IBD UPDATE 2007

1. IBD UPDATE 2007 DR STEPHEN BURMEISTER Gastroenterologist North Shore Hospital

2. 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

3. 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

4. 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.

6. 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.

7. 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

8. Rising incidence of Crohns

9. Stable incidence of UC

10. Geographical distribution of UC

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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%

23. 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

24. 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

25. 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.

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. 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

33. 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.

34. 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

35. 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

36. 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