Features of severe asthma response to anti-IL5/IL5r therapies: identikit of clinical remission.

Introduction: Clinical remission (CliR) achievement has been recognized as a new potential outcome in severe asthma. Nevertheless, we still lack a detailed profile of what features could better identify patients undergoing clinical remission. In this study, we aim to address this issue, tracing a possible identikit of patients fulfilling remission criteria. Methods: We enrolled 266 patients with severe eosinophilic asthma (SEA) treated with a 12-month course of anti-IL5/IL5 receptor (IL5r) monoclonal antibodies. Patients with no exacerbation, OCS withdrawal, ACT ≥ 20 and FEV1 ≥ 80% after 1 year of biologic treatment were classified as in clinical remission. Results: 30.5% of the enrolled patients achieved remission after biologic administration. CliR group showed a lower number of baseline asthma exacerbations and better lung function parameters, with a trend for higher ACT scores and a less frequent history of a positive skin prick test. CliR achievement was unlikely in presence of a higher BMI, a positive skin prick test, an increased number of asthma exacerbations before biologic treatment, anti-muscarinic administration, and a previous diagnosis of EGPA, bronchiectasis or osteoporosis. In contrast, a better lung function, an increased blood eosinophilic count, the presence of chronic rhinosinusitis with nasal polyps and a more frequent use of reliever therapy predicts remission development. Changes in exacerbations number, OCS use, ACT scores and FEV1% between remittent and non-remittent patients arise at specific follow up timepoints and are positively associated with CliR achievement. Discussion: anti-IL5/IL5r biologics can induce CliR in a proportion of patients with SEA. Patients achieving remission demonstrate specific clinical, functional and inflammatory features, as well as a specific moment of improvement in all the CliR items.

Real-world characteristics of "super-responders" to mepolizumab and benralizumab in severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis.

Background: The current definition of severe eosinophilic asthma (SEA) super-responders to biologic treatment does not include patients with other eosinophil-based comorbidities. Although eosinophilic granulomatosis with polyangiitis (EGPA) is frequently associated with SEA, we lack data on a possible super-response to biologic treatments in patients suffering from these two diseases. We aim to assess super-responder features in real-life patients with SEA and EGPA treated with mepolizumab and benralizumab. Methods: We enrolled 39 patients with SEA and EGPA eligible for treatment with mepolizumab or benralizumab. Super-responder assessment was performed considering oral corticosteroid (OCS) cessation, lack of exacerbations, forced expiratory volume in 1 s and Asthma Control Test (ACT) improvement. Results: Super-responders showed worse clinical baseline characteristics than non-super-responder patients, with a greater improvement in severe asthma exacerbations, OCS dose reduction and ACT score increase. Definition of super-responders was consistent only considering a 12-month course of monoclonal antibody, lacking sensitivity in earlier evaluations. Conclusion: Mepolizumab and benralizumab are safe and effective in patients with EGPA and SEA, since a consistent proportion of patients show a super-response after 12 months of treatment. Further studies will address specific criteria for super-responder assessment in these patients.

Exhaled Nitric Oxide as Biomarker of Type 2 Diseases.

Nitric oxide (NO) is a short-lived gas molecule which has been studied for its role as a signaling molecule in the vasculature and later, in a broader view, as a cellular messenger in many other biological processes such as immunity and inflammation, cell survival, apoptosis, and aging. Fractional exhaled nitric oxide (FeNO) is a convenient, easy-to-obtain, and non-invasive method for assessing active, mainly Th2-driven, airway inflammation, which is sensitive to treatment with standard anti-inflammatory therapy. Consequently, FeNO serves as a valued tool to aid the diagnosis and monitoring of several asthma phenotypes. More recently, FeNO has been evaluated in several other respiratory and/or immunological conditions, including allergic rhinitis, chronic rhinosinusitis with/without nasal polyps, atopic dermatitis, eosinophilic esophagitis, and food allergy. In this review, we aim to provide an extensive overview of the current state of knowledge about FeNO as a biomarker in type 2 inflammation, outlining past and recent data on the application of its measurement in patients affected by a broad variety of atopic/allergic disorders.

Early Ear, Nose and Throat Manifestations in Eosinophilic Granulomatosis with Poliangioitis: Results from Our Cohort Group and Literature Review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, systemic necrotizing vasculitis affecting small-to-medium-sized vessels. EGPA's clinical manifestations are heterogeneous, affecting different organs and systems, and the upper respiratory tract can be affected by ear, nose and throat (ENT) involvement. The aim of our study was to assess type manifestations at the time of diagnosis in a cohort of EGPA patients and correlate findings with baseline variables (sex, age, antineutrophil cytoplasmic antibodies-ANCA-status) and literature reports. The main ENT manifestations in our patients at the time of diagnosis were: chronic rhinosinusitis with nasal polyposis (CRSwNP) (52%), turbinate hypertrophy (48%), nasal swelling (40%), rhinorrhea (40%), chronic rhinosinusitis without nasal polyposis (CRSsNP) (32%), nasal bone deformities (32%), nasal crusts (20%), nasal mucosal ulcers (12%), corditis (12%), hoarseness/dysphonia (12%), hearing loss (12%), mucoceles (4%) and eosinophilic rhinitis (4%). No correlations were found between sex, age, ANCA status and ENT clinical manifestations. A polymorphic ENT involvement is often observed in the early stages of EGPA. The presence of nasal, sinus, ear and/or laryngeal manifestations in patients with asthma and hypereosinophilia, independently of sex, age or ANCA status, should raise an alert for further investigation and differential diagnosis for EGPA. ENT specialists should be aware of their leading position in this diagnostic race.

Severe Asthma Network Italy Definition of Clinical Remission in Severe Asthma: A Delphi Consensus.

Severe asthma affects about 10% of the population with asthma and is characterized by low lung function and a high count of blood leukocytes, mainly eosinophils. Various definitions are used in clinical practice and in the literature to identify asthma remission: clinical remission, inflammatory remission, and complete remission. This work highlights a consensus for asthma remission using a Delphi method. In the context of the Severe Asthma Network Italy, which accounts for 57 severe asthma centers and more than 2,200 patients, a board of six experts drafted a list of candidate statements in a questionnaire, which has been revised to minimize redundancies and ensure clear and consistent wording for the first round (R1) of the analysis. Thirty-two statements were included in the R1 questionnaire and then submitted to a panel of 80 experts, which used a 5-point Likert scale to measure agreement regarding each statement. Then, an interim analysis of R1 data was performed, and items were discussed and considered to produce a consistent questionnaire for round 2 (R2) of the analysis. Then, the board set the R2 questionnaire, which included only important topics. Panelists were asked to vote on the statements in the R2 questionnaire afterward. During R2, the criteria of complete clinical remission (the absence of the need for oral corticosteroids, symptoms, exacerbations or attacks, and pulmonary function stability) and those of partial clinical remission (the absence of the need for oral corticosteroids, and two of three criteria: the absence of symptoms, exacerbations or attacks, and pulmonary stability) were confirmed. This Severe Asthma Network Italy Delphi analysis defined a valuable and independent tool that is easy to use, to test the efficacy of different treatments in patients with severe asthma enrolled into the SANI registry.

Effectiveness and safety of anti-IL-5/Rα biologics in eosinophilic granulomatosis with polyangiitis: a two-year multicenter observational study.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis characterized by asthma, systemic manifestations, and blood and tissue eosinophilia. Objective: To assess the effectiveness and safety of mepolizumab (anti-IL-5) and benralizumab (anti-IL-5Rα) in EGPA for 24 months. Methods: We conducted a multicenter observational study, including patients with EGPA treated with anti-IL-5/Rα biologics in 9 Italian specialized facilities. Systemic disease activity, remission and relapse rate were evaluated from 3 to 24 months after treatment initiation. Respiratory outcomes, hematological parameters, corticosteroid (OCS) and immunosuppressants consumption were also assessed. Results: 49 patients with relapsing-refractory EGPA were included [26 (53.1%) benralizumab 30mg, 20 (40.8%) mepolizumab 100mg, 3 (6.1%) mepolizumab 300mg]. Overall, 38.8% and 57.1% achieved remission after 12 and 24 months, respectively (69.2% benralizumab and 43.5% mepolizumab). Lower OCS intake and higher blood eosinophil count at baseline were associated with remission at 24 months. Both biologics exerted beneficial effects on severe asthma outcomes. Indeed, 61.2% (61.5% benralizumab and 60.8% mepolizumab) remained exacerbation-free during treatment. Lung function parameters showed improvements in the overall cohort (all p<0.05), but began to decline from month 12, especially with mepolizumab. Marked reduction in blood eosinophils was registered with mepolizumab (p<0.0001), while benralizumab depleted both eosinophils (p<0.0001) and basophils (p<0.0001). In general, 69.6% (76% benralizumab and 61.9% mepolizumab) of OCS-dependent patients lowered their daily dose by 75%, while 28.3% discontinued these drugs. Immunosuppressants were suspended in 88.2% of cases. Adverse events were reported in 8.2% of patients. Conclusions: These real-world data suggest that anti-IL-5/Rα biologics are effective and safe in the long-term as add-on treatments for patients with EGPA.

A Multidisciplinary Approach for Type 2 Allergic Diseases: What Do Biologics Teach Us?

Patients with atopic/allergic disorders, including atopic dermatitis (AD), allergic rhino-conjunctivitis (AR), chronic rhinosinusitis with/without nasal polyps (CRSwNP/CRSsNP), bronchial asthma, food allergy, and eosinophilic esophagitis (EoE), often share a common genetic background, a type Th2 polarized immune response, and several environmental factors [...].

Functional Modulation of Human Macrophages by Secreted Phospholipases A2: Implications in Cancer.

Cancer-related inflammation has recently emerged as an important component of cancer pathogenesis that is able to promote tumor initiation and progression, and the acquisition of the known hallmark capabilities, including evasion from immunosurveillance. Several soluble and cellular mediators participate in tumor microenvironment formation, leading to cancer initiation and progression. In this view, Tumor-Associated Macrophages (TAMs) are pivotal players and, due to their characteristic plasticity, can acquire a variety of distinct phenotypes and contribute in different ways to the different phases of carcinogenesis. Different stimuli have been shown to modulate macrophage polarization. Secreted phospholipase A2 enzymes (sPLA2s) exert multiple biological effects on cancer-related inflammation due to their enzymatic activity and ability to activate inflammatory cells by non-enzymatic mechanisms. Among the different sPLA2 isoforms, several studies have suggested that group IIA and group X are mainly involved in a wide variety of cancer types. A deeper insight into the molecular mechanisms regulating the link between tumor-infiltrating immune cells and cancer could lead to identifying new prognostic/predictive biomarkers and a broader view of cancer immunotherapy.

The Role of Allergen-Specific Immunotherapy in ENT Diseases: A Systematic Review.

Previous studies have demonstrated that both subcutaneous (SCIT) and sublingual specific immunotherapy (SLIT) are effective in treating allergic rhinitis (AR). Further studies have evaluated the efficacy of allergen-specific immunotherapy (AIT) on different ear, nose, and throat (ENT) manifestations, in which allergy might have an etiopathogenetic role, such as local allergic rhinitis (LAR), rhinosinusitis (RS), otitis media (OM), and adenotonsillar (AT) disease. Nevertheless, the management of allergy in ENT diseases is still debated. To the best of our knowledge, this is the first systematic review assessing the efficacy of AIT in ENT diseases aside from AR. Literature data confirmed that AIT might be an effective therapeutic option in LAR, although its effect is restricted to studies with short-term follow-up. Furthermore, previous research demonstrated that AIT may improve symptoms and surgical outcomes of chronic rhinosinusitis when used as an adjunctive treatment. Few studies supported the hypothesis that AIT may exert positive therapeutic effects on recurrent upper airway infections as adenotonsillar disease. Finally, some clinical observations suggested that AIT may add some benefits in the management of otitis media with effusion (OME). The results of this systematic review allow us to conclude that the efficacy of AIT in ENT disorders has been only slightly investigated and additional studies are needed.

S. aureus and IgE-mediated diseases: pilot or copilot? A narrative review.

INTRODUCTION: S. aureus is a major opportunistic pathogen that has been implicated in the pathogenesis of several chronic inflammatory diseases including bronchial asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), chronic spontaneous urticaria (CSU), and atopic dermatitis. S. aureus can induce the production of both polyclonal and specific IgE that can elicit an inflammatory cascade. AREAS COVERED: The link between the sensitization to S. aureus enterotoxins and the severity of several chronic inflammatory diseases is reviewed in detail, as well as its therapeutic implications. EXPERT OPINION: An anti-IgE strategy to inhibit S. aureus enterotoxins would be a valid approach to treat several endotypes of severe asthma, CRSwNP and CSU in which IgE against S. aureus enterotoxins should represent, not only a marker of severity of the diseases but also a target of a treatment.

Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

BACKGROUND: Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. METHODS: We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). RESULTS: In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. CONCLUSIONS: These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Predictive Response to Immunotherapy Score: A Useful Tool for Identifying Eligible Patients for Allergen Immunotherapy.

A specific predictive tool of allergen immunotherapy (AIT) outcome has not been identified yet. This study aims to evaluate the efficacy of a disease score referred to as Predictive Response to Immunotherapy Score (PRIS) to predict the response to AIT and identify eligible patients. A total of 110 patients diagnosed with allergic rhinitis with or without concomitant asthma were enrolled in this study. Before beginning sublingual immunotherapy (SLIT), patients were evaluated by analyzing clinical and laboratory parameters. A specific rating was assigned to each parameter to be combined in a total score named PRIS. At baseline (T0) and follow-up [after 12 (T12) and 24 months (T24) of SLIT], a Visual Analogue Scale (VAS) was used to calculate a mean symptom score (MSS). Finally, the percentage variation between the MSS at T0 and at T12 [ΔMSS-12(%)] and T24 [ΔMSS-24 (%)] was measured. We observed a significant improvement of symptoms at T12 and T24 compared to T0 in all groups undergoing SLIT. PRIS was effective in predicting ΔMSS-24 (%) in patients treated with single-allergen SLIT. In addition, PRIS was effective in predicting ΔMSS-24 (%) in both patients with only rhinitis and with concomitant asthma. PRIS assessment can represent a useful tool to individuate potential responders before SLIT prescription.

Quality of life in patients with allergic and immunologic skin diseases: in the eye of the beholder.

Allergic and immunologic skin diseases negatively impact the quality of life (QoL) of affected patients with detrimental consequences. Nonetheless, in everyday clinical practice the evaluation of QoL is often overlooked. Considering the increasing prevalence of atopic dermatitis, allergic contact dermatitis, hereditary angioedema, cutaneous mastocytosis, and urticaria, it is essential to determine the effects of allergic and immunologic skin diseases on QoL. A joint meeting (GET TOGETHER 2021) of the Italian Society of Allergology, Asthma and Clinical Immunology (SIAAIC) and the Italian Society of Allergological, Occupational and Environmental Dermatology (SIDAPA) aimed to summarize the features of the main QoL tools used in these diseases and to describe the extent of QoL impairment as well as the impact of treatments on QoL, particularly biologic therapies. The assessment of QoL in patients with allergic and immunologic skin diseases relies on generic, organ-specific and disease-specific questionnaires. While generic and organ-specific questionnaires allow comparison between different diseases, disease-specific questionnaires are designed and validated for specific cohorts: the QoL Index for Atopic Dermatitis (QoLIAD) and the Childhood Atopic Dermatitis Impact Scale (CADIS) in atopic dermatitis, the ACD-11 in allergic contact dermatitis, the Angioedema QoL Questionnaire (AE-QoL) and the Hereditary Angioedema QoL questionnaire (HAE-QoL) in hereditary angioedema, the Mastocytosis QoL Questionnaires (MCQoL e MQLQ) in cutaneous mastocytosis, and the Chronic Urticaria QoL questionnaire (CU-Q2oL) in urticaria. Among the many factors that variably contribute to QoL impairment, pruritus can represent the leading cause of patient discomfort. Biologic therapies significantly ameliorate QoL in atopic dermatitis, hereditary angioedema, mastocytosis and chronic urticaria. In general, adequate management strategies are essential for improving QoL in patients with allergic and immunologic skin diseases.

Real-life evidence of low-dose mepolizumab efficacy in EGPA: a case series.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, small vessel, necrotizing vasculitis. The disease is mainly characterized by hypereosinophilia and asthma with frequent sinonasal involvement, although multiple organs can be affected, including the heart, lungs, skin, gastrointestinal tract, kidneys, and nervous system. IL-5 production is pathogenetically central for the development of the disease by promoting proliferation, transvascular migration and functional activation of eosinophils. The degree of blood and tissue eosinophilia appears to be associated with disease pathogenesis and eosinophil depletion represents a promising treatment approach for EGPA. We prospectively evaluated the efficacy and safety of a low dose (100 mg q4w), 12-month course of mepolizumab, an anti-IL-5 monoclonal antibody, in eight patients with severe asthma and active EGPA. Patients were recruited by the tertiary care center of Clinical Immunology and Allergy, University of Naples Federico II. The following outcomes were assessed before (T0), and after 6 (T6) and 12 months (T12) of mepolizumab treatment: Birmingham Vasculitis Activity Score (BVAS), prednisone intake, Sino-Nasal Outcome Test (SNOT-22), Total Endoscopic Polyp Score (TENPS), Asthma Control Test (ACT), Forced Expiratory Volume one second (FEV1)%, blood eosinophilia. BVAS score significantly decreased showing a sharp reduction in disease activity score. Clinical improvements in terms of sinonasal scores and asthma symptoms were observed, in parallel with a drastic drop in eosinophil blood count. Prednisone intake was significantly reduced. In two patients, asthma exacerbations led to discontinuation in mepolizumab therapy after 6 and 12 months despite BVAS reduction. Mepolizumab treatment was well tolerated, and no severe adverse drug effects were registered. In conclusion, our 12-month real-life study suggests that mepolizumab may be beneficial and safe in active EGPA patients by improving disease activity score, sinonasal and asthma outcomes while reducing the burden of prednisone intake.

Mepolizumab improves sino-nasal symptoms and asthma control in severe eosinophilic asthma patients with chronic rhinosinusitis and nasal polyps: a 12-month real-life study.

BACKGROUND: Severe eosinophilic asthma is frequently associated to chronic rhinosinusitis and nasal polyposis (CRSwNP) that contribute to poor asthma control. Mepolizumab is an anti-IL-5 monoclonal antibody, approved for the treatment of severe eosinophilic asthma. A limited number of studies have assessed the efficacy of mepolizumab on CRSwNP in severe asthmatics. We aim to evaluate the efficacy of mepolizumab on sino-nasal symptoms, polyp growth and asthma control in severe eosinophilic asthma patients with CRSwNP in real life. METHODS: In this study 44 severe eosinophilic asthma patients with CRSwNP were treated with mepolizumab (100 mg q4w) for 1 year. The following outcomes were assessed before (T0), after 6 (T6) and 12 months (T12) of treatment: sino/nasal outcome test (SNOT-22), Total Endoscopic Nasal Polyp Score (TENPS), %FEV1 (FEV1/FEV1 predicted) and Asthma control test (ACT). Blood eosinophil count, exhaled nitric oxide (FENO) and prednisone intake were measured. In a subgroup of patients, nasal cytology was performed before (T0), after 6 (T6) and after 12 months (T12) of treatment with mepolizumab. RESULTS: We reported a significant reduction of SNOT-22 [from 51.5 ± 21.2 at baseline (T0) to 31.70 ± 17.36 at T6 and 29.7 ± 21.5 at T12 (T0-T12 p < 0.001)] and a decrease of TENPS (from 2.88 ± 3.07 to 1.70 ± 2.37 and 1.77 ± 2.56 at T0, T6 and T12, respectively, T0-T12 p = 0.99). A significant improvement of %FEV1, ACT and a decrease in blood eosinophils and mean prednisone intake were also reported. No statistically significant decreasing trend was measured for FENO. Nasal cytology findings suggest a significant reduction of eosinophil percentage following mepolizumab treatment (from 16.8 ± 7.2% to 3.6 ± 6.2% and 0.8 ± 2.4% at T0, T6 and T12 respectively, T0 to T12: p < 0.001). CONCLUSIONS: Mepolizumab improves sino-nasal and asthma symptoms and reduces polyp growth in patients with severe eosinophilic asthma and concomitant CRSwNP in real life.The reviews of this paper are available via the supplemental material section.

Orofacial granulomatosis: Clinical and therapeutic features in an Italian cohort and review of the literature.

BACKGROUND: Orofacial granulomatosis (OFG) is characterized by granulomatous inflammation of the soft tissues of maxillofacial region. We explored OFG patients from 10 different Italian centers and summarized the most recent literature data. METHODS: A review of patients with OFG was carried out. An extensive online literature search was performed to identify studies reporting diagnosis and management of OFG. RESULTS: Thirty-nine patients were recruited between January 2018 and February 2020. Most of them (97.4%) displayed involvement of the lips, and 28.2% suffered from Melkersson-Rosenthal syndrome. Two patients received diagnosis of CD and one patient of sarcoidosis, suggesting secondary OFG. Oral aphthosis and cervical lymphadenopathy were also described. The mean diagnostic delay was 3.4 years. Histological evaluation was performed in 34/39 patients (87.2%); non-caseating granulomas were found in 73.5% of them. Neurological symptoms (28.2%), gastrointestinal symptoms in absence of overt inflammatory bowel disease (IBD) (20.5%), and atopy (35.9%) were also identified. Therapeutic approaches varied among the centers. Steroids (51.3%) were used with good or partial results. Anti-TNF-α and anti-IgE monoclonal antibodies were used in 6 (15.4%) and 1 (2.6%) patients, respectively, with variable results. Surgery was the choice for 2 patients with good response. CONCLUSIONS: OFG is a rare and neglected disease showing multiple clinical phenotypes. While early diagnosis is crucial, management is difficult and highly dependent on the expertise of clinicians due to the lack of international guidelines. There is a need to establish registry databases and address challenges of long-term management.