1 / 38

Immunomodulators and Biologics

Immunomodulators and Biologics. Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida. Management of Post-Operative Recurrence of IBD. David T. Rubin, MD, AGAF Associate Professor of Medicine Co-Director, Inflammatory Bowel Disease Center

curry
Download Presentation

Immunomodulators and Biologics

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Immunomodulators and Biologics Maria T. Abreu, MD University of Miami Miller School of Medicine Miami, Florida

  2. Management of Post-Operative Recurrence of IBD David T. Rubin, MD, AGAF Associate Professor of Medicine Co-Director, Inflammatory Bowel Disease Center University of Chicago Medicine

  3. Maintenance of remission off steroids and/or Mucosal healing (histology) Induction of remission IBD Maintenance of remission

  4. What do we know: Guiding principles Combination therapy is better than monotherapy Early therapy is better than late therapy (esp Crohn’s disease) Well timed surgery is ok

  5. Indications for Surgery • Crohn’s disease: • Obstruction • Medically refractory disease • Hemorrhage/transfusion requirements • High grade dysplasia or cancer • Growth delay • Fistula/abscess • Ulcerative colitis: • Medically refractory disease/fulminant disease • High grade dysplasia or cancer • Hemorrhage/transfusion requirements • Perforation

  6. Mouse Human PEG, polyethylene glycol. First-line Biologic Agents for the Treatment of CD Certolizumab Pegol Infliximab Adalimumab VL VH CH1 No Fc PEG IgG1 IgG1 PEG Human recombinant antibody (100% humanIgG1 isotype) Chimeric monoclonal antibody (75% humanIgG1 isotype) Humanized Fab’fragment (95% humanIgG1 isotype)

  7. SONIC • Moderate-to-severe CD in patients with no prior exposure to biologic agents or immunomodulators • Excluded intermediate TPMT activity • Average disease duration 2.3 years AZA 2.5mg/kg IFX 5mg/kg IFX + AZA • 1° endpoint: Induction + maintenance of steroid-free remission • 2° endpoint: Mucosal healing

  8. 9 SONIC Clinical Remission Without Corticosteroids at Week 26 Primary Endpoint 100 p<0.001 80 p=0.009 p=0.022 57 60 Proportion of Patients (%) 45 40 30 20 52/170 75/169 96/169 0 AZA + placebo IFX + placebo IFX+ AZA Colombel, J.F., et al., N Engl J Med. 362(15): p. 1383-95.

  9. Cumulative Probability of Surgeryin Crohn’s Disease 100 80 60 Patients* (%) 40 20 0 0 5 10 15 20 25 30 35 Years After Onset Mekhjian HS et al. Gastroenterol. 1979;77(4 pt 2):907-913.

  10. Preoperative Corticosteroids Increase Risk of Postoperative Complications in IBD *Major complications include sepsis, pneumonia, peritonitis, abscess, wound infection • 159 IBD patients (71 UC, 88 CD) undergoing elective bowel surgery CS, corticosteroids; 6-MP, 6-mercaptopurine; AZA, azathioprine Aberra FN et al. Gastroenterology. 2003;125:320.

  11. Postoperative infections CD1: Mayo Clinic 52 IFX vs 218 no IFX OR 0.9 (95% CI 0.4–1.9)1 UC2: Mayo Clinic 47 IFX vs. 254 no IFX OR 2.7 (95% CI 1.1–6.7) UC3: Cleveland Clinic Pelvic sepsis 46 IFX vs. 46 no IFX OR 13.8 (1.8–105) TNF Use Prior to Surgery CD ? UC 1. Colombel JF et al. Am J Gastroenterol. 2004;99:878. 2. Selvasekar CR et al. J Am Coll Surg. 2007;204:956. 3. Mor IJ. Dis Col Rectum. 2008;51:1202. IFX, infliximab; OR, odds ratio; CI, confidence interval

  12. SymptomaticInflammation SubclinicalInflammation Disability Health Post-op Ileocecectomy is the Perfect Opportunity for Prevention! Complications DiseasePrevention Prevention ofComplications Prevention ofSymptomatic Disease Prevention ofRelapse

  13. Recurrence After Surgery in Crohn’s Disease 100 N=89 80 Survival without surgery Survival withoutlaboratory recurrence 60 Patients (%) Survival without symptoms 40 Survival withoutendoscopic lesions 20 0 0 1 2 3 4 5 6 7 8 Years Rutgeerts P et al. Gastroenterol. 1990;99(4):956-963.

  14. Risk Stratification for Recurrence in Post-operative Crohn’s disease • Smoking • Perforating-type of disease • Small bowel disease • Ileocolonic disease • Perianal fistulas • Duration of disease • Age • ? Clear margins • ? Length of resection • ?Type of anastomosis Greenstein AJ et al. Gut. 1988;29(5):588-592. Bernell O et al. Ann Surg. 2000;231(1):38-45. Bernell O et al. Br J Surg. 2000;87(12):1697-1701. D'Haens GR et al. Gut. 1995;36(5):715-717. Lautenbach E et al. Gastroenterol.1998;115(2):259-267. Moskovitz D et al. Int J Colorectal Dis. 1999;14(4-5):224-226. Kono T et al. Dis Colon Rectum2011 May;54(5):586-92.

  15. The Neo-TI: The Rutgeerts’ ScorePatients should be scoped 6 months after surgery to re-stratify risk Rutgeerts 0 Rutgeerts 1 Rutgeerts 2 Normal ileal mucosa <5 aphthous ulcers >5 aphthous ulcers, normal intervening mucosa Ulceration without normal intervening mucosa Severe ulceration with nodules, cobblestoning, or stricture Rutgeerts 3 Rutgeerts 4

  16. The neo-terminal ileum is not the anastomosis! • Suture-related trauma • Marginal ulcerations/ischemia

  17. Symptoms after Crohn’s Surgery are Not Always Inflammatory!

  18. Medical Prevention of Clinical and Endoscopic Recurrence of Crohn’s Disease Regueiro M. Inflamm Bowel Dis. 2009 Oct;15(10):1583-90.

  19. Thiopurines for the prevention of postoperative recurrence in Crohn’s disease: meta-analysis Endoscopic Clinical Peyrin-Biroulet L et al. Am J Gastroenterol. 2009 Aug;104(8):2089-96.

  20. Metronidazole/azathioprine combination therapy for post-operative recurrence High risk pts (n=81) = (age <30, smokers, steroids <3 months, second resection, perforated/abscess) N=40 metronidazole 250 mg TID 3 months + AZA 2–3 tabs N=41 metronidazole 250 mg TID 3 months + placebo % patients with endoscopic recurrence (>i2) post surgery D'Haens GR et al.Gastroenterology. 2008 Oct;135(4):1123-9.

  21. Post-operative Endoscopic RecurrenceInfliximab vs. Placebo Infliximab vs placebop=0.0006 1/11 11/13 Endoscopic Recurrence defined as endoscopic scores of i2, i3, or i4. Regueiro M et al. 2009 Feb;136(2):441-50.e1; quiz 716.

  22. Proposed Algorithm for Prevention of Post-Op Recurrence in Crohn’s Assess risk of recurrence Low Moderate High Don’t Know Therapy? Start therapy Start therapy ? Metronidazole at discharge Metronidazole at discharge 4 weeks 4 weeks Thiopurine + MTX TNF + IMM Colonoscopy at 6 months Colonoscopy at 6 months Colonoscopy at 6 months Colonoscopy at 3-6 months i2-i4 i0-i1 i2-i4 i0-i1 i0-i1 i2-i4 Treatment Escalate Rx Change dose/ optimization Follow up

  23. Ulcerative colitis

  24. ACT 1 and ACT 2 Early mucosal healing a favorable prognostic factor in UC Infliximab-treated patients P<0.0001 Week 8 endoscopy Patients in Corticosteroid-free remission % Week 8 endoscopic score Colombel JF et al. Gastroenterology. 2011 Jun 29. [Epub ahead of print].

  25. Can Surgery for UC be Prevented?Mucosal Healing and Time to Colectomy in Infliximab-Treated Patients 0 = NORMAL 1 = MILD 2 = MODERATE 3 = SEVERE Colombel JF, Rutgeerts P, Reinisch W, et al. Gastroenterology. 2011 Oct;141(4):1194-201

  26. Ulcerative Colitis: Ileo-pouch Anal Anastomosis Colectomy Cuff/Anal Transition zone J pouch

  27. Better Outcomes at High Volume Hospitals 50 OR = 1.18 (0.99–1.41) Percent 40 35.4 30 25.6 20 OR = 2.42 (1.26–4.63) 10 Mortality Complications 4.0 0.7 0 High volume Low volume Kaplan GG et al. Gastroenterology. 2008;134:680.

  28. “Complications” of the Ileal Pouch Surgical/ Mechanical Inflammatory/ Infectious Functional Dysplasia/ Neoplasia Systemic/ Metabolic • Pouchitis • Crohn’s dis. • Cuffitis • Small • bowel bacterial • overgrowth • CMV • C. difficile • Polyps • Irritable • pouch syn. • Pelvic floor • dysfunction • Poor pouch • compliance • Pseudo- • obstruction • Afferent limb syn. • Efferent limb syn. • Strictures • - Leaks • Fistulae • Sinuses • - Abscess • Adhesions • Re-operation • Anemia • Osteoporosis • Vitamin B12 • deficiency • Malnutrition • Fertility • Sexuality • Dysplasia • Cancer Compliments of Bo Shen, MD

  29. Risk Factors for Pouchitis • Extensive UC • Backwash ileitis • Primary sclerosing cholangitis • p-ANCA • NOD2/ IL-1 receptor antagonist polymorphisms • Ex-smoker • NSAIDs • Arthralgias • Family history of Crohn’s disease Fazio VW et al. Ann Surg. 1995 August; 222(2): 120–127; Schmidt CM et al. Ann Surg. 1998 May; 227(5): 654–665; J L Lohmuller et al.Ann Surg. 1990 May; 211(5): 622–629; Fleshner P et al.Clin Gastroenterol Hepatol. 2007 Aug;5(8):952-8; quiz 887; Achkar JP et al.Clin Gastroenterol Hepatol. 2005 Jan;3(1):60-6; Shen B et al. Am J Gastroenterol. 2005 Jan;100(1):93-101; Le Q et al. Inflamm Bowel Dis. 2012 Mar 29 [Epub ahead of print]

  30. Figure: http://www.webmd.com accessed May, 2012.

  31. Management of Pouchitis (endoscopic confirmation is preferred) Pouchitis Cipro or Metronidazole x 2 wks Responded Not Responded Cipro or Metronidazole x 2 more wks Infrequent Relapse Frequent Relapse Responded Not Responded Antbx-responsive Pouchitis Antbx-dependent Pouchitis Antbx-refractory Pouchitis Cipro+ Metronidazole or Rifaximin or Tinidazole x 4 wks Antibiotics prn Probiotics or Antibiotics Not Responded 5-ASA/steroids/ Immunomodulators/Infliximab?

  32. Can Pouchitis be Prevented? Frequency of Pouchitis with Probiotic Prophylaxis P < 0.05 % cases with flare-up N = 20 6 grams QD x 12 months N = 20 Gionchetti P et al. Gastroenterol2003 May;124(5):1202-9.

  33. Key Take Home Messages

  34. IBD • Stratify patients for disease severity & potential long-term complications • Combination therapy better than monotherapy for sick patients naïve to both • Low Absolute risk of IS or Biologic therapy • Vaccines, DXAs and other health maintenance issues will eventually be used to measure quality

  35. Risks of IBD Therapy • Non-melanoma skin cancer (NMSC) associated with current or past IS therapy • No other solid tumors show clear association with IS or anti-TNF therapy • No clear signal that combination therapy leads to higher risk than monotherapy • HSTCL occurs AFTER 2 years of thiopurine exposure • Risk of PML after 2 years on natalizumab about 1 in 100 exposed patients

  36. Management of Post-operative Recurrence in IBD • Know patient’s risk of recurrence • Confirm endoscopic disease • Ulcerative colitis • Mucosal healing reduces risk of colectomy • Assess risk of pouchitis • Distinguish pouchitis/Crohn’s/pre-pouch ileitis • Crohn’s disease (ileo-colonic anastomosis) • Assess colonoscopic recurrence @ 6 months • Prophylaxis vs re-treatment based on risks and treatment history • Subsequent clinical/endoscopic f/u not defined

  37. Microscopic colitis • Incidence appears to have stabilized • Consider celiac disease if steatorrhea or weight loss • Consider drug-induced MC • Treat with bismuth or budesonide • -Right dose and right duration • Maintenance therapy with budesonide is effective

  38. Gut microbiota and IBS • Microbiota in IBS: • Differs from health & may contribute to pathogenesis • May lead novel diagnostic tests for IBS • May select or predict response to IBS treatments treatments • Provide potential target in IBS • Antibiotics, Probiotics, Therapeutic foods

More Related