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 • 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. 2 IBD in 2014: Medical Therapy Options • Aminosalicylates • Corticosteroids Mesalamine Balsalazide (UC) Olsalazine (UC) Sulfasalazine • Immunomodulators Azathioprine 6-mercaptopurine Cyclosporine (UC) Methotrexate (CD) Budesonide Systemic • Biologics TNF-α inhibitors • • • • Adalimumab Certolizumab pegol (CD) Golimumab (UC) Infliximab Anti-integrin • • Natalizumab vedolizumab Classification of UC Severity FULMINANT SEVERE • >6 bloody stools/day MODERATE • Fever • ≥4 stools/day • Tachycardia ± blood • Anemia or • Minimal signs MILD ESR of toxicity • <4 stools/day ± blood • Normal ESR • No signs of toxicity • • • • >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. Sequential Therapies for Ulcerative Colitis Disease Severity at Presentation Anti-TNF +/IS Anti-Integrin Severe Corticosteroid Cyclosporine Colectomy Anti-TNF/ Thiopurine Anti-Integrin Aminosalicylate/ Thiopurine Moderate Aminosalicylate Aminosalicylate Oral/Topical/Combo Oral/Topical/Combo Budesonide Induction Maintenance Mild Therapy is stepped up according to severity at presentation or failure at prior step Sequential Therapies for Crohn’s Disease Disease Severity at Presentation Surgery Anti-TNF +/IS Anti-Integrin Severe Corticosteroid Anti-TNF/ Thiopurine Anti-Integrin Thiopurine/ Methotrexate Moderate Budesonide (Aminosalicylate) Budesonide/ Thiopurine Induction Maintenance Mild Therapy is stepped up according to severity at presentation or failure at prior step 5-ASA Agents: Sites of Delivery Colon • Sulfasalazine • Olsalazine • Balsalazide Terminal Ileum Colon (release at pH 7) • Delayed release mesalamine • MMX mesalamine Terminal Ileum Colon (release at pH 6) • Granulated mesalamine Duodenum Ileum Colon • Controlled release mesalamine Baumgart DC, Sandborn WJ. Lancet. 2007;369:1641-1657. Sandborn WJ. J Clin Gastroenterol. 2008;42:338-344. 7 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) Budesonide Metabolism and Characteristics Oral budesonide1 pH release: ileum/right colon MMX: pan-colonic ~10% Budesonide ~90% metabolism in the liver o budesonide1 Rectal Enema/Foam o Budesonide characteristics2 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 Needs specifically designed release system Adapted from 1Brattsand R. Can J Gastroenterol. 1990;4(7):407-414; 2Gross V. Expert Opin Pharmacother. 2008;9(7):1257-1265. 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 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 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 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 Corticosteroid Therapeutic Monitoringdverse Effects to Steroids Annual ophthalmologic exams recommended Glaucoma Cataracts Vaccinations: flu, pneumonia Infection Osteoporosis Avascular Necrosis Myopathy Diabetes Palpitations Hypertension GI upset • Calcium + Vit D Nausea supplementation • Bone densitometry Fatty liver Monitor for adrenal insufficiency? Swelling Moon facies Abdominal striae Easy bruising Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C.Kornbluth and Sachar. Am JGastroenterol. 2010;105:501-523. Thiopurines: Azathioprine (AZA) & 6-Mercaptopurine (6-MP) –Minimal efficacy for induction versus placebo –More effective for maintenance versus placebo Thiopurine Pharmacology Inactive 6-TU Active Bone Marrow Suppression XO AZA HPRT 6-MP 6-TIMP TPMT TPMT 6-MMP Inactive Elevated LFTs 6-MMPR 6-TXMP 6-TGN 6-TGN Thiopurines: Therapeutic Monitoring Allergic reaction: Fever, rash, arthralgias, Myalgias, fatigue Vaccinations: flu, pneumonia Infection Pancreatitis GI disturbances Hepatotoxicity, ? Nodular regenerative hyperplasia Bone marrow suppression 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. 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! Risk of Developing Non-Hodgkin’s Lymphoma Patient with Crohn’s disease Estimated annual risk = 2 per 10,000 treated patients 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 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 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 Anti-TNF biologics: Fusion protein, antibodies and PEGylated Fab' fragment Etanercept Infliximab Fab Receptor Chimeric Certolizumab pegol Fab′ PEG IgG1 Fc IgG1 Fc Human recombinant receptor/Fc fusion protein Adalimumab Golimumab Human Monoclonal antibody PEGylated humanized Fab′ fragment 2 × 20 kDa PEG Therapeutic Levels for Anti-TNF Agents 5.0 10.0 50.0 Theoretical threshold 1.0 Adalimumab 160 mg (day 1), 80 mg (day 8) and 40 mg ev ery tw o w eek s Adalimumab 40 mg ev ery tw o w eek s 0.5 Simulated anti-TNF biologic conc Inflix imab 5 mg/k g at day 1, day 15, day 43 and ev ery 8 w eek s Inflix imab 3 mg/k g at day 1, day 15, day 43 and ev ery 8 w eek s Subtherapeutic 0 20 40 60 Time (day s ) 80 100 120 Therapeutic DrugMonitoring Monitoring of Tumor Therapeutic Drug of Tumor Necrosis FactorAntagonists Antagonists in IBD Necrosis Factor 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. Therapeutic Monitoring for Anti-TNF • Vaccinations: flu, Autoimmunity, immunogenicity Congestive heart failure • Use combination therapy with thiopurines? • Check anti-TNF levels? • Check for antibodies? pneumonia Demyelinating disease, • TB testing PML* • Hepatitis screening Infection Hepatotoxicity Bone marrow suppression Malignancy/ lymphoma Infusion reactions, injection-site reactions • Switch to another anti-TNF agent? • Switch to agent with different mechanism of action? *Reported with natalizumab. 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 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 Inappropriate and sustained recruitment of inflammatory cells Macrophage Vedolizumab Binds to α4β7 Integrin and Blocks Its Interaction With MAdCAM-1 Endothelial cell MAdCAM-1 Vedolizumab: A humanized monoclonal antibody (mAb) that binds to the α4β7 integrin α4 subunit β7 subunit Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1 α4 subunit Memory T lymphocyte β7 subunit Artist’s rendition Please see Important Safety Information contained on slides 33-34. 29 Anti-Integrins inhibit inflammatory cells from getting into the (gut) tissues Entyvio Memory T lymphocyte migration inhibited Memory T lymphocyte homing to gut tissue 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. 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. 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 Vaccinations in the IBD Patient Titers to check at first office visit: MMR Varicella Hepatitis A Hepatitis B If vaccination history unknown If vaccination history or history of chicken pox/zoster unknown Except those with evidence of protective titer within 5 years of vaccine administration Except those with evidence of protective titer within 5 years of vaccine administration Vaccinations to administer in specific patient groups regardless of immunosuppressive drug use: Vaccinations to consider if NO plans to start immunosuppressive therapy in 4-12 weeks: Tdap HPV Influenza Pneumococcal MMR Varicella Zoster * OK for thiopurines Hepatitis A Hepatitis B Meningococcal Wasan SK, et al. Am J Gastroenterol. 2010;105(6):1231-8. DiPalma J, et al. Gastroenterol Hepatol (N Y). 2011;7:163-9. Summary of Selective Therapeutic Monitoring 5-ASAs CBC1,2 x Liver enzymes3,4 x Creatinine/Urinalysis/BUN3 x Eye examination1 Opportunistic infections (e.g., TB, Hep B, and varicella) Immunizations1,4 TPMT Bone mineral density for >3 mo use Corticosteroids x Immunomodulators x Biologics x x x x x x x x x x x x x 1. Kornbluth A, et al. Am J Gastroenterol. 2010;105:501-23. 2. Lichtenstein GR, et al. Am J Gastroenterol. 2009;104(2):465-83. 3. Agency for Healthcare Research and Quality (AHRQ). http://guidelines.gov/content.aspx?id=15231. 4. Sands BE, et al. Inflamm Bowel Dis. 2004;10:677-92.