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IBD: What drugs in what patients?

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Presentation on theme: "IBD: What drugs in what patients?"— 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 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
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: Sandborn WJ. J Clin Gastroenterol. 2008;42:

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
~90% metabolism in the liver ~10% Budesonide Rectal budesonide1 Enema/Foam Oral budesonide1 pH release: ileum/right colon MMX: pan-colonic 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 1 Brattsand R. Overview of newer glucocorticosteroid preparations for inflammatory bowel disease. Canadian Journal of Gastroenterology 1990; 4: https://www.pulsus.com/journals/abstract.jsp?sCurrPg=journal&jnlKy=2&atlKy=11855&isuKy=1127&spage=1&isArt=t&fold=Abstract Image adapted from figure 4 in publication. Gross V. Oral pH-modified release budesonide for treatment of inflammatory bowel disease, collagenous and lymphocytic colitis. Expert Opinion on Pharmacotherapy. 2008; 9 (7): “Approximately 90% of an oral dose of budesonide undergoes first-pass metabolism in the liver.” “As budesonide is rapidly absorbed from the gastrointestinal tract it has to be administered as a retarded formulation, which allows release of the active compound in the ileum and colon, where inflammatory bowel diseases are located.” Adapted from 1Brattsand R. Can J Gastroenterol. 1990;4(7): ; 2Gross 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
Annual ophthalmologic exams recommended Vaccinations: flu, pneumonia GI upset Nausea Osteoporosis Avascular Necrosis Myopathy Fatty liver Infection Swelling Moon facies Abdominal striae Easy bruising Diabetes Palpitations Hypertension Glaucoma Cataracts Calcium + Vit D supplementation Bone densitometry Monitor for adrenal insufficiency? Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C.Kornbluth and Sachar. Am JGastroenterol. 2010;105:

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 AZA 6-MP 6-TIMP 6-TXMP 6-TGN 6-TGN TPMT TPMT 6-MMP 6-MMPR Inactive Elevated LFTs

17 Thiopurines: Therapeutic Monitoring
Vaccinations: flu, pneumonia 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 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 Anti-TNF biologics: Fusion protein, antibodies and PEGylated Fab' fragment
Certolizumab pegol PEG PEGylated humanized Fab′ fragment 2 × 20 kDa PEG Etanercept IgG1 Fc Receptor Infliximab Adalimumab Golimumab IgG1Fc Fab Fab′ Etanercept (Enbrel): Fusion of IgG1 Fc and TNF receptor Infliximab (Remicade): IgG1 Fc and FAB / bivalent with 25% murine component Adalimumab (Humira): IgG1 Fc and FAB / bivalent fully human Certolizumab pegol (Cimzia): IgG1 FAB fragment (Fc free) that is pegylated / univalent and ~ 95% humanized Chimeric Human Human recombinant receptor/Fc fusion protein Monoclonal antibody 23 23

24 Therapeutic Levels for Anti-TNF Agents
Theoretical threshold Subtherapeutic

25 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):

26 Therapeutic Monitoring for Anti-TNF
Vaccinations: flu, pneumonia TB testing Hepatitis screening 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? 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 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 of inflammatory cells

29 Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1
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 Entyvio is a humanized monoclonal antibody that binds to the α4β7 integrin receptor expressed on the surface of a discrete subset of memory T lymphocytes and blocks the interaction of these cells with MAdCAM-1. The α4β7 integrin is expressed on the surface of a discrete subset of memory T lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue. On the left, the adhesion molecule MAdCAM-1 is shown interacting with the α4β7 integrin receptor. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of UC and CD. On the right, the humanized monoclonal antibody Entyvio is shown bound to the α4β7 integrin receptor. This binding blocks the interaction of α4β7 integrin with MAdCAM-1 and inhibits the migration of memory T lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Reference Entyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; May 2014. α4 subunit β7 subunit α4 subunit β7 subunit Memory T lymphocyte Artist’s rendition

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
Titers to check at first office visit: MMR If vaccination history unknown Varicella If vaccination history or history of chicken pox/zoster unknown Hepatitis A Except those with evidence of protective titer within 5 years of vaccine administration Hepatitis B Vaccinations to administer in specific patient groups regardless of immunosuppressive drug use: Tdap Hepatitis A HPV Hepatitis B Influenza Meningococcal Pneumococcal Vaccinations to consider if NO plans to start immunosuppressive therapy in 4-12 weeks: MMR Varicella Zoster * OK for thiopurines Wasan SK, et al. Am J Gastroenterol. 2010;105(6): DiPalma J, et al. Gastroenterol Hepatol (N Y). 2011;7:163-9.

34 Summary of Selective Therapeutic Monitoring
5-ASAs Cortico-steroids Immuno-modulators Biologics CBC1,2 x Liver enzymes3,4 Creatinine/Urinalysis/BUN3 Eye examination1 Opportunistic infections (e.g., TB, Hep B, and varicella) Immunizations1,4 TPMT Bone mineral density for >3 mo use 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). Sands BE, et al. Inflamm Bowel Dis. 2004;10:


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