Diego Bagnasco

Interleukin-5 pathway inhibition in the treatment of eosinophilic respiratory disorders: evidence and unmet needs

Purpose of reviewHuman eosinophils were first identified and named by Paul Ehrlich in 1879 on the basis of the cells granular uptake of eosin. Although eosinophils represent approximately 1% of peripheral blood leukocytes, they have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophils and their mediators are critical effectors to asthma and eosinophilic granulomatosis with polyangiitis (EGPA). Eosinophils are equipped with a large number of cell-surface receptors and produce specific cytokines and chemokines. Recent findingsEosinophils are the major source of interleukin-5 and highly express the interleukin-5R&agr; on their surface. Clinical trials evaluating monoclonal antibodies to interleukin-5 (mepolizumab and reslizumab) and its receptor interleukin-5R&agr; (benralizumab) have been or are underway in patients with eosinophilic asthma, EGPA and chronic obstructive pulmonary disease (COPD). Overall, targeting interleukin-5/interleukin-5R&agr; is associated with a marked decrease in blood and sputum eosinophilia, the number of exacerbations and improvement of some clinical parameters in adult patients with severe eosinophilic asthma. Pilot studies suggest that mepolizumab might be a glucocorticoid-sparing treatment in patients with EGPA. A preliminary study found that benralizumab did not reduce the exacerbations and did modify lung function in patients with eosinophilic COPD. SummaryThe review examines recent advances in the biology of eosinophils and how targeting the interleukin-5 pathway might offer benefit to some patients with severe asthma, EGPA, and COPD. Interleukin-5/interleukin-5R&agr;-targeted treatments offer promises to patients with eosinophilic respiratory disorders.

A Critical Evaluation of Anti-IL-13 and Anti-IL-4 Strategies in Severe Asthma

Asthma is a high-prevalence disease, still accounting for mortality and high direct and indirect costs. It is now recognized that, despite the implementation of guidelines, a large proportion of cases remain not controlled. Certainly, adherence to therapy and the education of patients remain the primary objective, but the increasingly detailed knowledge about the pathogenic mechanisms and new biotechnologies offer the opportunity to better address and treat the disease. Interleukin (IL)-13 and IL-4 appear as the most suitable targets to treat the T helper 2 (TH2)-mediated forms (endotypes) of asthma. IL-13 and IL-4 partly share the same receptor and signaling pathways and both are deeply involved in immunoglobulin E (IgE) synthesis, eosinophil activation, mucus secretion and airways remodeling. Several anti-IL-13 strategies have been proposed (anrukinzumab, lebrikizunab and tralokinumab), with relevant clinical results reported with lebrikizumab. Such studies facilitate better definition of the possible predictive markers of response to a specific treatment (e.g. eosinophils, total IgE, fraction of exhaled nitric oxide and periostin). In parallel, anti-IL-4 strategies have been attempted (pascolizumab, pitakinra and dupilumab). So far, dupilumab was reported capable of reducing the severity of asthma and the rate of exacerbations. IL-13 and IL-4 are crucial in TH2-mediated inflammation in asthma, but it remains clear that only specific endotypes respond to these treatments. Although the use of anti-IL-14 and anti-IL-13 strategies is promising, the search for appropriate predictive biomarkers is urgently needed to better apply biological treatments.

Personalized Medicine in Allergy

Allergic disease is among the most common pathologies worldwide and its prevalence has constantly increased up to the present days, even if according to the most recent data it seems to be slightly slowing down. Allergic disease has not only a high rate of misdiagnosis and therapeutic inefficacy, but represents an enormous, resource-absorbing black hole in respiratory and general medicine. The aim of this paper is to summarize principal therapeutic innovations in atopic disease management befallen in the recent years in terms of personalized/precision medicine.

Molecular phenotyping and biomarker development: are we on our way towards targeted therapy for severe asthma?

Although different phenotypes of severe asthma can be identified, all are characterized by common symptoms. Due to their heterogeneity, they exhibit differences in pathogenesis, etiology and clinical responses to therapeutic approaches. The identification of distinct molecular phenotypes to define severe asthmatic patients will allow us to better understand the pathophysiology of the disease and thus to more precisely target the treatment for each patient. To achieve this goal, a systematic search for new, reliable and stable biomarkers specific for each phenotype is essential. This review focuses on the current known molecular phenotypes of severe asthma and highlights the need for biomarkers that could (either alone or in combination) be predictive of the treatment outcome.

Reslizumab and Eosinophilic Asthma: One Step Closer to Precision Medicine?

Human eosinophils represent approximately 1% of peripheral blood leukocytes. However, these cells have the propensity to leave the blood stream and migrate into inflamed tissues. Eosinophilic inflammation is present in a significant proportion of patients with severe asthma. Asthma is a chronic inflammatory disorder that affects more than 315 million people worldwide, with 10% having severe uncontrolled disease. Although the majority of patients can be efficiently treated, severe asthmatics continue to be uncontrolled and are at risk of exacerbations and even death. Interleukin-5 (IL-5) plays a fundamental role in eosinophil differentiation, maturation, activation and inhibition of apoptosis. Therefore, targeting IL-5 is an appealing approach to the treatment of patients with severe eosinophilic asthma. Reslizumab, a humanized anti-IL-5 monoclonal antibody, binds with high affinity to amino acids 89–92 of IL-5 that are critical for binding to IL-5 receptor α. Two phase III studies have demonstrated that reslizumab administration in adult patients with severe asthma and eosinophilia (≥400 cells/μL) improved lung function, asthma control, and symptoms. Thus, the use of blood eosinophils as a baseline biomarker could help to select patients with severe uncontrolled asthma who are likely to achieve benefits in asthma control with reslizumab. In conclusion, targeted therapy with reslizumab represents one step closer to precision medicine in patients with severe eosinophilic asthma.

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).

Update on immunotherapy for the treatment of asthma.

Purpose of review Despite that specific immunotherapy can boast being more than a century old, there is still skepticism about its real effectiveness, and therefore it is still used too little in clinical practice. The purpose of this review was to analyze the most recent articles in the literature to highlight scientific evidence for the proper use of allergen immunotherapy (AIT). Recent findings In the near future, the concept of medicine for trials will have to be revised and in certain cases abandoned in favor of a personalized medicine, able to use a drug more targeted for the individual patient and not for the disease. Summary For AIT, it will become increasingly important to use products designed properly, standardized and with a well documented effectiveness in clinical studies. We must overcome the disputes of subcutaneous immunotherapy versus sublingual immunotherapy, arrive at the concept of personalized medicine regarding AIT, framing in different phenotypes of asthma patients to use the optimal preparation for each particular patient.

IL-13 and idiopathic pulmonary fibrosis: Possible links and new therapeutic strategies

The recent advances in the knowledge of immunological aspects of many pulmonary diseases, allowed to identify cells, biological functions, cytokines, and receptors that are preferentially involved in each disease. This is the case of asthma, where IL-13 (together with IL-4) is recognized as a central mediator. The role of IL-13 is strictly related, via complex signaling pathways, to eosinophil recruitment and activation, to mucus secretion, periostin generation and to fibrogenic processes (which are part of the remodeling process). These peculiar roles of IL-13 have suggested the hypothesis of its role in Idiopathic Pulmonary Fibrosis, and consequently of its antagonists in the treatment of such disease. We review herein the immunological roles of IL-13 in asthma and IPF, and the currently ongoing attempts to treat IPF by IL-13 antagonism strategies.

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.