Background Adult patients with nasal polyps often have comorbid asthma, adding to the serious effect on the quality of life of these patients. Nasal polyps and asthma might represent a therapeutic ...challenge; inflammation in both diseases shares many features, such as airway eosinophilia, local IgE formation, and a TH 2 cytokine profile. Omalizumab is a human anti-IgE mAb with proved efficacy in patients with severe allergic asthma. Omalizumab could be a treatment option for patients with nasal polyps and asthma. Objective The goal of this study was to investigate the clinical efficacy of omalizumab in patients with nasal polyps and comorbid asthma. Methods A randomized, double-blind, placebo-controlled study of allergic and nonallergic patients with nasal polyps and comorbid asthma (n = 24) was conducted. Subjects received 4 to 8 (subcutaneous) doses of omalizumab (n = 16) or placebo (n = 8). The primary end point was reduction in total nasal endoscopic polyp scores after 16 weeks. Secondary end points included a change in sinus computed tomographic scans, nasal and asthma symptoms, results of validated questionnaires (Short-Form Health Questionnaire, 31-item Rhinosinusitis Outcome Measuring Instrument, and Asthma Quality of Life Questionnaire), and serum/nasal secretion biomarker levels. Results There was a significant decrease in total nasal endoscopic polyp scores after 16 weeks in the omalizumab-treated group (−2.67, P = .001), which was confirmed by means of computed tomographic scanning (Lund-Mackay score). Omalizumab had a beneficial effect on airway symptoms (nasal congestion, anterior rhinorrhea, loss of sense of smell, wheezing, and dyspnea) and on quality-of-life scores, irrespective of the presence of allergy. Conclusion Omalizumab demonstrated clinical efficacy in the treatment of nasal polyps with comorbid asthma, supporting the importance and functionality of local IgE formation in the airways.
Background There is little scientific evidence to support the current practice of using oral glucocorticosteroids and antibiotics to treat patients with chronic rhinosinusitis and nasal polyps. ...Objective We evaluated the effects of oral glucocorticoids and doxycycline on symptoms and objective clinical and biological parameters in patients with chronic rhinosinusitis and nasal polyps. Methods In a double-blind, placebo-controlled, multicenter trial, we randomly assigned 47 participants with bilateral nasal polyps to receive either methylprednisolone in decreasing doses (32–8 mg once daily), doxycycline (200 mg on the first day, followed by 100 mg once daily), or placebo for 20 days. Participants were followed for 12 weeks. Patients were assessed for nasal peak inspiratory flow and symptoms and by nasal endoscopy. Markers of inflammation such as eosinophilic cationic protein (ECP), IL-5, myeloperoxidase, matrix metalloproteinase 9, and IgE were measured in nasal secretions. Concentrations of eosinophils, ECP, and soluble IL-5 receptor α were measured in peripheral blood samples. Results Methylprednisolone and doxycycline each significantly decreased nasal polyp size compared with placebo. The effect of methylprednisolone was maximal at week 3 and lasted until week 8, whereas the effect of doxycycline was moderate but present for 12 weeks. Methylprednisolone significantly reduced levels of ECP, IL-5, and IgE in nasal secretions, whereas doxycycline significantly reduced levels of myeloperoxidase, ECP, and matrix metalloproteinase 9 in nasal secretions. Conclusion This is the first double-blind, placebo-controlled study to show a significant effect of oral methylprednisolone and doxycycline on size of nasal polyps, nasal symptoms, and mucosal and systemic markers of inflammation.
Background Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. Objective We ...sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. Methods Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. Results Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. Conclusion Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.
The quest for autoreactive antibodies in nasal polyps De Schryver, Els, MD; Calus, Lien, MD, PhD; Bonte, Henryk, MD ...
Journal of allergy and clinical immunology,
09/2016, Letnik:
138, Številka:
3
Journal Article
Recenzirano
Odprti dostop
...we extensively tested CRSwNP for autoimmune factors. By means of the Shapiro-Wilk test (considering the small sample size), the distribution of continuous variables was determined. Because the ...distribution is non-Gaussian, the nonparametric Mann-Whitney U test was used to verify that unpaired samples belong to the same population.
House dust mite (HDM)-induced allergic rhinitis (AR) is a major cause of allergic respiratory disease. The efficacy and safety of the 300 IR HDM sublingual immunotherapy (SLIT) tablet in patients ...with moderate-to-severe HDM-AR was confirmed in a large, international, phase 3 randomized controlled trials (RCTs). Here, we analyzed the results in the European population.
Data from 91 European centers that participated in the international, double-blind, RCT (EudraCT 2014-004223-46, NCT02443805) with the 300 IR HDM SLIT tablet versus placebo over 12 months were analyzed post hoc. The treatment effect in European adults and adolescents was notably assessed through the European Academy of Allergy and Clinical Immunology (EAACI)-recommended combined symptom and medication score (CSMS
, pre-defined endpoint) and the total combined rhinitis score (TCRS
, post hoc endpoint, also balanced) during the primary evaluation period (4 weeks at the end of treatment period) using analysis of covariance (ANCOVA).
There were 818 patients who comprised the modified full analysis set in Europe. Over the primary period, the differences in CSMS
and TCRS
between the 300 IR and placebo groups were statistically significant (p < 0.0001): -0.32 (95%CI -0.46; -0.17) and -1.28 (95%CI -1.63; -0.94), respectively, with relative differences of -20.9% and -21.2%. All post hoc and the rhinoconjunctivitis quality of life endpoints were significantly improved with 300 IR versus placebo. The 300 IR HDM tablet was generally well tolerated.
This RCT sub-analysis confirmed the 300 IR HDM SLIT tablet is an effective and safe treatment for European adults and adolescents with HDM-AR with clinically meaningful benefits from the patients' perspective.
NCT02443805. Registered on April 29, 2015./EudraCT 2014-004223-46. Registered on September 16, 2015.
Background Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. Objective The objective was to analyze the presence of TGF-β isoforms, receptors, ...intracellular signaling, and collagen deposition in chronic rhinosinusitis. Methods Sinonasal mucosal samples obtained from chronic rhinosinusitis with nasal polyps (CRSwNP; n = 13), chronic rhinosinusitis without nasal polyps (CRSsNP; n = 13), and controls (n = 10) were analyzed for TGF-β isoforms 1 and 2 by means of ELISA and IHC, and for TGF-β R1, 2, and 3 by RT-PCR and IHC. As downstream proteins, phospho-Smad 2 (pSmad 2) and collagen were analyzed by performing immunostaining and picrosirius red staining, respectively. Results TGF-β 1 and 2 protein concentrations, TGF-β receptor (R) I and TGF-β RIII mRNA expression, the number of pSmad 2–positive cells, and total collagen amount were significantly higher in CRSsNP versus controls. In CRSwNP, TGF-β 1 protein concentration, TGF-β RII and TGF-β RIII mRNA expression, the number of pSmad 2–positive cells, and total collagen amount were significantly lower versus controls. Only TGF-β 2 protein was found higher in CRSwNP versus controls. Conclusion A high TGF-β 1 protein expression, increased TGF-β RI expression, and a high number of pSmad 2–positive cells all indicate an enhanced TGF-β signaling in CRSsNP, whereas a low TGF-β 1 protein concentration, a decreased expression of TGF-β RII, and a low number of pSmad 2–positive cells in CRSwNP indicate a low level of TGF-β signaling in CRSwNP. These findings are compatible with the remodeling patterns observed, reflected by a lack of collagen in CRSwNP, and excessive collagen production with thickening of the collagen fibers in the extracellular matrix in CRSsNP.
T-cell regulation in chronic paranasal sinus disease Van Bruaene, Nicholas, MD; Pérez-Novo, Claudina Angela, PhD; Basinski, Tomasz M., MSc ...
Journal of allergy and clinical immunology,
06/2008, Letnik:
121, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Background Chronic rhinosinusitis is an inflammatory disease with distinct cytokine and remodeling patterns. Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a TH 2-skewed ...eosinophilic inflammation, whereas chronic rhinosinusitis without nasal polyps (CRSsNP) represents a predominant TH 1 milieu. Objective We aimed to study the direct tissue expression of transcription factors for T-cell subpopulations, including T regulatory cells, in relation to the cytokine expression patterns in the different disease subgroups. Methods The expression of forkhead box P3 (FOXP3), T-box transcription factor (T-bet), GATA-3, retinoid acid-related orphan receptor C (RORc), the suppressive cytokines TGF-β1 and IL-10, and TH 1/ TH 2/ TH 17 cytokines (IFN-γ, IL-4, IL-5, IL-13, IL-17) were analyzed by means of RT-PCR in 13 CRSsNP, 16 CRSwNP, and 10 control samples. Additional protein measurements were performed for TGF-β1 and IFN-γ. Results In CRSwNP, we observed a significantly lower FOXP3 mRNA and TGF-β1 protein expression, but a significantly higher T-bet, GATA-3, IL-5, and IL-13 mRNA expression compared with controls, whereas RORc was not significantly different compared with controls. In CRSsNP, FOXP3, T-bet, GATA-3, and RORc expression was not significantly different from controls, whereas TGF-β1 mRNA, IFN-γ mRNA, and protein were significantly higher in CRSsNP compared with controls. For IL-17, no significant differences were noted among all groups. Conclusion We demonstrate for the first time a decreased FOXP3 expression accompanied by an upregulation of T-bet and GATA-3 and a downregulation of TGF-β1 in CRSwNP versus controls and CRSsNP.
Background Increasing evidence points toward a modifying role of Staphylococcus aureus and its products in the pathogenesis of nasal polyposis. Objective The aim of this study was to investigate ...cytokine and mediator production after stimulation with S aureus –derived proteins enterotoxin B, protein A, and lipoteichoic acid in nasal polyp and control inferior turbinate tissue. Methods Tissue fragments were stimulated with RPMI (negative control), enterotoxin B, protein A, and lipoteichoic acid for 30 minutes and 24 hours. Supernatants were measured by multiplex for proinflammatory cytokines (IL-1β, TNF-α) and T-cell and subset–related cytokines (IFN-γ, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p70, IL-13). Histamine, TGF-β1, cysteinyl leukotrienes, and prostaglandin D2 were analyzed by ELISA. Results Thirty minutes of protein A stimulation resulted in a significant increase of histamine, leukotrienes, and prostaglandin D2 . Enterotoxin B stimulation over a period of 24 hours induced a significant increase of IL-1β, TNF-α, IFN-γ, IL-2, IL-4, IL-5, IL-10, and IL-13 in both groups, with this increase significantly higher in nasal polyps compared with controls. Conclusion We here show that S aureus products have various effects on mucosal tissues: surface protein A induces mast cell degranulation, whereas enterotoxins induce the release of cytokines, with a TH 2-skewed pattern in nasal polyps, supporting the stimulatory role of superantigens in the development of this inflammatory disease.
...HDM sIgE in NasSec predicted with 100% specificity, but poor sensitivity (FDs, 70%; SPs, 73%) the results in serum. The results of the first test were generally reproduced in the second test. ......this time, the prevalence of sIgE to group 1 molecules in serum and NasSec was more similar (serum, 77%; NasSec, 62%-77%; see Tables E5 and E6 in this article's Online Repository at www.jacionline.org). ...the microarray results in NasSec were very predictive for the serum results. ...testing nasal IgE to allergen molecules by a microarray approach may soon become a noninvasive alternative in the diagnostic workup of AR.
Allergic asthma and allergic rhinitis/conjunctivitis are characterized by a TH 2-dominated immune response associated with increased serum IgE levels in response to inhaled allergens. Because IgE is ...a key player in the induction and maintenance of allergic inflammation, it represents a prime target for therapeutic intervention. However, our understanding of IgE biology remains fragmentary. This article puts together our current knowledge on IgE in allergic airway diseases with a special focus on the identity of IgE-secreting cells (“who”), their location (“where”), and the circumstances in which they are induced (“when”). We further consider the therapeutic implications of the insights gained.
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