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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

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recent advances in medical treatment of inflammatory bowel disease

Recent advances in medical treatment of inflammatory bowel disease

Adrian Thomas, Booth Hall Childrens Hospital

Manchester, M9 7AA, UK

  • 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
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
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 nutrition5
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
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
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 diseaseWilschanski 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
EN mechanism of action
  • 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 diseaseAkobeng 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
Pharmacological treatment
  • 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
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
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 (0.36-0.62), 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 (0.86-1.99), 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
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
  • 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 diseaseSimms 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
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
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-analysisMarshall 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
Anti-tuberculous therapy for Crohn’s diseaseBorgaonkar 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 diseaseSandborn 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
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 (1.4-3.5), 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 diseaseMarkowitz 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
  • 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).

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
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 200229
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
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
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
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

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


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
Results continued

Most children received dosages of 5 (range 3-10) mg/kg

The median number of doses received was 3 (range 1-6)

6 children are receiving maintenance treatment (8 weekly infusions)

results continued37
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 continued38
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 continued39
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 continued40
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


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
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
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
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