Drugs 2009; 69 (11): 1403-1415 THERAPY IN PRACTICE 0012-6667/09/0011-1403/$55.55/0 ª 2009 Adis Data Information BV. All rights reserved. Endemic Fungal Infections in Patients Receiving Tumour Necrosis Factor-a Inhibitor Therapy Jeannina A. Smith and Carol A. Kauffman Division of Infectious Diseases, University of Michigan Medical School, Veterans Affairs Ann Arbor Healthcare System, Ann Arbor, Michigan, USA Contents Abstract. 1403 1. Role of Tumour Necrosis Factor (TNF)-a in Immunity and Chronic Inflammatory Diseases . 1404 2. Currently Licensed TNFa Inhibitors . 1404 3. TNFa Inhibitors and Infection with Intracellular Pathogens . 1405 4. TNFa Inhibitors and Infection with Endemic Mycoses . 1406 4.1 Histoplasmosis . 1406 4.2 Blastomycosis . 1408 4.3 Coccidioidomycosis. 1410 5. Prevention of Endemic Mycoses among Patients Receiving TNFa Inhibitor Therapy . 1412 6. Conclusions . 1413 Abstract Tumour necrosis factor (TNF)-a inhibitors are widely used agents in the treatment of a variety of inflammatory and granulomatous diseases. It has long been appreciated that these agents confer an increased risk of tubercu- losis; however, more recently it has been recognized that patients being treated with TNFa inhibitors are also at significant risk for infection with the endemic fungi, in particular Histoplasma capsulatum, and when infected, to develop severe disseminated infection. Patients often present in an atypical manner and the symptoms of the fungal infection can be mistaken for those of the underlying disease. Thus, delay in diagnosis and treatment is common, and mortality has been high. In an attempt to increase awareness of this problem, the US FDA issued a ‘black box’ warning for clinicians in Sep- tember 2008 to alert providers of the risks of endemic fungal infections in patients treated with TNFa inhibitors. The management of patients who develop endemic fungal infection while receiving TNFa inhibitor therapy should include discontinuation of the TNFa inhibitor and early use of anti- fungal agents including polyenes and/or azoles according to the Infectious Diseases Society of America guidelines for treatment of these infections in immunocompromised hosts. 1404 Smith & Kauffman 1. Role of Tumour Necrosis Factor FDA-approved for clinical use. These agents (TNF)-a in Immunity and Chronic differ in their structure, pharmacokinetic and Inflammatory Diseases pharmacodynamic properties, the mechanism of inhibition of TNFa and other biological activities Tumour necrosis factor (TNF)-a is a cytokine (table I). that is released by many cell types, including Infliximab (RemicadeÒ) is a chimeric IgG1 macrophages, monocytes and T lymphocytes, and monoclonal antibody with human constant and that promotes inflammation through multiple murine variable sequences. It binds to and neu- different mechanisms. TNFa activates nuclear tralizes both soluble and membrane-bound factor kappa B, induces interferon (IFN)-g and TNFa, preventing the binding of TNFa to its several interleukins (IL-1, IL-6 and IL-8), and receptor. Infliximab also fixes complement, in- upregulates adhesion molecules produced by ducing antibody-mediated lysis of cells expres- endothelial cells, resulting in enhanced leukocyte sing membrane-bound TNFa, and induces T-cell extravasation and migration.[1-3] TNFa is critical and monocyte apoptosis. Infliximab does not for effective granuloma formation and main- bind with TNFb (lymphotoxin). Infliximab was tenance, and is an essential component of host licensed in 1998 and is approved to treat moder- immunity against intracellular pathogens, in- ate to severe rheumatoid arthritis, psoriatic cluding mycobacteria and certain fungi. arthritis, ankylosing spondylitis, Crohn’s disease Aberrant activity of TNFa has been im- and ulcerative colitis.[4,7] It also has been used for plicated in a number of diseases, including rheu- uveitis, psoriasis, hidradenitis suppurativa and matoid arthritis, juvenile rheumatoid arthritis, sarcoidosis.[7-9] inflammatory bowel disease, psoriasis, graft Etanercept (EnbrelÒ) is a human soluble versus host disease, ankylosing spondylitis, uvei- TNFa receptor fusion protein composed of the tis and vasculitis. Because of this, a number of extracellular portion of two TNFa type II (p75) drugs that block the effects of TNFa have been receptors joined to the Fc portion of IgG1. Eta- developed for the treatment of these and other nercept binds to soluble TNFa and TNFb, inflammatory and granulomatous conditions.[4,5] thereby preventing receptor-mediated activation. For many patients, these agents have proved to Unlike infliximab, etanercept does not fix com- be extremely effective in dampening the immune plement, cause antibody-dependent cytotoxicity, response that causes their symptoms. However, or trigger T-cell or monocyte apoptosis. Eta- use of these agents has been associated with nercept was also licensed in 1998 and is approved an increased risk of developing certain types to treat moderate to severe rheumatoid arthritis of infections. The attributable excess risk for and juvenile rheumatoid arthritis, psoriatic ar- infection has been difficult to elucidate. In part, thritis, ankylosing spondylitis and moderate to this is because patients with granulomatous and severe plaque psoriasis.[5,9,10] autoimmune disorders already have impaired Adalimumab (HumiraÒ) is similar to in- immune responses to infection.[6] In addition, fliximab in its actions. However, it is a human individuals with the most severe disease are monoclonal IgG1 antibody, not a chimeric mo- most likely to receive TNFa inhibitors and, lecule like infliximab. It binds to both soluble additionally, many of these patients also receive and membrane-bound TNFa; it does not bind other immunosuppressive agents, making it with TNFb. Similarly to infliximab, it fixes difficult to ascribe the risk of infection solely to complement, causes lysis of cells expressing the TNFa inhibitor. membrane-bound TNFa and induces apoptosis. Adalimumab has been approved to treat 2. Currently Licensed TNFa Inhibitors rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis.[9,11,12] Four TNFa inhibitors, infliximab, etanercept, Certolizumab pegol (CimziaÒ) is a pegylated adalimumab and certolizumab, are currently US humanized Fab0 fragment with a high binding ª 2009 Adis Data Information BV. All rights reserved. Drugs 2009; 69 (11) Endemic Mycoses with TNFa Inhibitor Therapy 1405 Table I. Properties of the currently licensed tumour necrosis factor (TNF)-a inhibitors Agent TNFa binding TNFb Fixes complement; Elimination Route of Efficacy for Comparative binding antibody-mediated half-life administration granulomatous risk of infection cell lysis (days) diseases with endemic mycoses Infliximab Soluble and No Yes 9.5 IV Yes Greater membrane-bound TNFa Etanercept Soluble TNFa Yes No 4.2 SC No Lesser Adalimumab Soluble and No Yes 14 SC Yes Greater membrane-bound TNFa Certolizumab Soluble and No No 14 SC Yes Unknown membrane-bound TNFa IV = intravenous; SC = subcutaneous. affinity for TNFa. In contrast to infliximab 3. TNFa Inhibitors and Infection and adalimumab, certolizumab pegol does not with Intracellular Pathogens contain an Fc portion and therefore does not fix complement or induce apoptosis of T cells or All the TNFa inhibitors are associated with an monocytes. Certolizumab pegol has been ap- increased risk of infection.[17-21] It appears that proved in the US for Crohn’s disease and is the incidence of granulomatous infections is less under review for the treatment of rheumatoid with etanercept than infliximab and perhaps arthritis.[9,13,14] It is the newest of the TNFa adalimumab. Rates of development of active inhibitors, and thus there is little information on tuberculosis have been estimated to be 53.81 per adverse effects when compared with the other 100 000 persons for infliximab and 28.32 per three agents. 100 000 persons for etanercept.[17,18] Among 1200 The pharmacological variations among patients in Europe and 1700 patients in the US to these agents have clinical implications. For ex- whom adalimumab had been administered, there ample, in the case of granulomatous disorders, were eight cases of reactivation tuberculosis in such as sarcoidosis, Crohn’s disease and We- Europe and one case of primary tuberculosis in gener’s granulomatosis, etanercept appears to be the US.[19] Two large registries, one in France considerably less effective than infliximab.[15] and the other in Portugal, confirmed rates that This indicates that the specific type of TNFa were similar for the development of tuberculosis blockade may be important in the therapeutic in patients receiving either infliximab or adali- efficacy of these agents. Etanercept binds pri- mumab, and noted that the rate for etanercept marily to soluble TNFa, whereas infliximab was much lower.[17,22] These observations uni- binds to both soluble and membrane-bound formly suggest that both adalimumab and in- TNFa and has broader activities, including fliximab confer a greater risk of developing complement fixation and induction of apoptosis active tuberculosis than does etanercept. A of cells expressing membrane-bound TNFa.[16] smaller registry in Germany did not show a Thus, it is likely that this broader activity of difference in infection rates between infliximab infliximab against T cells and monocytes is and etanercept, but no invasive fungal infections reflected in a greater risk for intracellular patho- were reported and only one case of tuberculosis gens that are primarily controlled