Mepolizumab in chronic rhinosinusitis with severe nasal polyposis: Real-life Spanish cohort study

Abstract

Introduction

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a type 2 inflammation-driven condition that causes nasal blockage, olfactory loss, and diminished quality of life. Standard therapies often result in recurrence in severe cases. Mepolizumab, a monoclonal antibody targeting interleukin-5 (IL-5), has demonstrated efficacy in improving clinical symptoms and patient-reported outcomes in phase 3 trials and real-world studies.

Aims

To assess the real-life efficacy and safety of mepolizumab in patients with CRSwNP, both with and without comorbid asthma, over a 12-month period, focusing on nasal symptoms, polyp size, and olfactory function.

Methods

A multicentric, prospective observational study was conducted in three hospitals in Catalonia, Spain, involving 28 adult patients with severe CRSwNP treated with mepolizumab (100 mg subcutaneously every 4 weeks). Assessments were performed at baseline, 6, and 12 months. Outcomes included Nasal Polyp Score (NPS), Sinonasal Outcome Test-22 (SNOT-22), visual analogue scales (VAS) for symptoms and smell, and the 48- complete version of the Sniffin’ Sticks Smell Test.

Blood eosinophil count and adverse events were also recorded.

Results

Significant improvements were observed in NPS, SNOT-22, and symptom VAS at both 6 and 12 months (P < .05). Olfactory function improved significantly at 12 months, while subjective olfactory VAS did not. Blood eosinophils decreased sharply. Patients with asthma and Aspirin-Exacerbated Respiratory Disease (AERD) showed greater clinical benefit. No serious adverse events occurred.

Conclusions

Mepolizumab appears safe and effective for severe CRSwNP, offering substantial clinical and endoscopic improvement. Olfactory gains at one year suggest prolonged treatment may be necessary for sensory recovery.

Resumen

Introduccióm

La rinosinusitis crónica con pólipos nasales (RSCcPN) es una enfermedad inflamatoria de tipo 2 que se manifiesta con obstrucción nasal, pérdida del olfato y deterioro de la calidad de vida. En los casos graves, los tratamientos estándar suelen asociarse a recaídas frecuentes. El mepolizumab, un anticuerpo monoclonal dirigido contra la interleucina-5 (IL-5), ha mostrado eficacia en ensayos clínicos de fase 3 y estudios en vida real, mejorando tanto los síntomas clínicos como los resultados descritos por los pacientes.

Objetivos

Evaluar, en condiciones de práctica clínica real, la eficacia y seguridad del mepolizumab en pacientes con RSCcPN, con y sin asma comórbida, durante 12 meses de tratamiento. El estudio se centra específicamente en los síntomas nasales, incluyendo el tamaño de los pólipos, la obstrucción nasal y la función olfatoria.

Métodos

Se realizó un estudio observacional, prospectivo y multicéntrico en tres hospitales de Cataluña, España. Se incluyeron 28 pacientes adultos con RSCcPN grave tratados con mepolizumab (100 mg subcutáneo cada 4 semanas). Las evaluaciones se realizaron al inicio, a los 6 y a los 12 meses, utilizando el grado de poliposis nasosinusal (Nasal Polyp Score, NPS), el cuestionario Sinonasal Outcome Test-22 (SNOT-22), escalas visuales analógicas (EVA) para síntomas generales y olfato, y la versión completa (48 ítems) del test olfatorio Sniffin’ Sticks. Se registraron también los niveles de eosinófilos en sangre y los eventos adversos.

Resultados

Se observaron mejoras clínicas significativas y sostenidas a lo largo del seguimiento. A los 6 meses, se evidenció una reducción significativa en el NPS y en los puntajes de SNOT-22 y EVA de síntomas nasales (P < ,05), tendencia que se mantuvo o acentuó a los 12 meses. La función olfatoria, evaluada mediante el test Sniffin’ Sticks, mostró una mejora significativa al completar el año de tratamiento, mientras que la percepción subjetiva del olfato (EVA) no presentó cambios relevantes. Los niveles de eosinófilos en sangre descendieron de forma pronunciada desde los primeros meses de tratamiento. Además, los pacientes con asma y con enfermedad respiratoria exacerbada por aspirina (EREA) mostraron una respuesta clínica más favorable. No se registraron eventos adversos graves a lo largo del estudio.

Conclusiones

El mepolizumab demostró ser una opción terapéutica segura y eficaz para el tratamiento de la RSCcPN grave, con mejoras sostenidas en síntomas clínicos, hallazgos endoscópicos y función olfatoria. La ganancia olfatoria significativa tras un año de tratamiento sugiere que puede ser necesaria una duración prolongada de la terapia para lograr una mayor recuperación sensorial.

Introduction

Chronic Rhinosinusitis (CRS) is an inflammation of the nasal and sinus mucosa, persisting for over 12 weeks and often presenting with nasal congestion, excessive mucus production, facial discomfort, and an altered sense of smell.^1,2 Affecting an estimated 10%–11% of the global population, CRS not only reduces quality of life (QoL) but also places a considerable burden on healthcare systems and workplace productivity.^3,4

CRS is subdivided into two main phenotypes: with nasal polyps (CRSwNP) and without (CRSsNP). CRSwNP, present in 3%–4% of the European population, is predominantly mediated by type 2 (T2) inflammation, marked by elevated interleukins IL-4, IL-5, and IL-13.^1,5,6 This endotype is frequently associated with more severe disease, higher recurrence rates, and comorbid conditions such as asthma and aspirin-exacerbated respiratory disease (AERD).^5,7 Patients with severe CRSwNP often undergo repeated endoscopic sinus surgeries (ESS) and require systemic corticosteroids, underlining the need for more durable treatment strategies.^1,6,7

The introduction of biologic therapies has reshaped treatment approaches for CRSwNP, particularly for those with refractory disease.^1,2,6 Mepolizumab, a monoclonal antibody that targets IL-5, has shown promising results in reducing eosinophilic inflammation, shrinking nasal polyps, and alleviating symptoms.^8,9 The SYNAPSE trial, a phase 3 randomized controlled study, demonstrated that mepolizumab significantly improved nasal obstruction and reduced polyp size in patients with severe, recurrent CRSwNP who had failed standard therapy. These findings reinforce its value as an adjunct treatment, particularly in those who might otherwise face repeated surgeries and long-term steroid exposure.⁹

Real-world studies suggest that biologic therapies like mepolizumab not only help relieve nasal symptoms but also improve asthma control in patients with coexisting respiratory conditions, reinforcing their broader clinical benefits.^10,11 Additionally, observational research has shown that patients treated with mepolizumab experience fewer symptoms, require less healthcare intervention, and require fewer oral corticosteroids and surgical procedures. These findings highlight the increasing importance of biologics in tailoring treatment for individuals with severe treatment-resistant CRSwNP.^11,12

The primary aim of this study is to evaluate the efficacy and safety of mepolizumab in the treatment of CRSwNP, both in patients with and without comorbid asthma. Additionally, we aim to provide a comprehensive assessment of olfactory function using the full version of the Sniffin’ Sticks test, in line with the latest guidelines for olfaction evaluation in clinical research, making this one of the few studies to adopt such a thorough approach.¹³

Materials and methods

This was a multicenter, prospective observational study conducted between July 2022 and June 2024 across three hospitals in Catalonia, Spain. The study included a convenience sample comprising all eligible patients who met the inclusion criteria during the study period. Given the real-world and exploratory nature of this study (real-life clinical practice), no a priori sample size calculation was performed. The number of participants reflects the total population available within the defined timeframe which was considered adequate to meet the study objectives.

Eligible patients were adults diagnosed with CRSwNP according to EPOS 2020 criteria,² with or without coexisting asthma, who were prescribed Mepolizumab 100 mg subcutaneously every four weeks, for severe CRSwNP, as an add-on therapy to standard of care (intranasal corticosteroids and saline nasal irrigations). Patients were excluded if they had eosinophilic granulomatosis with polyangiitis (EGPA) or if Mepolizumab treatment was initiated after surgical intervention as a preventive measure to avoid recurrence.

Patients were assessed at three predefined visits: baseline (V0) before starting Mepolizumab, visit 1 (V1) at 6 months, and visit 2 (V2) at 12 months. Baseline data were collected, including demographic characteristics, history of AERD, prior biological treatments, and the number of previous endoscopic sinus surgeries. Baseline CRSwNP severity was defined according to EPOS criteria as the presence of nasal polyps (NPS ≥2) together with a high disease burden, reflected by a Sinonasal Outcome Test-22 (SNOT-22) score >40 and/or an overall symptom visual analog scale (VAS) score >7.²

At each follow-up visit, the following assessments were conducted:

• ●

  Disease severity was evaluated using the SNOT-22 (score range: 0–110) and VAS for overall nasal symptoms (score range: 0–10).

• ●

  The extent of nasal polyps was measured using the Nasal Polyp Score (NPS) (score range: 0–8).

• ●

  Olfactory function was assessed with the complete version of Sniffin’ Sticks Smell Test (SSST) with 48 odorants (score range: 1–48) (Burghardt®, Wedel, Germany) and a VAS for smell loss (score range: 0–10).

• ●

  Type 2 inflammatory markers, including total Immunoglobin E (IgE) and blood eosinophil counts, were also collected.

All investigators were trained in the use of the NPS scoring scale and reached consensus on its application before study initiation, ensuring consistency in assessments across institutions. Olfactory testing with the Sniffin’ Sticks test was performed according to the manufacturer’s recommended guidelines to ensure standardized administration across sites.

The primary endpoint of this study was to assess clinical improvement and effectiveness, defined as a decrease of at least 1 point in the Nasal Polyp Score (NPS) and a decrease of at least 8.9 points in the SNOT-22 test, in accordance with the established criteria.¹⁴ Patients were classified as responders (improvement in both NPS and SNOT-22), partial responders (improvement in only one of the two criteria), and non-responders (no improvement in either criterion).

The secondary endpoint was to analyse the changes in olfactory function. In order to evaluate it, we used the 48-item Sniffin' Sticks test, which provides a composite Threshold-Discrimination-Identification (TDI) score. Both any increase in the TDI score and improvements exceeding the Minimal Clinically Important Difference (MCID) of 5.5 points were considered in the evaluation of olfactory recovery.¹⁵ All adverse events were recorded throughout the observation period.

Continuous variables were summarized as mean and standard deviation (SD), and categorical variables as frequencies (n) and percentages (%). Baseline characteristics across clinical subgroups (No Asthma, Asthma, AERD) were compared using one-way ANOVA for continuous variables and Chi-square or Fisher’s exact tests for categorical variables, as appropriate.

To evaluate the effect of mepolizumab over time, repeated outcome measures were analysed using linear mixed-effects models (MMRM) with a random intercept for each patient. The model assumed that missing data were missing at random (MAR). No data imputation was performed. All models were adjusted for baseline values and visit (0, 6, and 12 months). Estimated marginal means for each visit were obtained, and pairwise post hoc comparisons between time points were performed with 95% confidence intervals.

A predefined subgroup analysis encompassing all study endpoints was performed using an extended MMRM model that included baseline score, visit, subgroup classification (No Asthma, Asthma, AERD), and the interaction between visit and subgroup, to evaluate potential differences in treatment response across inflammatory phenotypes.

A two-sided P-value <.05 was considered statistically significant. All analyses were performed using R statistical software (version 4.3.3).

The study protocol was reviewed and approved by the ethics committees of all three participating hospitals in Catalonia. Written informed consent was obtained from all patients prior to their enrolment in the study (Code EOM024/23).

Results

Baseline characteristics of the population

A total of 28 patients were included in the study, with a mean age of 53.5 years (Fig. 1). The cohort included 16 males (57.1%) and 12 females (42.9%). Twenty-two patients (53.6%) had comorbid asthma, and 7 (25%) met criteria for AERD. Four patients (14.3%) had previously been switched from another biologic treatment. The mean number of previous ESS was 2.36 (SD = 1.54), with 8 patients (28.6%) having undergone one surgery, 12 (42.9%) two surgeries, and 8 (28.6%) three or more (Table 1). When comparing baseline characteristics among subgroups (non-asthmatic, asthmatic, and AERD), no statistically significant differences were observed. The mean age and sex distribution were comparable. While prior biologic switching occurred only in the asthma group (26.7%), this difference was not significant (P = .142). The mean number of previous ESS was also similar across groups and did not reach statistical significance.

Figure 1.

Flowchart showing patient selection and follow-up. EGPA: Eosinophilic Granulomatosis with Polyangiitis.

Table 1.

Demographic characteristics between Asthma, AERD (Aspirin-Exacerbated Respiratory Disease) and non-asthmatic patients.

	Total	No comorbidities	Asthma	AERD
	N = 28	N = 6	N = 15	N = 7
Age, mean (sd)	53.5 (11.3)	52.5 (6.12)	54.6 (13.8)	52.0 (9.66)
Sex, n (%):
Male	16 (57.1%)	4 (66.7%)	9 (60.0%)	3 (42.9%)
Female	12 (42.9%)	2 (33.3%)	6 (40.0%)	4 (57.1%)
Number of Previous Surgeries, mean (sd)	2.36 (1.54)	2.83 (2.04)	2.07 (1.44)	2.57 (1.40)
Number of Previous Surgeries, n (%):
1	8 (28.6%)	0 (0.00%)	7 (46.7%)	1 (14.3%)
2	12 (42.9%)	5 (83.3%)	3 (20.0%)	4 (57.1%)
>=3	8 (28.6%)	1 (16.7%)	5 (33.3%)	2 (28.6%)
Severity of the disease, n (%)	27 (96.4%)	6 (100%)	14 (93.3%)	7 (100%)

The severity of CRSwNP was comparable between patients with and without comorbid asthma, with both groups presenting similar baseline severity and no significant differences observed (P = 1.000) (Table 1). Disease severity was defined according to EPOS based on NPS, SNOT-22 and VAS scores.^1,2

During the follow-up period, one patient was lost and could not be reached for subsequent evaluations, while another did not attend the 12-month visit due to severe clinical worsening that required surgical intervention at month 10 of treatment.

Assessment of mepolizumab's impact on clinical outcomes and measurement of its therapeutic effects

Following the study endpoints, 71.4% (20/28) of patients met the SNOT-22 response criteria and 60.7% (17/28) achieved the NPS response at 6 months. At 12 months, these proportions increased to 80.7% (21/26) and 61.5% (16/26), respectively. A total of 15 patients were identified as complete responders, fulfilling both endpoint criteria (Table 2).

Table 2.

Effectiveness of mepolizumab at 12 months. Patients were classified as responders (improvement in both NPS and SNOT-22), partial responders (improvement in only one of the two criteria), and non-responders (no improvement in either criteria).

	N = 26
Primary Endpoint (12M), n (%):
SNOT-22 & NPS	15 (57.7%)
Partial Responders	7 (26.9%)
Non-responders	4 (15.4%)
Improvement by individual criteria
NPS ( reduction > 1) n (%)	16 (61.5%)
SNOT-22 (decrease >= 8,9 ) n (%)	21 (80.7%)

Significant clinical improvements were observed across all outcome measures. The Nasal Polyp Score showed a statistically significant median reduction of 1.00 (IQR: 0.11–1.89; P = .024) at six months and 1.21 (IQR: 0.30–2.13; P = .006) at twelve months. Patient-reported outcomes also improved substantially, with mean SNOT-22 scores decreasing from 63.4 at baseline to 33.4 at six months and 33.0 at twelve months (both P < .001) (Fig. 2). Similarly, overall symptom severity assessed by VAS declined from 7.92 at baseline to 5.36 at six months and 5.51 at twelve months (both P < .001) (Fig. 3).

Figure 2.

Adjusted mean Nasal Polyp Score (NPS) and SNOT-22. Dots represent estimated marginal means obtained from a mixed model for repeated measures (MMRM), and vertical bars represent their 95% confidence intervals. NPS range: 0–8 points; SNOT-22 range: 0–110 points.

Figure 3.

Adjusted mean values of VAS (visual analogue scale), TDI score (Threshold, Discrimination and Identification), olfactory VAS and blood eosinophil count. Dots represent estimated marginal means obtained from a mixed model for repeated measures (MMRM), and vertical bars represent their 95% confidence intervals VAS and olfactory VAS (0–10 cm visual analogue scale); TDI range: 0–48 points; blood eosinophils are expressed as cells/µL.

Analysis of the olfactory function, measured by TDI score, showed a non-significant increase at 6 months (from 10.4 to 12.3; P = .405), followed by a statistically significant clinical improvement of more than 4 points at 12 months, rising from 10.4 at baseline to 14.3 (P = .036). Notably, 7 patients (25%) achieved the MCID (improvement of at least 5.5 points) at 6 months, and this proportion of patients increased to 42.3% at 12 months, underscoring a clinically meaningful recovery over time. Subjective olfactory assessment measured with VAS of smell loss showed minimal changes. The baseline score was 8.46, with a slight reduction to 7.98 at six months and 7.53 at twelve months with no statistical significance (P = .685 and P = .270, respectively) (Fig. 3).

In our cohort, eosinophil blood count levels experienced a sharp decline. The mean count at baseline was 803 cells/µL and these values decreased to 130 cells/µL at six months (P < .001) and further to 62 cells/µL at twelve months (P < .001) (Fig. 3).

Subgroup analysis showed a consistent trend toward greater improvement of all clinical variables in patients with asthma and AERD compared to non-asthmatics. While reduction in eosinophil count, NPS and improvement in TDI score appeared stronger in these groups than in non-asthmatics, statistical significance was only achieved in the SNOT-22 score (P: .05), highlighting a measurable reduction in symptom burden (Fig. 4).

Figure 4.

Adjusted mean SNOT-22 by subgroups. Dots represent estimated marginal means obtained from a mixed model for repeated measures (MMRM), and vertical bars represent their 95% confidence intervals. SNOT-22 range: 0–110 points.

A total of five patients did not achieve clinical response in any of the primary objectives (NPS and SNOT-22). These patients showed no measurable improvement, which required the administration of oral corticosteroids for symptom control. Subsequently, surgical intervention was indicated for three of these patients, while the remaining two were switched to Dupilumab as an alternative biological therapy.

Tolerability profile

No severe adverse events were reported. Mild reactions included one case of injection site swelling and two of pharyngitis, all self-limiting and non-disruptive to treatment.

Discussion

The efficacy of mepolizumab in chronic rhinosinusitis with nasal polyps (CRSwNP), both with and without comorbid asthma, has been well-documented in clinical trials and real-world studies. Additionally, mepolizumab has shown particular effectiveness in patients with both CRSwNP and eosinophilic asthma. Improved Asthma Control Test (ACT) scores and reduced exacerbation rates have been reported, with studies indicating decreased oral corticosteroid reliance and fewer emergency visits.^9,16 The shared inflammatory pathways between CRSwNP and eosinophilic asthma may explain mepolizumab’s dual benefit, as reductions in systemic eosinophilia likely contribute to improved upper and lower airway inflammation.^17,18

Our current study presents the findings of a multicentric Spanish cohort investigating the effectiveness of mepolizumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP).

In our cohort, there were no significant demographic differences between patients with and without comorbid asthma, ensuring a balanced comparison between groups. More importantly, for minimizing potential bias in treatment response evaluation, the baseline severity of CRSwNP was comparable across both groups, with no significant differences observed. This comparability in disease burden supports the validity of our findings by reducing potential confounding from baseline severity differences.

The consistent reductions in NPS and SNOT-22 scores observed in our study align with previous research, including reports by Domínguez-Sosa et al., Galleti et al., and Gallo et al., which have demonstrated that improvements in nasal polyp burden are directly associated with enhanced health-related quality of life.^11,12,17,19 These outcomes support the clinical relevance of mepolizumab for CRSwNP patients, particularly in reducing nasal obstruction and improving quality of life.

A unique aspect of this study is that, to date, no studies have specifically evaluated the efficacy of mepolizumab in nasal polyps using the complete 48-item Sniffin' Sticks test. The majority of existing research has relied on the shorter 16-item or 12-item versions to assess olfactory function.^11,19,20 This study is distinguished by its use of the full 48-item version—including threshold, discrimination, and identification—offering a more comprehensive and objective evaluation of olfactory performance, in alignment with the latest guidelines for olfactory assessment in clinical trials as recommended by the COMET initiative.¹⁴

Our findings showed a meaningful improvement in TDI scores at twelve months, indicating a clear enhancement in olfactory function following mepolizumab treatment. Although no significant change was observed at six months, the improvement at twelve months suggests that recovery of smell may require a longer period, likely reflecting the time needed to reduce chronic inflammation. Notably, 42.3% of patients achieved the Minimal Clinically Important Difference (MCID) at one year, underscoring not only statistically but also clinically meaningful gains. These results reinforce the importance of sustained treatment to achieve sensory recovery in patients with CRSwNP.

Interestingly, despite this measurable enhancement in semi-objective olfactory performance, the subjective olfactory function —evaluated using the loss of smell Visual Analog Scale (VAS)— exhibited minimal changes. This divergence between objective and perceived smell function is a well-documented phenomenon and has been observed in similar studies.²¹ It may reflect the complex interplay between sensory processing and patient perception, where individuals may not always be consciously aware of incremental improvements in olfactory capability. These results highlight the importance of utilizing comprehensive and more objective measurement tools, such as the full Sniffin' Sticks test, in assessing treatment outcomes for olfactory dysfunction.

Beyond clinical parameters our findings are consistent with previous studies demonstrating the anti-inflammatory effects of mepolizumab. Similar to Gallo et al. and Orlando et al.,^12,20 we observed a substantial reduction in eosinophil levels, decreasing from an 803 at baseline to 62 at twelve months. This reduction aligns with Mepolizumab’s mechanism of targeting type 2 inflammation, a known primary driver of CRSwNP.

In the subgroup analysis patients with asthma and AERD tended to show greater clinical improvement during treatment, which is consistent with the shared inflammatory pathways between CRSwNP and type 2–driven diseases. While outcomes like nasal polyp size, eosinophil count and TDI scores improved more noticeably in these patients, only the SNOT-22 score reached statistical significance highlighting a real, patient-perceived reduction in symptom burden. These results suggest a stronger therapeutic response in type 2–high inflammatory profiles with a greater benefit of the treatment with mepolizumab.

Our findings regarding the incidence of adverse events and overall tolerability are consistent with those reported in previous studies. The incidence and type of adverse events observed in our cohort, support the treatment’s established safety profile and its reproducibility across different settings. Given the low incidence of adverse events—only three mild cases—a multivariate analysis to identify potential predictors was not considered pertinent.

Limitations and future considerations

While mepolizumab has demonstrated strong efficacy, individual responses to treatment vary. Some patients experience only partial symptom relief, highlighting the need for improved predictive markers of therapeutic response. Additionally, although the treatment significantly reduces the need for further interventions, it does not eliminate this need entirely in all cases. Long-term studies assessing its effectiveness beyond one year will be essential to establish its role in sustained disease control. A further limitation of this study is the relatively small sample size, which may restrict the generalizability of the findings and reduce the power to detect subtle differences between subgroups. Larger, multicenter trials will be necessary to validate these results and to better understand the full clinical potential of mepolizumab in CRSwNP.

Conclusion

Mepolizumab is a valuable therapeutic option for CRSwNP, especially in patients with eosinophilic inflammation and comorbid asthma or AERD, where its efficacy is more pronounced. This study highlights its sustained long-term efficacy, highlighting the improvement in olfactory function, a symptom often resistant to conventional treatments. Importantly, the incorporation of a semi-objective olfactory assessment, routinely performed at our centers but not widely adopted, provides a more objective and reliable assessment of smell improvement. Further research is needed to identify predictors of response and evaluate outcomes in broader populations.

Declaration of Generative AI and AI-assisted technologies in the writing process

During the preparation of this work the authors used Scispace in order to enhance language clarity and readability. All scientific content, data interpretation, and conclusions remain the original work of the authors. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the publication.