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OBJECTIVE AND DESIGN: The discovery of new inflammatory pathways and the mechanism of action of inflammatory, autoimmune, genetic, and neoplastic diseases led to the development of immunologically driven drugs. We aimed to perform a narrative review regarding the rising of a new class of drugs capable of blocking important and specific intracellular signals in the maintenance of these pathologies: the small molecules. MATERIALS/METHODS: A total of 114 scientific papers were enrolled in this narrative review. RESULTS: We describe in detail the families of protein kinases-Janus Kinase (JAK), Src kinase, Syk tyrosine kinase, Mitogen-Activated Protein Kinase (MAPK), and Bruton Tyrosine Kinase (BTK)-their physiologic function and new drugs that block these pathways of intracellular signaling. We also detail the involved cytokines and the main metabolic and clinical implications of these new medications in the field of dermatology. CONCLUSIONS: Despite having lower specificity compared to specific immunobiological therapies, these new drugs are effective in a wide variety of dermatological diseases, especially diseases that had few therapeutic options, such as psoriasis, psoriatic arthritis, atopic dermatitis, alopecia areata, and vitiligo.
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Dermatología , Psoriasis , Vitíligo , Humanos , Autoinmunidad , Psoriasis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Quinasas Janus/metabolismoRESUMEN
Generalized verrucosis is a clinical manifestation of human papillomavirus infection. Patients with generalized verrucosis present with over 20 verrucae distributed over various anatomical sites. The disorder occurs in association with several genetic syndromes with immunodeficiency, including GATA2 deficiency. We report a 12-year-old boy with GATA2 deficiency and generalized verrucosis that worsened after cyclosporine use following bone marrow transplant. Systemic treatment with acitretin and topical application of trichloroacetic acid, likely along with immune reconstitution, led to complete remission.
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Deficiencia GATA2 , Verrugas , Acitretina/uso terapéutico , Niño , Factor de Transcripción GATA2 , Humanos , Masculino , Papillomaviridae , Ácido Tricloroacético , Verrugas/tratamiento farmacológicoRESUMEN
Localized cutaneous leishmaniasis (LCL) can ultimately progress to chronic ulcerated lesions with strong local inflammatory reactions. The functional role of certain inflammasomes in mediating inflammation caused by Leishmania braziliensis needs to be addressed. By combining PCR-array, quantitative real-time PCR and immunohistochemical analysis, we identified inflammasome genes, such as IL-1ß, NLRP3, NLRP1, NLRC5, AIM2 and P2RX7, that were upregulated in LCL patients. Temporal gene expression studies showed that the early phase of LCL displayed increased NLRP3 and reduced AIM2 and NLRP1 expression, while the late stages showed increased AIM2 and NLRP1 and lower NLRP3 expression. Our findings also showed that AIM2, NLRP1, and P2RX7 promoted susceptibility to experimental L. braziliensis infection. These results highlight the importance of inflammasome machinery in human LCL and suggest that inflammasome machinery plays a role in the acute and chronic phases of the disease.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Proteínas de Unión al ADN/genética , Inflamasomas/genética , Leishmaniasis Cutánea/genética , Receptores Purinérgicos P2X7/genética , Piel/inmunología , Proteínas Adaptadoras Transductoras de Señales/inmunología , Adulto , Animales , Proteínas Reguladoras de la Apoptosis/inmunología , Proteínas de Unión al ADN/inmunología , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Inflamasomas/inmunología , Interleucina-1beta/genética , Interleucina-1beta/inmunología , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/inmunología , Leishmania braziliensis/inmunología , Leishmania braziliensis/patogenicidad , Leishmaniasis Cutánea/inmunología , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteínas NLR , Receptores Purinérgicos P2X7/inmunología , Transducción de Señal , Piel/parasitología , Piel/patologíaRESUMEN
Atopic dermatitis is a chronic, recurrent, and multifactorial skin-mucosal manifestation resulting from the interaction between elements mainly associated with the skin barrier deficit, the homeostasis of the immune response, neurological aspects, and patterns of reactivity to environmental antigens, which are established in genetically predisposed individuals. In addition to the skin, atopic diathesis involves other organs such as the airways (upper and lower), eyes, digestive tract, and neuropsychiatric aspects, which inflict additional morbidity on the dermatological patient. The different phenotypes of the disease fundamentally depend on the participation of each of these factors, in different life circumstances, such as age groups, occupational exposure patterns, physical activity, pollution, genetic load, and climatic factors. A better understanding of the complexity of its pathogenesis allows not only the understanding of therapeutic targets but also how to identify preponderant elements that mediate disease activity in each circumstance, for selecting the best treatment strategies and mitigation of triggering factors. This narrative review presents an update on the pathogenesis of atopic dermatitis, especially aimed at understanding the clinical manifestations, the main disease phenotypes and the context of available therapeutic strategies.
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BACKGROUND: Dexamethasone-cyclophosphamide pulse (DCP) and dexamethasone pulse (DP) have been successfully used to treat pemphigus, but DCP/DP outcomes comparing pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are scarce. OBJECTIVE: To compare DCP/DP outcomes in a Brazilian cohort of PV and PF patients according to demographic and clinical data. METHODS: Retrospective analytical cohort study, reviewing medical charts of PV and PF patients (for DCP/DP Phases IâIV consult Pasricha et al.16â18). RESULTS: 37 PV and 41 PF patients non responsive to usual treatments were included similarly for DCP or DP therapy. Disease duration was longer among PF before DCP/DP prescription (pâ¯<â¯0.001); PF required a higher number of monthly pulses to acquire remission in Phase I (median 10 and 6 pulses, respectively; pâ¯=â¯0.005). DCP/DP outcomes were similar in both groups: remission in 37.8% of PV and 34.1% of PF after completed DCP/DP cycles following a median of 13 months (1-56 months follow-up); failure occurred in 13.5% of PV and 14.6% of PF in Phase I; relapse in 13.5% of PV and 12.2% of PF, and dropout in 27% of PV and 24.4% of PF in Phases II to IV. Mild side effects were documented. STUDY LIMITATIONS: The severity of PV and PF disease was not assessed by score indexes. CONCLUSIONS: PV and PF patients presented similar DCP/DP outcomes. DCP/DP should be initiated earlier in PF patients due to the longer duration of their disease in order to decrease the number of pulses and the duration of Phase I to acquire remission.
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Pénfigo , Humanos , Pénfigo/tratamiento farmacológico , Estudios de Cohortes , Dexametasona/uso terapéutico , Estudios Retrospectivos , Brasil , Resultado del Tratamiento , Ciclofosfamida/uso terapéuticoRESUMEN
BACKGROUND: Sensitization to house dust mites (HDMs) is frequent in patients with atopic dermatitis. OBJECTIVE: To investigate the efficacy of sublingual immunotherapy (SLIT) with Dermatophagoides pteronyssinus extract in patients with atopic dermatitis sensitized to HDM. METHODS: In this randomized, double-blind, placebo-controlled trial, we enrolled 91 patients 3 years or older, with SCORing Atopic Dermatitis (SCORAD) score greater than or equal to 15 and positive skin test result and/or IgE to D pteronyssinus. Patients were stratified according to age (<12 and ≥12 years) to receive HDM SLIT or placebo for 18 months. Primary outcome was a greater than or equal to 15-point decrease in SCORAD score. Secondary outcomes were decreases in SCORAD and objective SCORAD, Eczema Area and Severity Index, visual analog scale for symptoms, and pruritus scale scores; Investigator's Global Assessment 0/1; and decrease greater than or equal to 4 points in Dermatology Life Quality Index. Background therapy was maintained. RESULTS: A total of 66 patients completed the study (35 HDM SLIT, 31 placebo). After 18 months, 74.2% and 58% of patients in the HDM SLIT group and the placebo group, respectively, showed greater than or equal to 15-point decrease in SCORAD score (relative risk, 1.28; 95% CI, 0.89-1.83). Significant SCORAD score decreases from baseline of 55.6% and 34.5% in HDM SLIT and placebo groups (mean difference, 20.4; 95% CI, 3.89-37.3), significant objective SCORAD score decreases of 56.8% and 34.9% in HDM SLIT and placebo groups (mean difference, 21.3; 95% CI, 0.66-41.81), and more patients with Investigator's Global Assessment 0/1 in the HDM SLIT group as compared with the placebo group (14 of 35 vs 5 of 31; relative risk, 2.63; 95% CI, 1.09-6.39) were observed at 18 months. CONCLUSIONS: Our results suggest that HDM SLIT may be effective in HDM-sensitized patients as an add-on treatment for atopic dermatitis.
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Dermatitis Atópica , Eccema , Inmunoterapia Sublingual , Animales , Antígenos Dermatofagoides/uso terapéutico , Niño , Dermatitis Atópica/tratamiento farmacológico , Dermatophagoides pteronyssinus , Método Doble Ciego , Eccema/tratamiento farmacológico , Humanos , Pyroglyphidae , Inmunoterapia Sublingual/métodos , Resultado del TratamientoRESUMEN
BACKGROUND: Bullous pemphigoid (BP) associated with milia lesions has been increasingly reported, but its prevalence has not been reported in a Brazilian BP population yet. OBJECTIVES: To describe the occurrence and clinical-laboratorial findings of BP-milia association in a southeastern Brazilian sample. METHODS: A descriptive study based on the medical charts of 102 BP patients was accomplished. Clinical and laboratory data of BP-milia patients were compiled. Total serum IgE measurements, immunoblot assays based on basement membrane zone antigens, and HLA-DQ alleles typing were performed. RESULTS: Milia was evident in 8 (7.8%) BP patients, five males, aged between 46 and 88 years. Increased total IgE levels were determined in 7 (87.5%) of the eight patients. In five of eight patients, immunoblotting showed IgG reactivity against the BP180-NC16a domain but not against collagen VII or laminin-332; it also revealed reactivity against the BP180 C-terminal domain or LAD-1, or both in four of them. The HLA-DQB1*03:01 and HLA-DQA1*05:05 alleles were identified in three of five BP-milia patients. Moreover, three of five cases presented the HLA-DQB1*06 allelic group. STUDY LIMITATIONS: HLA determination was performed in five patients. CONCLUSIONS: Milia formation in BP patients seems to be less uncommon than previously admitted. Laboratory data revealed increased IgE; autoantibodies against the BP180 C-terminal domain or LAD-1, or both; and the HLA-DQB1*06 allelic group, described for the BP-milia association. Careful determination of antibodies against basement membrane zone molecules and HLA characterization in different populations may provide further insights into this association.
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Queratosis , Penfigoide Ampolloso , Anciano , Anciano de 80 o más Años , Autoanticuerpos , Autoantígenos , Brasil , Humanos , Inmunoglobulina E , Queratosis/patología , Laboratorios Clínicos , Masculino , Persona de Mediana Edad , Colágenos no Fibrilares , Penfigoide Ampolloso/patología , PrevalenciaRESUMEN
BACKGROUND: Chronic leg ulcers affect a large portion of the adult population and cause a significant social and economic impact, related to outpatient and hospital care, absence from work, social security expenses, and reduced quality of life. The correct diagnosis and therapeutic approach are essential for a favorable evolution. OBJECTIVE: To gather the experience of Brazilian dermatologists, reviewing the specialized literature to prepare recommendations for the diagnosis and treatment of the main types of chronic leg ulcers. METHODS: Seven specialists from six university centers with experience in chronic leg ulcers were appointed by the Brazilian Society of Dermatology to reach a consensus on the diagnosis and therapeutic management of these ulcers. Based on the adapted DELPHI methodology, relevant elements were considered in the diagnosis and treatment of chronic leg ulcers of the most common causes; then, the recent literature was analyzed using the best scientific evidence. RESULTS: The following themes were defined as relevant for this consensus - the most prevalent differential etiological diagnoses of chronic leg ulcers (venous, arterial, neuropathic, and hypertensive ulcers), as well as the management of each one. It also included the topic of general principles for local management, common to chronic ulcers, regardless of the etiology. CONCLUSION: This consensus addressed the main etiologies of chronic leg ulcers and their management based on scientific evidence to assist dermatologists and other health professionals and benefit the greatest number of patients with this condition.
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Dermatología , Úlcera de la Pierna , Úlcera Varicosa , Adulto , Brasil , Consenso , Humanos , Úlcera de la Pierna/diagnóstico , Úlcera de la Pierna/terapia , Calidad de Vida , Úlcera Varicosa/diagnóstico , Úlcera Varicosa/terapiaRESUMEN
INTRODUCTION: American tegumentary leishmaniasis (ATL) and leprosy share common areas of prevalence, but reports of coinfection are scarce. METHODS: We report a series of 9 ATL-leprosy cases and discuss the association. An integrative diagram to analyze the clinico-immunological features of coinfection with both diseases. RESULTS: Nine patients with leishmaniasis (5 cutaneous, 3 mucocutaneous, 1 disseminated case) exhibited concurrent infection with distinct clinical forms of leprosy. Our diagram-based analysis evidenced a divergent clinico-immunological spectrum for each disease in 8 out of 9 cases. CONCLUSIONS: The spectrum of ATL-leprosy comorbidity suggests that the host has a specific immune response against each pathogen.
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Coinfección/inmunología , Leishmaniasis Cutánea/inmunología , Lepra/inmunología , Células TH1/inmunología , Células Th2/inmunología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leishmaniasis Cutánea/complicaciones , Lepra/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Mohs micrographic surgery (MMS) promotes high cure rates, but accessibility to MMS is limited in distinctive realities and countries. OBJECTIVE: We sought to verify applicable criteria for MMS indication and prioritization regarding basal cell carcinoma (BCC) in the face of various limitations. METHODS: We analyzed MMS-excised BBC, without patient exclusion, through a retrospective cohort study at a single university center. RESULTS: Mohs micrographic surgery was performed in 101 BCCs, average size = 5.44 ± 11.91 cm2, 56.44% ≥ 20 mm. Most BCCs were in the H-zone (87.13%) and on the nose (52.47%). Histology showed high-risk pattern in most of tumors (69.31%), primary (64.71%), and recurrent (74.0%) BCC. Nasal (p = .01) and recurrent BCC (p = .03) had increased risk for two or more MMS stages. Appropriate use criteria were considered for all cases of BCC removed by a single stage (60.40%), two or more stages (39.60%), and three or more MMS stages (10.89%). The latter two conditions were associated with a higher number of MMS criteria (p = .02; p = .03, respectively). CONCLUSIONS: All excised BCCs fulfilled criteria for MMS indication, among them recurrent and nasal BCCs stood out. The greater number of criteria may be a predictive factor for subclinical extension and can help prioritize indications for MMS.
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Carcinoma Basocelular/cirugía , Cirugía de Mohs , Neoplasias Cutáneas/cirugía , Anciano , Brasil , Carcinoma Basocelular/patología , Estudios de Cohortes , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Neoplasias Cutáneas/patologíaAsunto(s)
Carcinoma de Células Escamosas , Leishmaniasis Cutánea , Neoplasias Cutáneas , Humanos , Leishmaniasis Cutánea/patología , Leishmaniasis Cutánea/tratamiento farmacológico , Carcinoma de Células Escamosas/patología , Neoplasias Cutáneas/patología , Masculino , Anciano , Femenino , Diagnóstico Diferencial , Biopsia , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Stevens-Johnson syndrome and toxic epidermal necrolysis are life-threatening blistering drug reactions with high incidence of ocular sequela. The term 'Epidermal Necrolysis' has been recently used to better describe the full spectrum of the disease that includes Stevens-Johnson syndrome and toxic epidermal necrolysis at opposite ends, which differ by the extent of body surface area with epidermal detachment. SCORTEN is a mortality prognosis score for 'Epidermal Necrolysis' cases that still needed validation in acquired immunodeficiency syndrome. OBJECTIVE: To evaluate the SCORTEN performance in acquired immunodeficiency syndrome, and the differences in outcomes between acquired immunodeficiency syndrome and non- acquired immunodeficiency syndrome cohorts. METHODS: Retrospective cohort study of AIDS and non-AIDS 'Epidermal Necrolysis' cases admitted to a Brazilian reference center from 1990-2014. RESULTS: Five deaths (16.7%) occurred as a consequence of EN in 30 AIDS patients, and seven (17.9%) in 39 non-AIDS patients, relative risk (RR) .92 (p=1.0). SCORTEN showed great performance, with an Area Under the Receiver Operating Curve (AUC) (ROC) of 0.90 with a 95% confidence interval ranging from .81 to .99. The performance of SCORTEN was better among non- AIDS patients than AIDS patients: AUC non- acquired immunodeficiency syndrome =0.99 (CI 05% 0.96-1.00), AUC acquired immunodeficiency syndrome = 0.74 (CI 95% 0.53-0.95), p=.02. STUDY LIMITATIONS: Heterogeneity of cases, wide variation of systemic corticosteroid doses when used. CONCLUSION: SCORTEN is valid for the Brazilian population, including among those patients with acquired immunodeficiency syndrome, and, as such, its use is recommended for aiding treatment choice in this subgroup of patients.
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Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/patología , Índice de Severidad de la Enfermedad , Síndrome de Stevens-Johnson/epidemiología , Síndrome de Stevens-Johnson/patología , Adolescente , Adulto , Anciano , Brasil/epidemiología , Niño , Preescolar , Femenino , Humanos , Lactante , Tiempo de Internación , Masculino , Persona de Mediana Edad , Distribución de Poisson , Pronóstico , Curva ROC , Estudios Retrospectivos , Factores de Riesgo , Estadísticas no Paramétricas , Centros de Atención Terciaria , Factores de Tiempo , Adulto JovenAsunto(s)
Quiste Epidérmico , Herpes Simple , Pénfigo , Humanos , Pénfigo/complicaciones , Conjuntiva , Herpes Simple/complicacionesRESUMEN
INTRODUCTION: Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS: Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS: Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS: Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.
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Corticoesteroides/administración & dosificación , Síndrome Antifosfolípido , Lepra Multibacilar/inmunología , Talidomida/administración & dosificación , Corticoesteroides/efectos adversos , Adulto , Anciano , Anticuerpos Antifosfolípidos/sangre , Anticuerpos Antifosfolípidos/efectos de los fármacos , Anticuerpos Antifosfolípidos/genética , Síndrome Antifosfolípido/sangre , Síndrome Antifosfolípido/tratamiento farmacológico , Síndrome Antifosfolípido/genética , Ensayo de Inmunoadsorción Enzimática , Factor V/análisis , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Lepra Multibacilar/tratamiento farmacológico , Lepra Multibacilar/genética , Masculino , Persona de Mediana Edad , Mutación , Polimorfismo Genético , Protrombina/análisis , Talidomida/efectos adversos , Tromboembolia Venosa/tratamiento farmacológico , beta 2 Glicoproteína I/sangreRESUMEN
Abstract Background Dexamethasone-cyclophosphamide pulse (DCP) and dexamethasone pulse (DP) have been successfully used to treat pemphigus, but DCP/DP outcomes comparing pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are scarce. Objective To compare DCP/DP outcomes in a Brazilian cohort of PV and PF patients according to demographic and clinical data. Methods Retrospective analytical cohort study, reviewing medical charts of PV and PF patients (for DCP/DP Phases I‒IV consult Pasricha et al.16‒18). Results 37 PV and 41 PF patients non responsive to usual treatments were included similarly for DCP or DP therapy. Disease duration was longer among PF before DCP/DP prescription (p < 0.001); PF required a higher number of monthly pulses to acquire remission in Phase I (median 10 and 6 pulses, respectively; p = 0.005). DCP/DP outcomes were similar in both groups: remission in 37.8% of PV and 34.1% of PF after completed DCP/DP cycles following a median of 13 months (1-56 months follow-up); failure occurred in 13.5% of PV and 14.6% of PF in Phase I; relapse in 13.5% of PV and 12.2% of PF, and dropout in 27% of PV and 24.4% of PF in Phases II to IV. Mild side effects were documented. Study limitations The severity of PV and PF disease was not assessed by score indexes. Conclusions PV and PF patients presented similar DCP/DP outcomes. DCP/DP should be initiated earlier in PF patients due to the longer duration of their disease in order to decrease the number of pulses and the duration of Phase I to acquire remission.
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Abstract Background: Bullous pemphigoid (BP) associated with milia lesions has been increasingly reported, but its prevalence has not been reported in a Brazilian BP population yet. Objectives: To describe the occurrence and clinical-laboratorial findings of BP-milia association in a southeastern Brazilian sample. Methods: A descriptive study based on the medical charts of 102 BP patients was accomplished. Clinical and laboratory data of BP-milia patients were compiled. Total serum IgE measurements, immunoblot assays based on basement membrane zone antigens, and HLA-DQ alleles typing were performed. Results: Milia was evident in 8 (7.8%) BP patients, five males, aged between 46 and 88 years. Increased total IgE levels were determined in 7 (87.5%) of the eight patients. In five of eight patients, immunoblotting showed IgG reactivity against the BP180-NC16a domain but not against collagen VII or laminin-332; it also revealed reactivity against the BP180 C-terminal domain or LAD-1, or both in four of them. The HLA-DQB1*03:01 and HLA-DQA1*05:05 alleles were identified in three of five BP-milia patients. Moreover, three of five cases presented the HLA-DQB1*06 allelic group. Study limitations: HLA determination was performed in five patients. Conclusions: Milia formation in BP patients seems to be less uncommon than previously admitted. Laboratory data revealed increased IgE; autoantibodies against the BP180 C-terminal domain or LAD-1, or both; and the HLA-DQB1*06 allelic group, described for the BP-milia association. Careful determination of antibodies against basement membrane zone molecules and HLA characterization in different populations may provide further insights into this association. © 2022 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).
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Abstract INTRODUCTION: American tegumentary leishmaniasis (ATL) and leprosy share common areas of prevalence, but reports of coinfection are scarce. METHODS: We report a series of 9 ATL-leprosy cases and discuss the association. An integrative diagram to analyze the clinico-immunological features of coinfection with both diseases. RESULTS: Nine patients with leishmaniasis (5 cutaneous, 3 mucocutaneous, 1 disseminated case) exhibited concurrent infection with distinct clinical forms of leprosy. Our diagram-based analysis evidenced a divergent clinico-immunological spectrum for each disease in 8 out of 9 cases. CONCLUSIONS: The spectrum of ATL-leprosy comorbidity suggests that the host has a specific immune response against each pathogen.