Terapie Biologiche nelOrticaria Cronica Massimo Triggiani Division - - PowerPoint PPT Presentation

Massimo Triggiani

Division of Allergy and Clinical Immunology Department of Medicine University of Salerno

Terapie Biologiche nel’Orticaria Cronica

Firenze, 11 Novembre 2016

Chronic Urticaria/Angioedema

Common clinical conditions in which stereotype clinical pictures are caused by heterogeneous mechanisms Common clinical conditions in which stereotype clinical pictures are caused by heterogeneous mechanisms

Zuberbier T et al, Allergy, 2014 - 69:868-87

Classification of Chronic Urticaria

Duration of Wheal-and-Flare

T = 0 T = 0 T = 12 h T = 12 h

< 2 hrs 15 % Acute urtj tjcaria (reactj tjve) 2 - 6 hrs 44 % Drug-induced, spontaneous 6 – 12 hrs 33 % Food-induced, physical, autoimmune > 12 hrs 8 % Urtj tjcarial vasculitj tjs, paraneoplastj tjc < 2 hrs 15 % Acute urtj tjcaria (reactj tjve) 2 - 6 hrs 44 % Drug-induced, spontaneous 6 – 12 hrs 33 % Food-induced, physical, autoimmune > 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

FcεRI FcγRII/III CCR3 CXCR1 CXCR3 CXCR4 uPAR

TLR2-7, 9

KIT WT or mutant CysLTR1 Kinin R H1-4 CysLTR2 IFN-γRα IL-4Rα IL-9Rα CD40L BUT:

• Actj

tjvatj tjon of these various receptors does not lead necessarily to release of mediators

• Several receptors

may cooperate to increase mediator release Exemple: TLR + FcεRI

• Actj

tjvatj tjng receptors may not lead to the same range of released mediators Exemple: TLR2 vs TLR4

Vasoactive Mediators of Human Mast Cells Vasoactive Mediators of Human Mast Cells

Histamine Heparin Tryptase Chymase Secreted PLA2

IL-13 IL-16 IL-31 TNF-α GM-CSF TGF-β IL-6 IL-5 SCF IL-3 VEGF-A IL-18 MCP/CCL2 MIP-1α/CCL3 I-309/CCL1 LTC4 PGD2 PAF/AAGP C IL-8/CXCL8

Triggiani et al. JACI 2009; 24: 558

1964

FcεR I IgE Antigen FcεRI Anti-FcεRIα

1980

Anti-IgE IgE FcεRI

1972

FcεR I IgE IgG Anti- IgE Anti-IgG

1990

Auto- antigens TPO dsDNA Auto- antigens TPO dsDNA

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

Treatment Algorithm for CU EAACI/GA2LEN/EDF/WAO

Zuberbier T et al, Allergy, 2014 - 69:868-87 Zuberbier T et al, Allergy, 2014 - 69:868-87

Interference with IgE-FcεRI Axis by Omalizumab

Peripheral, sputum and sub-mucosal eosinophilia1 Impact on T-lymphocytes and B-lymphocytes5 IL-2, IL-4, IL-5, IL-13 and GM-CSF1–4 Binds free IgE and down- regulates IgE receptors (FcεRI) on mast cells, basophils and DCs

Owen CE, Pharmacology & Therapeutics, 2007, 113, 121-133

EXPRESSION OF IgE RECEPTORS

• Omalizumab induces a down regulation of FcεRI and FcεRII expression -

EXPRESSION OF IgE RECEPTORS

• Omalizumab induces a down regulation of FcεRI and FcεRII expression -

Okayama Y et al, Ann Allergy Asthma Immunol 2012: 108, 188-194

FcεRα Expression FcεRα mRNA Omalizumab Reduces IgE Receptor Expression on Immature Mast Cells

Omalizumab Reduces IgE Production Omalizumab Reduces IgE Production

• In omalizumab-treated

patients, IgE production rate decreased with time

Lowe P, et al. J Allergy Clin Immunol 2009 Frequency Rate of change in IgE production (% per year) –100 –50 50 100 150 0.04 0.03 0.02 0.01 Omalizumab Placebo

Chronic Urtj tjcaria in HCV Hepatj tjtj tjs

175 kDa Dimer

Basophils Basophils and and Mast Cells Mast Cells

FcεRI FcεRI IgE

VH3 VH3

IgE

Protein Fv Protein Fv

FcεRI+ Cell

Viral Hepatitis Liver Protein Fv

Activation Activation

Staphylococcus aureus

Superallergen-Mediated Activation of Mast Cells Superallergen-Mediated Activation of Mast Cells and Basophils in CSU and Basophils in CSU

Protein A IgE VH3+ gp120 HIV-1 Peptostreptococcus magnus Protein L VH3 K light chains IgE VH3+

• 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
• malizumab 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 Andrea Bezzeccheri Chiara Cardamone Cristina Mascolo Giulia De Feo Tommaso Bucci

mtriggiani@unisa.it

Dermographism Dermographism

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

UAS-7 tjme to relapse

Response to Treatments in Patients with Chronic Idiopathic Urticaria

Responsive to glucocorticoids Non Responsive Responsive to anti-H1

67,7% 10,8% 21,5%

Triggiani et al., submitted

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

Cromones Syk Inhibitors TK Inhibitors PDE Inhibitors ß2 - agonists mTOR inhibitors Glucocorticoids

Omalizumab Omalizumab

Omalizumab in CSU Immunomodulatj tjon?

APC

T B

Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y

Mast Eos

IL-5; GM-CSF

IL-4, IL-13

V V Y Y Fc ε RI Free IgE Y IgE bound to FcεRII Y IgE bound 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

• f eosinophils by T lymphocyted and mastcells, etc.

Therapeutjc antj-infmammatory actjvity

V V Y Y FcεRII

X X

X

X

Bas PLT

FcεRII FcεRI

GM-CSF = granulocyte-monocyte colony stjmulatjng factor IL = interleukin.

X X

Maurer et al. NEJM 2013;368:924–35 Kaplan et al. J Allergy Clin Immunol 2013;132:101–9

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-FcεRI Complexes

Bax HJ et al. Frontiers Immunol 2012: 3:1

CSU – Response to Treatments

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

Ulteriori osservazioni

• In 5 pazientj su 7 (71%), il tratuamento con omalizumab ha permesso di

raggiungere il pieno risultato (UAS-7=0) già dopo la prima somministrazione (in 4 casi entro una settjmana dalla I somminsitrazione, in un altro caso dopo 4 settjmane). Nei restantj 2 pazientj non è mai stato raggiunto l'UAS-7 :0, e a parte la caduta iniziale, il punteggio UAS-7 s'è mantenuto pressochè costante, senza che si sia verifjcata una riduzione sensibile

• Tuttj i pazientj (anche i NR) mostrano un miglioramento dell'UAS-7 nelle prime

somminstrazioni (efgetuo placebo?)

• Dopo 2 e dopo 3 somministrazioni i due pazientj non responsivi si separano dai

responsivi

• Delle due pazientj non responsive, una aveva angioedema concomitante e l'altra

no; una aveva C3 e C4 consumatj, l'altra normali; una aveva il test al siero autologo positjvo e l'altra no; una dermografjsmo + e l'altra negatjvo; test ortjcaria fjsica una positjvo e l'altra negatjvo (quindi la presenza o meno di angioedema, il consumo o meno di complemento , la positjvità o meno del TSA/TOF, la positjvità al dermografjsmo non sembrano rilevantj nel prevedere la responsività)

Contjnuazione

• I diametri dei prick all'istamina, così come la positjvità del dermografjsmo

non si modifjcano sensibilmente durante il tratuamento con omalizumab in nessuno dei due gruppi.

• Entrambe le pazientj non responsive partjvano da bassi livelli di IgE (le IgE

di partenza mediamente più alte nei responsivi rispetuo ai non responsivi (169 vs. 23) e avevano eosinofjli a bassa concentrazione (mediana: 1)

• In totale 4 pazientj (2 resp e 2 non resp) hanno efgetuuato terapia con

Ciclosporina, in 4 pazientj sospesa per ineffjcacia (solo in un paziente è stata sospesa per insorgenza di efgettj collaterali): anche la pregressa responsività alla Ciclosporina non sembra signifjcatjva nel predire la successiva risposta all'omalizumab in quanto nei pazientj in cui è stata sospesa per ineffjcacia il 50% ha risposto e il 50% no

• CONCLUSIONI: i livelli di IgE di partenza, di eosinofjli, di VES/PCR più bassi

sembrano deporre verso una NON RESPONSIVITA' all'omalizumab. Le prime 3 somministrazioni sembrano cruciali nell'identjfjcare i pazientj che perdono risposta, passata la transitoria fase di caduta iniziale.