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Managing Risks of TNF Inhibitors: an Update for the Internist

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Managing Risks of TNF Inhibitors: an Update for the Internist REVIEW CME EDUCATIONAL OBJECTIVE: Readers will weigh the risks associated with anti-tumor necrosis factor therapies CREDIT JENNIFER HADAM, MD ELIE AOUN, MD, MS KOFI CLARKE, MD MARY CHESTER WASKO, MD, MSc Division of Gastroenterology, Division of Gastroenterology, Division of Gastroenterology, Division of Rheumatology, Allegheny Hepatology, and Nutrition, Allegheny Hepatology, and Nutrition, Allegheny Hepatology, and Nutrition, Allegheny Health Network, Pittsburgh, PA Health Network, Pittsburgh, PA Health Network, Pittsburgh, PA Health Network, Pittsburgh, PA Managing risks of TNF inhibitors: An update for the internist ■■ ABSTRACT iologic agents such as those that block B tumor necrosis factor (TNF) alpha have Tumor necrosis factor (TNF) inhibitors have many benefi- revolutionized the treatment of autoimmune cial effects, but they also pose infrequent but significant diseases like rheumatoid arthritis and inflam- risks, including serious infection and malignancy. These matory bowel disease, dramatically improving risks can be minimized by judicious patient selection, ap- disease control and quality of life. In addition, propriate screening, careful monitoring during treatment, they have made true disease remission possible and close communication between primary care physi- in some cases. However, as with any new therapy, a vari- cians and subspecialists. ety of side effects must be considered. ■■ KEY POINTS ■ WHAT ARE BIOLOGIC AGENTS? Over the past 10 years, TNF inhibitors have substantially altered the management of autoimmune diseases such as Biologic agents are genetically engineered rheumatoid arthritis and inflammatory bowel disease. drugs manufactured or synthesized in vitro from molecules such as proteins, genes, and antibodies present in living organisms. By tar- Safety concerns include risks of infection, reactivation of geting specific molecular components of the latent infection (eg, fungal infection, granulomatous infec- inflammatory cascade, including cytokines, tion), malignancy, and autoimmune and neurologic effects. these drugs alter certain aspects of the body’s inflammatory response in autoimmune diseas- Before treating, take a complete history, including expo- es. Because TNF inhibitors are the most widely sure to latent infections and geographic considerations, used biologic agents in the United States, this and bring patients’ immunizations up to date. review will focus on them. ■ TNF INHIBITORS Regular clinical and laboratory monitoring during treat- ment helps optimize therapy and minimize the risk of TNF inhibitors suppress the inflammatory cas- adverse effects. cade by inactivating TNF alpha, a cytokine that promotes inflammation in the intestine, Physicians must be aware of atypical presentations of synovial tissue, and other sites.1,2 infection and understand how their treatment may differ Several TNF inhibitors are available. Etan- in patients on biologic therapy. ercept and infliximab were the first two to receive US Food and Drug Administration (FDA) approval, and they are extensively used. Etanercept, a soluble TNF receptor giv- en subcutaneously, was approved for treating rheumatoid arthritis in 1998. Infliximab, a doi:10.3949/ccjm.81a.12121 chimeric monoclonal antibody (75% human CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 • NUMBER 2 FEBRUARY 2014 115 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. RISKS OF ANTI-TNF DRUGS Drugs mentioned in this article Take a focused history The clinical history should include inquiries acetaminophen (Tylenol) about previous bacterial, fungal, and tubercu- losis infections or exposure; diabetes; and oth- adalimumab (Humira) er immunocompromised states that increase certolizumab pegol (Cimzia) the risk of acquiring potentially life-threaten- diphenhydramine (Benadryl) ing infections. Details of particular geographic areas of entecavir (Baraclude) residence, occupational exposures, and social etanercept (Enbrel) history should be sought. These include histo- ry of incarceration (which may put patients at golimumab (Simponi) risk of tuberculosis) and residence in the Ohio infliximab (Remicade) River valley or in the southwestern or mid- western United States (which may increase lamivudine (Epivir) the risk of histoplasmosis, coccidioidomycosis, tenofovir (Viread) and other fungal infections). Bring vaccinations up to date and 25% mouse protein sequence) given in- Age-appropriate vaccinations should be dis- travenously, received FDA approval for treat- cussed and given, ideally before starting thera- ing Crohn disease in 1998 and for rheumatoid py. These include influenza vaccine every year arthritis in 1999. Other anti-TNF agents with and tetanus boosters every 10 years for all and, varying properties are also available. as appropriate, varicella, human papillomavi- TABLE 1 lists anti-TNF agents approved for rus, and pneumococcal vaccinations. The US treating rheumatoid arthritis and inflamma- Centers for Disease Control and Prevention tory bowel disease. These are chronic, relaps- recommend an additional dose of the pneu- ing diseases that significantly and dramati- mococcal vaccine if more than 5 years have TNF inhibitors cally reduce quality of life, especially when elapsed since the first one, and many clini- are for patients they are poorly controlled.3,4 Untreated cians opt to give it every 5 years. disease has been associated with malignan- In general, live-attenuated vaccines, in- with moderate cy, infection, pregnancy loss, and malnutri- cluding the intranasal influenza vaccine, are to severe tion.5–8 TNF inhibitors are aimed at patients contraindicated in patients taking biologic 9 disease who have moderate to severe disease or for agents. For patients at high risk of exposure whom previous treatments have failed, to or infection, it may be reasonable to hold the or for whom help them achieve and maintain steroid-free biologic agent for a period of time, vaccinate, previous remission. However, use of these agents is and resume the biologic agent a month later. tempered by the risk of potentially serious Recent data suggest that the varicella zos- treatments side effects. ter vaccine may be safely given to older pa- have failed Special thought should also be given to tients with immune-mediated diseases such as the direct costs of the drugs (up to $30,000 per rheumatoid arthritis and inflammatory bowel year, not counting the cost of their adminis- disease taking biologic agents.10 New guide- tration) and to the indirect costs such as time lines from the American College of Rheuma- away from work to receive treatment. These tology recommend age-appropriate vaccines are major considerations in some cases, and for rheumatoid arthritis patients age 60 and patients should be selected carefully for treat- older before biologic treatments are started. ment with these drugs. Case-by-case discussion with the subspecialist and the patient is recommended. ■ BEFORE STARTING THERAPY Screen for chronic infections Before starting anti-TNF therapy, several steps Tuberculosis screening with a purified pro- can reduce the risk of serious adverse events. tein derivative test or an interferon-gamma- release (Quantiferon) assay followed by chest 116 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 81 • NUMBER 2 FEBRUARY 2014 Downloaded from www.ccjm.org on September 25, 2021. For personal use only. All other uses require permission. HADAM AND COLLEAGUES TABLE 1 Anti-tumor necrosis factor agents Agent Mechanism of action Dosage schedule Approved indications* Infliximab Mouse chimeric monoclonal antibody Intravenously AS, CD, JIA, PP, PA, RA, UC to tumor necrosis factor (TNF) alpha every 6–8 weeks Etanercept Fully human soluble TNF receptor Subcutaneously AS, JIA, PP, PA, RA weekly Adalimumab Fully human monoclonal antibody Subcutaneously AS, CD, JIA, PP, PA, RA, UC against TNF alpha every other week Certolizumab Humanized Fab fragment directed Subcutaneously AS, CD, PA, RA pegol against TNF attached to two polyeth- every 4 weeks ylene glycol molecules Golimumab Human monoclonal antibody against Subcutaneously AS, PA, RA, UC TNF alpha every month *AS = ankylosing spondylitis, CD = Crohn disease, JIA = juvenile idiopathic arthritis, PA = psoriatic arthritis, PP = plaque psoriasis, RA = rheumatoid arthritis, UC = ulcerative colitis radiography in patients with a positive test is complete metabolic panel should be routinely mandatory before giving a TNF inhibitor. obtained before starting therapy (and thereaf- Hepatitis B virus status should be deter- ter at the discretion of the physician). In con- mined before starting anti-TNF therapy.11 junction with follow-up tests, they can help Hepatitis B vaccination has been recom- detect an unexpected decrease in white blood mended for patients with inflammatory bowel cell count or abnormal results on the liver In general, disease, but no clear recommendation exists panel.16 These baseline and follow-up tests are live-attenuated for patients with rheumatic disease. Patients generally performed by the subspecialist, and with inflammatory bowel disease tend to have the results are shared with the primary care vaccines are low rates of response to hepatitis B vaccina- physician. contraindicated 12,13 tion ; possible reasons include their lack TABLE 2 summarizes key information to be in patients of an appropriate innate immune response to sought before starting a patient on a TNF in- infectious agents, malnutrition, surgery, older hibitor. taking biologic age, and immunosuppressive
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