Chronic rhinosinusitis (CRS) is a prevalent medical condition globally, associated with significant healthcare costs, affecting an estimated 5%–12% of the population [1-5]. Initially, CRS was categorized into two types: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps. However, with growing recognition of CRS’s complex pathophysiology, the 2020 edition of the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS 2020) shifted to a classification based on endotypes rather than phenotypes [6].

The treatment of CRSwNP primarily involves nasal irrigation with saline and the application of topical corticosteroids, supplemented by oral corticosteroids and antibiotics when necessary [7]. However, some refractory CRSwNP cases, particularly those with a dominant type 2 (T2) inflammatory profile, do not respond adequately to standard therapies. These cases often require multiple surgeries or prolonged use of oral corticosteroids [8-10]. This challenge has spurred the development of biologics that target the T2 inflammatory pathway [11]. Following the approval of dupilumab by the U.S. Food and Drug Administration and the European Medicines Agency in 2019, new treatment avenues for T2 CRSwNP have opened up, and the introduction of additional monoclonal antibodies is expected [12].

Dupilumab is a human monoclonal antibody that specifically targets the interleukin (IL)-4Rα receptor subunit, inhibiting IL-4 and IL-13 signaling. It is now approved for use in treating patients with refractory CRSwNP [13]. Dupilumab is recommended for CRS patients with bilateral polyps who have undergone endoscopic sinus surgery (ESS) and meet at least three of the following five criteria: evidence of T2 inflammation, the need for systemic corticosteroids, significantly impaired quality of life, substantial loss of smell, and comorbid asthma [6]. The recommended dosage is 300 mg administered subcutaneously every 2 weeks. In the phase 3 trials (SINUS 24, 52) involving patients with CRSwNP, a 300 mg subcutaneous injection of dupilumab every 2 weeks reduced the nasal polyp score (NPS) by approximately 2 points at week 24 [14].

In Korea, dupilumab received approval from the Korean Food and Drug Administration and has been available for prescription since September 2018 [15]. Currently, the National Healthcare Insurance of Korea covers dupilumab for severe atopic dermatitis or asthma when specific criteria are met, but it does not extend coverage to patients with CRSwNP. Consequently, due to the burden of continuous biweekly injections of dupilumab, ESS, which is more cost-effective, is often prioritized as the treatment of choice over dupilumab in clinical practice [16].

Korean patients with T2 CRSwNP have a lower burden of T2 inflammation and fewer CRS comorbidities than patients from Western regions [17-19]. Since dupilumab, a monoclonal antibody, is cleared through a target-mediated mechanism, it is possible that fewer target molecules are present in Korean patients with a lower disease burden than in Western patients with a higher disease burden, such as asthma comorbidity. This suggests the possibility of extending the dosing interval in South Korea [18]. Notably, a randomized, double-blind phase 3 trial of dupilumab showed no statistically significant difference in efficacy between patients who received dupilumab every 2 weeks for 52 weeks and those who received it every 2 weeks for 24 weeks followed by every 4 weeks for the remaining 28 weeks [14]. This finding suggests the potential for extending dosing intervals in CRSwNP patients once the disease burden has been sufficiently reduced.

Despite the ongoing debate regarding the optimal frequency and duration of dupilumab prescriptions for Korean patients, particularly in light of cost-effectiveness concerns, a recent study has shown promising results. It reported that extending the interval between doses to 2 weeks was effective for those who had a moderate to excellent response after 24 weeks of biological treatment. This method of adjusting dupilumab dosage based on the biological response and control of CRS could potentially be applied to most patients, thereby improving cost-effectiveness over time [20]. Additionally, for Korean patients with a low disease burden, it is anticipated that increasing the dosing interval with minimal interim periods could be feasible. In our research, we adjusted the dosing intervals based on patient symptoms, utilizing the Sino-nasal Outcome Test (SNOT-22), and evaluated the outcomes. The goal of this study is to determine if adjusting the interdose intervals of dupilumab based on SNOT-22 results can maintain long-term efficacy and patient satisfaction in cases of CRSwNP.

CRS is classified into type 2 and non-type 2 based on the primary pathophysiological inflammation mechanism [13]. The prognosis varies depending on the type. T2 CRS is associated with a higher incidence of anosmia, asthma comorbidity, and a higher recurrence rate following ESS [23,24]. The primary treatments for CRS are intranasal corticosteroids and nasal irrigation [6,25]. If these are ineffective, treatment may include systemic montelukast and/or short-term systemic corticosteroids [6]. Conventional surgical treatment is considered for patients who do not respond to these medications [6]. While ESS can significantly reduce the disease burden in a short period, it is associated with a high recurrence rate and does not markedly improve olfaction [26]. After ESS, patients may occasionally need systemic oral steroids, a strategy that is not sustainable due to the potential for iatrogenic harm [27].

The emergence of biologics signifies a fundamental change in the treatment paradigm for CRSwNP. Conditions previously considered refractory to medical and surgical treatments for CRSwNP are now often effectively managed with biologic therapies [11,12]. A post hoc analysis of phase 3 studies on dupilumab revealed substantial improvements in nasal congestion symptom scores, NPS, and Lund-Mackay CT scores following biweekly administration of dupilumab for a minimum of 24 weeks in patients with CRSwNP [14].

Regarding cost-effectiveness, some ethical challenges have emerged in formulating individual treatment plans [28]. The strategy must benefit patients, avoid harm, respect patient autonomy, and ensure equitable resource distribution—these are the primary concerns. In Korea, for instance, patients are required to pay the full cost of dupilumab, which is 506.13 USD (675,807 KRW) per 300 mg dose. Consequently, biweekly dupilumab therapy incurs a monthly cost of 1,012.26 USD (1,351,625.23 KRW), representing a substantial financial burden for CRSwNP patients lacking national or private health insurance coverage. The application of real-world evidence and practical experience will continue to refine treatment methodologies, improving patient selection, optimizing therapies, and enhancing cost-effectiveness. This iterative process is designed to promote the long-term, sustainable use of this costly treatment option [29,30].

Tapering, also known as gradual dose reduction, is a strategy commonly employed in the clinical use of biological therapies across a wide range of medical conditions [31-35]. This approach is often associated with significant costs; therefore, the primary objective is to improve cost-efficiency while reducing risks, particularly when agents might lead to unpredictable or unintended effects [36]. By extending the intervals between doses of dupilumab, this method aims to lessen the burdens on patients by addressing issues related to the administration of the medication and its impact on daily life. Gradual dose reduction not only decreases the frequency of injections but also has the potential to mitigate common side effects [37]. Similar strategies have been evaluated in other medical conditions, such as rheumatoid arthritis, psoriasis, and closely related conditions like asthma and atopic dermatitis [38-40].

Although a formal evaluation of the cost-effectiveness of dupilumab for CRSwNP is still pending, it is likely that the direct costs associated with this treatment are significantly higher compared to conventional non-biological therapies. The annual cost of dupilumab is estimated at US $31,000, with single costs of US $8,968 for uncomplicated ESS and US $16,877 for an ESS with a major complication. In contrast, the surgical strategy incurs a total cost of US $50,436.99 and yields 9.80 quality-adjusted life years (QALYs), while the total cost of dupilumab treatment reaches US $536,420.22, generating 8.95 QALYs over a 10-year period. Consequently, treatment with dupilumab is more than 10 times as expensive per QALY, according to published improvements in quality of life [41]. It may be possible to extend the interval between treatments once disease control is achieved, as demonstrated in the LIBERTY NP SINUS-52 study. In this study, patients who transitioned to a 4-weekly dupilumab schedule maintained improvements comparable to those on a 2-weekly regimen [14]. This approach has been further validated in a large cohort of CRSwNP patients treated with dupilumab. The practice of gradually increasing dosage intervals, sometimes up to one injection every 8 weeks, is also being emphasized and attempted in Western countries, while still maintaining effective disease control [42]. A recent study suggested that tapering dupilumab by extending dosing intervals to at least every 8 weeks, based on biological response and CRS control assessments every 24 weeks, could be applicable to the majority of patients, potentially enhancing cost-effectiveness [20]. Additionally, the milder histological characteristics of T2 CRSwNP in Korea compared to Western countries may facilitate the feasibility of dupilumab tapering [1].

This study has several limitations due to its retrospective nature. Objective outcome measurements, including molecular biomarkers and smell tests, should be incorporated in future studies. Additionally, prospective studies involving larger patient populations and extended treatment periods with dupilumab are needed to assess the clinical efficacy of tapering the medication.

In conclusion, this study is the first to demonstrate in a real-life setting that gradually tapering dupilumab is highly effective for Korean patients with CRSwNP that is difficult to manage, in line with EPOS 2020 criteria. Adjusting the timing of dupilumab injections based on SNOT-22 scores consistently improves clinical outcomes and patient satisfaction. Further prospective trials and broader studies are necessary and will greatly aid in the development of clinical guidelines for dupilumab use.