Elevated inflammation, a hallmark of severe asthma, is associated with exacerbated symptoms and potentially diminishes the efficacy of steroid therapy 1. Tezepelumab, an anti-thymic stromal lymphopoietin (TSLP) antibody, has demonstrated efficacy in disrupting both type-2 and broad inflammatory responses in patients with asthma. However, whether inflammatory suppression by tezepelumab improves steroid efficacy remains unclear. This study aimed to investigate changes in steroid sensitivity following tezepelumab administration in patients with severe asthma. This study included 20 patients with severe asthma (Table S1). Of these, 17 completed 24 weeks of tezepelumab treatment, three discontinued oral corticosteroids (OCS), one initiated OCS, and seven experienced exacerbations by Week 24. Type-2 markers, including blood eosinophil count and serum IgE and FeNO levels, decreased, with a significant increase in FEV1 and improvements in the Asthma Control Questionnaire (ACQ) and Asthma Control Test (ACT) (Figure S1). By assessing steroid sensitivity using patient PBMCs 2, we observed changes in steroid sensitivity (Figure 1A). Higher scores indicate improved steroid sensitivity. Steroid sensitivity showed an upward trend from baseline to Week 4, with a significant increase at Week 8. This enhancement persisted at Week 16 and increased further at Week 24. This novel finding offers insights into the potential role of tezepelumab in improving steroid sensitivity. Regression analysis elucidated the relationship between changes in steroid sensitivity from baseline and clinical response to tezepelumab (Figure 1B). Enhanced steroid sensitivity was associated with OCS withdrawal, improved ACT and ACQ scores, and decreased IgE levels. Tezepelumab may augment corticosteroid efficacy by suppressing inflammation and increasing steroid sensitivity, thereby contributing to asthma symptom control and OCS reduction. Conversely, no statistically significant association was observed between FEV1 improvement and reduction in eosinophil count or FeNO (Figure 1B). While tezepelumab suppresses the upstream mechanisms of type 2 inflammation, further research is required to identify the inflammatory pathways involved in enhancing steroid sensitivity. The effectiveness of tezepelumab in reducing OCS dose has been studied. In the SOURCE trial, tezepelumab showed no statistically significant reduction in OCS dose versus placebo 3. However, in its extension trial DESTINATION, more patients on tezepelumab discontinued OCS by Week 104 4. Furthermore, in the WAYFINDER trial, 89.9% reduced daily OCS to ≤ 5 mg/day, and 50.3% discontinued OCS by Week 52 5. At Week 24 after tezepelumab administration, seven patients achieved clinical remission, defined by ACQ < 1.5, no OCS use, and no exacerbations up to 24 weeks. Steroid sensitivity at 24 weeks was higher in patients who achieved clinical remission than in those who did not (Figure S2). No significant difference was observed in the change in steroid sensitivity from baseline between the groups (p = 0.997). Achieving asthma control may require restoration of steroid sensitivity to a threshold. Continuous tezepelumab administration in patients without clinical remission may enhance steroid sensitivity; however, this requires further investigation. Activation of the PI3K and MAPK signaling pathways by inflammatory stimuli contributes to reduced steroid sensitivity 1. We focused on steroid-related molecules within these pathways and analyzed gene expression in T cells (Figure 2A). Tezepelumab upregulated the glucocorticoid receptor gene (NR3C1) and HDAC2 (Figure 2B), whose downregulation links to diminished steroid sensitivity. PI3K pathway activation impairs HDAC2 function and expression. We previously reported that benralizumab, an anti-IL-5 receptor antibody, increases HDAC2 expression 6. These results suggest that suppression of type-2 inflammation by biologics may link to inhibition of excessive PI3K pathway activation. Data S1 provides information on the methodologies, discussions, and study limitations. In conclusion, this study suggests that tezepelumab enhances steroid sensitivity in patients with severe asthma by suppressing inflammatory pathways that modulate steroid sensitivity molecules. Tezepelumab treatment is expected to restore steroid sensitivity, leading to better symptom control and outcomes. K.H. and T.S. conceptualized the research process. K.H. and T.S. designed experiments. T.S. and T.A. recruited the patients for the study. K.H., T.S., S.U., and T.A. collected clinical data. K.H. and S.U. performed experiments. K.H. and S.U. analyzed the data. K.H. and S.U. wrote the first draft of the manuscript. All authors have revised, approved, and agreed to be accountable for the submitted version of this manuscript. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1: Changes in peripheral blood eosinophil count (BEC), exhaled nitric oxide fraction (FeNO), serum total immunoglobulin E (IgE), forced expiratory volume in one second (FEV1), Asthma Control Questionnaire (ACQ) score, and Asthma Control Test (ACT) score after administration of tezepelumab. The points represent the weighted average and the error bars indicate the standard error. *p < 0.05, **p < 0.01, ***p < 0.001. Figure S2: Comparison of the time course of changes in steroid sensitivity during tezepelumab treatment between patients who achieved clinical remission and those who did not. The diamond points represent the weighted average and the error bars indicate the standard error. Table S1: Demographic and clinical characteristics of the study subjects at baseline. 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.
Hirai et al. (Sat,) studied this question.