EUFOREA consensus on biologics for CRSwNP with or without asthma

Abstract Novel therapies such as type 2 targeting biologics are emerging treatment options for patients with chronic inflammatory respiratory diseases, fulfilling the needs of severely uncontrolled patients. The majority of patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and over half of patients with asthma show a type 2 inflammatory signature in sinonasal mucosa and/or lungs. Importantly, both chronic respiratory diseases are frequent comorbidities, ensuring alleviation of both upper and lower airway pathology by systemic biological therapy. Type 2‐targeting biologics such as anti‐IgE, anti‐IL4Rα, anti‐IL5, and anti‐IL5Rα have entered the market for selected pheno/endotypes of asthma patients and may soon also become available for CRSwNP patients. Given the high prevalence of chronic respiratory diseases and the high cost associated with biologics, patient selection is crucial in order to implement such therapies into chronic respiratory disease care pathways. The European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) organized a multidisciplinary Expert Board Meeting to discuss the positioning of biologics into the care pathways for CRSwNP patients with and without comorbid asthma.


| INTRODUC TI ON
Chronic rhinosinusitis (CRS) is a chronic inflammatory condition of the sinonasal cavities that affects 5%-12% of the general population worldwide according to epidemiological studies. [1][2][3][4] The European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) defines CRS clinically based on symptoms supported by signs of mucosal inflammation found on imaging or with nasal endoscopy. 5 Recently, the prevalence of clinically based CRS has shown to be between 3% and 6.4%. 6,7 CRS is classically divided into a phenotype with and without nasal polyps (CRSwNP and CRSsNP, respectively). Using patient questionnaires to measure the prevalence of CRSwNP yielded estimates of 2.1% (France) to 4.3% (Finland) in Europe and 1.1% in China. 8 CRSwNP comprises a heterogeneous group of patients who differ with respect to coexisting asthma, allergy, NSAID-exacerbated respiratory disease (N-ERD), 9 smoking, age of onset, and disease severity. [10][11][12] Asthma affects 30%-70% of the CRSwNP patients. 8,10,13,14 Conversely, the presence of nasal polyps is associated with the severity of asthma, regardless of smoking status ranging from 10%-30% in mild asthma to 70%-90% in severe asthma. 15,16 Both CRSwNP and asthma share common underlying pathophysiological mechanisms driving the disease (endotype), of which type 2 inflammation is the most prominent. 13,[17][18][19] Type 2 inflammation is characterized by the presence of eosinophilic airway inflammation associated with type 2-related cytokines (IL4, IL5, and/or IL13) and circulating and/or local IgE. 13,20 The management guideline in Europe for CRS, the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS), has been developed to provide physicians with comprehensive tables of levels of evidence and helpful management algorithms. 5  The cornerstone of the management of both CRSwNP and asthma consists of anti-inflammatory treatment with local corticosteroids, aiming to achieve optimal disease control. 5,21,22 When this is insufficient, short courses of oral corticosteroids are used (usually 30-60 mg for 14 days, sometimes reducing over time). 23,24 Sinus surgery is the treatment option for CRSwNP patients in cases failing medical treatment. [25][26][27] Recently, also more attention has been paid to the concept of "treatable traits." Treatable traits have been postulated as a management concept which complements the traditional diagnostic labels such as CRSwNP or CRSsNP, thereby focusing on therapy targeted to a patient's individual disease-associated characteristics. 28,29 Typical treatable traits in the upper airways can be smoking, allergy, occupation, and mucociliary clearance deficits. 30 Biological therapies have entered the market for patients with asthma almost 15 years ago with anti-IgE as first-line therapy for patients with severe allergic asthma 31 and urticaria. [32][33][34][35] Recently, other monoclonal antibodies targeting type 2 inflammation 36 have been approved and are available now for patients with eosinophilic asthma, 37-41 atopic dermatitis, 42,43 and urticaria. 36,[42][43][44][45][46] A number of trials have been done with biological therapies for CRSwNP. [47][48][49][50] As these drugs enter the market, it necessitates the medical community to reflect on the positioning of these therapies in the current care pathways of the upper and lower airways. 51

| S E VERIT Y AND THE BURDEN OF UN CONTROLLED D IS E A S E IN CR Sw NP AND A S THMA
CRSwNP has a severe impact on quality of life comparable to asthma 53,54 and poses a significant burden on society. 54,55 In particular, the loss of sense of smell is a debilitating and often underappreciated component and can significantly impact one's quality of life. 56,57 The terms "disease control" and "disease severity" cannot be CRSwNP and asthma. The side effects of repeated use of systemic corticosteroids were also identified by the patient advisory board as a major concern. 61 Symptomatic nasal polyp recurrence rates, defined as patients undergoing revision endoscopic sinus surgery, are reported to be 20% within a 5-year period after surgery 62,63 but may be as high as 50% on endoscopic examination. 62 Type 2 disease is a strong predictor of recurrent disease with more than 50% of recurrences occurring in clusters with high eosinophilia. [62][63][64][65] The Global Initiative for Asthma (GINA) suggests assessing asthma severity retrospectively from the level of treatment required to control symptoms and exacerbations. Mild asthma is asthma that can be controlled with low-dose inhaled corticosteroids. Severe asthma is defined as asthma that requires treatment with highdose inhaled corticosteroids (ICS) plus a second controller and/or systemic corticosteroids to maintain symptom control (after other causes of lack of control, that is, treatment adherence and inhalation technique have been addressed) or asthma that remains uncontrolled despite this (maximal) therapy. 66 There is a clear correlation between control of upper and lower airways in patients with CRS and asthma and many patients with severe asthma have comorbid CRSwNP, which should be addressed to optimize asthma control. [67][68][69] To conclude, the management of CRSwNP and asthma patients who are uncontrolled despite medical and often surgical intervention remains a challenge. However, in recent years, there has been significant innovation and expansion in the treatment armamentarium since the advent of biological therapies.

| EFFIC AC Y OF B I OLOG I C AL TRE ATMENT FOR CR SwNP AND A S THMA
Omalizumab was the first biological therapy that entered the market for patients with moderate-to-severe allergic asthma. It have been shown to improve disease control, reduce the number of asthma exacerbations, the need for oral corticosteroid, and rescue medication use. 31,70 In recent years, several other biologics (anti-IL5, anti-IL5R, and anti-IL4Rα) have shown to be effective for the treatment of severe asthmatics with a type 2 inflammatory signature. 71,72 In most countries, biologics are indicated in moderate-to-severe asthma with insufficient level of control despite high dose of inhaled corticosteroids combined with at least one other asthma medication and where severe exacerbations and/or oral corticosteroid-dependent asthma have been demonstrated.
The first proof-of-concept studies in CRSwNP using anti-IgE, anti-IL5, and anti-IL4Rα strategies also showed promising results and have been summarized earlier. 50,73 Recent larger scale studies showed a moderate reduction in the need for surgery following treatment with anti-IL5 in patients with CRSwNP. 48 It was stated earlier that asthma is a frequent comorbidity in patients with CRSwNP.
All trials with biologics in CRSwNP also showed a positive impact on the lower airways with significant changes in either AQLQ, ACQ-5, or FEV 1 in patients with comorbid asthma. 47,48,74 Each of these biologics is tested in phase III clinical trials for CRSwNP patients with results to

| INDIC ATIONS FOR B IOLOG IC S
The high burden of uncontrolled disease, the recurrence of nasal polyps after sinus surgery, and the side effects associated with repeated courses of oral corticosteroids all underline the need for novel therapies. Given that biologics come with a high cost for the healthcare system, careful selection of patients is highly recom- There was an extensive discussion of whether there is a role for biologics in patients without previous sinus surgery. If these patients meet the criteria for severe asthma, they might fulfill the eligibility criteria to receive biological treatment by their pulmonologist.
In patients with severe CRSwNP and mild-moderate asthma, the question as to whether biologics may become a valid alternative for sinus surgery is difficult to answer before the approval and introduction of biologics into the market. While most patients are keen to avoid surgery if possible, the effectiveness of biologics in preventing or reducing the need for surgery is yet to be established.
The current evidence shows a significant but incomplete, relatively modest, reduction in polyp size, suggesting that a notable proportion of patients might still need surgery despite treatment with biologics. [37][38][39] On the other hand, given that repeated surgeries cannot prevent recurrence in CRSwNP subjects with type 2 inflammation, and in line with the principles of precision medicine that patients also will share in decision making, it is likely that biologics will in time become an alternative for sinus surgery as currently performed.
To date, one study evaluated omalizumab vs sinus surgery in patients with grade 3 CRSwNP and asthma. 49 It was concluded that omalizumab is equally effective in reducing SNOT-22 at 16 weeks to sinus surgery. However, large-scale studies are needed to confirm these findings in order to decide upon whether or not biologics could be a valid alternative to primary sinus surgery. Therefore, it was concluded that patients who have never had sinus surgery need to meet at least 4 of the above criteria in order to be eligible for biological treatment.  Patients with a high-risk phenotype (asthma and N-ERD) should be referred to specialist centers early in their disease to optimize multidisciplinary management.

| P OS ITI ONING OF B I OLOG IC S IN THE CHRONI C RE S PIR ATORY D IS E A S E-INTEG R ATED C ARE PATHWAY
Many patients will predominantly have upper or lower airway diseases. However, it is recommended that every patient with CRS gets at least one systematic evaluation for asthma and allergy preferably by a validated questionnaire and if at risk for asthma, spirometry to assess lung function; skin prick test or measurement of specific blood IgE; and measurement of blood eosinophil counts.
Similarly, for patients with asthma it is recommended that every patient is evaluated for upper airway problems (rhinitis or CRS) and allergy preferably by a validated questionnaire; nasal endoscopy, skin prick test, or measurement of specific blood IgE; and measurement of blood eosinophil counts. However, a subgroup of patients with severe CRS and asthma may benefit from an intensified collaboration between ENT and pulmonologist and where appropriate allergologist.
Remarkably, only a few of the physicians in the Expert Board admitted to having a multidisciplinary outpatient clinic in place.