度普利尤单抗治疗慢性鼻窦炎伴鼻息肉的疗效分析

目的 分析临床中IL-4Rα单克隆抗体(度普利尤单抗)治疗慢性鼻窦炎伴鼻息肉(CRSwNP)的疗效。方法 回顾性分析2020年8月—2021年4月使用度普利尤单抗治疗4例CRSwNP患者前后的临床疗效、实验室数据、主观及客观评分以及不良事件等情况,初步评价度普利尤单抗治疗CRSwNP的效果。结果 对4例CRSwNP患者随访4个月。在接受度普利尤单抗治疗前,4例患者慢性鼻-鼻窦炎急性加重次数平均为(3.25±1.50)次/年,在随访期间4例患者均未出现慢性鼻-鼻窦炎急性加重,其中3例患者的鼻窦炎症状得到完全控制。度普利尤单抗治疗前4例患者平均鼻腔鼻窦结局测试-22 (SNOT-22)、宾夕法尼亚大学的嗅觉测试(UPSIT)及副鼻窦CT扫描Lund-Mackay评分分别为52.00±9.42、7.25±1.26、14.50±5.45;治疗4个月后上述评分分别为8.25±5.74、29.25±6.34,7.00±6.38,治疗前后对比差异均具有统计学意义(P<0.05)。使用单抗治疗后4例患者平均口服糖皮质激素(OCS)量为(5.00±7.07)mg/d,对比治疗前(18.75±4.79) mg/d,差异具有统计学意义(P<0.05)。结论 通过特异性抑制白介素-4(IL-4)和白介素-13(IL-13)通路,度普利尤单抗可以显著改善CRSwNP患者鼻窦炎症状以及嗅觉水平,减少患者慢性鼻-鼻窦炎急性加重次数、鼻窦炎病变范围和全身糖皮质激素用量。     

TH2细胞因子在2型慢性鼻窦炎伴鼻息肉中的作用机制研究进展

慢性鼻窦炎(chronic rhinosinusitis with nasal polyps, CRS)根据其发病机制可分为2型和非2型炎症内型,其中2型炎症对应于嗜酸性粒细胞浸润为主的慢性鼻窦炎伴鼻息肉(chronic rhinosinusitis with nasal polyps, CRSwNP)。典型的2型CRSwNP患者通常对目前的治疗有耐药性,表现出较高的复发率。尽管生物制剂在其治疗上取得了一定的成功,但靶向单一TH2细胞因子并不能完全消除大多数患者的2型疾病,故靶向阻断TH2细胞因子及其下游的信号转导通路可能是针对内型治疗的一种新思路。论文对各2型细胞因子(IL-4、IL-5、IL-9、IL-13、IL-25和IL-33)在2型CRSwNP中与其特异性受体相互结合后激活的细胞内信号通路进行综述,旨在为治疗2型CRSwNP提供新的靶点。     

慢性鼻窦炎生物靶向药物治疗的研究进展

慢性鼻窦炎(CRS)是一种鼻腔鼻窦的慢性炎症性疾病,根据其发病机制可分为1型、2型和3型炎症内在型。目前CRS的药物治疗及手术治疗方法均存在发生各种不良反应和并发症的风险,其中部分难治性鼻窦炎虽经适当的药物和手术治疗仍不能取得满意效果并极易复发,严重影响患者的生活质量。生物靶向药物的应用和发展为CRS的治疗提供了一种有效和安全的替代方案。本文着重介绍针对CRS三种炎症内在型的相关细胞因子(包括TNF-α、IL-4、IL-5、IL-13、IgE和IL-17等)的生物靶向药物治疗的研究进展。     

IL-34对Th17细胞及其细胞因子在慢性鼻-鼻窦炎调节机制中的研究前景

慢性鼻-鼻窦炎(chronic rhinosinusitis,CRS)是一种慢性炎症性疾病,由多种炎性细胞参与,其病程大于12周,主要临床表现为黏性或黏脓性鼻涕、鼻塞、头痛、嗅觉丧失或减退,使得患者的生活质量受到了很大的变化。目前临床上一般将CRS分为慢性鼻-鼻窦炎伴鼻息肉(chronic rhinosinusitis with nasal polyps,CRSwNP)和慢性鼻-鼻窦炎不伴鼻息肉(chronic rhinosinusitis without nasal polyps,CRSsNP)。在炎症反应过程中,辅助性T淋巴细胞(Th)类细胞因子是最主要的一类细胞因子,Th细胞及其所产生的细胞因子在其炎症的发展过程中都起到了关键性的作用。CRS的发病机制目前为止还未完全阐释清楚,本文将对IL-34(interleukin-34,IL-34)、Th17细胞极其相关细胞因子在慢性鼻-鼻窦炎发病机制中的研究前景做一综述。     

转化生长因子-β1在慢性鼻-鼻窦炎中的作用及其相关影响因素研究进展

慢性鼻-鼻窦炎(chronic rhinosinusitis,CRS)是指发生于鼻腔、鼻窦黏膜的慢性炎症性疾病,病程≥12周。CRS可分为慢性鼻-鼻窦炎伴鼻息肉(chronic rhinosinusitis with nasal polyps,CRSwNP)和慢性鼻-鼻窦炎不伴鼻息肉(chronic rhinosinusitis without nasal polyps,CRSsNP)两型[1],其发病机制尚不完全清楚,不同类型的CRS表现为不同的黏膜炎症和组织重构[2]。     

慢性鼻窦炎伴鼻息肉与哮喘的相关性机制及治疗策略研究进展

慢性鼻窦炎伴鼻息肉(CRSwNP)和哮喘作为上下呼吸道最具代表性的慢性炎症性疾病,二者在发病过程中常相互并存,临床诊治棘手。目前对CRSwNP和哮喘的相互作用机制尚未阐明。欧洲鼻窦炎鼻息肉诊疗指南(EPOS 2012)对治疗CRSwNP伴或不伴哮喘已给出具体的指导意见,其常规治疗包括鼻用糖皮质激素、生理盐水洗鼻等,并进一步根据CRSwNP的特点、症状严重程度等进行后续的联合治疗。据报道,鼻窦手术和药物治疗CRSwNP对合并支气管哮喘的转归有益。但CRSwNP合并哮喘患者经药物与手术治疗后的疗效判定尚缺乏足够的随机对照试验证据。     

奥马珠单抗治疗慢性鼻-鼻窦炎伴鼻息肉的研究进展[综述]

慢性鼻-鼻窦炎伴鼻息肉（chronic rhinosinusitis with nasal polyps,CRSwNP）是临床常见疾病,复发率较高。对于部分应用传统鼻内镜手术和常规药物疗效并不理想的患者,奥马珠单抗可能成为他们的治疗选择之一。奥马珠单抗是一种重组人源化单克隆抗体,近年来国外应用其治疗CRSwNP的文献多显示出良好的应用前景。本文对目前奥马珠单抗治疗CRSwNP的临床研究进展做一综述。     

奥玛株单抗在慢性鼻窦炎伴鼻息肉患者治疗中的应用

慢性鼻窦炎伴鼻息肉(CRSwNP)的炎症机制复杂,现有治疗方式对其病情控制欠佳。奥玛株单抗可通过与IgE受体结合降低患者的免疫级联反应,已有研究证明其对缓解CRSwNP合并哮喘患者的鼻部症状有良好的效果,但针对伴嗜酸性粒细胞增多、IgE水平高的难治性复发性CRSwNP治疗效果的探索还需要更多、更大规模的随机对照实验来证明。本文结合该背景对奥玛株单抗的作用机制以及在CRSwNP中的应用进行阐述,为CRSwNP的治疗提供参考。     

奥马珠单抗治疗慢性鼻-鼻窦炎伴鼻息肉的研究进展

慢性鼻-鼻窦炎伴鼻息肉（chronic rhinosinusitis with nasal polyps,CRSwNP）是临床常见疾病,复发率较高。对于部分应用传统鼻内镜手术和常规药物疗效并不理想的患者,奥马珠单抗可能成为他们的治疗选择之一。奥马珠单抗是一种重组人源化单克隆抗体,近年来国外应用其治疗CRSwNP的文献多...     

慢性鼻窦炎的内表型研究进展及精准治疗

慢性鼻窦炎（CRS）是耳鼻咽喉头颈外科的常见疾病,其内在的病理机制复杂,目前治疗的主要方式有药物治疗和手术治疗,但对于某些特殊内表型的CRS,手术往往无效。近年在精准医学的倡导下,趋向于根据CRS的内表型,研制新的生物制剂,施予精准治疗方案,包括针对Ⅱ型炎症内表型、嗜酸粒细胞型内表型、上皮屏障功能和上皮来源细胞因子内表型等。     

嗜酸性粒细胞与慢性鼻-鼻窦炎伴鼻息肉的相关性研究进展

慢性鼻窦炎（chronic rhinosinusitis,CRS）是鼻腔黏膜和鼻窦黏膜的慢性炎性疾病,根据有无鼻息肉可分为慢性鼻-鼻窦炎伴鼻息肉（chronic rhinosinusitis with nasal polyps,CRSwNP）和慢性鼻-鼻窦炎（chronic rhinosinusitis without nasal polyps,CRSsNP）。鼻息肉组织常见有嗜酸性粒细胞(eosinophils,EOS) 浸润增多,根据嗜酸性粒细胞的浸润程度可将CRSwNP分为两个亚型：嗜酸粒细胞型慢性鼻窦炎伴鼻息肉(eosinophilic chronic rhinosinusitis with nasal polyps, ECRSwNP)和非嗜酸粒细胞型慢性鼻窦炎伴鼻息肉 (nonesinophilc chronic rhinosinusitis with nasal polyps,nonECRSwNP);将慢性鼻窦炎分为：嗜酸粒细胞型慢性鼻窦炎（eosinophilic chronic rhinosinusitis, ECRS)和非嗜酸粒细胞型慢性鼻窦炎(non eosinophilic,NECRS)。嗜酸性粒细胞在鼻息肉形成、发展机制中的作用多年来一直备受学者们关注。随着研究的不断深入,嗜酸性粒细胞在鼻窦炎鼻息肉炎症趋化、息肉形成、分型和预后中的作用得到越来越多的重视。     

Immunomodulators in chronic rhinosinusitis

ObjectiveTo provide new insight into how chronic rhinosinusitis (CRS) is conceptualized and treated with a focus on immunomodulator therapy.Data sourcesPubmed, Medline, and Embase.MethodsA current review of the evidence is provided for immunomodulators investigated for treatment of CRS with nasal polyps (CRSwNP).ResultsBiologic therapies targeting IgE, IL-4, IL-5, and IL-13 for the treatment of CRSwNP have shown promise and are currently in phase 3 trials. Anti-immunoglobin E (IgE) therapy with omalizumab was assessed in 6 studies, anti-interleukin (IL)-5 therapy in 3 studies (2 mepolizumab, 1 reslizumab) and anti IL-4/IL-13 (dupilumab) therapy in one study. Studied outcomes varied, but the majority of trials identified clinical benefit of therapy over placebo. Other potential targets include thymic stromal lymphopoetin (TSLP), IL-25, IL-33, and sialic acid-binding immunoglobulin-type lectin (Siglec)-8. Small molecule drugs that target the dysregulation of the immune system in CRS are also being investigated for their immunomodulatory effects on inflammation.ConclusionImmunomodulator therapies for CRS currently in development will likely provide another therapeutic option for patients who have severe disease unresponsive to corticosteroids and surgery. Targeted monoclonal antibody therapies have shown encouraging results and phase 3 trials are underway. IL-4/IL-13 inhibition has shown the most promise to date. Further larger, well-designed trials are needed to improve understanding of these molecules and to offer endotype-driven therapies in the management of CRS. None of these therapeutics have shown long-term immunomodulation when discontinued and therefore further investigation into the pathomechanism of disease continues to be needed.     

Increased expression of acidic mammalian chitinase in chronic rhinosinusitis with nasal polyps

BACKGROUND: Chitin is an abundant polysaccharide found in fungi, insects, and parasitic nematodes. Innate immune host defense against chitin-containing pathogens include production of chitinases. In human lower airways, acidic mammalian chitinase (AMCase) is produced in epithelial cells via a Th2-specific, IL-13-dependent pathway, and may act as an inflammatory mediator in asthma. The role of AMCase in chronic rhinosinusitis (CRS) has not been studied previously. METHODS: Eleven controls and 22 subjects with medically recalcitrant CRS were prospectively enrolled before undergoing endoscopic sinus surgery. RNA was extracted from surgically obtained ethmoid mucosa, and real-time PCR was used to determine expression of AMCase, eotaxin, and IL-13. Subjects were followed for at least 6 months postoperatively to assess for polyp recurrence. Based on the presence or absence of polyps, the subjects were classified as either recalcitrant or responsive to therapy. RESULTS: AMCase mRNA was detected in the sinus mucosa of 72% of control subjects and in 72% of patients with eosinophilic CRS with nasal polyps (CRSwNP). The expression of AMCase was significantly greater in recalcitrant CRSwNP than it was in treatment-responsive CRSwNP. There was no significant difference in IL-13 expression between these two groups. CONCLUSION: AMCase may be an important mediator in the pathogenesis of Th2 inflammatory diseases of the respiratory tract. Failure of medical and surgical therapy in CRSwNP is associated with significantly increased expression of AMCase, but not the Th2 cytokines IL-13 and eotaxin. Additional studies are needed to determine the potential of AMCase as a therapeutic target in CRSwNP.     

Chronic rhinosinusitis with nasal polyps is associated with decreased expression of mucosal interleukin 22 receptor

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is an inflammatory disorder of the sinonasal mucosa that is frequently associated with microbial colonization. Innate defense mechanisms at the mucosal surface are critical in protecting the host from airborne environmental pathogens. Recent studies of skin and gastrointestinal tract inflammatory diseases have shown that stimulation of the interleukin-22 receptor (IL-22R1) nonspecifically increases innate immune responses. The potential role of IL-22R1 in the pathogenesis of CRSwNP has never been explored. STUDY DESIGN: Prospective. METHODS: Nine controls and 19 subjects with CRS were prospectively enrolled prior to undergoing endoscopic sinus surgery. Nasal epithelial cells were cultured from surgically obtained ethmoid mucosa and IL-22R1 protein expression was examined via flow cytometry. RNA was extracted from whole mucosal samples and real-time polymerase chain reaction (PCR) was employed to determine expression of IL22 and IL-22R1. Subjects were followed for at least 6 months postoperative to assess for recurrence or persistence of polyps. RESULTS: Flow cytometry demonstrated the expression of IL-22R1 protein on the surface of cultured nasal epithelial cells. IL-22R1 mRNA was expressed in 100% of the controls and CRSsNP. However, IL-22R1 was only expressed in 55% of patients with recalcitrant CRSwNP. Additionally, levels of IL22R1 were significantly lower in recalcitrant CRSwNP compared to controls and CRSsNP. IL22 levels did not reach statistical significance. CONCLUSIONS: In this study, we demonstrate IL-22R1 mRNA and protein expression on nasal epithelial cells. Failure of medical and surgical therapy in CRSwNP is associated with significantly decreased expression of IL-22R1. Further research is needed to determine the potential of IL-22R1 as a therapeutic target in CRSwNP.     

Th2 cytokines associated with chronic rhinosinusitis with polyps down-regulate the antimicrobial immune function of human sinonasal epithelial cells

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNPs) is a disorder characterized by persistent eosinophilic Th2 inflammation and frequent sinonasal microbial colonization. It has been postulated that an abnormal mucosal immune response underlies disease pathogenesis. The relationship between Th2 inflammatory cytokines and the innate immune function of sinonasal epithelial cells (SNECs) has not been explored. METHODS: Human SNECs (HSNECs) isolated from control subjects and patients with CRS were assessed for expression of antimicrobial innate immune genes and proinflammatory cytokine genes by real-time polymerase chain reaction, ELISA, and flow cytometry. A model of the Th2 inflammatory environment was created by exposure of primary HSNEC to the Th2 cytokine interleukin (IL)-4 or IL-13 for 36 hours, with subsequent assessment of innate immune gene expression. RESULTS: HSNEC obtained from CRSwNP patients displayed decreased expression of multiple antimicrobial innate immune markers, including toll-like receptor 9, human beta-defensin 2, and surfactant protein A. Baseline expression of these genes by normal and CRS HSNEC in culture is significantly down-regulated after incubation with IL-4 or IL-13. CONCLUSION: Expression of multiple innate immune genes by HSNEC is reduced in CRSwNP. One mechanism appears to be a direct effect of the leukocyte-derived Th2 cytokines present in the sinonasal mucosa in CRSwNP. Impaired mucosal innate immunity may contribute to microbial colonization and abnormal immune responses associated with CRSwNP.     

Sinonasal epithelial cell expression of toll-like receptor 9 is decreased in chronic rhinosinusitis with polyps

BACKGROUND: Innate immune recognition of pathogens by sinonasal epithelial cells may play an important role in the pathogenesis of chronic rhinosinusitis (CRS). Previous studies have indicated that toll-like receptor (TLR) mRNA is present in sinonasal mucosa, and levels of TLR9 expression are decreased in recalcitrant CRS with nasal polyps (CRSwNP). However, the cellular source and function of TLR9 in the sinonasal epithelium is not known. In this study, primary epithelial cell cultures were analyzed from control subjects and CRSwNP patients to determine the presence and function of TLR9 protein. METHODS: Primary epithelial cell cultures were established from 5 controls and 10 CRSwNP patients undergoing sinus surgery. Flow cytometry was used to confirm purity of epithelial cells and to assess expression of TLR9 protein. Epithelial cells were stimulated with TLR9 agonist, and mRNA was analyzed by real-time PCR for expression of human beta-defensin (HBD) 2 and interleukin (IL)-8. RESULTS: Flow cytometry showed TLR9 protein in 100% of epithelial cells from controls and CRSwNP patients. The level of expression was 50% lower in CRS patients than in controls. Stimulation of epithelial cells with TLR9 agonist produced a 1.5- to 9-fold increase in HBD-2 and IL-8 mRNA expression. CONCLUSION: Functional TLR9 protein is expressed by normal and diseased sinonasal epithelial cells. The level of TLR9 expression is decreased in CRSwNP patients, consistent with the previous finding of decreased TLR9 mRNA in whole sinonasal tissue. These findings suggest that impaired innate immune responses to pathogens via TLR9 on sinonasal epithelial cells may represent a critical mechanism in chronic inflammatory sinus disease.     

口服糖皮质激素在慢性鼻窦炎伴鼻息肉围手术期的应用现状

鼻内镜鼻窦手术(ESS)已成为外科治疗慢性鼻窦炎伴鼻息肉(CRSwNP)的“金标准”,鼻内镜鼻窦手术围手术期管理对手术效果有重要影响。目前口服糖皮质激素因其抗炎和免疫抑制作用已作为ESS围术期辅助用药以增强手术效果,但在其剂量剂型及疗效等方面仍存在争议。回顾近年来研究口服糖皮质激素与CRSwNP围手术期疗效的相关文献,对口服糖皮质激素在围手术期的效果及治疗策略进行综述,以求提供更多的治疗选择和研究方向。     

Effect of Obstructive Sleep Apnea on Immunity in Cases of Chronic Rhinosinusitis With Nasal Polyps

Objectives.Chronic rhinosinusitis with nasal polyps (CRSwNP) is a more severe inflammatory form of CRS that often coexists with obstructive sleep apnea (OSA). However, little is known about the relationship between OSA and the immune profile in patients with CRSwNP. We aimed to investigate the immune profile of patients with CRSwNP according to OSA severity.Methods.This study included 63 patients with CRSwNP and nine control subjects. Protein levels of inflammatory mediators were determined using multiplex immunoassays. All patients underwent standard polysomnography.Results.In patients with eosinophilic CRSwNP (ECRSwNP), interleukin (IL)-6 and chemokine [C-X-C motif] ligand (CXCL)-1 (type 1 immune-related markers) were upregulated in cases of moderate-to-severe OSA. Additionally, IL-4, IL-13, C-C motif chemokine (CCL)-11, CCL-24 (type 2 immune-related markers), and IL-17A (a type 3 immune-related marker) were present at elevated levels in patients with moderate-to-severe OSA. Although there were no significant differences in type 1, 2, or 3 immune-related markers among patients with non-eosinophilic CRSwNP (NECRSwNP) according to the severity of OSA, transforming growth factor-beta expression was higher in those with moderate-to-severe OSA. Furthermore, in ECRSwNP with moderate-to-severe OSA, associations were detected between serum markers and some upregulated inflammatory markers.Conclusion.OSA may increase the heterogeneity of the immune profile (types 1, 2, and 3) in patients with ECRSwNP, but not in those with NECRSwNP.