crohn’s disease
  • Chronic inflammatory condition
  • Can affect any part of the gut
  • Commonly:
    • large bowel
    • terminal ileum
    • small bowel

- localised, diffuse

    • perianal
slide6
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
crohn s disease2
Crohn’s 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
slide8
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
macroscopic features
Macroscopic features
  • Bowel thickened and narrowed
  • Deep fissuring ulcers
    • cobblestoning
  • Fistulae and abcesses
microscopic features histology
Microscopic features(histology)
  • Inflammation extends throughout all layers of bowel
  • Chronic inflammatory cells
  • Granulomas
    • 60-75% only
  • Lymphoid hyperplasia
slide11
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
smoking
SMOKING !
  • Increased risk of:
    • Getting it in the first place
    • Aggressive disease
    • Relapse
    • Hospital admissions
    • Surgery
    • Cancer
genetics
Genetics
  • Long known that Crohn’s / 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
Genetics (2)

THE HUMAN GENOME PROJECT

  • 1996: Oxford group
  • Showed Crohn’s and UC share some susceptibilty genes
  • Chromosomes 3, 7 and 12
an infective cause for crohn s
An Infective Cause for Crohn’s?
  • M. Paratuberculosis
  • E. Coli
  • Viruses eg: measles
  • Post-infective bacteria
  • Clostridium
  • Bacteroides
  • Toothpaste
  • Cornflakes
  • Hygiene
  • “Allergy”
  • Refined sugars
  • Trauma
  • Pollutants
slide16
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
symptoms depend on site of disease
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
slide18
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
slide21
Erythema Nodosum
  • IBD
  • TB/ Sarcoid
  • OCP, sulphonamides
  • Streptococcal infections
  • Yersinia, psitticosis
  • Lymphogranuloma venereum
  • Connective tissue disorders
  • Tuleraemia
slide25
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
investigations
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
non invasive imaging
Non-invasive imaging
  • Virtual colonoscopy
    • Fast CT scan after usual bowel prep
    • Large memory computer
    • Accompanying software
slide30
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
complications
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
slide32
0 2 4 6 8 10 15 20 25 30

Increasing risk of colorectal cancer in colitis – years after diagnosis

slide33
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
differential diagnosis
Differential diagnosis
  • Initially often “IBS”
  • Ulcerative colitis
  • Infective diarrhoea
    • especially amoebic
  • Differential diagnosis of malabsorption and malnutrition
  • Ileal TB / lymphoma
  • Behçet’s disease
slide35
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
current treatments
Current treatments
  • 5-ASA drugs
  • Steroid enemas
  • Budesonide
  • Steroids
  • (Elemental diets)
  • Azathioprine
  • Methotrexate
  • Infliximab, adalimumab
  • Surgery
    • Diversion
    • Resection
5 asa drugs
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
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
slide42
IBD and azathioprine
  • Remission rates:

Crohn’sUC

Overall 45% 58%

>6/12 Rx 64% 87%

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

slide43
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
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???
slide46
Human RBC TPMT

TPMTH/TPMTH

TPMTL/TPMTH

TPMTL/TPMTL

pharmacogenetic based prescribing
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
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
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
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
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
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 crohn s
Smoking and Crohn’s
  • 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
crohn s patients and smoking
Crohn’s patients and smoking
  • 90% recognise dangers with respect to
    • Overall health
    • Lung cancer
    • Cardiovascular disease
  • 9% recognise an association with Crohn’s
  • 12% aware of  risk of reoperation
crohn s patients and smoking1
Crohn’s 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 crohn s
Methotrexate in Crohn’s
  • 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 crohn s side effects
Methotrexate in Crohn’s:Side effects
  • Bone marrow suppression
  • Muscle / joint aches
  • Intercurrent infections
  • Liver fibrosis
  • Pneumonitis
infliximab
Infliximab
  • Anti-TNF monoclonal antibody
  • Infusion
    • Single / multiple doses (5mg/kg)
  • Resistant and fistulating Crohn’s disease
  • Potential for anaphylaxis
  • 70% remission at 1 year
infliximab1
Infliximab
  • Licensed by NICE for those with:
    • Severe active Crohn’s with or without fistulae
    • Crohn’s 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
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
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
How is Infliximab given
  • As a single infusion (Day Case)
  • Repeat infusions at approximately 2 month intervals for maintenance
does infliximab work
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
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
Summary
  • There is no such thing as simply ‘Crohn’s disease’….

Proctitis

Colitis

Small bowel focal, diffuse

Peri-anal

Stricturing

Fistulating

summary1
Summary

Dear Dr….

Diagnosis:

  • Stricturing distal ileal Crohn’s disease: 1995
  • On azathioprine Sept 2002 (MCV 84 93)
  • TPMT 36.5
  • Normal DEXA scan Oct 2002
  • Last steroid course ended July 2001
summary2
Summary

Crohn’s

  • 5-ASA
  • Osteoporosis Rx
  • Methotrexate
  • Infliximab
  • Stop smoking

UC

  • 5-ASA
  • Osteoporosis Rx
  • Ciclosporin

Azathioprine

slide70
Description
  • Aetiology
  • Pathophysiology
  • Predisposing factors
  • Symptoms
  • Signs
  • Investigations
  • Complications
  • Alternatives
  • Management
  • Prognosis
prognosis
Prognosis
  • Average life expectancy = 10 years less than general population
ad