Cytokine inhibition in severe asthma: current knowledge and future directions

A growing list of cytokines that contribute to the pathogenesis of asthma has been identified. The purpose of this review is to explore the specific cytokines involved in asthma, including their functions, cell sources, and clinical evidence that they participate in asthma. Existing data from clinical trials of cytokine antagonists in asthmatic patients are then reviewed to determine the efficacy and safety of these compounds.

Cytokine antagonists that have been investigated recently in asthma include monoclonal antibodies directed against interleukin (IL)-5, tumor necrosis factor-alpha (TNF-α), and IL-4/IL-13. Although initial studies of anti-IL-5 in mild-to-moderate asthmatic patients demonstrated no clinical efficacy, two recent small studies of this agent in severe steroid-resistant asthma showed that anti-IL-5 reduced asthma exacerbations significantly. In studies of anti-TNF-α, there were no significant improvements in any asthma outcome, and the drug was associated with several serious adverse events, including pulmonary infections and malignancies. A very recently published study of an antibody with combined IL-4/IL-13 inhibition showed no efficacy in the analysis of the entire study population; however, in a subgroup with more severe asthma, improvements in some asthma endpoints were observed.

Studies of antibodies directed against IL-5 and IL-4/IL-13 have yielded some encouraging data in patients with more severe asthma; future large-scale clinical trials are necessary to make definitive conclusions. Ongoing and future clinical investigations of inhibitors directed at IL-9, IL-13, IL-17, and thymic stromal lymphopoietin may offer potential new agents that will play roles in the treatment of severe asthma.