Tumor Necrosis Factor Inhibitors Box Warnings Nina Elk, Pharm.D. Internal Medicine Resident (PGY2) Kingsbrook Jewish Medical Center Department of Pharmacy Brooklyn, New York

TNF Inhibitors Available on the Market Etanercept (Enbrel®) – soluble TNF receptor fusion protein Infliximab (Remicade®) – chimeric anti-TNF-alpha antibody Adalimumab (Humira®) – human monoclonal anti-TNF-alpha antibody Certolizumab pegol (Cimzia®) – antigen-binding fragment of humanized monoclonal antibody coupled to polyethylene glycol

TNF Inhibitors Box Warnings

TNF Inhibitors Box Warnings Infliximab (Remicade®) August 1998 Etanercept (Enbrel®) November 1998 Adalimumab (Humira®) January 2002 Certolizumab (Cimzia®) April 2008 Fungal infections (9/2008) √ Bacterial infections (5/2008) Hepatosplenic-T-cell lymphoma (5/2008)

FDA MedWatch Warning Malignancy Association with TNF Inhibitors “ [Posted 06/03/2008] FDA issued an Early Communication About an Ongoing Safety Review to inform healthcare professionals that the Agency is investigating a possible association between the use of Tumor Necrosis Factor (TNF) blockers and the development of lymphoma and other cancers in children and young adults. Until the evaluation is completed, healthcare providers, parents, and caregivers should be aware of the possible risk of lymphoma and other cancers in children and young adults when deciding how to best treat these patients.”

TNF Inhibitors Place in Therapy Rheumatoid arthritis Crohn’s disease Juvenile idiopathic arthritis Psoriatic arthritis Ankylosing spondylitis Plaque psoriasis

Role of TNF in Inflammation The cytokine network in inflammation. TNF is responsible for regulation of immune cells, induce apoptosis, inhibit tumorigenesis and inhibit viral production. This is a TNF-dependent cytokine cascade illustrating a crucial role of TNF. Key interacting cells are CD4+T and macrophages. Macrophages activate CD4+T cells by releasing inflammatory proteins including TNF which is the is the group of proteins which induce apoptosis in cells, so the role of TNF is crucial in conditions like rheumatoid arthritis and crohn’s disease where the destruction of the cells occurs. The existent TNF-alpha inhibitors work by blocking the destructive action of TNF.

Complications Associated with TNF Inhibitors Infections – bacterial, viral, fungal Mycobacterial infection – tuberculosis Malignancy Injection/infusion reactions Induction of autoimmunity Demyelinating disease Heart failure

Risk of Serious Infections Mechanism TNF important component of immune system Enhanced endothelial cell activation Inflammatory cell recruitment Procoagulant role (infection spread limited) Activates macrophages for phagocytosis Inhibition of TNF can cause serious infections

TNF Inhibitors Cause Severe Infections Evidence in Literature Drug Trial Patient # Duration Risk of infection Infliximab 3 mg/kg or 6 mg/kg Every 8 weeks ASPIRE 1049 54 weeks 2-fold Adalimumab 40 mg every other week PREMIER 799 2 years Etanercept Retrospective case review 23,733 N/A Certolizumab 200 mg or 400 mg every 2 weeks RAPID 2 619 24 weeks 2 ½ -fold

Infliximab – Induced Pneumocystis Jiroveci Pneumonia Case Report Patient 69 y/o female with PMH: RA X 5 years, diabetes mellitus, no history of infection RA treatment Infliximab + methotrexate Reaction onset 3 weeks after infliximab initiation (infliximab 3 doses received) Reaction Exertional dyspnea and fever. Broncho-alveolar lavage detected Pneumocystosis jiroveci Management Trimethoprim/sulfamethoxazole started and condition improved within 1 week NK et. al. 2007;45(4):366-71. Japanese

Link Between TNF Inhibitors and Tuberculosis Patients with latent tuberculosis infection (LTBI) have Mycobacterium tuberculosis (Mtb) bacilli contained in granulomas TNF is required for maintenance of granuloma structure Macrophages, multinucleated giant cells Tumor necrosis factors inhibit TNF which sets Mtb bacilli free Latent tuberculosis transforms into active tuberculosis MTb are viable organisms and exist in slow state of replication , in majority of people who are infected they will not cause active disease, however once Mtbs are activated disease occurs. Usually, prophylactic treatment for several months will reduce the risk of progression from LTBI to active TB.

TNF-inhibitors Cause Tuberculosis Infection Evidence Adalimumab Clinical trial data Infliximab Postmarketing data Etanercept Patients (Patient-years) 2,500 (4900) 198,235 (227,559) >150,000 (>230,000) TB reports: US Outside US 13 3 (33%) 10 (67%) 172 110 (64%) 62 (36%) 38 34 (90%) 4 (10%) Time to onset 3-8 months 3–6 months 11 months Certolizumab Pegol Study Duration Patient # TB cases TB onset RAPID 2 168 days 4,650 5 58 – 169 days

Adalimumab-Induced Disseminated Tuberculosis Case Report Patient 71 y/o woman PMH: COPD, sleep apnea, osteoporosis RA treatment Adalimumab 40 mg sq every other week Reaction onset 18 months after treatment initiation Reaction Ascites, asthenia, anorexia, miliary nodules of peritoneal surfaces Management Rifampin, isoniazid, pyrazinamide RA The Lancet 2007;370:564

TNF Inhibitors and Malignancy Patients with RA at risk for malignancy Autoimmune dysfunction Chronic inflammation TNF induces apoptosis of tumor cells Medications used concomitantly increase risk of cancer Methotrexate Azathioprine Cyclophosphamide

Trials Reporting TNF Inhibitors and Malignancy Risk Infliximab and Adalimumab Placebo N = 3493 N = 1512 Odd Ratio 3.3 (95%CI, 0%-25%) TB et al. JAMA 2006;295:2275-2285

FDA Investigates TNF Inhibitors Risk of Malignancy 30 cancer cases reported to FDA from 1998 – 2008 Infliximab Adalimumab Etanercept Ten year study planned for Certolizumab to evaluate long term risks www.fda.gov/medwAtch/safety/2008

Non-Small-Cell Lung Cancer Associated with Infliximab Case Report Patient 69 y/o female, former smoker X 35 years Crohn’s disease management MTX + Infliximab (2000 – 2004), adalimumab (2004 – 2006) Reaction Non-small cell lung cancer with TNF receptors Management Discontinuation of adalimumab and complete resolution of symptoms NEJM 2008;359:320 - 321

Recommendations to Prevent Serious Infections Routine screening Histoplasmosis, coccidiosis, listeria monocytogenes Avoid unpasteurized products and undercooked meat Educate patients to self report fever, respiratory problems Routine CBC test to check for left shift

Recommendations to Prevent Tuberculosis Thorough evaluation prior to TNF inhibitor treatment History of TB Risk factors Tuberculin skin test (TST) for LTBI > 5mm positive Immunocompromised patients false (+)ve TST results Chest X-ray prior to treatment BCG vaccination yield (+)ve TST T-SPOT TB test more sensitive to LTBI Positive for LTBI begin treatment Isoniazid 300 mg daily X 9 months Rifampicin 600 mg +/- isoniazid 300 mg X 4 months Monitor LFTs baseline and monthly

Recommendations to Reduce Risk of Malignancy Evaluate patient risk for malignancy prior to TNF inhibitors initiation Review medications which can further increase risk of malignancy Evaluate malignancy risk and benefit from immunosuppressants

Take Home Message TNF inhibitors possess risk on Infections Tuberculosis Malignancy Vigilant monitoring for signs and symptoms of adverse reactions Patient education related to risk of malignancy and serious infections Keep abreast with FDA warnings due to ongoing investigations with TNF inhibitors