Targeted Therapies in Allerglogy 2024 PDF

Targeted therapies in allergology By Viviana Marin-Esteban 2024 1  Targeted therapies in allergology Part 1- Mechanisms of type I hypersensitivity Part 2 - Current laboratory diagnosis of allergies - Prerequisi...

Targeted therapies in allergology By Viviana Marin-Esteban 2024 1  Targeted therapies in allergology Part 1- Mechanisms of type I hypersensitivity Part 2 - Current laboratory diagnosis of allergies - Prerequisite for allergen immunotherapy (AIT) Part 3 - Therapeutic management of allergies 2  Atopy and allergy general definition Atopy is a predisposition to respond immunologically to diverse antigens or allergens resulting in Th2 differentiation and “excessive” production of immunoglobulin E (IgE). Atopic disease includes atopic dermatitis, allergic rhinitis, allergic asthma, and food allergy Allergy is any exaggerated immune response against an otherwise harmless foreign substance (allergen). This response involve an allergen-specific adaptive response. 3  The burden of allergic diseases in Europe Epidemiology (2016) Burden on daily living and productivity Direct and Prevalence indirect costs Common allergic Potential savings conditions 4  Type I hypersensitivity Immediate hypersensitivity Requires prior exposure to the antigen Symptoms appear within minutes after allergen exposure Mediated by allergen-specific IgE antibodies The primary effector cells are tissue mast cells or blood basophils Immediate clinical symptoms result from biological effects of histamine Occurs in in genetically predisposed individuals, referred to as "atopic" Severe, live-threating reactions may occur: Anaphylaxis ! 5 Immediat hypersensitivity (IgE-mediated) 6 Immediat hypersensitivity (IgE-mediated) 7 Immediat hypersensitivity (IgE-mediated) 8  Immediat hypersensitivity (IgE-mediated) Anaphilactic reaction : mild to fatal symptom gravity - medical emergency 9 Mastcellhope.com Immediat hypersensitivity (IgE-mediated) 10 Immediat hypersensitivity (IgE-mediated) 11 Immunological mechanisms in allergic asthma Humbert et al. JACI in practice 2021 12  Targeted therapies in allergology Part 1- Mechanisms of type I hypersensitivity Part 2 - Current laboratory diagnosis of allergies: prerequisite for allergen immunotherapy (AIT) Part 3 - Therapeutic management of allergies 13  Etiological diagnosis of type I allergy Clinical history and examination Prick test Quantification of circulating specific IgE Basophil activation test → Demostration of the allergen ivolved (or allergens) 14  Quantification of circulating specific IgE Little useful of Total IgE assay Immuno enzymatic methods Sometimes less sensitive than skin tests, but simple and specific Presence of specific IgE reveals sensitization that is not necessarily symptomatic: To be confronted with the clinical history Test availability is growing, with huge diversity - IgE directed against the allergenic source - IgE directed against a protein component of this source 15  Molecular allergology Component Resolved Diagnosis Establish a precise and individual sensitization profile for each patient Document this profile according to allergen categories and molecular families Assess the clinical risk of a reaction: systemic / local Explain symptoms from cross reactivity indicate and guide, or even perform allergen immunotherapy 16 Clinical risk assesment according to molecular families Specific IgE to Ara h 2 and Ara h 6 are the best predictors of peanut allergy JACI in practice 2021 17 Clinical risk assesment according to molecular families 18  Targeted therapies in allergology Part 1- Mechanisms of type I hypersensitivity Part 2 - Current laboratory diagnosis of allergies: prerequisite for allergen immunotherapy (AIT) Part 3 - Therapeutic management of allergies Classic treatments Biologicals Allergen immunotherapy 19  Therapeutic principles in allergology Allergen avoidance (domestic animals, food, medication, etc.) « Classical » treatments, not allergen-specific Innovative therapies « not allergen specific » Biologicals Therapeutic approaches « allergen specific » Allergen immunotherapy (AIT) 20  Classical allergy medecine Inhibit action of Mast cell mediators 21  Biologicals in the treatment of allergies (MoAb) Typically prescribed in the context of chronic, severe allergies or those causing a significant decline in quality of life - Atopic dermatitis (atopic disease) - Certain forms of asthma, - Chronic forms of spontaneous urticaria Not used to treat immediate symptoms of allergies : Quincke's edema, anaphylactic shock ,or urticaria related to food allergies. Not used as first-line treatment Specific molecular targets: - soluble mediators (IgE, interleukins, alarmins) - cell surface molecules (receptors, …) 22  Atopic dermatitis Also called eczema, is a chronic, relapsing inflammatory skin disorder. 10% to 20% of children Features: recurrent eczematous lesions and intense itch, risk of skin infections. Increased risk of multiple comorbidities: food allergy, asthma, allergic rhinitis, and mental health disorders. Pathophysiology: Genetic predisposition Epidermal dysfunction T-cell driven inflammation onlymyhealth.com Type-2 immune mechanisms are dominant but multiple immune pathways are involved. 23  Asthma Chronic inflammatory disease affecting the lower airways. Symptoms: Respiratory distress, chest tightness, wheezing, coughing. Sputum formation and exercise intolerance. Features: Bronchial hyperresponsiveness, airway inflammation and obstruction caused by mucus plugs and airway wall remodeling. Uncontrolled asthma leads to reduced quality of life. Phenotypes and their endotypes: Type 2 Asthma: Driven by Th2 cytokines (IL-4, IL-5, IL-13). Involves eosinophils, ILC2, mast cells, Th2 cells. Associated with high risk of exacerbations and accelerated lung function decline. Includes: Allergic asthma. Non-allergic eosinophilic asthma. Non-Type 2 Asthma: Driven by IL-8, IL-17, IL-23. Involves Th17 lymphocytes, neutrophils, mast cells. Includes: Neutrophilic asthma. Minimal inflammation asthma. Gonzalez-Uribe et al. J Clin Med 2023 24 Mode of action of biologicals targeting Th2 immunity Eyerich et al. Allergy 2019 25 Mechanism of action of omalizumab Pelaiaet al. Therap Adv Resp Dis 2008 26  Indications of Omalizumab Omalizumab (anti-IgE) Moderate-to-sever persistent allergic asthma, Nasal Polyps, Chronic Spontaneous Urticaria Off-Label Use : in food allergy (2024*) and as adjuvant in ITA for drug and food allergies 27  Omalizumab in food allergies OUTMATCH trial: 177 children and adolescents, 1 to 17 years old, multiple food allergies (≥ 3 including to peanuts). Omalizumab vs Placebo 56% boys Median age 7 years (38% 1-5 ans) Median total circulating Ig : 700 UI/ml 79% AD, 52% asthma End of trial oral challenge Initial oral challenge Omalizumab every 2 to 4 weeks 1st - 600 mg peanuts or more Inclusion if reaction to for 16 to 20 weeks Other allergens >1000 mgeach ≤ 100 mg of peanut protein Without dose-limiting symptoms ≤ 300 mg of 2 other foods Random assignment Wood RA, et al. N Engl J Med 2024 2:1 omalizumab:placebo 28  Omalizumab in food allergies In persons as young as 1 year of age with multiple food allergies, omalizumab treatment for 16 weeks was superior to placebo in increasing the reaction threshold for peanut and other common food allergens. A total of 79 of the 118 participants (67%) receiving Results of key secondary end points: cashew, 41% vs. 3%; omalizumab met the primary end-point criteria, as milk, 66% vs. 10%; egg, 67% vs. 0%; P