Successful switch to tezepelumab for severe asthma and chronic rhinosinusitis with nasal polyps

Abstract

Chronic rhinosinusitis with nasal polyp (CRSwNP) is a type 2 inflammatory disease frequently associated with asthma. Patients with CRSwNP are typically treated with endoscopic sinus surgery and oral corticosteroids. However, they often experience recurrence; in addition, oral corticosteroids have several adverse effects. CRSwNP is an important factor influencing asthma control, and total control of both CRSwNP and asthma is important for treatment. Dupilumab and mepolizumab, which are anti-interleukin (IL)-4R and anti-IL-5 monoclonal antibodies, respectively, have been approved for the treatment of severe asthma and CRSwNP. Here, we discuss the successful treatment of a patient with severe asthma comorbid with CRSwNP after switching from dupilumab and mepolizumab to tezepelumab. The patient was initially treated with high-dose inhaled corticosteroids/long-acting β2-agonist/long-acting muscarinic antagonist treatment, without success. Treatment with dupilumab improved asthma and CRSwNP; however, it later induced hypereosinophilia with exacerbated asthma. Although subsequent treatment with mepolizumab improved asthma, the nasal symptoms recurred. After attempting dupilumab treatment again, the nasal symptoms improved; however, the asthma symptoms worsened parallel with an increased eosinophil count. Finally, the antithymic stromal lymphopoietin monoclonal antibody tezepelumab, was selected for treatment; the worsening asthma symptoms then improved with the control of CRSwNP. This report illustrates the potential utility of tezepelumab for the treatment of asthma and CRSwNP. Tezepelumab therapy may enhance total control of comorbidities of both the upper and lower airways. Further studies are required to identify effective therapies for asthma and CRSwNP.

1. Introduction

Severe asthma is frequently comorbid with chronic rhinosinusitis with nasal polyp (CRSwNP). CRSwNP is a type 2 inflammatory condition characterized by eosinophilic infiltration and can influence asthma control [1]. Dupilumab is an anti-interleukin-4 (IL-4) receptor-subunit α monoclonal antibody (mAb) that blocks IL-4 and IL-13 signaling. Mepolizumab is an anti-IL-5 mAb. Dupilumab and mepolizumab have both been approved for the treatment of severe asthma and CRSwNP [1]. However, dupilumab sometime induces hypereosinophilia and worsens asthma [2]. Tezepelumab is an antithymic stromal lymphopoietin (TSLP) mAb. We present a case of a patient with asthma complicated by CRSwNP who was initially unsuccessfully treated with dupilumab and mepolizumab before switching to tezepelumab. Tezepelumab might play an important role in the treatment of asthma and sinusitis symptoms.

2. Case report

A 75-year-old female nonsmoker with CRSwNP had been surgically treated twice in the past 7 and 10 years. In the last 7 years, she was diagnosed with asthma and CRSwNP relapse. She was treated with moderate-dose inhaled corticosteroids/long-acting β2 agonists. However, she experienced exertional dyspnea, continuous nasal congestion, and anosmia. Figure 1 shows the patient’s clinical course.

Figure 1.

Clinical course of the patient. Dupilumab therapy improved asthma and chronic rhinosinusitis with nasal polyp symptoms. However, the asthma worsened, with increasing eosinophil counts. After switching to mepolizumab, the asthma symptoms improved parallel with a decrease in the eosinophil count. However, the nasal symptoms worsened. After switching to dupilumab again, the nasal symptoms improved; however, asthma recurred parallel with increasing eosinophil counts. Finally, dupilumab was replaced with tezepelumab, after which the peripheral eosinophil count decreased, asthma symptoms improved, and nasal symptoms were well-controlled. ACT, asthma control test; Eo, eosinophil; FeNO, fractional exhaled nitric oxide; FEV1, forced expiratory volume in 1 s; Ig, immunoglobulin; TNSS, total nasal symptom score.

The total nasal symptom score (TNSS) and Nasal Polyp Score (NPS) were evaluated based on previous reports [3].

In January 2021, she was referred to our hospital because of poorly controlled severe asthma and CRSwNP. Asthma control test (ACT) score was 8. The TNSS for nasal obstruction, rhinorrhea, and olfaction was 9 (3-3-3). She was then treated with high-dose inhaled corticosteroids, long-acting β2 or muscarinic antagonists, and leukotriene receptor antagonists. However, her symptoms did not improve. Computed tomography (CT) revealed reduced mucus secretion in the paranasal sinus (NPS, 5) (Fig. 2). In February 2021, dupilumab was administered at a subcutaneous induction dose of 600 mg, followed by a maintenance dose of 300 mg/2 weeks. After 2 months, asthma and nasal symptoms improved (ACT score, 18; TNSS, 7 [3-2-2]); CT revealed reduced mucus secretion in the paranasal sinus (NPS, 0) (Fig. 2). In April 2022, asthma symptoms gradually recurred, with an increase in peripheral eosinophil count (ACT score, 15) but without sinusitis aggravation (TNSS, 5 [2-2-1]) (NPS, 0) (Fig. 2). Therefore, treatment was switched to mepolizumab with a subcutaneous dose of 300 mg for 4 weeks. Asthma symptoms improved slightly (ACT score, 18), and the eosinophil count dramatically decreased. However, after 7 months, the nasal symptoms recurred (TNSS, 8 [3-2-3]). CT of the paranasal sinus revealed no significant changes (NPS, 0) (Fig. 2). Mepolizumab was then replaced by dupilumab; subsequently, the nasal symptoms were well-controlled (TNSS, 4 [2-1-1]). However, the asthma symptoms recurred, along with increasing peripheral eosinophil count (ACT score, 16). In July 2023, the dupilumab was replaced by tezepelumab. Subsequently, the patient’s peripheral eosinophil count decreased from 702/μL to 112/μL. The asthma symptoms improved (ACT score, 25), and the nasal symptoms remained well-controlled (TNSS, 4 [2-1-1]). Mucus secretion in the paranasal sinuses was completely abrogated (NPS, 0) (Fig. 2), with no exacerbation of asthma or adverse events.

Figure 2.

Paranasal sinus computed tomography (CT) scans and Nasal Polyp Score (NPS) before (A), after 2 months (B), and 1 year and 2 months after (C) dupilumab treatment. Paranasal sinus CT before (D) and after 8 months (E) of tezepelumab treatment.

3. Discussion

We report a case of asthma with CRSwNP, successfully treated with tezepelumab after switching from dupilumab and mepolizumab treatment to tezepelumab. CRSwNP causes eosinophilic inflammation and mucus formation, playing an important role in asthma. Furthermore, the associated release of type 2 cytokines such as IL-4, IL-13, and IL-5 is key in CRSwNP pathogenesis [1, 4]. CRSwNP is associated with a higher frequency of asthma exacerbation and reduced health-related quality of life.

Dupilumab is an anti-IL-4Rα mAb that inhibits IL-4 and IL-13 signaling. However, it may be associated with increased peripheral eosinophil count and asthma exacerbation [2]. A clinical trial noted hypereosinophilia occurrence after dupilumab administration, with a return to baseline levels after 6 months without eosinophilic symptoms [5]. Dupilumab-induced eosinophilic pneumonia and vasculitis have also been reported [2].

In our patient, dupilumab and mepolizumab were replaced by tezepelumab, which has exhibited excellent clinical efficacy against both severe asthma and CRSwNP. TSLP is a type 2 inflammatory cytokine produced by airway epithelial cells in response to inflammatory agents and mechanical stimuli. Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (eotaxin and regulated on activation normal T cell expressed and secreted) induce eosinophil recruitment. IL-4 activates immunoglobulin-E-producing plasma cells [6]. Tezepelumab, thus, suppresses upstream factors that cause type 2 inflammation and extensively inhibits type 2 cytokines. The differences in the effects of dupilumab and tezepelumab may, therefore, be attributable to their targeted cytokines.

In the NAVIGATOR study, tezepelumab treatment resulted in fewer exacerbations and improved lung function, asthma control, and health-related quality of life [7]. Furthermore, in the CASCADE study, tezepelumab reduced type 2 airway inflammation levels [8]. In the present case, CT demonstrated amelioration of CRSwNP; in addition, the ACT and TNSS significantly improved. Tezepelumab improved asthma- and CRSwNP-related symptoms and exercise tolerance. Interestingly, after dupilumab treatment, the peripheral eosinophil count increased and the ACT score worsened despite continued control of CRSwNP. After switching to mepolizumab to control the hypereosinophilia, the ACT score associated with asthma improved, with a decrease in the eosinophil count. However, the TNSS associated with CRSwNP worsened. Dupilumab improved the TNSS for nasal obstruction, rhinorrhea, and olfaction. Tezepelumab maintained a good TNSS. After tezepelumab treatment, both asthma control and CRSwNP significantly improved. TSLP is highly expressed in the nasal polyps of CRS patients [9]. Additionally, group 2 innate lymphoid cells (ILC2) in nasal polyps of CRS patients respond to epithelial cell-derived cytokines such as IL-25, IL-33, and TSLP to produce the Th2-associated cytokines IL-4, IL-5, IL-9, and IL-13 [10]. ILC2-mediated inflammation plays a causal role in the development of nasal polyps in patients with CRS and asthma [10]. Neutralizing TSLP can help calm the immune response in chronically inflamed nasal and airway mucosa.

Unlike dupilumab, which blocks IL-4 and IL-13 signaling, and mepolizumab, which targets IL-5, tezepelumab acts upstream in the inflammatory cascade, affecting multiple type 2 inflammatory pathways. In clinical trials, tezepelumab demonstrated significant reductions in exacerbation rates and improvements in lung function compared to placebo, with efficacy comparable or superior to dupilumab and mepolizumab in eosinophilic asthma [11].

In network analysis, a comparison of different biologics for treating CRSwNP was reported. Dupilumab was more effective for decreasing NPS and nasal congestion severity compared with mepolizumab at 24 weeks of treatment [12]. In the NAVIGATOR study, tezepelumab improved CRSwNP and asthma-related symptoms [13]. However, there are no randomized controlled trials with head-to-head comparisons of the biologics.

Here, we report a case of severe asthma with CRSwNP effectively treated after switching from dupilumab and mepolizumab to tezepelumab. This suggests that tezepelumab may be effective in treating severe asthma comorbid with CRSwNP, involving both the upper and lower airway. Further studies are required to explore the general and specific roles of tezepelumab in the treatment of severe asthma comorbid with CRSwNPs.

Acknowledgments

Assistance with the study: We thank Mayu Isota, Kentaro Suzuki, and Ryosuke Kataoka for their assistance with the manuscript preparation. We thank Editage (www.editage.jp) for the English language editing.

Conflicts of interest

The authors declare no conflicts of interest.

Author contributions

Conceptualization: Yoshiro Kai, Keiji Yoneyama. Formal analysis: Yoshiro Kai, Keiji Yoneyama. Investigation: Yoshiro Kai, Keiji Yoneyama. Methodology: Yoshiro Kai, Keiji Yoneyama. Project administration: Yoshiro Kai, Keiji Yoneyama. Writing—original draft: Yoshiro Kai. Writing—review & editing: Yoshiro Kai, Keiji Yoneyama.