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Crohn disease

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Crohn disease Powered By Docstoc
					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
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 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 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)
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?
 M. Paratuberculosis        Toothpaste
 E. Coli                    Cornflakes
 Viruses eg: measles        Hygiene
 Post-infective bacteria    “Allergy”
 Clostridium                Refined sugars
 Bacteroides                Trauma
                             Pollutants
   Description
   Aetiology
   Pathophysiology
   Predisposing factors
 Symptoms
   Signs
   Investigations
   Complications
   Alternatives
   Management
   Prognosis
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
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
 Behçet’s 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
What’s 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:


                     Crohn’s          UC

Overall              45%              58%
>6/12 Rx             64%              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

                     TPMTH/TPMTH



       TPMTL/TPMTH

TPMTL/TPMTL
TPMT levels in Southampton 2002-3




        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
 Hepatotoxicity in 1/4            metabolites
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 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
 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 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
 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
 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 Crohn’s disease
 Potential for anaphylaxis
 70% remission at 1 year
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 ?
 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 ‘Crohn’s
    disease’….

     Proctitis
     Colitis
     Small bowel focal, diffuse
     Peri-anal

     Stricturing
     Fistulating
Summary
Dear Dr….

Diagnosis:
1. Stricturing distal ileal Crohn’s 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
          Crohn’s                   UC
 5-ASA                   5-ASA
 Osteoporosis Rx         Osteoporosis Rx
 Methotrexate            Ciclosporin
 Infliximab
 Stop smoking


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

 Average life expectancy = 10 years less than general
 population

				
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posted:8/15/2011
language:English
pages:72