1. A DVANCES IN I NFLAMMATORY B OWEL D ISEASE presented by The Foundation for Clinical Research in Inflammatory Bowel Disease www.clinicalresearchinibd.org 2004

2. A DVANCES IN I NFLAMMATORY B OWEL D ISEASE presented by The Foundation for Clinical Research in Inflammatory Bowel Disease www.clinicalresearchinibd.org 2004

3. A DVANCES IN I NFLAMMATORY B OWEL D ISEASE presented by The Foundation for Clinical Research in Inflammatory Bowel Disease www.clinicalresearchinibd.org 2004

4. Inflammatory Bowel Disease (IBD) vs. Irritable Bowel Syndrome (IBS) IBD = Inflammatory Bowel Disease –Chronic intestinal inflammation –Crohn’s disease, Ulcerative Colitis IBS = Irritable Bowel Syndrome –No tissue abnormality Change in bowel habits –Diarrhea/ Constipation/ Alternating bowel patterns Pain relieved with bowel movement Increased sensitivity to intestinal motility

5. IBD: Overview Total number of cases –More than 1 million cases estimated in United States –Ulcerative Colitis: 50% –Crohn’s disease: 50% Number of new cases annually –10 new cases per 100,000 people per year –Peak onset occurs between ages of 10 and 19 –Young children: 2%

6. IBD: Overview Scope of the disorder (United States) –700,000 physician visits per year –100,000 hospitalizations per year Long-term outlook –Chronic, lifelong disease without medical cures –Surgery for 50% to 80% of Crohn’s disease patients –Surgery for 20% of Ulcerative Colitis patients Most patients live normal, productive lives!

7. UC CD Indeterminate colitis The Spectrum of IBD

8. Inflammatory Bowel Disease Geographic Distribution Ulcerative Colitis and Crohn’s Disease Same Distribution High Incidence Moderate Incidence Unknown

9. Potential Causes of IBD Genetics Immune System Environment

10. Do All Causes Contribute Equally? Genetics Immune System Environment Genetics Immune System Genetics Environment Immune System

11. Evidence for Genetic Susceptibility to IBD Racial and ethnic risks of IBD Multiple family members with IBD Patterns of IBD in identical vs. fraternal twins

12. Genetic Susceptibility: Twin Studies Disease Presence in Twins Identical Fraternal twins (%) twins (%) UC6.30 CD583.9

13. Genetic Susceptibility: Twin Studies Disease Presence in Twins Identical Fraternal twins (%) twins (%) UC6.30 CD583.9

14. Searching for IBD Genes Candidate Gene Approach –Based on “hunch” –Investment low, likelihood of success low Genome Wide Screen –Better in families with multiply members affected –Looking for evidence of “linkage”

15. Searching for IBD Genes Candidate Gene Approach –Based on “hunch” –Investment low, likelihood of success low Genome Wide Screen –Better in families with multiply members affected –Looking for evidence of “linkage”

16. NOD2 is first Gene associated with Crohn’s disease Located at chromosome 16q12 Similar to plant disease resistance proteins Related to immune response to bacteria Activates “down-stream” inflammatory cell-signals 128124220273 577 744 1044 LRR CARD NBD

17. Significance of NOD2 Risk to Developing Crohn’s disease One copy of Mutated Gene –1.5-4.0 fold risk Two Copies: 15-40 fold risk –10% of CD patients carry two copies –28% of CD patients carry one copy –Actual disease presence with one or two gene copies is less than 10%

18. Environmental Triggers IBD Antibiotics Diet Smoking Infections NSAIDs Stress

19. Environmental Triggers IBD Antibiotics Diet Smoking Infections NSAIDs Stress

20. Smoking in IBD Ulcerative Colitis –Smoking can protect against UC –Ex-smokers are more likely to develop UC Crohn’s disease –Twofold risk in current smokers –Smokers are less responsive to treatment –Smokers are more likely to develop recurrence of disease after surgery

21. Environmental triggers (infection, bacteria) Moderately Inflamed gut Failure to control inflammation Chronic uncontrolled inflammation = Crohn’s disease Successful control of inflammation Normal gut Controlled inflammation Normal gut Controlled inflammation Genetic predisposition What Causes IBD?

22. How IBD is Diagnosed Clinical history Physical examination Laboratory tests Endoscopy (Gastroscopy/Colonoscopy) X-ray findings Tissue biopsy (pathology)

23. How IBD is Diagnosed Clinical history Physical examination Laboratory tests Endoscopy (Gastroscopy/Colonoscopy) X-ray findings Tissue biopsy (pathology)

24. How IBD is Diagnosed Clinical history Physical examination Laboratory tests Endoscopy (Gastroscopy/Colonoscopy) X-ray findings Tissue biopsy (pathology)

25. Colonoscopy in IBD Diagnosis of IBD (UC vs. CD) –Allows visualization of large intestine and ileum –Allows biopsies to examine colon tissue Determines activity of disease Important for pre-cancer surveillance in UC and CD

26. Colonoscopy in IBD Diagnosis of IBD (UC vs. CD) –Allows visualization of large intestine and ileum –Allows biopsies to examine colon tissue Determines activity of disease Important for pre-cancer surveillance in UC and CD

27. Colonoscopy Requires complete “cleansing” of colon to allow visualization of bowel lining Preparations include: –Golytely ® /Colyte ® purge Requires drinking 1 gallon of solution –Fleets prep ® Small volume of purge, large volume of water –Visicol ® tablets

28. GastrointestinaI Tract Stomach Colon Small Intestine (duodenum, jejunum, ileum) Esophagus Ileocecal Valve

29. GastrointestinaI Tract Stomach Colon Small Intestine (duodenum, jejunum, ileum) Esophagus Ileocecal Valve

30. Ulcerative Colitis: Clinical Features

31. Ulcerative Colitis Left-sided ColitisProctitisTotal Colitis The small intestine is not involved.

32. Symptoms of Ulcerative Colitis Symptoms depend on extent and severity of inflammation –Rectal bleeding and urgency to evacuate –Diarrhea –Abdominal cramping –Extraintestinal (systemic) symptoms Joint pain/swelling Eye inflammation Skin lesions

33. Ulcerative Colitis: Colonoscopy Appearance MildNormalSevere

34. Ulcerative Colitis Colonic Complications Perforation Stricture Bleeding Cancer

35. Ulcerative Colitis Colonic Complications Perforation Stricture Bleeding Cancer

36. Crohn’s Disease: Distribution Upper GI Ileocolic (most common) Colon Small Intestine

37. Common Symptoms of Crohn’s Disease Diarrhea Abdominal pain and tenderness Loss of appetite and weight Fever Fatigue Rectal bleeding and anal ulcers Stunted growth in children

38. Common Symptoms of Crohn’s Disease Diarrhea Abdominal pain and tenderness Loss of appetite and weight Fever Fatigue Rectal bleeding and anal ulcers Stunted growth in children

39. Crohn’s Disease: Colonoscopic Appearance CobblestoneDiscrete UlcerStricture (Narrowing)

40. Perforation Stricture Cancer Fistula Abscess Crohn’s Disease: Intestinal Complications

41. Crohn’s Disease: Clinical Features PeritonitisMesenteric Abscess

42. Crohn’s Disease: Clinical Features Internal Fistulae

43. Peri-Anal Fistulae and/or Abscesses External Fistula (via appendectomy incision) Crohn’s Disease: Clinical Features

44. Fistula Skin Tag Abscess Fissure Crohn’s Disease: Perianal Problems

45. IBD: Extra-intestinal Manifestations Skin Eye Bones and Joints Kidney Liver/ Gall Bladder

46. IBD: Extra-intestinal Manifestations Skin Eye Bones and Joints Kidney Liver/ Gall Bladder

47. IBD: Skin Lesions Erythema nodosum Pyoderma gangrenosum

48. Treatment of Inflammatory Bowel Disease Surgery Emotional Support Nutrition Medications

49. IBD: Management Goals Relieve symptoms Treat inflammation Treat complications Address psychosocial issues Identify dysplasia and detect cancer Improve daily functioning Replenish nutritional deficits Minimize treatment toxicity Maintain remission Establish Diagnosis

50. What Patients Should Expect Prior to diagnosis –Quick access/referral from Primary Care to Specialist (Gastroenterologist) At diagnosis –Thoughtful explanation of disease with opportunity for discussion

51. What Patients Should Expect Long-term follow-up –Continuity of care Primary Care Physician (if confident) Gastroenterologist should be available –Consideration of quality of life –Acknowledgement of problems –Access to second opinions –Maintain dignity!

52. What Patients Should Expect Hospital management –Knowledgeable MD/nursing staff –Willingness to refer to specialist center –Communication with patients/families –Encouragement of self-management –Choice in medical/surgical therapies –Access to dietitians, social workers

53. Medical Therapies for Inflammatory Bowel Disease 5-ASA agents –Asacol ® –Azulfidine ® –Colazal ® –Dipentum ® –Pentasa ® –Rowasa ® Enema –Canasa ® Suppository

54. Medical Therapies for Inflammatory Bowel Disease Antibiotics –Cipro ® –Flagyl ® Steroids –ACTH –Medrol ® –Prednisone –Cortenema ® –Cortifoam ®

55. Medical Therapies for Inflammatory Bowel Disease Immunologic agents –Imuran ® (Azathioprine) –Purinethol ® (6-MP) –Neoral ® (Cyclosporine) –Methotrexate Biologic agents –Remicade ® (Infliximab)

56. 5-ASA agents (Aminosalicylates) Induce remissions in mild-moderate –UC/CD Maintain remissions in mild-moderate UC Maintain remissions in CD after: –Medical treatment –Surgical resections

57. 5-ASA agents (Aminosalicylates) Benefits Well-tolerated Few side effects Relatively inexpensive Oral or Rectal Safe for all ages & pregnancy Risks Rare allergies/ side effects Not helpful in severe disease Not helpful after steroids (particularly CD)

58. Stomach Small Intestine Large Intestine Mesalamine in microgranules Pentasa ® Mesalamine w/ eudragit-S Asacol ® Azo bond Azulfidine ® Dipentum ® Colazal ® 5-ASA Release Sites Rowasa ® Canasa ®

59. Rationale for Topical Therapy 5-ASA or Steroids Treats the inflammation directly Best initial choice for active ulcerative proctitis

60. Corticosteriods Prednisone, Hydrocortisone, Medrol ®, Decadron ®, Cortenema ®, Cortifoam ®, ACTH Administered by pill, IV or enema Induce remissions in UC and CD No maintenance benefits

61. Corticosteriods Benefits Induces remissions in UC and CD Quick fix Inexpensive Oral or rectal Risks No long-term benefits Numerous side effects –Cushingoid changes –Hypertension –Diabetes –Osteoporosis –Acne –Cataracts –Depression –Growth retardation

62. Antibiotics Flagyl ® (Metronidazole), Cipro ® (Ciprofloxacin, Ampicillin, etc.) Treats mild symptoms of Crohn’s disease –Active disease when colon is involved –Peri-anal fistulae Intravenous to treat severe colitis or infections such as abscess

63. Antibiotics Benefits Mild-moderate CD Fistula and peri-anal CD Reduce recurrence after surgery (?) Risks Not effective in UC Flagyl ® (Metronidazole) –Neuropathy –Coated tongue –Yeast infections Cipro ® (Ciprofloxacin) –Yeast infections –Tendon injury

64. Immune-Modulators Imuran ® (azathioprine) & Purinetheol ® (6-MP) Long-term (maintenance) treatments for UC or CD –Can treat fistulas in CD over long-term Primarily for patients unable to get off steroids Requires continuous monitoring of blood counts

65. Immune-Modulators Imuran ® (azathioprine) & Purinetheol ® (6-MP) Benefits “Steroid-sparing” in UC and CD Long-term maintenance Relatively inexpensive Risks Can lower blood counts and “immunity” –Small risk of infections Requires long-term monitoring Occasional allergies –Pancreatitis –Fever

66. Immune-Modulators Imuran ® (azathioprine) & Purinetheol ® (6-MP) Myths Dangerous drugs used to treat cancer Cause cancer Should not be used longer than 3 years If they don’t work over 3-6 months, they will not work Must be stopped before or during pregnancy Facts Do not cause cancer Can be used for more than 3 years If they don’t seem to work at first, the dose needs to be reassessed Can be used during pregnancy, –Must be monitored

67. Cyclosporine Benefits Effective in severe UC Effective in Crohn’s disease? Works rapidly Risks Kidney damage Increased infection, tumors,?

68. Methotrexate Used for many decades in Rheumatoid Arthritis Useful in Crohn’s disease to reduce steroids More effective given as injection once a week Common side effects –Nausea, flu-like symptoms day of injection Rare side effects –Liver disease and Pneumonia Cannot be used if attempting pregnancy!!!

69. Biologic Therapy: Remicade ® (infliximab) Blocks the immune system reaction that causes inflammation Rapidly relieves symptoms Allows discontinuation of steroids without recurrence of symptoms Can be given repeatedly over time to maintain remission

70. Biologic Therapy: Remicade ® (infliximab) Benefits Induces and maintains remissions in CD Rapidly relieves symptoms & fistula drainage Steroid-sparing Effective even when other therapies fail Risks Allergic reactions to intravenous infusions Development of antibodies and loss of response Reactivation of TB and other rare infections Expensive

71. How is Remicade ® administered? Intravenous infusion Allergic infusion reactions:  20% of patients –Usually manageable –Often preventable with repeated infusions Discontinuation of therapy due to infusion reactions is rare

72. Weighing the Benefits and Risks of Treatment Potential Benefits Potential Risks Control inflammation Improve symptoms Improve quality of life Prevent relapse Reduce complications Reduce surgery Short-term side effects Long-term toxicity Cost

73. Managing Nutrition in IBD Malnutrition can occur in IBD –Decreased intake of food Symptoms Overly zealous restriction –Decreased absorption of nutrients Active disease, small intestine –Increased needs for calories and protein Professional nutritional assessment Tailor diet to individual needs & preferences Dietary supplements

74. Managing Nutrition in IBD Malnutrition can occur in IBD –Decreased intake of food Symptoms Overly zealous restriction –Decreased absorption of nutrients Active disease, small intestine –Increased needs for calories and protein Professional nutritional assessment Tailor diet to individual needs & preferences Dietary supplements

75. Surgery in IBD Ulcerative Colitis Surgery (colectomy, removal of colon) is curative Colectomy & ileostomy Colectomy & ileo-anal anastomosis (J-pouch) Crohn’s Disease Surgery does not cure Disease recurs after a resection –Less after an “ostomy” Resection of inflamed segments to treat complications or “refractory” disease

76. Surgery in IBD Ulcerative Colitis Surgery (colectomy, removal of colon) is curative Colectomy & ileostomy Colectomy & ileo-anal anastomosis (J-pouch) Crohn’s Disease Surgery does not cure Disease recurs after a resection –Less after an “ostomy” Resection of inflamed segments to treat complications or “refractory” disease

77. Ulcerative Colitis: Indications for Surgery Failure to control severe attacks or toxic megacolon Acute complications Chronic symptoms despite medical therapy Medication side effects without disease control Dysplasia or Cancer

78. Crohn’s Disease: Indications for Surgery Obstructing strictures Complicating fistula Peri-anal abscess Toxic megacolon Localized, unresponsive disease

79. Colorectal Cancer Risks in IBD Compared to general population –Risk is 20 times higher and –Occurs at lower age Risk is same for UC and CD according to: –How much of colon is affected –How long the disease is present –If patient has liver disease (PSC) Risk is may be related to severity/activity of disease

80. Preventing Colon Cancer in IBD Compliance with maintenance medications –5-ASA agents Regular follow-up and surveillance colonoscopies –Every 1-2 years after 10 years –Every year after 20 years Colectomy (removal of colon) if: –Dysplasia (confirmed pre-cancerous changes) –Unwilling to continue surveillance examinations

81. Osteoporosis and IBD Bone (skeletal) disease characterized by low bone density (mass) Increased “fragility” of bone Susceptibility to breaks (fractures) –Particularly of spine (vertebrae) and hip

82. Osteoporosis in IBD Risk Factors Steroid therapy Smoking Active disease –Crohn’s disease > Ulcerative Colitis Females –Small stature –Family history –Post-menopausal

83. Preventing Osteoporosis in IBD Check bone density (DEXA or heel scan) Control active disease Weight bearing exercise Supplement calcium and vitamin D (Crohn’s disease or steroids) Bisphosphonates if low bone density –Actonel ® or Fosomax ®

84. IBD & Pregnancy Fertility is normal if disease is controlled Fertility is reduced in active disease Pregnancy outcomes are normal –Low birth weight/prematurity if active disease –NO INCREASED RISK OF BIRTH DEFECTS Risk of active disease after delivery –Stay on maintenance medications

85. IBD Medications & Pregnancy Medications that are safe: –5-ASA agents –Steroids Low risk of cleft palate –Most antibiotics –Imuran ® (Azathioprine) and Purinethol ® (6-MP) – Remicade ® (Infliximab) MUST BE AVOIDED –Methotrexate

86. Research in IBD Where are We Heading?

87. Genetic Research Identify the gene locations –Family studies –Correlate genes with clinical patterns Identify the gene(s) –Likely multiple –Protective genes/harmful genes Identify function of genes How to manipulate genes

88. Research in the Environment Identify bacteria capable of causing disease –Measles virus, Mycobacteria Paratuberculosis Identify “normal” bacteria that produce “abnormal” immune response –Bacterial-Epithelial interactions Identify gene-microorganism interactions –Do immune systems mistake “self” for bacteria?

89. Options for Environmental Causes Treat patient if “infected” Eradicate from the environment Immunize to prevent “infection”

90. Research in Surgery Ileo-anal pouches –Preventing, treating Pouchitis Minimal invasive surgery –Laparoscopy Prevention of post-operative recurrence –Select subgroups –6-MP, 5-ASA, antibiotics, biologics(?)

91. IBD Summary Ulcerative Colitis and Crohn’s disease are chronic diseases requiring long- term medical therapy Quality of Life is impaired during flare-ups and should be normal during remissions Life expectancy is same as general population Surgery cures Ulcerative Colitis & treats complications in Crohn’s disease

92. Nonadherence Is Associated With Recurrence Follow-up Percentage of Medication Refilled in Previous 6 Months No Recurrence Recurrence Kane et al. Am J Med. 2003;114:39-41.

93. Adherence Decreases Risk of Relapse 0 25 50 75 100 Percentage of Patients (%) Remaining in Remission 403632Adherent n = Nonadherent n =593228 Adherent Nonadherent 01224Time (months)36 Kane et al. Am J Med. 2003;114:39-41.

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