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Acute systemic lupus erythematosus (SLE) courses with surges of antibody-secreting cells (ASCs) whose origin, diversity and contribution to serum autoantibodies remain unknown. Here, deep sequencing, proteomic profiling of autoantibodies and single-cell analysis demonstrated highly diversified ASCs punctuated by clones expressing the variable heavy-chain region VH4-34 that produced dominant serum autoantibodies. A fraction of ASC clones contained autoantibodies without mutation, a finding consistent with differentiation outside the germinal centers. A substantial ASC segment was derived from a distinct subset of newly activated naive cells of considerable clonality that persisted in the circulation for several months. Thus, selection of SLE autoreactivities occurred during polyclonal activation, with prolonged recruitment of recently activated naive B cells. Our findings shed light on the pathogenesis of SLE, help explain the benefit of agents that target B cells and should facilitate the design of future therapies.
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Diversidad de Anticuerpos/inmunología , Células Productoras de Anticuerpos/inmunología , Autoanticuerpos/inmunología , Proliferación Celular , Lupus Eritematoso Sistémico/inmunología , Enfermedad Aguda , Secuencia de Aminoácidos , Diversidad de Anticuerpos/genética , Células Productoras de Anticuerpos/metabolismo , Autoanticuerpos/genética , Autoanticuerpos/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Secuencia de Bases , Células Clonales/inmunología , Células Clonales/metabolismo , Citometría de Flujo , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/genética , Inmunoglobulina G/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Cadenas Pesadas de Inmunoglobulina/metabolismo , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Región Variable de Inmunoglobulina/metabolismo , Vacunas contra la Influenza/inmunología , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Datos de Secuencia Molecular , Proteoma/análisis , Proteoma/inmunología , Proteómica/métodos , Homología de Secuencia de Aminoácido , Análisis de la Célula Individual/métodos , Espectrometría de Masas en Tándem , Toxoide Tetánico/inmunologíaRESUMEN
BACKGROUND: Previous clinical trials have demonstrated that rituximab therapy combined with conventional steroid-sparing therapy (SST) has increased rates of disease control for mucous membrane pemphigoid compared with rituximab alone. However, limited data is available regarding the role of SST with rituximab therapy in pemphigus. OBJECTIVE: This study aimed to examine clinical outcomes in pemphigus patients treated with rituximab with SST versus without the addition of SST. METHODS: A retrospective chart review was performed for adult pemphigus patients in the Southeastern US at Emory between January 1, 2011, and December 31, 2021. Primary outcomes, including time to remission, time to prednisone dose of 10 mg or less, time to cessation of prednisone therapy, and time to relapse after a rituximab cycle, were compared between patients on SST and patients without SST. Results: Following rituximab therapy, there was no difference in time to remission, time to prednisone dose of 10 mg or less, time to cessation of prednisone therapy, or time to relapse for patients with or without SST. LIMITATIONS: Our study is limited by its retrospective decline, setting at a single academic center, and inclusion of a high proportion of patients with moderate disease. CONCLUSIONS: The use of SST with rituximab dosing did not improve clinical outcomes related to time to remission, reduction in prednisone dosing, or relapse. These data provide further evidence for the use of rituximab in the majority of pemphigus patients without the need for SST. J Drugs Dermatol. 2024;23(3):e97-e99 doi:10.36849/JDD.7949e.
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Pénfigo , Adulto , Humanos , Pénfigo/diagnóstico , Pénfigo/tratamiento farmacológico , Prednisona/uso terapéutico , Rituximab , Estudios Retrospectivos , RecurrenciaRESUMEN
Proliferative verrucous leukoplakia (PVL) is a rare, aggressive form of oral leukoplakia with a substantial risk of malignant transformation. The slowly progressive course and the lack of a single defining histopathologic characteristic for PVL make this entity a diagnostic challenge. We report on a patient who presented with a 7-year history of worsening oral lesions.
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Liquen Plano , HumanosRESUMEN
Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by recruitment of leucocytes into skin and release of damaging enzymes, resulting in epidermal detachment and blister formation. To better understand the role of leukotriene B4 (LTB4) and other inflammatory factors in BP pathophysiology, we conducted microscopic and immunohistochemical analyses of preserved skin biopsy sections and conducted flow cytometry and ELISA analyses of matched blood and blister fluid from BP patients. Neutrophils predominated in BP blister fluid, which also contained monocytes/macrophages and T cells, but few to no eosinophils and B cells. In contrast, BP skin histology showed a different pattern, with abundant neutrophils but eosinophils being the predominant immune cell type. LTB4 pathway and neutrophil activation markers were prevalent in BP skin lesions and strongly associated with perivascular neutrophils. Blister fluid neutrophils, monocytes/macrophages and eosinophils all exhibited increased surface expression of leukotriene A4 hydrolase and neutrophil elastase (P = .002 for both). Blister fluid was also enriched in interleukins (IL)-1α, IL-1ß, IL-8, IL-10, IL-18, monocyte colony-stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF). Our findings suggest differential leucocyte recruitment from blood into dermis and from dermis into blister, which correlates with disease activity, and presents potential new treatment opportunities for BP.
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Exudados y Transudados/citología , Leucotrieno B4/metabolismo , Penfigoide Ampolloso/sangre , Penfigoide Ampolloso/patología , Piel/patología , Anciano , Anciano de 80 o más Años , Eosinófilos , Epóxido Hidrolasas/metabolismo , Exudados y Transudados/metabolismo , Femenino , Citometría de Flujo , Humanos , Interleucinas/metabolismo , Elastasa de Leucocito/metabolismo , Factor Estimulante de Colonias de Macrófagos/metabolismo , Macrófagos/enzimología , Masculino , Persona de Mediana Edad , Monocitos/enzimología , Infiltración Neutrófila , Neutrófilos/enzimología , Penfigoide Ampolloso/inmunología , Factores Raciales , Factores Sexuales , Piel/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Several European countries recently developed international diagnostic and management guidelines for pemphigus, which have been instrumental in the standardization of pemphigus management. OBJECTIVE: We now present results from a subsequent Delphi consensus to broaden the generalizability of the recommendations. METHODS: A preliminary survey, based on the European Dermatology Forum and the European Academy of Dermatology and Venereology guidelines, was sent to a panel of international experts to determine the level of consensus. The results were discussed at the International Bullous Diseases Consensus Group in March 2016 during the annual American Academy of Dermatology conference. Following the meeting, a second survey was sent to more experts to achieve greater international consensus. RESULTS: The 39 experts participated in the first round of the Delphi survey, and 54 experts from 21 countries completed the second round. The number of statements in the survey was reduced from 175 topics in Delphi I to 24 topics in Delphi II on the basis of Delphi results and meeting discussion. LIMITATIONS: Each recommendation represents the majority opinion and therefore may not reflect all possible treatment options available. CONCLUSIONS: We present here the recommendations resulting from this Delphi process. This international consensus includes intravenous CD20 inhibitors as a first-line therapy option for moderate-to-severe pemphigus.
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Factores Inmunológicos/administración & dosificación , Pénfigo/diagnóstico , Pénfigo/terapia , Plasmaféresis , Guías de Práctica Clínica como Asunto , Academias e Institutos/normas , Administración Intravenosa , Antígenos CD20/inmunología , Terapia Combinada/métodos , Terapia Combinada/normas , Consenso , Técnica Delphi , Dermatología/métodos , Dermatología/normas , Quimioterapia Combinada/métodos , Quimioterapia Combinada/normas , Europa (Continente) , Glucocorticoides/administración & dosificación , Humanos , Pénfigo/inmunología , Rituximab/administración & dosificación , Índice de Severidad de la EnfermedadAsunto(s)
Dermatitis Atópica , Infecciones por VIH , Prurigo , Humanos , Dermatitis Atópica/diagnóstico , Dermatitis Atópica/complicaciones , Dermatitis Atópica/tratamiento farmacológico , Prurigo/diagnóstico , Prurigo/tratamiento farmacológico , Infecciones por VIH/complicaciones , Selección de Paciente , Ensayos Clínicos como AsuntoAsunto(s)
Hispánicos o Latinos , Hospitalización , Pénfigo , Índice de Severidad de la Enfermedad , Humanos , Pénfigo/etnología , Pénfigo/epidemiología , Pénfigo/diagnóstico , Estudios Retrospectivos , Hispánicos o Latinos/estadística & datos numéricos , Femenino , Masculino , Hospitalización/estadística & datos numéricos , Persona de Mediana Edad , Adulto , Factores de Riesgo , Anciano , Adulto JovenRESUMEN
Rituximab is an anti-CD20 antibody used to deplete B lymphocytes in lymphoma and autoimmune disease. Case reports in the literature describe patients who paradoxically develop autoimmune disease in response to rituximab therapy. We review the reports of autoimmune pathology in response to rituximab treatment and the proposed mechanisms of this reaction. These autoimmune diseases manifest in various organ systems, most frequently the skin and lungs, and involve distinct mechanisms of pathogenesis mediated by potential alterations in B and T lymphocytes, innate immune system, and specific environmental factors. Those clinicians utilizing rituximab should be aware of this unusual phenomenon.
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Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Linfocitos B/efectos de los fármacos , Factores Inmunológicos/efectos adversos , Rituximab/efectos adversos , Enfermedades Autoinmunes/epidemiología , Linfocitos B/inmunología , Femenino , Estudios de Seguimiento , Humanos , Inmunidad Celular/fisiología , Masculino , Medición de Riesgo , Rituximab/uso terapéuticoRESUMEN
BACKGROUND: Rituximab is an effective therapy for pemphigus, although relapses are common. OBJECTIVE: To identify biomarkers to predict relapse of pemphigus following rituximab treatment. METHODS: In this retrospective cohort study, 62 patients with pemphigus treated with 99 rituximab cycles provided longitudinal clinical scoring and biomarker data, including levels of CD19+ B cells, CD4+ T cells, and desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) autoantibodies. An extended time-variant Kaplan-Meier estimator and extended Cox model were applied. RESULTS: Relapse was rare before B-cell repopulation. Univariate analysis revealed low CD4 count (<400 cells/µL) to predict relapse (P < .001). A positive result of testing for Dsg1 (>20 IU) was predictive of relapse among patients with mucocutaneous disease (hazard ratio, 6.40; P = .019); a positive result of testing for Dsg3 (>20 IU) was predictive in patients with mucocutaneous and mucosal disease (hazard ratio, 32.92; P < .001). Multivariable analysis revealed that every CD4 value increase of 200 decreases the hazard ratio for relapse by 35% (P = .029). A positive result of testing for Dsg1 increases the risk for relapse by a factor of 12.32 in patients with mucocutaneous disease (P = .001); positive result of testing for Dsg3 increases risk for relapse by 28.38 in patients with mucosal and mucocutaneous disease (P = .006). LIMITATIONS: Limitations include the retrospective design and inconsistent follow-up. CONCLUSION: Relapse is associated with B-cell repopulation, low CD4+ T -cell count, and positive result of testing for Dsg1 and Dsg3.
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Factores Inmunológicos/uso terapéutico , Pénfigo/sangre , Pénfigo/tratamiento farmacológico , Rituximab/uso terapéutico , Autoanticuerpos/sangre , Linfocitos B , Biomarcadores/sangre , Estudios de Cohortes , Desmogleína 1/sangre , Desmogleína 3/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Recurrencia , Estudios RetrospectivosAsunto(s)
Penfigoide Ampolloso/complicaciones , Pénfigo/complicaciones , Prurito/epidemiología , Adulto , Anciano , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Penfigoide Ampolloso/diagnóstico , Pénfigo/diagnóstico , Prevalencia , Prurito/diagnóstico , Prurito/etiología , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Bullous pemphigoid (BP) is an autoimmune blistering disease resulting in pruritus and cutaneous blistering. Longitudinal studies characterizing the disease course of patients with BP on conventional therapy are lacking. We sought to characterize the changes in disease activity and pruritus of patients with BP on standard-of-care treatments. We conducted a retrospective cohort study on patients with BP on standard-of-care therapy. Generalized Estimating Equations were used to estimate the mean and standard errors for Bullous Pemphigoid Disease Activity Index (BPDAI) total activity score, BPDAI pruritus component score, and anti-BP180 autoantibody levels (BP180) over time. A total of 80 patients with BP showed consistent reductions in BPDAI total activity score and BPDAI pruritus component score, with a nadir at 4 months. BP180 decreased over time, with the largest reductions at 6 and 9 months. Median partial/complete remission was at 6.7 months, with relapses at a median time of 15.9 months. Receiving operating characteristic analysis determined an optimal BPDAI total activity score cutoff of 3.3 to discriminate partial/complete remission incidence (area under the curve = 0.895, sensitivity = 0.844, specificity = 0.78). In conclusion, in patients with BP on standard-of-care therapy, a natural course of BPDAI total activity score and BPDAI pruritus component score over time was comprehensively projected. BPDAI ≤ 3.3 was associated with partial/complete remission. These results provide reference data to guide future clinical trial design for BP.
RESUMEN
Over the last several decades, advances in the understanding of the pathogenesis of autoimmune blistering diseases has resulted in significant improvements in diagnosis and management. These improvements include new diagnostic assays and therapies targeted at specific disease mediators. Furthermore, the abundance of new therapies in clinic trials for autoimmune blistering diseases will translate to an enhanced therapeutic armamentarium for clinicians. The aim of this article is to review new developments in the understanding of autoimmune blistering diseases and to summarize advancements in their diagnosis and management.
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Enfermedades Autoinmunes/terapia , Enfermedades Cutáneas Vesiculoampollosas/terapia , Animales , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/fisiopatología , Humanos , Enfermedades Cutáneas Vesiculoampollosas/diagnóstico , Enfermedades Cutáneas Vesiculoampollosas/fisiopatologíaRESUMEN
ETS is a family of transcriptional regulators with functions in most biological processes. Dysregulated ETS factor function leads to altered expression of multiple genes that play critical roles in many of the processes required for cancer progression. While the Ets family gene, prostate-derived ETS factor (PDEF), is expressed in epithelial tissues including prostate, breast, and colon, PDEF protein expression has been found to be reduced or lost during prostate and breast cancer progression. The goal of this study was to examine the expression and biologic impact of altered PDEF expression in colon cancer. PDEF mRNA and protein are not detectable in several colon-cancer-derived cell lines. Re-expression of PDEF in colon cancer cells inhibits growth and migration. Growth affects are due to altered cellular proliferation, indicated by increased altered cell population in G(1) and S phases of the cell cycle, as well as increased apoptosis. Relevant to its modulation of growth and migration phenotypes, PDEF expression resulted in altered expression of genes with established roles in cell cycle, motility, and invasion. Furthermore, chromatin immunoprecipitation studies show that p21 and urokinase plasminogen activator (uPA) are direct PDEF transcriptional targets. While non-tumor colon epithelium expresses PDEF mRNA and protein, the majority of tumors showed decreased mRNA and/or protein expression. In human tumor tissue samples, PDEF expression was inversely correlated with the expression levels of uPA. Collectively, the data support the model that PDEF is a negative regulator of tumor progression by modulating the expression of growth and migration promoting genes.
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Movimiento Celular , Neoplasias del Colon/metabolismo , Proteínas Proto-Oncogénicas c-ets/genética , Células CACO-2/metabolismo , Procesos de Crecimiento Celular , Línea Celular Tumoral , Neoplasias del Colon/genética , Humanos , Proteínas Proto-Oncogénicas c-ets/metabolismo , ARN Mensajero/metabolismo , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/metabolismoRESUMEN
Importance: Hailey-Hailey disease is a severe genetic blistering disease of intertriginous skin locations that can lead to poor quality of life and increased morbidities. Multiple therapies are available with inconsistent outcomes and potentially severe adverse effects. Objective: To determine whether low-dose naltrexone is an effective treatment for Hailey-Hailey disease. Design, Setting, and Participants: This study was a case series performed at a dermatology outpatient clinic of 3 patients with severe Hailey-Hailey disease recalcitrant to at least 4 therapies. Interventions: Low-dose naltrexone, 3 mg nightly, titrated to 4.5 mg nightly in 2 patients. Main Outcomes and Measures: Reduction in size of lesions as well as subjective improvement of symptoms. Results: All 3 patients noted significant healing of erosions and plaques starting from the peripheral aspect within 1 to 2 weeks of treatment, and clinical resolution of lesions within 2 months. Discontinuation of low-dose naltrexone resulted in flaring of symptoms, which cleared within 2 to 3 days on rechallenge with low-dose naltrexone. Conclusions and Relevance: We present herein 3 cases of patients with severe Hailey-Hailey disease treated with low-dose naltrexone who achieved clinical resolution of symptoms. The success of these cases suggests low-dose naltrexone as a novel therapy for Hailey-Hailey disease. The possible mechanism may involve low-dose naltrexone influencing opioid or toll-like receptor signaling to improve calcium mobilization and improve keratinocyte differentiation and wound healing. Future studies are needed to clarify the mechanism and to define the role of low-dose naltrexone for treatment of Hailey-Hailey disease.
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Naltrexona/uso terapéutico , Antagonistas de Narcóticos/uso terapéutico , Pénfigo Familiar Benigno/tratamiento farmacológico , Calidad de Vida , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Naltrexona/administración & dosificación , Antagonistas de Narcóticos/administración & dosificación , Pénfigo Familiar Benigno/fisiopatología , Resultado del TratamientoRESUMEN
Importance: Dermatitis herpetiformis (DH) is an autoimmune blistering condition seen in the context of celiac disease. While typically managed by gluten-free diet and dapsone, treatment of DH refractory to standard treatments is not well defined. Observations: A man in his 80s with DH not controlled by gluten-free diet (with poor adherence), dapsone, and conventional immune-suppressing agents responded to treatment with rituximab according to the lymphoma protocol (4 weekly infusions of 375 mg/m2). Thirteen months after treatment, the patient had achieved complete resolution of pruritus and clinical manifestations of the disease, as well as normalization of antibodies against epidermal and tissue transglutaminases. He achieved complete clinical and serological remission and has remained symptom-free up to 18 months following treatment. Conclusions and Relevance: We present here the first case of a patient with DH treated with rituximab who achieved complete clinical and serological remission. We suggest rituximab as a viable treatment option for recalcitrant DH.