Long-Term Risks Associated With Biologic Response Modifiers Used
Long-Term Risks Associated With Biologic Response Modifiers Used
Purpose of Review: The introduction of tumor necrosis factor-α antagonists in 1998 has had a significant impact on the treatment of rheumatoid arthritis. However, as use of these agents has increased worldwide, infrequent adverse events that were not apparent in pivotal controlled clinical trials required for registration have emerged.
Recent Findings: These adverse events include serious infections, particularly tuberculosis, which may be atypical in presentation. Concern regarding increased risk of lymphoma has also emerged, although it remains unclear whether the risk exceeds that observed in other rheumatoid arthritis patients with comparable disease activity. Development of a systemic lupus erythematosuslike syndrome, which typically abates after discontinuation of the drug, is another rare complication that was further reported during the past year. Finally, additional cases of congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy) have been reported that appear to be related to the tumor necrosis factor-α antagonists.
Summary: Additional postmarketing surveillance of these and other serious adverse events is necessary to determine the true risk of their occurrence, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-α antagonists will be required.
Three tumor necrosis factor (TNF)-α antagonists that bind and neutralize TNF are available for clinical use. Etanercept, a protein composed of two p75 TNF-α receptors fused to the Fc portion of IgG1, is approved for rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, and juvenile chronic arthritis. Infliximab, a chimeric IgG1κ monoclonal antibody binding, is approved for RA, and Crohn disease. Adalimumab, a fully humanized IgG1κ monoclonal antibody, is approved for RA. Worldwide prescription data through December 2002 indicates that patient exposure for infliximab is estimated at 400,000, etanercept at 150,000, and 2468 in clinical trials for adalimumab.
These biologics have redefined therapy in RA, most notably because of their ability to improve disease activity in patients who have not responded to conventional disease-modifying antirheumatic drug (DMARD) treatment and to retard radiographic progression. Controlled phase III trials during clinical development for TNF-α antagonists failed to show an increase in overall serious adverse events (AEs) above active comparator controls. However, postmarketing reports, most notably of infections and lymphoma, have heightened awareness of potential AEs, and have led to Food and Drug Administration (FDA)-mandated label changes. The identification of postmarketing AEs relies on multifaceted efforts using the FDA MedWatch program (1-800-332-1088 or www.fda.gov/medwatch]), case reports, clinical population databases, patient registries, and phase IV clinical trials. There are limitations for each of these surveillance mechanisms, including potential over- or underreporting of events, unconfirmed diagnoses, absence of a control population, and imprecise calculations of event rates. However, taken together, these reports create a reasonable basis for the continued assessment of the overall safety of TNF-α antagonists. This article focuses on serious AEs reported during the past year from each of these sources, and provides a comprehensive overview of the best available evidence for each of the purported associations with TNF blockade.
Purpose of Review: The introduction of tumor necrosis factor-α antagonists in 1998 has had a significant impact on the treatment of rheumatoid arthritis. However, as use of these agents has increased worldwide, infrequent adverse events that were not apparent in pivotal controlled clinical trials required for registration have emerged.
Recent Findings: These adverse events include serious infections, particularly tuberculosis, which may be atypical in presentation. Concern regarding increased risk of lymphoma has also emerged, although it remains unclear whether the risk exceeds that observed in other rheumatoid arthritis patients with comparable disease activity. Development of a systemic lupus erythematosuslike syndrome, which typically abates after discontinuation of the drug, is another rare complication that was further reported during the past year. Finally, additional cases of congestive heart failure and demyelinating syndromes (including cases resembling progressive multifocal leukoencephalopathy) have been reported that appear to be related to the tumor necrosis factor-α antagonists.
Summary: Additional postmarketing surveillance of these and other serious adverse events is necessary to determine the true risk of their occurrence, and whether a reassessment of the overall risk-benefit of tumor necrosis factor-α antagonists will be required.
Three tumor necrosis factor (TNF)-α antagonists that bind and neutralize TNF are available for clinical use. Etanercept, a protein composed of two p75 TNF-α receptors fused to the Fc portion of IgG1, is approved for rheumatoid arthritis (RA), psoriatic arthritis, ankylosing spondylitis, and juvenile chronic arthritis. Infliximab, a chimeric IgG1κ monoclonal antibody binding, is approved for RA, and Crohn disease. Adalimumab, a fully humanized IgG1κ monoclonal antibody, is approved for RA. Worldwide prescription data through December 2002 indicates that patient exposure for infliximab is estimated at 400,000, etanercept at 150,000, and 2468 in clinical trials for adalimumab.
These biologics have redefined therapy in RA, most notably because of their ability to improve disease activity in patients who have not responded to conventional disease-modifying antirheumatic drug (DMARD) treatment and to retard radiographic progression. Controlled phase III trials during clinical development for TNF-α antagonists failed to show an increase in overall serious adverse events (AEs) above active comparator controls. However, postmarketing reports, most notably of infections and lymphoma, have heightened awareness of potential AEs, and have led to Food and Drug Administration (FDA)-mandated label changes. The identification of postmarketing AEs relies on multifaceted efforts using the FDA MedWatch program (1-800-332-1088 or www.fda.gov/medwatch]), case reports, clinical population databases, patient registries, and phase IV clinical trials. There are limitations for each of these surveillance mechanisms, including potential over- or underreporting of events, unconfirmed diagnoses, absence of a control population, and imprecise calculations of event rates. However, taken together, these reports create a reasonable basis for the continued assessment of the overall safety of TNF-α antagonists. This article focuses on serious AEs reported during the past year from each of these sources, and provides a comprehensive overview of the best available evidence for each of the purported associations with TNF blockade.