Guideline for the use of immunobiologicals in chronic rhinosinusitis with nasal polyps (CRSwNP) in Brazil

Wilma T. Anselmo-Lima Edwin Tamashiro Fabrizio R. Romano Marcel M. Miyake Renato Roithmann Eduardo M. Kosugi Márcio Nakanishi Marco A. Fornazieri Thiago F.P. Bezerra João F. Mello Jr. Marcus M. Lessa Richard L. Voegels Otávio B. Piltcher Eulalia Sakano Fabiana C.P. Valera About the authors

Highlights

  • The use of immunobiologicals is an option for the management of patients with chronic rinosinusitis with nasal polyps (CRSwNP) refractory to conventional treatment.

  • The guideline lists the main drugs currently available in Brazil, their indications, and recommendations for use.

Destaques

  • Uso dos imunobiologicos é uma opção de tratamento para os pacientes com rinossinusite crônica com pólipos nasais refratária ao tratamento convencional.

  • A diretriz traz os principais medicamentos disponíveis hoje no Brasil, suas indicações e recomendações atuais de uso.

Abstract

Introduction

Severe uncontrolled chronic rhinosinusitis with nasal polyps has a negative impact on an individual’s quality of life. Therefore, new biologics have emerged for use in specific phenotypes of chronic rhinosinusitis, changing the paradigms of its treatment.

Objective

To review the current status of biologic treatment indications in chronic rhinosinusitis.

Methods

The Brazilian Academy of Rhinology brought together different specialists to suggest a course of action, considering its particularities and aspects related to the national reality.

Results

Of particular interest for decision making will be the identification of subgroups of patients refractory to pre-existing treatment options and the construction of a strategy that improves their quality of life, with the best cost-benefit ratio.

Conclusion

The use of biologics is a valid option for treatment in more severe cases. This strategy must be better understood and improved in the future, with more studies and greater clinical experience.

Keywords
Immunobiologicals; Monoclonal antibody; Chronic rhinosinusitis; Nasal polyps

Resumo

Introdução

A rinossinusite crônica com pólipos nasais grave não controlada impacta negativamente na qualidade de vida do indivíduo. Para esses casos, novos imunobiológicos têm surgido, para uso em fenótipos específicos da rinossinusite crônica, e mudaram os paradigmas de seu tratamento.

Objetivo

Revisar o estado atual das indicações de imunobiológicos em rinossinusite crônica.

Método

A Academia Brasileira de Rinologia reuniu diferentes especialistas para sugerir uma conduta que considerasse suas particularidades e seus aspectos relacionados à realidade nacional.

Resultados

De particular interesse para a tomada de decisão serão a identificação dos subgrupos de pacientes refratários às opções de tratamento pré-existentes e a construção de uma estratégia que realmente melhore a qualidade de vida deles, dentro da melhor relação custo-benefício.

Conclusão

O uso de imunobiológicos é uma opção válida para tratamento em casos mais graves. Essa estratégia deve ser mais bem compreendida e aprimorada no futuro, com mais estudos e maior experiência clínica.

Palavras-chave
Imunobiológicos; Anticorpos monoclonais; Rinossinusite crônica; Pólipo nasal

Introduction

Currently, there is a significant increase in the publication of articles on the use of new immunobiologicals in specific phenotypes of chronic rhinosinusitis (CRS), changing the treatment paradigms in cases refractory to conventional therapy.11 Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020;58:1-464. In view of the rapid and growing supply of these new drugs, the Brazilian Academy of Rhinology brought together different specialists to review the current status of the indications for immunobiologicals in CRS, considering their particularities and aspects related to the national reality. Today, the immunobiologicals intended for chronic rhinosinusitis with nasal polyps (CRSwN) treatment act exclusively on type 2 inflammation.

Type 2 inflammation, formerly called T-helper type 2 (Th2) inflammation, is orchestrated by inflammatory mediators produced by Th2 cells, such as the cytokines IL-4, IL-5, IL-9 and IL-13, having eosinophil as the main cell marker, in addition to the high presence of local or circulating IgE. With the subsequent identification of the participation of other non-Th2 cells capable of producing the same cytokine profile, such as type 2 innate lymphoid ells (ILC2), the inflammation became known as type 2.

An essential aspect was the recognition that CRS encompasses a range of situations with different pathophysiological bases, although they have common clinical characteristics. Consequently, specific forms of CRS have different prognosis and responses to a given treatment. A recent multicenter study revealed that 35% of CRSwNP patients had recurrence within 6 months.22 DeConde AS, Mace JC, Levy JM, Rudmik L, Alt JA, Smith TL. Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. Laryngoscope. 2017;127:550-5. In the quest to identify the factors potentially associated with worsening outcomes, endotyping, through the use of biomarkers, can help identify which patients have type 2 inflammation and who would respond best to these new treatments.22 DeConde AS, Mace JC, Levy JM, Rudmik L, Alt JA, Smith TL. Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. Laryngoscope. 2017;127:550-5.,33 Damask CC, Ryan MW, Casale TB, Castro M, Franzese CB, Lee SE, et al. Targeted Molecular Therapies in Allergy and Rhinology. Otolaryngol Head Neck Surg. 2021;164:S1-21.

Type 2 interleukins and their effects on CRS

IL-5 is a cytokine that controls the differentiation and maturation of eosinophils in the bone marrow, in addition to inducing activation and increasing their survival in the tissue, reducing the degree of apoptosis.33 Damask CC, Ryan MW, Casale TB, Castro M, Franzese CB, Lee SE, et al. Targeted Molecular Therapies in Allergy and Rhinology. Otolaryngol Head Neck Surg. 2021;164:S1-21.

4 Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type-2 inflammation in disease. Nat Rev Drug Discov. 2016;15:35-50.
-55 Laidlaw TM, Buchheit KM. Biologics in chronic rhinosinusitis with nasal polyposis. Ann Allergy Asthma Immunol. 2020;124:326-32. The effects of IL-4 include the differentiation of T lymphocytes into Th2, induction of B lymphocytes for IgE production, chemotaxis for eosinophils and recruitment and activation of mast cells and basophils.33 Damask CC, Ryan MW, Casale TB, Castro M, Franzese CB, Lee SE, et al. Targeted Molecular Therapies in Allergy and Rhinology. Otolaryngol Head Neck Surg. 2021;164:S1-21.

4 Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type-2 inflammation in disease. Nat Rev Drug Discov. 2016;15:35-50.
-55 Laidlaw TM, Buchheit KM. Biologics in chronic rhinosinusitis with nasal polyposis. Ann Allergy Asthma Immunol. 2020;124:326-32. IL-13 is chemotactic for eosinophils, induces B lymphocytes to produce IgE and activates mast cells and basophils. In addition, it induces mucus secretion, goblet cell hyperplasia, and collagen production.33 Damask CC, Ryan MW, Casale TB, Castro M, Franzese CB, Lee SE, et al. Targeted Molecular Therapies in Allergy and Rhinology. Otolaryngol Head Neck Surg. 2021;164:S1-21.

4 Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type-2 inflammation in disease. Nat Rev Drug Discov. 2016;15:35-50.
-55 Laidlaw TM, Buchheit KM. Biologics in chronic rhinosinusitis with nasal polyposis. Ann Allergy Asthma Immunol. 2020;124:326-32. IL-33 is also a mediator of type 2 inflammation. It binds to a surface receptor on Th2, ILC2 lymphocytes, basophils, eosinophils, mast cells, and dendritic cells, among others, activating inflammation in the airways. Direct exposure of the airway epithelium to S. aureus increases the expression of IL-33 and TSLP, which induce the production of cytokines such as IL-5 and IL-13, playing a role in the onset and/or maintenance of type 2 inflammation in CRSwNP.22 DeConde AS, Mace JC, Levy JM, Rudmik L, Alt JA, Smith TL. Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. Laryngoscope. 2017;127:550-5.,55 Laidlaw TM, Buchheit KM. Biologics in chronic rhinosinusitis with nasal polyposis. Ann Allergy Asthma Immunol. 2020;124:326-32.

Immunobiologicals

Several immunobiological products are being studied for use in respiratory diseases, such as anti-IgE (omalizumab), anti-IL-5 (mepolizumab, reslizumab, benralizumab), anti-IL-4, and anti-IL-13 (dupilumab), among others.

Anti-IgE (omalizumab)

Omalizumab is an anti-IgE monoclonal antibody initially approved in 2003 by the FDA for the treatment of moderate-persistent allergic asthma, not controlled with inhaled corticosteroids, being the first immunobiological agente used for type 2 inflammatory diseases.66 Fokkens WJ, Lund V, Bachert C, Mullol J, Bjermer L, Bousquet J, et al. EUFOREA consensus on biologics for CRSwNP with or without asthma. Allergy. 2019;74:2312-9.

7 Casale TB. Biologics and biomarkers for asthma, urticaria, and nasal polyposis. J Allergy Clin Immunol. 2017;139:1411-21.

8 Codispoti CD, Mahdavinia M. A call for cost-effectiveness analysis for biologic therapies in chronic rhinosinusitis with nasal polyps. Ann Allergy Asthma Immunol. 2019;123:232-9.
-99 Bang LM, Plosker GL. Omalizumab - a review of its use in the management of allergic asthma. Treat Respir Med. 2004;3:183-99. Currently, it is indicated also for patients with chronic urticaria, and very recently, for patients with CRSwNP.1010 Kartush AG, Schumacher JK, Shah R, Patadia MO. Biologic agents for the treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019;33:203-11. For asthma, studies have shown improvement in disease control, reduction in the number of exacerbations and the need for oral corticosteroids as well as the use of rescue medications.77 Casale TB. Biologics and biomarkers for asthma, urticaria, and nasal polyposis. J Allergy Clin Immunol. 2017;139:1411-21.,1010 Kartush AG, Schumacher JK, Shah R, Patadia MO. Biologic agents for the treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019;33:203-11.

11 Xolair® (omalizumabe). VPS12 = Xolair Bula Profissional aprovada pela ANVISA em 11/01/2021. https://portal.novartis.com.br/upload/imgconteudos/1815.pdf.
https://portal.novartis.com.br/upload/im...
-1212 Kim H, Ellis AK, Fischer D, Noseworthy M, Olivenstein R, Chapman KR, et al. Asthma biomarkers in the age of biologics. Allergy Asthma Clin Immunol. 2017;13:48. After subcutaneous administration, omalizumab is slowly absorbed, reaching the peak of serum concentrations after an average of 7-8 days, with a terminal half-life of 26 days.1313 Mostafa BE, Fadel M, Mohammed MA, Hamdi TAH, Askoura AM. Omalizumab versus intranasal steroids in the post-operative management of patients with allergic fungal rhinosinusitis. Eur Arch Otorhinolaryngol. 2020;277:121-8.,1414 Lowe PJ, Tannenbaum S, Gautler A, Jimenez P. Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE-mediated) asthma. Br J Clin Pharmacol. 2009;68:61-76.

Review of the use in CRS

Given the high concentrations of mucosal IgE in the nasal polyp tissue and its relevance to the severity of the disease and comorbidity, its inhibition may have an impact on patients with CRSwNP.1515 Bachert C, Zhang L, Gevaert P. Current and future treatment options for adult chronic rhinosinusitis: focus on nasal polyposis. J Allergy Clin Immunol. 2015;136:1431-40.

In a randomized, double-blind, placebo-controlled phase II study with patients with CRSwNP and associated asthma, Gevaert et al. selected patients to receive 4-8 subcutaneous doses of omalizumab (n = 16) or placebo (n = 8) for 16 weeks.1616 Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013;131:110-6.e1. There was a significant reduction in the nasal polyp endoscopic score and in the Lund-MacKay tomographic score in the omalizumab group compared to the placebo group. In addition, omalizumab had a significantly greater beneficial effect on sinunasal symptoms, including nasal congestion, anterior rhinorrhea and loss of smell, as well as lower airway symptoms, including wheezing and dyspnoea. Finally, omalizumab was also associated with better quality of life scores in patients with CRSwNP and asthma.88 Codispoti CD, Mahdavinia M. A call for cost-effectiveness analysis for biologic therapies in chronic rhinosinusitis with nasal polyps. Ann Allergy Asthma Immunol. 2019;123:232-9.,1010 Kartush AG, Schumacher JK, Shah R, Patadia MO. Biologic agents for the treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019;33:203-11.,1616 Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013;131:110-6.e1.

Pinto et al., in another randomized, double-blind, placebo-controlled clinical trial of refractory CRSwNP, randomized the patients to receive omalizumab or placebo for 6 months.1717 Pinto JM, Mehta N, DiTineo M, Wang J, Baroody FM, Naclerio RM. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology. 2010;48:318-24. Treatment with omalizumab was associated with a significant improvement in quality of life (SNOT-20) at various time intervals, including 3, 5 and 6 months of followup compared to the baseline, whereas there were no significant changes in the control group.88 Codispoti CD, Mahdavinia M. A call for cost-effectiveness analysis for biologic therapies in chronic rhinosinusitis with nasal polyps. Ann Allergy Asthma Immunol. 2019;123:232-9.,1717 Pinto JM, Mehta N, DiTineo M, Wang J, Baroody FM, Naclerio RM. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology. 2010;48:318-24.

Rivero and Liang, in a systematic review including studies of anti-IgE therapy, found no statistically significant reduction in the nasal polyp score compared to the placebo group, although they did tend to improve.1818 Rivero A, Jonathan L. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47. However, in the post hoc analysis, the authors observed that patients who had concomitant severe asthma experienced a statistically significant reduction in the nasal polyp score. They concluded that anti-IgE therapy reduces the nasal polyps score in patients with associated severe asthma.1818 Rivero A, Jonathan L. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47.

In another systematic review, Tsetsos et al.1919 Tsetsos N, Goudakos JK, Daskalakis D, Konstantinidis I, Markou K. Monoclonal antibodies for the treatment of chronic rhinosinusitis with nasal polyposis: a systematic review. Rhinol. 2018;56:11-21. compared the results of randomized clinical trials performed by Gevaert et al.1616 Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013;131:110-6.e1. and by Pinto et al.1717 Pinto JM, Mehta N, DiTineo M, Wang J, Baroody FM, Naclerio RM. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology. 2010;48:318-24. assessing the efficacy of omalizumab in patients with CRSwNP and associated asthma. Clinical improvement was measured in both clinical trials through the total nasal polyp score, sinus opacification at paranasal sinus tomography, and measuments of quality of life, peak nasal airflow, nasal inspiratory flow, and sense of smell (UPSIT).1010 Kartush AG, Schumacher JK, Shah R, Patadia MO. Biologic agents for the treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019;33:203-11.,1919 Tsetsos N, Goudakos JK, Daskalakis D, Konstantinidis I, Markou K. Monoclonal antibodies for the treatment of chronic rhinosinusitis with nasal polyposis: a systematic review. Rhinol. 2018;56:11-21. While the clinical trial conducted by Pinto et al. found no statistically significant changes in any of the categories cited, the study by Gevaert et al. found significant improvement in all measurements, except for nasal airflow and smell. It should also be noted that the study by Gevaert et al. had as limitations the inclusion of a limited number of participants (n = 24), the highest baseline eosinophilic inflammation in subjects treated with placebo (despite randomization), and the high dropout rate in the placebo group (50%). Pinto et al. also highlighted the limitation regarding the number of participants enrolled in their study, emphasizing the need for a trial with a larger number of patients. Two other systematic reviews also reported the need for further evaluation of the effectiveness of anti-IgE therapy in these patients.2020 Hong CJ, Tsang AC, Quinn JG, Bonaparte JP, Stevens A, Kilty SJ. Anti-IgE monoclonal antibody therapy for the treatment of chronic rhinosinusitis: a systematic review. Syst Rev. 2015;4:166.,2121 Santos TS, Gonçalves P, Carvalho C. Effectiveness of omalizumab in the treatment of chronic rhinosinusitis with nasal polyps. Syst Rev. 2014;3:473-9.

More recently, Gevaert et al. published the results of the Phase III POLYP 1 and 2 studies.2222 Gevaert P, Omachi TA, Corren J, Mullol J, Han J, Lee SE, et al. Efficacy and safety of omalizumab in nasal polyposis: two randomized phase III trials. J Allergy Clin Immunol. 2020;146:595-605. They demonstrated that patients treated with omalizumab and intranasal mometasone achieved statistically significant improvements in nasal polyp score and daily nasal congestion score compared to standard therapy (placebo and intranasal mometasone). This difference in parameters was observed from the first assessment in the 4th week to the 24th week. Among the secondary objectives, improvements were observed in the nasosinusal quality of life score (sino-nasal outcome test-22 - SNOT-22), in the University of Pennsylvania smell identification test (UPSIT), in the total nasal symptom score (TNSS), and in the specific complaint of sense of smell. In addition, reductions in posterior and anterior rhinorrhea were observed. In these studies, omalizumab was generally well tolerated and its safety profile was consistent with previous studies.2222 Gevaert P, Omachi TA, Corren J, Mullol J, Han J, Lee SE, et al. Efficacy and safety of omalizumab in nasal polyposis: two randomized phase III trials. J Allergy Clin Immunol. 2020;146:595-605.

Omalizumab has also been shown to be clinically beneficial in patients with moderate to severe asthma and associated allergic fungal rhinosinusitis (AFRS).2323 Gan EC, Habib AR, Rajwani A, Javer AR. Omalizumab therapy for refractory allergic fungal rhinosinusitis patients with moderate or severe asthma. Am J Otolaryngol. 2015;36:672-7. Mostafa et al.1313 Mostafa BE, Fadel M, Mohammed MA, Hamdi TAH, Askoura AM. Omalizumab versus intranasal steroids in the post-operative management of patients with allergic fungal rhinosinusitis. Eur Arch Otorhinolaryngol. 2020;277:121-8. compared a single postoperative injection of omalizumab (at a dose of 150 mg; n = 10) with intranasal corticosteroid spray (budesonide or mometasone furoate, 100 μg twice daily, n = 10) for 6 months in patients with AFRS, with patients being evaluated at an interval of 4 weeks for 6 months. Both treatments were effective at the end of 24 weeks of followup, but the omalizumab group showed a more significant endoscopic and clinical response, particularly in allergic symptoms such as sneezing, itching and nasal discharge. There were no significant side effects in either group.22 DeConde AS, Mace JC, Levy JM, Rudmik L, Alt JA, Smith TL. Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. Laryngoscope. 2017;127:550-5.

Regarding the choice of therapy with anti-IL-5, the often proposed differentiation between non-allergic patients with nasal polyps and elevated blood eosinophils and patients allergic to anti-IgE is not supported by evidence. In comparison, it is worth mentioning that omalizumab worked at least as well in non-allergic individuals as it did in allergic individuals. Omalizumab is known to decrease free IgE antibodies, but it is not yet clear which biomarker is important for its clinical effect in nasal polyps. No biomarkers currently used, such as blood eosinophils or total serum IgE, have been shown to assist in the selection or prediction of responses to immunobiologicals.2424 Bachert C, Gevaert P, Hellings P. Biotherapeutics in chronic rhinosinusitis with and without nasal polyps. J Allergy Clin Immunol Pract. 2017;5:1512-6. In the study by Gevaert et al., there was improvement in the scores of total nasal polyps, opacification of paranasal sinuses and nasal symptoms, including smell, in both allergic and non-allergic individuals.1616 Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013;131:110-6.e1. In addition, omalizumab significantly improved asthma symptoms and quality of life, regardless of the presence of allergy.2525 Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, Erpenbeck VJ, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014;2:525-36.e1. Recent observations that demonstrate its efficacy in patients with non-allergic asthma support these findings.22 DeConde AS, Mace JC, Levy JM, Rudmik L, Alt JA, Smith TL. Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. Laryngoscope. 2017;127:550-5.

According to the medicine regulatory agencies, such as the European Medicines Agency (EMA) in Europe, Food and Drug Administration (FDA) in the United States, and Agência Nacional de Vigilância Sanitária (ANVISA) in Brazil, omalizumab is indicated for persistent moderate to severe allergic asthma uncontrolled with inhaled corticosteroids in adults and children (over 6 years of age), as additional therapy in adult and pediatric patients (over 12 years of age) with spontaneous chronic urticaria refractory to treatment with H1 antihistamines,1111 Xolair® (omalizumabe). VPS12 = Xolair Bula Profissional aprovada pela ANVISA em 11/01/2021. https://portal.novartis.com.br/upload/imgconteudos/1815.pdf.
https://portal.novartis.com.br/upload/im...
and for adult patients (over 18 years old) with CRSwNP refractory to conventional treatment, as complementary therapy to intranasal corticosteroids.1111 Xolair® (omalizumabe). VPS12 = Xolair Bula Profissional aprovada pela ANVISA em 11/01/2021. https://portal.novartis.com.br/upload/imgconteudos/1815.pdf.
https://portal.novartis.com.br/upload/im...

Omalizumab is administered by subcutaneous injection every 2-4 weeks, with a dosage based on the baseline serum IgE level (IU/mL), measured before starting treatment, and body weight (kg).1010 Kartush AG, Schumacher JK, Shah R, Patadia MO. Biologic agents for the treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019;33:203-11.

Because omalizumab does not bind to IgE, which is already bound to receptors on effector cells, the onset of clinical activity is somewhat delayed. Clinical trials have shown benefits over placebo after 4 weeks of therapy, although the maximum effects may take longer.99 Bang LM, Plosker GL. Omalizumab - a review of its use in the management of allergic asthma. Treat Respir Med. 2004;3:183-99. Therefore, systemic or inhaled corticosteroid therapy should not be stopped immediately after starting therapy with omalizumab. Corticosteroid dosage reduction should be attempted gradually over several weeks under medical guidance.99 Bang LM, Plosker GL. Omalizumab - a review of its use in the management of allergic asthma. Treat Respir Med. 2004;3:183-99.

Omalizumab was generally well tolerated in adolescents and adults with allergic asthma in clinical trials.99 Bang LM, Plosker GL. Omalizumab - a review of its use in the management of allergic asthma. Treat Respir Med. 2004;3:183-99. It should be administered in controlled center clinic, due to a 0.2% risk of anaphylaxis.1010 Kartush AG, Schumacher JK, Shah R, Patadia MO. Biologic agents for the treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019;33:203-11. Previously, there were concerns that omalizumab was associated with malignancy; however, this risk was discarded a after a prospective cohort study (EXCELS).2626 Long A, Rahmaoui A, Rothman KJ, Guinan E, Eisner M, Bradley MS, et al. Incidence of malignancy in patients with moderateto-severe asthma treated with or without omalizumab. J Allergy Clin Immunol. 2014;134:560-7. In 2014, the FDA added cardiovascular risks to the omalizumab label. The most common adverse events were upper respiratory tract infection, injection site reaction and headache, although the incidence of these events was similar to that of placebo.99 Bang LM, Plosker GL. Omalizumab - a review of its use in the management of allergic asthma. Treat Respir Med. 2004;3:183-99.,1010 Kartush AG, Schumacher JK, Shah R, Patadia MO. Biologic agents for the treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019;33:203-11. The most common local reactions include bruising, redness, heat and itching, most often within 1 h after taking the medication, but the frequency of these reactions generally decreases with continued use of the drug.99 Bang LM, Plosker GL. Omalizumab - a review of its use in the management of allergic asthma. Treat Respir Med. 2004;3:183-99. Although causal relationships have not been demonstrated, diseases similar to eosinophilic vasculitis, such as eosinophilic granulomatosis with polyangiitis (EGPA), have also been reported with omalizumab, usually with concomitant reduction in corticosteroid therapy.1818 Rivero A, Jonathan L. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47. Finally, opportunistic infection with herpes zoster and helminth infections are theoretical risks, and monitoring of these infections should be carried out at the physician’s discretion.1818 Rivero A, Jonathan L. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47.

Anti-IL-5 (mepolizumab, reslizumab and benralizumab)

IL-5 is a cytokine that plays a key role in the activation, differentiation, chemotaxis, and survival of eosinophils.2727 Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood. 1992;79:3101-9.,2828 Gevaert P, Bachert C, Holtappels G, Novo CP, Van der Heyden J, Fransen L, et al. Enhanced soluble interleukin-5 receptor alpha expression in nasal polyposis. Allergy. 2003;58:371-9. Together with the cytokines IL-4 and IL-13, it is a typical marker of type 2 inflammatory response, and it is increased in most patients with CRSwNP. However, in some populations such as the Chinese, the levels are not as high as in the Caucasian populations.2929 Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke F, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011;128, 989-95.e1-8.

Mepolizumab and reslizumab are IL-5 antagonist monoclonal antibodies. They bind to IL-5 and inhibit its signaling, consequently reducing the production, maturation, and survival of eosinophils.3030 Simon HU, Yousefi S, Schranz C, Schapowal A, Bachert C, Blaser K. Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia. J Immunol. 1997;158:3902-8.,3131 Nucala (mepolizumab) for injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; November 2015. Mepolizumab inhibits the bioactivity of IL-5 with nanomolar potency by blocking the binding of IL-5 to the alpha chain of the receptor complex of that cytokine expressed on the cell surface of the eosinophil, in order to inhibit IL-5 signaling and reduce the production and survival of eosinophils.3232 Fda.gov [Internet]. Nucala (mepolizumab) Label FDA. https://www.accessdata.fda.gov/drugsatfdadocs/label/2015/125526Orig1s000Lbl.pdf. Published 2017.
https://www.accessdata.fda.gov/drugsatfd...
Reslizumab specifically binds to IL-5 and interferes with the binding of IL-5 to its cell surface receptor.3333 Fda.gov [Internet]. Cinqair (reslizumab) Label FDA. https://www.accessdata.fda.gov/drugsatfdadocs/label/2016/761033lbl.pdf. Published 2017.
https://www.accessdata.fda.gov/drugsatfd...

Benralizumab is a monoclonal antibody directed at the IL-5 receptor. It binds to the alpha subunit of the human Interleukin-5 receptor (IL-5Rα) with high affinity and specificity. The IL-5 receptor is expressed specifically on the surface of eosinophils and basophils. The absence of fucose sugar in the Fc domain of benralizumab results in a high affinity for the FcɣRIII receptors of effector immune cells, such as natural killer cells, leading to apoptosis of eosinophils and basophils by increasing cellular cytotoxicity.3434 Fda.gov (Internet).Fasenra (benralizumab) https://www.astrazeneca.com/media-centre/pressreleases/2017/fasenra-benralizumab-receives-us-fdaapproval-for-severe-uncontrolled-eosinophilic-asthma14112017.html. Published 2017.
https://www.astrazeneca.com/media-centre...

Review of the use in CRS

To date, there are few randomized clinical trials (RCTs) evaluating these immunobiologicals in the treatment of CRS patients. There are two RCTs of benralizumab, one of which is in progress,3535 Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis (OSTRO) (https://clinicaltrials.gov/ct2/show/results/NCT03401229.
https://clinicaltrials.gov/ct2/show/resu...
three of mepolizumab (one still in progress),3636 Effect of Mepolizumab in Severe Bilateral Nasal Polyps https://clinicaltrials.gov/ct2/show/results/NCT03085797.
https://clinicaltrials.gov/ct2/show/resu...
and one of reslizumab, in addition to two systematic reviews on the use of these immunobiologicals for CRSwNP treatment.3737 Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-41. All of them demonstrate that the different anti-IL-5 immunobiologicals promote symptom improvement compared to the placebo group in the various parameters evaluated, among them: quality of life, nasal obstruction, need to use systemic corticosteroids to relieve nasal symptoms, sense of smell, size of polyps, opacification on computed tomography, and need for CRSwNP surgery.

Gevaert et al.3737 Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-41. were the first to investigate anti-IL-5 therapy for CRSwNP. In that study, the improvement in the CRSwNP score was approximately 50% in the reslizumab groups. The authors correlated better results with the pretreatment of higher levels of nasal IL-5. This same study showed eosinophilia rebound after the end of treatments at different times according to the dose administered.

On the other hand, studies of mepolizumab did not show a rebound effect on the serum eosinophil count after discontinuing anti-IL-5 therapy. Although mepolizumab therapy also shows globally benefits regarding polyp size and tomographic extension scores, the percentages of improvement also did not exceed 60% of the treated patients.2929 Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke F, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011;128, 989-95.e1-8.

Bachert et al.,3838 Bachert C, Souza AR, Lund VJ, Sccading GK, Gevaert P, Nasser S, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial. J Allergy Clin Immunol. 2017;140:1024-2031. in the largest RCT available to date, investigated whether anti-IL5 therapy would reduce the need for surgical treatments. This answer becomes even more relevant in view of the costs involved with surgical treatments and with the immunobiologicals themselves. The authors identified a significant reduction in the mepolizumab-treated group, compared to the placebo group in terms of surgical indication based on pre-established clinical criteria: a 30% reduction in surgical need compared to 10% of patients in the placebo arm over a period of 9 weeks of evaluation. However, the duration of the benefits conferred by this form of treatment has yet to be assessed.

Some studies are ongoing3535 Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis (OSTRO) (https://clinicaltrials.gov/ct2/show/results/NCT03401229.
https://clinicaltrials.gov/ct2/show/resu...
,3636 Effect of Mepolizumab in Severe Bilateral Nasal Polyps https://clinicaltrials.gov/ct2/show/results/NCT03085797.
https://clinicaltrials.gov/ct2/show/resu...
and more data will soon be available;3939 Kim C, Han J, Wu T, Bachert C, Fokkens W, Hellings P, et al. Role of biologics in chronic rhinosinusitis with nasal polyposis: state of the art review. Otolaryngol Head Neck Surg. 2021;164:57-66. for example, for benrazilumab with a significant number of patients with severe CRSwNP for a period of 56 weeks and mepolizumab for 52 weeks. These studies may collaborate in defining the real role and indication of these immunobiologicals in the treatment of CRSwNP. The available literature including the described RCTs and two systematic reviews4040 Rivero A, Liang J. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47.,4141 Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting [32-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27. have so far demonstrated that the blockade of the inflammatory response related to IL-5 is clearly proven to decrease systemic and nasal eosinophilia. However, studies involving eosinophilic CRS still need to be performed to predict which subgroups of patients will show better responses, in order to minimize the waste of resources and maximize the effects of anti-IL-5 therapy and define the real role of these immunobiologicals in CRS.

Mepolizumab is indicated for treating patients 12 years of age and older with severe eosinophilic asthma.3030 Simon HU, Yousefi S, Schranz C, Schapowal A, Bachert C, Blaser K. Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia. J Immunol. 1997;158:3902-8. Also, it is indicated for treating relapsing or refractory EGPA.3232 Fda.gov [Internet]. Nucala (mepolizumab) Label FDA. https://www.accessdata.fda.gov/drugsatfdadocs/label/2015/125526Orig1s000Lbl.pdf. Published 2017.
https://www.accessdata.fda.gov/drugsatfd...
Benralizumab is indicated for treating patients 12 years of age and older with severe eosinophilic asthma.3535 Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis (OSTRO) (https://clinicaltrials.gov/ct2/show/results/NCT03401229.
https://clinicaltrials.gov/ct2/show/resu...
Reslizumab is indicated for maintenance therapy of severe asthma associated with other drugs in patients over 18 years of age.3535 Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis (OSTRO) (https://clinicaltrials.gov/ct2/show/results/NCT03401229.
https://clinicaltrials.gov/ct2/show/resu...

Mepolizumab is used as a subcutaneous injection. For asthma, the recommended dosage is 100 mg every 4 weeks. In children aged 6-11 years, 40 mg should be administered every 4 weeks.3737 Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-41. The dosage for EGPA is 300 mg every 4 weeks.3232 Fda.gov [Internet]. Nucala (mepolizumab) Label FDA. https://www.accessdata.fda.gov/drugsatfdadocs/label/2015/125526Orig1s000Lbl.pdf. Published 2017.
https://www.accessdata.fda.gov/drugsatfd...

Reslizumab is used as an intravenous infusion every 4 weeks, at a dosage of 3 mg/kg.3131 Nucala (mepolizumab) for injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; November 2015.

Benralizumab is administered subcutaneously at a dosage of 30 mg every 4 weeks for the first three doses, and thereafter every 8 weeks.3333 Fda.gov [Internet]. Cinqair (reslizumab) Label FDA. https://www.accessdata.fda.gov/drugsatfdadocs/label/2016/761033lbl.pdf. Published 2017.
https://www.accessdata.fda.gov/drugsatfd...

The safety and tolerance of anti-IL-5 are already established.3737 Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-41.

38 Bachert C, Souza AR, Lund VJ, Sccading GK, Gevaert P, Nasser S, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial. J Allergy Clin Immunol. 2017;140:1024-2031.
-3939 Kim C, Han J, Wu T, Bachert C, Fokkens W, Hellings P, et al. Role of biologics in chronic rhinosinusitis with nasal polyposis: state of the art review. Otolaryngol Head Neck Surg. 2021;164:57-66. Anti-IL-5 drugs are safe and well tolerated, with the most common side effects being headache, reaction at the injection site, back pain, and fatigue.3737 Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-41. In a study of mepolizumab in severe CRSwNP, the most common side effects were: pharyngitis, increased serum creatine phosphokinase, and myalgia.2828 Gevaert P, Bachert C, Holtappels G, Novo CP, Van der Heyden J, Fransen L, et al. Enhanced soluble interleukin-5 receptor alpha expression in nasal polyposis. Allergy. 2003;58:371-9.,3838 Bachert C, Souza AR, Lund VJ, Sccading GK, Gevaert P, Nasser S, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial. J Allergy Clin Immunol. 2017;140:1024-2031. Reslizumab was considered safe and well tolerated in CRSwNP patients.3333 Fda.gov [Internet]. Cinqair (reslizumab) Label FDA. https://www.accessdata.fda.gov/drugsatfdadocs/label/2016/761033lbl.pdf. Published 2017.
https://www.accessdata.fda.gov/drugsatfd...
Side effects of benralizumab are headache, pharyngitis, and reaction at the injection site.4040 Rivero A, Liang J. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47.,4141 Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting [32-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27.

A concern related to the use of anti-IL-5 was the reduced host defense.3838 Bachert C, Souza AR, Lund VJ, Sccading GK, Gevaert P, Nasser S, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial. J Allergy Clin Immunol. 2017;140:1024-2031. However, in clinical trials of mepolizumab and benralizumab used for 1 year, the frequency of upper respiratory tract infections was less than that of the placebo group.4040 Rivero A, Liang J. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47.,4141 Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting [32-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27. Another concern was related to the association of anti-IL-5 with malignant tumors. However, the incidence rate of malignancy was similar to that seen in the placebo group.4040 Rivero A, Liang J. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47.

Systemic reactions with the use of mepolizumab and benralizumab were hypersensitivity reactions in 2% and 1%-3%, respectively. Headache occurred more frequently when using mepolizumab (20% higher compared to placebo group) and benralizumab (7%-9%) compared to the placebo group (5%-7%).4141 Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting [32-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27.

Anti-IL-4/IL-13 (dupilumab)

Dupilumab is the first immunobiological with indication of specific use for CRSwNP authorized by the main international regulatory agencies (FDA and EMA in 2019)4242 United States Food and Drug Administration. Dupixent Prescribing Information (approved March 28, 2017). https://www.accessdata.fda.gov/drugsatfdadocs/label/2019/761055s014lbl.pdf. Published 2019. [Accessed 30 November 2020].
https://www.accessdata.fda.gov/drugsatfd...
,4343 European Medicines Agency. Dupixent. Extension of indication variation assessment report. https://www.ema.europa.eu/en/documents/variation-report/dupixent-h-c-4390-ii-0017-epar-assessment-report-variation en.pdf. Published 2019. [Accessed 30 November 2020].
https://www.ema.europa.eu/en/documents/v...
and in Brazil (ANVISA in 2020).

IL-4 and IL-13 are potent mediators of type 2 inflammation, sharing the same receptor and signaling pathways, being involved in IgE synthesis, recruitment of eosinophils to inflamed tissue, mucus secretion, and airway remodeling. IL-4 is one of the main differentiating factors for the Th2 response, in addition to inducing the production of type 2 cytokines and chemokines such as IL-5, IL-9, IL-13, TARC and eotaxin. Additionally, IL-4 and IL-13 are responsible for changing the isotype of B cells for IgE11 Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020;58:1-464. production. Dupilumab is a recombinant human IgG4 monoclonal antibody directed against the interleukin-4 α-receptor (IL-4Rα). Its blockade inhibits IL-4/IL-13 signaling, decreasing the type 2 immune response.4444 Sastre J, Dávila I. Dupilumab: A new paradigm for the treatment of allergic diseases. J Investig Allergol Clin Immunol. 2018;28:139-50.

Review of the use in CRS

Bachert et al.4545 Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: A randomized clinical trial. JAMA. 2016;315:469-79. published a double-blind placebo controlled clinical trial that randomized 60 adults with CRSwNP into two groups. After four weeks of initial mometasone treatment, patients were randomized to subcutaneous dupilumab (initial dose of 600 mg followed by 15 weekly doses of 300 mg) or corresponding placebo for 16 weeks.Patients treated with dupilumab had a significant improvement in quality of life, intensity of rhinosinusitis, nasal obstruction, sense of smell, nasal polyp size, tomographic and asthma scores (clinical control and lung function).

Bachert et al.4646 Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. 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;394:1638-50. published the results of two randomized, double-blind, multicenter, placebo-controlled studies that evaluated dupilumab added to standard treatment in adults with severe CRSwNP. In the LIBERTY NP SINUS-24 study, patients were randomized 1:1 for 24 weeks with dupilumab 300 mg or placebo every two weeks. In LIBERTY NP SINUS-52, patients were randomized 1:1:1 with: a) 52 weeks with dupilumab 300 mg every two weeks, b) 24 weeks with dupilumab 300 mg every two weeks, and then 28 weeks with dupilumab 300 mg every four weeks or; c) 52 weeks with placebo every two weeks. In both studies, dupilumab significantly improved quality of life, intensity of rhinosinusitis, nasal obstruction, sense of smell, polyps size, nasal endoscopy, and lung function. It is interesting to note that the improvement in sense of smell is observed regardless of whether the patient has undergone previous surgery.1313 Mostafa BE, Fadel M, Mohammed MA, Hamdi TAH, Askoura AM. Omalizumab versus intranasal steroids in the post-operative management of patients with allergic fungal rhinosinusitis. Eur Arch Otorhinolaryngol. 2020;277:121-8. These results were also supported in several post-hoc analyzes4545 Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: A randomized clinical trial. JAMA. 2016;315:469-79.,4747 Bachert C, Hellings PW, Mullol J, Naclerio RM, Chao J, Amin N, et al. Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma. J Allergy Clin Immunol Pract. 2019;7:2447-9.e2.

48 Laidlaw TM, Mullol J, Fan C, Zhang D, Amin N, Khan A, et al. Dupilumab improves nasal polyp burden and asthma control in patients with CRSwNP and AERD. J Allergy Clin Immunol Pract. 2019;7:2462-5.e1.
-4949 Bachert C, Hellings PW, Mullol J, Hamilos DL, Gevaert P, Naclerio RM, et al. Dupilumab improves health-related quality of life in patients with chronic rhinosinusitis with nasal polyposis. Allergy. 2020;75:148-57. as well as in a recent systematic review.5050 Chong LY, Piromchai P, Sharp S, Snidvongs K, Philpott C, Hopkins C, et al. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2020;2. CD013513.

Dupilumab also reduced the concentrations of biomarkers of eosinophilic inflammation: serum IgE, eotaxin-3, periostin and TARC; IgE, eosinophilic cationic protein, eotaxin-2, eotaxin-3, PARC, IL-13, periostin, and tissue IL-5.5151 Jonstam K, Swanson BN, Mannent LP, Cardell LO, Tian N, Wang Y, et al. Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis. Allergy. 2019;74:743-52.

There is a proven beneficial effect in CRSwNP associated with AERD,5252 Laidlaw TM, Mullol J, Fan C, Zhang D, Amin N, Khan A, et al. Dupilumab improves nasal polyp burden and asthma control in patients with CRSwNP and AERD. J Allergy Clin Immunol Pract. 2019;7:2462-5.e1.,5353 Mustafa SS, Vadamalai K, Scott B, Ramsey A. Dupilumab as add-on therapy for chronic rhinosinusitis with nasal polyposis in aspirin exacerbated respiratory disease. Am J Rhinol Allergy. 2020, http://dx.doi.org/10.1177/1945892420961969. Online ahead of print.
http://dx.doi.org/10.1177/19458924209619...
and anecdotal evidence in allergic fungal rhinosinusitis.5454 Lo RM, Liu AY, Valdez TA, Gernez Y. Dupilumab use in recalcitrant allergic fungal rhinosinusitis. Ann Allergy Asthma Immunol. 2020;125:617-9. The relative risk for further surgery after starting dupilumab is considerably reduced.4646 Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. 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;394:1638-50.,4747 Bachert C, Hellings PW, Mullol J, Naclerio RM, Chao J, Amin N, et al. Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma. J Allergy Clin Immunol Pract. 2019;7:2447-9.e2. When combined with intranasal corticosteroids, it reduces sick leave and improves productivity at work.4747 Bachert C, Hellings PW, Mullol J, Naclerio RM, Chao J, Amin N, et al. Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma. J Allergy Clin Immunol Pract. 2019;7:2447-9.e2.

Dupilumab is indicated as a complementary treatment for CRSwNP in adults who have failed previous treatments, or who are intolerant or with contraindications to oral corticosteroids and/or surgery. It should not be used to treat patients with acute bronchospasm or asthmatic condition or patients with helminth infections; these conditions should be treated prior to starting treatment with Dupilumab.5555 Agência Nacional de Vigilância Sanitária. Consultas Anvisa Medicamentos Dupixent. https://consultas.anvisa.gov.br/#/medicamentos/25351189487201920/?substancia=26064. Published 2019.
https://consultas.anvisa.gov.br/#/medica...

The dosage of dupilumab for CRSwNP, administered subcutaneously, is 300 mg, which is usually administered for the first time in the clinic, and thereafter, every 2 weeks, at home. It can be self-administered by the patient, administered by a health professional or a caregiver. If the patient forgets to administer a dose, it should be administered as soon as possible. After that, the patient should resume the regularly established dosing regimen.5555 Agência Nacional de Vigilância Sanitária. Consultas Anvisa Medicamentos Dupixent. https://consultas.anvisa.gov.br/#/medicamentos/25351189487201920/?substancia=26064. Published 2019.
https://consultas.anvisa.gov.br/#/medica...

Contrary to what was seen in patients with atopic dermatitis, patients with asthma or CRSwNP did not present conjunctivitis as an adverse event.5656 Akinlade B, Guttman-Yassky E, de Bruin-Weller M, Simpson EL, Blauvelt A, Cork MJ, et al. Conjunctivitis in dupilumab clinical trials. Br J Dermatol. 2019;181:459-73. The most common adverse events (more frequent than placebo) were: nasopharyngitis, worsening of nasal polyps and asthma, headache, epistaxis, and erythema at the injection site.5555 Agência Nacional de Vigilância Sanitária. Consultas Anvisa Medicamentos Dupixent. https://consultas.anvisa.gov.br/#/medicamentos/25351189487201920/?substancia=26064. Published 2019.
https://consultas.anvisa.gov.br/#/medica...

This medication should not be used by pregnant or lactating women without medical advice. Safety and efficacy in pediatric patients, under the age of 18, have not been established.5656 Akinlade B, Guttman-Yassky E, de Bruin-Weller M, Simpson EL, Blauvelt A, Cork MJ, et al. Conjunctivitis in dupilumab clinical trials. Br J Dermatol. 2019;181:459-73.

Future immunobiologicals for eosinophilic chronic rhinosinusitis

While the current commercially available immunobiologicals focus on the type 2 adaptive immune response (mainly in the cytokines IL-5, IL-4 and IL-13, in addition to IgE), new potential immunobiologicals have been developed, focusing on the innate immune response.

Among the potential innate immunity cytokines as therapeutic targets, two stand out in the literature: IL-33 and TSLP. Both are produced in the epithelium, and have a more comprehensive ability to induce an eosinophilic response.

Of the new anti-IL-33 (etokimab)5757 Chinthrajah S, Cao S, Liu C, Lyu SC, Sindher SB, Long A, et al. Phase 2a randomized, placebo-controlled study of anti-IL-33 in peanut allergy. JCI Insight. 2019;4:e131347.,5858 Chen YL, Gutowska-Owsiak D, Hardman CS, Westmoreland M, MacKenzie T, Cifuentes L, et al. Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis. Sci Transl Med. 2019;11:eaax2945. and anti-TSLP (tezepelumab) immunobiologicals,5959 Sakamoto K, Matsuki S, Irie S, Uchida N, Hayashi N, Horiuchi M, et al. A Phase 1, Randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tezepelumab in healthy Japanese men. Clin Pharmacol Drug Dev. 2020;9: 833-40.

60 Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377:936-46.

61 Emson C, Diver S, Chachi L, Megally A, Small C, Downie J, et al. CASCADE: a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma. Respir Res. 2020;21:265.

62 Wechsler ME, Colice G, Griffiths JM, Almqvist G, Skärby T, Piechowiak T, et al. SOURCE: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma. Respir Res. 2020;21:264.
-6363 Menzies-Gow A, Ponnarambil S, Downie J, Bowen K, Hellqvist Å, Colice G. DESTINATION: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the long-term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir Res. 2020;21:279. only etokimab has an ongoing study for CRSwNP (Clinicaltrials.gov Identifier: NCT03614923).

Immunobiologicals for secondary CRS

EGPA (eosinophilic granulomatosis with polyangiitis)

The most studied immunobiologicals for EGPA, also known as Churg-Strauss syndrome, are the drugs that act on IL-5, either directly (mepolizumab) or through its receptor (benralizumab).6464 Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376:1921-32.

65 Steinfeld J, Bradford ES, Brown J, Mallett S, Yancey SW, Akuthota P, et al. Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol. 2019;143:2170-7.

66 Canzian A, Venhoff N, Urban ML, Sartorelli S, Ruppert AM, Groh M, et al. Use of biologics to treat relapsing and/or refractory eosinophilic granulomatosis with polyangiitis: data from a european collaborative study. Arthritis Rheumatol. 2021;73:498-503.
-6767 Guntur VP, Manka L, Denson JL, Dunn RM, Dollin YT, Gill M, et al. Benralizumab as a steroid-sparing treatment option in eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol Pract. 2021;9:1186-93.e1. It is worth mentioning that, to date, mepolizumab is the only one that has been approved by the regulatory agencies (FDA, EMA and ANVISA) for EGPA treatment.

Mepolizumab has been evaluated in two double-blind, randomized, multicentre phase 3 clinical studies. Wechsler et al.6464 Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376:1921-32. evaluated 136 patients with refractory EGPA who had been using systemic corticosteroids for at least 4 weeks, evaluating the effect of mepolizumab at a dose of 300 mg subcutaneously every 4 weeks for a total period of 52 weeks. In this study, participants using mepolizumab had a 16.74 times greater chance of disease remission at the end of the study, and 0.32 times less chance of having recurrences during the total evaluation period, both of which were significant. Additionally, patients receiving mepolizumab required a lower dose of prednisone or prednisolone on average (Odds Ratio: 0.20; p< 0.001). Interestingly, patients with more than 150 eosinophils/mm3 in peripheral blood had a response 26.10 times more robust than patients with less than 150 eosinophil/mm3.

In another multicenter double-blind randomized phase 3 study, Steinfeld et al.6565 Steinfeld J, Bradford ES, Brown J, Mallett S, Yancey SW, Akuthota P, et al. Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol. 2019;143:2170-7. evaluated 136 patients, using the same dose and frequency as the previous study. They observed that 78% of the patients using mepolizumab and 32% of the placebo group had the clinical benefit, when considered criteria: Birmingham vasculitis activity score (BVAS) of 0 and use of corticosteroids at a dose lower than 4 mg/day OR reduction of corticosteroid dose in more than 50% OR absence of recurrence of symptoms). With less strict criteria (BVAS score of 0 and use of corticosteroids at less than 7.5 mg/day OR reduction in the dose of corticosteroids by more than 50% OR absence of recurrence of symptoms), the clinical benefit was reached by 87% of the mepolizumab group and 53% of the placebo group during the study.

In a study of real life data of EGPA patients dependent on the use of systemic corticosteroids, in which patients were treated with mepolizumab (100 or 300 mg every 4 weeks) or omalizumab, Canzian et al.6666 Canzian A, Venhoff N, Urban ML, Sartorelli S, Ruppert AM, Groh M, et al. Use of biologics to treat relapsing and/or refractory eosinophilic granulomatosis with polyangiitis: data from a european collaborative study. Arthritis Rheumatol. 2021;73:498-503. observed that mepolizumab, in any of the prescribed doses, was better than omalizumab in reducing the use of corticosteroids to rescue symptom control, in remission after 12 months of use (78% vs 15%), and in therapeutic failures (8% vs 48%). The authors also reported that the remission rate was similar at different doses of mepolizumab. However, 2 patients experienced persistent symptoms at the dose of 100 mg, and benefited from increasing the dose to 300 mg.

Benralizumab is also being studied in EGPA patients, but only one open-label clinical study, with only 10 patients, has been published so far. In this article, Guntur et al.6767 Guntur VP, Manka L, Denson JL, Dunn RM, Dollin YT, Gill M, et al. Benralizumab as a steroid-sparing treatment option in eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol Pract. 2021;9:1186-93.e1. demonstrated that the concomitant use of benralizumab 30 mg was able to significantly reduce the dose of systemic corticosteroids. Double-blind, randomized studies, with a larger number of patients, are being carried out to confirm the ability of benralizumab to control the EGPA respiratory symptoms (ClinicalTrials.gov Identifier: NCT04157348, NCT03010436), as well as the use of reslizumab (ClinicalTrials. gov Identifier: NCT02947945).

In general, these drugs may lead to mild to moderate adverse events, the most common of which are headache, local reaction, back pain, fatigue, rhinorrhea, and nasal congestion. More serious adverse events are rare, with anaphylaxis being the most reported.6565 Steinfeld J, Bradford ES, Brown J, Mallett S, Yancey SW, Akuthota P, et al. Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol. 2019;143:2170-7.,6767 Guntur VP, Manka L, Denson JL, Dunn RM, Dollin YT, Gill M, et al. Benralizumab as a steroid-sparing treatment option in eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol Pract. 2021;9:1186-93.e1.

GPA (granulomatosis with polyangiitis)

Rituximab (anti-CD20 antibody) is the most widely used immunobiological agent for patients with granulomatosis with polyangiitis (GPA), formerly known as Wegener's granulomatosis.6868 Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, et al. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis. 2016;75:1166-9.

In the main double-blind, randomized multicenter clinical study, Unizony et al.6868 Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, et al. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis. 2016;75:1166-9. evaluated 197 patients, 148 with GPA, 48 with microscopic polyangiitis (MPA), and one undefined patient, who were divided into two groups: rituximab 375 mg/m2 intravenously per week for 4 weeks, or comparative treatment (cyclophosphamide and azathioprine). Patients using rituximab were 2.11 times more likely to experience clinical remission. The difference in response was even greater in the group refractory to treatment, with Odds Ratio of 3.57 at 6 months; 4.32 at 12 months, and 3.06 at 18 months.

Charles et al.6969 Charles P, Perrodeau É, Samson M, Bonnotte B, Néel A, Agard C, et al. Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2020;173:179-87. evaluated 68 patients with GPA and 29 with long-term MAP in a double-blind, randomized, multicenter clinical study. All patients received rituximab during the first 28 weeks, and were in control of the disease at this time. Subsequently, patients were randomized to rituximab 500 mg every 6 months, for an additional 18 months, or placebo. Disease-free survival after 28 weeks of the second cycle was 96% in the rituximab group, versus 74% in the placebo group (Hazard Ratio 7.5; p < 0.01), showing a potential long-term use of this medication for GPA control.

Puéchal et al.7070 Puéchal X, Iudici M, Calich AL, Vivot A, Terrier B, Régent A, et al. Rituximab for induction and maintenance therapy of granulomatosis with polyangiitis: a single-centre cohort study on 114 patients. Rheumatology (Oxford). 2019;58:401-9. used rituximab to induce GPA control in a cohort study involving 114 patients (65% with recurrent disease, 22% with difficult-to-control disease, and 13% with initial disease). All patients received rituximab at induction; in 90 of them, maintenance doses were necessary for symptom control (500 mg every 6 months, up to an accumulated dose of 2 g). Patients were followed for an average of 3.6 years, with disease-free survival of 85% after 2 years of follow-up. Serious infections occurred in 4.9% of patients/year, and more important adverse events occurred in 8.1%. Multivariate analysis showed that persistence of symptoms, presence of subglottic stenosis, otorhinolaryngological symptoms, and presence of skin lesions were all associated with a lower chance of remission.

Despite the studies presented above, two systematic reviews mention that there is still a low level of evidence on the benefit of using rituximab for GPA treatment.7171 Ho C, Spry C. Rituximab for granulomatosis with polyangiitis or microscopic polyangiitis: a review of the clinical effectiveness, cost-effectiveness, and guidelines [Internet]. Ottawa (ON): Can Agency Drugs Technol Health. 2017:29470031.,7272 Bala MM, Malecka-Massalska TJ, Koperny M, Zajac JF, Jarczewski JD, Szczeklik W. Anti-cytokine targeted therapies for ANCA-associated vasculitis. Cochrane Database Syst Rev. 2020;9. CD008333. An additional precaution is the risk of adverse events, including serious infections, which are more frequent with this immunobiological agent than with those previously mentioned.

Sense of smell and immunobiologicals

Among the most promising effects of immunobiologicals on CRSwNP patients is improved olfaction. Through objective and validated tests, studies have observed clinically significant improvement in patients with anosmia, in mild hyposmia or even normosmia, after treatment with immunobiologicals.

For this reason, anosmia is an important criterion established by the main guidelines for the indication of CRSwNP treatment with immunobiologicals.11 Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020;58:1-464.,7373 Bachert C, Han JK, Wagenmann M, Hosemann W, Lee SE, Backer V, et al. EUFOREA Expert Board Meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: definitions and management. J Allergy Clin Immunol. 2021;147:29-36. It is important to emphasize that the diagnosis of anosmia must be made by a validated psychophysical test, and not only through questionnaires that assess the patient’s perception of olfactory loss. The indication of immunobiologicals requires that the patient meets the loss of smell criterion, classified as severe hyposmia or anosmia, regardless of the test used. Mild to moderate hyposmia in CRSwNP tends to have a good resolution with the use of topical and systemic steroids.7474 Banglawala SM, Oyer SL, Lohia S, Psaltis AJ, Soler ZM, Schlosser RJ. Olfactory outcomes in chronic rhinosinusitis with nasal polyposis after medical treatments: a systematic review and meta-analysis. Int Forum Allergy Rhinol. 2014;4:986-94.

Criteria for the indication of immunobiologicals in CRSwNP

The indication of immunobiologicals in patients with eCRSwNP needs to meet two criteria: having type 2 inflammation (Table 1) and having serious and uncontrolled disease (Table 2).

Table 1
Clinical and laboratory criteria suggestive of CRS with type 2 inflammation (eosinophilic CRSwNP).
Table 2
Criteria for uncontrolled severe chronic rhinosinusitis.

Evaluation of the clinical response to an immunobiological agent

When an immunobiological agent is selected to treat severe uncontrolled CRSwNP, it is important to monitor the patient’s response to the drug. To avoid inappropriate treatment and unnecessary costs, the response to treatment should be reassessed every 4-6 months (Table 3). This period is considered more than adequate to observe the clinical response to the prescribed medication. Depending on the immunobiological agent and the outcome measurement used, an absence of response can be expected in 25%-50% of cases.

Table 3
Evaluation of response to initial treatment (4-6 months) with immunobiologicals.

If the degree of response with the drug is considered acceptable for the patient, drug continuation is recommended and the patient is instructed to be reassessed at least every 6 months.

If disease control is not acceptable for the patient, the associated use of oral corticosteroids for a short period during treatment with immunobiologicals may help to optimize symptom control. Another alternative is the surgical procedure, which can be considered to reduce the polypoid tissue and the disease burden, so that the immunobiological can be more effective. In both cases, the continued use of the immunobiological agent is justified. If the patient persists with symptoms after the above strategies, he is considered as not responding, and the option would be to change the immunobiological or a new surgery.

Considerations about immunobiologicals in Brazil

In Brazil, the use of immunobiologicals is already a reality for other specialties such as rheumatology, allergy, and pneumology, and it should be increasingly used in otorhinolaryngology, especially in type 2 CRSwNP patients. Issues such as the cost and possible financing by health insurance or public health system must still be addressed so that patients who are refractory to the currently available treatments can benefit from these drugs.

Final comments

Severe uncontrolled CRSwNP, associated with comorbidities (asthma, AERD, severe dermatitis) has a negative impact on health-related quality of life. Although there is a significant unmet need for treatment in patients with severe and uncontrolled CRSwNP, the pharmacoeconomic justification for the use of immunobiological products is under development. Of particular interest for decision making will be the identification of these subgroups of patients refractory to the existing treatment options and the construction of a strategy that is clinically effective and improves their quality of life.

So far, the use of immunobiologicals can provide important benefits for these patients and it should be an evaluated, understood, and improved strategy in the future, with more studies and greater clinical experience.

References

  • 1
    Fokkens WJ, Lund VJ, Hopkins C, Hellings PW, Kern R, Reitsma S, et al. European Position Paper on Rhinosinusitis and Nasal Polyps 2020. Rhinology. 2020;58:1-464.
  • 2
    DeConde AS, Mace JC, Levy JM, Rudmik L, Alt JA, Smith TL. Prevalence of polyp recurrence after endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis. Laryngoscope. 2017;127:550-5.
  • 3
    Damask CC, Ryan MW, Casale TB, Castro M, Franzese CB, Lee SE, et al. Targeted Molecular Therapies in Allergy and Rhinology. Otolaryngol Head Neck Surg. 2021;164:S1-21.
  • 4
    Gandhi NA, Bennett BL, Graham NM, Pirozzi G, Stahl N, Yancopoulos GD. Targeting key proximal drivers of type-2 inflammation in disease. Nat Rev Drug Discov. 2016;15:35-50.
  • 5
    Laidlaw TM, Buchheit KM. Biologics in chronic rhinosinusitis with nasal polyposis. Ann Allergy Asthma Immunol. 2020;124:326-32.
  • 6
    Fokkens WJ, Lund V, Bachert C, Mullol J, Bjermer L, Bousquet J, et al. EUFOREA consensus on biologics for CRSwNP with or without asthma. Allergy. 2019;74:2312-9.
  • 7
    Casale TB. Biologics and biomarkers for asthma, urticaria, and nasal polyposis. J Allergy Clin Immunol. 2017;139:1411-21.
  • 8
    Codispoti CD, Mahdavinia M. A call for cost-effectiveness analysis for biologic therapies in chronic rhinosinusitis with nasal polyps. Ann Allergy Asthma Immunol. 2019;123:232-9.
  • 9
    Bang LM, Plosker GL. Omalizumab - a review of its use in the management of allergic asthma. Treat Respir Med. 2004;3:183-99.
  • 10
    Kartush AG, Schumacher JK, Shah R, Patadia MO. Biologic agents for the treatment of chronic rhinosinusitis with nasal polyps. Am J Rhinol Allergy. 2019;33:203-11.
  • 11
    Xolair® (omalizumabe). VPS12 = Xolair Bula Profissional aprovada pela ANVISA em 11/01/2021. https://portal.novartis.com.br/upload/imgconteudos/1815.pdf.
    » https://portal.novartis.com.br/upload/imgconteudos/1815.pdf
  • 12
    Kim H, Ellis AK, Fischer D, Noseworthy M, Olivenstein R, Chapman KR, et al. Asthma biomarkers in the age of biologics. Allergy Asthma Clin Immunol. 2017;13:48.
  • 13
    Mostafa BE, Fadel M, Mohammed MA, Hamdi TAH, Askoura AM. Omalizumab versus intranasal steroids in the post-operative management of patients with allergic fungal rhinosinusitis. Eur Arch Otorhinolaryngol. 2020;277:121-8.
  • 14
    Lowe PJ, Tannenbaum S, Gautler A, Jimenez P. Relationship between omalizumab pharmacokinetics, IgE pharmacodynamics and symptoms in patients with severe persistent allergic (IgE-mediated) asthma. Br J Clin Pharmacol. 2009;68:61-76.
  • 15
    Bachert C, Zhang L, Gevaert P. Current and future treatment options for adult chronic rhinosinusitis: focus on nasal polyposis. J Allergy Clin Immunol. 2015;136:1431-40.
  • 16
    Gevaert P, Calus L, Van Zele T, Blomme K, De Ruyck N, Bauters W, et al. Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma. J Allergy Clin Immunol. 2013;131:110-6.e1.
  • 17
    Pinto JM, Mehta N, DiTineo M, Wang J, Baroody FM, Naclerio RM. A randomized, double-blind, placebo-controlled trial of anti-IgE for chronic rhinosinusitis. Rhinology. 2010;48:318-24.
  • 18
    Rivero A, Jonathan L. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47.
  • 19
    Tsetsos N, Goudakos JK, Daskalakis D, Konstantinidis I, Markou K. Monoclonal antibodies for the treatment of chronic rhinosinusitis with nasal polyposis: a systematic review. Rhinol. 2018;56:11-21.
  • 20
    Hong CJ, Tsang AC, Quinn JG, Bonaparte JP, Stevens A, Kilty SJ. Anti-IgE monoclonal antibody therapy for the treatment of chronic rhinosinusitis: a systematic review. Syst Rev. 2015;4:166.
  • 21
    Santos TS, Gonçalves P, Carvalho C. Effectiveness of omalizumab in the treatment of chronic rhinosinusitis with nasal polyps. Syst Rev. 2014;3:473-9.
  • 22
    Gevaert P, Omachi TA, Corren J, Mullol J, Han J, Lee SE, et al. Efficacy and safety of omalizumab in nasal polyposis: two randomized phase III trials. J Allergy Clin Immunol. 2020;146:595-605.
  • 23
    Gan EC, Habib AR, Rajwani A, Javer AR. Omalizumab therapy for refractory allergic fungal rhinosinusitis patients with moderate or severe asthma. Am J Otolaryngol. 2015;36:672-7.
  • 24
    Bachert C, Gevaert P, Hellings P. Biotherapeutics in chronic rhinosinusitis with and without nasal polyps. J Allergy Clin Immunol Pract. 2017;5:1512-6.
  • 25
    Humbert M, Busse W, Hanania NA, Lowe PJ, Canvin J, Erpenbeck VJ, et al. Omalizumab in asthma: an update on recent developments. J Allergy Clin Immunol Pract. 2014;2:525-36.e1.
  • 26
    Long A, Rahmaoui A, Rothman KJ, Guinan E, Eisner M, Bradley MS, et al. Incidence of malignancy in patients with moderateto-severe asthma treated with or without omalizumab. J Allergy Clin Immunol. 2014;134:560-7.
  • 27
    Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood. 1992;79:3101-9.
  • 28
    Gevaert P, Bachert C, Holtappels G, Novo CP, Van der Heyden J, Fransen L, et al. Enhanced soluble interleukin-5 receptor alpha expression in nasal polyposis. Allergy. 2003;58:371-9.
  • 29
    Gevaert P, Van Bruaene N, Cattaert T, Van Steen K, Van Zele T, Acke F, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. J Allergy Clin Immunol. 2011;128, 989-95.e1-8.
  • 30
    Simon HU, Yousefi S, Schranz C, Schapowal A, Bachert C, Blaser K. Direct demonstration of delayed eosinophil apoptosis as a mechanism causing tissue eosinophilia. J Immunol. 1997;158:3902-8.
  • 31
    Nucala (mepolizumab) for injection [prescribing information]. Research Triangle Park, NC: GlaxoSmithKline; November 2015.
  • 32
    Fda.gov [Internet]. Nucala (mepolizumab) Label FDA. https://www.accessdata.fda.gov/drugsatfdadocs/label/2015/125526Orig1s000Lbl.pdf. Published 2017.
    » https://www.accessdata.fda.gov/drugsatfdadocs/label/2015/125526Orig1s000Lbl.pdf
  • 33
    Fda.gov [Internet]. Cinqair (reslizumab) Label FDA. https://www.accessdata.fda.gov/drugsatfdadocs/label/2016/761033lbl.pdf. Published 2017.
    » https://www.accessdata.fda.gov/drugsatfdadocs/label/2016/761033lbl.pdf
  • 34
    Fda.gov (Internet).Fasenra (benralizumab) https://www.astrazeneca.com/media-centre/pressreleases/2017/fasenra-benralizumab-receives-us-fdaapproval-for-severe-uncontrolled-eosinophilic-asthma14112017.html Published 2017.
    » https://www.astrazeneca.com/media-centre/pressreleases/2017/fasenra-benralizumab-receives-us-fdaapproval-for-severe-uncontrolled-eosinophilic-asthma14112017.html
  • 35
    Efficacy and Safety Study of Benralizumab for Patients With Severe Nasal Polyposis (OSTRO) (https://clinicaltrials.gov/ct2/show/results/NCT03401229.
    » https://clinicaltrials.gov/ct2/show/results/NCT03401229
  • 36
    Effect of Mepolizumab in Severe Bilateral Nasal Polyps https://clinicaltrials.gov/ct2/show/results/NCT03085797.
    » https://clinicaltrials.gov/ct2/show/results/NCT03085797
  • 37
    Gevaert P, Lang-Loidolt D, Lackner A, Stammberger H, Staudinger H, Van Zele T, et al. Nasal IL-5 levels determine the response to anti-IL-5 treatment in patients with nasal polyps. J Allergy Clin Immunol. 2006;118:1133-41.
  • 38
    Bachert C, Souza AR, Lund VJ, Sccading GK, Gevaert P, Nasser S, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: randomized trial. J Allergy Clin Immunol. 2017;140:1024-2031.
  • 39
    Kim C, Han J, Wu T, Bachert C, Fokkens W, Hellings P, et al. Role of biologics in chronic rhinosinusitis with nasal polyposis: state of the art review. Otolaryngol Head Neck Surg. 2021;164:57-66.
  • 40
    Rivero A, Liang J. Anti-IgE and Anti-IL5 biologic therapy in the treatment of nasal polyposis: a systematic review and metaanalysis. Ann Otol Rhinol Laryngol. 2017;126:739-47.
  • 41
    Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting [32-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet. 2016;388:2115-27.
  • 42
    United States Food and Drug Administration. Dupixent Prescribing Information (approved March 28, 2017). https://www.accessdata.fda.gov/drugsatfdadocs/label/2019/761055s014lbl.pdf. Published 2019. [Accessed 30 November 2020].
    » https://www.accessdata.fda.gov/drugsatfdadocs/label/2019/761055s014lbl.pdf
  • 43
    European Medicines Agency. Dupixent. Extension of indication variation assessment report. https://www.ema.europa.eu/en/documents/variation-report/dupixent-h-c-4390-ii-0017-epar-assessment-report-variation en.pdf Published 2019. [Accessed 30 November 2020].
    » https://www.ema.europa.eu/en/documents/variation-report/dupixent-h-c-4390-ii-0017-epar-assessment-report-variation en.pdf
  • 44
    Sastre J, Dávila I. Dupilumab: A new paradigm for the treatment of allergic diseases. J Investig Allergol Clin Immunol. 2018;28:139-50.
  • 45
    Bachert C, Mannent L, Naclerio RM, Mullol J, Ferguson BJ, Gevaert P, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: A randomized clinical trial. JAMA. 2016;315:469-79.
  • 46
    Bachert C, Han JK, Desrosiers M, Hellings PW, Amin N, Lee SE, et al. 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;394:1638-50.
  • 47
    Bachert C, Hellings PW, Mullol J, Naclerio RM, Chao J, Amin N, et al. Dupilumab improves patient-reported outcomes in patients with chronic rhinosinusitis with nasal polyps and comorbid asthma. J Allergy Clin Immunol Pract. 2019;7:2447-9.e2.
  • 48
    Laidlaw TM, Mullol J, Fan C, Zhang D, Amin N, Khan A, et al. Dupilumab improves nasal polyp burden and asthma control in patients with CRSwNP and AERD. J Allergy Clin Immunol Pract. 2019;7:2462-5.e1.
  • 49
    Bachert C, Hellings PW, Mullol J, Hamilos DL, Gevaert P, Naclerio RM, et al. Dupilumab improves health-related quality of life in patients with chronic rhinosinusitis with nasal polyposis. Allergy. 2020;75:148-57.
  • 50
    Chong LY, Piromchai P, Sharp S, Snidvongs K, Philpott C, Hopkins C, et al. Biologics for chronic rhinosinusitis. Cochrane Database Syst Rev. 2020;2. CD013513.
  • 51
    Jonstam K, Swanson BN, Mannent LP, Cardell LO, Tian N, Wang Y, et al. Dupilumab reduces local type 2 pro-inflammatory biomarkers in chronic rhinosinusitis with nasal polyposis. Allergy. 2019;74:743-52.
  • 52
    Laidlaw TM, Mullol J, Fan C, Zhang D, Amin N, Khan A, et al. Dupilumab improves nasal polyp burden and asthma control in patients with CRSwNP and AERD. J Allergy Clin Immunol Pract. 2019;7:2462-5.e1.
  • 53
    Mustafa SS, Vadamalai K, Scott B, Ramsey A. Dupilumab as add-on therapy for chronic rhinosinusitis with nasal polyposis in aspirin exacerbated respiratory disease. Am J Rhinol Allergy. 2020, http://dx.doi.org/10.1177/1945892420961969. Online ahead of print.
    » http://dx.doi.org/10.1177/1945892420961969
  • 54
    Lo RM, Liu AY, Valdez TA, Gernez Y. Dupilumab use in recalcitrant allergic fungal rhinosinusitis. Ann Allergy Asthma Immunol. 2020;125:617-9.
  • 55
    Agência Nacional de Vigilância Sanitária. Consultas Anvisa Medicamentos Dupixent. https://consultas.anvisa.gov.br/#/medicamentos/25351189487201920/?substancia=26064 Published 2019.
    » https://consultas.anvisa.gov.br/#/medicamentos/25351189487201920/?substancia=26064
  • 56
    Akinlade B, Guttman-Yassky E, de Bruin-Weller M, Simpson EL, Blauvelt A, Cork MJ, et al. Conjunctivitis in dupilumab clinical trials. Br J Dermatol. 2019;181:459-73.
  • 57
    Chinthrajah S, Cao S, Liu C, Lyu SC, Sindher SB, Long A, et al. Phase 2a randomized, placebo-controlled study of anti-IL-33 in peanut allergy. JCI Insight. 2019;4:e131347.
  • 58
    Chen YL, Gutowska-Owsiak D, Hardman CS, Westmoreland M, MacKenzie T, Cifuentes L, et al. Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis. Sci Transl Med. 2019;11:eaax2945.
  • 59
    Sakamoto K, Matsuki S, Irie S, Uchida N, Hayashi N, Horiuchi M, et al. A Phase 1, Randomized, placebo-controlled study to evaluate the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tezepelumab in healthy Japanese men. Clin Pharmacol Drug Dev. 2020;9: 833-40.
  • 60
    Corren J, Parnes JR, Wang L, Mo M, Roseti SL, Griffiths JM, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377:936-46.
  • 61
    Emson C, Diver S, Chachi L, Megally A, Small C, Downie J, et al. CASCADE: a phase 2, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effect of tezepelumab on airway inflammation in patients with uncontrolled asthma. Respir Res. 2020;21:265.
  • 62
    Wechsler ME, Colice G, Griffiths JM, Almqvist G, Skärby T, Piechowiak T, et al. SOURCE: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy and safety of tezepelumab in reducing oral corticosteroid use in adults with oral corticosteroid dependent asthma. Respir Res. 2020;21:264.
  • 63
    Menzies-Gow A, Ponnarambil S, Downie J, Bowen K, Hellqvist Å, Colice G. DESTINATION: a phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the long-term safety and tolerability of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir Res. 2020;21:279.
  • 64
    Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med. 2017;376:1921-32.
  • 65
    Steinfeld J, Bradford ES, Brown J, Mallett S, Yancey SW, Akuthota P, et al. Evaluation of clinical benefit from treatment with mepolizumab for patients with eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol. 2019;143:2170-7.
  • 66
    Canzian A, Venhoff N, Urban ML, Sartorelli S, Ruppert AM, Groh M, et al. Use of biologics to treat relapsing and/or refractory eosinophilic granulomatosis with polyangiitis: data from a european collaborative study. Arthritis Rheumatol. 2021;73:498-503.
  • 67
    Guntur VP, Manka L, Denson JL, Dunn RM, Dollin YT, Gill M, et al. Benralizumab as a steroid-sparing treatment option in eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol Pract. 2021;9:1186-93.e1.
  • 68
    Unizony S, Villarreal M, Miloslavsky EM, Lu N, Merkel PA, Spiera R, et al. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Ann Rheum Dis. 2016;75:1166-9.
  • 69
    Charles P, Perrodeau É, Samson M, Bonnotte B, Néel A, Agard C, et al. Long-term rituximab use to maintain remission of antineutrophil cytoplasmic antibody-associated vasculitis: a randomized trial. Ann Intern Med. 2020;173:179-87.
  • 70
    Puéchal X, Iudici M, Calich AL, Vivot A, Terrier B, Régent A, et al. Rituximab for induction and maintenance therapy of granulomatosis with polyangiitis: a single-centre cohort study on 114 patients. Rheumatology (Oxford). 2019;58:401-9.
  • 71
    Ho C, Spry C. Rituximab for granulomatosis with polyangiitis or microscopic polyangiitis: a review of the clinical effectiveness, cost-effectiveness, and guidelines [Internet]. Ottawa (ON): Can Agency Drugs Technol Health. 2017:29470031.
  • 72
    Bala MM, Malecka-Massalska TJ, Koperny M, Zajac JF, Jarczewski JD, Szczeklik W. Anti-cytokine targeted therapies for ANCA-associated vasculitis. Cochrane Database Syst Rev. 2020;9. CD008333.
  • 73
    Bachert C, Han JK, Wagenmann M, Hosemann W, Lee SE, Backer V, et al. EUFOREA Expert Board Meeting on uncontrolled severe chronic rhinosinusitis with nasal polyps (CRSwNP) and biologics: definitions and management. J Allergy Clin Immunol. 2021;147:29-36.
  • 74
    Banglawala SM, Oyer SL, Lohia S, Psaltis AJ, Soler ZM, Schlosser RJ. Olfactory outcomes in chronic rhinosinusitis with nasal polyposis after medical treatments: a systematic review and meta-analysis. Int Forum Allergy Rhinol. 2014;4:986-94.

Publication Dates

  • Publication in this collection
    27 June 2022
  • Date of issue
    May-Jun 2022

History

  • Received
    08 Mar 2021
  • Accepted
    09 Mar 2021
Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Sede da Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico Facial, Av. Indianópolia, 1287, 04063-002 São Paulo/SP Brasil, Tel.: (0xx11) 5053-7500, Fax: (0xx11) 5053-7512 - São Paulo - SP - Brazil
E-mail: revista@aborlccf.org.br