Anticuerpos monoclonales para el manejo del asma: de las guías a la medicina personalizada

Diana L. Silva E. MD., Luis Fernando Ramírez Z., MD., Carlos Daniel Serrano R., MD.

Resumen


El asma es una enfermedad multifactorial y compleja, con diferentes grados de riesgo y gravedad, así como de respuesta al tratamiento. La mayoría de veces, los medicamentos disponibles son efectivos en el asma grave; sin embargo, existe un porcentaje de pacientes que no responde al tratamiento que sugieren las guías. En los últimos años ha venido investigándose el papel de moléculas inflamatorias que contribuyen a la fisiopatología del asma, y muchas de ellas se han considerado posibles dianas en el manejo del asma grave. Como consecuencia de esto, se han desarrollado algunos anticuerpos monoclonales que han probado su efectividad en el tratamiento de la enfermedad. El estudio de estas nuevas terapias ha permitido a su vez identificar nuevas vías inflamatorias específicas. Este artículo pretende dar una visión crítica de las guías actuales para el manejo del asma grave, así como discutir su tratamiento actual y futuro, a la luz de las nuevas evidencias moleculares. Mediante una caracterización adecuada, se podrán reconocer diferentes fenotipos que a su vez están asociados con un determinado biomarcador, el cuál deberá utilizarse para seleccionar el tratamiento que pueda ofrecer la mayor efectividad en estos pacientes. De esta forma, el tratamiento estará dirigiéndose hacia una medicina personalizada.

Palabras clave


asma grave; guías de manejo; anticuerpos monoclonales; fenotipos; endotipos; interleucinas 4, 5, 13; linfoproteína tímica estromal; biomarcadores

Texto completo:

PDF

Referencias


Bagnasco D, Ferrando M, Bernardi S, Passalacqua G, Canonica GW. The path to personalized medicine in asthma. Expert Rev Respir Med. 2016; 10:957-65.

Wensel S. Severe asthma: from characteristics to phenotypes to endotypes. Clin Exp Allergy. 2012;42:650-8.

Dahlen SE. Asthma phenotyping: noninvasive biomarkers suitable for bedside science are the next step to implement precision medicine. J Intern Med. 2016;279:205-7.

Boluyt N, Rottier BL, de Jongste JC, Riemsma R, Vrijlandt EJ, Brand PL. Assessment of controversial pediatric asthma management options using GRADE. Pediatrics. 2012;130:658-68.

Bel EH. Clinical phenotypes of asthma. Curr Opin Pulm Med. 2004;10:44-50.

Chung F, Adcock I. Asthma: application of cell and molecular biology techniques to unravel causes and pathophysiological mechanisms. Methods Mol Med. 2000;44:1-29.

Abraham B, Anto JME, Barreiro E, Bel EHD, Bonsignore G, Bousquet J, et al. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J. 2003;22:470-7.

Kupczyk M, Dahlén B, Sterk PJ, Nizankowska-Mogilnicka E, Papi A, Bel EH, et al. Stability of phenotypes defined by physiological variables and biomarkers in adults with asthma. Allergy. 2014;69:1198-204.

Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T helper type 2- driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180:388-95.

Zhang Q, Illing R, Hui CK, Downey K, Carr D, Stearn M, et al. Bacteria in sputum of stable severe asthma and increased airway wall thickness. Respir Res. 2012;18:13-35.

Almagro JC, Fransson J. Humanization of antibodies. Front Biosci. 2008;13:1619-33.

Ballow M. -ximab this and -zumab that! Has the magic bullet arrived in the new millennium of medicine and science? J Allergy Clin Immunol. 2005;116:738-43.

Reichert JM, Rosensweig CJ, Faden LB, Dewitz MC. Monoclonal antibody successes in the clinic. Nat Biotechnol. 2005;23:1073-8.

Abbas A, Lichtman A. cellular and molecular immunology. 8th. edition. Elsevier; 2015. p. 94-98.

Yamada T. Therapeutic monoclonal antibodies. Keio J Med. 2011;60:37-46.

Torrego A, Pujols L, Picado C. Response to glucocorticoid treatment in asthma. The role of alpha and beta isoforms of the glucocorticoid receptor. Arch Bronconeumol. 2002;38:436-40.

Peters-Golden M, Henderson WR. Leukotrienes. N Engl J Med. 2007;357:1841-54.

Barnes PJ. Scientific rationale for inhaled combination therapy with long-acting beta2-agonist and corticosteroids. Eur Respir J. 2002;19:182-91.

Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for atsthma in adults and children. Cochrane Database Syst Rev. 2014;139:28-35.

Kopp MV. Omalizumab: Anti-IgE therapy in allergy. Curr Allergy Asthma Rep. 2011;11:101-6.

Humbert M, Beasley R, Ayres J, Slavin R, Hebert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60:309-16.

Wills-Karp M. Interleukin 13 in asthma pathogenesis. Immunol Rev. 2004;202:175-90.

Sokol CL, Barton GM, Farr AG, Medzhitov R. A mechanism for the initiation of allergen-induced T helper type 2 responses. Nat Immunol. 2008;9:310–8.

Brusselle GG, Maes T, Bracke KR. Eosinophils in the spotlight: Eosinophilic airway inflammation in nonallergic asthma. Nat Med. 2013;19:977–9.

Boyman O, Kaegi C, Akdis M, Bavbek S, Bossios A, Chatzipetrou A, et al. EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders. Allergy. 2015;70:727-54.

Oboki K, Nakae S, Matsumoto K, Saito H. IL-33 and Airway Inflammation. Allergy Asthma Immunol Res. 2011;3(2):81–8.

Laviolette M, Gossage DL, Katial R, Leigh R, Olivenstein R, Katial R, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132:1086-96.

Busse WW, Katial R, Gossage D, Sari S, Wang B, Kolbeck R, et al. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol. 2010;125:1237–44.

Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27.

FitzGerald JM, Bleecker ER, Nair P, Korn S, Ohta K, Lommatzsch M, et al. Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2016;388;2128-41.

Wang FP, Liu T, Lan Z, Li SY, Mao H. Efficacy and Safety of Anti-Interleukin-5 therapy in patients with asthma: a systematic review and meta-analysis. PLoS One. 2016;11:e0166833.32.

Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisonedependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985-93.

Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma. Am J Respir Crit Care Med. 2007;176:1062–71.

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. 2009;360:973–84.

Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab treatment in patients with severe eosinophilic asthma. N Engl J Med. 2014;371:1198-207.

Brusselle G, Germinaro M, Weiss S, Zangrilli J. Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils. Pulm Pharmacol Ther. 2017;pii:S1094-5539(17)30035-4.

Li J, Lin C, Du J, Xiao B, Du C, Sun J, et al. The efficacy and safety of Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: a systematic review and meta-analysis. J Asthma. 2016. In press.

Wensel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosionophil levels. N Engl J Med. 2013;368:2455-66.

Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b doseranging trial. Lancet. 2016;388:31-44.

Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet. 2007;370:1422-31.

Slager RE, Otulana BA, Hawkins GA, Yen YP, Peters SP, Wenzel SE, et al. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an anti-IL-4 receptor α antagonist. J Allergy Clin Immunol. 2012;130:516-22.

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.

Hanania NA, Noonan M, Corren J, Korenblat P, Zheng Y, Fischer SK, et al. Lebrikizumab in moderate-to-severe asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70:748-56.

Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebo-controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41:330-8.

Brightling CE, Chanez P, Leigh R, O’Byrne PM, Korn S, She D, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, doubleblind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3:692-701.

Gauvreau GM, O’Byrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al. Effects of an anti-TSLP antibody on allergen induced asthmatic response. N Engl J Med. 2014;370:2102-10.

Parker JM, Oh CK, LaForce C, Miller SD, Pearlman DS, Le C, et al. safety profile and clinical activity of multiple sub-cutaneous doses of MEDI-58, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a studies in subjects with asthma. BMC Pulm Med. 2011:11-14.

Krinner EM, Raum T, Petsch S, Bruckmaier S, Schuster I, Petersen L, et al. A human monoclonal IgG1 potently neutralizing the proinflammatory cytoquine GM-CSF. Mol Immunol. 2007;44:916-25.

Erin EM, Leaker BR, Nicholson GC, Tan AJ, Green LM, Neighbour H, et al. The effects of a monoclonal antibody directed against tumor necrosis factor alpha in asthma. Am J Respir Crit Care Med. 2006;174:753-62.

Ballantyne SJ, Barlow JL, Jolin HE, Nath P, Williams AS, Chung KF, et al. Blocking IL-25 prevents airway hyperresponsiveness in allergic asthma. J Allergy Clin Immunol. 2007;120:1324-31.

Liu X, Li M, Wu Y, Zhou Y, Zeng L, Huang T, et al. Anti IL-33 antibody treatment inhibits airway inflammation in a murine model of allergic asthma. Biochem Biophys Res Commun. 2009;386:181-5.

Jatakanon A, Uasuf C, Maziak W, Lim S, Chung KF, Barnes PJ. Neutrophilic inflammation in severe persistent asthma. Am J Respir Crit Care Med. 2000;160:1532–9.

Barnes PJ, Adcock IM. Glucocorticoid resistance in inflammatory diseases. Lancet. 2009;373:1905–17.

Oreo KM, Gibson PG, Simpson JL, Wood LG, McDonald VM, Baines KJ. Sputum ADAM-8 expression in increased in severe asthma and COPD. Clin Exp Allergy. 2013;44:342–52.

Hilvering B, Pavord ID. What goes up must come down: biomarkers and novel biologicals in severe asthma. Clin Exp Allergy. 2015;45:1162–69.

Al-Alawi M, Hassan T, Chotirmall SH Transforming growth factor ß and severe asthma: a perfect storm. Respir Med. 2014;108:1409–23.

Wadsworth S, Sin D, Dorscheid D. Clinical update on the use ofbiomarkers of airway inflammation in the management of asthma. J Asthma Allergy. 2011;4:77–86.

Newby C, Agbetile J, Hargadon B, Monteiro W, Green R, Pavord I, et al. Lung function decline and variable airway inflammatory pattern: longitudinal analysis of severe asthma. J Allergy Clin Immunol. 2014;134:287–94.

Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet. 2012;380:651-9.

Malinovschi A, Fonseca JA, Jacinto T, Alving K, Janson C. Exhaled nitric oxide levels and blood eosinophil counts independently associate with wheeze and asthma events in National Health and Nutrition Examination Survey subjects. J Allergy Clin Immunol. 2013;132:821–7.

Hanania NA, Wenzel S, Rosén K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring the effects of omalizumab in allergic asthma: an analysis of biomarkers in the EXTRA study. Am J Respir Crit Care Med. 2013;187:804-11.

Yang S, Park J, Lee YK, Kim H, Hahn YS. Association of longitudinal fractional exhaled nitric oxide measurements with asthma control in atopic children. Respir Med. 2015;109:572–9.

Gemicioglu B, Musellim B, Dogan I, Guven K. Fractional exhaled nitric oxide (FeNo) in different asthma phenotypes. Allergy Rhinol (Providence). 2014;5:157-61.

Sippel JM, Holden WE, Tilles SA, O’Hollaren M, Cook J, Thukkani N et al Exhaled nitric oxide levels correlate with measures of disease control in asthma. J Allergy Clin Immunol. 2000;106:645–50.

Masuoka M, Shiraishi H, Ohta S, Suzuki S, Arima K, Aoki S, et al. Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest. 2012;122:2590–600.

Jia G, Erickson RW, Choy DF, Mosesova S, Wu LC, Solberg OD, et al. Periostin is a systemic biomarker of eosinophilic airway inflammation in asthmatic patients. J Allergy Clin Immunol. 2012;130:647–54.

Serrano CD, Valero A, Bartra J, Roca-Ferrer J, Muñoz-Cano R, Sánchez-López J, et al. Nasal and bronchial inflammation after nasal allergen challenge: assessment using noninvasive methods. J Investig Allergol Clin Immunol. 2012;22:351-6.




DOI: http://dx.doi.org/10.30789/rcneumologia.v28.n2.2016.219

Métricas de artículo

Vistas de resumen
359




Cargando métricas ...

Enlaces refback

  • No hay ningún enlace refback.


Asociación Colombiana de Neumología y Cirugía de Tórax.
Dirección: Carrera 7 Bis # 123-52 Of. 202, Teléfono: 57(1)3222335 - Bogotá - Colombia.
Sistema OJS - Metabiblioteca |