Page 372 - Basic _ Clinical Pharmacology ( PDFDrive )

358 SECTION IV Drugs with Important Actions on Smooth Muscle

FUTURE DIRECTIONS OF ASTHMA expression of T2-dependent genes (https://clinicaltrials.gov/ct2/
THERAPY show/NCT02066298).
The pace of advance in the scientific description of the immuno-
Ironically, the effectiveness of ICS as a treatment for most patients pathogenesis of asthma has spurred the development of many new
with asthma, especially young adults with allergic asthma, may therapies that target different sites in the immune cascade. Beyond
have retarded recognition that the term “asthma” encompasses a the monoclonal antibodies directed against cytokines (IL-4, IL-5,
heterogeneous collection of disorders, many of which are poorly IL-13) already reviewed (Table 20–1), these include antagonists of
responsive to corticosteroid treatment. The existence of different cell adhesion molecules, protease inhibitors, and immunomodulators
forms or subtypes of asthma has actually long been recognized, aimed at shifting CD4 lymphocytes from the Th2 to the Th1 subtype
as implied by the use of modifying terms such as “extrinsic,” or at selective inhibition of the subset of Th2 lymphocytes directed
“intrinsic,” “aspirin-sensitive,” “adult-onset,” “steroid-dependent,” against particular antigens. As these new therapies are developed, it
“exacerbation-prone,” “seasonal,” “postviral,” and “obesity-related” will become increasingly important to identify biomarkers of specific
to describe asthma in particular patients. More rigorous descrip- phenotypes of asthma that are most likely to benefit from specific
tion of asthma phenotypes, based on cluster analysis of multiple therapies. This will enable truly personalized asthma therapy.
clinical, physiologic, and laboratory features, including analysis of
blood and sputum inflammatory cell assessments, has identified as ■ CLINICAL PHARMACOLOGY OF
many as five different asthma phenotypes. The key question raised
by this approach is whether the phenotypes respond differently to DRUGS USED IN THE TREATMENT
available asthma treatments. OF ASTHMA
Persuasive evidence of the existence of different asthma pheno-
types requiring different approaches to therapy is the demonstra- National and international guidelines for asthma emphasize the
tion of differences in the pattern of gene expression in the airway need for adjusting the intensity of asthma therapy to the under-
epithelium of asthmatic and healthy subjects. Compared with lying severity of the disease and the level of control achieved
healthy controls, half of the asthmatic participants overexpressed by the patient’s current treatment (https://www.nhlbi.nih.gov/
genes for periostin, CLCA1, and serpinB2, genes known to be up- health-pro/guidelines/current/asthma-guidelines; ginasthma.org).
regulated in airway epithelial cells by IL-13, a signature cytokine An underlying principle common to these guidelines is that
of T2 lymphocytes. The other half of the asthmatic participants asthma should be considered in two time domains. In the present
did not. These findings suggest that fundamentally different domain, asthma is important for the symptoms and impairments
pathophysiologic mechanisms exist even among patients with it causes—cough, nocturnal awakenings, and shortness of breath
mild asthma. The participants with overexpression of genes up- that interfere with the ability to exercise or to pursue desired
regulated by IL-13 are referred to as having a “T2-high molecular activities. For mild asthma, occasional inhalation of a broncho-
phenotype” of asthma. The other subjects, who did not overex- dilator may be all that is needed to control these symptoms. For
press these genes, are described as having a “non-T2”or “T2-low” more severe asthma, treatment with a long-term controller, like an
molecular phenotype. The T2-high asthmatic subjects on average ICS, is necessary to relieve symptoms and restore function. The
tended to have more sputum eosinophilia and blood eosinophilia, second domain of asthma is the risk it presents of future events,
positive skin test results, higher levels of IgE, and greater expres- such as exacerbations or progressive loss of pulmonary function.
sion of certain mucin genes. The response to ICS treatment of Satisfaction with the ability to control symptoms and maintain
these two groups was quite different. Six weeks of treatment with function by frequent use of an inhaled β agonist does not mean
2
an ICS improved forced expiratory volume in 1 second (FEV ) that the risk of future events is also controlled. In fact, use of two
1
only in the T2-high subjects. The implications of these findings or more canisters of an inhaled β agonist per month is a marker
are far reaching because they indicate that perhaps as many as half for increased risk of asthma fatality.
of patients with mild to moderate asthma do not respond to ICS The challenges of assessing severity and adjusting therapy for
therapy. The proportion of non-ICS responders among patients these two domains of asthma are different. For relief of distress
with severe “steroid-resistant” asthma could be much higher. in the present domain, the key information is obtained by asking
Current research focuses on further exploring molecular pheno- specific questions about the frequency and severity of symptoms,
types in asthma and in finding effective treatments for each group. the frequency of rescue use of an inhaled β agonist, the frequency
An investigational IL-13 receptor antagonist, lebrikizumab, of nocturnal awakenings, and the ability to exercise, and by mea-
for example, has been shown to be more effective in asthmatic suring lung function with spirometry. The best predictor of the
subjects with elevated serum levels of periostin (one of the genes risk for future exacerbations is the frequency and severity of their
up-regulated in the “T2-high molecular phenotype”). occurrence in the past. Without such a history, estimation of
To examine whether tiotropium might be an alternative risk is more difficult. In general, patients with poorly controlled
to ICS therapy for “T2-low” asthma, a NIH–sponsored mul- symptoms have a heightened risk of exacerbations in the future,
ticenter trial is embarking on a prospective, double-blind, but some patients seem unaware of the severity of their airflow
placebo-controlled trial of ICS versus tiotropium in asthmatic obstruction (sometimes described as “poor perceivers”) and can be
subjects characterized as T2-high or non-T2-high by analysis of identified only by measurement of pulmonary function. Reduc-
their induced sputum samples for eosinophil number and for tions in the FEV 1 correlate with heightened risk of future attacks