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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


  • 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


  • 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


  • 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


  • 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


  • 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


  • Description

  • Aetiology

  • Pathophysiology

  • Predisposing factors

  • Symptoms

  • Signs

  • Investigations

  • Complications

  • Alternatives

  • Management

  • Prognosis




Erythema Nodosum

  • IBD

  • TB/ Sarcoid

  • OCP, sulphonamides

  • Streptococcal infections

  • Yersinia, psitticosis

  • Lymphogranuloma venereum

  • Connective tissue disorders

  • Tuleraemia



Arthropathy with effusion supra patellar
Arthropathy with effusion (supra-patellar)



  • 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


  • 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


0 2 4 6 8 10 15 20 25 30

Increasing risk of colorectal cancer in colitis – years after diagnosis


  • Description 30

  • Aetiology

  • Pathophysiology

  • Predisposing factors

  • Symptoms

  • Signs

  • Investigations

  • Complications

  • Alternatives

  • Management

  • Prognosis


Differential diagnosis
Differential diagnosis 30

  • Initially often “IBS”

  • Ulcerative colitis

  • Infective diarrhoea

    • especially amoebic

  • Differential diagnosis of malabsorption and malnutrition

  • Ileal TB / lymphoma

  • Behçet’s disease


  • Description 30

  • Aetiology

  • Pathophysiology

  • Predisposing factors

  • Symptoms

  • Signs

  • Investigations

  • Complications

  • Alternatives

  • Management

  • Prognosis


Current treatments
Current treatments 30

  • 5-ASA drugs

  • Steroid enemas

  • Budesonide

  • Steroids

  • (Elemental diets)

  • Azathioprine

  • Methotrexate

  • Infliximab, adalimumab

  • Surgery

    • Diversion

    • Resection





5 asa drugs
5-ASA drugs 30

  • 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 30

  • 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 30

  • Remission rates:

    Crohn’sUC

    Overall 45% 58%

    >6/12 Rx 64% 87%

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


IBD patients on azathioprine 30

  • 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 30

  • 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???



Human RBC TPMT 30

TPMTH/TPMTH

TPMTL/TPMTH

TPMTL/TPMTL



Pharmacogenetic based prescribing
Pharmacogenetic based prescribing 30

  • ‘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 30

  • 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 30

  • 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 30

  • 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 30

  • 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 30

  •  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 30

  • 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 30

  • 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 30

  • 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 30

  • 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: 30Side effects

  • Bone marrow suppression

  • Muscle / joint aches

  • Intercurrent infections

  • Liver fibrosis

  • Pneumonitis


Infliximab
Infliximab 30

  • 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 30

  • 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 ? 30

  • 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 30?

  • 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 30

  • As a single infusion (Day Case)

  • Repeat infusions at approximately 2 month intervals for maintenance


Does infliximab work
Does Infliximab work? 30

  • 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? 30

  • 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 30

  • There is no such thing as simply ‘Crohn’s disease’….

    Proctitis

    Colitis

    Small bowel focal, diffuse

    Peri-anal

    Stricturing

    Fistulating


Summary1
Summary 30

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 30

Crohn’s

  • 5-ASA

  • Osteoporosis Rx

  • Methotrexate

  • Infliximab

  • Stop smoking

UC

  • 5-ASA

  • Osteoporosis Rx

  • Ciclosporin

Azathioprine


  • Description 30

  • Aetiology

  • Pathophysiology

  • Predisposing factors

  • Symptoms

  • Signs

  • Investigations

  • Complications

  • Alternatives

  • Management

  • Prognosis


Prognosis
Prognosis 30

  • Average life expectancy = 10 years less than general population



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