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Treatment of Inflammatory Bowel Disease

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How do we know a treatment works. How do we know a ... Yes - teratogenic. Not demonstrated. Established. Methotrexate. Yes. Established. Established 55 ... – PowerPoint PPT presentation

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Title: Treatment of Inflammatory Bowel Disease


1
Treatment of Inflammatory Bowel Disease
  • Dr John Wyeth
  • Capital and Coast DHB

2
A Cure?
3
Treating Crohns Disease
  • The Basics
  • How do we know a treatment works
  • How do we know a treatment is safe
  • The Specifics
  • What drugs do we use
  • How effective are they
  • What are the limitations and side effects
  • The Alternatives
  • Are there non-drug treatments?

4
Crohns Disease Activity Index (CDAI)
  • 8 point questionnaire used to assess disease
    severity
  • CDAI is accepted by regulatory authorities as the
    marker to evaluate response to therapy
  • Limitations include
  • Influenced by other non-inflammatory symptoms
  • Relies on subjective data
  • Cumbersome and not routinely used in clinical
    practice

5
Crohns Disease Activity Index (CDAI)
6
Goals of Treatment
Remission
Maintenance
7
How do we know a treatment works?
We do a clinical trial
8
Statistical Analysis
  • Toss a coin 7 times
  • About 1 in 20 (5) chance of getting 6 or 7 heads
  • In medicine, this is considered significant
  • Treatment being tested is better

9
Levels of Clinical Trials
Increasing Risk
10
Side Effects of Therapy
  • Clinical trials
  • Participants record all events during trial
  • Headaches, nausea etc.
  • Theoretical
  • Based on mechanism of drug
  • E.g. prednisone has effects of glucocorticoids
  • Post marketing
  • Increased use after general release
  • Less common or rare events likely to show up

11
Drug Therapies
  • Glucocorticoids (steroids)
  • 5-aminosalicylates (5-ASA)
  • Immunosuppressants
  • Antibiotics
  • Biological Therapy

12
What are steroids?
  • A natural hormone
  • Secreted by the adrenal glands
  • Derived from cholesterol
  • Control metabolism, especially glucose and
    protein
  • Synthetic steroids (e.g. prednisone) many times
    more potent than natural steroids

13
Steroid Effectiveness
  • Highly effective for the induction of remission
    in patients with active disease
  • Short-term response rates (1216 weeks) range
    from 7090
  • Not effective in maintenance of remission

14
Steroid Side Effects
-Depression -Anxiety
-Acne -Moon face -Hair growth
-Buffalo hump
-Obesity -Purple / red streaks (striae)
-Bruising
-Bone thinning
-Muscle wekaness
15
Prolonged Steroid Therapy
16
5-ASA Drugs
  • Sulphasalazine first agent discovered
  • Group now includes
  • Pentasa (mesalazine)
  • Asacol (mesalazine)
  • Dipentum (olsalazine)
  • Salazopyrin-EN (sulphasalazine)
  • Work locally on the lining of the gut to reduce
    inflammation

17
Salazopyrin
  • 5-ASA joined to a sulphur group
  • To be active it requires sulphur group to be
    removed
  • This happens in the large bowel
  • Sulphur group also has an anti-inflammatory
    effect on the joints

X-S
X-S
X
18
Dipentum
  • Two 5-ASA molecules joined together
  • Need to be broken apart to be effective
  • Bacteria in colon break the molecules apart
  • Diarrhoea a common side effect

X-X
X
X-X
X
19
Pentasa
  • Pure 5-ASA molecules
  • In micro pellets
  • Breaks up in the stomach
  • Slowly dissolve as it travels through the
    intestine

20
Asacol
  • Pure 5-ASA molecules
  • In a solid capsule
  • Capsule responds to changes in acidity
  • Slowly dissolves to release 5-ASA
  • Some patients report undissolved tablets passed
    into toilet

21
Efficacy of 5-ASA
  • Remission
  • Up to 40 of patients brought into remission
  • But , 30 will go into remission with placebo
  • Maintenance
  • Possibly 1-2 less acute relapses per year
  • Average relapses per year is 3-4
  • Real benefit
  • Reduced risk of bowel cancer longer term

22
The Role of Pro-inflammatory Cytokines in
Crohns Disease
Inflammation and tissue damage of intestinal
mucosa
IL-6
B cell
Plasma cell
Activation of T cells
IL-8
Humoral immune response
Antigen-presenting cell
TNF?
IL-1
GM-CSF
Antigen
Leukotrienes, superoxides, nitric oxide and
prostaglandins
Inflammatory cell adhesion
Sands BE. Inflammatory Bowel Dis 1997 3 95113.
23
Immunosupressants
  • Drugs include
  • Azathioprine
  • 6-mercaptopurine
  • Methotrexate
  • Interfere with inflammatory pathway
  • Effective
  • Up to 75 of patients brought into remission
  • Slow
  • Optimal effect often not seen until after 12
    weeks of treatment
  • Need close monitoring for toxicity
  • Safety
  • Methotrexate not to be used in pregnancy

24
Azathioprine Metabolism
TPMT thiopurine methyltransferase 6-TGN
6-thioguanine nucleotide 6-MMPN
6-methylmercaptopurine ribonucleotide
25
Use of TPMT and 6-TGN
  • TPMT
  • Tested before initiating therapy
  • Low TPMT activity related to high 6-TGN levels,
    increasing risk of toxicity
  • 6-TGN
  • Used to monitor therapy
  • Levels above 230 associated with better effect
  • Levels above 480 associated with more side
    effects

26
Antibiotics
  • Metronidazole, ciprofloxacin
  • Precise role in management is unclear
  • Treatment of complications such as abscesses and
    skin infections
  • No data from controlled trials have shown a
    benefit on remission rates in patients with
    active disease
  • No benefit for the maintenance of remission has
    been demonstrated for antibiotic therapy
  • No controlled data exist that show antibiotics
    are successful for closing perianal fistulae

27
Immune Therapy for Crohns Disease
  • TNF-a is a key mediator of inflammation
  • TNF-a expressed in bowel wall in Crohns disease
    and faecal concentrations reflect disease
    severity
  • Products neutralising TNF-a are beneficial in
    treatment of Crohns disease
  • Infliximab (Remicade) infusion

28
REMICADETM (infliximab)Mechanisms of Action
Infliximab
Neutralisation of transmembrane TNF?
Neutralisation of soluble TNF?
TNF? producing macrophages of activated T cells
van Deventer SJH. Gut 1997 40 4438. Scallon BJ
et al. Cytokine 1995 7 2519. Feldmann M et al.
Adv Immunol 1997 64 283350.
29
Remission-level ControlWith REMICADETM
(infliximab)
Control (n 24)
p lt 0.001
75
Infliximab 5 mg/kg (n 27)
48
50
Patients achieving clinical response ()
39
25
4
4
0
Week 2
Week 4
Clinical remission defined as a CDAI score lt
150.
Targan SR et al. N Engl J Med 1997 337
102935. Data on file, Centocor, Inc.
30
Endoscopic Improvement With REMICADETM
(infliximab)
4 weeks post-treatment
  • Pre-treatment

Reprinted with permission of van Dullemen HM et
al. Gastroenterology 1995 109 12935.
31
Abdominal Fistula Case Study
Pre-treatment
2 weeks
10 weeks
18 weeks
Data on file, Schering-Plough.
32
Remission-Level Control with Repeated Infusions
of REMICADE (infliximab)
p 0.013
60
Control (n 36)
53
50
Infliximab (n 37)
40
30
Patients in clinical remission ()
20
20
10
0
Week 44 (8 weeks after final infusion)
Rutgeerts P et al. Gastroenterology 1999 117
7619.
Clinical remission defined as a CDAI score lt 150.
33
Remicade (Infliximab) Safety
  • Hypersensitivity
  • Allergic reaction at time of infusion 5
  • Autoimmune syndromes
  • Lupus like illness rare and recovers on
    stopping on therapy
  • Infection
  • Profound immunosuppression occurs
  • Opportunistic infections can occur
  • Tuberculosis high risk
  • Hepatitis B can be reactivated
  • Cancer
  • Recent data suggests that overall cancer rates
    may be reduced
  • Hepatosplenic T-cell lymphomas 1 in 20000
    patients

34
Summary of Standard Therapy
35
Non-Drug Approaches Cigarette Smoking
  • Smokers with Ulcerative Colitis
  • Have less relapses
  • Smokers with Crohns disease
  • Have more relapses
  • Disease more difficult to treat
  • Stopping smoking reported to have same effect on
    Crohns disease as giving steroids.

36
Fish Oil
  • What is it?
  • Derived from fish
  • Contains omega-3 fatty acids
  • What do they do?
  • Anti-inflammatory effect
  • Reduces leukotriene B4
  • How do you take it?
  • Enteric coated capsules to avoid fishy smell

37
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38
Another Option
  • 42 yr old male with Crohns disease 20 yrs
  • several bowel resections for strictures
  • ileostomy eventually formed
  • maximal medical therapy
  • azathioprine, budesonide, mesalazine
  • ongoing ulceration of stoma site and flares of
    disease
  • over last 6 months, no further ulcers...

39
What did he do?
  • Probiotics
  • about 6 months ago started using a combination of
    probiotic products available over the counter
  • no further problems with ulcers and no flares of
    disease symptoms

40
Probiotics
...living micro-organisms which upon ingestion
in certain numbers exert health benefits beyond
inherent general nutrition
41
Trichuris suis ova (TSO)
  • Pig whipworm ova taken as a drink
  • Does not survive long in humans
  • Need repeated drinks
  • High rate of remission reported
  • 50 in UC, 70 in Crohns
  • Intestinal helminthes induce cytokine release and
    downregulate cell mediated responsiveness
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