Investigation and Characterization of the RAS/RAF/MEK/ERK Pathway and Other Signaling Pathways in Chronic Sinusitis with Nasal Polyps.

BACKGROUND: The clinical outcomes of drug treatments and surgical interventions for chronic sinusitis with nasal polyps (CRSwNPs) are suboptimal, and the high recurrence rate remains a significant challenge in clinical practice. Targeted therapies such as biologics provide new perspectives and directions for treating CRSwNP. SUMMARY: With the continuous investigation of signaling pathways, RAS/RAF/MEK/ERK signaling pathway and other signaling pathways including Hippo, JAK-STAT, Wnt, TGF-ß, PI3K, Notch, and NF-κB were confirmed to play an important role in the progression of CRSwNP. Among them, the abnormality of RAS/RAF/MEK/ERK signaling pathway is accompanied by the abnormality of this apoptotic component, which may provide new research directions for targeting the components of signaling pathways to mediate apoptosis. KEY MESSAGES: Abnormalities in signaling pathways are particularly important in studying the pathogenesis and treatment of CRSwNP. Therefore, this review summarizes the ongoing investigation and characterization of RAS/RAF/MEK/ERK signaling pathway and other signaling pathways in CRSwNP, which provides constructive ideas and directions for improving the treatment of CRSwNP.

Dupilumab-related late adverse events in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Anti-IL-4 receptor α antibody (dupilumab) has demonstrated favorable sinonasal outcomes for chronic rhinosinusitis with nasal polyps (CRSwNP), which is mainly caused by type 2 inflammation. Although increased blood eosinophil levels and injection site symptoms are frequently observed as acute adverse events (AEs) of dupilumab, limited knowledge is available regarding the late AEs of dupilumab for CRSwNP. OBJECTIVES: We investigated the late AEs following the initiation of dupilumab treatment for CRSwNP. MATERIAL AND METHODS: Fifty-one patients with CRSwNP treated with dupilumab for > 3 months were enrolled, and their clinical data were collected from their medical records. RESULTS: Six (11.8%) patients experienced late AEs. One case of eczema with pruritus, one case of psoriasis-like dermatitis, two cases of severe rash, one case of malignant lymphoma, and one case of alopecia areata were observed. Skin disorders were the most common late AEs in this study. It is a Th1-inflammatory disease, and its mechanism is thought to be due to the immune imbalance caused by dupilumab. We could not confirm whether malignant lymphoma in our case was caused by dupilumab use. CONCLUSIONS AND SIGNIFICANCE: Skin disorders are often late AEs associated with dupilumab; therefore, careful monitoring after dupilumab initiation should be considered.

Neutrophil Extracellular Traps as a Biomarker in Refractory Non-Type 2 CRSwNP.

PURPOSE: Chronic rhinosinusitis (CRS) is classified into type 2 (T2) and non-T2 inflammation. T2 CRS presents as a severe form, CRS with nasal polyps (CRSwNP), which often occurs with asthma as a comorbidity worldwide. Some cases of non-T2 CRS show nasal polyposis and refractoriness, mainly in Asian countries. However, its mechanism remains elusive. To investigate a biomarker for the refractoriness of non-T2 CRSwNP via RNA sequencing. METHODS: RNA sequencing by using nasal polyps (NPs) and ethmoidal mucosa (EM) from CRS subjects and uncinate tissues from controls was performed, and differentially expressed genes (DEGs) were analyzed (cutoffs: expression change > 2-fold, P < 0.01). Immunofluorescence staining and enzyme-linked immunosorbent assay were performed. RESULTS: We identified DEGs among T2-NP, non-T2-NP, T2-EM, non-T2-EM, and controls (NP vs. controls: 1,877 genes, EM vs. controls: 1,124 genes, T2-NP vs. controls: 1,790 genes, non-T2-NP vs. controls: 2,012 genes, T2-EM vs. controls: 740 genes, non-T2-EM vs. controls: 1,553 genes). The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that neutrophil extracellular trap (NET) formation, systemic lupus erythematosus, and the phagosome were enriched in non-T2-NP vs. controls and non-T2-EM vs. controls. Immunofluorescence staining confirmed that NETs were elevated in non-T2-NP. Cytokine analysis demonstrated that NETs were significantly related to the refractoriness in non-T2-NPs. CONCLUSIONS: This study demonstrated DEGs between T2 and non-T2 inflammation. These results suggest that NETs may contribute to the refractoriness in non-T2-NPs and have a promise as a therapeutic strategy for patients with refractory non-T2-NP.

Efficacy of dupilumab on chronic rhinosinusitis with nasal polyps and concomitant asthma in biologic-naive and biologic-pretreated patients.

OBJECTIVES: Dupilumab, an anti-IL-4 receptor monoclonal antibody (mAb), was recently approved for the treatment of severe chronic rhinosinusitis with nasal polyps (CRSwNP). The main objective of this study was to assess whether previous exposure to biological treatment affected the clinical outcomes in CRSwNP and asthma patients, treated with dupilumab over time. A collateral secondary objective was to analyse the effects over time of dupilumab in patients with and without aeroallergen sensitization. METHODS: Single-centre retrospective observational study on severe CRSwNP patients treated with dupilumab. Nasal polyp score (NPS), visual analogue scale (VAS) symptom score, sinonasal outcome test (SNOT-22), aeroallergen sensitization, total serum IgE levels, and blood eosinophil counts were assessed at baseline and after 4, 6 and 12 months. RESULTS: 42 patients were included, 40 (95.2%) had asthma. Twenty-one (50%) patients received dupilumab without prior biological treatment (Group A: naive) and 50% switched to dupilumab from previous biological treatment (Group B: pre-treated). NPS, VAS symptoms, SNOT-22 improved significantly after 12 months treatment in both groups of patients (p < 0.001). After 12 months, VAS overall symptom score showed a significant reduction from 6 (IQR, 4.6-8.6) and 6 (IQR, 3.8-7.1) for Group A and Group B patients respectively, to 1.2 (IQR, 0.8-2.7) and 1.2 (IQR, 0.2-2.5); NPS from 6 (IQR, 4.0-7.0) and 5 (IQR, 3.5-6.0), respectively, to 1 (IQR, 0.0-2.0) and 0 (IQR, 0.0-3.0) and SNOT-22 from 64 (IQR, 56-78) and 71 (IQR, 47.5-76.0) respectively, to 5.5 (IQR, 4-21) and 6 (IQR, 4-15). IgE reduced from 57 to 22.1 and from 46.9 to 30.2 in Group A and Group B respectively (p < 0.001). CONCLUSIONS: Dupilumab improves symptom severity, polyp size, and health-related quality of life, regardless of the presence or absence of comorbid aeroallergen sensitization and previous administration of biologic therapy.

Dupilumab proved to be effective in patients with severe chronic rhinosinusitis with nasal polyps (CRSwNP).We observed that dupilumab for CRSwNP leads to a very rapid improvement in polyps, symptoms, and quality of life, regardless of previous biologic treatment status and presence or absence of allergic rhinitis.VAS, SNOT-22 and NPS may be established as outcome markers in everyday clinical practice during dupilumab treatment.

Management of Nasal Polyposis in Pediatric Patients With Cornelia de Lange Syndrome: A Case Series and Literature Review.

Cornelia de Lange syndrome (CdLS) is a rare genetic multiple malformation disorder with many otolaryngologic comorbidities. Patients with CdLS appear to have an increased prevalence of chronic rhinosinusitis (CRS) and chronic rhinosinusitis with nasal polyposis (CRSwNP), however, there is limited literature describing the presentation, evaluation, and management of CRSwNP within the CdLS population. Here we performed a literature review from Embase, PubMed, Cochrane Library, and Google Scholar and reported a case of CRSwNP with concomitant CdLS that was identified at our institution. We describe an 8-year-old male with CdLS and CRSwNP confirmed by history, physical exam, nasal endoscopy, and computed tomography. Symptoms of nasal obstruction were refractory to medical management and required repeat surgical management with improvement in nasal obstruction. Literature review identified 2 additional cases of nasal polyposis with similar management strategies. Additionally, one case series showed 33% of CdLS patients had recurrent sinusitis while a second series identified 39% of CdLS patients with CRS and 12% with CRSwNP. These data suggest that CRSwNP is more prevalent in patients with CdLS compared to the general public and can be both safely and effectively managed with a combination of medical and surgical therapy.

Canadian Real-World Study Long-Term Clinical Results Using Dupilumab for Chronic Rhinosinusitis With Polyps.

BACKGROUND: Dupilumab, an anti-IL4 receptor-α monoclonal antibody, was the first biologic to be approved in Canada for the treatment of Chronic Rhinosinusitis with Nasal Polyps (CRSwNP). In phase III clinical trials, it has demonstrated to be effective in reducing nasal polyp size and the severity of symptoms, improve disease-specific quality of life, and to have an acceptable safety profile. This study aims to present long-term follow-up data on disease-specific sinonasal outcomes of patients with CRSwNP who have been treated with dupilumab for up to 3 years in a real-world setting. METHODS: Retrospective review of electronic medical records of a single Canadian rhinology center evaluating disease-specific sinonasal outcomes that are routinely collected for clinical care. This study included all patients who received dupilumab for the treatment of CRSwNP and who had completed at least one follow-up visit. The Sino-Nasal Outcome Test (SNOT)-22 was used to evaluate treatment symptom improvement. RESULTS: Ninety-nine patients started dupilumab therapy during the study period. The mean SNOT-22 at the start of therapy was 61.1 (±22.91) At the time of the review, 65 patients had completed 1 year of therapy, 40 had completed 2 years of therapy, and 18 had completed 3 years of therapy. The mean SNOT-22 score at these timepoints was 16.75 (±13.86), 15.02 (±14.40), and 10.22 (±11.56), respectively. CONCLUSION: This real-world study shows that in patients with CRSwNP treated with dupilumab, improvement in disease-specific quality of life seen after 1 year continues and can be maintained at 3 years of treatment.

TIM-3-driven macrophage polarisation is associated to recalcitrant chronic rhinosinusitis with nasal polyps.

Objective: This study evaluated the expression of TIM-3 and its influence on macrophage polarisation in recalcitrant chronic rhinosinusitis with nasal polyps (CRSwNP). Methods: We detected TIM-3 expression in serum and tissue samples of healthy controls (HC), primary CRSwNP, and patients with recurrent CRSwNP. Macrophage markers were detected among three groups, and their correlations with TIM-3 levels were examined. Macrophages from circulating blood were collected and used to examine the impact of TIM-3 on polarisation in vitro. Results: TIM-3 levels were enhanced in the CRSwNP group compared to the HC group. Tissue immunofluorescence revealed elevated TIM-3 expression in patients with CRSwNP, and patients with multiple recurrences exhibited higher TIM-3 levels compared to their first recurrence and baseline levels. Tissue CD163 and CD206 levels were higher in recurrent CRSwNP in comparison with primary cases and HCs, and had a positive correlation with TIM-3 levels. TIM-3 overexpression promoted M2 polarisation and enhanced TGF-ß1 and IL-10 secretion. Conclusions: TIM-3 expression was enhanced in patients with CRSwNP, especially in those undergoing revision surgeries. TIM-3 may be a novel biomarker for recalcitrant CRSwNP. TIM-3-driven M2 polarisation might be involved in the mechanisms of recurrent CRSwNP.

Risk factors investigation for different outcomes between unilateral and bilateral chronic rhinosinusitis with nasal polyps patients.

BACKGROUND: Studies involving chronic rhinosinusitis with nasal polyps (CRSwNP) have mostly focused on bilateral cases, making unilateral CRSwNP inadequately recognized. This study examined the differences in clinical characteristics, outcomes, and risk factors for poor outcomes between unilateral and bilateral CRSwNP to facilitate a better assessment in the two groups. METHODS: Demographic information, tissue and blood cells, endoscopic scores, Lund-Mackay scores, recurrence rates, and disease control conditions were compared between 310 unilateral and 596 bilateral CRSwNP patients. Furthermore, the stepwise regression multivariate Cox proportional hazard models were performed to generate risk factors for poor outcomes in the two groups. RESULTS: Bilateral cases exhibited higher rates of smoking, AR, and asthma comorbidities, along with higher numbers of tissue eosinophils and blood inflammatory cells when compared to unilateral patients. Endoscopic nasal polyp score, total computed tomography (CT) score (with scores for each sinus cavity), and adjusted CT scores were significantly higher in the bilateral group, except for a markedly higher adjusted maxillary score in the unilateral group. Furthermore, significantly higher proportions of bilateral patients experienced nasal polyp recurrence, uncontrolled status, and most disease control-related symptoms at follow-up. The primary risk factors for poor outcomes were asthma, tissue eosinophils, and total CT score in the bilateral group and blood basophils in the unilateral group. CONCLUSIONS: Bilateral CRSwNP patients experience worse disease severity and outcomes than their unilateral counterparts. Primarily, asthma, tissue eosinophils, and total CT score were risk factors for poor outcomes in bilateral CRSwNP patients, with blood basophils in unilateral cases.

Mupirocin Ointment Effect on Polyposis Recurrence After Sinus Surgery.

Introduction: Staphylococcus aureus is an identified pathogen involved in the recurrence of symptoms in patients with chronic rhinosinusitis with nasal polyps. We investigated the effectiveness of a topical ointment of mupirocin applied in the nasal vestibule in lessening symptom recurrence and improving the efficiency of functional endoscopic sinus surgery. Materials and Methods: Patients with chronic rhinosinusitis, nasal polyps, and a positive nostril culture for Staphylococcus aureus were included in a clinical trial. The right nostril was determined as the intervention group (applying mupirocin ointment) and the left as the control group (applying vitamin A ointment). Lund-Mackay radiological scores and Lund-Kennedy endoscopic scores were examined at the time of diagnosis and six months later. Results: Among 60 patients with chronic rhinosinusitis with nasal polyps, 91.6% were positive for nostril Staphylococcus aureus. Comparing the average of the diagnostic radiological and endoscopic scores with the follow-up values in both groups indicated a significant improvement after surgery (P-value=0.001, 0.001). However, there was no significant difference in the radiological and endoscopic score improvements between the study and control groups (P-value > 0.56, 0.74). Conclusion: Nasal mupirocin administration following endoscopic sinus surgery cannot significantly prevent symptom recurrence in chronic rhinosinusitis with nasal polyps.

Rheumatoid Arthritis Exacerbates Eosinophilic Inflammation Contributing to Postoperative Recurrence in Chronic Rhinosinusitis with Nasal Polyps.

Objective: To assess the impact of rheumatoid arthritis (RA) on histopathological features and the risk of postoperative recurrence in chronic rhinosinusitis with nasal polyps (CRSwNP) patients. Methods: A retrospective cohort study of CRSwNP patients who underwent functional endoscopic sinus surgery was performed. Patients were followed up for more than two years, and classified into RA and Non-RA groups, recurrent and non-recurrent groups. The influence of RA on histopathological features and the risk of CRSwNP recurrence was explored. Results: A total of 517 CRSwNP patients were finally recruited, including 78 RA patients. The RA group exhibited a higher recurrence rate, tissue eosinophil counts and percentages compared to the non-RA group (P < 0.05). Tissue eosinophil count and percentage, and the prevalence of allergic rhinitis were significantly higher in the recurrent group in compared to the non-recurrent group (P < 0.05). Multivariate logistic regression analysis identified tissue eosinophil count and percentage, RA, and allergic rhinitis as significant predictors of increased recurrence risk (P < 0.05). Both adjusted and unadjusted models affirmed RA as an independent risk factor for CRSwNP postoperative recurrence (P < 0.05). Kaplan-Meier curves further indicated a higher recurrence risk in CRSwNP patients with RA than those without (P < 0.05). Conclusion: Our findings suggest that RA significantly exacerbates tissue eosinophilic inflammation and independently heightens the risk of postoperative recurrence in CRSwNP patients. These insights underscore the need for tailored therapeutic strategies addressing the complex interplay between CRSwNP and RA to mitigate recurrence risks and improve clinical outcomes.