Evaluation of Mepolizumab Effectiveness in Patients With Chronic Rhinosinusitis With Nasal Polyps and Comorbid Severe Eosinophilic Asthma: an Integrative Multi-omics Approach to Assess Biomarker Signatures of Responsive Disease Endotypes

Chronic rhinosinusitis (CRS) has been divided into two subtypes: CRS with (CRSwNP) and without nasal polyps (CRSsNP), which not only differ in terms of presence of polyps, but also appear to have distinct pathogenesis and clinical presentations. It is known that CRSwNP patients have a greater disease burden compared with those suffering from CRSsNP with respect to disease severity and poor treatment. More specifically, approximately 85% of CRSwNP patients are characterized by severe symptoms, recurrent disease and a dominant Th2 endotype associated with a marked infiltration of eosinophils and mast cells, goblet hyperplasia and increased levels of Th2 inflammatory cytokines including Interleukin IL-4, IL-5, and IL-13. An additional hallmark of CRSwNP is the loss of healthy barrier function in sinonasal epithelial cells, increased permeability, decreased epithelial resistance, and a high degree of tissue remodeling compared with cells from CRSsNP patients and control individuals. This loss of barrier function is reflective of a general inflammatory process, though it is unclear if the epithelial cells are inherently abnormal or if the state is induced. Treatment for CRS is most frequently glucocorticoid-based, but response is quite variable in patients with nasal polyps and side-effects from oral steroids limit their long-term efficacy. An inverse relationship between glucocorticoid receptor β expression in nasal polyp tissue and steroid efficacy has been observed. Furthermore, neutrophil accumulation in nasal polyp tissue has been related to corticosteroid insensitivity. Some individuals exhibit a very high level of resistance to steroid therapy thus underscoring the need for therapeutics targeting non-steroid-responsive pathophysiologic mechanisms involved in sinus polyp formation.

Asthma is frequently a comorbid condition sharing similar pathophysiology in CRSwNP patients, which affects 20-60% of diseased individuals. Yet, specific subsets of patients such as those with IL-5-enriched nasal polyps are characterized by a greater percentage of asthma and revision surgery. Clinically, CRSwNP with comorbid asthma (CRSwNP + AS) is associated with even more severe sinonasal symptoms and worse quality of life, and it is more difficult to treat both medically and surgically. Correspondingly, asthma in the presence of nasal polyposis is harder to control, being more exacerbation prone, with increased airway obstruction and more extensive eosinophilic inflammation.

Although a clear correlation apparently exists between sinonasal and lower airway inflammation in patients with CRSwNP+AS, the definitive underlying mechanism(s) remains poorly elucidated. The airways microbiota, i.e. the niche-specific communities of microbes including bacteria, fungi, archaea and viruses that inhabit the respiratory tract, has been proved to play a critical role in airway health and immune cells homeostasis -including eosinophils regulation- through its constant interaction with the mucosal immune system. Alterations in the composition and diversity of microbiome across the respiratory tract may contribute to the observed inflammatory crosstalk in CRSwNP + AS, and perhaps influence patients' response to treatment. Nasal and lower airway microbiota dysbiosis have been proved to be implicated in the persistence of characteristic inflammatory endotypes in both CRSwNP and asthma. It has been shown that bacterial dysbiosis is correlated with CRS status and that specific microbiota taxonomic classifications are correlated with patient phenotypes, including the presence of nasal polyps. A high proportion of patients with CRSwNP are colonized with Staphylococcus (S.) aureus and IgE antibodies to S. aureus enterotoxins are frequently found in diseased tissue specimens. Both S. aureus and Pseudomonas aeruginosa bacteria can disrupt the epithelial barrier contributing to presumed physiologic mechanisms for CRSwNP development. It has been previously demonstrated that S. aureus is able to drive Th2 type inflammation in CRSwNPand that the expression of IL-5 and of IgE against S. aureus superantigens (SE-IgE) within polyp tissue is associated with comorbid asthma and CRSwNP recurrence. Furthermore, antimicrobial compounds including lysozyme, S100 proteins, and β-defensins all are decreased in CRSwNP patients compared to matched controls. This reduction in natural defenses could play a key role in shifting the balance towards dysbiosis. Furthermore, in addition to bacterial microbiome which has been the focus of most recent studies, the contribution of fungal microbiota to allergic airway diseases has been recently emerged. An alternative proposed pathogenic mechanism for Th2-biased CRS is that T-cells are allergically sensitized to fungi in the ambient environment, leading to allergic inflammation characterized by a Th2-high state. Overall, a distinct microbiome role in CRSwNP and asthma pathogenesis is actually recognized. However, the significance of interactions between the lower/upper airways flora and the host local and systemic inflammatory response has not yet been well defined neither such a knowledge is exploited for a more accurate patients classification and selection of best possible therapeutic manipulation to change disease progression.

Evidently, an optimal diagnostic approach for CRSwNP + AS would include use of very specific biomarkers ensuring a detailed endotyping, whereas, there is a growing consensus that both diseases should be treated to improve therapeutic outcome. However, the management of CRSwNP + AS patients who remain uncontrolled despite medical and often surgical intervention poses a great challenge to clinicians. Fortunately, there has been significant innovation and expansion in the treatment armamentarium since the advent of biological therapies. Targeted biologics (monoclonal antibodies against IL-4, IL-5, IL-13 and IgE) for treating asthma are now being used for CRSwNP with encouraging results.

Recently, mepolizumab (Nucala; GlaxoSmithKline), an anti-IL5 humanized mab known to efficiently down-regulate the eosinophilic inflammatory pathway and to exhibit clinical benefit in patients with severe, eosinophilic asthma, has completed a phase 3 trial (SYNAPSE; NCT03085797) including 413 subjects with CRSwNP. Early results showed treatment with mepolizumab had a significant difference in median nasal polyp score compared to baseline (-0.73; 95% CI: -1.11 to -0.34) and nasal obstruction visual analog score compared to baseline (-3.14; 95% CI: -4.09 to -2.18; unpublished data). However, there are only limited longitudinal studies evaluating this biologic's efficacy in CRSwNP+AS patients, while the assessment of action mode and biomarkers predicting responsiveness, remain to be elucidated.