Lien Calus

Omalizumab is effective in allergic and nonallergic patients with nasal polyps and asthma.

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 T(H)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.

Local free light chain expression is increased in chronic rhinosinusitis with nasal polyps.

Free light chain (FLC) concentrations are demonstrated to be increased in different inflammatory disorders and are proposed to mediate mast cell–dependent immune responses. A role for mast cells is suggested in chronic rhinosinusitis with nasal polyposis (CRSwNP), which is characterized by a local Th2 inflammatory response. However, clear mast cell–activating factors are not always apparent. In this study, the presence of FLCs in CRS patients with or without nasal polyps (CRSw/sNP) was investigated and the effect of different treatments on FLC expression was analyzed.

Local inflammation in chronic upper airway disease.

Chronic Rhinosinusitis (CRS), a chronic upper airway inflammation, is an inflammation of the nose and the paranasal cavities and is highly prevalent. Chronic rhinosinusitis is currently classified as CRS with nasal polyps or CRS without nasal polyps. This review highlights the pathophysiological differences in CRS on remodeling and on T-cell patterns. Nasal polyps have a high co-morbidity with the lower airway inflammatory disease, asthma. Evidence is accumulating for the role of superantigens, Staphylococcus aureus enterotoxins, in CRS with nasal polyps and asthma, both T helper 2 -biased diseases. Until today there are no biomarkers involved in the diagnosis of CRS or the treatment follow-up. Further differentiation of the phenotype of the disease is needed, which will reflect in the development of new biomarkers and in new innovative treatment options. Defining and predicting response to therapy in individual CRS patients is a challenge for future research.

The quest for autoreactive antibodies in nasal polyps

26 BACKGROUND: Chronic rhinosinusitis with nasal polyp s is an incapacitating disease of the sinonasal muc osa. 27 Recurrence after surgery often occurs despite recom mended medical treatment. Inflammation is often T-h elper 28 2-skewed and characterized by local hyperglobulinem a and the presence of mucosal lymphoid accumulatio ns. 29 OBJECTIVE: To investigate whether autoreactivity is a contributing factor in the pathogenesis of nasal polyps. 30 METHODS: Autoreactivity was assessed in chronic rhi nos nusitis with nasal polyps (CRSwNP) and in a con trol 31 group by means of multiple methods. First, an autol og us serum skin test (ASST) was performed to ident fy 32 systemic anti-IgE or systemic antiFc εRI autoantibodies of the IgG isotype. Next, the pre sence of local 33 autoantibodies in nasal polyp tissue was assessed in vitro. The presence of IgE targeting human epithelial ce ll 34 proteins, IgG targeting dsDNA and other nuclear com p nents, and IgG targeting IgE was assessed in nasa l tissue 35 of CRSwNP and control patients. 36 RESULTS: The ASST was negative in all patients, sug gesting the absence of circulating anti-IgE or anti -FcεRI 37 autoantibodies. Anti-dsDNA was significantly elevat ed in nasal polyp tissue, but none of the other 38 autoantibodies tested was elevated locally. Anti-ds DNA antibodies were inversely associated with the l oca 39 levels of interferon-gamma (IFNγ). 40 CONCLUSION: During our quest for autoreactivity in nasal polyps we found no evidence for IgE autoreact ivity, 41 nor did we detect significantly elevated local or s ystemic IgG antibodies against IgE or Fc εRI. We confirmed 42 the presence of anti-dsDNA IgG antibodies and these autoantibodies were elevated when IFNγ was low. 43 Whether these autoantibodies are relevant to the pa thogenesis in CRSwNP remains to be determined. 44

The response to nasal allergen provocation with grass pollen is reduced in patients with chronic rhinosinusitis with nasal polyposis and grass sensitization.

The majority of grass pollen–sensitized rhinitis patients develops allergic symptoms when exposed to the causal allergen and shows a positive nasal allergen provocation test (NAPT). Chronic rhinosinusitis with nasal polyposis (CRSwNP) patients, also characterized by eosinophilic inflammation and local IgE production, can suffer from comorbid inhalant allergy, but may show a different response to allergens.

IL-21 Is Increased in Nasal Polyposis and after Stimulation with Staphylococcus aureus Enterotoxin B

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) is an inflammatory disease associated with lymphoid aggregates and local IgE production related to Staphylococcus aureus enterotoxins. T-follicular helper cells and their effector cytokine interleukin (IL)-21 play an important role in germinal center proliferation. Methods: IL-21 was determined on the mRNA level by qPCR in nasal tissue of 3 groups of patients: control (n = 17), chronic rhinosinusitis without nasal polyposis (CRSsNP; n = 23), and CRSwNP (n = 35). The expression of IL-21 by CD4+ T cells was analyzed in tissue at baseline and after 24-h stimulation of tissue fragments with S. aureus enterotoxin B (SEB) using flow cytometry. Finally, human nasal IL-21+CXCR5+CD4+ T cells were isolated and coincubated with human blood naive B cells to investigate their functionality. Results: IL-21 mRNA expression was increased in the CRSwNP group (p < 0.05) compared to the control group, and B-cell lymphoma-6 and B-lymphocyte-induced maturation protein-1 were upregulated in CRSwNP versus CRSsNP. Furthermore, SEB was able to increase IL-21 mRNA expression significantly (p < 0.01) in nasal polyps. Flow cytometry revealed that the source of IL-21 was predominantly CD4+ T cells and that IL-21+CD4+ T cells were significantly increased in polyp tissue and further increased after SEB stimulation. Finally, tissue CXCR5+CD4+ T cells derived from nasal polyp tissue were able to induce maturation of human naive B cells. Conclusions: IL-21- and IL-21-producing CD4+ T cells were increased in CRSwNP. In addition, SEB induced an increase in IL-21 and IL-21+CD4+ T cells, suggesting that S. aureus can modulate the function of Tfh cells in nasal polyps. We speculate that T-follicular helper cells and IL-21 are important in the pathophysiology of CRSwNP.

Poster 1021: Use of paper filter discs for measurement of local biomarkers of nasal mucosal inflammation

Methods Nasal secretions from 12 patients with AR to grass pollen and 12 healthy controls were collected. Two preweighed filter discs were placed bilaterally under direct visualization on the anterior third of the nasal septum. Five minutes later, they were removed and weighted again. After adding 2 ml 0,9% NaCl solution to the discs and centrifugation, the nasal secretions were stored in aliquots at -20°C until analysis. Biomarkers such as total IgE, grass pollen specific (gx3) IgE, total IgG, IgG4 and tryptase were measured. Patients with AR were selected based on symptoms during the grass pollen season and based on a positive skin prick test for grass pollen. Control patients were healthy patients without rhinological or allergic disease and with negative skin prick test to the standard panel of allergens.

Comparison of different medical treatment options for CRSwNP: doxycycline, methylprednisolone, mepolizumab and omalizumab

Methods In total, 100 patients were randomly assigned to receive doxycycline for 20 days (n=14), methylprednisolone in decreasing doses for 20 days (n=14), mepolizumab 2 single intravenous injections (n=20), omalizumab 2 to 4 subcutaneous doses (n=15) or placebo (n=37) in three separate clinical double-blind, placebo-controlled trials. Participants were followed for 8 weeks. Endoscopic evaluation of nasal polyp score, assessment of symptom score and measurement of markers of inflammation in nasal secretions and serum occurred at baseline, week 4 and week 8. All treatments were completed at week 4, except for 2 patients who received a fourth subcutaneous dose of omalizumab at week 6.

Local Nasal Inflammation: T Cells and B Cells

The nose is a filter for air particles and infectious agents. The local immune system is well developed in the nose and the paranasal sinuses and is of major importance in controlling incoming infections. In the first part, we will describe this innate and adaptive immunity with its cells and mediators. However, under certain circumstances, the local inflammation persists and can result in diseases such as allergic and nonallergic rhinitis and chronic rhinosinusitis with and without nasal polyposis. These pathologies and their characterizing inflammation are described in the second part. Recent insights have emphasized the importance of this local nasal inflammation. The understanding of inflammatory cells, mediators, and pathways in different populations is essential to have a clear insight into the pathogenesis. Finally, we focus on local inflammation as a target for therapy. Phenotyping and endotyping based on local inflammation are important in tailoring the right treatment for the right patient. In nasal polyposis, we find a local IgE-mediated inflammation, independent of the presence of allergy, which can be treated successfully by anti-IgE treatment.