Diego Peroni Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione Diego Peroni U.O.S. Allergologia Pediatrica Azienda Ospedaliera Universitaria Integrata Verona diego.peroni@univr.it

Orticaria cronica- Angioedema Orticaria associata o meno a angioedema che dura per più di 6-8 settimane con sintomatologia quotidiana. Orticaria Angioedema Pomfo: lesione cutanea evanescente, con centro edematoso, pallido e margini iperemici. Interessa gli strati superficiali del derma. Edema per stravaso capillare dai vasi del derma profondo o del sottocute Istamina LT C5a

Orticaria cronica- Angioedema Orticaria associata o meno a angioedema che dura per più di 6-8 settimane con sintomatologia quotidiana. 80% dei casi di orticaria cronica presenta lesioni da orticaria associate a angioedema. Orticaria Angioedema Pomfo: lesione cutanea evanescente, con centro edematoso, pallido e margini iperemici. Interessa gli strati superficiali del derma. Edema per stravaso capillare dai vasi del derma profondo o del sottocute Istamina LT C5a

Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione L’orticaria acuta diego.peroni@univr.it 4

Una causa evidenziata in meno del 50% dei casi: Almeno un episodio di orticaria acuta nella vita con prevalenza del 15-20% nella popolazione generale Una causa evidenziata in meno del 50% dei casi: 40% postinfettiva 10% FANS 1% alimenti Un alimento è sospettato nel 63% dei casi, ma viene dimostrato solo nell’1%

November 2012

Terapia orticaria EAACI/GA2LEN/EDF/WAO guideline: management of urticaria. T. Zuberbier, R. Asero et al. Allergy 2009: 64: 1417–1426 8

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Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione L’orticaria acuta L’orticaria cronica La diagnosi diego.peroni@univr.it

Orticaria cronica Orticaria associata a angioedema che dura da più di 6-8 settimane …. Orticaria Angioedema Pomfo: lesione cutanea evanescente, con centro edematoso, pallido e margini iperemici. Interessa gli strati superficiali del derma. Edema per stravaso capillare dai vasi del derma profondo o del sottocute Istamina LT C5a

Orticaria Cronica: Diagnosi Eziologica 1° valutazione: Anamnesi Esame obiettivo (se presenti valutare le lesioni cutanee) Somministrare questionario e consegnare diario giornaliero Test per dermografismo Emocromo, VES, PCR. Prescrivere antistaminici Informare genitori del carattere benigno della malattia Informare i genitori che nella maggior parte dei casi la causa rimane ignota Laboratory tests and identified diagnoses in patients with physical and chronic urticaria and angioedema: A systematic review Martina M. et al. J Am Acad Dermatol 2003

Questionario - Orticaria 1. Quando e’iniziato 2. Frequenza e durata dei ponfi 3. Variazioni nel corso del giorno 4. Capita in occasione di weekend, vacanze, e soggiorni all’estero 5. Forma, diametro, e distribuzione dei ponfi 6. Angioedema associato 7. Sintomi soggettivi associati, come dolore 8. Storia familiare e/o personale di atopia, orticaria 9. Precedenti o in corso allergie, infezioni, patologie interne, o altre possibili cause 10. Patologie Psicosomatiche e/o psichiatriche 11. Trattamenti chirurgici ed eventi durante l’intervento 12. Problemi gastrici/intestinali (feci, flatulenza) 13. Induzione da agenti fisici o da sforzo 14. Uso di farmaci (NSAIDs, iniezioni, vaccinazioni, ACE inibitori, ormoni, lassativi, gocce per orecchie e occhi e rimedi alternativi) 15. Correlazione con l’ingestione di alimenti 16. Relazione con il ciclo menstruale 17. Abitudine al fumo 18. Tipo di lavoro 19. Hobby 20. Stress (eustress e distress) 21. Qualita’ della vita in relazione all’orticaria ed impatto and emotivo 22. Terapia precedente e risposta alla terapia EAACI/GA2LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria. T. Zuberbier, R. Asero et al. Allergy 2009: 64: 1417–1426

DIARIO - ORTICARIA Giorno Terapia in corso Assunzione di cibi Assunzione di farmaci Prurito Dolore Altri sintomi (febbre, g.e, artralgia) Estensione Durata Luogo e situazione (sport, doccia ..) Data e ora Nome del paziente ……………………... Settimana dal…………. al ……………..

BSACI guidelines for the management of chronic urticaria and angio-oedema. R. J. Powell. CEA, 2007; 37, 631–650.

Orticaria cronica Diagnosi eziologica 2° valutazione: Valutazione andamento clinico (visione diario) Esame obiettivo Esecuzione esami diagnostici di 2° livello in base ai dati raccolti. Eventuale sospensione di farmaci considerati triggers. Prescrivere antistaminici (eventuale progressione negli step terapeutici). Laboratory tests and identified diagnoses in patients with physical and chronic urticaria and angioedema: A systematic review Martina M. J Am Acad Dermatol 2003

EAACI/GA2LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria Zuberbier T, Allergy 2009; 64: 1417 Recommended diagnostic tests in frequent urticaria subtypes

Esami diagnostici di 2° livello – BSACI guidelines. CEA 2007 Eziologia Che esami Idiopatica (40-50%) Indagini negative Autoimmune ANA, ab antitiroide, ASST Da stimolo fisico Challenge con lo stimolo appropriato Da farmaci Sospensione (beneficio settimane-mesi) Infezioni Sierologie in base alla storia clinica Allergia SPTs, ImmunoCAP Deficit C1 esterasi-inibitore C4, C1 inibitore (Ag., Funz.) Vasculite ANCA, ANA, C3, Ig, sierologie epatite, funzionalita’ epatica e renale, biopsia cutanea Pat. linfoproliferativa Paraproteine Additivi alimentari Esclusione e reintroduzione

..ma non dimentichiamo altre cause di Orticaria…. Pseudoallergeni (conservanti, coloranti, additivi). Infezione da Helicobacter Pylori. Infezioni parassitarie. Infezioni delle vie urinarie. Celiachia. Manifestazione iniziale di malattie reumatologiche sistemiche (JRA, SLE). L’ OC rappresenta spesso il sintomo di esordio. BSACI guidelines for the management of chronic urticaria and angio-oedema R. J. Powell. CEA 2007; 37, 631–650.

Patogenesi di asma e CU esacerbati da FANS FANS e COX 1 inibitori Asma Urticaria angioedema Cutaneous Reactions to Aspirin and Nonsteroidal Antiinflammatory Drugs Mario Sánchez-Borges, Clinical Reviews in Allergy & Immunology Volume 24, 2003

Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione L’orticaria acuta L’orticaria cronica La diagnosi Le nuove evidenze diego.peroni@univr.it

Activation of blood coagulation in chronic urticaria: pathophysiological and clinical implications Cugno Intern Emerg Med; 2010, 5:97

Cugno Intern Emerg Med; 2010, 5:97 Activation of blood coagulation in chronic urticaria: pathophysiological and clinical implications Cugno Intern Emerg Med; 2010, 5:97 Mechanisms of eosinophil and mast cell activation in chronic urticaria (CU).

Cugno Intern Emerg Med; 2010, 5:97 Activation of blood coagulation in chronic urticaria: pathophysiological and clinical implications Cugno Intern Emerg Med; 2010, 5:97 Mechanisms of eosinophil and mast cell activation in chronic urticaria (CU). Mast cells release histamine and other inflammatory mediators after stimulation by autoantibodies directed against the high-affinity IgE receptor (FceRI) and IgE, complement anaphylatoxin C5a, eosinophil-derived major basic protein (MBP) and possibly other molecules

Presenza di IgG e IgM anti IgE Pathogenesis of chronic urticaria A. P. Kaplan Clin Exp All, 2009, 39, 777 Presenza di IgG e IgM anti IgE o anti recettore IgE con attività istamino liberatrice sulle mast cells nel 40-60% dei pazienti con orticaria cronica.

Cugno Intern Emerg Med; 2010, 5:97 Activation of blood coagulation in chronic urticaria: pathophysiological and clinical implications Cugno Intern Emerg Med; 2010, 5:97 Mechanisms of eosinophil and mast cell activation in chronic urticaria (CU). Eosinophils are activated by autoantibodies directed against the low-affinity IgE receptor (FceRII) and potentially by other factors, release MBP and express tissue factor which in turn activates the coagulation cascade (factors VII, X, V and prothrombin) leading to thrombin generation.

D-dimer in CU patients with Thrombin generation is demonstrated in CU patients by the increased plasma levels of the fragment F1+2 released from prothrombin after its activation. Finally, fibrin degradation is documented by elevated plasma levels of the fibrin fragment D-dimer in CU patients with active disease Activation of blood coagulation in chronic urticaria: pathophysiological and clinical implications Cugno Intern Emerg Med; 2010, 5:97 Mechanisms of eosinophil and mast cell activation in chronic urticaria (CU). Eosinophils are activated by autoantibodies directed against the low-affinity IgE receptor (FceRII) and potentially by other factors, release MBP and express tissue factor which in turn activates the coagulation cascade (factors VII, X, V and prothrombin) leading to thrombin generation.

Effetto della trombina Vasodilatazione Trombina Attivazione diretta di C5a bypassando C3 Produzione di mediatori infiammatori Attivazione diretta degranulazione mastocitaria

Pathogenesis of chronic urticaria A. P. Kaplan Clin Exp All, 2009, 39, 777 ASST - Autologous Serum Skin Test - Circa il 50% dei pazienti con Orticaria cronica idiopatica presenta ASST + ma: In circa il 50% non c’ è corrispondenza tra test in vivo e in vitro; Decomplementazione e deplezione di IgG dal siero non riducono la capacità di indurre reazione in vivo; Il 50% delle orticarie idiopatiche rimane comunque inspiegato.

Pathogenesis of chronic urticaria A. P. Kaplan Clin Exp All, 2009, 39, 777 ASST - Autologous Serum Skin Test - Circa il 50% dei pazienti con Orticaria cronica idiopatica presente ASST + ma: In circa il 50% non c’ è corrispondenza tra test in vivo e in vitro; Decomplementazione e deplezione di IgG dal siero non riducono la capacità di indurre reazione in vivo; Il 50% delle orticarie idiopatiche rimane comunque inspiegato. Altri fattori istaminoliberatori potrebbero essere implicati nella patogenesi della malattia.

Orticaria cronica, ASST, APST e HRA APST positivo nel 75-85% dei casi ASST positivo nel 50-60% dei casi HRA positivo nel 25-30% dei casi

Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione L’orticaria acuta L’orticaria cronica La diagnosi Le nuove evidenze La terapia

Terapia orticaria cronica EAACI/GA2LEN/EDF/WAO guideline: management of urticaria. T. Zuberbier, R. Asero et al. Allergy 2009: 64: 1417–1426

UAS-Score How to assess disease activity in patients with chronic urticaria? A. Młynek et al. Allergy 2008: 63: 777–780

EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria. Konstantinou GN Allergy 2013 Functional autoantibodies in chronic urticaria (CU) patient sera have been demonstrated against IgE and FcεRIα by basophil and mast cell histamine release assays and by basophil activation assays Approximately 25% of CU patients have a positive basophil histamine release assay and show autoreactivity (a positive autologous serum skin test), whereas 50% are negative regarding both. Functionality of CU sera appears to be complement dependent on mast cells but not exclusively on basophils. Basophil activation by CU sera is predominantly restricted to IgG1 and IgG3 subclasses.

Circumstantial evidence for CU being an autoimmune disease comes from EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria. Konstantinou GN Allergy 2013 Circumstantial evidence for CU being an autoimmune disease comes from an observed association with other autoimmune diseases, a strong association between serum functionality and HLA-DR4 haplotype and the good response of CU patients to immunotherapies

Chronic urticaria and autoimmunity: Associations found in a large population study Confino-Cohen, JACI 2012;129:1307 In patients with CU OR for 30 – 25 – 20 – 15 – 10 – 05 – 12,778 patients with CU during 17 years in a large health maintenance organization. A control group of 10,714 patients who had no CU. 28.8 17.3 13.2 6% Hypo- thyroidism Hyper-thyroidism Rheumatoid arthritis

Type I diabetes mellitus Chronic urticaria and autoimmunity: Associations found in a large population study Confino-Cohen, JACI 2012;129:1307 In patients with CU OR for 30 – 25 – 20 – 15 – 10 – 05 – 12,778 patients with CU during 17 years in a large health maintenance organization. A control group of 10,714 patients who had no CU. 26.9 15.2 14.6 7.7 6% Type I diabetes mellitus Sjögren syndrome Celiac disease Systemic LE

Konstantinou G. N, Allergy 2013;68:27-36 EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria Konstantinou G. N, Allergy 2013;68:27-36 Chronic urticaria (CU). Approximately 25% of CU patients have a positive basophil histamine release assay and show autoreactivity (a positive autologous serum skin test), whereas 50% are negative regarding both. Basophil activation by CU sera is predominantly restricted to IgG1 and IgG3 subclasses. Circumstantial evidence for CU being an autoimmune disease comes from an observed association with other autoimmune diseases, a strong association between serum functionality and HLA-DR4 haplotype and the good response of CU patients to immunotherapies.

Konstantinou G. N, Allergy 2013;68:27-36 EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria Konstantinou G. N, Allergy 2013;68:27-36

How not to miss autoinflammatory diseases masquerading as urticaria Krause K, Allergy 2012;67:1465-1474

Prospettive terapeutiche Eparina si è dimostrata efficace nel trattamento dell’ O.C TAO (warfarin) migliora i sintomi di pazienti con O.C non responsivi all’ antistaminico Agenti antifibrinolitici (Ac. Tranaxemico) determinano una buona risposta clinica nell’ O.C. EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria. Konstantinou GN Allergy 2013

Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione L’orticaria acuta L’orticaria cronica La diagnosi Le nuove evidenze Il caso clinico

2 mesi di sintomi continui. APR: Otiti ricorrenti; Bronchiti asmatiformi ricorrenti; Autismo. P.P 5 aa e 6 mesi Persistenza del quadro: 10/02/2012: PS VR. MT dx iperemica e bombata: Deltacortene 2.5 mg/die Aerius + Fenistil Singulair Orelox (OM persistente). 20/12/2011 Otite  Amoxicillina  comparsa di rash orticarioide  Cetirizina 0.25 mg/kg + Bentelan 4 mg/die DH allergologia 20/02/2012 Peggioramento orticaria  PS a BZ: Deltacortene 15 mg/die Peggioramento  PS BZ: Augmentin Zinnat; Zirtec  Aerius + Fenistil la sera Ancora deltacortene 2.5 mg Totale: 2 mesi di sintomi continui. 2 mesi di CSO; 8 visite specialistiche; 4 Abt diverse. Visita allergologica BZ: Controllo esami ematici: TAS 329IU/ml, resto normale. Allergia agli acari. Scalo deltacortene a 5 mg  2.5 mg/die + Augmentin (MT iperemiche + TAS elevato). Profilassi ambientale. 2 visite dermatologiche BZ  dieta bianca senza nessun beneficio

diego.peroni@univr.it DH allergologia 20/02/2012 APST + Immunoglobuline: nella norma; Sierologie HBV, HCV, EBV, Parvovirus B19: nella norma; Ricerca parassiti fecali: neg; Ab antigliadina anti TG: neg; Ricerca HP Pylori nelle feci: neg. D-dimero: 1.2 mg/l . diego.peroni@univr.it

Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione L’angioedema I meccanismi diego.peroni@univr.it 48

BSACI guidelines for the management of chronic urticaria and angio-oedema. R. J. Powell. CEA, 2007; 37, 631–650. 49

Hereditary angio-oedema. Longhurst H. Lancet 2012; 379:474 Angio-oedema of hand Capsule endoscopy during abdominal attack Erythema marginatum on anterior chest wall 50

C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Cugno M, Trends in Molecular Medicine, 2009; 15: 69 Simplified representation of the kinin system. Bradykinin is generated through the cleavage of high molecular weight kininogen (HK) by plasma kallikrein during contact-system activation The contact system (green box) consists of the substrate HK and the two zymogens prekallikrein and factor XII (FXII), which activate each other to form the enzymes kallikrein and activated factor XII (FXIIa), respectively. The cleavage of HK enables the release of bradykinin, which is located inside the HK molecule, and other breakdown products (cleaved HK). Bradykinin release is facilitated by the presence of plasmin. The most important inhibitor of the contact system is C1- INH, which inactivates kallikrein and FXIIa. Tissue kallikrein cleaves low molecular weight kininogen (LK), generating kallidin, which is converted to bradykinin by aminopeptidases. The physiological inhibitor of tissue kallikrein is kallistatin. Tissue kallikrein activates prorenin to rennin, which, in turn, activates angiotensinogen to angiotensin I (purple box). Bradykinin is degraded by peptidases, such as human kininase I, also called carboxypeptidase N, and kininase II, also called angiotensinconverting enzyme (ACE). Other important kininases are aminopeptidase P and neutral endopeptidase. kininase II (i.e. ACE) not only degrades bradykinin but also activates angiotensin I to angiotensin II. 51

C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Cugno M, Trends in Molecular Medicine, 2009; 15: 69 The contact system (green box) consists of the substrate HK (high MW kininogen) and the two zymogens prekallikrein and factor XII (FXII), which activate each other to form the enzymes kallikrein and activated factor XII (FXIIa), respectively. The cleavage of HK enables the release of bradykinin, which is located inside the HK molecule, and other breakdown products (cleaved HK). The contact system (green box) consists of the substrate HK and the two zymogens prekallikrein and factor XII (FXII), which activate each other to form the enzymes kallikrein and activated factor XII (FXIIa), respectively. The cleavage of HK enables the release of bradykinin, which is located inside the HK molecule, and other breakdown products (cleaved HK). Bradykinin release is facilitated by the presence of plasmin. The most important inhibitor of the contact system is C1- INH, which inactivates kallikrein and FXIIa. Tissue kallikrein cleaves low molecular weight kininogen (LK), generating kallidin, which is converted to bradykinin by aminopeptidases. The physiological inhibitor of tissue kallikrein is kallistatin. Tissue kallikrein activates prorenin to rennin, which, in turn, activates angiotensinogen to angiotensin I (purple box). Bradykinin is degraded by peptidases, such as human kininase I, also called carboxypeptidase N, and kininase II, also called angiotensinconverting enzyme (ACE). Other important kininases are aminopeptidase P and neutral endopeptidase. kininase II (i.e. ACE) not only degrades bradykinin but also activates angiotensin I to angiotensin II. 52

C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Cugno M, Trends in Molecular Medicine, 2009; 15: 69 The most important inhibitor of the contact system is C1-INH, which inactivates kallikrein and FXIIa. Bradykinin is degraded by peptidases, such as human kininase I, also called carboxypeptidase N, and kininase II, also called angiotensinconverting enzyme (ACE). The contact system (green box) consists of the substrate HK and the two zymogens prekallikrein and factor XII (FXII), which activate each other to form the enzymes kallikrein and activated factor XII (FXIIa), respectively. The cleavage of HK enables the release of bradykinin, which is located inside the HK molecule, and other breakdown products (cleaved HK). Bradykinin release is facilitated by the presence of plasmin. The most important inhibitor of the contact system is C1- INH, which inactivates kallikrein and FXIIa. Tissue kallikrein cleaves low molecular weight kininogen (LK), generating kallidin, which is converted to bradykinin by aminopeptidases. The physiological inhibitor of tissue kallikrein is kallistatin. Tissue kallikrein activates prorenin to rennin, which, in turn, activates angiotensinogen to angiotensin I (purple box). Bradykinin is degraded by peptidases, such as human kininase I, also called carboxypeptidase N, and kininase II, also called angiotensinconverting enzyme (ACE). Other important kininases are aminopeptidase P and neutral endopeptidase. kininase II (i.e. ACE) not only degrades bradykinin but also activates angiotensin I to angiotensin II. 53

C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Cugno M, Trends in Molecular Medicine, 2009; 15: 69 Representation of the pathogenesis of angioedema due to C1-INH deficiency In HAE, the deficiency of C1-INH is due to a mutation in the C1-INH gene, which impairs C1-INH synthesis or function. In AAE, C1-INH deficiency is due to the cleavage of C1-INH by autoantibodies or to its consumption by neoplastic, mainly lymphoproliferative, tissue. 54

reduction of its plasma level. C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Cugno M, Trends in Molecular Medicine, 2009; 15: 69 Representation of the pathogenesis of angioedema due to C1-INH deficiency Reduced C1-INH plasma levels result in hyperactivation of the classical complement pathway with increased consumption of C1-INH and further reduction of its plasma level. 55

Criteria for diagnosis of hereditary angio-oedema Hereditary angio-oedema. Longhurst H. Lancet 2012; 379:474 Criteria for diagnosis of hereditary angio-oedema 56

Type III hereditary angioedema: defined, but not understood Type III hereditary angioedema: defined, but not understood. Kaplan, Ann Allergy Asthma Immunol 2012;109:153 Type III hereditary angioedema (HAE) is a familial form of angioedema in which complement C4 and C1 inhibitor (C1 INH) protein and function are normal. Most patients are women, although an occasional male is identified, and a close association with estrogen as a precipitant of attacks of angioedema is seen (contraception, postmenopausal symptom control). Like types I and II HAE, angioedema is recurrent, it is not associated with urticaria, and it is unresponsive to antihistamines or corticosteroids. 57

We do not have a test that can be used to make the diagnosis. Type III hereditary angioedema: defined, but not understood. Kaplan, Ann Allergy Asthma Immunol 2012;109:153 Type III hereditary angioedema (HAE) is a familial form of angioedema in which complement C4 and C1 inhibitor (C1 INH) protein and function are normal. Most patients are women, although an occasional male is identified, and a close association with estrogen as a precipitant of attacks of angioedema is seen (contraception, postmenopausal symptom control). Like types I and II HAE, angioedema is recurrent, it is not associated with urticaria, and it is unresponsive to antihistamines or corticosteroids. We do not have a test that can be used to make the diagnosis. 58

Overproduction of bradykinin is assumed, but not proven. Type III hereditary angioedema: defined, but not understood. Kaplan, Ann Allergy Asthma Immunol 2012;109:153 Type III hereditary angioedema (HAE) is a familial form of angioedema in which complement C4 and C1 inhibitor (C1 INH) protein and function are normal. Most patients are women, although an occasional male is identified, and a close association with estrogen as a precipitant of attacks of angioedema is seen (contraception, postmenopausal symptom control). Like types I and II HAE, angioedema is recurrent, it is not associated with urticaria, and it is unresponsive to antihistamines or corticosteroids. Overproduction of bradykinin is assumed, but not proven. 59

Type III hereditary angioedema: defined, but not understood Type III hereditary angioedema: defined, but not understood. Kaplan, Ann Allergy Asthma Immunol 2012;109:153 A mutation in factor XII, exon 9 consisting of either Thr 309 lys or Thr 309 arg has been associated with type III HAE patients, and, although specific for this disorder, it is found only in 25-30% of patients whose swelling is unexplained but is clearly familial. The mutation was reported to cause excessive conversion of prekallikrein to kallikrein and was described as a “gain of function” mutation. 60

Marcos, Ann Allergy Asthma Immunol 2012;109:195 Clinical, biochemical, and genetic characterization of type III hereditary angioedema in 13 Northwest Spanish families. Marcos, Ann Allergy Asthma Immunol 2012;109:195 22 of these patients had the estrogen-dependent phenotype. All had functional C1 inhibitor activity within the normal range in periods without high estrogen levels, but during attacks (in female patients) and pregnancy, activity decreased to below 50%. The C4 and antigenic C1 inhibitor levels were always normal. Population with type III hereditary angioedema. 29 patients (26 female, 3 male). 61

Marcos, Ann Allergy Asthma Immunol 2012;109:195 Clinical, biochemical, and genetic characterization of type III hereditary angioedema in 13 Northwest Spanish families. Marcos, Ann Allergy Asthma Immunol 2012;109:195 22 of these patients had the estrogen-dependent phenotype. All had functional C1 inhibitor activity within the normal range in periods without high estrogen levels, but during attacks (in female patients) and pregnancy, activity decreased to below 50%. The C4 and antigenic C1 inhibitor levels were always normal. Population with type III hereditary angioedema. 29 patients (26 female, 3 male). All studied patients had the c.1032C>A, Thr309Lys mutation in the factor XII gene. 62

BSACI guidelines for the management of chronic urticaria and angio-oedema. R. J. Powell. CEA, 2007; 37, 631–650. 63

BSACI guidelines for the management of chronic urticaria and angio-oedema. R. J. Powell. CEA, 2007; 37, 631–650. 64

Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione L’angioedema I meccanismi La terapia diego.peroni@univr.it 65

C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Cugno M, Trends in Molecular Medicine, 2009; 15: 69 Current and potentially new treatments for angioedema due to hereditary or acquired C1-INH deficiency 66

Terapia angioedema Terapia cronica profilattica Terapia attacco acuto Idratazione, Antidolorifici, Androgeni blandi: Danazolo Stanazolo Metiltestosterone Antifibrinolitici Berinert (pdC1- INH pastorizzato, liofilizzato concentrato); Ecallantide (inibitore della Kallikreina); Icatibant (antagonista competitivo di BK2R); Rhucin (C1-INH ricombinante umano) FPP (fresh frozen plasma) SDP (solvent detergent- treated plasma) Effetti collaterali 67

pdcC1 INH umano, indicato per gli attachi acuti di HAE con interessamento addominale, facciale e laringeo negli adulti e negli adolescenti. 68

Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione L’angioedema I meccanismi La terapia Il caso clinico diego.peroni@univr.it 69

Angioedema – Francesca 4 anni Accesso al PS per comparsa di edema importante a livello dell’arto sup di sin Pregressa faringite trattata con Amox-Clavul Familiarita’ per angioedema ereditario (madre) E.O. Edema a livello della mano e avambraccio di sin, cute calda, pallida. Non dolore Rx avambraccio e mano: non lesioni ossee a focolaio Ecodoppler: pervio l’asse venoso succlavio-ascellare-omerale. Diffuso infarcimento dei tessuti molli Complemento C4 0.04 g/L (vn 0.10-0.40), C1 inibitore 0.06 g/L (vn 0.15-0.35) Conclusioni: Angioedema ereditario Si consiglia visita specialistica presso la Clinica Medica Milano In caso di emergenza Berinert f. 500 UI 70

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Cugno M, Trends in Molecular Medicine, 2009; 15: 69 C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Cugno M, Trends in Molecular Medicine, 2009; 15: 69 73

Diego Peroni Le sindromi da attivazione mastocitaria Le manifestazioni allergologiche particolari: Le sindromi da attivazione mastocitaria Diego Peroni U.O.S. Allergologia Pediatrica Azienda Ospedaliera Universitaria Integrata Verona diego.peroni@univr.it 74

Characteristics of human mast cell subsets 75

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Mast cell activation syndrome: Proposed diagnostic criteria. Selected mast cell activators of clinical relevance Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 77

Mast cell activation syndrome: Proposed diagnostic criteria Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 Activation of mast cells results in (1) degranulation with resulting release of preformed mediators stored in granules, including histamine, heparin, proteases, and cytokines, such as TNF-a; (2) De novo synthesis of arachidonic acid metabolites (most notably prostaglandin D2 and leukotriene C4) from membrane lipids; (3) synthesis and secretion of cytokines and chemokines 78

Le sindromi da attivazione mastocitaria Le manifestazioni allergologiche particolari: Le sindromi da attivazione mastocitaria The mast cell Mast cell activation syndrome MCAS, SM or MMCA diego.peroni@univr.it 79

Disease states associated with evidence of mast cell activation Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 Disease states associated with evidence of mast cell activation 80

Mast cell activation syndrome: Proposed diagnostic criteria Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 Classification of diseases associated with mast cell activation 81

Mast cell activation syndrome: Proposed diagnostic criteria Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 Signs and symptoms suggested to potentially occur in MCAS or mast cell activation disorder These symptoms are attributed to mast cell degranulation in mastocytosis, and those with mast cell activation disorder/ MCAS are said to have many of the same symptoms. 82

Mast cell activation syndrome: Proposed diagnostic criteria Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 MCAS as a distinct clinical entity has not been generally accepted, nor do there exist definitive criteria for diagnosis. Based on current understanding of this disease ‘‘syndrome’’ and on what we do know about mast cell activation and resulting pathology, we will explore and propose criteria for its diagnosis. 83

The minor diagnostic criteria WHO classification of tumours of haematopoietic and lymphoid tissues. Horny HP, Lyon:IARC Press; 2008. p. 54-63. The diagnostic standard for systemic mastocytosis has been the demonstration of: Major criterion multifocal mast cell clusters of atypical morphology in a bone marrow biopsy specimen. The minor diagnostic criteria a tryptase level of greater than 20 ng/mL, atypical (spindle-shaped and hypogranulated) mast cell morphology, aberrant expression of CD2 and CD25 on mast cells, detection of a codon 816 mutation in c-Kit. 84

Proposed criteria for the diagnosis of MCAS Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 Proposed criteria for the diagnosis of MCAS Episodic symptoms consistent with mast cell mediator release affecting >2 organ systems evidenced as follows: a. Skin: urticaria, angioedema, flushing b. Gastrointestinal: nausea, vomiting, diarrhea, abdominal cramping c. Cardiovascular: hypotensive syncope or near syncope, tachycardia d. Respiratory: wheezing e. Naso-ocular: conjunctival injection, pruritus, nasal stuffiness Plus 85

Proposed criteria for the diagnosis of MCAS Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 Proposed criteria for the diagnosis of MCAS 2. A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1- and H2-histamine receptor agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizers (cromolyn sodium) 3. Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on >2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-b-prostaglandin F2. 4. Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities 86

Proposed criteria for the diagnosis of MCAS Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099 Proposed criteria for the diagnosis of MCAS MCAS for now remains an idiopathic disorder; however, in some cases it could be an early reflection of a monoclonal population of mast cells, in which case with time it could meet the criteria for MMAS as 1 or 2 minor criteria for mastocytosis are fulfilled 2. A decrease in the frequency or severity or resolution of symptoms with antimediator therapy: H1- and H2-histamine receptor agonists, antileukotriene medications (cysteinyl leukotriene receptor blockers or 5-lipoxygenase inhibitor), or mast cell stabilizers (cromolyn sodium) 3. Evidence of an increase in a validated urinary or serum marker of mast cell activation: documentation of an increase of the marker to greater than the patient’s baseline value during a symptomatic period on >2 occasions or, if baseline tryptase levels are persistently >15 ng, documentation of an increase of the tryptase level above baseline value on 1 occasion. Total serum tryptase level is recommended as the marker of choice; less specific (also from basophils) are 24-hour urine histamine metabolites or PGD2 or its metabolite 11-b-prostaglandin F2. 4. Rule out primary and secondary causes of mast cell activation and well-defined clinical idiopathic entities 87