Rochester, Minnesota, USA Understanding Contraindications to the Use of Immunomodulators and Biologics for Inflammatory Bowel Disease Edward V. Loftus, Jr., M.D. Professor of Medicine Mayo Clinic Rochester, Minnesota, USA

Loftus Disclosures (last 12 months) Research support AbbVie UCB Bristol-Myers Squibb Shire Genentech Janssen Amgen Pfizer Takeda GlaxoSmithKline Robarts Clinical Trials Consultant AbbVie UCB Janssen Takeda Immune Pharmaceuticals MedImmune Celgene Progentec Biosciences Theradiag

Overview of Contraindications Thiopurines Methotrexate Calcineurin inhibitors (tacrolimus, cyclosporine) Anti-TNF agents Infliximab Adalimumab Certolizumab pegol Golimumab Anti-integrins Natalizumab Vedolizumab

Contraindications to Thiopurines (Azathioprine, Mercaptopurine) Known hypersensitivity to drug Examples: fever, pancreatitis, influenza-like symptoms Not necessarily nausea/vomiting: half of IBD patients with nausea on AZA will tolerate 6MP Homozygous deficiency to TPMT (1 in 300) TPMT testing is recommended in prescribing information of Purinethol® Active untreated infection Young male who has negative EBV serology? Higher risk of hemophagocytic syndrome if primary EBV infection occurs while on thiopurine?

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 interactions Trimethoprim-sulfamethoxazole Angiotensin converting enzyme inhibitors 5-ASA’s cause partial inhibition of TPMT

Contraindications to Methotrexate Known hypersensitivity to MTX or an ingredient in the formulation Pregnancy Can result in fetal death, embryotoxicity, abortion or teratogenicity Childbearing women, unless they understand the serious risk to the fetus should they become pregnant Breastfeeding Alcoholism, alcoholic liver disease, other chronic liver disease

Relative Contraindications to MTX Drug-drug interactions Concurrent NSAIDs may potentiate bone marrow suppression, aplastic anemia, gastrointestinal toxicity Use with caution if there is already a hematologic abnormality, MTX may cause bone marrow depression in all cell lines Chronic hepatitis B or C infection Active infection

Contraindications to Anti-TNF Therapies Previous severe hypersensitivity reaction to the drug Doses >5mg/kg infliximab in moderate to severe heart failure Active serious infections including invasive fungal infections (histoplasmosis, coccidioidomycosis, aspergillosis, blastomycosis, and pneumocystosis) Recent serious histoplasmosis, consider 3 months prophylaxis itraconazole Hepatitis B virus infection Chronic or recurrent infection

Contraindications to Anti-TNF (cont) Latent TB—start treatment for TB before starting anti-TNF Duration of anti-TB treatment before anti-TNF start is unclear Personal history of multiple sclerosis, optic neuritis, or other demyelinating disease Concurrent 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”

Who Is Most at Risk for Dying From Sepsis Related to Anti-TNF? Older Average age = 63 years (systematic review); 67 years (Mayo first 500 on IFX) Multiple co-morbidities Concomitant medications (steroids, narcotics) Long-standing disease Young “healthy” patients are not in the clear, but probably less at risk Siegel, CGH 2006; Colombel, Gastro 2004; Lichtenstein CGH 2006

Infections and Mortality in the TREAT Registry: 15,000 Patient-Years of Experience Serious infections Steroids AZA 6-MP MTX Steroids AZA 6-MP MTX IFX IFX P<.001 P=.006 P=.002 AZA = azathioprine; IFX = infliximab; MTX = methotrexate. Lichtenstein GR et al. Am J Gastroenterol. 2012;107:1409-1422..

Meta-Analysis of Safety of Anti-TNF Agents in CD: Placebo-Controlled Trials 21 studies, N=5356 Mortality: no difference Malignancy: no difference Serious infection: no difference Peyrin-Biroulet L et al. Clin Gastroenterol Hepatol. 2008;6:644-653.

Hospitalization, Follow-up, Abscess Size, and Recurrence Medical Management n = 55 Surgical Management n = 40 p-value Median length of hospitalization, days (range) 5 (0-36) 16 (2-169) < 0.001 Median length of follow-up after abscess resolution, months (range) 45 (6-130) 43 (6-120) 0.72 Abscess size, maximum diameter (cm) 6.9 ± 3.2 7.4 ± 3.7 0.59 Abscess recurrence during follow-up a) Total b) Within 3 months of resolution c) After 3 months of resolution 17 (31%) 14 3 8 (20%) 5 0.25 Nguyen DL et al, Clin Gastroenterol Hepatol 2012;10:400-4

Medical Therapy and Abscess Recurrence Pharmacologic Therapy* at Abscess Resolution (n=95) Recurrence (n=25) Hazard Ratio for Abscess Reoccurrence (95% CI) p-value No therapy (n=13) 13 1.00 (reference) Overall < 0.01 Immunomodulator monotherapy (n=44) 10 0.42 (0.17 - 1.03) 0.059 Any anti-TNF therapy (n=38) 2 0.10 (0.02 - 0.36) 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

Medical Therapy and Abscess Recurrence on Anti-TNF Therapy Pharmacologic Therapy* at Abscess Resolution (n=38) Recurrence Hazard Ratio for Abscess Reoccurrence (95% CI) p-value Anti-TNF monotherapy (n=18) 2 0.32 (0.07 - 1.48) 0.14 Combination 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

Other Neurologic Side Effects Reported with Anti-TNF Therapy Guillain-Barre syndrome Peripheral neuropathy Aseptic meningoencephalitis Leukoencephalopathy Transverse myelitis Chronic inflammatory demyelinating polyneuropathy Progressive multifocal leukoencephalopathy Posterior reversible encephalopathy syndrome Singh S et al, Inflamm Bowel Dis 2013; 19:864-72.

Congestive Heart Failure and Anti-TNF Therapy Etanercept trials to treat CHF were negative Infliximab trial of CHF: highest mortality rate in IFX 10 mg/kg arm Adalimumab: event rate of CHF <0.26 per 1000 p-y Use with caution in patients with CHF or reduced LVEF IFX contraindicated at doses >5mg/kg in NYHA Class III/IV Consider ECHO ± Cards consult in those with suspected CHF Mann DL et al, Circulation 2004; Chung ES et al, Circulation 2003; Schiff MH et al, EULAR 2005; Kent JD et al, ACR 2005.

Hepatotoxicity with Anti-TNF Most commonly described with infliximab but has been describe with all PI contains warning Hepatocellular > cholestatic injury, often with autoimmune characteristics Slowly improves after drug cessation Rare cases of hepatic failure/liver transplant Ghabril M et al, Clin Gastroenterol Hepatol 2013;11:558-64.

Contraindications to Natalizumab Therapy Known hypersensitivity to natalizumab Known or suspected progressive multifocal leukoencephalopathy Positive JC virus serology is relative contraindication Concomitant immunosuppressants are not allowed, and steroids need to tapered within 6 months

Natalizumab and PML Risk Based on anti-JC Virus Antibody Status Anti-JCV Antibody Status Negative < 0.11/1000 Positive (and prior IS use) 0-2 years 2/1000 (1 in 500) 2+ years 11/1000 (≈1 in 100) To ORDER anti-JC Virus antibody test: Quest Labs test # 90257, JC Virus Antibody with Reflex Inhibition Assay About 50% of Crohn’s patients will be positive Bloomgren, et al. NEJM 2012;366.20.

Natalizumab: Adverse Events Beyond PML Headache Infusion reactions, generally mild Hepatotoxicity Rare but severe cholestatic liver injury reported

Contraindications to Vedolizumab Known hypersensitivity to vedolizumab Active severe infections (until controlled) History of recurring severe infections Consider screening for TB Warning about PML in prescribing info, but no cases of PML observed Discontinue drug in face of rising transaminases and bilirubin

Conclusions A wide variety of side effects can occur with our commonly used medications for IBD Many of the contraindications relate to infectious risks Screen for latent TB and chronic viral hepatitis in all patients starting a biologic