Hypereosinophilic Syndromes
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1 Hypereosinophilic Syndromes ACR 2011 Hereditary Angioedema Virginia Commonwealth University Lawrence B. Schwartz, MD, PhD 1. Diagnosis 2. Subtypes/Presentations 3. Treatment Disclosure Slide Lawrence B. Schwartz, MD, PhD Employment VCU/HS Research Interests NIH Genentech, Novartis, GSK, Pharming, Ception, Cephalon Science Advisory Board - Mast Cell Pharm - Genentech J Clin Immunol Associate Editor Consulting Sanofi-Aventis, Exoxemis Financial Interests VCU-Phadia: Royalties for tryptase test VCU-Millipore, -Santa Cruz, -BioLegend, -Hycult BioTec: Royalties for mabs Up-To-Date Card royalties Cecil s Textbook of Medicine chapter royalties NIH Study Section Diagnosis of HES Eosinophilia Differential Diagnosis Blood 1500/mm 3 6 mo Unknown trigger of Signs and symptoms of organ involvement Blood 1500/mm 3 2 occasions or prominent tissue a/w symptoms and marked blood Exclude secondary causes of (parasitic or viral, allergic, drug/chemical-induced, hypoadrenal, and neoplasms) Delete Worms Parasitic (Helminth) Infections strongyloidiasis, trichinosis, visceral larva migrans Fungi: acute coccidioidomycosis, ABPA Protozoa: intestinal isospora Wheezes Allergic Diseases rhinoconjunctivitis, asthma, eczema, drugs Weird Diseases Eosinophilic Syndromes pulmonary, GI, endocrine, malignancies, cholesterol embolism Simon, et al. J Allergy Clin.Immunol 126:45-49, 2010 Weller
2 Eosinophils LTC 4, O 2 radicals Cytokines Chemokines Eosinophil Development ECP EDN EPO MBP ~basal Eotax-2~lung Eotax-3~EE Schwartz R. NEJM 348: 2003 HES Etiologies FIP1L1-PDGFRA Fusion Mutation Myeloproliferative (1 ) Lymphocytic (IL-5+) (2 ) Familial Clonal T cells Activated T cells Overlap Idiopathic Associated KIT + CHIC2 - Clonal: FIP1L1-PDGFRA(4q12) PDGRB(5q31-33), FGFR1(8p11-13) Non-clonal: myeloid/mc dysplasia Simon, et al. J Allergy Clin Immunol 126:45-9, 2010 Organrestricted N/EAE NERDS Benign Complex Cyclical CSS SMCD IBD HIV Sarcoid CHIC2 + KIT + 2
3 CD4 CD8 CD8 CD3 11/9/2011 PDGFRA: JM Domain Truncation Permits Spontaneous Dimerization and Activation -Ligand Inactive Active Effect of imatinib mesilate on peripheral blood Side Effects: Myelosuppression Resolution Transaminases of: Anemia Diarrhea Thrombocytopenia Rash Splenomegaly Edema B12 Muscle cramps Tryptase Mucosal Oligospermia ulcers Fevers, Cardiomyopathy night sweats, 2 fatigue, malignancy myalgias Acute necrotizing myocarditis Stover et al. PNAS 103: , mg imatinib/day Gleich et al. Lancet 359: , 2002 Lymphocytic HES T cell clones or activated T cells TH2 cytokines (IL-5) CD3 - /4 +, CD3 + /4 - /8 -, etc T cells or TCR clonality CD3-4 + CD CD lo CD3 CD7 CD5 CD dim CD3 + 4 dim 8 + CD HES Treatment T Cell Eosinophil Prednisone INF-α ++ + Hydroxyurea +/- + Imatinib* +/- ++ (PDGFRα/β) a-il-5(mepolizumab, reslizumab) - ++ a-cd52(alemtuzumab) + + CD4 Roufosse et al. J Allergy Clin Immunol 126:828-35, 2010 CD4 CD25 *First decrease AEC with glucocorticosteroids (apoptosis) to diminish cardiotoxic effects of necrotic eosinophils. 3
4 HES: Presenting Signs/Symptoms & Organ Involvement Pathophysiology of Eosinophilic Endomyocardial Disease Symptom % Organ % Weakness/fatigue 24 Hematologic 100 Cough 24 Neurologic 64 Dyspnea 16 Skin 56 Myalgia 14 Cardiovascular 54 Angioedema 14 Spleen 46 Rash 12 Pulmonary 40 Fever 12 Liver 32 rhinitis 10 Nose/sinuses 26 Ocular 18 Gastrointestinal 14 Lymph nodes 12 Muscles 12 Mitral regurgitation Organizing thrombus, Endomyocardial fibrosis Endocardial thrombi Ao LA LV Aggregates of eosinophils Myocardial inflammatory infiltration, Aggregates of fibrin + eosinophil granule proteins platelet activation Emboli Tethering of the chorda tendineae Gleich, 2005 Hypereosinophilic Syndrome Neurologic Involvement (64%) Central Nervous System: encephalopathy, behavioral changes, confusion, memory loss, ataxia, upper motor neuron signs, optic neuritis, MRI demyelinating lesions Thromboembolic complications: TIA, CVA Hypereosinophilic Syndrome Hepatobiliary Involvement 38 AAF N/V, fatigue, 20 lbs, abdominal pain, no pruritis, BR 6.1, APase 349, Hb 7.9, AEC 8200, CA , panca - CT ~?CholangioAC Surgical bx planned, HES considered; prednisone 20 mg/d AEC, BR & CA19-9 and all sxs, wt; repeat CT ~ near resolution Peripheral neuropathy: sensory/motor polyneuropathy with paresthesias or numbness Before steroids Reyes et al. Ann Allergy Asthma Immunol 94:25-8, 2005 After steroids x several months 4
5 Eosinophilia-Associated Angioedema Eosinophilia/Angioedema Episodic angioedema + (EAE, Gleich s Syndrome) Non-episodic angioedema + (NEAE) Angioedema Hives Ig Fever Other features Episodic +/- IgM, E + Single episode - No % Weight Pruritis; Oliguria Dermal eosinophils No visceral organs Asian females (20-40 y/o) Painful 3 months duration EAE Songsiridej et al. Ann Int Med 503-6, M 4-5 y hx of recurrent facial angioedema episodes, each lasting several months. Afebrile, erythema and induration, C1in C4 and C3 wnl, ( /mm 3 ); responded to prednisone. NERDS Episodic +/- IgE - Nodules, articular Eosinophilia Rheumatism Dermatitis Swelling H&E a-mbp Dermis NEAE Jang et al. Korean J Int Med 21:275-8, Korean female, edema of hands + lower legs eos in skin bx Treatment of Patients with the Hypereosinophilic Syndrome with Mepolizumab [a-il-5] ClinicalTrials.gov Identifier: NCT ; Supported by GlaxoSmithKline ME Rothenberg, AD Klion, FE Roufosse, JE Kahn, PF Weller, HU Simon, LB Schwartz, LJ Rosenwasser, J Ring, AE Haig, PIH Frewer, JM Parkin, GJ Gleich, Mepolizumab HES Study Group N Engl J Med 358: , 2008 Mild knee arthralgia, afebrile, 2 kg weight, AEC 6300/mm3, IgE 1,423 IU/ml, other labs wnl. Eosinophilia and sxs spontaneously resolved 4 months Non-steroid HES medication washout; prednisone (20-60 mg) run-in and stabilization. 1:1 Randomization Mepolizumab (anti-il-5) 750 mg or placebo iv q4w x 36 w; prednisone taper 5
6 Treatment of Patients with the Hypereosinophilic Syndrome with Mepolizumab [a-il-5] Mepolizumab Case Clinical worsening ~ other HES treatment, prednisone (>60 mg/day), or study withdrawal for any clinical reason AEC <600 8 consec weeks 48 M with -associated gastroenteritis, asthma and pancreatitis causing DM. Prednisone: eos, but DM, HBP & osteoporosis/bone fxs. Failed hydroxyurea, CS-A, aza, mtx and mycophenolate & for 20 y required mg prednisone/d. Mepo (750 mg/month) begun 2001 prednisone mepo to q8-12 wk with respiratory, GI and neurologic sxs, most steroid side-effects, insulin and AEC (<500/μl). Resumed full-time work, walk distance improved from 60 feet to 6 miles and resumed piano playing. No mepo side-effects. Summary of Hypereosinophilic Syndromes 1. Diagnosis: /organ dysfunction 2. Subtypes/presentations: myelocytic, lymphocytic, others 3. Treatment: Glucocorticosteroids, INF-α, hydroxyurea, imatinib, a-il-5 6
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