Effects of Inhaled Corticosteroids, Leukotriene Receptor Antagonists, or Both, Plus Long-Acting β2-Agonists on Asthma Pathophysiology: a Review of the Evidence
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- Vignola, A.M. Drugs (2003) 63: 35. doi:10.2165/00003495-200363002-00004
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Chronic inflammation and smooth muscle dysfunction are consistent features of asthma, and are responsible for disease progression and airway remodelling. The development of chronic airway inflammation depends upon the recruitment and activation of inflammatory cells and the subsequent release of inflammatory mediators, including cytokines.
Cellular and histological evaluation of drugs with anti-inflammatory activity, such as inhaled corticosteroids (ICSs), is achieved by analysing samples of lung tissue or biological fluids, obtained by techniques such as bronchial biopsy, bronchoalveolar lavage and sputum induction. These provide valuable information on the inflammatory processes occurring in the lung, although not all are equal in value.
The beneficial effects of ICSs in asthma treatment are a consequence of their potent and broad anti-inflammatory properties. Furthermore, there have been promising results indicating that ICSs can reverse some of the structural changes that contribute to airway remodelling. Long-acting β2-agonists (LABAs) added to ICSs provide greater clinical efficacy than ICSs alone, suggesting the possibility of complementary activity on the pathophysiological mechanisms of asthma: inflammation and smooth muscle dysfunction.
Leukotrienes play a part in the pathogenesis of asthma. Leukotriene receptor antagonists (LTRAs) directly inhibit bronchoconstriction and may have some antiinflammatory effects, although the extent to which inhibiting one set of inflammatory mediators attenuates the inflammatory response is questionable.
In concert with their effect on a broad variety of inflammatory mediators and cells, treatment with ICSs (including ICSs and LABAs) results in superior control of the pathophysiology of asthma and superior clinical efficacy as assessed by the greater improvements in pulmonary function and overall control of asthma compared with LTRAs.
Asthma is a chronic disease of the airways characterised by inflammation and smooth muscle dysfunction.[1–3] Chronic inflammation causes pathological alterations in the airways of patients with asthma, resulting in structural changes, or ‘remodelling’.[1,4]
Numerous cells are responsible for the pathogenesis of asthma; once activated, these cells release a variety of inflammatory mediators, including cytokines and growth factors. The limited human data available suggest that these mediators have a key role in initiating and perpetuating the inflammatory cycle.[2,5,6]
On the basis that chronic inflammation causes airway remodelling and disease progression, the aim of anti-asthma treatment is not only to provide relief of respiratory symptoms and improve lung function, but also to attenuate long-term inflammation and smooth muscle dysfunction, thus preventing permanent changes (remodelling).
Leukotriene receptor antagonists (LTRAs), such as montelukast, pranlukast and zafirlukast, have recently been licensed as first-line monotherapy or as add-on therapy in patients whose asthma is uncontrolled by ICSs alone. However, LTRAs are not the preferred agents for the treatment of persistent asthma, whether used alone or as add-ons to ICS regimens, according to the National Asthma Education and Prevention Program in the USA. Moreover, as discussed in the other reviews in this Supplement, the use of ICSs and LABAs provides greater clinical benefits in overall control of asthma than does that use of LTRAs, as measured by improvements in pulmonary lung function, use of rescue medication, number of exacerbations and the number of symptom-free days and symptom-free nights.[19,20]
The purpose of this review is to discuss the effect of various treatment strategies on chronic inflammation, smooth muscle dysfunction and airway remodelling in patients with asthma. The article focuses on the effects of ICSs and LTRAs (including ICS plus LABA or LTRA combinations) on inflammatory cells and mediators as measured in clinical samples, including bronchial biopsies, sputum and blood samples.
2. Effects of Treatment on Inflammatory Cells and Mediators
ICSs are the most effective anti-inflammatory agents currently available for the long-term treatment of asthma. Many studies have documented the suppressive effects of ICSs on inflammatory mediators in the airways of patients with asthma. This is reflected by a marked reduction in the numbers of mast cells, eosinophils, macrophages and T cells in bronchial biopsy specimens from these patients.[15,21,22] A reduction in markers of airway inflammation can also be demonstrated in samples of induced sputum.[15,23]
Several studies have documented how the effect of fluticasone propionate on inflammatory cells runs parallel with improvements in lung function. In a study by Booth et al., 20 patients with asthma received fluticasone propionate 1 000μg twice daily for 3 months. Data were compared with those from 26 healthy individuals and differences in inflammatory indices were measured in both bronchoalveolar lavage (BAL) and bronchial biopsies. After 3 months of treatment, considerable improvements in lung function and airway responsiveness were paralleled by a reduction in the number of activated eosinophils in bronchial biopsies. Differences in inflammatory indices in BAL specimens between patients with asthma and healthy individuals were less pronounced, although a trend towards a reduction in BAL eosinophils and mast cells in the fluticasone propionate-treated group was evident. Bronchial biopsies allow assessment of the mucosal structure, including the epithelium, basement membrane, lamina propria and vasculature; this information cannot be gained from BAL. In addition, significant changes in the number of inflammatory cells may be difficult to detect in BAL specimens.
Meijer et al. compared the effects of fluticasone propionate 500 and 2 000 μg/day and oral prednisolone 30 mg/day on sputum eosinophil numbers and eosinophil cationic protein (ECP) concentrations in a double-blind parallel-group study of 120 patients with asthma. Eosinophil numbers and ECP concentrations did not change significantly with fluticasone propionate 500 μg/day, but fluticasone propionate 2 000 μg/day and oral prednisolone caused a significant decrease in both variables. These changes were accompanied by improvements in lung function and airway hyperresponsiveness that were greater for those in the group receiving fluticasone propionate 2 000 μg/day than for those in the group receiving oral prednisolone.
Improved lung function and airway hyperresponsiveness, associated with a reduction in inflammatory cells, have also been demonstrated in studies with BDP and budesonide. In one study, BDP 2 000 μg/day for 2 weeks followed by 1 000 μg/day for 4 weeks in 10 patients with asthma produced a significant reduction in epithelial and mucosal mast cells and eosinophils and in submucosal T cells, compared with baseline; this was accompanied by a decrease in asthma symptoms. Laitinen et al. compared the effect of budesonide with that of the inhaled short-acting β2-agonist, terbutaline, on airway inflammation in 14 patients with newly diagnosed asthma. Treatment with budesonide was associated with significantly fewer inflammatory cells, including eosinophils; these changes were not observed in specimens from terbutaline-treated patients. Although both groups improved clinically, budesonide was more effective than terbutaline in improving morning and evening peak expiratory flow (PEF) rates and airway hyperresponsiveness to inhaled histamine.
The reduction in numbers of inflammatory cells observed after treatment with ICSs may be brought about by the inhibition of the cytokines responsible for their recruitment and stimulation. ICSs are potent inhibitors of tumour necrosis factor (TNF)-α and interleukin (IL)-1, which are released from macrophages and monocytes, and are responsible for the expression of the adhesion molecules E- and P-selectin, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1. These adhesion molecules actively recruit neutrophils, eosinophils and basophils from the circulation.[32,33] ICSs also disrupt the expression of specific endothelial activators, such as IL-4 and IL-13,[32,34] and cytokines that are responsible for eosinophil priming, namely IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor. Furthermore, ICSs are able to upregulate anti-inflammatory cytokines such as IL-10.[22,35] This cytokine inhibits the proliferation of T cells and is an antagonist of IL-1 and TNF-α.
Overall, these findings indicate that ICSs have a broad spectrum of anti-inflammatory effects, producing reductions in inflammatory cell numbers and mediator concentrations and stimulating the production of anti-inflammatory cytokines. This evidence, coupled with the clinical confirmation of their effectiveness over other regimens in improving overall control of asthma and quality of life, supports their use as first-line controller therapy for asthma.
The effect of addition of montelukast 10mg once daily to fluticasone propionate 100μg twice daily, compared with fluticasone propionate 100μg twice daily alone, was investigated in bronchial biopsy specimens from 36 adults with asthma. After 8 weeks of treatment, there was no significant difference between the two treatment regimens in reduction of T cell or eosinophil numbers, demonstrating that the addition of montelukast does not appear to benefit the anti-inflammatory effect over that achieved with fluticasone propionate treatment alone.
Because there are so few published studies directly comparing LTRAs with ICSs, it is useful to review some of the studies that have compared the effects of treatment with an LTRA on inflammatory cells and mediators with those of placebo. Minoguchi et al. examined the effects of 4 weeks of treatment with montelukast 10 mg/day or placebo on sputum eosinophil numbers, and the correlation between sputum eosinophils and bronchodilatation, in 29 patients with asthma. Montelukast significantly decreased the number of sputum eosinophils compared with placebo, and although PEF values significantly improved after montelukast treatment, there was no correlation between the decrease in sputum eosinophils and the increase in PEF.
Attenuation of eosinophilic inflammation by montelukast has also been reported in three other studies. In a group of 19 patients with asthma, Pizzichini et al. showed that, compared with placebo, montelukast 10mg once daily for 4 weeks significantly reduced blood and sputum eosinophils, asthma symptoms and use of β2-agonist. Similarly, in a study of 17 patients with asthma by Nakamura et al., 4 weeks of treatment with pranlukast 225mg twice daily resulted in significant reductions in the number of eosinophils (EG2-positive, but not EG1-positive, cells), T cells and mast cells in bronchial mucosa compared with placebo. These authors concluded that the antagonism of leukotrienes C4 (LTC4), D4 (LTD4) and E4 (LTE4) by pranlukast inhibited the activation of eosinophils and the influx of inflammatory cells into the airways. In contrast, the third study, by Ramsay et al., showed, in 77 patients with asthma, that the reduction in numbers of chromotrope 2R-positive cells (markers for the total number of eosinophils) in bronchial biopsies of those treated with montelukast 10mg once daily for 6 weeks was not significant compared with that obtained with placebo.
Bisgaard et al. studied children with asthma and showed that exhaled NO was significantly reduced after 2 weeks of treatment with montelukast 5mg once daily compared with placebo. However, these results are not supported by data from other trials, which report that LTRAs have no significant effect on exhaled NO concentrations.[9,49]
In summary, there is evidence that LTRAs reduce serum eosinophil numbers in children and adults, and eosinophil numbers in induced sputum. However, data from bronchial biopsies are conflicting, with some studies showing a significant reduction in eosinophil numbers compared with placebo and others showing no significant difference. There is also some evidence to indicate that LTRAs are able to reduce the serum concentrations of the cytokines IL-4 and ICAM-1 compared with baseline values. To date, the effects of LTRAs on other inflammatory cytokines in vivo have not been reported. The anti-inflammatory effects of LTRAs also seem to be independent of their bronchodilatory action. The available comparative data suggest that the effect of LTRAs on inflammatory cells and mediators are much more variable, and generally less pronounced than that of ICSs. Their selectivity for leukotrienes means that they are less effective than ICSs on the broad-range inflammatory cells and mediators involved in asthma, and this may be responsible for their lesser efficacy compared with ICSs.
3. Effects of ICSs and LTRAs on Airway Remodelling
The assessment of airway remodelling in clinical studies is complicated because many distinct processes are involved in airway structural changes. Currently, the most frequently assessed marker is reticular basement membrane thickness; however, with the advent of electron microscopy, assessments of vascularity and the numbers of myocyte or fibroblasts and phenotypic changes to airway smooth muscle are now possible. Other markers that can be measured are the amount of mucus in the airway lumen and the degree of hypertrophy of the mucosal gland.
Despite the substantial evidence available on the effects of ICSs on inflammatory cells and mediators, data on their effects on remodelling are more limited. A number of studies have investigated the effect of ICSs on the thickness of the reticular basement membrane, although the results have been contradictory. For example, no significant change was found in basement membrane thickness in a small group (n = 11) of patients with asthma treated for 4 weeks with inhaled budesonide 200μg twice daily, or in 32 patients treated for 8 weeks with fluticasone propionate 1 000 μg/day. However, these results are not surprising, because of the short duration of the studies. Conversely, in a 4-month study, Trigg et al. reported a small but significant reduction in basement membrane thickness in 13 patients with asthma after treatment with BDP 500μg twice daily. In this study, basement membrane thickness was quantified by measuring the deposition of type III collagen in the lamina reticularis. There was a significant reduction in thickness in the BDP-treated group: 9.83 ± 4.62μm (mean ± 95% confidence interval) and no significant change in the placebo group (decrease of 2.25 ± 6.72μm); the difference between the two treatments was significant.
Olivieri et al. have shown that fluticasone propionate 250μg twice daily may reduce basement membrane thickness. Treatment with fluticasone propionate in nine patients with asthma caused a small but significant decrease from baseline in basement membrane thickness (from 14.0 ± 1.4μm to 10.7 ± 1.5μm). Laitinen et al. examined the effect of budesonide on the distribution of the glycoprotein, tenascin, the accumulation of which may contribute towards thickening of the basement membrane. Bronchial biopsies from patients with asthma (n = 7) receiving budesonide 400μg twice daily for 4–6 weeks showed a significant reduction from baseline in the thickness of subepithelial tenascin staining (from 6.7 ± 0.7μm to 4.1 ± 0.6μm). In addition, beneficial effects of ICSs on basement membrane thickness were identified in a placebo-controlled, parallel-group study of 35 patients with asthma, although these effects became evident only after 12 months of treatment. In a trial by Sont et al., 75 patients with mild-to-moderate asthma were allocated randomly to groups to receive treatment with an ICS (budesonide or BDP) up to 1 600μg/day for 2 years. Dosage was adjusted in accordance with existing guideline recommendations (reference strategy), but the investigators also adjusted dosage according to the severity of airway hyperresponsiveness (AHR strategy). Bronchial biopsies were obtained from 49 patients, at baseline and after 2 years of follow-up. The authors found that ICSs reduced the thickness of the subepithelial reticular layer, and this effect was greater in the AHR strategy group than in the reference strategy group (mean difference 1.7 μmol). The possibility that ICSs can reduce the thickness of the sub-basement and basement membranes suggests that they may have a potential therapeutic role in reversing the airway remodelling process. Furthermore, the findings of the study by Sont et al. suggest that treatment strategies should take into account the degree of airway hyperresponsiveness, in addition to the presence of symptoms and impairment of lung function.
Overall, the ability of anti-asthma treatments to prevent or reverse airway remodelling is uncertain. Studies investigating the capacity of ICSs to reverse established structural changes have produced some promising results, but findings have been inconsistent; one possible explanation for this is that some of these trials were of short duration. There is little information currently available on the effects of LTRAs on remodelling, apart from a demonstrated effect on airway hyperresponsiveness. Further studies are required to investigate the effect of ICSs and LTRAs on chronic inflammation, and how these changes relate to airway remodelling.
4. Enhancing the Anti-Inflammatory Effects of ICSs
There is some evidence that, when administered in conjunction with ICSs, LABAs and LTRAs may target complementary aspects of asthma pathophysiology, thus providing a rationale for combination therapy. The majority of the supportive evidence for combination therapy comes from the use of ICSs in combination with LABAs.
4.1 ICSs and LABAs
The clinical benefits of combining ICSs with LABAs such as salmeterol include greater improvements in lung function, increased control of symptoms and reduced exacerbations, compared with higher doses of ICSs alone.[66–70] This has raised the question of whether LABAs, in addition to their effects on airway smooth muscle, add to or complement the effect of ICSs on inflammatory cells and mediators. Indeed, studies have shown that LABAs exhibit a range of non-bronchodilatory properties, mediated through a prolonged increase in intracellular cyclic adenosine monophosphate (cAMP) concentrations in target cells. The β2-agonists salbutamol and salmeterol have been shown to have a direct inhibitory effect on mitogen-induced airway smooth muscle cell proliferation,[71–73] and on the production of the eosinophil chemoattractant, eotaxin.[74,75] Other effects include stimulation of mucociliary transport and cytoprotection of the respiratory mucosa.[76,77]
LABAs also have a direct influence on ICS action by exerting an effect on glucocorticoid receptors, by priming glucocorticoid receptors for subsequent steroid binding, and by promoting the translocation of glucocorticoid receptor—steroid complex from the cytosol into the nucleus. In addition, ICSs can modulate β2-receptor density and function by a number of mechanisms, including protection against desensitisation/tolerance and inflammation-induced receptor downregulation and uncoupling.
Two studies on bronchial biopsies and BAL from patients with asthma treated with salmeterol, fluticasone propionate or placebo in addition to low-dose ICS, have shown that add-on salmeterol produces additional reductions in the concentrations of several inflammatory cells and mediators compared with ICS alone.[79,80] In the first study, 50 patients received their normal dose of ICS (BDP or budesonide) up to 500 μg/day during a run-in period and were then allocated randomly to groups to receive add-on treatment with one of the following for 12 weeks: salmeterol 50μg twice daily, fluticasone propionate 100μg twice daily, or placebo. After treatment, the number of EG1-positive eosinophils was significantly reduced from baseline in the salmeterol group, but not in the other two groups. In the second study, 56 patients with asthma were allocated randomly to groups to receive twice daily treatment with fluticasone propionate 200μg or 500μg, or fluticasone propionate 200μg plus salmeterol 50mg, for 12 weeks. Fluticasone propionate plus salmeterol caused a significant reduction in submucosal mast cell numbers compared with baseline and fluticasone propionate 200μg alone (p < 0.05), and a significant reduction in the expression of IL-4-positive cells (p < 0.01). No other changes of significance were observed for any treatment regimen. Taken together, the results of these studies indicate that the combination of LABAs and ICSs reduces a number of inflammatory cells and mediators to a greater degree than do ICSs alone, suggesting a complementary anti-inflammatory effect. Indeed, Pang and Knox have shown a synergistic action of β2-agonists and steroids on TNF-α-induced release of IL-8 in airway smooth muscle cells in vitro. Combination therapy is therefore an effective alternative to administering higher doses of ICSs.
It is not clear whether the effects of LABAs are caused via an independent pathway or by increasing the sensitivity of inflammatory cells to corticosteroids, or both. In some studies it was apparent that, whereas the LABA may have little effect on the inflammatory process alone, there is an enhancement of the ICS effect when both LABA and ICS are administered together, suggesting that they are acting synergistically. A possible clue to the molecular mechanism underlying this effect comes from a small study that examined the ability of salmeterol to induce glucocorticoid receptor translocation in vivo. Upon activation, glucocorticoid receptors translocate to the nucleus and bind to DNA in order to regulate expression of target genes. In this study, four steroid-naïve patients with asthma inhaled single doses of fluticasone propionate 100μg or 500μg, salmeterol 50μg, or a salmeterol 50μg/fluticasone propionate 100μg combination. For each treatment, induced sputum was analysed after inhalation. The results showed that the addition of salmeterol enhanced the action of fluticasone propionate on glucocorticoid receptor translocation.
4.2 ICSs and LTRAs
Results of studies designed to show whether ICSs are able to suppress the production of leukotrienes in vivo are contradictory. O’Shaughnessy et al. demonstrated that fluticasone propionate did not alter allergen-evoked urinary excretion of LTE4, although this did not affect the ability of fluticasone propionate to produce significant inhibition of both early and late responses to allergen and the allergen-evoked increase in bronchial reactivity. In contrast, two recent studies showed that ICSs suppress LTE4 synthesis. Tanaka et al. demonstrated that urinary concentrations of LTE4 are lower in patients with asthma treated with ICSs than in those treated with β2-agoinsts, whereas Zurek et al. showed that suppression of LTE4 by fluticasone propionate paralleled improvements in lung function. However, as there is conflicting evidence that ICSs have a direct inhibitory impact on leukotriene synthesis, there is some basis for the theory that a combination of an LTRA with an ICS would have additive efficacy.
The positive effects of combining an LTRA with an ICS have been demonstrated in terms of clinical outcome parameters. Löfdahl et al. found that, compared with placebo, montelukast 10 mg/day allowed reduction of moderate-to-high doses of ICSs while maintaining clinical effectiveness, in patients with chronic asthma. However, the observation that patients in the placebo group reduced their ICS dosage by 30% during the study suggests that many of them were receiving too high a dose of ICS beforehand (mean dosage of more than 1 600 μg/day). Thus, definitive conclusions as to the steroid-sparing properties of LTRAs cannot be made on the basis of this study. This is further supported by the findings of another study, which showed that montelukast, when added to low-dose BDP, resulted in a maximum increase in FEV1 of only 6% from baseline during the 16-week treatment period.
At present, there is a paucity of data showing complementary effects of LTRAs on inflammatory mediators. Consequently, it remains to be determined whether the combination of an ICS with an LTRA has an additive effect on the inflammatory process in asthma, or whether the primary benefit of an LTRA in combination with an ICS is simply its bronchodilatory action.
ICSs have a broad and potent anti-inflammatory effect on many of the cells and mediators involved in airway inflammation. Studies have demonstrated that ICSs are able to attenuate the effects of eosinophils, mast cells, T cells and macrophages, and to inhibit the cytokines responsible for their recruitment and stimulation. The anti-inflammatory activities of ICSs run parallel with improvements in asthma symptoms. In addition, promising results have been obtained in studies assessing the ability of ICSs to reverse established structural changes in the bronchial wall.
LTRAs are bronchodilators primarily because of their inhibition of the cysteinyl leukotrienes, LTC4, LTD4 and LTE4. These mediators may also have a role in the cellular recruitment of eosinophils, and LTRAs have been shown to inhibit the influx and activation of these cells. However, LTRAs have a limited effect on many other inflammatory markers when compared with ICSs, as demonstrated in the small number of comparative studies available. LTRAs instigate their moderate anti-inflammatory effects through inhibition of a few mediators, compared with ICSs that have a much broader anti-inflammatory action and a direct effect on many of the cells involved in airway inflammation. There are currently insufficient data to indicate that LTRAs are able to influence airway remodelling.
Persuasive evidence exists showing that the substantial clinical benefits obtained when ICSs and LABAs are used together in the treatment of asthma are a result of their complementary effects on the inflammatory process. Additive effects are seen on some inflammatory/remodelling variables when an LABA is added to fluticasone propionate. As for LTRAs, their bronchodilator action, rather than a complementary effect on airway inflammation, most likely explains their beneficial anti-asthma effects when combined with ICS therapy. Evidence from examining inflammatory mediators and cells supports the complementary mechanisms of action of ICSs and LABAs. In concert with their effect on a broader variety of inflammatory mediators and cells, treatment with ICSs and LABAs results in superior clinical efficacy as assessed by the greater improvements in pulmonary function and overall control of asthma compared with LTRAs alone or ICSs and LTRAs.