RESUMEN
INTRODUCTION: Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is an acquired autoinflammatory monogenic disease with a poor prognosis whose determinants are not well understood. We aimed to describe serious infectious complications and their potential risk factors. METHODS: Retrospective multicentre study including patients with VEXAS syndrome from the French VEXAS Registry. Episodes of serious infections were described, and their risk factors were analysed using multivariable Cox proportional hazards models. RESULTS: Seventy-four patients with 133 serious infections were included. The most common sites of infection were lung (59%), skin (10%) and urinary tract (9%). Microbiological confirmation was obtained in 76%: 52% bacterial, 30% viral, 15% fungal and 3% mycobacterial. Among the pulmonary infections, the main pathogens were SARS-CoV-2 (28%), Legionella pneumophila (21%) and Pneumocystis jirovecii (19%). Sixteen per cent of severe infections occurred without any immunosuppressive treatment and with a daily glucocorticoid dose ≤10 mg. In multivariate analysis, age >75 years (HR (95% CI) 1.81 (1.02 to 3.24)), p.Met41Val mutation (2.29 (1.10 to 5.10)) and arthralgia (2.14 (1.18 to 3.52)) were associated with the risk of serious infections. JAK inhibitors were most associated with serious infections (3.84 (1.89 to 7.81)) compared with biologics and azacitidine. After a median follow-up of 4.4 (2.5-7.7) years, 27 (36%) patients died, including 15 (56%) due to serious infections. CONCLUSION: VEXAS syndrome is associated with a high incidence of serious infections, especially in older patients carrying the p.Met41Val mutation and treated with JAK inhibitors. The high frequency of atypical infections, especially in patients without treatment, may indicate an intrinsic immunodeficiency.
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Bacteriófagos , Inhibidores de las Cinasas Janus , Síndromes Mielodisplásicos , Enfermedades Cutáneas Genéticas , Anciano , Humanos , Artralgia , Azacitidina , Mutación , Estudios RetrospectivosRESUMEN
BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) occur in 10-20% of patients with myelodysplastic syndrome (MDS). Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, associated with somatic mutations in UBA1 (Ubiquitin-like modifier-activating enzyme 1), encompasses a range of severe inflammatory conditions along with hematological abnormalities, including MDS. The pathophysiological mechanisms underlying the association between MDS and SIADs remain largely unknown, especially the roles of different myeloid immune cell subsets. The aim of this study was to quantitatively evaluate peripheral blood myeloid immune cells (dendritic cells (DC) and monocytes) by flow cytometry in MDS patients with associated SIAD (n = 14, most often including relapsing polychondritis or neutrophilic dermatoses) and to compare their distribution in MDS patients without SIAD (n = 23) and healthy controls (n = 7). Most MDS and MDS/SIAD patients had low-risk MDS. Eight of 14 (57%) MDS/SIAD patients carried UBA1 somatic mutations, defining VEXAS syndrome.Compared with MDS patients, most DC and monocyte subsets were significantly decreased in MDS/SIAD patients, especially in MDS patients with VEXAS syndrome. Our study provides the first overview of the peripheral blood immune myeloid cell distribution in MDS patients with associated SIADs and raises several hypotheses: possible redistribution to inflammation sites, increased apoptosis, or impaired development in the bone marrow.
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Monocitos , Síndromes Mielodisplásicos , Humanos , Síndromes Mielodisplásicos/genética , Inflamación , Células Dendríticas , MutaciónRESUMEN
Azacitidine can be effective in myelodysplastic syndromes (MDS) associated with inflammatory/autoimmune diseases. Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) is a new monogenic autoinflammatory syndrome caused by somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutation, often associated with MDS, whose treatment is difficult and not yet codified. Based on a French nationwide registry of 116 patients with VEXAS, we report the efficacy and safety of azacitidine treatment in 11 patients with VEXAS with MDS. Clinical response of VEXAS to azacitidine was achieved in five patients (46%), during 6, 8+, 12, 21, 27+ months respectively, suggesting that azacitidine can be effective in selected patients with VEXAS and associated MDS.
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Antimetabolitos Antineoplásicos/uso terapéutico , Azacitidina/uso terapéutico , Genes Ligados a X/genética , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Síndromes Mielodisplásicos/tratamiento farmacológico , Enfermedades Cutáneas Genéticas/tratamiento farmacológico , Anciano , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Sistema de RegistrosRESUMEN
OBJECTIVES: Systemic inflammatory and autoimmune diseases can be associated with myelodysplastic syndromes. Current treatments (steroids, immunosuppressive agents, biologics) are unsatisfactory because of their low response rate, dependence or adverse events. We aimed at evaluating the effects of low doses of IL-2 (ld-IL2) as a regulatory T-cell inducer in this context. METHODS: We treated three patients with ld-IL2 with myelodysplastic syndromes and an associated dysimmune disorder (polymyalgia rheumatic, relapsing polychondritis associated with Sweet's syndrome and vasculitis with cutaneous and joint involvement, respectively). All three patients were dependent on steroids and refractory to biologics or azacitidine. They received doses of 1-1.5 million units of proleukin/day during 5 days and then every fortnight. RESULTS: The treatment led to a clinical improvement and steroid sparing in 2/3 patients with no serious adverse events, and no progression of the disease. CONCLUSION: Our results support the investigation of ld-IL2 in MDS associated with immune disorders in controlled clinical studies.
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Glucocorticoides/uso terapéutico , Interleucina-2/administración & dosificación , Síndromes Mielodisplásicos/complicaciones , Policondritis Recurrente/tratamiento farmacológico , Polimialgia Reumática/tratamiento farmacológico , Síndrome de Sweet/tratamiento farmacológico , Vasculitis/tratamiento farmacológico , Anciano , Femenino , Humanos , Masculino , Policondritis Recurrente/complicaciones , Polimialgia Reumática/complicaciones , Síndrome de Sweet/complicaciones , Vasculitis/complicacionesRESUMEN
BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) associated with myelodysplastic syndromes are often difficult to treat. Corticosteroids are efficient but only usually at high doses. The use of biologics needs to be specified. METHODS: In a French multicenter retrospective study, we analyzed the efficacy and safety of biologics (tumor necrosis factor-α [TNF-α] antagonists, tocilizumab, rituximab and anakinra) for SIADs associated with myelodysplastic syndromes (MDSs). Clinical, biological and overall treatment responses were evaluated. When several lines of treatment were used, data were analyzed before and at the end of each treatment line and were pooled to compare overall response among steroids, disease-modifying anti-rheumatic drugs (DMARDs) and biologics. RESULTS: We included 29 patients (median age 67years [interquartile range 62-76], 83% males) with MDS-related SIADs treated with at least one biologic. The MDSs were predominantly refractory anemia with excess blasts 1 (38%) and refractory cytopenia with multilineage dysplasia (21%). The SIADs were mainly arthritis (n=6; 20%), relapsing polychondritis (n=8; 30%) and vasculitis (n=10; 34%). During a 3-year median follow-up (IQR 1.3-4.5), a total of 114 lines of treatments were used for all patients: steroids alone (22%), DMARDs (23%), TNF-α antagonists (14%), anakinra (10%), rituximab (10%), tocilizumab (7%) and azacytidine (9%). Considering all 114 lines, overall response (complete and partial) was shown in 54% cases. Overall response was more frequent with steroids (78%) and rituximab (66%) than DMARDs (45%) and other biologics (33%) (p<0.05). Rituximab had better response in vasculitis and TNF-α antagonists in arthritis. During follow-up, 20 patients (71%) presented at least one severe infection. CONCLUSION: This nationwide study demonstrates the efficacy of steroids for SIAD-associated MDSs but a high frequency of steroid dependence. The response to biologics seems low, but rituximab and azacytidine seem promising.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Síndromes Mielodisplásicos/tratamiento farmacológico , Policondritis Recurrente/tratamiento farmacológico , Anciano , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/farmacología , Artritis Reumatoide/mortalidad , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Supervivencia sin Enfermedad , Quimioterapia Combinada , Femenino , Francia , Humanos , Factores Inmunológicos/uso terapéutico , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Policondritis Recurrente/mortalidad , Estudios Retrospectivos , Rituximab/farmacología , Rituximab/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: Giant cell arteritis (GCA) is the most frequently occurring vasculitis in elderly individuals, and its pathogenesis is not fully understood. The objective of this study was to decipher the role of the major CD4+ T cell subsets in GCA and its rheumatologic form, polymyalgia rheumatica (PMR). METHODS: A prospective study of the phenotype and the function of major CD4+ T cell subsets (Th1, Th17, and Treg cells) was performed in 34 untreated patients with GCA or PMR, in comparison with 31 healthy control subjects and with the 27 treated patients who remained after the 7 others withdrew. RESULTS: Compared with control subjects, patients with GCA and patients with PMR had a decreased frequency of Treg cells and Th1 cells, whereas the percentage of Th17 cells was significantly increased. Furthermore, an analysis of temporal artery biopsy specimens obtained from patients affected by GCA for whom biopsy results were positive demonstrated massive infiltration by Th17 and Th1 lymphocytes without any Treg cells. After glucocorticoid treatment, the percentages of circulating Th1 and Th17 cells decreased, whereas no change in the Treg cell frequency was observed. The frequency of CD161+CD4+ T cells, which are considered to be Th17 cell precursors, was similar in patients and control subjects. However, these cells highly infiltrated GCA temporal artery biopsy specimens, and their ability to produce interleukin-17 in vitro was significantly enhanced in patients with GCA and patients with PMR and was correlated with a decrease in the phosphorylated form of STAT-1. CONCLUSION: This study is the first to demonstrate that the frequency of Treg cells is decreased in patients with GCA and patients with PMR, and that CD161+CD4+ T lymphocytes, differentiated into Th1 cells and Th17 cells, are involved in the pathogenesis of GCA and PMR.
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Arteritis de Células Gigantes/inmunología , Subfamilia B de Receptores Similares a Lectina de Células NK/inmunología , Polimialgia Reumática/inmunología , Células TH1/inmunología , Células Th17/inmunología , Adulto , Anciano , Diferenciación Celular/inmunología , Células Cultivadas , Femenino , Citometría de Flujo , Arteritis de Células Gigantes/patología , Humanos , Masculino , Persona de Mediana Edad , Polimialgia Reumática/patología , Estudios Prospectivos , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Células TH1/citología , Células Th17/citologíaRESUMEN
Giant cell arteritis is the most frequent form of vasculitis characterized by a high risk of vascular thrombosis. Major complications are blindness and other vascular ischemia but bowel ischemic involvement is rare. Treatment is based on long-term steroid therapy with numerous side effects. The efficacy of immunosuppressive drugs like azathioprine methotrexate or anti-tumor necrosis factor antibodies appears to be too low to reduce the use of steroids. Th17 lymphocytes and interleukin-6 play an important role in pathogenesis of giant cell arteritis. We report here a case of effective interleukin-6 blocker in the treatment of refractory giant cell arteritis with ileitis and high-dose steroid dependence despite 2 years of treatment with steroids and methotrexate. After infusions of tocilizumab, no relapse at 6 months was found despite the decrease in corticosteroids.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Arteritis de Células Gigantes/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Resistencia a Medicamentos , Quimioterapia Combinada , Femenino , Arteritis de Células Gigantes/inmunología , Humanos , Interleucina-6/antagonistas & inhibidores , Persona de Mediana Edad , Prevención SecundariaRESUMEN
PURPOSE: To report on two patients with refractory uveitis treated with tocilizumab; a new humanized monoclonal antibody against the interleukin-6 receptor (IL-6R). DESIGN: Retrospective interventional case series. METHODS: Both patients received a monthly infusion of tocilizumab 8 mg/kg; associated with corticosteroids. Outcome measures were visual acuity and central retinal thickness evaluated with optical coherence tomography. RESULTS: An improvement in visual acuity and a decrease in macular edema were observed in these two patients. CONCLUSIONS: Tocilizumab seems to be a promising treatment in refractory uveitis. A prospective study is needed to evaluate the role of this new agent in the management of refractory uveitis.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunosupresores/uso terapéutico , Uveítis/tratamiento farmacológico , Corticoesteroides/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Edema Macular/tratamiento farmacológico , Receptores de Interleucina-6/antagonistas & inhibidores , Retina/anatomía & histología , Retina/efectos de los fármacos , Tomografía de Coherencia Óptica , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Agudeza Visual/efectos de los fármacosRESUMEN
Known for years as professional APCs, dendritic cells (DCs) are also endowed with tumoricidal activity. This dual role of DC as killers and messengers may have important implications for tumor immunotherapy. However, the tumoricidal activity of DCs has mainly been investigated in animal models. Cancer cells inhibit antitumor immune responses using numerous mechanisms, including the induction of immunosuppressive/ tolerogenic DCs that have lost their ability to present Ags in an immunogenic manner. In this study, we evaluated the possibility of generating tumor killer DCs from patients with advanced-stage cancers. We demonstrate that human monocyte-derived DCs are endowed with significant cytotoxic activity against tumor cells following activation with LPS. The mechanism of DC-mediated tumor cell killing primarily involves peroxynitrites. This observed cytotoxic activity is restricted to immature DCs. Additionally, after killing, these cytotoxic DCs are able to activate tumor Ag-specific T cells. These observations may open important new perspectives for the use of autologous cytotoxic DCs in cancer immunotherapy strategies.
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Citotoxicidad Inmunológica/inmunología , Células Dendríticas/inmunología , Inmunoterapia/métodos , Neoplasias/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Humanos , Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Activación de Linfocitos/inmunología , Neoplasias/terapia , Ácido Peroxinitroso/inmunología , Ácido Peroxinitroso/metabolismo , Linfocitos T/inmunologíaAsunto(s)
Linfoma de Células B de la Zona Marginal/etiología , Síndrome de Sjögren/diagnóstico , Anciano , Femenino , Humanos , Linfoma de Células B de la Zona Marginal/patología , Síndrome de Sjögren/complicaciones , Glándula Submandibular/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Lengua/patologíaRESUMEN
PURPOSE: The ankle brachial pressure index (ABPI) makes it possible to diagnose peripheral artery disease (PAD) and identify patients with a vascular risk. Recently, the Haute Autorité de santé (HAS) issued guidelines. We wanted to determine the interest and impact of these guidelines when applied to patients hospitalised in an internal medicine department. METHODS: We systematically measured the ABPI in two internal medicine departments. We compared the results obtained with the screening criteria and the good practices recommended by the HAS. RESULTS: The screening criteria recommended by the HAS were already applied in 91% of our 97 patients. PAD was found in 37.1% of patients. In 83% of cases, the diagnosis was unknown (p = 0.02). The PAD was symptomatic in 83% of the known PAD cases, and 3.3% in newly-diagnosed cases (p < 0.001)). The sensitivity of the HAS screening criteria applied to our population was 100% but almost patients justifies ABPI screening. The specificity was 11.5%, the positive predictive value 40% and the negative predictive value 100%. The optimal treatment recommended was implemented in only 50% of patients with known arteriopathy and in 10% of newly-diagnose PAD (p = 0.04). CONCLUSION: PAD prevalence is high in internal medicine department and systematic measurement of ABPI is effective. Determining patients to screen with the HAS criteria has a poor impact in our patients. The optimal treatment is still extremely under-prescribed even in patients with known PAD.
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Índice Tobillo Braquial , Arteriopatías Oclusivas/diagnóstico , Adhesión a Directriz , Isquemia/diagnóstico , Tamizaje Masivo/métodos , Adolescente , Antagonistas Adrenérgicos beta/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Arteriopatías Oclusivas/tratamiento farmacológico , Arteriopatías Oclusivas/fisiopatología , Glucemia/metabolismo , Bloqueadores de los Canales de Calcio/uso terapéutico , Comorbilidad , Angiopatías Diabéticas/diagnóstico , Angiopatías Diabéticas/tratamiento farmacológico , Angiopatías Diabéticas/fisiopatología , Femenino , Francia , Departamentos de Hospitales , Humanos , Hiperlipidemias/diagnóstico , Hiperlipidemias/tratamiento farmacológico , Hiperlipidemias/fisiopatología , Claudicación Intermitente/diagnóstico , Claudicación Intermitente/tratamiento farmacológico , Claudicación Intermitente/fisiopatología , Medicina Interna , Isquemia/tratamiento farmacológico , Isquemia/fisiopatología , Pierna/irrigación sanguínea , Lípidos/sangre , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios Prospectivos , Valores de Referencia , Factores de Riesgo , Vasodilatadores/uso terapéutico , Adulto JovenRESUMEN
Churg-Strauss Syndrome (SCS) is a systemic vasculitis associated with asthma and eosinophilia. The aim of our work is to describe this pathology in the Burgundian population in France. We counted from the hospitalisation data-processing summaries, the whole of the SCS hospitalised in Burgundy between 1998 and 2008. During the follow-up, the clinical and paraclinical characteristics of every patient were collected. The average prevalence is of 11.3 per million inhabitants and the incidence is of 1.2 new cases per million inhabitants per annum. There exists however, a great prevalence disparity and incidence amongst the various departments of the area. The patient's average follow-up is of 7.7 years. In 23% of the cases one finds a starting factor for vasculitis. The delay between the first signs and the diagnostic is an average of 61 months. The ANCA are positive in 26% of cases and of anti-myeloperoxidase specificity in 83% of cases (P < 0.001). The most profitable biopsies are essentially cutaneous and neuromuscular. At the diagnostic, two-third of the patients have had a treatment adapted according to the current recommendations based on the Five Factor Score. The remission rate within a 1-year period is of 77%. The remission is strongly correlated to the therapeutic protocol associating corticoids and cyclophosphamide (P < 0.05). In conclusion, the prevalence of SCS in our area is similar to that observed in other European regions. However, this vasculitis remains a difficult and often a tardive diagnostic pathology.
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Síndrome de Churg-Strauss/epidemiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamiento farmacológico , Femenino , Francia/epidemiología , Adhesión a Directriz , Hospitalización/estadística & datos numéricos , Humanos , Inmunosupresores/uso terapéutico , Incidencia , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Prevalencia , Características de la Residencia , Estudios Retrospectivos , Análisis de Supervivencia , Tasa de Supervivencia , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
When an adult suffers from muscular symptoms, the diagnosis of polymyositis is often accepted if muscular biopsy reveals necrosis, fibrosis and cellular infiltrate with high expression of major histocompatibility complex class I. Late-onset limb-girdle muscular dystrophy (LGMD) can also be considered. We report the case of a young woman who suffers from dysferlin deficiency, and who was mistakenly treated for refractory polymyositis for 5 years. In LGMD, standard pathological analysis can indeed wrongly give a diagnosis of polymyositis. Immunofixation must be performed to avoid this mistake.