Medicina de precisão na asma
Precision medicine in asthma
Ataualpa Pereira dos Reis; José Augusto Nogueira Machado
Resumo
O objetivo deste trabalho é fazer uma revisão atual de uma medicina de precisão personalizada e dirigida para fenótipos e endótipos de asma. As fontes de dados incluíram artigos originais, revisões e publicações indexadas nos bancos de dados PubMed, MEDLINE, LILACS, SciELO e publicadas on line nos últimos 20 anos. Os resultados mostram que a asma tem sido considerada uma doença única por anos, e que estudos mais recentes cada vez mais focam na sua heterogeneidade. Esta heterogeneidade resulta em que a asma contém múltiplos fenótipos ou grupos de características consistentes. Um endótipo é um subtipo desta doença, definido por um distinto mecanismo fisiopatológico, e é associado a um biomarcador. Múltiplos modificadores da resposta imune estão sendo avaliados na asma denominada T2 alta, bloqueando as interleucinas IL-5, IL-13, imunoglobulina E e outras vias. Assim, muitas destas terapias visando a asma T2 alta têm demonstrado melhor eficácia quando certos biomarcadores estão elevados, especialmente os eosinófilos. Já o tipo de asma T2 baixo, que não apresenta biomarcadores precisos, é geralmente diagnosticada pela ausência de biomarcadores para T2 alta. Estes pacientes tendem a ter mais resistência a tratamento com esteroides e o desenvolvimento de novas terapias são muito menos apreciáveis do que as com o tipo T2 alto. As conclusões são que a disponibilidade de agentes bioterapêuticos dirigidos especificamente a IgE, IL-5 e IL-13 é uma excitante evolução da medicina molecular. Contudo, estes agentes bioterapêuticos somente são efetivos quando dirigidos a fenótipos específicos de asma.
Palavras-chave
Abstract
The objective of this study was to conduct an updated review of the role of personalized phenotype-endotype driven precision medicine in asthma. Sources of data included original articles, reviews and other publications indexed in PubMed, MEDLINE, LILACS, and SciELO and published online over the last 20 years. The results showed that asthma has been considered as a single disease for years, and more recent studies have increasingly focused on its heterogeneity. This heterogeneity has promoted the concept that asthma consists of multiple phenotypes or consistent groupings of characteristics. An endotype is a subtype of a condition, defined by a distinct pathophysiological mechanism and linked to a biomarker. Several immune response modifiers have been evaluated in T2-high asthma geared at blocking interleukins IL-5, IL-13, immunoglobulin E, and other pathways. Thus, many of the T2-high asthma therapies available have shown improved effectiveness when certain biomarkers are elevated, especially eosinophils. Conversely, T2-low asthma does not currently have any readily available point-of-care biomarkers, and therefore is often diagnosed based on the absence of T2-high biomarkers. These patients tend to present greater resistance to steroids, and the development of therapies has lagged behind that observed for T2-high asthma. In conclusion, the availability of biotherapeutic agents specifically targeted at IgE, IL-5, and IL-13 is an exciting vindication of molecular medicine. However, these biotherapeutic agents are only effective when targeted at specific asthma phenotypes.
Keywords
Referências
1. Dunn RM, Lehman E, Chinchilli VM, Martin RJ, Boushey HA, Israel E, et al. Impact of age and gender on response to asthma therapy. Am J Respir Crit Care Med. 2015;192:551-8.
2. Zissler UM, Esser-von Bieren J, Jakwerth CA, Chaker AM, SchmidtWeber CB. Current and future biomarkers in allergic asthma. Allergy. 2015;71:475‑94.
3. Dunn R, Wechsler ME. Anti-interleukin therapy in asthma. Clin Pharmacol Ther. 2015;97:55-65.
4. Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun WJ, et al. Effect of beta2-adrenergic receptor polymorphism on response to long acting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomized, placebo-controlled, crossover trial. Lancet. 2009;374:1754-64.
5. Jameson JL, Longo DL. Precision medicine – personalized, problematic, and promising. N Engl J Med. 2015;372:2229‑34.
6. Agache I, Akdis C, Jutel M, Virchow JC. Untangling asthma phenotypes and endotypes. Allergy. 2012;67:835-46.
7. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18:716-25.
8. Fahy JV. Type 2 inflammation in asthma – present in most, absent in many. Nat Rev Immunol. 2015;15:57-65.
9. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16:45-56.
10. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18:716-25.
11. Agache I, Akdis CA. Endotypes of allergic diseases and asthma: an important step in building blocks for the future of precision medicine. Allergology International. 2016;65:243-52.
12. Muraro A, Lemanske RF Jr, Hellings PW, Akdis CA, Bieber T, Casale TB, et al. Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis – PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology 2016. J Allergy Clin Immunol. 2016;137:1347-58.
13. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nature Medicine. 2012;18:716-25.
14. Stokes JR, Casale TB. Characterization of asthma endotypes: implications for therapy. Ann Allergy Asthma Immunol. 2016;117:121-5.
15. Steiling K , Christenson SA. Targeting ’types: Precision Medicine in Pulmonary Disease- Editorial. Am J Respir Crit Care Med. 2015;191;1093‑105.
16. Akdis CA. The underlying mechanisms in allergy (overview). EAACI Global Atlas of Allergy. Disponível em: http://www.eaaci. org/resources/scientific-output/globalatlas-of-allergy.html.
17. Dougherty RH, Sidhu SS, Raman K, Solon M, Solberg OD, Caughey GH, et al. Accumulation of intraepithelial mast cells with a unique protease phenotype in T(H)2-high asthma. J Allergy Clin Immunol. 2010;125:1046-53.
18. Irvin C, Zafar I, Good J, Rollins D, Christianson C, Gorska MM, et al. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol. 2014;134:1175-86.
19. Steinke JW, Liu L, Huyett P, Negri J, Payne SC, Borish L. Prominent role of IFN-g in patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2013;132:856-65.
20. Marijsse GS, Seys SF, Schelpe A-S, Dilissen E, Goeminne P, Dupont LJ, et al. Obese individuals with asthma preferentially have a high IL-5/IL-17A/IL-25 sputum inflammatory pattern. Am J Respir Crit Care Med. 2014;189:1284-5.
21. Hammad H, Lambrecht BN. Barrier epithelial cells and the control of type 2 immunity. Immunity. 2015;43:29-40.
22. Agache I, Sugita K, Morita H, Akdis M, Akdis CA. The complex type 2 endotype in allergy and asthma: from laboratory to bedside. Curr Allergy Asthma Rep. 2015;15:29.
23. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002;57:875-9.
24. 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.
25. Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med. 2009;360:985-93.
26. Rajan JP, Wineinger NE, Stevenson DD, White AA. Prevalence of aspirin exacerbated re spiratory disease among asthmatic patients: a meta-analysis of the literature. J Allergy Clin Immunol. 2015;135:676-81.
27. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189-97.
28. Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27:483-94.
29. 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.
30. Guo FH, Uetani K, Haque SJ, Williams BR, Dweik RA, Thunnissen FB, et al. Interferon gamma and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators. J Clin Invest. 1997;100:829-38.
31. Hanania NA, Wenzel S, Rosen 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.
32. Modena BD, Tedrow JR, Milosevic J, Bleecker ER, Meyers DA, Wu W, et al. Gene expression in relation to exhaled nitric oxide identifies novel asthma phenotypes with unique biomolecular pathways. Am J Respir Crit Care Med. 2014;190:1363-72.
33. Smith AD, Cowan JO, Filsell S, McLachlan C, Monti-Sheehan G, Jackson P, et al. Diagnosing asthma: comparisons between exhaled nitric oxide measurements and conventional tests. Am J Respir Crit Care Med. 2004;169:473-8.
34. Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455-66.
35 Gogate S, Katial R. Pediatric biomarkers in asthma: exhaled nitric oxide, sputum eosinophils and leukotriene E4. Curr Opin Allergy Clin Immunol. 2008;8:154-7.
36. Takayama G, Arima K, Kanaji T, Toda S, Tanaka H, Shoji S, et al. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol. 2006;118:98-104.
37. Conway SJ, Izuhara K, Kudo Y, Litvin J, Markwald R, Ouyang G, et al. The role of periostin in tissue remodeling across health and disease. Cell Mol Life Sci. 2014;71:1279-88.
38. Konradsen JR, Skantz E, Nordlund B, Lidegran M, James A, Ono J, et al. Predicting asthma morbidity in children using proposed markers of Th2-type inflammation. Pediatr Allergy Immunol. 2015;26:772-9.
39. Song JS, You JS, Jeong SI, Yang S, Hwang IT, Im YG, et al. Serum periostin levels correlate with airway hyper-responsiveness to methacholine and mannitol in children with asthma. Allergy. 2015;70:674-81.
40. Kanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, et al. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013;132:305.
41. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. National Heart, Lung, and Blood Institute’s Severe Asthma Research Program Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med. 2010;181:315-23.
42. Green RH, Brightling CE, Woltmann G, Parker D, Wardlaw AJ, Pavord ID. Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids. Thorax. 2002;57:875-9.
43. Pene J, Chevalier S, Preisser L, Venereau E, Guilleux M-H, Ghannam S, et al. Chronically inflamed human tissues are infiltrated by highly differentiated Th17 lymphocytes. J Immunol. 2008;180:7423-30.
44. Simpson JL, Gibson PG, Yang IA, Upham J, James A, Reynolds PN, et al. Impaired macrophage phagocytosis in non-eosinophilic asthma. Clin Exp Allergy. 2013;43:29-35.
45. Baines KJ, Simpson JL, Wood LG, Scott RJ, Fibbens NL, Powell H, et al. Sputum gene expression signature of 6 biomarkers discriminates asthma inflammatory phenotypes. J Allergy Clin Immunol. 2014;133:997-1007.
46. Raedler D, Ballenberger N, Klucker E, B€ock A, Otto R, Prazeres da Costa O, et al. Identification of novel immune phenotypes for allergic and nonallergic childhood asthma. J Allergy Clin Immunol. 2015;135:81-91.
47. Truyen E, Coteur L, Dilissen E, Overbergh L, Dupont LJ, Ceuppens JL, et al. Evaluation of airway inflammation by quantitative Th1/ Th2 cytokine mRNA measurement in sputum of asthma patients. Thorax. 2006;61:202-8.
48. Raundhal M, Morse C, Khare A, Oriss TB, Milosevic J, Trudeau J, et al. High IFN-g and low SLPI mark severe asthma in mice and humans. J Clin Invest. 2015;125:3037-50.
49. Wilson RH, Whitehead GS, Nakano H, Free ME, Kolls JK, Cook DN. Allergic sensitization through the airway primes Th17-dependent neutrophilia and airway hyperresponsiveness. Am J Respir Crit Care Med. 2009;180:720-30.
50. Zhao J, Lloyd CM, Noble A. Th17 responses in chronic allergic airway inflammation abrogate regulatory T-cell-mediated tolerance an contribute to airway remodeling. Mucosal Immunol. 2013;6:335‑46.
51. Bullens DM, Truyen E, Coteur L, Dilissen E, Hellings PW, Dupont LJ, et al. IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx? Respir Res. 2006;7:135.
52. Agache I, Ciobanu C, Agache C, Anghel M. Increased serum IL17 is an independent risk factor for severe asthma. Respir Med. 2010;104:1131-7.
53. Molet S, Hamid Q, Davoine F, Nutku E, Taha R, Page N, et al. IL-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines. J Allergy Clin Immunol. 2001;108:430-8.
54. Chien JW, Lin CY, Yang KD, Lin CH, Kao JK, Tsai YG. Increased IL-17A secreting CD41 T cells, serum IL-17 levels and exhaled nitric oxide are correlated with childhood asthma severity. Clin Exp Allergy. 2013;43:1018-26.
55. Gupta A, Dimeloe S, Richards DF, Chambers ES, Black C, Urry Z, et al. Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma. Thorax. 2014;69:508‑15.
56. Avni O, Lee D, Macian F, Szabo SJ, Glimcher LH, Rao A. TH cell differentiation is accompanied by dynamic changes in histone acetylation of cytokine genes. Nat Immunol. 2002;3:643-51.
57. Chen GY, Osada H, Santamaria-Babi LF, Reiji K. Interaction of GATA- 3/T-bet transcription factors regulates expression of sialyl Lewis X homing receptors on Th1/Th2 lymphocytes. Proc Natl Acad Sci. 2006;103:16894-9.
58. Jones B, Chen J. Inhibition of IFN-gamma transcription by site specific methylation during T helper cell development. EMBO J. 2006;25:2443-52.
59. Lee DU, Agarwal S, Rao A. Th2 lineage commitment and efficient IL-4 production involves extended demethylation of the IL-4 gene. Immunity. 2002;16:649-60.
60. Ansel KM, Djuretic I, Tanasa B, Rao A. Regulation of Th2 differentiation and Il4 locus accessibility. Annu Rev Immunol. 2006;24:607-56.
61. Lal G, Zhang N, van der Touw W, Ding Y, Ju W, Bottinger EP, et al. Epigenetic regulation of Foxp3 expression in regulatory T cells by DNA methylation. J Immunol. 2009;182:259-73.
62. Tao R, de Zoeten EF, Ozkaynak E, Chen C, Wang L, Porrett PM, et al. Deacetylase inhibition promotes the generation and function of regulatory T cells. Nat Med. 2007;13:1299-307.
63. Akimzhanov AM, Yang XO, Dong C. Chromatin remodeling of interleukin-17 (IL-17)-IL-17F cytokine gene locus during inflammatory helper T cell differentiation. J Biol Chem. 2007;282:5969-72.
64. Ansel KM, Lee DU, Rao A. An epigenetic view of helper T cell differentiation. Nat Immunol. 2003;4:616-23.
65. Barczyh A, Pierzchala, Caramori G, Wiaderkiewicz, Kaminsk M, Barnes PJ, et al. Decreased percentage of CD4+FOP3+TGF+ and increase of CD4+IL-17+ in brochoalveolar lavage of asthmatics. J Inflamm. 2014;11:22.
66. Sawant DV, Yao W, Wright Z, Sawyers C, Tepper RS, Gupta SK, et al. Serum MicroRNA-21 as a biomarker for allergic inflammatory disease in children. Microrna. 2015;4:36-40.
67. Midyat L, Gulen F, Karaca E, Ozkinay F, Tanac R, Demir E, et al. MicroRNA expression profiling in children with different asthma phenotypes. Pediatr Pulmonol. 2016; 51:582-7.
68. Brown HM. Treatment of chronic asthma with prednisolone; significance of eosinophils in the sputum. Lancet. 1958;2:1245-7.
69. Cowan DC, Cowan JO, Palmay R, Williamson A, Taylor DR. Effects of steroid therapy on inflammatory cell subtypes in asthma. Thorax. 2010;65:384-90.
70. Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180:388-95.
71. Li L-B, Leung DYM, Goleva E. Activated p38 MAPK in peripheral blood monocytes of steroid resistant asthmatics. PLoS One. 2015;10:e0141909.
72. Xiao C, Biagini Myers JM, Ji H, Metz K, Martin LJ, Lindsey M, et al. Vanin-1 expression and methylation discriminate pediatric asthma corticosteroid treatment response. J Allergy Clin Immunol. 2015;136:923-33.
73. Irvin C, Zafar I, Good J, Rollins D, Christianson C, Gorska MM, et al. Increased frequency of dual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma. J Allergy Clin Immunol. 2014;134:1175-86.
74. Lipworth BJ. Biomarkers to predict inhaled corticosteroid response. J Allergy Clin Immunol. 2015;136:515.
75. Goleva E, Jackson LP, Harris JK, Robertson CE, Sutherland ER, Hall CF, et al. The effects of airway microbiome on corticosteroid responsiveness in asthma. Am J Respir Crit Care Med. 2013;188:1193-201.
76. Clemmer GL, Wu AC, Rosner B, McGeachie MJ, Litonjua AA, Tantisira KG, et al. Measuring the corticosteroid responsiveness endophenotype in asthmatic patients. J Allergy Clin Immunol. 2015;136:274-81.
77. Baird B, Shopes RJ, Oi VT, Erickson J, Kane P, Holowka D. Interaction of IgE with its high-affinity receptor. Structural basis and requirements for effective cross-linking. Int Arch Allergy Appl Immunol. 1989;88:23‑8.
78. Hams E, Armstrong ME, Barlow JL, Saunders SP, Schwartz C, Cooke G, et al. IL-25 and type 2 innate lymphoid cells induce pulmonary fibrosis. Proc Natl Acad Sci USA. 2014;111:367‑72.
79. Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa GD, et al. Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma. J Allergy Clin Immunol. 2001;108:184‑90.
80. Sorkness CA, Wildfire JJ, Calatroni A, Mitchell HE, Busse WW, O’Connor GT, et al. Reassessment of omalizumab-dosing strategies and pharmacodynamics in inner-city children and adolescents. J Allergy Clin Immunol Pract. 2013;1:163‑71.
81. Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364:1005‑15.
82. Rodrigo GJ, Neffen H, Castro-Rodriguez JA. Efficacy and safety of subcutaneous omalizumab vs placebo as add-on therapy to corticosteroids for children and adults with asthma: a systematic review. Chest. 2011;139:28‑35.
83. Arm JP, Bottoli I, Skerjanec A, Floch D, Groenewegen A, Maahs S, et al. Pharmacokinetics, pharmacodynamics and safety of QGE031 (ligelizumab), a novel high-affinity anti-IgE antibody, in atopic subjects. Clin Exp Allergy. 2014;44:1371‑85.
84. Gauvreau GM, Harris JM, Boulet LP, Scheerens H, Fitzgerald JM, Putnam WS, et al. Targeting membrane-expressed IgE B cell receptor with an antibody to the M1 prime epitope reduces IgE production. Sci Transl Med. 2014;6:243-85.
85. Nowak RM, Parker JM, Silverman RA, et al. A randomized trial of benralizumab, an anti interleukin 5 receptor a monoclonal antibody, after acute asthma. Am J Emerg Med. 2015;33:14-20.
86. O’Byrne PM, Inman MD, Parameswaran K. The trials and tribulations of IL-5, eosinophils, and allergic asthma. J Allergy Clin Immunol. 2001;108:503‑8.
87. Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med. 2014;371:1189‑97.
88. 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.
89. Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo- controlled, phase 3 trials. Lancet Respir Med. 2015;3:355‑66.
90. Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW, et al. Benralizumab, an anti-interleukin 5 receptor alpha monoclonal antibody, versus placebo for uncontrolled eosinophilic asthma: a phase 2b randomised dose-ranging study. Lancet Respir Med. 2014;2:879‑90.
91. Kolbeck R, Kozhich A, Koike M, Peng L, Andersson CK, Damschroder MM, et al. MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody- dependent cell-mediated cytotoxicity function. J Allergy Clin Immunol. 2010;125:1344‑53.
92. Varricchi G, Bagnasco D, Borriello F, Heffler E, Canonica GW. IL-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs. Curr Opin Allergy Clin Immunol. 2016;16:186‑200.
93. Hanania NA, Noonan M, Corren J, et al. Lebrikizumab in moderate-tosevere asthma: pooled data from two randomised placebo-controlled studies. Thorax. 2015;70:748-56.
94. Piper E, Brightling C, Niven R, et al. A phase II placebo controlled study of tralokinumab in moderate-to-severe asthma. Eur Respir J. 2013;41:330-8.
95. Brightling CE, Chanez P, Leigh R, et al. Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial. Lancet Respir Med. 2015;3:692-701.
96. Wenzel S, Ford L, Pearlman D, et al. Dupilumab in persistent asthma with elevated eosinophil levels. N Engl J Med. 2013;368:2455-66.
97. Positive phase 2b data for treatment of asthma with dupilumab. Disponível em: http://www.rtmagazine.com/2015/05/positive-phase2b-data-asthma-dupilumab/. Acessado em 21/05/2015.
98. 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.
99. Slager RE, Otulana BA, Hawkins GA, et al. IL-4 receptor polymorphisms predict reduction in asthma exacerbations during response to an antieIL-4 receptor a antagonist. J Allergy Clin Immunol. 2012;130:516-22.
Submetido em:
25/06/2017
Aceito em:
03/10/2017
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