Terapie Biologiche nelOrticaria Cronica Massimo Triggiani Division - PowerPoint PPT Presentation

Terapie Biologiche nel’Orticaria Cronica Massimo Triggiani Division of Allergy and Clinical Immunology Department of Medicine University of Salerno Firenze, 11 Novembre 2016

Chronic Urticaria/Angioedema Common clinical conditions in which Common clinical conditions in which stereotype clinical pictures are caused by stereotype clinical pictures are caused by heterogeneous mechanisms heterogeneous mechanisms

Classification of Chronic Urticaria Zuberbier T et al, Allergy, 2014 - 69:868-87

Duration of Wheal-and-Flare T = 0 T = 12 h T = 0 T = 12 h < 2 hrs 15 % Acute urtj tjcaria (reactj tjve) < 2 hrs 15 % Acute urtj tjcaria (reactj tjve) 2 - 6 hrs 44 % Drug-induced, spontaneous 2 - 6 hrs 44 % Drug-induced, spontaneous 6 – 12 hrs 33 % Food-induced, physical, autoimmune 6 – 12 hrs 33 % Food-induced, physical, autoimmune > 12 hrs 8 % Urtj tjcarial vasculitj tjs, paraneoplastj tjc > 12 hrs 8 % Urtj tjcarial vasculitj tjs, paraneoplastj tjc

Human MCs express a wide variety of receptors involved in the excessive release of mediators in allergic diseases Fc ε RI Fc γ RII/III KIT WT or mutant BUT:  Actj tjvatj tjon of these IL-9R α CCR3 various receptors does IL-4R α not lead necessarily to CXCR1 release of mediators CXCR3 IFN- γ R α  Several receptors may cooperate to TLR2-7, 9 CXCR4 increase mediator release uPAR Exemple: TLR + Fc ε RI Kinin R CD40L  Actj tjvatj tjng receptors CysLTR 2 H1-4 may not lead to the CysLTR 1 same range of released mediators Exemple: TLR2 vs TLR4

Vasoactive Mediators of Human Mast Cells Vasoactive Mediators of Human Mast Cells Histamine PGD 2 Tryptase LTC 4 Chymase PAF/AAGP Heparin C I-309/CCL1 Secreted PLA 2 MCP/CCL2 MIP-1 α /CCL3 IL-8/CXCL8 SCF IL-3 VEGF-A IL-5 TNF- α IL-6 GM-CSF IL-13 TGF- β IL-16 IL-18 IL-31 Triggiani et al . JACI 2009; 24: 558

Anti-IgE Antigen 1964 1972 IgE IgE Auto- Auto- antigens antigens TPO FcεRI TPO FcεR dsDNA dsDNA I IgG Anti- 1980 1990 Anti-FcεRIα IgE Anti-IgG IgE FcεR I FcεRI

Degranulatjon and mediator release by mast cells/ basophils (immediate hypersensitjvity reactjon) Mast cell maturatjon, survival and cytokine productjon Monocytes/macrophages (allergen independent mechanism) actjvatjon Allergen presentatjon by antjgen presentjng cells (APCs) Actjvatjon of Th2 cells Transport of immune complexes through epithelial cells (early sensitjzatjon to allergens) Actjvatjon, proliferatjon and cytokine release by smooth muscle cells

Treatment Algorithm for CU EAACI/GA 2 LEN/EDF/WAO Zuberbier T et al, Allergy, 2014 - 69:868-87 Zuberbier T et al, Allergy, 2014 - 69:868-87

Interference with IgE-Fc ε RI Axis by Omalizumab Impact on Binds free IgE and down- IL-2, IL-4, Peripheral, sputum T-lymphocytes regulates IgE receptors IL-5 , IL-13 and sub-mucosal and (Fc ε RI) on mast cells, and GM-CSF 1–4 eosinophilia 1 B-lymphocytes 5 basophils and DCs

EXPRESSION OF IgE RECEPTORS EXPRESSION OF IgE RECEPTORS - Omalizumab induces a down regulation of Fc ε RI and Fc ε RII expression - - Omalizumab induces a down regulation of Fc ε RI and Fc ε RII expression - Owen CE, Pharmacology & Therapeutics, 2007, 113, 121-133

Omalizumab Reduces IgE Receptor Expression on Immature Mast Cells Fc ε R α Expression Fc ε R α mRNA Okayama Y et al, Ann Allergy Asthma Immunol 2012: 108, 188-194

Omalizumab Reduces IgE Production Omalizumab Reduces IgE Production Frequency • In omalizumab-treated patients, IgE production 0.04 rate decreased with time Omalizumab Placebo 0.03 0.02 0.01 0 –100 –50 0 50 100 150 Rate of change in IgE production (% per year) Lowe P, et al. J Allergy Clin Immunol 2009

Chronic Urtj tjcaria in HCV Hepatj tjtj tjs

IgE Fc ε RI V H 3 Dimer Basophils Basophils Protein Fv Protein Fv and and Mast Cells Mast Cells 175 kDa V H 3 Fc ε RI IgE

Superallergen-Mediated Activation of Mast Cells Superallergen-Mediated Activation of Mast Cells and Basophils in CSU and Basophils in CSU Viral Hepatitis Staphylococcus aureus Protein Fv Protein A IgE V H 3 + V H 3 Liver K light chains IgE V H 3 + gp120 Protein L Fc ε RI + Cell HIV-1 Peptostreptococcus magnus Activation Activation Clin. Exp. Allergy Rev. 4: 64, 2004

CU Response to Omalizuma Kaplan A et al JACI 2015 Kaplan A et al JACI 2015

Effect of Omalizumab on Angioedema X-ACT Study Staubach P et al. Allergy 2016:71: 1135-44 Staubach P et al. Allergy 2016:71: 1135-44

Response to Omalizumab is Rapid Metz M et al. J Dermatol Sci 2014: 73:57

UAS-7 Score

Blood Eosinophil Count

Erythrocyte Sedimentatjon Rate

C-Reactjve Protein

Key Questions and Answers on Omalizumab in CU Gimenez-Arnau AM et al. JEADV 2016: 30 (suppl 5) 25-32 Gimenez-Arnau AM et al. JEADV 2016: 30 (suppl 5) 25-32

Key Questions and Answers on Omalizumab in CU Gimenez-Arnau AM et al. JEADV 2016: 30 (suppl 5) 25-32 Gimenez-Arnau AM et al. JEADV 2016: 30 (suppl 5) 25-32

Conclusions • Omalizumab (anti-IgE) is a highly effective treatment for chronic urticaria unresponsive to antihistamines • Most patients have complete response to omalizumab including those resistant to corticosteroids and other immunosuppressive agents • Response to omalizumab in many patients is very rapid and independent from serum IgE levels • Further understanding of the mechanisms of action of omalizumab in chronic urticaria will optimize treatment strategies but will also provide important information on the pathogenesis of this common and invalidating disease

Division of Allergy and Clinical Immunology University of Salerno Italy Roberta Parente Chiara Cardamone Giulia De Feo Andrea Bezzeccheri Cristina Mascolo Tommaso Bucci mtriggiani@unisa.it

Dermographism Dermographism Detectable in 50% of CSU Detectable in 50% of CSU Pressure-dependent Pressure-dependent (threshold as indicator of (threshold as indicator of CSU severity ?) CSU severity ?) Can be transient Can be transient Never associated with pruritus Never associated with pruritus Highly responsive to antihistami Highly responsive to antihistami (even when urticaria is NOT) (even when urticaria is NOT) Duration correlates with that of Duration correlates with that of CSU lesions CSU lesions

UAS-7 tjme to relapse

Response to Treatments in Patients with Chronic Idiopathic Urticaria 21,5% 10,8% 67,7% Responsive to anti-H 1 Responsive to glucocorticoids Non Responsive Triggiani et al., submitted

Omalizumab Omalizumab Cromones Syk Inhibitors TK Inhibitors PDE Inhibitors ß 2 - agonists mTOR inhibitors Glucocorticoids Modified from Metcalfe et al. J. Allergy Clin. Immunol. 124: 639, 2009

Omalizumab in CSU Immunomodulatj tjon? IgE bound X Y to FcεRII IL-5; GM-CSF Eos Y Free IgE Y Y X Y Y Y X Y Y Y V Y FcεRII Y X Y Y Y Y V Y V V Fc ε RI Y Y Y APC Y Y T B Mast Y Y Y FcεRI X Y IL-4, IL-13 Bas X IgE bound FcεRII PLT to FcεRII Reductjon in circulatjng IgE; Reductjon of FcεRI RII; Reduced actjvatjon of basophils and mast cells; Reduced productjon of pro-infmammatory mediators; Reduced productjon and actjvatoin of eosinophils by T lymphocyted and mastcells, etc. Therapeutjc antj-infmammatory actjvity Maurer et al. NEJM 2013;368:924–35 GM-CSF = granulocyte-monocyte colony stjmulatjng factor Kaplan et al. J Allergy Clin Immunol 2013;132:101–9 IL = interleukin.

Metcalfe et al. J. Allergy Clin. Immunol. 124: 639, 2009

Cytokinergic IgE and Mast Cell Actj tjvatj tjon Bax HJ et al. Frontiers Immunol 2012: 3:1

Cytokinergic Crosslinking of IgE-Fc ε RI Complexes Bax HJ et al. Frontiers Immunol 2012: 3:1

CSU – Response to Treatments Antj tj-H1/Ketotj tjfen (KF) n= 69 2 weeks Response Evaluatj tjon (UAS7) Yes = 48 No = 21 Contj tjnuous Treatment Updosing antj tj-H1 (3 months) Response Evaluatj tjon (UAS7) Yes = 29 No = 16 Yes = 5 No = 19 Updosing antj tj-H1 (15) Montelukast (8) Ciclosporin (3) Ciclosporin (4) Omalizumab (1) Glucocortj tjcoid (2) Omalizumab (1) Colchicine (1)