Response to “Comment on ‘Dupilumab Beyond the Airway: Decreased Morbidity in a Real‐World Analysis’”

To the Editor: We thank Shridevi et al. for their thoughtful commentary on our recent publication [1, 2]. We share their interest in understanding potential systemic implications of dupilumab and the mechanisms underlying the associations observed in our study. We, too, are optimistic about the anti-inflammatory effects of dupilumab in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and/or asthma, though we remain cautious of extrapolating these data to patients who do not have an underlying systemic inflammatory disease process. As mentioned in their correspondence, our study observed associations between dupilumab use and reduced cardiovascular, thromboembolic, and sleep apnea-related diagnoses compared with non-biologic users and to those using other biologic drugs. Given the central role of interleukin (IL)-4 and IL-13 signaling in type II inflammation, these findings are intriguing and biologically plausible [3]. However, our analysis was an observational study from a large, de-identified database and was limited to CRSwNP and/or asthma populations, characterized predominantly by systemic type II inflammation. Chronic rhinosinusitis (CRS) is a heterogeneous condition encompassing several inflammatory endotypes [4]. CRSwNP and asthma are often associated with eosinophilic, type II inflammation, whereas chronic rhinosinusitis without nasal polyps (CRSsNP) and other inflammatory phenotypes may exhibit more variable immunologic profiles. As such, patients treated with dupilumab in our cohort may represent a population uniquely affected by systemic type II inflammation. While the associations observed in our cohort are encouraging, they should not be generalized to patients without nasal polyps or to inflammatory conditions with differing pathophysiology. We also agree that the lack of association between coded eosinophilia and cardiovascular events warrants further investigation. Although eosinophils have been implicated in vascular inflammation and thrombosis, circulating eosinophil counts may not fully reflect their functional activity [2, 5]. Additionally, reliance on data from ICD code-based databases, such as TriNetX, presents many opportunities for possible confounding despite propensity score matching and exclusion of patients with prior events. Coding practices vary across institutions and may incompletely capture diagnoses, such as eosinophilia or sleep apnea, potentially affecting observed associations. However, our findings that dupilumab patients do not appear to be at increased risk of cardiovascular events are reassuring within the context of systemic inflammatory disease. Prospective studies would be required to clarify relationships. In summary, we share the optimism expressed by Shridevi et al. regarding the potential systemic benefits of dupilumab therapy when prescribed for type II inflammatory airway disease. These results highlight that at minimum, the risks of major cardiovascular, oncologic, and sleep apnea outcomes are not increased in patients treated with dupilumab in the short term. However, these results require careful interpretation within the context of CRSwNP and asthma, recognition of disease heterogeneity, and acknowledgment of the inherent limitations of observational data. We also share the sentiment that future prospective studies will be required to determine whether the associations identified reflect the true modification of cardiovascular disease and/or sleep apnea risk. The authors received no specific grant from any funding agency to sponsor this work. Dr. Elina Toskala has received consulting fees from GSK and AstraZenica, a research grant from GSK, and was a member of the speaker's bureau for Sanofi. Dr. Gurston Nyquist has received consulting fees from Sanofi. Dr. Mindy Rabinowitz has been a consultant to Medtronic and Integra Life Sciences. All other authors have nothing to disclose.