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IBD: What drugs in what patients?

IBD: What drugs in what patients?. Stephen B. Hanauer, MD Professor of Medicine Feinberg School of Medicine Medical Director, Digestive Health Center Northwestern Medicine. Conflicts AbbVie , Actavis , Janssen, Pfizer, Prometheus, Salix, Shire, Takeda, UCB. IBD in 2014: Therapeutic Goals.

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IBD: What drugs in what patients?

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  1. IBD: What drugs in what patients? Stephen B. Hanauer, MD Professor of Medicine Feinberg School of Medicine Medical Director, Digestive Health Center Northwestern Medicine Conflicts AbbVie, Actavis, Janssen, Pfizer, Prometheus, Salix, Shire, Takeda, UCB

  2. IBD in 2014: Therapeutic Goals • Rapid and safe induction of remission • Absence of inflammatory symptoms • Normalized laboratory results • Healing of the bowel • Patient feeling healthy and well • Corticosteroid-free durable maintenance of remission • Restoration of growth and development; correction of malnutrition • Avoidance of drug-related and disease-related complications Kornbluth A, et al. Am J Gastroenterol. 2010;105:501-523; Lichtenstein GR, et al. Am J Gastroenterol. 2009;104:465-483.

  3. IBD in 2014: Medical Therapy Options • Aminosalicylates • Mesalamine • Balsalazide (UC) • Olsalazine (UC) • Sulfasalazine • Immunomodulators • Azathioprine • 6-mercaptopurine • Cyclosporine (UC) • Methotrexate (CD) • Corticosteroids • Budesonide • Systemic • Biologics • TNF-α inhibitors • Adalimumab • Certolizumab pegol (CD) • Golimumab (UC) • Infliximab • Anti-integrin • Natalizumab • vedolizumab

  4. Classification of UC Severity • FULMINANT • >10 stools/day • Continuous bleeding • Toxicity • Abdominal tenderness/distension • Transfusion requirement • Colonic dilation on x-ray • SEVERE • >6 bloody stools/day • Fever • Tachycardia • Anemia or  ESR • MODERATE • ≥4 stools/day • ± blood • Minimal signs of toxicity • MILD • <4 stools/day ± blood • Normal ESR • No signs of toxicity Truelove SC, Witts LJ. Br Med J. 1955;2:1041. Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.

  5. Sequential Therapies for Ulcerative Colitis Disease Severity at Presentation Cyclosporine Colectomy Anti-TNF/ Thiopurine Anti-Integrin Anti-TNF +/IS Anti-Integrin Severe Moderate Mild Aminosalicylate/ Thiopurine Corticosteroid Aminosalicylate Oral/Topical/Combo Budesonide Aminosalicylate Oral/Topical/Combo Induction Maintenance Therapy is stepped up according to severity at presentation or failure at prior step

  6. Sequential Therapies for Crohn’s Disease Disease Severity at Presentation Surgery Anti-TNF/ Thiopurine Anti-Integrin Anti-TNF +/IS Anti-Integrin Severe Moderate Mild Thiopurine/ Methotrexate Corticosteroid Budesonide (Aminosalicylate) Budesonide/ Thiopurine Induction Maintenance Therapy is stepped up according to severity at presentation or failure at prior step

  7. 5-ASA Agents: Sites of Delivery Colon Terminal Ileum Colon (release at pH  7) Terminal Ileum Colon (release at pH  6) Duodenum Ileum Colon • Sulfasalazine • Olsalazine • Balsalazide • Delayed release mesalamine • MMX mesalamine • Granulated mesalamine • Controlled release mesalamine Baumgart DC, Sandborn WJ. Lancet. 2007;369:1641-1657. Sandborn WJ. J Clin Gastroenterol. 2008;42:338-344.

  8. Aminosalicylates (5-ASA) Monitoring • Sulfasalazine: • Nausea, vomiting, headache, reversible male infertility, anemia • Olsalazine: • Diarrhea • All: • Paradoxical worsening of colitis (rare) • Pancreatitis/Hepatitis/Pericarditis/Pneumonitis (rare) • Requires Monitoring • Renal Function (~yearly) Interstitial nephritis (rare)

  9. Budesonide Metabolism and Characteristics Oral budesonide1 pH release: ileum/right colon MMX: pan-colonic ~10% Budesonide ~90% metabolism in the liver • Budesonide characteristics2 • Non-halogenated corticosteroid, highly lipophilic • Good tissue penetration • 9x greater receptor binding than dexamethasone • Rapidly absorbed in GI tract • Metabolites are almost inactive • Terminal half-life 2.7 +/- 0.6 hours • Needs specifically designed release system Rectal budesonide1 Enema/Foam Adapted from 1Brattsand R. Can J Gastroenterol. 1990;4(7):407-414; 2Gross V. Expert OpinPharmacother. 2008;9(7):1257-1265.

  10. Mild-Moderate UC • Most UC patients present with mild to moderate disease • Aminosalicylates: • Do not have a clear dose response from 2.4 to 4.8 grams • 4.8 g/day may be more effective than 2.4 g/day in patients with a history of more difficult to treat disease (e.g., previous use of oral 5-ASAs, rectal therapies, steroids, or multiple medications) • Topical steroids: • Effective to treat active UC • Fewer adverse effects than oral corticosteroids

  11. Mild-Moderate UC • Patients with left-sided UC are most effectively treated with topical mesalamine therapy • Topical mesalamine demonstrated to be more effective than oral mesalamine in left-sided UC • Budesonide MMX is effective for left-sided colitis and pancolitis • Positioning will depend upon future clinical trials

  12. Management of Moderate UC: • Maximize 5-ASA therapy first • Increase to maximal dose of 5-ASA • Add topical therapy • Confirm medication adherence, simplify regimen if indicated • ? 5-ASA hypersensitivity • Rule out Clostridium difficile infection at least once for change in UC symptoms

  13. Management of Moderate UC: • If corticosteroids are necessary, plan for an exit strategy on Day 1 • Recurrent steroid tapers are not efficacious • Calcium + Vitamin D supplementation while on steroids • Bone densitometry if indicated • Routine vaccinations prior to starting immunosuppression

  14. Corticosteroid Therapeutic MonitoringdverseEffects to Steroids Annual ophthalmologic exams recommended Vaccinations: flu, pneumonia Glaucoma Cataracts Infection Osteoporosis Avascular Necrosis Myopathy Diabetes Palpitations Hypertension GI upset Nausea • Calcium + Vit D supplementation • Bone densitometry Swelling Moon facies Abdominal striae Easy bruising Fatty liver Monitor for adrenal insufficiency? Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C.Kornbluth and Sachar. Am JGastroenterol. 2010;105:501-523.

  15. Thiopurines: Azathioprine (AZA) & 6-Mercaptopurine (6-MP) • Minimal efficacy for induction versus placebo • More effective for maintenance versus placebo

  16. Thiopurine Pharmacology Inactive 6-TU Active Bone Marrow Suppression XO HPRT 6-TXMP AZA 6-MP 6-TIMP 6-TGN 6-TGN TPMT TPMT 6-MMP 6-MMPR Inactive Elevated LFTs

  17. Thiopurines: Therapeutic Monitoring Vaccinations: flu, pneumonia Allergic reaction: Fever, rash, arthralgias, Myalgias, fatigue Infection Pancreatitis Bone marrow suppression GI disturbances TPMT testing Routine CBC, LFT monitoring Hepatotoxicity, ? Nodular regenerative hyperplasia Malignancy/ lymphoma Routine dermatology exams Sun protection Kornbluth A, Sachar DB. Am J Gastroenterol. 2004;88:1371. deBoer N et al. Nature Clin Pract Gastroenterol Hepatol. 2007;4:686.

  18. Timing of CBCs with Thiopurine Therapy • Close monitoring during first 8 weeks of therapy appears warranted • If mild leukopenia during the first 8 weeks and/or large reduction in WBC from baseline, hold drug and recheck CBC • After the first 8 weeks, less frequent monitoring is reasonable • Continue Monitoring every 3 months!

  19. Risk of Developing Non-Hodgkin’sLymphoma Patient withCrohn’sdisease Estimatedannualrisk= 2 per10,000treatedpatients

  20. Risk of Developing Non-Hodgkin’sLymphoma Patient withCrohn’sdiseasereceiving6MPorAzathioprine Estimatedannualrisk= 4 per10,000treatedpatients

  21. Methotrexate Side Effects • Rash • Nausea, mucositis, diarrhea • Bone marrow suppression • Hypersensitivity pneumonitis • Increased liver enzymes • Hepatic fibrosis/cirrhosis • Known abortifacient • No documented increased risk of lymphoma or skin cancer

  22. Methotrexate Therapeutic Monitoring • Regular counseling regarding birth control • 1 mg folic acid supplementation daily • Monitor CBC, liver enzymes every 6 weeks • Evaluate risk factors for liver disease • Diabetes • Obesity • Alcohol abuse • Routine dose based liver biopsy no longer recommended

  23. Certolizumab pegol Etanercept Infliximab Adalimumab Golimumab Receptor Fab PEG IgG1 Fc IgG1Fc PEGylated humanized Fab′ fragment 2 × 20 kDa PEG Anti-TNF biologics:Fusion protein, antibodies and PEGylated Fab' fragment Fab′ Chimeric Human Human recombinant receptor/Fc fusion protein Monoclonal antibody

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

  25. Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in IBD Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in IBD Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomes Patient-related factors* may influence the pharmacokinetics of these agents Recent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomes Incorporation of therapeutic drug monitoring into clinical practice may allow clinicians to optimize treatment by maintaining effective drug concentrations over time * Sex and/or body size, and disease severity, including TNF burden and serum albumin concentration Ordás I, Feagan BG, Sandborn WJ. Clin Gastroenterol Hepatol.2012;10(10):1079-87.

  26. Therapeutic Monitoring for Anti-TNF • Vaccinations: flu, pneumonia • TB testing • Hepatitis screening Autoimmunity, immunogenicity Demyelinating disease, PML* • Use combination therapy with thiopurines? • Check anti-TNF levels? • Check for antibodies? Congestive heart failure Infection Bone marrow suppression Hepatotoxicity Malignancy/ lymphoma Infusion reactions, injection-site reactions • Switch to another anti-TNF agent? • Switch to agent with different mechanism of action? *Reported with natalizumab.

  27. Risk of Developing Non-Hodgkin’sLymphoma Patient withCrohn’sdiseasereceivingcombinationanti-TNF+6MPorazathioprine Estimatedannualrisk= 6 per10,000treatedpatients

  28. α4β7 Integrin–MAdCAM-1 Is One of the Interactions that Contributes to Chronic Inflammation in UC and CD Gut lumen Dendritic cells Infiltrating lymphocytes Chemokines/ILs Macrophage Inappropriate and sustained recruitment ofinflammatory cells

  29. Vedolizumab Binds to α4β7 Integrin and Blocks Its Interaction With MAdCAM-1 Endothelial cell MAdCAM-1 vedolizumab Vedolizumab: A humanized monoclonal antibody (mAb) that binds to the α4β7 integrin Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1 α4 subunit β7 subunit α4 subunit β7 subunit Artist’s rendition Memory T lymphocyte

  30. Anti-Integrins inhibit inflammatory cells from getting into the (gut) tissues Entyvio Memory T lymphocyte migration inhibited Vedolizumab inhibits the migration of memory T lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Entyvio does not bind to or inhibit function of the α4β1 or αεβ7 integrins. Memory T lymphocyte homing to gut tissue inhibited Artist’s rendition

  31. Therapeutic Monitoring and Adverse Events with Vedolizumab • Rare Infusion-related reactions & hypersensitivity • 30 minute infusion and no post-infusion monitoring • Not recommended in patients with active, severe infections until the infections are controlled • No cases of PML have been observed • Rare reports of elevations of transaminase and/or bilirubin • All patients should be brought up to date with all immunizations Patients may receive non-live vaccines and may receive live vaccines if the benefits outweigh the risks. • Most common adverse reactions (incidence ≥3% and ≥1% higher than placebo): nasopharyngitis, headache, arthralgia, nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain, and pain in extremities.

  32. High Risk Patients • Older • Multiple co-morbidities • Concomitant steroids and/or narcotics • Long-standing disease • Young “healthy” patients are not in the clear, but probably much less at risk • ? Prior malignancy

  33. Vaccinations in the IBD Patient *OK for thiopurines Wasan SK, et al. Am J Gastroenterol. 2010;105(6):1231-8. DiPalmaJ, et al. Gastroenterol Hepatol (N Y). 2011;7:163-9.

  34. Summary of Selective Therapeutic Monitoring • Kornbluth A, et al. Am J Gastroenterol. 2010;105:501-23. 2. Lichtenstein GR, et al. Am J Gastroenterol. 2009;104(2):465-83. • Agency for Healthcare Research and Quality (AHRQ). http://guidelines.gov/content.aspx?id=15231. • Sands BE, et al. Inflamm Bowel Dis. 2004;10:677-92.

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