PDF
Citation
Print
INTRODUCTION
Chronic rhinosinusitis with nasal polyps (CRSwNP) is one of the most common diseases encountered in the field of otorhinolaryngology [1]. It is typically characterized by a persistent disease burden that leads to long-term socioeconomic challenges and diminished quality of life [2]. Standard medical treatments include nasal saline irrigation, topical steroid sprays, long-term antibiotic therapy, and short courses of systemic glucocorticoids [3]. However, even repeated endoscopic sinus surgeries have proven insufficient in curing challenging refractory cases. Biologics targeting type 2 immune effectors—such as interleukin (IL)-4, IL-5, IL-13, and free immunoglobulin E (IgE)—have provided novel therapeutic options for patients with severe and uncontrolled CRSwNP [3,4].
The introduction of biologics for CRSwNP has given physicians an additional therapeutic option for patients with severe and/or uncontrolled disease [4]. However, at that time, detailed clinical data regarding their use were limited. Clinical decisions were primarily guided by the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS) 2020 and the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) guidelines [3,4]. Since then, several clinical studies and review articles have been published on the use of biologics in CRSwNP. We also published review papers on the practical use of biologics for CRSwNP, tailored to the Korean context, in the Journal of Rhinology in 2021 [5] and in the online book Chronic Rhinosinusitis Update in 2022 [6].
As the body of knowledge expands, guidelines for indications, effectiveness, response definitions, administration intervals, treatment switches, cessation, and termination timing are gradually being established. In light of the EPOS/ EUFOREA 2023 update [7], we aim to review and update the relevant information to better reflect the current situation in Korea.
More specifically, we will discuss the following topics: updates on the clinical indications for biologics in CRSwNP, definitions of response and treatment duration, criteria for discontinuing or switching biologics, and recent regulatory updates and emerging biologic agents.
UPDATED INDICATIONS OF BIOLOGICS FOR CRSWNP
In the new EPOS/EUFOREA 2023 criteria [7], the presence of bilateral polyps in patients who have undergone endoscopic sinus surgery remains the primary criterion, as in EPOS 2020 (Fig. 1). Debate has arisen regarding the extent of surgery [8]; however, evidence is limited to suggest that more extensive surgery yields improved outcomes for CRSwNP [9,10]. Therefore, the extent of surgery was not incorporated into the updated EPOS/EUFOREA 2023 criteria [7].
Next, defining type-2 inflammation clinically is crucial for successful biologic treatments. Specifically, the blood eosinophil threshold was reduced from ≥250 cells/μL to ≥150 cells/ μL, in alignment with the updated Global Initiative for Asthma (GINA) guidelines [11]. This adjustment is the only revision; the other four criteria—including the need for systemic steroids (or a contraindication to them), a Sinonasal Outcome Test (SNOT)-22 score of ≥40, anosmia on smell testing, and comorbid asthma—remain unchanged from EPOS 2020. Biologic treatment for CRSwNP should be considered when at least three of these five criteria are met.
There was also discussion regarding whether other type-2 inflammatory diseases, apart from asthma, should serve as criteria for biologic use. However, the lack of correlation between CRSwNP and other type-2 conditions such as allergic rhinitis [3], atopic dermatitis [12,13] or eosinophilic esophagitis [14,15], resulted in the exclusion of these diseases from the criteria.
Recent studies have increasingly focused on the use of biologics in CRSwNP patients without a surgical history rather than solely in cases of postoperative recurrence. According to the previous EUFOREA consensus, patients without a surgical history must meet at least four of the aforementioned criteria to qualify for biological treatment [4]. Additionally, Huang et al. [16] provided a clinical commentary on the development of the mucosal concept in CRS, suggesting that preoperative biologic use may improve postoperative wound healing. Furthermore, a review by an expert group from the Asia-Pacific region and Russia suggested that biologics could serve as an alternative to surgery for patients who are either unsuitable for or decline surgical intervention. However, current guidelines still lack detailed discussion on biologic use in patients who have not undergone surgical treatment. Conversely, dupilumab has shown promise as a short-term adjuvant therapy for CRSwNP in the postoperative setting [17]. Additionally, a retrospective case-control study of 32 CRSwNP patients indicated that combining surgical therapy with biologics resulted in the greatest reduction in polyp burden compared to biologic therapy alone, although this difference did not reach statistical significance [18].
In pregnant women, omalizumab remains the only available biologic agent for CRSwNP. A cohort study showed no increase in congenital anomalies or adverse outcomes in a registry of pregnant asthmatics treated with omalizumab [19].
Given the strong efficacy of biologics in treating CRSwNP, their preventive use may be beneficial. However, there is currently no definitive evidence that biologics can prevent the development of nasal polyps [7]. A previous pediatric study on omalizumab in patients with pre-wheezing or non-asthmatic wheezing demonstrated that biologics could prevent additional sensitization, although they did not clinically prevent asthma [20]. In clinical practice, early use of biologics to prevent postoperative recurrence may be a viable preventive strategy. Nonetheless, the high cost of biologics remains a significant barrier to their widespread prescription.
DEFINING THE RESPONSE AND TREATMENT INTERVALS
Similar to the EPOS 2020 guidelines, the updated EPOS/EUFOREA defines response to biologics using five criteria: reduction in nasal polyp size, decreased need for systemic corticosteroids, improved quality of life, enhanced sense of smell, and impact on comorbidities (Fig. 2) [7].
The response was initially categorized into four levels based on EPOS 2020: no response (0 criteria met), poor (1–2 criteria met), moderate (3–4 criteria met), and excellent (5 criteria met). However, inherent limitations in this classification prevented certain patient groups, such as those with asthma, from achieving an “excellent” response. Thus, the response classification was simplified into three categories: no response (0 criteria met), poor–moderate (1–3 criteria met), and good–excellent (4–5 criteria met). Additionally, the reduced impact of comorbidities should only be considered in patients who actually have them. Furthermore, a reduced need for surgery is regarded as analogous to a decreased need for systemic corticosteroids, as both are considered rescue therapies.
The initial evaluation time for response was previously set at 16 weeks after the first administration [3], but this was considered too early [21,22]. Therefore, EPOS/EUFOREA 2023 has adjusted the first evaluation time from 16 weeks to 6 months. A second evaluation is recommended at 1 year, with subsequent assessments conducted annually. For patients showing no response, options include discontinuing biologics, switching to an alternative biologic, or considering revision surgery. For a poor-to-moderate response, various strategies may be implemented based on patient preferences. If improvement is not deemed significant by either the physician or the patient, switching biologics, revision surgery, or a short course of systemic steroids may be warranted [21]. In cases of a good-to-excellent response, biologic treatments should be continued.
Although the effectiveness of biologics varies depending on the agent and patient severity, approximately 60% of patients experience an improved sense of smell following treatment [23]. Typically, it takes about one month to notice an effect, although this varies significantly among individuals—from a few days to several months [24,25]. Interestingly, contrary to common expectations, there is no positive correlation between reductions in polyp size and improvements in the sense of smell [26]. Once olfactory function improves, olfactory training is recommended to help reactivate the neurogenic pathways responsible for smell [27]. A prospective study of 111 patients using the Korean version of the Sniffin’ Sticks II (KVSS-II) test demonstrated that a 12-week regimen of repeated short-term odor exposure effectively improved olfactory function in patients who had undergone sinonasal surgery to address sensorineural olfactory impairment [28]. However, definitive data on the time required for overall improvement beyond olfactory gains remain lacking. Meanwhile, the new EPOS/EUFOREA updates emphasize the need to collect real-life data, particularly regarding the use of biologics in non-operated or less severe patients [7].
The administration durations in previously published key studies—including LIBERTY SINUS-24 and -52 for dupilumab—were as follows: every two weeks for 24 weeks (SINUS-24) and every two weeks for 24 weeks followed by monthly dosing for an additional six months (SINUS-52) [29]. Other key studies on omalizumab (POLYP1 and POLYP2) used 2- or 4-week intervals [30]. However, in real-world clinical settings, physicians and patients have expressed concerns about these short administration intervals due to cost-effectiveness considerations. In these studies, reducing dupilumab dosing to once every four weeks produced outcomes comparable to biweekly administration. Additionally, a retrospective analysis of 44 CRSwNP patients in Korea revealed no significant difference in symptomatic satisfaction—measured by changes in SNOT-22 scores—between patients with administration intervals of less than 2 months and those with intervals of 2 months or longer [31]. Therefore, longer administration intervals may be a viable option for patients whose condition remains well controlled. Unfortunately, no specific guidelines have yet been established for dosing intervals in practical clinical settings.
REASONS TO SWITCH OR STOP BIOLOGICS AND TREATMENT TERMINATION
Although the unified airway concept emphasizes similarities between the upper and lower airways [32,33], the effectiveness of biologic agents varies according to their target site. Some biologics are more effective for upper airway conditions such as CRSwNP, while others demonstrate greater efficacy in lower airway conditions like asthma. In such cases, switching biologic agents should be considered; however, predicting which agent will be most beneficial remains challenging. Therefore, thorough investigation into biomarkers that predict favorable outcomes for specific biologics is essential. Moreover, no practical, evidence-based criteria exist for determining when to switch from one biologic to another or for selecting the preferred agent. It is crucial to gather data to establish practical guidelines for switching biologics in CRSwNP that are appropriate for the Korean context.
Hypereosinophilia is a common, transient phenomenon following the administration of anti-IL-4α, typically lasting between 2 and 6 months [29]. However, if hypereosinophilia persists alongside clinical symptoms, close monitoring is necessary, as it may lead to organ damage [34,35]. Routine blood eosinophil counts are recommended at one and three months after the initial administration. More frequent monitoring is advised for patients with high baseline eosinophil counts (>500/μL) or those with a history of long-term systemic steroid use prior to biologic treatment. Additionally, a thorough evaluation of symptoms and signs of vasculitis, along with regular monitoring for hypereosinophilia, is essential. In cases where eosinophil counts exceed 3,000 cells/μL, adjustments such as extending the administration interval to every four weeks or initiating a short course of systemic steroids may be warranted. Persistent vasculitis-related symptoms should prompt consultation with the internal medicine department [36].
Regarding the termination of biologics in CRSwNP, definitive guidelines are lacking. EPOS/EUFOREA 2023 recommends discontinuing biologics if there is no response based on the specified criteria [7]. However, clear guidance on the duration of treatment for well-controlled patients is absent. In previous CRSwNP trials, the maximum treatment duration with biologics has been one year [29,30]. Asthma trials may offer insights and serve as references for defining biologic treatment endpoints. For instance, the Xolair Persistency Of Response After Long-Term Therapy (XPORT) study—a multicenter, randomized, double-blind trial—concluded that many patients with severe asthma remained well controlled even after discontinuing omalizumab [37]. Additionally, a prospective study on omalizumab in severe asthma patients found that long-term positive effects persisted for at least four years post-termination in 60% of participants [38]. Interestingly, the failure group in that study was more likely to have CRSwNP than the success group. Similarly, a randomized controlled trial on mepolizumab demonstrated only a modest 14% increase in asthma exacerbations during the year following discontinuation [39]. There was no significant increase in severe asthma exacerbations, and clinical parameters—including pulmonary function tests—showed no deterioration 1 year post-discontinuation.
Based on these findings, although the exact duration of biologic administration cannot be predetermined, discontinuation should be considered in clinically well-controlled CRSwNP patients. Comorbidities should be carefully assessed, as they may increase the risk of treatment failure [40].
RECENT REGULATORY UPDATES AND NOVEL BIOLOGIC AGENTS
As of November 2024, dupilumab and omalizumab remain the only biologics approved and available for CRSwNP in Korea (Table 1). The details related to the approval of each biologic agent by disease and country are as follows.
Dupilumab (an IL-4Rα antagonist) has been approved for multiple conditions, including atopic dermatitis, asthma (primarily type 2, eosinophilic, or systemic corticosteroid-dependent), CRSwNP, eosinophilic esophagitis, and prurigo nodularis in Europe, the United States, Korea, and Japan (Table 1). Recently, dupilumab became the first biologic approved in Japan for the treatment of chronic spontaneous urticaria. Additionally, it has been approved for chronic obstructive pulmonary disease in Europe. Notably, in Japan, dupilumab’s approval for asthma encompasses the broader indication of bronchial asthma.
Omalizumab (a free IgE antagonist) has also been approved for allergic asthma, CRSwNP, and chronic spontaneous urticaria in Europe, the United States, and Korea. Interestingly, omalizumab has been approved for IgE-mediated food allergy in the United States and for seasonal allergic rhinitis in Japan.
Mepolizumab (an IL-5 antagonist) has been approved for eosinophilic asthma, CRSwNP, and eosinophilic granulomatosis with polyangiitis in Europe, the United States, and Japan. However, in Korea it is approved only for eosinophilic asthma, and it has not yet received approval for CRSwNP. In Japan, mepolizumab has recently been approved for CRSwNP, and its asthma indication covers a broader spectrum of bronchial asthma rather than being limited to eosinophilic asthma, similar to dupilumab. Additionally, reslizumab (an IL-5 antagonist) is approved for eosinophilic asthma in Europe, the United States, and Korea. Benralizumab (an IL-5Rα antagonist) is also approved for eosinophilic asthma in Europe, the United States, and Korea. In Japan, benralizumab’s approval for asthma is as broad as that for bronchial asthma, similar to the approvals for dupilumab and mepolizumab.
Beyond suppressing type 2 cytokines, biological agents that target type 1 cytokines or mucosa-derived cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin—or that regulate B cell isotype switching—represent potential new therapeutic concepts. The following novel biologics and their latest approval details are described below.
Tralokinumab (an IL-13 antagonist) was approved for atopic dermatitis in the US (2021), Europe (2021), and Korea (2023). Lebrikizumab (also an IL-13 antagonist) received approval for atopic dermatitis in the US (2021), Europe (2023), and Korea (2024). Tezepelumab (a thymic stromal lymphopoietin antagonist) has been approved for asthma in the US (2021), Europe (2022), and Korea (2023). Tezepelumab targets thymic stromal lymphopoietin, an epithelial cytokine that activates multiple downstream inflammatory pathways, thereby reducing the overall inflammatory response.
SPECIFIC CONSIDERATIONS REGARDING THE USE OF BIOLOGICS FOR TREATING CRSWNP IN KOREA
A Korean Rhinologic Society study group surveyed 44 members regarding their experience with biologic treatments for CRSwNP [41]. The study revealed that 86.4% of respondents had prescribed biologics, with dupilumab as the preferred choice (71.1%). The primary indication for biologic use was recurrent nasal polyps after surgery (87.2%). However, high cost (48.6%) was the most common reason for discontinuation. Given the differences in CRS endotypes between Korea and Western countries, 93.2% of respondents agreed on the need for Korean-specific guidelines.
From a cost-effectiveness perspective, a comparative study has shown that even in the United States—where surgery and anesthesia costs are high—endoscopic sinus surgery is more cost-effective than biologics for CRSwNP [42]. Currently, no cost-effectiveness studies comparing surgery and biologics for CRSwNP have been conducted in Korea. However, because surgery and anesthesia costs are significantly lower in Korea than in the U.S., the high cost of biologics remains a major barrier to their widespread use, making surgical treatment the more accessible option.
In Korea, neither dupilumab nor omalizumab is covered by national health insurance for CRSwNP, meaning that patients must bear the full cost. As of August 2024, the publicly announced price of Dupixent in South Korea—according to the Ministry of Food and Drug Safety (MFDS)—is approximately 680,000 KRW, while Xolair is priced at approximately 216,000 KRW. Due to this substantial financial burden, many patients are unable to adhere to the originally recommended biweekly dosing schedule and instead receive monthly or even less frequent doses.
A retrospective study involving 44 Korean patients demonstrated that, even with adjusted dosing intervals, subjective quality of life was well maintained. Therefore, the authors suggest that if symptoms are adequately controlled and endoscopic findings remain stable, extending the dosing interval to one month or longer may be a feasible approach in Korea.
Recently, the indications for biologics in Korea have expanded. In addition to patients with recurrent CRSwNP after surgery, as recommended by the EPOS/EUFOREA update [7], biologics are also being used as an alternative to surgery in patients who have not undergone surgical intervention.
The articles published by Korean authors are summarized in Table 2 [5,31,41,43-52]. Since biologic use for CRSwNP began in Korea in 2021, most early publications were narrative reviews. However, more recently, original articles—including observational studies, case-controlled studies, and meta-analyses—have emerged. Practical considerations specific to Korea, such as interval dosing and comparisons to surgery, have been analyzed [31,43-45]. Despite this progress, well-controlled prospective studies are still lacking.
CONCLUSION
In the new EPOS/EUFOREA guidelines, the criterion for type 2 inflammation has been relaxed from a blood eosinophil count of ≥250 cells/μL to ≥150 cells/μL, while other indications remain unchanged. Although recurrence after endoscopic sinus surgery remains the primary criterion, positive results have recently been reported in non-operated CRSwNP patients and in less severe cases that do not fully meet the EPOS criteria. This suggests that, in practice, biologics may be effectively applied to a broader patient population in the future.
Regarding response evaluation, the categories have been simplified and the initial evaluation time extended from 16 weeks to 6 months. Originally, administration intervals were recommended every 2 or 4 weeks, but recent data demonstrating effective control with intervals of 4 weeks or even 2 months provide a rationale for extending dosing intervals. For patients with prolonged hypereosinophilia accompanied by symptoms or signs of vasculitis and a blood eosinophil count of 3,000 cells/μL, clinicians should consider extending the administration interval to every four weeks, initiating a short course of systemic steroids, and consulting with internal medicine.
This update reviews changes in practice profiles based on EPOS/EUFOREA 2023, incorporating relevant clinical data. We anticipate that this review will aid rhinologists in managing patients with severe and/or uncontrolled CRSwNP. Nevertheless, challenges remain—both clinical, such as the use in non-operated patients and optimal treatment intervals, and administrative, such as high costs and lack of insurance reimbursement. Further studies, such as multicenter surveys tailored to the Korean context, are needed to inform actual practice.
XML Download