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Strategies for improving the efficacy and therapeutic ratio of glucocorticoids
Available online at www.sciencedirect.com
Strategies for improving the efficacy and therapeutic ratio of glucocorticoids Ian M Adcock1, Gaetano Caramori2 and Paul A Kirkham1 Although glucocorticoids are very effective in suppressing inflammation there is a clear clinical unmet need for new or improved glucocorticoids in patients with severe asthma and COPD. Recent developments include the targeted deposition of ultrafine glucocorticoid particles to treat small airways and the potential of novel agents that have a reduced side effect profile. Understanding the drivers of relative glucocorticoid resistance in these patients may lead to the development of newer drugs aimed at subsets of patients, for example asthmatics with high periostin levels. Alternatively, inhibitors of kinase pathways that are associated with inflammatory responses may be able to modulate glucocorticoid function and combinations of these inhibitors along with novel glucocorticoids may provide the combination therapy of the future. Addresses 1 Airways Disease, National Heart & Lung Institute, Imperial College London, SW3 6LY, UK 2 Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell’Apparato Respiratorio (CEMICEF; formerly Centro di Ricerca su Asma e BPCO), Universita` di Ferrara, Via Savonarola 9, 44100 Ferrara, Italy Corresponding author: Adcock, Ian M ([email protected])
Current Opinion in Pharmacology 2012, 12:246–251 This review comes from a themed issue on Respiratory Edited by M Gabriella Matera and Mario Cazzola
although those with concomitant asthma may show benefit [3]. These patients suffer side-effects from prolonged high-dose glucocorticoid use including effects on bones and increased risk of pneumonia [3]. Furthermore, glucocorticoids are also scarcely effective during COPD exacerbations. There is, therefore, a need to design better glucocorticoids or improve their efficacy. Alternatively, it may be possible to restore glucocorticoid function by inhibiting processes that interfere with their normal actions or, if the underlying driver of disease is known, to use novel drugs to suppress the lower airways inflammation and remodelling seen in patients with severe asthma and COPD. Cluster analysis of inflammatory mediators and cell profiles, transcriptomes and lung function have supported the possibility of several distinct phenotypes of patients with severe asthma and COPD. Targeting nodal points in these clusters may highlight potential novel sites for drug intervention. Furthermore, different subtypes of asthma occur in children and in adults and even within children and adults, resulting in distinct patterns of glucocorticoid treatment sensitivity [4]. Indeed, the classic Th2 asthma phenotype that is exquisitely glucocorticoid sensitive may reflect only a small proportion of asthmatic subjects [5]. This is also exemplified by the clinical effects of anti-IL-13 therapy in severe asthma where a greater improvement in lung function is seen in patients with higher periostin levels [6].
Available online 23rd March 2012 1471-4892/$ – see front matter # 2012 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2012.02.006
Glucocorticoids are the most effective anti-inflammatory drugs currently in use despite their narrow therapeutic window and extreme side effect profile [1]. Most patients with asthma respond well to inhaled glucocorticoids (ICS) particularly when used in combination with long acting b-agonists (LABAs) [2]. However, a small percentage of asthmatics, 5–10%, do not respond well to ICS or combination therapy and are not adequately controlled with oral glucocorticoids or develop the serious side effects associated with the long term use of systemic glucocorticoids [1]. Furthermore, ICS, even at high doses, fail to reduce disease progression or mortality in patients with chronic obstructive pulmonary disease (COPD) and do not affect the underlying inflammation Current Opinion in Pharmacology 2012, 12:246–251
Elucidation of the underlying processes that control these disease subtypes in asthma may indicate selective responsiveness to novel therapies. These nodal points could be considered as being akin to the narrow part of an hour glass controlling a multitude of upstream signalling pathways and the regulation of a plethora of downstream cellular functions. A complete analysis of each patient’s genome, proteome and kinome is beyond current technology but could eventually lead to patient-centred therapy and highlight why some treatments are only effective in small subsets of patients. Integrated programmes such as the US Severe Asthma Research Programme (SARP) and the European UBIOPRED and AIRPROM projects will take us a step closer to this aim [7].
Mechanism of glucocorticoid function Glucocorticoids are nuclear hormones [3] and act by binding to glucocorticoid receptors (GR) that are expressed in all cell types. Glucocorticoids pass from www.sciencedirect.com
Strategies for improving glucocorticoids Adcock, Caramori and Kirkham 247
the circulation into the cell and bind to the cytoplasmic GR inducing a conformational change in the receptor and its nuclear localisation. Classically, two GR proteins interact and bind to DNA at glucocorticoid response elements (GREs) in the regulatory regions of glucocorticoid responsive genes to enhance the expression of anti-inflammatory genes such as annexin 1, IL-10 and glucocorticoid-inducible leucine zipper (GILZ) [3]. DNA-bound GR complexes recruit transcriptional coactivator proteins and basic transcription factors that have intrinsic histone acetyltransferase (HAT) activity. Acetylation of histones (H3 and H4) allows the correct chromatin structure to allow gene induction [3]. By contrast, hypoacetylation induced by histone deacetylases (HDACs) is correlated with reduced transcription or gene silencing [5]. The major anti-inflammatory effects of glucocorticoids are likely to be through repression of inflammatory and immune genes activated by the pro-inflammatory transcription factors nuclear factor (NF)-kB and activating protein (AP)-1 [3]. GRE-associated chromatin patterns including histone acetylation and methylation pre-determine cell-specific responses to glucocorticoids [8] and suggest that the altered glucocorticoid responsiveness seen in cells from patients with severe asthma and COPD may result from changes in the chromatin architecture. Drugs that are capable of altering this architecture such as bromodomain mimics [9] may be able to reset the epigenetic structure of cells from patients with severe asthma or COPD towards that of a normal cell.
Improved lung deposition and clinical efficacy Glucocorticoids (GC) are the most effective anti-inflammatory treatments for asthma and asthma severity is sometimes defined according to glucocorticoid responsiveness [10]. However, the relatively short duration of action of current inhaled glucocorticoids and their lack of immediate obvious benefit to the patient may account for the lack of compliance that is often seen with these agents [1]. As reported previously when changing from shortacting inhaled b2 agonists (SABAs) to LABAs, extending the duration of action to produce a once-a-day glucocorticoid may have profound effects on patient compliance and improve control of the disease particularly if combined with an ultra-long acting inhaled b2 agonist (uLABA) [2]. A once-a-day ICS will improve compliance in patients with severe asthma [2] and fluticasone furoate [200 mg once-daily (OD)] has already been shown to be as effective as fluticasone propionate [(500 mg bis in die (BD)] in an 8 week trial in moderate asthmatics [11] with a reduced side effect profile. Current ICS are very potent and it is unlikely that more potent ICS need to be developed in order to increase clinical efficacy [1]. The systemic side effects of high dose ICS and oral glucocorticoids prevents their use in www.sciencedirect.com
ever increasing doses and has led to a ‘steroid phobia’ in many countries [12]. These side-effects are due to oral deposition and lung absorption and several approaches have been taken to reduce these problems including systemic or local inactivation or administration of an inactive pro-drug that is only converted to active drug in the airways, for example, ciclesonide [13] that is esterified in the lung to produce the active form desciclesonide. Further advances in producing topical inhaled drugs with reduced systemic effects are likely. The particle size of ICS will affect deposition and drug efficacy. Alteration of ICS deposition by changing the particle size as with the extrafine-particle formulation of (EF HFA-BDP; hydrofluoroalkane-beclometasone Qvar1) demonstrated improved total and small airway deposition and greater effects on lung function compared with large-particle chlorofluorocarbon (CFC)-BDP indicating increased glucocorticoid efficacy [14]. Barnes and colleagues have recently reported that during the year after initiating treatment, patients who received EF HFA-BDP were more likely to achieve asthma control than those receiving twice the dose of CFC-BDP validating the hypothesis that altering ICS formulation, particle size, and deposition characteristics can retain good clinical outcomes in real-life asthma therapy despite reducing the ICS daily dose [15]. Similarly, studies on extrafine combination therapy indicate better asthma control in the real life situation owing to improved drug deposition and/or less need for optimal inhalation technique [16]. During the development of new ICS, it is important to be able to indicate bioequivalence (BE) or even therapeutic equivalence (TE) of the compounds in man. The sensitivity of pharmacodynamic models of ICS to determine BE as a drug moves from early in vitro to man is lost. As a result a recent Workshop on the role of pharmacokinetics (PK) in establishing bioequivalence for orally inhaled drug products was convened and recommended that PK alone, or in conjunction with in vitro assays, be used to determine BE for ICS rather than PD [17].
Dissociated steroids Many, but not all, of the side-effects of glucocorticoids are due to GRE binding whereas the anti-inflammatory effects are predominantly due to targeting of NF-kB and AP-1 [1,3]. For example, lipopolysaccharide (LPS)-treated cells from GRdim mice where GR is unable to form a dimer and bind to DNA, are unable to respond to dexamethasone any great extent with respect to morphology, cell surface markers and inflammatory gene expression [1,3]. The 5a reduced forms of glucocorticoids demonstrate dissociated properties and these naturally occurring glucocorticoids may a novel class of dissociated glucocorticoids [18]. The results of trials of dissociated glucocorticoids examining biomarker profiles and clinical efficacy in asthmatics are awaited (ClinicalTrials.gov Identifier NCT00483899). Current Opinion in Pharmacology 2012, 12:246–251
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These dissociated glucocorticoids may prove to be just as effective as conventional ICS, have a better safety profile and might even lead to safer oral glucocorticoids [1,3]. One of the problems with conventional glucocorticoids is that their steroid backbone can also bind to other nuclear hormone receptors such as mineralcorticoid receptor and progesterone receptor causing side-effects. The development of dissociated glucocorticoids with a non-steroidal backbone such as AL-438 and ZK 216348 may further improve the therapeutic index as these drugs as would extending their duration of action to a once-a-day therapy [1,3].
Improving glucocorticoid function with combination therapies New combinations of LABAs and ICS have provided further evidence of a greater efficacy of the combination drugs in asthma compared to the individual components as exemplified by the data of mometasone/formoterol [19] and fluticasone/formoterol [20]. Furthermore, the addition of a long-acting anti-muscarinic agent (LAMA) to an ICS is as effective as LABA/ICS combinations in both asthma and COPD [21] and with the development of newer inhaler devices capable of delivering three once-aday drugs are likely to provide the stable therapy for most patients with severe asthma and COPD in the near future. Selective inhibitors of phosphodiesterase 4 (PDE4) are a class of promising novel anti-inflammatory treatment for asthma and COPD. PDE4 is expressed in macrophages, eosinophils, neutrophils, T cells, bronchial epithelial and airway smooth muscle cells [1]. PDE4 inhibitors specifically prevent the hydrolysis of cAMP resulting in bronchodilation and broad spectrum anti-inflammatory effects such as inhibition of cell trafficking, and activation of many inflammatory cells, such as neutrophils, eosinophils, macrophages and T cells [1]. Many compounds within this class of drugs are in development and the second generation inhibitor, roflumilast, has been marketed for clinical use in the subset of severe COPD patients [22]. A potential problem with PDE4 inhibitors is their side effects profile, particularly nausea, vomiting and other gastrointestinal effects. Topical administration of PDE4 inhibitors by inhalation may provide a wider therapeutic range [23]. Human PDE4 is comprised of four isoenzymes (PDE4A to D) that are differentially expressed in tissue and cells. PDE4D is particularly important in nausea and vomiting and is expressed in the chemosensitive trigger zone in the brain stem. By contrast, PDE4B is more important in inflammatory cells. PDE4B-selective inhibitors may, therefore, have a greater therapeutic ratio [24]. Cilomilast is selective for PDE4D and this explains its propensity to cause emesis, whereas roflumilast, which is nonselective for PDE4 isoenzymes, has a more favourable therapeutic ratio. Indeed, for many of Current Opinion in Pharmacology 2012, 12:246–251
these compounds, it is likely that the maximum tolerated dose is either subtherapeutic or at the very bottom of the efficacy dose–response curve. Thus, there is a significant ongoing challenge to synthesise compounds with therapeutic ratios that are superior to roflumilast based on the assumption that additive or synergistic anti-inflammatory effects can be produced with inhibitors that target either two or more PDE families or with a PDE4 inhibitor in combination with other anti-inflammatory drugs such as glucocorticoids [24].
Novel combination therapies Kinases have a critical role in the expression and activation of inflammatory mediators in the lower airways, in both resident and infiltrating cell function and airway remodelling [25]. Although different kinase pathways can activate specific downstream transcription factors, there is considerable cross-talk between pathways [25]. Changes in kinase activation status have been reported in asthmatic and COPD patients, but particularly in those with more severe disease where an association with reduced glucocorticoid responsiveness has been proposed [25]. p38 mitogen activated protein kinase (MAPK) is involved in a plethora of inflammatory processes within the airways driven by both cytokines and by bacterial and viral infections resulting in enhanced airway inflammation and in tissue remodelling [26]. Second generation p38 MAPK inhibitors including SB2439063 (GlaxoSmithKline, UK) reduce inflammatory mediator expression and AHR in animal models with minimal toxicity [26]. Inhibition of p38 MAPK has been reported to have some clinical efficacy in COPD [26] and to modify airway smooth muscle (ASM) contraction in bronchial rings from chronic ozone-exposed mice [27]. In the same model dexamethasone was able to inhibit acetylcholine (Ach)-mediated ASM contraction through effects on p38 MAPK phosphorylation. Safety issues remain a concern for long-term use, although delivery to the airways by aerosol may reduce side-effects. In addition, the use of p38 MAPK inhibitors as a monotherapy may not be effective as first proposed owing to feedback inhibition redirecting the inflammatory drive from p38 MAPK to the Jun N-terminal kinase/stress-activated kinase (JNK/ SAPK) pathway [28]. This suggests that alternative approaches to using these drugs may be warranted either as an acute monotherapy or in conjunction with ICS [29]. Activation of the p38 MAPK pathway by cellular stressors induces phosphorylation of GR on serine 134 that affects GR-dependent genome-wide transcription profiles and cell function [30]. In previous studies, the combination of IL-2 and IL-4 that induces a relative glucocorticoid insensitivity also induced GR serine phosphorylation act by stimulation of p38 MAPK [26]. These data may explain the glucocorticoid insensitivity seen in peripheral blood cells and www.sciencedirect.com
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macrophages obtained from bronchoalveolar lavage (BAL) in patients with severe asthma [29] and COPD [31] can be overcome by the combination of a p38 MAPKa inhibitor and dexamethasone [1]. In other studies, combined p38 MAPKg and JNK inhibition induced by LABAs was also able to modulate GR phosphorylation and reverse glucocorticoid insensitivity [32]. Alternatively, the anti-inflammatory gaseous signalling molecule hydrogen sulphide may also provide be effective since it can downregulate p38 MAPK activity and ASM function [33]. Metabolic syndrome is also associated with a relative glucocorticoid insensitivity and recent evidence has indicated a feed-forward mechanism that may regulate this at least partly [34]. A master regulator of energy homeostasis is the enzyme AMP-activated protein kinases (AMPK) that can be phosphorylated GR on serine 211 via a p38 MAPK pathway to modulate GR function. Drugs such as the oral hypoglycaemic agent metformin that target AMPK, or p38 MAPK inhibitors, may therefore be useful in patients with severe asthma or COPD who have metabolic syndrome and have an abnormal glucocorticoid responsiveness. Generally anti-oxidant approaches to COPD and severe asthma have proved ineffective [35]. The transcription factor nuclear factor (erythroid-derived 2)-like 2 [also known as NFE2L2 or Nrf2]-mediated induction of anti-oxidant genes is an alternative approach that shows much promise [36]. Nrf2 has recently been shown to control the resolution of inflammation in airway epithelial cells [37] a process that is attenuated in chronic airway inflammatory diseases including severe asthma and COPD [38]. Recent phase II studies using the Nrf2 activator bardoxolone in chronic kidney disease provides support for the potential of threes drugs in severe asthma and COPD [39]. Importantly, alteration of the oxidative stress load will also improve glucocorticoid function [1,3]. Oxidative stress causes a reduction in HDAC2 expression and activity via an effect on phosphoinositide 3-kinase (PI3K)d and that this lack of HDAC2 in COPD is important for the lack of steroid responsiveness in COPD and severe asthma [35]. We had previously reported that HDAC activity could be enhanced by non-PDE4 subbronchodilator doses of theophylline both in vitro and in vivo [3]. In a small proof of concept study in 30 patients with COPD we were able to demonstrate that low dose theophylline was able to restore the anti-inflammatory effects of ICS with respect to sputum neutrophilia and lung function in patients with mild/moderate COPD [40]. The role of acetylation is more complex since trichostatin A, a non-selective inhibitor of most HDACs, was able to www.sciencedirect.com
attenuate airway hyperresponsiveness in murine models of asthma [41] although airway inflammation was not affected. Further research in this area is needed. The pro-inflammatory cytokine interleukin (IL)-17A can induce relative glucocorticoid insensitivity in human bronchial epithelial cells by reducing HDAC2 expression via a PI3K pathway [42]. GR transactivation, however, was not affected by IL-17A in this study. In other studies, IL-17A has been reported to enhance the expression of the inactive form of GR, GRb in primary epithelial cells from asthmatics [43]. These mechanisms may be linked as in BAL macrophages at least, GRb can down regulate HDAC2 expression [44] and this may account for the glucocorticoid resistance seen in some but not all patients with severe asthma [45].
Biomarkers of the response to glucocorticoids Since the initial observations that mRNA patterns in peripheral blood CD8+ T-cells were more predictive of severity and exacerbation of chronic inflammatory diseases [46,47] much interest has focused on whether this pattern is also predictive in airways disease. Transcriptome analysis of CD8+ T-cells in patients with severe asthma has revealed a distinct pattern of mRNA and microRNAs in these patients not seen in patients with non-severe disease [48]. It is unclear whether these changes represent the severe asthma phenotype per se or the presence of high dose glucocorticoid treatment. In addition, studies are ongoing to investigate whether similar differences are observed in patients with COPD. MicroRNAs are able to modify patterns of mRNA expression by acting post-transcriptionally and have been implicated in driving inflammatory airways diseases including asthma [49,50]. Interestingly, in an animal model of asthma miR-145, but not miR-21 or let-7b treatment is as effective as dexamethasone in suppressing airway eosinophilia, mucus production and airway hyperresponsiveness [50]. The effects on small airway remodelling were not reported. Whether glucocorticoids act through control of master microRNAs in the lung is unclear but the ability of microRNAs to affect multiple mRNAs in concert suggests that this may be an area of interest.
Future aspects of glucocorticoid development Recent discoveries have emphasised the important role of several key signalling pathways in the inflammatory response in asthma and COPD and also in the modulation of glucocorticoid responsiveness in asthma and COPD [3,26]. This raises the potential of novel combination therapies utilising selective inhaled p38 MAPK or PI3K pathway inhibitors and new glucocorticoids that reduce the dose of each component necessary to produce a clinically effective response. The future is also likely to see the development of multi-combination therapies involving glucocorticoids and bronchodilators, pathway Current Opinion in Pharmacology 2012, 12:246–251
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inhibitors and other nuclear hormone receptor ligands as seen in other chronic inflammatory diseases such as rheumatoid arthritis [51]. Asthma is predominantly a disease of the large airways whereas COPD is more associated with small airways disease and targeted site-specific airway deposition using mono-dispersed particles may lead to good clinical efficacy with a much reduced ICS dose. New delivery devices that combine targeted deposition with the new once-a-day glucocorticoids in a variety of combinations may prove to be particularly effective.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Adcock IM, Caramori G, Chung KF: New targets for drug development in asthma. Lancet 2008, 372:1073-1087. An extensive overview of mechanisms and development of drugs for severe asthma. 2.
Chung KF, Caramori G, Adcock IM: Inhaled corticosteroids as combination therapy with beta-adrenergic agonists in airways disease: present and future. Eur J Clin Pharmacol 2009, 65:853-871.
3. Barnes PJ: Inhaled corticosteroids in COPD: a controversy. Respiration 2010, 80:89-95. A summary of the benefits and risks of the use of inhaled steroids in COPD. 4.
Bhakta NR, Woodruff PG: Human asthma phenotypes: from the clinic, to cytokines, and back again. Immunol Rev 2011, 242:220-232. An excellent state of the art review of the current concepts in asthma subphenotypes.
5.
Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV: T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009, 180:388-395. One of the first papers to use transcriptomic analysis to define an asthma phenotype and importantly link this to drug responsiveness.
6.
Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z et al.: Lebrikizumab treatment in adults with asthma. N Engl J Med 2011, 365:1088-1098. This paper describes how measurement of a blood biomarker is able predict the responsive of a patient with severe asthma to novel anti-IL-13 therapy. 7.
Auffray C, Adcock IM, Chung KF, Djukanovic R, Pison C, Sterk PJ: An integrative systems biology approach to understanding pulmonary diseases. Chest 2010, 137:1410-1416.
8.
John S, Sabo PJ, Thurman RE, Sung MH, Biddie SC, Johnson TA, Hager GL, Stamatoyannopoulos JA: Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet 2011, 43:264-268.
9.
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J et al.: BET bromodomain inhibition as a therapeutic strategy to target cMyc. Cell 2011, 146:904-917.
10. Ito K, Chung KF, Adcock IM: Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2006, 117:522-543. 11. Woodcock A, Bateman ED, Busse WW, Lotvall J, Snowise NG, Forth R, Jacques L, Haumann B, Bleecker ER: Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized, placebo-controlled trial. Respir Res 2011, 12:132. Current Opinion in Pharmacology 2012, 12:246–251
12. Adcock IM, Ford PA, Bhavsar P, Ahmad T, Chung KF: Steroid resistance in asthma: mechanisms and treatment options. Curr Allergy Asthma Rep 2008, 8:171-178. 13. Derendorf H: Pharmacokinetic and pharmacodynamic properties of inhaled ciclesonide. J Clin Pharmacol 2007, 47:782-789. 14. Busse WW, Brazinsky S, Jacobson K, Stricker W, Schmitt K, Vanden BJ, Donnell D, Hannon S, Colice GL: Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol 1999, 104:1215-1222. 15. Barnes N, Price D, Colice G, Chisholm A, Dorinsky P, Hillyer EV, Burden A, Lee AJ, Martin RJ, Roche N et al.: Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a realworld observational study. Clin Exp Allergy 2011, 41:1521-1532. 16. Muller V, Galffy G, Eszes N, Losonczy G, Bizzi A, Nicolini G, Chrystyn H, Tamasi L: Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation. BMC Pulm Med 2011, 11:40. 17. O’Connor D, Adams WP, Chen ML, ey-Yates P, Davis J, Derendorf H, Ducharme MP, Fuglsang A, Herrle M, Hochhaus G et al.: Role of pharmacokinetics in establishing bioequivalence for orally inhaled drug products: workshop summary report. J Aerosol Med Pulm Drug Deliv 2011, 24:119-135. This workshop report summarizes important recommendations as to how to compare novel steroids in man. 18. Nixon M, Upreti R, Andrew R: 5alpha-Reduced glucocorticoids: a story of natural selection. J Endocrinol 2012, 212:111-127. 19. Meltzer EO, Kuna P, Nolte H, Nayak AS, LaForce C: Mometasone furoate/formoterol reduces asthma deteriorations and improves lung function. Eur Respir J 2012, 39:279-289. 20. Bodzenta-Lukaszyk A, Dymek A, McAulay K, Mansikka H: Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study. BMC Pulm Med 2011, 11:28. 21. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, Boushey HA, Calhoun WJ, Castro M, Cherniack RM et al.: Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010, 363:1715-1726. 22. Pinner NA, Hamilton LA, Hughes A: Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. Clin Ther 2012, 34:56-66. 23. Singh D, Petavy F, MacDonald AJ, Lazaar AL, O’Connor BJ: The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 2010, 11:26. 24. Giembycz MA, Newton R: Harnessing the clinical efficacy of phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual-selective phosphodiesterase inhibitors and novel combination therapies. Handb Exp Pharmacol 2011:415-446. This is a comprehensive review of the the current a future role of PDE4 inhibitors in airways disease. 25. Barnes PJ, Adcock IM: Glucocorticoid resistance in inflammatory diseases. Lancet 2009, 373:1905-1917. 26. Chung KF: p38 mitogen-activated protein kinase pathways in asthma and COPD. Chest 2011, 139:1470-1479. A comprehensive summary of the rationale behind the development of p38 MAPK-directed drugs as mono- and combination-therapies in airways disease. 27. Li F, Zhang M, Hussain F, Triantaphyllopoulos K, Clark AR, Bhavsar PK, Zhou X, Chung KF: Inhibition of p38 MAPKdependent bronchial contraction after ozone by corticosteroids. Eur Respir J 2011, 37:933-942. 28. Hammaker D, Firestein GS: ‘‘Go upstream, young man’’: lessons learned from the p38 saga. Ann Rheum Dis 2010, 69(Suppl. 1):i77-i82. www.sciencedirect.com
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29. Bhavsar P, Khorasani N, Hew M, Johnson M, Chung KF: Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur Respir J 2010, 35:750-756.
A small clinical proof of concept study to demonstrate that sub-bronchodilating doses of theophylline can improve lung function and inflammation in COPD.
30. Galliher-Beckley AJ, Williams JG, Cidlowski JA: Ligandindependent phosphorylation of the glucocorticoid receptor integrates cellular stress pathways with nuclear receptor signaling. Mol Cell Biol 2011, 31:4663-4675.
41. Banerjee A, Trivedi CM, Damera G, Jiang M, Jester W, Hoshi T, Epstein JA, Panettieri RA Jr: Trichostatin a abrogates airway constriction, but not inflammation, in murine and human asthma models. Am J Respir Cell Mol Biol 2012, 46:132-138.
31. Armstrong J, Harbron C, Lea S, Booth G, Cadden P, Wreggett KA, Singh D: Synergistic effects of p38 mitogen-activated protein kinase inhibition with a corticosteroid in alveolar macrophages from patients with chronic obstructive pulmonary disease. J Pharmacol Exp Ther 2011, 338:732-740.
42. Zijlstra GJ, ten Hacken NH, Hoffmann RF, Van Oosterhout AJ, Heijink IH: IL-17A induces glucocorticoid insensitivity in human bronchial epithelial cells. Eur Respir J 2012, 39:439-445. This paper is the first to provide a link in human airway cells between excessive IL-17 expression, inflammation and steroid sensitivity.
32. Mercado N, To Y, Kobayashi Y, Adcock IM, Barnes PJ, Ito K: p38 mitogen-activated protein kinase-gamma inhibition by longacting beta2 adrenergic agonists reversed steroid insensitivity in severe asthma. Mol Pharmacol 2011, 80:1128-1135.
43. Vazquez-Tello A, Semlali A, Chakir J, Martin JG, Leung DY, Eidelman DH, Hamid Q: Induction of glucocorticoid receptorbeta expression in epithelial cells of asthmatic airways by Thelper type 17 cytokines. Clin Exp Allergy 2010, 40:1312-1322.
33. Perry MM, Hui CK, Whiteman M, Wood ME, Adcock I, Kirkham P, Michaeloudes C, Chung KF: Hydrogen sulfide inhibits proliferation and release of IL-8 from human airway smooth muscle cells. Am J Respir Cell Mol Biol 2011, 45:746-752. The first report of how the novel inflammatory/immune signal transmitter, H2S, can affect the function of key cells in the airways.
44. Li LB, Leung DY, Martin RJ, Goleva E: Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid resistant asthma. Am J Respir Crit Care Med 2010, 182:877-883.
34. Nader N, Ng SS, Lambrou GI, Pervanidou P, Wang Y, Chrousos GP, Kino T: AMPK regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 MAPK. Mol Endocrinol 2010, 24:1748-1764. 35. Marwick JA, Adcock IM, Chung KF: Overcoming reduced glucocorticoid sensitivity in airway disease: molecular mechanisms and therapeutic approaches. Drugs 2010, 70:929948. A summary of many of the mechanisms involved in steroid resistance in a subset of patients with airways disease. 36. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P et al.: Decline in NRF2regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 2008, 178:592-604. 37. Reddy NM, Potteti HR, Mariani TJ, Biswal S, Reddy SP: Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. Am J Respir Cell Mol Biol 2011, 45:1161-1168. 38. Hallett JM, Leitch AE, Riley NA, Duffin R, Haslett C, Rossi AG: Novel pharmacological strategies for driving inflammatory cell apoptosis and enhancing the resolution of inflammation. Trends Pharmacol Sci 2008, 29:250-257. 39. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H et al.: Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011, 365:327-336. 40. Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ: Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 2010, 137:1338-1344.
www.sciencedirect.com
45. Butler CA, McQuaid S, Taggart CC, Weldon S, Carter R, Skibinski G, Warke TJ, Choy DF, McGarvey LP, Bradding P et al.: Glucocorticoid receptor beta and histone deacetylase 1 and 2 expression in the airways of severe asthma. Thorax 2011. Dec 8. [Epub ahead of print]. 46. McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DR, Willcocks LC, Koukoulaki M, Brazma A, Jovanovic V, Kemeny DM et al.: A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 2010, 16:586-591 1 p.. 47. Lee JC, Lyons PA, McKinney EF, Sowerby JM, Carr EJ, Bredin F, Rickman HM, Ratlamwala H, Hatton A, Rayner TF et al.: Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest 2011, 121:4170-4179. 48. Tsitsiou E, Williams AE, Moschos SA, Patel K, Rossios C, Jiang X, Adams OD, Macedo P, Booton R, Gibeon D et al.: Transcriptome analysis shows activation of circulating CD8(+) T cells in patients with severe asthma. J Allergy Clin Immunol 2012, 129:95-103. 49. Williams AE, Larner-Svensson H, Perry MM, Campbell GA, Herrick SE, Adcock IM, Erjefalt JS, Chung KF, Lindsay MA: MicroRNA expression profiling in mild asthmatic human airways and effect of corticosteroid therapy. PLoS ONE 2009, 4:e5889. The first paper to describe the expression of microRNAs in patients with asthma. 50. Collison A, Mattes J, Plank M, Foster PS: Inhibition of house dust mite-induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment. J Allergy Clin Immunol 2011, 128:160-167. 51. Rothschild BM: Review: individual DMARDs have similar efficacy for RA, but combination therapy improves response. Evid Based Med 2008, 13:76.
Current Opinion in Pharmacology 2012, 12:246–251
Strategies for improving the efficacy and therapeutic ratio of glucocorticoids Ian M Adcock1, Gaetano Caramori2 and Paul A Kirkham1 Although glucocorticoids are very effective in suppressing inflammation there is a clear clinical unmet need for new or improved glucocorticoids in patients with severe asthma and COPD. Recent developments include the targeted deposition of ultrafine glucocorticoid particles to treat small airways and the potential of novel agents that have a reduced side effect profile. Understanding the drivers of relative glucocorticoid resistance in these patients may lead to the development of newer drugs aimed at subsets of patients, for example asthmatics with high periostin levels. Alternatively, inhibitors of kinase pathways that are associated with inflammatory responses may be able to modulate glucocorticoid function and combinations of these inhibitors along with novel glucocorticoids may provide the combination therapy of the future. Addresses 1 Airways Disease, National Heart & Lung Institute, Imperial College London, SW3 6LY, UK 2 Centro per lo Studio delle Malattie Infiammatorie Croniche delle Vie Aeree e Patologie Fumo Correlate dell’Apparato Respiratorio (CEMICEF; formerly Centro di Ricerca su Asma e BPCO), Universita` di Ferrara, Via Savonarola 9, 44100 Ferrara, Italy Corresponding author: Adcock, Ian M ([email protected])
Current Opinion in Pharmacology 2012, 12:246–251 This review comes from a themed issue on Respiratory Edited by M Gabriella Matera and Mario Cazzola
although those with concomitant asthma may show benefit [3]. These patients suffer side-effects from prolonged high-dose glucocorticoid use including effects on bones and increased risk of pneumonia [3]. Furthermore, glucocorticoids are also scarcely effective during COPD exacerbations. There is, therefore, a need to design better glucocorticoids or improve their efficacy. Alternatively, it may be possible to restore glucocorticoid function by inhibiting processes that interfere with their normal actions or, if the underlying driver of disease is known, to use novel drugs to suppress the lower airways inflammation and remodelling seen in patients with severe asthma and COPD. Cluster analysis of inflammatory mediators and cell profiles, transcriptomes and lung function have supported the possibility of several distinct phenotypes of patients with severe asthma and COPD. Targeting nodal points in these clusters may highlight potential novel sites for drug intervention. Furthermore, different subtypes of asthma occur in children and in adults and even within children and adults, resulting in distinct patterns of glucocorticoid treatment sensitivity [4]. Indeed, the classic Th2 asthma phenotype that is exquisitely glucocorticoid sensitive may reflect only a small proportion of asthmatic subjects [5]. This is also exemplified by the clinical effects of anti-IL-13 therapy in severe asthma where a greater improvement in lung function is seen in patients with higher periostin levels [6].
Available online 23rd March 2012 1471-4892/$ – see front matter # 2012 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2012.02.006
Glucocorticoids are the most effective anti-inflammatory drugs currently in use despite their narrow therapeutic window and extreme side effect profile [1]. Most patients with asthma respond well to inhaled glucocorticoids (ICS) particularly when used in combination with long acting b-agonists (LABAs) [2]. However, a small percentage of asthmatics, 5–10%, do not respond well to ICS or combination therapy and are not adequately controlled with oral glucocorticoids or develop the serious side effects associated with the long term use of systemic glucocorticoids [1]. Furthermore, ICS, even at high doses, fail to reduce disease progression or mortality in patients with chronic obstructive pulmonary disease (COPD) and do not affect the underlying inflammation Current Opinion in Pharmacology 2012, 12:246–251
Elucidation of the underlying processes that control these disease subtypes in asthma may indicate selective responsiveness to novel therapies. These nodal points could be considered as being akin to the narrow part of an hour glass controlling a multitude of upstream signalling pathways and the regulation of a plethora of downstream cellular functions. A complete analysis of each patient’s genome, proteome and kinome is beyond current technology but could eventually lead to patient-centred therapy and highlight why some treatments are only effective in small subsets of patients. Integrated programmes such as the US Severe Asthma Research Programme (SARP) and the European UBIOPRED and AIRPROM projects will take us a step closer to this aim [7].
Mechanism of glucocorticoid function Glucocorticoids are nuclear hormones [3] and act by binding to glucocorticoid receptors (GR) that are expressed in all cell types. Glucocorticoids pass from www.sciencedirect.com
Strategies for improving glucocorticoids Adcock, Caramori and Kirkham 247
the circulation into the cell and bind to the cytoplasmic GR inducing a conformational change in the receptor and its nuclear localisation. Classically, two GR proteins interact and bind to DNA at glucocorticoid response elements (GREs) in the regulatory regions of glucocorticoid responsive genes to enhance the expression of anti-inflammatory genes such as annexin 1, IL-10 and glucocorticoid-inducible leucine zipper (GILZ) [3]. DNA-bound GR complexes recruit transcriptional coactivator proteins and basic transcription factors that have intrinsic histone acetyltransferase (HAT) activity. Acetylation of histones (H3 and H4) allows the correct chromatin structure to allow gene induction [3]. By contrast, hypoacetylation induced by histone deacetylases (HDACs) is correlated with reduced transcription or gene silencing [5]. The major anti-inflammatory effects of glucocorticoids are likely to be through repression of inflammatory and immune genes activated by the pro-inflammatory transcription factors nuclear factor (NF)-kB and activating protein (AP)-1 [3]. GRE-associated chromatin patterns including histone acetylation and methylation pre-determine cell-specific responses to glucocorticoids [8] and suggest that the altered glucocorticoid responsiveness seen in cells from patients with severe asthma and COPD may result from changes in the chromatin architecture. Drugs that are capable of altering this architecture such as bromodomain mimics [9] may be able to reset the epigenetic structure of cells from patients with severe asthma or COPD towards that of a normal cell.
Improved lung deposition and clinical efficacy Glucocorticoids (GC) are the most effective anti-inflammatory treatments for asthma and asthma severity is sometimes defined according to glucocorticoid responsiveness [10]. However, the relatively short duration of action of current inhaled glucocorticoids and their lack of immediate obvious benefit to the patient may account for the lack of compliance that is often seen with these agents [1]. As reported previously when changing from shortacting inhaled b2 agonists (SABAs) to LABAs, extending the duration of action to produce a once-a-day glucocorticoid may have profound effects on patient compliance and improve control of the disease particularly if combined with an ultra-long acting inhaled b2 agonist (uLABA) [2]. A once-a-day ICS will improve compliance in patients with severe asthma [2] and fluticasone furoate [200 mg once-daily (OD)] has already been shown to be as effective as fluticasone propionate [(500 mg bis in die (BD)] in an 8 week trial in moderate asthmatics [11] with a reduced side effect profile. Current ICS are very potent and it is unlikely that more potent ICS need to be developed in order to increase clinical efficacy [1]. The systemic side effects of high dose ICS and oral glucocorticoids prevents their use in www.sciencedirect.com
ever increasing doses and has led to a ‘steroid phobia’ in many countries [12]. These side-effects are due to oral deposition and lung absorption and several approaches have been taken to reduce these problems including systemic or local inactivation or administration of an inactive pro-drug that is only converted to active drug in the airways, for example, ciclesonide [13] that is esterified in the lung to produce the active form desciclesonide. Further advances in producing topical inhaled drugs with reduced systemic effects are likely. The particle size of ICS will affect deposition and drug efficacy. Alteration of ICS deposition by changing the particle size as with the extrafine-particle formulation of (EF HFA-BDP; hydrofluoroalkane-beclometasone Qvar1) demonstrated improved total and small airway deposition and greater effects on lung function compared with large-particle chlorofluorocarbon (CFC)-BDP indicating increased glucocorticoid efficacy [14]. Barnes and colleagues have recently reported that during the year after initiating treatment, patients who received EF HFA-BDP were more likely to achieve asthma control than those receiving twice the dose of CFC-BDP validating the hypothesis that altering ICS formulation, particle size, and deposition characteristics can retain good clinical outcomes in real-life asthma therapy despite reducing the ICS daily dose [15]. Similarly, studies on extrafine combination therapy indicate better asthma control in the real life situation owing to improved drug deposition and/or less need for optimal inhalation technique [16]. During the development of new ICS, it is important to be able to indicate bioequivalence (BE) or even therapeutic equivalence (TE) of the compounds in man. The sensitivity of pharmacodynamic models of ICS to determine BE as a drug moves from early in vitro to man is lost. As a result a recent Workshop on the role of pharmacokinetics (PK) in establishing bioequivalence for orally inhaled drug products was convened and recommended that PK alone, or in conjunction with in vitro assays, be used to determine BE for ICS rather than PD [17].
Dissociated steroids Many, but not all, of the side-effects of glucocorticoids are due to GRE binding whereas the anti-inflammatory effects are predominantly due to targeting of NF-kB and AP-1 [1,3]. For example, lipopolysaccharide (LPS)-treated cells from GRdim mice where GR is unable to form a dimer and bind to DNA, are unable to respond to dexamethasone any great extent with respect to morphology, cell surface markers and inflammatory gene expression [1,3]. The 5a reduced forms of glucocorticoids demonstrate dissociated properties and these naturally occurring glucocorticoids may a novel class of dissociated glucocorticoids [18]. The results of trials of dissociated glucocorticoids examining biomarker profiles and clinical efficacy in asthmatics are awaited (ClinicalTrials.gov Identifier NCT00483899). Current Opinion in Pharmacology 2012, 12:246–251
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These dissociated glucocorticoids may prove to be just as effective as conventional ICS, have a better safety profile and might even lead to safer oral glucocorticoids [1,3]. One of the problems with conventional glucocorticoids is that their steroid backbone can also bind to other nuclear hormone receptors such as mineralcorticoid receptor and progesterone receptor causing side-effects. The development of dissociated glucocorticoids with a non-steroidal backbone such as AL-438 and ZK 216348 may further improve the therapeutic index as these drugs as would extending their duration of action to a once-a-day therapy [1,3].
Improving glucocorticoid function with combination therapies New combinations of LABAs and ICS have provided further evidence of a greater efficacy of the combination drugs in asthma compared to the individual components as exemplified by the data of mometasone/formoterol [19] and fluticasone/formoterol [20]. Furthermore, the addition of a long-acting anti-muscarinic agent (LAMA) to an ICS is as effective as LABA/ICS combinations in both asthma and COPD [21] and with the development of newer inhaler devices capable of delivering three once-aday drugs are likely to provide the stable therapy for most patients with severe asthma and COPD in the near future. Selective inhibitors of phosphodiesterase 4 (PDE4) are a class of promising novel anti-inflammatory treatment for asthma and COPD. PDE4 is expressed in macrophages, eosinophils, neutrophils, T cells, bronchial epithelial and airway smooth muscle cells [1]. PDE4 inhibitors specifically prevent the hydrolysis of cAMP resulting in bronchodilation and broad spectrum anti-inflammatory effects such as inhibition of cell trafficking, and activation of many inflammatory cells, such as neutrophils, eosinophils, macrophages and T cells [1]. Many compounds within this class of drugs are in development and the second generation inhibitor, roflumilast, has been marketed for clinical use in the subset of severe COPD patients [22]. A potential problem with PDE4 inhibitors is their side effects profile, particularly nausea, vomiting and other gastrointestinal effects. Topical administration of PDE4 inhibitors by inhalation may provide a wider therapeutic range [23]. Human PDE4 is comprised of four isoenzymes (PDE4A to D) that are differentially expressed in tissue and cells. PDE4D is particularly important in nausea and vomiting and is expressed in the chemosensitive trigger zone in the brain stem. By contrast, PDE4B is more important in inflammatory cells. PDE4B-selective inhibitors may, therefore, have a greater therapeutic ratio [24]. Cilomilast is selective for PDE4D and this explains its propensity to cause emesis, whereas roflumilast, which is nonselective for PDE4 isoenzymes, has a more favourable therapeutic ratio. Indeed, for many of Current Opinion in Pharmacology 2012, 12:246–251
these compounds, it is likely that the maximum tolerated dose is either subtherapeutic or at the very bottom of the efficacy dose–response curve. Thus, there is a significant ongoing challenge to synthesise compounds with therapeutic ratios that are superior to roflumilast based on the assumption that additive or synergistic anti-inflammatory effects can be produced with inhibitors that target either two or more PDE families or with a PDE4 inhibitor in combination with other anti-inflammatory drugs such as glucocorticoids [24].
Novel combination therapies Kinases have a critical role in the expression and activation of inflammatory mediators in the lower airways, in both resident and infiltrating cell function and airway remodelling [25]. Although different kinase pathways can activate specific downstream transcription factors, there is considerable cross-talk between pathways [25]. Changes in kinase activation status have been reported in asthmatic and COPD patients, but particularly in those with more severe disease where an association with reduced glucocorticoid responsiveness has been proposed [25]. p38 mitogen activated protein kinase (MAPK) is involved in a plethora of inflammatory processes within the airways driven by both cytokines and by bacterial and viral infections resulting in enhanced airway inflammation and in tissue remodelling [26]. Second generation p38 MAPK inhibitors including SB2439063 (GlaxoSmithKline, UK) reduce inflammatory mediator expression and AHR in animal models with minimal toxicity [26]. Inhibition of p38 MAPK has been reported to have some clinical efficacy in COPD [26] and to modify airway smooth muscle (ASM) contraction in bronchial rings from chronic ozone-exposed mice [27]. In the same model dexamethasone was able to inhibit acetylcholine (Ach)-mediated ASM contraction through effects on p38 MAPK phosphorylation. Safety issues remain a concern for long-term use, although delivery to the airways by aerosol may reduce side-effects. In addition, the use of p38 MAPK inhibitors as a monotherapy may not be effective as first proposed owing to feedback inhibition redirecting the inflammatory drive from p38 MAPK to the Jun N-terminal kinase/stress-activated kinase (JNK/ SAPK) pathway [28]. This suggests that alternative approaches to using these drugs may be warranted either as an acute monotherapy or in conjunction with ICS [29]. Activation of the p38 MAPK pathway by cellular stressors induces phosphorylation of GR on serine 134 that affects GR-dependent genome-wide transcription profiles and cell function [30]. In previous studies, the combination of IL-2 and IL-4 that induces a relative glucocorticoid insensitivity also induced GR serine phosphorylation act by stimulation of p38 MAPK [26]. These data may explain the glucocorticoid insensitivity seen in peripheral blood cells and www.sciencedirect.com
Strategies for improving glucocorticoids Adcock, Caramori and Kirkham 249
macrophages obtained from bronchoalveolar lavage (BAL) in patients with severe asthma [29] and COPD [31] can be overcome by the combination of a p38 MAPKa inhibitor and dexamethasone [1]. In other studies, combined p38 MAPKg and JNK inhibition induced by LABAs was also able to modulate GR phosphorylation and reverse glucocorticoid insensitivity [32]. Alternatively, the anti-inflammatory gaseous signalling molecule hydrogen sulphide may also provide be effective since it can downregulate p38 MAPK activity and ASM function [33]. Metabolic syndrome is also associated with a relative glucocorticoid insensitivity and recent evidence has indicated a feed-forward mechanism that may regulate this at least partly [34]. A master regulator of energy homeostasis is the enzyme AMP-activated protein kinases (AMPK) that can be phosphorylated GR on serine 211 via a p38 MAPK pathway to modulate GR function. Drugs such as the oral hypoglycaemic agent metformin that target AMPK, or p38 MAPK inhibitors, may therefore be useful in patients with severe asthma or COPD who have metabolic syndrome and have an abnormal glucocorticoid responsiveness. Generally anti-oxidant approaches to COPD and severe asthma have proved ineffective [35]. The transcription factor nuclear factor (erythroid-derived 2)-like 2 [also known as NFE2L2 or Nrf2]-mediated induction of anti-oxidant genes is an alternative approach that shows much promise [36]. Nrf2 has recently been shown to control the resolution of inflammation in airway epithelial cells [37] a process that is attenuated in chronic airway inflammatory diseases including severe asthma and COPD [38]. Recent phase II studies using the Nrf2 activator bardoxolone in chronic kidney disease provides support for the potential of threes drugs in severe asthma and COPD [39]. Importantly, alteration of the oxidative stress load will also improve glucocorticoid function [1,3]. Oxidative stress causes a reduction in HDAC2 expression and activity via an effect on phosphoinositide 3-kinase (PI3K)d and that this lack of HDAC2 in COPD is important for the lack of steroid responsiveness in COPD and severe asthma [35]. We had previously reported that HDAC activity could be enhanced by non-PDE4 subbronchodilator doses of theophylline both in vitro and in vivo [3]. In a small proof of concept study in 30 patients with COPD we were able to demonstrate that low dose theophylline was able to restore the anti-inflammatory effects of ICS with respect to sputum neutrophilia and lung function in patients with mild/moderate COPD [40]. The role of acetylation is more complex since trichostatin A, a non-selective inhibitor of most HDACs, was able to www.sciencedirect.com
attenuate airway hyperresponsiveness in murine models of asthma [41] although airway inflammation was not affected. Further research in this area is needed. The pro-inflammatory cytokine interleukin (IL)-17A can induce relative glucocorticoid insensitivity in human bronchial epithelial cells by reducing HDAC2 expression via a PI3K pathway [42]. GR transactivation, however, was not affected by IL-17A in this study. In other studies, IL-17A has been reported to enhance the expression of the inactive form of GR, GRb in primary epithelial cells from asthmatics [43]. These mechanisms may be linked as in BAL macrophages at least, GRb can down regulate HDAC2 expression [44] and this may account for the glucocorticoid resistance seen in some but not all patients with severe asthma [45].
Biomarkers of the response to glucocorticoids Since the initial observations that mRNA patterns in peripheral blood CD8+ T-cells were more predictive of severity and exacerbation of chronic inflammatory diseases [46,47] much interest has focused on whether this pattern is also predictive in airways disease. Transcriptome analysis of CD8+ T-cells in patients with severe asthma has revealed a distinct pattern of mRNA and microRNAs in these patients not seen in patients with non-severe disease [48]. It is unclear whether these changes represent the severe asthma phenotype per se or the presence of high dose glucocorticoid treatment. In addition, studies are ongoing to investigate whether similar differences are observed in patients with COPD. MicroRNAs are able to modify patterns of mRNA expression by acting post-transcriptionally and have been implicated in driving inflammatory airways diseases including asthma [49,50]. Interestingly, in an animal model of asthma miR-145, but not miR-21 or let-7b treatment is as effective as dexamethasone in suppressing airway eosinophilia, mucus production and airway hyperresponsiveness [50]. The effects on small airway remodelling were not reported. Whether glucocorticoids act through control of master microRNAs in the lung is unclear but the ability of microRNAs to affect multiple mRNAs in concert suggests that this may be an area of interest.
Future aspects of glucocorticoid development Recent discoveries have emphasised the important role of several key signalling pathways in the inflammatory response in asthma and COPD and also in the modulation of glucocorticoid responsiveness in asthma and COPD [3,26]. This raises the potential of novel combination therapies utilising selective inhaled p38 MAPK or PI3K pathway inhibitors and new glucocorticoids that reduce the dose of each component necessary to produce a clinically effective response. The future is also likely to see the development of multi-combination therapies involving glucocorticoids and bronchodilators, pathway Current Opinion in Pharmacology 2012, 12:246–251
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inhibitors and other nuclear hormone receptor ligands as seen in other chronic inflammatory diseases such as rheumatoid arthritis [51]. Asthma is predominantly a disease of the large airways whereas COPD is more associated with small airways disease and targeted site-specific airway deposition using mono-dispersed particles may lead to good clinical efficacy with a much reduced ICS dose. New delivery devices that combine targeted deposition with the new once-a-day glucocorticoids in a variety of combinations may prove to be particularly effective.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest 1. Adcock IM, Caramori G, Chung KF: New targets for drug development in asthma. Lancet 2008, 372:1073-1087. An extensive overview of mechanisms and development of drugs for severe asthma. 2.
Chung KF, Caramori G, Adcock IM: Inhaled corticosteroids as combination therapy with beta-adrenergic agonists in airways disease: present and future. Eur J Clin Pharmacol 2009, 65:853-871.
3. Barnes PJ: Inhaled corticosteroids in COPD: a controversy. Respiration 2010, 80:89-95. A summary of the benefits and risks of the use of inhaled steroids in COPD. 4.
Bhakta NR, Woodruff PG: Human asthma phenotypes: from the clinic, to cytokines, and back again. Immunol Rev 2011, 242:220-232. An excellent state of the art review of the current concepts in asthma subphenotypes.
5.
Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth LL, Arron JR, Fahy JV: T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med 2009, 180:388-395. One of the first papers to use transcriptomic analysis to define an asthma phenotype and importantly link this to drug responsiveness.
6.
Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, Harris JM, Scheerens H, Wu LC, Su Z et al.: Lebrikizumab treatment in adults with asthma. N Engl J Med 2011, 365:1088-1098. This paper describes how measurement of a blood biomarker is able predict the responsive of a patient with severe asthma to novel anti-IL-13 therapy. 7.
Auffray C, Adcock IM, Chung KF, Djukanovic R, Pison C, Sterk PJ: An integrative systems biology approach to understanding pulmonary diseases. Chest 2010, 137:1410-1416.
8.
John S, Sabo PJ, Thurman RE, Sung MH, Biddie SC, Johnson TA, Hager GL, Stamatoyannopoulos JA: Chromatin accessibility pre-determines glucocorticoid receptor binding patterns. Nat Genet 2011, 43:264-268.
9.
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J et al.: BET bromodomain inhibition as a therapeutic strategy to target cMyc. Cell 2011, 146:904-917.
10. Ito K, Chung KF, Adcock IM: Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2006, 117:522-543. 11. Woodcock A, Bateman ED, Busse WW, Lotvall J, Snowise NG, Forth R, Jacques L, Haumann B, Bleecker ER: Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized, placebo-controlled trial. Respir Res 2011, 12:132. Current Opinion in Pharmacology 2012, 12:246–251
12. Adcock IM, Ford PA, Bhavsar P, Ahmad T, Chung KF: Steroid resistance in asthma: mechanisms and treatment options. Curr Allergy Asthma Rep 2008, 8:171-178. 13. Derendorf H: Pharmacokinetic and pharmacodynamic properties of inhaled ciclesonide. J Clin Pharmacol 2007, 47:782-789. 14. Busse WW, Brazinsky S, Jacobson K, Stricker W, Schmitt K, Vanden BJ, Donnell D, Hannon S, Colice GL: Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol 1999, 104:1215-1222. 15. Barnes N, Price D, Colice G, Chisholm A, Dorinsky P, Hillyer EV, Burden A, Lee AJ, Martin RJ, Roche N et al.: Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a realworld observational study. Clin Exp Allergy 2011, 41:1521-1532. 16. Muller V, Galffy G, Eszes N, Losonczy G, Bizzi A, Nicolini G, Chrystyn H, Tamasi L: Asthma control in patients receiving inhaled corticosteroid and long-acting beta2-agonist fixed combinations. A real-life study comparing dry powder inhalers and a pressurized metered dose inhaler extrafine formulation. BMC Pulm Med 2011, 11:40. 17. O’Connor D, Adams WP, Chen ML, ey-Yates P, Davis J, Derendorf H, Ducharme MP, Fuglsang A, Herrle M, Hochhaus G et al.: Role of pharmacokinetics in establishing bioequivalence for orally inhaled drug products: workshop summary report. J Aerosol Med Pulm Drug Deliv 2011, 24:119-135. This workshop report summarizes important recommendations as to how to compare novel steroids in man. 18. Nixon M, Upreti R, Andrew R: 5alpha-Reduced glucocorticoids: a story of natural selection. J Endocrinol 2012, 212:111-127. 19. Meltzer EO, Kuna P, Nolte H, Nayak AS, LaForce C: Mometasone furoate/formoterol reduces asthma deteriorations and improves lung function. Eur Respir J 2012, 39:279-289. 20. Bodzenta-Lukaszyk A, Dymek A, McAulay K, Mansikka H: Fluticasone/formoterol combination therapy is as effective as fluticasone/salmeterol in the treatment of asthma, but has a more rapid onset of action: an open-label, randomized study. BMC Pulm Med 2011, 11:28. 21. Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, Boushey HA, Calhoun WJ, Castro M, Cherniack RM et al.: Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med 2010, 363:1715-1726. 22. Pinner NA, Hamilton LA, Hughes A: Roflumilast: a phosphodiesterase-4 inhibitor for the treatment of severe chronic obstructive pulmonary disease. Clin Ther 2012, 34:56-66. 23. Singh D, Petavy F, MacDonald AJ, Lazaar AL, O’Connor BJ: The inhaled phosphodiesterase 4 inhibitor GSK256066 reduces allergen challenge responses in asthma. Respir Res 2010, 11:26. 24. Giembycz MA, Newton R: Harnessing the clinical efficacy of phosphodiesterase 4 inhibitors in inflammatory lung diseases: dual-selective phosphodiesterase inhibitors and novel combination therapies. Handb Exp Pharmacol 2011:415-446. This is a comprehensive review of the the current a future role of PDE4 inhibitors in airways disease. 25. Barnes PJ, Adcock IM: Glucocorticoid resistance in inflammatory diseases. Lancet 2009, 373:1905-1917. 26. Chung KF: p38 mitogen-activated protein kinase pathways in asthma and COPD. Chest 2011, 139:1470-1479. A comprehensive summary of the rationale behind the development of p38 MAPK-directed drugs as mono- and combination-therapies in airways disease. 27. Li F, Zhang M, Hussain F, Triantaphyllopoulos K, Clark AR, Bhavsar PK, Zhou X, Chung KF: Inhibition of p38 MAPKdependent bronchial contraction after ozone by corticosteroids. Eur Respir J 2011, 37:933-942. 28. Hammaker D, Firestein GS: ‘‘Go upstream, young man’’: lessons learned from the p38 saga. Ann Rheum Dis 2010, 69(Suppl. 1):i77-i82. www.sciencedirect.com
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29. Bhavsar P, Khorasani N, Hew M, Johnson M, Chung KF: Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur Respir J 2010, 35:750-756.
A small clinical proof of concept study to demonstrate that sub-bronchodilating doses of theophylline can improve lung function and inflammation in COPD.
30. Galliher-Beckley AJ, Williams JG, Cidlowski JA: Ligandindependent phosphorylation of the glucocorticoid receptor integrates cellular stress pathways with nuclear receptor signaling. Mol Cell Biol 2011, 31:4663-4675.
41. Banerjee A, Trivedi CM, Damera G, Jiang M, Jester W, Hoshi T, Epstein JA, Panettieri RA Jr: Trichostatin a abrogates airway constriction, but not inflammation, in murine and human asthma models. Am J Respir Cell Mol Biol 2012, 46:132-138.
31. Armstrong J, Harbron C, Lea S, Booth G, Cadden P, Wreggett KA, Singh D: Synergistic effects of p38 mitogen-activated protein kinase inhibition with a corticosteroid in alveolar macrophages from patients with chronic obstructive pulmonary disease. J Pharmacol Exp Ther 2011, 338:732-740.
42. Zijlstra GJ, ten Hacken NH, Hoffmann RF, Van Oosterhout AJ, Heijink IH: IL-17A induces glucocorticoid insensitivity in human bronchial epithelial cells. Eur Respir J 2012, 39:439-445. This paper is the first to provide a link in human airway cells between excessive IL-17 expression, inflammation and steroid sensitivity.
32. Mercado N, To Y, Kobayashi Y, Adcock IM, Barnes PJ, Ito K: p38 mitogen-activated protein kinase-gamma inhibition by longacting beta2 adrenergic agonists reversed steroid insensitivity in severe asthma. Mol Pharmacol 2011, 80:1128-1135.
43. Vazquez-Tello A, Semlali A, Chakir J, Martin JG, Leung DY, Eidelman DH, Hamid Q: Induction of glucocorticoid receptorbeta expression in epithelial cells of asthmatic airways by Thelper type 17 cytokines. Clin Exp Allergy 2010, 40:1312-1322.
33. Perry MM, Hui CK, Whiteman M, Wood ME, Adcock I, Kirkham P, Michaeloudes C, Chung KF: Hydrogen sulfide inhibits proliferation and release of IL-8 from human airway smooth muscle cells. Am J Respir Cell Mol Biol 2011, 45:746-752. The first report of how the novel inflammatory/immune signal transmitter, H2S, can affect the function of key cells in the airways.
44. Li LB, Leung DY, Martin RJ, Goleva E: Inhibition of histone deacetylase 2 expression by elevated glucocorticoid receptor beta in steroid resistant asthma. Am J Respir Crit Care Med 2010, 182:877-883.
34. Nader N, Ng SS, Lambrou GI, Pervanidou P, Wang Y, Chrousos GP, Kino T: AMPK regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 MAPK. Mol Endocrinol 2010, 24:1748-1764. 35. Marwick JA, Adcock IM, Chung KF: Overcoming reduced glucocorticoid sensitivity in airway disease: molecular mechanisms and therapeutic approaches. Drugs 2010, 70:929948. A summary of many of the mechanisms involved in steroid resistance in a subset of patients with airways disease. 36. Malhotra D, Thimmulappa R, Navas-Acien A, Sandford A, Elliott M, Singh A, Chen L, Zhuang X, Hogg J, Pare P et al.: Decline in NRF2regulated antioxidants in chronic obstructive pulmonary disease lungs due to loss of its positive regulator, DJ-1. Am J Respir Crit Care Med 2008, 178:592-604. 37. Reddy NM, Potteti HR, Mariani TJ, Biswal S, Reddy SP: Conditional deletion of Nrf2 in airway epithelium exacerbates acute lung injury and impairs the resolution of inflammation. Am J Respir Cell Mol Biol 2011, 45:1161-1168. 38. Hallett JM, Leitch AE, Riley NA, Duffin R, Haslett C, Rossi AG: Novel pharmacological strategies for driving inflammatory cell apoptosis and enhancing the resolution of inflammation. Trends Pharmacol Sci 2008, 29:250-257. 39. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H et al.: Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011, 365:327-336. 40. Ford PA, Durham AL, Russell RE, Gordon F, Adcock IM, Barnes PJ: Treatment effects of low-dose theophylline combined with an inhaled corticosteroid in COPD. Chest 2010, 137:1338-1344.
www.sciencedirect.com
45. Butler CA, McQuaid S, Taggart CC, Weldon S, Carter R, Skibinski G, Warke TJ, Choy DF, McGarvey LP, Bradding P et al.: Glucocorticoid receptor beta and histone deacetylase 1 and 2 expression in the airways of severe asthma. Thorax 2011. Dec 8. [Epub ahead of print]. 46. McKinney EF, Lyons PA, Carr EJ, Hollis JL, Jayne DR, Willcocks LC, Koukoulaki M, Brazma A, Jovanovic V, Kemeny DM et al.: A CD8+ T cell transcription signature predicts prognosis in autoimmune disease. Nat Med 2010, 16:586-591 1 p.. 47. Lee JC, Lyons PA, McKinney EF, Sowerby JM, Carr EJ, Bredin F, Rickman HM, Ratlamwala H, Hatton A, Rayner TF et al.: Gene expression profiling of CD8+ T cells predicts prognosis in patients with Crohn disease and ulcerative colitis. J Clin Invest 2011, 121:4170-4179. 48. Tsitsiou E, Williams AE, Moschos SA, Patel K, Rossios C, Jiang X, Adams OD, Macedo P, Booton R, Gibeon D et al.: Transcriptome analysis shows activation of circulating CD8(+) T cells in patients with severe asthma. J Allergy Clin Immunol 2012, 129:95-103. 49. Williams AE, Larner-Svensson H, Perry MM, Campbell GA, Herrick SE, Adcock IM, Erjefalt JS, Chung KF, Lindsay MA: MicroRNA expression profiling in mild asthmatic human airways and effect of corticosteroid therapy. PLoS ONE 2009, 4:e5889. The first paper to describe the expression of microRNAs in patients with asthma. 50. Collison A, Mattes J, Plank M, Foster PS: Inhibition of house dust mite-induced allergic airways disease by antagonism of microRNA-145 is comparable to glucocorticoid treatment. J Allergy Clin Immunol 2011, 128:160-167. 51. Rothschild BM: Review: individual DMARDs have similar efficacy for RA, but combination therapy improves response. Evid Based Med 2008, 13:76.
Current Opinion in Pharmacology 2012, 12:246–251