INTRODUCTION
The worldwide prevalence of allergic diseases poses a major health problem nowadays. Allergic diseases constitute a health and social problem but also reduce the patient’s quality of life. Allergic diseases are typically associated with diverse symptoms and exert an impact on different body tissues. However, a body of evidence suggests that hyperactivity of T2 immune response is a hallmark feature in the pathogenesis common to all allergic diseases. The scientific research proved that interleukin 4 (IL-4) and interleukin 13 (IL-13) play a prominent role in the pathogenesis of allergic diseases e.g. atopic dermatitis (AD), asthma, chronic rhinosinusitis with nasal polyps, prurigo nodularis, eosinophilic esophagitis and chronic obstructive pulmonary disease (COPD). IL-4 or IL-13 binds to its receptor and activates a tyrosine kinase proteins Janus kinase 1 (JAK1) and a tyrosine kinase 2 (TYK2). The activation of JAK kinases triggers phosphorylation cascade of the cytoplasmic domain of the IL-4R, which induces the activation of signaling proteins and transcription activators known as STAT proteins. STAT proteins activate or inhibit transcription pathway which they regulate. The activation of these pathway by IL-4 induces B cell class switching to IgE [1, 2].
There is a core need for investigating novel treatment targeting T2 immune response in the realm of allergic diseases because immune dysregulation hampers the overall control of disease. There is a wide range of biological drugs targeting interleukin receptors investigated in the allergic diseases. One of biological drugs, dupilumab, is a promising treatment option for severe forms of allergic diseases. Dupilumab is a humanized, IgG4 monoclonal antibody which binds to the α subunit of interleukin 4 receptor (IL-4R) and interleukin 13 receptor (IL-13R) common to both IL-4 (type 1 receptor) and IL-4/IL-13 receptor (type 2 receptor) complexes. Dupilumab acts as an antagonist, thereby it inhibits the JAK-STAT signaling pathways induced by these cytokines and decreases the number of type 2 inflammatory mediators [3]. Dupilumab is registered by the U.S. Food and Drug Administration (FDA) for the treatment of asthma, moderate-to-severe atopic dermatitis and chronic rhinosinusitis with nasal polyps and eosinophilic esophagitis. The aim of this literature review is to present the current state of knowledge about the therapeutic indications of dupilumab and associated therapeutic consequences. Moreover, we endeavor to elucidate the clinical effectiveness of dupilumab in allergic diseases.
THE ROLE AND APPLICATION OF DUPILUMAB IN ATOPIC DERMATITIS
Dupilumab was registered by the FDA in April 2017 for the treatment of moderate-to-severe AD inadequately controlled with topical corticosteroids for patients aged above 12 years and in the European Union it is registered for patients with moderate-to-severe AD qualified for systemic treatment. Moreover, the European Medicines Agency (EMA) approved dupilumab for the treatment of severe atopic dermatitis in children aged 6 months to 5 years qualified for systemic treatment. Dupilumab is administered subcutaneously at an initial dose of 600 mg and then 300 mg every 2 weeks as a treatment in AD.
The phase 3 randomized clinical trials LIBERTY SOLO 1 and LIBERTY SOLO 2 elucidated the effect of dupilumab monotherapy administered at a dose of 300 mg once a week and 300 mg every 2 weeks for patients with moderate/severe AD. Both studies revealed that dupilumab alleviates AD outcome assessed by diagnostic scales mainly the Eczema Area and Severity Index (EASI) and the Investigator’s Global Assessment (IGA). Moreover, dupilumab decreased the frequency of AD exacerbations and improved the patient’s quality of life assessed by the Dermatology Life Quality Index (DLQI). Dupilumab markedly reduced pruritus within 1–3 days of treatment initiation measured by pruritus rating scales. Furthermore, non-herpetic skin infections were observed less frequently during dupilumab treatment [4].
The novel research also acknowledged the effect of dupilumab on the skin lesions in AD patients also at the molecular level. The recent studies proved that dupilumab caused a decline in transepidermal water loss in skin lesions and improved the hydrolipid skin barrier in patients with moderate and severe atopic dermatitis after 8 weeks of dupilumab treatment. Dupilumab altered lipid content in the skin hydrolipid barrier and concurrently increased the level of esterified omega-hydroxy fatty acid-containing ceramides and decreased levels of ceramides with non-hydroxy fatty acids and C18-sphingosine [5]. Dupilumab therapy in a clinical trial resulted in the alterations in transcriptomic analyses of pretreatment and posttreatment skin biopsy specimens from patients with moderate-to-severe AD treated with dupilumab. The blockage of IL-4 and IL-13 signaling with dupilumab decreased the expression of several interleukins and chemokines e.g. IL-13, IL-31, CCL17, CCL18 and CCL26 involved in the development of type 2 inflammation. Moreover, this biological treatment decreased the expression of genes related to epidermal hyperplasia including keratin 16 and MKi67 and enhanced the expression of genes associated with epidermal differentiation, skin hydrolipid barrier e.g. filaggrin, loricrin and claudins [6]. Another clinical trial proved that dupilumab improved the transcriptome in AD patients in a dose-dependent manner – a more potent effect on altering gene expression was observed in a group which was treated with 300 mg of dupilumab compared to 150 mg. The changes in gene expression in patients during dupilumab therapy included a decline in mRNA expression of genes associated with T cells, dendritic cells (CD1b and CD1c) and chemokines involved in T2 immune response e.g. CCL17, CCL18, CCL22, and CCL26 [7]. The analysis of 3 randomized clinical trials proved that dupilumab decreased the level of type 2 inflammatory serum biomarkers e.g. thymus and activation-regulated/chemokine ligand 17 (TARC/CCL17), total IgE, lactate dehydrogenase LDH and eosinophils at week 16 in pediatric patients [8]. However, the randomized, blinded head-to-head clinical trial comparing the effectiveness of dupilumab and upadacitinib (inhibitor of JAK) demonstrated that dupilumab caused 75% improvement in EASI at week 16 of treatment in a smaller group of patients than upadacitinib. [9]. Therefore, there is a core need to compare thoroughly the effectiveness of dupilumab with other biological drugs and inhibitors of JAK.
THE ROLE AND APPLICATION OF DUPILUMAB IN ASTHMA
Dupilumab is indicated for the treatment of severe asthma. Dupilumab received approval from the FDA for the treatment of severe asthma in 2018 for patients aged above 12 years. Dupilumab constitutes an add-on maintenance treatment for severe type 2 asthma characterized by increased blood eosinophils and/or increased exhaled nitric oxide (FENO), which is not adequately controlled with high doses of inhaled corticosteroids and another maintenance medication in adults and adolescents aged ≥ 12 years or in children aged 6–11 years. Dupilumab is administered subcutaneously for patients with severe asthma using oral corticosteroids, or patients with severe asthma and concomitant moderate-to-severe atopic dermatitis, or with severe chronic rhinosinusitis and nasal polyps, at an initial dose of 600 mg and then 300 mg every 2 weeks. In other cases of asthma, the initial dose is 400 mg and then 200 mg every 2 weeks. It was revealed that dupilumab decreased concentration of nitric oxide in exhaled air (FENO), serum IgE, plasma, eotaxin-3, periostin, TARC, blood eosinophils after a 24-week treatment in patients with asthma. These indicators are pivotal biomarkers of type 2 inflammation [10, 11]. However, clinical trials acknowledged that dupilumab also induces transient increase in blood eosinophils in patients with asthma and AD. However, it does not decrease the efficacy and rarely leads to major clinical consequences [12].
The efficacy and safety of dupilumab administered subcutaneously at a dose of 200 or 300 mg every 2 weeks for 52 weeks in patients with uncontrolled, moderate-to-severe asthma (inadequately controlled with medium-to-high dose inhaled corticosteroids or dependent on oral corticosteroids) was studied in several clinical trials including Liberty Asthma QUEST, VENTURE and TRAVERSE [11, 13, 14]. Liberty Asthma QUEST trial revealed that dupilumab reduced a rate of annualized severe exacerbations after 52 weeks of the therapy and caused an alteration in pre-bronchodilator forced expiratory volume in 1 s (FEV1) at week 12 [11]. Moreover, the long-term efficiency of dupilumab administered every 2 weeks was assessed in the TRAVERSE open-label extension study up to 148 weeks. Long-term efficiency of dupilumab in moderate-to-severe asthma was consistent with previous short-term results [14]. Another clinical trial demonstrated that dupilumab treatment reduced oral glucocorticoid use in glucocorticoid-dependent severe asthma and decreased annualized exacerbations rate (AER) and increased FEV1 [13]. Moreover, dupilumab was more effective in the reduction of annualized exacerbations rate than other drugs such as mepolizumab and benralizumab [15].
THE ROLE AND APPLICATION OF DUPILUMAB IN CHRONIC RHINOSINUSITIS WITH NASAL POLYPS
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a long-term clinical condition that is characterized by persistent subjective and objective symptoms. These symptoms include runny nose, loss of smell, nasal congestion and facial pain or pressure. Moreover, the signs should last for at least 12 weeks. Nasal polyps, originating from ethmoid sinuses, are inflammatory growths that frequently develop in both nostrils. Although polyps are commonly found in patients with chronic rhinosinusitis, they are not a pathognomonic symptom of this disease and are often formed in other conditions such as cystic fibrosis and malignancy [16]. CRSwNP primarily affects people in middle age, with an average onset at the age of 42. While chronic rhinosinusitis is more common in men, women may experience a more severe form of the disease. Female patients who underwent surgery were more likely to be on systemic corticosteroids at the time of surgery and required additional revision sinus surgeries compared to men [17].
Recent research has shown promising results for including biological treatments in severe CRSwNP. Dupilumab blocks the signaling of IL-4 and IL-13, two key inflammatory molecules involved in chronic rhinosinusitis [18]. Two significant global clinical trials, SINUS-24 and SINUS-52, investigated benefits of adding dupilumab to standard forms of treatment for severe CRSwNP. Both studies were conducted across numerous centers and enrolled adults with persistent CRSwNP symptoms. In both studies, patients were given 300 mg of dupilumab in subcutaneous injections every 2 or 4 weeks. Combined data from multiple studies showed a significant 76% decrease in the requirement for oral steroids or sinus surgery among patients treated with dupilumab [19].
The results of clinical trials show that dupilumab not only reduces nasal polyps and sinus inflammation but also greatly improves key symptoms like runny nose, nasal and loss of smell [19, 20]. One of the most distinct benefits of dupilumab is its ability to quickly enhance the sense of smell. This rapid improvement suggests that type 2 inflammation plays a crucial role in smell loss associated with CRSwNP and that dupilumab can effectively target and modify this inflammatory process. By alternating the effect of inflammatory cytokines, IL-4 and IL-13, dupilumab has demonstrated rapid and lasting improvements of the sense of smell, even in patients with severe CRSwNP who may have limited treatment options. These improvements were observed regardless of factors like previous surgeries, asthma, or allergies [21]. While indirect comparisons suggest dupilumab may be the most effective biological treatment for improving the sense of smell, direct head-to-head comparisons are needed for more accurate conclusions. The variability in the study design and measuring outcomes limits the strength of these comparisons [22, 23]. Dupilumab’s effectiveness was consistent across different patient groups, such as those with chronic disease, previous surgeries, asthma or other allergies. This broad effectiveness suggests that dupilumab could be a valuable treatment for many patients with CRSwNP [21].
THE ROLE AND USE OF DUPILUMAB IN EOSINOPHILIC ESOPHAGITIS
Eosinophilic esophagitis (EoE) is a chronic and inflammatory gastrointestinal disorder affecting the esophagus. This condition is characterized by eosinophilic infiltration of the esophageal epithelium and dysfunction of the esophagus, which results in difficulty in swallowing (dysphagia). As mentioned in previous sections, this disease is mainly driven by type 2 inflammation which is connected to T helper 2 cells (Th2). Th2 cells in response to some food antigens release proinflammatory cytokines IL-4, IL-5 and IL-13, which leads to eosinophil and mast cell infiltration [24]. Despite a steady rise in EoE occurrence over the past 30 years [25], treatment options are limited, among which most applied are topical corticosteroids (STC/TC) in the form of orally disintegrating tablets, proton pump inhibitors (PPI) and dietary elimination. Due to the limitations, new pharmacologic options for EoE are being explored [26].
Due to its modulating effect on the release of specific proinflammatory cytokines dupilumab was approved in May 2022 by the FDA for treating eosinophilic esophagitis in both adults and children [27]. Clinical trials have proven dupilumab’s effectiveness in reducing inflammation by lowering eosinophil count in the esophageal epithelium. This effect leads to improvement of esophageal functioning reducing dysphagia and facilitating swallowing. Dupilumab is typically used as a second-line treatment for EoE, if patients did not respond to first-line treatment such as PPI, STC/TC or dietary elimination. It is also recommended for patients who experienced side effects or are at risk of using steroids [28]. Another study was conducted on 7 young patients with EoE and other corresponding allergic conditions like asthma or eczema in 2022. The study found that dupilumab may be effective in treating severe phenotypes of EoE. Additionally, drug administration not only improved EoE symptoms but also helped with their primary allergic condition, which suggests that dupilumab can be effective in managing multiple concurrent atopic conditions [26]. Patients who were given placebo showed stable eosinophil levels, but those treated with dupilumab experienced a consistent decrease, with counts halving by week 12. However, contrary to asthma and AD, transient eosinophilia was not observed after dupilumab treatment [12].
THE USE AND ROLE OF DUPILUMAB IN OFF-LABEL INDICATIONS
Dupilumab has shown promising results in various smaller scale studies, indicating its potential use for the future beyond its initial approval for atopic dermatitis. This biological medicine modulates T2 type inflammation, which may lead to implementing it in a wide range of diseases which pathology includes this inflammatory pathway. Researchers are exploring effectiveness of dupilumab in treating a wide range of chronic dermatological diseases (prurigo nodularis, allergic contact dermatitis, chronic pruritus, chronic hand eczema, chronic spontaneous urticaria, cholinergic urticaria, chronic inducible cold urticaria, bullous pemphigoid, nummular eczema, localized scleroderma and Netherton syndrome), respiratory diseases (allergic bronchopulmonary aspergillosis (ABPA), chronic eosinophilic pneumonia) and gastrointestinal conditions (eosinophilic esophagitis (EoE), food allergies). Although dupilumab has shown promising results, particularly for diseases like EoE, it remains uncertain if it will be effective for other conditions [29].
THE SIDE EFFECTS AND CONTRAINDICATIONS OF DUPILUMAB USAGE
Dupilumab, while being effective in treatment of allergic diseases, may cause numerous side effects which include conjunctivitis, psoriasis and psoriasiform manifestations, facial and neck erythema, arthritis, alopecia, injection site reaction and transient increase in blood eosinophil counts [30–32].
Dupilumab like any other drug has its own contraindications and carries safety risks. Though rare, hypersensitivity reactions may occur. Main concern is eosinophilia, which might lead to blood vessel or lung inflammation. Due to limited data, safety of dupilumab treatment in pregnancy and breastfeeding is unclear. Furthermore, live vaccines should be avoided during therapy [33].
Another limitation concerning usage of dupilumab is the differences in its availability and reimbursement in different countries. Though patients can access biological drugs, healthcare systems create barriers. Biosimilars, despite being favored for cost savings, are not always available. Many countries regulate prices for both original and biosimilar drugs using a reference system. Experts advocate for improved education, fair pricing, easier medication switches, and clearer substitution guidelines [34].
Dupilumab can lead to ocular-related side effects like conjunctivitis, particularly in patients with severe eczema or at older age. Real-world data suggest a higher incidence of conjunctivitis than reported in clinical trials. Additionally, the severity of atopic dermatitis and patient age were found to be exacerbating factors associated with dupilumab-related ocular surface disease (OSD). Several hypotheses have been proposed to explain this side effect, the unmasking of underlying inflammation, tear production issues and potential effects on the ocular microbiome and mucus production. Understanding these mechanisms is crucial for developing strategies to prevent and manage dupilumab-associated conjunctivitis [35].
Dupilumab-associated psoriasis (DAPs) or psoriasiform manifestations (PsM) are uncommon side effects primarily driven by T-cell subset imbalances and various contributing factors. This phenomenon serves as an example of a paradoxical reaction induced by biologic therapies, providing strong evidence that AD and psoriasis represent opposite ends of the Th17-Th2 cell polarization spectrum. Given the increasing global use of dupilumab in clinical practice, clinicians need to be aware of this occurrence. Further research is required to better understand the underlying mechanisms of DAPs/PsM and to develop more effective strategies for prevention and management [36].
Dupilumab can cause facial or neck redness in some patients. This can be caused due to various reasons, including rosacea or allergic reactions. To diagnose the cause of this implication, doctors may consider factors like the patient’s history and the appearance of the rash. Treatments often include topical medications, and in some cases, systemic antifungals. Early diagnosis and treatment can help minimize discomfort and prevent unnecessary discontinuation of dupilumab [37].
Dupilumab can temporarily increase blood eosinophil counts in patients with asthma, chronic rhinosinusitis with nasal polyps and atopic dermatitis. While this effect typically does not cause problems or affect treatment, doctors should be aware of this potential side effect and monitor patients who may be at risk of eosinophilic-related conditions [31].
SUMMARY
Clinical trials have shown that dupilumab may have an indication for allergic disease treatment. Currently, dupilumab is registered for the treatment of asthma, moderate-to-severe atopic dermatitis and chronic rhinosinusitis with nasal polyps and eosinophilic esophagitis. However, availability and funding of biological treatment is associated with national rules, thus treatment options are frequently limited. Clinical trials acknowledged that dupilumab is highly effective in alleviating the symptoms of allergic diseases. However, dupilumab also leads to numerous side effects which clinicians must bear in mind and should easily diagnose.
