Transcript IBD UPDATE 2005 - Auckland District Health Board (ADHB)

IBD UPDATE 2007
DR STEPHEN BURMEISTER
Gastroenterologist
North Shore Hospital
Hot Topics
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
 Crohns
Recent Questions 2003
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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
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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
 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?
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Codeine, High fibre diet, Cholestyramine,
Sulphasalazine, Prednisolone.
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
Rising incidence of Crohns
Stable incidence of UC
Geographical distribution of UC
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
 What
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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
 Antibody
formation 13% (anti HACA)
 Infusion reactions in 17%, but only 0.5%
are serious
 Anti – dsDNA antibodies develop in 9%
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Schiabe T. Can J Gastroent 2000; 14: 29
Important papers 1
 Targan
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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
 Present
DH et al, NEJM 1999; 340: 1398-
1404
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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
 Rutgeerts
P et al, Gastroenterology 1999;
117: 761-9
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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
 Accent
1: Hanauer S et al, Lancet 2002;
May 4:359(9317)1541-9
573pts
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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
 Accent
2: Sands B et al, NEJM 2004 Feb
26; 350(9)876-85
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IFB for maintenance in fistulising CD
64% response
Response duration 40 v 14 weeks for the
ongoing treatment
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
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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
 Inhibit
leucotriene, PG and cytokine
synthesis
 Scavenge oxygen free radicals
 Induce apoptosis & aid DNA mismatch
repair
 Impair WBC adhesion & function
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Mesalazine any dose reduces dysplasia/CRC in IBD
Lab data - reduces spontaneous mutation rate by70%
5 ASA drugs
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Reduce the long term risk of cancer in Crohns
Eaden et al Aliment Pharm Ther 2000; 14: 145-33
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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
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Lochs H et al, Gastroenterology 2001; 118: 264-273
Hanauer S et al, Clin.Gastro.Hepatol. 2004; May(5):379-88
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
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McLeod RS. et al, Gastroenterology 1997; 113: 182327
CRC risk in IBD
 Ulcerative
colitis: with PSC is highest risk
 Pancolitis 2.4RR, cumulative incidence 510% 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
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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)
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Cosne et al, Gastroenterology 2001; 120: 1093-99
Ulcerative colitis
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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, 23g/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?
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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?
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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
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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
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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
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slide courtesy Dr John Perry
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
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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
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Outcomes worse if active disease at conception
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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)
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Contraindicated
• Methotrexate (D) – spontaneous abortion and
teratogenicity
• Slide courtesy Dr John Perry
Caprilli R. Gut 2006;55:36-58
Summary Crohns vs UC
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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
 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