An international Delphi study on the burden of allergic rhinoconjunctivitis and urticaria and the role of bilastine among current treatment options

ABSTRACT

Background

Allergic rhinoconjunctivitis and chronic urticaria are common histamine-driven diseases, exerting detrimental effects on cognitive functions, sleep, daily activities, and quality of life. Non-sedating second-generation H₁-antihistamines are the first-line treatment of choice. Aim of the study was to define the role of bilastine among second-generation H₁-antihistamines in the treatment of allergic rhinoconjunctivitis and urticaria in patients of different ages.

Methods

An international Delphi study was carried out to assess consensus among experts from 17 European and extra-European countries on three main topics: 1) Burden of disease; 2) Current treatment options; 3) Specific characteristics of bilastine among second-generation antihistamines.

Results

Here, we present the results obtained for a selection of 15 out of 27 consensus statements, focused on disease burden, role of second-generation antihistamines and bilastine profile. The rate of concordance was ≥98% for 4 statements, ≥ 96% for 6, ≥ 94% for 3, and ≥90% for 2.

Conclusions

The high degree of agreement obtained suggests a wide awareness of the burden of allergic rhinoconjunctivitis and chronic urticaria among experts from all over the world and reflects a broad consensus on the role of second-generation antihistamines in general and of bilastine in particular for their management.

KEYWORDS:

• Allergic rhinitis
• anti-histamines
• bilastine
• Delphi process
• urticaria

1. Introduction

Allergic rhinoconjunctivitis, which affects 10–40% of individuals worldwide [1] and chronic urticaria, which has an estimated prevalence of 0.6–1.5% [2], both have a significant burden on patients, their families, and society.

In children and adolescents, rhinoconjunctivitis is common with an average global prevalence of 8.5% in children aged 6–7 years and 14.6% in those aged 13–14 years [3]. Allergic rhinoconjunctivitis has adverse effects on quality of life (QoL) in causing emotional and practical problems, limitations in daily activities, and sleep disturbances [4–8]. Of particular note are the detrimental effects on cognitive functions [9], leading to a negative impact on school attendance and academic achievement [6]. Although less common in prevalence, chronic urticaria has similar effects [10].

In adults, both seasonal rhinitis and chronic urticaria also have a negative impact for patients, through reduced physical, psychological, social, educational and work functioning, for healthcare systems, through increased care costs, and for society, through lost work productivity [1,2,11–14].

In the elderly, a decline in immune function and age-related changes in tissue structures contribute to the clinical manifestations of allergies, whose outcome is often complicated by comorbidities and related treatments [15]. Common complications of allergic rhinitis, such as chronic sinusitis or chronic cough, often caused by postnasal drip, may produce sleep abnormalities and subsequent daytime fatigue [15]. Similarly, in chronic urticaria, the general consequences of skin aging, including impaired skin barrier function, may worsen the clinical course of the disease [16].

Given the role of histamine in allergic rhinoconjunctivitis and urticaria, H₁-antihistamines are the first-line treatment of choice [2,17,18]. H₁-antihistamines, inverse agonists stabilizing H₁-receptors in their inactive conformation, include older first-generation H₁-antihistamines and more recent second-generation H₁-antihistamines [19].

Because of their poor receptor selectivity, first-generation agents often interact with other receptors, causing anti-cholinergic, anti-adrenergic, and anti-serotonin effects. Given their ability to penetrate the blood – brain barrier, they interfere with histamine action in the central nervous system (CNS), causing adverse effects such as drowsiness, sedation, somnolence, fatigue and leading to impairment of cognitive function, memory and psychomotor performance [19]. They also impair sleep quality, by interfering with rapid eye movement sleep [20]. Consequently, current guidelines recommend against the use of first-generation H₁-antihistamines for the routine management of chronic urticaria and allergic rhinitis [2,21].

In contrast, modern second-generation H₁-antihistamines are minimally or non-sedating because of their poor penetration of the blood – brain barrier. Compared with first-generation H₁-antihistamines, second-generation agents are highly selective for the H₁-receptor and have a better side-effect profile, being free of anti-cholinergic effects or cardiac toxicity. For these reasons, they are currently recommended as first-line therapeutic options for patients with allergic rhinitis and urticaria [2,17,18].

The ability of different second-generation H₁-antihistamines to cross the blood-brain barrier and cause brain H₁-receptor occupancy (H₁RO) has been investigated as an index of sedative potential [22]. Agents are classified as sedating, less sedating, or non-sedating according to their level of H₁RO (>50%, 20–50%, or <20%, respectively) [23]. Among the antihistamines belonging to the non-sedating group, bilastine and fexofenadine are defined as ‘non-brain-penetrating antihistamines’ having H₁ROs near to 0% [22].

Among second-generation agents indicated for allergic rhinitis or urticaria, bilastine, fexofenadine, cetirizine, levocetirizine, and ebastine show high specificity for H₁-histamine receptors. These agents tend to possess a short time to maximum plasma concentration (Tmax), within approximately 3 h, and a long elimination half-life (t_1/2), ≥10 h (with the exceptions of levocetirizine and loratadine). Bilastine, fexofenadine, and cetirizine are minimally or not metabolized. No dose adjustment according to the level of hepatic or renal dysfunction is required for fexofenadine and bilastine [22].

Bilastine, the antihistamine that is the subject of this Delphi study, is the most recently developed and licensed H₁-antihistamine for the treatment of patients with allergic rhinoconjunctivitis or urticaria. Bilastine is a potent and highly selective oral second-generation H₁-antihistamines with a long receptor residency, which may explain its prolonged duration of action [24,25]. Bilastine has minimal H₁RO in the CNS, similar to placebo, resulting in its classification as a non-brain-penetrating antihistamine [22]. This limits the potential for sedation, impairment of cognitive performance or ability to drive, and enhancement of alcohol effects [26,27]. Unlike first-generation H₁-antihistamines, bilastine does not exhibit anti-cholinergic action [28] or cardiotoxic effects [29,30]. Bilastine is rapidly absorbed after oral administration [31] and, due to an active uptake mechanism, it has a faster onset and longer duration of action than fexofenadine, desloratadine, and rupatadine [26,32]. It has a low potential for metabolic drug–drug interaction as it does not interact significantly with the CYP enzyme system in vitro [27,33]. Since bilastine does not undergo significant metabolism, dose adjustments are not needed in patients with renal or hepatic impairment [34–36]. Moreover, no dose adjustments are required in older patients [37].

The aim of the present study was to define the role of bilastine in the symptomatic treatment of allergic rhino-conjunctivitis (seasonal and perennial) and urticaria in patients of different ages.

2. Methods

A board of eight key opinion leaders with long-term experience as specialists in the field of allergy (allergology, otolaryngology, pediatric pulmonology, pediatric allergology, and dermatology) was appointed as a scientific committee, in charge of designing and supervising the study. A Delphi method was adopted by the scientific committee to reach the above-mentioned aim [38].

Fifty specialists from 17 European and extra-European countries (Brasil, Corea, Cuba, France, Germany, Great Britain, Greece Hungary, Italy, The Netherlands, Peru, Poland, Slovenia, Spain, Turkey, United Arab Emirates, United States) were selected on the basis of their clinical and scientific expertise in the field of allergic rhinoconjunctivitis and chronic urticaria and invited to participate as members of an expert panel in the online voting.

A total of 27 statements were elaborated by the scientific committee based on their personal clinical experience and according to the most relevant and updated literature on three main topics, judged by the committee as relevant: 1) Burden of allergic rhinoconjunctivitis and urticaria and their impact on QoL; 2) Current treatment options of rhinoconjunctivitis and urticaria and unmet needs; 3) Specific characteristics of bilastine among second-generation antihistamines.

The statements were uploaded onto a dedicated online platform to be voted on by the panel of experts, who expressed their degree of agreement with the proposed statements on a five-point Likert scale (1 = strongly disagree; 2 = disagree; 3 = undecided; 4 = agree; 5 = strongly agree).

According to the most frequently adopted Delphi method, the definition of consensus was set at least 80% agreement, i.e. 80% of experts agree or strongly agree.

The complete list of statements is reported in Supplementary Table S1. The present publication focuses on a selection of 15 statements related to: i) allergic rhinoconjunctivitis and urticaria and their detrimental effect on QoL, sleep and daily activities, including job and school performance (statements 1–3); ii) current treatment options (including first-generation H₁-antihistamines and second-generation H₁-antihistamines) and unmet needs (statements 4–8); iii) characteristics of bilastine (statements 13a, 13b, 14, 21, 22, 23, 24). A subsequent publication will present results for statements specifically related to the treatment of allergic rhinoconjunctivitis and urticaria, with a focus on the potential benefits of bilastine in each condition.

3. Results and discussion

Among the 15 consensus statements selected for reporting and discussion with this publication, the percentage of concordance was ≥98% for 4 statements, ≥ 96% for 6, ≥ 94% for 3, and ≥90% for 2.

Disease burden

Statement 1: The significant prevalence of allergic rhinitis and urticaria, in adults, elderly and children, has important financial implications for healthcare systems and for society, because of the negative effect on patients’ physical, psychological, social, educational, and work functioning: 50 respondents, 98% agreement (70% strongly agree).

This consensus statement reflects the substantial burden and costs associated with allergic diseases reported in the literature [1,2]. Allergic rhinitis is a frequent reason for general practice office visits, causing high annual direct medical costs; indirect costs associated with lost work productivity are substantial as well, greater than those incurred by asthma [1,14]. Similarly, allergic rhinitis reduces the QoL of many patients, impairing cognitive function and sleep quality, thus causing irritability and fatigue; this results in decreased school and work performance, especially during the peak pollen season [1]. Similarly, chronic urticaria has a substantial individual and societal impact due to debilitating symptoms such as severe pruritus and secondary loss of sleep and productivity [39]. A real-world study performed in Germany found that more than 20% of patients with chronic urticaria reported ≥1 h per week of missed work, with a 27% productivity impairment [13]. Moreover, disease activity affected work performance, suggesting that a better disease control might contribute to indirect costs containment [13]. Higher prevalence of mood and anxiety spectrum disorders have been shown in pediatric chronic urticaria patients as opposed to controls [40].

Statement 2: Allergic rhinitis and chronic urticaria have a detrimental effect on patients’ QoL, sleep and daily activities, including job performance (with a negative impact on work productivity): 49 respondents, 98% agreement (84% strongly agree).

The recorded consensus is supported by a large body of evidence. A recent study, for example, demonstrated that chronic spontaneous urticaria markedly interferes with sleep and daily activities, particularly in patients with greater disease activity, who experience greater QoL impairments: more than 20% of patients reported ≥1 h per week of missed work, with a productivity impairment of 27% [13]. Similarly, allergic rhinitis reduces the QoL of many patients, impairing sleep quality and cognitive function and causing irritability and fatigue; this causes decreased school and work performance, especially during the peak pollen season [1]. The social component of QoL has been found to be particularly impaired in patients with rhinitis, mainly due to nasal symptoms [14,21]. Appropriate treatment of allergic rhinitis is able to improve symptoms, QoL, and work and school performance [1].

Statement 3: Allergic symptoms frequently interfere with a child’s ability to participate in daily activities and disrupt normal sleeping patterns, causing emotional distress and impacting negatively on learning and cognition: 50 respondents, 98% agreement (71% strongly agree).

A recent literature review highlighted that allergic rhinitis and allergic rhinoconjunctivitis may limit daily activities and functioning in adolescents, exerting a significant impact on the QoL in terms of both physical and mental components [6]. They generally experience poor sleep, with a consequent negative impact on school attendance, performance, and academic achievement. Improved management of allergic rhinitis could help in reducing the disease burden in children and adolescents [6]. Children with chronic urticaria were found to have severe impairment in their health-related QoL, similar to other chronic diseases such as epilepsy and diabetes [41], and a significantly lower school performance compared to those with other allergic diseases [42].

Treatment

Statement 4: First-generation antihistamines are associated with side effects such as sedation and reduced psychomotor and cognitive function, which may impair learning and reduce work efficiency: 50 respondents, 98% agreement (80% strongly agree).

The negative effects on psychomotor and cognitive functions of first-generation H₁-antihistamines are well known, as are guideline recommendations that they should be replaced by second-generation molecules, based on their better tolerability profile. Compared to new-generation agents, classic antihistamines increased daytime sleepiness and decreased the sleep quality scores [43]. However, differences have been documented among second-generation agents as well: for instance, in comparison with fexofenadine and loratadine, cetirizine was shown to be associated with increased somnolence and less motivation to perform activities during the workday [44,45]. Similarly, compared with bilastine, cetirizine reduced attention and vigilance in subjects exposed to hypobaric hypoxia, increasing the number of errors [46].

Statement 5: When taken at night, first-generation H1-antihistamines increase the latency to the onset and reduce the duration of REM sleep, causing impairment of attention, vigilance, working memory, and sensory-motor performance the next day, also as a consequence of their long half life: 49 respondents, 90% agreement (47% strongly agree).

The fact that some, albeit few experts were undecided on this statement may reflect that most clinicians, who manage allergic rhinitis and urticaria, do not assess sleep stages in their patients and therefore cannot be certain that impairing effects of first-generation antihistamines are due to specific effects on sleep. On the other hand, there is still a widespread belief that sleep is aided by adding a sedating first-generation H₁-antihistamine, as hydroxyzine, at night, although this is not supported by available data [47]. Moreover, with a terminal half-life of 20–25 h [48], hydroxyzine has hangover effects into the next day, with a negative impact on overall performance [47]. Similarly, the first-generation antihistamine chlorpheniramine has shown to cause a significant worsening of next day cognitive functioning and psychomotor performance, whereas a single nocturnal dose of fexofenadine has advantages over chlorpheniramine, demonstrating to be free of disruption of nighttime sleep and detrimental effects on cognitive performance the next day [49]. Further information on the effects of antihistamines on sleep and sensory-motor performance may be a good target for further analysis.

Statement 6: In contrast to first generation H₁-antihistamines, modern second generation H₁-antihistamines cause lower or minimal sedation, are free of anti-cholinergic effects and are recommended as first-line therapeutic options for patients with allergic rhinitis and urticaria: 49 respondents, 94% agreement (69% strongly agree).

First- and second-generation antihistamines differ in their safety profiles, and this is well known among physicians who prescribe them. Although first-generation H₁-antihistamines have been used for treatment of allergic diseases for long time, many studies demonstrated that they can affect sleep quality, impair learning, and reduce work efficiency. Their use has been implicated in motor vehicle, civil aviation, and boating accidents, deaths as a result of intentional or accidental overdosing in infants and young children, and also suicide in teenagers and adults [50]. Because of this, the use of first-generation H₁-antihistamines for self-medication of allergic diseases should be avoided: the availability at competitive prices of newer second-generation nonsedating H₁-antihistamines with superior risk/benefit ratios will hopefully discourage the use of older agents, although they are still available over-the-counter as prescription-free drugs [19].

Statement 7: The reduction of learning ability in children and the poor examination performance in teenagers associated with allergic diseases may be worsened by first generation H₁-antihistamines:49 respondents, 98% agreement (59% strongly agree).

The negative effects of allergic disease on the one hand and the use of first-generation H₁-antihistamines on the other are well known, especially the detrimental effects of first-generation H₁-antihistamines on cognitive performance and the ability to learn. For instance, in an analysis of 1834 UK teenager students taking national examinations, those with untreated allergic rhinitis were 40% more likely to drop one or more grades than healthy teenagers. Moreover, when they took a first-generation H₁-antihistamine, the likelihood to drop one or more grades increased to 70% [51].

Statement 8: In elderly patients, it is important to avoid drugs which can cause confusion or sedation/drowsiness, as well as those which have effects on the cholinergic system and which exacerbate dementia, such as first-generation H1-antihistamines: 49 respondents, 94% agreement (61% strongly agree).

Older subjects may have reduced cognitive performance, executive function, and memory dysfunction [52], as well as an increased risk of developing drug-induced delirium, (deriving from a reduction in cholinergic function) [53], or dementia (as a consequence of cumulative use of first-generation antihistamines with anticholinergic activity) [54]. The potential for negative impact of first-generation H₁-antihistamines in elderly patients is therefore substantial. For example, a prospective population-based cohort study performed in U.S.A., including >3000 patients, recorded a higher cumulative anticholinergic medication use (including first-generation H₁-antihistamines) associated with an increased risk for dementia [54].

Bilastine

Statement 13a: Bilastine is a highly selective oral H₁-antihistamine with a fast onset and long duration of action:48 respondents, 96% agreement (65% strongly agree).

The pharmacologic profile of bilastine, including its fast onset and long duration of effects are well known. The long residence time at the H₁-receptor results in prolonged receptor antagonism, with 60–70% inhibition evident 24 h after dosing. Bilastine meets most of the features that an ideal oral H₁-antihistamine should possess according to the EAACI/ARIA guidelines [21].

Statement 13b: Bilastine has a low propensity for drug-drug interactions, since it does not interact significantly with the CYP enzyme system and does not undergo significant metabolism in humans; this contributes in defining its good tolerability profile: 48 respondents, 96% agreement (58% strongly agree).

This statement focuses on a key feature of bilastine (low propensity for drug-drug interactions), which is particularly relevant for patients with comorbidities and under polypharmacy and contributes to its good tolerability profile. The in vitro inhibitory effects of bilastine were assessed on 12 human membrane transporters generally regarded as clinically relevant, to evaluate potential interactions that may affect pharmacokinetics, efficacy, or toxicity of concomitantly administered drugs. Among the 12 transporters studied, only negligible inhibition was identified for bilastine on MDR1, OATP2B1, and OCT1, while no inhibition was observed against the remaining transporters. Based on these results, drug-drug interactions caused by bilastine inhibition of drug transporters are unlikely. Moreover, bilastine is not a substrate and therefore is not affected by inhibition of human BCRP, OAT1, OAT3, or OCT2 [26]. Further, bilastine is not metabolized by the cytochrome P450 (CYP) enzyme system, suggesting a low propensity for drug–drug interactions involving this metabolic pathway [33].

Statement 14: Bilastine 20 mg displays one of the lowest cerebral histamine H₁-receptor occupancy, when compared to other antihistamines: for that reason, it has a low propensity in affecting cognitive performance or the ability to drive, and has been demonstrated not to potentiate the effects of alcohol or lorazepam: 48 respondents, 94% agreement (61% strongly agree).

The predominant opinion expressed by the Expert Panel demonstrates a complete awareness of the pharmacologic characteristics of bilastine, whose cerebral H₁RO is one of the lowest among first- and second-generation H₁- antihistamines [55], resulting in the classification of bilastine as a non-brain-penetrating antihistamine [22]. A close correlation exists between H₁RO and the incidence of sedation: antihistamines with H₁RO <20% are classified as non-sedating. A single oral dose of bilastine 20 mg showed minimal H₁RO, and did not cause subjective sedation or objective impairment of psychomotor performance, thus satisfying the most relevant PET criteria as a non-sedating antihistamine [23]. In adult patients, bilastine showed minimal adverse effects on psychomotor performance and did not augment the CNS effects of alcohol or lorazepam [34,56]. Driving ability was not altered by bilastine 20 mg in healthy volunteers [57,58].

Statement 21. Bilastine approval based on data from a Paediatric Investigation Plan in respect of EU regulation, will be relevant when it comes to choose the treatment in children with allergic rhinitis and/or urticaria: 48 respondents, 96% agreement (69% strongly agree).

The high consensus suggests that the availability of data in children is important to support the use of bilastine in the management of rhinitis and urticaria in the pediatric population. In the main bilastine clinical development program, clinical trials in perennial and seasonal allergic rhinoconjunctivitis or urticaria enrolled 198 patients aged 12 to 18 years, of whom 81 received bilastine 20 mg, with 68 patients that received it for 12 months [59]. Bilastine 20 mg once daily was shown to be effective and well tolerated in this age group, and the drug was originally approved for adults and adolescents aged ≥12 years [34]. More recently, results from the studies of the bilastine Paediatric Investigation Plan approved by the EMA Pediatric Committee, including a pediatric pharmacokinetic study [60,61] and an international, double-blind, randomized, placebo-controlled study assessing safety and tolerability [8], both performed in children aged >2 years to <12 years, became available: on the basis of these new data bilastine was approved also for use in children aged 6–11 years (≥20 kg). Although limited, bilastine data in the pediatric population fulfill the current regulatory requirements for its use in children, which include population pharmacokinetic/pharmacodynamic modeling to accurately define pediatric dosing [62], as well as evaluation of the safety of the intervention in children [63], according to the European Regulation 1901/2006 on medicines for pediatric use [64]. EMA regulation aims to ensure that medicines for use in children derive from ethical and quality research and are specifically authorized for administration to this population. Ema regulations further state that these objectives be met without subjecting the pediatric population to unnecessary clinical trials, and that development of pediatric drugs be based on an approved Pediatric Investigation Plan (PIP). The proposed bilastine PIP was approved by the EMA’s Pediatric Committee (PDCO) in April 2009. As the committee agreed that existing bilastine age-independent PD data (preclinical and animal models) were sufficient to predict its safety in children aged 2–<12 years, no further studies were necessary in young animals. Likewise, because the committee agreed that bilastine efficacy in children with allergic rhinitis and urticaria could be extrapolated from data obtained in adolescents and adults, no additional efficacy studies were needed in the pediatric population [65].

In addition to clinical trial results, real-world evidence on the usefulness of bilastine in the management of allergic rhinoconjunctivitis and urticaria in children is growing, confirming the efficacy and safety profile demonstrated in everyday clinical practice [65].

Statement 22: Bilastine 10 mg resulted in a placebo-like effect in the four domains of the Paediatric Sleep Questionnaire in children with allergic rhinitis and urticaria; this makes this drug a suitable treatment for children attending school, with a potential favorable impact on school performance, cognitive activities and conduct: 48 respondents, 96% agreement (50% strongly agree).

The good safety profile of bilastine as well as its favorable impact on school performance, cognitive activities, and conduct in children appear to be well recognized by physicians who treat pediatric patients with allergic rhinitis and urticaria [10]. According to pharmacological data and clinical studies, bilastine has a very low risk to induce somnolence, which makes this drug a suitable treatment for children attending school [8,23,66].

Statement 23: Thanks to its good tolerability and low interaction profile, the non-sedating second-generationH₁-antihistamine bilastine should be preferred in elderly patients with allergic disorders, often undergoing multi-pharmacological therapy for comorbidities: 48 respondents, 92% agreement (56% strongly agree).

The use of modern, well tolerated, and low interaction antihistamines such as bilastine is especially important when treating elderly patients. In order to overcome the limitation of insufficient data from phase I studies in the elderly population, the posology of bilastine in these subjects was evaluated using two different mechanistic-based models, the Senescence (PopPK-based semi-mechanistic model) and the PBPK model, both indicating that a 20 mg q.d. dose is safe and effective for geriatrics of any age [37]. A recent prospective observational study in a real-world practice setting evaluated the safety profile in 146 patients aged ≥65 years with urticaria and/or allergic rhinoconjunctivitis who were prescribed bilastine 20 mg once daily and followed up for 3 months (mean age 74.8 ± 6.6 years) [67]. This study showed the favorable safety profile and the low incidence of TEAEs of bilastine 20 mg once daily in elderly patients with urticaria and/or allergic rhinoconjunctivitis [67].

Statement 24: Owing to its properties, bilastine could be considered an attractive option for the treatment of patients with allergic rhinoconjunctivitis or urticaria across the ages (from school-age children to elderly patients), helping to counteract the detrimental impact that allergic diseases can have on patients’ health-related QoL: 48 respondents, 96% agreement (71% strongly agree).

Specifically, lack of potential to induce sedation allows prolonged administration without causing an impairment of performance and learning abilities in children [10], whereas lack low propensity for drug-drug interactions makes it a valuable option for elderly patients [26,33]. This confirms the central role of bilastine in the management of allergic diseases, aiming at reducing the disease burden and improving QoL in patients of any age.

4. Conclusions

The results of the presented Delphi study demonstrate a high level of awareness of the burden of allergic rhinoconjunctivitis and chronic urticaria among clinicians. Despite currently available treatment options, these conditions still have a relevant impact on functioning of affected patients, regardless of age. A broad consensus was recorded on the use of second-generation anti-histamines in general and of bilastine in particular to reduce symptoms and improve QoL.

Declaration of interest

M Church has been a speaker or consultant for Almirall, FAES Pharma, Menarini, Moxie, MSD, Novartis, UCB Pharma, Sanofi-Aventis and Uriach. G Canonica reports having received in the last 3 years research grants as well as lecture or advisory board fees from: Menarini, Alk-Abello,’ Allergy-Therapeutics, Astra Zeneca, MedImmune, Boehringer Ingelheim, Chiesi, Faes, Genentech, Guidotti, Malesci, GlaxoSmithKlin, HAL Allergy, Novartis, OM Pharma, Sanofi-Aventis, Sanofi-Genzyme, Regeneron, Stallergenes, Greer, Thermo Fisher, Valeas. P Kuna reports personal fees from Adamed, AstraZeneca, Berlin Chemie Menarini, FAES, Glenmark, Novartis, Polpharma, Boehringer Ingelheim, Teva, and Zentiva, all outside the submitted work. M Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Alvotech, Amgen, Aquestive, Aralez, AstraZeneca, Bayer, Celldex, Celltrion, Evommune, FAES, GSK, Ipsen, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Mitsubishi Tanabe Pharma, Moxie, Noucor, Novartis, Orion Biotechnology, Resonance Medicine, Sanofi/Regeneron, Septerna, Trial Form Support International AB, Third HarmonicBio, ValenzaBio, Yuhan Corporation, and Zurabio R Mösges reports personal fees from Menarini during the conduct of the study; personal fees from ALK, Allergopharma and Allergy Therapeutics, Bencard, Lofarma, Stallergenes, Friulchem, Hexal, Servier, Klosterfrau, Bayer, FAES, GSK, MSD, Johnson&Johnson, Meda, Novartis, Stada, UCB, Nuvo, Ursapharm, Menarini, Mundipharma, Pohl-Boskamp, Laboratoire de la Mer, Sidroga, HAL BV, Lek, PRO-AdWise, Angelini Pharma and Bitop; grants from Bencard, ASIT Biotech, Leti, Lofarma, Optima, Hulka, Ursapharm, Inmunotek, Cassella-med GmbH & Co. KG, HAL BV, JGL, Bitop and Sanofi; non-financial support from Lofarma, Roxall, Atmos, Bionorica, Novartis, Otonomy, Ferrero, JGL; all outside the submitted work. Z Novak has been a speaker and/or advisory board member for AbbVie Pharma, AstraZeneca, Berlin-Chemie, Boehringer, Chiesi, FAES Pharma, GlaxoSmithKline, Menarini, MSD, Orion Pharma, TEVA, Viatris. N Papadopoulos has been a speaker and/or advisory board member for Abbott, Abbvie, ALK, Asit Biotech, AstraZeneca, Biomay, Boehringer Ingelheim, GSK, HAL, Faes Farma, Medscape, Menarini, MSD, Novartis, Nutricia, OM Pharma, Regeneron, Sanofi, Takeda, Viatris. P Rodriguez del Rio has been a speaker or consultant for GSK, FAES, Novartis, ALK-Abelló, Merck, HAL Allergy Group, LETI and Aimmune Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

All the authors contributed to the conception and design of the study, interpretation of the data, drafting and critical revision of the paper and final approval of the version to be published. All authors agree to be accountable for all aspects of the work.

Ethics

No ethical approval was required for this consensus study, which was conducted according to the Delphi technique to assess agreement among participants, all of whom are also coauthors of the paper.

Acknowledgments

Menarini Group also funded the editorial assistance provided by Content Ed Net. The medical writing service was provided by Elena Sarugeri on behalf of Content Ed Net.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/1744666X.2023.2214729

Additional information

Funding

The study was performed thanks to an unconditioned grant of Menarini Group.