Omalizumab and modification of bronchial asthma natural course

Clinical and molecular heterogeneity of bronchial asthma has been documented in recent years. The search for novel solutions to enhance efficient patient support related first of all to understanding of asthma heterogenic nature and allows to personalize each patient treatment. Biological therapy application can influence to achieve better control at greater extent for patients with severe uncontrolled asthma. Nowadays 5 biological drugs are registered on Russian Federation territory and implemented according to severe asthma phenotypes: anti-IgE, anti-IL-4,13 and anti-IL-5 class therapies. Omalizumab become the first target drug for uncontrolled allergic asthma patients (monoclonal antibody against IgE). This medication is prescribed for uncontrolled moderate and severe allergic (atopic) asthma in patients on basic asthma therapy according GINA step 4 and 5 (Level of evidence A). Clinical trials confidently reported that anti- IgE-therapy reduces the rate of asthma exacerbations, severity of disease in patients with chronic severe asthma on high doses of inhaled steroids or systemic steroids and allows to reduce or withdraw systemic steroids doses in case of steroid-dependent asthma. For the last years special attention led to and demonstrated omalizumab positive effect on airways remodeling and modification of bronchial asthma natural course in adults and children. Antiinflammatory effect of omalizumab is documented. Omalizumab significantly reduces eosinophilic infiltration of submucosal bronchi layer among patients with atopic asthma, sputum eosinophilia, which correlates with reduction of FeNO during biologic treatment, reduces mast cells infiltration of smooth muscle cells in bronchi. Omalizumab significantly reduces the thickness of the bronchial wall, increases the lumen of the bronchi (positive dynamics of CT-scan parameters), which is clinically manifested by increased of FEV1.

1. Chuchalin A.G. Bronchial asthma. Moscow: Meditsina; 1985. 160 p. (In Russ.) Available at: https://studfile.net/preview/1564756/.

2. Dahlén S.E. Asthma phenotyping: noninvasive biomarkers suitable for bedside science are the next step to implement precision medicine. J Intern Med. 2016;279(2):205–207. https://doi.org/10.1111/joim.12466.

3. Ishizaka T., Ishizaka K., Johansson S.G., Bennich H. Histamine release from human leukocytes by anti-gamma E antibodies. J Immunol. 1969;102(4):884–892. Available at: https://www.jimmunol.org/content/102/4/884/tab-article-info.

4. Ishizaka K., Ishizaka T. Identification of gamma-E-antibodies as a carrier of reaginic activity. J Immunol. 1967;99(6):1187–1198. Available at: https://www.jimmunol.org/content/99/6/1187.long.

5. Johansson S.G. Discovery and development of IgE assays. Clin Exp Allergy. 1997;27(1 Suppl.):60–63. https://doi.org/10.1111/j.1365-2222.1997.tb01828.x.

6. Johansson S.G., Hourihane J.O., Bousquet J., Bruijnzeel-Koomen C., Dreborg S., Haahtela T. et al. A revised nomenclature for allergy. An EAACI position statement from the EAACI nomenclature task force. Allergy. 2001;56(9): 813–824. https://doi.org/10.1034/j.1398-9995.2001.t01-1-00001.x.

7. Johansson S.G. Raised levels of a new immunoglobulin class (IgND) in asthma. Lancet. 1967;2(7523):951–953. https://doi.org/10.1016/s0140-6736(67)90792-1.

8. Stanworth D.R. The discovery of IgE. Allergy. 1993;48(2):67–71. https://doi.org/10.1111/j.1398-9995.1993.tb00687.x.

9. Johansson S.G. The History of IgE: From discovery to 2010. Curr Allergy Asthma Rep. 2011;11(2):173–177. https://doi.org/10.1007/s11882-010-0174-3.

10. Macharadze D.Sh. Modern clinical aspects of total and specific IgE evaluation. Pediatriya. Zhurnal imeni G.N. Speranskogo = Pediatria. Journal named after G.N. Speransky. 2017;96(2):121–127. (In Russ.) Available at: https://pediatriajournal.ru/archive?show=357&section=4881.

11. Lloyd C.M., Robinson D.S. Allergen-induced airway remodelling. Eur Respir J. 2007;29(5):1020–1032. https://doi.org/10.1183/09031936.00150305.

12. Romagnoli M., Caramori G., Braccioni F., Ravenna F., Barreiro E., Siafakas N.M. et al. Near-fatal asthma phenotype in the ENFUMOSA Cohort. Clin Exp Allergy. 2007;37(4):552–557. https://doi.org/10.1111/j.1365-2222.2007.02683.x.

13. Osborne M., Deffebach M. The epidemiology and natural history of asthma: Outcomes and Treatment Regimens (TENOR) study. Ann Allergy Asthma Immunol. 2004;92(1):3. https://doi.org/10.1016/S1081-1206(10)61702-4.

14. Pearce N., Beasley R., Crane J., Burgess C., Jackson R. End of the New Zealand asthma mortality epidemic. Lancet. 1995;345(8941):41–44. https://doi.org/10.1016/s0140-6736(95)91159-6.

15. Kinoshita H., Kubota A., Kasuda S., Nishiguchi M., Ouchi H., Minami T. et al. An autopsy case of asthmatic death – usefulness of biochemical examination. Vojnosanit Pregl. 2008;65(5):404–406. https://doi.org/10.2298/vsp0805404k.

16. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet. 1998;351(9111):1225–1232. https://doi.org/10.1016/S0140-6736(97)07302-9.

17. Asher M.I., Stewart A.W., Mallol J., Montefort S., Lai C.K., Aït-Khaled N., Odhiambo J. Which population level environmental factors are associated with asthma, rhinoconjunctivitis and eczema? Review of the ecological analyses of ISAAC Phase One. Respir Res. 2010;11(1):8. https://doi.org/10.1186/1465-9921-11-8.

18. Shaaban R., Zureik M., Soussan D., Neukirch C., Heinrich J., Sunyer J. et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008;372(9643):1049–1057. https://doi.org/10.1016/S0140-6736(08)61446-4.

19. Fokkens W., Lund V., Mullol J. European position paper on rhinosinusitis and nasal polyps 2007. Rhinol Suppl. 2007;20:1–136. Available at: https://pubmed.ncbi.nlm.nih.gov/17844873/.

20. Brożek J.L., Bousquet J., Agache I., Agarwal A., Bachert C., Bosnic-Anticevich S. et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines-2016 revision. J Allergy Clin Immunol. 2017;140(4):950–958. https://doi.org/10.1016/j.jaci.2017.03.050.

21. Kwah J.H., Peters A.T. Nasal polyps and rhinosinusitis. Allergy Asthma Proc. 2019;40(6):380–384. https://doi.org/10.2500/aap.2019.40.4252.

22. Agache I., Beltran J., Akdis C., Akdis M., Canelo-Aybar C., Canonica G.W. et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines – recommendations on the use of biologicals in severe asthma. Allergy. 2020;75(5):1023–1042. https://doi.org/10.1111/all.14221.

23. Molimard M., Mala L., Bourdeix I., Le Gros V. Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control. Respir Med. 2014;108(4):571–576. https://doi.org/10.1016/j.rmed.2014.02.003.

24. Kozlov V.A., Savchenko A.A., Kudryavtsev I.V., Kozlov I.G., Kudlay D.A., Prodeus A.P., Borisov A.G. Clinical immunology. Krasnoyarsk: Polikor; 2020. 386 p. (In Russ.) https://doi.org/10.17513/np.438.

25. Gandhi N.A., Pirozzi G., Graham N.M.H. Commonality of the IL-4/ IL-13 pathway in atopic diseases. Expert Rev Clin Immunol. 2017;13(5):425–437. https://doi.org/10.1080/1744666X.2017.1298443.

26. Castro M., Zangrilli J., Wechsler M.E., Bateman E.D., Brusselle G.G., 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(5):355–366. https://doi.org/10.1016/S2213-2600(15)00042-9.

27. Ortega H.G., Yancey S.W., Mayer B., Gunsoy N.B., Keene O.N., Bleecker E.R. et al. Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies. Lancet Respir Med. 2016;4(7):549–556. https://doi.org/10.1016/S2213-2600(16)30031-5.

28. Bleecker E.R., FitzGerald J.M., Chanez P., Papi A., Weinstein S.F., 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(10056):2115–2127. https://doi.org/10.1016/S0140-6736(16)31324-1.

29. Ivanov R., Sekareva G., Kravtsova O., Kudlay D., Lukyanov S., Tikhonova I. et al. Guidelines of research biosimilar drugs. Farmakokinetika i farmakodinamika = Pharmacokinetics and Pharmacodynamics. 2014;(1):21–36. (In Russ.) Available at: https://www.pharmacokinetica.ru/jour/article/view/138.

30. Nenasheva N.M., Averyanov A.V., Il’ina N.I., Avdeev S.N., Osipova G.L., Rubanik T.V. et al. Comparative Study of Biosimilar Genolar® Clinical Efficacy оп the Randomized Phase III Study Results. Pulmonologiya = Russian Pulmonology. 2020;30(6):782–796. (In Russ.) https://doi.org/10.18093/0869-0189-2020-30-6-782-796.

31. Palomares Ó., Sánchez-Ramón S., Dávila I., Prieto L., Pérez de Llano L., Lleonart M. et al. dIvergEnt: How IgE Axis Contributes to the Continuum of Allergic Asthma and Anti-IgE Therapies. Int J Mol Sci. 2017;18(6):1328. https://doi.org/10.3390/ijms18061328.

32. Ayres J.G., Higgins B., Chilvers E.R., Ayre G., Blogg M., Fox H. Efficacy and tolerability of anti-immunoglobulin E therapy with omalizumab in patients with poorly controlled (moderate-to-severe) allergic asthma. Allergy. 2004;59(7):701–708. https://doi.org/10.1111/j.1398-9995.2004.00533.x.

33. Heymann P.W., Platts-Mills T.A.E., Woodfolk J.A., Borish L., Murphy D.D., Carper H.T. et al. Understanding the asthmatic response to an experimental rhinovirus infection: Exploring the effects of blocking IgE. J Allergy Clin Immunol. 2020;146(3):545–554. https://doi.org/10.1016/j.jaci.2020.01.035.

34. Henriksen D.P., Bodtger U., Sidenius K., Maltbaek N., Pedersen L., Madsen H. et al. Efficacy of omalizumab in children, adolescents, and adults with severe allergic asthma: a systematic review, meta-analysis, and call for new trials using current guidelines for assessment of severe asthma. Allergy Asthma Clin Immunol. 2020;16:49. https://doi.org/10.1186/s13223-020-00442-0.

35. Pfaller B., José Yepes-Nuñez J., Agache I., Akdis C.A., Alsalamah M., Bavbek S. et al. Biologicals in atopic disease in pregnancy: An EAACI position paper. Allergy. 2021;76(1):71–89. https://doi.org/10.1111/all.14282.

36. Djukanović R., Wilson S.J., Kraft M., Jarjour N.N., Steel M., Chung K.F. et al. Effects of treatment with anti-immunoglobulin E antibody omalizumab on airway inflammation in allergic asthma. Am J Respir Crit Care Med. 2004;170(6):583–593. https://doi.org/10.1164/rccm.200312-1651OC.

37. Van Rensen E.L., Evertse C.E., van Schadewijk W.A., van Wijngaarden S., Ayre G., Mauad T. et al. Eosinophils in bronchial mucosa of asthmatics after allergen challenge: effect of anti-IgE treatment. Allergy. 2009;64(1):72–80. https://doi.org/10.1111/j.1398-9995.2008.01881.x.

38. Noga O., Hanf G., Brachmann I., Klucken A.C., Kleine-Tebbe J., Rosseau S. et al. Effect of omalizumab treatment on peripheral eosinophil and T-lymphocyte function in patients with allergic asthma. J Allergy Clin Immunol. 2006;117(6):1493–1499. https://doi.org/10.1016/j.jaci.2006.02.028.

39. Simeone-Penney M.C., Severgnini M., Rozo L., Takahashi S., Cochran B.H., Simon A.R. PDGF-induced human airway smooth muscle cell proliferation requires STAT3 and the small GTPase Rac1. Am J Physiol Lung Cell Mol Physiol. 2008;294(4):L698–L704. https://doi.org/10.1152/ajplung.00529.2007.

40. Rabe K.F., Calhoun W.J., Smith N., Jimenez P. Can anti-IgE therapy prevent airway remodeling in allergic asthma? Allergy. 2011;66(9):1142–1145. https://doi.org/10.1111/j.1398-9995.2011.02617.x.

41. Dal Negro R.W., Micheletto C., De Ferrari L., Folli C., Chiappori A., Canonica G.W. Omalizumab modulates bronchial reticular basement membrane thickness and eosinophil infiltration in severe persistent allergic asthma patients. Int J Immunopathol Pharmacol. 2012;25(2):475–484. https://doi.org/10.1177/039463201202500217.

42. Riccio A.M., Mauri P., De Ferrari L., Rossi R., Di Silvestre D., Benazzi L. et al. Galectin-3: an early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36 months. Clin Transl Allergy. 2017;7:6. https://doi.org/10.1186/s13601-017-0143-1.

43. Solidoro P., Patrucco F., de Blasio F., Brussino L., Bellocchia M., Dassetto D. et al. Predictors of reversible airway obstruction with omalizumab in severe asthma: a real-life study. Ther Adv Respir Dis. 2019;13:1753466619841274. https://doi.org/10.1177/1753466619841274.

44. Hoshino M., Ohtawa J. Effects of adding omalizumab, an anti-immunoglobulin E antibody, on airway wall thickening in asthma. Respiration. 2012;83(6):520–528. https://doi.org/10.1159/000334701.

45. Tajiri T., Niimi A., Matsumoto H., Ito I., Oguma T., Otsuka K. et al. Comprehensive efficacy of omalizumab for severe refractory asthma: a timeseries observational study. Ann Allergy Asthma Immunol. 2014;113(4):470.e2–475.e2. https://doi.org/10.1016/j.anai.2014.06.004.

46. Pan S., Conaway S. Jr, Deshpande D.A. Mitochondrial regulation of airway smooth muscle functions in health and pulmonary diseases. Arch Biochem Biophys. 2019;663:109–119. https://doi.org/10.1016/j.abb.2019.01.002.

47. Roth M., Zhao F., Zhong J., Lardinois D., Tamm M. Serum IgE induced airway smooth muscle cell remodeling is independent of allergens and is prevented by omalizumab. PLoS ONE. 2015;10(9):e0136549. https://doi.org/10.1371/journal.pone.0136549.

48. Roth M., Tamm M. The effects of omalizumab on IgE induced cytokine synthesis by asthmatic airway smooth muscle cells. Ann Allergy Asthma Immunol. 2010;104(2):152–160. https://doi.org/10.1016/j.anai.2009.11.022.

49. Vennera M.D.C., Sabadell C., Picado C. Duration of the efficacy of omalizumab after treatment discontinuation in ‘real life’ severe asthma. Thorax. 2018;73(8):782–784. https://doi.org/10.1136/thoraxjnl-2017-210017.

50. Baena-Cagnani C.E., Teijeiro A., Canonica G.W. Four-year follow-up in children with moderate/severe uncontrolled asthma after withdrawal of a 1-year omalizumab treatment. Curr Opin Allergy Clin Immunol. 2015;15(3):267–271. https://doi.org/10.1097/ACI.0000000000000161.

51. Kim D.H., Park K.Y., Kim B.J., Kim M.N., Mun S.K. Anti-immunoglobulin E in the treatment of refractory atopic dermatitis. Clin Exp Dermatol. 2013;38(5):496–500. https://doi.org/10.1111/j.1365-2230.2012.04438.x.

52. Naclerio R.M., Baroody F.M., Pinto J.M. Should clinicians use omalizumab for the treatment of nasal polyps? J Allergy Clin Immunol. 2013;132(1):247. https://doi.org/10.1016/j.jaci.2013.04.001.

53. Gevaert P., Calus L., Van Zele T., Blomme K., De Ruyck N., Bauters W. et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013;131(1):110.e1–116.e1. https://doi.org/10.1016/j.jaci.2012.07.047.