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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
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 COLITISExtraintestinal FeaturesRelated 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 36.7%• Left sided proctocolitis 17.0%• Proctitis 46.2%
Extension of Disease over time
• 54% 5-28 yr FU • 10-30% 10 yr FU
UC – Clinical Course
Relapse Rates• First year after diagnosis 50%• 3-7yrs after diagnosis:
In remission 25%Relapse every year 18%Intermittent relapses 57%
• At any one time only 50% of patients in remission
Colectomy Rates – by extent of disease at presentation• Pancolitis 5 yr 32-44%• Proctosigmoiditis 5yr 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 ladyKnown to have Proctitis
• Presents with x6 bloody motions per day• Urgency• Second attack• Smoker
What would you do?
Tests 1
• FBC
• CRP
• Stool culture (C. difficile)
• Examination
- Abdomen, pulse, temp
Options 1
• Oral 5 ASA
• Topical 5 ASA
• Topical steroids
• Oral 5ASA and topical 5ASA
• Steroids
• Other
Oral 5-ASA in UC
• 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
• 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
• 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
• 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)– 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
• Not very common – usually mild - <2%
• May mimic active colitis
• Confusing – link from rechallenge
• Class specific
5-ASA interstitial nephritis
• 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
1. Other topical treatment
2. Oral steroids
3. Immunosuppressants
4. Re-assess
5. Admit
• Admit for intensive treatment
• iv steroids
• Re-hydration
• Topical treatment
• Avoid food
• DVT prophylaxis
• Surgeons
Severe attack
The Natural History of UC• On day 3
if more than 8 stools/dor 3-8 stools/d + CRP > 45 mg/l85% will need colectomy
• 40% in remission day 5, 30%deteriorate and have colectomy, 30% partial response
• Surgerytoxic dilatation, perforation, haemorrhage, sustained temp of 38C, >8 stools at 24h, d
Travis et al 1996
Surgery
• 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 Long Term
Response % Remiss. %
N’ham 22 91% 53% at 3yr
Hawkey 98
Oxford 50 56% 40% at 2yr
Jewell 98
Dublin 46 69% 26% at 2yr
O’Donoghue 02
Cyclosporin A
• 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
• 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
• 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 No
Admit
Iv steroids 3 days
Surgery CyA, AZT,
Topical, oral 5ASA
Topical steroids
Refer Oral steroids
