Infectious Complications of Treatment with Biologic Agents
Infectious Complications of Treatment with Biologic Agents
Purpose of Review: There are three tumor necrosis factor-α inhibitors on the US and European markets today, and uncommon but devastating infectious complications accompany their use. This review describes the most important pathogen-specific infections and their relative frequency. Recent literature is summarized that has helped elucidate the pathophysiologic basis for their occurrence. Finally, evolving sets of recommendations for prevention, diagnosis, and treatment of infectious complications of their use are explored.
Recent Findings: Tuberculosis has continued to be the most common pathogen reported in association with infliximab, and less so with etanercept and adalimumab. Determining treated population case rates depends on having an accurate denominator and reflects the local population's latent infection rate. The same is true for histoplasmosis. Other pathogens requiring intact cellular immunity for control of latent infection have also been reported. Specific recommendations for preventive therapy are being made, but prospective clinical trials are needed to assess the risk-benefit of any particular approach.
Summary: Microorganisms responsible for the infectious complications associated with anticytokine therapy are generally intracellular pathogens or pathogens that commonly exist in a chronic, latent state and are normally held in check by cell-mediated immunity. Diagnosis requires a high index of suspicion and prompt acquisition of appropriate tissue for microscopic examination and microbiologic culture. Prompt empiric therapy that focuses on the most likely infections is necessary to prevent mortality.
Rheumatologists are well aware of the myriad infectious complications associated with rheumatoid arthritis (RA) and the use of traditional disease-modifying antirheumatic drugs. However, the newer anticytokine agents have been associated with an increased risk of disease caused by specific pathogens. In 2003, the tumor necrosis factor (TNF)-α inhibitors infliximab (Remicade; Centocor, Malvern, PA) and etanercept (Enbrel; Immunex Corporation, Seattle, WA; reviewed by Criscione and St Clair) were joined by adalimumab (Humira; Abbott Laboratories, Abbott Park, IL; approval 12/30/2002) for treatment of RA. Off- and on-label use of these agents, along with the interleukin-1 receptor antagonist anakinra (Kineret; Amgen, Thousand Oaks, CA), appears to be increasing.
There is no evidence at this time that anakinra is associated with increased pathogen-specific infectious complications. There are two new agents that may be shown useful in inflammatory conditions. These include rituximab (Rituxan; IDEC Pharmaceuticals Corporation, San Diego, CA), a monoclonal antibody reacting with CD20 antigens on B-lymphocytes, and alemtuzumab (Campath; Berlex Laboratories, Wayne, NJ), reacting with CD52 antigen expressed on normal and malignant lymphocytes and monocytes. Until these agents are tested in a population without underlying leukopenia, their propensity to cause infection can only be speculative.
This review focuses on recent reports of infection associated with the use of TNF-α inhibitors, as well as publications that help elucidate the pathophysiologic basis for their occurrence. Evolving sets of recommendations for prevention, diagnosis, and treatment of infectious complications of their use are explored.
Purpose of Review: There are three tumor necrosis factor-α inhibitors on the US and European markets today, and uncommon but devastating infectious complications accompany their use. This review describes the most important pathogen-specific infections and their relative frequency. Recent literature is summarized that has helped elucidate the pathophysiologic basis for their occurrence. Finally, evolving sets of recommendations for prevention, diagnosis, and treatment of infectious complications of their use are explored.
Recent Findings: Tuberculosis has continued to be the most common pathogen reported in association with infliximab, and less so with etanercept and adalimumab. Determining treated population case rates depends on having an accurate denominator and reflects the local population's latent infection rate. The same is true for histoplasmosis. Other pathogens requiring intact cellular immunity for control of latent infection have also been reported. Specific recommendations for preventive therapy are being made, but prospective clinical trials are needed to assess the risk-benefit of any particular approach.
Summary: Microorganisms responsible for the infectious complications associated with anticytokine therapy are generally intracellular pathogens or pathogens that commonly exist in a chronic, latent state and are normally held in check by cell-mediated immunity. Diagnosis requires a high index of suspicion and prompt acquisition of appropriate tissue for microscopic examination and microbiologic culture. Prompt empiric therapy that focuses on the most likely infections is necessary to prevent mortality.
Rheumatologists are well aware of the myriad infectious complications associated with rheumatoid arthritis (RA) and the use of traditional disease-modifying antirheumatic drugs. However, the newer anticytokine agents have been associated with an increased risk of disease caused by specific pathogens. In 2003, the tumor necrosis factor (TNF)-α inhibitors infliximab (Remicade; Centocor, Malvern, PA) and etanercept (Enbrel; Immunex Corporation, Seattle, WA; reviewed by Criscione and St Clair) were joined by adalimumab (Humira; Abbott Laboratories, Abbott Park, IL; approval 12/30/2002) for treatment of RA. Off- and on-label use of these agents, along with the interleukin-1 receptor antagonist anakinra (Kineret; Amgen, Thousand Oaks, CA), appears to be increasing.
There is no evidence at this time that anakinra is associated with increased pathogen-specific infectious complications. There are two new agents that may be shown useful in inflammatory conditions. These include rituximab (Rituxan; IDEC Pharmaceuticals Corporation, San Diego, CA), a monoclonal antibody reacting with CD20 antigens on B-lymphocytes, and alemtuzumab (Campath; Berlex Laboratories, Wayne, NJ), reacting with CD52 antigen expressed on normal and malignant lymphocytes and monocytes. Until these agents are tested in a population without underlying leukopenia, their propensity to cause infection can only be speculative.
This review focuses on recent reports of infection associated with the use of TNF-α inhibitors, as well as publications that help elucidate the pathophysiologic basis for their occurrence. Evolving sets of recommendations for prevention, diagnosis, and treatment of infectious complications of their use are explored.
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