1. IBD Cases Stephen B. Hanauer, MD Professor of Medicine Feinberg School of Medicine Medical Director, Digestive Health Center

5. What options are available for treatment of this patient ?

6. Management Algorithm Admit + IV steroids 3-5 days IFX therapy or cyclosporine +/- AZA IFX therapy or cyclosporine +/- AZA SurgerySurgery SEVERESEVERE Unable to taper prednisone Steroid dependent 5ASA +/- prednisone MODERATE Respond to 1-2 rounds of steroid tapered over 6-8 weeks Continue 5-ASA Respond to 1-2 rounds of steroid tapered over 6-8 weeks Continue 5-ASA Fail 2-4 weeks MILD Oral 5-ASA/ SASP +/- topical 5-ASA Budesonide MMX Oral 5-ASA/ SASP +/- topical 5-ASA Budesonide MMX Modified from Panaccione R, et al. Aliment Pharmacol Ther. 2008;28:674-88. Ulcerative Colitis Steroid refractory 2-4 weeks No response No response SASP=sulfasalazine IFX=infliximab ADA=adalimumab GOL=golimumab AZA/6MP alone or IFX/ ADA/GOL and AZA/6MP evaluate after 12 weeks AZA/6MP alone or IFX/ ADA/GOL and AZA/6MP evaluate after 12 weeks Fail AZA/6MP alone IFX/ADA/GOL +/-AZA/6MP evaluate after 12 weeks IFX/ADA/GOL +/-AZA/6MP evaluate after 12 weeks

8. What should be done at this point ?

9. 1.Continue current therapy for 4 more weeks 2.Stop Budesonide MMX and treat with prednisone 3.Add 6MP or Azathioprine after checking TPMT 4.Switch Budesonide MMX to Budesonide EC What are her options?

11. Steroid-Dependent Ulcerative Colitis: Treatment Choices Treatment choices in the steroid- dependent ulcerative colitis patient Biologic therapy? Surgery? Immunomodulator therapy? Continue steroids?

12. Steroid-Dependent Ulcerative Colitis: Treatment Choices Continue steroids? Surgery? Treatment choices in the medically refractory or severe ulcerative colitis patient Immunomodulator therapy? Continue steroids? Biologic therapy? Surgery?

13. Steroid-Dependent Ulcerative Colitis: Treatment Choices Continue steroids? Immunomodulator therapy? Surgery? Treatment choices in the medically refractory or severe ulcerative colitis patient Biologic therapy?

14. Steroid-Dependent Ulcerative Colitis: Treatment Choices Surgery? Treatment choices in the medically refractory or severe ulcerative colitis patient Surgery? Biologic therapy? Immunomodulator therapy? Continue steroids?

15. Who should NOT be offered continued medical therapy? Emergent indications for surgery ‒Fulminant disease activity unresponsive to maximal medical therapy ‒Toxic megacolon ‒Colonic perforation ‒Massive hemorrhage Elective indications for surgery ‒Disease activity refractory to medical therapy ‒Mucosal dysplasia ‒Diagnosis of carcinoma ‒Colonic stricture ‒Growth retardation in children Ford D; American Society of Colon & Rectal Surgeons. Ulcerative colitis. Available at http://www.fascrs.org/physicians/education/core_subjects/2005/ulcerative_colitis/http://www.fascrs.org/physicians/education/core_subjects/2005/ulcerative_colitis/ Cyma RR, et al. Arch Surg. 2005;140:300-310.

16. Colectomy for UC Delay in surgery more important predictor of poor outcome than hospital volume OR for death 2.12 (1.1-3.9) if colectomy after 6 days of hospitalization OR increases to 2.89 (1.4-5.9) if colectomy after 11 days Emergently admitted patients 5 times more likely to die compared to electively Kaplan G. Gastroenterology. 2008;134:680-687.

17. Risk-Benefit Ratio of Surgery in UC Probably reduces rate of mortality in the sickest patients Considered “cure” for UC Subtotal colectomy during acute phase –IPAA –Permanent ileostomy Post-surgical complications –Infection –Small bowel obstruction –Sepsis –Leak –Pouch dysfunction –Irritable pouch Pouchitis/Cuffitis Crohn’s disease Reduced female fertility Risk male erectile dysfunction BenefitRisk

18. Case 2  40-Yr-Old Man With Long-Standing Ileocolonic Crohn’s Disease  s/p 2 ileocecal resections  Recurrent disease in small and large bowel despite steroids and azathioprine 2.5 mg/kg with therapeutic 6-TGN levels

19. Case 2 Treatment History  Treated with single infusion of infliximab Excellent response lasting ~6 mo  Second infliximab infusion Complicated by an acute infusion reaction Response lasted ~8 wk  Third infliximab infusion Pretreated with prednisone, diphenhydramine, and acetaminophen Flushing and headache Response lasted ~4 wk  Fourth infliximab infusion Pretreated as above and increased dose to 10 mg/kg Headache and flushing Benefits lasted only 1  2 wk

20. What is the mechanism for his loss of response? Case 2

21. Comments on Biologics Despite “humanness” they are all immunogenic  Immunogenicity is reduced by Immune suppressants….. Anticipate dose adjustment with all There will be diminishing returns with 2 nd and/or 3 rd agent  Duration of Disease  Refractory Disease  Immunogenicity

22. Theoretical threshold Subtherapeutic Therapeutic Levels for Anti-TNF Agents

23. Implications of Low Drug (trough) Levels Disease Recurs  No longer maintenance but re-treatment Development of anti-drug antibodies  Eventual loss of response

24. Factors that Influence the Pharmacokinetics of Biologics Impact on Pharmacokinetics Presence of Anti-Drug Antibodies (ADAs) Decreases drug concentration Increases clearance Worse clinical outcomes Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087.24

25. Impact on Pharmacokinetics Concomitant use of immunosuppressivesReduces ADA formation Increases drug concentration Decreases drug clearance Better clinical outcomes Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087.25 Factors that Influence the Pharmacokinetics of Biologics

26. Impact on Pharmacokinetics Low serum albumin concentrationIncreases drug clearance Worse clinical outcome High baseline CRP concentrationIncrease drug clearance High baseline TNF concentrationMay decrease drug concentration by increasing clearance Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087.26 Factors that Influence the Pharmacokinetics of Biologics

27. Impact on Pharmacokinetics High body sizeMay increase drug clearance SexMales have higher clearance Ordas I et. al. Clin Gastroenterol Hepatol. 2012; 10:1079-1087.27 Factors that Influence the Pharmacokinetics of Biologics

28. Case 2 Continued How should loss of response in this patient be assessed? What are your current options to treat him?

29. Algorithm for loss of response to Anti-TNF Is there active disease? Yes Measure Drug Level and Anti- Drug Antibodies Undetectable Drug & undetectable ADA Suboptimal Dosing Increase Drug dose or frequency Undetectable Drug & Detectable ADA Loss of response due to ADA Switch within same Drug Class Therapeutic Levels IBD refractory to anti-TNF Alternative Class (e.g. vedolizumab) No IBS SBBO Bile-acid diarrhea Strictures

30. Case 2 continued Patient was prescribed adalimumab 160 mg at wk 0; 80 mg at wk 2; and then 40 mg EOW He initially responded with resolution of diarrhea and abdominal pain He then developed recurrent abdominal pain and loose stools

31. Case 2 Continued How should loss of response in this patient be assessed? What are your current options to treat him?

32. Case 2 Summary Several mechanisms can lead to loss of response to a biologic  For patients who respond to anti-TNF therapy and then lose response or become intolerant, switching within the anti-TNF class is a reasonable option Absolute likelihood of response to second anti-TNF agent is lower than response in naïve patients  Loss of response requires Evaluation for active inflammation (eg, CRP, imaging, endoscopy) Exclusion of inflammatory and non-inflammatory complications