IBD Therapy

1. IBD Therapy October 27, 2008

3. Other Studies

4. Crohn�s Disease Therapy

5. Factors that affect therapy How sick is the patient? What is the disease distribution? Are there complications ? abscess, fistula, obstuction Has the patient had prior surgery for Crohn�s disease?

6. Budesonide in Crohn�s Disease Budesonide - Entocort Budesonide vs. Mesalamine 3 mg capsules Ileal release based on pH dependent mechanism Steroid with rapid 1st pass metabolism ? less systemic effects

7. Less adrenal suppression but still some Indicated in mild to moderate ileal Crohn�s disease Prescribing information ? for 9 week course of therapy � 3 weeks at each dose 9 mg, 6 mg, 3 mg We do use it more long term in some patients Still need to follow bone density

8. 5-Aminosalicylates What are the drugs? What are the issues? Sulfasalazine Mesalamine Pentasa � 250 mg or 500 mg Asacol � 400 mg Rowasa � 4 gram enema Canasa � 1,000 mg supp Lialda � 1.2 gram tablet Balsalazide � (Colazal) Osalazine (Dipentum) Differ in release characteristics Evidence based medicine ?greater role in UC than CD Sulfasalazine has some data to suggest efficacy in colonic CD Use in mild disease Adverse events: worsening of disease activity, increased creatinine, pancreatitis, allergic reaction (rash)

9. Location of Oral Mesalamine Release

10. 5-Aminosalicylates for induction of remission in active Crohn�s Disease 5 �ASAs in Crohn�s Singleton et al study Singleton study � 16 weeks 2 subsequent studies did not show significant difference May have mild efficacy Currently use of 5-ASAs in CD not considered primary therapy

11. Mesalamine for Maintenance of Remission in Crohn�s Disease Slide 18 Mesalamine for Maintenance of Remission in Crohn�s Disease: Meta-Analysis of Clinical Trials A meta-analysis by Camma and colleagues evaluated randomized controlled trials examining the efficacy of mesalamine in the maintenance of remission in CD1 The results across the trials were variable, perhaps due to differences in dose, mesalamine formulations utilized, duration of treatment, and baseline disease characteristics. However, the pooled estimate of treatment effect was significant (P = .0028) 1. Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn�s disease: a meta-analysis adjusted for confounding variables. Gastroenterology. 1997;113:1465-1473.Slide 18 Mesalamine for Maintenance of Remission in Crohn�s Disease: Meta-Analysis of Clinical Trials A meta-analysis by Camma and colleagues evaluated randomized controlled trials examining the efficacy of mesalamine in the maintenance of remission in CD1 The results across the trials were variable, perhaps due to differences in dose, mesalamine formulations utilized, duration of treatment, and baseline disease characteristics. However, the pooled estimate of treatment effect was significant (P = .0028) 1. Camma C, Giunta M, Rosselli M, Cottone M. Mesalamine in the maintenance treatment of Crohn�s disease: a meta-analysis adjusted for confounding variables. Gastroenterology. 1997;113:1465-1473.

12. Case continued Patient started on 4 grams of Pentasa per day and 9 mg of Entocort Partial response initially but then develops worse abdominal pain and diarrhea. Prednisone is initiated

13. Steroids and IBD Role Side effects Historically important role in the management of acute disease No maintenance role No beneficial role for doses greater than 40 � 60 mg/day For acute disease 40 mg/day x 3 weeks then start taper at 5 mg q 1-2 weeks IV steroids for hospitalized, severely ill patient Osteoporosis Cataracts Poor tissue healing Increased complications Infections

14. Induction of Remission in IBD with Azathioprine/6MP 425 patients (209 AZA/6-MP, 216 placebo) End-points: steroid sparing effect, clinical response Time to respond � average 3.1 months

15. Azathioprine/6MP in IBD Efficacy/Issues Intolerance/Risks Effective in 50 � 70% of patients with IBD 30% failure due to intolerance (15%) or no response (15%) Metabolism issues TPMT Uses Steroid sparing Post operative prophylaxis Bone marrow suppression Pancreatitis Hepatotoxicity Nausea Myalgias � flu like symptoms Other Risks Lymphoma � 4 fold Abnormal PAP / HPV Infection

16. AZA/6MP Metabolism As mentioned earlier, the majority of 6-MP is lost to first pass metabolism, largely via xanthine oxidase, producing 6-thiouric acid (6-TU), an inactive metabolite. The 6-MP that escapes this pathway crosses cell membranes, and the remainder of its metabolism then takes place intracellularly. Once intracellular, there are two competing routes of metabolism that reveal the reasons for therapeutic successes as well as failures. One route of metabolism is via HPRT (hypoxanthine phosphoribosyl transferase), considered an anabolic enzyme. This metabolic route eventually produces 6-thioguanine nucleotides (6-TG). These 6-TG nucleotides are incorporated into the DNA of cells and interfere with cell replication and production of messenger RNA and DNA. This results in interference with cell proliferation and the ability of the cells to have normal metabolic function, including cytokine production. The competing route is via TPMT (thiopurine methytransferase) enzyme (shown on bottom). This enzyme produces 6-methylmercaptopurine ribonucleotides (6-MMP). This is a catabolic pathway that results in an end product that has much less impact on the response to therapeutic use of AZA or 6-MP. However, 6-MMP can interfere with purine synthesis, resulting in macrocytosis. As mentioned earlier, the majority of 6-MP is lost to first pass metabolism, largely via xanthine oxidase, producing 6-thiouric acid (6-TU), an inactive metabolite. The 6-MP that escapes this pathway crosses cell membranes, and the remainder of its metabolism then takes place intracellularly. Once intracellular, there are two competing routes of metabolism that reveal the reasons for therapeutic successes as well as failures. One route of metabolism is via HPRT (hypoxanthine phosphoribosyl transferase), considered an anabolic enzyme. This metabolic route eventually produces 6-thioguanine nucleotides (6-TG). These 6-TG nucleotides are incorporated into the DNA of cells and interfere with cell replication and production of messenger RNA and DNA. This results in interference with cell proliferation and the ability of the cells to have normal metabolic function, including cytokine production. The competing route is via TPMT (thiopurine methytransferase) enzyme (shown on bottom). This enzyme produces 6-methylmercaptopurine ribonucleotides (6-MMP). This is a catabolic pathway that results in an end product that has much less impact on the response to therapeutic use of AZA or 6-MP. However, 6-MMP can interfere with purine synthesis, resulting in macrocytosis.

17. 6-TG Level Correlates WithClinical Response 6-TG levels correlated with clinical response, as shown by this graph. The likelihood of response to therapy increases linearly as you go from left to right (lower to higher quartiles of 6-TG). Data analysis using a receiver-operator curve revealed that the best probability of treatment response in these pediatric patients was not significantly increased until RBC 6-TG levels exceeded a threshold of 235 pmol/8x108 RBCs. Recently, additional studies in adult patients have shown cut-off ranges of 250-260 for 6-TG.6-TG levels correlated with clinical response, as shown by this graph. The likelihood of response to therapy increases linearly as you go from left to right (lower to higher quartiles of 6-TG). Data analysis using a receiver-operator curve revealed that the best probability of treatment response in these pediatric patients was not significantly increased until RBC 6-TG levels exceeded a threshold of 235 pmol/8x108 RBCs. Recently, additional studies in adult patients have shown cut-off ranges of 250-260 for 6-TG.

18. TPMT (thiopurine methyltransferase)

19. How to use TPMT activity in initiation of therapy.

20. Monitoring Azathioprine/6MP therapy TPMT phenotype at baseline CBC/LFTs at baseline and 1-2 weeks after initiation Q month the first 3 months If dose stable then q 3 months and if acute illness develops

21. Case continued Patient unable to taper completely off of steroids despite the addition of 6-MP six months ago Metabolites checked 6 TG 124 pmol 6 MMP 12,178 pmol With these levels it is unlikely that we will be able to get to a point where patient will have therapeutic 6 TG levels without toxicity. Theoretic alternative is 6-TG (unfortunately associated with liver toxicity)

22. Methotrexate Methotrexate Pivotal Induction Study Immunomodulatory vs. Immunosuppressant Active both in induction and maintenance of remission 25 mg sc/week x 16 weeks then dosage reduce to 15 mg sc/week Give folate on off days Monitor LFTs, CBC,

23. Adverse effects of Methotrexate Serious Adverse Events Common Adverse Events Hepatotoxicity Hypersensitivity pneumonitis Myelosuppression Birth defects in offspring Nausea and vomiting (42%) Diarrhea (7%) Headache (17%) Abdominal pain (18%) Joint pain (16%) Elevated AST, ALT Stomatitis Methotrexate has a number of disadvantages in the treatment of CD. Of particular concern are the risks of hepatic and pulmonary toxicity, myelosuppression, and birth defects in offspring.66 Common AEs associated with methotrexate therapy are seen frequently during induction therapy. The significance of sustained elevated aminotransferases and their contribution to liver disease is not known. Myelosuppression should be monitored with periodic blood counts. Methotrexate has a number of disadvantages in the treatment of CD. Of particular concern are the risks of hepatic and pulmonary toxicity, myelosuppression, and birth defects in offspring.66 Common AEs associated with methotrexate therapy are seen frequently during induction therapy. The significance of sustained elevated aminotransferases and their contribution to liver disease is not known. Myelosuppression should be monitored with periodic blood counts.

24. Anti-TNF Antibodies

25. Induction of Remission at 4 weeks

26. Long Term Maintenance of Clinical Response to Anti-TNF therapy

27. How do they differ? Route of administration Infliximab IV Certilizumab and Adalimumab: SC Amount of Mouse protein Apoptosis � yes for Infliximab and Adalimumab, no for certilizumab

28. Anti-TNF therapy Infliximab (infusion) Induction 5mg/kg IV at weeks 0, 2 and 6 Maintenance 5mg/k IV at 8 weeks LOR Escalate dose or shorten interval Cetolizumab pegol ( SC , nurse administered) Loading dose: 400 mg sc at weeks 0, 2 and 4 Maintenance 400 mg sc at 4 weeks LOR ? Attempt re-induction Adalimumab ( SC, prefilled syringe) Loading dose 160 mg at week 0, 80 mg at week 2 Maintenance 40 mg sc EOW or weekly LOR Shorten dosing interval

29. Case # 2 24 year old male presents with 2 months of bloody diarrhea Travel to Tanzania � at the end of the trip developed acute diarrhea Toxic symptoms resolved but continued progressive bloody diarrhea

30. Ulcerative Colitis

31. Ulcerative Colitis Treatment Pyramid

32. Treatment of UC Induction vs. Maintenance Left-sided vs. pan-colonic Fulminate disease Steroid dependent disease Chemoprevention of colon cancer

33. What do we know? 5-Aminosalicylates Steroids Immunomodulators Anti-TNF Antibiotics Nicotine Probiotics

34. Types of 5-ASA Trials Topical vs. systemic therapy Different preparations, different release characteristics Combination therapy (oral + topical, oral + AZA) Dose ranging studies

35. Ulcerative ColitisOral mesalamine

36. Oral vs Oral + Rectal Mesalamine

37. Corticosteroids Rapid clinical benefit Treatment related side effects Preparations Route of administration IV vs. Oral vs. topical Steroid dependence

38. Preparations and Potency Hydrocortisone 1x Prednisone 4x Methylprednisolone 5x Dexamethasone 10x Budesonide 16x

39. Steroids in UC: Landmark Study

40. Azathioprine Thiopruine analogue that modulates the immune response AZA ? 6-mercaptopurine Mixed results in controlled trials in UC Indications Induction of remission in moderate to severe disease (takes time) Maintenance of remission Steroid sparing

41. UC maintenance of remission with AZA ? 1 year remission Jewell (Gut 1974) AZA 1.5 - 2.5 mg/kg (n=40) Placebo (n=40) 11 months Hawthorne (BMJ, 1992) AZA (x 100mg) (n=33) Placebo (n=34) 12 months [withdrawal trial]

42. Other AZA trials AZA vs. MTX (Paoluzi et al Aliment Pharmacol Ther 2003; 17:479-80) (MTX good alternative to AZA in AZA intolerant patients) AZA vs. AZA/Osalazine (Mantzaris et al Am J Gastro 2004; 99:1122-8) (Don�t need 5-ASA to maintain remission) AZA vs. Mycophenolate mofetil (Orth, Am J Gastro 2000 95:1201-7) (AZA/Prednisonlone better than Mycophenolate/Prednisolone) AZA steroid sparing trials (4 controlled trials/3 positive)

43. Infliximab in UC 37 � 50 % had extensive disease 33 � 44% were on steroids greater than 20 mg/day37 � 50 % had extensive disease 33 � 44% were on steroids greater than 20 mg/day

44. Infliximab for steroid refractory UC: Oxford outcome data (2000 � 2006) 30 patients treated with infliximab for refractory ulcerative colitis 16 (53%) went on to colectomy 5 (17%) steroid free remission after a median follow-up of 13 months (2 � 72) No difference in colectomy rate for acute severe UC failing IV steroids (8/14) and steroid refractory (8/16)

45. Cyclosporin in Severe UC Inhibition of immune responses initiated by T lymphocytes Randomized, double blind controlled trial N= 20 Severe UC, still active despite 7 days of IV steroids 4mg/kg cyclosporin in continuous IV infusion for up to 14 days vs. placebo

46. Cyclosporin in Severe UC

47. E Coli Nissle 1917 vs. Mesalazine Probiotic Double blind, double dummy trial Maintenance of remission n = 327 UC in remission 12 month treatment trial of probiotic 200 mg/day or mesalazine 500 mg tid

48. E Coli Nissle 1917 vs. Mesalazine

49. Transdermal Nicotine in UC

50. Surgical Therapy