URTICARIA SI ANGIOEDEMULDr. Roxana BumbaceaSef de lucrariMedic primar alergolog

DEFINITIE: Urticaria este o reactie cutanata produsa de factori multiplii, caracterizata prin papule si placi eritemato-edematoase, fugace (1-24 ore), pruriginoase; ele sunt consecinta vasodilatatiei sau edemului localizat la nivelul dermului superficial.

Angioedemul (edem angioneurotic, edem Quincke) reprezinta un edem masiv al dermului profund si al tesutului subcutanat si/ sau submucos.

Urticaria- diagnostic facil

Clasificarea urticarieiZuberbier et al. Allergy. 2005. Urticaria spontanaUrticariafizicalaAlte forme clinice de urticarie Urticaria acuta Urticaria cronica(> 6 saptamani) Urticaria de contact la receUrticaria presionala tardiva Urticaria de contact la cald Urticaria solaraUrticaria factitia/ Urticaria dermograficaUrticaria/Angioedema vibrator Urticaria aquagenica Urticaria colinergica Urticaria de contactAnafilaxia/urticaria indusa de efort

Mastocitele sunt celulele cheie in reactiile alergiceMC FceRIIgE +Courtesy of Prof. M. Maurer.

Mastocitele= principalele celule efectorii in urticarieKovarova and Rivera. Curr Med Chem. 2004;11:2083. Mastocitele sunt principala sursa de mediatori:HistaminaCitokineProstaglandine/leukotriene

MastCai patogenice de eliberare a mediatorilor mastocitari Factori Nonimunologici Factori Imunologici Eleberatori directi de histaminaEfect direct-fizicalEfecte colinergiceModulatingFactorsHormoni Agenti vasodilatatori Mediatori eliberatiEfecte pe vasele miciPapule si/ sau angioedem Mecanisme IgE-mediateAnafilatoxineAutoanticorpiActivare de complementMBPNeuropeptideEozinofileMonociteLimfociteNeutrofileHRFsProdusi inflamatoriIgE = immunoglobulin E; MBP = major basic protein; HRF = histamine-releasing factor.Zuberbier et al. J Investig Dermatol Symp Proc. 2001;6:123.Greaves. Int Arch Allergy Immunol. 2002;127:3.

Mastocitele mediaza reactiile alergice inflamatoriiIL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNFa, MIPs, IFNg, GM-CSF, TGFb, bFGF, VPF/VEGF, PGD2, LTB4, LTC4, PAF, Serotonin,Heparin,Chondroitin-sulfate,Chymase, Tryptase, Cathepsin GCourtesy of Prof. M. Maurer.

URTICARIA - ASPECTE CLINICE (I)papule sau placi eritematoase, cu centrul palid, bine delimitate, rotunde sau policiclice, de consistenta elastica, localizate asimetric, oriunde pe tegument, putand interesa si mucoaseleapar brusc, precedate si insotite de prurit intens, uneori cu senzatie de arsurapalesc/cedeaza la vitropresiunese remit in cateva ore fara sa lase urme, in timp ce alte elemente continua sa apara in pusee succesivein zonele bogate in tesut lax (buze, pleoape, regiunea genitala), leziunile prezinta edem moale, difuzla nivelul palmelor, palntelor si in pielea capului se formeaza papule mici, mai ferme, foarte pruriginoase, uneori dureroase

URTICARIA - ASPECTE CLINICE (II)starea generala este nemodificata de obicei

poate exista afectarea altor organe, determinand tulburari functionale:disfonie, dispnee (afectare laringiana)varsaturi, diaree (afectare intestinala)dureri abdominale (afectare peritoneala)artralgii si artrita (edem sinovial) cefalee, hipotensiune, soc anafilactic (urticarie, angioedem, insuficienta respiratorie si cardiovasculara)

HISTOPATOLOGIC

in leziunile urticariene:-edemul dermului superficial -dilatarea vaselor sanguine mici si a limfaticelor in dermul superficial-largirea papilelor dermice-infiltrat inflamator dermic cu LT CD4 > LT CD8, neutrofile, eozinofile, bazofile, fara LB si NK-MBP si ECP in jurul vaselor si dispersate in dermul afectat

edemul dermului profund si al tesutului subcutanat in angioedem

Etiologie (I)

MedicamenteAlimente; aditivi alimentariSeruriVeninuri de insecteAntigene de contact;inhalante; injectateInfectii: bacteriene, virale, fungice, helminticeAgenti fizici ( caldura, frigul, lumina, presiunea, vibratiile, apa)Boli sistemice (LES, Artrita reumatoida juvenila, Cioglobulinemii, Boala serului, Vasculita cutanate)

Etiologie (II)Boli endocrine:Hipertiroidiile, hipotiroidiileDiabetul zaharatHiperparatiroidismulBoli maligne: limfoame, tumori solideBoli ereditare:Angioedemul ereditarUrticaria familiala la receDeficitul de C3b inactivatorAmiloidaza cu surditate si urticarieUrticaria pigmentara: Mastocitoza sistemicaUrticaria cronica idiopatica si angioedemul cronic

Urticaria clasica

CLASIFICAREA URTICARIILOR FIZICE

URTICARIA DATORATA STIMULILOR MECANICI

Dermografism

Imediat: simplu sau simptomatic

Tardiv

Urticaria presionala tardiva

Angioedemul vibrator

Ereditar

Dobandit

URTICARIA DATORATA MODIFICARILOR DE TEMPERATURA

Caldura si stressul

Urticaria colinergica

Urticaria localizata la caldura

Stressul

Urticaria adrenergica

Frigul

Urticaria de contact la rece: primara si secundara (crioglobuline, aglutinine la rece)

Urticaria la rece atipica

Urticaria indusa de exercitiu fizic

Anafilaxiile induse de exercitiu fizic

Anafilaxiile induse de exercitiu fizic si alimente

URTICARIA SOLARA

URTICARIA ACVAGENICA

Urticaria Factitia ECARF 2005 - www.ecarf.orgCourtesy of Prof. T. Zuberbier.

Urticaria colinergica

Investigatii recomandate pentru diagnosticul diferitelor subtipuri de urticarie

TipulSubtipulTeste recomandate de rutinaInvestigatii de diagnostic extinseUrticaria spontanaUrticaria spontana acutaNu existaNu existaUrticaria spontana cronicaHLG, VSH,CRP, excluderea unor medicamente precum AINSCautarea unei cauze infectioase(H.Pylori), tipul I de alergie, autoanticorpi, hormoni tiroidieni, testare cutanata, dieta pentru 3 saptamani, triptaza, testare cutanata cu ser autolog, biopsie cutanata

TipulSubtipulTeste diagnostice de rutinaTeste diagnostice extinseUrticaria inductibilaUrticaria la receTest de provocare(cubul de gheata , apa rece, vant rece)HLG, VSH, CRP, crioproteine, excluderea altor cauze ex- infectioaseUrticaria presionala intarziata Testul presiuniiNu existaUrticaria la caldTest de provocare la caldNu existaUrticaria solaraRaze UV si lumina vizibila cu diferite lungimi de undaSe exclud alte dermatoze induse de luminaDermografism simptomatic Obtinerea dermatografismuluiHLG,VSH,CRPUrticaria aquagenicaSe aplica haine ude la temperatura corpului timp de 20minNu existaUrticaria colinergicaProvocare prin exercitiu fizic si bai fierbintiNu existaUrticaria de contactNu exista

ANGIOEDEM - ASPECTE CLINICE

se manifesta printr-o tumefactie elastica, localizata mai ales in zonele bogate in tesut celular lax (fata, extremitati, organe genitale externe)culoarea tegumentelor este normalaedemul nu are o limita precisaeste nepruriginosare tendinta la recurenta in aceleasi regiuni

poate fi acut/cronicse poate asocia cu urticarie acuta/cronicaafecteaza mai frecvent femeilemedia de varsta = 22-44 ani

Angioedem facial

Angioedem al mainilor

COMPLICATIILE ANGIOEDEMULUI

edemul lingual poate perturba masticatia si fonatia

edemul laringian determina disfonie, dispnee

edemul traheobronsic determina dispnee, tiraj suprasternal

edemul intestinal determina dureri abdominale, varsatura, diaree

edemul cerebromeningeal determina cefalee, vertij, crize comitiale, afazii, pierderea constientei, plegii

Dg DifUrt/AE

Eczema-in special eczema de contactEritem polimorfIntepaturi de insecteEritem inelarExanteme viraleEruptii cutanate prepemfigoidePrurigo

Dermatita acuta de contactSindromul Melkersson- RosenthalLimfedemulCelulitaLupus eritematosDermatomiozitaTumori orbitale sau facialeBoala Sjogren (localizare palpebrala)Tromboza sinusului cavernosObsructia venei cave superioareEdeme ciclice (perimenstruale)

DIAGNOSTIC DIFERENTIAL1. eritemul polimorf eruptii edematoase / papuloveziculoase / buloase, cu afectare mucoasa si leziuni tipice in tinta

2. eritemul migrator (borrelioza = boala Lyme) una / mai multe placi inelare, eritematoase

3. pemfigoidul bulos placi eritematoase si edematoase, cu / fara bule

4. urticaria pigmentosa eruptie maculo-papuloasa rosie-maronie sau infiltrare mastocitara nodulara, in care pielea devine edematoasa la frictiune

5. amiloidoza urticarie, febra, insuficienta renala, surditate de perceptie

6. ICC, IR, mixedem, celulita, TVP, sd. VCS, sd. Melkersson-Rosenthal, edemul idiopatic scrotal sunt cauze de edem ce trebuie diferentiate de angioedem

DIAGNOSTIC POZITIV1.anamneza atenta

2.ex clinic general, cu teste pentru urticaria fizica (frictiune, presiune, stimuli reci/calzi, exercitiu fizic, fototeste)

3.probele paraclinice

4.proba terapeutica

5.dieta de excludere / reintroducere

Tratamentul de prima-linie in urticaria cronica: Recomandarile EAACI/GA2LEN/EDF*Increased sedation vs placebo.NS 2nd-G H1-AH = nonsedating 2nd-generation H1 antihistamine.Zuberbier et al. Allergy. 2005.

TreatmentMethodologic QualityLevel of EvidenceGrade of RecommendationNS 2nd-G H1-AHAzelastineCetirizine*DesloratadineEbastineFexofenadineLevocetirizine*LoratadineMizolastine++++++++++++++1++1-1+1+1-1+1+1+1+AIncrease dosage if necessary3C

Urticaria cronica non-responsiva: Recomandarile EAACI/GA2LEN/EDF NS 2nd-G H1-AH = nonsedating 2nd-generation H1-antihistamine; RCT = randomised controlled trial.Zuberbier et al. Allergy. 2005. In press.

TreatmentMethodologic QualityLevel of EvidenceGrade of RecommendationCombinationNS 2nd-G H1-AH + Cyclosporin A+ Montelukast+ H2-AHMonotherapyTricyclic (doxepin)KetotifenHydroxychloroquineDapsoneSulfasalasineMethotrexateCorticosteroids

++++

+++-No RCTNo RCTNo RCTNo RCT

2++2-2-

2+2++2-3334

CDD

DCDDDDD

Tratament

Allergy 2009: 64: 14271443 EAACI/GA2LEN/EDF/WAO guideline: management of urticaria

***Urticaria is characterized by raised, markedly pruritic erythematous skin lesions (wheals) that tend to be evanescent, and generally are worsened by scratching. Angioedema is also frequently associated with urticaria, typically occurs in deeper tissues, and is clinically characterized by asymmetric swelling tissue.

*Urticaria can be classified as spontaneous, physical, or other, based on duration, frequency, and causes of symptoms.Spontaneous urticaria occurs in the absence of external physical stimuli, and is classified as chronic if symptoms persist for >6 weeks.Physical urticaria is caused by external physical stimuli. Some cases of physical urticaria may be considered chronic; however, physical urticaria is distinguished from chronic urticaria based on clear evidence that physical factors are eliciting urticaria.Other urticaria disorders are those induced by exercise or contact, anaphylactic reactions, cholinergic mechanisms, and aquagenic factors.According to the latest guidelines, urticaria pigmentosa, urticarial vasculitis, familial cold urticaria and nonhistaminergic angioedema are no longer considered to be subtypes of urticaria.

Zuberbier et al. Allergy. 2005. In press.**Mast cells within the skin lesions represent the major source of histamine, cytokines, and prostaglandins/leukotrienes, molecules that mediate dermatologic manifestations of urticaria.

Kovarova and Rivera. Curr Med Chem. 2004;11:2083.*The pathogenesis of mast cell mediator release is complex and involves both immunologic (immunoglobulin E [IgE]-mediated) and nonimmunologic pathways, as well as modulating factors.Pathways of mast cell mediator release are illustrated in this schematic.1IgE-mediated mast cell degranulation leads to increases in histamine release, followed by an increase in the numbers of basophils, neutrophils, and eosinophils, as well as the mediator release from these cells.Many cases of chronic urticaria (CU) may be due to non-IgE causes.2 Physical urticaria and cholinergic urticaria are examples of non-IgEmediated urticaria.In approximately 50% to 60% of patients with CU, wheals have been attributed to circulating histamine-releasing factors, many of which are elicited by IgG autoantibodies.2Hormones and other vasoactive agents can modulate the severity of CU directly at the level of the mast cell or indirectly via effects on the microvasculature.1-2

Zuberbier et al. J Investig Dermatol Symp Proc. 2001;6:123.Greaves. Int Arch Allergy Immunol. 2002;127:3.*In addition to histamine, mast cells are also a major source of inflammatory mediators; the release of these inflammatory mediators may exacerbate allergic reactions induced primarily by histamine.Inflammatory mediators released by mast cells include interleukins, tumor necrosis factor alpha (TNF), prostaglandins, and leukotrienes.These inflammatory mediators promote endothelial cell activation, vasodilation, and movement of inflammatory cells from circulation into tissues (extravasation).Illustration courtesy of Prof. M. Maurer.********Die disseminierte makulopapulre Form ist die hufigste Manifestation im Erwachsenenalter.Selten ist die Form der Teleangiectasia macularis eruptiva perstans, die sich durch solitre oder multiple Teleangieektasien am Stamm auszeichnet. **********The 2005 EAACI/GA2LEN/EDF guidelines strongly recommend a nonsedating second-generation H1 antihistamine as first-line therapy for chronic urticaria (level of evidence: 1++, grade A recommendation).1Cetirizine and levocetirizine have been associated with increased sedation vs placebo in clinical trials.2,3The level of evidence for azelastine and ebastine is less strong than for other second-generation antihistamines.The level of evidence and grade of recommendation for using higher than recommended doses of antihistamines if necessary is less strong.Zuberbier et al. Allergy. 2005. In press.Zyrtec PI. At: http://www.pfizer.com/download/uspi_zyrtec.pdf.Xyzal Summary of Product Characteristics. At: http://emc.medicines.org.uk/emc/industry/default.asp?page=displaydoc.asp&documentid=7739.*For patients with chronic urticaria who do not respond adequately to first-line treatment with nonsedating antihistamines, the 2005 EAACI/GA2LEN/EDF guidelines suggest several treatment options, including the combination of nonsedating antihistamines with cyclosporin A (level of evidence 2++, grade of recommendation C), or montelukast (level of evidence 2-, grade of recommendation D), or the H2-antihistamine cimetidine (level of evidence 2-, grade of recommendation D).The level of evidence and grade of recommendation for alternative monotherapies (eg, tricyclic antidepressants, ketotifen, hydroxychloroquine, dapsone, sulfasalazine, methotrexate, and corticosteroids) is generally low, and the need for use of these therapies in clinical practice is much lower than that of antihistamines.Zuberbier et al. Allergy. 2005. In press.