Sporadic Antihistamine-Resistant Angioedema Potential Pathophysiological Mechanisms

Transcription

1 Sporadic Antihistamine-Resistant Angioedema Potential Pathophysiological Mechanisms Massimo Triggiani, MD, PhD Division of Allergy and Clinical Immunology University of Salerno HAWK Consensus Meeting Gargnano, 1 October 2012

2 Kumar et al Expert Rev Mol Med 2009; 11: 1-19

3 Vasoactive Mediators Secreted by Human Mast Cells Histamine Tryptase Chymase Heparin PGD 2 LTC 4 PAF/AAGPC I-309/CCL1 Secreted PLA 2 MCP/CCL2 MIP-1α/CCL3 SCF IL-8/CXCL8 IL-3 IL-5 VEGF-A IL-6 IL-13 IL-16 IL-18 IL-25 TGF-β TNF-α GM-CSF Triggiani et al. JACI 2009; 24: 558

4 1964 Antigen 1972 Anti-IgE IgE IgE FcεRI FcεRI 1980 Anti-FcεRIα 1990 IgG Anti-IgE Anti-IgG FcεRI IgE FcεRI

5 Receptors on Human Mast Cells and Basophils Mast Cells Basophils Marone et al. Adv Immunol 2005; 88: 97

6 T Helper Cells H 1 H 2 Modulation of Cytokine Release Mast Cells - Basophils H 1 Smooth Muscle Cells Bronchoconstriction Vasodilation Eosinophils H 1 Regulatory T Cells H 1 H 4 Modulation of Suppressor Function Histamine H 4 H 2 Chemotaxis Degranulation Basophils Dendritic cells H 1 H 2 H 3 CD86 Expression IL-6 and TNF-α Release Inhibition of IL-12 Release H 1 H 2 H 3 Macrophages Exocytosis IL-6 and TNF-α Release Inhibition of IL-12 Release Inhibition of histamine release H 1 H 4 Mast Cells Chemotaxis

7 The Histamine Receptor Family H 1 H 2 H 3 H 4 Agonist HTMT Dimaprit Rα-Methylhistamine 4-Methylhistamine Antagonists Desloratadine Levocetirizine Fexofenadine etc. Cimetidine Ranitidine etc. Ciproxifan Tiprolisant Thioperamide (high concentr.) Location Smooth muscle Endothelium CNS, Heart Lung Stomach, Uterus Vascular smooth muscle, Heart CNS CNS, Peripheral Nervous System Endothelium Bone Marrow Lung, Eosinophils, Basophils, Mast Cells CNS? Transduction PLC Ca 2+ Signaling Adenylate Cyclase camp Adenylate Cyclase camp PLC Ca 2+ Signaling

8 H4 Histamine Receptors in Inflammation Walter M et al. Eur j Pharmacol 2011:668,1

9 The Network of Vasoactive Mediators Endothelial Cells Thrombin Platelet-Activating Factor H 1 PAF-R H 1 Bradikynin B 2 Serotonin Plasma Anaphylatoxins (C3a, C5a) Heparin Tryptase Mast Cell- Derived Mediators (histamine, proteases) H 1 H 1 /H 3 VEGF Nerve endings H 1 /H 3 Neurokinins (Substance P, VIP, etc) H 1 TNF-α Macrophages

10 Kinin-Induced Histamine Release from Human Mast Cells 25 μm 50 μm 1μM Cross L.J.M. Inflamm Res 1997; 46: 306

11 Mast Cell-Derived Heparin Induces BK formation Oschatz C et al. Immunity,34, 258,2011

12 Metabolic Pathways of Lipid Mediators cpla 2 /spla 2 COOH Eicosanoids CoAdAT Acetyl-CoA PAF (active) LysoPAF (inactive)

13 Biological Effects of Platelet Activating Factor Activation of platelet aggregation and release reaction Contraction of airway smooth muscle Bronchospasm Increased mucus secretion Bronchial hyperreactivity Vasodilation and increased vascular permeability Wheal-and-flare Angioedema Hypotension Coronary constriction / Reduced coronary blood flow Myocardial dysfunction Arrhythmias Ventricular failure

14 Platelet Activating Factor Induced Wheal-and-Flare

15 Synthesis of 2-Acetylated Phospholipids In Human Inflammatory Cells PAF (ng/10 6 cells) 1 Acyl- PAF (ng/10 6 cells) Mast cells 14 ± 3 22 ± 5 Basophils 3 ± 1 6 ± 2 Endothelial cells 4 ± 1 20 ± 4 Neutrophils 12 ± Eosinophils 8 ± Macrophages 10 ± Triggiani M. et al. J Immunol 1991; 147: 660

16 Antihistamine-Resistant Angioedema Beside histamine, many vasoactive mediators, including leukotrienes, prostaglandins, PAF and bradykinin, may be involved in the pathogenesis of angioedema The role of H3 and H4 histamine receptors in angioedema remains to be determined These mediators often cooperate to enhance and prolong the microvascular response seen in angioedema We have currently limited possibilities to antagonize all mediators

17 Non Hereditary Angioedema without Urticaria Division of Allergy and Clinical Immunology University of Naples Federico II ( ) 14% Food Allergy 7% Contact Hypersensitivity 17% Acquired (Sarcoidosis, SLE, MGUS) 31% Idiopathic 24% Drug-induced (ACE-I, ASA) 7% Other N=85 Triggiani et al., unpublished

18 Angioedema: Differential Diagnosis Allergic (e.g. Anaphylaxis) Bradykinin Mediated (e.g. HAE) Urticaria + - Course Rapid (min) Slow (hours) Duration h h Laryngeal Edema +/- + Bronchospasm Frequent Absent Abdominal Pain Rare Frequent Hypotension + - Treatment Epinephrine Antihistamines Steroids C1 inhibitor Icatibant

19 Therapy

20 Treatment: Beyond Antihistamines Tranexamic acid Cyclosporine (other immunosuppressive agents?) Omalizumab Icatibant

21

22 TRANEXAMIC ACID AND IDIOPATHIC AE Du-Thanh, 2010

23 TREATMENT IN 88 PATIENTS WITH AE WITH No.pts (%) with No.pts (%) with hereditary NORMAL sporadic C1-INH AE NON RESPONSIVE AE TO ANTI- HISTAMINE LTP withta (starting dose of 20 to 40 mg/kg/die split 2 to 3 times daily, with daily maximum 3 gr) Acute treatment with TA (6 gr split 6 times daily) 36 (58) pts with symptoms relief 1 (1.6) pt without symptoms relief 12 (19) pts with symptoms relief 6 pts with symptoms relief 2 pts with symptoms relief 1 AMI Adverse events 1 AMI 1 migraine 1 menstrual cycle delay 1 dyspepsia Icatibant (Firazyr) 30 mg injected subcutaneously in abdominal area - 1 pt with symptoms relief 1 pt with FXII mutation without symptoms relief * - C1-INH plasma derived (Berinert) 10 to 20 UI /kg administred intravenously 1 (1.6) pt with symptoms relief ** 1 pt *** - 1 pt (3U) with symptoms Fresh frozen plasma 2U - relief Missing data 6 pts 3 pts * 2 doses of 30 mg ** 1 attack involving tongue treated with 1000 U with complete symptoms resolution *** 1 attack involving face and tongue treated with 500 U with slow symptoms resolution and 1 attack involving face and abdomen treated with 1000 U with prompt symptoms resolution -

24 Effects of Omalizumab Omalizumab improves early- and late-phase responses to allergen challenge Dentritic cell Omalizumab decreases free-ige Omalizumab complexes IgE B cell Mast cell/basophil Clinical effects Omalizumab decreases allergen dendritic presentation of allergen to T cell T cell Eosinophil Tissue infiltration Omalizumab reduces Th 2 cell mediated production of eosinophils Clinical effects Holgate and Polosa. Lancet 2006

25 Successful treatment of 3 patients with recurrent idiopathic angioedema with Omalizumab To the Editor: Omalizumab is a recombinant humanized monoclonal anti-ige antibody that is US Food and Drug Administration approved for the treatment of moderate-to-severe persistent asthma. Omalizumab also has demonstrable effects on inflammation in other conditions. We report 3 cases of refractory idiopathic angioedema that resolved on treatment with omalizumab. Sands MF et al, J Allergy Clin Immunol 2007: 120, 979

26 Omalizumab in Chronic Urticaria and Recurrent AE Buyutozturk S et al J. Dermatol 2012: 39, 439

27 Angioedema attacks completely ceased immediately after the first injection of omalizumab in patient no. 2, while the symptoms gradually decreased until its disappearance after the fourth dose in patient no. 1.

28 Icatibant and Idiopathic Non-Istaminergic Angioedema Treatment of idiopathic non-histaminergic angioedema with bradikinin B2-receptor antagonist icatibant Del Corso I et al. Ann Allergy Asthma Immunol 2012: 108: 460-1