Program Schedule: Sunday, September 18, 2016

Transcription

1 Program Schedule: Sunday, September 18, :30 a.m. Registration / Continental Breakfast / Posters / Exhibits 6:55 a.m. Announcements Amy S. Oxentenko, M.D. Laura E. Raffals, M.D. William Sanchez, M.D. 7:00 a.m. Inflammatory Bowel Disease: Clinical Features.2 Edward V. Loftus, Jr., M.D. 7:30 a.m. Inflammatory Bowel Disease: Extraintestinal Manifestations...57 Laura E. Raffals, M.D. 8:00 a.m. Inflammatory Bowel Disease: Therapy Edward V. Loftus, Jr., M.D. 8:55 a.m. Inflammatory Bowel Disease: Miscellaneous..247 Laura E. Raffals, M.D. 9:20 a.m. Optional: Questions and Answers 9:20 a.m. Refreshment Break / Posters / Exhibits 9:45 a.m. Colorectal Neoplasms and Hereditary Polyposis Syndromes 281 John B. Kisiel, M.D. 10:25 a.m. Board-Style Practice Questions: Colon 338 Glenn L. Alexander, M.D. Jeffrey A. Alexander, M.D. 11:15 a.m. Optional: Questions and Answers 11:30 a.m. Adjourn

2 Edward V. Loftus, Jr., M.D. Professor of Medicine Faculty photo will be placed here 2015 MFMER

3 Inflammatory Bowel Disease Clinical Features Edward V. Loftus, Jr., M.D. Gastroenterology and Hepatology Board Review September 18, MFMER

4 EVL Disclosures Research Support UCB Janssen Takeda Genentech AbbVie Pfizer Amgen Celgene Receptos Robarts Clinical Trials MedImmune Seres Gilead Consultant UCB Janssen Takeda AbbVie Amgen Seres Eli Lilly Mesoblast Bristol-Myers Squibb 2015 MFMER

5 Objectives Epidemiology Clinical Features Diagnostic testing Clinically relevant Dispel misconceptions 2015 MFMER

6 Epidemiology 2015 MFMER

7 Age-Related Incidence of Crohn s Disease in Olmsted County, Loftus CG, IBD 2007 Courtesy EV Loftus 2015 MFMER

8 Age-Related Incidence of Ulcerative Colitis in Olmsted County, Loftus CG, IBD 2007 Courtesy EV Loftus 2015 MFMER

9 Temporal Trend in the Incidence of Crohn s Disease in Olmsted County, Ingle SB, et al. Gastroenterology 2007 Suppl 2015 MFMER

10 Temporal Trend in the Incidence of Ulcerative Colitis in Olmsted County, Ingle SB, et al. Gastroenterology 2007 Suppl 2015 MFMER

11 IBD: Clinical Features Crohn s Ulcerative colitis Extent Any GI Colon Continuity Segmental Continuous Rectal involvement Variable Yes Bloody Depends Usually diarrhea Smoking Yes No Granulomas Yes No 2015 MFMER

12 Disease Extent Crohn s can involve any part of GI tract But colon alone in 25-30% UC involves only the colon But backwash ileitis in 7-15% Contiguous with pancolitis 2015 MFMER

13 Ulcerative Colitis Disease Extent Proctitis 28% Left-sided Colitis 25% Extensive Colitis 47% Backwash ileitis 7% Loftus, EV Jr. Gut (3): MFMER

14 Continuity UC involves rectum and extends proximally But UC-PSC often has rectal sparing Cecal patch in up to 75% Rectal sparing and skip areas can be seen with partially treated UC Diverticula-associated colitis has rectal sparing but acts more like UC 2015 MFMER

15 2015 MFMER

16 UC: Bloody diarrhea in most Diarrhea + bleeding Bloody mucus, alone Diarrhea no bleeding Cramps Extra-intestinal sx 75% 15% 10% 53% 13% Both H, et al. Scand J Gastro 1983: 18: N = MFMER

17 Crohn s: Location & Symptoms Ileocolonic Ileal Colonic Diarrhea 91% 89% 93% Abdominal pain 66% 67% 68% Rectal bleeding 19% 9% 41% Perianal Disease 24% 7% 27% Weight loss 28% 22% 38% Tremaine W. in IBD: From Bench to Bedside: MFMER

18 Smoking status Crohn s disease a/w smoking Incidence Disease course UC associated with non-smoking Many present after d/c smoking Incidence Nicotine patches 2015 MFMER

19 Granulomas Crohn s disease a/w granulomas % A/w severity in some studies but not all UC can have foreign body granulomas a/w ruptured crypts 2015 MFMER

20 IBD: Diagnostic tests 2015 MFMER

21 Ulcerative Colitis 2015 MFMER

22 UC: Sharp Demarcations 2015 MFMER

23 CT Findings 2015 MFMER

24 Histology 2015 MFMER

25 Crypt Distortion 2015 MFMER

26 Crohn s Disease 2015 MFMER

27 CROHN S DISEASE OF THE COLON 2015 MFMER

28 COBBLESTONING 2015 MFMER

29 Crohn s Colitis 2015 MFMER

30 DESCENDING COLON STRICTURE 2015 MFMER

31 Crohn s ileitis 2015 MFMER

32 Capsule Endoscopy: Yield vs. CTE Triester, SL. Am J Gastro (5): MFMER

33 Problems with Capsule Endoscopy Retention Specificity (false positive) 2015 MFMER

34 Diagnostic tests: Small Bowel Crohn s Test Sensitivity Specificity Accuracy Capsule 83% 53% 67% CTE 82% 89% 85% Colonoscopy 74% 100% 86% SBFT 65% 94% 79% Solem GI Endo MFMER

35 Diagnostic tests in Combination Tests Sensitivity Specificity Accuracy CE + CTE 92% 53% 70% CE + colon 100% 57% 77% CTE + colon SBFT + colon 84% 94% 89% 78% 100% 88% Solem GI Endoscopy MFMER

36 Crohn s Disease: Histology Patchy inflammation Granulomas At best, 30% of resections Less in mucosal biopsies 2015 MFMER

37 Crohn s Disease: Granuloma 2015 MFMER

38 IBD Serologic Markers Antibody Antigen Non-IBD (%) CD (%) UC (%) ASCA Saccharomyces cerevisiae cell wall 5-10% 29 69% 5-15% DNase Sensitive panca Unclear <5-48% 2 28% 45 82% OmpC E. coli OMP <5% 24 55% 5-28% I2 Pseudomonas protein 15% 38-60% 42% Cbir-1 Bacterial flagellin 8-15% 50-57% 6-16% From: Papp and Lakatos, Curr Op Gastro MFMER

39 Value of Serologies in Indeterminate Colitis 80% 64% Joossens Gastroenterology MFMER

40 Serologies - Conclusions Not sensitive or specific enough for routine screening May not add to routine diagnostic tests in distinguishing Crohn s from UC May help with indeterminate colitis (but does it matter?) 2015 MFMER

41 Perianal Crohn s Disease 2015 MFMER

42 Perianal Fistulas - MRI 2015 MFMER

43 Perianal Fistulas EUS and EUA Schwartz Gastroenterology MFMER

44 Diagnostic tests: Perianal Crohn s Test Correct Classification EUS 91% Pelvic MRI 87% EUA 91% Any Two 100% Schwartz Gastroenterology MFMER

45 Park s Classification 2015 MFMER

46 Simplified Clinical Classification Simple Superficial, low inter- or transsphincteric Single track No abscess, stricture, RV fistula Complex Everything else With or without proctitis 2015 MFMER

47 Natural History of IBD 2015 MFMER

48 Cumulative Risk Of Colectomy UC, Olmsted County, % 19.4% 27.5% Ingle SB et al, UEGW 2007 and ACG 2007 abstracts. Samuel S et al, Inflamm Bowel Dis 2013;19: MFMER

49 Associations with Time to Colectomy UC, Olmsted County, Characteristic Hazard Ratio 95% CI P-value Male gender Diagnosis Diagnosis Ingle SB et al, UEGW 2007 and ACG 2007 abstracts. Samuel S et al, Inflamm Bowel Dis 2013;19: MFMER

50 Cumulative Risk of Intestinal Resection Among 314 Crohn's Disease Patients Olmsted County, Minnesota ( ) Cumulative incidence (%) Years from Crohn's diagnosis No. at risk Dhillon S et al, Am J Gastroenterol 2005 (abstract) Peyrin-Biroulet L et al, Am J Gastroenterol 2012;107(11): CP MFMER

51 Cumulative Risk of Second Resection Among 159 Crohn's Patients Who Required Intestinal Resection Olmsted County, Minnesota Cumulative incidence (%) Years from first resection No. at risk Dhillon S et al, Am J Gastroenterol 2005 (abstract) Peyrin-Biroulet L et al, Am J Gastroenterol 2012;107(11): CP MFMER

52 Baseline Factors Associated with Time to Surgery: Crohn s, Olmsted County, Characteristic Hazard Ratio 95% CI P-value Male Small bowel < Ileocolonic < Upper gut Current smoker Penetrating Stricturing Early steroids Peyrin-Biroulet L et al, Gastroenterology Suppl 2010 (DDW) Peyrin-Biroulet L et al, Am J Gastroenterol 2012;107(11): MFMER

53 1.0 Cumulative Probability of Change in Crohn s Disease Behavior Among B1 Disease at Diagnosis (n = 249) Years from Crohn s disease diagnosis Thia KT et al. Gastroenterology 2010;139: MFMER

54 Risk Factors Associated With Intestinal Complications: Crohn s, Olmsted County Characteristic Hazard 95% CI Ratio Terminal ileum Ileocolonic Upper GI Perianal fistula Thia KT et al. Gastroenterology 2010;139: MFMER

55 Summary Epidemiology Clinical features help distinguish CD from UC, but caveats Colonoscopy + CTE best for dx of CD Capsule specificity a concern Do serologies add to other tests? Worth $$? For perianal disease, EUA + EUS or MRI 2015 MFMER

56 Thank You 2015 MFMER

57 Laura Raffals, MD, MS Associate Professor of Medicine 2015 MFMER

58 Inflammatory Bowel Disease Extraintestinal Manifestations Laura Raffals, MD, MS No disclosures Mayo Clinic Gastroenterology & Hepatology Board Review September MFMER

59 Objectives Recognize common extraintestinal manifestations of IBD Identify extraintestinal manifestations that correlate with IBD disease activity and those that do not correlate with disease activity Describe treatment of extraintestinal manifestations of IBD Understand PSC surveillance practices 2015 MFMER

60 Most common Extraintestinal Manifestations of IBD Musculoskeletal Dermatologic & oral Hepatopancreatobiliary Ocular Renal EIM can involve any organ system 2015 MFMER

61 EIM in IBD Most patients have colonic involvement EIM may precede onset of luminal symptoms Patients with 1 EIM likely to develop another 2015 MFMER

62 Case 1 An 18 year old woman recently diagnosed with Crohn s colitis develops an increase in bowel frequency (8 BM/day), associated with urgency and nocturnal bowel movements. Two weeks prior to these symptoms she developed painful red nodules on her shins, and pain in her right knee and left wrist. Her right knee is swollen and warm to touch. She is started on a medrol dose pack and while her rash improves her joint pains are preventing her from getting a good night s sleep. Which of the following treatments is the most appropriate treatment for her joint pains? A.Oxycodone B.Budesonide C.Cyclooxygenase-2 inhibitor D.Methotrexate E.Cephalexin 2015 MFMER

63 Musculoskeletal Manifestations Most common EIM (up to 53% of IBD patients) Can affect spine, sacroiliac joint, or peripheral joints 2015 MFMER

64 IBD Arthropathy Seronegative (RF negative) Pain, increased local temperature, joint swelling (with or without effusion), stiffness Differentiate from OA by morning stiffness and improvement with ambulation 2015 MFMER

65 Peripheral Arthritis Occurring in 5-20% of IBD patients Seronegative Plain radiographs typically do not show destructive changes Sulfasalazine better than placebo 2015 MFMER

66 Peripheral Arthritis Type 1 Type 2 Pauciarticular (<5 joints) Associated with IBD activity Large joints (knee) Associated with other EIM Self limited Polyarticular Independent of IBD activity Small joints (metacarpophalangeal joint) Not associated with other EIM (except uveitis) Chronic 2015 MFMER

67 Case 2 A 42 year old man, HLA B27+, with CUC presents with lower back and chest pain for 6 months. The pain is worse when he first awakens and improves as his day gets going. Physical exam reveals slightly limited spinal flexion. What treatment should you recommend? A.Ibuprofen 600mg TID B.Physical therapy C.Colectomy D.Hydrocodone / acetaminophen 2015 MFMER

68 Axial Arthritis Spondylitis occurs in 1-26% of IBD patients Males > females Independent of disease activity Suspect in patients with inflammatory back pain 2015 MFMER

69 Ankylosing spondylitis 1-6% of IBD patients Almost all IBD patients HLA B27 + will develop AS Variable course, often progressive PE reveals limited spinal flexion, reduced chest expansion Radiographic findings include squaring of vertebral bodies progressing to bamboo spine 2015 MFMER

70 Sacroiliitis Often not recognized Many patients asymptomatic Sacroiliitis present on MRI in 24% of asymptomatic IBD patients 2015 MFMER

71 Spondylitis Treatments For patients with sacroiliitis, if asymptomatic & HLA B27 negative, treatment not necessary Physical therapy NSAIDs and COX-2 inhibitors Anti-TNFα effective for AS Colectomy has no effect on axial arthritis 2015 MFMER

72 Osteoporosis Common in IBD overall fracture risk in IBD patients 40% higher than general population Risk Factors Corticosteroids Decreased physical activity Increased cytokines, contributing to bone resorption Malabsorption of calcium & magnesium Vitamin D deficiency Ileal resorption 2015 MFMER

73 DEXA Scan Corticosteroid use >3 months or recurrent courses Low trauma or fragility fracture Postmenopausal females Males > 50 years of age Hypogonadism The AGA recommendations for management of osteoporosis in IBD 2015 MFMER

74 Osteoporosis T score > -1 T score -2.5 to -1 T score less than -2.5 Calcium/ vit D Repeat DEXA in 2 years Exercise Tobacco cessation Consider bisphosphonate & DEXA in 1 year if prolonged CS use Screen for other causes Bisphosphonate or referral to bone specialist Minimize CS Treat hypogonadism The AGA recommendations for management of osteoporosis in IBD 2015 MFMER

75 Dermatologic Manifestations Prevalence 2-34% of IBD patients Erythema nodosum Pyoderma gangrenosum Psoriasis Sweet syndrome Oral aphthous stomatitis Metastatic Crohn s 2015 MFMER

76 Case 3 A 54 year old morbidly obese woman with Crohn s colitis undergoes total proctocolectomy with end ileostomy. One year later she develops the following rash. Which treatment is most likely to effective in preventing recurrence of this rash? A. Diflucan B. Cephalexin C. Weight loss D. Sulfasalazine E. Stoma revision 2015 MFMER

77 Erythema Nodosum Most common cutaneous lesion 10-20% of IBD patients Deep, tender nodules usually on extensor surfaces of lower extremities (arms & trunk can be affected) Activity correlates with IBD activity Treatment directed towards the underlying disease MFMER

78 Erythema nodosum & other conditions TB Coccidiodomycosis Histoplasmosis Blastomycosis Yersinia Behcet syndrome Sarcoidosis Medications Sulfonamides, iodides, bromides, estrogen 2015 MFMER

79 Erythema Nodosum in IBD 2015 MFMER

80 Pyoderma Gangrenosum Pustule, papule, or nodule breaks down into ulcer with violaceous undermined borders Pathergy (Pathergy seen in 2 conditions: PG & Behcet s) Location (think trauma) LE s Peristomal May or may not parallel disease activity 2015 MFMER

81 Pyoderma Gangrenosum 2015 MFMER

82 PG Treatment Avoid trauma Treat active luminal disease Oral corticosteroids Topical tacrolimus Dapsone Cyclosporine or tacrolimus Azathioprine Anti-TNF agent 2015 MFMER

83 Aphthous Stomatitis Common in UC & CD Histology can reveal noncaseating granulomas in CD Treatment is symptomatic 2015 MFMER

84 Metastatic Crohn s Ulcerating nodules with noncaseating granulomas on biopsy Anterior abdominal wall, submammary area, arms, legs, perianal May or may not parallel luminal activity Steroids, immunosuppressives Metronidazole 2015 MFMER

85 Sweet Syndrome Raised, tender nodules on face, arms, trunk Fever, constitutional symptoms Histology: intense neutrophilic infiltrates without vasculitis Treat with CS and treat underlying luminal disease 2015 MFMER

86 Hepatopancreatobiliary Manifestations PSC Portal vein thrombosis Cholelithiasis CD with ileal disease (impaired bile salt absorption) Drug induced hepatitis Drug induced pancreatitis 2015 MFMER

87 Case 4 A 28 year old man is diagnosed with extensive ulcerative colitis 6 months ago. Colonoscopy at diagnosis revealed no evidence of dysplasia or polypoid lesions. He is in clinical remission on mesalamine, 4.8 grams daily. Routine blood work reveals an elevated alkaline phosphatase. MRCP shows stricturing and dilation of the intra- and extra-hepatic bile ducts, suggestive of PSC. When should he undergo his next colonoscopy? A.Six and one-half years B.Six months C.Eighteen months D.One year E.Nine and one-half years 2015 MFMER

88 Primary Sclerosing Cholangitis Inflammation, stricturing, and fibrosis of medium and large intra- and extrahepatic bile ducts 75% PSC patients have UC 5-10% of PSC patients have CD Only 5% of UC and 2% of CD patients have PSC 2015 MFMER

89 PSC & UC Extensive colonic involvement 2:1 male prevalence Does not parallel disease activity PSC may develop years before or after bowel symptoms mayoclinic.org 2015 MFMER

90 PSC & IBD Cholestasis in IBD patient warrants work up for PSC Elevated Alk phos, normal AST, ALT Autoantibodies 33% ANA + 80% panca + MRCP and ERCP reveal multi-focal strictures in intra- and extra-hepatic bile ducts beads on a string 2015 MFMER

91 PSC Increased risk for cholangiocarcinoma Increased risk of colorectal cancer Annual surveillance colonoscopy after diagnosis of PSC 2015 MFMER

92 Treatment of PSC No effective medical treatment Efficacy of ursodeoxycholic acid controversial High doses of UDCA may be harmful Liver transplant often effective, although PSC may recur after transplant 2015 MFMER

93 Pancreatitis Drug induced Azathioprine, 6MP 5-ASA Corticosteroids CD of duodenum Gallstones CD-associated granulomatous inflammation of pancreas 2015 MFMER

94 Ocular Manifestations Up to 5% of IBD patients Often concurrent with other EIM (arthritis & EN) 2015 MFMER

95 Episcleritis Most common ocular complication Acute redness in 1 or both eyes Irritation, burning of eye No change in vision 2015 MFMER

96 Scleritis May impair vision Immediate evaluation by ophthalmologist Clinical presentation may be similar to episcleritis 2015 MFMER

97 Uveitis Anterior uveitis (iritis) occurs in up to 6% of IBD patients Associated with skin and joint EIM Eye pain, redness, visual blurring, photophobia, headaches Immediate referral to ophthalmologist Does not parallel luminal activity Prompt treatment with oral & topical CS 2015 MFMER

98 Uveitis Ciliary flush Redness most intense in center, diminishing outward Slit lamp shows corneal clouding and conjunctival injection 2015 MFMER

99 Renal Manifestations Nephrolithiasis Calcium oxalate stones in ileal CD Fat malabsorption due to intestinal inflammation or resection leads to binding of calcium with fatty acids. Free oxalate (which normal binds to luminal calcium) is absorbed from colonic lumen Secondary amyloidosis Extracellular deposition of fibrils composed of serum amyloid A (SAA) protein May complicate many inflammatory conditions (RA, IBD, AS, familial periodic fever syndrome, and neoplasms) Treat underlying condition 2015 MFMER

100 Suggested Readings Levine JS, Burakoff R, Extraintestinal Manifestations of Inflammatory Bowel Disease, Gastroenterology & Hepatology, volume 7, issue 4, April 2011 Larsen S, Bendtzen K, Nielsen OH. Extraintestinal manifestation of inflammatory bowel disease: epidemiology, diagnosis, and management. Ann Med Mar;42(2): Loftus EV Jr. Management of extraintestinal manifestations and other complications of inflammatory bowel disease. Curr Gastroenterol Rep Dec;6(6): Williams H, Walker D, Orchard TR. Extraintestinal manifestations of inflammatory bowel disease. Curr Gastroenterol Rep Dec;10(6): Rothfuss, KS. Stange EF, Herrlinger KR. Extraintestinal manifestations and complications in inflammatory bowel diseases. World Journal of Gastroenterology; (30): MFMER

101 Questions & Discussion 2015 MFMER

102 Edward V. Loftus, Jr., M.D. Professor of Medicine Faculty photo will be placed here 2015 MFMER

103 Inflammatory Bowel Disease Therapy Edward V. Loftus, Jr., M.D. Gastroenterology and Hepatology Board Review September 18, MFMER

104 EVL Disclosures Research Support UCB Janssen Takeda Genentech AbbVie Pfizer Amgen Celgene Receptos Robarts Clinical Trials MedImmune Seres Gilead Consultant UCB Janssen Takeda AbbVie Amgen Seres Eli Lilly Mesoblast Bristol-Myers Squibb 2015 MFMER

105 Overview Clinical scenarios More slides in your syllabus Clinical update as well as board material Please give feedback 2015 MFMER

106 Case 1 19 F college student with 4 weeks tenesmus and rectal bleeding No fever, travel, weight loss Flex sig showed proctosigmoiditis Biopsies c/w ulcerative colitis 2015 MFMER

107 What treatment would be best for this patient? 1. Mesalamine suppository 2. Mesalamine enema 3. Steroid suppository 4. Steroid enema 5. Steroid orally 2015 MFMER

108 Distal Ulcerative Colitis Proctitis Mesalamine suppository 1 gm HS Steroid suppository, foam Proctosigmoiditis, left sided colitis Mesalamine enemas (4 gm/day) Steroid enemas (100 mg HC) Oral therapy for refractory symptoms or unable/unwilling to use topical Tx 2015 MFMER

109 Topical Steroids or 5-ASA in distal UC? Several RCTs have shown rectal 5-ASA superior to rectal steroids for inducing remission In a meta-analysis, pooled OR was 2.42 for clinical remission Marshall Gut MFMER

110 Case 2 24 M with 4-5 bloody BM/d, cramps No fever, orthostasis, anemia Colonoscopy: mild to moderate pancolitis, normal TI Biopsies c/w ulcerative colitis 2015 MFMER

111 What treatment would be best first line therapy for this patient? 1. Mesalamine enema 4 gm qhs 2. Oral mesalamine 2.4 gm/d 3. Oral mesalamine 4.8 gm/d 4. Oral prednisone 40 mg/d 5. Infliximab 5 mg/kg 2015 MFMER

112 5-Aminosalicylates SAS, olsalazine, balsalazide have azo bond, delivered to colon Asacol, Delzicol ph dependent, TI/colon Pentasa is controlled release, delivered thru small bowel and colon Lialda, Apriso delayed and extended release in colon 2015 MFMER

113 Location of Oral 5-ASA Release Stomach Jejunum Ileum Colon Sulfasalazine Dipentum (olsalazine) Colazal (balsalazide) Asacol (mesalamine) delayed-release tablets Lialda (mesalamine) delayed-sustained-release Apriso (mesalamine) Delayed-sustained-release Pentasa (mesalamine) controlled-release capsules 2015 MFMER

114 Key Questions for 5-ASA Therapy in Ulcerative colitis? Is 5-ASA efficacy dose-dependent? Is split dosing necessary? 2015 MFMER

115 Delayed-Release Oral Mesalamine Mild-to-Moderate Active UC Patients (%) 80 p < Significant Improvement Placebo Mesalamine 1.6 g Mesalamine 4.8 g Patients (%) Remission Placebo Mesalamine 1.6 g Mesalamine 2.4 g 4.8 gm superior to 1.6 gm Schroeder et al. N Engl J Med. 1987;317: MFMER

116 Mesalamine Dose Response in Active UC Ascend I and II Patients (%) Mild UC P=NS Response Remission Moderate UC p= g 4.8 g Daily 5-ASA Dose 2.4 g 4.8 g In mild UC, no difference b/w 2.4 gm and 4.8 gm In moderate UC, slight advantage of 4.8 over 2.4 gm 1 Hanauer American Journal of Gastroenterology MFMER

117 Dose Response with Delayed- Release Mesalamine in Moderate UC ASCEND III Tx Success at Week 6 (%) % p = NS 70% 2.4 g/day 4.8 g/day Sandborn WJ, Gastroenterology MFMER

118 5-ASA Dose Response Several additional studies in your syllabus showing no clear dose-response 2015 MFMER

119 Conclusion No clear evidence for dose dependent efficacy of 5-ASA drugs in mild-moderate UC Start with 2.4 gm/d and escalate if no response in 4-6 weeks 2015 MFMER

120 For our patient, how would you administer the 5-ASA? mg QID mg TID mg BID mg QD 5. Depends on patient s preference 2015 MFMER

121 Multiple studies in syllabus showing no evidence of benefit for split dosing, including older 5-ASA drugs In one study, efficacy better with QD dosing due to better compliance Patient preference is important 2015 MFMER

122 Summary: Mild-moderate UC Active Treatment Oral 5-ASA drugs 2.4 gm/d vs. 4.8 gm/d SAS vs others Topical therapy also for rectal sx 2015 MFMER

123 Steroid Therapy in UC 2015 MFMER

124 Oral Steroids for UC - RCTs Prednisone mg/d is effective for induction in mild to severe UC MMX budesonide 9 mg/d is effective for induction Prednisone 15 mg/d or 40 mg qod is NOT effective for maintenance of remission 2015 MFMER

125 Steroid Induction in UC mg PO cortisone vs placebo. At 6 wks: Mild Mod Severe Cortisone Placebo Truelove and Witts. BMJ 1955; 2: MFMER

126 MMX Budesonide in UC: CORE I Week 8 Sandborn WJ et al, Gastroenterology MFMER

127 MMX Budesonide in UC: CORE II Travis SP et al, Gut MFMER

128 Case 3 32 F, 2 year h/o pan UC on 2.4 gm ASA 5 weeks into flare 12 bloody BM/d, anorexia, mod pain Stools negative for infection Flex sig shows severe inflammation 5-ASA 4.8 gm/day x 2 wks, prednisone 40 mg/d x 2 wks no better 2015 MFMER

129 What treatment would be best for this patient? 1. Continue prednisone 40 mg/d 2. Oral Prednisone 80 mg/d 3. IV methylprednisolone 40 mg QD 4. IV methylprednisolone 40 mg BID 5. Adalimumab 80 mg 40 mg 2015 MFMER

130 Other Options for Severe UC IFX 5 mg/kg (?) at week 0, 2, 6 ADA 160 mg 80 mg GOL 200 mg 100 mg VED 300 mg at week 0, 2, MFMER

131 2015 MFMER

132 UC Severity Index Variable Mild Severe Stools (number/d) <4 >6 Blood in stool Intermittent Frequent Temperature (C) Normal >37.5 Pulse (beats/minute) Normal >90 Hemoglobin Normal < 75% of normal ESR (mm/hr) <30 >30 Fulminant: >10 BM, toxicity, tenderness/distension, need transfusion, colonic dilation Kornbluth, Sachar AJG MFMER

133 Severe Ulcerative Colitis Rule out infection, megacolon Avoid anti-motility agents IV methylprednisolone mg/d vs. anti TNF vs. vedolizumab Often need time for screening tests Discussion of medical options vs surgery 2015 MFMER

134 IV Corticosteroids for UC There are no controlled trials of IV corticosteroids for severely active UC Uncontrolled studies suggest that IV methylprednisolone up to 60 mg/day is efficacious for severely active UC 2015 MFMER

135 IV Steroid Remission in UC Mild Moderate Severe Jarnerot et al. Gastroenterology MFMER

136 IV Steroids and UC Meta-Analysis 32 studies, 1991 patients Early colectomy 29% 22 (1%) died Doses beyond 60 mg/day provide no additional benefit Turner, Clin Gastro Hep MFMER

137 Steroid Non-response Predictive Factors Pancolitis Elevated CRP on day 3 >8 BMs day 3 Endoscopically or clinically severe Fever Low serum albumin Tachycardia Duration >6 wks 2015 MFMER

138 Azathioprine / 6-MP in Ulcerative colitis 2015 MFMER

139 METABOLISM OF AZATHIOPRINE AND 6-MERCAPTOPURINE 2015 MFMER

140 2015 MFMER

141 Summary AZA/6-MP in UC Little or no evidence for induction Usually used for steroid sparing and maintenance or as combination therapy with anti-tnf 2-4 month mean time to efficacy 2015 MFMER

142 Anti-TNF therapy in Ulcerative colitis 2015 MFMER

143 Infliximab in Ulcerative colitis ACT 1 and patients with mod-severe UC failing 5-ASA, steroids, AZA Infliximab 5 or 10 mg/kg vs. placebo at 0, 2, 6 then Q8 wks 2015 MFMER

144 2015 MFMER

145 Infliximab in Ulcerative Colitis Clinical Response ACT 1 ACT 2 Placebo IFX 5 mg/kg IFX 10 mg/kg Placebo IFX 5 mg/kg IFX 10 mg/kg % of Patients % of Patients Weeks 30 Weeks 54 Weeks 0 8 Weeks 30 Weeks p vs placebo p < vs placebo Rutgeerts P et al. N Engl J Med. 2005;353: MFMER

146 Infliximab in Ulcerative Colitis Clinical Remission % of Patients ACT 1 ACT 2 Placebo IFX 5 mg/kg IFX 10 mg/kg Placebo IFX 5 mg/kg IFX 10 mg/kg Weeks 30 Weeks 54 Weeks % of Patients Weeks 30 Weeks p vs placebo p <.001 vs placebo 1/3 : 1/3 : 1/3 Rutgeerts P et al. N Engl J Med. 2005;353: MFMER

147 Infliximab Rescue for Steroid-refractory UC 1º Endpoint at 3 months Colectomy or death Colectomy > 6 mo Placebo 76% IFX 38% Fulminant 47% v. 69% colectomy (p=ns) Non-fulminant 0% v. 63% (p<0.01) 3 placebo pts had septic complications % Colectomy at 3 mo Placebo Infliximab N = 21 N = 24 p = % Järnerot, Gastroenterology MFMER

148 Adalimumab RCT in Mod-Severe UC ULTRA pts, steroid +/- IMM refractory, TNF naive 160/80, 80/40 induction and 40 EOW maint vs. placebo SAE 4% vs. 3.8% vs. 7.6% Week 8 * Remission Response Mucosal PGA healing *p = vs. pbo p = vs. pbo Reinisch, Gut /80 80/40 placebo 2015 MFMER

149 Adalimumab for Mod-Severe UC ULTRA 2 N=494 ADA 160 mg/80 mg then 40 mg EOW or placebo Week 8 Week 52 60% 50% 40% 30% 20% * * * 60% 50% 40% 30% 20% * * * Placebo ADA Wk 8 RR 10% 10% 0% Remission Response MH 0% Remission Response MH Sandborn, Gastroenterology 2012 Sandborn APT MFMER

150 Adalimumab in UC: ULTRA 2 Remission by TNF exposure status p = Week p = 0.56 Adalimumab Placebo 5 0 TNF naïve Prior TNF Sandborn, Gastroenterology MFMER

151 Adalimumab in UC: ULTRA 2 Response by TNF exposure status p < Week 8 p = 0.23 Sandborn, Gastroenterology MFMER

152 Golimumab in UC Week 6 Response PURSUIT-SC p<0.001 Proportion of patients (%) p<0.001 Placebo (n=256) GLM 200/100 mg (n=257) GLM 400/200 mg (n=258) Decrease in Mayo score by 30% and 3 points, with either a decrease in the rectal bleeding score of 1 or a rectal bleeding score of 0 or 1. Week 6 response was primary end point. Sandborn, Gastro MFMER

153 Golimumab in UC Week 6 Remission PURSUIT-SC Proportion of patients (%) p<0.001 p<0.001 Placebo (n=256) GLM 200/100 mg (n=257) GLM 400/200 mg (n=258) Sandborn, Gastro MFMER

154 Golimumab Maintenance of Response Week 54 PURSUIT-SC Maintenance Randomized responders Monthly injections Proportion of patients (%) p=0.010 p<0.001 Placebo (n=156) GLM 50 mg (n=153) GLM 100 mg (n=154) Defined as a decrease from Week 0 of the induction studies in the Mayo score by 30% and 3 points, with either a decrease from baseline in the rectal bleeding subscore of 1 or a rectal bleeding subscore of 0 or 1 Sandborn, Gastro MFMER

155 Anti TNFs in Ulcerative colitis Also evidence for steroid sparing mucosal healing reduced hospitalizations less colectomy 2015 MFMER

156 Network Meta-analysis Putting it all together? IFX>ADA for induction, GOL>ADA for maintenance, IFX~GOL 1 IFX>ADA for induction, comparisons not done for maintenance 2 No differences for induction or MOR 3 1) Thorlund Exp Rev Gastro Hep ) Danese Ann Int Med ) Stidham APT MFMER

157 Comparative efficacy of biological induction therapy for mod-severe UC Danese, et al. Ann Intern Med 2014;160: Downloaded: 8/10/2015 Copyright American College of Physicians. All rights reserved 2015 MFMER

158 What about Combination Therapy in Ulcerative colitis? 2015 MFMER

159 UC SUCCESS Combo Vs. Monotherapy in Mod to Severe UC Week 16 Panaccione, Gastroenterology MFMER

160 Leukocyte Trafficking Blockers 2015 MFMER

161 Recruitment of Neutrophils Into Inflamed Tissue L-selectin β 2 -integrin activation α4 vs. α4ß7 E/P-selectin IL-8 PAF ICAM-1 Endothelium Rolling Tight adhesion Transmigration 2015 MFMER

162 Vedolizumab in Ulcerative colitis 2015 MFMER

163 Vedolizumab in UC Gemini 1 Anti a4b7 integrin (gut specific) IV infusion 300 mg week 0, 2, 6 Maintenance 300 mg Q8 weeks Study details in syllabus 2015 MFMER

164 Vedolizumab in Moderate-severe UC GEMINI 1 Percent * Week 6 * p<0.001 Placebo (N=149) Vedolizumab (N=225) Clinical response Clinical remission Mucosal healing * Feagan BG et al, N Engl J Med 2013;369(8): * 2015 MFMER

165 GEMINI I: Outcomes by Anti-TNF Exposure Prior Anti-TNF Failure Week 6 Anti-TNF Naive Patients (%) * Placebo (N=63) Vedolizumab (N=82) * Placebo (N=76) Vedolizumab (N=130) Clinical response Clinical remission 0 Clinical response Clinical remission Feagan BG et al, N Engl J Med 2013;369: MFMER

166 Vedolizumab Maintenance in UC GEMINI I * * * * * Randomized responders Week * 45.2 Placebo Vedo Q8wks Vedo Q4wks 10 0 Clinical Remission Mucosal Healing Steroid-Free Remission Feagan B et al, N Engl J Med 2013;369(8): MFMER

167 Vedo Safety in Ulcerative colitis Not much different than Placebo See syllabus for details 2015 MFMER

168 Anti TNF vs Vedolizumab in Ulcerative colitis As first line biologic After first TNF failure 2015 MFMER

169 Cyclosporine in Ulcerative colitis See syllabus 2015 MFMER

170 Cyclosporine vs. Infliximab for Acute Severe UC 110 patients steroid refractory UC Treatment failure No response day 7 No steroid-free remission day 98 Relapse between days 7 and 98 Colectomy Death Conclusion: CyA was not superior to IFX in acute severe UC 80% 70% 60% 50% 40% 30% 20% 10% 0% Treatment Failure, % 54% Infliximab Laharie D et al, Lancet 2012;380: % Cyclosporine 2015 MFMER

171 CSA & IFX Sequential therapy Retrospective study patients Cyclosporine to Infliximab 76% (med 2d) Infliximab to cyclosporine 24% (med 17d) Colectomy 57% in ~1 year 1 Death, 9 serious infections Sequential treatment avoided colectomy in <1/2 of patients, with significant risk Leblanc S Am J Gastro MFMER

172 Conclusions: Severe UC Severe UC is a serious disorder Oral and IV steroids effective for induction Anti TNF and vedolizumab effective in moderate to severe disease Infliximab may be effective in IV steroid refractory inpatients Limited by small trials May not be effective in fulminant colitis 2015 MFMER

173 Conclusions: Severe UC Cyclosporine delays colectomy Risk of serious side effects Sequential anti TNF and CSA therapy not recommended Surgery preferable to prolonged ineffective medical therapy 2015 MFMER

174 Ulcerative colitis: Maintenance of Remission Oral and rectal 5-ASA effective Oral or rectal steroids not effective Azathioprine effective Methotrexate not effective (?) Anti TNFs and vedolizumab are effective 2015 MFMER

175 Case 4 22 M with abdominal pain, mild diarrhea Tender RLQ fullness Colonoscopy: mild patchy colitis in cecum and ascending with ulcers in TI CTE: Ileocolonic inflammation, no other small bowel involvement, no abscess 2015 MFMER

176 What treatment would be least helpful this patient? 1. Pentasa 3 gm/d 2. Prednisone 40 mg/d 3. Budesonide 9 mg/d 4. Infliximab 5 mg/d 5. Adalimumab 160 mg 80 mg 2015 MFMER

177 Crohn s disease Treatment Stop smoking, avoid NSAIDs,? dairy Mild-moderate disease?5-asa?antibiotics (see syllabus) Steroids Immunomodulators Biologics 2015 MFMER

178 Oral Mesalamine for Active Crohn s Disease - RCTs Data for induction are conflicting If there is a benefit, it is small Mesalamine is less effective than budesonide 2015 MFMER

179 Sulfasalazine for Crohn s Disease NCCDS 1 and ECCDS 2 2 large multicenter studies SAS superior to placebo for ileocolonic or colonic CD Not effective for small bowel CD 1 Summers Gastroenterology Malchow Gastroenterology MFMER

180 Mesalamine Induction in Crohn s Disease Change in CDAI in 3 Trials Pentasa 4 g Placebo Pentasa 4 g minus Placebo Change in CDAI p= p=0.7 p=0.5 p= Crohn's I n=155 p=0.005 Crohns' II n=150 p=0.5 Crohn's III n=310 p=0.04 Overall n= p=0.005 Crohn's I n=155 Crohn's II n=150 Crohn's III n=310 Overall n=615 Hanauer, Clin Gastroenterol Hepatol MFMER

181 Metaanalysis of Mesalamine Induction Therapy in Crohn s Disease SAS and mesalamine not better than placebo for inducing remission SAS (2 trials): OR 0.83 [0.69, 1.0] Mesalamine (4): OR 0.91 [0.77, 1.06] Combining the two resulted in barely significant benefit OR 0.89 [0.80, 0.99] Ford, Am J Gastro 2011;106: MFMER

182 Oral Mesalamine for Crohn s MOR Data for MOR in Crohn s conflicting Ford meta-analysis = No benefit (OR 0.97 [0.90, 1.05]) Camma meta-analysis = No benefit in medically induced remission, small benefit post-op Oral mesalamine 4 g/day not steroid sparing 2015 MFMER

183 Oral Steroids for Crohn s - RCTs Oral methylprednisolone 48 mg/d and prednisone 60 mg/d are effective for induction therapy Oral methylprednisolone 8 mg/d and prednisone 20 mg/d are not effective for maintenance therapy 2015 MFMER

184 Budesonide for Crohn s - RCTs Budesonide 9-15 mg/day is effective for induction in mild to moderate CD Budesonide 9 mg/day is more effective than mesalamine 4 g/day and equivalent to prednisolone Budesonide 3-6 mg/day is not effective for MOR beyond 6 months 2015 MFMER

185 ORAL BUDESONIDE IN ACTIVE CROHN S DISEASE 2015 MFMER

186 Budesonide Maintenance in Crohn s Disease % relapse lower in 6 mg/d group at 3 and 6 months, but not 9 or 12 months *p < 0.05, p < MFMER

187 Immunomodulators in Crohn s Disease 2015 MFMER

188 Meta Analysis: Induction of Remission Chande Cochrane Database Syst Rev. 2013;4:CD MFMER

189 Response by Duration Chande Cochrane Database Syst Rev. 2013;4:CD MFMER

190 Maintenance of remission with AZA in Crohn s Disease Study Candy 1995 Summers 1979 Treatment n/n Azathioprine 2.5 mg/kg/day 14/25 16/19 Subtotal (95% CI) 44 Azathioprine 2.0 mg/kg/day O Donoghue 1978 Rosenberg1975 Willoughby /23 7/10 4/5 Subtotal (95% CI) 38 Azathioprine 1.0 mg/kg/day Summers /54 Control n/n 2/20 15/ /27 4/10 2/ /101 Odds ratio 95% CI Weight (%) Odds ratio 95% CI 7.12 ( ) 1.73 ( ) 4.13 ( ) 2.95 ( ) 3.16 ( ) 4.48 ( ) 3.17 ( ) 1.20 ( ) Subtotal (95% CI) ( ) Total (95% CI) ( ) Favors placebo Favors AZA Pearson, Cochrane Database 2007; 1: CD000067

191 Methotrexate for Crohn s Methotrexate 25 mg/wk IM is effective for induction Methotrexate mg/wk IM is effective for maintenance and steroid sparing 2015 MFMER

192 MTX in Moderate - Severe CD 2015 MFMER

193 Methotrexate MOR in Crohn s 76 steroid-dependent patients In remission after MTX 25 mg IM 15 mg IM or placebo x 40 weeks Remission (%) p = % 65% of 45% responders = 30% overall Methotrexate Placebo Weeks since randomization 39% Feagan et al, NEJM MFMER

194 IMM Summary Right dose, duration Less often as induction monotherapy Steroid sparing and maintenance Combination therapy with biologics 2015 MFMER

195 Biologics in Crohn s Disease 2015 MFMER

196 Anti-TNF-α Biologic Proteins Chimeric Monoclonal Antibody Human Recombinant Antibody Humanized Fab Fragment Mouse Human VL VH Cκ CH1 Infliximab Adalimumab PEG PEG Certolizumab Hanauer. Rev Gastroenterol Disord. 2004;4(suppl 3):S MFMER

197 Infliximab for Crohn s Infliximab 5 mg/kg is effective for induction in luminal and fistulizing disease Infliximab 5-10 mg/kg every 8 weeks is effective for maintenance 2015 MFMER

198 Infliximab in Active Crohn s Disease Placebo 5 mg of ca2/kg 10 mg of ca2/kg 20 mg of ca2/kg All ca2 Groups Response (%) * * * * Remission (%) P<.001 P= Baseline Week 0 Baseline Week Clinical response: 70-point decrease in CDAI. Clinical remission: CDAI <150. Targan et al. N Engl J Med. 1997;337: MFMER

199 Infliximab Maintenance of Remission: ACCENT I Clinical Remission at Week p <0.001 p = NS p = Proportion Of Patients (%) Single Dose 5 mg/kg q 8 wk 10 mg/kg q 8 wk Hanauer, Lancet 2002;359: MFMER

200 Adalimumab for Crohn s ADA 160/80 is effective for induction (and probably for closing fistulas) ADA 40 mg QOWk and QWk is effective for maintenance 2015 MFMER

201 Adalimumab in Active Crohn's CLASSIC I 299 patients (INF naïve) SQ adalimuamb dose ranging at wk 0 and 2 Hanauer et al. Gastroenterology 2006 Remission (%) *p < Week 4 * 36 Placebo Adalimumab 40/20 Adalimumab 80/40 Adalimumab 160/ MFMER

202 Maintenance of Remission: CHARM Patients in Remission (%) /170 47* No statistically significant difference between 40 mg EOW and 40 mg weekly dose groups. 40* 41* 12 36* 68/172 73/157 20/170 62/172 65/157 Week 26 Week 56 Placebo 40 mg EOW 40 mg Weekly *p < Colombel et al. Gastroenterology MFMER

203 % of Patients ADA for Infliximab LOR or Intolerance GAIN PBO 7 * /80 mg /166 34/159 56/166 82/159 41/166 61/159 Remission Response CR-70 Response CR-100 * 38 *p <0.001, p <0.01 Sandborn WJ, et al. Ann Intern Med MFMER

204 Certolizumab for Crohn s Disease CMZ 400 mg at week 0 and 2 is effective for induction (and probably for closing fistulas) CMZ 400 mg every 4 weeks is effective for maintenance 2015 MFMER

205 Certolizumab for Crohn s Maintenance PRECiSE 2 Response At Week Certolizumab 400 mg At Weeks 0, 2, And 4 Patients (%) All (N=668) CRP 10 (N=339) Schreiber et al. Gut. 2005;54(suppl VII):A MFMER

206 Certolizumab for Crohn s Maintenance PRECiSE 2 Remission at week Injections + Placebo Certolizumab 400 mg 80 Patients (%) * * 20 0 All CRP 10 *P<.01 N=210 N=215 N=101 N=112 Schreiber et al. Gut. 2005;54(suppl VII):A MFMER

207 Anti-TNF Maintenance of Remission in CD Week Percent of Patients Infliximab 5 mg/kg (ACCENT I) Adalimumab 40 mg EOW (CHARM) Certolizumab 400 mg 4-weekly (PRECiSE 2) Placebo N = 113 N = 172 N = 215 Remission (CDAI <150) Hanauer, et al. Lancet 2002 Schreiber S, et al. UEGW 2005 Colombel JF, et al. Gastroenterology MFMER

208 Network Meta-analysis Putting it all together? IFX + AZA and ADA > CZP for induction and MOR 1 IFX most effective for induction, ADA most effective for MOR 2 No evidence of clinical superiority 3 In the absence of head-to-head comparisons, confidence in these estimates is low 2 1) Hazelwood Gastro ) Singh Mayo Clin Proc ) Stidham APT MFMER

209 Anti-TNF Safety See Syllabus 2015 MFMER

210 Crohn s Disease Serious Infections Predictor Adjusted HR p value Moderate/severe disease 2.24 <0.001 Infliximab Prednisone Immune modulators Narcotics 1.98 <.001 * * * * Lichtenstein et al. TREAT Registry. Am J Gastro MFMER

211 Crohn s Disease Mortality Predictor Adjusted HR p value Moderate/severe disease Infliximab Prednisone 2.14 <0.001 Immune modulators Narcotics 1.79 <0.001 * * Lichtenstein et al. TREAT Registry. Am J Gastro MFMER

212 What about combination therapy? 2015 MFMER

213 Combination Therapy in Crohn s Disease SONIC Mode to severely active 508 pt on steroids Randomized: AZA 2.5 mg/kg/d IFX 5 mg/kg infusions AZA + INF Colombel JF NEJM ^ p< * p<0.009 AZA * IFX AZA+IFX ^ Remission at 26 wk 2015 MFMER

214 Combination Therapy in Crohn s Disease SONIC Serious Infections # AZA 8 IFX 4 AZA+IFX 6 25 AZA IFX 20 AZA+IFX Colombel JF NEJM Serious AE at 30 wk 2015 MFMER

215 Anti-TNF Failures Consider Differential Diagnosis SIBO IBS Bile acid malabsorption Medications Stricture, abscess Drug levels and anti-drug antibody tests can be helpful 2015 MFMER

216 Therapeutic Drug Monitoring Emerging Paradigm Assessment of drug level and ADA may direct anti TNF therapy Dose modification ( or ) based on prospective monitoring of drug levels May need different dose at different stages of disease 2015 MFMER

217 Therapeutic Drug Monitoring Test Result Response Low drug level and - ADA Low drug level and + ADA Therapeutic drug level 2015 MFMER

218 Therapeutic Drug Monitoring Test Result Low drug level and - ADA Response Increase dose Low drug level and + ADA Therapeutic drug level 2015 MFMER

219 Therapeutic Drug Monitoring Test Result Low drug level and - ADA Low drug level and + ADA Response Increase dose Switch to another anti TNF Therapeutic drug level 2015 MFMER

220 Therapeutic Drug Monitoring Test Result Low drug level and - ADA Low drug level and + ADA Therapeutic drug level Response Increase dose Switch to another anti TNF Switch to another class 2015 MFMER

221 Leukocyte Trafficking Blockers in Crohn s Disease 2015 MFMER

222 Natalizumab Alpha 4 blocker 2015 MFMER

223 60 50 ENACT-2: Remission P< P=0.005 P< Placebo Natalizumab P= Patients (%) n=171 n=168 n=40 n=32 n=171 n=168 n=40 n=32 ITT Failed ITT Failed Month 9 Month 15 Anti-TNF failure is defined as: 1) no response to initial treatment, or 2) lost response with continued treatment, or 3) discontinuation due to adverse event, or 4) discontinuation due to infusion reaction MFMER

224 Natalizumab for Crohn s Maintenance ENACT P=0.217 P<0.05 P< Patients (%) Natalizumab 300mg (n=130) Placebo (n=120) Contingent primary endpoint Months Start ENACT-2 Sandborn WJ, et al. NEJM MFMER

225 Natalizumab: Progressive Multifocal Leukoencephalopathy 3 cases of PML in MS and CD clinical trials FDA review: voluntary suspension of the program 2/05 Reinstituted for MS 06 Approved for Crohn s 08 Van Assche G et al. NEJM 2005; Langer-Gould A et al. NEJM 2005 Kleinschmidt-DeMasters and Tyler NEJM MFMER

226 Pepio et al. DDW 2011; Abstract # MFMER

227 Vedolizumab in Crohn s Disease α4 β MFMER

228 Vedolizumab in Crohn s Gemini 2 Anti a4b7 integrin (gut specific) IV infusion 300 mg week 0, 2, 6 Maintenance 300 mg Q8 weeks Study details in syllabus 2015 MFMER

229 Vedolizumab in Crohn s Disease Patients % Week 6 p = Induction ITT Population p = Placebo VDZ 5 0 Clinical Remission CDAI-100 Response 95% CI: Δ , 14.3 Δ , 15.0 Sandborn WJ et al, N Engl J Med MFMER

230 Vedolizumab Maintenance in Crohn s Disease Patients % Week 52 Randomized Responders Placebo VDZ Q8wk ** VDZ Q4wk * ** 39.0 ** 36.4 * 31.7 * Clinical Remission CDAI-100 Response CS-Free Remission Durable Remission Δ17.4 Δ14.7 Δ13.4 Δ15.3 Δ7.2 Δ2.0 Δ15.9 Δ12.9 *p<0.05 **p<0.01 Sandborn WJ et al, N Engl J Med MFMER

231 Induction in CD with prior anti-tnf Failure GEMINI 3 Week 6 Week 10 Sands, et al Gastroenterology MFMER slide MFMER

232 Week 52 Outcomes by Prior Anti-TNF Exposure: GEMINI 2 * * Prior TNF Exposure TNF Naive Sandborn WJ, N Engl J Med MFMER slide MFMER

233 Vedo Safety in Crohn s disease Induction safety not much different than placebo SAEs (24.4% v 15.3%) and serious infections (5.5% v 3%) in maintenance See syllabus for details 2015 MFMER

234 UNITI-2 Trial Ustekinumab in Anti-TNF-Naïve CD Patients Clinical Response at Week 6 ( 100 point CDAI reduction) P<0.001 P<0.001 P<0.001 Patients, % n=209 n=209 n=209 n=418 Placebo 130 mg ~6 mg/kg* Combined Ustekinumab *Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight 55 kg), 390 mg (weight >55 mg and 85 kg), 520 mg (weight >85 kg). Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated analysis endpoint are considered not to be in clinical response. Feagan BG et al. UEGW MFMER

235 UNITI-1 Trial Ustekinumab in CD Patients Failing Anti-TNF Therapy Clinical Response at Week 6 ( 100 point CDAI reduction) p=0.001 P= P=0.002 Subjects, % n=247 n=245 n=249 Placebo 130 mg ~6 mg/kg* Ustekinumab *Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight 55 kg), 390 mg (weight >55 mg and 85 kg), 520 mg (weight >85 kg). Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis time point are considered not to be in clinical response, regardless of their CDAI score. Subjects who had insufficient data to calculate the CDAI score at designated analysis endpoint are considered not to be in clinical response. Sandborn WJ, et al. CCFA MFMER

236 Severe Crohn s disease Low threshold for CT(enterogaphy) Anti-TNF vs steroids Vedo/Natalizumab, other immune modulators (CSA, MTX, tacrolimus, ustekinumab, etc), or surgery for anti-tnf failures 2015 MFMER

237 Case 5 28 F with h/o ileal and rectal Crohn s disease presents with diarrhea, rectal pain, perianal soiling Exam: RLQ tenderness, perianal induration, multiple fistula openings 2015 MFMER

238 Perianal Crohn s disease Rule out abscess and define anatomy (EUA + EUS or pelvic MRI) Mild disease may not need Rx Metronidazole + ciprofloxacin Anti-TNF + AZA/6-MP Setons, drains PRN Proctectomy 2015 MFMER

239 Case 5 Colonoscopy Proctitis, ulcers in TI CT Enterography 15 cm ileitis, no abscess Pelvic MRI Trans-sphincteric fistulas with complex branching, few small abscesses 2015 MFMER

240 Exam under Anesthesia Tracks probed, curetted Abscesses drained Setons placed Antibiotics, IFX, azathioprine F/u over 4 months = progressive healing of fistulas 2015 MFMER

241 Case 5 Setons removed Maintained on IFX and AZA 2015 MFMER

242 Treat to Target A New Paradigm in Crohn s Disease Therapy 2015 MFMER

243 From: WJ Sandborn online CME activity 3/ MFMER

244 Treatment of Crohn s Disease Mild to mod induction: (5-ASA), (antibiotics), budesonide, prednisone, anti-tnf, (Vedo) Persistent or severe: prednisone, (AZA/6-MP, MTX), anti-tnf, NAT/ Vedo [anti-tnf failure], or surgery 2015 MFMER

245 Treatment of Crohn s Disease Perianal disease: Abx + AZA/6-MP + anti- TNF + surgery (I+D, setons, drains, fistulotomy) Maintain with whatever induced response, except for steroids 2015 MFMER

246 Thank you 2015 MFMER

247 Laura Raffals, MD, MS Associate Professor of Medicine 2015 MFMER

248 Inflammatory Bowel Disease Miscellaneous Laura Raffals, MD, MS No disclosures Mayo Clinic Gastroenterology & Hepatology Board Review September MFMER

249 Objectives Recognize clinical presentation and treatment strategies of microscopic colitis Recognize common complications associated with an ileal pouch anal anastomosis and treatments of pouchitis Understand the effect of IBD on pregnancy and the effect of pregnancy on IBD Describe the risk of postoperative recurrence of Crohn s disease and strategies to reduce the risk of disease recurrence 2015 MFMER

250 A 36 year-old woman with celiac disease follows a gluten-free diet for 6 months. Despite strict adherence, she continues to experience watery diarrhea with nocturnal bowel movements. She denies recent antibiotic use or travel. Which of the following should be done next? a. MR enterography b. Double balloon enteroscopy with small bowel biopsies c. Colonoscopy with random biopsies d. GI Transit studies 2015 MFMER

251 Microscopic colitis Describes both lymphocytic and collagenous colitis Chronic watery diarrhea > 22% have more than 10 BM per day 27% have nocturnal BM Mild abdominal pain and weight loss possible Associated with other autoimmune diseases Thyroid dysfunction RA Psoriasis Celiac disease Diabetes mellitus Yen EF., Pardi DS. Non-IBD colitides. Best Practice & Research Clinical Gastroenterology 26 (2012) MFMER

252 Celiac and MC MC seen times more commonly in pt with celiac than in general population Consider MC in celiac patient not responding to gluten-free diet Consider celiac in MC patient with refractory disease, malabsorption, iron deficiency anemia, severe weight loss Serologies may be negative Biopsy small bowel to confirm diagnosis Yen EF, Pardi DS. Non-IBD colitides (eosinophilic, microscopic). Best Practice & Research Clinic Gastroenterology 26 (2012) MFMER

253 Pathogenesis of MC Mechanism poorly understood Reduced sodium and chloride absorption and active chloride secretion Cigarette smoking risk factor (current or former) Certain medications may trigger MC NSAIDs Histamine-2 receptor blockers Proton pump inhibitors Selective serotonin reuptake inhibitors Simvastatin Carbamazepine Ticlopidine 2015 MFMER

254 Diagnosis Colonic mucosa normal on colonoscopy Erythema and edema rarely described Histologic evaluation of colonic biopsies Intraepithelial lymphocytosis, >20 IELs per 100 epithelial cells No architectural distortion Thickened subepithelial collagen band(>10μm) Lymphocytic infiltration higher and collagen band thicker in right colon 2015 MFMER

255 2015 MFMER

256 Treatment of MC Consider severity of symptoms Smoking cessation Antidiarrheal meds Bismuth subsalicylate (2-3 [262 mg] tabs 3-4 times daily for several weeks) +/- aminosalicylates Cholestyramine Budesonide Consider long-term, low-dose treatment Immunomodulators 2015 MFMER

257 A 24 year-old man with a history of ulcerative colitis underwent colectomy with ileal pouch anal anastomosis develops bloody diarrhea and low grade fever. Which of the following is the most appropriate treatment? a. Asacol b. Prednisone c. Ciprofloxacin d. Rifaximin e. Budesonide 2015 MFMER

258 The Ileal pouch About 20% of patients with ulcerative colitis undergo colectomy after 15 years Average stool frequency is 4-8 BM/day, semi-formed stool Typical to have 1 nocturnal bowel movement Fecal incontinence not uncommon Pouchitis symptoms typically include: Increased stool frequency Urgency Tenesmus Rectal bleeding Fever Gionchetti et al. Best Practice & Research Clinical Gastroenterology 2003; 17: MFMER

259 The Ileal pouch 50% of patients with an ileal pouch anal anastomosis develop pouchitis 60% have a recurrence 5-10% will have chronic pouchitis Pouchitis rare in FAP patients Gionchetti et al. Best Practice & Research Clinical Gastroenterology 2003; 17: MFMER

260 Risk factors for pouchitis Extensive UC Backwash ileitis EIM PSC Ex-smoker panca + Polymorphisms of IL-1 receptor antagonist gene and TNF gene Regular NSAID use 2015 MFMER

261 Secondary pouchitis Infectious pathogens Clostridium difficile, CMV Immune mediated pouchitis PSC Celiac disease Pouch ischemia NSAID use 2015 MFMER

262 Treatment for acute pouchitis Ciprofloxacin (1000 mg/day) for 7-10 days Metronidazole ( mg/day) for 7-10 days Can use combination of antibiotics if patient fails to respond to single antibiotic 2015 MFMER

263 Chronic or relapsing pouchitis Chronic antibiotic therapy (often with cipro) Can taper to lowest effective dose Other commonly used antibiotics Xifaxin, erythromycin, tetracycline, amoxicillin/clauvanate, tinidazole Probiotics (VSL#3) Oral budesonide Oral or topical mesalamine 6-mercaptopurine or azathioprine Anti-TNFα agents 2015 MFMER

264 Karen is a 20 year old woman with ileal Crohn s disease transitioning from her pediatric gastroenterologist to an adult GI practice. She is currently maintained on methotrexate, 12.5 mg subcutaneously weekly. She has heard that she may not be able to conceive due to her history of Crohn s disease. Which of the following is true? a. Her fertility is significantly reduced due to her current use of methotrexate. b. Karen is not a greater risk for infertility, however the risk of her future children developing IBD approaches 20% c. In the future, Karen should be able to safely conceive if she has a 1 month washout off methotrexate d. Approximately 1/3 of patients with quiescent IBD at time of conception will have relapse of IBD during pregnancy 2015 MFMER

265 Fertility in IBD Fertility: achieving pregnancy within 1 year of intercourse without contraception background rate 1 in 7 couples (14%) Majority of women with IBD have normal fertility Potential impact on infertility Disease activity Medication Voluntary Surgery (IPAA) 2015 MFMER

266 IBD and Fertility Men Sulfasalazine causes reversible sperm abnormalities in 60%; not dose related Azathioprine has not been shown to reduce male fertility in IBD Infliximab has not been observed to significantly affect semen quality 2015 MFMER

267 Heritability of IBD Risk of IBD among offspring of parent with IBD is 2-12 times higher than general population risk Children of CD parent have 5-10% lifetime risk of IBD (2% with UC) 2 parents affected (1 with CD) have 35% lifetime risk Yang et al. Gut 34(4), (1993) Bennett et al. Gastroenterology 100(6), (1991) 2015 MFMER

268 Effect of Pregnancy on IBD 25 % with Relapse 40 % Pregnant IBD Pt with Relapse Pregnant IBD Patients Nonpregnant IBD patients 5 0 Medication No Medication Adherence to therapy most important factor for avoidance of relapse Habal FM, Grover SC. Presented at 69 th Annual Scientific Meeting of ACG. Orlando, Fla; Abstract MFMER

269 Effect of IBD on Pregnancy Outcomes Case-controlled studies and population based studies suggest: Increased risk Low birth weight Preterm delivery C-section rate No major impact congenital abnormalities No increased risk of maternal complications Likely influenced by disease activity 2015 MFMER

270 Effect of Pregnancy on UC: Disease Activity at Conception n=528 66% n=227 45% 34% 24% 27% No Relapse Relapse Worsened Activity Continued Activity Decreased Activity Inactive Active Miller JP. J R Soc Med. 1986;79: MFMER

271 Effect of Pregnancy on CD: Disease Activity at Conception n=186 73% n=93 27% 33% 32% 34% No Relapse Relapse Worsened Activity Continued Activity Decreased Activity Inactive Active Miller JP. J R Soc Med. 1986;79: MFMER

272 Summary: Safety of IBD Medications During Pregnancy Safe to Use When Indicated Limited Data Available Contraindicated Oral mesalamine Cyclosporine Methotrexate Topical mesalamine Natalizumab Thalidomide Sulfasalazine Vedolizumab Metronidazole/Cipro? Anti-TNF agents Azathioprine/6-MP Corticosteroids 2015 MFMER

273 Margaret is a 32 yo woman with ileocolonic Crohn s disease complicated by a enterocolonic fistula. Prior to surgery she had been treated with azathioprine, 200 mg daily, for 5 years. Following surgery, what is the most appropriate management of her disease? a. Pentasa 4 gram daily b. Azathioprine 250 mg daily c. No medical therapy, monitor disease progression with serial colonoscopies. Treat as appropriate. d. Infliximab 2015 MFMER

274 Post-operative recurrence of Crohn s disease Recurrence most common at site of surgical anastomosis Histologic recurrence reported one week after surgery 70-90% endoscopic recurrence after one year 30% clinical recurrence at 3 years, 60% clinical recurrence at 10 years Recurrence less for colonic Crohn s patients who undergo colectomy with ileostomy 10% recurrence at 10 years Cigarette smoking only known modifiable risk factor [1] D Haens G, Geboes K, Peeters M, et al. Gastroenterology 1998;114: [2] Olaison G, S medh K, Sjodahl R. Gut 1992;33: [3] Rutgeerts P, Geboes K, Vantrappen G, et al Gastroenterology 1990;99: [4] Sachar DB. Med Clin North Am 1990;74: MFMER

275 Postoperative surveillance Colonoscopy preferred modality General recommendation to perform colonoscopy within 1 st year after surgery MRE or CTE as appropriate Possible role for fecal calprotectin in low risk patients 2015 MFMER

276 Randomized Controlled Post-Operative Trials: One Year Recurrence Rates Clinical Recurrence Endoscopic recurrence Placebo 25% 77% 53% - 79% 5 ASA 24% - 58% 63% - 66% Budesonide 19% - 32% 52% - 57% Nitroimidazole 7% - 8% 52% - 54% AZA/6MP 34% 50% 42 44% Regueiro M. Inflammatory Bowel Diseases MFMER

277 Endoscopic recurrence in infliximab treated patients % patients Infliximab (n=11) Infliximab vs placebo p= /11 11/13 Recurrence Placebo (n=13) 84.6 Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i MFMER

278 Postoperative recurrence of Crohn s POCER Trial Step up therapy in response to endoscopic recurrence At 18 months Active arm vs Standard of care, 49 vs 67% endoscopic recurrence (p=0.03) De Cruz Aliment Pharmacol Ther 2015; MFMER

279 Postoperative treatment Low Risk Intermediate Risk High Risk Treatment Metronidazole x 3 months Metronidazole x 3 months Thiopurines Metronidazole x 3 months Anti-TNF Monitoring plan Serial fecal calprotectin Serial fecal calprotectin Low threshold for colonoscopy Colonoscopy De Cruz, P. et al. Lancet 2015 April 11;385 (9976): Wright EK et al. Gastroenterology 2015; 148: MFMER

280 Questions & Discussion 2015 MFMER

281 John B. Kisiel, M.D. Assistant Professor of Medicine 2015 MFMER

282 Colorectal Neoplasms and Hereditary Polyposis Syndromes John B. Kisiel, M.D. Mayo GIH Board Reviews September 18, MFMER

283 Part I: The Basics 2015 MFMER

284 SEER: 2016 USA Colorectal Cancer (CRC) Incidence- 4 th (~134,490) Deaths 2 nd (~ 49,190) Siegel, et al. Cancer Statistics CA CANCER J CLIN 2016;66: MFMER

285 Global Colorectal Cancer Incidence US: 2-3 % / year over last 15 years Most western countries: stable to slight Eastern Asia and Eastern Europe: Torre, et al. Global Cancer Statistics, CA CANCER J CLIN 2015;65: MFMER

286 CRC Rates per 100,000 Incidence Mortality Race/ethnicity Men Women Men Women All White African-American Hispanic Asian & Pacific Nat. Am. & Alaskan Siegel, et al. Cancer Statistics CA CANCER J CLIN 2016;66: MFMER

287 CRC Site Distribution 13% 33% 54% 29% - rectum CA Cancer J Clin MFMER

288 CRC Site Distribution by Age 80 Proportion (%) Distal Proximal Age (yr) 2015 MFMER

289 Clinical Presentation Abdominal pain 44% Change in bowel habit 43% Hematochezia or melena 40% Anemia w/o other GI symptoms 11% Weight loss 6% 20% - distant metastatic disease Origin of adenocarcinoma of unknown primary site 6% Contained perforation or local invasion Can mimic diverticulitis FUO, intraabdominal abscess Bacteremia (S. bovis, B. fragilis, other anaerobes, C. difficile) 2015 MFMER

290 Adenoma-Carcinoma Sequence Normal Mucosa Mucosa at risk Adenoma Adenocarcinoma 7-10 years 2015 MFMER

291 TNM Stage & 5-year Survival Stage TNM Grouping 5-Yr. Survival 0 Tis; N0; M0 100% I T1-2; N0; M % II a,b T3-4; N0 M % III a,b,c Any T; N1-3; M % IV Any T; Any N; M1 5-8% 2010 AJCC Staging Criteria 2015 MFMER

292 Question # 1 Choose the most accurate statement: 1. Environmental factors contribute to about 40% of all CRC cases. 2. Calcium supplementation likely increases CRC risk. 3. BMI is inversely associated with CRC risk 4. CRC can be considered a tobacco-related disease MFMER

293 Modifiable Risk Factors Harmful Obesity Tobacco use Dietary fats Red meat (charred) Refined carbohydrates Alcohol Protective ASA COX-2 inhibitors Calcium Folate Selenium Physical activity Estrogen compounds 2015 MFMER

294 Algorithm for CRC Screening and Surveillance in Average-risk and Increased-risk Populations 2015 MFMER

295 Effectiveness of Screening Colonoscopy? Large case-control & cohort studies CRC mortality (Ann Intern Med 2009;150:1) L side ~ 70% R side 0% CRC incidence (JNCI 2010;102:89) L side ~ 70% R side 0% CRC incidence (NEJM 2013; 356:1106) L side 76% R side 24% MFMER

296 Detection Rates Variation among Gastroenterologists Number doctors Lowest Highest Fold Difference Barclay (2006) % 32.7% 3X Chen (2007) % 41.1% 3X Imperiale (2009) 25 7% 44% 6X Shaukat (2009) 51 10% 39% 4X Hetzel (2010) % 7.6% 7X Kahi (2011) 15 1% 18% 18X = Right-sided lesion detection Adapted from Dr Doug Rex 2015 MFMER

297 Subtle Endoscopic Appearance of SSA/P 2015 MFMER

298 Serrated Neoplasm Pathways Normal mucosa BRAF mutation KRAS mutation DNA methylation? Molecular changes SSA/P TSA SSA/P w/dysplasia MSI cancer MSS cancer Majority of interval cancers follow this route* *Nishihara, et al. NEJM ; 356:1106 MSS Cancer 2015 MFMER

299 Surveillance - CR Neoplasia 5 prox to sigmoid, 2 10mm 20 anywhere 1 prox to sigmoid in FDR of SP 2015 MFMER

300 Part II: The Syndromes 2015 MFMER

301 Colorectal Cancer 2015 MFMER

302 Cumulative CRC Risk Lifetime Risk, % > Gen Popn Prior CRN IBD 1-2 FDRs FAP Lynch Other Syndrome Syndromes 2015 MFMER

303 Recognition of Familial CRC Family history of CRC or extracolonic cancers Age at diagnosis Extracolonic malignancies and other manifestations Histologic features of the polyp or cancer Lifetime polyp burden 2015 MFMER

304 Importance of Diagnosing Familial CRC Prophylactic interventions Chemopreventive strategies Surgical intervention for cancer Post-op cancer surveillance Predictive genetic testing for at-risk family members Appropriate screening for mutation carriers and atrisk individuals 2015 MFMER

305 You diagnose a 45 year old man with colon cancer (arrow). You carefully elicit the following family cancer history Uterus (36) Colon (64) Colon (47) Colon (53) Colon (45) GU (40) 2015 MFMER

306 Lynch Syndrome Terminology: HNPCC patients who meet Amsterdam Criteria Deficiency of mismatch repair (dmmr) enzymes or microsatellite instability (MSI) are phenotypes caused by Lynch or other somatic events Lynch is a genotype defined by the presence of germline mutations in 1 of the MMR genes: MLH1, MSH2 (or EPCAM), MSH6, or PMS2 Autosomal dominant genetic syndrome; 2-7% of all CRC Cancer after a 2nd hit in somatic tissue Loss of wild-type allele inherited from the unaffected parent Accelerated adenoma-carcinoma sequence (35 months) Lifetime CRC risk depends on sex and specific mutation 2015 MFMER

307 Gene Specific Cumulative Risk of Colorectal Cancer by age 70 in Lynch syndrome Giardello et al. Am J Gastroenterol.2014 Aug;109(8): MFMER

308 Cumulative Risk of Extracolonic cancer by age 70 in Lynch Syndrome Giardello et al. Am J Gastroenterol.2014 Aug;109(8): MFMER

309 How to Screen for Lynch? Screening by family history-based strategies Identify patients who may benefit from tumor testing Poorly sensitive, not useful if no tissue Software models Identify those who might have genetic testing Multi-gene panels Missing tissue or syndrome screen inconclusive May identify variants of unclear significance Universal tumor testing Most sensitive for Lynch, cost-effective Additional prognostic and therapeutic benefits 2015 MFMER

310 Amsterdam I & II Vasen et al. Dis Colon Rect 1991; 34: Vasen et al. Gastroenterology 1999;116: MFMER

311 Revised Bethesda Criteria Umar et al. J Natl Cancer Inst 2004;96: MFMER

312 Microsatellite Instability: A phenotype of mismatch repair Abnormal expansion or contraction of the microsatellite repeats MSI-H (>30% of markers are unstable) MSI-L (<30% of markers are unstable) >90% of CRC in patients with LS 15% of patients with sporadic CRC (BRAF) Sensitivity 85% and specificity of 90% for LS 2015 MFMER

313 Immunohistochemistry (ICH): A phenotype of mismatch repair Utilizes antibodies to the MMR gene proteins MLH1, MSH2, MSH6, & PMS2- loss of expression Sensitivity and specificity 83% and 89% for LS Missing MLH1/PSM2 MLH1 hyper-methylation BRAF mutation Palomaki et al. Genet Med 2009, MFMER

314 All CRC Universal Testing Algorithm Clinician and pathology lab Tumor available? No tissue IHC or MSI Bethesda Amsterdam II Software model >5% Known LS in family No criteria Return to nonsyndrome surveillance Genetic counsellor Germline sequence specific MMR gene Or Multi-gene panel BRAF and methylation studies Germline sequence MMR genes sequentially Or Multi-gene panel USPSTF-endorsed for all <70; NCCN-endorsed for ALL 2015 MFMER

315 Additional Benefits of Universal Testing BRAF and hyper-methylated tumors: average risk BRAF (and KRAS) mutants unlikely to respond to EGFR inhibitor drugs MSI-H stage II tumors have good prognosis and low 5-FU response MSI status may direct therapy in metastatic disease 2015 MFMER

316 Lynch: Cancer surveillance Colorectal* Endometrial Ovary Uro-epithelial Stomach Age or 2-5 years before proband Annual Endometrial sampling - age Annual transvaginal US - age TAH / BSO after childbearing Annual urine cytology (FISH) EGD at 30-35, then (?) Q 2-3 yrs *Recommend, Offer Giardello, et al, Am J Gastroenterol Aug MFMER

317 Question # 2 You are asked to perform a screening colonoscopy on an asymptomatic 35 y/o man, because of his family history of CRC (his father died of CRC at age 40). His examination demonstrated nearly 100 small polyps. Biopsies from numerous polyps --- tubular adenoma MFMER

318 This man could have any of the following except: 1. Cowden syndrome 2. Familial Adenomatous Polyposis 3. Gardner Syndrome 4. Attenuated FAP 5. MYH Polyposis 2015 MFMER

319 Polyposis Inherited Non-inherited Adenomatous Hamartomatous FAP afap MUTYH Peutz-Jeghers Juvenile Polyposis Cowden s Syndrome Bannayan-Riley-Ruvalcaba 2015 MFMER

320 FAP Gene: APC (5q21) Inheritance: AD Incidence:1 in 8,000 ~ 20-25% de novo Diagnosis: 2 nd decade Major features: > 100 CR adenomas ~ 100% CRC risk without proctocolectomy 2015 MFMER

321 Extracolonic Features (FAP) Duodenal neoplasm Gastric polyps Multifocal, bilataral CHRPEs Desmoid tumor Images from Mayo archives and emedicine Skull osteoma 2015 MFMER

322 FAP Variants Gardner s Syndrome Additional features: CHRPEs, desmoids, epidermoid cysts, fibromas, lipomas Extracolonic cancers: thyroid, adrenal, hepatoblastoma [Turcot s Syndrome] CNS tumors + familial CRC Medulloblastoma + CRC = FAP variant Glioblastoma + CRC = Lynch variant 2015 MFMER

323 Attenuated FAP Gene: APC mutation (5' or 3 ' end) Inheritance: AD Incidence: undefined Diagnosis: 5 th -6 th decade Major features: CR adenomas; prox. > distal Average age of CRC is years 70% risk of CRC by age 65 Extracolonic cancers: -likely similar to classic FAP Burt RW et al Gastroenterology 2004;127: MFMER

324 MUTYH-Associated Polyposis (MAP) MutYH (DNA repair); Damage to APC and KRAS Recessive (biallelic) Diagnosis: 5 th -6 th decade Major features: CR adenomas; proximal > distal Extra-colonic manifestations Benign: FAP-like > 20 pathogenic mutations Desmoids, CHRPE, osteoma, sebaceous Malignant: Duodenum, ovaries, bladder, thyroid, and skin Sampson, et al - Biochem Soc Trans. 2005;33: MFMER

325 Polyposis Inherited Non-inherited Adenomatous Hamartomatous FAP afap MUTYH Peutz-Jeghers Juvenile Polyposis Cowden s Syndrome Bannayan-Riley-Ruvalcaba 2015 MFMER

326 Hamartomatous Polyposis Syndromes Large, smooth, long stalk (JPS) Broad bands of smooth muscle Images from Mayo Pathology Archives 2015 MFMER

327 2015 MFMER

328 Peutz-Jeghers Syndrome Gene: STK11/LKB1 (chromosome 19pD) Inheritance: AD Incidence: 1 in 50, ,000 Diagnosis: 2 nd -4 th decade Major features: mucocutaneous hyperpigmentation; small bowel polyposis; known Fm Hx (need 2/3 for dx) or mutation Cancers outside GI tract: breast, ovary, cervix, thyroid, testes, HB, pancreas 2015 MFMER

329 Peutz-Jeghers Polyposis Hamartomatous polyps 96% small bowel 27% colon 24% rectum 24% stomach Also: Nose, bronchi, bladder, ureter, renal pelvis Bartholomew LG et al Gastroenterology 1957;32: MFMER

330 2015 MFMER

331 PJS -- Cancer Predisposition hamartoma adenoma carcinoma Relative risk of cancer RR All cancers 15 Esophagus 57 Stomach 213 Small intestine 520 Pancreas 132 Colon 84 Giardiello FM et al Gastroenterology 2000;119: MFMER

332 PJS -- Management Genetic testing available GI polyposis: intussusception, bleeding, & malignancy Colonoscopy, EGD, SB: age 10, q 2 yrs Uterus, ovary: age 20, q 1 yr Breast: age 25, q 1-2 yrs Pancreas: age 30, q 1-2 yrs 2015 MFMER

333 Juvenile Polyposis Syndrome Genes: BMPR1A; SMAD4 Inheritance: AD (25-40% de novo) Incidence: <1/100,000 Diagnosis: 2 nd -3 rd decade Need 1/3: > 5 juvenile polyps in colorectum; > 1 juvenile polyp outside colorectum; > 1 juvenile polyp with known FmHx Present with GI bleed, obstruction < age 20 Hamartomas of stomach, SB, colon JPS from SMAD4 associated with hereditary hemorrhagic telangiectasia Images from Mayo archives 2015 MFMER

334 JPS Cancer Predisposition CRC risk 12 x Mean age at CRC dx = 37* Diffuse polyposis -- risk of gastric ca 2015 MFMER

335 JPS -- Recommendations BMPR1A and SMAD4 germline testing Genetic testing of FDR s Surveillance: colonoscopy & EGD Age 12 and annually if polyps Every 2-3 years if mutation but no polyps Surgery if endoscopic management fails 2015 MFMER

336 The PTEN1 hamartoma syndromes Eponym Inheritance Age of onset Cowden AD Young adults Bannayan- Riley- Ruvalcaba Skin findings Trichilemmomas Oral fibromas Palmoplantar karatoses AD Childhood Macrocephaly Penile lentigenes Proteus Sporadic? Post-natal overgrowth of tissues, variable expression; probable diagnosis of Joseph Merrick Associated cancers Breast, endometrial, thyroid, kidney, CRC Low cancer penetrance? 2015 MFMER

337 Questions & Discussion 2015 MFMER

338 Glenn L. Alexander, M.D. Assistant Professor of Medicine Jeffrey A. Alexander, M.D. Associate Professor of Medicine MFMER

339 Colon Jeffrey A. Alexander, M.D. Glenn L. Alexander, M.D. Gastroenterology & Hepatology Board Review Sunday, September 18, MFMER

340 Glenn Alexander No disclosures Disclosures Jeffrey Alexander Research Funding: Merck, Meritage Financial Interest: Meritage 2015 MFMER

341 Case A 52 yo man comes to see you after his first screening colonoscopy. He has no family history of colon cancer and his exam revealed 3 polyps a 7-mm ascending polyp, a 5-mm transverse polyp and a 2-mm rectal polyp. Histology revealed a sessile serrated adenoma, a tubular adenoma with low grade dysplasia and a hyperplastic polyp respectively MFMER

342 When would you recommend that he have his next colonoscopy? A. 1 year B. 3 years C. 5 years D. 10 years 2015 MFMER

343 Colonic Polyps Recommended Surveillance Finding Surveillance interval (years) No polyps 10 Small (<10 mm) hyperplastic polyps in rectum or sigmoid small (<10 mm) tubular adenoma tubular adenomas 3 >10 adenomas <3 One or more tubular adenomas 10 mm 3 One or more villous adenomas 3 Adenoma with HGD 3 Sessile adenomatous polyp >1.5 cm <1 Gastro 2012; 143: MFMER

344 Serrated Adenomas Recommended Surveillance Finding Serrated lesions Surveillance interval (years) Sessile serrated polyp(s) <10 mm with no dysplasia 5 Sessile serrated polyp(s) 10 mm 3 OR Sessile serrated polyp with dysplasia OR Traditional serrated adenoma Serrated polyposis syndrome 1 Gastro 2012; 143: MFMER

345 Serrated Adenoma Characteristics Predominantly right sided lesion Difficult to identify CIMP pathway MSI predilection BRAF Mutation Gastro 2010:138; MFMER

346 Serrated Adenoma Endoscopic Features 2015 MFMER

347 Colonic Polyps Recommended Surveillance Previous non-advanced adenoma then negative exam 10 yrs Previous advanced adenoma then negative exam 5 yrs Gastro 2012; MFMER

348 Case A 28 yo woman has a 3 year history of Crohn s disease involving the colon and perianal area. She is contemplating pregnancy and she asks you for information about pregnancy and Crohn s disease MFMER

349 Which of the following is most likely to be true? A. Her methotrexate should be continued during pregnancy. B. It is likely that she will be able to get pregnant even if her disease is active. C. Her infliximab should be stopped if she is attempting to become pregnant D. Her child will have a 30% chance of developing UC or Crohn's disease. E. Worsening of her symptoms is most likely to occur during the 2nd or 3rd trimester MFMER

350 Fertility may be slightly decreased in Crohn s disease but the majority of patients are able to conceive. Methotrexate is category X. It is clearly teratogenic and abortifacient. Infliximab is safe in early pregnancy, but some might stop it in 3 rd trimester First degree relatives of patients with CD have a 2-10% risk of CD or UC. About 1/3 of patients have worsening of symptoms during pregnancy most commonly during the first trimester or post-partum MFMER

351 Case A 28 yo woman presents with a 2 year history of intermittent crampy abdominal pain and bloating relieved with bowel movements. Her pain typically tends to lead to frequent loose stools and she occasionally notes mucus in the stool. Her weight is stable and she denies any signs of GI bleeding. Her physical exam including stool guaiac is negative MFMER

352 The most appropriate testing at this time would be: A. EGD with SB biopsy B. Small bowel x-ray C. CBC and sed rate D. TTG E. Colonoscopy with biopsy 2015 MFMER

353 Irritable Bowel Syndrome Rome III Criteria Recurrent pain or discomfort at least 3 days per month in the last 3 months (with symptoms onset at least 6 months prior to diagnosis) and 2 or more of the following: 1) Improved with defecation 2) Onset associated with change in frequency of stool 3) Onset associated with change in form of stool Gastro 2006; 130: MFMER

354 Irritable Bowel Syndrome Evaluation ACG Task Force If classic symptoms: 1) TTG 2) Consider lactose hydrogen breath test No routine blood studies No structural or imaging studies AJG 2009; 104:S1-S MFMER

355 Irritable Bowel Syndrome When to Investigate Again Alarm symptoms Change in symptoms Remember colonic screening 2015 MFMER

356 Case 43 yr old heterosexual WM with 6 month hx of intermittent small volume bright red rectal bleeding Hx constipation Ibuprofen 400 mg BID PE: nl rectal and abd exams 2015 MFMER

357 2015 MFMER

358 This patient would best be treated with? A. Fiber and liquids B. 5-ASA suppositories C. Surgical resection and colostomy D. Tetracycline 500 mg qid x 14 days E. Avoidance of NSAID 2015 MFMER

359 Solitary Rectal Ulcer Syndrome Constipation / bleeding Single or multiple ulcers Classic histologic finding Rectal prolapse / ischemia induced 2015 MFMER

360 Disorganization/hypertrophy of muscularis mucosa LP replaced by fibroblasts, smooth muscle, collagen CP MFMER

361 Case A 66 yo male with a history of severe COPD was admitted 48 hours ago with fever and LLQ pain. A presumptive diagnosis of diverticulitis was made, and he was started on IV ciprofloxacin and metronidazole but has not noticed any improvement in symptoms MFMER

362 Physical Exam Temp 102ºF P 104 BP 120/70 Appears uncomfortable Lungs: Scattered wheezes Abd: Soft with marked tenderness LLQ Hgb 13.8 CT obtained WBC 18.4 pl 384K 2015 MFMER

363 2015 MFMER

364 Which of the following would you recommend? A. Ongoing observation on IV antibiotics B. Colonoscopy C. CT directed abscess drainage D. Surgical exploration 2015 MFMER

365 Acute Diverticulitis Surgical Indications Urgent Elective Diffuse peritonitis Undrainable abscess Failure to improve with Abx 2 or more episodes Immunocompromised pt Complicated attack stricture fistula 2015 MFMER

366 Case 26 yo white female with history of panulcerative colitis has new uncontrolled diarrhea on 40 mg of prednisone daily.. She is currently having ten bloody, liquid bowel movements per day. PE: BP 98/60. P 100. Temp She appears ill but not acutely toxic. Abdominal is soft with mild rebound tenderness in both lower quadrants. BS MFMER

367 Labs: Hgb 11.2, CRP 22, albumin 3.5. Stool cul and C. diff toxin are negative. Abd flat and upright xray shows non dilated bowel. Flexible sigmoidoscopy to 20 cm shows diffuse active colitis. Biopsies are consistent with active colitis and are negative for CMV MFMER

368 Which of the following is not a good option? A. Admit to the hospital for 10 days of IV steroids. B. Colectomy with ileoanal anastomosis. C. IV cyclosporin 2 mg/kg/day as a bridge to oral azathioprine therapy. D. Infliximab 5mg/kg IV infusion and repeat in 2 and 6 weeks. E. Adalimumab 160mg SQ and 80mg in two weeks MFMER

369 IV Steroids Response Assess Response at 3 Days Non Response CRP > stools/d or > 8 stools/day Surgery Non Response Cyclosporine Assess response at 5-7 days Infliximab Response UC Consensus Group. AJG 2012

370 Colectomy with ileoanal operation is associated with at least a 50-75% decrease in fertility. IV steroids should generally not be continued more than 5 days if not responding. IV cyclosporin can be associated with significant complications but is effective in 80% of patients with severe colitis IV cyclosporin + AZA colectomy rates in initial responders: 20% at 1 year, > 40% at 7 years MFMER

371 Infliximab therapy in 50-70% effective in hospitalized patients with moderate-severe UC Adalimumab slightly less effective than infliximab but less well studied 2015 MFMER

372 Case Regarding multitarget stool DNA testing (Cologuard, Exact Sciences), which of the following is FALSE? A) It is a combination stool DNA study and immunochemical assay for human hgb B) It identifies >90% of cancers C) It identifies >70% of advanced adenomas D) Model predicts 45% of positive tests will have a normal colonoscopy E) It costs approximately $ MFMER

373 Cologuard Testing Sensitivity Colorectal Cancer 92.3% Advanced precancerous lesions 42.4% High grade Dysplasia 69.2% SSA >1 cm 42.4% Nonadvanced adenoma 17.2% NEJM 2014; 370: MFMER

374 Stool DNA Who should get it? Anyone who feels strongly about it Difficult previous exam Patients who fail eyeball test 2015 MFMER

375 Mayo Cologuard Results Positive Tests True Positive (70%) False Positive (30%) Advanced adenoma (40%) Bleeding pathology (5%) Hyperplastic polyp (8%) No abnormality (17%) 2015 MFMER

376 Cologuard (FIT-DNA) USPSTF There are no empirical data on the appropriate longitudinal follow-up for an abnormal FIT-DNA test result followed by a negative colonoscopy; there is potential for overly intensive surveillance due to clinician and patient concern about the implications of the genetic component of the test MFMER

377 Stool DNA Test Positive Colonoscopy sdna in 3 yrs Colonoscopy + - Polyp or CRC Stool DNA Testing Positive Negative - + Negative Polyp or CRC Repeat sdna within 6 months Extracolonic Evaluation -EGD -CT abdomen High Quality exam: excellent/good bowel preparation? Yes + - No Treat as indicated Screen in 3 - years stool DNA Repeat stool DNA every 3 years Surveillance Colonoscopy Repeat Colonoscopy Negative Positive

378 Mayo Experience 160 false positive DNA studies Median follow-up 4 years 2 cancers (Colon Ca 3 yrs, Lung Ca 4.5 yrs) SEER data would predict 7 cancers Appears reasonable to stop evaluation after negative colonoscopy Cotton, DDW MFMER

379 Case A married 28 yo man presents to you for an insurance physical. The patient recalls that his father died from colon cancer at age 45. Also, the patient s paternal grandfather had colon cancer in his sixties and a paternal aunt underwent surgery for a female cancer in her fifties MFMER

380 Which test (s) would be most appropriate? A. Colonoscopy now B. Colonoscopy and EGD at age 35 C. Colonoscopy and EGD now D. Colonoscopy at age 35 E. Mutational analysis of his APC gene 2015 MFMER

381 HNPCC Amsterdam Criteria 3 primary relatives 2 generations 1 cancer before age 50 colon, endometrium, SB, renal pelvis, ureter 2015 MFMER

382 Lynch Syndrome Guidelines for Screening At-Risk or Affected Persons Gastro Endosc 2014; 80: MFMER

383 Lynch Guidelines Perform pre-op testing for MMR deficiency of newly diagnosed CRC Colectomy with ileorectal anastomosis preferred surgery Recommend TAH-BSO post-childbearing or age 40 Screening of small bowel and pancreas not recommended ASA can be considered for chemo prevention Gastro Endosc 2014; 80: MFMER

384 Case A 79 yo male is 4 days out from a right THA. Over the last 48 hours he has developed progressive abdominal distension which has not been relieved with discontinuation of his pain medicine, NPO status and NG suction. His electrolytes are normal and a colonoscopy 6 months ago was unremarkable. He has a history of coronary artery disease and asthmatic bronchitis. His exam is only remarkable for scattered wheezes and a moderately tender distended abdomen without peritoneal signs. An abdominal film was obtained MFMER

385 2015 MFMER

386 Which of the following would you recommend next? A. Continued conservative care B. IV neostigmine C. IV erythromycin D. Colonic decompression E. Endoscopic or surgical cecostomy 2015 MFMER

387 Colonic Pseudo-obstruction Frequently seen following orthopedic or intraabdominal surgery or spinal cord trauma Exacerbated by electrolyte disorders and medications Risk of spontaneous perforation 3-15% Diameter Cecum > 12cm, Tx Colon > 9cm Time > 6 days 2015 MFMER

388 2015 MFMER

389 Intestinal Pseudo-Obstruction ASGE Guideline Conservative measures (20-92%) Neostigmine (60-90%) Colonic Decompression (61-78%) Surgical Percutaneous Endoscopic Cecostomy ASGE Guideline GE MFMER

390 Neostigmine Anti-cholinesterase parasympathomimetic agent Frequently causes bradycardia, hypotension, bronchoconstriction, seizures Relatively contraindicated in patients with recent MI, conduction system disease, reactive airways disease, and a history of seizures MFMER

391 Based on current guidelines, the minimum acceptable adenoma detection rate for screening colonoscopy is A) 15% (m:20% f:10%) B) 20% (m:25% f:15%) C) 25% (m:30% f:20%) D) 30% (m:35% f:25%) E) 35% (m:40% f:30%) 2015 MFMER

392 Rates of Lesion Detection Mean Withdrawal Time All exams <6 min >6 min P value Pt with adenoma (%) <0.001 Adenomas per pt screened (#) Advanced lesion per pt screened (#) NEJM 2006; 355: MFMER

393 Kaminski, NEJM 362: MFMER

394 Kaiser Permanente Study 223,842 pts followed for 10 yrs or until developed colon cancer or left health care system 264,792 colonoscopies 135 gastroenterologists ADRs % Codley, NEJM 2014; 370: MFMER

395 ADR and Cancer Rate Codley, NEJM 2014; 370: MFMER

396 ADR and Cancer Rate For each 1% increase in ADR there is a 3% decrease in CRC incidence and a 5% decrease in CRC mortality Codley, NEJM 2014; 370: MFMER

397 Case A 41 yo woman with a 25 year history of ulcerative colitis undergoes surveillance. Random surveillance biopsies show no dysplasia. In the ascending colon, three small sessile polyps are noted, and these are all removed by cold snare. Histology of these polyps reveals tubular adenoma with low-grade dysplasia MFMER

398 What is your recommendation to the patient? A. Proctocolectomy with ileal pouch-anal anastomosis for multifocal LGD B. Repeat surveillance colonoscopy with biopsies in three months. C. Repeat surveillance colonoscopy with biopsies in one year. D. Repeat surveillance colonoscopy with biopsies in three years. E. Right hemicolectomy with ileo-transverse colonic anastomosis MFMER

399 Confirm pathology IBD Dysplasia Invisible HGD Ca risk 40% Colectomy vs close surveillance* * (High def / chromo exam by expert) Invisible LGD Ca risk 20% To HGD/cancer 40% over 5 years Colectomy vs close surveillance* Polyp in area of colitis Atypical Colectomy Endoscopic resection by experienced endoscopist with close surveillance* Typical (Adenoma like mass (ALM)) Typical adenomatous polyp can be followed if no dysplasia in surrounding mucosa 2015 MFMER

400 Case A 36 yo malpractice attorney whom you have treated intermittently for symptoms of gastroesophageal reflux disease presents for a routine follow-up appointment. During your comprehensive interview, the patient discloses that her mother was diagnosed with an adenomatous polyp at age 56. No other family members are known to have had colorectal polyps or cancer MFMER

401 Based on current CRC screening guidelines, which test (s) should be performed at the present time? A. Fecal occult blood test + flexible sigmoidoscopy B. Flexible sigmoidoscopy + double-contrast barium enema C. Colonoscopy D. Punitive brain biopsy E. None of the above 2015 MFMER

402 Colon Cancer Moderately Increased Risk AGA Single family member with colon cancer or an adenomatous polyp before age 60: ACG Single family member with colon cancer or advanced adenoma before age 60: Colonoscopy q 5 years but begin at age 40 Gastroenterology 2003; 124: MFMER

403 Colon Cancer Screening Average Risk USMSTF Begin at age 50 (45 for African American) Colonoscopy q 10 yrs Flex sig q 5 yrs +/- annual FOBT ACBE or CTC q 5 yrs FOBT or FIT annually Fecal DNA? Interval CA Cancer J Clin MFMER

404 Colon Cancer Screening Average Risk ACG Begin age 50 (45 in African-American,? smoker,? obese) Cancer Prevention Tests Colonoscopy q 10 yrs* Flex Siq 5-10 yrs CTC q 5 yrs Cancer Detection Tests FIT q yr* Hemoccult Sensa q yr Fecal DNA q 3 yrs * preferred AJG 2009;104: MFMER

405 American College of Physicians Screening Guidelines Average Risk Age 50 Age 40 African American Colonoscopy q 10 yrs Flex Sig q 5 yrs Stool based test Stop age 75 or 10 yr life expectancy High Risk Age 40 or 10 yrs younger than earliest Ca Colonoscopy recommended Ann Int Med 2012;156: MFMER

406 USPSTF Screening Recommendation Statement Ages yes based on health and previous screening Stool Based Tests Frequency (yr) FOBT q 1 FIT q 1 FIT-DNA q 1-3 Direct Visualization Tests Colonoscopy q 10 CT colonography q 5 Flex sig q 5 Flex sig/fit Flex q 10 FIT q 1 JAMA 2016; 315(23) MFMER

407 Case A 25-year-old woman has a 4-week history of rectal pain and tenesmus. 4-6 loose but not watery bowel movements per day are blood streaked. Also, she intermittently passes blood without a bowel movement. She states that she does not have any notable abdominal pain, nausea, vomiting, or weight loss. Initial laboratory studies are unremarkable except for hemoglobin of 10.2 mg/dl. Physical exam findings are normal other than blood on the examining finger on rectal examination. Colonoscopy shows normal mucosa in the distal ileum and throughout the colon down to the sigmoid colon. The rectum and sigmoid colon have colitis with diffuse inflammation and mucosal ulcerations. Biopsy findings are consistent with ulcerative colitis MFMER

408 Case She is started on mesalamine 2.4 gms per day orally. Four weeks later she is having 1-3 soft to sometimes loose bowel movements per day and still some occasional blood MFMER

409 Which of the following would be the most appropriate therapy? A. Add mesalamine suppositories B. Stop mesalamine + start hydrocortisone enema C. Add mesalamine enema D. Stop mesalamine + start prednisone E. Stop mesalamine + start oral Entocort (budesonide) 2015 MFMER

410 Combination of oral and topical mesalamine is better than oral mesalamine alone. Ford AJG 12 Toronto Consensus Gastro MFMER

411 Suppositories inadequate for disease into the sigmoid colon. Mesalamine enema more effective than HC. Entocort budesonide is absorbed in the terminal ileum and proximal colon Prednisone would not be a first-line agent for mild-moderate disease MFMER

412 Case 67 yo male comes for follow-up recommendations. 18 months ago he underwent transanal excision of a 1.5 cm well-differentiated rectal cancer that was found at a screening colonoscopy. One year later (6 months ago) a follow-up colonoscopy was normal MFMER

413 Which of the following would you recommend? A. Repeat colonoscopy in 2.5 years B. Repeat colonoscopy in 4.5 years C. Repeat flex sig now D. Repeat flex sig in 6 months 2015 MFMER

414 Locally Treated Rectal Cancer Follow-up Guidelines Flex sig or EUS q 3-6 months for the first 2-3 years in addition to standard colonoscopy surveillance Am J Gastro 2016; 111: MFMER

415 Colonoscopy Surveillance After Curative CRC Resection 1 year post-resection 3 years 4 years post-resection 5 years 9 years post-resection Am J Gastro 2016; 111: MFMER

416 Case A 50-year-old white female in good health develops moderately severe left lower quadrant abdominal discomfort followed by some loose stools that become blood-streaked. PE: p = 100, mod L mid abd tenderness with localized rebound tenderness WBC = 15.2 CT Mural thickening of the descending colon Colonoscopy the following day demonstrates a segmental well-demarcated area of superficial ulceration and erythema in the mid left colon MFMER

417 What is not true of this disease? A. Can be associated with constipating medications B. This disease recurs in 30% of patients C. A hypercoagulation workup is indicated in young and recurrent disease patients only D. Can occur with abdominal surgery E. This is infrequently embolic in origin 2015 MFMER

418 Ischemic Colitis Can be associated with constipation medications Recurrence rates 7-15% over 5 years time Generally not associated with hypercoaguable state Can frequently occur after abdominal surgery involving IMA ligation Left sided disease usually associated with small vessel disease ACG Guideline AJG MFMER

419 Case You are consulted to perform a colonoscopy on a 78-year-old adopted male, who presents with a two month history of anorexia, altered taste, diarrhea, and 20 pound weight loss. On PE, he has thinning alopecia, patchy brown macules on his palms, dystrophic nails, and a normal abdominal exam. Hgb 9.9 Alb 2.6 LFTs normal You perform a colonoscopy 2015 MFMER

420 2015 MFMER

421 2015 MFMER