Asthma. These changes cause bronchial hyperresponsiveness and airflow limitation Affects over 300 million people worldwide
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1 Michael A. Venditto DO, FACOI, FCCP Professor and Chairman Division of Pulmonary and Critical Care Medicine Philadelphia College of Osteopathic Medicine Philadelphia, Pennsylvania Asthma Chronic disease of the airways Inflammatory changes Structural changes Functional changes These changes cause bronchial hyperresponsiveness and airflow limitation Affects over 300 million people worldwide May 4-7,
2 Severity of Asthma Treatment of Asthma May 4-7,
3 Global Initiative for Asthma (GINA) Treatment Short acting β 2 -adrenergic receptor agonist (SABA) Inhaled corticosteroids Long acting β 2 -adrenergic receptor agonist (LABA) Leukotriene inhibitors 80% of difficult to treat asthma patients have poor adherence to regular inhaled therapy Gamble, Am J Respiratory and Crit Care Med, 180(2009), p % remain symptomatic and inadequately controlled. Asthma Chronic Bronchitis Emphysema May 4-7,
4 The Dutch Hypothesis Dutch vs. British May 4-7,
5 Dutch Hypothesis Dutch Hypothesis Asthma and COPD have common origins They are NOT the same disease Clinical expressions were determined by Endogenous - heredity, age and sex Exogenous allergens, smoking, viruses, and air pollution Suggested: phenotyping patients, a hereditary component, age and sex play a role (male preponderance of asthma in childhood), and eosinophilia can be linked to allergy May 4-7,
6 Asthma Phenotypes Includes several different phenotypes each of which is defined by a distinct clinical, functional and pathobiological patternanderson, Lancet, 372 (2008). Pp May involve more than one organ system and may change over time or in response to the environment Original Phenotypic Classification- Rackermann, 1921 Intrinsic vs extrinsic Atopic vs non-atopic Extrinsic (Allergic) Phenotype 50-80% of all asthma Haselkorn, Journal of Asthma 43, (2006), p Early onset Male > Female Family History History of allergies Better response to steroids Seasonal rhinorrhea May 4-7,
7 May 4-7,
8 Intrinsic Phenotype Later onset Female > Male No family history of allergies Higher incidence of sinusitis and nasal polyps Usually triggered by infection, irritants, GERD and stress Causational Phenotypes Atopy Aspirin Infection Occupation Exercise Obesity May 4-7,
9 Radiologic Phenotypes Airway Dilatation Air Trapping hyperinflation Bronchial wall thickening Radiologic Phenotypes Bronchiectasis and wall thickening correlate with disease duration and poorer lung function Air Trapping Indirect evidence of small airway disease Correlates with asthma related hospitalization and ICU stays May 4-7,
10 Inflammatory Mediator Phenotype Eosinophilic Periostin Neutrophilic Combined/mixed inflammation Paucigranulocytic Inflammatory Phenotype Most scientific Insight into underlying pathobiology Nature of inflammation may vary during successive exacerbations Eosinophilic is most common 36% of all asthmad silva L, Canadian Repis Journal 2011:18(3): Sputum eos > 3% Usually T-helper 2 cells Predicts steroid responsiveness (REMEMBER CHARCOT-LEYDEN CRYSTALS???) May 4-7,
11 Airway Inflammation Activation of Mast cells Infiltration of eosinophils Increased number of T helper 2 cells Release cytokines 3 and 4 Some patients with increased numbers of neutrophils Pattern similar to COPD Increased number of Th 1 and Th 17 cells Corticosteroids May 4-7,
12 Corticosteroids Large side effect profile Weight gain Avascular necrosis of bone Cataract formation Fluid retention Hypertension Psychosis Myopathies Anxiety Insomnia Leukotriene Receptor Antagonist Zyflo, Accolate, Singulair May 4-7,
13 Leukotriene Receptor Antagonists Singulair blocks Cysteinyl LT1 ---blocks the action of Leukotrience C4, D4, E4 Accolate and Zyflo blocks 5-lipoxygenase Leukotriene C4,D4,E4 induces bronchospasm and induces chemokine production from mast cells For those of you who went to school before Ronald Reagan---leukotrienes are the old SRS-A May 4-7,
14 New Therapies IgE-targeted Antibodies Omalizumab (Xolair ) First approved in Australia in 2002 IgG molecule with high affinity binding to IgE preventing the IgE from binding to mast cells, basophils, eosinophils and dendritic cells. Lowers free IgE levels by 96-99% Reduces allergic bronchial inflammation Reduces endothelin 1---peptide involved in the pathogenesis of structural changes of airway. (Riccio, A.M. Intern Journal of Immunopathology Pharm 25, (2012) May 4-7,
15 Omalizumab Not tested on IgE levels > 700 Not tested on patients > 330 lbs. Not tested in patients < 12 years old For moderate or severe persistent asthma (Step 5-6) Dosing: mg SQ every 2-4 weeks Local reaction: Mild 45% vs 43% placebo Severe 12% vs 9 % placebo Common side effects: arthalgias 8% pain 7% leg pain 4% May 4-7,
16 IL-5 Targeted Antibodies IL-5 crucial role in the growth, maturation and activation of eosinophils Suppresses infiltration of eos into the airway ad reduces number of eos in sputum and blood In moderate persistent asthma, Mepolizumab reduced blood and sputum eos counts BUT there was no significant improvement in clinical and functional end points Food-Page, Am J Respir Critical care Med, 176, (2007) Haldar (2009)showed that when used in the eos phenotype group, there was significant reduction in exacerbation and prednisone dosing and improvement in FeV1. May 4-7,
17 IL-5 targeted Antibodies Mepolizumab (Nucala ) Interleukin 5 antagonist monoclonal antibody Reduces eosinophil production Eos count > 150/microliter at start of treatment or >300/microliter in past 12 months Dose: 100 mg SC every 4 weeks Side Effects: Headache 19% vs 18 % placebo Local reaction 8% vs 3% placebo Back pain 5% vs 4% placebo IL-5 Targeted Therapy On the horizon Benralizumab An IgG1 monoclonal antibody directed against the α-chain of IL-5R Potentially more beneficial effect than mepolizumab Reslizumab An IgG4 monoclonal antibody Decreased sputum and serum eos and positive trend toward better asthma control May 4-7,
18 IL-4 Specific Therapies IL-4 switches B cells to IgE synthesis, induces eosinophil recruitment and helps induce mast cells IL-4 upregulates collagen and fibronectin production Studies have not been conclusive in proving a beneficial effect on FeV1 or asthma control There is a biological redundancy between IL-4 and IL-13 Pitrakinra antagoinsit to both IL-4 and IL-13 is under study May 4-7,
19 IL-13 Specific Therapies IL-13 : recruitment of eos, mucous production, proliferation of bronchial fibroblasts and airway smooth muscle cells (bronchial remodeling) Lebrikizumab is a specific monoclonal antibody very effective in periostin asthmatic phenotype Periostin extracellular protein produced by bronchial epithelial cells Seen in asthma, scleroderma, cancer, bone marrow fibrosis Involved in fibrosis, eos recruitment, angiogenesis Tumor Necrosis Factor α Induced the recruitment of neutrophils and eos Directly stimulates airway smooth muscle contraction Infliximab is a TNFα blocking antibody Conflicting study results Enhances susceptibility to respiratory infection Golimumab No significant improvement in lung function Serious infections Lymphoma, breast, colon and cervical cancer May 4-7,
20 .3 IL-17 and IL-23 Targeted Therapy Involved in Neutrophilic inflammation Extreme Caution as IL-17 is involved in immune protection against infectious and carcinogenic agents Potentially increased risk of opportunistic infection and cancer May 4-7,
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