Proactive infectious disease approach to dermatologic patients who are taking tumor necrosis factorealfa antagonists Part II. Screening for patients on 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 implement appropriate screening protocols in the pretherapeutic evaluation of psoriatic patients
considering TNF inhibitor therapy and initiate appropriate preventive and therapeutic interventions before and during such therapies, in order to best avoid infectious complications. 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.2014.01.879 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 II of this continuing medical education article reviews recommended screening methods for patients undergoing evaluations for tumor necrosis factor inhibitor therapy for psoriasis or other dermatologic diseases, and discusses possible prophylactic strategies to use, including the appropriate use of immunizations. ( J Am Acad Dermatol 2014;71:11.e1-7.) Key words: biologic therapy; immunizations; opportunistic infection; psoriasis; tumor necrosis factor.
SCREENING AND PROPHYLAXIS: ‘‘WHAT TO DO’’ Key points d
d
d
d
Tuberculosis reactivation is a wellrecognized potential complication of tumor necrosis factor inhibitor therapy, and screening for latent tuberculosis should occur at baseline and yearly Certain patient populations may benefit from the use of an interferon gamma release assay instead of a purified protein derivative for tuberculosis screening Screening for endemic mycoses is controversial and should only be considered in patients with an appropriate epidemiologic exposure history A review of vaccination history before the initiation of tumor necrosis factor inhibitor therapy is a critical part of the baseline evaluation in order to determine need for additional vaccination
Recommended screening strategies for patients receiving tumor necrosis factor inhibitor therapy are shown in Table I.
Tuberculosis Perhaps the best-described infectious complication associated with tumor necrosis factor inhibitors (TNFIs) is tuberculosis (TB). Beginning in 2002, recommendations for screening and potential treatment of latent TB infection were implemented. Adherence to these guidelines later caused a significant decrease in the rates of TB in a population of infliximab-treated patients.1 The Centers for Disease 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.
Control and Prevention (CDC) recommend TB testing before starting treatment with TNFIs.2 Most of the initial recommendations involve using a tuberculin skin test (TST) for the diagnosis of latent TB infection (LTBI). Using a boosted TST (2-stage TST) has led to increased LTBI detection in these patients.1 Over the last few years, interferon gamma release assays (IGRAs) have been increasingly used to diagnose LTBI, and available data suggest that their performance is not inferior to TSTs. The benefits to using this test as a screening tool include ease of testing (ie, no follow-up visit required, less subjectivity in interpreting results) and increased specificity in patients previously given Bacillus-CalmetteGuerin (BCG) vaccine.3 There are limited data in patients receiving TNFIs, and the test’s ability to detect LTBI compared to TSTs has yet to be comprehensively evaluated in this population. One small retrospective study in the psoriasis population, however, advocates for using IGRA over TST given its stronger association with LTBI diagnosis, but it is important to note that 90% of the patients in the study had a previous BCG vaccination4—a population in which IGRAs are known to be more specific. Certain patients undergoing evaluation for TNFI therapy may warrant the use of an IGRA over a TST, such as those who have a history of BCG vaccination or those who are less likely to return for repeat examination. Histoplasmosis In terms of the existing data regarding endemic mycoses, histoplasmosis is the best studied in the setting of TNFI therapy. Initially, there was some speculation regarding potential screening for this infection before the initiation of biologic therapy 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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Table I. Recommended screening strategies for patients receiving tumor necrosis factor inhibitor therapy Disease entity
Screening test
Tuberculosis HIV Hepatitis B
Histoplasmosis
PPD or serum IGRA Serology (ELISA) and confirmatory Western blot Hepatitis B surface antigen, surface antibody, and core total antibody (HBV DNA quantitative level if surface antigen or core antibody positive) Serology (EIA) and HCV RNA quantitative level if serology positive Serology and chest radiolography
Coccidiodomycosis
Serology and chest radiolography
HPV Strongyloidiasis
Cervical Papanicolaou testing/HPV DNA testing Serology
Hepatitis C
Timing
Baseline and annually Baseline* Baseline*
Baseline* Consider at baseline ONLY IF appropriate epidemiologic history Consider at baseline, ONLY IF appropriate epidemiologic history Baseline and annually Baseline if appropriate epidemiologic history
EIA, Enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; HPV, human papillomavirus; IGRA, interferon gamma release assay; PPD, purified protein derivative; RNA, ribonucleic acid. *Patients who have ongoing increased risk because of behavior, exposure, etc may warrant serial screening.
using serology or antigen testing. At this point, in an asymptomatic patient, there appears to be no role in actively screening patients given the lack of clear-cut benefits in predicting infection. If a patient, however, engages in high-risk activities in endemic areas, such as those mentioned previously, or has had recent symptoms consistent with histoplasmosis, then a chest radiograph to look for active disease should be performed before the initiation of therapy. Antifungal prophylaxis is not currently recommended for asymptomatic patients living in endemic area because of the uncertainty of the actual risk of reactivation.5 Coccidioidomycosis There is a paucity of data regarding screening for Coccidioides immitis before TNFI therapy. In an endemic area, coccidioidal serologic tests could be considered before starting TNFI therapy to establish a baseline; a chest radiograph to look for evidence of active disease could also be performed. Like histoplasmosis, many cases are acute rather than a reactivation, so these tests may not be clinically useful.6 Hepatitis B Management with TNFI therapy can be challenging in the hepatitis Bepositive patient. Previous guidelines have addressed hepatitis B as being a relative contraindication to these medications. A recent review in the dermatology literature summarizes key aspects of hepatitis B infection, including differences in serologic status and risk of infection.7,8 Many experts recommend beginning therapy for confirmed chronic hepatitis B infection (positive surface antigen and HBV DNA) with a
nucleos(t)ide inhibitor before initiating TNFI therapy in order to avoid potential exacerbations. Uncertainty exists when patients have negative surface antigen and antibody results but have positive core antibody with or without detectable DNA, suggesting exposure to the virus in the past. Although the large majority of these patients have cleared the virus, the lack of surface antibody suggests a lack of protective immunity, thereby raising concern for reactivation on immunosuppressive drugs. While the risk of reactivation in these patients is likely quite low (approximately 10% according to some authors), many experts recommend considering prophylactic treatment with antivirals in these patients.7,8 Hepatitis C As mentioned above, acute exacerbation of hepatitis C is less common in patients treated with TNFI therapy than in patients with hepatitis B.9-11 There are limited data, however, addressing the relative long-term risks of these agents and their contribution to the development of chronic liver disease, including cirrhosis and fibrosis. Treatment, however, does appear to be less complicated than in hepatitis B. Patients with active hepatitis C disease should be treated appropriately with standard therapy regardless of the need for TNFI therapy. Close monitoring and follow-up with an expert is recommended, especially in patients with more advanced stages of liver disease.7 HIV The role of TNFI therapy in HIV is controversial. Like hepatitis C, it appears that the experience in
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treating HIV patients has been relatively safe, although limited conclusive evidence is available.12 However, administering an immunosuppressive medication to an already immunosuppressed individual is disconcerting. There was some suggestion that starting highly active antiretroviral therapy (HAART) earlier would be prudent in patients concomitantly on TNFI therapy; however, this point has become moot, with recent guidelines suggesting that most HIV patients be started on HAART regardless of CD4 counts.13 Another interesting but unclear topic is whether to use prophylaxis at higher CD4 counts against pathogens, like Pneumocystis jirovecii, that are common in AIDS and are associated with TNFI therapy. It appears that TNFI therapy may be considered if indicated in patients who are controlled on HAART with satisfactory CD4 counts and who have no evidence of ongoing opportunistic infections. These patients should have close follow-up with an HIV specialist.7 Strongyloides There have been multiple reports of strongyloides infections in patients taking a variety of different immunosuppressive medications. In patients from endemic areas, screening for latent infections may be beneficial to prevent active disease before the initiation of TNFI therapy. Serologic testing is probably the most widely available and sensitive method of diagnosing chronic asymptomatic infections, and chemoprophylaxis with an agent such as ivermectin may prevent disseminated disease.14
IMMUNIZATIONS: ‘‘WHAT I NEED TO KNOW’’ The prevention of illness through appropriate vaccinations before TNFI therapy is an important consideration for the practitioner. Patients planning to undergo TNFI therapy may be at an increased risk of vaccine-preventable illnesses. The immunosuppressive nature of therapy may reduce the response to vaccination once TNFI therapy is initiated. A thorough vaccination history should be elicited to identify gaps in pediatric vaccine coverage, current vaccination needs, and the potential need for future vaccinations. Generally, the administration of live attenuated vaccines is contraindicated in immunocompromised individuals. Patients who have already begun or who have recently stopped TNFI should be considered immunocompromised. In general, the half-life of the biologic agent should guide timing of vaccination, with a minimum of 4 to 5 half-lives as a conservative estimate.15,16 Therefore,
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patients who are anticipating the initiation of TNFI therapy in the near future should receive any indicated vaccinations before therapy whenever possible. In some cases, the clinician may wish to consider vaccination outside of standard guidelines for patients who are likely to meet accepted indications during the period of anticipated immunosuppression. Live vaccinations are a particular concern for the TNFI-treated patient. The live vaccines that are usually recommended in patients include measles, mumps, rubella (MMR), varicella vaccine, and herpes zoster vaccine. Special circumstances, such as anticipated international travel, may lead to vaccination with other live vaccines, such as yellow fever or typhoid, under normal circumstances, and should be addressed before beginning TNFI therapy whenever possible. Any adult with an unknown vaccination status to MMR should have serologic titers assessed, and if immunity is documented, further vaccination is not warranted. If no documented immunity exists, then the patient should be vaccinated, usually with trivalent MMR vaccine, although univalent vaccine for the individual components may be available in some settings. Given the risk of prolonged viremia in any patient, a waiting time of at least 6 weeks should take place between the time of vaccination and the start of immunosuppressive therapy. The varicella vaccine is administered to persons without a history of varicella infection. Titers can be drawn for all those without a known history, and if positive do no warrant vaccination. There are limited data for an acceptable interval between vaccination and the onset of immunosuppressive therapy. Extrapolated from information regarding the herpes zoster vaccine, which contains a significantly larger amount of varicella zoster virus, an interval of at least 4 weeks is recommended before the initiation of TNFI therapy.15,16 To prevent the reactivation of varicella zoster virus, the herpes zoster vaccine is routinely recommended for individuals $ 60 years of age. The CDC recommends this age as a cutoff, but the US Food and Drug Administration approved a lowered age limit of 50 in 2011.17 Although the vaccine is more effective for this age range, the risk of herpes zoster is also lower.18 If a patient is to undergo future immunosuppression, administration of the vaccine to patients in this younger age range should be considered. Data are limited, but waiting 4 weeks to 3 months between vaccination and commencement of immunosuppressive therapy has been proposed to avoid the risk of dissemination.15,19
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Killed or inactivated vaccines are generally safe in immunosuppressed individuals. These vaccinations, however, should be administered before immunosuppression whenever possible to minimize the blunting of subsequent immune responses. Vaccination with inactivated vaccines generally follows the current guidelines for the nonimmunosuppressed adult. Patients should receive the tetanus and diphtheria vaccine every 10 years, with the tetanus, diphtheria, and acellular pertussis vaccine administered 1 time during the time period before therapy initiation. The inactivated influenza vaccine should be given yearly at the beginning of the influenza season. The live, intranasal form should be avoided while treating with biologic agents.15 The recent recommendation by the Advisory Committee on Immunization Practices (ACIP) is that adults with immunocompromised conditions who are $ 19 years of age receive the 13-valent pneumococcal conjugate vaccine (PCV13), followed by the PPSV23 vaccine, which is routinely recommended for adults 19 to 64 years of age who are receiving immunosuppressive therapy.20 Vaccination in the setting of anticipated immunosuppression in the near term may be prudent to assure a maximal vaccine response. As mentioned above, hepatitis B serologies should be checked, and if a patient has been unexposed a vaccination series should be instituted. Hepatitis A vaccination should also be offered alone or in combination with hepatitis B vaccination to previously unvaccinated or unexposed individuals. Meningococcal vaccination should be given to at-risk individuals (ie, college students and military recruits) that have previously not received it.15 There are currently 2 types of HPV vaccines available. The quadrivalent human papillomavirus vaccine (Gardasil, Merck and Co, Whitehouse Station, NJ) can routinely be given in males and females at 11 to 12 years of age and considered as early as 9 years of age. Catch-up vaccination is also recommended for 13- through 26-year-old females and 13- through 21-year-old males who have not completed the series. Vaccination in males is routinely recommended for men 22 to 26 years of age who either have sex with men or who are immunocompromised.21-23 The most recent iteration of the ACIP Recommended Immunization Schedule for Adults Aged 19 Years and Older is summarized in Table II.24 Specific recommendations pertaining to immunocompromised patients are relevant to those who have already begun TNFI therapy. As stated above,
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the administration of live vaccines is contraindicated in these patients, and any live vaccine should be administered a minimum of 6 to 12 weeks before initiating therapy.15 Inactivated vaccines may be administered once therapy has begun, but all vaccines require time after administration to induce an adequate immune response. Data on the exact timing of inactivated vaccine administration are anecdotal at best, but a reasonable approach would be to vaccinate as early as possible before beginning TNFI therapy, ideally 2 to 4 weeks earlier.
ADDITIONAL COUNSELING: ‘‘WHAT TO SAY’’ Given that the majority of reports of infections associated with TNFI therapy comes from case reports and small series, it is difficult to stratify infectious risk when counseling about avoiding future exposures. Patients should be made aware of possible areas where they may be more susceptible to an endemic infection. If travel to these areas cannot be avoided, then patients should stay away from activities that may put them at higher risk for acquiring these infections. It is important that individuals who have to travel internationally be evaluated by a travel specialist—especially when traveling to underdeveloped nations. Required live vaccines, such as yellow fever vaccine, should be considered and administered well before the initiation of TNFI therapy. Vaccination for Salmonella typhi may be inactivated or live-attenuated. The live-attenuated vaccine, which is longer-acting, should only be given well in advance of TNFI therapy; the patient who is already undergoing TNFI therapy should be given the inactivated typhoid vaccine for anticipated potential exposure. Patients should restrict their participation in recreational or occupational activities that may place them at risk of acquiring an environmental infectious agent (ie, Nocardia species, atypical mycobacteria, and Aspergillus species). If patients have occupations that place them at risk (ie, housing demolition) then the proper precautions should be taken, such as wearing a respirator. Patients should avoid living in buildings contaminated with mold spores. They should make sure to minimize contact with decomposing plant matter or soil that may harbor fungi in their homes. Undercooked meats or unpasteurized dairy products may transmit Listeria monocytogenes. Classic associations, such as processed meats, including previously cooked or cured deli meats or hot dogs, should be avoided or reheated thoroughly before ingestion. Soft cheeses and meat pates should be avoided.
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Table II. Advisory Committee on Immunization Practices recommended immunization schedule for patients [19 years of age, including immunocompromised patients (2013)24 Vaccine
Influenza Td/Tdap Human papillomavirus PPSV23 PCV13
Meningococcal Hepatitis A Hepatitis B
Varicella Zoster MMR
Dosing schedule
Notes for immunocompromised patients*
1 dose annually Substitute 1-time Tdap for booster; then boost with Td every 10 years 3 doses through age 26 1 or 2 doses 1 dose
Inactivated vaccine ONLY Same
1 or 2 dosesy 2 doses if titer negative 3 doses if titer negative; check postvaccine titer 1 month after series completion; if negative revaccinate 2 doses in adults if titer negative and/or no history of varicella infection 1 dose in adults $ 60 of age 1 or 2 doses if titer negative
Same 1 or 2 doses 1 dose (if PPSV23 na€ıve, patients should receive a single dose of PCV 13 followed by a dose of PPSV at least 8 weeks later; patients who previously received PPSV23 should receive a dose of PCV13 $ 1 years after the last PPSV23 dose) 1 or 2 dosesy 2 doses if titer negative 3 doses if titer negative; check postvaccine titer 1 month after series completion; if negative revaccinate; consider use of 40 g/mL dose Contraindicated Contraindicated Contraindicated
MMR, Measles, mumps, rubella; PCV13, pneumococcal 13-valent conjugate; PPSV23, pneumococcal polysaccharide; Td, tetanus/diphtheria; Tdap, tetanus, diphtheria, and pertussis. *Patients already receiving tumor necrosis factor inhibitor therapy are considered ‘‘immunocompromised.’’ y Patients with functional asplenia or complement component deficiencies should receive 2 doses of conjugate vaccine quadrivalent at least 2 months apart. See full Advisory Committee on Immunization Practices recommendations24 for other at-risk populations.
Patients should exercise caution with any animal exposures. Although most standard household pets do not represent an overwhelming risk to patients, some extra care may be able to prevent infections. Avoiding the inhalation of soil contaminated with stool or droppings of bird species such as pigeons or chickens is important. Hand washing after animal contact, even pets, should be stressed; this is especially true for amphibians and reptiles. Animal scratches and bites should be cleansed thoroughly and reported to a health care professional. If a person has never been around cats or is known to be serologically negative to toxoplasmosis, care should be taken to avoid exposure while undergoing TNFI therapy and to avoid activities such as cleaning litter boxes. Patients with aquarium fish can minimize risk of Mycobacterium marinum infections by not cleaning tanks or by wearing gloves with any fish or aquarium water contact. In addition, patients should be encouraged to always practice safe sex. Condoms are the most effective barrier to transmitting infectious diseases via coitus, although the transmission of certain pathogens like HPV can still be transmitted despite their use. Papanicolaou smears must be routinely performed in females.
Patients with active, acute infections should not be started on TNFI therapy. If an infection develops while undergoing TNFI therapy, these medications should be held until there is resolution. In addition, patients should not hesitate to report any medical illness, because they may develop infections that are quicker in onset and progression than in the normal host. In certain unusual circumstances (eg, long geographic distance or delay to an appropriate location for urgent evaluation), the clinician may consider providing antibiotics for self-administration to avoid delays in initiating therapy for serious bacterial sepsis. Frequent hand washing, especially after contact with sick individuals or potential environmental sources, should be encouraged. A full history and comprehensive physical examination should be performed at least yearly in patients receiving TNFI therapy. Any new or unusual complaints or physical findings should prompt careful consideration and investigation, given the myriad possibilities of potential infectious complications, from typical bacterial infections to unusual parasitic infestations. Additional workup should be guided by specific findings, and may require assistance from an infectious diseases specialist.
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CONCLUSION The advent of biologic therapies, including inhibitors of tumor necrosis factorealfa, represents an important advance in the management of several refractory dermatologic inflammatory conditions. Because of the anticipated drug-induced altered immunity, appropriate screening (via obtaining a patient’s medical history, surgical history, previous immunizations, and travel history) and prophylactic treatment when appropriate are advised. The clinician should counsel patients how to minimize their exposure to potential pathogens, and encourage rapid reevaluation for any question of new infectious complications of TNFI therapy. These recommendations serve as guidelines for dermatologists, in consultation with infectious disease specialists, to help manage their patients who would benefit from TNFI therapy. REFERENCES 1. Wallis RS. Biologics and infections: lessons from tumor necrosis factor blocking agents. Infect Dis Clin North Am 2011;25:895-910. 2. Centers for Disease Control and Prevention. Tuberculosis associated with blocking agents against tumor necrosis factor-alpha—California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004;53:683-6. 3. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K, et al. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Recomm Rep 2010;59:1-25. 4. Laffitte E, Janssens JP, Roux-Lombard P, Thielen AM, Barde C, Marazza G, et al. Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release assay vs. tuberculin skin test. Br J Dermatol 2009;161:797-800. 5. Hage CA, Bowyer S, Tarvin SE, Helper D, Kleiman MB, Wheat LJ. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis 2010;50:85-92. 6. Bergstrom L, Yocum DE, Ampel NM, Villanueva I, Lisse J, Gluck O, et al. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum 2004;50:1959-66. 7. 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. 8. Laurenti R, Giovannangeli F, Gubinelli E, Viviano MT, Errico A, Leoni L, et al. Long term safety of anti-TNF adalimumab in HBc antibody-positive psoriatic arthritis patients: a retrosepctive case series of 8 patients. Clin Dev Immunol 2013;2013:410521. 9. De Simone C, Paradisi A, Capizzi R, Carbone A, Siciliano M, Amerio PL. Etanercept therapy in two patients with psoriasis and concomitant hepatitis C. J Am Acad Dermatol 2006;54: 1102-4.
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10. Rokhsar C, Rabhan N, Cohen SR. Etanercept monotherapy for a patient with psoriasis, psoriatic arthritis, and concomitant hepatitis C infection. J Am Acad Dermatol 2006;54:361-2. 11. Magliocco MA, Gottlieb AB. Etanercept therapy for patients with psoriatic arthritis and concurrent hepatitis C virus infection: report of 3 cases. J Am Acad Dermatol 2004;51: 580-4. 12. 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. 13. AIDSinfo web site. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo. nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed March 23, 2014. 14. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17: 208-17. 15. Wasan SK, Baker SE, Skolnik PR, Farraye FA. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol 2010;105:1231-8. 16. Ortleb M, Levitt JO. Practical use of biologic therapy in dermatology: some considerations and checklists. Dermatol Online J 2012;18:2. 17. ZOSTAVAX [package insert]. Whitehouse Station (NJ): Merck Sharp and Dohme Corp; 2006. 18. Centers for Disease Control and Prevention web site. Vaccines and immunizations. Available at: http://www.cdc.gov/vaccines/ vpd-vac/shingles/vacc-need-know.htm. Accessed March 23, 2014. 19. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. MMWR Morb Mortal Wkly Rep 2011;60:1-61. 20. Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2012;61:816-9. 21. Centers for Disease Control and Prevention. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010;59:626-9. 22. Centers for Disease Control and Prevention. FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010;59:630-2. 23. Centers for Disease Control and Prevention. Recommendations on the use of quadrivalent human papillomavirus vaccine in males—Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep 2011; 60:1705-8. 24. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years and older—United States, 2013. MMWR Morb Mortal Wkly Rep 2013;62:9-19.
considering TNF inhibitor therapy and initiate appropriate preventive and therapeutic interventions before and during such therapies, in order to best avoid infectious complications. 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.2014.01.879 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 II of this continuing medical education article reviews recommended screening methods for patients undergoing evaluations for tumor necrosis factor inhibitor therapy for psoriasis or other dermatologic diseases, and discusses possible prophylactic strategies to use, including the appropriate use of immunizations. ( J Am Acad Dermatol 2014;71:11.e1-7.) Key words: biologic therapy; immunizations; opportunistic infection; psoriasis; tumor necrosis factor.
SCREENING AND PROPHYLAXIS: ‘‘WHAT TO DO’’ Key points d
d
d
d
Tuberculosis reactivation is a wellrecognized potential complication of tumor necrosis factor inhibitor therapy, and screening for latent tuberculosis should occur at baseline and yearly Certain patient populations may benefit from the use of an interferon gamma release assay instead of a purified protein derivative for tuberculosis screening Screening for endemic mycoses is controversial and should only be considered in patients with an appropriate epidemiologic exposure history A review of vaccination history before the initiation of tumor necrosis factor inhibitor therapy is a critical part of the baseline evaluation in order to determine need for additional vaccination
Recommended screening strategies for patients receiving tumor necrosis factor inhibitor therapy are shown in Table I.
Tuberculosis Perhaps the best-described infectious complication associated with tumor necrosis factor inhibitors (TNFIs) is tuberculosis (TB). Beginning in 2002, recommendations for screening and potential treatment of latent TB infection were implemented. Adherence to these guidelines later caused a significant decrease in the rates of TB in a population of infliximab-treated patients.1 The Centers for Disease 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.
Control and Prevention (CDC) recommend TB testing before starting treatment with TNFIs.2 Most of the initial recommendations involve using a tuberculin skin test (TST) for the diagnosis of latent TB infection (LTBI). Using a boosted TST (2-stage TST) has led to increased LTBI detection in these patients.1 Over the last few years, interferon gamma release assays (IGRAs) have been increasingly used to diagnose LTBI, and available data suggest that their performance is not inferior to TSTs. The benefits to using this test as a screening tool include ease of testing (ie, no follow-up visit required, less subjectivity in interpreting results) and increased specificity in patients previously given Bacillus-CalmetteGuerin (BCG) vaccine.3 There are limited data in patients receiving TNFIs, and the test’s ability to detect LTBI compared to TSTs has yet to be comprehensively evaluated in this population. One small retrospective study in the psoriasis population, however, advocates for using IGRA over TST given its stronger association with LTBI diagnosis, but it is important to note that 90% of the patients in the study had a previous BCG vaccination4—a population in which IGRAs are known to be more specific. Certain patients undergoing evaluation for TNFI therapy may warrant the use of an IGRA over a TST, such as those who have a history of BCG vaccination or those who are less likely to return for repeat examination. Histoplasmosis In terms of the existing data regarding endemic mycoses, histoplasmosis is the best studied in the setting of TNFI therapy. Initially, there was some speculation regarding potential screening for this infection before the initiation of biologic therapy 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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Table I. Recommended screening strategies for patients receiving tumor necrosis factor inhibitor therapy Disease entity
Screening test
Tuberculosis HIV Hepatitis B
Histoplasmosis
PPD or serum IGRA Serology (ELISA) and confirmatory Western blot Hepatitis B surface antigen, surface antibody, and core total antibody (HBV DNA quantitative level if surface antigen or core antibody positive) Serology (EIA) and HCV RNA quantitative level if serology positive Serology and chest radiolography
Coccidiodomycosis
Serology and chest radiolography
HPV Strongyloidiasis
Cervical Papanicolaou testing/HPV DNA testing Serology
Hepatitis C
Timing
Baseline and annually Baseline* Baseline*
Baseline* Consider at baseline ONLY IF appropriate epidemiologic history Consider at baseline, ONLY IF appropriate epidemiologic history Baseline and annually Baseline if appropriate epidemiologic history
EIA, Enzyme immunoassay; ELISA, enzyme-linked immunosorbent assay; HPV, human papillomavirus; IGRA, interferon gamma release assay; PPD, purified protein derivative; RNA, ribonucleic acid. *Patients who have ongoing increased risk because of behavior, exposure, etc may warrant serial screening.
using serology or antigen testing. At this point, in an asymptomatic patient, there appears to be no role in actively screening patients given the lack of clear-cut benefits in predicting infection. If a patient, however, engages in high-risk activities in endemic areas, such as those mentioned previously, or has had recent symptoms consistent with histoplasmosis, then a chest radiograph to look for active disease should be performed before the initiation of therapy. Antifungal prophylaxis is not currently recommended for asymptomatic patients living in endemic area because of the uncertainty of the actual risk of reactivation.5 Coccidioidomycosis There is a paucity of data regarding screening for Coccidioides immitis before TNFI therapy. In an endemic area, coccidioidal serologic tests could be considered before starting TNFI therapy to establish a baseline; a chest radiograph to look for evidence of active disease could also be performed. Like histoplasmosis, many cases are acute rather than a reactivation, so these tests may not be clinically useful.6 Hepatitis B Management with TNFI therapy can be challenging in the hepatitis Bepositive patient. Previous guidelines have addressed hepatitis B as being a relative contraindication to these medications. A recent review in the dermatology literature summarizes key aspects of hepatitis B infection, including differences in serologic status and risk of infection.7,8 Many experts recommend beginning therapy for confirmed chronic hepatitis B infection (positive surface antigen and HBV DNA) with a
nucleos(t)ide inhibitor before initiating TNFI therapy in order to avoid potential exacerbations. Uncertainty exists when patients have negative surface antigen and antibody results but have positive core antibody with or without detectable DNA, suggesting exposure to the virus in the past. Although the large majority of these patients have cleared the virus, the lack of surface antibody suggests a lack of protective immunity, thereby raising concern for reactivation on immunosuppressive drugs. While the risk of reactivation in these patients is likely quite low (approximately 10% according to some authors), many experts recommend considering prophylactic treatment with antivirals in these patients.7,8 Hepatitis C As mentioned above, acute exacerbation of hepatitis C is less common in patients treated with TNFI therapy than in patients with hepatitis B.9-11 There are limited data, however, addressing the relative long-term risks of these agents and their contribution to the development of chronic liver disease, including cirrhosis and fibrosis. Treatment, however, does appear to be less complicated than in hepatitis B. Patients with active hepatitis C disease should be treated appropriately with standard therapy regardless of the need for TNFI therapy. Close monitoring and follow-up with an expert is recommended, especially in patients with more advanced stages of liver disease.7 HIV The role of TNFI therapy in HIV is controversial. Like hepatitis C, it appears that the experience in
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treating HIV patients has been relatively safe, although limited conclusive evidence is available.12 However, administering an immunosuppressive medication to an already immunosuppressed individual is disconcerting. There was some suggestion that starting highly active antiretroviral therapy (HAART) earlier would be prudent in patients concomitantly on TNFI therapy; however, this point has become moot, with recent guidelines suggesting that most HIV patients be started on HAART regardless of CD4 counts.13 Another interesting but unclear topic is whether to use prophylaxis at higher CD4 counts against pathogens, like Pneumocystis jirovecii, that are common in AIDS and are associated with TNFI therapy. It appears that TNFI therapy may be considered if indicated in patients who are controlled on HAART with satisfactory CD4 counts and who have no evidence of ongoing opportunistic infections. These patients should have close follow-up with an HIV specialist.7 Strongyloides There have been multiple reports of strongyloides infections in patients taking a variety of different immunosuppressive medications. In patients from endemic areas, screening for latent infections may be beneficial to prevent active disease before the initiation of TNFI therapy. Serologic testing is probably the most widely available and sensitive method of diagnosing chronic asymptomatic infections, and chemoprophylaxis with an agent such as ivermectin may prevent disseminated disease.14
IMMUNIZATIONS: ‘‘WHAT I NEED TO KNOW’’ The prevention of illness through appropriate vaccinations before TNFI therapy is an important consideration for the practitioner. Patients planning to undergo TNFI therapy may be at an increased risk of vaccine-preventable illnesses. The immunosuppressive nature of therapy may reduce the response to vaccination once TNFI therapy is initiated. A thorough vaccination history should be elicited to identify gaps in pediatric vaccine coverage, current vaccination needs, and the potential need for future vaccinations. Generally, the administration of live attenuated vaccines is contraindicated in immunocompromised individuals. Patients who have already begun or who have recently stopped TNFI should be considered immunocompromised. In general, the half-life of the biologic agent should guide timing of vaccination, with a minimum of 4 to 5 half-lives as a conservative estimate.15,16 Therefore,
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patients who are anticipating the initiation of TNFI therapy in the near future should receive any indicated vaccinations before therapy whenever possible. In some cases, the clinician may wish to consider vaccination outside of standard guidelines for patients who are likely to meet accepted indications during the period of anticipated immunosuppression. Live vaccinations are a particular concern for the TNFI-treated patient. The live vaccines that are usually recommended in patients include measles, mumps, rubella (MMR), varicella vaccine, and herpes zoster vaccine. Special circumstances, such as anticipated international travel, may lead to vaccination with other live vaccines, such as yellow fever or typhoid, under normal circumstances, and should be addressed before beginning TNFI therapy whenever possible. Any adult with an unknown vaccination status to MMR should have serologic titers assessed, and if immunity is documented, further vaccination is not warranted. If no documented immunity exists, then the patient should be vaccinated, usually with trivalent MMR vaccine, although univalent vaccine for the individual components may be available in some settings. Given the risk of prolonged viremia in any patient, a waiting time of at least 6 weeks should take place between the time of vaccination and the start of immunosuppressive therapy. The varicella vaccine is administered to persons without a history of varicella infection. Titers can be drawn for all those without a known history, and if positive do no warrant vaccination. There are limited data for an acceptable interval between vaccination and the onset of immunosuppressive therapy. Extrapolated from information regarding the herpes zoster vaccine, which contains a significantly larger amount of varicella zoster virus, an interval of at least 4 weeks is recommended before the initiation of TNFI therapy.15,16 To prevent the reactivation of varicella zoster virus, the herpes zoster vaccine is routinely recommended for individuals $ 60 years of age. The CDC recommends this age as a cutoff, but the US Food and Drug Administration approved a lowered age limit of 50 in 2011.17 Although the vaccine is more effective for this age range, the risk of herpes zoster is also lower.18 If a patient is to undergo future immunosuppression, administration of the vaccine to patients in this younger age range should be considered. Data are limited, but waiting 4 weeks to 3 months between vaccination and commencement of immunosuppressive therapy has been proposed to avoid the risk of dissemination.15,19
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Killed or inactivated vaccines are generally safe in immunosuppressed individuals. These vaccinations, however, should be administered before immunosuppression whenever possible to minimize the blunting of subsequent immune responses. Vaccination with inactivated vaccines generally follows the current guidelines for the nonimmunosuppressed adult. Patients should receive the tetanus and diphtheria vaccine every 10 years, with the tetanus, diphtheria, and acellular pertussis vaccine administered 1 time during the time period before therapy initiation. The inactivated influenza vaccine should be given yearly at the beginning of the influenza season. The live, intranasal form should be avoided while treating with biologic agents.15 The recent recommendation by the Advisory Committee on Immunization Practices (ACIP) is that adults with immunocompromised conditions who are $ 19 years of age receive the 13-valent pneumococcal conjugate vaccine (PCV13), followed by the PPSV23 vaccine, which is routinely recommended for adults 19 to 64 years of age who are receiving immunosuppressive therapy.20 Vaccination in the setting of anticipated immunosuppression in the near term may be prudent to assure a maximal vaccine response. As mentioned above, hepatitis B serologies should be checked, and if a patient has been unexposed a vaccination series should be instituted. Hepatitis A vaccination should also be offered alone or in combination with hepatitis B vaccination to previously unvaccinated or unexposed individuals. Meningococcal vaccination should be given to at-risk individuals (ie, college students and military recruits) that have previously not received it.15 There are currently 2 types of HPV vaccines available. The quadrivalent human papillomavirus vaccine (Gardasil, Merck and Co, Whitehouse Station, NJ) can routinely be given in males and females at 11 to 12 years of age and considered as early as 9 years of age. Catch-up vaccination is also recommended for 13- through 26-year-old females and 13- through 21-year-old males who have not completed the series. Vaccination in males is routinely recommended for men 22 to 26 years of age who either have sex with men or who are immunocompromised.21-23 The most recent iteration of the ACIP Recommended Immunization Schedule for Adults Aged 19 Years and Older is summarized in Table II.24 Specific recommendations pertaining to immunocompromised patients are relevant to those who have already begun TNFI therapy. As stated above,
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the administration of live vaccines is contraindicated in these patients, and any live vaccine should be administered a minimum of 6 to 12 weeks before initiating therapy.15 Inactivated vaccines may be administered once therapy has begun, but all vaccines require time after administration to induce an adequate immune response. Data on the exact timing of inactivated vaccine administration are anecdotal at best, but a reasonable approach would be to vaccinate as early as possible before beginning TNFI therapy, ideally 2 to 4 weeks earlier.
ADDITIONAL COUNSELING: ‘‘WHAT TO SAY’’ Given that the majority of reports of infections associated with TNFI therapy comes from case reports and small series, it is difficult to stratify infectious risk when counseling about avoiding future exposures. Patients should be made aware of possible areas where they may be more susceptible to an endemic infection. If travel to these areas cannot be avoided, then patients should stay away from activities that may put them at higher risk for acquiring these infections. It is important that individuals who have to travel internationally be evaluated by a travel specialist—especially when traveling to underdeveloped nations. Required live vaccines, such as yellow fever vaccine, should be considered and administered well before the initiation of TNFI therapy. Vaccination for Salmonella typhi may be inactivated or live-attenuated. The live-attenuated vaccine, which is longer-acting, should only be given well in advance of TNFI therapy; the patient who is already undergoing TNFI therapy should be given the inactivated typhoid vaccine for anticipated potential exposure. Patients should restrict their participation in recreational or occupational activities that may place them at risk of acquiring an environmental infectious agent (ie, Nocardia species, atypical mycobacteria, and Aspergillus species). If patients have occupations that place them at risk (ie, housing demolition) then the proper precautions should be taken, such as wearing a respirator. Patients should avoid living in buildings contaminated with mold spores. They should make sure to minimize contact with decomposing plant matter or soil that may harbor fungi in their homes. Undercooked meats or unpasteurized dairy products may transmit Listeria monocytogenes. Classic associations, such as processed meats, including previously cooked or cured deli meats or hot dogs, should be avoided or reheated thoroughly before ingestion. Soft cheeses and meat pates should be avoided.
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Table II. Advisory Committee on Immunization Practices recommended immunization schedule for patients [19 years of age, including immunocompromised patients (2013)24 Vaccine
Influenza Td/Tdap Human papillomavirus PPSV23 PCV13
Meningococcal Hepatitis A Hepatitis B
Varicella Zoster MMR
Dosing schedule
Notes for immunocompromised patients*
1 dose annually Substitute 1-time Tdap for booster; then boost with Td every 10 years 3 doses through age 26 1 or 2 doses 1 dose
Inactivated vaccine ONLY Same
1 or 2 dosesy 2 doses if titer negative 3 doses if titer negative; check postvaccine titer 1 month after series completion; if negative revaccinate 2 doses in adults if titer negative and/or no history of varicella infection 1 dose in adults $ 60 of age 1 or 2 doses if titer negative
Same 1 or 2 doses 1 dose (if PPSV23 na€ıve, patients should receive a single dose of PCV 13 followed by a dose of PPSV at least 8 weeks later; patients who previously received PPSV23 should receive a dose of PCV13 $ 1 years after the last PPSV23 dose) 1 or 2 dosesy 2 doses if titer negative 3 doses if titer negative; check postvaccine titer 1 month after series completion; if negative revaccinate; consider use of 40 g/mL dose Contraindicated Contraindicated Contraindicated
MMR, Measles, mumps, rubella; PCV13, pneumococcal 13-valent conjugate; PPSV23, pneumococcal polysaccharide; Td, tetanus/diphtheria; Tdap, tetanus, diphtheria, and pertussis. *Patients already receiving tumor necrosis factor inhibitor therapy are considered ‘‘immunocompromised.’’ y Patients with functional asplenia or complement component deficiencies should receive 2 doses of conjugate vaccine quadrivalent at least 2 months apart. See full Advisory Committee on Immunization Practices recommendations24 for other at-risk populations.
Patients should exercise caution with any animal exposures. Although most standard household pets do not represent an overwhelming risk to patients, some extra care may be able to prevent infections. Avoiding the inhalation of soil contaminated with stool or droppings of bird species such as pigeons or chickens is important. Hand washing after animal contact, even pets, should be stressed; this is especially true for amphibians and reptiles. Animal scratches and bites should be cleansed thoroughly and reported to a health care professional. If a person has never been around cats or is known to be serologically negative to toxoplasmosis, care should be taken to avoid exposure while undergoing TNFI therapy and to avoid activities such as cleaning litter boxes. Patients with aquarium fish can minimize risk of Mycobacterium marinum infections by not cleaning tanks or by wearing gloves with any fish or aquarium water contact. In addition, patients should be encouraged to always practice safe sex. Condoms are the most effective barrier to transmitting infectious diseases via coitus, although the transmission of certain pathogens like HPV can still be transmitted despite their use. Papanicolaou smears must be routinely performed in females.
Patients with active, acute infections should not be started on TNFI therapy. If an infection develops while undergoing TNFI therapy, these medications should be held until there is resolution. In addition, patients should not hesitate to report any medical illness, because they may develop infections that are quicker in onset and progression than in the normal host. In certain unusual circumstances (eg, long geographic distance or delay to an appropriate location for urgent evaluation), the clinician may consider providing antibiotics for self-administration to avoid delays in initiating therapy for serious bacterial sepsis. Frequent hand washing, especially after contact with sick individuals or potential environmental sources, should be encouraged. A full history and comprehensive physical examination should be performed at least yearly in patients receiving TNFI therapy. Any new or unusual complaints or physical findings should prompt careful consideration and investigation, given the myriad possibilities of potential infectious complications, from typical bacterial infections to unusual parasitic infestations. Additional workup should be guided by specific findings, and may require assistance from an infectious diseases specialist.
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CONCLUSION The advent of biologic therapies, including inhibitors of tumor necrosis factorealfa, represents an important advance in the management of several refractory dermatologic inflammatory conditions. Because of the anticipated drug-induced altered immunity, appropriate screening (via obtaining a patient’s medical history, surgical history, previous immunizations, and travel history) and prophylactic treatment when appropriate are advised. The clinician should counsel patients how to minimize their exposure to potential pathogens, and encourage rapid reevaluation for any question of new infectious complications of TNFI therapy. These recommendations serve as guidelines for dermatologists, in consultation with infectious disease specialists, to help manage their patients who would benefit from TNFI therapy. REFERENCES 1. Wallis RS. Biologics and infections: lessons from tumor necrosis factor blocking agents. Infect Dis Clin North Am 2011;25:895-910. 2. Centers for Disease Control and Prevention. Tuberculosis associated with blocking agents against tumor necrosis factor-alpha—California, 2002-2003. MMWR Morb Mortal Wkly Rep 2004;53:683-6. 3. Mazurek GH, Jereb J, Vernon A, LoBue P, Goldberg S, Castro K, et al. Updated guidelines for using interferon gamma release assays to detect Mycobacterium tuberculosis infection—United States, 2010. MMWR Recomm Rep 2010;59:1-25. 4. Laffitte E, Janssens JP, Roux-Lombard P, Thielen AM, Barde C, Marazza G, et al. Tuberculosis screening in patients with psoriasis before antitumour necrosis factor therapy: comparison of an interferon-gamma release assay vs. tuberculin skin test. Br J Dermatol 2009;161:797-800. 5. Hage CA, Bowyer S, Tarvin SE, Helper D, Kleiman MB, Wheat LJ. Recognition, diagnosis, and treatment of histoplasmosis complicating tumor necrosis factor blocker therapy. Clin Infect Dis 2010;50:85-92. 6. Bergstrom L, Yocum DE, Ampel NM, Villanueva I, Lisse J, Gluck O, et al. Increased risk of coccidioidomycosis in patients treated with tumor necrosis factor alpha antagonists. Arthritis Rheum 2004;50:1959-66. 7. 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. 8. Laurenti R, Giovannangeli F, Gubinelli E, Viviano MT, Errico A, Leoni L, et al. Long term safety of anti-TNF adalimumab in HBc antibody-positive psoriatic arthritis patients: a retrosepctive case series of 8 patients. Clin Dev Immunol 2013;2013:410521. 9. De Simone C, Paradisi A, Capizzi R, Carbone A, Siciliano M, Amerio PL. Etanercept therapy in two patients with psoriasis and concomitant hepatitis C. J Am Acad Dermatol 2006;54: 1102-4.
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10. Rokhsar C, Rabhan N, Cohen SR. Etanercept monotherapy for a patient with psoriasis, psoriatic arthritis, and concomitant hepatitis C infection. J Am Acad Dermatol 2006;54:361-2. 11. Magliocco MA, Gottlieb AB. Etanercept therapy for patients with psoriatic arthritis and concurrent hepatitis C virus infection: report of 3 cases. J Am Acad Dermatol 2004;51: 580-4. 12. 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. 13. AIDSinfo web site. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at: http://aidsinfo. nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed March 23, 2014. 14. Keiser PB, Nutman TB. Strongyloides stercoralis in the immunocompromised population. Clin Microbiol Rev 2004;17: 208-17. 15. Wasan SK, Baker SE, Skolnik PR, Farraye FA. A practical guide to vaccinating the inflammatory bowel disease patient. Am J Gastroenterol 2010;105:1231-8. 16. Ortleb M, Levitt JO. Practical use of biologic therapy in dermatology: some considerations and checklists. Dermatol Online J 2012;18:2. 17. ZOSTAVAX [package insert]. Whitehouse Station (NJ): Merck Sharp and Dohme Corp; 2006. 18. Centers for Disease Control and Prevention web site. Vaccines and immunizations. Available at: http://www.cdc.gov/vaccines/ vpd-vac/shingles/vacc-need-know.htm. Accessed March 23, 2014. 19. Centers for Disease Control and Prevention. Epidemiology and prevention of vaccine-preventable diseases. MMWR Morb Mortal Wkly Rep 2011;60:1-61. 20. Centers for Disease Control and Prevention. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2012;61:816-9. 21. Centers for Disease Control and Prevention. FDA licensure of bivalent human papillomavirus vaccine (HPV2, Cervarix) for use in females and updated HPV vaccination recommendations from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010;59:626-9. 22. Centers for Disease Control and Prevention. FDA licensure of quadrivalent human papillomavirus vaccine (HPV4, Gardasil) for use in males and guidance from the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2010;59:630-2. 23. Centers for Disease Control and Prevention. Recommendations on the use of quadrivalent human papillomavirus vaccine in males—Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep 2011; 60:1705-8. 24. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices recommended immunization schedule for adults aged 19 years and older—United States, 2013. MMWR Morb Mortal Wkly Rep 2013;62:9-19.
