Leukotriene modifiers may provide benefit and should be used in stepwise fashion as an alternative to LABA in appropriately selected patients. Cromolyn may be considered as alternative to ICS in mild persistent asthma, but is rarely used. Theophylline may be considered if other options have not been successful. Serum levels should be maintained between 5 and 15 μg/mL, and routine monitoring is indicated due to significant toxicities and medication interactions. Omalizumab can be considered as adjunctive therapy in patients with elevated IgE in the prescribed target ranges (30-700 IU/mL) and sensitivity to relevant allergies. In patients with chronic, refractory symptoms there may be a role for oral corticosteroid therapy outside the setting of acute exacerbations. This decision should be individualized and balance the
benefits obtained from therapy against the risks of chronic steroid use (impaired glucose control, immunosuppression, poor wound healing, adverse effects on bone density, and adverse psychiatric effects).
Novel biologic therapies for asthma include antagonists of cytokines interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), and tumor necrosis factor (TNF)-α inhibitors. These agents have been evaluated in phase 2 and phase 3 studies thus far. The eosinophilic asthma phenotype is described as increased blood or sputum eosinophil levels correlating with disease activity. T-helper 2 cells that express IL-4, IL-5, and IL-13 coordinate eosinophilic inflammation in asthma. 21
Mepolizumab (anti–IL-5) has been shown to be effective in reduction of exacerbations in patients with eosinophilic asthma phenotype, particularly those with frequent exacerbations. 22 Reslizumab (humanized anti–IL-5) has been shown to significantly reduce symptoms and is currently undergoing phase 3 trials. 21 Benralizumab is a humanized fucosylated IgG1κ monoclonal antibody (mAb) that binds IL-5Ra in order to induce apoptosis in eosinophils and basophils. It is currently under investigation for use in asthma and COPD. 21
Lebrikizumab (anti–IL-13) has been shown to improve lung function in inadequately controlled asthma patients with elevated periostin levels. 23 Tralokinumab (anti–IL-13 humanized IgG4) improved FEV1 and reduced symptoms in patients with moderate to severe uncontrolled asthma in comparison with placebo. 24 Pitrakinra is a recombinant IL-4 variant that competitively inhibits the IL-4Rα receptor, inhibiting the function of both IL-4 and IL-13. This agent may prove beneficial in patients with atopic asthma. 21
Dupilumab, a fully humanized mAb to the IL-4Rα/IL-13Rα receptor complex inhibiting actions of both IL-4 and IL-13 signaling, and has demonstrated > 80% relative reduction in asthma exacerbations, improved symptoms and led to improvement in FEV1 in patients with
moderate to severe asthma and increased serum or sputum eosinophils. 25 It may represent a promising avenue for future asthma research, as its initial investigation has shown both improvement in function and clinical outcomes. Ultimately, ongoing research will be needed to determine the long-term effects of these agents and whether they offer efficacy in asthma patients in general vs specific asthma-phenotypes.
The TNF-α inhibitors have also been investigated for use in asthma. TNF-α is an innate cytokine implicated in chronic inflammatory conditions, including rheumatoid arthritis and Crohn’s disease. Macrophages are a major source of TNF-α along with contributions from monocytes, dendritic cells, B lymphocytes, T cells,neutrophils, mast cells, and eosinophils. TNF-α has a proinflammatory effect on eosinophils, neutrophils, T cells, epithelial cells, and endothelial cells. Studies of asthma have revealed increased TNF-α within respiratory epithelial tissue biopsies and airway lavages of patients with severe asthma compared with those with good control. Etanercept, a soluble TNF-α receptor linked to human IgG1, has been reported to significantly improve symptoms and lung function in severe refractory asthma. 26
However golimumab, an anti-TNF biologic, was shown to have deleterious effects, including an increased rate of serious infections, potential increased risk of malignancy, and 1 death in the treatment group. 27 Identification of the correct patient population may improve clinical outcomes, but a potentially unfavorable risk benefit ratio may limit the future of anti–TNF-α therapy in severe asthma.