Targeting interleukin-4 and interleukin-13 in the treatment of severe eosinophilic asthma

Asthma is a chronic inflammatory airway disease affecting about 300 million people and responsible for 500,000 deaths annually globally. Eosinophilic asthma is one of the most common phenotypes of asthma. It constitutes about 50% to 60% of all cases of asthma, and it is the most common phenotype in children presenting with severe acute asthma. The mechanism of eosinophilic asthma is chronic airway inflammation which leads to airway hyperresponsiveness, and remodeling due to the immunopathological effects of inflammatory cytokines. The duet cytokines interleukin-4 (IL-4) and IL-13 play the most central role in the pathophysiology of eosinophilic asthma. The two sister cytokines are slightly similar with a 25% homology, they share a common signaling IL-4Rα chain, and have identical biological effects. Their principal biological effect is the development of Th2 cells from naïve T helper type 0 (Th0) lymphocytes. Th2 cells produce several cytokines responsible for inducing airway eosinophilic inflammation. They induce the ε isotype switch and the switching of the B cell immunoglobulin (Ig) production from IgM to IgE. Furthermore, they stimulate eosinophil proliferation, and migration to the allergic airways and promote eosinophil survival by suppressing eosinophil apoptosis. Activated eosinophils secrete several cytotoxic cationic proteins which damage the airway epithelium, and amplify the inflammatory cascade and airway remodeling. Most patients with eosinophilic asthma can achieve control on a long-acting β2-agonist, inhaled corticosteroid, and a leukotriene receptor antagonist. However, about 3.6-10% do not achieve asthma control. These patients usually benefit from treatment with a biologic. Dupilumab is the only biologic targeting IL-4 and IL-13 approved for the treatment of moderate-to-severe eosinophilic asthma. Clinical trials have shown that treatment with dupilumab results in good asthma control, and significantly reduces moderate-to-severe exacerbation rates (p < 0.001). Additionally, treatment with dupilumab has been shown to significantly improve lung function (p < 0.001), and health-related quality of life, and allows patients to taper or discontinue corticosteroid treatment.

Introduction

Asthma is a chronic inflammatory airway disease affecting about 300 million people and is accountable for 500,000 deaths annually globally [1]. It contributes to a significant healthcare burden and imparts a disproportionate pharmaco-economical cost. The prevalence of asthma has reached a plateau in most developed countries, but it is continuing to rise in low- and middle-income countries [2-4].

Asthma is a heterogenous chronic inflammatory airway disease comprising four phenotypes, classified based on sputum cytology, and biomarkers of airway inflammation [5]. The four phenotypes of asthma include eosinophilic, neutrophilic, paucigranulocytic, and mixed cellularity [5-7]. Eosinophilic asthma constitutes about 50% to 60% of all cases of asthma [8-10] and it is the most common phenotype in children presenting with severe acute asthma [11]. Above all, approximately 40-60% of patients with severe, uncontrolled asthma have an eosinophilic phenotype [12-15].

Eosinophilic asthma is associated with atopy, eczema, allergic rhinitis, Chronic Rhinosinusitis with Nasal Polyps (CRSwNP), Aspirin-Exacerbated Respiratory Disease (AERD) and Eosinophilic Esophagitis (EoE) [16-19]. These diseases significantly increase the severity and burden of eosinophilic asthma. Table 1 shows the diseases associated with eosinophilic asthma. Additional features of eosinophilic asthma include elevated blood and sputum eosinophil count and raised Immunoglobulin E (IgE). Unlike neutrophilic asthma, eosinophilic asthma has specific diagnostic biomarkers. They include elevated levels of Fractional exhaled Nitric Oxide (FeNO), raised serum Dipeptidyl Peptidase-4 (DPP-4), periostin, and osteopontin [20-23]. Evaluation of biomarkers of airway inflammation is very useful in stratifying patients for precision, personalized biological therapy because patients with neutrophilic asthma do not respond to eosinophilic targeted biologics.

The pathophysiological mechanism underlying eosinophilic asthma is chronic airway inflammation due to the hypersecretion of cytokines by CD4+ T helper 2 (Th2) cells and innate lymphoid group 2 cells (ILC2). Hematopoietic cells, such as eosinophils, and basophils, and non-hematopoietic cells, including mast cells, epithelial cells, fibroblasts, myofibroblasts, and airway smooth muscle (ASM) cells also secrete Th2 cytokines. The Th2 cytokines consists of interleukin-5 (IL-5), IL-4 and IL-13. Injured or damaged airway epithelium due to viral, bacterial, and fungal infections, aeroallergen, particulate matter, air pollutants, and trauma can generate another set of cytokines known as epithelial cytokines or “alarmins”. Alarmin cytokines include IL-25, IL-33 and Thymic Stromal Lymphopoietin (TSLP).

Conversely, Th1 cells secrete interleukin-12, interferon-α (IFN-α), IFN-γ and transforming growth factor-β, which play an inhibitory role in Th2 cytokine production and eosinophilic inflammation. Interferon-γ has an inhibitory effect on IgE production, eosinophilic functions, and eosinophilic inflammation. In children with moderate asthma, it has been shown that the concentration of IFN-γ in supernatants of cultures of stimulated Peripheral Blood Mononuclear Cells (PBMCs) was significantly lower and the ratio of IFN-γ/IL-4 was also significantly lower [24]. This indicates that during eosinophilic inflammation in asthmatic patients, there is excessive production of Th2 cytokines, such as Il-5, IL-4 and Il-13 and suppression of the secretion of Th1 cytokines, including IFN-β.

During an asthmatic response, there is the activation of Th2, ILC2, epithelial cells, hemopoietic, and non-hemopoietic cells. This results in the secretions of both Th2 and epithelial cytokines, chemokines, adhesion molecules, and growth factors. These inflammatory mediators result in eosinophilic inflammation, Airway Hyperresponsiveness (AHR) and remodeling.

Airway remodeling is responsible for airway narrowing, severe airway obstruction and difficult-to-treat eosinophilic asthma. The airway structural changes which occur during the remodeling crusade include laying of the extracellular matrix proteins secreted by fibroblasts and myofibroblasts, subepithelial fibrosis and thickening, goblet cell hyperplasia and mucus hypersecretion, airway smooth muscle hyperplasia and hypertrophy, and neovascularization. Airway remodeling ultimately leads to airway wall thickening, severe airway obstruction, and severe asthma. Furthermore, airway remodeling results in difficulty to control asthma with the Standard of Care (SoC), which includes Long-Acting β2-Agonists (LABA) and low-dose Inhaled Corticosteroids (ICS).

Interleukin-4

The duet sister cytokines IL-4 and IL-13 play a key role in the pathogenesis of eosinophilic asthma and other allergic diseases, such as atopic dermatitis, allergic rhinitis, chronic rhinosinusitis with nasal polyps, and aspirin-exacerbated respiratory disease.

Interleukin-4 is a pleiotropic type 1 cytokine that controls the growth and differentiation of immune, hematopoietic, and non-hematopoietic cells. It was simultaneously discovered by two separate groups led by Maureen Howard, William E. Paul; and Ellen Vitetta, in 1982 [25]. It was initially identified as a soluble factor responsible for B-cell proliferation, and as a class-switching cytokine [26].

Interleukin-4 is a compact, globular cytokine, stabilized by three disulfide bonds. One-half of the molecule is composed of a four alpha-helix bundle and is closely related to IL-13 with a 25% homology. Interleukin-4 and IL-13 are encoded by adjacent genes located on chromosome 5q31-33 and are closely linked to one another [27]. They share a number of regulatory elements, such as GATA-3 [28] and transmit signals through a shared functional receptor complex (IL-4Rα/IL-13Rα1) [29]. IL-4 and IL-13 have almost the same biological effects, although each of these cytokines has its own independent immunopathological functions.

Interleukin-4 plays a central role in the pathogenesis of severe eosinophilic asthma [30-32]. It is secreted mainly by Th2 lymphocytes [33,34], and ILC2 cells [35,36]. IL-4 is also produced by mast cells, eosinophils and basophils [37,38].

Interleukin 4 controls both the growth and differentiation of immune, hemopoietic and non-hemopoietic cells. It is a key factor for the development of Th2 cells from naïve T helper type 0 (Th0) lymphocytes. Th2 cells produce and secrete several cytokines, and chemokines responsible for inducing allergic reactions, including IL-4 in a positive feedback loop. Interleukin-4 also controls ILC2 cells and Natural Killer (NK) T cells proliferation, which contribute to airway inflammation, and eosinophilic asthma by secretion of Th2 cytokines, and chemokines [39,40].

Interleukin-4 has several other biological and immunological effects. Most importantly, it induces the ε isotype switch and switching of B cell immunoglobulin production from IgM to IgE [41,42]. Additionally, IL-4 enhances IgE-mediated responses by upregulating IgE receptors on various immune cells, such as the high-affinity IgE receptors (FcεRI) on mast cells and basophils, and the low-affinity IgE receptors (FcεRII; CD23) on lymphocytes and mononuclear cells [30,43]. IgE plays an important role in activating mast cells, eosinophils, and basophils, which upon activation degranulate and release numerous cationic proteins, cytokines, chemokines, growth factors and enzymes. These inflammatory mediators are responsible for airway epithelial injury, eosinophilic inflammation, AHR and airway remodeling.

Interleukin-4 stimulates the migration of eosinophils into allergic airways through increases in the expression of eotaxin 1, 2 and 3 [44,45]. It also prolongs eosinophil survival by preventing eosinophil apoptosis [46]. Activated eosinophils degranulate and release several cytotoxic cationic proteins, such as Major Basic Protein (MBP), Eosinophil Cationic Protein (ECP), Eosinophil-Derived Neurotoxin (EDN) and Eosinophil-Derived Peroxide (EDPX) [47]. In addition, eosinophils release mediators, such as leukotrienes, prostaglandins, cytokines, chemokines, enzymes, and reactive oxygen species. These inflammatory mediators cause epithelial injury, bronchial smooth muscle contraction, microvascular leakage and airway edema, goblet cell hyperplasia, and mucus secretion [48-50]. Table 2 shows the inflammatory mediators secreted by activated eosinophils.

The cationic proteins (MBP, ECP, EDN, and EDPX) are very cytotoxic to the airway epithelium and myelinated neurons and can cause epithelial and neuronal injury, and damage. EDPX forms reactive oxygen species and reactive nitrogen metabolites that promote oxidative stress, causing cell death by apoptosis and necrosis of epithelial cells. Furthermore, eosinophilic cation proteins are associated with airway smooth muscle hypertrophy, AHR, and airway remodeling [48-50].

Interleukin-4 induces mucin-encoding gene (MUC5AC) expression which results in goblet cells hyperplasia, and mucus hypersecretion, which can obstruct the airways and cause severe airflow limitation [51]. Accumulation of sticky mucus causes diffuse airway obstruction and is an important feature of severe, near-fatal, and fatal asthma [52].

Interleukin-4 has been demonstrated to have 15-lipoxygenase activity, and to promote the production of Leukotrienes (LT), such as LTB4, LTC4, and LTD4 [53]. Leukotrienes are potent bronchoconstrictor, secretagogues, and vasodilators and promote vascular leakage, resulting in airway mucosal edema. This may lead to severe airway obstruction.

IL-4 also plays an important role in the proliferation of fibroblasts, and myofibroblasts, which deposit extracellular matrix (ECM proteins). This leads to subepithelial fibrosis and thickening of the basement membrane, airway remodeling, and partially irreversible airflow limitation [54].

Another biological effect of IL-4 is the induction of adhesion molecule production, such as Vascular Cell Adhesion Molecule-1 (VCAM-1), Intercellular Adhesion Molecule-1 (ICAM-1) and E-selection by vascular endothelial cells. VCAM-1 and ICAM-1 are responsible for the lining of inflammatory cells along the blood vessel wall. VACM-1 or ICAM-1 and IL-4 facilitate diapedesis and migration of eosinophils, basophils, T lymphocytes, and mast cells from blood vessels to the inflamed allergic airways. Activation of these cells amplifies eosinophilic airway inflammation by secreting more cytokines, chemokines, adhesion molecules, and enzymes which orchestrate eosinophilic inflammation, and airway remodeling. Table 2 shows the cationic proteins and pro-inflammatory mediators synthesized and secreted by activated eosinophils.

Interleukin-4 signaling

The interleukin-4 receptor complex (IL-4R) is a heterodimer composed of a common α-subunit (IL-4Rα), and the γc chain to form the IL-4R type I. The γc subunit also functions as a subunit for other cytokines, such as IL-2, IL-7, IL-9, IL-15, and IL-21 receptor complexes. Type I receptor is expressed predominantly on several hematopoietic cells and binds exclusively to IL-4 [55,56]. IL-4Rα also binds to the IL-13 receptor (IL-13Rα1), to form a high-affinity type II heterodimeric complex (IL-4Rα/IL-13Rα1), which binds to both IL-4, and IL-13. Interleukin-4 signals through both types I and II receptors, whereas IL-13 signals only through type II [55,56]. Type II IL-4/IL-13 receptor binds to hematopoietic cells, and non-hematopoietic cells, such as epithelial cells, fibroblasts, and airway smooth muscle cells to mediate the immunopathological effects of both IL-4 and IL-13 [57].

The binding of IL-4 to its receptors stimulates the transphosphorylation and activation of receptor subunits of the Janus Family Protein Kinases (JAKs), such as JAK1, JAK2, JAK3, and Tyrosine Kinase (Tyk2) [58-61]. Type I receptors activate Jak1 and Jak3, type II receptors activate Jak1, Jak2, and Tyk2 [62,63].

Activation of the JAK family initiates phosphorylation of specific tyrosine residues of the cytoplasmic domain of the IL-4Rα [64-67]. Phosphorylation of the three tyrosine residues IL-4Rα Y575, IL-4α 603 and IL-4Rα Y633 leads to the recruitment of the transcription factor Signal Transducer and Activator of Transcription 6 (STAT6), through the domains of STAT6 [66]. STAT6 molecules in turn are phosphorylated, dimerized, and translocate to the nucleus where they regulate gene transcription leading to the production of Th2 cytokines, and chemokines involved in the pathogenesis of eosinophilic asthma [68,69]. Gene transcription leads to the secretion of Th2 cytokines, such as IL-3, IL-4, IL-5, and GM-CSF and chemokines, including CCL11 (eotaxin 1), CCL24 (eotaxin 2), CCL26 (eotaxin 3), CCL13 (MCP4) and CCL5 (RANTES) [70,71].

Both types I and II receptors initiate activation of the STA6 pathway [72], but only type I IL-4 receptors activate the Insulin Receptor Substrate (IRS-2) pathway [73,74]. However, activation of type II receptors and STAT6 is essential for most of the features of eosinophilic asthma [75].

Interleukin-13

Interleukin-13 (IL-13) plays a pivotal role in the pathogenesis of severe eosinophilic asthma [76,77]. It is produced by activated Th2 lymphocytes [78,79], ILC2 cells [80,81], B cells [82], mast cells [83-85], macrophages [86], eosinophils [87,88] and basophils [89,90].

Interleukin-13 was initially discovered in 1993 and was identified by molecular cloning in activated human T-lymphocytes [91]. It has a molecular weight of 13 kDa and is composed of four alpha helical bundles, A, B, C and D. It shares 25% sequence homologies with interleukin-4; however, it is capable of independent signaling, and distinctive immunobiological functions [92,93]. Interleukin-13 plays the most important role in the pathogenesis of severe, uncontrolled eosinophilic asthma [94,95].

Like its sister IL-4, IL-13 also plays an important role in switching B-cell immunoglobulin production from IgM to IgE and IG1 [96,97]. It promotes eosinophil recruitment and activation into inflamed airways [98] and fosters eosinophil survival by preventing apoptosis [99,100]. Additionally, IL-13 induces goblet cell hyperplasia and mucus hypersecretion [101-104]. Goblet cell hyperplasia and mucus overproduction are features of severe asthma. Excessive airway mucus plugging due to thick tenacious mucus is associated with fatal asthma [105].

Interleukin-13 stimulates the proliferation of fibroblasts [106,107] and myofibroblasts [108,109]. It is responsible for the deposition of ECM proteins produced by fibroblasts, and myofibroblasts, leading to subepithelial fibrosis, airway wall thickening, AHR and remodeling [108]. Additionally, IL-13 induces ASM cell proliferation [110,111] and enhances differentiation and contractility of airway smooth muscle cells via up-regulation of the RhoA protein [112]. Interleuki-13 has been shown to enhance the proliferation of ASM cells, and in enhancing the cholinergic-induced contraction of ASM cells [113], thus intensifying severe bronchoconstriction in asthma.

Interleukin-13 increases the activity of vascular cell adhesion molecules, such as β-integrin, VACM-1 and ICAM-1 [114,115], which promote eosinophilic migration and recruitment in allergic airways, thus promoting eosinophilic inflammation. IL-13 is a very potent inducer of VACM-1 on endothelial cells and plays a major role in eosinophil migration from the blood vessels, and recruitment into allergic airways [116]. The recruited activated eosinophils liberate more cytotoxic cationic proteins, cytokines, chemokines, and reactive oxygen species, which intensify airway inflammation, AHR, and remodeling.

Additionally, IL-13 induces the expression of Vascular Endothelial Cell Growth Factors (VEGF-A, B, C, D, E, F. VEGFA (VEGF) is one of the most powerful and potent endothelial cell mitogens. It promotes angiogenesis in asthmatic airways, expanding the airway vascular network, which contributes to airway remodeling and severe asthma [117-119].

Interleukin-13 induces the expression of pro-fibrotic matricellular proteins periostin and osteopontin [120,121]. Periostin and osteopontin play an important role in fibroblast activation and increase collagen gel elasticity. They play a central role in promoting fibroblast and myofibroblast proliferation, subepithelial fibrosis, and mucus hypersecretion which lead to progressive structural changes in the airways [120,121]. Periostin-induced airway remodeling leads to a progressive decline in lung function (forced expired volume in one second, FEV1) and fixed airflow limitation [122,123].

Furthermore, periostin is associated with corticosteroid resistance. It induces a reduction in the affinity of the glucocorticoid receptor in inflammatory cells, such as T cells, and monocytes, resulting in local resistance to the anti-inflammatory effects of corticosteroids [124,125]. Interleukin-13 induces activation of epithelial nitric oxide synthase through its effect on STAT-6 [126], which results in the production of exhaled nitric oxide from airway epithelial cells. Fractional exhaled nitric oxide mirrors IL-13 biological activity and is a pharmacodynamic biomarker of eosinophilic asthma [127,128]. Table 3 shows the immunopathological mechanisms of IL-4/13 in the pathogenesis of severe eosinophilic asthma.

Interleukin-13 signaling

Interleukin-13 signaling is via IL-13 receptors (IL-13Rs) which are heterodimer complexes consisting of an IL-13Rα1 or IL-13Rα2 chain, bound to an IL-4Rα chain. However, IL-13 mediates most of its effects by binding to IL-13Rα1 and IL-4Rα (type II receptor) [129,130]. The IL-4Rα chain is similar to both IL-4 and IL-13, and shares similarities in signal transduction, and in the regulation of antibody production, and allergic inflammation. However, IL-13 is capable of independent signaling and has some different immunopathologic functions from those of IL-4. Nevertheless, the signaling pathways are common to both receptors and are largely JAK-STAT6-dependent. The binding of IL-13 to type II receptors leads to the activation of JAK1, JAK2 and tyrosine kinase 2 (TYK2). Activation of JAKS leads to the recruitment of STAT6 to the receptors, with subsequent phosphorylation and dimerization of STAT6. Activated STAT6 dimers translocate to the nucleus, where they bind to specific DNA elements, and result in the transcription of downstream genes [58,59]. This results in the production of several cytokines, and chemokines by immune cells, such as Th2 lymphocytes, ILC2 cells, eosinophils, mast cells, and macrophages. IL-13 can also bind to the high-affinity IL-13Rα2. Signaling through this receptor has been reported to induce TGF-β production in mice and humans, and promotion of fibrosis [60].

Treatment of severe eosinophilic asthma

Most patients with eosinophilic asthma respond to treatment with standard therapies, such as Long-Acting β-Agonists (LABA), Low-Dose Inhaled Corticosteroids (ICS) and Leukotriene Receptor Antagonists (LTRA). For patients who still experience asthma exacerbations, the addition of a Long-Acting Muscarinic Antagonist (LAMA) usually can control asthma. Patients with severe, uncontrolled eosinophilic asthma can benefit from a single inhaler dual therapy, or a Single Inhaler Triple Therapy (SITT), comprising a LABA, an ICS, and a LAMA in a single inhaler. SITT is very effective in treating difficult-to-control asthma, and it improves compliance [61,131,132]. Single inhaler triple therapy significantly reduces moderate-to-severe exacerbations and improves lung function (FEV1) compared with single inhaler dual therapy. In the TRIMARAN clinical trial, Virchow, et al. [61] have shown that SITT significantly reduced moderate-to-severe exacerbation (p < 0.033), and significantly improved FEV1 (p < 0.008) compared with single inhaler dual therapy [61]. Table 4 shows drug combinations in the single-inhaler dual therapy and single-inhaler triple therapy.

However, about 15% - 20% of patients with asthma remain uncontrolled, with frequent exacerbations, increased use of ICS or OCS, recurrent emergency room admissions, and impaired quality of life [133]. Approximately, 3.6% - 10% of asthmatics have severe refractory corticosteroid-resistant disease, which is uncontrolled despite treatment with high dose ICS, LABA, and/or LTRA [134,135]. About 50% of these patients have Th2-mediated severe eosinophilic asthma.

Treatment of patients with severe eosinophilic asthma may necessitate the use of biologics. There are several monoclonal antibodies (mAb) targeting the inflammatory cytokines implicated in the pathophysiology of eosinophilic asthma. There is only one biologic targeting IL-4 and IL-13 signaling pathways that have been approved for the treatment of moderate-to-severe eosinophilic asthma in adults and children 12 years and older. Dupilumab (Dupixent®) is a fully humanized IgG4 monoclonal antibody to the IL-4Rα, which mediates signaling to both IL-4 and IL-13. It was approved for the treatment of moderate-to-severe asthma on October 19, 2018. It is administered subcutaneously. In adults and children 12 years and older, it is administered as 400 mg (two 200 mg injections) as the initial loading dose. Thereafter, the subsequent dose is 200 mg every two weeks.

In most clinical trials, dupilumab has been shown to improve asthma control, and significantly reduce exacerbations (p < 0.001) compared with a placebo. Additionally, it has been demonstrated to significantly improve lung function (p <0.001), and health-related quality of life (HLQoL) and allow patients to taper or discontinue corticosteroids [136-139] compared with placebo.

Dupixent is also approved for the treatment of eczema [140,141], chronic rhinosinusitis with nasal polyps [142,143] and eosinophilic esophagitis [144]. Comorbid diseases, particularly CRSwNP and EoE make asthma control very difficult unless the associated diseases are treated adequately. Dupilumab is beneficial and effective in treating severe eosinophilic asthma in patients with the above comorbidities [145].

Recently, dupilumab has been shown to have a long-term effect and safety for 96 weeks in patients with asthma with or without chronic rhinosinusitis and nasal polyps [146] and for 148 weeks in patients with moderate-to-severe asthma [147]. Notably, it reduces oral corticosteroid use in patients with corticosteroid-dependent asthma [146,148], thus reducing the serious side effects due to prolonged corticosteroid treatment.

Conclusion

The duet sister cytokines IL-4, and IL-13 play a central role in the pathogenesis of eosinophilic asthma. IL-4 and Il-13 are related and they share the same signaling pathway via the IL-4R chain and have similar biological functions. Most patients with eosinophilic asthma respond to a LABA, low-dose ICS, and LTRA. However, approximately 3.6-10% are refractory to the treatment, including oral corticosteroids (OCS). These patients benefit from treatment with a biologic. Dupilumab is the only approved biologic that inhibits the biological and immunological effects of both IL-4 and IL-13. Treatment with dupilumab results in good asthma control, reduction in exacerbation rates, improvement in lung function, and HLQoL. Noteworthy, Dupilumab is also very useful in ameliorating the comorbid allergic diseases associated with eosinophilic asthma.

Conflict of interest

The author declares that the publication was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1204-1222. doi: 10.1016/S0140-6736(20)30925-9. Erratum in: Lancet. 2020 Nov 14;396(10262):1562. PMID: 33069326; PMCID: PMC7567026.
2. Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, Williams H; ISAAC Phase Three Study Group. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet. 2006 Aug 26;368(9537):733-43. doi: 10.1016/S0140-6736(06)69283-0. Erratum in: Lancet. 2007 Sep 29;370(9593):1128. PMID: 16935684.
3. Pearce N, Aït-Khaled N, Beasley R, Mallol J, Keil U, Mitchell E, Robertson C; ISAAC Phase Three Study Group. Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax. 2007 Sep;62(9):758-66. doi: 10.1136/thx.2006.070169. Epub 2007 May 15. PMID: 17504817; PMCID: PMC2117323.
4. The Global Asthma Network. The Global Asthma Report 2014. Available at: htt://www.globalasthmanetwork.org/publications/Global_Asthma_Report_2014.
5. Wenzel SE, Schwartz LB, Langmack EL, Halliday JL, Trudeau JB, Gibbs RL, Chu HW. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med. 1999 Sep;160(3):1001-8. doi: 10.1164/ajrccm.160.3.9812110. PMID: 10471631.
6. Simpson JL, Scott R, Boyle MJ, Gibson PG. Inflammatory subtypes in asthma: assessment and identification using induced sputum. Respirology. 2006 Jan;11(1):54-61. doi: 10.1111/j.1440-1843.2006.00784.x. PMID: 16423202.
7. Chung KF. Asthma phenotyping: a necessity for improved therapeutic precision and new targeted therapies. J Intern Med. 2016 Feb;279(2):192-204. doi: 10.1111/joim.12382. Epub 2015 Jun 15. PMID: 26076339.
8. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004 Jan;113(1):101-8. doi: 10.1016/j.jaci.2003.10.041. PMID: 14713914.
9. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008 Aug 1;178(3):218-224. doi: 10.1164/rccm.200711-1754OC. Epub 2008 May 14. PMID: 18480428; PMCID: PMC3992366.
10. de Groot JC, Ten Brinke A, Bel EH. Management of the patient with eosinophilic asthma: a new era begins. ERJ Open Res. 2015 Sep 23;1(1):00024-2015. doi: 10.1183/23120541.00024-2015. Erratum in: ERJ Open Res. 2016 Aug 25;2(3): PMID: 27730141; PMCID: PMC5005141.
11. Wang F, He XY, Baines KJ, Gunawardhana LP, Simpson JL, Li F, Gibson PG. Different inflammatory phenotypes in adults and children with acute asthma. Eur Respir J. 2011 Sep;38(3):567-74. doi: 10.1183/09031936.00170110. Epub 2011 Jan 13. PMID: 21233265.
12. Miranda C, Busacker A, Balzar S, Trudeau J, Wenzel SE. Distinguishing severe asthma phenotypes: role of age at onset and eosinophilic inflammation. J Allergy Clin Immunol. 2004 Jan;113(1):101-8. doi: 10.1016/j.jaci.2003.10.041. PMID: 14713914.
13. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, Wardlaw AJ, Green RH. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008 Aug 1;178(3):218-224. doi: 10.1164/rccm.200711-1754OC. Epub 2008 May 14. PMID: 18480428; PMCID: PMC3992366.
14. Hekking PW, Wener RR, Amelink M, Zwinderman AH, Bouvy ML, Bel EH. The prevalence of severe refractory asthma. J Allergy Clin Immunol. 2015 Apr;135(4):896-902. doi: 10.1016/j.jaci.2014.08.042. Epub 2014 Oct 16. PMID: 25441637.
15. Varsano S, Segev D, Shitrit D. Severe and non-severe asthma in the community: A large electronic database analysis. Respir Med. 2017 Feb;123:131-139. doi: 10.1016/j.rmed.2016.12.017. Epub 2016 Dec 28. PMID: 28137489.
16. Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, Zuberbier T, Baena-Cagnani CE, Canonica GW, van Weel C, Agache I, Aït-Khaled N, Bachert C, Blaiss MS, Bonini S, Boulet LP, Bousquet PJ, Camargos P, Carlsen KH, Chen Y, Custovic A, Dahl R, Demoly P, Douagui H, Durham SR, van Wijk RG, Kalayci O, Kaliner MA, Kim YY, Kowalski ML, Kuna P, Le LT, Lemiere C, Li J, Lockey RF, Mavale-Manuel S, Meltzer EO, Mohammad Y, Mullol J, Naclerio R, O'Hehir RE, Ohta K, Ouedraogo S, Palkonen S, Papadopoulos N, Passalacqua G, Pawankar R, Popov TA, Rabe KF, Rosado-Pinto J, Scadding GK, Simons FE, Toskala E, Valovirta E, van Cauwenberge P, Wang DY, Wickman M, Yawn BP, Yorgancioglu A, Yusuf OM, Zar H, Annesi-Maesano I, Bateman ED, Ben Kheder A, Boakye DA, Bouchard J, Burney P, Busse WW, Chan-Yeung M, Chavannes NH, Chuchalin A, Dolen WK, Emuzyte R, Grouse L, Humbert M, Jackson C, Johnston SL, Keith PK, Kemp JP, Klossek JM, Larenas-Linnemann D, Lipworth B, Malo JL, Marshall GD, Naspitz C, Nekam K, Niggemann B, Nizankowska-Mogilnicka E, Okamoto Y, Orru MP, Potter P, Price D, Stoloff SW, Vandenplas O, Viegi G, Williams D; World Health Organization; GA(2)LEN; AllerGen. Allergic Rhinitis and its Impact on Asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008 Apr;63 Suppl 86:8-160. doi: 10.1111/j.1398-9995.2007.01620.x. PMID: 18331513.
17. Ciprandi G, Caimmi D, Miraglia Del Giudice M, La Rosa M, Salpietro C, Marseglia GL. Recent developments in United airways disease. Allergy Asthma Immunol Res. 2012 Jul;4(4):171-7. doi: 10.4168/aair.2012.4.4.171. Epub 2012 Feb 8. PMID: 22754709; PMCID: PMC3378922.
18. Giavina-Bianchi P, Aun MV, Takejima P, Kalil J, Agondi RC. United airway disease: current perspectives. J Asthma Allergy. 2016 May 11;9:93-100. doi: 10.2147/JAA.S81541. PMID: 27257389; PMCID: PMC4872272.
19. Syabbalo NC. Anti-interleukin antagonists in the treatment of diseases of the atopic march Open J Pulm Respir Med 2021; 3:1-27. https://orcid.org/0000-0002-9435-5456.
20. Bagnasco D, Ferrando M, Varricchi G, Passalacqua G, Canonica GW. A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma. Int Arch Allergy Immunol. 2016;170(2):122-31. doi: 10.1159/000447692. Epub 2016 Aug 3. PMID: 27637004.
21. Wan XC, Woodruff PG. Biomarkers in Severe Asthma. Immunol Allergy Clin North Am. 2016 Aug;36(3):547-57. doi: 10.1016/j.iac.2016.03.004. PMID: 27401625; PMCID: PMC6057475.
22. Yancey SW, Keene ON, Albers FC, Ortega H, Bates S, Bleecker ER, Pavord I. Biomarkers for severe eosinophilic asthma. J Allergy Clin Immunol. 2017 Dec;140(6):1509-1518. doi: 10.1016/j.jaci.2017.10.005. PMID: 29221581.
23. Syabbalo N. Biomarkers for the diagnosis of eosinophilic asthma. J Lung 2020; 1:2. DOI: 10.36648/lung.1.1.2.
24. Hoekstra MO, Hoekstra Y, De Reus D, Rutgers B, Gerritsen J, Kauffman HF. Interleukin-4, interferon-gamma and interleukin-5 in peripheral blood of children with moderate atopic asthma. Clin Exp Allergy. 1997 Nov;27(11):1254-60. PMID: 9420128.
25. Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol. 1999;17:701-38. doi: 10.1146/annurev.immunol.17.1.701. PMID: 10358772.
26. Coffman RL, Ohara J, Bond MW, Carty J, Zlotnik A, Paul WE. B cell stimulatory factor-1 enhances the IgE response of lipopolysaccharide-activated B cells. J Immunol. 1986 Jun 15;136(12):4538-41. PMID: 3486902.
27. Marsh DG, Neely JD, Breazeale DR, Ghosh B, Freidhoff LR, Ehrlich-Kautzky E, Schou C, Krishnaswamy G, Beaty TH. Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. 1994 May 20;264(5162):1152-6. doi: 10.1126/science.8178175. PMID: 8178175.
28. Chatila TA, Li N, Garcia-Lloret M, Kim HJ, Nel AE. T-cell effector pathways in allergic diseases: transcriptional mechanisms and therapeutic targets. J Allergy Clin Immunol. 2008 Apr;121(4):812-23; quiz 824-5. doi: 10.1016/j.jaci.2008.02.025. PMID: 18395547.
29. Wills-Karp M. Interleukin-13 in asthma pathogenesis. Immunol Rev. 2004 Dec;202:175-90. doi: 10.1111/j.0105-2896.2004.00215.x. PMID: 15546393.
30. Steinke JW, Borish L. Th2 cytokines and asthma. Interleukin-4: its role in the pathogenesis of asthma, and targeting it for asthma treatment with interleukin-4 receptor antagonists. Respir Res. 2001;2(2):66-70. doi: 10.1186/rr40. Epub 2001 Feb 19. PMID: 11686867; PMCID: PMC59570.
31. Gour N, Wills-Karp M. IL-4 and IL-13 signaling in allergic airway disease. Cytokine. 2015 Sep;75(1):68-78. doi: 10.1016/j.cyto.2015.05.014. Epub 2015 Jun 9. PMID: 26070934; PMCID: PMC4532591.
32. Bagnasco D, Ferrando M, Varricchi G, Passalacqua G, Canonica GW. A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma. Int Arch Allergy Immunol. 2016;170(2):122-31. doi: 10.1159/000447692. Epub 2016 Aug 3. PMID: 27637004.
33. Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015 Jan;16(1):45-56. doi: 10.1038/ni.3049. PMID: 25521684.
34. Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019 Apr 16;50(4):975-991. doi: 10.1016/j.immuni.2019.03.018. PMID: 30995510.
35. Dunican EM, Fahy JV. The Role of Type 2 Inflammation in the Pathogenesis of Asthma Exacerbations. Ann Am Thorac Soc. 2015 Nov;12 Suppl 2(Suppl 2):S144-9. doi: 10.1513/AnnalsATS.201506-377AW. PMID: 26595730; PMCID: PMC5467082.
36. Denlinger LC, Phillips BR, Ramratnam S, Ross K, Bhakta NR, Cardet JC, Castro M, Peters SP, Phipatanakul W, Aujla S, Bacharier LB, Bleecker ER, Comhair SA, Coverstone A, DeBoer M, Erzurum SC, Fain SB, Fajt M, Fitzpatrick AM, Gaffin J, Gaston B, Hastie AT, Hawkins GA, Holguin F, Irani AM, Israel E, Levy BD, Ly N, Meyers DA, Moore WC, Myers R, Opina MT, Peters MC, Schiebler ML, Sorkness RL, Teague WG, Wenzel SE, Woodruff PG, Mauger DT, Fahy JV, Jarjour NN; National Heart, Lung, and Blood Institute’s Severe Asthma Research Program-3 Investigators. Inflammatory and Comorbid Features of Patients with Severe Asthma and Frequent Exacerbations. Am J Respir Crit Care Med. 2017 Feb 1;195(3):302-313. doi: 10.1164/rccm.201602-0419OC. Erratum in: Am J Respir Crit Care Med. 2018 Apr 1;197(7):971. PMID: 27556234; PMCID: PMC5328178.
37. Gordon ED, Simpson LJ, Rios CL, Ringel L, Lachowicz-Scroggins ME, Peters MC, Wesolowska-Andersen A, Gonzalez JR, MacLeod HJ, Christian LS, Yuan S, Barry L, Woodruff PG, Ansel KM, Nocka K, Seibold MA, Fahy JV. Alternative splicing of interleukin-33 and type 2 inflammation in asthma. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):8765-70. doi: 10.1073/pnas.1601914113. Epub 2016 Jul 18. PMID: 27432971; PMCID: PMC4978244.
38. Bal SM, Bernink JH, Nagasawa M, Groot J, Shikhagaie MM, Golebski K, van Drunen CM, Lutter R, Jonkers RE, Hombrink P, Bruchard M, Villaudy J, Munneke JM, Fokkens W, Erjefält JS, Spits H, Ros XR. IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat Immunol. 2016 Jun;17(6):636-45. doi: 10.1038/ni.3444. Epub 2016 Apr 25. PMID: 27111145.
39. Bal SM, Bernink JH, Nagasawa M, Groot J, Shikhagaie MM, Golebski K, van Drunen CM, Lutter R, Jonkers RE, Hombrink P, Bruchard M, Villaudy J, Munneke JM, Fokkens W, Erjefält JS, Spits H, Ros XR. IL-1β, IL-4 and IL-12 control the fate of group 2 innate lymphoid cells in human airway inflammation in the lungs. Nat Immunol. 2016 Jun;17(6):636-45. doi: 10.1038/ni.3444. Epub 2016 Apr 25. PMID: 27111145.
40. Motomura Y, Morita H, Moro K, Nakae S, Artis D, Endo TA, Kuroki Y, Ohara O, Koyasu S, Kubo M. Basophil-derived interleukin-4 controls the function of natural helper cells, a member of ILC2s, in lung inflammation. Immunity. 2014 May 15;40(5):758-71. doi: 10.1016/j.immuni.2014.04.013. PMID: 24837103.
41. Maes T, Joos GF, Brusselle GG. Targeting interleukin-4 in asthma: lost in translation? Am J Respir Cell Mol Biol. 2012 Sep;47(3):261-70. doi: 10.1165/rcmb.2012-0080TR. Epub 2012 Apr 26. PMID: 22538865.
42. .Bartemes KR, Kita H. Dynamic role of epithelium-derived cytokines in asthma. Clin Immunol. 2012 Jun;143(3):222-35. doi: 10.1016/j.clim.2012.03.001. Epub 2012 Mar 20. PMID: 22534317; PMCID: PMC3358585.
43. Pawankar R, Okuda M, Yssel H, Okumura K, Ra C. Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the Fc epsilonRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J Clin Invest. 1997 Apr 1;99(7):1492-9. doi: 10.1172/JCI119311. PMID: 9119992; PMCID: PMC507968.
44. Coleman JM, Naik C, Holguin F, Ray A, Ray P, Trudeau JB, Wenzel SE. Epithelial eotaxin-2 and eotaxin-3 expression: relation to asthma severity, luminal eosinophilia and age at onset. Thorax. 2012 Dec;67(12):1061-6. doi: 10.1136/thoraxjnl-2012-201634. Epub 2012 Sep 26. PMID: 23015684; PMCID: PMC3652589.
45. Jose PJ, Griffiths-Johnson DA, Collins PD, Walsh DT, Moqbel R, Totty NF, Truong O, Hsuan JJ, Williams TJ. Eotaxin: a potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. J Exp Med. 1994 Mar 1;179(3):881-7. doi: 10.1084/jem.179.3.881. PMID: 7509365; PMCID: PMC2191401.
46. Hogan SP, Rosenberg HF, Moqbel R, Phipps S, Foster PS, Lacy P, Kay AB, Rothenberg ME. Eosinophils: biological properties and role in health and disease. Clin Exp Allergy. 2008 May;38(5):709-50. doi: 10.1111/j.1365-2222.2008.02958.x. Epub 2008 Apr 1. PMID: 18384431.
47. Maes T, Joos GF, Brusselle GG. Targeting interleukin-4 in asthma: lost in translation? Am J Respir Cell Mol Biol. 2012 Sep;47(3):261-70. doi: 10.1165/rcmb.2012-0080TR. Epub 2012 Apr 26. PMID: 22538865.
48. Kotsimbos TC, Ghaffar O, Minshall EM, Humbert M, Durham SR, Pfister R, Menz G, Kay AB, Hamid QA. Expression of the IL-4 receptor alpha-subunit is increased in bronchial biopsy specimens from atopic and nonatopic asthmatic subjects. J Allergy Clin Immunol. 1998 Nov;102(5):859-66. doi: 10.1016/s0091-6749(98)70029-6. PMID: 9819306.
49. Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z, Elias JA, Sheppard D, Erle DJ. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med. 2002 Aug;8(8):885-9. doi: 10.1038/nm734. Epub 2002 Jul 1. PMID: 12091879.
50. Kuperman DA, Schleimer RP. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Curr Mol Med. 2008 Aug;8(5):384-92. doi: 10.2174/156652408785161032. PMID: 18691065; PMCID: PMC4437630.
51. Dabbagh K, Takeyama K, Lee HM, Ueki IF, Lausier JA, Nadel JA. IL-4 induces mucin gene expression and goblet cell metaplasia in vitro and in vivo. J Immunol. 1999 May 15;162(10):6233-7. PMID: 10229869.
52. Kuyper LM, Paré PD, Hogg JC, Lambert RK, Ionescu D, Woods R, Bai TR. Characterization of airway plugging in fatal asthma. Am J Med. 2003 Jul;115(1):6-11. doi: 10.1016/s0002-9343(03)00241-9. PMID: 12867228.
53. Hsieh FH, Lam BK, Penrose JF, Austen KF, Boyce JA. T helper cell type 2 cytokines coordinately regulate immunoglobulin E-dependent cysteinyl leukotriene production by human cord blood-derived mast cells: profound induction of leukotriene C(4) synthase expression by interleukin 4. J Exp Med. 2001 Jan 1;193(1):123-33. doi: 10.1084/jem.193.1.123. PMID: 11136826; PMCID: PMC2195887.
54. Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol. 2015 May;15(5):271-82. doi: 10.1038/nri3831. Epub 2015 Apr 17. PMID: 25882242.
55. Nelms K, Keegan AD, Zamorano J, Ryan JJ, Paul WE. The IL-4 receptor: signaling mechanisms and biologic functions. Annu Rev Immunol. 1999;17:701-38. doi: 10.1146/annurev.immunol.17.1.701. PMID: 10358772.
56. Izuhara K, Yang G, Miyajima A, Howard M, Harada N. Structure of the IL4 receptor and signal transduction mechanism of IL4. Res Immunol. 1993 Oct;144(8):584-90. doi: 10.1016/s0923-2494(05)80007-0. PMID: 8303077.
57. Kelly-Welch AE, Melo ME, Smith E, Ford AQ, Haudenschild C, Noben-Trauth N, Keegan AD. Complex role of the IL-4 receptor alpha in a murine model of airway inflammation: expression of the IL-4 receptor alpha on nonlymphoid cells of bone marrow origin contributes to severity of inflammation. J Immunol. 2004 Apr 1;172(7):4545-55. doi: 10.4049/jimmunol.172.7.4545. PMID: 15034072.
58. Walford HH, Doherty TA. STAT6 and lung inflammation. JAKSTAT. 2013 Oct 1;2(4):e25301. doi: 10.4161/jkst.25301. Epub 2013 Jun 10. PMID: 24416647; PMCID: PMC3876430.
59. Goenka S, Kaplan MH. Transcriptional regulation by STAT6. Immunol Res. 2011 May;50(1):87-96. doi: 10.1007/s12026-011-8205-2. PMID: 21442426; PMCID: PMC3107597.
60. Fichtner-Feigl S, Strober W, Kawakami K, Puri RK, Kitani A. IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2006 Jan;12(1):99-106. doi: 10.1038/nm1332. Epub 2005 Dec 4. PMID: 16327802.
61. Virchow JC, Kuna P, Paggiaro P, Papi A, Singh D, Corre S, Zuccaro F, Vele A, Kots M, Georges G, Petruzzelli S, Canonica GW. Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Lancet. 2019 Nov 9;394(10210):1737-1749. doi: 10.1016/S0140-6736(19)32215-9. Epub 2019 Sep 30. PMID: 31582314.
62. Keegan AD, Johnston JA, Tortolani PJ, McReynolds LJ, Kinzer C, O'Shea JJ, Paul WE. Similarities and differences in signal transduction by interleukin 4 and interleukin 13: analysis of Janus kinase activation. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7681-5. doi: 10.1073/pnas.92.17.7681. PMID: 7544000; PMCID: PMC41209.
63. Murata T, Obiri NI, Puri RK. Structure of and signal transduction through interleukin-4 and interleukin-13 receptors (review). Int J Mol Med. 1998 Mar;1(3):551-7. doi: 10.3892/ijmm.1.3.551. PMID: 9852261.
64. LaPorte SL, Juo ZS, Vaclavikova J, Colf LA, Qi X, Heller NM, Keegan AD, Garcia KC. Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell 2008; 132:259-272.
65. Kuperman DA, Schleimer RP. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Curr Mol Med. 2008 Aug;8(5):384-92. doi: 10.2174/156652408785161032. PMID: 18691065; PMCID: PMC4437630.
66. Oh CK, Geba GP, Molfino N. Investigational therapeutics targeting the IL-4/IL-13/STAT-6 pathway for the treatment of asthma. Eur Respir Rev. 2010 Mar;19(115):46-54. doi: 10.1183/09059180.00007609. PMID: 20956165; PMCID: PMC9491642.
67. Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD. Interleukin-4 and interleukin-13 signaling connections maps. Science. 2003 Jun 6;300(5625):1527-8. doi: 10.1126/science.1085458. PMID: 12791978.
68. Ryan JJ, McReynolds LJ, Huang H, Nelms K, Paul WE. Characterization of a mobile Stat6 activation motif in the human IL-4 receptor. J Immunol. 1998 Aug 15;161(4):1811-21. PMID: 9712048.
69. Goenka S, Kaplan MH. Transcriptional regulation by STAT6. Immunol Res. 2011 May;50(1):87-96. doi: 10.1007/s12026-011-8205-2. PMID: 21442426; PMCID: PMC3107597.
70. Mikita T, Campbell D, Wu P, Williamson K, Schindler U. Requirements for interleukin-4-induced gene expression and functional characterization of Stat6. Mol Cell Biol. 1996 Oct;16(10):5811-20. doi: 10.1128/MCB.16.10.5811. PMID: 8816495; PMCID: PMC231582.
71. Chatila TA, Li N, Garcia-Lloret M, Kim HJ, Nel AE. T-cell effector pathways in allergic diseases: transcriptional mechanisms and therapeutic targets. J Allergy Clin Immunol. 2008 Apr;121(4):812-23; quiz 824-5. doi: 10.1016/j.jaci.2008.02.025. PMID: 18395547.
72. Kuperman DA, Schleimer RP. Interleukin-4, interleukin-13, signal transducer and activator of transcription factor 6, and allergic asthma. Curr Mol Med. 2008 Aug;8(5):384-92. doi: 10.2174/156652408785161032. PMID: 18691065; PMCID: PMC4437630.
73. Jiang H, Harris MB, Rothman P. IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol. 2000 Jun;105(6 Pt 1):1063-70. doi: 10.1067/mai.2000.107604. PMID: 10856136.
74. Heller NM, Qi X, Junttila IS, Shirey KA, Vogel SN, Paul WE, Keegan AD. Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages. Sci Signal. 2008 Dec 23;1(51):ra17. doi: 10.1126/scisignal.1164795. PMID: 19109239; PMCID: PMC2739727.
75. Kuperman D, Schofield B, Wills-Karp M, Grusby MJ. Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. J Exp Med. 1998 Mar 16;187(6):939-48. doi: 10.1084/jem.187.6.939. PMID: 9500796; PMCID: PMC2212182.
76. Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL, Donaldson DD. Interleukin-13: central mediator of allergic asthma. Science. 1998 Dec 18;282(5397):2258-61. doi: 10.1126/science.282.5397.2258. PMID: 9856949.
77. Ingram JL, Kraft M. IL-13 in asthma and allergic disease: asthma phenotypes and targeted therapies. J Allergy Clin Immunol. 2012 Oct;130(4):829-42; quiz 843-4. doi: 10.1016/j.jaci.2012.06.034. Epub 2012 Aug 27. PMID: 22951057.
78. Finkelman FD, Shea-Donohue T, Morris SC, Gildea L, Strait R, Madden KB, Schopf L, Urban JF Jr. Interleukin-4- and interleukin-13-mediated host protection against intestinal nematode parasites. Immunol Rev. 2004 Oct;201:139-55. doi: 10.1111/j.0105-2896.2004.00192.x. PMID: 15361238.
79. Wynn TA. Type 2 cytokines: mechanisms and therapeutic strategies. Nat Rev Immunol. 2015 May;15(5):271-82. doi: 10.1038/nri3831. Epub 2015 Apr 17. PMID: 25882242.
80. Shimokawa C, Kanaya T, Hachisuka M, Ishiwata K, Hisaeda H, Kurashima Y, Kiyono H, Yoshimoto T, Kaisho T, Ohno H. Mast Cells Are Crucial for Induction of Group 2 Innate Lymphoid Cells and Clearance of Helminth Infections. Immunity. 2017 May 16;46(5):863-874.e4. doi: 10.1016/j.immuni.2017.04.017. PMID: 28514691.
81. Wallrapp A, Riesenfeld SJ, Burkett PR, Kuchroo VK. Type 2 innate lymphoid cells in the induction and resolution of tissue inflammation. Immunol Rev. 2018 Nov;286(1):53-73. doi: 10.1111/imr.12702. PMID: 30294962; PMCID: PMC7370855.
82. Hajoui O, Janani R, Tulic M, Joubert P, Ronis T, Hamid Q, Zheng H, Mazer BD. Synthesis of IL-13 by human B lymphocytes: regulation and role in IgE production. J Allergy Clin Immunol. 2004 Sep;114(3):657-63. doi: 10.1016/j.jaci.2004.05.034. PMID: 15356573.
83. Burd PR, Thompson WC, Max EE, Mills FC. Activated mast cells produce interleukin 13. J Exp Med. 1995 Apr 1;181(4):1373-80. doi: 10.1084/jem.181.4.1373. PMID: 7535336; PMCID: PMC2191950.
84. Fushimi T, Okayama H, Shimura S, Saitoh H, Shirato K. Dexamethasone suppresses gene expression and production of IL-13 by human mast cell line and lung mast cells. J Allergy Clin Immunol. 1998 Jul;102(1):134-42. doi: 10.1016/s0091-6749(98)70064-8. PMID: 9679857.
85. Varricchi G, Rossi FW, Galdiero MR, Granata F, Criscuolo G, Spadaro G, de Paulis A, Marone G. Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019. Int Arch Allergy Immunol. 2019;179(4):247-261. doi: 10.1159/000500088. Epub 2019 May 28. PMID: 31137021.
86. Varricchi G, Rossi FW, Galdiero MR, Granata F, Criscuolo G, Spadaro G, de Paulis A, Marone G. Physiological Roles of Mast Cells: Collegium Internationale Allergologicum Update 2019. Int Arch Allergy Immunol. 2019;179(4):247-261. doi: 10.1159/000500088. Epub 2019 May 28. PMID: 31137021.
87. Schmid-Grendelmeier P, Altznauer F, Fischer B, Bizer C, Straumann A, Menz G, Blaser K, Wüthrich B, Simon HU. Eosinophils express functional IL-13 in eosinophilic inflammatory diseases. J Immunol. 2002 Jul 15;169(2):1021-7. doi: 10.4049/jimmunol.169.2.1021. PMID: 12097410.
88. Varricchi G, Galdiero MR, Loffredo S, Lucarini V, Marone G, Mattei F, Marone G, Schiavoni G. Eosinophils: The unsung heroes in cancer? Oncoimmunology. 2017 Nov 13;7(2):e1393134. doi: 10.1080/2162402X.2017.1393134. PMID: 29308325; PMCID: PMC5749653.
89. Gibbs BF, Haas H, Falcone FH, Albrecht C, Vollrath IB, Noll T, Wolff HH, Amon U. Purified human peripheral blood basophils release interleukin-13 and preformed interleukin-4 following immunological activation. Eur J Immunol. 1996 Oct;26(10):2493-8. doi: 10.1002/eji.1830261033. PMID: 8898965.
90. Ochensberger B, Daepp GC, Rihs S, Dahinden CA. Human blood basophils produce interleukin-13 in response to IgE-receptor-dependent and -independent activation. Blood. 1996 Oct 15;88(8):3028-37. PMID: 8874201.
91. Minty A, Chalon P, Derocq JM, Dumont X, Guillemot JC, Kaghad M, Labit C, Leplatois P, Liauzun P, Miloux B. Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature. 1993 Mar 18;362(6417):248-50. doi: 10.1038/362248a0. PMID: 8096327.
92. Moy FJ, Diblasio E, Wilhelm J, Powers R. Solution structure of human IL-13 and implication for receptor binding. J Mol Biol. 2001 Jun 29;310(1):219-30. doi: 10.1006/jmbi.2001.4764. PMID: 11419948.
93. Zurawski SM, Vega F Jr, Huyghe B, Zurawski G. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 1993 Jul;12(7):2663-70. doi: 10.1002/j.1460-2075.1993.tb05927.x. PMID: 8101483; PMCID: PMC413514.
94. Grünig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, Sheppard D, Mohrs M, Donaldson DD, Locksley RM, Corry DB. Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998 Dec 18;282(5397):2261-3. doi: 10.1126/science.282.5397.2261. PMID: 9856950; PMCID: PMC3897229.
95. Marone G, Granata F, Pucino V, Pecoraro A, Heffler E, Loffredo S, Scadding GW, Varricchi G. The Intriguing Role of Interleukin 13 in the Pathophysiology of Asthma. Front Pharmacol. 2019 Dec 6;10:1387. doi: 10.3389/fphar.2019.01387. PMID: 31866859; PMCID: PMC6908970.
96. Punnonen J, Aversa G, Cocks BG, McKenzie AN, Menon S, Zurawski G, de Waal Malefyt R, de Vries JE. Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3730-4. doi: 10.1073/pnas.90.8.3730. PMID: 8097323; PMCID: PMC46375.
97. Van der Pouw Kraan TC, Van der Zee JS, Boeije LC, De Groot ER, Stapel SO, Aarden LA. The role of IL-13 in IgE synthesis by allergic asthma patients. Clin Exp Immunol. 1998 Jan;111(1):129-35. doi: 10.1046/j.1365-2249.1998.00471.x. PMID: 9472672; PMCID: PMC1904850.
98. Pope SM, Brandt EB, Mishra A, Hogan SP, Zimmermann N, Matthaei KI, Foster PS, Rothenberg ME. IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxin-dependent mechanism. J Allergy Clin Immunol. 2001 Oct;108(4):594-601. doi: 10.1067/mai.2001.118600. PMID: 11590387.
99. Horie S, Okubo Y, Hossain M, Sato E, Nomura H, Koyama S, Suzuki J, Isobe M, Sekiguchi M. Interleukin-13 but not interleukin-4 prolongs eosinophil survival and induces eosinophil chemotaxis. Intern Med. 1997 Mar;36(3):179-85. doi: 10.2169/internalmedicine.36.179. PMID: 9144009.
100. Luttmann W, Knoechel B, Foerster M, Matthys H, Virchow JC Jr, Kroegel C. Activation of human eosinophils by IL-13. Induction of CD69 surface antigen, its relationship to messenger RNA expression, and promotion of cellular viability. J Immunol. 1996 Aug 15;157(4):1678-83. PMID: 8759755.
101. Fahy JV. Goblet cell and mucin gene abnormalities in asthma. Chest. 2002 Dec;122(6 Suppl):320S-326S. doi: 10.1378/chest.122.6_suppl.320s. PMID: 12475809.
102. Zhu Z, Homer RJ, Wang Z, Chen Q, Geba GP, Wang J, Zhang Y, Elias JA. Pulmonary expression of interleukin-13 causes inflammation, mucus hypersecretion, subepithelial fibrosis, physiologic abnormalities, and eotaxin production. J Clin Invest. 1999 Mar;103(6):779-88. doi: 10.1172/JCI5909. PMID: 10079098; PMCID: PMC408149.
103. Dudley KL, Chiaramonte W, Wills-Karp M. Upregulation of mucin related genes is associated with susceptibility to allergen-induced hyperresponsiveness. Am J Respir Crit Care Med 2002; 163:A693.
104. Shimura S, Andoh Y, Haraguchi M, Shirato K. Continuity of airway goblet cells and intraluminal mucus in the airways of patients with bronchial asthma. Eur Respir J. 1996 Jul;9(7):1395-401. doi: 10.1183/09031936.96.09071395. PMID: 8836649.
105. Aikawa T, Shimura S, Sasaki H, Ebina M, Takashima T. Marked goblet cell hyperplasia with mucus accumulation in the airways of patients who died of a severe acute asthma attack. Chest 1992; 101:916-921.
106. Kraft M, Lewis C, Pham D, Chu HW. IL-4, IL-13, and dexamethasone augment fibroblast proliferation in asthma. J Allergy Clin Immunol. 2001 Apr;107(4):602-6. doi: 10.1067/mai.2001.113760. PMID: 11295646.
107. Doucet C, Brouty-Boyé D, Pottin-Clémenceau C, Canonica GW, Jasmin C, Azzarone B. Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma. J Clin Invest. 1998 May 15;101(10):2129-39. doi: 10.1172/JCI741. PMID: 9593769; PMCID: PMC508801.
108. Ingram JL, Rice A, Geisenhoffer K, Madtes DK, Bonner JC. Interleukin-13 stimulates the proliferation of lung myofibroblasts via a signal transducer and activator of transcription-6-dependent mechanism: a possible mechanism for the development of airway fibrosis in asthma. Chest. 2003 Mar;123(3 Suppl):422S-4S. doi: 10.1378/chest.123.3_suppl.422s. PMID: 12629010.
109. Lee CG, Homer RJ, Zhu Z, Lanone S, Wang X, Koteliansky V, Shipley JM, Gotwals P, Noble P, Chen Q, Senior RM, Elias JA. Interleukin-13 induces tissue fibrosis by selectively stimulating and activating transforming growth factor beta(1). J Exp Med. 2001 Sep 17;194(6):809-21. doi: 10.1084/jem.194.6.809. PMID: 11560996; PMCID: PMC2195954.
110. Espinosa K, Bossé Y, Stankova J, Rola-Pleszczynski M. CysLT1 receptor upregulation by TGF-beta and IL-13 is associated with bronchial smooth muscle cell proliferation in response to LTD4. J Allergy Clin Immunol. 2003 May;111(5):1032-40. doi: 10.1067/mai.2003.1451. PMID: 12743568.
111. Bossé Y, Thompson C, Audette K, Stankova J, Rola-Pleszczynski M. Interleukin-4 and interleukin-13 enhance human bronchial smooth muscle cell proliferation. Int Arch Allergy Immunol. 2008;146(2):138-48. doi: 10.1159/000113517. Epub 2008 Jan 18. PMID: 18204280.
112. Chiba Y, Nakazawa S, Todoroki M, Shinozaki K, Sakai H, Misawa M. Interleukin-13 augments bronchial smooth muscle contractility with an up-regulation of RhoA protein. Am J Respir Cell Mol Biol. 2009 Feb;40(2):159-67. doi: 10.1165/rcmb.2008-0162OC. Epub 2008 Aug 7. PMID: 18688040.
113. Chiba Y, Nakazawa S, Todoroki M, Shinozaki K, Sakai H, Misawa M. Interleukin-13 augments bronchial smooth muscle contractility with an up-regulation of RhoA protein. Am J Respir Cell Mol Biol. 2009 Feb;40(2):159-67. doi: 10.1165/rcmb.2008-0162OC. Epub 2008 Aug 7. PMID: 18688040.
114. McKenzie GJ, Bancroft A, Grencis RK, McKenzie AN. A distinct role for interleukin-13 in Th2-cell-mediated immune responses. Curr Biol. 1998 Mar 12;8(6):339-42. doi: 10.1016/s0960-9822(98)70134-4. PMID: 9512421.
115. Bochner BS, Klunk DA, Sterbinsky SA, Coffman RL, Schleimer RP. IL-13 selectively induces vascular cell adhesion molecule-1 expression in human endothelial cells. J Immunol. 1995 Jan 15;154(2):799-803. PMID: 7529288.
116. Corne J, Chupp G, Lee CG, Homer RJ, Zhu Z, Chen Q, Ma B, Du Y, Roux F, McArdle J, Waxman AB, Elias JA. IL-13 stimulates vascular endothelial cell growth factor and protects against hyperoxic acute lung injury. J Clin Invest. 2000 Sep;106(6):783-91. doi: 10.1172/JCI9674. PMID: 10995789; PMCID: PMC381393.
117. Detoraki A, Granata F, Staibano S, Rossi FW, Marone G, Genovese A. Angiogenesis and lymphangiogenesis in bronchial asthma. Allergy. 2010 Aug;65(8):946-58. doi: 10.1111/j.1398-9995.2010.02372.x. Epub 2010 Apr 23. PMID: 20415716.
118. Detoraki A, Granata F, Staibano S, Rossi FW, Marone G, Genovese A. Angiogenesis and lymphangiogenesis in bronchial asthma. Allergy. 2010 Aug;65(8):946-58. doi: 10.1111/j.1398-9995.2010.02372.x. Epub 2010 Apr 23. PMID: 20415716.
119. Keglowich LF, Borger P. The Three A's in Asthma - Airway Smooth Muscle, Airway Remodeling & Angiogenesis. Open Respir Med J. 2015 Jun 17;9:70-80. doi: 10.2174/1874306401509010070. PMID: 26106455; PMCID: PMC4475688.
120. Takayama G, Arima K, Kanaji T, Toda S, Tanaka H, Shoji S, McKenzie AN, Nagai H, Hotokebuchi T, Izuhara K. Periostin: a novel component of subepithelial fibrosis of bronchial asthma downstream of IL-4 and IL-13 signals. J Allergy Clin Immunol. 2006 Jul;118(1):98-104. doi: 10.1016/j.jaci.2006.02.046. Epub 2006 Apr 27. PMID: 16815144.
121. Kanemitsu Y, Ito I, Niimi A, Izuhara K, Ohta S, Ono J, Iwata T, Matsumoto H, Mishima M. Osteopontin and periostin are associated with a 20-year decline of pulmonary function in patients with asthma. Am J Respir Crit Care Med. 2014 Aug 15;190(4):472-4. doi: 10.1164/rccm.201403-0562LE. PMID: 25127307.
122. Kanemitsu Y, Matsumoto H, Izuhara K, Tohda Y, Kita H, Horiguchi T, Kuwabara K, Tomii K, Otsuka K, Fujimura M, Ohkura N, Tomita K, Yokoyama A, Ohnishi H, Nakano Y, Oguma T, Hozawa S, Nagasaki T, Ito I, Oguma T, Inoue H, Tajiri T, Iwata T, Izuhara Y, Ono J, Ohta S, Tamari M, Hirota T, Yokoyama T, Niimi A, Mishima M. Increased periostin associates with greater airflow limitation in patients receiving inhaled corticosteroids. J Allergy Clin Immunol. 2013 Aug;132(2):305-12.e3. doi: 10.1016/j.jaci.2013.04.050. Epub 2013 Jun 19. PMID: 23791506.
123. Takahashi K, Meguro K, Kawashima H, Kashiwakuma D, Kagami SI, Ohta S, Ono J, Izuhara K, Iwamoto I. Serum periostin levels serve as a biomarker for both eosinophilic airway inflammation and fixed airflow limitation in well-controlled asthmatics. J Asthma. 2019 Mar;56(3):236-243. doi: 10.1080/02770903.2018.1455855. Epub 2018 Apr 12. PMID: 29648484.
124. Spahn JD, Szefler SJ, Surs W, Doherty DE, Nimmagadda SR, Leung DY. A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity. J Immunol. 1996 Sep 15;157(6):2654-9. PMID: 8805670.
125. Novosad J, Krčmová I, Bartoš V, Drahošová M, Vaník P, Růžičková-Kirchnerová O, Teřl M, Krejsek J. Serum periostin levels in asthma patients in relation to omalizumab therapy and presence of chronic rhinosinusitis with nasal polyps. Postepy Dermatol Alergol. 2020 Apr;37(2):240-249. doi: 10.5114/ada.2020.94842. Epub 2020 May 6. PMID: 32489361; PMCID: PMC7262810.
126. Chibana K, Trudeau JB, Mustovich AT, Hu H, Zhao J, Balzar S, Chu HW, Wenzel SE. IL-13 induced increases in nitrite levels are primarily driven by increases in inducible nitric oxide synthase as compared with effects on arginases in human primary bronchial epithelial cells. Clin Exp Allergy. 2008 Jun;38(6):936-46. doi: 10.1111/j.1365-2222.2008.02969.x. Epub 2008 Apr 1. Erratum in: Clin Exp Allergy. 2008 Aug;38(8):1409. Mustovitch, A T [corrected to Mustovich, A T]. PMID: 18384429.
127. Dweik RA, Boggs PB, Erzurum SC, Irvin CG, Leigh MW, Lundberg JO, Olin AC, Plummer AL, Taylor DR; American Thoracic Society Committee on Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications. An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FENO) for clinical applications. Am J Respir Crit Care Med. 2011 Sep 1;184(5):602-15. doi: 10.1164/rccm.9120-11ST. PMID: 21885636; PMCID: PMC4408724.
128. Syabbalo N. Biomarkers for the diagnosis and management of eosinophilic asthma. Ann Clin Med Res 2020; 1:1003.
129. Graber P, Gretener D, Herren S, Aubry JP, Elson G, Poudrier J, Lecoanet-Henchoz S, Alouani S, Losberger C, Bonnefoy JY, Kosco-Vilbois MH, Gauchat JF. The distribution of IL-13 receptor alpha1 expression on B cells, T cells and monocytes and its regulation by IL-13 and IL-4. Eur J Immunol. 1998 Dec;28(12):4286-98. doi: 10.1002/(SICI)1521-4141(199812)28:12<4286::AID-IMMU4286>3.0.CO;2-H. PMID: 9862366.
130. Rael EL, Lockey RF. Interleukin-13 signaling and its role in asthma. World Allergy Organ J. 2011 Mar;4(3):54-64. doi: 10.1097/WOX.0b013e31821188e0. PMID: 23283176; PMCID: PMC3651056.
131. Gessner C, Kornmann O, Maspero J, van Zyl-Smit R, Krüll M, Salina A, Gupta P, Bostel S, Fucile S, Conde LG, Pfister P. Fixed-dose combination of indacaterol/glycopyrronium/mometasone furoate once-daily versus salmeterol/fluticasone twice-daily plus tiotropium once-daily in patients with uncontrolled asthma: A randomised, Phase IIIb, non-inferiority study (ARGON). Respir Med. 2020 Aug-Sep;170:106021. doi: 10.1016/j.rmed.2020.106021. Epub 2020 May 27. Erratum in: Respir Med. 2020 Dec;175:106186. PMID: 32843164.
132. Lee LA, Bailes Z, Barnes N, Boulet LP, Edwards D, Fowler A, Hanania NA, Kerstjens HAM, Kerwin E, Nathan R, Oppenheimer J, Papi A, Pascoe S, Brusselle G, Peachey G, Sule N, Tabberer M, Pavord ID. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial. Lancet Respir Med. 2021 Jan;9(1):69-84. doi: 10.1016/S2213-2600(20)30389-1. Epub 2020 Sep 9. Erratum in: Lancet Respir Med. 2021 Jan 4;: PMID: 32918892.
133. Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004 Oct 15;170(8):836-44. doi: 10.1164/rccm.200401-033OC. Epub 2004 Jul 15. PMID: 15256389.
134. Holgate ST, Polosa R. The mechanisms, diagnosis, and management of severe asthma in adults. Lancet. 2006 Aug 26;368(9537):780-93. doi: 10.1016/S0140-6736(06)69288-X. PMID: 16935689.
135. Peters MC, Kerr S, Dunican EM, Woodruff PG, Fajt ML, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, Johansson MW, Jarjour NN, Coverstone AM, Castro M, Hastie AT, Bleecker ER, Wenzel SE, Fahy JV; National Heart, Lung and Blood Institute Severe Asthma Research Program 3. Refractory airway type 2 inflammation in a large subgroup of asthmatic patients treated with inhaled corticosteroids. J Allergy Clin Immunol. 2019 Jan;143(1):104-113.e14. doi: 10.1016/j.jaci.2017.12.1009. Epub 2018 Mar 7. PMID: 29524537; PMCID: PMC6128784.
136. Wenzel S, Castro M, Corren J, Maspero J, Wang L, Zhang B, Pirozzi G, Sutherland ER, Evans RR, Joish VN, Eckert L, Graham NM, Stahl N, Yancopoulos GD, Louis-Tisserand M, Teper A. 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 dose-ranging trial. Lancet. 2016 Jul 2;388(10039):31-44. doi: 10.1016/S0140-6736(16)30307-5. Epub 2016 Apr 27. PMID: 27130691.
137. Castro M, Corren J, Pavord ID, Maspero J, Wenzel S, Rabe KF, Busse WW, Ford L, Sher L, FitzGerald JM, Katelaris C, Tohda Y, Zhang B, Staudinger H, Pirozzi G, Amin N, Ruddy M, Akinlade B, Khan A, Chao J, Martincova R, Graham NMH, Hamilton JD, Swanson BN, Stahl N, Yancopoulos GD, Teper A. Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma. N Engl J Med. 2018 Jun 28;378(26):2486-2496. doi: 10.1056/NEJMoa1804092. Epub 2018 May 21. PMID: 29782217.
138. Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, Zhu H, Hamilton JD, Swanson BN, Khan A, Chao J, Staudinger H, Pirozzi G, Antoni C, Amin N, Ruddy M, Akinlade B, Graham NMH, Stahl N, Yancopoulos GD, Teper A. Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma. N Engl J Med. 2018 Jun 28;378(26):2475-2485. doi: 10.1056/NEJMoa1804093. Epub 2018 May 21. PMID: 29782224.
139. Corren J, Castro M, O'Riordan T, Hanania NA, Pavord ID, Quirce S, Chipps BE, Wenzel SE, Thangavelu K, Rice MS, Harel S, Jagerschmidt A, Khan AH, Kamat S, Maroni J, Rowe P, Lu Y, Amin N, Pirozzi G, Ruddy M, Graham NMH, Teper A. Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Allergic Asthma. J Allergy Clin Immunol Pract. 2020 Feb;8(2):516-526. doi: 10.1016/j.jaip.2019.08.050. Epub 2019 Sep 12. PMID: 31521831.
140. Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, Weisman J, Pariser D, Simpson EL, Papp KA, Hong HC, Rubel D, Foley P, Prens E, Griffiths CEM, Etoh T, Pinto PH, Pujol RM, Szepietowski JC, Ettler K, Kemény L, Zhu X, Akinlade B, Hultsch T, Mastey V, Gadkari A, Eckert L, Amin N, Graham NMH, Pirozzi G, Stahl N, Yancopoulos GD, Shumel B. Long-term management of moderate-to-severe atopic dermatitis with dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised, double-blinded, placebo-controlled, phase 3 trial. Lancet. 2017 Jun 10;389(10086):2287-2303. doi: 10.1016/S0140-6736(17)31191-1. Epub 2017 May 4. PMID: 28478972.
141. De Bruin-Weller M, Thaçi D, Smith CH, Reich K, Cork MJ, Radin A. Dupilumab with concomitant topical corticosteroid treatment in adults with atopic dermatitis with an inadequate response or intolerance to ciplosporin A or when this treatment is medically inadvisable: a placebo-controlled, randomized phase III clinical trial (LIBERTY CAFE). Br J Dermatol 2018; 178:1083-1101.
142. Pavord ID, Ford L, Sher L, Rabe KF, Park H-S, Cosio BG, Staudinger H, Maroni J, Rowe P. Dupilumab efficacy in asthma patients with comorbid chronic rhinosinusitis or nasal polyposis (CRS/NP) in LIBERTY ASTHMA QUEST. Eur Respir J 2018; 52:A01651. DOI: 10.1183/13993002.congress-2018.0A1651.
143. Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, Mullol J, Greos LS, Bosso JV, Laidlaw TM, Cervin AU, Maspero JF, Hopkins C, Olze H, Canonica GW, Paggiaro P, Cho SH, Fokkens WJ, Fujieda S, Zhang M, Lu X, Fan C, Draikiwicz S, Kamat SA, Khan A, Pirozzi G, Patel N, Graham NMH, Ruddy M, Staudinger H, Weinreich D, Stahl N, Yancopoulos GD, Mannent LP. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet. 2019 Nov 2;394(10209):1638-1650. doi: 10.1016/S0140-6736(19)31881-1. Epub 2019 Sep 19. Erratum in: Lancet. 2019 Nov 2;394(10209):1618. PMID: 31543428.
144. Dellon E, Rothenberg M, Hirano I. Dupilumab improves health-related quality of life (HRQol) and reduces symptom burden in patients with eosinophilic esophagitis (EoE): results from part A of a randomized, placebo-controlled three-part phase 3 study. Presented at: the American Academy of Allergy, Asthma & Immunology (AAAAI) Virtual Annual Meeting; February 26-March 1, 2021. Abstract 290.
145. Wechsler M, Klion A, Paggiaro P, Ruddy M, Rowe P, Deniz Y. Effect of dupilumab treatment on blood eosinophil levels in patients with asthma, chronic rhinosinusitis nasal polyposis (CRSwNP), eosinophilic esophagitis (EoE), or atopic dermatitis (AD). J Allergy Clin Immunol 2021; 147(2):Suppl AB 140. DOI: https://doi.org/10.1016/j.jaci.2020.12.507.
146. Berger P, Menzies-Gow A, Peters AT, Kuna P, Rabe KF, Altincatal A, Soler X, Pandit-Abid N, Siddiqui S, Jacob-Nara JA, Deniz Y, Rowe PJ. Long-term efficacy of dupilumab in asthma with or without chronic rhinosinusitis and nasal polyps. Ann Allergy Asthma Immunol. 2022 Nov 7:S1081-1206(22)01912-3. doi: 10.1016/j.anai.2022.11.006. Epub ahead of print. PMID: 36356712.
147. Wechsler ME, Ford LB, Maspero JF, Pavord ID, Papi A, Bourdin A, Watz H, Castro M, Nenasheva NM, Tohda Y, Langton D, Cardona G, Domingo C, Park HS, Chapman KR, Mao X, Zhang Y, Khan AH, Deniz Y, Rowe PJ, Kapoor U, Khokhar FA, Mannent LP, Ruddy M, Laws E, Amin N, Hardin M. Long-term safety and efficacy of dupilumab in patients with moderate-to-severe asthma (TRAVERSE): an open-label extension study. Lancet Respir Med. 2022 Jan;10(1):11-25. doi: 10.1016/S2213-2600(21)00322-2. Epub 2021 Sep 28. PMID: 34597534.
148. Sher LD, Wechsler ME, Rabe KF, Maspero JF, Daizadeh N, Mao X, Ortiz B, Mannent LP, Laws E, Ruddy M, Pandit-Abid N, Jacob-Nara JA, Gall R, Rowe PJ, Deniz Y, Lederer DJ, Hardin M. Dupilumab Reduces Oral Corticosteroid Use in Patients With Corticosteroid-Dependent Severe Asthma: An Analysis of the Phase 3, Open-Label Extension TRAVERSE Trial. Chest. 2022 Jul;162(1):46-55. doi: 10.1016/j.chest.2022.01.071. Epub 2022 Feb 22. PMID: 35217003.