Dupilumab Improves Clinical Symptoms and Biomarkers in Comorbid Seasonal Timothy Grass Pollen Allergic Rhinitis in Patients With <scp>CRSwNP</scp>

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory condition, often associated with Type 2 inflammation, characterised by elevated levels of eosinophils and cytokines such as IL-4, IL-5 and IL-13 [1, 2]. Allergic rhinitis (AR), another common Type 2 inflammation-driven condition, frequently coexists with CRSwNP, leading to a compounded impact on patients' quality of life [3]. Interlinked AR and asthma may increase the burden of the primary disease, forming a disease complex that presents significant therapeutic challenges [3]. Despite the recognised overlap in their immunopathogenesis, the specific interactions between CRSwNP and AR, especially in response to current biologics, remain underexplored [3, 4]. Therefore, we evaluated the effects in a subgroup of CRSwNP patients treated with biologics according to current standards [5] on AR biomarkers and symptoms, validated by active anterior rhinomanometry (AAR)-controlled nasal allergen challenge (NAC) [6]. Our single-centre prospective study included 12 adult patients with CRSwNP, both with and without AR (n = 6 per group), receiving standard 300 mg dupilumab biweekly treatment. Baseline characteristics revealed similar high initial total nasal polyp scores (NPS) and high scores in the SNOT-22, Nasal Congestion Score (NCS) and VAS (overall symptom severity and olfactory function) assessments (Figure 1). Patients with comorbid AR (all moderate to severe during the grass-pollen season) had notably higher baseline levels of blood eosinophils, total IgE, a higher prevalence of comorbid asthma and more frequent previous functional endoscopic sinus surgeries at baseline. After 24 weeks of dupilumab, significant improvements were observed in NPS, olfactory function tests and patient-reported disease outcomes (PROMs) demonstrating an excellent response in all patients according to the EPOS/EUFOREA guidelines for CRSwNP [5]. In CRSwNP+AR patients, the baseline burden of symptoms was high in almost all RQLQ domains (most affected in the domains ‘nose and practical problems’, data not shown). Significant improvements were observed, with RQLQ scores dropping substantially, indicating a decrease in AR symptom severity (Figure 1). After treatment with dupilumab, the follow-up AAR-controlled NAC turned from positive to negative for all AR patients, according to the current European recommendations [6]. Nasal fluids were collected after NAC with cotton discs custom-made by one co-author (MW), as reported earlier [7]. Analysis of biomarkers showed significant reductions after dupilumab treatment. Serum level of sIgE to timothy grass decreased (p = 0.0625), total IgE levels decreased significantly, both in nasal secretions and serum, as previously shown [2, 4]. Additionally, notable reductions in periostin and eotaxin-3 levels in nasal fluids were observed as well as significant decrease of serum periostin without any direct effects on nasal IL-8 or eosinophil numbers. These biomarkers are crucial indicators of Type 2 inflammation and their reduction aligns with the clinical improvements observed, supporting the efficacy of dupilumab in modulating the underlying inflammatory processes in CRSwNP and AR. All other nasal cytokines analysed either had protein content below the assay limit of detection (IL-4, IL-1β, IFN-γ, IL-10, IL-13, MIP 3α, TARC, IL-12/IL-23p40, MCP-4, eotaxin, MIP 1α, IL-31, IL-22, IL-23 and IL-17A/F) or remained unchanged in NAC before and after dupilumab treatment (IL-5, IL-6, MCP-1, MIP 1β, TNF-α, TSLP and MDC). The improvements in objective NAC results, PROMs and biomarker levels highlight dupilumab's potential of collateral efficacy for CRSwNP and AR. Our findings are consistent with previous studies that demonstrated similar biomarker changes [2-4, 8] and significant clinical benefits of dupilumab in conditions driven by Type 2 inflammation [1, 3, 4]. In earlier trials, prevalence of patient-reported AR in CRSwNP patients was reported from 47% to 74%, which was not verified by physician's diagnosis [3]. Some studies on AR–comorbid CRSwNP patients were based on analysis of serological sensitisation [3], without further verification of clinical relevance. We addressed this by persistent use of AAR-controlled NAC to objectively validate the AR diagnosis and its improvements, providing robust evidence of dupilumab's efficacy (even at baseline in our patients without AR). Although a reduced response to NAC in CRSwNP patients has been discussed [9], NAC offered a reliable measure of treatment efficacy for simultaneous AR in our hands. The significant reductions in biomarkers such as IgE, periostin and eotaxin-3 further elucidate the mechanisms by which dupilumab may exert its effects. Periostin and eotaxin-3 are involved in eosinophil recruitment and activation, which are key processes in the pathogenesis of both CRSwNP and AR [2, 3]. Our study has several limitations. Firstly, we present a limited sample size due to the detailed workup and the absence of another control groups consisting of patients with possible comorbid local AR or isolated AR without CRSwNP. Additionally, the variability in pollen seasons during RQLQ recordings could have influenced the severity of symptoms reported by patients, potentially introducing variability in the data. Finally, our study duration was relatively short and future studies are needed to monitor any long-term effects. In conclusion, this study demonstrates that dupilumab significantly improves objective and PROMs of both CRSwNP and comorbid AR, as substantiated by objective NAC results and substantial reductions in Type 2 biomarkers in nasal fluids as well as blood workup. These findings support dupilumab's potential as a comprehensive treatment for patients with these coexisting conditions, emphasising its role in reducing Type 2 inflammation and improving patient quality of life. The data underscore the therapeutic value and the collateral efficacy of dupilumab for patients suffering from the dual burden of CRSwNP and AR. This comprehensive assessment provides a strong foundation for further research into the long-term effects of dupilumab and its integration with other treatment modalities such as allergen immunotherapy, as this combination may offer synergistic benefits for those with AR and CRSwNP. C.B., M.W. and T.B. designed the study. C.B., M.P.S. and D.B. were involved with patient treatment and sample acquisition. C.B., S.T., M.M.H. and T.B. processed and analysed data. C.B. and T.B. drafted the manuscript and all authors jointly discussed, reviewed and amended the final manuscript. The study was approved by the ethics committee of University Medical Center Goettingen, reference number 24/7/20. The research was conducted ethically in accordance with the World Medical Association's Declaration of Helsinki. All authors reviewed the final manuscript version and consented to its submission. M.P.S. has received honoraria as advisor or speaker or has served as investigator in trials sponsored by AbbVie, Almirall, BMC, Janssen, Leo, Novartis and UCB. T.B. reports relevant lectures, advisory board membership, research grants and/or investigator roles in clinical trials for ALK-Abello, AstraZeneca, Bencard, Eli Lilly, Leo Pharma, Novartis, R-Biopharm, Sanofi and Thermo Fisher. C.B. has been a speaker/advisor for ALK-Abello, GlaxoSmithKline, Novartis and Sanofi-Genzyme for the past 5 years. S.T. received research grants from Sanofi and Novartis Foundation. He served as a consultant and lecturer for Janssen, LeoPharma, Lilly Pharma, Novartis and Sanofi. M.M.H. and D.B. report no conflicts of interest. M.W. reports fees for lectures and/or participation in scientific advisory boards for Allergopharma, ALK-Abelló, AstraZeneca, CSL Behring, Genzyme, GSK, HAL Allergie, Infectopharm, LETI Pharma, Novartis, Sanofi and Stallergenes. Grants (to MW's institution): ALK-Abelló, AstraZeneca, EU, GlaxoSmithKline, Novartis, Regeneron, Sanofi-Aventis and Takeda. All data generated or analysed during this study are included in this article. Further enquiries can be directed to the corresponding author.