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IBD: What drugs in what patients? Stephen B. Hanauer, MD Professor of Medicine Feinberg School of Medicine Medical Director, Digestive Health Center Northwestern.

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Presentation on theme: "IBD: What drugs in what patients? Stephen B. Hanauer, MD Professor of Medicine Feinberg School of Medicine Medical Director, Digestive Health Center Northwestern."— Presentation transcript:

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 2 Kornbluth A, et al. Am J Gastroenterol. 2010;105: ; Lichtenstein GR, et al. Am J Gastroenterol. 2009;104:

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 MILD <4 stools/day ± blood Normal ESR No signs of toxicity MODERATE ≥4 stools/day ± blood Minimal signs of toxicity SEVERE >6 bloody stools/day Fever Tachycardia Anemia or  ESR FULMINANT >10 stools/day Continuous bleeding Toxicity Abdominal tenderness/distension Transfusion requirement Colonic dilation on x-ray 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 Therapy is stepped up according to severity at presentation or failure at prior step Aminosalicylate Oral/Topical/Combo Budesonide Corticosteroid Anti-TNF +/IS Anti-Integrin Disease Severity at Presentation Cyclosporine Colectomy Aminosalicylate/ Thiopurine Anti-TNF/ Thiopurine Anti-Integrin Induction Maintenance Severe Moderate Mild Aminosalicylate Oral/Topical/Combo

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

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

8 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) Aminosalicylates (5-ASA) Monitoring

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

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

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

16 Thiopurine Pharmacology AZA6-MP6-TIMP 6-TXMP 6-TGN 6-TU 6-MMP6-MMPR XO TPMT HPRT TPMT Inactive Active Bone Marrow Suppression Inactive Elevated LFTs 6-TGN

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

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 ’ s Lymphoma Patient with Crohn ’ s disease Estimated annual risk = 2 per 10,000 treated patients

20 Risk of Developing Non-Hodgkin ’ s Lymphoma Patient with Crohn ’ s disease receiving 6MP or Azathioprine Estimated annual risk = 4 per 10,000 treated patients

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

24 Theoretical threshold Subtherapeutic Therapeutic Levels for Anti-TNF Agents

25 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 Ordás I, Feagan BG, Sandborn WJ. Clin Gastroenterol Hepatol. 2012;10(10): * Sex and/or body size, and disease severity, including TNF burden and serum albumin concentration Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in IBD

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

27 Risk of Developing Non-Hodgkin ’ s Lymphoma Patient with Crohn ’ s disease receiving combination anti-TNF + 6MP or azathioprine Estimated annual risk = 6 per 10,000 treated patients

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

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

30 Anti-Integrins inhibit inflammatory cells from getting into the (gut) tissues Entyvio Memory T lymphocyte homing to gut tissue inhibited Memory T lymphocyte migration inhibited Artist’s rendition 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.

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 Wasan SK, et al. Am J Gastroenterol. 2010;105(6): DiPalma J, et al. Gastroenterol Hepatol (N Y). 2011;7: Vaccinations in the IBD Patient * OK for thiopurines

34 Summary of Selective Therapeutic Monitoring 1.Kornbluth A, et al. Am J Gastroenterol. 2010;105: Lichtenstein GR, et al. Am J Gastroenterol. 2009;104(2): Agency for Healthcare Research and Quality (AHRQ). 4.Sands BE, et al. Inflamm Bowel Dis. 2004;10:


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