Inflammatory Bowel Disease Recent Advances in Management

1. Dr.Chaitanya Vemuri Inflammatory Bowel Disease Recent Advances in Management

2. Immune mediated chronic intestinal condition 2 major types Ulcerative Colitis Crohns Disease Introduction

3. More in developed countries when compared to developing countries. Epidemiology

4. IBD runs in families Proven association with : Turner Syndrome Hypogammaglobulinemia Selective IgA deficiency Heriditary Angioedema Epidemiology If a patient has IBD, the lifetime risk of that first degree relative will be affected is 10 % . If 2 parents have IBD, each child has 36 % of chance being affected.If a patient has IBD, the lifetime risk of that first degree relative will be affected is 10 % . If 2 parents have IBD, each child has 36 % of chance being affected.

5. Polygenic disorder Few predisposing genes : Mutations in CARD 15 ( caspase associated recruitment domain containing protein 15 ) on chromosome 16 Polymorphisms in DLG5 and IL-23 receptor Genetic Considerations

6. In genetically predisposed Exogenous factors ( normal luminal flora ) Host factors ( intestinal epithelial cell barrier function, innate and adaptive immune function ) cause a chronic state of dysregulated mucosal immune system. IBD currently considered an inappropriate response to an unidentified infectious microbial flora within the intestine , with or without some component of autoimmunity. Pathogenesis

7. Inflammatory pathway emerges from genetic predisposition � activated CD4 + T cells in lamina propria secrete inflammatory cytokines. Some activate Macrophages & B cells Act indirectly to recruit lymphocytes, inflammatory leukocytes, mononuclear cells from bloodstream to intestine . In both UC & CD :

8. CD4 +T cells � 3 major types � associated with colitis TH 1 cells : induce transmural granulomatous inflammation that resembles Crohns disease TH2 cells & NK T cells that secrete IL � 13 induce superficial mucosal inflammation resembling Ulcerative Colitis. TH 17 cells : responsible for neutrophilic recruitment

9. Once initiated in IBD, immune inflammatory response is perpetuated by T cell activation. A sequential cascade of inflammatory mediators extends the response ; each step is a potential target for therapy. Inflammatory cytokines � IL-1, IL-6, TNF � diverse effects on tissues. Therapies such as 5-ASA are potent inhibitors of these inflammatory mediators Inflammatory cascade in IBD

10. Yet unidentified infectious etiology Multiple pathogens Salmonella Shigella Campylobacter Clostridium difficile Bacteroides Clostridia E.coli Exogenous factors

11. Probiotics like lactobacillus, bifidobacterium � inhibit inflammation in animal and human models Psychosocial factors � worsen the disease Daily stress � worsen the disease

12. Pathology

13. A mucosal disease Involving rectum Extend proximally to involve all / part of colon Proximal spread : with continuity; no skip lesions Back wash ileitis Ulcerative Colitis : Macroscopic

15. Mild inflammation : mucosa is erythematous fine granular surface : sand paper Severe inflammation : mucosa is hemorrhagic, edematous, ulcerated Long standing disease : pseudopolyps colon : narrowed & shortened Fulminant disease : toxic megacolon Ulcerative Colitis

17. Limited to mucosa & submucosa Deeper layers � in fulminant cases only ! Crypt architecture of colon : distorted may be bifid reduced in number Basal plasma cells & multiple basal lymphoid aggregates. Neutrophils invade epithelium : cryptitis crypt abscess Ulcerative Colitis : microscopic

19. Any part of GIT : from mouth to anus is involved 30 � 40 % : small bowel 40 � 55 % : small & large bowel 15 � 25 % : colitis Rectum is often spared Segmental involvement Skip lesions Perirectal fistulas Fissures Abscesses Anal stenosis Crohn's Disease: macroscopic

20. Transmural process Cobble stone appearance Endoscopic features : Mild disease : aphthous / superficial ulcerations Active disease : stellate ulcerations fuse longitudinally & transversely � cobble stone Fistula formation Resolve by fibrosis and stricturing of bowel Crohn's Disease

21. Bowel wall : thickens � becomes narrowed , fibrotic leading to chronic recurrent bowel obstruction Projections of thickened mesentery encase bowel : creeping fat & serosal, mesenteric inflammation � promote adhesions & fistula formation

23. Earliest lesion : aphthoid ulcerations and focal crypt abscesses with loose aggregations of macrophages. Granulomas : lymph nodes, mesentery, peritoneum, liver, pancreas Submucosal lymphoid aggregates Skip lesions Transmural inflammation with fissures Fistulas Crohn's Disease : microscopic

25. Clinical Presentation

26. Diarrhea Rectal bleeding Tenesmus Passage of mucus Crampy abdominal pain Severity of symptoms correlates with extent of disease Ulcerative Colitis

27. PROCTITIS : Pass fresh blood / blood stained mucus either mixed with stool / streaked onto normal/hard stool. Tenesmus Rarely have abdominal pain DISEASE EXTENDING BEYOND RECTUM : blood mixed with stool bloody diarrhea Ulcerative Colitis

28. Diarrhea : usually Nocturnal Active disease : vague lower abdominal discomfort / mild central abdominal cramping Anorexia Nausea Vomiting Fever Weight loss Also��.

29. Tender anal canal Blood on rectal examination Extensive disease : tenderness to palpation directly over colon. Physical signs

30. Ulcerative Colitis

31. Active disease : Raised CRP Raised Platelet count Raised ESR Decrease in Hb Low serum albumin Leukocytosis Fecal Calprotein : correlates with histological inflammation, predict relapses & detects Pouchitis Lab

32. Clinical history Clinical symptoms Negative stool examination for bacteria , C.difficile toxin, ova & parasite Sigmoidoscopic appearance Rectal / colonic biopsy Diagnosis

33. To assess the disease activity Performed before treatment If there is no active disease � colonoscopy can be done to assess the disease extent and activity . Sigmoidoscopy

34. Earliest radiological change � Single contrast Barium Enema : FINE MUCOSAL GRANULARITY Severe disease : thickened mucosa, superficial ulcers deep ulcers appear as collar button ulcers Long standing ds : loss of haustrations colon : narrowed & shortened pseudopolyps

35. Mucosal granularity

36. Collar button ulcers

37. CT scan is not as helpful as endoscopy / barium enema in making diagnosis of ulcerative colitis CT findings : Mild mural thickening ( < 1.5 cm ) Inhomogeneous wall density Absence of small bowel thickening Increased perirectal and presacral fat

38. Ulcerative colitis

39. 15 % - present initially with catastrophic illness Massive hemorrhage during severe attacks of disease - 1 % If pt requires 6 � 8 units of blood within 24 � 48 hrs, COLECTOMY is indicated. Toxic Megacolon : tranverse colon with diameter > 5 � 6 cm, with loss of haustrations in pts with severe ds. triggered by electrolyte imbalance & narcotics 50 % resolve with medical therapy resistant : need colectomy Complications

40. Perforation : most dangerous Toxic colitis Severe ulcerations Stricturing : 5 � 10 % Possibility of underlying malignancy is there Rarely develop anal fissures, perianal abscesses Complications

41. 2 patterns of disease Fibro-stenotic obstructing pattern Penetrating � fistulous pattern The site of disease � influences the clinical manifestations Crohn's Disease

42. Most common site : terminal ileum Chronic history of recurrent episodes of right lower quadrant pain & diarrhea Initial presentation mimics : acute appendicitis Pain is usually colicky & relieved by defecation Low grade fever High spiking fever : intraabdominal abscess formation Wt loss : 10 � 20 % of body weight Ileocolitis

43. Inflammatory mass palpable in Rt.lower quadrant of abdomen Composed of inflamed bowel, adherent & indurated mesentery, enlarged abdominal lymph nodes Can cause obstruction of ureter / bladder inflammation : dysuria & fever Radiographic String sign Bowel obstruction : bowel wall edema / fibrosis Severe disease : localized wall thinning with microperforation , fistula formation

44. Enterovesical fistula : dysuria recurrent bladder infections pneumaturia fecaluria Enterocutaneous fistula : follow pathways of least resistance Enterovaginal fistula : dyspareunia feculant painful vaginal discharge

45. Malabsorption Steatorrhea Nutritional deficiencies Intestinal malabsorption : hypoalbuminemia, hypocalcemia, hypomagnesemia, coagulopathy, hyperoxaluria with nephrolithiasis Vertebral fractures Pellagra Megaloblastic anemia Diarrhea : active disease Jejunoileitis

46. Low grade fever Malaise Diarrhea Crampy abdominal pain Hematochezia No gross bleeding Pain : d/t passage of fecal material through narrowed and inflamed bowel. Rarely toxic megacolon Stricturing : 4 � 6 % Fistulas Colitis

47. 1/3rd of patients with Crohns colitis Incontinence Large hemorrhoidal tags Anal strictures Anorectal fistulae Perirectal abscesses Perianal Disease

48. Nausea Vomiting Epigastric pain H.pylori negative gastritis 2nd portion of duodenum : commonly involved Fistulas Chronic gastric outlet obstruction Gastroduodenal Disease

49. Elevated ESR Elevated CRP Hypoalbuminemia Anemia Leukocytosis Lab

50. Gastroduodenoscopy Colonoscopy Wireless capsule endoscopy ( higher diagnostic yield ) CT Enterography ( 1st line in suspected cases of crohn�s ds ) CT MRI Endoscopic & Radiological features

51. Earliest radiographic findings : thickened folds aphthous ulcerations Cobblestone apperance Advanced cases : strictures, fistulas, abscesses String Sign : represents long areas of circumferential inflammation & fibrosis : resulting in long segments of luminal narrowing.

53. Aphthous ulceration

54. Cobble stone appearance

55. String sign

56. Serosal adhesions fistula Perforation : 1 � 2 % ; in ileum Peritonitis Intrabdominal, pelvic abscesses : 10 � 30 % CT guided percutaneous drainage : standard therapy Intestinal obstruction : 40 % Massive hemorrhage Malabsorption Complications

57. P � ANCA ASCA Cbir 1 flagellin : Crohn�s disease patients : 50 % + Ulcerative colitis patients : little / no reactivity Serological markers

58. 60 � 70 % of Ulcerative Colitis patients 5 � 10 % of Crohn�s Disease patients P-ANCA positivity : associated with pancolitis Early surgery Pouchitis Primary sclerosing cholangitis P-ANCA in Crohn�s : associated with colonic disease that resembles ulcerative colitis P - ANCA

59. 60 � 70 % of crohn�s disease patients 10 � 15 % of ulcerative colitis patients ASCA + : Early complications Patients of Crohn�s disease : Omp �C + : Internal perforating disease I2 + : fibrostenosing disease ASCA

60. Differential diagnosis Infectious Etiology Bacterial : Salmonella Shigella E.coli Campylobacter jejuni Clostridium difficile Mycobacterial : Tuberculosis Mycobacterium avium Parasitic : Amebiasis Hook worm Viral : CMV Herpes simplex HIV Fungal : Histoplasmosis Candida Aspergillus

61. Differential diagnosis Non infectious etiology Inflammatory : Appendicitis Diverticulitis Lymphocytic colitis Radiation colitis/enteritis Eosinophilic gastroenteritis Neoplastic : Lymphoma Metastatic carcinoma Carcinoma of ileum Carcinoid Drugs : NSAIDs Gold OCP Cocaine Chemotherapy

62. 1/3rd of patients of IBD have at least one extraintestinal manifestation Dermatologic Rheumatologic Ocular Hepatobilary Urologic Metabolic bone disorders Thromboembolic phenomenon others Extraintestinal manifestations

63. Erythema nodosum : 15 % of crohn�s disease patients Pyoderma gangrenosum : 1 -12 % of ulcerative colitis patients Pyoderma vegetans Pyostomatitis vegetans Sweet�s syndrome Psoriasis : 5 � 10 % of patients with IBD Dermatologic

64. Peripheral arthritis : 15 � 20 % of IBD patients More common in crohn�s disease Arthritis : asymmetric, polyarticular, migratory large joints of upper & lower extremities Ankylosing spondylitis : 10 % IBD patients more common in Crohn�s Sacroilitis : symmetric occurs equally in UC and CD Rheumatologic

65. Hypertrophic osteoarthropathy Pelvic / femoral osteomyelitis Relapsing polychondritis Rheumatologic

66. 1 � 10 % of IBD patients have ocular manifestations Conjunctivitis Anterior uveitis Episcleritis Uveitis is associated with both Ulcerative colitis and Crohn�s Colitis Ocular

67. Hepatic steatosis Cholelithiasis : CD > UC Primary Sclerosing Cholangitis : 1 � 5 % of patients with IBD have PSC 50 � 75 % of patients with PSC have IBD Hepatobiliary

68. Calculi Ureteral obstruction Fistulas Urologic

69. Low bone mass : 3 � 30 % of IBD patients Vertebral fractures Osteonecrosis Metabolic Bone Disease

70. Increased risk of both vemous and arterial thrombosis Thromboembolic disorders

71. Endocarditis Myocarditis Pleuripericarditis Interstitial lung disease Pancreatitis Amyloid deposition systemically : diarrhea constipation renal failure Other disorders

72. Treatment

73. Distal Ulcerative Colitis

74. Extensive Ulcerative Colitis

75. Inflammatory Crohn's Disease

76. Fistulizing Crohn's Disease

77. Thalidomide : inhibits TNF production by monocytes and other cells Thalidomide : Glucocorticoid refractory cases Fistulous Crohn�s Disease Adalimumab : recombinant human monoclonal IgG 1 antibody  binds to TNF alpha & neutralizes its function by blocking interaction b/w TNF and cell surface receptor Newer Immunosuppressive agents

78. Indications for Surgery Ulcerative Colitis Intractable disease Fulminant disease Toxic megacolon Colonic perforation Massive colonic hemorrhage Extracolonic disease Colonic obstruction Colon cancer prophylaxis Colon dysplasia / cancer Crohn�s Disease Small Intestine Stricture & obstruction unresponsive to medical therapy Massive hemorrhage Refractory fistula Abscess Colon & Rectum Intractable disease Fulminant disease Refractory fistula Colonic obstruction Cancer prophylaxis

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