DERMATITIS ATOPICA Dra. Lilian Pérez JULIO 2011

Dermatitis = eccema Inflamación cutánea Pruriginosa Eritema con o sin descamación Vesículas y costras Aguda, subaguda y crónica Histología: espongiosis

Clasificación dermatitis Exógenas: - de contacto (alérgica e irritativa) - fotodermatitis Endógenas: - dermatitis atópica - dermatitis seborreica - dishidrosis (pompholix)

Dermatitis atópica

Atopia (diferente, fuera de lugar) Paciente atópico: individuo que tiene tendencia a desarrollar hipersensibilidad a algunos alergenos y que se manifiesta clínicamente como: - Asma - Rinitis - Dermatitis

DEFINICION Dermatosis inflamatoria genéticamente determinada prurito *** xerosis (piel seca) y eritema Curso crónico, reactivaciones Importante morbilidad

Subtipos de DA Extrínseco: 80%, Ig E elevada, precoz, asma asociada, empeora con alergenos, mas severa, evolución tórpida Intrínseco ,“no atopica“ “atopiforme”: no asociado a sensibilización alérgica , tardía, mas frecuente en mujeres, puede ir a IgE +. According to the available data, it seems that IgE specific responses are not necessary for the development of AD. However, they may trigger disease flares or contribute to worsen AD. Indeed they are more likely a consequence of abnormal skin barrier. More important, high IgE levels are predictive of respiratory atopy (asthma and rhinitis) in patients with AD.

ETIOLOGIA Eccema: enfermedad cutánea multifactorial Relación entre factor genético y exposición ambiental GENETICA imbalance between proteinase and proteinase inhibitors as well as lipid abnormalities may also have a very important role AMBIENTE

GRUPOS DE GENES IMPLICADOS genes que codifican proteínas estructurales epidérmicas (FLG y SPINK5) genes que codifican para elementos del sistema inmune: IL-4, IL-5, IL-13, relacionados con la inmunidad innata y adaptativa (función barrera) (alteracion de inmunidad)

SISTEMA INMUNE INMUNIDAD INNATA INMUNIDAD ADAPTATIVA From a functional view, the human immune system may be divided into an adaptive and an innate immune system. Whereas the latter is defined by and has the advantage of a learning capacity, the former does not learn but is quicker in its reaction

Inmunidad innata Es la que “no se aprende”, congénita Requiere la barrera cutánea intacta Es inmediata Secreción de péptidos antimicrobianos Queratinocito Células dendríticas Linfocitos These “noneed-to-learn” mechanisms start with an intact epidermalbarrier, but also include the expression and secretion of antimicrobial peptides (AMP) upon recognition of pathogens by toll-like receptors (TLRInnate immunity includes resident cells such as keratinocytes as well as dendritic cell (DC) and lymphocyte subsets.

Inmunidad adaptativa Se “aprende” Mecanismos de defensa adquiridos frente a patógenos o cualquier estructura proteica Mejora con exposiciones repetidas Es mas lenta Es específica (clones diferentes ) all of the acquired but time-delayed defense mechanisms against pathogens. This part of the immune system is able to “learn”, i.e., it is able to improve its reactions with repeated exposure. any structural protein. In contrast to innate immunity, adaptive immunity mechanisms possess a much higher risk of autoimmunity

Andreas Wollenberg , Helen-Caroline Räwer, Jürgen Schauber. 2010

BARRERA CUTANEA E INMUNIDAD Es el elemento mas importante de la inmunidad innata Alterada en DA Consecuencia: sensibilización alérgica This can be tested by the atopy patch test technique, which is standardized by the European Task Force on Atopic Dermatitis, and a highly specific procedure. This test relies on intact protein allergen penetration through clinically uninvolved skin without prior destruction of the epidermal barrier by tape stripping or other Procedures Although research shows a significant association of the 2 filaggrin mutations with asthma and allergic rhinitis, there is no apparent association between filaggrin and asthma without the coexistence of atopic dermatitis.10

Teorías patogenia dermatitis atópica “Inside- outside” “Outside-inside”

BARRERA CUTANEA Componentes estructurales Células efectoras Péptidos antimicrobianos Receptores de patógenos An impaired epidermal skin barrier is the key factor in the pathogenesis of AD as it causes skin xerosis and induces homeostatic responses which favor inflammation The layer of apoptosed keratinocytes is reinforced by other structural proteins that prevent allergen penetration.32Mutations of the filaggrin genes cause complete loss or reduction of filaggrin, which in turn leads to impaired keratinization Epidermal-barrier dysfunction is a prerequisite for the penetration of high-molecular-weight allergens in pollens, house-dust-mite products, microbes, and food

Componente lipídico de la barrera cutánea Ceramidas, colesterol, ac grasos libres

DISFUNCION DE BARRERA EN DA Estructural (filagrina) Desequilibrio entre proteasas e inhibidores de proteasas (funcional) Alteración en composición lipídica (cambios en lípidos epidérmicos altera el estrato corneo) Each of these abnormalities may be expressed and contribute differently to AD pathogenesis in each patientaltered epidermal barrier induces by itself homeostatic responses which favor inflammation, and unbalanced proteinase activation can directly promote inflammatory responses Filaggrin mutations are in general associated with a more severe and persistent eczema. In particular, they are more common in patients with early onset AD and in those with the disease persisting in adulthood

Defecto de barrera en DA Herencia: mutaciones en gen filagrina. Es el principal factor de riesgo para DA DA e ictiosis vulgar mismos genes implicados Otros trastornos de queratinización This is mirrored by the well-established clinical relevance of daily emollient application to non-lesional skin of AD patients FLG is the main component of F-type keratohyalin granules, responsible for the designation of the stratum granulosum. Decreased FLG expression results in a paucity of keratohyalin granules, a hallmark of IV26 and reduced FLG is also common in AD While it is widely hypothesized that FLG deficiency provokes a permeability barrier abnormality25, until very recently, the cellular basis for such an abnormality is unknown

Funciones de Filagrina - Agregación de filamentos en citoesqueleto - Parte esencial del Factor Humectación Natural --Mantiene el pH cutáneo - Contribución a formación del manto ácido

FACTOR AMBIENTAL TABACO relación con asma es clara, no así con DA Contaminación ambiental Ácaros pólenes Alimentos Agentes infecciosos

Defecto en la barrera epidérmica S. aureus Alérgenos Ácaros P P P P P P P C C D P C C P D D C C P C C CD Th1 Th2 IL-13 IL-4 P= Proteasas C= Corneocitos D= Desmosomas Defecto en la barrera epidérmica

Clínica Inicio durante la infancia Historia familiar o personal de atopia Impacto negativo en la vida familiar Recaídas frecuentes: Stress y cansancio en los padres

EPIDEMIOLOGIA Afecta 10-20% niños, en aumento Zonas urbanas Contaminación ambiental, dieta 35 - 60 % presentan signos durante el 1º año de vida 47-85% antes del 5º año

FISIOPATOLOGIA Familiar (genética) Ambientales Alteración barrera cutánea Alteraciones regulación inmunológica

Desregulación inmunológica Ig E elevada Alteración subpoblaciones de linfocitos T Predominio Th2 (aumento de producción de IL4 e IgE, eosinofilia) Célula de Langerhans: receptores para IgE

Inmunología Humoral: 70% aumento de IgE Celular: Linfocito T, rel CD4/CD8 disminución hipersen. Retardada degranulación de mastocito

DIAGNOSTICO Criterios diagnósticos de Hanifin y Rajka (en revisión) Mayores Prurito Distribución y morfología de las lesiones Evolución crónica Historia personal o familiar de atopia

DIAGNOSTICO criterios menores Cataratas subcapsular anterior Hiperpigmentación periocular Palidez o eritema facial Pitiriasis alba Prurito por sudor Intolerancia a la lana Acentuación perifolicular Intolerancia a los alimentos Curso influenciado por el ambiente y situaciones emocionales Dermografismo blanco Xerosis Ictiosis, hiperlinealidad palmar o queratosis pilar Ig E  Edad temprana de inicio Tendencia a infecc. Eccema de pezones Queilitis Conjuntivitis crónica Pliegue de Dennie-Morgan Queratocono

CLINICA Aguda Pápulas o pápulovesículas intensamente pruriginosas, exudado y eritema

CLINICA Subaguda Placas eritematosas con escamas finas

CLINICA Crónica Liquenificación

Bebés y niños pequeños Cara y cuero cabelludo,tronco, superficies extensoras Pápulas eritematosas, vesículas, exudación Prurito intenso Niños mayores (4-10a) Superficies flexoras: pliegues cuello, antecubital y poplíteo, rodillas y codos Excoriaciones y liquenificación Adolescentes y adultos Dorso de manos,párpados,superficies de flexión Liquenificación

DIAGNOSTICO criterios menores Cataratas subcapsulares anteriores Hiperpigmentación periocular Palidez o eritema facial Pitiriasis alba Prurito por sudor Intolerancia a la lana Acentuación perifolicular Intolerancia a los alimentos Curso influenciado por el ambiente y situaciones emocionales Dermografismo blanco Xerosis Ictiosis, hiperlinealidad palmar o queratosis pilar Ig E  Edad temprana de inicio Tendencia a infecc. Eccema de pezones Queilitis Conjuntivitis crónica Pliegue de Dennie-Morgan Queratocono

COMPLICACIONES Infecciones bacterianas, virales y micóticas Alteraciones psicosociales y del crecimiento

Diagnóstico diferencial Dermatitis seborreica (niños) Dermatitis pañal Dermatitis de contacto (adultos) Fitofotodermatitis Prúrigo insectario Sarna Pompholix (dishidrosis)

Gatillantes Irritantes tópicos Aeroalergenos Alimentos Bacterias y hongos Estrés Sudoración Clima Radiación UV

Barrera cutánea y alergia alimentaria Muchos están sensibilizados pero no todos tienen alergia propiamente tal ALERGIA = Sensibilización + actividad sintomática por el alimento dentro de 2- 4 horas de ingerido

Dañan la barrera cutánea Agentes irritantes Alergenos: proteasas del acaro del polvo o de s aureus . Esto produce inflamación y eccema Prurito excoriaciones inflamación daño en la barrera Trauma : activan la secreción de citokinas inflamatorias por el QC sensitive skin, which became inflamed after exposure to minimal irritant doses. Indeed, altered epidermal barrier induces by itself homeostatic responses which favor inflammation, and unbalanced proteinase activation can directly promote inflammatory responses. Moreover, epidermal keratinocytes from AD patients have a propensity to an exaggerated Epidermal skin barrier integrity and function may be impaired by a range of irritants and allergens, such as exogenous proteases from house dust mites or Staphylococcus aureus, which may lead to cytokine production, inflammation, and the development of eczematous lesions

AGENTES INFECCIOSOS Ácaros Cucarachas Hongos Staphylococcus aureus otros Ademas de producir proteasas son alergenos propiamente tal

Xerosis Signo clínico muy frecuente , (asociado a prurito) Expresión clínica de la anormalidad en la barrera cutánea Elemento diagnóstico y de monitorización del tto AUMENTO DE PERDIDA TRANSEPIDERMICA,DISMINUCION DEL GRADO DE HIDRATACION,INCREMENTO DEL PH,CAPACIDAD DE RTETENCIOND EL AGUA ALTERADA

Estrés Altera la respuesta inmune de células T Altera la inmunidad antimicrobiana Induce prurito -> excoriaciones Aumento endógeno de glucocorticoides : inhibirían la sintesis de lipidos epidermicos sustained psychological stress aggravates permeability barrier function in humans74, and PS is both a well-known precipitant of AD, and cause of resistance to therapy. In experimental animals, PS induces an increase in endogenous glucocorticoids (GC), which in turn alter permeability barrier homeostasis, SC integrity and epidermal antimicrobial defense70,71. The putative mechanism for the negative effects of PS is GC-mediated inhibition of synthesis of the three key epidermal lipids that mediate barrier function; i.e., Cer, cholesterol, and FFA. Accordingly, a topical mixture of these three lipids largely normalizes all of these functions, even in the face of ongoing PS or GC therapy75,76, and should comprise particularly effective therapy for AD patients with unusual levels of stres

Contactantes Jabones Detergentes Lavado excesivo Dureza del agua Ropa Ropa de cama, almohadas, colchones colorantes, preservantes Perfumes Cloro: disminuye la capacidad de retención de agua Ropa nueva lavar, (formaldehido), etiquetas, generos especiales , forrar almohadas y colchones Sauna: efecto protector de la barrera cutánea

Humedad ambiental El ambiente seco predispone a brotes (calefacción) El ambiente húmedo : sudoración La proteólisis de la filagrina es regulada por cambios en la humedad externa ( ) Humedad ideal: 45 -55% Tº ideal: 20-24º Prolonged exposure to a reduced environmental humidity, as occurs in radiant-heated homes in temperate climates during the winter, is also a well-known risk factor for AD. Under these conditions, transcutaneous water loss would accelerate across a defective SC, aggravating the underlying hydration and permeability barrier abnormalities, and amplifying cytokine signaling of inflammation. Because FLG proteolysis is regulated by changes in external humidity38, sustained reductions in environmental relative humidity could further deplete residual FLG in single-allele FLG-deficient patients.

TRATAMIENTO Cuidados generales de la piel Tratamientos tópicos Tratamientos sistémicos

Tratamiento Eliminar los gatillantes específicos e inespecíficos Antimicrobiano Prevenir el daño de la barrera cutánea EMOLIENTES en toda la piel y por tiempo prolongado, aplicación frecuente Inmunomoduladores tópicos As noted above, recent studies have shown that topical immunomodulators compromise barrier function in normal skin83, as do topical glucocorticoids76,84. Thus, as AD improves, continued topical applications of steroids and immunosuppressants (IS) likely begin to compromise barrier function. In contrast, studies in both AD animal models and in patients show that corrective lipid replacement therapy reduces the inflammatory component of disease by promoting normal epidermal function Although emollient moisturizers decrease steroid use through moisturization87, they consist of non-physiologic lipids, such as petrolatum and lanolin, which actually impede, rather than correct the underlying biochemical response to a defective in barrier in AD88. Yet, effective, disease-specific formulations that correct the underlying barrier abnormality have only become available recently. The permeability barrier defect in AD is characterized by a global reduction in the contents of all three key lipids (i.e., cholesterol, FFA, and Cer), with a further reduction in ceramide content54, Thus, correction of the barrier abnormality in AD requires topical applications not only of sufficient quantities of all three key lipids that mediate barrier function, but also provision of the lipids in a ceramide-dominant proportion that corrects the underlying lipid biochemical abnormality in AD88. Under these conditions, restoration of normal skin barrier function then can down-regulate inflammation in deeper skin layers several other currently-available products that make ‘barrier repair’ claims incorporate either incomplete mixtures of the 3 key lipids, incorrectly formulated mixtures, incorrect types of the three lipids, or in some cases, insufficient quantities of the three lipids

CUIDADOS DE LA PIEL Baños cortos, agua tibia evitar jabones Jabón blanco para la ropa No suavizante, doble enjuague Toallas algodón, no frotar Humectación cutánea (después del baño) Ropa de algodón No cosméticos ni perfumes Evitar abrigo excesivo Evitar exposición a ácaros

Fallas en el tratamiento Mal diagnostico Lubricación deficiente No se eliminan todos los gatillantes Mala relación medico paciente Considerar realidades individuales Corticofobia

ROL EN PREVENCION Prevenir la marcha atópica con intervenciones precoces ¿reparación de barrera cutánea? Inmunoestimulación estimularía la tolerancia alergénica Diversas drogas ; inhaladores, antihistamínicos Accordingly, correction of the barrier abnormality alone should ameliorate both the cytokine cascade and allergen-induced inflammation in AD. Taken together, in vitro studies on human immune cells and in vivo data obtained from murine models support the immunomodulatory role of the H4R on various cell types relevant in AD. Histamine might promote inflammation in AD via the H4R acting on Th cells with enhanced release of proinflammatory cytokines, and on APCs as a potent chemoattractant. In contrast, H4R controls inflammation by suppressing the production of cytokines as well as chemokines in APCs and thereby can influence Th-cell polarization linking innate and adaptive immune pathways. In the context of these conflicting activities of the H4R, additional research is needed to clarify whether H4R agonists or antagonists can yield promising drugs in the treatment of Primary preventive strategies for interrupting the atopic march have been unable to demonstrate a consistent effect on disease development, and, to date, intervention studies generally have not reportedany long-term benefit. Further research is warranted before any definitive recommendations can be made.

TRATAMIENTO TOPICOS Lubricantes Antibióticos locales Corticoides locales Baja potencia Mediana potencia No alta potencia ni fluorados

TRATAMIENTOS SISTEMICOS Antihistamínicos (hidroxicina, clorfenamina, ceterizina, fexofenadina) Antibióticos Ciclosporina,Gamma globulina EV,interferon, fototerapia

INMUNOMODULADORES Tacrolimus 0,03% , 0,1% (PROTOPIC, CROMIDIN,T-INMUN) Pimecrolimus 1% (ELIDEL)

MECANISMO DE ACCION Se unen a proteínas citoplasmáticas específicas e inhiben la actividad de la calcineurina Impiden la activación de los linfocitos T luego de ser estimulados por células presentadoras de antígenos

DERMATITIS ATOPICA DISFUNCION DE BARRERA ESTRUCTURAL Y FUNCIONAL PENETRACION DE ANTIGENOS DERMATITIS ATOPICA PRURITO RASQUIDO RESPUESTA INFLAMATORIA