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Prospective Asthma Treatments; Future Perspectives
Firestone Institute for Respiratory Diseases, Department of Medicine, McMaster University, Most asthma patients can be well controlled on medications that are currently available, and which are both effective and safe (1). However, 5-10% of asthma patients have severe refractory asthma, and do not achieved asthma control, even with high doses of inhaled corticosteroids (ICS), usually in combination with long-acting inhaled β2-agonists (LABAs), and other maintenance treatments (2). A variety of approaches have been used to attempt to improve outcomes in patients with severe refractory asthma. These have included optimizing bronchodilation; reducing airway smooth muscle; reducing airway inflammatory cell number and/or activity; and targeting specific airway effector mediators. The most promising treatment approaches currently under investigation are those which reduce airway eosinophils in patients with severe refractory asthma and a persisting airway eosinophilia. Monoclonal antibodies (hMab) against IL-5 have been shown to improve lung function, improve asthma control, reduce exacerbation risk and allow reduction or elimination of maintenance oral corticosteroids in this subset of patients Bronchial thermoplasty may provide benefit in improving control and reducing exacerbations in selected patients (5). Bronchial thermoplasty is a bronchoscopic therapeutic procedure where the airways are heated using radiofrequency energy to 65oC. The procedure is done using a catheter passed through the bronchoscope, and can only treat the larger airways (6). A complete period of treatment requires three bronchoscopies, spaced several weeks apart. There is convincing evidence that the procedure reduced the volume of airway smooth muscle in the treated airways (7). The addition of the muscarinic antagonist, tiotropium also improves airflow obstruction (8;9). One issue that the studies did not address, however, is whether tiotropium plus ICS has a beneficial effect in reducing the risks of severe asthma exacerbations that is an important benefit of the combination of ICS plus LABA (10). Other developments being evaluated in severe refractory asthma are CXCR2 (the IL-8 receptor) antagonists in patients with a persisting neutrophilic airway inflammation (11), and CRTh2 antagonists (12), both of which are small molecule antagonists, and hMabs against IL4 and IL-13 (13;14). Finally, another approach to reduce receptor numbers, using inhaled anti-sense, has shown to reduce allergen-induced airway eosinophilia (15), and combining different anti-sense against different targets may become a feasible A variety of new treatment options are being investigated to help improve overall asthma control in patients with severe refractory asthma. These include medications to optimize lung function; bronchial thermoplasty to reduce airway smooth muscle in central airways; and those which target specific inflammatory cells or receptors of (1) Bateman ED, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, Fitzgerald M et al. Global strategy for asthma management and prevention: GINA executive (2) Bel EH, Sousa A, Fleming L, Bush A, Chung KF, Versnel J et al. Diagnosis and definition of severe refractory asthma: an international consensus statement from the Innovative Medicine Initiative (IMI). Thorax. 2011;66:910-917. (3) Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl (4) Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A et al. Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J Med. (5) Castro M, Musani AI, Mayse ML, Shargill NS. Bronchial thermoplasty: a novel technique in the treatment of severe asthma. Ther Adv Respir Dis. 2010;4:101- (6) Cox G, Thomson NC, Rubin AS, Niven RM, Corris PA, Siersted HC et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med. (7) Miller JD, Cox G, Vincic L, Lombard CM, Loomas BE, Danek CJ. A prospective feasibility study of bronchial thermoplasty in the human airway. Chest. (8) Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J (9) Kerstjens HA, Disse B, Schroder-Babo W, Bantje TA, Gahlemann M, Sigmund R et al. Tiotropium improves lung function in patients with severe uncontrolled asthma: A randomized controlled trial. J Allergy Clin Immunol. 2011;128:308-14. (10) Pauwels RA, Lofdahl CG, Postma DS, Tattersfield AE, O'Byrne P, Barnes PJ et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. Formoterol and Corticosteroids Establishing Therapy (FACET) International Study Group. N Engl J Med. 1997;337:1405-11. (11) Gaga, M., Nair, P., Hargreave, F. E., Sadeh, J., and Chanez, P. SCH527123, a Novel Treatment Option For Severe Neutrophilic Asthma. Am J Respir Crit Care (12) Barnes N, Pavord I, Chuchalin A, Bell J, Hunter M, Lewis T et al. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Exp Allergy. 2012;42:38-48. (13) Gauvreau GM, Boulet LP, Cockcroft DW, FitzGerald JM, Carlsten C, Davis BE et al. Effects of interleukin-13 blockade on allergen-induced airway responses in mild atopic asthma. Am J Respir Crit Care Med. 2011;183:1007-14. (14) Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR et al. Lebrikizumab treatment in adults with asthma. N Engl J Med. 2011;365:1088-98. (15) Gauvreau GM, Pageau R, Seguin R, Carballo D, Gauthier J, D'Anjou H et al. Dose-response effects of TPI ASM8 in asthmatics after allergen. Allergy.

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