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IBD UPDATE 2007. DR STEPHEN BURMEISTER Gastroenterologist North Shore Hospital. Hot Topics . Crohns treatment – Infliximab Crohns genetics & IBD cancer risk 5 ASA drugs – reduce cancer risk, needed in higher doses in U.Colitis Actions of Aminosalicylates Effect of smoking on IBD

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ibd update 2007

IBD UPDATE 2007

DR STEPHEN BURMEISTER

Gastroenterologist

North Shore Hospital

hot topics
Hot Topics
  • Crohns treatment – Infliximab
  • Crohns genetics & IBD cancer risk
  • 5 ASA drugs – reduce cancer risk, needed in higher doses in U.Colitis
  • Actions of Aminosalicylates
  • Effect of smoking on IBD
  • Azathioprine monitoring with 6TGN & TPMT
recent questions 2003
Recent Questions 2003
  • A 54 year old man with colonic Crohns is in remission after an 8wk course of prednisone. Which Rx is most likely to maintain remission?
    • Salazopyrin
    • Prednisolone
    • Azathioprine
    • Metronidazole
    • Methotrexate
recent questions
Recent Questions
  • A 45 year old with Crohns presents with fever, rigors & RLQ pain. Meds include Pred 10mg & Sulphasalazine. Temp 37.8, very tender RLQ but no general peritonitis. CT abdo shown. Best initial Rx?
    • IV Abs, IV hydrocortisone & IV Abs, Laparotomy, IV hydrocort only, Change sulphasalazine.
recent questions 3
Recent Questions 3
  • A 43 year old man 6/12 post resection 50cm terminal ileum for Crohns presents with diarrhoea & abdo pain. Examination and tests normal including colonoscopy. Best treatment?
    • Codeine, High fibre diet, Cholestyramine, Sulphasalazine, Prednisolone.
ibd pathogenesis
IBD pathogenesis
  • IBD is a cycle of inflammation, repair and healing
  • Probably as a result of inappropriate immune perception of normal gut flora
  • As SES rises, IBD rates rise – probably due to reduced exposure to infections in childhood
  • Also a genetic component present
crohns genetics
Crohns Genetics
  • First genetic susceptibility factor found:
  • CARD15/NOD 2 gene mutations on Chrom 16
  • A toll-like receptor involved in sensing the bacterial environment
  • Present in 20% Crohns patients, but not in UC
  • Phenotypic link to ileal disease +/- fistulae
  • Twins 58% concordance in Crohns
infliximab in crohns
Infliximab in Crohns
  • What is infliximab?
    • Anti – TNF alpha chimeric antibody
    • Safe and effective for refractory chronic active and fistulous Crohns disease
    • Expensive, but saves money on later hospital/surgical care
    • Increases the risk of infections (esp. Tb) and possibly lymphoproliferative disorders
safety profile
Safety profile
  • Antibody formation 13% (anti HACA)
  • Infusion reactions in 17%, but only 0.5% are serious
  • Anti – dsDNA antibodies develop in 9%
    • Schiabe T. Can J Gastroent 2000; 14: 29
important papers 1
Important papers 1
  • Targan S et al, NEJM 1997; 337: 1029-35
    • First placebo controlled trial
    • 65% of chronic CD patients healed up vs. 17% placebo response
    • 5mg/kg dose appeared best
important papers 2
Important papers 2
  • Present DH et al, NEJM 1999; 340: 1398-1404
    • Second placebo trial, in patients with fistulising disease
    • 55% closure of fistulas vs. 13% placebo
    • All responders by time of second infusion
    • Median duration of response 3 months
important papers 3
Important papers 3
  • Rutgeerts P et al, Gastroenterology 1999; 117: 761-9
    • Longer term study looking at retreatment
    • 73 patients who had maintained response at 8weeks rerandomised to further infusions or placebo
    • 53% patients in remission vs. 13% placebo
    • Benefit maintained for 44 weeks
    • Those on 6MP had a 75% response
important papers 4
Important papers 4
  • Accent 1: Hanauer S et al, Lancet 2002; May 4:359(9317)1541-9 573pts
    • Non fistulising CD ongoing Rx – 83% respond, but only 1/3 were on Aza/6MP
    • 32% infections needing Abs, 3.8% serious
    • 10>5mg/kg dosing 8weekly
    • Overall Tb rate ~100/170,000 pts with at least 14 deaths
important papers 5
Important papers 5
  • Accent 2: Sands B et al, NEJM 2004 Feb 26; 350(9)876-85
    • IFB for maintenance in fistulising CD
    • 64% response
    • Response duration 40 v 14 weeks for the ongoing treatment
other important papers
Other important papers
  • Cohen RD. Am J Gastroent 2000; 95: 3469-77. 129 patients, 65% luminal, 78% fistulas respond. 54% off steroids
  • Rutgeerts P. NEJM 2005; 353: 2467-76 ACT 1 & 11 trials in 728pts showed 70% response to 0,2,6wkly Infliximab infusions in mod/severe UC at week 8 and 45% response at 1year to 8weekly infusions
extra colonic features
Extra-Colonic Features
  • Related or not to disease activity
  • Joints
    • Arthropathies – small and large joint (SI)
    • Ankylosing spondylitis
  • Eyes - uveitis and episcleritis
  • Skin -erythema nodosum

pyoderma gangrenosum

  • Sclerosing cholangitis
    • Cholestatic LFTs
  • Renal amyloid (rare)
  • Venous and arterial thromboembolism
  • Earlier treatment with steroids +/- infliximab
aminosalicylate actions are chemopreventative
Aminosalicylate actionsare Chemopreventative
  • Inhibit leucotriene, PG and cytokine synthesis
  • Scavenge oxygen free radicals
  • Induce apoptosis & aid DNA mismatch repair
  • Impair WBC adhesion & function
    • Mesalazine any dose reduces dysplasia/CRC in IBD
    • Lab data - reduces spontaneous mutation rate by70%
5 asa drugs
5 ASA drugs
  • Reduce the long term risk of cancer in Crohns

Eaden et al Aliment Pharm Ther 2000; 14: 145-33

  • No role in keeping remission in CD post operatively over 18months except in a subgroup of patients with only small bowel disease
  • This is in contrast to earlier trials
    • Lochs H et al, Gastroenterology 2001; 118: 264-273
    • Hanauer S et al, Clin.Gastro.Hepatol. 2004; May(5):379-88
crohns post surgery
Crohns post surgery
  • Recurrence is high – 50% symptomatic, 80% radiologic/endoscopic at 3years
  • These patients were on no treatment
  • Therefore put higher risk patients (smokers, perforating disease, repeat surgery & ileocolonic anastomosis) onto Azathioprine/ 6MP
    • McLeod RS. et al, Gastroenterology 1997; 113: 1823-27
crc risk in ibd
CRC risk in IBD
  • Ulcerative colitis: with PSC is highest risk
  • Pancolitis 2.4RR, cumulative incidence 5-10% after 20years (i.e. 0.5%/yr)
  • Left sided colitis - risk is delayed by a decade
  • Proctitis - no increased cancer risk
  • Crohns colitis is probably similar but data is limited.
nicotine
Nicotine
  • Smoking lessens risk of UC by 40%
  • Crohns disease is 2-4 times more common in smokers than non-smokers
  • Relapse rate decreases by 40% in CD patients who stop smoking
  • Need for steroids and immunosuppressives increases in smokers (i.e. more steroid dependence)
    • Cosne et al, Gastroenterology 2001; 120: 1093-99
ulcerative colitis
Ulcerative colitis
  • Use higher doses aminosalicylates to treat flares (2.4-4.8g/day)
  • Meta-analysis of placebo controlled trials show odds ratio for remission with doses <2g/day, 2-3g/day & >3g/day were 1.5, 1.9, 2.7 respectively
  • No clear dose response with maintenance mesalazine treatment
  • Topical ASA drugs are more effective than topical steroids for active distal disease
uc what doesn t work
UC – What doesn’t work?
  • Rectal steroid is not as good as rectal mesalazine for remission in flares of left sided UC (Lee FL et al, Gut 1996; 38: 229-33)
  • Steroids do not maintain remission therefore avoid long term use
  • Antibiotics/Heparin/Probiotics unproven
cd what doesn t work
CD - What doesn’t work?
  • Steroids have no maintenance benefit in Crohns (Steinhart AH et al, Cochrane Library, issue 3, 2000)
  • This includes budesonide (Gross V et al Gut 1998; 42: 493-6)
  • Cyclosporin doesn’t help in Crohns
  • NSAIDs also worsen the disease
  • Probiotics unproven
mesalazine in crohn s
Mesalazine in Crohn’s
  • Initial reports showed a benefit
    • Sulfasalazine 3 – 6g daily effective in ileal, ileocolic, colonic
    • Asacol 3.2 g/day effective in ileocolic or colonic
    • Pentasa 4g/day effective in ileal, ileocolic, colonic
  • 2004 meta-analysis, 615 patients 3 RCTs of Mesalazine1
    • CDAI dropped 63 points vs 45 points for placebo (p = 0.04)
    • Better than placebo, but debatable clinical significance

1. Hanauer SB. Clin Gastro and Hepatol. 2004;2:379-88

other therapies
Other Therapies
  • Nicotine Patches
    • Effective in two RCTs of mild colitis
    • Ineffective as maintenance therapy
    • High incidence of side-effects
  • Aloe Vera Gel
    • 100ml bd for mild to moderate colitis
    • RCT: 30 treated vs 14 placebo
    • Clinical response 47% vs 14% (p < 0.05)
    • Histological score decreased significantly (p = 0.01)
    • $150 - $250 per month
    • slide courtesy Dr John Perry
probiotics in ibd
Probiotics in IBD
  • Probiotics are commensuals that benefit humans (e.g VSL3 treats pouchitis)
  • Prebiotics are foods that influence growth of certain gut organisms (e.g. oligosaccharides to treat Ab associated diarrhoea and reduce Cl.difficule relapse)
  • Probiotics are currently unproven in IBD
asca panca
ASCA & pANCA
  • Anti saccharomyces cerevisine antibodies
  • High specificity (over 95%) for Crohns disease, but not sensitive
  • Antigen is found in Bakers yeast
  • pANCA is more assoc with UC, but PPV is only 76%
  • At present these tests do not reliably predict how indeterminant colitis will proceed.
treatment of ibd in pregnancy
Treatment of IBD in Pregnancy
  • Outcomes worse if active disease at conception
    • Aim to induce remission before conception
  • Risk to foetus if ongoing active disease
  • Most meds used in IBD are safe:
      • Mesalazine (C)
      • Corticosteroids (A)
      • Aza/6-MP (from transplant and AIH literature) (D)
      • Cyclosporin (C) (increased prematurity/low birth weight but high survival)
      • Infliximab (>250 births now – no increased risk) (C)
      • Metronidazole (B), Ciprofloxacin (B)
      • Budesonide (B3)
    • Contraindicated
      • Methotrexate (D) – spontaneous abortion and teratogenicity
      • Slide courtesy Dr John Perry

Caprilli R. Gut 2006;55:36-58

summary crohns vs uc
Summary Crohns vs UC
  • Mesalazine is less effective in Crohns
  • Steroids work in both but not long term
  • Azathioprine/6MP very effective in both
  • Antibiotics may help in active Crohns
  • Stopping smoking very impt in Crohns
  • Infliximab well established for induction and maintenance treatment of Crohns but only rescue therapy for UC
  • Elemental/polymeric diet can treat CD
azathioprine monitoring with 6 tgn tpmt
Azathioprine monitoring with6-TGN & TPMT
  • Thiopurine methyl transferase activity can be measured before starting treatment:

Non-metabolisers should not have AZA/6MP

Intermediate metabolisers start at 50% dose

High metabolisers may need early dose increase

6-Thioguanine Nucleotide is the active metabolite of AZA/6MP, so levels can be measured to ensure peak activity without toxicity

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