Inflammatory Bowel Disease (IBD) Victor Roque FALU, FLMI, ARA Sr. Underwriting Consultant RGA Reinsurance Company Underw

1. Inflammatory Bowel Disease (IBD) Victor RoqueFALU, FLMI, ARA Sr. Underwriting Consultant RGA Reinsurance Company Underwriting NEHOUA Meeting October 15, 2009

2. Inflammatory Bowel Disease (IBD) • Chronic inflammatory diseases of GI tract of unknown etiology • Commonly refers to 1) ulcerative colitis and 2) Crohn’s disease • Ulcerative colitis (UC) affects only the large intestine (*) • Crohn’s disease (CD) can affect any part of the gastrointestinal tract but most frequently attacks the distal third of the small intestine & the colon

3. IBD (continued) • Diagnosed using clinical, endoscopic, and histologic criteria • No single finding is absolutely diagnostic for one disease or the other • Approx. 20% of patients have clinical picture that falls between ulcerative colitis and Crohn’s disease (indeterminate colitis) • Many of the treatments available are effective for both diseases • Extraintestinal manifestations may be present in both

4. IBD • Approx. 1 million people in U.S. have ulcerative colitis (UC) or Crohn’s disease (CD) • Most commonly observed in industrialized nations;lowest in developing regions (also higher rate in urban areas vs. rural areas) • Incidence higher in Ashkenazi Jews • Incidence is slightly higher in females than males • Vast majority diagnosed between ages 15-40

5. Pathophysiology • Still under investigation • ? Defect in function of the intestinal immune system (breakdown in defense barrier) • Exposure of mucosa to microorganisms results in inflammatory process causing ulceration, bleeding and loss of fluids and electrolytes • ? Genetic predisposition (esp. when ileal disease involved)

7. IBD • Both UC and CD have waxing and waning in intensity and severity • In most cases, symptoms correspond with degree of inflammation • When patient is actively symptomatic, significant inflammation = flare-up of IBD • When asymptomatic, inflammation absent (or less) = in remission

8. Ulcerative colitis (UC) • Affects only the large intestine (very rarely terminal ileum may be inflamed superficially) • Always starts in rectum and is continuous until some proximal part of the colon • Involves the mucosa and submucosa • Ulcerated, friable and granular appearance of mucosa;formation of crypt abscesses • With a severe attack, mucosa becomes hemorrhagic & ulcerated • As UC becomes chronic, colon becomes rigid and loses its haustral (pouch-like) markings • Confined to rectum in 25% of cases; pancolitis in 10% of cases

10. Crohn’s disease (CD) • Also referred to as granulomatous or regional enteritis, granulomatous ileitis, ileocolitis • Can affect any part of GI tract • Can have non-continuous pattern-”skip lesions”, with areas of severe inflammation with intervening normal mucosa • Most frequently affects distal third of small intestine + the colon • Affects all layers of the affected bowel • May be complicated by strictures,fistulas and abscesses

12. Crohn’s disease • Histologically, may show granulomas (aggregates of giant cells) • Late in disease, mucosa develops a cobblestone appearance (deep ulcerations intervening with normal mucosa)

13. Major patterns of involvement • Disease in ileum and cecum (40%) • Disease confined to small intestine (30%) • Disease confined to colon (25%) • Less commonly involves more proximal parts of GI tract (tongue, esophagus, stomach & duodenum)

14. Crohn’s Disease

16. Crohn’s disease • Increased incidence of gall stones and kidney stones (due to malabsorption of fats and bile salts) • Additional mortality: • Multiple surgeries reduce the absorptive capacity of the small bowel • Multiple recurrences • Recurrent infections • Long-term use of steroids & cytotoxic drugs • Suicide

17. Extraintestinal manifestations of IBD • Iritis • Episcleritis • Arthritis • Skin involvement • Pericholangitis • Sclerosing cholangitis

18. Rectal bleeding common Abdominal pain uncommon Rectal involvement almost 100% Fistula formation rare Stricture & obstruction rare Perirectal, perianal abscesses uncommon Continuous involvement Mucosa & submucosa involved Small bowel not involved (*) Risk of malignancy greatly increased Occasional rectal bleeding Abdominal pain common Rectal involvement 50% Fistula formation common Stricture and obstruction common Perirectal, perianal abscesses common Discontinuous involvement Transmural Small bowel often involved Risk of malignancy increased Ulcerative colitis vs. Crohn’s

19. Risk of Malignancy in IBD • In Crohn’s disease, increased risk of cancer of the affected areas (*) • In ulcerative colitis, 8-10 years after initial diagnosis, there is a steady, significant increased risk of developing cancer • Prognostic factors increasing malignancy risk in UC: • Duration of disease 10 yrs or more • Pancolonic involvement • Continuous progressive disease • Severe initial onset • Associated liver disease

20. Differential diagnosis • Anorexia nervosa • Appendicitis • Celiac sprue • Clostridium difficile colitis • Giardiasis • Lactose intolerance • Chronic pelvic pain • Diverticulitis • Pseudomembranous colitis • Salmonellosis • IBS (Irritable Bowel Syndrome)

21. IBS • Recurrent abdominal pain with constipation and/or diarrhea • No detectable structural disease • Cause unknown;associated with stress or anxiety and may follow severe infection • No impact on mortality

22. Clinical history (UC) • Bloody diarrhea common • Abdominal pain, fever, cramping & weight loss in severe cases • Greater extent of involvement, greater probability of diarrhea • As degree of inflammation increases, more systemic symptoms develop (low-grade fever, sweats, dehydration, tachycardia, arthralgias) • In chronic disease, there may be regenerative patches of mucosa called pseudopolyps rising above the diseased surface • Formed stools indicate UC confined to rectum

23. Findings on imaging studies and endoscopies • Irregular colon with “thumb printing” (air in colonic wall) • Toxic megacolon :long, continuous segment of air-filled colon greater than 6 cm in diameter (esp. in transverse colon) • On barium enema, shortened colon in UC, with loss of haustrations & destruction of mucosal pattern (“lead pipe colon”) • Skip areas & rectal sparing in CD • In CD, areas of segmental narrowing w/loss of normal mucosa, fistula formation & string sign (narrow band of barium flowing through an inflamed or scarred area) • Ileitis in UC (without the skip pattern)

28. Findings (imaging studies, endoscopies) • CT & U/S best for demonstrating mesenteric inflammation, intra-abdominal abscesses and fistulas • Mucosal surface irregular and friable (esp. in UC) • Colonoscopy recommended for making diagnosis and determining severity of disease

31. Lab Findings in IBD • CBC’s: • Anemia is common due to blood loss or malabsorption (iron, folate, B12) or may relect the chronic disease state • Leukocytosis & thrombocytosis also common;modestly elevated WBC counts in active disease • Erythrocyte sedimentation rate (ESR or sed. rate) typically elevated;monitors disease activity • Abnormal LFTs may represent pericholangitis or sclerosing cholangitis • Low serum albumin (protein-losing enteropathy) suggests extensive colitis

33. Complications • Toxic megacolon (can be caused by narcotics, cathartics, enemas, antidiarrheal meds) in UC-inflammation impedes ability to contract (peristalsis) & move gas;abdominal pain, distention • Dilated colon – allows bacteria to leak into bloodstream, increases risk of perforation and peritonitis • If no improvement, usually treated with colectomy

34. Complications • Strictures which can lead to obstruction • Fistulas & abscesses (more common in CD, but also 20% UC) • Fistula types: enterovesical, enteroenteric, enteromesenteric, enterocutaneous, rectovaginal & perianal • Stenosis and obstruction • In CD, obstructive hydronephrosis (RLQ compressing rt. ureter) • Sepsis, malnutrition in Crohn’s

36. Extraintestinal complications • Arthritis • Ankylosing spondylitis (HLA-B27) • Episcleritis (3-4%)-parallels course of disease • Iritis • Erythema nodosum (often at disease onset)-esp. anterior tibia • Pyoderma gangrenosum • Aphthous ulcers

39. Complications • Pericholangitis • Chronic active hepatitis • Primary sclerosing cholangitis • Gall stones • Hypercoagulable state

40. Treatment (Medical) • Anti-inflammatory agents (aminosalicylates, corticosteroids) • Immunosupressants • Antibiotics • TNF (Tumor Necrosis Factor) inhibitors • Anti-diarrheal agents • Antispasmodic agents • Supportive therapy • ** 75% of ulcerative colitis patients respond well to medical management

41. Anti-inflammatories (aminosalicylates) • Sulfasalazine (Azulfidine)-combination of sulfapyradine (anti-bacterial) + 5-aminosalicylic acid (5-ASA) • Greatest effect on IBD; mainstay of outpatient medical treatment for mild-mod. active UC & CD • Originally used to treat rheumatoid arthritis • Possesses both anti-inflammatory & antibacterial properties • Partially absorbed in jejunum but remainder passes to colon • Therapeutic action of 5-ASA compounds: inhibition of prostaglandin & leukotriene synthesis, free radical scavenging, impairment of white cell adhesion and function, inhibition of cytokine synthesis • Watch for folate deficiency, abdominal discomfort & allergies to sulfa compounds

42. Anti-inflammatories (aminosalicylates) • Mesalamine group- Asacol, Pentasa, Rowasa • Coating 5-ASA with acrylic resins- permits drug delivery to distal bowel & colon • Effective for ileal & colon involvement • Rapid absorption • Enemas and suppositories • Fewer side effects than sulfasalazine • Olsalazine-delayed absorption;useful in colonic disease

43. Anti-inflammatories corticosteroids • Treatment of choice for acute attack IBD (including IV treatment; enemas for acute proctitis) • Generally used for moderate-severe IBD • Not to be used for maintaining remission due to multiple & severe side effects * • Prednisone-synthetic glucocorticoid;powerful anti-inflammatory action • Usually tapered doses • IV use- methylprednisolone, dexamethasone • Budesonide (Entocort EC)- newer type • Synthetic steroid coated with ethylmethylcellulose which delays its release until ileum & descending colon • **Side effects often outweigh benefits if used for prolonged period of time

44. Immunosuppressants • Reduce inflammation by suppressing immune system’s response (which might damage digestive tissue) to invading virus or bacterium • Azathioprine (Imuran) & mercaptopurine (6-MP, Purinethol) • help reduce signs and sx of IBD and heal fistulas from CD • inhibits mitosis • Increases risk of neoplasia • Serious hepatic, renal, & hematological side effects

45. Immunosuppressants • Methotrexate (Rheumatrex)- used for patients who do not respond to other medications • Cyclosporine (Neoral, Sandimmune)- administered IV for CD with fistulas

46. Antibiotics • IBD is associated with frequent bacterial infections especially with toxic megacolon, fistulas and fulminant disease • Most effective antibiotics: metronidazole (Flagyl), ampicillin, cephalosporins, amonioglycosides, ciprofloxacin (Cipro)

47. TNF (tumor necrosis factor) inhibitors • TNF is a protein produced by immune system; chemical messenger that can cause inflammation & tissue damage • Etanercept (Enbrel) – TNF receptor blocker; binds to alpha & beta TNF • Used to treat RA; not yet FDA approved for treating Crohn’s

48. TNF Inhibitors • Infliximab (Remicade)- neutralizes cytokine TNF alpha • Increased risk infections (reactivation of TB or granulomatous disease) • Usually for moderate-severe disease • May be used for long-term therapy

49. Antidiarrheal agents • Decrease peristalsis & therefore intestinal motility • Improves diarrhea& prevents loss of fluid & electrolytes • Loperamide (Imodium), Atropine (Lomotil) • Cholestyramine (Questran)- inhibits enterohepatic reuptake of bile salts

50. Antispasmodic agents • Treat functional disturbances of GI motility • Dicyclomine (Bentyl)- anticholinergic; blocks action of acetylcholine at parasympathetic sites in secretory glands, smooth muscle & CNS