Effectiveness of Dupilumab Treatment in Patients With Type 2 Inflammation: A Real-Life Integrated Experience

Abstract

Background

Type 2 inflammation plays a pivotal role in various allergic and inflammatory diseases, including chronic rhinosinusitis, asthma, atopic dermatitis, and eosinophilic esophagitis. Dupilumab is one of the emerging therapeutic targets that modulate the key mediators and cellular players involved in type 2 inflammation, aiming to improve the immune response and the quality of life of the patient.

Objective

Here, we describe the experience made on 792 patients enrolled by several specialists of a multidisciplinary team working on inflammatory type 2 diseases.

Design

Retrospective study.

Methods

Patients were treated with dupilumab according to the prescribed indications and were evaluated by several exams, tests, and questionnaires at baseline (T0) and after 12 (T1), 18 (T2), and 24 (T3) months.

Results

Overall, dupilumab exerts beneficial effects as demonstrated both by patients-reported outcomes and by objective assessments. Compared to baseline, all examined efficacy indicators showed an improvement after 12 months, with positive effects sustained through the 2 years of observation. Our results align with several previous trials.

Conclusion

Understanding the interconnection between different type 2 inflammatory diseases provides insight into potential avenues for precision medicine approaches and targeted therapies.

Introduction

In recent years, biologics have been extensively prescribed for the treatment of severe asthma to control exacerbations. These biologics target the type 2 inflammatory pathway. Some biologics are also authorized for therapeutic indications beyond asthma. Among these treatments, dupilumab could be used for chronic rhinosinusitis (CRS) with nasal polyposis, moderate-to-severe atopic dermatitis (AD), prurigo nodularis (PN), and eosinophil esophagitis.

Although the etiology of these diseases is multifactorial, growing evidence implicates type 2 inflammation as a central driver in their pathogenesis. ¹ Type 2 inflammation is characterized by the activation of T-helper 2 (Th2) cells and the release of cytokines such as interleukin (IL)-4, IL-5, and IL-13, leading to eosinophil recruitment, IgE production, and tissue remodeling. ²

Dupilumab (DUPIXENT^®, a registered trademark of Sanofi Biotechnology/^© 2022 Regeneron Pharmaceuticals, Inc./Sanofi-Aventis U.S. LLC) is a humanized monoclonal IgG₄ antibody that inhibits IL-4 and IL-13 signaling by specifically binding to the IL-4Rα subunit shared by the IL-4 and IL-13 receptor complexes. ³ It inhibits IL-4 signaling via the Type I receptor and both IL-4 and IL-13 signaling through the Type II receptor. Multiple cell types that express IL-4Rα (eg, mast cells, eosinophils, macrophages, lymphocytes, epithelial cells, goblet cells) and inflammatory mediators such as histamine, eicosanoids, leukotrienes, cytokines, and chemokines are involved in inflammation. Dupilumab inhibits IL-4 and IL-13 cytokine-induced inflammatory responses, blocking IL-4Rα, including the release of pro-inflammatory cytokines, chemokines, nitric oxide, and IgE. Inflammation driven by IL-4 and IL-13 is crucial in the pathogenesis of asthma, CRS with nasal polyposis, AD, PN, and eosinophilic esophagitis (EE), and these diseases often coexist in the same patient. ⁴

According to AIFA (Agenzia Italiana del Farmaco), ⁵ in Italy, Dupilumab is indicated for the following conditions:

1. Asthma, as an add-on maintenance treatment for adult and pediatric patients aged 6 years and older with moderate-to-severe asthma characterized by an eosinophilic phenotype (increased eosinophilia and/or increased Fractional Exhaled Nitric Oxide [FeNO]) or poorly controlled with a high dose of inhaled corticosteroids (ICS) plus another maintenance medication.

2. Chronic rhinosinusitis with nasal polyposis (CRSwNP), as an add-on maintenance treatment to intranasal corticosteroids in adult patients with inadequately controlled severe CRS with nasal polyposis. Dupilumab is the first biologic available for nasal polyp treatment.

3. Atopic dermatitis, for the treatment of adult and pediatric patients aged 6 year and older with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Dupilumab can be used with or without topical corticosteroids.

4. Prurigo nodularis, for the treatment of adult patients with PN.

5. Eosinophilic esophagitis, for the treatment of adult and pediatric patients aged 12 years and older, weighing at least 40 kg, with EE.

Dupilumab, by focusing on the treatment of the underlying type 2 inflammation, allows for a holistic approach to the patient and their comorbidities, as the same pathogenesis is involved. ⁶

The aim of the study was to evaluate the effectiveness of dupilumab treatment in a cohort of patients affected by one or more of the abovementioned “type 2-related diseases” who were regularly followed-up for a total of 24 months at the “Type 2-disease center,” a multidisciplinary study group at the Fondazione IRCCS Policlinico in Milan, Italy.

Patients and Methods

This is a nonprofit, real-life, single-center, retrospective observational study that includes patients referred to Ospedale Policlinico in Milan, Italy, from July 2021 to July 2023. The study involves a multidisciplinary team managing patients affected by type 2 inflammation diseases. The team includes pulmonologists, immunoallergologists, otolaryngologists, dermatologists, gastroenterologists, and ophthalmologists, all collaborating together, though not all at the same time. A statistician is involved in the collection and processing of data.

The study was performed in accordance with the Declaration of Helsinki and is part of a larger project evaluating the effectiveness and safety of Dupilumab treatment. The project has been approved by the Ethics Committee of “Milano Area 2” (protocol n° 0003629) for including patients as potential candidates for dupilumab treatment.

The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology statement (Supplementary file). ⁵

Inclusion criteria: Patients aged 18 years or older, affected by one or more type-2-related diseases according to the AIFA criteria ⁶ for dupilumab prescription.

Exclusion criteria were: patients refusing biologic treatment, those with known or suspected immune defects and/or autoimmune diseases, patients younger than 18 years old, individuals with known allergy to dupilumab or its excipients, pregnant women and patients refusing to undergo the full follow-up.

Dupilumab is administered via subcutaneous injection at varying dosages depending on the primary indication:

• Asthma (adult patients): An initial loading dose of 400 mg, followed by 200 mg every 2 weeks or a higher dose with an initial loading dose 600 mg, followed by 300 mg every 2 weeks for patients with comorbid moderate-to-severe AD or severe CRSwNP.

• Chronic rhinosinusitis with nasal polyposis: The recommended dosage for adult patients is 300 mg given every other week.

• Atopic dermatitis: The recommended dosage for adults is an initial dose of 600 mg (or 400 mg for patients weighing <60 kg), followed by 300 mg (or 200 mg for patients weighing <60 kg) every other week.

The first medical visit should be conducted by the specialist whose disease is prominent in the clinical presentation. However, the patient will also consult other specialists depending on their main symptoms, such as pulmonologist for shortness of breath, an otolaryngologists for nasal blockage, or a dermatologist for prurigo and/or skin manifestations. The predominant disorder is considered the “driver-disease” of type 2 inflammation, which determines the patient's inclusion in the multidisciplinary treatment pathway. Figure 1 illustrates the functioning of the multidisciplinary team.

Figure 1.

The diagram shows how the “type-2 disease center” works and collaborates in a multidisciplinary way.

During the initial evaluation (baseline, T0), the specialist must identify the patient's predominant disease and administer a series of questionnaires to evaluate “red flags” that may indicate other type 2 comorbidities and the need for further specialized evaluation. ⁷

Each specialist will assess the severity, quality of life (QoL), disease trend, and treatment response. The first specialist to evaluate the patient will request the following blood tests: eosinophils count, lymphocyte subpopulations (T, B, NK cells), liver enzymes; serum protein, serum creatinine, C-reactive protein (CRP), serum IgA, IgG, IgM, IgE levels, and eosinophil cationic protein serum level (ECP). These tests are essential for the patient's endotyping. Follow-up visits were scheduled at 12 (T1), 18 (T2), and 24 (T3) months after T0.

All patients have been enrolled in the study after signing an informed consent.

ENT Evaluations

All historical data regarding the first appearance of nasal symptoms, previous ENT evaluations, surgeries, and prescribed therapies, as well as their effects on symptom control were collected for each patient. At the time of the first visit (T0), patients underwent wide-screening blood tests, a complete urine test, and nasal cytology. The initial blood tests included a complete blood count with formula, lymphocyte subpopulation analysis, eosinophils count, liver enzymes, serum proteins, serum creatinine, CRP, serum IgA, IgG, IgM, IgE levels, serum perinuclear antineutrophil cytoplasmatic antibodies, extractable nuclear antigens, creatine phosphokinase serum level, and ECP serum level. These results helped in identifying the patient's underlying clinical endotype and making a differential diagnosis, distinguishing other immunological and autoimmune diseases, primary immunodeficiencies, and IgG₄-related diseases. Blood tests, including IgE levels and eosinophil counts, were performed at baseline, after 12 months, 18 months, and 24 months.

All patients underwent a physical examination at baseline and during scheduled visits, including fiberoptic nasal endoscopy using a rhinolaryngoscope (Olympus ENF rhinolaryngo-fiberscope type GP; 33 cm in length, 3.4 mm in diameter; Olympus Medical System Corporation). The endoscopy assessed the Bilateral Endoscopic Nasal Polyp Score (NPS) according to EPOS 2023. ⁸ The endoscopic scores were determined by the sum of scores for each nostril, as follows: score 0: no polyps; score 1: small polyps in the middle meatus not reaching below the inferior border of the middle concha; score 2: polyps reaching below the lower border of the middle turbinate; score 3: large polyps reaching the lower border of the inferior turbinate or polyps medial to the middle concha; and score 4: large polyps causing almost complete congestion/nasal obstruction of the inferior meatus. Additionally, nasal endoscopy focused on evaluating the patency of surgical sinusotomies, as well as the presence of mucosal edema, crusting, and mucinous secretions, according to Lund-Kennedy classification. ⁹

All the patients underwent a maxillofacial computed tomography (CT) scan, to evaluate the extent of previous surgery (graded based on the ACCESS score), ¹⁰ inflammatory involvement of the paranasal sinuses and ostiomeatal complex (graded according to the Lund-McKay classification), ¹¹ and the presence of possible iatrogenic sequelae.

ENT evaluations were complemented by a series of questionnaires submitted to patients during each visit:

• Sino-Nasal Outcome Test (SNOT-22): A validated 22-item questionnaire assessing the impact of CRSwNP on HRQoL. ¹² It uses a 6-point scale to assess 22 symptoms and the social or emotional consequences of CRSwNP. The score ranges from 0 to 110, with lower scores indicating less impact. A score higher than 40 is associated with a compromised QoL.

• Nasal Congestion Score (NCS): A self-evaluation of symptoms of congestion symptoms rated from 0 (“absent”) to 3 (“severe”).

• Visual Analog Scale (VAS): Used to assess the severity of the main nasal symptoms, including smell impairment. Scores are categorized as mild impairment (VAS 0-3), moderate impairment (VAS >3-7), and severe impairment (VAS >7-10).

• Sniffin’ Sticks test: A test to evaluate smell impairment. The Identification test was used for this purpose (Burghardt^®).

The efficacy of treatment was assessed by a change of at least 3 points in the NPS and a change of at least 36 points in the SNOT-22 score, as indicative of good response to treatment. ¹³

Dermatological Evaluations

The dermatologist performs a comprehensive clinical evaluation and prescribes the necessary tests, including blood chemistry tests, patch tests, biopsies for histological exams, and cultural exams. The results of these tests help confirm the diagnosis of AD and assist in differentiating it from other conditions, such as lymphoproliferative disorders, contact dermatitis, psoriasis, and fungal or bacterial infections.

Once the diagnosis of AD is confirmed, a series of questions (referred to as “red flags”) are asked to assess the presence of other type 2 comorbidities. If needed, referrals to other specialists are scheduled for further evaluation. Dermatologists also recommend an ophthalmological evaluation at the start of treatment to assess the entire ocular surface, as patients with AD often present with ocular surface disorders, including atopic keratoconjunctivitis. Addressing these conditions early can help prevent the development of dupilumab-induced conjunctivitis, one of the most common side effects of dupilumab therapy. If the patient has additional comorbidities, they are referred to the appropriate specialist for further management. Follow-up visits are scheduled at 4 months, 12 months, and subsequently every 6 months following the initiation of biological therapy.

To assess the severity of AD, several tests are submitted to patients, including the Eczema Area and Severity Index (EASI), ¹⁴ the Dermatology Life Quality Index (DLQI), ¹⁵ the Itch Numerical Rating Scale (I-NRS), and the Sleep Quality Numeric Rating Scale (SQ-NRS). The EASI scores, which assess the severity and extent of the erythema, induration, papulation, edema, excoriation, and lichenification, range from 0 to 72, with higher scores indicating greater severity and extent of AD. The DLQI score ranges from 0 to 30, and an improvement in ≥4 points from baseline is considered the minimal clinically important difference. The I-NRS score, based on symptoms during the past 7 days, ranges from 0 to 10, while the SQ-NRS scores ranges from 0 to 10, with higher scores indicating greater impact on sleep disturbances. These follow-up tests are performed at each visit.

Approved topical treatments are allowed as needed. If topical therapy is initiated, subsequent check-ups are scheduled every 4 months (3 visits per year). If systemic biological therapy with dupilumab is prescribed, a clinical and photographic evaluation is performed at 1 month, and then every 4 months thereafter. To better monitor treatment effects (especially the development of eosinophilia, a potential side effect), a restricted panel of blood tests is recommended at baseline and at 1, 4, 8, and 12 months after the start of treatment. This panel includes a complete blood count with formula, ECP, and total IgE. For patients receiving systemic immunosuppressive therapy, follow-ups after the first month are scheduled every 3 months. Normal values for total IgE are considered to be <100 KU/L, and the normal peripheral blood eosinophil count is <500/mm³.

Pneumology Evaluations

The pulmonologist performs a comprehensive clinical evaluation and prescribes the necessary tests, including blood chemistry tests (complete blood count with formula, ECP, and total IgE), spirometry with DLCO measurement, and a bronchodilation test. If the spirometry results are within normal limits, a bronchoprovocative challenge with methacholine is carried out. Additionally, a chest x-ray or thoracic CT scan is performed, and FeNO is measured. The results of these tests help confirm the diagnosis of asthma, differentiate it from other conditions, and assess the presence of Type 2 inflammation in asthma.^16–18

Once asthma is diagnosed, a series of questions (referred to as “red flags”) are asked to assess the presence of other type 2 comorbidities. If necessary, referrals to appropriate specialists are scheduled for further evaluation.

Based on tests results and symptoms, the pulmonologist prescribes inhaled therapy, typically a combination of ICS and a bronchodilator (LABA). In cases where additional management is needed, inhaled tiotropium may be prescribed.

The Asthma Control Test (ACT) (score range: 0-25) ¹⁹ is administered at each visit to assess the level of asthma control. A score ≥20 indicates good disease control, and if necessary, treatment adjustments are made (step-up or step-down of therapy). Clinical response is defined as an improvement in FEV₁ of at least 15% and FeNO reduction of 20% or more, indicating a positive treatment response.

Exacerbations, hospitalization rates, oral corticosteroids (OCS) use, FEV₁, and forced vital capacity are evaluated at each visit. Asthma exacerbation is defined as requiring the use of oral corticosteroids for at least 3 days, hospitalization, or an emergency room visit. ²⁰

Immuno-Allergology Evaluations

The first step in the allergist's evaluation is a complete medical history and physical examination. Based on the information collected, the allergist prescribes skin prick tests to confirm sensitization to inhalant, food, and/or occupational allergens. If necessary, additional tests such as serum total IgE, specific IgE, and IgE to recombinant proteins are performed. Blood tests, including a complete blood cells count, ECP, and FeNO levels, are also evaluated. Patients with suspected asthma undergo pulmonary function tests including spirometry and a reversibility test with a bronchodilator. If needed, a nonspecific bronchial challenge with methacholine is performed. The results of these tests help confirm the diagnosis of allergic asthma and/or rhinoconjunctivitis according to international guidelines and assist in defining the patient's endotype. The ACT ¹⁹ (for asthmatic patients) and the SNOT-22 ¹² questionnaire (for patients with rhinosinusitis, with or without nasal polyps) are administered as part of the evaluation.

Once the diagnosis of allergic rhinoconjunctivitis and/or asthma is confirmed, a series of “red flags” questions are used to assess the presence of other type 2 comorbidities. If necessary, the patient is referred to other specialists for further evaluation.

For patients with severe asthma and/or severe CRSwNP, dupilumab treatment is proposed if not already initiated. Prior to starting dupilumab therapy, all patients are referred for an ophthalmologic evaluation to assess the entire ocular surface.

Patients receiving dupilumab treatment are reevaluated at 1 month, 4 months, 8 months, and 12 months to assess the treatment's effectiveness and tolerability. For this study, we evaluated data collected after 12, 18, and 24 months of therapy. During each follow-up examination, the following tests are performed: serum total IgE, blood cells count, FeNO levels, pulmonary function testing, and the ACT and/or SNOT-22 questionnaries, as appropriate.

Statistical Analysis

Demographic and clinical characteristics of participants were described by means with SDs for normally distributed continuous data or as absolute frequency and percentages for categorical data. Differences from means were tested by analysis of variance. Statistical significance was estimated for P < .05. Statistical analysis was performed using R software.

Results

A total of 792 patients were enrolled: 45 by the otolaryngologists, 661 by dermatologists, 21 by pulmonologists, and 65 by immuno-allergologists.

ENT Evaluations

A total of 45 patients with CRSwNP from the Otorhinolaryngology Unit were enrolled in the study. Throughout the study, 7 patients were lost to follow-up: 2 patients withdrew voluntarily, 2 patients discontinued due to treatment ineffectiveness, and 3 patients dropped out due to adverse effects (1 due to hypereosinophilia and 2 due to arthralgia, synovitis, and tendinopathy).

The primary demographic and clinical characteristics of the patients are summarized in Table 1.

Table 1.

Demographics of the Patients With CRSwNP.

Demographic data of ENT population
Total patients (n, %)	45
Males (n, %)	28 (62.2%)
Age (mean ± SD)	54.9 ± 12.5
Previous surgery (n, %)	41 (91.1%)
Number of surgeries (mean ± SD)	1.8 ± 1.2
T2 comorbidities (n, %)	35 (77.8%)
AD	7 (17.1%)
Asthma	24 (58.5%)
Allergy	24 (58.5%)
EE	0 (0%)

Abbreviations: AD, atopic dermatitis; CRSwNP, chronic rhinosinusitis with nasal polyposis; EE, eosinophilic esophagitis.

Of the 45 patients, 41 (91%) had previously undergone surgery for nasal polyposis. During the observation period, only one patient (2.2%) required additional surgery.

Efficacy indicators examined by the ENT specialists showed sustained improvement after 12 months (T1), and these beneficial effects were maintained at 18 and 24 months (T2 and T3, respectively) (Table 2). A comparison of QoL scores between baseline (T0) and 24 months (T3) revealed substantial improvements. Specifically, the SNOT-22 score, which measures the impact of CRSwNP on health-related QoL, decreased from a baseline mean score of 56.8 ± 19.4 to 20.1 ± 19.2 at T3 (P < .001). Similarly, the NPS showed a significant reduction, from a baseline mean score of 5.7 ± 1.5 to 0.3 ± 0.7 at T3 (P < .001). The NCS also decreased significantly, from 2.4 ± 0.7 at baseline to 0.2 ± 0.5 at T3 (P < .001). Visual Analog Scale for smell impairment decreased from 8.8 ± 2.2 at baseline to 1.8 ± 2.9 at T3 (P < .001). In addition, the Sniffin’ Stick tests, which evaluates olfactory function, showed a significant improvement, with scores increasing from 4.5 ± 2.4 at T0 to 6.5 ± 0.5 at T3 (P = .001). Peripheral blood eosinophils count showed a significant reduction over time (P = .02), with values decreasing from 0.5 ± 0.2 × 10³/µL at T0 to 0.3 ± 0.2 × 10³/µL at T3. Similarly, serum IgE levels decreased significantly, with the most substantial change occurring between T0 and T1 (P = .03).

Table 2.

Main Results of the ENT Patients (Mean ± SD).

	Baseline	12 months	18 months	24 months
SNOT-22 (22-item sino-nasal outcome test 0-110)	56.8 ± 19.4	19.5 ± 16.9	19.3 ± 16.7	20.1 ± 19.2
NPS (Nasal Polyp Score 0-8)	5.7 ± 1.5	0.9 ± 1.7	0.3 ± 0.5	0.3 ± 0.7
NCS (Nasal Congestion Score 0-3)	2.4 ± 0.7	0.4 ± 0.6	0.3 ± 0.5	0.2 ± 0.5
VAS smelling (Visual Analog Score 0-10)	8.8 ± 2.2	1.8 ± 2.5	1.9 ± 3	1.8 ± 2.9
Sniffin’ Sticks test® Identification score (0-16)	4.5 ± 2.4	6.1 ± 1.9	6.7 ± 2	6.5 ± 0.5
Eosinophils (×103/µL)	0.5 ± 0.2	0.8 ± 0.8	0.6 ± 0.4	0.3 ± 0.2
IgE level (UI/mL)	359.3 ± 682	42.8 ± 37.4	53.6 ± 30.5	19.1 ± 16.5

Abbreviation: VAS, Visual Analog Scale.

Dermatology Evaluations

A total of 661 patients from the Dermatology Unit participated in the study.

During the course of study, 232 patients dropped out for the following reasons: treatment uneffectiveness (19 patients) and occurrence of side effects (213 patients). The reported side effects included: conjunctivitis: 91 patients (13.8%); hypereosinophilia: 56 patients (8.5%); facial redness: 54 (8.2%); synovitis/arthritis/tendinopathy: 5 patients (0.7%); psoriasis: 5 patients (0.7%); and headache: 2 patients (0.3%).

The primary demographic and clinical characteristics of the patients are summarized in Table 3.

Table 3.

Distribution of T2 Comorbidities in Patients with AD.

Demographic data of dermatology population
Total patients (n, %)	661
Males (n, %)	352 (53.2%)
Age (mean ± SD)	38 ± 10.6
Previous treatment with cyclosporine (n, %)	508 (76.8%)
More than one immunosuppressant (n, %)	44 (6.6%)
T2 comorbidities (n, %)	484 (73.2%)
CRSwNP	12 (1.8%)
Asthma	263 (39.8%)
Allergy	457 (69.1%)
EE	3 (0.4%)

Abbreviations: AD, atopic dermatitis; CRSwNP, chronic rhinosinusitis with nasal polyposis; EE, eosinophilic esophagitis.

Over the 2 years of treatment with dupilumab, significant improvement was observed in patients’ dermatological conditions. After 24 months of treatment, notable improvements in all rating scale scores were recorded (Table 4). The EASI score decreased significantly, from a baseline mean of 23.4 ± 10.9 to 2.5 ± 4.2 at 12 months (T1) and remained low at 1.8 ± 3.9 at 24 months (T3) (P < .001). Both the I-NRS and SQ-NRS also showed significant reductions over time (P < .001). The DLQI score demonstrated a substantial improvement, indicating enhanced QoL, decreasing from 15.3 ± 10.8 at baseline (T0) to 2.7 ± 3.1 at 24 months (T3) (P < .001). Additionally, serum total IgE levels decreased significantly from 308.6 ± 482 UI/mL at baseline to 69.2 ± 71.3 UI/mL at 24 months (P < .001). There were also significant differences from baseline in the mean total blood eosinophil count at 24 months (P < .001).

Table 4.

Main Results in Patients With AD (Mean ± SD).

	Baseline	12 months	18 months	24 months
EASI (Eczema Area and Severity Index)	23.4 ± 10.9	2.5 ± 4.2	1.9 ± 4.1	1.8 ± 3.9
I-NRS (Itch numerical rating scale	8.5 ± 3.1	2.9 ± 3.3	2.6 ± 3.5	2.5 ± 4
SQ-NRS (Sleep Quality Numeric Rating Scale)	6.6 ± 4.1	0.9 ± 0.8	0.7 ± 0.9	0.6 ± 0.6
DLQI (Dermatology Life Quality Index)	15.3 ± 10.8	3.5 ± 4.5	3.2 ± 3.8	2.7 ± 3.1
Eosinophils (×103/µL)	0.5 ± 0.4	0.5 ± 0.3	0.4 ± 0.3	0.3 ± 0.2
IgE level (UI/mL)	308.6 ± 482	99 ± 84.5	87.1 ± 66.7	69.2 ± 71.3

Abbreviations: AD, atopic dermatitis; I-NRS, Itch Numerical Rating Scale.

Pneumology Evaluations

A total of 21 patients with severe asthma were enrolled in the study. The primary demographic and clinical characteristics of the patients are summarized in Table 5.

Table 5.

Demographic Data of Patients With Asthma.

Demographic data of pneumology population
Patients (n, %)	21
Males (n, %)	8 (38.1%)
Age (mean ± SD)	53.4 ± 11.3
Rescue inhalatory therapy/week (n, %)	8 (38.1%)
BMI ≥ 30 (n, %)	2 (9.5%)
Smokers/ex-smokers (n, %)	10 (47.6%)
Occupational exposure (n, %)	3 (14.3%)
Previous biological therapy (n, %)	8 (38.1%)
T2 comorbidities	13 (61.9%)
CRSwNP	11 (52.3%)
AD	1 (4.8%)
Allergy	11 (52.4%)
ABPA	0 (0%)
Non-T2 comorbidities (n, %)	19 (90.5%)
Bronchiectasis (n, %)	8 (38.1%)
ILD (n, %)	3 (14.3%)
GERD (n, %)	7 (33.3%)

Abbreviations: AD, atopic dermatitis; CRSwNP, chronic rhinosinusitis with nasal polyposis.

During the course of study, one patient discontinued the treatment due to ineffectiveness.

At T3, the majority of patients (80.9%) exhibited controlled asthma (Table 6). The ACT score showed significant improvement, increasing from a mean of 18.3 ± 4.2 at baseline to 24.3 ± 3.1 at T3 (P < .001). This clinical improvement was further supported by a reduction in FeNO levels, which decreased from 42.7 ± 26.4 ppb at baseline to 18.5 ± 8.9 ppb at T3 (P = .009).

Table 6.

Main Results From Patients With Asthma (Mean ± SD).

	Baseline	12 months	18 months	24 months
ACT (score 0-25)	18.3 ± 4.2	23.1 ± 3.8	23.8 ± 2.5	24.3 ± 3.1
FENO (ppb)	42.7 ± 26.4	25.9 ± 16.3	20.6 ± 15.8	18.5 ± 8.9
FEV1 (% of the predicted value)	70.8 ± 41.7	77 ± 38.9	89 ± 32.4	93 ± 34.3
Need for OCS courses (n)	2 ± 0.8	0.3 ± 0.5	0.4 ± 0.5	0.3 ± 0.5
Exacerbations per year (n)	1 ± 0.7	0.5 ± 0.9	0.1 ± 0.4	0 ± 0
Eosinophils (×103/µL)	0.7 ± 0.4	0.8 ± 0.8	0.6 ± 0.7	0.6 ± 0.8
IgE level (UI/mL)	282.6 ± 136.5	167.5 ± 102.4	146.8 ± 99.6	128.4 ± 84.7

Abbreviation: ACT, Asthma Control Test.

There was also a reduction in airflow limitation, as measured by the predicted FEV₁: the mean FEV₁ improved from 70.8 ± 41.7% at T0 to 93 ± 34.3% at T3. However, this change did not reach statistical significance (P = .25).

A notable decrease in the number of asthma exacerbations was observed, with the average number of exacerbations dropping from 1.05 ± 0.7 at baseline to 0 ± 0 at T3 (P = .002).

Additionally, OCS intake was significantly reduced, from a mean of 2 ± 0.8 at baseline to 0.3 ± 0.5 at T3 (P < .001).

There was no significant change in eosinophil count over time (P = .85). However, serum IgE levels decreased significantly from baseline, with a reduction from 282.6 ± 136.5 UI/mL at T0 to 128.4 ± 84.7 UI/mL at T3 (P = .002).

Immuno-Allergology Evaluations

A total of 65 patients were enrolled for dupilumab treatment. Three patients dropped out during the study: 2 due to ineffectiveness of the treatment and one due to the appearance of side effects (synovitis–arthritis–tendinopathy).

The primary demographic and clinical characteristics of the included patients are summarized in Table 7.

Table 7.

Demographic Data of Patients From Immuno-Allergology.

Demographic data of allergology population
Patients (n, %)	65
Males (n, %)	41 (63%)
Age (mean ± SD)	39.6 ± 15.2
Allergic rhinoconjunctivitis (n, %)	60 (92%)
Inhaled allergy (n, %)	62 (95.4%)
Food allergy (n, %)	30 (46%)
T2 comorbidities (n, %)	64 (98%)
CRSwNP (n, %)	5 (8%)
AD (n, %)	63 (97%)
Asthma	65 (100%)
Uncontrolled asthma	19 (29%)
EE	1 (1.5%)

Abbreviations: AD, atopic dermatitis; CRSwNP, chronic rhinosinusitis with nasal polyposis; EE, eosinophilic esophagitis.

Type 2 immune comorbidities were common. Among these were asthma (100%), allergic rhinocongiuntivitis (92%), AD (97%), food allergy (46%), CRSwNP (9%), and EE (1.5%). Sensitization to at least one inhalant allergen was observed in 95.4% of patients.

Table 8 shows the main outcomes at each timepoint. When comparing ACT scores at T0 and T3, a significant increase was observed: 20.4 ± 3.1 versus 23.9 ± 1.7 (P < .001); SNOT-22 scores also showed significant improvement as early as T1 compared to baseline: 18.6 ± 8.2 versus 57.5 ± 3.5 (P < .001) with a low score maintained over time: 5 ± 0.3 at T3 in comparison to T0 (P < .001). Similarly, the mean FeNO value decreased from 38.7 ± 29.1 ppb at T0 to 10 ± 1.9 ppb at T3 (P < .001). FEV₁ improved significantly from T0 to T1, increasing from 93.9 ± 15.1 to 102.3 ± 14.8% of the predicted value (P < .001). In parallel with clinical improvements, serum total IgE levels significantly decreased over the time (P = .01). However, eosinophil count at T3 were comparable to those at T0 (P = .34).

Table 8.

Main Results in Patients of Immuno-Allergology (Mean ± SD).

	Baseline	12 months	18 months	24 months
Asthma Control Test (ACT)	20.4 ± 3.1	23.6 ± 1.2	24 ± 1.2	23.9 ± 1.7
SNOT-22	57.5 ± 3.5	18.6 ± 8.2	7 ± 2.8	5 ± 0.3
FeNO (ppb)	38.7 ± 29.1	12.5 ± 3.5	10.7 ± 1.5	10 ± 1.9
FEV1 (% of the predicted value)	93.9 ± 15.1	102.3 ± 14.8	91.9 ± 11.9	89 ± 14.7
Eosinophils (×103/µL)	0.6 ± 0.4	0.6 ± 0.5	0.5 ± 0.4	0.5 ± 0.4
IgE level (UI/mL)	517.9 ± 930.4	200.7 ± 312.8	212.4 ± 338.2	118.7 ± 166.4

Abbreviation: FeNO, Fractional Exhaled Nitric Oxide.

Discussion

The use of biologics for the treatment of several inflammatory Th2-type diseases requires precise endophenotyping of patient, necessitating immunotyping, and monitoring of specific parameters. ²¹

This study presents our experience at a “Centre of Excellence for Type 2 Inflammation,” a multidisciplinary group reporting outcomes from specialists employing biologic therapy with dupilumab.

Symptoms associated with CRSwNP, asthma, and AD negatively impact the QoL in patients, particularly those with severe disease. In our study, dupilumab demonstrated beneficial effects, as evidenced by both patients-reported outcomes and objective assessments.

Our real-life experience aligns with results from prior controlled trials. The efficacy of dupilumab in severe asthma was first observed in studies by Wenzel et al.^22,23 Subsequent research^24–26 highlighted improvements in asthma symptoms and FEV₁, particularly in patients with blood eosinophils count ≥300 cell/μL or higher doses of OCS. These studies also noted improvement in QoL, reduction in asthma exacerbations, and decreases in FeNO and serum IgE levels, without changes in blood eosinophils levels. Moreover, a study on 38 severe asthmatic patients switched to dupilumab from other biologics reported enhanced asthma control, improved lung function, reduced exacerbations, and lower FeNO and IgE levels. ²⁷

In our study, we observed significant optimization and stabilization of lung function in most asthmatic patients. OCS requirements decreased, ACT scores improved over time, and both SNOT22 and FeNO scores were significantly lowered, indicating clinical remission. Biological remission was also evident, as IgE levels decreased, although eosinophil counts remained unchanged.

Dupilumab also showed high efficacy in CRSwNP. The phase 3 SINUS-24 (NCT02912468) and SINUS-52 (NCT02898454) trials^28,29 demonstrated that dupilumab added to intranasal corticosteroids significantly improved patient-reported symptoms and objective outcomes versus placebo.

Several multicenter real-life studies have later confirmed the findings observed in randomized controlled trials. In patients with both CRSwNP and asthma, dupilumab improved clinical outcome for both conditions.^30,31

A large real-life study (DUPIREAL) ³² found that dupilumab (300 mg subcutaneously every 2 weeks) reduced symptom severity, nasal congestion, and polyps size, while SNOT-22 scores decreased regardless of asthma comorbidity. Olfactory function, assessed by Sniffin’ Sticks tests and subjective smell VAS scores, also improved.

Treatment with dupilumab in poorly controlled CRSwNP patients significantly improved radiological outcomes, such as sinus opacification, in addition to reducing endoscopic and clinical disease severity. ³³ In a comparative study evaluating outcomes of dupilumab versus endoscopic sinus surgery for the treatment of severe CRSwNP patients, both treatments were effective in improving QoL and symptoms. However, patients treated with dupilumab demonstrated greater improvements in SNOT-22 and Sniffin’ Stick test scores, better control of local inflammation as detected by nasal cytology, and reduced intake of oral corticosteroids. ³⁴

Regarding moderate-to-severe AD, 3 major placebo-controlled trials^35–37 reported significant improvements in disease outcomes after 16 weeks of dupilumab treatment, either as monotherapy ³⁵ or with topical corticosteroids.^36,37 An Italian multicenter retrospective study ³⁸ of 543 adult AD patients confirmed significant improvements in EASI score, pruritus, sleep, and QoL at 16 weeks, with 98% of patients achieving clinically relevant improvement in at least one key domain of AD.

In our study, a substantial number of AD patients demonstrated significant improvements in dermatologic outcomes, as indicated by amelioration across all rating scale scores after 24 months of treatment.

Overall, our data demonstrate that dupilumab provides sustained improvement across multiple endpoints for up to 2 years in various coexisting type 2 inflammatory diseases. These findings suggest that dupilumab may change the natural history of these conditions.

Conclusion

This study reports real-life outcomes of dupilumab across a range of setting. Our findings confirm its effectiveness in improving QoL in patients with asthma, CRSwNP, and AD.

The study's primary limitation is its retrospective design and the absence of measurements for additional biomarkers, such as IL-4 and IL-13. However, its strength lies in the inclusion of a large patient sample, treated with dupilumab and followed by multiple specialists over 2 years.

Type 2 inflammation plays a central role in the pathogenesis of CRSwNP, asthma, AD, and EE. Targeting the key cytokines and mediators of type 2 inflammation has revolutionized disease management, offering new hope for patients with refractory symptoms. Further research into the mechanisms underlying type 2 inflammation and the development of novel therapies is warranted to improve clinical outcomes and QoL for affected individuals.