Presentation on theme: "Rochester, Minnesota, USA"— Presentation transcript:
1 Rochester, Minnesota, USA Understanding Contraindications to the Use of Immunomodulators and Biologics for Inflammatory Bowel DiseaseEdward V. Loftus, Jr., M.D.Professor of MedicineMayo ClinicRochester, Minnesota, USA
3 Overview of Contraindications ThiopurinesMethotrexateCalcineurin inhibitors (tacrolimus, cyclosporine)Anti-TNF agentsInfliximabAdalimumabCertolizumab pegolGolimumabAnti-integrinsNatalizumabVedolizumab
4 Contraindications to Thiopurines (Azathioprine, Mercaptopurine) Known hypersensitivity to drugExamples: fever, pancreatitis, influenza-like symptomsNot necessarily nausea/vomiting: half of IBD patients with nausea on AZA will tolerate 6MPHomozygous deficiency to TPMT (1 in 300)TPMT testing is recommended in prescribing information of Purinethol®Active untreated infectionYoung male who has negative EBV serology?Higher risk of hemophagocytic syndrome if primary EBV infection occurs while on thiopurine?
5 Possible/Relative Contraindications to Thiopurines Concurrent use of allopurinol (unless dose of thiopurine is reduced to 25% of normal weight-based dose and CBC is monitored CLOSELY)Other possible drug-drug interactionsTrimethoprim-sulfamethoxazoleAngiotensin converting enzyme inhibitors5-ASA’s cause partial inhibition of TPMT
6 Contraindications to Methotrexate Known hypersensitivity to MTX or an ingredient in the formulationPregnancyCan result in fetal death, embryotoxicity, abortion or teratogenicityChildbearing women, unless they understand the serious risk to the fetus should they become pregnantBreastfeedingAlcoholism, alcoholic liver disease, other chronic liver disease
7 Relative Contraindications to MTX Drug-drug interactionsConcurrent NSAIDs may potentiate bone marrow suppression, aplastic anemia, gastrointestinal toxicityUse with caution if there is already a hematologic abnormality, MTX may cause bone marrow depression in all cell linesChronic hepatitis B or C infectionActive infection
8 Contraindications to Anti-TNF Therapies Previous severe hypersensitivity reaction to the drugDoses >5mg/kg infliximab in moderate to severe heart failureActive serious infections including invasive fungal infections (histoplasmosis, coccidioidomycosis, aspergillosis, blastomycosis, and pneumocystosis)Recent serious histoplasmosis, consider 3 months prophylaxis itraconazoleHepatitis B virus infectionChronic or recurrent infection
9 Contraindications to Anti-TNF (cont) Latent TB—start treatment for TB before starting anti-TNFDuration of anti-TB treatment before anti-TNF start is unclearPersonal history of multiple sclerosis, optic neuritis, or other demyelinating diseaseConcurrent use of anakinra or abatacept“Consider the risks and benefits of TNF-blocker treatment prior to initiating therapy in patients with known malignancy other than a successfully treated non-melanoma skin cancer”
10 Who Is Most at Risk for Dying From Sepsis Related to Anti-TNF? OlderAverage age = 63 years (systematic review); 67 years (Mayo first 500 on IFX)Multiple co-morbiditiesConcomitant medications (steroids, narcotics)Long-standing diseaseYoung “healthy” patients are not in the clear, but probably less at riskSiegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006
11 Infections and Mortality in the TREAT Registry: 15,000 Patient-Years of Experience Serious infectionsSteroidsAZA 6-MP MTXSteroidsAZA 6-MP MTXIFXIFXP<.001P=.006P=.002AZA = azathioprine; IFX = infliximab; MTX = methotrexate.Lichtenstein GR et al. Am J Gastroenterol. 2012;107:
12 Meta-Analysis of Safety of Anti-TNF Agents in CD: Placebo-Controlled Trials 21 studies, N=5356Mortality: no differenceMalignancy: no differenceSerious infection: no differencePeyrin-Biroulet L et al. Clin Gastroenterol Hepatol. 2008;6:
13 Hospitalization, Follow-up, Abscess Size, and Recurrence Medical Managementn = 55SurgicalManagementn = 40p-valueMedian length of hospitalization, days (range)5 (0-36)16 (2-169)< 0.001Median length of follow-up after abscess resolution, months (range)45 (6-130)43 (6-120)0.72Abscess size, maximum diameter (cm)6.9 ± 3.27.4 ± 3.70.59Abscess recurrence during follow-upa) Totalb) Within 3 months of resolutionc) After 3 months of resolution17 (31%)1438 (20%)50.25Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4
14 Medical Therapy and Abscess Recurrence Pharmacologic Therapy* at Abscess Resolution(n=95)Recurrence(n=25)Hazard Ratio for Abscess Reoccurrence (95% CI)p-valueNo therapy(n=13)131.00 (reference)Overall< 0.01Immunomodulator monotherapy(n=44)100.42 ( )0.059Any anti-TNF therapy (n=38)20.10 ( )0.001*Therapy assessed as a time dependent covariate for association with abscess recurrence.Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4
15 Medical Therapy and Abscess Recurrence on Anti-TNF Therapy Pharmacologic Therapy* at Abscess Resolution(n=38)RecurrenceHazard Ratio for Abscess Reoccurrence (95% CI)p-valueAnti-TNF monotherapy(n=18)20.32 ( )0.14Combination therapy(n=20)0.00< 0.001*Therapy assessed as a time dependent covariate for association with abscess recurrence.Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4
16 Other Neurologic Side Effects Reported with Anti-TNF Therapy Guillain-Barre syndromePeripheral neuropathyAseptic meningoencephalitisLeukoencephalopathyTransverse myelitisChronic inflammatory demyelinating polyneuropathyProgressive multifocal leukoencephalopathyPosterior reversible encephalopathy syndromeSingh S et al, Inflamm Bowel Dis 2013; 19:
17 Congestive Heart Failure and Anti-TNF Therapy Etanercept trials to treat CHF were negativeInfliximab trial of CHF: highest mortality rate in IFX 10 mg/kg armAdalimumab: event rate of CHF <0.26 per 1000 p-yUse with caution in patients with CHF or reduced LVEFIFX contraindicated at doses >5mg/kg in NYHA Class III/IVConsider ECHO ± Cards consult in those with suspected CHFMann DL et al, Circulation 2004; Chung ES et al, Circulation 2003; Schiff MH et al, EULAR 2005; Kent JD et al, ACR 2005.
18 Hepatotoxicity with Anti-TNF Most commonly described with infliximab but has been describe with allPI contains warningHepatocellular > cholestatic injury, often with autoimmune characteristicsSlowly improves after drug cessationRare cases of hepatic failure/liver transplantGhabril M et al, Clin Gastroenterol Hepatol 2013;11:
19 Contraindications to Natalizumab Therapy Known hypersensitivity to natalizumabKnown or suspected progressive multifocal leukoencephalopathyPositive JC virus serology is relative contraindicationConcomitant immunosuppressants are not allowed, and steroids need to tapered within 6 months
20 Natalizumab and PML Risk Based on anti-JC Virus Antibody Status Anti-JCV Antibody StatusNegative< 0.11/1000Positive (and prior IS use)0-2 years2/1000 (1 in 500)2+ years11/1000(≈1 in 100)To ORDER anti-JC Virus antibody test:Quest Labs test # 90257, JC Virus Antibody with Reflex Inhibition AssayAbout 50% of Crohn’s patients will be positiveBloomgren, et al. NEJM 2012;
21 Natalizumab: Adverse Events Beyond PML HeadacheInfusion reactions, generally mildHepatotoxicityRare but severe cholestatic liver injury reported
22 Contraindications to Vedolizumab Known hypersensitivity to vedolizumabActive severe infections (until controlled)History of recurring severe infectionsConsider screening for TBWarning about PML in prescribing info, but no cases of PML observedDiscontinue drug in face of rising transaminases and bilirubin
23 ConclusionsA wide variety of side effects can occur with our commonly used medications for IBDMany of the contraindications relate to infectious risksScreen for latent TB and chronic viral hepatitis in all patients starting a biologic
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