IBD UPDATE 2005 - Auckland District Health Board (ADHB)
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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
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
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?
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
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%
Schiabe T. Can J Gastroent 2000; 14: 29
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
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
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
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
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
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
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
Mesalazine any dose reduces dysplasia/CRC in IBD
Lab data - reduces spontaneous mutation rate by70%
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
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: 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
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
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?
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?
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
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
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
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
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
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
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