Treatment of Inflammatory Bowel Disease
Dr John Wyeth Capital and Coast DHB
A Cure?
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?
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
Crohns Disease Activity Index (CDAI)
Goals of Treatment
Remission
Maintenance
How do we know a treatment works?
We do a clinical trial
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
Levels of Clinical Trials
New Therapeutic Group
Increasing Risk
New Agent - Infliximab
New Therapeutic Group
Known Agent - Salazopyrin
Known Therapeutic Group
Known Agent - Asacol
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
Drug Therapies
Glucocorticoids (steroids) 5-aminosalicylates (5-ASA) Immunosuppressants Antibiotics
Biological Therapy
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
Steroid Effectiveness
Highly effective for the induction of remission in patients with active disease Short-term response rates (12–16 weeks) range from 70–90% Not effective in maintenance of remission
Steroid Side Effects
-Acne -“Moon” face -Hair growth -Depression -Anxiety -“Buffalo” hump -Obesity -Purple / red streaks (striae) -Muscle wekaness
-Bruising
-Bone thinning
Prolonged Steroid Therapy
Side Effect “Moon” face Acne Bruising Raised Blood Pressure Increased Body Hair Striae Frequency 45% 30% 15% 15% 7% 6%
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
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
X-S
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
Pentasa
Pure 5-ASA molecules In micro pellets Breaks up in the stomach Slowly dissolve as it travels through the intestine
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
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
The Role of Pro-inflammatory Cytokines in Crohn’s Disease
IL6
B cell
Inflammation and tissue damage of intestinal mucosa
Activation of T cells Antigenpresenting cell
IL8
TNF IL1 GM-CSF
Plasma cell Humoral immune respons e
Antigen
Inflammatory cell adhesion
Leukotrienes, superoxides, nitric oxide and prostaglandins
Sands BE. Inflammatory Bowel Dis 1997; 3: 95–113.
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
Azathioprine Metabolism
Azathioprine 6-Mercaptopurine TPMT 6-TGN 6-MMPN
TPMT = thiopurine methyltransferase 6-TGN = 6-thioguanine nucleotide 6-MMPN = 6-methylmercaptopurine ribonucleotide
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
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
Immune Therapy for Crohns Disease
TNF-α is a key mediator of inflammation TNF-α expressed in bowel wall in Crohns disease and faecal concentrations reflect disease severity Products neutralising TNF-α are beneficial in treatment of Crohns disease Infliximab (Remicade) infusion
REMICADE (infliximab) Mechanisms of Action
Infliximab
TM
Neutralisatio n of soluble TNF TNF producing macrophages of activated T cells
Neutralisation of transmembran e TNF
van Deventer SJH. Gut 1997: 40; 443–8. Scallon BJ et al. Cytokine 1995: 7; 251–9. Feldmann M et al. Adv Immunol 1997; 64: 283–350.
Remission-level Control TM With REMICADE (infliximab)
75 p < 0.001 Control (n = 24) Infliximab 5 mg/kg (n = 27)
50
48% 39%
25 4% 0 Week 2 Week 4
Targan SR et al. N Engl J Med 1997; 337: 1029– 35. Data on file, Centocor, Inc.
4%
*Clinical remission defined as a CDAI score < 150.
Endoscopic Improvement With TM REMICADE (infliximab)
Pre-treatment
4 weeks post-treatment
Reprinted with permission of van Dullemen HM et al. Gastroenterology 1995; 109: 129–35.
Abdominal Fistula: Case Study
Pre-treatment
2 weeks
10 weeks
18 weeks
Data on file, Schering-Plough.
Remission-Level Control with Repeated Infusions of REMICADE™ (infliximab)
p = 0.013 60 Patients in clinical remission (%)
53%
50
Control (n = 36) Infliximab (n = 37)
40
30
20
10 0
20%
Week 44 (8 weeks after final infusion)
Clinical remission defined as a CDAI score < 150. Rutgeerts P et al. Gastroenterology 1999; 117: 761–9.
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
Summary of Standard Therapy
Induction of Remission Steroids 5-ASA Antibiotics Immune Suppresants Methotrexate Biologicals Established 7090% Minor effect No Established 55% Established Established Maintenance of Remission Ineffective Conflicting evidence No Established Not demonstrated Established Yes Yes - teratogenic Yes Adverse Effects Yes Yes
Non-Drug Approaches – Cigarette Smoking
Smokers with Ulcerative Colitis
– Have less relapses
Smokers with Crohn’s disease
– Have more relapses – Disease more difficult to treat – Stopping smoking reported to have same effect on Crohn’s disease as giving steroids.
Fish Oil
What is it?
– Derived from fish – Contains omega-3 fatty acids
Patients in Remission at 1 Year
60 50 40 % 30 20 10 0 Fish Oil Placebo
What do they do?
– Anti-inflammatory effect – Reduces leukotriene B4
How do you take it?
– Enteric coated capsules to avoid “fishy smell”
Authors Tsujikawa et al
Subjects 20 Crohn's Disease patients 39 IBD patients (29 Crohn's Disease patients ) 10 IBD patients 204 Crohn's Disease patients in remissio n 78 Crohn's Disease patients in remissio n 10 IBD patients (5 Crohn's Disease, 5 Ulcerativ e Colitis
Duration
Intervention/Design Open trial using diet containing n-3:n-6 ratio of 0.5
Dosage
Outcome Decreased CRP, improved remission rates Decreased inflammatory mediators TXB2 & LTB4, improved morphology, no change in disease activity Decreased inflammatory mediators PGE2, TXB2, & LTB4
1 month
Not given
Lorenz et al
7 months
Double-blind, placebocontrolled crossover of fish oil
1.8 g EPA and 1.3 g DHA daily
Hillier et al
12 weeks
Open label - fish oil versus olive oil
18 g per day, containing 3.2 g EPA, 2.2 g DHA 6 g daily (containing 3.3 g EPA, 1.8 g DHA)
LorenzMeyer et al
1 year
Fish oil supplementation compared with placebo or lowcarbohydrate diet
No Difference in relapse rate in fish oil vs. placebo
Belluzzi et al
1 year
Double-blind, placebo controlled study of fish oil
4.5 g daily (containing 1.8 g EPA, 0.9 g DHA)
41% fewer relapses in fish oil group; 33% more patients in remission at 1 year
Arslan at al
10 days
Open label pilot study of seal oil
30 mL daily (containing 1.8 g EPA, 2.6 g DHA, 1.0 g DPA)
Decreased disease activity, decreased joint pain
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...
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
Probiotics
“...living micro-organisms which upon ingestion in certain numbers exert health benefits beyond inherent general nutrition…”
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