Presentation on theme: "IBD: What drugs in what patients?"— Presentation transcript:
1IBD: What drugs in what patients? Stephen B. Hanauer, MDProfessor of MedicineFeinberg School of MedicineMedical Director, Digestive Health CenterNorthwestern MedicineConflictsAbbVie, Actavis, Janssen, Pfizer, Prometheus, Salix, Shire, Takeda, UCB
2IBD in 2014: Therapeutic Goals Rapid and safe induction of remissionAbsence of inflammatory symptomsNormalized laboratory resultsHealing of the bowelPatient feeling healthy and wellCorticosteroid-free durable maintenance of remissionRestoration of growth and development; correction of malnutritionAvoidance of drug-related and disease-related complicationsKornbluth A, et al. Am J Gastroenterol. 2010;105: ; Lichtenstein GR, et al. Am J Gastroenterol. 2009;104:
3IBD in 2014: Medical Therapy Options AminosalicylatesMesalamineBalsalazide (UC)Olsalazine (UC)SulfasalazineImmunomodulatorsAzathioprine6-mercaptopurineCyclosporine (UC)Methotrexate (CD)CorticosteroidsBudesonideSystemicBiologicsTNF-α inhibitorsAdalimumabCertolizumab pegol (CD)Golimumab (UC)InfliximabAnti-integrinNatalizumabvedolizumab
4Classification of UC Severity FULMINANT>10 stools/dayContinuous bleedingToxicityAbdominal tenderness/distensionTransfusion requirementColonic dilation on x-raySEVERE>6 bloody stools/dayFeverTachycardiaAnemia or ESRMODERATE≥4 stools/day± bloodMinimal signs of toxicityMILD<4 stools/day ± bloodNormal ESRNo signs of toxicityTruelove SC, Witts LJ. Br Med J. 1955;2:1041.Kornbluth A, Sachar DB. Am J Gastroenterol. 2010;105:501.
5Sequential Therapies for Ulcerative Colitis Disease Severityat PresentationCyclosporineColectomyAnti-TNF/ThiopurineAnti-IntegrinAnti-TNF +/ISAnti-IntegrinSevereModerateMildAminosalicylate/ThiopurineCorticosteroidAminosalicylateOral/Topical/ComboBudesonideAminosalicylateOral/Topical/ComboInductionMaintenanceTherapy is stepped up according to severity at presentation or failure at prior step
6Sequential Therapies for Crohn’s Disease Disease Severityat PresentationSurgeryAnti-TNF/ThiopurineAnti-IntegrinAnti-TNF +/ISAnti-IntegrinSevereModerateMildThiopurine/MethotrexateCorticosteroidBudesonide(Aminosalicylate)Budesonide/ThiopurineInductionMaintenanceTherapy is stepped up according to severity at presentation or failure at prior step
8Aminosalicylates (5-ASA) Monitoring Sulfasalazine:Nausea, vomiting, headache, reversible male infertility, anemiaOlsalazine:DiarrheaAll:Paradoxical worsening of colitis (rare)Pancreatitis/Hepatitis/Pericarditis/Pneumonitis (rare)Requires MonitoringRenal Function (~yearly) Interstitial nephritis (rare)
9Budesonide Metabolism and Characteristics ~90% metabolism in the liver~10% BudesonideRectal budesonide1Enema/FoamOral budesonide1pH release: ileum/right colonMMX: pan-colonicBudesonide characteristics2Non-halogenated corticosteroid, highly lipophilicGood tissue penetration9x greater receptor binding than dexamethasoneRapidly absorbed in GI tractMetabolites are almost inactiveTerminal half-life 2.7 +/- 0.6 hoursNeeds specifically designed release system1 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=AbstractImage 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):
10Mild-Moderate UCMost UC patients present with mild to moderate diseaseAminosalicylates:Do not have a clear dose response from 2.4 to 4.8 grams4.8 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 UCFewer adverse effects than oral corticosteroids
11Mild-Moderate UCPatients with left-sided UC are most effectively treated with topical mesalamine therapyTopical mesalamine demonstrated to be more effective than oral mesalamine in left-sided UCBudesonide MMX is effective for left-sided colitis and pancolitisPositioning will depend upon future clinical trials
12Management of Moderate UC: Maximize 5-ASA therapy firstIncrease to maximal dose of 5-ASAAdd topical therapyConfirm medication adherence, simplify regimen if indicated? 5-ASA hypersensitivityRule out Clostridium difficile infection at least once for change in UC symptoms
13Management of Moderate UC: If corticosteroids are necessary, plan for an exit strategy on Day 1Recurrent steroid tapers are not efficaciousCalcium + Vitamin D supplementation while on steroidsBone densitometry if indicatedRoutine vaccinations prior to starting immunosuppression
14Corticosteroid Therapeutic Monitoringdverse Effects to Steroids Annual ophthalmologic exams recommendedVaccinations: flu, pneumoniaGI upsetNauseaOsteoporosisAvascularNecrosisMyopathyFatty liverInfectionSwellingMoon faciesAbdominal striaeEasy bruisingDiabetesPalpitationsHypertensionGlaucomaCataractsCalcium + Vit D supplementationBone densitometryMonitor for adrenal insufficiency?Sandborn WJ. Can J Gastroenterol. 2000;14(suppl C):17C-22C.Kornbluth and Sachar. Am JGastroenterol. 2010;105:
15Thiopurines: Azathioprine (AZA) & 6-Mercaptopurine (6-MP) Minimal efficacy for induction versus placeboMore effective for maintenance versus placebo
17Thiopurines: Therapeutic Monitoring Vaccinations: flu, pneumoniaGI disturbancesAllergic reaction:Fever, rash, arthralgias,Myalgias, fatigueHepatotoxicity, ? Nodular regenerative hyperplasiaInfectionMalignancy/lymphomaPancreatitisKornbluth A, Sachar DB. Am J Gastroenterol. 2004;88:1371.deBoer N et al. Nature Clin Pract Gastroenterol Hepatol. 2007;4:686.Bone marrowsuppressionTPMT testingRoutine CBC, LFT monitoringRoutine dermatology examsSun protection
18Timing of CBCs with Thiopurine Therapy Close monitoring during first 8 weeks of therapy appears warrantedIf mild leukopenia during the first 8 weeks and/or large reduction in WBC from baseline, hold drug and recheck CBCAfter the first 8 weeks, less frequent monitoring is reasonableContinue Monitoring every 3 months!
19Risk of Developing Non-Hodgkin’s Lymphoma Patient with Crohn’s diseaseEstimated annual risk =2 per 10,000 treated patients
20Risk of Developing Non-Hodgkin’s Lymphoma Patient with Crohn’s disease receiving 6MP or AzathioprineEstimated annual risk =4 per 10,000 treated patients
21Methotrexate Side Effects RashNausea, mucositis, diarrheaBone marrow suppressionHypersensitivity pneumonitisIncreased liver enzymesHepatic fibrosis/cirrhosisKnown abortifacientNo documented increased risk of lymphoma or skin cancer
22Methotrexate Therapeutic Monitoring Regular counseling regarding birth control1 mg folic acid supplementation dailyMonitor CBC, liver enzymes every 6 weeksEvaluate risk factors for liver diseaseDiabetesObesityAlcohol abuseRoutine dose based liver biopsy no longer recommended
23Anti-TNF biologics: Fusion protein, antibodies and PEGylated Fab' fragment Certolizumab pegolPEGPEGylated humanized Fab′ fragment2 × 20 kDa PEGEtanerceptIgG1FcReceptorInfliximabAdalimumabGolimumabIgG1FcFabFab′Etanercept (Enbrel): Fusion of IgG1 Fc and TNF receptorInfliximab (Remicade): IgG1 Fc and FAB / bivalent with 25% murine componentAdalimumab (Humira): IgG1 Fc and FAB / bivalent fully humanCertolizumab pegol (Cimzia): IgG1 FAB fragment (Fc free) that is pegylated / univalent and ~ 95% humanizedChimericHumanHuman recombinant receptor/Fc fusion proteinMonoclonal antibody2323
24Therapeutic Levels for Anti-TNF Agents Theoretical thresholdSubtherapeutic
25Therapeutic Drug Monitoring of Tumor Necrosis Factor Antagonists in IBD Drug adjustment empirically based on clinical symptoms often is inaccurate and may lead to suboptimal outcomesPatient-related factors* may influence the pharmacokinetics of these agentsRecent evidence shows that maintenance of an optimal therapeutic drug concentration is associated with improved clinical outcomesIncorporation 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 concentrationOrdás I, Feagan BG, Sandborn WJ. Clin Gastroenterol Hepatol. 2012;10(10):
26Therapeutic Monitoring for Anti-TNF Vaccinations: flu, pneumoniaTB testingHepatitis screeningCongestiveheart failureAutoimmunity,immunogenicityDemyelinating disease, PML*InfectionMalignancy/lymphomaInfusion reactions,injection-site reactionsHepatotoxicityBone marrowsuppression*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?
27Risk of Developing Non-Hodgkin’s Lymphoma Patient with Crohn’s disease receiving combination anti-TNF + 6MP or azathioprineEstimated annual risk =6 per 10,000 treated patients
28α4β7 Integrin–MAdCAM-1 Is One of the Interactions that Contributes to Chronic Inflammation in UC and CDGut lumenDendritic cellsInfiltrating lymphocytesChemokines/ILsMacrophageInappropriate and sustained recruitment of inflammatory cells
29Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1 Vedolizumab Binds to α4β7 Integrin and Blocks Its Interaction With MAdCAM-1Endothelial cellMAdCAM-1vedolizumabVedolizumab:A humanized monoclonal antibody (mAb) that binds to the α4β7 integrinVedolizumab blocks the interaction of α4β7 integrin with MAdCAM-1Entyvio 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.ReferenceEntyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; May 2014.α4subunitβ7subunitα4subunitβ7subunitMemory T lymphocyteArtist’s rendition
30Anti-Integrins inhibit inflammatory cells from getting into the (gut) tissues EntyvioMemory T lymphocyte migration inhibitedVedolizumab 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 inhibitedArtist’s rendition
31Therapeutic Monitoring and Adverse Events with Vedolizumab Rare Infusion-related reactions & hypersensitivity30 minute infusion and no post-infusion monitoringNot recommended in patients with active, severe infections until the infections are controlledNo cases of PML have been observedRare reports of elevations of transaminase and/or bilirubinAll 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.
32High Risk Patients Older Multiple co-morbidities Concomitant steroids and/or narcoticsLong-standing diseaseYoung “healthy” patients are not in the clear, but probably much less at risk? Prior malignancy
33Vaccinations in the IBD Patient Titers to check at first office visit:MMRIf vaccination history unknownVaricellaIf vaccination history or history of chicken pox/zoster unknownHepatitis AExcept those with evidence of protective titer within 5 years of vaccine administrationHepatitis BVaccinations to administer in specific patient groups regardless of immunosuppressive drug use:TdapHepatitis AHPVHepatitis BInfluenzaMeningococcalPneumococcalVaccinations to consider if NO plans to start immunosuppressive therapy in 4-12 weeks:MMRVaricellaZoster* OK for thiopurinesWasan SK, et al. Am J Gastroenterol. 2010;105(6):DiPalma J, et al. Gastroenterol Hepatol (N Y). 2011;7:163-9.
34Summary of Selective Therapeutic Monitoring 5-ASAsCortico-steroidsImmuno-modulatorsBiologicsCBC1,2xLiver enzymes3,4Creatinine/Urinalysis/BUN3Eye examination1Opportunistic infections (e.g., TB, Hep B, and varicella)Immunizations1,4TPMTBone mineral density for >3 mo useKornbluth 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: