Dupilumab is a completely human monoclonal antibody, belonging to the IgG4 immunoglobulin class, whose mechanism of action consists of the dual antagonism of the interleukin 4 (IL-4) and 13 (IL-13) receptors (1). In addition to the treatment of severe asthma and atopic dermatitis, dupilumab is also indicated for the biological therapy of nasal polyposis, which is a frequent comorbidity of severe asthma (2).

IL-4 and IL-13 play critical roles in the pathogenesis of severe type 2 asthma (3). In particular, IL-4 is crucial in the development and maintenance of the acquired immune response mediated by T helper 2 (Th2) lymphocytes. At the level of B lymphocytes of allergic patients, IL-4 and IL-13 induce the so-called isotypic switch, responsible for the synthesis of immunoglobulins E (IgE), which degranulate mast cells and basophils, facilitate the presentation of allergens by dendritic cells to T lymphocytes, and inhibit eosinophil apoptosis (4). IL-4 and IL-13 promote the trafficking of eosinophils to inflammatory sites and impair the integrity of the airway epithelial barrier. Furthermore, IL-13 stimulates mucus secretion and goblet cell hyperplasia, and also up-regulates the expression of the inducible form of the enzyme nitric oxide (NO) synthase (iNOS), which increases NO production within the airways (5, 6). Chronic rhinosinusitis with nasal polyps (CRSwNP) is a frequent comorbidity of severe asthma, and type 2 inflammation very often contributes significantly to the pathogenesis of nasal polyposis. Indeed, at the level of upper airways IL-4 and IL-13 play a key role in both inflammatory and structural changes (tissue remodelling) that underlie the formation of nasal polyps (7).

The efficacy of dupilumab as biological treatment of severe asthma and nasal polyposis depends on its remarkable ability to inhibit the pathophysiologic mechanisms involved in type 2 inflammation. In fact, dupilumab is an efficient dual antagonist of both IL-4 and IL-13 receptors 13 (3). Specifically, dupilumab binds with high affinity to the IL-4 receptor α subunit (IL-4Rα). This receptor subunit is a key component of the type I receptor, consisting of the IL-4Rα/γC dimer, which is activated by IL-4 (8). The type II receptor is instead constituted by the IL-4Rα subunit and the α1 chain of the IL-13 receptor (IL-4Rα/IL-13Rα1 dimer), and can therefore be stimulated by IL-4 and IL-13. The type I receptor is predominantly expressed by immune-inflammatory cells such as T and B lymphocytes, dendritic cells, monocytes/macrophages, mast cells, basophils and eosinophils. The type II receptor is also present on airway structural cells such as goblet cells, fibroblasts and smooth muscle cells (9). Upon pharmacological blockade of both type I and type II receptors, dupilumab neutralizes the biological effects of IL-4 and IL-13.

Due to this powerful mechanism of action, within the context of add-on biological treatment of severe asthma and nasal polyposis dupilumab exerts remarkable therapeutic effects, well documented by several randomized controlled trials (RCTs) (10). In particular, the “LIBERTY ASTHMA QUEST” study demonstrated that dupilumab was capable of significantly reducing the annual rate of severe asthma exacerbations and improving lung function (11). Furthermore, the “LIBERTY ASTHMA VENTURE” trial highlighted the ability of dupilumab to significantly decrease the consumption of oral corticosteroids (OCS) (12). These results were recently confirmed by the open-label extension study LIBERTY ASTHMA TRAVERSE, which further monitored for additional 96 weeks many patients previously enrolled in the LIBERTY ASTHMA QUEST and LIBERTY ASTHMA VENTURE (13). As regards the adjunctive biological therapy of nasal polyposis, the studies “LIBERTY NP SINUS-24” and “LIBERTY NP SINUS-52” documented the efficacy of dupilumab by evaluating the improvement of many relevant parameters (14).

However, only a few real-world studies referring to a quite low number of patients have been published so far (15–19). Hence, the aim of our present real-life observational investigation was to evaluate, in a larger sample of subjects with severe asthma, also including many patients with nasal polyposis, the therapeutic impact of dupilumab on upper and lower airway symptoms, severe asthma exacerbations, OCS intake and lung function, as well as on the overall clinical expression of nasal polyposis.

Taken together, the results of the present multicenter real-life study, performed in patients with severe asthma and frequent nasal polyposis, show that dupilumab induced relevant therapeutic effects. Firstly, six months of treatment with this biologic drug cleared asthma exacerbations. This made it possible to effectively prevent any access to the emergency room, the use of short-acting bronchodilators as needed, and the intake of OCS. The latter aspect is of considerable importance as it further exceeds the efficacy data reported by the Liberty Asthma VENTURE trial (12). Indeed, VENTURE authors reported that 52.4% of patients interrupted OCS after 24 weeks of treatment with dupilumab, whereas after the same period of time OCS withdrawal was achieved by 92.9% of our steroid-dependent patients. The relevance of zeroing the use of OCS is closely related to the possibility of abrogating the well-known side effects of oral corticosteroid therapy, including adrenal insufficiency, respiratory infections, diabetes mellitus, arterial hypertension, osteoporosis, glaucoma and cataract (34, 35).

When compared to QUEST (Q) and VENTURE (V) trials, other important differences with our real-life study regard the baseline characteristics of recruited patients. In particular, we enrolled a population of asthmatic subjects with a greater percentage of male patients (50.4% vs. Q 37.8% and V 39.8%, respectively), a higher number of asthma exacerbations (4.00 vs. Q 2.02 and V 2.01, respectively), a greater blood eosinophil count (400.0 cells/µL vs. Q 250 cells/µL and V 280 cells/µL, respectively), and especially a much higher percentage of patients presented with CRSwNP (61.4% vs. Q 22.9% and V 32.0%, respectively).

Dupilumab significantly reduced asthma symptoms, as demonstrated by the significant increase in ACT score, which after 24 weeks of biological therapy reached and exceeded the threshold of 20, which expresses a satisfactory control of asthma symptoms, despite the baseline pre-treatment score stood at a rather low value of 14. This result confirms, in a real-life context, the data reported by the Liberty Asthma QUEST trial, in which the ACQ (Asthma Control Questionnaire) was utilized. However, compared to the ACQ test, the ACT questionnaire administered by us seems to be more appropriate to respond to the needs of practicality and easiness of completion wished by patients who refer to our severe asthma assessment centers. In fact, ACT is clearly preferred to ACQ in the few real-life studies that have recently evaluated the efficacy of dupilumab in the biological therapy of severe asthma (15–19).

In patients with both asthma and nasal polyposis, dupilumab elicited a significant improvement in the score of SNOT-22 questionnaire. In such a group of subjects, this result was associated with a complete prevention of the relapses of nasal polyposis. These findings corroborate in a real-life setting the efficacy of dupilumab in the treatment of CRSwNP, previously demonstrated by the Liberty NP trials SINUS-24 and SINUS-52 (14).

In addition to the clinical effects, the results of our study regarding the respiratory function are also of marked relevance. Indeed, after 6 months of therapy dupilumab significantly increased FEV₁, and also incremented FVC and FEF_25-75. These findings indicate that dupilumab can improve lung function by increasing airway patency from the central proximal sector to the distal periphery of the respiratory tree. The clinical and functional results of the present observational study strongly suggest that clinical remission was achieved by a relevant number of our patients. Although this very important therapeutic target should be evaluated after 12 months of continuous treatment, already after 6 months we noticed that 47.24% of our patients reached the criteria of clinical remission, including significant improvements in asthma exacerbations, OCS intake, symptom control and lung function (32, 33). Such a real-life observation further confirms that dupilumab is characterized by a very fast onset of its therapeutic action, as already shown by previous data referring to the short-term clinical, functional and biological effects of this monoclonal antibody (18, 36). However, a few weeks of observation do not allow to assess the effects of dupilumab on severe asthma exacerbations. Thus, we decided to prolong up to 6 months the last time point for evaluation of dupilumab efficacy. Indeed, this approach made it possible to appreciate the impressive reduction of asthma exacerbations induced by dupilumab.

With regard to the biomarkers of type 2 inflammation, dupilumab dramatically reduced the concentration of FeNO. This outcome is closely linked to the ability of dupilumab to antagonize at the receptor level the biological activities of IL-4 and IL-13, the latter being responsible for the induction of iNOS expression in the bronchial epithelium (37, 38). Indeed, it is reasonable that inhibition of iNOS-dependent FeNO production, induced by dupilumab in airway epithelial cells, leads to relevant decrements of FeNO levels. FeNO is a reliable indicator of type 2 inflammation, and FeNO levels correlate with asthma severity, deterioration of respiratory function, and risk of asthma exacerbations (39). Furthermore, FeNO represents a valuable aid in guiding the choice and monitoring of biological treatments for severe asthma, within the context of a personalized therapeutic approach, based on the treatable traits pertinent to specific inflammatory pheno-endotypes (40).

Hence, the efficacy of dupilumab in inhibiting the pathobiologic mechanisms underlying type 2 inflammation, strongly dependent on IL-4 and IL-13 actions, explains the extension of the therapeutic effects of this monoclonal antibody to both asthma and nasal polyposis in our patients. In fact, asthma and CRSwNP share common cellular and molecular pathogenic substrates (41), which outline a very good responsiveness to dupilumab. In our observational investigation, the add-on biological therapy with dupilumab provided similar patterns of efficacy in allergic and non-allergic patients, suffering from severe asthma and possibly also from nasal polyposis. Indeed, dupilumab induced overlapping clinical and functional effects in subjects characterized by positive or negative skin prick tests. This is probably due to the specific properties of the mechanism of action of dupilumab, which by blocking IL-4 and IL-13 receptors effectively intercepts the pathogenic pathways responsible for type 2 inflammation sustained by either allergic or non-allergic traits. In particular, by neutralizing the biological activities of IL-4 and IL-13, dupilumab inhibits the functions of the main cells producing these cytokines, including Th2 lymphocytes and type 2 innate lymphoid cells (ILC2) (42). In this way dupilumab interrupts the close interactions between innate immunity and acquired adaptive immunity, mediated by the intercellular crosstalk between ILC2 and Th2 cells, which underlies the development and progression of type 2 inflammation characterizing many cases of severe asthma and nasal polyposis, driven by either allergic or non-allergic events (41, 43, 44).

Another interesting aspect of our real-life study concerns the finding of a greater decrease in FeNO values ​​detected in allergic patients, compared to non-allergic ones. This result suggests that patients characterized by a higher expression of multiple endotypic traits referable to type 2 inflammation, respond to dupilumab treatment by experiencing a greater decrement in FeNO levels. On the other hand, IL-4 and IL-13 are intensely involved in the cellular pathophysiology of type 2 inflammation, which could imply an enhanced predisposition of allergic patients to dupilumab-induced FeNO reduction. Furthermore, we did not detect significant correlations between serum IgE levels and the clinical and functional effects of dupilumab, whose therapeutic activity does not appear to be affected by the presence or absence of an atopic state. In our case series, the clinical and functional effects of dupilumab also occurred without substantial differences among severe asthmatic patients who presented or did not manifest the comorbidity of nasal polyposis. However, compared to patients without nasal polyps, we observed a greater reduction in FeNO values ​​in subjects with severe asthma and concomitant nasal polyposis. This suggests that patients characterized by type 2 inflammation involving both upper and lower airways are more susceptible to the therapeutic action of dupilumab. Therefore, it is plausible to speculate that the coexistence of severe asthma and nasal polyposis could be associated with a higher expression of IL-4 and IL-13 in the airways of patients reporting both these diseases, who would therefore respond to dupilumab with a more relevant decrease in FeNO levels. Finally, our real-life evaluation shows an excellent tolerability and safety profile of dupilumab, which did not induce significant adverse events. Differently from what occurred in some individuals recruited in the Liberty Asthma QUEST and Liberty Asthma VENTURE trials, though not confirmed by the open label extension TRAVERSE study, no increases in blood levels of eosinophils were found in our patients. Based on the specific mechanism of action of dupilumab, it is thus possible to explain the lack of effects of this drug on the number of blood eosinophils, as we report. In fact, dupilumab acts as a highly efficient dual receptor antagonist of IL-4 and IL-13, but does not interfere with the biological activity of IL-5, which is the main cytokine responsible for the maturation, activation, proliferation and survival of eosinophils (45).

In conclusion, the present observational study confirms and expands, in the real-life of pulmonary clinical practice, the data reported by randomized controlled trials investigating the efficacy of dupilumab in the treatment of severe asthma. In particular, we herein show that after 6 months of treatment this biological therapy had a very positive impact on asthma exacerbations, OCS consumption, symptom control in both asthma and nasal polyposis, respiratory function and FeNO levels. Such findings have been recently extended up to one year by the results of other real-world clinical investigations (46–48). In addition, we also detected these therapeutic benefits in both allergic and non-allergic patients, as well as in asthmatics with or without nasal polyposis. Therefore, our results further consolidate the strategic position of dupilumab in its role as an excellent therapeutic option currently available within the context of modern biological treatments of severe asthma and CRSwNP, frequently driven by type 2 airway inflammation.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Local Ethics Committee of Calabria Region, Italy (Catanzaro, Italy; document n. 182 – 20 May 2021). The patients/participants provided their written informed consent to participate in this study.

All authors contributed to data analysis, drafting or revising the article, have agreed on the journal to which the article will be submitted, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.