Edward V. Loftus, Jr., M.D.

Transcription

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

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

3 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

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

5 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

6 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

7 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

8 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

9 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

10 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

11 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

12 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

13 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

14 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

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

16 Patients (%) Patients (%) Delayed-Release Oral Mesalamine (Asacol) Mild-to-Moderate Active UC 80 p < Significant Improvement Placebo Mesalamine 1.6 g Mesalamine 4.8 g 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

17 Patients (%) Mesalamine Dose Response in Active UC Ascend I and II 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

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

19 5-ASA Dose Response Several additional studies in your syllabus showing no clear dose-response 2015 MFMER

20 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

21 Patients (%) Balsalazide: Mild-to-Moderate Active UC 50 No difference b/w low and high dose balsalazide NS NS mg balsalazide ~ 2.4 gm mesalamine 10 0 Remission Balsalazide 2.25 g (0.8 g 5ASA) Delayed Release 5ASA 2.4 g Balsalazide 6.75 g (2.4 g 5ASA) Levine et al. Am J Gastro MFMER

22 Patients (%) Controlled-Release Oral 5-ASA (Pentasa): Mild-to-Moderate Active UC PGA Success PGA Remission Sigmoidoscopy Remission Placebo 5-ASA 1 g Placebo 5-ASA 1 g 5-ASA 2 g 5-ASA 4 g 5-ASA 2 g 5-ASA 4 g No difference b/w 2 gm and 4 gm mesalamine Hanauer et al. Am J Gastroenterol. 1993;88: MFMER

23 Percent of Patients Delayed-Release Oral 5-ASA (Asacol): Mild-to-Moderate Active UC Significant Improvement (N=158) 0 Remission (N=158) Placebo 5-ASA 1.6 g 5-ASA 2.4 g Placebo 5-ASA 1.6 g 5-ASA 2.4 g Not much difference b/w 1.6 gm and 2.4 gm Sninsky CA, et al. Ann Intern Med. 1991;115: MFMER

24 Patients (%) Delayed-Release Oral Mesalamine (Asacol): Maintenance of Endoscopic Remission of UC p = p = Placebo Mesalamine 0.8 g Mesalamine 1.6 g Not much difference 0 Treatment Success at 6 months Hanauer et al. Ann Intern Med. 1996;124: MFMER

25 Patients (%) Patients (%) MMX Oral 5-ASA (Lialda) in Mild-to-Mod Active UC * ** *** ** ** NS Clinical Improvement 0 Remission Placebo Delayed release 5ASA 0.8 g tid MMX 5ASA 2.4 g q day MMX 5ASA 4.8 g q day Placebo Delayed release 5ASA 0.8 g tid MMX 5ASA 2.4 g q day MMX 5ASA 4.8 g q day No difference b/w 2.4 gm and 4.8 gm QD Kamm et al. Gastroenterology MFMER

26 Patients (%) Patients (%) MMX Oral 5-Aminosalicylate (Lialda): Mild-to- Moderate Active UC Clinical Improvement 0 Remission Placebo MMX 5ASA 4.8 g q day MMX 5ASA 1.2 g bid Placebo MMX 5ASA 4.8 g q day MMX 5ASA 1.2 g bid No difference b/w 1.2 gm BID and 4.8 gm QD Lichtenstein et al. Clin Gastro Hepatol MFMER

27 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

28 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

29 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

30 Remission with once vs. twice daily mesalazine MMX mesalamine 2.4 g/day No difference b/w 1.2 gm BID and 2.4 gm QD in early or late remission rates Kamm, M A et al. Gut 2008;57: MFMER

31 Clinical Remission at 8 Weeks, % Once Daily vs. Split dosing of Mesalamine granules in UC 3 g QD 1 g TID Per Protocol (N=345) Intent-to-treat (n=380) No difference b/w 1 gm TID and 3 gm QD 80% of patients preferred QD dosing Kruis W et al. Gut MFMER

32 Patients (%) Maintenance of Remission in UC Extended Release Mesalamine* *Salofalk p=0.02 p<0.001 p=0.03 p= g QD 1.5 g QD 0.5g TID Relapse-free at 12 Months Endoscopic Remission at 12 Months No difference b/w 0.5 gm TID and 1.5 gm QD 3 gm/d was better than 1.5 gm/d Kruis W et al. Gastroenterology 2008;134(Suppl 1):A MFMER

33 Daily vs. Split dose Mesalamine for Maintenance in UC Adherence was better in QD group Dignass. Clin Gastro Hep MFMER

34 % Remission Daily vs. Split dose Mesalamine for Maintenance Treatment in UC 100% 80% 94.8% 95.6% 90.5% 91.8% 85.4% 85.4% 60% 40% QD BID 20% 0% Month 3 Month 6 Month 12 Asacol, g/d No difference b/w QD and BID dosing Sandborn WJ. Gastroenterology MFMER

35 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

36 Steroid Therapy in UC 2015 MFMER

37 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

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

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

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

41 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

42 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

43 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

44 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

45 2015 MFMER

46 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

47 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

48 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

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

50 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

51 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

52 Azathioprine / 6-MP in Ulcerative colitis 2015 MFMER

53 METABOLISM OF AZATHIOPRINE AND 6-MERCAPTOPURINE 2015 MFMER

54 2015 MFMER

55 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

56 Anti-TNF therapy in Ulcerative colitis 2015 MFMER

57 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

58 2015 MFMER

59 % of Patients % of Patients 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 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

60 % of Patients % of Patients Infliximab in Ulcerative Colitis Clinical Remission 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 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

61 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 p = % N = 24 Järnerot, Gastroenterology MFMER

62 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

63 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% Placebo ADA 20% * * * Placebo ADA Wk 8 RR 10% 10% 0% Remission Response MH 0% Remission Response MH Sandborn, Gastroenterology 2012 Sandborn APT MFMER

64 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

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

66 Proportion of patients (%) Golimumab in UC Week 6 Response PURSUIT-SC p<0.001 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

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

68 Proportion of patients (%) Golimumab Maintenance of Response Week 54 PURSUIT-SC Maintenance Randomized responders Monthly injections p<0.001 p=0.010 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

69 Proportion of patients (%) Remission and Mucosal Healing Week 30 and 54 PURSUIT-SC Maintenance Monthly injections p = p =0.003 p = N/A* p = * p value is not available due to testing procedures Defined as Mayo score 2 points, with no individual subscore >1 Defined as Mayo endoscopy subscore of 0 or 1 Sandborn, Gastro MFMER

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

71 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

72 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

73 What about Combination Therapy in Ulcerative colitis? 2015 MFMER

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

75 Leukocyte Trafficking Blockers 2015 MFMER

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

77 Vedolizumab in Ulcerative colitis 2015 MFMER

78 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

79 Vedolizumab in UC Gemini 1 Humanized mab against a4b7 integrin Blocks leucocyte trafficking to the gut 374 patients with mod-severe UC randomized 3:2 to vedo vs placebo 521 patients in open-label induction Week 6 responders re-randomized to vedo (Q4 or Q8 weeks) vs placebo thru week MFMER

80 Percent Vedolizumab in Moderate-severe UC GEMINI * 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

81 Patients (%) GEMINI I: Outcomes by Anti-TNF Exposure Prior Anti-TNF Failure Week 6 Anti-TNF Naive * 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

82 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

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

84 GEMINI I: Vedolizumab in UC Induction Phase Adverse Events Placebo (n=149) Vedolizumab (n = 746) Any AE 69 (46%) 337 (45%) Serious AE 10 (7%) 25 (3%) Any Infection 22 (15%) 104 (14%) Serious Infection 3 (2%) 4 (<1%) Infusion reaction 1 (<1%) 3 (<1%) Cancer MFMER slide-84 Feagan BG et al, N Engl J Med 2013;369(8): MFMER

85 GEMINI I: Vedolizumab in UC Maintenance Adverse Events Placebo (n=275) Vedolizumab (n=620) Any adverse event 80% 80% Serious AE 13% 12% UC Exacerbation 21% 16% Headache 10% 13% Nasopharyngitis 10% 13% Serious infection 3% 2% Malignant neoplasm 1% 0.2% 2010 MFMER slide-85 Feagan BG et al, N Engl J Med 2013;369(8): MFMER

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

87 Cyclosporine in Ulcerative colitis See syllabus 2015 MFMER

88 Cyclosporine for Severe Ulcerative Colitis Response Study N IV CSA dose Outcome measure CyA 4 mg/kg Placebo Steroids CyA 2 mg/kg Lichtiger mg/kg LS to < 10 for 2 days 82% 0% D Haens mg/kg LS 3 to < 10 on days 7 & 8 64% % --- Van Assche mg/kg LS 3 to < 10 on day 8 84% % 2015 MFMER

89 Cyclosporine: long-term efficacy? 65% 58% 90% Oxford 1996 to patients with severe UC 56 responders to CSA Campbell S et al. Eur J Gastroenterol Hepatol 2015 MFMER

90 Survival free of colectomy in patients Rx with cyclosporine Moskovitz Clin Gastro Hepatol MFMER

91 Serious Infections and Death in Patients Rx with IV Cyclosporine for IBD 142 patients Death in 4 patients (2.8%) Pneumocystis carinii - 1 Systemic aspergillosis 2 CML Moskowitz. Clin Gastro Hepatol MFMER

92 Cyclosporine in severe UC 2-4 mg/kg/d infusion 60-80% effective initially 10-60% long -term success Renal insufficiency, HTN, seizures, paresthesias, infections Monitor levels, creatinine Response oral CSA + AZA/6-MP 2015 MFMER

93 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

94 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

95 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

96 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

97 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

98 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

99 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

100 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

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

102 Antibiotics for Active Crohn s Disease - RCTs Metronidazole mg/d not effective Metronidazole 800 mg/day equivalent to sulfasalazine 3 g/d Metronidazole 1 g/day + cipro 1 g/day less effective than methylprednisolone 1 mg/kg Cipro 1 g/day equivalent to mesalamine 4 g/day 2015 MFMER

103 Antibiotics for Crohn s Metronidazole 1500 mg/day effective for postoperative maintenance Uncontrolled studies suggest that metronidazole mg/day and ciprofloxacin 1 g/day are effective for fistulizing Crohn s 2015 MFMER

104 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

105 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

106 Change in CDAI Mesalamine Induction in Crohn s Disease Change in CDAI in 3 Trials Pentasa 4 g Placebo Pentasa 4 g minus Placebo p=0.7 p= p= 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

107 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

108 Ford, Am J Gastro 2011;106: MFMER

109 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

110 2015 MFMER

111 Mesalamine MOR in Crohn s Disease Study Year Pt (n) Caprilli McLeod Brignola Sutherland Overall % Post-op MOR Thomson Prantera Brignola Gendre Bresci Thomson Arber Modigliani Sutherland De Franchis Overall , % Medical MOR Cammà Gastro Favors Tx Favors Control 2015 MFMER

112 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

113 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

114 ORAL BUDESONIDE IN ACTIVE CROHN S DISEASE 2015 MFMER

115 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

116 Immunomodulators in Crohn s Disease 2015 MFMER

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

118 Response and Remission Chande Cochrane Database Syst Rev. 2013;4:CD MFMER

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

120 Induction of remission with AZA/6-MP in Crohn s Disease Study Treatment n/n Control n/n Odds ratio 95% CI Weight (%) Odds ratio 95% CI Azathioprine vs placebo trials Candy 1995 Ewe 1993 Klein 1974 Rhodes 1971 Summers 1979 Willoughby /33 16/21 6/13 0/9 21/59 6/6 20/30 8/21 6/13 0/7 20/77 1/ ( ) 4.57 ( ) 1.00 ( ) Not estimable 1.57 ( ) ( ) Subtotal (95% CI) ( ) 6-Mercaptopurine vs placebo trials Present 1980 Oren /36 13/32 5/36 12/ ( ) 0.80 ( ) Subtotal (95% CI) ( ) Total (95% CI) ( ) Favors placebo Favors AZA Sandborn, Cochrane Database 2000; 2: CD000545

121 Maintenance of remission with AZA in Crohn s Disease Study Treatment n/n Azathioprine 2.5 mg/kg/day Candy 1995 Summers /25 16/19 Subtotal (95% CI) 44 Azathioprine 2.0 mg/kg/day O Donoghue 1978 Rosenberg1975 Willoughby 1971 Subtotal (95% CI) 13/23 7/10 4/5 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

122 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

123 MTX in Moderate - Severe CD 2015 MFMER

124 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

125 Methotrexate Dosing Issues Typically administered SC Induction dose: 25 mg weekly Maintenance dose: 15 mg weekly Co-administer folic acid 1 mg daily 2015 MFMER

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

127 Biologics in Crohn s Disease 2015 MFMER

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

129 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

130 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

131 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

132 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

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

134 Patients in Remission (%) Maintenance of Remission: CHARM * 40* 41* 36* Placebo 40 mg EOW 40 mg Weekly 30 *p < /170 No statistically significant difference between 40 mg EOW and 40 mg weekly dose groups /172 73/157 20/170 62/172 65/157 Week 26 Week 56 Colombel et al. Gastroenterology MFMER

135 % of Patients ADA for Infliximab LOR or Intolerance GAIN PBO * /80 mg * /166 34/159 56/166 82/159 41/166 61/159 Remission Response CR-70 Response CR-100 *p <0.001, p <0.01 Sandborn WJ, et al. Ann Intern Med MFMER

136 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

137 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

138 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

139 Percent of Patients Anti-TNF Maintenance of Remission in CD Week 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

140 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

141 Anti-TNF Safety See Syllabus 2015 MFMER

142 Anti-TNF Agents: Adverse Events Immunogenicity Infection granulomatous (TB, histo, Listeria) other Autoimmunity Lymphoma/malignancy Demyelinating disorders Congestive heart failure (rare) Hepatotoxicity (rare) 2015 MFMER

143 Mayo First 500 Crohn s Disease Patients Treated with Infliximab Infection attributed to drug: 41 (8.2%) Serious infections: 20 (4%) Fatal sepsis in 2 Pneumonia in 8 (2 fatal) Viral infection in 6 Abdominal abscess in 2 Arm cellulitis in 1 Histoplasmosis in 1 Colombel JF et al. Gastroenterology MFMER

144 Infliximab: Adverse Events % Sandborn Gut MFMER

145 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

146 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

147 What about combination therapy? 2015 MFMER

148 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

149 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

150 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

151 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

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

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

154 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

155 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

156 Leukocyte Trafficking Blockers in Crohn s Disease 2015 MFMER

157 Natalizumab Alpha 4 blocker 2015 MFMER

158 Patients (%) ENACT-2: Remission P< P=0.005 P< Placebo Natalizumab P= 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

159 Natalizumab for Crohn s Maintenance ENACT-2 Patients (%) 100 P=0.217 P<0.05 P< Natalizumab 300mg (n=130) Placebo (n=120) Contingent primary endpoint Months Start ENACT-2 Sandborn WJ, et al. NEJM MFMER

160 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

161 Pepio et al. DDW 2011; Abstract # MFMER

162 Vedolizumab in Crohn s Disease α4 β MFMER

163 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

164 Vedolizumab in Crohn s Gemini patients with mod-severe Crohn s randomized 3:2 to vedo vs placebo 747 patients in open-label induction Week 6 responders re-randomized to vedo (Q4 and Q8 weeks) vs placebo thru week MFMER

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

166 Patients % Vedolizumab Maintenance in Crohn s Disease 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

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

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

169 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

170 GEMINI 2: Adverse Events in Induction PBO/PBO (n=148) VDZ (n=967) Any adverse event 59% 57% Serious adverse event 6% 7% Nausea 6% 6% CD exacerbation 7% 6% URI 7% 7% SBO <1% <1% Any infection 18% 17% Serious infection 1% 1% Infusion reaction 5% 3% Malignant neoplasm 0% <1% Sandborn WJ et al, N Engl J Med 2013;369(8): MFMER slide MFMER

171 GEMINI 2: Adverse Events in Maintenance Combined PBO (n=301) Combined VDZ (n=814) Any AE 82% 87% Serious AE 15% 24% Crohn s exacerbation 22% 20% Arthralgia 13% 14% Pyrexia 13% 13% Headache 16% 12% Nausea 10% 11% Abdominal pain 13% 10% URI 19% 23% Any Infection 40% 44% Serious Infection 3% 6% Infusion reaction 5% 4% Malignant neoplasm <1% <1% 2010 MFMER slide-171 Sandborn WJ et al, N Engl J Med 2013;369(8): MFMER

172 Patients, % 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< 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

173 Subjects, % 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= 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

174 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

175 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

176 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

177 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

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

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

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

181 From: WJ Sandborn online CME activity 3/ MFMER

182 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

183 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

184 Thank you 2015 MFMER