Are biologics grabbing the spotlight?
As vastly proved, initial treatment of CRS includes topical and systemic corticosteroids, long-term antibiotics and surgical intervention. However, some patients suffer from a recalcitrant form of disease despite best practice. In recent years, the advancement in pharmaceutical therapies has reached application also in CRSwNP, with molecules (monoclonal antibodies) that specifically target the major players in the inflammation cascade of CRSwNP [36]. For what concerns the use of biologics, the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) suggested five criteria that should be satisfied to prescribe them in CRSwNP [44]. Besides having undergone sinus surgery, three criteria have to be met among the following: the evidence of type 2 inflammation, the need for systemic corticosteroids in the past 2 years, a significant impairment in quality-of-life because of the disease, reduced sense of smell and comorbid asthma. The fact that biologics may become an alternative to surgery is still a matter of discussion and it will be established after their approval for CRSwNP and post-marketing surveillance phase.
The critical players that have been targeted so far are IgE, IL-5, IL-4 and IL-13, as well as some of their receptors [36]. The continuous local activation of mast cells, basophils and dendritic cells by IgE can be reduced by selective binding to free circulating IgE, thanks to an anti-IgE antibody (omalizumab) [45]. Two pivotal old studies [45,46] in a small number of patients (<30) gave contradictory results, but very recently the first results of two phase III clinical trials (POLYP 1 and POLYP 2) showed that omalizumab significantly improved endoscopic, clinical and PROs in patients with corticosteroid-refractory CRSwNP [47].
Other drugs that block circulating IL-5 (mepolizumab and reslizumab) and therefore interrupting eosinophilic inflammation, have undergone testing through randomized controlled studies: the only large study that was conducted with 105 severe CRSwNP patients is by Bachert et al. [48], showing that mepolizumab reduced the need for sinonasal surgery compared to placebo. Significant improvement in symptoms (rhinorrhea, nasal blockage and hyposmia), quality of life (by means of Sino-nasal Outcome Test, SNOT-22, questionnaire), as well as increase in Peak Nasal Inspiratory Flow (PNIF) in patients treated with mepolizumab. Similarly, blood eosinophils decreased. Results of phase 3 trials for mepolizumab in CRSwNP are expected to be published within a year [36]. Also, RCTs on benralizumab, a monoclonal antibody directed towards the alpha subunit of IL-5 receptor (IL-5Rα), are ongoing.
Interleukin-4 (IL-4) and interleukin-13 (IL-13) have overlapping biological effects because of their partly shared receptor complex [29]. IL-4 may interact with either a type I receptor (made of IL-4 receptor alfa, IL-4Rα, and the common γ-chain of the IL-2R) or a type II receptor (made of IL-4Rα and an IL-13 binding chain, IL-13Rα1). This type II receptor complex is also a functional receptor for IL-13, which is the reason or IL-4/IL-13 common pathways and functional properties [49]. Dupilumab is a monoclonal antibody against the IL-4Rα that inhibits both IL-4 and IL-13 signaling. Dupilumab significantly improved nasal polyp score (NPS), nasal congestion or obstruction, and sinus Lund-Mackay CT scores in two phase-3 big trials (SINUS-24 and SINUS-52) [50]. At the moment, it is the only monoclonal antibody approved for the treatment of CRSwNP [1,36].