IBD UPDATE 2007IBD UPDATE 2007

DR STEPHEN BURMEISTERDR STEPHEN BURMEISTER

GastroenterologistGastroenterologist

North Shore HospitalNorth Shore Hospital

Hot Topics Hot Topics

Crohns treatment – InfliximabCrohns treatment – Infliximab Crohns genetics & IBD cancer riskCrohns genetics & IBD cancer risk 5 ASA drugs – reduce cancer risk, needed 5 ASA drugs – reduce cancer risk, needed

in higher doses in U.Colitisin higher doses in U.Colitis Actions of AminosalicylatesActions of Aminosalicylates Effect of smoking on IBDEffect of smoking on IBD Azathioprine monitoring with 6TGN & Azathioprine monitoring with 6TGN &

TPMTTPMT

Recent Questions 2003Recent Questions 2003

A 54 year old man with colonic Crohns A 54 year old man with colonic Crohns is in remission after an 8wk course of is in remission after an 8wk course of prednisone. Which Rx is most likely to prednisone. Which Rx is most likely to maintain remission?maintain remission?• Salazopyrin Salazopyrin • Prednisolone Prednisolone • Azathioprine Azathioprine • Metronidazole Metronidazole • MethotrexateMethotrexate

Recent Questions Recent Questions

A 45 year old with Crohns presents with fever, A 45 year old with Crohns presents with fever, rigors & RLQ pain. Meds include Pred 10mg & rigors & RLQ pain. Meds include Pred 10mg & Sulphasalazine. Temp 37.8, very tender RLQ Sulphasalazine. Temp 37.8, very tender RLQ but no general peritonitis. CT abdo shown. Best but no general peritonitis. CT abdo shown. Best initial Rx?initial Rx? IV Abs, IV hydrocortisone & IV Abs, IV Abs, IV hydrocortisone & IV Abs,

Laparotomy, IV hydrocort only, Change Laparotomy, IV hydrocort only, Change sulphasalazinesulphasalazine..

Recent Questions 3Recent Questions 3

A 43 year old man 6/12 post resection A 43 year old man 6/12 post resection 50cm terminal ileum for Crohns presents 50cm terminal ileum for Crohns presents with diarrhoea & abdo pain. Examination with diarrhoea & abdo pain. Examination and tests normal including colonoscopy. and tests normal including colonoscopy. Best treatment?Best treatment? Codeine, High fibre diet, Cholestyramine, Codeine, High fibre diet, Cholestyramine,

Sulphasalazine, Prednisolone.Sulphasalazine, Prednisolone.

IBD pathogenesisIBD pathogenesis

IBD is a cycle of inflammation, repair and IBD is a cycle of inflammation, repair and healinghealing

Probably as a result of inappropriate Probably as a result of inappropriate immune perception of normal gut floraimmune perception of normal gut flora

As SES rises, IBD rates rise – probably As SES rises, IBD rates rise – probably due to reduced exposure to infections in due to reduced exposure to infections in childhoodchildhood

Also a genetic component presentAlso a genetic component present

Rising incidence of CrohnsRising incidence of Crohns

Stable incidence of UCStable incidence of UC

Geographical distribution of UCGeographical distribution of UC

Crohns GeneticsCrohns Genetics

First genetic susceptibility factor found:First genetic susceptibility factor found: CARD15/NOD 2 gene mutations on CARD15/NOD 2 gene mutations on

Chrom 16Chrom 16 A toll-like receptor involved in sensing the A toll-like receptor involved in sensing the

bacterial environmentbacterial environment Present in 20% Crohns patients, but not in Present in 20% Crohns patients, but not in

UCUC Phenotypic link to ileal disease +/- fistulaePhenotypic link to ileal disease +/- fistulae Twins 58% concordance in CrohnsTwins 58% concordance in Crohns

Infliximab in Crohns Infliximab in Crohns

What is infliximab?What is infliximab? Anti – TNF alpha chimeric antibodyAnti – TNF alpha chimeric antibody Safe and effective for refractory chronic active Safe and effective for refractory chronic active

and fistulous Crohns diseaseand fistulous Crohns disease Expensive, but saves money on later Expensive, but saves money on later

hospital/surgical carehospital/surgical care Increases the risk of infections (esp. Tb) and Increases the risk of infections (esp. Tb) and

possibly lymphoproliferative disorderspossibly lymphoproliferative disorders

Safety profileSafety profile

Antibody formation 13% (anti HACA)Antibody formation 13% (anti HACA) Infusion reactions in 17%, but only 0.5% Infusion reactions in 17%, but only 0.5%

are seriousare serious Anti – dsDNA antibodies develop in 9%Anti – dsDNA antibodies develop in 9%

Schiabe T. Can J Gastroent 2000; 14: 29Schiabe T. Can J Gastroent 2000; 14: 29

Important papers 1Important papers 1

Targan S et al, NEJM 1997; 337: 1029-Targan S et al, NEJM 1997; 337: 1029-3535 First placebo controlled trialFirst placebo controlled trial 65% of chronic CD patients healed up vs. 65% of chronic CD patients healed up vs.

17% placebo response17% placebo response 5mg/kg dose appeared best5mg/kg dose appeared best

Important papers 2Important papers 2

Present DH et al, NEJM 1999; 340: 1398-Present DH et al, NEJM 1999; 340: 1398-14041404 Second placebo trial, in patients with Second placebo trial, in patients with

fistulising diseasefistulising disease 55% closure of fistulas vs. 13% placebo55% closure of fistulas vs. 13% placebo All responders by time of second infusionAll responders by time of second infusion Median duration of response 3 monthsMedian duration of response 3 months

Important papers 3Important papers 3

Rutgeerts P et al, Gastroenterology 1999; Rutgeerts P et al, Gastroenterology 1999; 117: 761-9117: 761-9 Longer term study looking at retreatmentLonger term study looking at retreatment 73 patients who had maintained response at 73 patients who had maintained response at

8weeks rerandomised to further infusions or 8weeks rerandomised to further infusions or placeboplacebo

53% patients in remission vs. 13% placebo53% patients in remission vs. 13% placebo Benefit maintained for 44 weeksBenefit maintained for 44 weeks Those on 6MP had a 75% responseThose on 6MP had a 75% response

Important papers 4Important papers 4

Accent 1: Hanauer S et al, Lancet 2002; Accent 1: Hanauer S et al, Lancet 2002; May 4:359(9317)1541-9May 4:359(9317)1541-9 573pts573pts Non fistulising CD ongoing Rx – 83% Non fistulising CD ongoing Rx – 83%

respond, but only 1/3 were on Aza/6MPrespond, but only 1/3 were on Aza/6MP 32% infections needing Abs, 3.8% serious32% infections needing Abs, 3.8% serious 10>5mg/kg dosing 8weekly10>5mg/kg dosing 8weekly Overall Tb rate ~100/170,000 pts with at least Overall Tb rate ~100/170,000 pts with at least

14 deaths14 deaths

Important papers 5Important papers 5

Accent 2: Sands B et al, NEJM 2004 Feb Accent 2: Sands B et al, NEJM 2004 Feb 26; 350(9)876-8526; 350(9)876-85 IFB for maintenance in fistulising CD IFB for maintenance in fistulising CD 64% response64% response Response duration 40 v 14 weeks for the Response duration 40 v 14 weeks for the

ongoing treatmentongoing treatment

Other important papersOther important papers

Cohen RD. Am J Gastroent 2000; 95: Cohen RD. Am J Gastroent 2000; 95: 3469-77. 129 patients, 65% luminal, 78% 3469-77. 129 patients, 65% luminal, 78% fistulas respond. 54% off steroidsfistulas respond. 54% off steroids

Rutgeerts P. NEJM 2005; 353: 2467-76 Rutgeerts P. NEJM 2005; 353: 2467-76 ACT 1 & 11 trials in 728pts showed 70% ACT 1 & 11 trials in 728pts showed 70% response to 0,2,6wkly Infliximab infusions response to 0,2,6wkly Infliximab infusions in mod/severe UC at week 8 and 45% in mod/severe UC at week 8 and 45% response at 1year to 8weekly infusionsresponse at 1year to 8weekly infusions

Extra-Colonic FeaturesExtra-Colonic Features Related or Related or notnot to disease activity to disease activity JointsJoints

Arthropathies – small and large joint (SI)Arthropathies – small and large joint (SI) Ankylosing spondylitisAnkylosing spondylitis

Eyes - uveitis and episcleritisEyes - uveitis and episcleritis Skin -erythema nodosumSkin -erythema nodosum

pyoderma gangrenosumpyoderma gangrenosum Sclerosing cholangitisSclerosing cholangitis

Cholestatic LFTsCholestatic LFTs Renal amyloid (rare)Renal amyloid (rare) Venous and arterial thromboembolismVenous and arterial thromboembolism Earlier treatment with steroids +/- infliximabEarlier treatment with steroids +/- infliximab

Aminosalicylate actionsAminosalicylate actionsare Chemopreventativeare Chemopreventative

Inhibit leucotriene, PG and cytokine Inhibit leucotriene, PG and cytokine synthesissynthesis

Scavenge oxygen free radicalsScavenge oxygen free radicals Induce apoptosis & aid DNA mismatch Induce apoptosis & aid DNA mismatch

repairrepair Impair WBC adhesion & functionImpair WBC adhesion & function

Mesalazine any dose reduces dysplasia/CRC in IBDMesalazine any dose reduces dysplasia/CRC in IBD Lab data - reduces spontaneous mutation rate by70%Lab data - reduces spontaneous mutation rate by70%

5 ASA drugs5 ASA drugs

Reduce the long term risk of cancer in CrohnsReduce the long term risk of cancer in CrohnsEaden et al Aliment Pharm Ther 2000; 14: 145-33Eaden et al Aliment Pharm Ther 2000; 14: 145-33

No role in keeping remission in CD post No role in keeping remission in CD post operatively over 18months except in a subgroup operatively over 18months except in a subgroup of patients with only small bowel diseaseof patients with only small bowel disease

This is in contrast to earlier trialsThis is in contrast to earlier trials Lochs H et al, Gastroenterology 2001; 118: 264-273Lochs H et al, Gastroenterology 2001; 118: 264-273 Hanauer S et al, Clin.Gastro.Hepatol. 2004; May(5):379-88Hanauer S et al, Clin.Gastro.Hepatol. 2004; May(5):379-88

Crohns post surgeryCrohns post surgery

Recurrence is high – 50% symptomatic, 80% Recurrence is high – 50% symptomatic, 80% radiologic/endoscopic at 3yearsradiologic/endoscopic at 3years

These patients were on no treatmentThese patients were on no treatment Therefore put higher risk patients (smokers, Therefore put higher risk patients (smokers,

perforating disease, repeat surgery & ileocolonic perforating disease, repeat surgery & ileocolonic anastomosis) onto Azathioprine/ 6MPanastomosis) onto Azathioprine/ 6MP McLeod RS. et al, Gastroenterology 1997; 113: 1823-McLeod RS. et al, Gastroenterology 1997; 113: 1823-

2727

CRC risk in IBDCRC risk in IBD

Ulcerative colitis: with PSC is highest riskUlcerative colitis: with PSC is highest risk Pancolitis 2.4RR, cumulative incidence 5-Pancolitis 2.4RR, cumulative incidence 5-

10% after 20years (i.e. 0.5%/yr)10% after 20years (i.e. 0.5%/yr) Left sided colitis - risk is delayed by a Left sided colitis - risk is delayed by a

decadedecade Proctitis - no increased cancer riskProctitis - no increased cancer risk Crohns colitis is probably similar but data Crohns colitis is probably similar but data

is limited.is limited.

NicotineNicotine

Smoking lessens risk of UC by 40%Smoking lessens risk of UC by 40% Crohns disease is 2-4 times more common in Crohns disease is 2-4 times more common in

smokers than non-smokerssmokers than non-smokers Relapse rate decreases by 40% in CD patients Relapse rate decreases by 40% in CD patients

who stop smokingwho stop smoking Need for steroids and immunosuppressives Need for steroids and immunosuppressives

increases in smokers (i.e. more steroid increases in smokers (i.e. more steroid dependence)dependence) Cosne et al, Gastroenterology 2001; 120: 1093-99Cosne et al, Gastroenterology 2001; 120: 1093-99

Ulcerative colitisUlcerative colitis

Use higher doses aminosalicylates to treat flares Use higher doses aminosalicylates to treat flares (2.4-4.8g/day)(2.4-4.8g/day)

Meta-analysis of placebo controlled trials show Meta-analysis of placebo controlled trials show odds ratio for remission with doses <2g/day, 2-odds ratio for remission with doses <2g/day, 2-3g/day & >3g/day were 1.5, 1.9, 2.7 respectively3g/day & >3g/day were 1.5, 1.9, 2.7 respectively

No clear dose response with maintenance No clear dose response with maintenance mesalazine treatmentmesalazine treatment

Topical ASA drugs are more effective than Topical ASA drugs are more effective than topical steroids for active distal diseasetopical steroids for active distal disease

UC – What doesn’t work?UC – What doesn’t work?

Rectal steroid is not as good as rectal Rectal steroid is not as good as rectal mesalazine for remission in flares of left sided mesalazine for remission in flares of left sided UC (Lee FL et al, Gut 1996; 38: 229-33)UC (Lee FL et al, Gut 1996; 38: 229-33)

Steroids do not maintain remission therefore Steroids do not maintain remission therefore avoid long term useavoid long term use

Antibiotics/Heparin/Probiotics unprovenAntibiotics/Heparin/Probiotics unproven

CD - What doesn’t work?CD - What doesn’t work?

Steroids have no maintenance benefit in Crohns Steroids have no maintenance benefit in Crohns (Steinhart AH et al, Cochrane Library, issue 3, (Steinhart AH et al, Cochrane Library, issue 3, 2000)2000)

This includes budesonide (Gross V et al Gut This includes budesonide (Gross V et al Gut 1998; 42: 493-6)1998; 42: 493-6)

Cyclosporin doesn’t help in CrohnsCyclosporin doesn’t help in Crohns NSAIDs also worsen the diseaseNSAIDs also worsen the disease Probiotics unprovenProbiotics unproven

Mesalazine in Crohn’sMesalazine in Crohn’s Initial reports showed a benefitInitial reports showed a benefit

Sulfasalazine 3 – 6g daily effective in ileal, Sulfasalazine 3 – 6g daily effective in ileal, ileocolic, colonicileocolic, colonic

Asacol 3.2 g/day effective in ileocolic or colonicAsacol 3.2 g/day effective in ileocolic or colonic Pentasa 4g/day effective in ileal, ileocolic, Pentasa 4g/day effective in ileal, ileocolic,

coloniccolonic 2004 meta-analysis, 615 patients 3 RCTs of 2004 meta-analysis, 615 patients 3 RCTs of

MesalazineMesalazine11 CDAI dropped 63 points vs 45 points for CDAI dropped 63 points vs 45 points for

placebo (p = 0.04)placebo (p = 0.04) Better than placebo, but debatable clinical Better than placebo, but debatable clinical

significancesignificance

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

Other TherapiesOther Therapies Nicotine PatchesNicotine Patches

Effective in two RCTs of mild colitisEffective in two RCTs of mild colitis Ineffective as maintenance therapyIneffective as maintenance therapy High incidence of side-effectsHigh incidence of side-effects

Aloe Vera Gel Aloe Vera Gel 100ml bd for mild to moderate colitis100ml bd for mild to moderate colitis RCT: 30 treated vs 14 placeboRCT: 30 treated vs 14 placebo Clinical response 47% vs 14% (p < 0.05)Clinical response 47% vs 14% (p < 0.05) Histological score decreased significantly Histological score decreased significantly

(p = 0.01)(p = 0.01) $150 - $250 per month$150 - $250 per month

slide courtesy Dr John Perryslide courtesy Dr John Perry

Probiotics in IBDProbiotics in IBD

Probiotics are commensuals that benefit Probiotics are commensuals that benefit humans (e.g VSL3 treats pouchitis)humans (e.g VSL3 treats pouchitis)

Prebiotics are foods that influence growth Prebiotics are foods that influence growth of certain gut organisms (e.g. of certain gut organisms (e.g. oligosaccharides to treat Ab associated oligosaccharides to treat Ab associated diarrhoea and reduce Cl.difficule relapse)diarrhoea and reduce Cl.difficule relapse)

Probiotics are currently unproven in IBDProbiotics are currently unproven in IBD

ASCA & pANCAASCA & pANCA

Anti saccharomyces cerevisine antibodiesAnti saccharomyces cerevisine antibodies High specificity (over 95%) for Crohns disease, High specificity (over 95%) for Crohns disease,

but not sensitivebut not sensitive Antigen is found in Bakers yeastAntigen is found in Bakers yeast pANCA is more assoc with UC, but PPV is only pANCA is more assoc with UC, but PPV is only

76%76% At present these tests do not reliably predict how At present these tests do not reliably predict how

indeterminant colitis will proceed.indeterminant colitis will proceed.

Treatment of IBD in PregnancyTreatment of IBD in Pregnancy Outcomes worse if active disease at conception Outcomes worse if active disease at conception

Aim to induce remission before conceptionAim to induce remission before conception Risk to foetus if ongoing active diseaseRisk to foetus if ongoing active disease Most meds used in IBD are safe:Most meds used in IBD are safe:

• Mesalazine (Mesalazine (CC))• Corticosteroids (Corticosteroids (AA))• Aza/6-MP (from transplant and AIH literature) (Aza/6-MP (from transplant and AIH literature) (DD))• Cyclosporin (Cyclosporin (CC))

(increased prematurity/low birth weight but (increased prematurity/low birth weight but high survival)high survival)

• Infliximab (>250 births now – no increased risk) (Infliximab (>250 births now – no increased risk) (CC))• Metronidazole (Metronidazole (BB), Ciprofloxacin (), Ciprofloxacin (BB))• Budesonide (Budesonide (B3B3))

ContraindicatedContraindicated• Methotrexate (Methotrexate (DD) – spontaneous abortion and teratogenicity) – spontaneous abortion and teratogenicity

• Slide courtesy Dr John PerrySlide courtesy Dr John Perry

Caprilli R. Gut 2006;55:36-58

Summary Crohns vs UCSummary Crohns vs UC

Mesalazine is less effective in CrohnsMesalazine is less effective in Crohns Steroids work in both but not long termSteroids work in both but not long term Azathioprine/6MP very effective in bothAzathioprine/6MP very effective in both Antibiotics may help in active CrohnsAntibiotics may help in active Crohns Stopping smoking very impt in CrohnsStopping smoking very impt in Crohns Infliximab well established for induction and Infliximab well established for induction and

maintenance treatment of Crohns but only maintenance treatment of Crohns but only rescue therapy for UCrescue therapy for UC

Elemental/polymeric diet can treat CDElemental/polymeric diet can treat CD

Azathioprine monitoring withAzathioprine monitoring with6-TGN & TPMT6-TGN & TPMT

Thiopurine methyl transferase activity can Thiopurine methyl transferase activity can be measured before starting treatment:be measured before starting treatment:Non-metabolisers should not have AZA/6MPNon-metabolisers should not have AZA/6MPIntermediate metabolisers start at 50% doseIntermediate metabolisers start at 50% doseHigh metabolisers may need early dose High metabolisers may need early dose

increaseincrease6-Thioguanine Nucleotide is the active 6-Thioguanine Nucleotide is the active

metabolite of AZA/6MP, so levels can be metabolite of AZA/6MP, so levels can be measured to ensure peak activity without measured to ensure peak activity without toxicitytoxicity