INTRODUCTION
The prevalence of chronic rhinosinusitis with nasal polyps (CRSwNP) ranges from 2.1% to 8.4% worldwide [1-4]. CRSwNP has a poorer prognosis than CRS without polyps; many refractory CRSwNP cases exhibit marked eosinophil and mast cell infiltration into the nasal mucosa and polyp tissues [5]. The principal feature of eosinophilic-dominant CRSwNP is an inflammatory response induced by T-helper 2 (Th2) cells, as revealed by local and systemic increases in the levels of type 2 cytokines, including eosinophil cationic protein, eotaxin, interleukin (IL)-4, IL-5, and IL-13. These Th2 cytokines play important roles in the pathophysiology of CRSwNP [6]. Intranasal corticosteroids are often prescribed; in severe cases, short-term systemic steroids are also given [7]. Endoscopic sinus surgery (ESS) with or without polypectomy is recommended for patients who do not respond to drugs [5]. However, the underlying inflammatory process may not resolve after surgery; symptoms and polyps may recur, particularly when type 2 inflammation is severe [8]. Therefore, treatment that directly targets type 2 inflammation is desirable, since such an approach would minimize the side effects of systemic immunosuppression via selective immunomodulation and ultimately induce immune tolerance by restoring the balance of the immune system [9]. Dupilumab inhibits IL-4/IL-13 signaling and type 2 inflammation, and is currently approved as a maintenance treatment for adults with refractory CRSwNP [6].
Evidence bearing on the safety and efficacy of dupilumab in CRSwNP patients has recently been presented by researchers from various institutions. Therefore, this meta-analysis evaluated the effect of dupilumab on CRSwNP in terms of clinical findings, patient-reported symptom changes, and morbidity.
METHODS
Study selection
We extracted studies published in or before December 2022 from the PubMed, Scopus, Embase, Web of Science, and Cochrane databases using the search terms “nasal congestion,” ‘nasal obstruction,” “dupilumab,” “quality of life,” “olfaction,” “chronic sinusitis,” “chronic rhinosinusitis,” “nasal polyp,” and “polyps.” Two authors (JK and DHK) independently checked all abstracts. When the relevance was not clear from the abstract alone, the full text was checked. If the reviewers disagreed, the issue was solved by discussion with a third reviewer (SHH). The inclusion criteria were a comparison of dupilumab treatment outcomes to pretreatment status or the outcomes of a control (placebo) group and a comparison of dupilumab to ESS. Studies using biologics other than dupilumab were excluded, as were studies that lacked a clear presentation of quantifiable data. Fig. 1 summarizes the search strategy.
Data extraction and risk of bias assessment
Data were extracted using a standardized form [10,11]. We analyzed two types of outcomes [9,12-18]. Objective clinical markers included the endoscopic nasal polyp score (0–8; higher values correspond to poorer results), the Lund-Mackay computed tomography (LMCT) score (0–24; higher values indicate more opacification), the University of Pennsylvania Smell Identification Test results (0–40; higher values [35–40] reflect normal olfaction), and the results of other smell tests. Subjective clinical markers included the 22-item SinoNasal Outcome Test (SNOT-22) scores (0–110; higher values correspond to poorer outcomes), nasal congestion/obstruction symptoms (0=none, 1=mild, 2=moderate, 3=severe), and sinusitis symptom severity (visual analog scale; VAS) (0–10; higher scores indicate more severe symptoms). We also compared pre- and post-treatment or control and post-treatment ESS outcomes during the follow-up period (12–13 months). Furthermore, we extracted patient numbers, age, and sex, as well as the study design. For non-randomized controlled studies, the Newcastle-Ottawa Scale was used to assess the risk of bias. The quality assessment of randomized controlled trials employed the Cochrane Risk of Bias tool.
Statistical analysis
The meta-analysis employed R software ver. 4.2.2 (R Foundation for Statistical Computing, Vienna, Austria). When the measured outcome was a continuous variable, the effect size was expressed using the mean difference (MD) and 95% confidence interval (CI), corresponding to the difference between the means of the treatment and control groups. The results of studies that used the same outcomes and measurement modes (the VAS nasal congestion score for sinusitis; and the SNOT22, LMCT, and nasal polyp scores) were pooled and subjected to MD calculations. In the olfactory function test, the standardized mean difference (SMD) was calculated using various methods that evaluated the same outcome. In the clinical context of SMDs, an effect size of about 0.206 is considered small, 0.506 medium, and ≥0.806 both large and clinically significant. Heterogeneity was assessed using the Cochrane Q and I2 tests. Funnel plots were drawn and the Egger test applied to seek potential publication bias. We used the trimand-fill method of Duval and Tweedie to evaluate publication bias based on the summed effect size.
RESULTS
Eight studies (1,251 patients) met the inclusion criteria, and the characteristics of the studies included in the meta-analysis are listed in Supplementary Table 1 (in the online-only Data Supplement). The bias assessment results are shown in Supplementary Tables 2 and 3 (in the online-only Data Supplement).
Changes in CRS-related outcomes after dupilumab treatment
Dupilumab reduced LMCT score compared to baseline at 3–4 months (MD, -9.2000; 95% CI, -11.7557 to -6.6443; I2 not applicable) and 6–8 months (MD, -6.8723; 95% CI, -8.6181 to -5.1265; I2=88.8%) (Supplementary Fig. 1 in the online-only Data Supplement). The difference between the two periods was significant (p=0.1405) (Table 1). Dupilumab reduced baseline nasal congestion at 3–4 months (MD, -1.0000; 95% CI, -1.3542 to -0.6458; I2 not applicable), 6–8 months (MD, -1.3849; 95% CI, -1.7195 to -1.0503; I2=93.1%), and 12–13 months (MD, -1.7814; 95% CI, -2.5751 to -0.9876; I2=97.8%) (Supplementary Fig. 2 in the online-only Data Supplement). The differences were significant at both 3 and 12 months (p=0.1189) (Table 1). Dupilumab reduced the nasal polyp score at 3–4 months (MD, -2.6903; 95% CI, -4.1582 to -1.2225; I2=91.7%), 6–8 months (MD, -2.9647; 95% CI, -3.8076 to -2.1218; I2=96.1%), and 12–13 months (MD, -3.7891; 95% CI, -5.4599 to -2.1183; I2=97.0%) (Supplementary Fig. 3 in the online-only Data Supplement). The 3- and 12-month differences varied significantly (p=0.6002) (Table 1). Dupilumab improved olfactory function compared to baseline at 3–4 months (SMD, 1.9022; 95% CI, 1.2857 to 2.5187; I2 not applicable), 6–8 months (SMD, 1.2167; 95% CI, 1.0905 to 1.3429; I2=0.0%), and 12–13 months (SMD, 1.4139; 95% CI, 1.1156 to 1.7123; I2=59.8%) (Supplementary Fig. 4 in the online-only Data Supplement). The 3- and 12-month values differed significantly (p=0.0602) (Table 1). Dupilumab improved the SNOT-22 score from baseline to 3–4 months (MD, -31.4118; 95% CI, -36.2351 to -26.5886; I2=0.0%), 6–8 months (MD, -32.5001; 95% CI, -38.6271 to -26.3731; I2=89.7%), and 12–13 months (MD, -41.5717; 95% CI, -56.1916 to -26.9518; I2=96.4%) (Supplementary Fig. 5 in the online-only Data Supplement). The differences between the 3- and 12-month values were significant (p=0.4331) (Table 1). Dupilumab improved the sinusitis VAS score compared to baseline at 3–4 months (MD, -4.9519; 95% CI, -5.9546 to -3.9492; I2=56.4%), 6–8 months (MD, -4.8422; 95% CI, -5.4014 to -4.2831; I2=86.8%), and 12–13 months (MD, -5.8090; 95% CI, -6.5847 to -5.0333; I2=62.1%) (Supplementary Fig. 6 in the online-only Data Supplement). The differences between the 3- and 12-month values were significant (p=0.1299) (Table 1).
We explored whether ESS (the current standard treatment) was better than biologic treatment. ESS significantly reduced the disease-specific quality of life SNOT-22 score and the olfactory function and nasal congestion scores from baseline to 6–8 and 12–13 months postoperatively (Supplementary Figs. 7-9 in the online-only Data Supplement). Compared to the ESS group, dupilumab treatment was associated with poorer outcomes, as revealed by the postoperative disease-specific SNOT-22 quality of life score (6–8 months: MD, 4.2021; 95% CI, 1.5954 to 6.8089; I2=98.9%; 12–13 months: MD, 2.7431; 95% CI, -1.5734 to 7.0596; I2=51.0%) and the nasal congestion score (6–8 months: MD, 0.6051; 95% CI, 0.5169 to 0.6933; I2=97.6%; 12–13 months: MD, 0.7500; 95% CI, 0.7116 to 0.7884; I2 not applicable) (Table 2); however, the difference in olfactory function was not significant (MD, 1.9849; 95% CI, -1.6190 to 5.5888; I2=0.0%). Dupilumab may be less effective than ESS in terms of improving nasal congestion and quality of life. However, only two studies featured sham-operated groups, and the results must thus be interpreted with caution.
Risk of bias assessment
There was no evident publication bias in terms of the nasal polyp score (p=0.05959), SNOT-22 score (p=0.07339), or the sinusitis VAS score (p=0.9539) (Supplementary Fig. 10 in the online-only Data Supplement). Publication bias in terms of the nasal congestion score, the LMCT, and olfactory function was not assessed because the number of trials included was too small to allow for funnel plot evaluation or advanced regression-based assessments.
DISCUSSION
In this meta-analysis, we evaluated the efficacy of dupilumab in CRSwNP patients and compared the effects to those of ESS. Dupilumab improved the nasal polyp and LMCT scores, as well as nose-related quality of life indicators, including olfactory function, the SNOT-22 score, and the sinusitis VAS score. Compared to ESS, which is the current standard of care for patients with intractable CRSwNP, the improvements in olfactory function afforded by dupilumab and ESS were similar, but ESS led to greater improvements in the SNOT-22 score and nasal congestion.
The classification of CRS by the endotype rather than the phenotype has recently become gradually systematized, and the treatment strategies have been optimized [5,19]. With the exceptions of some Asian cases, most patients with severe CRSwNP exhibit a type 2-dominant endotype [20,21]. The initial treatment is nasal saline irrigation and intranasal corticosteroid administration [5,22]. ESS is recommended when there is no improvement despite appropriate medical treatment. However, the polyp recurrence rate after surgery is quite high (40%–60%) [23,24]. Polyps recur after surgical removal if the underlying cause of inflammation is not appropriately addressed [7]. Treatment must consider the underlying pathophysiology; anti-immunoglobulin E (IgE; omalizumab), anti-IL-4/IL-13 (dupilumab), and anti-IL-5 (mepolizumab) antibodies have thus been developed. Several biologics targeting type 2 inflammation, including anti-IL-5 receptor α (benralizumab) monoclonal antibodies, have been commercialized, and others are under development [25]. Dupilumab was the first such drug to receive approval from the Food and Drug Administration for use in CRSwNP patients, and more clinical trial data are thus available than is the case for other biologics. The efficacy and side-effects of dupilumab inform the use of biologics to target type 2 inflammation-dominant CRSwNP. After the large, randomized controlled trials of Bachert et al. [9], various clinical studies have shown that dupilumab exerts significant effects on CRSwNP without major side effects. Dupilumab is a good treatment option for CRSwNP patients with various underlying diseases.
However, special considerations arise when employing biologics, including dupilumab. As mentioned above, patients with severe CRSwNP often exhibit a type 2-dominant endotype, but mixed-type or neutrophil-dominant cases also exist. Therefore, the standard definition of type 2 inflammation (tissue eosinophil level ≥10/high-power field, blood eosinophil level ≥250 cells/mm3, or total IgE level ≥100 kU/L) of the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 [5] may require correction because of drug reactions. Studies on patients with asthma and atopic dermatitis prescribed biologics earlier than CRSwNP cases found that assays of type 2 inflammatory biomarkers displayed certain limitations in terms of determining individual responses to biologics, and prognoses [26,27]. A follow-up study after dupilumab discontinuation reported polyp recurrence [9]. A cost–benefit analysis suggested that the annual drug cost of US $36,000 drug cost was excessive [28,29]. Although there are few relevant studies, we found that dupilumab cannot completely replace ESS. For patients with contraindications to or concerns about general anesthesia, dupilumab may be the first choice. Otherwise, the drug may be appropriate only when nasal polyps recur after surgery.
Although we present evidence supporting the use of dupilumab in patients with CRSwNP and compare the effects of the drug to ESS, our analysis has certain limitations. First, although all recent clinical studies on dupilumab were included, the number of studies was small and the follow-up periods were relatively short; therefore, the results should be generalized only with caution. Second, neither the treatment nor maintenance period was standardized. The effects of drug cessation and periodic administration should be explored to reveal the duration of drug efficacy and enable standardization of the dose and the intervals between maintenance treatment. Third, the efficacy of combination therapies other than dupilumab and intranasal steroids should be evaluated.
In future studies, it would be necessary to subjectively and objectively compare the effects of biologic agents other than dupilumab and ESS.
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