RESUMO
BACKGROUND: Non-bullous pemphigoid (NBP) is a pemphigoid variant which frequently resembles other pruritic skin diseases. In contrast with bullous pemphigoid (BP), blisters are absent. In BP, previous studies showed that IgE autoantibodies may be involved in its pathogenesis. IgE-activated mast cells, basophils and eosinophils may participate in BP by inducing pruritus and possibly blister formation, although the differential role of IgE in NBP compared with BP has not yet been described. OBJECTIVE: To assess IgE in serum and skin of NBP and BP patients. METHODS: We examined total IgE and pemphigoid-specific IgE in the serum of 68 NBP and 50 BP patients by enzyme-linked immunosorbent assay (ELISA). Sera of 25 pemphigus patients and 25 elderly patients with pruritus were included as controls. Skin biopsies of 14 NBP and 14 BP patients with the highest IgE titres to NC16A were stained for IgE by immunofluorescence techniques. RESULTS: Total IgE was elevated in 63% of NBP and 60% of BP patients, and in 20% of pemphigus controls, as well as 60% of elderly controls. IgE ELISAs were more frequently positive in BP than in NBP (NC16A 18% vs. 9%, P = 0.139; BP230 34% vs. 22%, P = 0.149). IgE ELISAs for NC16A and BP230 were positive in 8% and 20% of elderly controls, respectively, while all pemphigus controls were negative. Two of 28 biopsies (7%; one NBP, one BP) showed linear IgE along the basement membrane zone, while in most biopsies (71% NBP; 86% BP) IgE was bound to dermal cells. CONCLUSION: Since IgE was present in the serum and skin of both NBP and BP patients, this supports IgE-dependent mechanisms common to both diseases, such as pruritus. However, it remains to be elucidated whether IgE contributes to blister formation in BP.
Assuntos
Penfigoide Bolhoso , Idoso , Autoanticorpos , Autoantígenos , Ensaio de Imunoadsorção Enzimática , Humanos , Imunoglobulina E , Colágenos não FibrilaresRESUMO
BACKGROUND: Epidermolysis bullosa (EB) is a heterogeneous group of rare and incurable genetic disorders characterized by fragility of the skin and mucosae, resulting in blisters and erosions. Several epidemiological studies in other populations have been carried out, reporting varying and sometimes inconclusive figures, highlighting the need for standardized epidemiological analyses in well-characterized cohorts. OBJECTIVES: To evaluate the epidemiological data on EB in the Netherlands, extracted from the molecularly well-characterized cohort in the Dutch EB Registry. METHODS: In this observational study all EB-patients that were based in the Netherlands and captured in the Dutch EB Registry between 1988 and 2018 were included. The epidemiological outcomes were based on complete diagnostic data (clinical features, immunofluorescence, electron microscopy and mutation analysis), with longitudinal follow-up. RESULTS: A total of 464 EB-patients (287 families) were included. The incidence and point-prevalence of EB in the Netherlands were 41.3 per million live births and 22.4 per million population, respectively. EB Simplex (EBS), Junctional EB (JEB), Dystrophic EB (DEB) and Kindler EB were diagnosed in 45.7%, 18.8%, 34.7% and 0.9% of the EB-patients, respectively, with an incidence and point-prevalence of 17.5 and 11.9 (EBS), 9.3 and 2.1 (JEB), 14.1 and 8.3 (DEB), 0.5 and 0.2 (Kindler EB). In 90.5% of the EB-patients the diagnosis was genetically confirmed. During the investigated time period 73 EB-patients died, 72.6% of whom as a direct consequence of their EB. CONCLUSION: The epidemiological outcomes of EB in the Netherlands are high, attributed to a high detection rate in a well-organized set-up, indicating that EB might be more common than previously assumed. These epidemiological data help to understand the extensive need for (specialized) medical care of EB-patients and is invaluable for the design and execution of therapeutic trials. This study emphasizes the importance of thorough reporting systems and registries worldwide.
Assuntos
Epidermólise Bolhosa Distrófica , Epidermólise Bolhosa Juncional , Epidermólise Bolhosa , Epidermólise Bolhosa/epidemiologia , Epidermólise Bolhosa/genética , Humanos , Países Baixos/epidemiologia , Sistema de RegistrosRESUMO
BACKGROUND: Antilaminin-332 mucous membrane pemphigoid is a chronic severe pemphigoid disease characterized by autoantibodies to laminin-332. At present no commercial assay is available to demonstrate antilaminin-332 antibodies, and diagnosis relies on in-house techniques with limited sensitivities. OBJECTIVES: In order to move, keratinocytes cultured in vitro secrete laminin-332 to attach to the culture dish. In that way, they leave behind a unique footprint trail of laminin-332. We aimed to develop a sensitive and specific laboratory assay to determine antilaminin-332 autoantibodies in patient serum based on binding of patient IgG to these unique footprints. METHODS: Normal human keratinocytes were grown on glass coverslips and incubated with patient or control serum for 1 h. The binding of IgG was then investigated by immunofluorescence. After validating the test for its ability to identify antilaminin-332 autoantibodies it was converted into a daily available test based on binding of IgG to dried coverslips that can be stored frozen. The staining patterns of sera from patients with antilaminin-332 pemphigoid were then compared with those of sera from patients with other autoimmune bullous diseases and normal human sera. RESULTS: IgG of all antilaminin-332 pemphigoid sera (n = 16) bound to laminin-332 footprints, while all normal human controls (n = 55) were negative. From the sera of patients with other diseases (n = 72) four sera tested positive. The footprint assay was also positive for sera that were negative by salt-split skin analysis, demonstrating that it is a very sensitive technique. CONCLUSIONS: The keratinocyte footprint assay is a fast and specific assay to confirm or rule out the presence of antilaminin-332 autoantibodies. What's already known about this topic? Antilaminin-332 mucous membrane pemphigoid is a severe form of pemphigoid, and patients may have an increased risk of malignancies. The diagnosis of antilaminin-332 mucous membrane pemphigoid is complicated by the lack of specific commercial tests for antilaminin-332 antibodies and can be confirmed only in specialized laboratories. Keratinocytes in culture need laminin-332 for adhesion and migration and therefore deposit it on the bottom of the culture dish. What does this study add? The keratinocyte footprint assay detects antilaminin-332 autoantibodies in patient serum using the native laminin-332 produced by cultured keratinocytes. What is the translational message? The keratinocyte footprint assay is a fast and specific assay to confirm or rule out the presence of antilaminin-332 autoantibodies.
Assuntos
Doenças Autoimunes , Penfigoide Mucomembranoso Benigno , Penfigoide Bolhoso , Autoanticorpos , Autoantígenos , Feminino , Humanos , Queratinócitos , Masculino , Penfigoide Bolhoso/diagnósticoRESUMO
Epidermolysis bullosa (EB) is a genetic blistering disorder characterized by intense pain related to disease pathology and care-based interventions. Opioid-based therapies underpin pain care in EB; however, they are unable to provide adequate analgesia in a significant proportion of patients. Cannabinoid-based medicines (CBMs) have been studied increasingly for pain conditions of various aetiologies and pose as a novel dimension for pain care in EB. We present three patients with EB who were prescribed pharmaceutical-grade sublingually administered CBMs comprising tetrahydrocannabinol and cannabidiol. All three patients reported improved pain scores, reduced pruritus and reduction in overall analgesic drug intake.
Assuntos
Canabidiol/administração & dosagem , Dronabinol/administração & dosagem , Epidermólise Bolhosa/complicações , Dor/tratamento farmacológico , Óleos de Plantas/administração & dosagem , Administração Sublingual , Adulto , Analgésicos Opioides/administração & dosagem , Cannabis/química , Combinação de Medicamentos , Quimioterapia Combinada/métodos , Epidermólise Bolhosa/tratamento farmacológico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Dor/diagnóstico , Dor/etiologia , Medição da Dor , Resultado do TratamentoAssuntos
Cardiomiopatia Dilatada/genética , Epidermólise Bolhosa Simples/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/cirurgia , Membrana Celular/metabolismo , Células Cultivadas , Análise Mutacional de DNA , Epidermólise Bolhosa Simples/complicações , Epidermólise Bolhosa Simples/patologia , Transplante de Coração , Humanos , Queratinócitos/citologia , Queratinócitos/metabolismo , Queratinócitos/ultraestrutura , Masculino , Microscopia Eletrônica , Mutação , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Proteínas Repressoras/metabolismo , Pele/citologia , Pele/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a complex autoimmune bullous disease disease with variable clinical presentations and multiple possible diagnostic tests, making an international consensus on the diagnosis of EBA essential. OBJECTIVES: To obtain an international consensus on the clinical and diagnostic criteria for EBA. METHODS: The International Bullous Diseases Group (IBDG) met three times to discuss the clinical and diagnostic criteria for EBA. For the final voting exercise, 22 experts from 14 different countries voted on 50 different items. When > 30% disagreed with a proposal, a discussion was held and re-voting carried out. RESULTS: In total, 48 of 50 proposals achieved consensus after discussion. This included nine diagnostic criteria, which are summarized in a flow chart. The IBDG was unable to determine one procedure that would be applicable worldwide. A limitation of the study is that differential diagnosis of bullous systemic lupus erythematosus has not been addressed. CONCLUSIONS: This first international consensus conference established generally agreed-upon clinical and laboratory criteria defining the clinical classification of and diagnostic testing for EBA. Holding these voting exercises in person with the possibility of discussion prior to voting has advantages in reaching consensus over Delphi exercises with remote voting.
Assuntos
Epidermólise Bolhosa Adquirida/diagnóstico , Técnicas de Laboratório Clínico/métodos , Consenso , Diagnóstico Diferencial , Ensaio de Imunoadsorção Enzimática/métodos , Imunofluorescência/métodos , Humanos , Immunoblotting/métodos , Microscopia Eletrônica de Transmissão e Varredura , Microscopia Imunoeletrônica/métodosAssuntos
Antígenos de Histocompatibilidade Classe II/genética , Pênfigo/genética , Brasil/etnologia , Estudos Transversais , Frequência do Gene/genética , Predisposição Genética para Doença/etnologia , Predisposição Genética para Doença/genética , Heterozigoto , Homozigoto , Humanos , Países Baixos/etnologia , Pênfigo/etnologiaAssuntos
Colite Ulcerativa/complicações , Imunoglobulina A/sangue , Dermatose Linear Bolhosa por IgA/complicações , Pênfigo/complicações , Adulto , Autoantígenos/imunologia , Feminino , Humanos , Imunoglobulina A/metabolismo , Dermatose Linear Bolhosa por IgA/sangue , Dermatose Linear Bolhosa por IgA/patologia , Neutrófilos/patologia , Colágenos não Fibrilares/imunologia , Pênfigo/metabolismo , Pênfigo/patologia , Colágeno Tipo XVIIRESUMO
Subcorneal pustular dermatosis (SPD), or Sneddon-Wilkinson disease, is a rare pustular skin disease that follows a chronic relapsing course. A well-known association exists between SPD and IgA monoclonal gammopathy of undetermined significance (MGUS), which exists in up to 40% of cases. SPD has also been observed in patients with IgA myeloma. In SPD, direct and indirect immunofluorescence studies do not reveal in vivo bound IgA to the epithelial cell surface, in contrast to IgA pemphigus, which has similar clinicopathological features. Here we describe the case of a male patient with SPD and a concurrent IgA MGUS who had been treated with dapsone for 20 years with frequent relapses. Following development of multiple myeloma, the patient was treated with intensive antimyeloma treatment consisting of high-dose melphalan with autologous stem cell transplantation. This resulted in a complete remission of the myeloma with disappearance of the M-protein. In addition, a sustained remission of SPD was achieved without further treatment. Twenty-eight months after melphalan therapy the M-protein reappeared in the serum, and 2 months later SPD reappeared with histopathologically proven skin lesions at predilection sites. Presence and absence of skin lesions was found to correlate with the presence and absence of the M-protein in the serum. This is the first report of antimyeloma therapy inducing a long-lasting remission in SPD. The findings in this patient strongly suggest a causal role for circulating IgA antibodies in the pathogenesis of SPD. Antimyeloma treatment should be considered in patients with IgA MGUS-associated SPD refractory to other therapies.
Assuntos
Melfalan/uso terapêutico , Mieloma Múltiplo/terapia , Dermatopatias Vesiculobolhosas/terapia , Transplante Autólogo , Terapia Combinada , Dapsona/uso terapêutico , Humanos , Imunoglobulina A , Masculino , Pessoa de Meia-Idade , Gamopatia Monoclonal de Significância Indeterminada/complicações , Proteínas do Mieloma/efeitos dos fármacos , Indução de Remissão , Dermatopatias Vesiculobolhosas/complicações , Transplante de Células-Tronco/métodos , Resultado do TratamentoRESUMO
Treatment approaches for bullous pemphigoid (BP), the most common autoimmune skin blistering disease, are largely based on national and international guidelines. We conducted a national survey among dermatologists in the Netherlands to explore the current treatment of BP, and compared the results with those of a previously published survey from the UK. Almost all responders in the Netherlands (n = 175) used very potent topical corticosteroids, both as monotherapy and as adjunctive therapy. In contrast to UK dermatologists, the majority recommended whole-body application rather than local application to lesions. Systemic antibiotics were used by > 70% of responders. Half of the responders in the Netherlands considered systemic steroids the first-choice treatment, with the majority also using adjunctive therapy as a routine. Despite many similarities in treatment approach between the two countries, these surveys provide an important insight into the gap between actual and recommended practice at a country level in relation to the best external evidence.
Assuntos
Penfigoide Bolhoso/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Fármacos Dermatológicos/uso terapêutico , Dermatologia/estatística & dados numéricos , Glucocorticoides/uso terapêutico , Humanos , Países Baixos , Esteroides/uso terapêutico , Reino UnidoRESUMO
This article summarizes recommendations reached following a systematic literature review and expert consensus on the diagnosis and management of cutaneous squamous cell carcinomas in people with epidermolysis bullosa. The guidelines are intended to help inform decision making by clinicians dealing with this complex complication of a devastating disease.
Assuntos
Carcinoma de Células Escamosas/terapia , Epidermólise Bolhosa/complicações , Neoplasias Cutâneas/terapia , Amputação Cirúrgica/métodos , Membros Artificiais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/prevenção & controle , Consenso , Humanos , Metástase Linfática , Procedimentos Cirúrgicos Minimamente Invasivos/métodos , Metástase Neoplásica , Estadiamento de Neoplasias , Dor/prevenção & controle , Guias de Prática Clínica como Assunto , Psicoterapia/métodos , Retinoides/uso terapêutico , Biópsia de Linfonodo Sentinela/métodos , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/prevenção & controle , Assistência Terminal/métodos , Técnicas de Fechamento de FerimentosAssuntos
Anticorpos Monoclonais/imunologia , Autoantígenos/genética , Autoantígenos/imunologia , Epidermólise Bolhosa Juncional/diagnóstico , Colágenos não Fibrilares/genética , Colágenos não Fibrilares/imunologia , Epidermólise Bolhosa Juncional/genética , Epidermólise Bolhosa Juncional/imunologia , Humanos , Mutação , Colágeno Tipo XVIIAssuntos
Hidradenite Supurativa/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Estudos de Casos e Controles , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Hidradenite Supurativa/sangue , Humanos , Glicoproteínas de Membrana/metabolismo , Proteínas de Membrana/metabolismo , Presenilina-1/metabolismo , RNA Mensageiro/metabolismo , Pele/metabolismoRESUMO
Mutations in the COL17A1 gene lead to the genetic blistering disorder junctional epidermolysis bullosa generalized intermediate type (JEB-gen-intermed). Antisense oligonucleotide-mediated exon skipping is a strategy that aims to skip the mutation-containing exon and thereby produce a smaller but functional protein. COL17A1 is an interesting candidate, as 53 of the 55 exons (96%) can be skipped without disturbing the reading frame. Information on the functionality of the shortened protein product is important in order to obtain support for this therapeutic strategy. Here we report a patient with JEB-gen-intermed with amelioration of the phenotype due to exon 49 skipping by two distinct mechanisms - premature termination codon-induced exon skipping and revertant mosaicism - both of which induced skipping of the same exon. The patient was compound heterozygous for two inherited COL17A1 mutations, a frameshift mutation in exon 18 (c.1490_1491delinsT, p.Ala497Valfs*23) and a nonsense mutation in exon 49 (c.3487G>T, p.Glu1163Ter). Upon clinical examination, skin patches were found that were resistant to blister formation. In these patches, naturally corrected cells were present that harboured an additional splice-site mutation, c.3419-1G>T, resulting in skipping of the mutation-containing exon 49. This natural gene therapy phenomenon shows that type XVII collagen with residues 1140-1169 deleted is largely functional. In addition, in affected skin cells a low level of exon 49 skipping was observed. Our results support the notion that skipping of a mutated in-frame exon in COL17A1 ameliorates the phenotype.