Therapeutic Options for Persistent Asthma

During the 140 years that followed Henry Hyde Salter's first description of asthma¹ as a distinct syndrome characterized by paroxysmal episodes of bronchospasm, there has been a relentless search to understand the mechanisms by which this disease affects the conducting airways. The specific airway inflammation in asthma involves mast cells, macrophages, and eosinophils orchestrated by cytokines secreted from a subset of T cells (T_H2-like) and is accompanied by increased bronchial hyperresponsiveness to both direct (eg, methacholine) and indirect (eg, exercise) stimuli. These characteristics may in part explain the disordered airway function in asthma, its relationship to environmental exposures, and therapeutic responses observed with inhaled corticosteroids and β₂-agonists.^{2 - 3} For both inhaled corticosteroids and β₂-agonists, the last 2 decades have witnessed a progressive improvement in drug efficacy, delivery, duration of action, and therapeutic index, making twice daily inhaled therapy for asthma feasible.

As principal objectives of asthma management, consensus asthma treatment guidelines^{4 - 5} reinforce the importance of achieving symptom control, preventing exacerbations, and normalizing lung function. For the treatment of persistent asthma, current guidelines recommend anti-inflammatory controller therapy, usually with an inhaled corticosteroid, and inhaled short-acting β₂-agonists to treat breakthrough symptoms.

However, for patients who remain symptomatic despite receiving low to moderate doses of inhaled corticosteroids on a regular basis, supplementation of their controller therapy with an inhaled long-acting β₂-agonist has proven superior to increasing the dose of inhaled corticosteroids. In a meta-analysis of 9 randomized controlled trials in which salmeterol xinafoate added to inhaled corticosteroid therapy was compared with at least a doubling in the dose of inhaled corticosteroids, improvement in lung function (peak expiratory flow [PEF], forced expiratory volume in 1 second [FEV₁]) and symptom reduction were greater with combined therapy, and exacerbations were decreased.⁶ This finding is consistent with the results from another trial by Pauwels et al⁷ in which formoterol fumarate was added to inhaled budesonide.

These important clinical findings raise the question of whether long-acting β₂-agonists exert beneficial effects in asthma by mechanisms that extend beyond simply relaxing airway smooth muscle, such as by inhibiting some aspects of airway inflammation. In allergen challenge, salmeterol inhibits both the early and late asthmatic responses and the attendant increase in bronchial hyperresponsiveness.⁸ However, it is unclear whether these effects are accompanied by reduced airway inflammation. In 1 study,⁹ salmeterol inhibited the increase in the percentage of eosinophils after allergen challenge but had no effect on sputum eosinophilia in a second study.¹⁰ Bronchoalveolar lavage and mucosal biopsy studies performed before and 6 to 9 weeks after treatment with a long-acting β₂-agonist have shown either no¹¹ or a variable inhibitory effect on the mast cell, eosinophil, and T-cell components of airway inflammation.^{12 - 13}

Because of these conflicting findings on the effect of long-acting β₂-agonists on airway inflammation, it is important to establish whether a long-acting β₂-agonist can be used to replace inhaled corticosteroids in the maintenance treatment of mild to moderate asthma. In this issue of THE JOURNAL, Lazarus and colleagues¹⁴ report that for patients with persistent asthma that is well controlled with low-dose inhaled triamcinolone acetonide alone, switching to salmeterol results in appreciable loss of disease control whether assessed by frequency of exacerbations, change in symptoms, or indices of inflammation in induced sputum. The conclusion from this study is that long-acting β₂-agonists, despite their subtle effects on airway inflammation, cannot replace inhaled corticosteroid therapy and maintain optimal asthma control.

Concerns over the use of long-acting β₂-agonists as monotherapy for asthma are further enhanced by evidence showing that regular use of these agents results in down-regulation of β₂-adrenoceptor function manifested as loss of protection against exercise, adenosine, and allergen challenge.^{15 - 16} Thus, warnings about the risks of using regularly scheduled short-acting β₂-agonists alone for asthma control¹⁷ can be confidently extended to their long-acting counterparts.

The persistence of symptoms and impaired quality of life for many patients with asthma despite regular use of inhaled corticosteroids and the shallow dose-response curve that this drug class has on many asthma outcome measures justifies the use of long-acting β₂-agonists to supplement inhaled corticosteroids. Once a patient is stabilized using combination therapy, however, the question becomes whether it is safe to reduce the dose of inhaled corticosteroids. A second study by Lemanske and colleagues¹⁸ reported in this issue of THE JOURNAL shows that among patients who remained symptomatic while taking low doses of inhaled corticosteroid, the addition of a long-acting β₂-agonist not only improved asthma control but also enabled the inhaled corticosteroid dose to be reduced by approximately 50% without apparent loss of asthma control. In contrast to the study by Lazarus et al,¹⁴ Lemanske et al did not report measures of airway inflammation. Furthermore, it is not known whether asthma control would be maintained beyond the 8 weeks of the inhaled corticosteroid reduction phase of the trial or whether asthma control equivalent to that achieved with the original dose of inhaled corticosteroid plus added salmeterol could be maintained if patients were exposed to an environmental asthmogenic challenge, such as exercise, allergen, or viral infection.

Although current asthma treatment guidelines^{4 - 5} emphasize the importance of controlling asthma with the lowest possible dose of inhaled corticosteroids to minimize systemic adverse effects, it is now clear that the choice of dosage varies depending on the outcome measure used. For example, when compared with the dose of inhaled corticosteroid required to normalize baseline pulmonary function, a much higher dose may be required over a longer time to normalize bronchial hyperresponsiveness and prevent asthma exacerbations.^{19 - 20} In contrast, treatment with long-acting β₂-agonists, which combine bronchodilatation with functional antagonism of bronchoconstriction may achieve full benefit on symptoms and pulmonary function within 24 hours.²¹ However, underlying airway inflammation might continue such that, if several doses of the long-acting β₂-agonist were omitted, control of asthma would be lost rapidly, especially in the presence of an added environmental challenge. When the dose of inhaled corticosteroid is progressively reduced in patients with well-controlled asthma, an increase in sputum eosinophils precedes the onset of clinical deterioration.²² But in the presence of a long-acting β₂-agonist, symptoms and pulmonary function measures reflecting this failure would be masked.²³

Thus, although the study by Lemanske et al¹⁸ showed that patients receiving combination therapy with salmeterol and triamcinolone had no statistical difference in outcomes after the inhaled corticosteroid dosage was reduced by half compared with patients who continued combination therapy with the original inhaled corticosteroid dosage, it is premature to conclude that the 2 therapies are equivalent. Longer-term effectiveness studies under "real world" conditions during which patients with variable medication adherence experience a variety of environmental exposures are needed to establish the efficacy and safety of inhaled corticosteroid dosage reduction after the addition of a long-acting β₂-agonist.

There is some evidence to suggest that the effects of combination therapy with an inhaled corticosteroid and a long-acting β₂-agonist relate not only to their cellular targets in the airways, but their combined mechanisms of action may improve disease control. Long-acting β₂-agonists have been shown to prime corticosteroid receptors for increased corticosteroid binding and nuclear translocation,²⁴ and corticosteroids help prevent the development of tolerance acquired on repeated exposure to long-acting β₂-agonists by up-regulating β₂-adrenoceptor synthesis.²⁵

However, neither of these observations satisfactorily explains how long-acting β₂-agonists are able to protect asthmatic airways against exacerbations, especially those caused by a respiratory viral infection. By simply increasing baseline airway caliber and providing functional antagonism against released bronchoconstrictor mediators, some protection from an asthma exacerbation could result. Another possibility is that long-acting β₂-agonists directly affect airway epithelial cells by increasing their resistance to injury. In addition to inflammation, abnormal epithelial-mesenchymal signaling is an important component of asthma that contributes to both airway inflammation and tissue remodeling.²⁶ Long-term studies are needed to show whether combining long-acting β₂-agonists with inhaled corticosteroids produces sustained benefit in asthma compared with other additive treatments, such as leukotriene inhibitors or theophylline, and whether any of these interventions are able to alter the natural history of the disease, including airway remodeling.

In contrast to other chronic inflammatory disorders, such as rheumatoid arthritis, the natural history of asthma is not well understood, and those drugs that may benefit or adversely affect the long-term outcome of chronic asthmatic inflammation are not known. Until this information becomes available, it seems prudent to reinforce current asthma management guidelines that emphasize the principle of controlling airway inflammation as a primary objective, generally with inhaled corticosteroids, and not to use long-acting β₂-agonist monotherapy as first-line controller therapy. Adding a long-acting β₂-agonist to inhaled corticosteroid therapy may be a reasonable strategy for the treatment of patients with persistent asthma, but only if the physician is satisfied that the patient is receiving an adequate anti-inflammatory dose of an inhaled corticosteroid.