Transcript Treatment of inflammatory bowel disease

Recent advances in medical treatment
of inflammatory bowel disease
Adrian Thomas, Booth Hall Childrens Hospital
Manchester, M9 7AA, UK
Treatment
• Not curative
• Induction and maintenance of remission
• Anticipation and prevention of complications
• Correction of malnutrition and growth failure
• Improvement of quality of life
Nutritional treatment in IBD
• Uses
- For improving nutritional status
- As primary therapy for active disease
- For the maintenance of remission
• Types
- parenteral nutrition
- elemental diets
- polymeric diets
- specific nutrients e.g. fish oil, glutamine
- exclusion diets
Parenteral nutrition
• Improved disease activity and nutritional status
reported in several small uncontrolled studies
• Multicentre prospective study Greenberg 1988
• TPN alone, partial PN + normal food and a polymeric
diet were equally effective
• Concluded bowel rest not necessary and PN should
be supportive, not primary therapy
Parenteral nutrition
• May help to achieve remission in patients with
strictures or short bowel syndrome
• Perioperative PN results in less small bowel
resection but longer hospitalisation
• More complications with PN (esp sepsis)
Elemental diets
• Chemically defined liquid diets containing amino acids,
simple carbohydrates, fats etc.
• First RCT by O’Morain 1984 suggested elemental diets
were as effective as steroids at inducing remission
• Similar results and improved growth confirmed by
Sanderson 1987 in first paediatric RCT
Enteral nutritional therapy for inducing
remission of Crohn’s disease
Zachos M, Tondeur M, Griffiths AM Cochrane Library 2001
• Part A: Meta-analysis 9 RCTs comparing elemental diet
(n=170) to non-elemental diet (n=128) showed N.S.
difference in remission rate [OR 1.15, 95% CI: 0.64-2.08]
• Part B: Meta-analysis 4 RCTs comparing enteral nutrition
(n=130) to steroids (n=123) showed steroids better at
inducing remission [OR 0.30, 95% CI: 0.17-0.52, NNT=4]
Enteral nutrition in growth failure
• 15-50% children with Crohn’s disease have
growth failure
• Malnutrition probably most important cause
• Macro/micronutrient deficiencies common
• Inflammatory mediators and IGF-I
• Improved growth with long-term oral
supplements
Supplementary enteral nutrition maintains remission
in pediatric Crohn’s disease
Wilschanski M et al, Gut 1996;38:543-8
• Retrospective review of 65 children with active Crohn’s
disease treated with enteral nutrition
• 47 (72%) achieved remission (PCDAI<20)
• 20 relapsed by 6 months & 28 by 12 months
• Longer remission in those continuing nasogastric
supplements after resumption of normal diet
EN mechanism of action
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improved nutritional status (macro/micro)
improved luminal nutrition
improved immune function
reduced antigenic load to gut
altered gut flora
reduced inflammatory mediator production
Double-blind RCT of glutamine-enriched polymeric
diet in the treatment of active Crohn’s disease
Akobeng AK et al, J Pediatr Gastroenterol Nutr 2000;30:78-84
• 18 children with active Crohn’s received for 4/52 a
glutamine rich (42% amino acids) or low glutamine (4%
amino acids) polymeric diet in DBRCT
• Diets were isocaloric & isonitrogenous with iddentical
essential amino acid profile
• 2 patients in high glutamine group did not tolerate the diet
• N.S. diff. in remission rates [OR 0.64, 95% CI 0.10-4.11]
Pharmacological treatment
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Sulphasalazine/5-ASA
Corticosteroids/budesonide
Antibiotics/antimycobacterial therapy
Azathioprine/6-mercaptopurine
Cyclosporine A
Methotrexate
Mycophenolate mofetil
Tacrolimus
Anti-TNF agents: thalidomide, infliximab
Oral 5-ASA for inducing remission in ulcerative
colitis. Sunderland L et al, Cochrane Review 1998
• OR (95% CI) for failure to induce remission/improvement
= 0.51 (0.36-0.76), dose response curve observed
• Compared to sulphasalazine, OR (95% CI) for failure to
induce remission/improvement = 0.87 (0.63-1.21) & 0.66
(0.42-1.04) for failure to induce endoscopic improvement
• Sulphasalazine not as well tolerated as 5-ASA
• 5-ASA superior to placebo for all outcomes and tended
towards benefit over sulphasalazine but benefits may not
be economically justifiable
Oral 5-ASA for maintaining remission in ulcerative
colitis. Sutherland L et al, Cochrane Review 1998
• OR (95% CI) for failure to maintain clinical or
endoscopic remission for 5-ASA v placebo = 0.47 (0.360.62), NNT = 6
• OR (95% CI) for failure to maintain clinical or
endoscopic remission for sulphasalazine v 5-ASA = 1.29
(1.05-1.57), NNT = -19
• Sulphasalazine & 5-ASA had similar adverse event
profiles, OR (95% CI) = 1.16 (0.62-2.16) & 1.31 (0.861.99), NNH = 171 & 78
• 5-ASA superior to placebo but inferior to sulphasalazine
in maintenance therapy
Corticosteroids for maintaining remission of Crohns
disease. Steinhart AH et al, Cochrane Review 2001
• 3 eligible studies identified
• No. of subjects included at 6, 12 & 24 months =
142, 131 & 95 for steroid group &
161, 138 & 87 for control group
• OR (95% CI) for relapse = 0.71 (0.39-1.31) at 6/12,
0.82 (0.47-1.43) at 12/12 & 0.72 (0.38-1.35) at 24/12
• The use of corticosteroids in patients with quiescent
Crohn’s disease does not appear to reduce the risk of
relapse over a 24 month period of follow-up
Budesonide
• Potency 15x that of prednisolone
• Delayed release capsule facilitates delivery to terminal
ileum and proximal colon
• Rapid liver metabolism means only 10%
bioavailability cf. 80% for prednisolone
• Efficacy comparable to prednisolone with fewer side
effects in adults with ileocaecal Crohns
• Multinational paediatric study completed
Budesonide for maintenance of
remission in Crohn’s disease
Simms L, Steinhart AH Cochrane Review 2000
• 3 RCTs of oral budesonide 6mg/day, 3 mg/day and
placebo
• Budesonide 6mg/day ineffective at preventing relapse
over 12 months. RR relapse = 0.89 (95% CI: 0.71-1.13)
• Similar results with 3mg/day
Topical agents
5-ASA enemas
• Low systemic absorption
• In DBRCT 63% much improved after 6/52 cf.
29% in placebo gp.
• No proven benefit of 4g cf. 1g
• May be more effective than hydrocortisone
• High relapse rate after cessation
• No data in L. sided Crohns colitis
Topical agents continued
Corticosteroid enemas
• Hydrocortisone & prednisolone based preparations active
after absorption, risk of systemic side effects
• Beclomethasone, fluticasone & budesonide have rapid 1st
pass hepatic metabolism & low systemic bioavailability
after rectal administration
• Budesonide enemas probably have highest topical
potency with lowest risk of side effects
Rectal corticosteroids versus alternative treatments in
ulcerative colitis: a meta-analysis
Marshall JK et al, Gut 1997;40:775-81
• 56 RCTs identified = 4288 patients
• Conventional rectal steroids, remission rates:
symptomatic 45%, endoscopic 34%, histological 30%
• Topically active steroids, remission rates:
symptomatic 46%, endoscopic 31%, histological 23%
• Aminosalicylates, remission rates:
symptomatic 52%, endoscopic 39%, histological 32%
• Placebo, remission rates:
symptomatic 9%, endoscopic 17%
Anti-tuberculous therapy for Crohn’s disease
Borgaonkar MR et al, Cochrane Library 1999
• 7 RCTs identified (2 abstracts)
• 2 trials (n=89) used ATT + steroids to induce remission
then maintenance ATT, OR for maintaining remission in
ATT v control = 3.37 (95% CI 1.38-8.24, NNT=3)
• 3 trials used ATT + standard therapy v standard therapy
alone, OR for maintaining remission in treatment v
control = 0.70 (95% CI 0.39-1.25)
• ATT may be effective in maintaining remission induced
with steroids + ATT but cannot be recommended as
conclusion based on only 2 small studies
Azathioprine or 6-Mercaptopurine for
inducing remission of Crohn’s disease
Sandborn W et al, Cochrane Review 1998
• 8 placebo controlled RCTs identified
• OR (95% CI) of response to AZA / 6-MP in active CD =
2.36 (1.57-3.53), NNT = 5, OR (95% CI) for steroid
sparing effect = 3.86 (2.14-6.96), NNT = 3
• OR (95% CI) for adverse event (allergy, leukopenia,
pancreatitis, nausea) = 3.01 (1.30-6.96), NNH = 14
• Azathioprine & 6-MP are effective at inducing remission
in active Crohn’s disease. Treatment >17/52 improved
response
Azathioprine for maintenance of remission in Crohns
disease. Pearson DC et al, Cochrane Review 1998
• 5 placebo controlled DBRCTs identified
• OR (95% CI) for maintenance of remission = 2.16 (1.43.5), NNT = 7
• Higher dose improved response (OR = 1.2 at 1mg/kg/day,
3. 2 at 2mg/kg/day & 4.1 at 2.5mg/kg/day)
• OR for steroid sparing effect = 5.22 (1.1-25.7), NNT = 3
• OR for withdrawal due to adverse events = 4.36 (1.6-11.7),
NNH = 19
A multicenter trial of 6-MP & prednisone in children
with newly diagnosed Crohn’s disease
Markowitz J et al, Gastroenterology 2000;119:895-902
• 55 newly diagnosed Crohns children randomised to
prednisone & 6-MP or placebo for 18 months
• Prednisone dose tailored to disease activity according to
predefined schedule
• Remission in 89% of both groups, relapse rate 47% in
controls & 9% in 6-MP group
• In 6-MP group duration of steroid use shorter and
cumulative dose lower at 6, 12 & 18 months
Topical tacrolimus may be effective in the treatment of
oral and perineal Crohn’s disease
Casson DH et al, Gut 2000;47:436-40.
• Topical tacrolimus given to 8 children with refractory
oral (3) &/or perineal (6) Crohn’s
• Marked improvement in 7/8 within 6 wks & healing in
1-6 months, undetectable serum levels
• 2/7 rebound worsening when tacrolimus stopped & 1
required proctocolectomy
• Slower weaning successful in 6/8 with 4 on intermittent
treatment & 2 on reduced dosage
TNF
• Potent proinflammatory cytokine
• Can elicit fever, shock, tissue injury, induction of other
cytokines, cell proliferation, differentiation &
apoptosis (Papadikas 2000)
• In Crohn’s disease production increased in GI mucosa
(Reimund 1996, MacDonald 1990, Breese 1994) and
serum concentrations increased (Murch 1991).
Infliximab
Neutralises TNF effects (in vitro & in vivo) by
blocking soluble TNF & binding to trans-membrane
TNF (Siegel 1995, Scallon 1995)
Several studies have shown clinical or endoscopic
benefits in adults with fistulising or refractory Crohn’s
disease (Targan 1997, Baert 1999, Rutgeerts 1999) but
studies are small & limited paediatric data
Remicade - safety alert January 2002
~200,000 patients have received Remicade since
1st licensed in 1998
Commonest serious adverse effect is infection. By
mid 2001 130 cases of TB and 202 deaths
reported
Other safety concerns include heart failure,
hypersensitivity reactions, neurological events &
malignancies
Remicade - safety alert January 2002
Indications for treatment of Crohns disease
Severe, active Crohn’s disease in patients who have not
responded despite a full and adequate course of therapy
with a corticosteroid & an immuno-suppressant; or who
are intolerant to or have contraindications for such
treatment
Fistulising Crohn’s disease, in patients who have not
responded despite a full & adequate course of
conventional treatment including antibiotics, drainage &
immunosuppressives
National Institute for Clinical Excellence (NICE)
Guidelines I (April 2002)
Patients must fulfil all three criteria:
• Severe active Crohn’s disease (CDAI 300+,
Harvey-Bradshaw 8/9+)
• Refractory to immunomodulators & steroids or
intolerant of these
• Surgery is inappropriate (e.g. because of diffuse
disease &/or risk of short bowel syndrome)
NICE Guidelines II (April 2002)
Treatment can be repeated if respond to initial
course then relapse (episodic treatment)
Infliximab not licensed for maintenance treatment
(repeated dosing each 8 weeks)
Cost per QALY:
• £6,700 for single infusion
• £10,400 for episodic treatment
• £84,400 for maintenance treatment
Not recommended for fistulising disease without
other criteria for severe active Crohns
Maintenance infliximab for Crohn’s disease:
the ACCENT I randomised trial Hanauer SB et al.
Lancet 2002;359;1541-1549
573 adults with CDAI 220+ given 5mg/kg infliximab
335 responders randomised to receive: placebo (gp ) I
5mg/kg (gp II), 10mg/kg (gp III) 8 weekly to week 46
Wk 30: remission in 21% gp I, 39% gp II, 45% gp III
Median time to loss response: 19 weeks gp I, 38 weeks
gp II, >54 weeks gp III
Incidence serious infections similar across groups
BSPGHAN survey
• Audit proposed by BSPGHAN IBD working
group
• BSPGHAN members notified at AGM & via
newsletters
• Aims: to identify benefits & side-effects in UK
children with Crohns disease
Methods
Data collected:
• extent of disease
• indication for using infliximab
• number of doses & total dose given
• other treatments
• outcome including side effects
Data collected on forms and sent to coordinator
Results
45 children (aged 0.3 - 17yr, median 12yr) reported
Indications for treatment included:
• severe unresponsive disease 33
• perianal fistulae 18
• other fistulae 7
• steroid dependence 7
Results continued
Most children received dosages of 5 (range 310) mg/kg
The median number of doses received was 3
(range 1-6)
6 children are receiving maintenance treatment
(8 weekly infusions)
Results continued
• in 3 children there was no reported improvement after
infliximab
• improvement of fistulae was reported in 16
• improvement in perianal disease in 15
• avoidance of surgery in 12
• reduced need for other drugs in 18
• improvement in symptoms/quality of life in 35
Results continued
The median duration of response was 4.5 months
(range 1 week to >20 months)
Reported side effects included:
anaphylactic reaction (1) (with 3rd dose)
hepatitis (1)
fever (2)
lupus like reaction (1)
candidal endophthalmitis (1)
worse after initial improvement (1)
Results continued
12 of 15 patients with severe unresponsive disease
alone appear to have fulfilled recommendations
following safety alert
1 of these patients didn’t receive steroids, 1 didn’t
receive immunomodulators and 1 didn’t receive
either before infliximab
Results continued
22 of 24 patients with fistulae improved but only 4
completely fulfilled the manufacturers
recommendations, most had not had drainage of
fistulae and many appeared to have not received
antibiotics
10 of the 24 with fistulae did not have other criteria
for severe active disease but improvement reported
in all 10
Conclusions
Infliximab appears to be beneficial in many patients with
fistulising or refractory Crohns disease
There is increasing concern in adults about serious adverse
effects, especially infections
Although infliximab is being widely used there are limited
data especially in children
This audit raises questions over relevance of
manufacturers and NICE recommendations
Data from adequately powered RCTs needed to answer
these questions
Summary I: Nutritional Treatment
• Bowel rest unnecessary, parenteral nutrition should be
supportive
• Steroids are significantly better than enteral nutrition at
inducing remission in active Crohn’s disease
• Enteral nutrition promotes growth & may help to prolong
remission
• Glutamine of no proven benefit in active Crohn’s disease
Summary II: 5-ASA & steroids
• 5-ASA has less side effects than sulphasalazine & of
benefit in treatment & maintenance of UC & Crohns
• Rectal 5-ASA better than steroids in distal UC
• Corticosteroids effective in ileal & ileocolic Crohns,
isolated colonic Crohns benefits from adding 5-ASA
• Steroids do not prevent relapse
Summary III: Anti TNF agents
• Infliximab of short-term benefit in fistulising & severe
Crohns (refractory or intolerant to immunosuppressives)
• Additional doses may be necessary but little data about
long-term effects or side effects