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IBD Cases

IBD Cases. Stephen B. Hanauer, MD Professor of Medicine Feinberg School of Medicine Medical Director, Digestive Health Center. What options are available for treatment of this patient ?. Management Algorithm. Ulcerative Colitis. MODERATE. MILD. SEVERE. 5ASA +/- prednisone.

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IBD Cases

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

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

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

  4. What should be done at this point ?

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

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

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

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

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

  10. Ford D; American Society of Colon & Rectal Surgeons. Ulcerative colitis. Available at http://www.fascrs.org/physicians/education/core_subjects/2005/ulcerative_colitis/Cyma RR, et al. Arch Surg. 2005;140:300-310. 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

  11. Kaplan G. Gastroenterology. 2008;134:680-687. 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

  12. Risk-Benefit Ratio of Surgery in UC Benefit Risk • 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 • Probably reduces rate of mortality • in the sickest patients • Considered “cure” for UC • Subtotal colectomy during acute phase • IPAA • Permanent ileostomy

  13. 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

  14. 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

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

  16. 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 2nd and/or 3rd agent • Duration of Disease • Refractory Disease • Immunogenicity

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

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

  19. Factors that Influence the Pharmacokineticsof Biologics Ordas I et. al. ClinGastroenterolHepatol. 2012; 10:1079-1087.

  20. Factors that Influence the Pharmacokineticsof Biologics Ordas I et. al. ClinGastroenterolHepatol. 2012; 10:1079-1087.

  21. Factors that Influence the Pharmacokineticsof Biologics Ordas I et. al. ClinGastroenterolHepatol. 2012; 10:1079-1087.

  22. Factors that Influence the Pharmacokineticsof Biologics Ordas I et. al. ClinGastroenterolHepatol. 2012; 10:1079-1087.

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

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

  25. 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

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

  27. 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

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