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Current Management of Hereditary Angioedema - Considerations to Optimize Individualized Care PowerPoint Presentation

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Description : This medical presentation titled "Current Management of Hereditary Angioedema - Considerations to Optimize Individualized Care" tells us how to differentiate key signs and symptoms of HAE from other common conditions and review the diagnostic tests in HAE, review the kallikrein-bradykinin system in HAE attacks, discusses the role of bradykinin receptors in HAE attacks and potential pathophysiologic explanations for multi-site attacks, and identifies key considerations in development of individualized treatment plans for patients with HAE.

Tags : Management, Hereditary Angioedema, signs, symptoms, diagnostic tests in HAE, kallikrein-bradykinin, bradykinin receptors, pathophysiologic

Published on : Apr 25, 2021 | Views : 2026 | Downloads : 2

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Faculty Panel Joshua S. Jacobs, MD Medical Director of Clinical Research Allergy & Asthma Medical Group Walnut Creek, California William R. Lumry, MD Clinical Professor Department of Internal Medicine/Allergy University of Texas Southwestern Medical School Private Practice Dallas, Texas Michael E. Manning, MD, FACAAI President and Medical Director Medical Research of Arizona Allergy, Asthma & Immunology Associates, Ltd. Scottsdale, Arizona Marc A. Riedl, MD, MS Professor of Medicine Clinical Director of US HAEA Angioedema Center Fellowship Program Director Division of Rheumatology, Allergy, and Immunology University of California, San Diego La Jolla, California 2
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Current Management of Hereditary Angioedema: Considerations to Optimize Individualized Care Disclosures of Financial Relationships Michael E. Manning, MD, FACAAI, Moderator Consultant/Advisor: CSL Behring, Pharming, Shire, Contracted Research: AstraZeneca, CSL Behring, Dyax, GlaxoSmithKline, Regeneron, Shire Speaker: Circassia, CSL Behring, Genentech, Pharming, Shire, Teva Joshua S. Jacobs, MD Consultant/Advisor: CSL Behring, Pharming, Regeneron, Shire, Teva Contracted Research: CSL Behring, Genentech, Regeneron, Sanofi, Shire, Teva Speaker: Shire, Teva
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Current Management of Hereditary Angioedema: Considerations to Optimize Individualized Care Disclosures of Financial Relationships William R. Lumry, MD Consultant: Biocryst, CSL Behring, Genentech, Pharming, Shire Contracted Research: Bio Products Lab, Circassia, CSL Behring, Genentech, Kedrion, Shire, Teva, Therapure Speaker: AstraZeneca, CSL Behring, Greer, Meda, Pharming, Shire Marc A. Riedl, MD, MS Consultant/Advisor: Biocryst, CSL Behring, Dyax, Pharming, Shire Contracted Research: Biocryst, CSL Behring, Dyax, Pharming, Shire Speaker: CSL Behring, Dyax, Pharming, Salix, Shire, Valeant
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Current Management of Hereditary Angioedema: Considerations to Optimize Individualized Care Learning Objectives Differentiate key signs and symptoms of HAE from other common conditions and review the diagnostic tests in HAE Review the kallikrein-bradykinin system in HAE attacks Discuss the role of bradykinin receptors in HAE attacks and potential pathophysiologic explanations for multi-site attacks Identify key considerations in development of individualized treatment plans for patients with HAE
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Agenda Welcome and Introductions Michael E. Manning, MD HAE Overview Michael E. Manning, MD Case Study I – Accurate Diagnosis of HAE Joshua S. Jacobs, MD Case Study II – Acute Management of HAE Marc A. Riedl, MD, MS Case Study III – Considerations for Prophylaxis in HAE William R. Lumry, MD Questions and Discussion Adjourn 6
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Michael E. Manning, MD HAE Overview 15
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Hereditary Angioedema A rare autosomal genetic disorder affecting an estimated 1:10,000 to 1:50,000 patients Positive family history in ~75% of cases Angioedema often severe Attacks unpredictable Increase over 24 hours Resolve over 2 to 4 days Unresponsive to treatment with antihistamines, corticosteroids, and epinephrine Associated with considerable morbidity and mortality 16
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HAE Burden of Disease 17
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Causes of Angioedema Allergies: foods, drugs, insect stings/bites Radiocontrast media ASA and other NSAIDs Autoimmune ACE inhibitor-induced C1 inhibitor deficiency Hereditary: Types I, II Acquired Hereditary with normal C1-INH Idiopathic Histamine-induced/Mast cell-mediated Bradykinin-induced Agostoni A. J Allergy Clin Immunol. 2004;114:S51-S131. Cichon S. Am J Hum Genet. 2006;79:1098-1104. 18 ACE, angiotensin-converting enzyme; ASA, acetylsalicylic acid; C1-INH, C1 inhibitor; NSAID, nonsteroidal anti-inflammatory drug.
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HAE Attacks Caused by the extravasation of plasma into the deeper cutaneous or mucosal layers due to bradykinin release Manifest as swelling of the skin, abdominal pain, and/or potentially life-threatening upper airway obstruction Are recurrent and unpredictable May be frequent and/or severe, but are highly variable between patients and within families Nzeako UC, et al. Arch Intern Med. 2001;161:2417-2429. Agostoni A, et al. J Allergy Clin Immunol. 2004;114:S51-S131. Bork K, et al. Mayo Clin Proc. 2000;75:349-354. 19
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HAE Extremity Attacks Peripheral angioedema Affects 96% of patients Functionally disabling Hands: difficulty holding, typing, use of phone Feet: impedes walking, standing Interferes with school Rarely results in hospitalization Frank MM, et al. Ann Intern Med. 1976;82:580-593. Frank MM. Immunol Allergy Clin North Am. 2006;26:653-668. 20
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Abdominal Attacks Occur in 93% of patients with HAE Mild to severe colicky pain Vomiting common; constipation/diarrhea may occur Functional intestinal obstruction Fluid loss may lead to hemoconcentration and hypovolemic shock Protuberant abdomen, tenderness, and rebound possible Symptoms mimic surgical emergencies, resulting in misdiagnosis and unnecessary surgery Frank MM, et al. Ann Intern Med. 1976;84:580-593. Agostoni A, et al. J Allergy Clin Immunol. 2004;114:S51-S131. Frank MM. Immunol Allergy Clin North Am. 2006;26:653-668. Agostoni A, Cicardi M. Medicine. 1992;71:206-215. Pictures courtesy of Dr. Marco Cicardi. After Treatment Edematous Ileum Bowel Edema 21
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HAE Laryngeal Attacks Occur in ~50% of patients during their lifetime Require airway management to prevent asphyxiation Are of particular concern in children, given the heightened risk for asphyxiation associated with a smaller airway Bork K, et al. Arch Intern Med. 2003;163:1229-1235. Bork K, et al. Mayo Clin Proc. 2000;75:349-354. Bork K, et al. Arch Intern Med. 2001;161:714-718. Radiographs courtesy of William Lumry, MD. 22
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Recognition of Clinical Symptoms 23
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Onset of Symptoms Occurs Early in the First 2 Decades in Majority of Cases Frank MM, et al. Ann Intern Med. 1976;84:580-593; Nzeako UC, et al. Arch Intern Med. 2001;161:2417-2429; Farkas H, et al. Pediatr Allergy Immunol. 2002;13:153-161; Agostoni A, et al. J Allergy Clin Immunol. 2004;114:S51-131; Frank MM. Curr Opin Pediatr. 2005;17:686-689; Bork K, et al. Am J Med. 2006;119:267-274; Bygum A. Br J Dermatol. 2009;161(5):1153-1158; Farkas H. Allergy Asthma Clin Immunol. 2010;6:18; Nielsen EW, et al. Pediatr Res. 1994;35(2):184-187. 24
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Anatomical Location of HAE Symptoms 221 patients with HAE 5,736 patient-years of observation 131,110 angioedema attacks 50% 48% 3.6% 100% 97% 54% 22% 9% 8% 5% 5% 4% 4% 4% 2% Bork K, et al. Am J Med. 2006;119:267-274. Per-patient Analysis Per-episode Analysis 25
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Airway Angioedema 182 families: 728 patients Death from asphyxiation: 7/527 (1.3%) in diagnosed patients 63/201 (31%) in undiagnosed patients Bork K, et al. J Allergy Clin Immunol. 2012;130:627-629. Age at time of death from asphyxiation in 70 patients with HAE-C1-INH 26
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Unmet Needs in HAE Understanding of the underlying pathways Improving HAE symptom recognition and accurate diagnosis Strategies to implement appropriate acute and prophylactic treatments To treat at home or not to treat at home? Creating an HAE action plan/ensuring attack preparedness 27
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Accurate Diagnosis of HAE Joshua S. Jacobs, MD 28
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Pathways Underlying HAE 29
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Bradykinin is the Mediator of Angioedema in HAE Kaplan AP, et al. Clin Rev Allergy Immunol. 2016;51:207-215. 30 FXI, factor XI; PK, prekallikrein.
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Systemic Contact Activation Leads to Local Angioedema 31 BK, bradykinin; B1R, bradykinin receptor 1; B2R, bradykinin receptor 2; CPN, carboxypeptidase N; CPM, carboxypeptidase M. Hofman ZL, et al. J Allergy Clin Immunol. 2016;138:359-366. On initial triggering by BK, B2R becomes functionally inactive because of desensitization. BK levels are preferentially degraded by CPN or CPM into desArg9-BK, which induces angioedema at sites where B1R is expressed. Minor trauma? Not necessarily at site of attack? Low C1-INH Initial BK Cytokines, endotoxins, kinins Initial contact activation Dissemination of contact activation throughout the circulation Desensitization of B2R Angioedema where B1R is present Elevated BK Cleaved HK Prodromal symptoms No hypotension From 0 up to 5 locations
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Discussion How does our understanding of the pathways underlying HAE guide treatment? 32
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Major Types of Angioedema 33
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C1 inhibitor antigen C1q antigen C1 inhibitor function Not a C1-INH deficiency C4 Type II HAE Acq C1-INH Def Type I HAE Idiopathic Low Normal Normal Low Normal Low Normal Low Diagnostic Algorithm for Angioedema 34 Acq, acquired; Def, deficiency.
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Evaluating for Angioedema Skin Episodic Photographs valuable Non-pitting Localized Involves skin or mucosa Relatively rapid onset: minutes to hours Frequently asymmetric distribution Distribution not in dependent areas Differential diagnosis: granulomatous cheilitis (Melkersson-Rosenthal), SVC syndrome, lymphedema, capillary leak syndrome (Clarkson), autoinflammatory syndromes, contact dermatitis, cellulitis SVC, superior vena cava. 35
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Evaluating for Angioedema (Cont’d) Airway symptoms, “throat closing/choking” challenging to evaluate VCD Tracheomalacia Exercise-induced asthma Recurrent abdominal pain: consider other potential causes Normal With Symptoms VCD, vocal cord dysfunction. 36
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Additional Questions and History Any history of urticaria, angioedema, skin or airway swelling? Treatment received and efficacy of that treatment? Any family history of similar issues? Exacerbating factors? 37
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Case Study #1: Chris, 12-year-old Male Chris presents to your office with a complaint of recurrent abdominal pain Previously diagnosed with inflammatory bowel disease by internist and has been referred to you following gastroenterology consult Description of complaint: Abdominal pain lasting between a few hours to 2-3 days Pain and duration have increased in intensity recently Most recent attack accompanied by nausea and vomiting with mild diarrhea 38
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Chris, 12-year-old Male: History No notable medical history prior to recent abdominal pain Family history of irritable bowel syndrome (grandfather and aunt) Recently relocated to your area and started in a new school 6 months ago 39
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Chris, 12-year-old Male: Physical Exam and Previous Test Results Vital signs are normal Exam reveals: Normal abdomen No organomegaly or masses Previous test results found normal: WBC counts Amylase, lipase, metabolic panel, and C-reactive protein Stool analysis Urine analysis Abdominal ultrasound Fecal calprotectin Upper and lower endoscopies 40 WBC, white blood cell.
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Differential Diagnosis of Abdominal Pain Biliary disease Acute pancreatitis Dyspepsia Hiatus hernia Pneumonia Myocardial infarction Splenic abscess or infarction Appendicitis Diverticular disease Kidney stones Bladder distension Pelvic pain Mesenteric ischemia and infarction Ruptured aneurysm Peritonitis Intestinal obstruction Sickle cell disease Women Pelvic inflammatory disease Adnexal pathology Endometriosis Ectopic pregnancy Endometritis Leiomyomas Celiac artery compression syndrome Painful rib syndrome Wandering spleen syndrome Abdominal wall pain Abdominal migraine Mesenteric lymphadenitis Eosinophilic gastroenteritis Epiploic appendagitis Abdominal compartment syndrome Fitz-Hugh-Curtis syndrome Familial Mediterranean fever 41
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HAE Abdominal Attacks Bork K. Am J Gastroenterol. 2006;101:619-627. 153 patients reporting abdominal HAE attacks: 169 prospective; 33,671 retrospective No. of Attacks (Prospective Part) 80 70 60 50 40 30 20 10 0 42
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Phases and Time Course of Typical HAE Abdominal Attack 43 Bork K. Am J Gastroenterol. 2006;101:619-627.
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Clinical Pearl: Testing C4 level is an excellent screening test for HAE Readily available in most hospitals and clinical labs No special handling of blood specimen (serum red-top tube) 95% of time will be low between attacks in patients with HAE >99.5% of time will be low during an attack Borderline-low results should be repeated if clinical suspicion high for HAE Can be confirmed with C1-INH antigenic or functional assay Inexpensive 44
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Frank MM, et al. Ann Intern Med. 1976;84:580-593. C4 Levels in HAE Due to C1-INH Deficiency C4 Units per mL Serum 1,000,000 100,000 10,000 <500 Normals Mean ± 2 SD SD, standard deviation. 45
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C1-INH Functional Assay Differences Wagenaar-Bos IG, et al. J Immunol Methods. 2008;338:14-20, with permission. Chromogenic Assay Complex ELISA Assay (Quidel) Manufacturer-recommended “normal” reference value On-site individual lab-determined reference value 150 100 50 0 Confirmed HAE Healthy % fC1-INH P H % fC1-INH P H 140 120 100 80 60 40 20 0 ELISA, enzyme-linked immunosorbent assay; fC1-INH, functional C1-INH; H, healthy; P, patients. 46
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Comparison of C1-INH Functional Assays 93% agreement between chromogenic and ELISA assays Chromogenic: 45/45 C1-INH-deficient patients low (<74%): 100% sensitivity 29/30 Normal patients normal (≥74%): 97% specificity ELISA: 10/45 C1-INH-deficient patients with equivocal (41% to 67%) results 2/45 C1-INH-deficient patients with normal (>67%) results 33/45 C1-INH-deficient patients with low (<41%) results: 73% sensitivity 30/30 Normal patients with normal results: 100% specificity Sensitivity of baseline C4 in detecting C1-INH deficiency: 86% Li H, et al. J Allergy Clin Immunol Pract. 2015;3:200-205. 47
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Chris, 12-year-old Male: Laboratory Results CBC, amylase, lipase, CMP, and CRP normal Complement testing C4: low C1-INH quantitative: normal C1-INH functional: low C1q: normal 48 CBC, complete blood cell count; CMP, comprehensive metabolic profile; CRP, C-reactive protein.
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Clinical Pearl: Complement Testing in Recurrent Angioedema Zuraw BL, et al. J Allergy Clin Immunol. 2013;131:1491-1493. 49
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Chris, 12-year-old Male: Diagnosis Zuraw BL, et al. J Allergy Clin Immunol. 2013;131:1491-1493. 50
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Importance of Correct Diagnosis Familial implications of angioedema conditions Uneasy lies the head that wears a “genetic crown” Informed and appropriate counseling Preventing unnecessary anxiety and guilt for patients 51
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Faculty Discussion Testing of family members Age dependency Potential triggers or precipitating events in HAE 52
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Marc A. Riedl, MD, MS Acute Therapies and Maximizing Treatment Effectiveness 53
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On-demand treatment: - Available for all patients - Arrange in advance - Treat early in an attack - All attack locations eligible - Assess efficacy on ongoing basis Prophylactic treatment: - Short term: dependent on stress - Long term: no rigid criteria - Decision must be individualized - Use lowest effective dose - Avoid use of indwelling ports Monitoring plan: - Monitor attack frequency and severity - Adjust medications accordingly - Find best on-demand treatment - Monitor adverse events - Continuous patient education Develop a management plan: - Involvement of an expert clinician - Extensive patient education - Consider all treatment options - Coordination of care - Treatment logistics Zuraw B, et al. J Allergy Clin Immunol. 2013;1(5):458-467. Recommended Components of HAE Management 54
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Benefits of HAE Expert Physician Involvement Referral centers or networks Collaborative care with other physicians Optimal patient education regarding condition and treatment options Iterative process to adjust/adapt treatment plan over time 55
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HAE-C1-INH Tourangeau LM, et al. Curr Allergy Asthma Rep. 2011;11(5):345-351. To decrease the frequency and severity of ongoing attacks To rapidly stop an existing attack before the patient experiences M&M To prevent an attack when the patient will be exposed to a known stimulus Treatment for HAE must be individualized to provide optimal care and normalize QOL. Required for ALL patients Used as needed for individual patients Three Treatment Strategies for HAE-C1-INH On-demand Short-term prophylaxis Long-term prophylaxis 56 M&M, morbidity and mortality; QOL, quality of life.
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Recommendations for Treatment of Acute Attacks of HAE All patients with HAE should have acute therapy available for treating an attack: C1-INH inhibitor (plasma-derived or recombinant) Ecallantide (Kalbitor) Icatibant (Firazyr) Patients should have at least 2 doses of an on-demand therapy at home and be trained in self-administration whenever possible Early treatment of attacks beneficial to reduce morbidity and complications All attacks are eligible for treatment as soon as they are recognized Hospital evaluation is recommended for laryngeal involvement 57 Cicardi M, et al. Allergy. 2012;67(2):147-157; Craig T, et al. World Allergy Organ J. 2012;5(12):182-199; Lang D, et al. Ann Allergy Asthma Immunol. 2012;109(6):395-402; Betschel, et al. Allergy Asthma Clin Immunol. 2014;10:50; Zuraw B, et al. J Allergy Clin Immunol Pract. 2013;1(5):458-467.
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Case Study #2: Jason, 22-year-old Male Jason presents to your office following a recent acute HAE attack History: Diagnosed with Type I HAE at 18 years old Family history of fatal laryngeal attacks due to HAE Has experienced 2 to 3 attacks per year since diagnosis Treatment history: Following diagnosis received C1-INH therapy for acute attacks administered in ED Switched to self-administered icatibant on demand when he started college (current therapy) 58 ED, emergency department.
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Jason, 22-year-old Male: Recent History Two most recent attacks have required ED visits First attack presented with laryngeal swelling Second attack, he experienced relapse of symptoms 30 hours after symptom relief from treatment Recently graduated from college and began working Expresses desire to review his treatment plan 59
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Comparison of Acute Treatments AAE, acquired angioedema; FDA, US Food and Drug Administration; FFP, fresh frozen plasma; IV, intravenous; N, no; nl, normal; pdC1-INH, plasma-derived C1 inhibitor; rhC1-INH, recombinant human C1 inhibitor; SC, subcutaneous; w/, with; Y, yes. *Not FDA-approved indications. 60
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Current Acute HAE Therapies Factor XII Factor XIIa Prekallikrein Kallikrein Bradykinin Bradykinin type 2 receptor Ecallantide C1-INH Angioedema Adapted from Chen M, et al. Immunol Allergy Clin North Am. 2017. C1-INH Icatibant High-molecular-weight kininogen 61
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Comparison of HAE Acute Therapies EDEMA, Evaluation of the DX-88 Effect in Mitigating Angioedema Subcutaneous Treatment (study); FAST, For Angioedema Subcutaneous Treatment (trial); TOS, treatment outcome score; VAS, visual analogue scale. Riedl MA. Curr Allergy Asthma Rep. 2011;11:300-308. 62
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Berinert Registry Data: Location of C1-INH Infusions Riedl MA. Curr Allergy Asthma Rep. 2011;11:300-308. 296 subjects with prospective data: 2 thrombotic events (DVT – indwelling port; MI – 8 months after last C1-INH infusion) Attack Treatment (11,720 infusions) Prophylaxis (3,089 infusions) 63 DVT, deep vein thrombosis; MI, myocardial infarction.
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C1-INH Use in Pregnancy Berinert Registry data: 11 pregnancies in 10 subjects who used pdC1-INH for HAE treatment 261 doses during pregnancy 8 pregnancies concluded in the birth of a healthy baby Remaining 3 pregnancies: 1 voluntarily terminated at 9 weeks of gestation 1 ended as a first-trimester spontaneous abortion 1 week after the subject's most recent pdC1-INH infusion; considered unrelated to C1-INH treatment 1 occurred in a subject who exited the registry approximately 2 months before her due date, with no further follow-up As assessed for 30 days after each pdnfC1-INH infusion, there were no AEs that were considered related to pdnfC1-INH therapy Fox J. Allergy Asthma Proc. 2017;38(3):216-221. 64 AE, adverse event; pdnfC1-INH, plasma-derived nanofiltered C1 inhibitor.
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C1-INH Use in Children and the Elderly Berinert registry: 18 children, 275 infusions 77% of infusions completed in non-health care setting 3 AEs in 3 children (toothache, nasopharyngitis, ankle fracture) None considered related to pdC1-INH Adults 65 or older: 27 subjects, 1,701 infusions 95% of infusions completed in non-health care setting 19 AEs in 8 subjects – 2 severe (prostatectomy and GI bleeding) None considered related to pdC1-INH Busse P, et al. J Allergy Clin Immunol Pract. 2017;4:1142. Bygum A, et al. Drugs Aging. 2016;33:819-827. 65 GI, gastrointestinal.
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Sheffer A, et al. J Allergy Clin Immunol. 2011;128:153-159. Craig TJ, et al. J Allergy Clin Immunol Pract. 2015;3:206-212. Ecallantide (n=35) (n=34) (n=42) (n=47) (n=67) (n=67) P= .041 P= .010 P= .001 Ecallantide Placebo Improvement in Mean MSCS at 4 hours Improvement in Mean TOS at 4 hours MSCS=mean symptom complex score TOS=treatment outcome score EDEMA3 EDEMA4 Integrated Analysis† (n=34) (n=35) (n=67) (n=67) P= .045 P= .003 P= .001 Unique HAE Patients N = 297 SC: n=230 IV: n=67 Patients with HSR N = 32 SC: n=20 IV: n=12 Meets NIAID Criteria for Anaphylaxis N = 13 SC: n=8 IV: n=5 Does Not Meet NIAID Criteria for Anaphylaxis N = 19 SC: n=10; IV: n=7; SC&IV: n=2* 66 HSR, hypersensitivity reaction; NIAID, National Institute of Allergy and Infectious Disease.
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Home-based Treatment with Ecallantide HCP administration required due to 3% to 4% rate of anaphylaxis seen in clinical trials 158 patients enrolled in home nursing acute treatment program Most likely time for patient calls: 6:00 am – 5:00 pm Average time to relief onset was 43.5 minutes One dose sufficient to treat the majority of attacks; second dose was needed in 23.6% of patients Tachdjian R, et al. Allergy Asthma Proc. 2015;36:151-159. 67 HCP, health care provider.
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Icatibant Study in Children and Adolescents Farkas H, et al. J Allergy Clin Immunol Pract. 2017. [epub ahead of print] Composite Investigator-assessed Symptom Score 0 1 2 3 4 5 6 7 8 Time From Icatibant Administration (Hours) 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Overall Children Adolescents Pubertal status No. of patients Children 11 11 11 11 11 Adolescents 11 11 11 11 11 2 Overall 22 22 22 22 22 2 68
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Icatibant in Children and Adolescents Values are n (%). *Two TEAEs occurring in 1 adolescent were considered possibly related to icatibant: dry mouth and fatigue. TEAE, treatment-emergent adverse event. Farkas H, et al. J Allergy Clin Immunol Pract. 2017. [epub ahead of print] Summary of TEAEs Occurring in ≥2 Patients, by System Organ Class (Safety Population)* 69
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Icatibant Outcomes Study Three SAEs (drug inefficacy, gastritis, reflux esophagitis) in 2 patients considered possibly or probably related to icatibant Zanichelli A, et al. Allergy. 2017;72:994-998. 70 SAEs, serious adverse events.
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Recombinant Human C1-INH – Sustained Response Bernstein JA, et al. Ann Allergy Asthma Immunol. 2017;118:452-455. Lack of hereditary angioedema attack recurrence or new hereditary angioedema attack onset within 72 hours of rhC1-INH treatment 71
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Recombinant Human C1-INH for Upper Airway HAE Attacks Pooled analysis of 3 clinical trials: 683 HAE attacks 45 with upper airway involvement treated with rhC1-INH Median time to the beginning of symptom relief: 67 minutes (95% confidence interval, 60–120 minutes) 91% achieved the beginning of relief within 4 hours of rhC1-INH treatment All attacks resolved without the need for any additional medication No patients required intubation or tracheostomy 72 Riedl M, et al. Allergy Asthma Proc. 2017;38:462-466.
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Future Acute HAE Treatment ZENITH-1: a Clinical Trial to Evaluate BCX7353 (oral kallikrein inhibitor) as an Acute Treatment of Hereditary Angioedema Attacks Single-dose liquid formulation Phase 2 trial ongoing in Europe 73
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Optimizing Acute Treatment Plans Your patient has a prescription for an acute HAE medication. Now what? “I’m writing you a prescription. Do you want a longer life with less quality or vice versa?” 74
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Access to On-Demand Medication Zanichelli A, et al. Allergy. 2015;70:1553-1558. 75
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Access to Medication Christiansen SC, et al. Allergy Asthma Proc. 2015;36:145-150. 76 Emot, emotional; Psych, psychological.
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Access to Medication Riedl MA, et al. J Allergy Clin Immunol Pract. 2014;3:220-227. 77
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Early Treatment Reduces Attack Burden 78 Analysis of 436 attacks from 136 subjects; duration of attack by interval to treatment Maurer M, et al. PLoS One. 2013;8(2):e53773. *P<.001.
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Icatibant Self-administration Time in minutes from attack onset to (A) treatment and (B) complete symptom resolution was significantly shorter for self-administration compared to HCP administration. Data presented as mean with standard deviation. *P < .0001; †P < .01. Otani IM, et al. J Allergy Clin Immunol Pract. 2017;5(2):442-447. Hours HCP (n=29) Self (n=50) 15 12 9 6 3 * Hours HCP (n=29) Self (n=49) 30 27 24 21 18 15 12 9 6 3 † 79
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Disease burden and treatment outcomes before and after switching to home therapy C1-INH Home Therapy Petraroli A, et al. Int Arch Allergy Immunol. 2015;166:259-266. 80
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Improvements in Quality of Life with C1-INH IRT 81 Kreuz et al. Transfusion. 2009;49:1987-1995. Item Scale Family/Home Social Occupation Life General Condition Responsibility Activities Support Condition During Activity Attacks Life Activity Items Total of the 6 items 10 9 8 7 6 5 4 3 2 1 0   Total Score   Retrospective phase Prospective phase 60 55 50 45 40 35 30 25 20 15 10 5 0 IRT, individual replacement therapy.
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Self-administration Barriers Wang A, et al. Ann Allergy Asthma Immunol. 2015;115:120-125. 82
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Barriers to Optimal Treatment of HAE Attacks Lack of access to medication Appropriate prescription provided Cost/coverage of medication Logistics of refills Medication administration Lack of self-administration planning or education Uninformed ED care Patient not knowing when to use medication Adverse events Failing to recognize danger of airway events 83
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Both patients and healthcare providers need an action plan in place before an attack. Patient Education Provide patients with education on: Signs and symptoms of attacks Risks of attacks Attack triggers Family counseling Information about all therapies Self-administration 84
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Bork Laryngeal Edema Data 182 Families: 728 patients Death from asphyxiation: 7/527 (1.3%) in diagnosed patients 63/201 (31%) in undiagnosed patients Bork et al. J Allergy Clin Immunol. 2012;130:629-637. Age at time of death from asphyxiation in 70 patients with HAE-C1-INH 81.6% 15.1% 3.3 % Phase 1: 3.7 ± 3.2 hours; range, 0-11 hours Phase 2: 41 ± 49 minutes; range, 2 minutes to 4 hours Phase 3: 8.9 ± 5.1 minutes; range, 2-20 minutes Mean durations of the 3 phases of fatal laryngeal attacks in 36 patients with HAE-C1-INH 85
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Physical Trauma - Incidental - Iatrogenic Medications - Estrogens - ACE inhibitors Emotional Stress - HANE - Holidays Infections - Helicobacter pylori? - Viral? Known or Suspected Triggers HANE, hereditary angioneurotic edema. Zuraw B, et al. J Allergy Clin Immunol Pract. 2013;1:458. Anticipating and Managing Triggers 86
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Optimizing Non-pharmacologic Treatment Management of Trigger Factors Stress: Physical or Mental Iatrogenic Trauma: Surgical or Dental Procedures Infection Medications: Estrogen and ACE-I Joseph K. J Allergy Clin Immunol. 2017;140(1):170-176. Hsp90 (ng/mL) Interleukin 1 beta TNF alpha Estradiol 4 3.5 3 2.5 2 1.5 1 0.5 0 * * * * * * * * * * * * * Concentration (ng/mL) 0 1 5 10 20 30 IL-1 TNF-α Estradiol Control Kallikrein Activity (Absorbance, OD at 405 mm) 0 30 60 90 120 150 180 Time (Minutes) 0.5 0.4 0.3 0.2 0.1 0 PK HK+PK HK+ PK+FXII PK HK+PK HK+ PK+FXII Kallikrein Activity (Absorbance, OD at 405 mm) 0 30 60 90 120 150 180 Time (Minutes) 0.5 0.4 0.3 0.2 0.1 0 PK HK+PK HK+ PK+FXII 0 30 60 90 120 150 180 Time (Minutes) 0.5 0.4 0.3 0.2 0.1 0 0 30 60 90 120 150 180 Time (Minutes) 0.5 0.4 0.3 0.2 0.1 0 PK HK+PK HK+ PK+FXII Kallikrein Activity (Absorbance, OD at 405 mm) Kallikrein Activity (Absorbance, OD at 405 mm) 87
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Health Care Provider Education Otani IM, et al. J Allergy Clin Immunol Pract. 2017;5:128-134. 88
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Patient Perspective of ED Management of HAE ED management of HAE has been hindered by misdiagnosis and limited treatment options Recent survey of 105 patients with HAE: 99% indicated understanding of HAE in ED needed improvement Areas that needed improvement included recognition of HAE as a diagnosis (48%), appreciation of HAE as a serious disease (45%), and medication management (59%) Among 68 patients whose plan was to receive home therapy, 26 required ED care because of inability to receive therapy at home Having a treatment plan was associated with a higher likelihood of receiving HAE therapy in the ED vs corticosteroids, epinephrine, etc Otani IM, et al. J Allergy Clin Immunol Pract. 2017;5:128-134. 89
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Written Action Plans Provide guidance on navigating the health care system Treatment plan should include: Pre-placement of therapies When to treat Who will administer therapies Monitoring of prescriptions Method to obtain refill Travel planning Emergency card Zuraw B, et al. J Allergy Clin Immunol Pract. 2013;1:458. 91
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Emergency Treatment Plan – Cards or Letters 92
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Between Appointments Tracking of HAE symptoms and medication used (calendar, smartphone app, etc) Patient to notify HCP if: Difficulties getting or using medication Treatment seems ineffective Side effects occur Dental or surgical procedures are necessary Advise patient on family testing “How can I trust your information when you’re using such outdated technology?” 93
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Thank You 94
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Faculty Discussion Frequency with which acute treatment plan should be reviewed Considerations for at-home administration of acute therapy Attack duration, location, and symptom relapse 95
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William Lumry, MD Consideration for Prophylaxis in HAE 96
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Case Study #3: Allison, 29-year-old Female Allison presents to your office following treatment in the ED for an acute attack of HAE Diagnosed with Type I HAE at 24 years old Family history of HAE (mother and grandmother) Physical exam is unremarkable with normal vital signs Previous laboratory results: C4 level: 6 mg/dL (normal: 13-75 mg/dL) C1-INH quantitative: 8 mg/dL (normal: 16-33 mg/dL) C1-INH functional level: 44% (normal: >67%) C1q level: 18 mg/dL (normal: 12-22 mg/dL) 97
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Allison, 29-year-old Female: Recent History Current acute treatment plan of self-administered icatibant Previous course of short-term prophylaxis with C1-INH for dental procedure Description of recent attack: Multi-site attack that included laryngeal and extremity swelling Icatibant treatment resulted in reduced swelling but 8 hours passed before complete symptom resolution Second attack in past month Attack frequency has increased over past 2 years 98
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Considerations when Selecting Prophylactic Therapy Lunn M, et al. J Blood Med. 2010;1:163-170. Craig T, et al. Ann Allergy Immunol. 2009;102:366-372. 99 ICU, intensive care unit.
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Allison, 29-year-old Female 100
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Comparison of Prophylactic Treatments *Not FDA approved. bid, twice a day; PO, by mouth. 101
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Short-term Prophylaxis On-demand therapy should be available at all times post procedure. An HAE-specific therapy is preferred. Zuraw BL, et al. J Allergy Clin Immunol Pract. 2013;1:458-467. Joint Task Force on Practice Parameters. J Allergy Clin Immunol. 2013;131:1491-1493. 102
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Efficacy and Effective Therapeutic Dose of Danazol Frank MM. Immunol Allergy Clin N Am. 2006;26:653-668. 103
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Side Effects of Danazol Therapy Frank MM. Immunol Allergy Clin North Am. 2006;26:653-668. CPK, creatine phosphokinase; LFT, liver function test. 104
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Alkylated Androgens Recent reevaluation of alkylated androgen use 650 subjects; 3 groups Never users of alkylated androgens (n=126) Previous users (n=180) Current users (n=344) Confirmed decrease in attack frequency and severity (83% reduction) Improved outcomes (decrease in ED visits, hospitalizations, narcotic use, and negative impact on QOL) Zuraw BL, et al. J Allergy Clin Immunol Pract. 2016;4:948-955. 105
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Alkylated Androgens: Side Effects Important findings No relationship between AA dose and efficacy No relationship between AA dose and ED use, hospitalization, or attack severity Strong correlation between AA dose and side effects including mental health measures (anxiety, depression, sadness, aggressiveness), weight gain, headache, and hypertension Duration of treatment associated with ↑ LFTs, HTN, and HA Zuraw BL, et al. J Allergy Clin Immunol Pract. 2016;4:948-955. 106 AA, 17-a-alkylated androgens; HA, headache; HTN, hypertension.
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Intravenous pd-nf-C1-INH Prophylaxis Associated with Lower HAE Attack Rate Average normalized attack rate: 12.73 vs 6.26, placebo vs pd-nf-C1-INH Average difference in attack rates: 6.47 (P<.001) Zuraw B, et al. N Engl J Med. 2010;363:513-522. 107
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Intravenous nf-C1-INH Prophylaxis Associated with Lower HAE Attack Rates Zuraw B, et al. N Engl J Med. 2010;363:513-522. 108 nf-C1-INH, nanofiltered C1 inhibitor.
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Longhurst H, et al. N Engl J Med. 2017;376(12):1131-1139. 95% CI 94% median attack reduction with active vs placebo *LS mean (95% CI) estimate. CI, confidence interval; COMPACT, Clinical Study for Optimal Management of Preventing Angioedema With Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy; LS, least squares; n, number of subjects with data. –3.5* (–4.2; –2.8) –2.4* (–3.4; –1.5) Median 88.6% reduction Median 95.1% reduction Paired comparison: High-Volume Placebo n=44 Low-Volume Placebo n=42 40 IU/kg CSL830 n=43 60 IU/kg CSL830 n=43 Subcutaneous pdC1-INH COMPACT Trial: Phase 3 Primary End Point – Median Number of Attacks/Mo 109
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Subcutaneous pdC1-INH COMPACT: Phase 3 Secondary End Point – Use of Rescue Medication/Month –3.6* (–4.5; –2.6) –4.4* (–8.0; –0.8) Median 89.4% reduction Median 100.0% reduction Paired comparison: *LS mean (95% CI). High-Volume Placebo n=44 Low-Volume Placebo n=42 40 IU/kg CSL830 n=43 60 IU/kg CSL830 n=43 P<.001 Longhurst H, et al. N Engl J Med. 2017;376(12):1131-1139. 95% CI 110
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Subcutaneous pdC1-INH COMPACT: Phase 3 – Attack Diaries for 60 IU/kg Dosing Schedule Longhurst H, et al. N Engl J Med. 2017;376(12):1131-1139. *Rescue treatment 111
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Prophylactic Therapies in Development 112 BLA, biologics license application.
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Lanadelumab: Key Results from the HELP Study http://investors.shire.com/~/media/Files/S/Shire-IR/presentations-webcast/year-2017/shire-investor-presentation-2017-05-18.pdf. Accessed June 1, 2017. 113
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Recombinant C1-INH Prophylaxis Mean Reduction in Attacks and Clinical Response of rhC1-INH vs Placebo *All patients in the ITT population who completed the study and did not have any major protocol violations; n = 23. †Defined as reduction of 50% or more in the number of attacks that occurred during rhC1-INH treatment vs number of attacks that occurred during placebo treatment. Riedl MA, et al. Lancet. Published online July 27, 2017. Up to 95.7% of patients had a clinical response, per-protocol population* rhC1-INH reduced attack frequency by up to 72.1% 114
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Highly Efficacious Large HAE Prevention Trial of 28-Week Duration Favorable Safety Profile https://www.shire.com/en/newsroom/2017/september/cwabkg. Accessed September 14, 2017. Results of SHP-616 pd nf C1-INH SC Study Study met the primary and all secondary end points showing superiority over PBO Starting at Day 0 79% reduction in NNA (P < .001) From Day 14: 85% reduction in NNA (P < .001) 78% have at least 50% HAE attack reduction 38% attack free No treatment-related serious or severe adverse events Most commonly noted treatment-emergent adverse event was URTI (7% PBO vs 12.5% SHP616); viral URTI (5.3% PBO vs 12.5% SHP616); and headache (10.5% PBO vs 10.7% SHP616) No VTE events. No anti-C1-INH antibodies detected 115 LTP, long-term prophylaxis; PBO, placebo; RCT, randomized controlled trial; URTI, upper respiratory tract infection; VTE, venous thromboembolic.
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http://investor.shareholder.com/biocryst/releasedetail.cfm?ReleaseID=1039048. Accessed September 6, 2017. Aygören-Pürsün E, et al. Presented interim results. 10th HAE Workshop; May 2017; Budapest, Hungary. BCX7353 Results of the APeX-1 Study: Attack Rate/Week 116 APeX-1, Efficacy and Safety of BCX7353 to Prevent Angioedema Attacks in Subjects With Hereditary Angioedema; qd, once a day.
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Allison, 29-year-old Female: Treatment Preferences Allison is open to prophylactic therapy Has access to treatment facility but prefers to administer therapy at home Explains that she and her husband are considering having children 117
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Pregnancy and Attack Rate in Women With HAE 118 Bouillet L, et al. Am J Obstet Gynecol. 2008;199:484.e1-34. ↑ in attacks 38% No change in number of attacks 32% ↓ in attacks 30% Only 6% of women had an attack of HAE within 48 hours of labor and delivery.
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HAE in Pregnancy C1-INH may be low during pregnancy due to dilutional effects Symptoms during previous pregnancy do not predict symptoms during current pregnancy Fetus with HAE may cause more attacks in mother during third trimester HAE attacks are rare during labor and delivery Androgens are contraindicated Tranexamic acid for LTP only if C1-INH is not available Cabellero T. J Allergy Clin Immunol. 2012;129:308-320. 119
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Special Populations: Pediatrics Characteristics At birth antigenic and functional C1-INH levels correspond to 70% and 61.8% of adult values, respectively, and increase to the normal level by the age of 1 year Angioedema episodes usually begin between 5 and 11 years of age Mean age at disease onset was 11.2 years (Bork), 9.5 years (Bygum), and 4.4 years (Martinez) Laryngeal attacks are rare: 0.9% of all attacks Compared to adults, asphyxia may ensue more rapidly because of smaller airway diameter The earlier the onset of symptoms, the more severe the course of HAE Farkas H. Allergy Asthma Clin Immunol. 2010;6:1-10. 120
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Special Populations: Pediatrics (Cont’d) Treatment Long-term prophylaxis options include tranexamic acid, attenuated androgens, and pdC1-INH Older consensus statements by various authorities unanimously advocate tranexamic acid as the agent of choice because of its safety profile. When antifibrinolytics fail, treat with the lowest effective maintenance dose of danazol (2.5 mg/kg per day); 50 mg/day initial dose More recent data suggest pdC1-INH as best acute and prophylactic treatment FDA approved pdC1-INH (Berinert®*) for acute therapy in children (July 2016) Experience is limited with ecallantide, icatibant, and rhC1-INH for acute treatment *Kankakee, IL: CSL Behring LLC. Farkas H. Allergy Asthma Clin Immunol. 2010;6:1-10. Wahn V. Eur J Pediatr. 2012;171:1339–1348. 121
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HAEA Medical Advisory Board Prophylactic Treatment Suggestions Long-term prophylaxis is appropriate for patients who do not achieve sufficient benefit from on-demand therapy Androgens should not be used if the patient does not tolerate them, in patients under the age of 16, or in pregnant/breastfeeding women Caution should be exercised if the danazol dose exceeds 200 mg/day Patients on prophylaxis still require on-demand treatment be available Prophylaxis should be used at the lowest effective dose that controls disease activity 122 Zuraw B, et al. J Allergy Clin Immunol Pract. 2013;1:458. HAEA, Hereditary Angioedema Association.
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At Home Treatment of HAE Current clinical guidelines recommend home-based treatment where feasible and that all patients have access to medication supply at all times Postmarketing studies show home therapy is a convenient and safe option preferred by many HAE patients Administration in a healthcare facility may be hindered by accessibility and convenience factors Li HH. Patient Prefer Adherence. 2016;10:1727-1737. 123
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Faculty Discussion Considerations for prophylaxis therapy Home vs healthcare facility administration of therapy Expanding treatment options 124
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Summary HAE is a rare, but serious, disease that imposes a substantial health and economic burden due to recurrent, unpredictable, and potentially fatal attacks Patients with clinical symptoms and a family history of angioedema should be promptly evaluated for HAE to ensure early diagnosis and optimal disease management Several agents effective for acute and prophylactic treatment of HAE attacks are currently available All patients with HAE should have access to on-demand treatment to reduce the duration of attacks and the risk of asphyxiation Short- and long-term prophylactic treatment plans should be individualized based upon patient characteristics, including age, gender, and attack burden, to achieve optimal care and normalize QOL 125
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Questions & Answers 134
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Thank you! 135