Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione Diego Peroni U.O.S. Allergologia Pediatrica Azienda Ospedaliera Universitaria

Le manifestazioni allergologiche particolari:

Orticaria / Angioedema

La definizioneDiego Peroni

U.O.S. Allergologia Pediatrica

Azienda Ospedaliera Universitaria

Integrata Verona [email protected]

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

LTC5a

Istamina

Orticaria associata o meno a angioedema che dura per più di 6-8 settimane con sintomatologia quotidiana.

Orticaria



LTC5a

Istamina

80% dei casi di orticaria cronica presenta lesioni

da orticaria associate a

angioedema.

Orticaria cronica- Angioedema



La definizione

L’orticaria acuta

[email protected]

• 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



La definizione

L’orticaria acuta

L’orticaria

cronica

La diagnosi

[email protected]

Orticaria cronica

Orticaria associata a angioedema che dura da più di 6-8 settimane ….

Orticaria



LTC5a

Istamina

Orticaria Cronica:Diagnosi Eziologica

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

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

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.

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).

Orticaria cronicaDiagnosi eziologica

Laboratory tests and identified diagnoses in patients with physical and chronic urticaria and angioedema: A systematic review

Martina M. J Am Acad Dermatol 2003

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 dimentichiamoaltre 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

Cutaneous Reactions to Aspirin and Nonsteroidal Antiinflammatory DrugsMario Sánchez-Borges, Clinical Reviews in Allergy & Immunology Volume 24, 2003

AsmaUrticaria

angioedema

FANS e COX 1 inibitori



La definizione

L’orticaria acuta

L’orticaria

cronica

La diagnosi

Le nuove [email protected]

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 inflammatorymediators after stimulation by autoantibodies directed against the high-affinity IgE receptor (FceRI) and IgE, complement anaphylatoxin C5a, eosinophil-derived major basic protein (MBP) andpossibly other molecules




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.




Eosinophils are activated by autoantibodies directed against the low-affinity IgE receptor (FceRII) and potentiallyby 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.

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

Effetto della trombina

Trombina

Vasodilatazione

Produzione di mediatori infiammatori

Attivazione diretta di C5a bypassando C3

Attivazione diretta degranulazione mastocitaria

• 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.

ASST - Autologous Serum Skin Test -

Pathogenesis of chronic urticaria A. P. Kaplan Clin Exp All, 2009, 39, 777

• 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.

ASST - Autologous Serum Skin Test -

Pathogenesis of chronic urticaria A. P. Kaplan Clin Exp All, 2009, 39, 777

Altri fattori istaminoliberatori potrebbero essere

implicati nella patogenesi della

malattia.

Orticaria cronica, ASST, APST e HRA

• Orticaria cronica• APST positivo nel 75-

85% dei casi• ASST positivo nel 50-

60% dei casi • HRA positivo nel 25-

30% dei casi



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

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

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.

17.3

6% Rheumato

id arthritis

28.8

13.2

Hyper-thyroidis

m

Hypo-thyroidis

m

In patients with CU OR for

30 –

25 –

20 –

15 –

10 –

05 –

0

Chronic urticaria and autoimmunity: Associations found in a large

population study Confino-Cohen, JACI 2012;129:1307

15.2

6% Systemi

c LE

26.9

14.6

Celiac disease

Sjögren syndro

me

In patients with CU OR for

30 –

25 –

20 –

15 –

10 –

05 –

0

7.7

Type I diabete

s mellitus

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.


diagnostic criteriaKonstantinou 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.


diagnostic criteriaKonstantinou G. N, Allergy 2013;68:27-36

How not to miss autoinflammatory diseases masquerading as urticaria

Krause K, Allergy 2012;67:1465-1474



La definizione

L’orticaria acuta

L’orticaria

cronica

La diagnosi

Le nuove evidenze

Il caso clinico

P.P 5 aa e 6 mesi APR:

- Otiti ricorrenti;

- Bronchiti asmatiformi ricorrenti;

- Autismo.

20/12/2011

Otite Amoxicillina comparsa di rash orticarioide Cetirizina 0.25 mg/kg + Bentelan 4 mg/die

Peggioramento orticaria PS a BZ: Deltacortene 15 mg/die

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

Peggioramento PS BZ:

Augmentin Zinnat;

Zirtec Aerius + Fenistil la sera

Ancora deltacortene 2.5 mg

Persistenza del quadro:

10/02/2012: PS VR.

MT dx iperemica e bombata:

Deltacortene 2.5 mg/die

Aerius + Fenistil

Singulair

Orelox (OM persistente).

DH allergologia 20/02/2012

Totale:

• 2 mesi di sintomi continui.

• 2 mesi di CSO;

• 8 visite specialistiche;

• 4 Abt diverse.

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 .

[email protected]



La definizione

L’angioedema

I meccanismi

[email protected]

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

Hereditary angio-oedema. Longhurst H. Lancet 2012; 379:474

Angio-oedema of hand

Capsule endoscopy during abdominal attack

Erythema marginatum on anterior chest wall

C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Cugno M, Trends in Molecular Medicine, 2009; 15: 69Simplified representation of the kinin system. Bradykinin is generated through the cleavage of high molecular weight kininogen (HK) by plasma kallikrein during contact-system activation

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).


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, whichimpairs 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, mainlylymphoproliferative, tissue.


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 furtherreduction of its plasma level.

Hereditary angio-oedema. Longhurst H. Lancet 2012; 379:474

Criteria for diagnosis of hereditary angio-oedema

Type III hereditary angioedema: defined, but not understood. Kaplan, Ann Allergy Asthma

Immunol 2012;109:153

1) 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.

2) 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).

3) Like types I and II HAE, angioedema is recurrent, it is not associated with urticaria, and it is unresponsive to antihistamines or corticosteroids.


Immunol 2012;109:153




We do not have a test that can be used to

make the diagnosis.


Immunol 2012;109:153




Overproduction of bradykinin is assumed,

but not proven.


Immunol 2012;109:153

a) 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.

b) The mutation was reported to cause excessive conversion of prekallikrein to kallikrein and was described as a “gain of function” mutation.

Clinical, biochemical, and genetic characterization of type III hereditary angioedema in

13 Northwest Spanish families. Marcos, Ann Allergy Asthma Immunol 2012;109:195

Population with type III hereditary angioedema.

29 patients (26 female, 3 male).

1) 22 of these patients had the estrogen-dependent phenotype.

2) 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%.

3) The C4 and antigenic C1 inhibitor levels were always normal.

Population with type III hereditary angioedema.

29 patients (26 female, 3 male).

1) 22 of these patients had the estrogen-dependent phenotype.

2) 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%.

3) The C4 and antigenic C1 inhibitor levels were always normal.

All studied patients had the c.1032C>A, Thr309Lys mutation

in the factor XII gene.

Clinical, biochemical, and genetic characterization of type III hereditary angioedema in

13 Northwest Spanish families. Marcos, Ann Allergy Asthma Immunol 2012;109:195



La definizione

L’angioedema

I meccanismi

La terapia

[email protected]


Current and potentially new treatments for angioedema due to hereditary or acquired C1-INH deficiency

Terapia angioedema

Terapia attacco acuto Terapia cronica profilattica

• Berinert (pdC1- INH pastorizzato, liofilizzato concentrato);

• Ecallantide (inibitore della Kallikreina);

• Icatibant (antagonista competitivo di BK2R);

• Rhucin (C1-INH ricombinante umano)

• Androgeni blandi:

• Danazolo

• Stanazolo

• Metiltestosterone

• Antifibrinolitici

FPP (fresh frozen plasma)

SDP (solvent detergent- treated plasma)

• Idratazione,

• Antidolorifici,

Effetti collaterali

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

http://www.berinert.com/patient

http://www.berinert.com/professional/



La definizione

L’angioedema

I meccanismi

La terapia

Il caso clinico

[email protected]

Angioedema – Francesca 4 anni

Accesso al PS per comparsa di edema importante a livello dell’arto sup di sinPregressa faringite trattata con Amox-ClavulFamiliarita’ per angioedema ereditario (madre)

E.O.Edema a livello della mano e avambraccio di sin, cute calda, pallida. Non doloreRx avambraccio e mano: non lesioni ossee a focolaioEcodoppler: pervio l’asse venoso succlavio-ascellare-omerale. Diffuso infarcimento dei tessuti molliComplemento C4 0.04 g/L (vn 0.10-0.40), C1 inibitore 0.06 g/L (vn 0.15-0.35)

Conclusioni: Angioedema ereditarioSi consiglia visita specialistica presso la Clinica Medica MilanoIn caso di emergenza Berinert f. 500 UI

C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress.

Cugno M, Trends in Molecular Medicine, 2009; 15: 69


Le sindromi da attivazione mastocitaria

Diego Peroni

U.O.S. Allergologia Pediatrica

Azienda Ospedaliera Universitaria

Integrata Verona [email protected]

Characteristics of human mast cell subsets

Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099

Selected mast cell activators of clinical relevance


(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

Activation of mast cells results in

The mast cell

Mast cell

activation

syndrome

MCAS, SM or MMCA

[email protected]


Le sindromi da attivazione mastocitaria


Disease states associated with evidence of mast cell activation

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

Mast cell activation syndrome: Proposed diagnostic criteria. Akin C, JACI; 2010; 126:1099Signs and symptoms suggested to potentially occur in MCAS or mast cell activation disorder

These symptoms are attributed tomast cell degranulation in mastocytosis, and those with mast cell activation disorder/MCAS are said to have many of the same symptoms.


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.

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.

WHO classification of tumours of haematopoietic and lymphoid tissues. Horny HP, Lyon:IARC Press; 2008. p. 54-63.


Proposed criteria for the diagnosis of MCAS

1.Episodic symptoms consistent with mast cell mediator release affecting >2 organ systems evidenced as follows:

a. Skin: urticaria, angioedema, flushingb. Gastrointestinal: nausea, vomiting, diarrhea,

abdominal crampingc. Cardiovascular: hypotensive syncope or near

syncope, tachycardiad. Respiratory: wheezinge. Naso-ocular: conjunctival injection, pruritus,

nasal stuffiness Plus



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



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

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

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

Documents

Le manifestazioni allergologiche particolari: Orticaria / Angioedema La definizione Diego Peroni U.O.S. Allergologia Pediatrica Azienda Ospedaliera Universitaria