1. IBD What’s New Shawinder Johal MRCP, PhD Consultant Gastroenterologist Northern General Hospital

2. When patients are unwell 52% contact GP (52% inappropriate/delay) 26% contact Consultant Gastroenterologist 20% wait until next clinic visit

3. UC

4. 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

5. ULCERATIVE COLITIS Clinical features Bloody diarrhoea and lower abdominal pain of gradual onset Anaemia Weight loss Fever Abdominal pain / tenderness

6. 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)

7. UC – Clinical Course Extent of Disease at Diagnosis Pancolitis36.7% Left sided proctocolitis17.0% Proctitis46.2% Extension of Disease over time 54%5-28 yr FU 10-30%10 yr FU

8. UC – Clinical Course Relapse Rates First year after diagnosis50% 3-7yrs after diagnosis: In remission25% Relapse every year18% Intermittent relapses57% At any one time only 50% of patients in remission Colectomy Rates – by extent of disease at presentation Pancolitis 5 yr32-44% Proctosigmoiditis5yr 4-9 %

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

10. Case 1 -Dr R. 40 Year old lady Known to have Proctitis Presents with x6 bloody motions per day Urgency Second attack Smoker What would you do?

11. Tests 1 FBC CRP Stool culture (C. difficile) Examination - Abdomen, pulse, temp

12. Options 1 Oral 5 ASA Topical 5 ASA Topical steroids Oral 5ASA and topical 5ASA Steroids Other

13. 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

14. 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.

15. 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

16. 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)

17. 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.

18. Suppository plus enema Enemas mostly not retained in rectum Consider suppositories Disease usually prominent if not maximal in rectum Combination therapy Intermittent topical therapy

19. 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

20. 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

21. Case 1 1.Still not feeling better 2.Worried about toxicity and monitoring 3.What benefit? DEMANDS ANSWERS AND ACTION!

22. 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

23. 5-ASA toxicity Available for many years Approved for use in pregnancy Very safe

24. 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

25. 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

26. 5-ASA diarrhoea Not very common – usually mild - <2% May mimic active colitis Confusing – link from rechallenge Class specific

27. 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

28. Monitoring

29. Renal monitoring of 5-ASA Caution in patients with –pre-treatment abnormality –co-morbidity –other nephrotoxic drugs Otherwise need not anticipate problems

30. 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

31. PROGRESS Feels better Re-assured Monitored 1 yearly Taking mesalazine (M/WF)

32. Case 2 64 M 3/12 Unwell X10 per day (nocturnal) Lost weight Abd. Pain OPTIONS

33. Options 1.Other topical treatment 2.Oral steroids 3.Immunosuppressants 4.Re-assess 5.Admit

35. Admit for intensive treatment iv steroids Re-hydration Topical treatment Avoid food DVT prophylaxis Surgeons Severe attack

36. 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 Travis et al 1996

37. Surgery Only cure Does not effect extra GI manifestations Ileo-anal pouch Proctocolectomy and ileostomy

38. Cyclosporin-Long Term Outcomes – Steroid-resistant – 3 Series CentrePt NoInitialLong Term Response %Remiss. % N’ham2291%53% at 3yr Hawkey 98 Oxford5056%40% at 2yr Jewell 98 Dublin4669%26% at 2yr O’Donoghue 02

39. 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

40. 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?

41. Other Immunomodulators Methotrexate Tacrolimus Cyclophosphamide

42. UC – other THERAPIES Infliximab Heparin Nicotine Probiotics/antibiotics Short Chain Fatty Acids Heavy metals Miscellaneous Biologicals Experimental – Leukocytapheresis

43. 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

44. Progress Improves with steroids Azathioprine Bone protection Clinical remission

45. Case 3 35 year old lady, stable, pregnant?? Advice Azathioprine steroids Mode of delivery Risk of IBD

46. 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

47. Acute colitis Yes No Admit Iv steroids 3 days SurgeryCyA, AZT, Topical, oral 5ASA Topical steroids Refer Oral steroids

48. Shawinder.Johal@sth.nhs.uk Shawinder.Johal@sth.nhs.uk (Sweeny)