CONTINUING
MEDICAL EDUCATION
Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factorealfa antagonists Part I. Risks associated with tumor necrosis factor–alfa antagonists Lisa M. Chirch, MD,a Philip R. Cataline, MD,a Kevin D. Dieckhaus, MD,a and Jane M. Grant-Kels, MDb Farmington, Connecticut CME INSTRUCTIONS The following is a journal-based CME activity presented by the American Academy of Dermatology and is made up of four phases: 1. Reading of the CME Information (delineated below) 2. Reading of the Source Article 3. Achievement of a 70% or higher on the online Case-based Post Test 4. Completion of the Journal CME Evaluation CME INFORMATION AND DISCLOSURES Statement of Need: The American Academy of Dermatology bases its CME activities on the Academy’s core curriculum, identified professional practice gaps, the educational needs which underlie these gaps, and emerging clinical research findings. Learners should reflect upon clinical and scientific information presented in the article and determine the need for further study. Target Audience: Dermatologists and others involved in the delivery of dermatologic care. Accreditation The American Academy of Dermatology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Credit Designation The American Academy of Dermatology designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditsÔ. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AAD Recognized Credit This journal-based CME activity is recognized by the American Academy of Dermatology for 1 AAD Credit and may be used toward the American Academy of Dermatology’s Continuing Medical Education Award. Disclaimer: The American Academy of Dermatology is not responsible for statements made by the author(s). Statements or opinions expressed in this activity reflect the views of the author(s) and do not reflect the official policy of the American Academy of Dermatology. The information provided in this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to the diagnostic, management and treatment options of a specific patient’s medical condition. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors of this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners Dr Brodell is a planner and has reported the following financial relationships: Allergan, Speaker, Honorarium; Galderma, Consultant, Honorarium; Galderma, Speaker, Honorarium; Genentech, Principle Investigator, Honorarium; Pharmaderm, Speaker, Honorarium. The other peer-reviewer involved with this journal-based CME activity has reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Resolution of Conflicts of Interest In accordance with the ACCME Standards for Commercial Support of CME, the American Academy of Dermatology has implemented mechanisms, prior to the planning and implementation of this Journal-based CME activity, to identify and mitigate conflicts of interest for all individuals in a position to control the content of this Journal-based CME activity. Learning Objectives After completing this learning activity, participants should be able to describe the many infectious risks potentially associated with the use of biologic therapy for the
treatment of psoriasis and obtain appropriate historical data specific to the risks of various infectious entities. Date of release: July 2014 Expiration date: July 2017 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.01.875 Technical requirements: American Academy of Dermatology: d Supported browsers: FireFox (3 and higher), Google Chrome (5 and higher), Internet Explorer (7 and higher), Safari (5 and higher), Opera (10 and higher). d JavaScript needs to be enabled. Elsevier: Technical Requirements This website can be viewed on a PC or Mac. We recommend a minimum of: d PC: Windows NT, Windows 2000, Windows ME, or Windows XP d Mac: OS X d 128MB RAM d Processor speed of 500MHz or higher d 800x600 color monitor d Video or graphics card d Sound card and speakers Provider Contact Information: American Academy of Dermatology Phone: Toll-free: (866) 503-SKIN (7546); International: (847) 240-1280 Fax: (847) 240-1859 Mail: P.O. Box 4014; Schaumburg, IL 60168 Confidentiality Statement: American Academy of Dermatology: POLICY ON PRIVACY AND CONFIDENTIALITY Privacy Policy - The American Academy of Dermatology (the Academy) is committed to maintaining the privacy of the personal information of visitors to its sites. Our policies are designed to disclose the information collected and how it will be used. This policy applies solely to the information provided while visiting this website. The terms of the privacy policy do not govern personal information furnished through any means other than this website (such as by telephone or mail). E-mail Addresses and Other Personal Information - Personal information such as postal and e-mail address may be used internally for maintaining member records, marketing purposes, and alerting customers or members of additional services available. Phone numbers may also be used by the Academy when questions about products or services ordered arise. The Academy will not reveal any information about an individual user to third parties except to comply with applicable laws or valid legal processes. Cookies - A cookie is a small file stored on the site user’s computer or Web server and is used to aid Web navigation. Session cookies are temporary files created when a user signs in on the website or uses the personalized features (such as keeping track of items in the shopping cart). Session cookies are removed when a user logs off or when the browser is closed. Persistent cookies are permanent files and must be deleted manually. Tracking or other information collected from persistent cookies or any session cookie is used strictly for the user’s efficient navigation of the site. Links - This site may contain links to other sites. The Academy is not responsible for the privacy practices or the content of such websites. Children - This website is not designed or intended to attract children under the age of 13. The Academy does not collect personal information from anyone it knows is under the age of 13. Elsevier: http://www.elsevier.com/wps/find/privacypolicy.cws_home/privacypolicy
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Tumor necrosis factorealfa levels are linked to disease severity in patients with inflammatory conditions, such as psoriasis. Inhibitors of this cytokine are commonly used with significant success in the treatment of such inflammatory disorders. Their use, however, can be plagued by infectious complications. An awareness of potential infections associated with these therapies is critical in order to maximize preventive efforts both before and during therapy. This review provides a guide for dermatologists caring for patients in need of this type of biologic therapy to preemptively address the infectious risks. Part I of this continuing medical education article reviews background information on the various infectious risks associated with tumor necrosis factor inhibitor therapy and appropriate historical data to obtain in the context of pretherapy evaluations. ( J Am Acad Dermatol 2014;71:1.e1-8.) Key words: biologic therapy; endemic mycoses; opportunistic infection; psoriasis; tuberculosis; tumor necrosis factor.
INTRODUCTION Tumor necrosis factorealfa (TNFa) antagonists have revolutionized our approach to patients with life-altering inflammatory conditions, such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis. Levels of TNFa are increased in both the skin and serum of patients with psoriasis, correlate with disease severity, and return to normal after successful treatment.1 These therapies can be highly effective, but they can also be associated with significant infectious complications. Although relatively common illnesses predominate, such as upper respiratory tract infections, there are multiple infectious associations with pathogens, including bacteria, mycobacteria, fungi, viruses, and parasites. The tuberculosis risk for patients receiving tumor necrosis factor inhibitors (TNFIs) has prompted the addition of black box warnings to the labels of these agents. The existing literature to guide dermatologists in their evaluation of patients who are beginning TNFI therapy is not comprehensive. Much of this relates to the fact that the quality of evidence quantifying infectious risk is limited, especially for infectious agents that are unusual causes of illness in normal hosts. Many pathogenic associations with these medications are reported in postmarketing case reports and in other clinical disease states, such as rheumatoid arthritis and inflammatory bowel disease. It is important that the clinician be cognizant of the potential for infectious complications of TNFIs before therapy begins so that appropriate preventive measures may be undertaken to prevent future morbidity and mortality. We provide a framework From the Department of Medicine,a Division of Infectious Diseases, and the Department of Dermatology,b University of Connecticut Health Center, Farmington. Funding sources: None. Conflicts of interest: None declared.
for the dermatologist to address the many potential infection-related concerns before the initiation of biologic therapy.
POTENTIAL PATHOGENS IN TUMOR NECROSIS FACTOR INHIBITOR PATIENTS: ‘‘WHAT I NEED TO KNOW’’ Key points d
d
d
Dermatologists who are considering treating patients with severe psoriasis with tumor necrosis factor inhibitor therapy may not be familiar with the complex and diverse potential infectious complications associated with such therapy Knowledge of the specific risk factors associated with such entities results in more comprehensive pretherapeutic evaluation and may result in reduced morbidity associated with these therapies by informing preventive strategies A comprehensive baseline history directed at specific epidemiologic and exposure risks is critical for minimizing infectious complications associated with tumor necrosis factor inhibitor therapy
TNFa plays a critical role in the clearance of intracellular bacterial pathogens, such as Streptococcus pneumonia and Listeria monocytogenes.3 Patients receiving TNFI therapy therefore have a significantly increased risk of developing a serious infection with such pathogens. Infections with typical organisms have been described, such as streptococcal and staphylococcal species, including invasive, severe manifestations, such as necrotizing fasciitis.3,4
Correspondence to: Jane M. Grant-Kels, MD, University of Connecticut Health Center, Department of Dermatology, 21 South Rd, Farmington, CT 06032. E-mail: [email protected]. 0190-9622/$36.00
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Infection with atypical bacterial pathogens, such as Salmonella enteritidis and Legionella pneumophila, may be related to specific exposures, as discussed below. Some of the more common pathogens associated with TNFI therapy are Mycobacterium tuberculosis and the endemic mycoses. M tuberculosis infects one-third of the world’s population and causes 9 million new cases of tuberculosis and approximately 2 million deaths annually. The tuberculosis rate in foreign-born persons is 10 times higher than that in individuals born in the United States, and foreign-born persons now account for most of the reported cases in the United States. This is likely because of increasing immigration from countries with a high prevalence of tuberculosis—especially Mexico, the Philippines, Vietnam, India, and China, which account for [50% of foreign-born tuberculosis cases. Overall, developing nations are the most impacted with tuberculosis, and 12 countries account for 70% of all cases.2 M tuberculosis is an aerobic, nonespore-forming, nonmotile bacillus that is primarily spread by the inhalation of droplet nuclei from a person with pulmonary involvement after becoming aerosolized by coughing, sneezing, or talking.2 Most cases of tuberculosis are localized to the lungs, but approximately 15% to 20% of infections are extrapulmonary, most often affecting the lymph nodes and solid organs.3 The species M tuberculosis within the M tuberculosis complex causes the vast majority of human tuberculosis. Coccidioidomycosis is limited to the western hemisphere and is commonly found in the southwestern United States, including parts of California, Arizona, Nevada, New Mexico, and Texas (Fig 1). It is also found in northern Mexico and parts of Central and South America, such as Argentina and Paraguay, where the climate is similar to the locations in the United States. Infection with Coccidioides immitis, a dimorphic fungus, is acquired after inhalation of arthroconidia that are present in soil. Disease may develop after primary infection, and in normal hosts is usually subclinical or mild. Reactivation of dormant disease may also occur, and is more likely in immunodeficient persons. Primary clinical manifestations include acute respiratory infections, but extrapulmonary manifestations can occur in the skin, lymph nodes, bone, joints, or central nervous system.3,5 Histoplasmosis is an endemic mycosis found commonly in the United States. Histoplasma capsulatum is concentrated in the states bordering the Mississippi and Ohio River valleys, and focused pockets exist in multiple eastern states. It is also found throughout North and Central America and in
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many places around the world (Fig 1).5 Caused by the dimorphic fungus H capsulatum, it is acquired through the inhalation of microconidia (spores) and other fungal elements in the soil. Clinical disease may be primary, reactivated, or reinfection. Most patients with primary infection remain asymptomatic. The most common clinical presentation is pneumonia. The organism can also disseminate to the bones, joints, kidneys, endovascular sites, and the central nervous system (CNS).3,6,7 Blastomycosis is caused by the dimorphic fungus Blastomyces dermatitidis. B dermatitidis is found in the Mississippi and Ohio River valleys, parts of the United States and Canada near the Great Lakes, and the St Lawrence Seaway, as well as certain areas of Africa (Fig 1).8 Blastomycosis can be a subclinical illness, but it may present with progressive disease with either pulmonary or extrapulmonary involvement. Lung involvement may mimic bacterial pneumonia, although chronic presentations do exist. The skin is a common site of extrapulmonary disease, followed by bone, prostate, and CNS involvement.9 Chronic hepatitis B infection may be exacerbated by TNFI therapy.10,11 Hepatitis B is a DNA virus that affects [350 million people worldwide. Uncontrolled chronic hepatitis B infection can lead to complications, such as cirrhosis and hepatocellular carcinoma. It is endemic to certain regions of the world, and transmission often occurs at birth in these areas. It can also be readily transmitted by contact with infected bodily fluids, such as blood.12 Other bloodborne pathogens that can be associated with TNFI therapy include hepatitis C virus and HIV. These viruses can be transmitted to health care workers in a similar way to hepatitis B and via exposure to bodily fluids through unprotected sex or contaminated needles. Hepatitis C is an RNA virus that infects up to 2% of the US population and can lead to cirrhosis and hepatocellular carcinoma. The effect of TNFI therapy in patients with hepatitis C is unclear, but it has been theorized that it may be less concerning than in hepatitis B, and may even lead to improved outcomes.10 HIV is a retrovirus responsible for significant global morbidity and mortality. It causes immunosuppression via infection and destruction of immunoregulatory T cells, resulting in opportunistic infections. There has been general concern regarding the use of TNFI therapy in patients with HIV infection given the additional immunosuppression in an already compromised population. Although there are limited data regarding the safety of TNFI therapy in HIV-infected individuals, it appears to be relatively well-tolerated in select patients.10,13
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Fig 1. Areas of endemicity in the United States for coccidioidomycosis (orange), histoplasmosis (blue), and blastomycosis (green).
Because TNF is critical in the control of viral infection, it has been theorized that its blockade with TNFI therapy may increase the risk of acute or reactivation of other viral infections, such as herpesviruses, EpsteineBarr virus (EBV), cytomegalovirus (CMV), and varicella zoster virus (VZV).14 Cases of both primary and reactivation/disseminated CMV infection, including retinitis and colitis, have been reported in the literature in patients who are undergoing TNFI therapy, although the majority of these cases were either inflammatory bowel disease or arthritis.14,15 Leishmaniasis is one example of a rarer infection that has been associated with the use of TNFIs and a history of travel to endemic regions. Leishmaniasis is caused by a protozoan hemoflagellate transmitted by the bite of a sandfly. There are a variety of disease manifestations, including skin, mucous membrane, or even internal organ involvement, which depends on the host’s immunity and particular infecting species. In recent reports, most cases of visceral leishmaniasis occur in 6 countries: India, Bangladesh, Sudan, South Sudan, Brazil, and Ethiopia. Cutaneous leishmaniasis has a larger endemic area and is primarily found in 3 areas: the Americas, the Mediterranean, and western Asia from the Middle East to Central Asia.16 Recently, cases of opportunistic leishmaniasis in patients treated with TNFI therapy in Europe have been reported.17,18 There have also been case reports describing infections of Strongyloides stercoralis associated with TNFI therapy.19,20 S stercoralis is an intestinal
nematode that is acquired from skin contact with contaminated soil that is found in many tropical and subtropical areas, including Africa, Southeast Asia, Latin America, and parts of the southeastern United States. This organism can cause acute or chronic infections with primarily gastrointestinal, cutaneous, or pulmonary manifestations. A hyperinfection process can take place in patients with impaired immune function, where there is a rapid increase in parasite burden and dissemination to areas, such as the CNS, that are traditionally unaffected. This phenomenon can lead to complications, including sepsis, pneumonia, and meningitis.21 Other uncommon pathogens have been reported in patients receiving TNFI therapy. Of particular note, atypical bacteria found in soil, such as nocardia species and nontuberculous mycobacterial species (eg, Mycobacterium avium, Mycobacterium terrae, Mycobacterium chelonae, and Mycobacterium marinum) that may be inhaled or contaminate cutaneous injuries are important considerations.15
TAKING A HISTORY: ‘‘WHAT TO ASK FROM AN INFECTIOUS DISEASE PERSPECTIVE’’ A complete history should be performed during a patient encounter before the initiation of TNFI therapy. Given the risks, this should include a review of the indications for therapy and whether the patient has been recently ill or is experiencing symptoms that are possibly consistent with an active infectious process. There are a myriad of pathogens
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that can cause common or confusing symptoms; taking a thorough travel, social, and exposure history may provide the only clues as to the causative agent. Once TNFI therapy is considered, current or future infectious risks may be identified by a complete exposure history. In addition to a standard medical history, the patient should be questioned regarding a history of infections—even those that may have occurred in childhood and those of household members. Importantly, the clinician should elicit an accurate childhood vaccination history and adult vaccinations and international travelerelated vaccinations. Travel history and plans Obtaining a detailed travel history is one of the most important components of an effective infectious disease exposure history. It is important to obtain information regarding patients’ most recent travel experiences and those in the more remote past, including areas of prolonged residence. Future travel plans must be explored. Exposure to TNFI therapy may increase the risk of acquiring infections that may be acquired via travel or residence in certain endemic areas. Occupation Because the risk of infection with endemic mycoses in the setting of TNFI use is increased and these dimorphic fungi are present in soil, patients whose occupations bring them into contact with or during which they disturb the soil may be at risk. This may include activities such as farming, soil excavation, construction, or demolition.7 Health care workers may also be at increased risk for infectious complications of TNFI therapy by virtue of their interaction with patients harboring communicable diseases. One example is tuberculosis. Health care workers are more likely to encounter or care for patients with active tuberculosis. In the health care worker who is undergoing TNFI therapy, this is especially concerning. Bloodborne pathogens, such as hepatitis B and C and HIV, also present a concern in this setting. Another theoretical occupational infection concern is L pneumophila, a Gram-negative bacillus acquired from an aerosolized water source. Patients are exposed through the inhalational route after having contact with water fountains, air conditioners, or cooling towers that are colonized with these bacteria. Patients undergoing TNFI therapy in occupations in these settings may be at an increased risk of infection.3,22
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Hobbies and leisure activities Some hobbies or leisure activities may overlap with pathogens found in occupational activities, although the route of exposure may differ. For example, histoplasmosis can be associated with activities like spelunking (cave exploration) given the association of soil contaminated with bird or bat feces serving as nidus for the growth of this fungus.6,7 Other activities that disturb the soil as mentioned above can lead to a risk of fungal infection. There have been reports of infections, such as sporotrichosis, occurring in patients who are undergoing TNFI therapy.23 Sporothrix schenkii is another fungal pathogen that can reside in the soil and is commonly associated with farming or gardening. This disease classically presents with lymphangitis or pneumonitis.24 Diet A person’s diet may occasionally be the source of infection, such as the consumption of raw or undercooked meats or unpasteurized dairy products. One of the better-described associations of foodborne illness and TNFI therapy is listeriosis.25,26 Listeria monocytogenes is a Grampositive intracellular bacterium that usually affects the elderly, immunosuppressed hosts, pregnant females, or neonates. It can cause CNS disease, such as meningitis or cerebritis, or even sepsis.27 The disease has been linked to the consumption of processed meats or unpasteurized dairy products.28 There are also occasional sporadic outbreaks caused by nondairy foods, such as cantaloupe.29 Another foodborne pathogen with some link to TNFI therapy is salmonellosis.30 Salmonella is a genus of Gram-negative rods that causes gastroenteritis in normal hosts and bacteremia and osteomyelitis in compromised hosts.31 Foods that can be associated with salmonella infections include poultry, meats, and dairy products, such as eggs. Occasional food-specific outbreaks also occur.32 Animal exposures Contact with animals is a concern in patients who are initiating TNFI therapy. It is important to gather information regarding not only pets but also animals with which the patient may have experienced indirect contact (ie, rodents in the home). Some infections are transmitted between animals and humans (zoonoses), or the pathogen may reside in the animal’s environment. There have been a few pathogens that have been reported with patients receiving TNFI therapy. H capsulatum can be found in soil contaminated with bird or bat
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Table I. Example of patient-administered history flow sheet designed to elicit important information related to potential infectious complications of tumor necrosis factorealfa inhibitor therapy Exposure
Yes
No
Comments
Travel/residence Have you traveled or lived outside the United States? (Please list) Have you lived outside of (state or residence)? Where? When? Do you have future international travel plans? Does your home have known mold problems? Well water? Animals/pets Do you have any pets in the home, including fish? Have you had recent contact with farm animals? Wild animals or birds? Occupation What do you do for a living? Do you ever work outdoors? In the course of your work, do you disturb soil or participate in construction or demolition? Are you involved in health care? Are you a caretaker for the very young or elderly? Hobbies/behavioral Do you spend a lot of time outdoors? Do you garden? Wear gloves? Do you spend time in caves? Go spelunking? Do you have a lot of freshwater or saltwater exposure? Do you smoke cigarettes? Drink alcohol? Have you ever used drugs? Shared needles? Have you ever had a blood transfusion? Do you have any tattoos? Dietary Do you consume unpasteurized dairy products? Do you consume undercooked or raw meats or fish? Do you consume processed meats, including deli meats or hot dogs? Do you consume soft cheeses? Sexual Have you ever been tested for HIV or hepatitis? Have you had multiple sexual partners? Men, women, or both? Do you have any history of sexually transmitted infections, including herpes (oral or genital), syphilis, gonorrhea, or chlamydia? Have you ever had an abnormal Pap smear?
droppings. Patients who own chickens or spend time near chicken coops, for example, could be at risk. In addition, this fungus is associated with bat droppings from other bird species.7 Cryptococcus, a ubiquitous environmental encapsulated fungus, has also been associated with the use of TNFI. Cryptococcus neoformans can cause CNS, pulmonary, or disseminated infections, usually in immunocompromised hosts. The fungus can be found around bird roosting sites and also has been particularly associated with pigeon droppings.33 There appears to be an increased incidence of nontuberculous mycobacteria in the TNFI-treated patient. One species patients may encounter from pets is M marinum. M marinum is an acid-fast bacterium that typically lives in an aquatic environment. It can cause solitary or multiple skin lesions, usually on the extremities, after breaks in the
skin are exposed to ocean, salt, or fresh aquarium water. Accordingly, these lesions are commonly called ‘‘fish-tank granulomas.’’ Patients with nontuberculous mycobacteria who are undergoing TNFI therapy are more likely to have disseminated manifestations.34-36 There have been reports of toxoplasmosis occurring in patients who are undergoing TNFI therapy. Toxoplasmosis is caused by the protozoan Toxoplasma gondii.37,38 The primary host of this parasite is the cat family. Humans are usually infected primarily through the consumption of infected meat or hand contamination with cat feces (ie, cleaning litter boxes). Patients who become symptomatic after exposure develop a subclinical or mild influenza or mononucleosis-like illness. Afterward, healthy adults rarely experience any additional symptoms. The parasite can reactivate in
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the setting of immunosuppression and disseminate to the CNS, eyes, heart, liver, or lungs.39 Salmonella infections have been associated with animal exposures, including pets. A higher incidence of salmonella infection has been observed in patients with pet reptiles (eg, lizards, snakes, and turtles) or amphibians (eg, frogs).40,41 Sexual history Clinicians should obtain a comprehensive sexual history in order to identify possible sexually transmitted infections and to address risk factors. HIV and hepatitis B and C may be sexually transmitted; links between these viral pathogens and TNFI were discussed above. Human papillomavirus (HPV) infections may also be affected by TNFIs. HPV, a DNA virus responsible for infections of the skin and mucus membranes, manifests most commonly as warts, including anogenital condyloma. Certain strains are associated with malignancies of the cervix, vulva, penis, anus, and oropharynx. HPV is one of the most common sexually transmitted infections.42 There have been limited reports that TNFI may worsen anogenital warts, but there is no evidence at this time that they increase the incidence of the cancers associated with this virus.43 Herpes simplex virus in a normal host can cause recurrent oral or genital lesions but occasionally is responsible for CNS infections. There have been a small number of reports of patients treated with TNFIs who developed herpes encephalitis.44 Table I shows an example of a patientadministered history flow sheet that is designed to elicit important information related to potential infectious complications of TNFI therapy.
2.
3.
4.
5. 6. 7. 8.
9. 10.
11.
12. 13.
14. 15.
CONCLUSION The advent of biologic therapies, including inhibitors of TNFa, represents an important advance in the management of refractory dermatologic inflammatory conditions, such as psoriasis. However, it is important to consider their mechanisms of action, their many intricate effects on immune function, and the potential for infectious consequences. Similar to patients anticipating solid or bone marrow transplantation and associated immunosuppression, it is critical to consider patients’ medical and surgical histories, exposures, travel and immunization history, and to tailor necessary preventive interventions before proceeding with such therapies. REFERENCES 1. American Academy of Dermatology Work Group: Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, et al. Guidelines of care for the management of psoriasis and
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21. 22.
psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol 2011;65:137-74. Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Vol 1. 7th ed. Philadelphia: Churchill Livingstone; 2010. Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-alpha antagonists. Medicine (Baltimore) 2005;84:291-302. Chan AT, Cleeve V, Daymond TJ. Necrotizing fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J 2002;78:47-8. Parish JM, Blair JE. Coccidioidomycosis. Mayo Clin Proc 2008; 83:343-8. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007;20:115-32. Wheat LJ, Kauffman CA. Histoplasmosis. Infect Dis Clin North Am 2003;17:1-19. Smith JA, Kauffman CA. Endemic fungal infections in patients receiving tumour necrosis factor-alpha inhibitor therapy. Drugs 2009;69:1403-15. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am 2003;17:21-40. Shale MJ, Seow CH, Coffin CS, Kaplan GG, Panaccione R, Ghosh S. Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease. Aliment Pharmacol Ther 2010;31:20-34. Abramson A, Menter A, Perrillo R. Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: a review and recommendations for management. J Am Acad Dermatol 2012;67:1349-61. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45: 507-39. Cepeda EJ, Williams FM, Ishimori ML, Weisman MH, Reveille JD. The use of anti-tumour necrosis factor therapy in HIV-positive individuals with rheumatic disease. Ann Rheum Dis 2008;67:710-2. Kim SY, Solomon DH. Tumor necrosis factor bloackade and the risk of viral infection. Nat Rev Rheumatol 2010;6:165-74. Salmon-Ceron D, Tubach F, Lortholary O, Chosidow O, Bretagne S, Nicolas N, et al. Drug specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3 year prospective French RATIO registry. Ann Rheum Dis 2011;70:616-23. Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One 2012;7:e35671. Garcia-Gonzalez E, Guidelli GM, Bardelli M, Maggio R. Mucocutaneous leishmaniasis in a patient treated with anti-TNF-a therapy. Rheumatology (Oxford) 2012;51:1517-8. Zanger P, Kotter I, Kremsner PG, Gabrysch S. Tumor necrosis factor alpha antagonist drugs and leishmaniasis in Europe. Clin Microbiol Infect 2012;18:670-6. Boatright MD, Wang BW. Clinical infection with Strongyloides sterocoralis following etanercept use for rheumatoid arthritis. Arthritis Rheum 2005;52:1336-7. Krishnamurthy R, Dincer HE, Whittemore D. Strongyloides stercoralis hyperinfection in a patient with rheumatoid arthritis after anti-TNF-alpha therapy. J Clin Rheumatol 2007; 13:150-2. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis 2001;33:1040-7. Tubach F, Ravaud P, Salmon-Ceron D, Petitpain N, Brocq O, Grados F, et al. Emergence of Legionella pneumophila
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pneumonia in patients receiving tumor necrosis factor-alpha antagonists. Clin Infect Dis 2006;43:e95-100. Gottlieb GS, Lesser CF, Holmes KK, Wald A. Disseminated sporotrichosis associated with treatment with immunosuppressants and tumor necrosis factor-alpha antagonists. Clin Infect Dis 2003;37:838-40. Barros MB, de Almeida Paes R, Schubach AO. Sporothrix schenckii and Sporotrichosis. Clin Microbiol Rev 2011;24:633-54. Slifman NR, Gershon SK, Lee JH, Edwards ET, Braun MM. Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor alpha-neutralizing agents. Arthritis Rheum 2003;48:319-24. Pena-Sagredo JL, Hernandez MV, Fernandez-Llanio N, Gimenez-Ubeda E, Munoz-Fernandez S, Ortiz A, et al. Listeria monocytogenes infection in patients with rheumatic diseases on TNF-alpha antagonist therapy: the Spanish Study Group experience. Clin Exp Rheumatol 2008;26:854-9. Schuchat A, Swaminathan B, Broome CV. Epidemiology of human listeriosis. Clin Microbiol Rev 1991;4:169-83. Cartwright EJ, Jackson KA, Johnson SD, Graves LM, Silk BJ, Mahon BE. Listeriosis outbreaks and associated food vehicles, United States, 1998-2008. Emerg Infect Dis 2013;19:1-9. Centers for Disease Control and Prevention. Multistate outbreak of listeriosis associated with Jensen Farms cantaloupe—United States, August-September 2011. MMWR Morb Mortal Wkly Rep 2011;60:1357-8. Qutre A, Demoux AL, Soussan J, Frances Y, Rossi P. Clinical image: salmonella mycotic aneurysm in a patient receiving etanercept for rheumatoid arthritis. Arthritis Rheum 2012;64:942. Gordon MA. Salmonella infections in immunocompromised adults. J Infect 2008;56:413-22. Centers for Disease Control and Prevention. Surveillance for foodborne disease outbreaks—United States, 2009-2010. MMWR Morb Mortal Wkly Rep 2013;62:41-7. Negroni R. Cryptococcosis. Clin Dermatol 2012;30:599-609. Caron J, Michot C, Fabre S, Godreuil S, Guillot B, Dereure O. Aggressive cutaneous infection with Mycobacterium marinum
35.
36.
37. 38.
39. 40.
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42.
43.
44.
in two patients receiving anti-tumor necrosis factor-alfa agents. J Am Acad Dermatol 2011;65:1060-2. Ferreira J, Grochowsky J, Krakower D, Zuromskis P, Baden R, Cheifetz AS. Mycobacterium marinum: an increasingly common opportunistic infection in patients on infliximab. Am J Gastroenterol 2012;107:1268-9. Kump PK, Hogenauer C, Wenzl HH, Petritsch W. A case of opportunistic skin infection with Mycobacterium marinum during adalimumab treatment in a patient with Crohn’s disease. J Crohns Colitis 2013;7:e15-8. Young JD, McGwire BS. Infliximab and reactivation of cerebral toxoplasmosis. N Engl J Med 2005;353:1530-1. Lassoued S, Zabraniecki L, Marin F, Billey T. Toxoplasmic chorioretinitis and antitumor necrosis factor treatment in rheumatoid arthritis. Semin Arthritis Rheum 2007;36:262-3. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet 2004;363: 1965-76. Centers for Disease Control and Prevention. Multistate outbreak of human Salmonella typhimurium infections associated with aquatic frogs—United States, 2009. MMWR Morb Mortal Wkly Rep 2010;58:1433-6. Mermin J, Hutwagner L, Vugia D, Shallow S, Daily P, Bender J, et al. Reptiles, amphibians, and human Salmonella infection: a population-based, case-control study. Clin Infect Dis 2004; 38(suppl 3):S253-61. Dunne EF, Friedman A, Datta SD, Markowitz LE, Workowski KA. Updates on human papillomavirus and genital warts and counseling messages from the 2010 Sexually Transmitted Diseases Treatment Guidelines. Clin Infect Dis 2011;53(suppl 3):S143-52. Nordgaard-Lassen I, Dahlerup JF, Belard E, Gerstoft J, Kjeldsen J, Kragballe K, et al. Guidelines for screening, prophylaxis and critical information prior to initiating anti-TNF-alpha treatment. Dan Med J 2012;59:C4480. Bradford RD, Pettit AC, Wright PW, Mulligan MJ, Moreland LW, McLain DA, et al. Herpes simplex encephalitis during treatment with tumor necrosis factor-alpha inhibitors. Clin Infect Dis 2009;49:924-7.
To claim CME credit, complete this case-based posttest online at http://www.aad.org/JAAD/. Note: CME quizzes are available after the first of the month in which the article is published. A minimum score of 70% must be achieved to claim CME credit. If you have any questions, please contact the Member Resource Center of the American Academy of Dermatology at toll-free (866) 503-SKIN (7546), (847), 240-1280 (for international members), or by e-mailing [email protected].
CME examination Identification No. JA0714 July 2014 issue of the Journal of the American Academy of Dermatology.
Chirch LM, Cataline PR, Dieckhaus KD, Grant-Kels JM. J Am Acad Dermatol 2014;71:1-8.
MEDICAL EDUCATION
Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factorealfa antagonists Part I. Risks associated with tumor necrosis factor–alfa antagonists Lisa M. Chirch, MD,a Philip R. Cataline, MD,a Kevin D. Dieckhaus, MD,a and Jane M. Grant-Kels, MDb Farmington, Connecticut CME INSTRUCTIONS The following is a journal-based CME activity presented by the American Academy of Dermatology and is made up of four phases: 1. Reading of the CME Information (delineated below) 2. Reading of the Source Article 3. Achievement of a 70% or higher on the online Case-based Post Test 4. Completion of the Journal CME Evaluation CME INFORMATION AND DISCLOSURES Statement of Need: The American Academy of Dermatology bases its CME activities on the Academy’s core curriculum, identified professional practice gaps, the educational needs which underlie these gaps, and emerging clinical research findings. Learners should reflect upon clinical and scientific information presented in the article and determine the need for further study. Target Audience: Dermatologists and others involved in the delivery of dermatologic care. Accreditation The American Academy of Dermatology is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. AMA PRA Credit Designation The American Academy of Dermatology designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditsÔ. Physicians should claim only the credit commensurate with the extent of their participation in the activity. AAD Recognized Credit This journal-based CME activity is recognized by the American Academy of Dermatology for 1 AAD Credit and may be used toward the American Academy of Dermatology’s Continuing Medical Education Award. Disclaimer: The American Academy of Dermatology is not responsible for statements made by the author(s). Statements or opinions expressed in this activity reflect the views of the author(s) and do not reflect the official policy of the American Academy of Dermatology. The information provided in this CME activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to the diagnostic, management and treatment options of a specific patient’s medical condition. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors of this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners Dr Brodell is a planner and has reported the following financial relationships: Allergan, Speaker, Honorarium; Galderma, Consultant, Honorarium; Galderma, Speaker, Honorarium; Genentech, Principle Investigator, Honorarium; Pharmaderm, Speaker, Honorarium. The other peer-reviewer involved with this journal-based CME activity has reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Resolution of Conflicts of Interest In accordance with the ACCME Standards for Commercial Support of CME, the American Academy of Dermatology has implemented mechanisms, prior to the planning and implementation of this Journal-based CME activity, to identify and mitigate conflicts of interest for all individuals in a position to control the content of this Journal-based CME activity. Learning Objectives After completing this learning activity, participants should be able to describe the many infectious risks potentially associated with the use of biologic therapy for the
treatment of psoriasis and obtain appropriate historical data specific to the risks of various infectious entities. Date of release: July 2014 Expiration date: July 2017 Ó 2014 by the American Academy of Dermatology, Inc. http://dx.doi.org/10.1016/j.jaad.2014.01.875 Technical requirements: American Academy of Dermatology: d Supported browsers: FireFox (3 and higher), Google Chrome (5 and higher), Internet Explorer (7 and higher), Safari (5 and higher), Opera (10 and higher). d JavaScript needs to be enabled. Elsevier: Technical Requirements This website can be viewed on a PC or Mac. We recommend a minimum of: d PC: Windows NT, Windows 2000, Windows ME, or Windows XP d Mac: OS X d 128MB RAM d Processor speed of 500MHz or higher d 800x600 color monitor d Video or graphics card d Sound card and speakers Provider Contact Information: American Academy of Dermatology Phone: Toll-free: (866) 503-SKIN (7546); International: (847) 240-1280 Fax: (847) 240-1859 Mail: P.O. Box 4014; Schaumburg, IL 60168 Confidentiality Statement: American Academy of Dermatology: POLICY ON PRIVACY AND CONFIDENTIALITY Privacy Policy - The American Academy of Dermatology (the Academy) is committed to maintaining the privacy of the personal information of visitors to its sites. Our policies are designed to disclose the information collected and how it will be used. This policy applies solely to the information provided while visiting this website. The terms of the privacy policy do not govern personal information furnished through any means other than this website (such as by telephone or mail). E-mail Addresses and Other Personal Information - Personal information such as postal and e-mail address may be used internally for maintaining member records, marketing purposes, and alerting customers or members of additional services available. Phone numbers may also be used by the Academy when questions about products or services ordered arise. The Academy will not reveal any information about an individual user to third parties except to comply with applicable laws or valid legal processes. Cookies - A cookie is a small file stored on the site user’s computer or Web server and is used to aid Web navigation. Session cookies are temporary files created when a user signs in on the website or uses the personalized features (such as keeping track of items in the shopping cart). Session cookies are removed when a user logs off or when the browser is closed. Persistent cookies are permanent files and must be deleted manually. Tracking or other information collected from persistent cookies or any session cookie is used strictly for the user’s efficient navigation of the site. Links - This site may contain links to other sites. The Academy is not responsible for the privacy practices or the content of such websites. Children - This website is not designed or intended to attract children under the age of 13. The Academy does not collect personal information from anyone it knows is under the age of 13. Elsevier: http://www.elsevier.com/wps/find/privacypolicy.cws_home/privacypolicy
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Tumor necrosis factorealfa levels are linked to disease severity in patients with inflammatory conditions, such as psoriasis. Inhibitors of this cytokine are commonly used with significant success in the treatment of such inflammatory disorders. Their use, however, can be plagued by infectious complications. An awareness of potential infections associated with these therapies is critical in order to maximize preventive efforts both before and during therapy. This review provides a guide for dermatologists caring for patients in need of this type of biologic therapy to preemptively address the infectious risks. Part I of this continuing medical education article reviews background information on the various infectious risks associated with tumor necrosis factor inhibitor therapy and appropriate historical data to obtain in the context of pretherapy evaluations. ( J Am Acad Dermatol 2014;71:1.e1-8.) Key words: biologic therapy; endemic mycoses; opportunistic infection; psoriasis; tuberculosis; tumor necrosis factor.
INTRODUCTION Tumor necrosis factorealfa (TNFa) antagonists have revolutionized our approach to patients with life-altering inflammatory conditions, such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis. Levels of TNFa are increased in both the skin and serum of patients with psoriasis, correlate with disease severity, and return to normal after successful treatment.1 These therapies can be highly effective, but they can also be associated with significant infectious complications. Although relatively common illnesses predominate, such as upper respiratory tract infections, there are multiple infectious associations with pathogens, including bacteria, mycobacteria, fungi, viruses, and parasites. The tuberculosis risk for patients receiving tumor necrosis factor inhibitors (TNFIs) has prompted the addition of black box warnings to the labels of these agents. The existing literature to guide dermatologists in their evaluation of patients who are beginning TNFI therapy is not comprehensive. Much of this relates to the fact that the quality of evidence quantifying infectious risk is limited, especially for infectious agents that are unusual causes of illness in normal hosts. Many pathogenic associations with these medications are reported in postmarketing case reports and in other clinical disease states, such as rheumatoid arthritis and inflammatory bowel disease. It is important that the clinician be cognizant of the potential for infectious complications of TNFIs before therapy begins so that appropriate preventive measures may be undertaken to prevent future morbidity and mortality. We provide a framework From the Department of Medicine,a Division of Infectious Diseases, and the Department of Dermatology,b University of Connecticut Health Center, Farmington. Funding sources: None. Conflicts of interest: None declared.
for the dermatologist to address the many potential infection-related concerns before the initiation of biologic therapy.
POTENTIAL PATHOGENS IN TUMOR NECROSIS FACTOR INHIBITOR PATIENTS: ‘‘WHAT I NEED TO KNOW’’ Key points d
d
d
Dermatologists who are considering treating patients with severe psoriasis with tumor necrosis factor inhibitor therapy may not be familiar with the complex and diverse potential infectious complications associated with such therapy Knowledge of the specific risk factors associated with such entities results in more comprehensive pretherapeutic evaluation and may result in reduced morbidity associated with these therapies by informing preventive strategies A comprehensive baseline history directed at specific epidemiologic and exposure risks is critical for minimizing infectious complications associated with tumor necrosis factor inhibitor therapy
TNFa plays a critical role in the clearance of intracellular bacterial pathogens, such as Streptococcus pneumonia and Listeria monocytogenes.3 Patients receiving TNFI therapy therefore have a significantly increased risk of developing a serious infection with such pathogens. Infections with typical organisms have been described, such as streptococcal and staphylococcal species, including invasive, severe manifestations, such as necrotizing fasciitis.3,4
Correspondence to: Jane M. Grant-Kels, MD, University of Connecticut Health Center, Department of Dermatology, 21 South Rd, Farmington, CT 06032. E-mail: [email protected]. 0190-9622/$36.00
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Infection with atypical bacterial pathogens, such as Salmonella enteritidis and Legionella pneumophila, may be related to specific exposures, as discussed below. Some of the more common pathogens associated with TNFI therapy are Mycobacterium tuberculosis and the endemic mycoses. M tuberculosis infects one-third of the world’s population and causes 9 million new cases of tuberculosis and approximately 2 million deaths annually. The tuberculosis rate in foreign-born persons is 10 times higher than that in individuals born in the United States, and foreign-born persons now account for most of the reported cases in the United States. This is likely because of increasing immigration from countries with a high prevalence of tuberculosis—especially Mexico, the Philippines, Vietnam, India, and China, which account for [50% of foreign-born tuberculosis cases. Overall, developing nations are the most impacted with tuberculosis, and 12 countries account for 70% of all cases.2 M tuberculosis is an aerobic, nonespore-forming, nonmotile bacillus that is primarily spread by the inhalation of droplet nuclei from a person with pulmonary involvement after becoming aerosolized by coughing, sneezing, or talking.2 Most cases of tuberculosis are localized to the lungs, but approximately 15% to 20% of infections are extrapulmonary, most often affecting the lymph nodes and solid organs.3 The species M tuberculosis within the M tuberculosis complex causes the vast majority of human tuberculosis. Coccidioidomycosis is limited to the western hemisphere and is commonly found in the southwestern United States, including parts of California, Arizona, Nevada, New Mexico, and Texas (Fig 1). It is also found in northern Mexico and parts of Central and South America, such as Argentina and Paraguay, where the climate is similar to the locations in the United States. Infection with Coccidioides immitis, a dimorphic fungus, is acquired after inhalation of arthroconidia that are present in soil. Disease may develop after primary infection, and in normal hosts is usually subclinical or mild. Reactivation of dormant disease may also occur, and is more likely in immunodeficient persons. Primary clinical manifestations include acute respiratory infections, but extrapulmonary manifestations can occur in the skin, lymph nodes, bone, joints, or central nervous system.3,5 Histoplasmosis is an endemic mycosis found commonly in the United States. Histoplasma capsulatum is concentrated in the states bordering the Mississippi and Ohio River valleys, and focused pockets exist in multiple eastern states. It is also found throughout North and Central America and in
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many places around the world (Fig 1).5 Caused by the dimorphic fungus H capsulatum, it is acquired through the inhalation of microconidia (spores) and other fungal elements in the soil. Clinical disease may be primary, reactivated, or reinfection. Most patients with primary infection remain asymptomatic. The most common clinical presentation is pneumonia. The organism can also disseminate to the bones, joints, kidneys, endovascular sites, and the central nervous system (CNS).3,6,7 Blastomycosis is caused by the dimorphic fungus Blastomyces dermatitidis. B dermatitidis is found in the Mississippi and Ohio River valleys, parts of the United States and Canada near the Great Lakes, and the St Lawrence Seaway, as well as certain areas of Africa (Fig 1).8 Blastomycosis can be a subclinical illness, but it may present with progressive disease with either pulmonary or extrapulmonary involvement. Lung involvement may mimic bacterial pneumonia, although chronic presentations do exist. The skin is a common site of extrapulmonary disease, followed by bone, prostate, and CNS involvement.9 Chronic hepatitis B infection may be exacerbated by TNFI therapy.10,11 Hepatitis B is a DNA virus that affects [350 million people worldwide. Uncontrolled chronic hepatitis B infection can lead to complications, such as cirrhosis and hepatocellular carcinoma. It is endemic to certain regions of the world, and transmission often occurs at birth in these areas. It can also be readily transmitted by contact with infected bodily fluids, such as blood.12 Other bloodborne pathogens that can be associated with TNFI therapy include hepatitis C virus and HIV. These viruses can be transmitted to health care workers in a similar way to hepatitis B and via exposure to bodily fluids through unprotected sex or contaminated needles. Hepatitis C is an RNA virus that infects up to 2% of the US population and can lead to cirrhosis and hepatocellular carcinoma. The effect of TNFI therapy in patients with hepatitis C is unclear, but it has been theorized that it may be less concerning than in hepatitis B, and may even lead to improved outcomes.10 HIV is a retrovirus responsible for significant global morbidity and mortality. It causes immunosuppression via infection and destruction of immunoregulatory T cells, resulting in opportunistic infections. There has been general concern regarding the use of TNFI therapy in patients with HIV infection given the additional immunosuppression in an already compromised population. Although there are limited data regarding the safety of TNFI therapy in HIV-infected individuals, it appears to be relatively well-tolerated in select patients.10,13
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Fig 1. Areas of endemicity in the United States for coccidioidomycosis (orange), histoplasmosis (blue), and blastomycosis (green).
Because TNF is critical in the control of viral infection, it has been theorized that its blockade with TNFI therapy may increase the risk of acute or reactivation of other viral infections, such as herpesviruses, EpsteineBarr virus (EBV), cytomegalovirus (CMV), and varicella zoster virus (VZV).14 Cases of both primary and reactivation/disseminated CMV infection, including retinitis and colitis, have been reported in the literature in patients who are undergoing TNFI therapy, although the majority of these cases were either inflammatory bowel disease or arthritis.14,15 Leishmaniasis is one example of a rarer infection that has been associated with the use of TNFIs and a history of travel to endemic regions. Leishmaniasis is caused by a protozoan hemoflagellate transmitted by the bite of a sandfly. There are a variety of disease manifestations, including skin, mucous membrane, or even internal organ involvement, which depends on the host’s immunity and particular infecting species. In recent reports, most cases of visceral leishmaniasis occur in 6 countries: India, Bangladesh, Sudan, South Sudan, Brazil, and Ethiopia. Cutaneous leishmaniasis has a larger endemic area and is primarily found in 3 areas: the Americas, the Mediterranean, and western Asia from the Middle East to Central Asia.16 Recently, cases of opportunistic leishmaniasis in patients treated with TNFI therapy in Europe have been reported.17,18 There have also been case reports describing infections of Strongyloides stercoralis associated with TNFI therapy.19,20 S stercoralis is an intestinal
nematode that is acquired from skin contact with contaminated soil that is found in many tropical and subtropical areas, including Africa, Southeast Asia, Latin America, and parts of the southeastern United States. This organism can cause acute or chronic infections with primarily gastrointestinal, cutaneous, or pulmonary manifestations. A hyperinfection process can take place in patients with impaired immune function, where there is a rapid increase in parasite burden and dissemination to areas, such as the CNS, that are traditionally unaffected. This phenomenon can lead to complications, including sepsis, pneumonia, and meningitis.21 Other uncommon pathogens have been reported in patients receiving TNFI therapy. Of particular note, atypical bacteria found in soil, such as nocardia species and nontuberculous mycobacterial species (eg, Mycobacterium avium, Mycobacterium terrae, Mycobacterium chelonae, and Mycobacterium marinum) that may be inhaled or contaminate cutaneous injuries are important considerations.15
TAKING A HISTORY: ‘‘WHAT TO ASK FROM AN INFECTIOUS DISEASE PERSPECTIVE’’ A complete history should be performed during a patient encounter before the initiation of TNFI therapy. Given the risks, this should include a review of the indications for therapy and whether the patient has been recently ill or is experiencing symptoms that are possibly consistent with an active infectious process. There are a myriad of pathogens
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that can cause common or confusing symptoms; taking a thorough travel, social, and exposure history may provide the only clues as to the causative agent. Once TNFI therapy is considered, current or future infectious risks may be identified by a complete exposure history. In addition to a standard medical history, the patient should be questioned regarding a history of infections—even those that may have occurred in childhood and those of household members. Importantly, the clinician should elicit an accurate childhood vaccination history and adult vaccinations and international travelerelated vaccinations. Travel history and plans Obtaining a detailed travel history is one of the most important components of an effective infectious disease exposure history. It is important to obtain information regarding patients’ most recent travel experiences and those in the more remote past, including areas of prolonged residence. Future travel plans must be explored. Exposure to TNFI therapy may increase the risk of acquiring infections that may be acquired via travel or residence in certain endemic areas. Occupation Because the risk of infection with endemic mycoses in the setting of TNFI use is increased and these dimorphic fungi are present in soil, patients whose occupations bring them into contact with or during which they disturb the soil may be at risk. This may include activities such as farming, soil excavation, construction, or demolition.7 Health care workers may also be at increased risk for infectious complications of TNFI therapy by virtue of their interaction with patients harboring communicable diseases. One example is tuberculosis. Health care workers are more likely to encounter or care for patients with active tuberculosis. In the health care worker who is undergoing TNFI therapy, this is especially concerning. Bloodborne pathogens, such as hepatitis B and C and HIV, also present a concern in this setting. Another theoretical occupational infection concern is L pneumophila, a Gram-negative bacillus acquired from an aerosolized water source. Patients are exposed through the inhalational route after having contact with water fountains, air conditioners, or cooling towers that are colonized with these bacteria. Patients undergoing TNFI therapy in occupations in these settings may be at an increased risk of infection.3,22
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Hobbies and leisure activities Some hobbies or leisure activities may overlap with pathogens found in occupational activities, although the route of exposure may differ. For example, histoplasmosis can be associated with activities like spelunking (cave exploration) given the association of soil contaminated with bird or bat feces serving as nidus for the growth of this fungus.6,7 Other activities that disturb the soil as mentioned above can lead to a risk of fungal infection. There have been reports of infections, such as sporotrichosis, occurring in patients who are undergoing TNFI therapy.23 Sporothrix schenkii is another fungal pathogen that can reside in the soil and is commonly associated with farming or gardening. This disease classically presents with lymphangitis or pneumonitis.24 Diet A person’s diet may occasionally be the source of infection, such as the consumption of raw or undercooked meats or unpasteurized dairy products. One of the better-described associations of foodborne illness and TNFI therapy is listeriosis.25,26 Listeria monocytogenes is a Grampositive intracellular bacterium that usually affects the elderly, immunosuppressed hosts, pregnant females, or neonates. It can cause CNS disease, such as meningitis or cerebritis, or even sepsis.27 The disease has been linked to the consumption of processed meats or unpasteurized dairy products.28 There are also occasional sporadic outbreaks caused by nondairy foods, such as cantaloupe.29 Another foodborne pathogen with some link to TNFI therapy is salmonellosis.30 Salmonella is a genus of Gram-negative rods that causes gastroenteritis in normal hosts and bacteremia and osteomyelitis in compromised hosts.31 Foods that can be associated with salmonella infections include poultry, meats, and dairy products, such as eggs. Occasional food-specific outbreaks also occur.32 Animal exposures Contact with animals is a concern in patients who are initiating TNFI therapy. It is important to gather information regarding not only pets but also animals with which the patient may have experienced indirect contact (ie, rodents in the home). Some infections are transmitted between animals and humans (zoonoses), or the pathogen may reside in the animal’s environment. There have been a few pathogens that have been reported with patients receiving TNFI therapy. H capsulatum can be found in soil contaminated with bird or bat
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Table I. Example of patient-administered history flow sheet designed to elicit important information related to potential infectious complications of tumor necrosis factorealfa inhibitor therapy Exposure
Yes
No
Comments
Travel/residence Have you traveled or lived outside the United States? (Please list) Have you lived outside of (state or residence)? Where? When? Do you have future international travel plans? Does your home have known mold problems? Well water? Animals/pets Do you have any pets in the home, including fish? Have you had recent contact with farm animals? Wild animals or birds? Occupation What do you do for a living? Do you ever work outdoors? In the course of your work, do you disturb soil or participate in construction or demolition? Are you involved in health care? Are you a caretaker for the very young or elderly? Hobbies/behavioral Do you spend a lot of time outdoors? Do you garden? Wear gloves? Do you spend time in caves? Go spelunking? Do you have a lot of freshwater or saltwater exposure? Do you smoke cigarettes? Drink alcohol? Have you ever used drugs? Shared needles? Have you ever had a blood transfusion? Do you have any tattoos? Dietary Do you consume unpasteurized dairy products? Do you consume undercooked or raw meats or fish? Do you consume processed meats, including deli meats or hot dogs? Do you consume soft cheeses? Sexual Have you ever been tested for HIV or hepatitis? Have you had multiple sexual partners? Men, women, or both? Do you have any history of sexually transmitted infections, including herpes (oral or genital), syphilis, gonorrhea, or chlamydia? Have you ever had an abnormal Pap smear?
droppings. Patients who own chickens or spend time near chicken coops, for example, could be at risk. In addition, this fungus is associated with bat droppings from other bird species.7 Cryptococcus, a ubiquitous environmental encapsulated fungus, has also been associated with the use of TNFI. Cryptococcus neoformans can cause CNS, pulmonary, or disseminated infections, usually in immunocompromised hosts. The fungus can be found around bird roosting sites and also has been particularly associated with pigeon droppings.33 There appears to be an increased incidence of nontuberculous mycobacteria in the TNFI-treated patient. One species patients may encounter from pets is M marinum. M marinum is an acid-fast bacterium that typically lives in an aquatic environment. It can cause solitary or multiple skin lesions, usually on the extremities, after breaks in the
skin are exposed to ocean, salt, or fresh aquarium water. Accordingly, these lesions are commonly called ‘‘fish-tank granulomas.’’ Patients with nontuberculous mycobacteria who are undergoing TNFI therapy are more likely to have disseminated manifestations.34-36 There have been reports of toxoplasmosis occurring in patients who are undergoing TNFI therapy. Toxoplasmosis is caused by the protozoan Toxoplasma gondii.37,38 The primary host of this parasite is the cat family. Humans are usually infected primarily through the consumption of infected meat or hand contamination with cat feces (ie, cleaning litter boxes). Patients who become symptomatic after exposure develop a subclinical or mild influenza or mononucleosis-like illness. Afterward, healthy adults rarely experience any additional symptoms. The parasite can reactivate in
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the setting of immunosuppression and disseminate to the CNS, eyes, heart, liver, or lungs.39 Salmonella infections have been associated with animal exposures, including pets. A higher incidence of salmonella infection has been observed in patients with pet reptiles (eg, lizards, snakes, and turtles) or amphibians (eg, frogs).40,41 Sexual history Clinicians should obtain a comprehensive sexual history in order to identify possible sexually transmitted infections and to address risk factors. HIV and hepatitis B and C may be sexually transmitted; links between these viral pathogens and TNFI were discussed above. Human papillomavirus (HPV) infections may also be affected by TNFIs. HPV, a DNA virus responsible for infections of the skin and mucus membranes, manifests most commonly as warts, including anogenital condyloma. Certain strains are associated with malignancies of the cervix, vulva, penis, anus, and oropharynx. HPV is one of the most common sexually transmitted infections.42 There have been limited reports that TNFI may worsen anogenital warts, but there is no evidence at this time that they increase the incidence of the cancers associated with this virus.43 Herpes simplex virus in a normal host can cause recurrent oral or genital lesions but occasionally is responsible for CNS infections. There have been a small number of reports of patients treated with TNFIs who developed herpes encephalitis.44 Table I shows an example of a patientadministered history flow sheet that is designed to elicit important information related to potential infectious complications of TNFI therapy.
2.
3.
4.
5. 6. 7. 8.
9. 10.
11.
12. 13.
14. 15.
CONCLUSION The advent of biologic therapies, including inhibitors of TNFa, represents an important advance in the management of refractory dermatologic inflammatory conditions, such as psoriasis. However, it is important to consider their mechanisms of action, their many intricate effects on immune function, and the potential for infectious consequences. Similar to patients anticipating solid or bone marrow transplantation and associated immunosuppression, it is critical to consider patients’ medical and surgical histories, exposures, travel and immunization history, and to tailor necessary preventive interventions before proceeding with such therapies. REFERENCES 1. American Academy of Dermatology Work Group: Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, et al. Guidelines of care for the management of psoriasis and
16.
17.
18.
19.
20.
21. 22.
psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol 2011;65:137-74. Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Vol 1. 7th ed. Philadelphia: Churchill Livingstone; 2010. Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-alpha antagonists. Medicine (Baltimore) 2005;84:291-302. Chan AT, Cleeve V, Daymond TJ. Necrotizing fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J 2002;78:47-8. Parish JM, Blair JE. Coccidioidomycosis. Mayo Clin Proc 2008; 83:343-8. Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev 2007;20:115-32. Wheat LJ, Kauffman CA. Histoplasmosis. Infect Dis Clin North Am 2003;17:1-19. Smith JA, Kauffman CA. Endemic fungal infections in patients receiving tumour necrosis factor-alpha inhibitor therapy. Drugs 2009;69:1403-15. Bradsher RW, Chapman SW, Pappas PG. Blastomycosis. Infect Dis Clin North Am 2003;17:21-40. Shale MJ, Seow CH, Coffin CS, Kaplan GG, Panaccione R, Ghosh S. Review article: chronic viral infection in the anti-tumour necrosis factor therapy era in inflammatory bowel disease. Aliment Pharmacol Ther 2010;31:20-34. Abramson A, Menter A, Perrillo R. Psoriasis, hepatitis B, and the tumor necrosis factor-alpha inhibitory agents: a review and recommendations for management. J Am Acad Dermatol 2012;67:1349-61. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45: 507-39. Cepeda EJ, Williams FM, Ishimori ML, Weisman MH, Reveille JD. The use of anti-tumour necrosis factor therapy in HIV-positive individuals with rheumatic disease. Ann Rheum Dis 2008;67:710-2. Kim SY, Solomon DH. Tumor necrosis factor bloackade and the risk of viral infection. Nat Rev Rheumatol 2010;6:165-74. Salmon-Ceron D, Tubach F, Lortholary O, Chosidow O, Bretagne S, Nicolas N, et al. Drug specific risk of non-tuberculosis opportunistic infections in patients receiving anti-TNF therapy reported to the 3 year prospective French RATIO registry. Ann Rheum Dis 2011;70:616-23. Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PLoS One 2012;7:e35671. Garcia-Gonzalez E, Guidelli GM, Bardelli M, Maggio R. Mucocutaneous leishmaniasis in a patient treated with anti-TNF-a therapy. Rheumatology (Oxford) 2012;51:1517-8. Zanger P, Kotter I, Kremsner PG, Gabrysch S. Tumor necrosis factor alpha antagonist drugs and leishmaniasis in Europe. Clin Microbiol Infect 2012;18:670-6. Boatright MD, Wang BW. Clinical infection with Strongyloides sterocoralis following etanercept use for rheumatoid arthritis. Arthritis Rheum 2005;52:1336-7. Krishnamurthy R, Dincer HE, Whittemore D. Strongyloides stercoralis hyperinfection in a patient with rheumatoid arthritis after anti-TNF-alpha therapy. J Clin Rheumatol 2007; 13:150-2. Siddiqui AA, Berk SL. Diagnosis of Strongyloides stercoralis infection. Clin Infect Dis 2001;33:1040-7. Tubach F, Ravaud P, Salmon-Ceron D, Petitpain N, Brocq O, Grados F, et al. Emergence of Legionella pneumophila
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24. 25.
26.
27. 28.
29.
30.
31. 32.
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To claim CME credit, complete this case-based posttest online at http://www.aad.org/JAAD/. Note: CME quizzes are available after the first of the month in which the article is published. A minimum score of 70% must be achieved to claim CME credit. If you have any questions, please contact the Member Resource Center of the American Academy of Dermatology at toll-free (866) 503-SKIN (7546), (847), 240-1280 (for international members), or by e-mailing [email protected].
CME examination Identification No. JA0714 July 2014 issue of the Journal of the American Academy of Dermatology.
Chirch LM, Cataline PR, Dieckhaus KD, Grant-Kels JM. J Am Acad Dermatol 2014;71:1-8.
