Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389722
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Advances in our understanding of asthma pathophysiology have led to the advent of multiple targeted asthma therapies such as biologics. However, partial response to biologics occurs, indicating residual disease activity...Advances in our understanding of asthma pathophysiology have led to the advent of multiple targeted asthma therapies such as biologics. However, partial response to biologics occurs, indicating residual disease activity in some patients. Hence, there exists a need for new therapies that focus on novel pathways, alongside perhaps evaluation of combination biologic therapies and modulators of downstream cytokine activation. Therefore, although our current focus is on biologics; it is critical to take a more holistic approach including consideration for nonbiologic therapies that have the potential to significantly advance asthma care.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389721
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Presently, there are 6 biologic agents available for treatment of asthma. Each of these agents has undergone robust clinical trials in their approval programs. Such studies rely upon very rigid entry criteria that may no...Presently, there are 6 biologic agents available for treatment of asthma. Each of these agents has undergone robust clinical trials in their approval programs. Such studies rely upon very rigid entry criteria that may not translate to real-world efficacy. Thus, exploring the efficacy of these agents in a larger, more heterogeneous, population brings a sense of comfort regarding their efficacy in the real-world. This review explores the available literature regarding the use of biologics in the real world, with a focus on markers of likely response to therapy.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389720
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Establishing a universal definition for asthma remission has the potential to improve asthma outcomes and advance research. However, there is still no consensus definition despite broad multidisciplinary efforts to achie...Establishing a universal definition for asthma remission has the potential to improve asthma outcomes and advance research. However, there is still no consensus definition despite broad multidisciplinary efforts to achieve this goal. This study explores the evolving concept of asthma remission, emphasizing the potential of biologics to achieve this state. We will discuss various proposed definitions of asthma remission, international guidelines, and studies evaluating the effectiveness of biologics at achieving clinical remission. We highlight the need for a consensus definition of asthma remission to standardize treatment goals and improve patient outcomes.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389719
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Our modern understanding of asthma mainly concerns identification of inflammatory endotype to guide management. The distinction mostly concerns identification of type-2 inflammation, for which different biomarkers have b...Our modern understanding of asthma mainly concerns identification of inflammatory endotype to guide management. The distinction mostly concerns identification of type-2 inflammation, for which different biomarkers have been well characterized. Blood eosinophils corroborate activity in the interleukin (IL)-5 axis while fraction of exhaled nitric oxide is indicative of the IL-4/IL-13 axis, giving us an indication of activity in these distinct but complementary pathways. These biomarkers predict disease activity, with increased risk of exacerbations when elevated, and a further, multiplicative increase when both are elevated. Serum immunoglobulin E is also implicated in this pathway, and can represent allergen-related stimulation.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389718
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The development of multiple targeted biologic therapies over the past two decades has revolutionized the management of asthma. Currently, there are 6 monoclonal antibodies that target specific inflammatory mediators invo...The development of multiple targeted biologic therapies over the past two decades has revolutionized the management of asthma. Currently, there are 6 monoclonal antibodies that target specific inflammatory mediators involved in the pathophysiology of asthma, and together, they provide the opportunity for personalized treatment options beyond bronchodilators and inhaled or systemic glucocorticoids in severe and difficult-to-control cases of asthma. These agents are the anti-IgE antibody omalizumab, the anti-IL-5 antibodies mepolizumab and reslizumab, the IL-5 receptor alpha antagonist benralizumab, the IL-4 receptor alpha antagonist dupilumab, and the anti-thymic stromal lymphopoietin antibody tezepelumab.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389717
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Biologic medications have dramatically altered the landscape for treatment of allergic conditions including aspirin-exacerbated respiratory disease (AERD) and allergic bronchopulmonary aspergillosis (ABPA). Biologics sho...Biologic medications have dramatically altered the landscape for treatment of allergic conditions including aspirin-exacerbated respiratory disease (AERD) and allergic bronchopulmonary aspergillosis (ABPA). Biologics should be considered for patients who are refractory to first line therapies for ABPA. Biologics should be discussed with patients with AERD. Variable responses to different biologics indicate that there may be various endotypes of AERD and ABPA, similar to asthma. Alternative biologics may be considered in patients who fail to respond to initial treatment.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389716
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Chronic rhinosinusitis (CRS) is categorized phenotypically into CRS with and without nasal polyps (CRSwNP, CRSsNP). Endotyping categorizes the disease based on immune cell activity and inflammatory mechanisms into Type 1...Chronic rhinosinusitis (CRS) is categorized phenotypically into CRS with and without nasal polyps (CRSwNP, CRSsNP). Endotyping categorizes the disease based on immune cell activity and inflammatory mechanisms into Type 1, Type 2, and Type 3. The Type 2 endotype is the most researched and associated with asthma, atopic disease, and severe CRSwNP. For patients with poorly controlled CRSwNP, there are 3 approved biologic treatments: omalizumab, dupilumab, and mepolizumab. Many other biologics are being tested in Type 2, non-Type 2, and mixed endotypes in CRSwNP and CRSsNP. These studies will play a significant role in shaping the future of CRS management.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389715
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Immunoglobuin E (IgE)-mediated food allergies greatly impact patients and their families, causing financial and emotional stress, and placing them at risk for lifethreatening reactions. Until recently, food allergies hav...Immunoglobuin E (IgE)-mediated food allergies greatly impact patients and their families, causing financial and emotional stress, and placing them at risk for lifethreatening reactions. Until recently, food allergies have been treated with allergen avoidance and emergency treatment of allergic reactions. Omalizumab was recently approved in adults and children greater than one year who are allergic to one or more foods for the prevention of serious allergic reactions in the setting of accidental exposure. Omalizumab also shows promise when combined with oral immunotherapy for possible allergen ingestion. Other classes of biologics and small molecule inhibitors have also demonstrated potential for use in preventing and treating food allergy.
Ezekwe E, Weskamp AL, Pittman LM
… +1 more, Klion AD
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389714
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Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are complex disorders defined by blood and tissue eosinophilia and heterogeneous clinical manifestations. Historically, the mainst...Hypereosinophilic syndrome (HES) and eosinophilic granulomatosis with polyangiitis (EGPA) are complex disorders defined by blood and tissue eosinophilia and heterogeneous clinical manifestations. Historically, the mainstay of therapy for both conditions has been systemic glucocorticoids. However, recent availability of biologics that directly or indirectly target eosinophils has provided new avenues to pursue improved outcomes with decreased toxicity. In this article, we summarize the evidence supporting the use of specific biologics in HES and/or EGPA and provide a framework for their clinical use in patients.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389713
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Eosinophilic gastrointestinal diseases (EGIDs) encompass a group of disorders characterized by an abnormal accumulation of eosinophils in various parts of the gastrointestinal tract. EGIDs present with a wide range of sy...Eosinophilic gastrointestinal diseases (EGIDs) encompass a group of disorders characterized by an abnormal accumulation of eosinophils in various parts of the gastrointestinal tract. EGIDs present with a wide range of symptoms such as abdominal pain, vomiting, diarrhea, difficulty swallowing, and food impaction. Monoclonal antibodies, targeting inflammatory cytokines or eosinophils, are the next emerging therapy for EGIDs. The only Food and Drug Administration-approved monoclonal antibody is dupilumab, and it has been approved for the treatment of eosinophilic esophagitis (EoE). In this article, the authors will discuss biologics that have been used in the treatment of eosinophilic gastrointestinal diseases.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389712
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Antihistamine refractory chronic spontaneous urticaria (CSU) has a prevalence of up to 50%. Anti-immunoglobulin E (IgE) therapies have revolutionized management of CSU, yet refractory cases persist, suggesting a role for...Antihistamine refractory chronic spontaneous urticaria (CSU) has a prevalence of up to 50%. Anti-immunoglobulin E (IgE) therapies have revolutionized management of CSU, yet refractory cases persist, suggesting a role for biologic agents that impact alternative routes of mast cell stimulation independent of cross-linking at FcεR1. This review addresses anti-IgE and Th2-targeted therapies in the management of CSU. In addition, we explore novel treatments targeting alternative pathways of mast cell activation including MAS-related G protein-coupled receptor-X2 and sialic acid-binding immunoglobulin-like lectin-6, inhibiting intracellular signaling via Bruton's tyrosine kinase, and disrupting KIT activation by SCF.
Immunol Allergy Clin North Am
· 2024 Nov · PMID 39389711
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Atopic dermatitis (AD) is a common chronic pruritic inflammatory skin disease that affects all ages and is recognized as a global health problem. Pathophysiology is complex with skin barrier abnormalities, immune dysregu...Atopic dermatitis (AD) is a common chronic pruritic inflammatory skin disease that affects all ages and is recognized as a global health problem. Pathophysiology is complex with skin barrier abnormalities, immune dysregulation, and microbial dysbiosis all implicated. Markers of immune and inflammatory activation in the circulation provide a rationale for systemic therapy. Type 2 immune polarization is central, though other cytokine pathways including Th22 and Th17/IL-23 have been described, suggesting additional therapeutic targets in a subset of patients. Dupilumab and tralokinumab are monoclonal antibodies currently approved for moderate-to-severe AD with lebrikizumab and nemolizumab in late stages of development.
Immunol Allergy Clin North Am
· 2024 Aug · PMID 38937016
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Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditio...Angioedema is characterized by transient movement of fluid from the vasculature into the interstitial space leading to subcutaneous or submucosal non-pitting edema. Current evidence suggests that most angioedema conditions can be grouped into 2 categories: mast cell-mediated (previously termed histaminergic) or bradykinin-mediated angioedema. Although effective therapies for mast cell-mediated angioedema have existed for decades, specific therapies for bradykinin-mediated angioedema have more recently been developed. In recent years, rigorous studies of these therapies in treating hereditary angioedema (HAE) have led to regulatory approvals of medication for HAE management thereby greatly expanding HAE treatment options.
Immunol Allergy Clin North Am
· 2024 Aug · PMID 38937015
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The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1...The role of contact system activation has been clearly established in the pathogenesis of hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH). C1 inhibitor (C1INH)-protease complexes, levels of functional C1INH, plasma kallikrein activation, and cleavage of high-molecular-weight kininogen have each been associated with disease activity. More recently, HAE with normal levels of C1INH (HAE-nl-C1INH) has been recognized. Six genetic mutations have been identified which are linked to HAE-nl-C1INH phenotypes. The majority of individuals with HAE-nl-C1INH fall into the unknown category. There is substantial evidence that bradykinin generation underlies the recurrent attacks of swelling in some of these cohorts.
Immunol Allergy Clin North Am
· 2024 Aug · PMID 38937014
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A clear disease classification schema coupled with an understanding of the specific mechanisms involved in the different types of angioedema without hives informs the diagnostic assessment. The recommended approach invol...A clear disease classification schema coupled with an understanding of the specific mechanisms involved in the different types of angioedema without hives informs the diagnostic assessment. The recommended approach involves several key steps. Foremost is the recognizing of the clinical clues which allow for the differentiation of mast cell-mediated disorders from bradykinin-mediated angioedema. Enhanced vascular permeability related to bradykinin is of critical importance to identify given the implications for disease morbidity and risk of mortality. The ability to efficiently categorize and diagnose all forms of angioedema results in improved patient outcomes.
Muñoz M, Kocatürk E, Maurer M
… +1 more, Kolkhir P
Immunol Allergy Clin North Am
· 2024 Aug · PMID 38937013
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Chronic urticaria (CU) is a common and long-lasting mast cell-mediated skin disease associated with psychiatric and autoimmune comorbidities, high economic costs, and considerable impact on quality of life. Available the...Chronic urticaria (CU) is a common and long-lasting mast cell-mediated skin disease associated with psychiatric and autoimmune comorbidities, high economic costs, and considerable impact on quality of life. Available therapies show limited efficacy in many CU patients, which may be related to distinct underlying pathophysiology. Targeted and disease-modifying treatments with higher and broader efficacy are needed and are under development for CU. These novel drugs, small molecules, and monoclonal antibodies target mast cells and their receptors, signaling pathways, or mediators and other immune cells. In this article, the authors focus on the most promising emerging therapeutics in advanced development and discuss their potential place in future management of CU.