key: cord-0749525-mcql2p0s
authors: Sree sudha, TY; Pugazhenthan, T; Krishna sasanka, KSBS; Sri Hari, TY; vijayakumar, AR
title: Dupilumab: Una revisión de su potencial en el tratamiento de la rinosinusitis crónica con poliposis nasal (RSCPN)
date: 2020-10-16
journal: nan
DOI: 10.1016/j.opresp.2020.10.001
sha: 5bd97c85ade1ef2d431cbc50aa9e938ef975a7ec
doc_id: 749525
cord_uid: mcql2p0s

Chronic rhino sinusitis with nasal polyps (CRSwNP) is a chronic inflammatory condition of the sinuses, commonly seen in between 40-60 years aged population. In CRSwNP patients the main focus of treatment is to promote patient’s quality of life, to reduce sinonasal symptoms and nasal polyp size by usage of both oral as well as topical corticosteroids and nasal saline irrigations. If symptoms persists after using medical therapy surgical excision is the last option but relapse of disease is present in most cases even after surgical intervention. Overall, from the various recent past and recent trials, Dupilumab was very well tolerated in maximum number of the patients and no serious adverse events were noted. In addition the patients with asthma noticed good improvement in endoscopic nasal polyp scores, asthma control, and lung function, inflammation of both the upper and lower airways.

 ABSTRACT:  Chronic rhino sinusitis with nasal polyps (CRSwNP) is a chronic inflammatory condition of the sinuses, commonly seen in between 40-60 years aged population. In CRSwNP patients the main focus of treatment is to promote patient's quality of life, to reduce sinonasal symptoms and nasal polyp size by usage of both oral as well as topical corticosteroids and nasal saline irrigations. If symptoms persists after using medical therapy surgical excision is the last option but relapse of disease is present in most cases even after surgical intervention. Overall, from the various recent past and recent trials, Dupilumab was very well tolerated in maximum number of the patients and no serious adverse events were noted. In addition the patients with asthma noticed good improvement in endoscopic nasal polyp scores, asthma control, and lung function, inflammation of both the upper and lower airways.  Keywords: Chronic rhino sinusitis; nasal polyps; CRSwNP; Dupilumab; corticosteroids  Dupilumab: Una revisión de su potencial en el tratamiento de la rinosinusitis crónica con poliposis nasal (RSCPN)  RESUMEN:  La rinosinusitis crónica con poliposis nasal (RSCPN) es una enfermedad inflamatoria crónica de los senos nasales, que se observa con mayor frecuencia en la población de entre 40 y 60 años. En los pacientes con RSCPN, el objetivo principal del tratamiento es mejorar su calidad de vida mediante la reducción de los síntomas nasosinusales y el tamaño de los pólipos nasales con el uso de corticosteroides tanto orales como tópicos y lavados nasales con solución salina. Si los síntomas persisten después del tratamiento médico, la última opción es la extirpación quirúrgica, pero en la mayoría de los casos se produce recaída de la enfermedad incluso después de la intervención quirúrgica. En general, según los múltiples ensayos clínicos recientes, el dupilumab fue muy bien tolerado por el número máximo de pacientes y no se observaron eventos adversos graves. Además, los pacientes con asma mostraron mejoría en las puntuaciones endoscópicas de los pólipos nasales, el control del asma, la función pulmonar y la inflamación de las vías respiratorias superiores e inferiores.  Palabras clave: Rinosinusitis crónica, pólipos nasales, RSCPN, dupilumab, corticosteroides  INTRODUCTION:  Chronic rhino sinusitis with nasal polyps (CRSwNP) is a chronic inflammatory condition of the sinuses, commonly seen in between 40-60 years aged and with higher prevalence in Western populations [1] [2] [3] [4] . The observed increased risk of disease is seen in first-degree relatives of a patient with CRSwNP 5 . The origin of nasal polyps is ethmoidal sinuses and the disease presents as bilateral inflammatory lesions and protruding into the nasal airway just beneath the middle turbinate. Routine common complaints observed in most of the people are nasal obstruction, hyposmia/anosmia, rhinorrhea, severe nasal congestion or obstruction, loss of smell/taste [6] [7] [8] . In trials, it is noticed that asthmatics is associated with CRSwNP after radiographic evidence of sinonasal inflammation and in patients with CRSwNP, asthma is diagnosed and reported 9, 10 .  CRSwNP is a chronic type-2 inflammation and with diverted host immune response, with impaired sinonasal epithelial barrier and this acts as easy entry of pathogens and antigens into the nasal cavity. It has altered epithelial tissue resistance, acanthosis, acantholysis and increased tissue permeability. Higher number of mast cells, basophils, innate type-2 lymphoid cells 12, type-2 cytokines, including IL-5 and IL-13 and also the epithelial cell-derived thymic stromal lymphopoietin (TSLP) are present [11] [12] [13] [14] . Antimicrobial proteins derived from epithelial tissues like lysozyme, beta-defensins, palate, lung, and nasal epithelial clone (PLUNC) proteins are all in reduced levels [15] [16] [17] whereas elevated levels of eosinophil chemotactic proteins (eotaxin-1, 2, 3 & MCP-4), eosinophilic granular proteins, IL-5 18-23 , Pendrin and MUC5AC which is a type of mucin 24, 25 are observed in CRSwNP when compared to healthy controls. All these findings facilitate chronic inflammatory response or sinonasal inflammation. The line of treatment in CRSwNP patients is to improve patient's quality of life, sinonasal symptoms, nasal polyp size by usage of both oral as well as topical corticosteroids and nasal saline irrigations according to the most recent US guidelines [26] [27] [28] . Surgical excision is the last option if a still symptom exists on medical therapy, but in 50% of patients it is noticed that relapse of disease symptoms even after surgical excision 29 . To evaluate the safety and efficacy of varied therapies in CRSwNP many studies has been conducted. Finally the new drug dupilumab along with intranasal steroid medical therapies which benefits in minimizing the nasal polyp size and also reduce sinonasal symptoms in CRSwNP patients. This article reviews a recently approved and developed drug dupilumab for CRSwNP, including its mechanism of action, pharmacokinetics, dosage forms, drug interactions, side effects, as well as the reviewing its phase II and III clinical trial evidence on its clinical efficacy and safety.  DUPILUMAB  Dupilumab approved by the US Food and Drug Association (FDA) on June 26, 2019 for chronic rhino sinusitis with nasal polyps (CRSwNP) patients whom not responding to intranasal steroids, even after prolonged use. It is a human monoclonal IgG4 antibody with a molecular weight of 147 kDa. It binds to the alpha subunit of the interleukin-4 receptor, blocking the signal of both type -2 cytokines IL-4 and IL-13. Expression of IL-4Rα was in epithelial cells, goblet cells, mast cells, lymphocytes, macrophages and eosinophils. Both IL-4, 13 signaling properties got inhibited by Type II receptors, whereas inhibition of IL-4 only occurs through Type I receptors 30 . IL 4, 13 cytokines play a key role in the pathogenesis of CRSwNP and are produced by T helper cells (TH2) cells. The major components in the pathogenesis of CRSwNP are inflammatory mediators (histamine, cytokines, eicosanoids, leukotrienes, and chemokines). Dupilumab shows its clinical efficacy in minimizing nasal polyp size and quality of life by reducing sinonasal symptoms in patients with co-morbid asthma, by releasing proinflammatory cytokines, chemokines, nitric oxide and IgE in type 2 helper T-cell-mediated diseases [31] [32] [33] (Figure 1 ). In adults, it is administered by subcutaneous route (SC) at a dose of 300 mg every alternate week. The bioavailability is approx. 60 %. Maximum concentration of drug is obtained within one week after following doses of 600 mg, 400 mg, 300 mg, respectively, whereas steady-state concentrations were achieved by the 16 th week. It has a minimal volume of distribution 4 L (4.8 ± 1.3 L). It takes 9-11 weeks for degradation of drug after taking the last dose 33 . There is possibility of drug interactions with drugs which are CYP450 substrates, due to reduced levels of CYP450 enzymes and elevated levels of inflammatory cytokines 33 . After initiation and discontinuation of dupilumab, monitoring drug effects and dosage adjustment of midazolam, omeprazole, warfarin, caffeine, Metaprolol (CYP substrates) is essential 33 . Table 1 .  16 week Phase II (NCT01920893) Trial 34 :  Initially, patients were treated up to four weeks with a nasal spray of mometasone furoate 100 microgram in twice a day in both the nostril; thereafter patients were randomly taken 1:1 ratio. Based on the findings of nasal polyp score improvement it is evident that dupilumab is also helpful in patients who also have asthma in 75.0% cases. All scores like self-reported sense of smell loss, LM CT score, UPSIT score, SNOT-22 score and other clinical end points were improved with dupilumab in patients who are non asthmatics. However, dupilumab did not show any significant reduction in endoscopic nasal polyp score. The limitations of this study were very small sample size with only 60 patients and short duration of only 16 weeks, no appropriate comparative drug available and with no established minimally clinically important difference (MCID) for NPS which interpret the importance of dupilumab on primary end points ( Table 2) .  SINUS-24-phase III study 35 :  The trial checked for the efficacy of the drug in 24 weeks in chronic rhino sinusitis with nasal polyps (CRSwNP) with/without comorbid asthma with randomly assigned to 1:1. Dupilumab treatment reduced systemic corticosteroids (SCS) use/NP surgery (P<0.001), and in comorbid asthma patients (58.3%) improved lung function (FEV1; P<0.001) and asthma control (ACQ-6; P<0.0001) ( Table 3) .  SINUS-52 -phase III study 35 :  In the SINUS-52 study, 448 patients were randomly assigned to 1:1:1 into group A, B and C. 73%

to 90% subjects included with evidence of sinus opacification. The effects of dupilumab on the primary endpoints -Nasal polyp score and nasal congestion and the secondary endpoint of LMK sinus CT scan score were consistent in patients with prior surgery and without prior surgery. In co-morbid asthmatic patients, improvements in pre-bronchodilator FEV1 were similar to patients in the asthma program. The efficacy of dupilumab was shown both in the overall population, NSAID-exacerbated respiratory disease and in patients with previous sinonasal surgery. In conclusion of the study, dupilumab treated patients reduced use of systemic corticosteroids (SCS) and requirement for sino-nasal surgery (Table 3 ). In all the 3 trials, dupilumab plus mometasone furoate nasal spray (MFNS) combination treatment showed significant improvements in endoscopic, clinical, radiographic, and pharmacodynamic end points after 16 weeks, Quality of life (assessed by , UPSIT scores, sense of smell decreases in morning anterior/posterior rhinorrhea, morning symptoms of nasal congestion or obstruction, evening symptoms and nocturnal awakenings, increases in subjective sense of smell. Injection site reactions were more frequent, well tolerated and no serious adverse events noted. Patients who were not benefited with medical therapy, surgery are advised as the next treatment option. An MCID for nasal polyp score however, dupilumab did not lead to a significant reduction in endoscopic nasal polyp score, but it is supported by changes in clinical and radiographic parameters in CT scores. The improvements observed in patients with nasal polyposis and comorbid asthma observed with dupilumab are it improved both upper and lower airway inflammation, nasal polyp scores and in asthma control and lung function in patients with asthma ant the inflammatory biomarker levels are reduced such as total serum IgE, blood eosinophil count, serum thymus and activation regulated chemokine (TARC) level, and plasma eotaxin-3 level. These data suggests that IL-4 and IL-13mediated signaling pathways are important for the pathogenesis of chronic sinusitis with nasal polyposis, and by blocking these pathways lead to significant clinical benefit. These findings suggest the objective improvements observed in dupilumab-treated patients are associated with subjective improvements.  Pharmacodynamic:  On blockade of IL-4 and IL-13 mediated signaling pathways leads to significant clinical benefit in chronic rhino sinusitis with nasal polyps (CRSwNP). As per trial 1, after16-week treatment period of dupilumab along with mometasone furoate nasal spray (MFNS), there were reduced total serum IgE, serum thymus and activation regulated chemokine (TARC) (P = 0.13) and plasma eotaxin-3 levels (P ≤ 0.001). As per Trial 2 (sinus-52), noticed decreased levels of serum total IgE, periostin, serum thymus and activation regulated chemokine (TARC) and plasma eotoxin-3 at 24, and 52 weeks and there is reduced concentrations of total IgE, IL-5, Eosinophil Cationic Protein (ECP), and eotaxin -3 in nasal secretions at week 24. (Table 4 )  Adverse events: The various adverse events seen in trials for CRSwNP were nasopharyngitis 47%, injection site reactions 40%, headache 20%, herpes zoster, arrhythmia and upper extremity pain or numbness, constipation, conjunctivitis, cough, bronchitis, arthralgia, gastritis, insomnia, eosinophilia, toothache, eosinophilic granulomatosis with polyangiitis, and epistasis.  Current Clinical indications: Dupilumab has been recently approved for use in Adults with chronic sinusitis and nasal polyposis based on the trial findings. And it was already approved for use in the management of Atopic dermatitis. The drug used as an add on therapy in steroid dependant cases 33 . A few review substantiate is significance 36 .  Dupilumab in COVID settings:  We have published a non systematic critical analysis based on isolated case reports and or series in milder category of COVID-19 infected patients who were already been on this drug for atopic dermatitis and chronic rhino-sinusitis with nasal polyp [37] [38] [39] [40] [41] .  Future Evaluation:  In clinical trials yet no drug has shown efficacy and safety outcomes in CRSwNP except the only drug Dupilumab. Further evaluation is needed in a larger sample size and longer duration clinical trials to assess unknown adverse events and long-term efficacy of the drug. Still need to know whether dupilumab could delay or reduce the need for surgery. Studies have yet to find and report the withdrawal effects of the drug and should evaluate whether drug discontinuation will results in any rebound flaring up of the disease.  Conclusion:  Dupilumab was the first approved targeted biologic therapy for CRSwNP with/without comorbid asthma and it will be a successful optional treatment for patients. The safety and efficacy has to be explored in larger populations and in long duration studies with severe chronic rhino sinusitis with Nasal Polyps (CRSwNP) with/without comorbid asthma. Treatment with Dupilumab was associated with significant improvements in subjective clinical, betterment in quality of life, i.e., reduce major symptoms like patients able to sense of smell, cleared the nasal obstruction or congestion, and nocturnal awakening and in objective parameters in endoscopic, radiographic, CT scores, and pharmacodynamic end points. Overall, from the various recent past and recent trials, Dupilumab was very well tolerated in maximum number of the patients and no serious adverse events were noted. In addition the patients with asthma noticed good improvement in endoscopic nasal polyp scores, asthma control, and lung function, inflammation of both the upper and lower airways. La rinosinusitis crónica con poliposis nasal (RSCPN) es una enfermedad inflamatoria crónica de los senos nasales, que se observa con mayor frecuencia en la población de entre 40 y 60 años. En los pacientes con RSCPN, el objetivo principal del tratamiento es mejorar su calidad de vida mediante la reducción de los síntomas nasosinusales y el tamaño de los pólipos nasales con el uso de corticosteroides tanto orales como tópicos y lavados nasales con solución salina.

Si los síntomas persisten después del tratamiento médico, la última opción es la extirpación quirúrgica, pero en la mayoría de los casos se produce recaída de la enfermedad incluso después de la intervención quirúrgica. En general, según los múltiples ensayos clínicos recientes, el dupilumab fue muy bien tolerado por el número máximo de pacientes y no se observaron eventos adversos graves. Además, los pacientes con asma mostraron mejoría en las puntuaciones endoscópicas de los pólipos nasales, el control del asma, la función pulmonar y la inflamación de las vías respiratorias superiores e inferiores.

Palabras clave: Rinosinusitis crónica, pólipos nasales, RSCPN, dupilumab, corticosteroides

Chronic rhino sinusitis with nasal polyps (CRSwNP) is a chronic inflammatory condition of the sinuses, commonly seen in between 40-60 years aged and with higher prevalence in Western populations [1] [2] [3] [4] . The observed increased risk of disease is seen in first-degree relatives of a patient with CRSwNP 5 . The origin of nasal polyps is ethmoidal sinuses and the disease presents as bilateral inflammatory lesions and protruding into the nasal airway just beneath the middle turbinate. Routine common complaints observed in most of the people are nasal obstruction, hyposmia/anosmia, rhinorrhea, severe nasal congestion or obstruction, loss of smell/taste [6] [7] [8] . In trials, it is noticed that asthmatics is associated with CRSwNP after radiographic evidence of sinonasal inflammation and in patients with CRSwNP, asthma is diagnosed and reported 9, 10 .

CRSwNP is a chronic type-2 inflammation and with diverted host immune response, with impaired sinonasal epithelial barrier and this acts as easy entry of pathogens and antigens into the nasal cavity. It has altered epithelial tissue resistance, acanthosis, acantholysis and increased tissue permeability. Higher number of mast cells, basophils, innate type-2 lymphoid cells 12, type-2 cytokines, including IL-5 and IL-13 and also the epithelial cell-derived thymic stromal lymphopoietin (TSLP) are present [11] [12] [13] [14] . Antimicrobial proteins derived from epithelial tissues like lysozyme, beta-defensins, palate, lung, and nasal epithelial clone (PLUNC) proteins are all in reduced levels [15] [16] [17] whereas elevated levels of eosinophil chemotactic proteins which is a type of mucin 24, 25 are observed in CRSwNP when compared to healthy controls.

All these findings facilitate chronic inflammatory response or sinonasal inflammation. The line of treatment in CRSwNP patients is to improve patient's quality of life, sinonasal symptoms, nasal polyp size by usage of both oral as well as topical corticosteroids and nasal saline irrigations according to the most recent US guidelines [26] [27] [28] . Surgical excision is the last option if a still symptom exists on medical therapy, but in 50% of patients it is noticed that relapse of disease symptoms even after surgical excision 29 . To evaluate the safety and efficacy of varied therapies in CRSwNP many studies has been conducted. Finally the new drug dupilumab along with intranasal steroid medical therapies which benefits in minimizing the nasal polyp size and also reduce sinonasal symptoms in CRSwNP patients. This article reviews a recently approved and developed drug dupilumab for CRSwNP, including its mechanism of action, pharmacokinetics, dosage forms, drug interactions, side effects, as well as the reviewing its phase II and III clinical trial evidence on its clinical efficacy and safety. helper T-cell-mediated diseases [31] [32] [33] (Figure 1 ). In adults, it is administered by subcutaneous route (SC) at a dose of 300 mg every alternate week. The bioavailability is approx. 60 %.

Maximum concentration of drug is obtained within one week after following doses of 600 mg, 400 mg, 300 mg, respectively, whereas steady-state concentrations were achieved by the 16 th week. It has a minimal volume of distribution 4 L (4.8 ± 1.3 L). It takes 9-11 weeks for degradation of drug after taking the last dose 33 . There is possibility of drug interactions with drugs which are CYP450 substrates, due to reduced levels of CYP450 enzymes and elevated levels of inflammatory cytokines 33 . After initiation and discontinuation of dupilumab, monitoring drug effects and dosage adjustment of midazolam, omeprazole, warfarin, caffeine, Metaprolol (CYP substrates) is essential 33 .

The primary outcome is an improvement of nasal polyp score (NPS) in patients who were Table 1 .

Initially, patients were treated up to four weeks with a nasal spray of mometasone furoate 100 microgram in twice a day in both the nostril; thereafter patients were randomly taken 1:1 ratio.

Based on the findings of nasal polyp score improvement it is evident that dupilumab is also helpful in patients who also have asthma in 75.0% cases. All scores like self-reported sense of smell loss, LM CT score, UPSIT score, SNOT-22 score and other clinical end points were improved with dupilumab in patients who are non asthmatics. However, dupilumab did not show any significant reduction in endoscopic nasal polyp score. The limitations of this study were very small sample size with only 60 patients and short duration of only 16 weeks, no appropriate comparative drug available and with no established minimally clinically important difference (MCID) for NPS which interpret the importance of dupilumab on primary end points (Table 2) .

The trial checked for the efficacy of the drug in 24 weeks in chronic rhino sinusitis with nasal polyps (CRSwNP) with/without comorbid asthma with randomly assigned to 1:1. Dupilumab treatment reduced systemic corticosteroids (SCS) use/NP surgery (P<0.001), and in comorbid asthma patients (58.3%) improved lung function (FEV1; P<0.001) and asthma control (ACQ-6; P<0.0001) ( Table 3) .

In the SINUS-52 study, 448 patients were randomly assigned to 1:1:1 into group A, B and C.

73% to 90% subjects included with evidence of sinus opacification. The effects of dupilumab on the primary endpoints -Nasal polyp score and nasal congestion and the secondary endpoint of LMK sinus CT scan score were consistent in patients with prior surgery and without prior surgery. In co-morbid asthmatic patients, improvements in pre-bronchodilator FEV1 were similar to patients in the asthma program. The efficacy of dupilumab was shown both in the overall population, NSAID-exacerbated respiratory disease and in patients with previous sinonasal surgery. In conclusion of the study, dupilumab treated patients reduced use of systemic corticosteroids (SCS) and requirement for sino-nasal surgery (Table 3) 

On blockade of IL-4 and IL-13 mediated signaling pathways leads to significant clinical benefit in chronic rhino sinusitis with nasal polyps (CRSwNP). As per trial 1, after16-week treatment period of dupilumab along with mometasone furoate nasal spray (MFNS), there were reduced total serum IgE, serum thymus and activation regulated chemokine (TARC) (P = 0.13) and plasma eotaxin-3 levels (P ≤ 0.001). As per Trial 2 (sinus-52), noticed decreased levels of serum total IgE, periostin, serum thymus and activation regulated chemokine (TARC) and plasma eotoxin-3 at 24, and 52 weeks and there is reduced concentrations of total IgE, IL-5, Eosinophil Cationic Protein (ECP), and eotaxin -3 in nasal secretions at week 24. (Table 4) Adverse events: The various adverse events seen in trials for CRSwNP were nasopharyngitis 47%, injection site reactions 40%, headache 20%, herpes zoster, arrhythmia and upper extremity pain or numbness, constipation, conjunctivitis, cough, bronchitis, arthralgia, gastritis, insomnia, eosinophilia, toothache, eosinophilic granulomatosis with polyangiitis, and epistasis.

Dupilumab has been recently approved for use in Adults with chronic sinusitis and nasal polyposis based on the trial findings. And it was already approved for use in the management of Atopic dermatitis. The drug used as an add on therapy in steroid dependant cases 33 . A few review substantiate is significance 36 .

We have published a non systematic critical analysis based on isolated case reports and or series in milder category of COVID-19 infected patients who were already been on this drug for atopic dermatitis and chronic rhino-sinusitis with nasal polyp [37] [38] [39] [40] [41] .

In clinical trials yet no drug has shown efficacy and safety outcomes in CRSwNP except the only drug Dupilumab. Further evaluation is needed in a larger sample size and longer duration clinical trials to assess unknown adverse events and long-term efficacy of the drug. Still need to know whether dupilumab could delay or reduce the need for surgery. Studies have yet to find and report the withdrawal effects of the drug and should evaluate whether drug discontinuation will results in any rebound flaring up of the disease.

Dupilumab was the first approved targeted biologic therapy for CRSwNP with/without comorbid asthma and it will be a successful optional treatment for patients. The safety and efficacy has to be explored in larger populations and in long duration studies with severe chronic rhino sinusitis with Nasal Polyps (CRSwNP) with/without comorbid asthma.

Treatment with Dupilumab was associated with significant improvements in subjective clinical, betterment in quality of life, i.e., reduce major symptoms like patients able to sense of smell, cleared the nasal obstruction or congestion, and nocturnal awakening and in objective parameters in endoscopic, radiographic, CT scores, and pharmacodynamic end points. Overall, from the various recent past and recent trials, Dupilumab was very well tolerated in maximum number of the patients and no serious adverse events were noted. In addition the patients with asthma noticed good improvement in endoscopic nasal polyp scores, asthma control, and lung function, inflammation of both the upper and lower airways.

Summary health statistics for US adults. Vital Health Stat 10

Chronic rhinosinusitis in Europe--an underestimated disease. A GA²LEN study

European Position Paper on Rhinosinusitis and Nasal Polyps

Nasal polyps in patients with rhinitis and asthma

Familial risk of chronic rhinosinusitis with and without nasal polyposis: genetics or environment

Chronic rhinosinusitis patients with polyps or polypoid mucosa have a greater burden of illness

Symptoms in chronic rhinosinusitis with and without nasal polyps

A pilot study of symptom profiles from a polyp vs an eosinophilic-based classification of chronic rhinosinusitis

European Position Paper on Rhinosinusitis and Nasal Polyps

Prevalence of confirmed asthma varies in chronic rhinosinusitis subtypes

Basophils are elevated in nasal polyps of patients with chronic rhinosinusitis without aspirin sensitivity

Increased ILC2s in the eosinophilic nasal polyp endotype are associated with corticosteroid responsiveness

T-cell regulation in chronic paranasal sinus disease

Thymic stromal lymphopoietin activity is increased in nasal polyps of patients with chronic rhinosinusitis

Reduced expression of antimicrobial PLUNC proteins in nasal polyp tissues of patients with chronic rhinosinusitis

Evidence for diminished levels of epithelial psoriasin and calprotectin in chronic rhinosinusitis

Different activations of toll-like receptors and antimicrobial peptides in chronic rhinosinusitis with or without nasal polyposis

Eosinophilic nasal polyps are a rich source of eotaxin, eotaxin-2 and eotaxin-3

Eotaxin-1, -2, and -3 immunoreactivity and protein concentration in the nasal polyps of eosinophilic chronic rhinosinusitis patients

Differentiation of chronic sinus diseases by measurement of inflammatory mediators

T-cell regulation in chronic paranasal sinus disease

Cytokines in Chronic Rhinosinusitis. Role in Eosinophilia and Aspirin-exacerbated Respiratory Disease

Mixed T helper cell signatures in chronic rhinosinusitis with and without polyps

Expression of pendrin and periostin in allergic rhinitis and chronic rhinosinusitis

Increased expression of the epithelial anion transporter pendrin/SLC26A4 in nasal polyps of patients with chronic rhinosinusitis

Diagnosis and management of rhinosinusitis: a practice parameter update

Effect of fluticasone in severe polyposis

Impact of topical nasal steroid therapy on symptoms of nasal polyposis: a meta-analysis

The importance of local eosinophilia in the surgical outcome of chronic rhinosinusitis: a 3-year prospective observational study

Dupilumab treatment in adults with moderate-to-severe atopic dermatitis

Dupilumab in persistent asthma with elevated eosinophil levels

Dupilumab improves lung function in patients with uncontrolled, moderate-to-severe asthma

Therapeutic protein-drug interactions and implications for drug development

Effect of Subcutaneous Dupilumab on Nasal Polyp Burden in Patients with Chronic Sinusitis and Nasal Polyposis: A Randomized Clinical Trial

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

Therapeutic Potential of Dupilumab in the Treatment of Chronic Rhinosinusitis with Nasal Polyps: Evidence to Date

Role of Dupilumab in Approved Indications of COVID-19 Patient: an Efficacy-Based Nonsystematic Critical Analysis

European Task Force on Atopic Dermatitis statement on severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection and atopic dermatitis

Dupilumab and COVID-19: What should we expect?

COVID-19 in a patient with severe chronic rhinosinusitis with nasal polyps during therapy with dupilumab

Biologics for psoriasis in COVID-19 era: What do we know? Dermatol Ther