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Opportunistic infections secondary to biologic therapy
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Biologic therapies have become mainstays of treatment for a number of immune-mediated disease states, including Crohn’s disease, rheumatoid arthritis and psoriasis. By targeting key components of the immune system, these agents have greatly improved control of these disease states and improved quality of life for patients. However, inhibition of certain immune system functions can also put patients at risk for a number of important opportunistic infections, and clinicians must consider both risks and benefits of biologic therapies.
Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine responsible for many important host responses to infection, and also plays a pathogenic role in immune-mediated disease states. Currently available TNF-alpha antagonists are infliximab (Remicade, Janssen), etanercept (Enbrel, Amgen), adalimumab (Humira, AbbVie), certolizumab (Cimzia, UCB) and golimumab (Simponi, Janssen). Through slightly different mechanisms, each of these agents inhibits the binding of TNF-alpha to TNF-alpha receptors, thus preventing the pathologic inflammation underlying the targeted disease states.
Biological therapy options
Besides TNF-alpha antagonists, other biologic therapies are available for the treatment of rheumatoid arthritis and other immune-mediated disease states. Similar to the TNF-alpha inhibitors, anakinra (Kineret, Sobi) also is a direct cytokine antagonist; however, it is targeted against interleukin (IL)-1. Abatacept (Orencia, Bristol-Myers Squibb) and rituximab (Rituxan, Genentech/Biogen Idec) work elsewhere in the inflammatory response cascade: Abatacept prevents T-cell activation and rituximab inhibits B cells by targeting the CD20 antigen. In a meta-analysis comparing each of these agents with placebo, no significantly increased risk for serious infections was observed. However, higher incidence of infection was observed among patients receiving high doses of each of the three agents studied, and the impact was statistically significant among those receiving anakinra, which also had the highest risk for infection when all dosage strengths were considered.
A recent Cochrane review (Table 1) found similar results for anakinra compared with abatacept and rituximab, and also evaluated risk for serious infection with the TNF-alpha antagonists and the IL-6 antagonist tocilizumab (Actemra, Genentech) compared with placebo. In this review, a serious infection was defined as requiring hospitalization and/or IV antimicrobial therapy.
Leah Molloy
Tuberculosis
TNF-alpha plays an important role in the management of active tuberculosis by facilitating the phagocytosis and killing of mycobacteria. Additionally, in the setting of latent TB, mycobacterial growth is restricted to intracellular granulomas, which are largely regulated by TNF-alpha. Thus, inhibition of this cytokine is expected to impair host defenses against active TB and increase the risk for reactivation of latent TB.
Hepatitis
Reactivation or increased viral load has been described with biologic therapies, particularly hepatitis B virus among patients receiving rituximab, possibly owing to the antigen-presenting role of B cells. HBV reactivation is also a concern among patients treated with TNF-alpha inhibitors, as TNF-alpha functions to stimulate T-cell-mediated viral killing and contain viral replication.
Fungal infections
Endemic fungal infections such as histoplasmosis, blastomycosis and coccidioidomycosis are associated with TNF-alpha inhibitors through mechanisms similar to TB, namely inhibition of granuloma formation impaired cell-mediated immune response. Of note, although screening for and possibly treatment of mycobacterial and viral infections is recommended before and during treatment with biologic therapies, screening for fungal infections is not routinely practiced. Additionally, most endemic fungal infections emerging during immune therapy appear to be new-onset infection and not reactivation of latent infection.
Other infections
A variety of other infections have been associated with biologic therapies, including those caused by intracellular pathogens such as Legionella pneumophila, Listeria monocytogenes and leishmaniasis. Additionally, infections caused by Salmonella and viruses such as herpes zoster have been reported among patients treated with TNF-alpha inhibitors.
Data evaluating infection risks are varied and limited, owing to an evolution of exclusion criteria in clinical studies of each biologic agent. Because more recent studies excluded all patients with latent TB or hepatitis infections, specific information describing risk for reactivation is unavailable for some agents. However, the general recommendation for all biologic therapies supports vigilant screening and treatment as appropriate.
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Leah Molloy, PharmD, is a clinical pharmacist, specialist in infectious diseases, at Children’s Hospital of Michigan, Detroit.
Disclosure: Molloy reports no relevant financial disclosures.