Dupilumab reduces symptom burden in allergic rhinitis and suppresses allergen‐specific <scp>IgE</scp> production

Abstract

To the Editor, Type 2 immune responses underlie many respiratory diseases including allergy and chronic rhinosinusitis. Dupilumab, a monoclonal antibody blocking the IL-4 receptor alpha component, has been shown to not only successfully reduce polyp burden but also type 2 serum biomarkers including total IgE.1, 2 Furthermore, studies administering dupilumab in combination with subcutaneous allergen-immunotherapy have shown that dupilumab may improve the tolerability of SCIT but does not enhance suppression of allergen-induced skin late phase reactions as compared to SCIT alone.3, 4 However, the impact of dupilumab on aeroallergen-specific IgE levels within nasal mucosal lining fluid (nMLF) has not yet been elucidated. In this single-centre retrospective analysis, we analysed nMLF, serum samples and clinical parameters from 16 allergic patients treated for 6 months with dupilumab due to suffering from chronic rhinosinusitis with nasal polyps (CRSwNP). All patients were part of a study cohort suffering from non-steroidal anti-inflammatory drugs (NSAID)-exacerbated respiratory disease (N-ERD) which is made up of a triad of coexistent asthma, CRSwNP as well as hypersensitivity to NSAID. All participants received nasal corticosteroids as part of their routine therapy. At sampling timepoints, patients were not suffering from acute exacerbations, acute infections nor were they actively taking oral corticosteroid therapy. All patients were sensitised to at least one aeroallergen or insect venom (serum or nasal allergen-specific IgE > 0.35 kUA/L) as determined by the ALEX2 (Allergy Explorer) used for specific IgE measurements in this study (Figure 1; Table S1). For further details on the methodology, please refer to the online repository. After 6 months of dupilumab treatment, we observed a strong decline in allergen-specific IgE levels in the majority of patients regardless of the allergen analysed, which was more pronounced in nMLF than in serum (Figure 1A; Figure S1). In some patients, allergen-specific IgE levels in nMLF dropped even below the detection limit (e.g. patient #1, 2 and #3 for selected allergens). Furthermore, this decrease occurred for seasonal aeroallergens in selected patients despite ongoing allergen exposure (Figure 1B). Median reduction of the major birch pollen allergen Bet v 1-specific IgE was −59.1% (Serum: −34.9% to −98.1%, n = 5) and −98.7% (nMLF: −65.3% to −99.6%, n = 4). In the major grass pollen allergen Phl p 1, a reduction of −28.7% (Serum: −15.9% to −80.4%, n = 7) and −80.8% (nMLF: −63.6% to −98.0%, n = 2) was seen in IgE levels. Despite some timepoints occurring only during and then after the season, the decrease in allergen-specific IgE cannot only be explained by a post-seasonal decrease due to the following: First, published data suggest that allergen exposure leads to a strong increase in specific IgE 6–8 weeks after allergen contact which declines slowly, reaching pre-seasonal levels only shortly before the next season.5 However, most of our patients were sampled before allergen-induced IgE rise (i.e. April–May) or well after (October) and nevertheless showed a pronounced decrease. Second, we measured allergen-specific IgE levels dropping even below pre-seasonal levels (e.g. Patient #2, 3 and 4 showed lower values in October than in April). A comparable effect has only been observed after complete allergen avoidance for at least one season by spending the summer in Antarctica.6 Third, we also detected a decrease in IgE levels for perennial allergens (e.g. house dust mite and animal dander), which is in line with previous observations in allergic asthmatic patients treated with dupilumab.7 As previously reported, the reduction in specific IgE levels was accompanied by a significant decrease in total IgE levels both in serum and nMLF (Figure 2A,B).1, 8 The observed decrease in IgE levels was independent of age and smoking status as well as initial total polyp score (TPS), total nasal symptom score (TNSS) and smell performance as determined by the University of Pennsylvania smell test (UPSIT) (Tables S2 and S3). Male patients experienced on average a larger reduction in total IgE in nMLF but not in serum and the percentage reduction in serum IgE levels correlated negatively with the number of allergens a patient was sensitised to (Tables S2 and S3). Out of the 16 patients, 14 reported allergic rhinitis and/or conjunctivitis in response to aeroallergen exposure. Two patients reported rhinitis symptoms upon aspirin exposure only, despite aeroallergen sensitisation and were thus excluded from the analysis for symptomatic allergen improvement. Notably, there was also a trend in these patients towards reduced usage of antihistamines and steroids which may also partly have been caused by improved CRSwNP symptoms (Figure 2C). However, this was accompanied by a significant improvement in allergic symptoms as measured by a visual analogue scale and total nasal symptom score (Figure 2D,E). In addition, symptoms of their primary disease such as impaired smell and polyp score improved significantly (Figure 2F,G). Limitations of our study include that all patients suffered from CRSwNP and may thus have altered cytokine profiles in nasal secretion as compared to patients suffering from isolated allergic rhinoconjunctivitis and that they all continued nasal corticosteroid therapy as part of their standard treatment. However, it is unlikely that the corticosteroid intake has biased our findings as 4 weeks of nasal corticosteroid treatment has not previously been shown to attenuate the allergen-specific IgE rise induced by allergen provocation.9, 10 Furthermore, we did not have control groups available (e.g. without asthma or not treated with dupilumab) as the samples were derived from a trial focusing on the effect of dupilumab, solely in patients suffering from N-ERD. Finally, due to the small sample size of the study and the comorbidity of nasal polyposis which also causes nasal symptoms responsive to dupilumab, some of the results such as the reduction in medication intake needs to be interpreted with caution. Despite the small sample size, our data suggest a strong effect of dupilumab on reducing allergen-specific IgE levels in sensitised patients not only in serum, but also in nMLF and support the hypothesis that blockage of IL-4/IL-13 signalling leads to reduced IgE production and amelioration of allergic symptoms in sensitised patients. As the costs of biological therapy (>€10,000 annually)11 by far exceed the annual direct cost of medication and health-care for allergic rhinitis (approx. €210/year in Northern Europe),12 it is likely that these drugs will be reserved for the most severely affected patients. Although further trials characterising the local cellular and cytokine responses are warranted, our data suggest a potential role for dupilumab in treatment-resistant allergic rhinitis. NJC, AD, SS, CB and JE-D designed the study, wrote the study protocol and gained ethical approval for the study. NJC, KP, TQ, KG, CS, TB, DTL, LDL, CB and SS recruited all the patients, carried out the study and sampled the patients. MB and UB collected and analysed the pollen data. CL, VS and AT performed the experiments. JB performed the statistical analysis. NJC, AD, KP, CB, SS, CL and JE-D performed the analysis and wrote the manuscript. All authors critically revised the manuscript together. We thank MacroArray Diagnostics GmbH for the measurement of the serum and nMLF samples. None. SS served as a speaker and/or consultant and/or advisory board member for Sanofi and Novartis. SS is an investigator for Novartis and AstraZeneca (grants paid to his institution). TB received personal fees from Sanofi and Novartis. LDL served as an independent consultant for Conclave Capital and Gerson Lehrman Group. LDL is an investigator for Decibel Therapeutics and Amgen (grants paid to his institution). CB has received personal fees from Mylan, LEO Pharma, Pfizer, Sanofi Genzyme, Eli Lilly, Novartis and AbbVie. CB is an investigator for Novartis, Sanofi, Abbvie, Elli Lilly, LEO Pharma and Galderma (grants paid to her institution). CL is an employee of Macro Array Diagnostics. JE-D served as a speaker and/or consultant and/or advisory board member for Sanofi, Allergopharma, AstraZeneca, GSK and Novartis. JE-D is an investigator for Novartis and AstraZeneca (grants paid to her institution). All other authors declare no conflict of interest. Figure S1 Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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