RESUMEN
BACKGROUND: Patients with rare diseases usually go through years of diagnostic odysseys. The large number of rare diseases and the associated lack of expertise pose a major challenge to physicians. There are few physicians dealing with patients with rare diseases and they usually work in a limited number of specialized centers. The aim of this study was to evaluate the diagnostic efficiency of an expert center. METHODS: The diagnostic pathway of 78 patients of the outpatient clinic for rare inflammatory systemic diseases with renal involvement was analyzed retrospectively. For this purpose, each examination day was documented with the corresponding examinations performed from the onset of initial symptoms. Three time points were considered: The time when patients first visited a physician with symptoms, the time when patients consulted an expert, and the time when they received the correct diagnosis. In addition, it was documented whether the diagnosis could be made without the expert, or only with the help of the expert. The examinations that confirmed the diagnosis were also documented for each patient. RESULTS: A correct diagnosis was made without the help of the expert in only 21% of cases. Each patient visited an average of 6 physicians before consulting the expert. Targeted diagnostics enabled the expert to make the correct diagnosis with an average of seven visits, or one inpatient stay. However, referral to the expert took an average of 4 years. CONCLUSION: The data show that rapid and targeted diagnostics were possible in the expert center due to the available expertise and the interdisciplinary exchange. Early diagnosis is of great importance for many patients, as an early and correct therapy can be decisive for the course of the disease.
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Instituciones de Atención Ambulatoria , Enfermedades Raras , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/terapia , Estudios Retrospectivos , Examen Físico , Derivación y ConsultaRESUMEN
The concept of autoinflammation includes a heterogeneous group of monogenic and polygenic diseases. These are characterized by excessive activation of the innate immune system without antigen-specific T cells or autoantibodies. The diseases are characterized by periodic episodes of fever and increased inflammation parameters. Monogenic diseases include familial Mediterranean fever (FMF) and the newly described VEXAS (vacuoles, E1 enzyme, Xlinked, autoinflammatory, somatic) syndrome. Heterogeneous diseases include adult-onset Still's disease and Schnitzler syndrome. Treatment is aimed at preventing the excessive inflammatory reaction in order to avoid long-term damage, such as amyloid A (AA) amyloidosis.
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Periodic fever syndromes (PFS) are a group of rare autoinflammatory diseases, which are characterized by disorders of the innate immune reaction and life-long recurrent episodes of inflammatory symptoms. This article describes the diagnostic approach. In addition to the patient medical history, physical examination and laboratory determinations, gene tests are becoming increasingly more important. The panel diagnostics using high throughput sequencing or next generation sequencing (NGS) is the method of choice for the detection of a genetic cause of PFS. This article discusses the diagnostic decision support systems (DDSS) that can play a future role in the diagnosis of rare diseases, especially those with complex patterns of symptoms.
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Enfermedades Autoinflamatorias Hereditarias , Fiebre/diagnóstico , Pruebas Genéticas , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , SíndromeRESUMEN
In the last 20 years the clarification of monogenic periodic febrile diseases has led to the independent concept of autoinflammation. In this heterogeneous group polygenic complex diseases are also now included. The spectrum of symptoms is continuously growing. The main difference to autoimmunity is an excessive activation of the innate immune system without formation of autoantibodies or antigen-specific Tcells. The cardinal symptom is recurrent fever episodes accompanied by signs of inflammation, which in the periodic manifestations alternate with intervals of general well-being. The classical monogenic diseases are also known as hereditary recurrent fever (HRF). Examples are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor 1associated periodic syndrome (TRAPS), adenosine deaminase 2 (ADA2) deficiency and mevalonate kinase deficiency (MKD, hyper-IgD syndrome). The polygenic diseases are also known as nonhereditary fever syndromes. These include adult-onset Still's disease (AoSD), Adamantiades-Behçet disease, the PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and gouty arthritis. All autoinflammatory fever syndromes are accompanied by a long-term risk of development of amyloid A amyloidosis, depending on the individual severity and treatment success. In some diseases severe complications can sometimes occur.
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Fiebre Mediterránea Familiar , Enfermedades Autoinflamatorias Hereditarias , Amiloidosis , Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Fiebre Mediterránea Familiar/genética , Fiebre , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Enfermedades Autoinflamatorias Hereditarias/genética , Enfermedades Autoinflamatorias Hereditarias/terapia , Humanos , Proteína Amiloide A Sérica , SíndromeAsunto(s)
Inteligencia Artificial , Enfermedades Raras/diagnóstico , Evaluación de Síntomas , Adolescente , Sistemas de Apoyo a Decisiones Clínicas , Diagnóstico por Computador , Registros Electrónicos de Salud , Fiebre Mediterránea Familiar/diagnóstico , Predicción , Pruebas Genéticas , Humanos , Masculino , Enfermedades Raras/tratamiento farmacológico , Programas Informáticos , Evaluación de Síntomas/métodosRESUMEN
The concept of autoinflammation includes a heterogeneous group of monogenic and polygenic diseases. These are characterized by excessive activation of the innate immune system without antigen-specific T cells or autoantibodies. The diseases are characterized by periodic episodes of fever and increased inflammation parameters. Monogenic diseases include familial Mediterranean fever (FMF) and the newly described VEXAS (vacuoles, E1 enzyme, Xlinked, autoinflammatory, somatic) syndrome. Heterogeneous diseases include adult-onset Still's disease and Schnitzler syndrome. Treatment is aimed at preventing the excessive inflammatory reaction in order to avoid long-term damage, such as amyloid A (AA) amyloidosis.
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Fiebre Mediterránea Familiar , Enfermedades Autoinflamatorias Hereditarias , Humanos , Adulto , Enfermedades Autoinflamatorias Hereditarias/diagnóstico , Fiebre/terapia , InflamaciónRESUMEN
Introduction: Checkpoint-Inhibition (CPI) with PD-1- and PD-L1-inhibitors is a well-established therapy for advanced stage melanoma patients. CPI mainly acts via T-lymphocytes. However, recent literature suggests also a role for B cells modulating its efficacy and tolerability of CPI. Case Report: We report a 48-year-old female patient with metastatic melanoma affecting brain, lung, skin and lymph nodes. A preexisting granulomatosis with polyangiitis was treated with rituximab over five years prior to the diagnosis of melanoma, resulting in a complete depletion of B cells both in peripheral blood as well as the tumor tissue. In the absence of the mutation of the proto-oncogene b-raf, treatment with the PD-1 inhibitor nivolumab was initiated. This therapy was well tolerated and resulted in a deep partial response, which is ongoing for 14+ months. Flow cytometric analysis of peripheral blood mononuclear cells revealed 15% IL-10 producing and 14% CD24 and CD38 double positive regulatory B cells. Conclusion: The exceptional clinical response to nivolumab monotherapy in our patient with depleted B cells sheds a new light on the relevance of B cells in the modulation of immune responses to melanoma. Obviously, B cells were not required for the efficacy of CPI in our patient. Moreover, the depletion of regulatory B cells may have improved efficacy of CPI.
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Linfocitos B Reguladores/inmunología , Granulomatosis con Poliangitis/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Melanoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Femenino , Humanos , Interleucina-10/metabolismo , Depleción Linfocítica , Persona de Mediana Edad , Metástasis de la Neoplasia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Inducción de Remisión , Rituximab/uso terapéuticoRESUMEN
A 41 -year old female patient was admitted with acute onset of dyspnea and chest pain. Previous history revealed asthma, chronic sinusitis and eosinophilic proctitis. Electrocardiogram showed anterior ST-segment elevations and inferior ST-segment depression. Immediate heart catheterization revealed a distally occluded left anterior descending coronary artery, the occlusion being reversible after nitroglycerine. Cardiac magnetic resonance imaging was consistent with perimyocarditis. Hypereosinophilia and IgE elevation were present and Churg-strauss syndrome was diagnosed.
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Síndrome Coronario Agudo/complicaciones , Síndrome Coronario Agudo/patología , Síndrome de Churg-Strauss/complicaciones , Síndrome de Churg-Strauss/patología , Adulto , Angiografía , Síndrome de Churg-Strauss/sangre , Síndrome de Churg-Strauss/enzimología , Creatina Quinasa/sangre , Eosinófilos/citología , Femenino , Estudios de Seguimiento , Humanos , Recuento de Leucocitos , Imagen por Resonancia MagnéticaRESUMEN
Infection with Chlamydia pneumoniae, a human respiratory pathogen, has been associated with various chronic diseases such as asthma and atherosclerosis, possibly because the pathogen can exist in a persistent form. C. pneumoniae persistently infect DCs in a TNF-alpha dependent manner. The present study investigated whether C. pneumoniae infection can induce indoleamine 2,3-dioxygenase (IDO) activity in dendritic cells, and whether the restriction of chlamydial growth in the DCs by TNF-alpha is IDO dependent. Our data indicate that infection of DCs with C. pneumoniae resulted in the induction of IDO expression. Reporting on our use of anti-TNF-alpha antibody adalimumab and varying concentrations of TNF-alpha, we further demonstrate that IDO induction following infection of DCs with C. pneumoniae is TNF-alpha dependent. The anti-chlamydial activity induced by TNF-alpha and the expression of chlamydial 16S rRNA gene, euo, groEL1, ftsk and tal genes were correlated with induction of IDO. Addition of excess amounts of tryptophan to the DC cultures resulted in abrogation of the TNF-alpha-mediated chlamydial growth restriction. These findings suggest that infection of DCs by C. pneumoniae induces production of functional IDO, which subsequently causes depletion of tryptophan. This may represent a potential mechanism for DCs to restrict bacterial growth in chlamydial infections.
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Infecciones por Chlamydophila/inmunología , Chlamydophila pneumoniae/crecimiento & desarrollo , Células Dendríticas/inmunología , Interacciones Huésped-Patógeno , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Adalimumab , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Procesos de Crecimiento Celular/efectos de los fármacos , Infecciones por Chlamydophila/genética , Chlamydophila pneumoniae/genética , Chlamydophila pneumoniae/metabolismo , Células Dendríticas/enzimología , Células Dendríticas/metabolismo , Células Dendríticas/microbiología , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/biosíntesis , Indolamina-Pirrol 2,3,-Dioxigenasa/inmunología , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Análisis de Secuencia por Matrices de Oligonucleótidos , Reacción en Cadena de la Polimerasa , Reproducibilidad de los Resultados , Triptófano/metabolismo , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Regulación hacia ArribaRESUMEN
Dendritic cells (DCs) produce tumor necrosis factor (TNF)-alpha upon infection and contribute in various ways to defense against pathogenic agents. Several biological agents have been designed to inhibit TNF-alpha activity. However, the use of these inhibitors has been associated with an increased rate of certain opportunistic infections. To study the effect of TNF-alpha inhibition, human monocyte-derived DCs were infected with Chlamydia pneumoniae. TNF-alpha was neutralized by adalimumab, a human anti-TNF-alpha monoclonal antibody. Chlamydiae induced the maturation of DC as determined by flow cytometry and quantitative real-time PCR. However, DC maturation was impaired in the presence of adalimumab. Moreover, neutralization of TNF-alpha resulted in a significant increase of infectious progeny, 16S rRNA gene copy number and development of larger inclusions consisting of different stages of chlamydial development. Additionally, chlamydial infection induced secretion of cytokines/chemokines, which were downregulated by adalimumab treatment. Our data reveal an indirect effect on maturation of DC by C. pneumoniae and that maturation is crucial for the restriction of chlamydial development. The results also demonstrate an increase in infectious progeny after TNF-alpha inhibition, suggesting a contribution of TNF-alpha produced by DCs to chlamydial growth arrest. These data suggest a possible mechanism by which TNF-alpha inhibition enhances the risk of intracellular infections.