Treatment of Inflammatory Bowel Disease

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Treatment of Inflammatory Bowel Disease

• Dr John Wyeth
• Capital and Coast DHB

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A Cure?
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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?

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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

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Crohns Disease Activity Index (CDAI)
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Goals of Treatment
Remission
Maintenance
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How do we know a treatment works?
We do a clinical trial
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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

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Levels of Clinical Trials
Increasing Risk
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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

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Drug Therapies

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

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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

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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

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Steroid Side Effects
-Depression -Anxiety
-Acne -Moon face -Hair growth
-Buffalo hump
-Obesity -Purple / red streaks (striae)
-Bruising
-Bone thinning
-Muscle wekaness
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Prolonged Steroid Therapy
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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

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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
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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
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Pentasa

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

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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

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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

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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.
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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

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Azathioprine Metabolism
TPMT thiopurine methyltransferase 6-TGN
6-thioguanine nucleotide 6-MMPN
6-methylmercaptopurine ribonucleotide
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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

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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

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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

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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.
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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 ()
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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.
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Endoscopic Improvement With REMICADETM
(infliximab)
4 weeks post-treatment

• Pre-treatment

Reprinted with permission of van Dullemen HM et
al. Gastroenterology 1995 109 12935.
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Abdominal Fistula Case Study
Pre-treatment
2 weeks
10 weeks
18 weeks
Data on file, Schering-Plough.
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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.
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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

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Summary of Standard Therapy
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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.

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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

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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...

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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

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Probiotics
...living micro-organisms which upon ingestion
in certain numbers exert health benefits beyond
inherent general nutrition
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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