Resistance Thwarts Asthma Control

TORONTO — Steroid resistance is increasingly being recognized as a factor contributing to uncontrolled asthma and progression of lung disease, according to a pediatric allergy/immunology expert.

Resistance to inhaled corticosteroids is more common than was previously recognized, and can be found in 25%–35% of patients with asthma.

“In general, steroids are extremely effective in asthma, and really are the most effective anti-inflammatory drugs we have; but in any study of inhaled steroids in asthma, there is remarkable variability in response,” said Dr. Donald Y.M. Leung, head of pediatric allergy and immunology at the National Jewish Medical and Research Center, Denver.

Multiple factors can contribute to steroid resistance, including genetics and ethnicity, with blacks being affected more commonly than whites, he said at an international conference of the American Thoracic Society. Allergen exposure, smoking, and obesity also have been implicated.

Steroid sensitivity is defined as a greater-than-20% improvement in FEV1 (forced expiratory volume in 1 second) from baseline after a week of treatment with oral prednisone in doses of 20 mg twice a day, whereas steroid resistance is a less-than-15% improvement, Dr. Leung said.

Investigations of patients who are steroid resistant found that they have persistent airway activation, with elevations in interleukin-2, -4, -5, -8, and -13, as well as tumor necrosis factor, despite the use of prednisone. Those cytokines target different cell types, with IL-2 and IL-4 being capable of inducing steroid resistance in T cells, IL-8 inducing resistance in neutrophils, and IL-13 inducing resistance in monocytes and macrophages, he said.

Recent studies have shown that steroid-resistant patients also have increased levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in their bronchoalveolar lavage samples. Those molecules control collagen deposition, and a correct ratio of them is needed to prevent airway remodeling. Patients who are steroid resistant have an imbalance between MMPs and TIMPs, and more ongoing protease activity. Steroids' inability to enhance TIMP-1 production contributes to the abnormal MMP/TIMP ratio in steroid resistant patients. The result of those abnormalities is modification of airway wall matrix deposition, remodeling, and irreversible lung disease (J. Allergy Clin. Immunol. 2007;120:1065-72).

“We have also investigated the mechanisms by which resistance develops [and] have found that a key element in corticosteroid action is the ability to induce nuclear translocation of the glucocorticoid receptor from the cytoplasm into the nucleus,” Dr. Leung said. The anti-inflammatory effects of those drugs are mediated through the a (rather than the b) isoform of the glucocorticoid receptor, he explained.

Bronchoalveolar lavage samples from patients who have steroid-resistant asthma have been shown to have reduced a-receptor translocation in response to the drugs, as well as overexpression of its endogenous inhibitor, the b receptor. “The inflammatory milieu in the airways of these patients is driving up the expression of the b receptor.” Microbial superantigens also can induce T-cell resistance to steroids, suggesting a possible role for infection in the development of resistance, he said.

That superantigen-induced resistance can occur via a specific T-cell receptor signaling pathway involving the mitogen-activated protein kinase and the extracellular signal-regulated kinase, leading to phosphorylation of the a receptor of the glucocorticoid receptor and inhibition of nuclear translocation (J. Allergy Clin. Immunol. 2004; 114:1059-69). Those studies suggest that the glucocorticoid receptor itself might be a potential therapeutic target in resistant asthma, he noted. Dr. Leung said he has no financial relationship with a commercial entity involved in this work.

TORONTO — Steroid resistance is increasingly being recognized as a factor contributing to uncontrolled asthma and progression of lung disease, according to a pediatric allergy/immunology expert.

Resistance to inhaled corticosteroids is more common than was previously recognized, and can be found in 25%–35% of patients with asthma.

“In general, steroids are extremely effective in asthma, and really are the most effective anti-inflammatory drugs we have; but in any study of inhaled steroids in asthma, there is remarkable variability in response,” said Dr. Donald Y.M. Leung, head of pediatric allergy and immunology at the National Jewish Medical and Research Center, Denver.

Multiple factors can contribute to steroid resistance, including genetics and ethnicity, with blacks being affected more commonly than whites, he said at an international conference of the American Thoracic Society. Allergen exposure, smoking, and obesity also have been implicated.

Steroid sensitivity is defined as a greater-than-20% improvement in FEV1 (forced expiratory volume in 1 second) from baseline after a week of treatment with oral prednisone in doses of 20 mg twice a day, whereas steroid resistance is a less-than-15% improvement, Dr. Leung said.

Investigations of patients who are steroid resistant found that they have persistent airway activation, with elevations in interleukin-2, -4, -5, -8, and -13, as well as tumor necrosis factor, despite the use of prednisone. Those cytokines target different cell types, with IL-2 and IL-4 being capable of inducing steroid resistance in T cells, IL-8 inducing resistance in neutrophils, and IL-13 inducing resistance in monocytes and macrophages, he said.

Recent studies have shown that steroid-resistant patients also have increased levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in their bronchoalveolar lavage samples. Those molecules control collagen deposition, and a correct ratio of them is needed to prevent airway remodeling. Patients who are steroid resistant have an imbalance between MMPs and TIMPs, and more ongoing protease activity. Steroids' inability to enhance TIMP-1 production contributes to the abnormal MMP/TIMP ratio in steroid resistant patients. The result of those abnormalities is modification of airway wall matrix deposition, remodeling, and irreversible lung disease (J. Allergy Clin. Immunol. 2007;120:1065-72).

“We have also investigated the mechanisms by which resistance develops [and] have found that a key element in corticosteroid action is the ability to induce nuclear translocation of the glucocorticoid receptor from the cytoplasm into the nucleus,” Dr. Leung said. The anti-inflammatory effects of those drugs are mediated through the a (rather than the b) isoform of the glucocorticoid receptor, he explained.

Bronchoalveolar lavage samples from patients who have steroid-resistant asthma have been shown to have reduced a-receptor translocation in response to the drugs, as well as overexpression of its endogenous inhibitor, the b receptor. “The inflammatory milieu in the airways of these patients is driving up the expression of the b receptor.” Microbial superantigens also can induce T-cell resistance to steroids, suggesting a possible role for infection in the development of resistance, he said.

That superantigen-induced resistance can occur via a specific T-cell receptor signaling pathway involving the mitogen-activated protein kinase and the extracellular signal-regulated kinase, leading to phosphorylation of the a receptor of the glucocorticoid receptor and inhibition of nuclear translocation (J. Allergy Clin. Immunol. 2004; 114:1059-69). Those studies suggest that the glucocorticoid receptor itself might be a potential therapeutic target in resistant asthma, he noted. Dr. Leung said he has no financial relationship with a commercial entity involved in this work.

TORONTO — Steroid resistance is increasingly being recognized as a factor contributing to uncontrolled asthma and progression of lung disease, according to a pediatric allergy/immunology expert.

Resistance to inhaled corticosteroids is more common than was previously recognized, and can be found in 25%–35% of patients with asthma.

“In general, steroids are extremely effective in asthma, and really are the most effective anti-inflammatory drugs we have; but in any study of inhaled steroids in asthma, there is remarkable variability in response,” said Dr. Donald Y.M. Leung, head of pediatric allergy and immunology at the National Jewish Medical and Research Center, Denver.

Multiple factors can contribute to steroid resistance, including genetics and ethnicity, with blacks being affected more commonly than whites, he said at an international conference of the American Thoracic Society. Allergen exposure, smoking, and obesity also have been implicated.

Steroid sensitivity is defined as a greater-than-20% improvement in FEV1 (forced expiratory volume in 1 second) from baseline after a week of treatment with oral prednisone in doses of 20 mg twice a day, whereas steroid resistance is a less-than-15% improvement, Dr. Leung said.

Investigations of patients who are steroid resistant found that they have persistent airway activation, with elevations in interleukin-2, -4, -5, -8, and -13, as well as tumor necrosis factor, despite the use of prednisone. Those cytokines target different cell types, with IL-2 and IL-4 being capable of inducing steroid resistance in T cells, IL-8 inducing resistance in neutrophils, and IL-13 inducing resistance in monocytes and macrophages, he said.

Recent studies have shown that steroid-resistant patients also have increased levels of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in their bronchoalveolar lavage samples. Those molecules control collagen deposition, and a correct ratio of them is needed to prevent airway remodeling. Patients who are steroid resistant have an imbalance between MMPs and TIMPs, and more ongoing protease activity. Steroids' inability to enhance TIMP-1 production contributes to the abnormal MMP/TIMP ratio in steroid resistant patients. The result of those abnormalities is modification of airway wall matrix deposition, remodeling, and irreversible lung disease (J. Allergy Clin. Immunol. 2007;120:1065-72).

“We have also investigated the mechanisms by which resistance develops [and] have found that a key element in corticosteroid action is the ability to induce nuclear translocation of the glucocorticoid receptor from the cytoplasm into the nucleus,” Dr. Leung said. The anti-inflammatory effects of those drugs are mediated through the a (rather than the b) isoform of the glucocorticoid receptor, he explained.

Bronchoalveolar lavage samples from patients who have steroid-resistant asthma have been shown to have reduced a-receptor translocation in response to the drugs, as well as overexpression of its endogenous inhibitor, the b receptor. “The inflammatory milieu in the airways of these patients is driving up the expression of the b receptor.” Microbial superantigens also can induce T-cell resistance to steroids, suggesting a possible role for infection in the development of resistance, he said.

That superantigen-induced resistance can occur via a specific T-cell receptor signaling pathway involving the mitogen-activated protein kinase and the extracellular signal-regulated kinase, leading to phosphorylation of the a receptor of the glucocorticoid receptor and inhibition of nuclear translocation (J. Allergy Clin. Immunol. 2004; 114:1059-69). Those studies suggest that the glucocorticoid receptor itself might be a potential therapeutic target in resistant asthma, he noted. Dr. Leung said he has no financial relationship with a commercial entity involved in this work.