Transcript Document

IBD What’s New
Shawinder Johal MRCP, PhD
Consultant Gastroenterologist
Northern General Hospital
When patients are unwell
• 52% contact GP
(52% inappropriate/delay)
• 26% contact Consultant
Gastroenterologist
• 20% wait until next clinic visit
UC
ULCERATIVE COLITIS
Epidemiology
• Disease of the West (and immigrants thereof)
• Twice as common in Winter
• Incidence 7/100, 000
• 10% have an affected relative (UC or Crohns)
• Young
Pathogenesis
Unclear. Familial and environmental factors. Abnormal
colonic mucosa, luminal contents and immune response
Diagnosis
Endoscopy and Histology
ULCERATIVE COLITIS
Clinical features
• Bloody diarrhoea and lower abdominal
pain of gradual onset
• Anaemia
• Weight loss
• Fever
• Abdominal pain / tenderness
ULCERATIVE COLITIS
Extraintestinal Features
Related to disease activity
-mouth ulcers
-erythema nodosum
-episcleritis
-arthritis (pyoderma gangrenosum)
Unrelated to disease activity
-Saro-ileitis
-Small joint disease
-(Ank spond, liver disease)
UC – Clinical Course
Extent of Disease at Diagnosis
• Pancolitis
• Left sided proctocolitis
• Proctitis
36.7%
17.0%
46.2%
Extension of Disease over time
• 54%
• 10-30%
5-28 yr FU
10 yr FU
UC – Clinical Course
Relapse Rates
• First year after diagnosis
• 3-7yrs after diagnosis:
In remission
Relapse every year
Intermittent relapses
50%
25%
18%
57%
• At any one time only 50% of patients in remission
Colectomy Rates – by extent of disease at presentation
• Pancolitis
• Proctosigmoiditis
5 yr
5yr
32-44%
4-9 %
Mortality
• ?Increase in Mortality
• 1950’s – 25% mortality in first severe attack
Even now:• 29% of patients with a severe attack of UC
will require a colectomy during the same
hospital admission and
• further 14% within 1 year of that admission
Case 1 -Dr R.
40 Year old lady
Known to have Proctitis
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Presents with x6 bloody motions per day
Urgency
Second attack
Smoker
What would you do?
Tests 1
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FBC
CRP
Stool culture (C. difficile)
Examination
- Abdomen, pulse, temp
Options 1
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Oral 5 ASA
Topical 5 ASA
Topical steroids
Oral 5ASA and topical 5ASA
Steroids
Other
Oral 5-ASA in UC
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Efficacy uncontroversial
Reduces frequency of relapse~40%
Modest definite value in acute flare
More effective topically than steroids
- acute therapy and maintenance
• Avoid switching
• Not all 5-ASAs the same
Figure 2 Remission and improvement rates. Percentage of patients achieving remission
(ulcerative colitis disease activity index (UCDAI) of 0 or 1) or improvement (decrease in
UCDAI >2 points). Rem, remission; Imp, improvement.
Oral and topical
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DBRCT n = 127
4 g/day oral for eight weeks
initial four weeks also enema
1 g of mesalazine or placebo
Marteau 2005
Oral and topical
Remission
• 44% v 34% at four weeks (NS)
• 64% v 43% at eight weeks (p=0.03)
Improvement
• 89% v 62% at four weeks (p=0.0008)
• 86% v 68% at eight weeks (p=0.026)
Figure 3 Time to cessation of rectal bleeding in patients with frank bleeding at
baseline. SDF, survival distribution function from Kaplan-Meier survival analysis
(proportion of patients with rectal bleeding). All patients without cessation of rectal
bleeding by day 56 or who withdrew prematurely were censored.
Suppository plus enema
• Enemas mostly not retained in rectum
• Consider suppositories
• Disease usually prominent if not
maximal in rectum
• Combination therapy
• Intermittent topical therapy
Oral 5ASA - chemoprotective
• Cumulative cancer risk in UC is
• 2% at 10 years
• 8% at 20 years
• 18% by 30 years
• Cumulative cancer risk in CD IS 7%
• If age of onset below 25 year, risk increased
to 18% and 19% (UC and CD respectively)
• May reduce Ca risk by up to 81% in UC
patients
5-ASA in post-op Crohn’s
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Still somewhat controversial
Post-operative prophylaxis
Clinical relapse rate reduced by ~15%
Endoscopic relapse rate reduced by 18%
• 6 best studies – n = 1141
• Positive result if >2g/d
Case 1
1. Still not feeling better
2. Worried about toxicity
and monitoring
3. What benefit?
DEMANDS ANSWERS
AND ACTION!
Resistant proctitis-Options
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Poor compliance
Re-assess disease
?IBS
AXR-Treat proximal constipation
Mesalazine 1gm at night and predsol am (sup
vs enema)
• Prednisolone +/- azathioprine
• Anecdotal lignocaine 2% gel bd, Bismuth or
butyrate enemas
• Surgery
5-ASA toxicity
• Available for many years
• Approved for use in pregnancy
• Very safe
Sulfasalazine toxicity
• occurs in >20%, dose dependent
• headache, nausea, epigastric pain
• serious idiosyncratic reactions all rare and
less frequent than in RA (<1:10,000)
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Stevens Johnson
pancreatitis
agranulocytosis
alveolitis
5-ASA toxicity
• Not common – usually mild
• Headache (2%), nausea (2%), rash
(1%) and thrombocytopenia (<1%)
• Adverse events ~ placebo
• Very similar for mesalazine, olsalazine
and balsalazide
5-ASA diarrhoea
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Not very common – usually mild - <2%
May mimic active colitis
Confusing – link from rechallenge
Class specific
5-ASA interstitial nephritis
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Probably not dose-related
Very rare – max estimate 1:100,000
More likely if severe colitis
Highest risk if pre-existing renal
impairment
• No apparent difference between 5-ASAs
Monitoring
Renal monitoring of 5-ASA
• Caution in patients with
– pre-treatment abnormality
– co-morbidity
– other nephrotoxic drugs
• Otherwise need not anticipate problems
Renal monitoring of 5-ASA
• BSG guidelines are relaxed (2004)
• Monitoring not “required”
• Wise to check creatinine
– Before starting therapy
– At 6 months
– Annually thereafter
• Probably fully reversible if identified early in
rare event that renal impairment occurs
• ECCO (2006) more cautious than BSG
PROGRESS
• Feels better
• Re-assured
• Monitored 1 yearly
• Taking mesalazine (M/WF)
Case 2
64 M 3/12 Unwell
• X10 per day (nocturnal)
• Lost weight
• Abd. Pain
OPTIONS
Options
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Other topical treatment
Oral steroids
Immunosuppressants
Re-assess
Admit
Severe attack
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Admit for intensive treatment
iv steroids
Re-hydration
Topical treatment
Avoid food
DVT prophylaxis
Surgeons
The Natural History of UC
• On day 3
if more than 8 stools/d
or 3-8 stools/d + CRP > 45 mg/l
85% will need colectomy
• 40% in remission day 5, 30%deteriorate and have
colectomy, 30% partial response
• Surgery
toxic dilatation, perforation, haemorrhage, sustained
temp of 38C, >8 stools at 24h, d
Surgery
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Only cure
Does not effect extra GI manifestations
Ileo-anal pouch
Proctocolectomy and ileostomy
Cyclosporin-Long Term Outcomes –
Steroid-resistant – 3 Series
Centre Pt No
Initial
91%
Long Term
Remiss. %
53% at 3yr
56%
40% at 2yr
69%
26% at 2yr
Response %
N’ham 22
Hawkey 98
Oxford 50
Jewell 98
Dublin 46
O’Donoghue 02
Cyclosporin A
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2mg/kg infusion over 6h (2-5 days)
Oral 3 months
Azathioprine last month as steroids stopped
60-70% response rate
Continuing worries over safety/ toxicity
Renal dysfunction/superinfection
• Deaths reported
Immunomodulators in UC
AZATHIOPRINE / 6-MP
• 2-2.5mg/kg (or half for 6-MP)
• Mechanism of action – unknown
• One controlled study – Hawthorne 92 – Aza
withdrawal RCT – 79 pts – placebo relapse
x2
• 30yr retrospective review - Fraser 02 –
effective
• Unknown – how long to continue?
Other Immunomodulators
• Methotrexate
• Tacrolimus
• Cyclophosphamide
UC – other THERAPIES
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Infliximab
Heparin
Nicotine
Probiotics/antibiotics
Short Chain Fatty Acids
Heavy metals
Miscellaneous
Biologicals
Experimental – Leukocytapheresis
Steroids???
How do you use steroids?
• Prednisolone vs budesonide
• 30-40 mg
• Reduce by 5mg per week to 2 weekly
• 30mg 1 week, 20mg 1 month and
5mg/week after to zero
• Bone protections
Progress
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Improves with steroids
Azathioprine
Bone protection
Clinical remission
Case 3
35 year old lady, stable , pregnant??
• Advice
• Azathioprine steroids
• Mode of delivery
• Risk of IBD
Pregnant
• Fertility normal except active disease
• Best during a period of sustained
remission (>6 months)
• Continue maintenance therapy (risk of
relapse higher)
• Joint decision
• Relapse, treat with steroids
Acute colitis
Yes
Admit
Iv steroids 3 days
Surgery
CyA, AZT,
No
Topical, oral 5ASA
Topical steroids
Refer
Oral steroids
[email protected]
(Sweeny)