Francesca Puggioni

Anti-Interleukin 5 (IL-5) and IL-5Ra Biological Drugs: Efficacy, Safety, and Future Perspectives in Severe Eosinophilic Asthma

The definition of asthma has changed considerably in recent years, to the extent that asthma is no longer considered a single disease but a heterogeneous disorder that includes several phenotypes and, possibly, endotypes. A more detailed analysis of the immunological mechanisms underlying the pathogenesis of asthma shows interleukin 5 (IL-5) to be a crucial cytokine in several asthma phenotypes. In fact, IL-5 exerts selective action on eosinophils, which, in turn, sustain airway inflammation and worsen asthma symptoms and control. Clinical trials have shown drugs targeting IL-5 or its receptor alpha subunit (IL-5Ra) to be a promising therapeutic approach to severe asthma, whose characteristics render standard therapy of little use: systemic corticosteroids only partially control the disease and have well-known adverse effects, and omalizumab is used for allergic subtypes. Analysis of the design process of clinical trials reveals the importance of patient selection, taking into account both clinical data (e.g., exacerbations, lung function, and quality of life) and biomarkers (e.g., eosinophils, which are predictive of therapeutic response).

Targeting Interleukin-5 or Interleukin-5Rα: Safety Considerations

Asthma is a highly prevalent chronic disease of the airways; approximately 10% of patients with asthma will experience a severe form of the disease. New understanding of the pathogenesis of asthma has enabled the development of novel drugs and provided hope for patients with asthma. Interleukin (IL)-5 and IL-5 receptor subunit α (IL-5-Rα) plays a crucial role in the development, maturation, and operation of eosinophils so were the first important therapeutic target of these new drugs. While the results of early clinical trials of these drugs were not promising, results improved once researchers discovered the drugs worked best in patients with high eosinophil levels. Patients treated with both anti-IL-5 and IL-5-Rα experienced significant decreases in exacerbations. Trials have also demonstrated promising safety profiles; adverse events have been few and frequently only observed with placebo or considered unrelated to the study drug. The positive efficacy and safety profiles of these drugs has led to trials with interesting results in other diseases that are also secondary to the action of eosinophils: Churg–Strauss syndrome, hypereosinophilic syndrome, nasal polyposis, chronic obstructive pulmonary disease, atopic dermatitis, and esophagitis. In this review, we explore the main clinical trials of anti-IL-5 and IL-5-Rα, both in asthma and in other pathologies, with particular reference to the interesting safety and efficacy results.

Mepolizumab in the management of severe eosinophilic asthma in adults: current evidence and practical experience.

Eosinophils represent approximately 1% of peripheral blood leukocytes in normal donors and their maturation and differentiation in the bone marrow are mainly regulated by interleukin (IL)-5 [Broughton et al. 2015]. IL-5, a cytokine that belongs to the β common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils and, to some extent, of basophils. IL-5 binds to a heterodimer receptor composed of the specific subunit IL-5Rα and a common subunit βc shared with IL-3 and GM-CSF. Human eosinophils express approximately a three-fold higher level of IL-5Rα compared with basophils. Major sources of IL-5 are T-helper 2 (Th2) cells, mast cells, CD34+ progenitor cells, invariant natural killer (NK) T-cells, group 2 innate lymphoid cells (ILC2s), and eosinophils themselves. ILC2s control not only eosinophil number but also their circadian cycling through the production of IL-5.

Asthma:: personalized and precision medicine

Purpose of review In this review, we herein describe the progress in management of severe asthma, evolving from a ‘blockbuster approach’ to a more personalized approach targeted to the utilization of endotype-driven therapies. Recent findings Severe asthma characterization in phenotypes and endotypes, by means of specific biomarkers, have led to the dichotomization of the concepts of ‘personalized medicine’ and ‘precision medicine’, which are often used as synonyms, but actually have conceptual differences in meaning. The recent contribute of the omic sciences (i.e. proteomics, transcriptomics, metabolomics, genomics, …) has brought this initially theoretic evolution into a more concrete level. Summary This step-by-step transition would bring to a better approach to severe asthmatic patients as the personalization of their therapeutic strategy would bring to a better patient selection, a more precise endotype-driven treatment, and hopefully to better results in terms of reduction of exacerbation rates, symptoms, pulmonary function and quality of life.

Current insights in allergen immunotherapy

OBJECTIVE Allergen-specific immunotherapy (AIT) in its subcutaneous and sublingual forms is currently a well-established and experimentally supported treatment for respiratory allergy and hymenoptera venom allergy. There have been advances in its use linked strictly to the advancement in the knowledge of the molecular mechanisms of allergy, the production of well-characterized extracts, and diagnostic techniques. The use of AIT in asthma and the application of new approaches are expanding. We briefly review the advances and concerns in the use of AIT. DATA SOURCES PubMed and Scopus. STUDY SELECTIONS The most recent and clinically relevant literature was selected and reviewed. RESULTS The introduction of high-quality products supported by large dose-finding trials has yielded better defined indications, contraindications, and modalities of use. Some specific products in tablet form have recently been approved in the United States. Sublingual immunotherapy has been found to be effective in asthma, which until recently had been a matter of debate. Another promising therapy is oral and sublingual desensitization for food allergy, for which encouraging results have recently been reported. In the near future, other options will be available, including new routes of administration (intralymphatic and epicutaneous), allergoids, engineered allergens, and peptides. The use of component-resolved diagnosis techniques will further refine and target AIT prescriptions. CONCLUSION This condensed and updated review shows that AIT remains a viable treatment option, especially after the introduction of standardized tablets for some allergens. Food allergy and new administration routes represent a promising expansion.

Inhaled Corticosteroids Safety and Adverse Effects in Patients with Asthma

Asthma is a common inflammatory airway disease for which the most commonly used controller medications are inhaled corticosteroids (ICS). Asthma control is difficult to achieve in individuals with severe asthma, which comprise 5% to 10% of individuals with asthma, even with high doses of ICS and other anti-inflammatory drugs. In this clinical context, the adverse effects of ICS (including hypothalamic-pituitary-adrenal axis suppression, reduction in growth velocity, osteoporosis, diabetes, and respiratory infections) become more probable and impacting on the quality of life of severe asthmatics. We here summarize the evidence of ICS-related adverse effects, particularly in patients with asthma. The possibility of using biologic agents earlier for severe asthma has the potential to prevent or reduce the occurrence of corticosteroid-related adverse effects, and also reduce corticosteroid-related costs.

Umeclidinium for the treatment of uncontrolled asthma

ABSTRACT Introduction: Smooth muscle cell contraction in the airways is the principal therapeutic target in asthmatic subjects and its insufficient treatment is often a cause of uncontrolled disease. For this reason, research has focused on targeting smooth muscle activity with anticholinergic agents, including umeclidinium. Areas covered: This review highlights the potential application of umeclidinium, a long acting muscarinic antagonist, as a novel therapeutic approach for patients with severe uncontrolled asthma, despite maximal therapy. Expert opinion: Umeclidinium, similarly to tiotropium, which has been recently included in guidelines, may act by contrasting cholinergic activation in airways, preventing or at least reducing smooth muscle cells contraction and the consequent bronchoconstriction. This is similar to what occurs in chronic obstructive pulmonary disease, for which umeclidinium has been regularly approved. However, available data is not sufficient and further studies are needed before regulatory approval can be sought, since only phase II clinical trials have been conducted at present. Both quality of life and objectifiable clinical data and parameters must be assessed, including lung function improvements, reduction of exacerbations and reduction of as required medications.

Extended IgE profile based on an allergen macroarray: a novel tool for precision medicine in allergy diagnosis

BackgroundPrecision medicine (PM) is changing the scope of allergy diagnosis and treatment. An in vitro IgE assay, a prototype PM method, was developed in the sixties and has garnered increasing interest because of the introduction of recombinant components in the test. More recently, microarrays of allergen components have significantly improved the ability to describe the IgE profile. Aim of this study was to evaluate the characteristics of the newly developed Allergy Explorer (ALEX), a macroarray containing both extracted “whole” allergens and molecular components. This method allows the acquisition of an IgE profile comprising 282 reagents (157 allergen extracts and 125 components), resulting in the widest screening of potential allergens available.MethodsSera from 43 patients with allergies were assayed with ALEX and then with ImmunoCAP ISAC. The results of the two tests were compared, and the consistency of the molecular results with the presence of IgE in the relevant extract was also evaluated.ResultsA good correlation between ISAC and ALEX was observed. The ALEX results for second-level tests (i.e., specific IgE to complete extracted allergens) were consistent with the results obtained for the relevant components.DiscussionDespite differences in the methodology, the IgE profiles detected for molecular allergens by ALEX and ISAC were very similar. The differences were mainly related to the lower dynamic range of ALEX and to the use of a CCD inhibitor in the first incubation phase, which reduced the binding of IgE to CCD, as represented in the extracted allergens and components.ConclusionBased on our findings, ALEX is a novel tool for describing the IgE profile in a PM setting, where the IgE assay must be performed on many allergens and components. In particular, polysensitized patients and patients with pollen-food syndrome will have a real advantage due the combination of the second and third levels of allergy diagnostics in the same chip.

New Suggestions in Sublingual Immunotherapy for House Dust Mite- Related Allergic Diseases

BACKGROUND The indications for Allergen immunotherapy (AIT) in patients suffering from House Dust Mite (HDM)-related allergic diseases are presently based on incomplete data. This is essentially based on the fact that HDM allergy is difficult to evaluate in clinical trials, due to the largely variable allergen exposure and symptoms, and to the long periods of observation needed to assess the effects. In addition, at variance with pollen allergy, in HDM allergy asthma is more prevalent. However, several AIT products have been approved for HDM-induced allergic rhinitis, according to their ascertained clinical efficacy, tolerability and safety profile, particularly in the sublingual form (SLIT). OBJECTIVE We reviewed herein the available data on AIT in patients with HDM-induced allergic diseases, with a particular attention to the new product MK-8237 HDM-SLIT tablets, concerning its efficacy and safety profile. METHOD In the recent years, several randomized placebo-controlled clinical trials have been performed in Europe, North America and Japan to evaluate the efficacy of HDM-sublingual tablets in patients with HDM-induced allergic asthma and allergic rhinitis, mainly assessing the reduction of symptoms, exacerbations and corticosteroid intake. RESULTS The results of the published clinical trials were encouraging and led to the approval and commercialization of MK-8237 HDM-SLIT tablet. CONCLUSION The favorable efficacy and safety profile of MK-8237 HDM-SLIT tablets provided a consolidated therapeutic option for patients with HDM-induced allergic rhinitis and asthma.

Misdiagnosis of asthma and COPD and underuse of spirometry in primary care unselected patients

BACKGROUND The diagnosis of both asthma and chronic obstructive pulmonary disease (COPD) consists of a combination of classical symptoms and signs, and the evidence of consistent lung function abnormalities. Spiromety has been reported to be underused, possibly for practical difficulties in accessing to a lung function lab. This may lead to misdiagnosis of both asthma and COPD. We aimed to evaluate the frequency of spirometry use and the concordance between doctor-diagnosed asthma and COPD and spirometric patterns, in an unselected cohort of patients sent by general practitioners to perform a spirometry. METHODS The first 300 patients consecutively enrolled patients performed spirometry and bronchodilator test with salbutamol 400 mcg. Demographic, clinical and lung function data have been collected. RESULTS 128 patients (42.7%) declared a doctor-diagnosed asthma and 75 (25%) a doctor-diagnosis of COPD; the remaining subjects never had received any respiratory diagnosis. Only 112 patients with doctor-diagnosed asthma (55.2%) and 114 (56.2%) with doctor-diagnosed COPD have ever performed a spirometry in their entire life (average time since the last spirometry was about 47.0 months). Eighty-nine (69.5%) and 10 (13.3%) patients with respectively doctor-diagnosed asthma and COPD had concordant spirometric patterns with their known diseases. DISCUSSION we described a worrying lack of use of spirometry and a high proportion of misdiagnosis, in patients with suspect chronic airway inflammatory diseases and cared by primary care physicians. Novel strategies to overcome this situation include should be implemented to give a better care to our patients.