RESUMEN
BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series. METHODS: A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN. Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants. RESULTS: Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers. CONCLUSIONS: These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.
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Síndrome de Birt-Hogg-Dubé , Carcinoma de Células Renales , Pólipos del Colon , Neoplasias Renales , Humanos , Masculino , Femenino , Anciano , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Birt-Hogg-Dubé/patología , Penetrancia , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , Neoplasias Renales/epidemiología , Neoplasias Renales/genética , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/genéticaRESUMEN
OBJECTIVE: To study a muscle-to-muscle standardised uptake value (SUV) ratio with FDG-PET/CT (FDG-PET) as a marker for the detection of disease activity in dermatomyositis (DM). METHODS: Patients with DM (n = 24) who met the European Neuro-Muscular Centre diagnostic criteria were retrospectively identified over a 3-year period through a national survey. Muscle biopsy was performed in all patients. Maximum SUV was measured in proximal muscles (SUVPROX) that had the highest radiotracer uptake on visual grading as well as in the musculus longissimus thoracis (SUVMLT), whereas mean SUV was measured for the liver (SUVLIV). Muscle-to-liver SUV ratios for either muscle group were compared and a SUVPROX/SUVMLT ratio was calculated. SUVPROX/SUVMLT of DM patients were compared with age- and sex-matched control subjects (n = 24) with melanoma who had received FDG-PET scans. RESULTS: DM patients presented with proximal and symmetrical muscle uptake. Differences in SUVPROX/SUVLIV and SUVMLT/SUVLIV ratios in DM subjects were significant (p < 0.001). SUVPROX/SUVMLT ratios in DM and their controls also differed significantly (p = 0.0012). The SUVPROX/SUVMLT ratio threshold between DM subjects and controls was 1.73 with a sensitivity of 50% (CI95%, 29.1 to 70.9%) and specificity at 83.3% (CI95%, 62.6 to 95.3%). When amyopathic DM patients were removed from the analysis, specificity was increased to 95% (CI95%, 75.1 to 99.9%) with a likelihood ratio of 10 and an AUC of 83.4% (CI95%, 71.4 to 95.4%). CONCLUSION: A muscle-to-muscle SUVPROX/SUVMLT ratio with a cut-off value of 1.73 in FDG-PET imaging might serve as a non-invasive marker to determine disease activity in dermatomyositis. KEY POINTS: ⢠[18F]-FDG PET-scanner standardised uptake value (SUV) could reflect disease activity in dermatomyositis (DM). ⢠A ratio of SUV in proximal muscles (SUVPROX) to SUV in musculus longissimus thoracis (SUVMLT) could be used to determine active DM. ⢠Active disease is suspected for SUV PROX /SUV MLT ratios greater than 1.73.
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Dermatomiositis/diagnóstico por imagen , Fluorodesoxiglucosa F18/farmacocinética , Músculo Esquelético/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Radiofármacos/farmacocinética , Adulto , Anciano , Anciano de 80 o más Años , Dermatomiositis/metabolismo , Dermatomiositis/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
OBJECTIVES: To determine the causes of death and risk factors in systemic sclerosis (SSc). METHODS: Between 2000 and 2011, we examined the death certificates of all French patients with SSc to determine causes of death. Then we examined causes of death and developed a score associated with all-cause mortality from the international European Scleroderma Trials and Research (EUSTAR) database. Candidate prognostic factors were tested by Cox proportional hazards regression model by single variable analysis, followed by a multiple variable model stratified by centres. The bootstrapping technique was used for internal validation. RESULTS: We identified 2719 French certificates of deaths related to SSc, mainly from cardiac (31%) and respiratory (18%) causes, and an increase in SSc-specific mortality over time. Over a median follow-up of 2.3 years, 1072 (9.6%) of 11 193 patients from the EUSTAR sample died, from cardiac disease in 27% and respiratory causes in 17%. By multiple variable analysis, a risk score was developed, which accurately predicted the 3-year mortality, with an area under the curve of 0.82. The 3-year survival of patients in the upper quartile was 53%, in contrast with 98% in the first quartile. CONCLUSION: Combining two complementary and detailed databases enabled the collection of an unprecedented 3700 deaths, revealing the major contribution of the cardiopulmonary system to SSc mortality. We also developed a robust score to risk-stratify these patients and estimate their 3-year survival. With the emergence of new therapies, these important observations should help caregivers plan and refine the monitoring and management to prolong these patients' survival.
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Esclerodermia Sistémica/mortalidad , Anciano , Causas de Muerte , Bases de Datos Factuales , Certificado de Defunción , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Factores de Riesgo , Factores de TiempoRESUMEN
OBJECTIVES: This study describes clinical characteristics, prognostic factors, and quality of life in patients with newly diagnosed (incident) digital ulcers (DU). METHODS: Observational cohort study of 189 consecutive SSc patients with incident DU diagnosis identified from the EUSTAR database (22 centres in 10 countries). Data were collected from medical charts and during one prospective visit between 01/2004 and 09/2010. RESULTS: Median age at DU diagnosis was 51 years, majority of patients were female (88%), and limited cutaneous SSc was the most common subtype (61%). At incident DU diagnosis, 41% of patients had one DU and 59% had ≥2 DU; at the prospective visit 52% had DU. Pulmonary arterial hypertension (PAH) and multiple DU at diagnosis were associated with presence of any DU at the prospective visit (odds ratios: 4.34 and 1.32). During the observation period (median follow-up was 2 years) 127 patients had ≥1 hospitalisation. The event rate of new DU per person-year was 0.66, of DU-associated complications was 0.10, and of surgical or diagnostic procedures was 0.12. At the prospective visit, patients with ≥1 DU reported impairment in daily activities by 57%, those with 0 DU by 37%. The mean difference between patients with or without DU in the SF-36 physical component was 2.2, and in the mental component 1.4. DU patients were not routinely prescribed endothelin receptor antagonists or prostanoids. CONCLUSIONS: This real world cohort demonstrates that DU require hospital admission, and impair daily activity. PAH and multiple DU at diagnosis were associated with future occurrence of DU.
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Dedos/irrigación sanguínea , Esclerodermia Sistémica/epidemiología , Úlcera Cutánea/epidemiología , Actividades Cotidianas , Adulto , Costo de Enfermedad , Bases de Datos Factuales , Europa (Continente)/epidemiología , Femenino , Hospitalización , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/epidemiología , Incidencia , Modelos Logísticos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pronóstico , Estudios Prospectivos , Calidad de Vida , Recurrencia , Factores de Riesgo , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/fisiopatología , Esclerodermia Sistémica/psicología , Esclerodermia Sistémica/terapia , Úlcera Cutánea/diagnóstico , Úlcera Cutánea/fisiopatología , Úlcera Cutánea/psicología , Úlcera Cutánea/terapia , Factores de TiempoAsunto(s)
Autoanticuerpos/sangre , Dermatomiositis/inmunología , Exantema/inmunología , Complejo Desacetilasa y Remodelación del Nucleosoma Mi-2/inmunología , Neoplasias/epidemiología , Adulto , Anciano , Autoanticuerpos/inmunología , Dermatomiositis/sangre , Dermatomiositis/complicaciones , Dermatomiositis/mortalidad , Exantema/sangre , Exantema/patología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Músculo Esquelético/inmunología , Músculo Esquelético/patología , Necrosis/inmunología , Neoplasias/inmunología , Pronóstico , Estudios Retrospectivos , Medición de Riesgo/estadística & datos numéricos , Factores de Riesgo , Piel/inmunología , Piel/patologíaRESUMEN
Data on the clinical spectrum and therapeutic management of noninfectious mixed cryoglobulinemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. We analyzed data from 242 patients with noninfectious mixed CryoVas included in the French multicenter CryoVas survey. Baseline manifestations were purpura (75%), peripheral neuropathy (52%), arthralgia or arthritis (44%), glomerulonephritis (35%), cutaneous ulcers (16%), and cutaneous necrosis (14%). A connective tissue disease was diagnosed in 30% and B-cell non-Hodgkin lymphoma in 22%, whereas the CryoVas was considered to be essential in 48%. With the use of Cox-marginal structural models, rituximab plus corticosteroids showed the greater therapeutic efficacy compared with corticosteroids alone and alkylating agents plus corticosteroids to achieve complete clinical, renal, and immunologic responses and a prednisone dosage < 10 mg/d at 6 months. However, this regimen was also associated with severe infections, particularly when high doses of corticosteroids were used, whereas death rates did not differ between the therapeutic regimens. The role of each of these strategies remains to be defined in well-designed randomized controlled trials.
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Crioglobulinemia/complicaciones , Crioglobulinemia/terapia , Vasculitis/complicaciones , Vasculitis/terapia , Corticoesteroides/administración & dosificación , Corticoesteroides/efectos adversos , Anciano , Algoritmos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Anticuerpos Monoclonales de Origen Murino/efectos adversos , Estudios de Cohortes , Terapia Combinada , Crioglobulinemia/epidemiología , Recolección de Datos , Femenino , Humanos , Infecciones/complicaciones , Infecciones/epidemiología , Infecciones/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Rituximab , Resultado del Tratamiento , Vasculitis/epidemiologíaRESUMEN
Pericardial effusion in patients with giant cell arteritis has been described in case reports. The exact prevalence of this manifestation is unknown. The objective of this study was to determine the prevalence and characteristics of pericardial effusion in patients with giant cell arteritis. Retrospective data were collected from 114 patients at a single hospital with giant cell arteritis diagnosed between October 1999 and July 2013. Pericardial effusion was found in four patients (3.5 %, 95 % confidence intervals 1-8.7). In three cases, pericardial effusion was present at initial presentation and was asymptomatic. In one case, pericardial effusion was associated with aortitis and diagnosed at 6 months on thoracic CT scan because of relapse of the disease when corticosteroid was reduced. Prognosis was good in all cases. The present study confirms that pericardial effusion could occur in patients with giant cell arteritis. However, pericardial effusion is a rare manifestation of giant cell arteritis. Clinical course of pericardial effusion in the setting of giant cell arteritis is usually benign and rarely symptomatic. Recognition of this manifestation may contribute to early diagnosis of the disease.
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Arteritis de Células Gigantes/complicaciones , Derrame Pericárdico/complicaciones , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Data on the prognosis of non-infectious mixed cryoglobulinaemia vasculitis (CryoVas) in the era of hepatitis C virus screening are lacking. METHODS: The French multicentre and retrospective CryoVas survey included 242 patients with non-infectious mixed CryoVas. Causes of death and prognostic factors of survival were assessed and a prognostic score was determined to predict survival at 5 years. RESULTS: After a median follow-up of 35 months, 42 patients (17%) died. Causes of death were mainly serious infections (50%) and vasculitis flare (19%). One-, 2-, 5- and 10-year overall survival rates were 91%, 89%, 79% and 65%, respectively. A prognostic score, the CryoVas score (CVS), for the prediction of survival at 5 years was devised. Pulmonary and gastrointestinal involvement, glomerular filtration rate <60 ml/min and age >65 years were independently associated with death. At 5 years the death rates were 2.6%, 13.1%, 29.6% and 38.5% for a CVS of 0, 1, 2 and ≥3, respectively. At 1 year the death rates were 0%, 3.2%, 18.5% and 30.8% for a CVS of 0, 1, 2 and ≥3, respectively. The CVS was strongly correlated with the Five Factor Score (FFS) 2009, another prognostic score validated in primary necrotising vasculitis (r=0.82; p<0.0001). The area under the curve for the CVS was 0.74 compared with 0.67 for the FFS, indicating a better performance of the CVS (p=0.052). CONCLUSIONS: In patients with non-infectious mixed CryoVas, the main prognostic factors are age >65 years, pulmonary and gastrointestinal involvement and renal failure. A score including these variables is significantly associated with the prognosis.
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Crioglobulinemia/mortalidad , Enfermedades Genéticas Congénitas/mortalidad , Vasculitis/mortalidad , Anciano , Área Bajo la Curva , Crioglobulinemia/complicaciones , Recolección de Datos , Femenino , Enfermedades Genéticas Congénitas/complicaciones , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Vasculitis/etiologíaRESUMEN
The objective of this study was to determine the characteristics of cerebrovascular accidents at time of diagnosis in patients with giant cell arteritis. Retrospective data were collected from 98 patients at a single hospital with giant cell arteritis (according to the American College of Rheumatology classification criteria) diagnosed between October 1999 and January 2012. Cerebrovascular accident was found at initial presentation in 6 patients (6.1 %, 95 % CIs 2.3-12.9). Most of them had other symptoms of giant cell arteritis when the disease began. Signs reflecting the involvement of vertebro-basilar territory were present in 3 cases. No other case of cerebrovascular accident was described during the follow-up of patient; particularly no case of cerebrovascular accident occurred once corticosteroid therapy for the treatment of giant cell arteritis had been initiated. No differences in the epidemiologic, clinical and laboratory features at the time of diagnosis between patients who had cerebrovascular accidents and the rest of the giant cell arteritis patients were observed. Prognosis was good in our survey. However, there was no case of bilateral vertebral artery occlusion, a condition associated with poor prognosis. The present study confirms that cerebrovascular accidents may be the initial manifestation of giant cell arteritis, an argument in favor of a direct effect of the vasculitis in the development of cerebrovascular accidents rather than a complication of the corticosteroid therapy. The diagnosis of giant cell arteritis should always be considered in an elderly patient with stroke and an unexplained elevation of inflammatory biomarkers.
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Arteritis de Células Gigantes/complicaciones , Arteritis de Células Gigantes/diagnóstico , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/etiología , Anciano , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Arteritis de Células Gigantes/patología , Humanos , Incidencia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Accidente Cerebrovascular/patología , Tomografía Computarizada por Rayos X , Arteria Vertebral/diagnóstico por imagen , Arteria Vertebral/patologíaRESUMEN
Physicians need to be familiar with the typical manifestations of giant cell arteritis. However, the challenge lies in recognizing atypical cases that lack the more specific manifestations or reflect vasculitis in less frequently involved territories. Among atypical clinical manifestations, dry cough has been reported in recent years. The literature contains sporadic reports mainly single case report. The objective of this study was to determine the frequency of dry cough in patients with giant cell arteritis. Clinical data were collected from 88 patients with giant cell arteritis. Relationships between dry cough and other clinical manifestations or biological data were analyzed. Dry cough of recent appearance was found at initial presentation of giant cell arteritis in 12 patients (13.6%). In 2 cases, dry cough was isolated. The 2 patients sought attention because of chronic dry cough associated with inflammation of unknown origin. In 10 cases, dry cough was associated with typical clinical manifestations of giant cell arteritis. A correlation was found between inflammatory biomarkers and presence of dry cough. The mean CRP was 153.8 mg/l (SD 85.1) in patients with dry cough and 94 mg/l (SD 72.2) in patients without dry cough (p = 0.0131). We conclude that the diagnosis of giant cell arteritis should always be considered in an elderly patient with an unexplained elevation of inflammatory markers and chronic dry cough. Dry cough in giant cell arteritis was not correlated with other clinical manifestations of this vasculitis, including pulmonary manifestations, but was correlated with inflammatory biomarkers.
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Tos/etiología , Arteritis de Células Gigantes/complicaciones , Anciano , Anciano de 80 o más Años , Femenino , Arteritis de Células Gigantes/diagnóstico , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Camptocormia, an abnormal truncal flexion posture that occurs while walking or standing, is usually caused by various hypokinetic movement disorders, mainly Parkinson disease. We describe the case of a man with subacute onset of camptocormia. Quadriceps muscle biopsy showed significant rhabdomyolysis, few isolated inflammatory cells and mild expression of type I MHC in few fibers, a pattern usually found in immune-mediated necrotizing myopathies. Myositis was associated with Raynaud's phenomenon, mild sclerodactyly, and anti-Ku antibodies leading to the diagnosis of polymyositis/systemic sclerosis overlap myositis. The posture showed modest improvement in response to treatment.
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Antígenos Nucleares/inmunología , Autoanticuerpos/sangre , Proteínas de Unión al ADN/inmunología , Atrofia Muscular Espinal/etiología , Polimiositis/complicaciones , Esclerodermia Sistémica/complicaciones , Curvaturas de la Columna Vertebral/etiología , Anciano , Humanos , Autoantígeno Ku , Masculino , Polimiositis/patología , Esclerodermia Sistémica/patologíaRESUMEN
The risk of malignant non-Hodgkin lymphoma is increased in primary Sjögren syndrome. In the literature, most studies evaluating this risk were conducted in tertiary reference university hospital. So, selection bias in series exists, in particular selection of the most severe cases in tertiary reference university care centers. Some studies had also a selection bias because patients were hospitalized (data were obtained from hospital discharge registries) and therefore the more severe cases were considered. Between October 1999 and November 2009, 109 adult patients were admitted to our department of internal medicine (non-university hospital, secondary level of the healthcare system, hospitalized patients and outpatient) with diagnosis of primary Sjögren syndrome. Two cases of parotid gland lymphoma occurred during the period of follow-up. No other lymphoma was detected. In this study, clinically identifiable parotid gland non-Hodgkin lymphoma occurs in 1.8% of patients with primary Sjögren syndrome. Because most non-Hodgkin lymphoma initially involves the neck organs, meticulous imaging studies mainly focused on the cervical regions are recommended in the follow-up of patients with primary Sjögren syndrome. Patients whose main complaint is persistent parotid gland swelling may have a parotid biopsy in order to diagnose non-Hodgkin lymphoma.
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Linfoma de Células B de la Zona Marginal/etiología , Linfoma de Células B Grandes Difuso/etiología , Neoplasias de la Parótida/etiología , Síndrome de Sjögren/complicaciones , Anciano , Biopsia , Resultado Fatal , Femenino , Humanos , Inmunosupresores/uso terapéutico , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/terapia , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/terapia , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Neoplasias de la Parótida/diagnóstico , Neoplasias de la Parótida/terapia , Valor Predictivo de las Pruebas , Síndrome de Sjögren/diagnóstico , Síndrome de Sjögren/tratamiento farmacológico , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Background: Few studies of daily practice for patients with giant cell arteritis (GCA) are available. This French study aimed to describe the characteristics and management of GCA in a real-life setting. Methods: Cross-sectional, non-interventional, multicenter study of patients ≥50 years old who consulted hospital-based specialists for GCA and were under treatment. Patient characteristics and journey, diagnostic methods and treatments were collected. Descriptive analyses were performed. Results: In total, 306 patients (67% females, mean age 74 ± 8 years old) were recruited by 69 physicians (internists: 85%, rheumatologists: 15%); 13% of patients had newly diagnosed GCA (diagnosis-to-visit interval <6 weeks). Overall median disease duration was 13 months (interquartile range 5-26). Most patients were referred by general practitioners (56%), then ophthalmologists (10%) and neurologists (7%). Most common comorbidities were hypertension (46%), psychiatric disorders (10%), dyslipidemia (12%), diabetes (9%), and osteoporosis (6%). Initial GCA presentations included cranial symptoms (89%), constitutional symptoms (74%), polymyalgia rheumatica (48%), and/or other extra-cranial manifestations (35%). Overall, 85, 31, 26, and 30% of patients underwent temporal artery biopsy, high-resolution temporal artery Doppler ultrasonography, 18FDG-PET, and aortic angio-CT, respectively. All patients received glucocorticoids, which were ongoing for 89%; 29% also received adjunct medication(s) (methotrexate: 19%, tocilizumab: 15%). A total of 40% had relapse(s); the median time to the first relapse was 10 months. Also, 37% had comorbidity(ies) related to or aggravated by glucocorticoids therapy. Conclusion: This large observational study provides insight into current medical practices for GCA. More than one third of patients had comorbidities related to glucocorticoid therapy for a median disease duration of 13 months. Methotrexate and tocilizumab were the most common adjunct medications.
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OBJECTIVE: To report the incidence, predictors, and outcome of rituximab (RTX)-associated autoimmune disease flare. METHODS: We conducted a retrospective study in a tertiary referral center from 2005 to 2015. Disease flare was defined as the onset of a new organ involvement or worsening of autoimmune disease within 4 weeks following RTX. RESULTS: Among the 185 patients, we identified 7 disease flares (3.4%). All were due to type II mixed cryoglobulinemia vasculitis. Vasculitis flare occurred after a median time of 8 days (range 2-16) following RTX infusion and included acute kidney insufficiency (n = 7), purpura with cutaneous (n = 7), gastrointestinal (GI) tract involvement (n = 4), and myocarditis (n = 1). Patients with RTX-associated cryoglobulinemia vasculitis flare had these conditions more frequently: renal involvement (p = 0.0008), B cell lymphoproliferation (p = 0.015), higher level of cryoglobulin (2.1 vs 0.4 g/l, p = 0.0004), and lower level of C4 (0.02 vs 0.05, p = 0.023) compared to patients without flare after RTX (n = 43). Four patients (57%) died after a median time of 3.3 months. The 1-year survival rate was poorer in patients with vasculitis flare after RTX compared to their negative counterpart [43% (95% CI 18-100) vs 97% (95% CI 92-100), p < 0.001]. Immunofluorescence analysis of kidney biopsy in patients with worsening RTX-associated vasculitis highlighted the presence of RTX-, IgM-, and IgG1-positive staining of endomembranous deposits and thrombi within kidney lesions. CONCLUSION: RTX-associated cryoglobulinemia vasculitis flare is associated with high mortality rate. We provided evidence that kidney lesions are due to immune complex deposition and to glomerular obstruction by cryoglobulinemia and RTX.
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Crioglobulinemia , Vasculitis , Crioglobulinemia/epidemiología , Humanos , Incidencia , Estudios Retrospectivos , Rituximab/efectos adversos , Resultado del Tratamiento , Vasculitis/inducido químicamente , Vasculitis/epidemiologíaRESUMEN
BACKGROUD: Fabry disease (OMIM #301 500), the most prevalent lysosomal storage disease, is caused by enzymatic defects in alpha-galactosidase A (GLA gene; Xq22.1). Fabry disease has historically been characterized by progressive renal failure, early stroke and hypertrophic cardiomyopathy, with a diminished life expectancy. A nonclassical phenotype has been described with an almost exclusive cardiac involvement. Specific therapies with enzyme substitution or chaperone molecules are now available depending on the mutation carried. Numerous clinical and fundamental studies have been conducted without stratifying patients by phenotype or severity, despite different prognoses and possible different pathophysiologies. We aimed to identify a simple and clinically relevant way to classify and stratify patients according to their disease severity. METHODS: Based on data from the French Fabry Biobank and Registry (FFABRY; n = 104; 54 males), we applied unsupervised multivariate statistics to determine clusters of patients and identify clinical criteria that would allow an effective classification of adult patients. Thanks to these criteria and empirical clinical considerations we secondly elaborate a new score that allow the severity stratification of patients. RESULTS: We observed that the absence of acroparesthesia or cornea verticillata is sufficient to classify males as having the nonclassical phenotype. We did not identify criteria that significantly cluster female patients. The classical phenotype was associated with a higher risk of severe renal (HR = 35.1; p <10-3) and cardiac events (HR = 4.8; p = 0.008) and a trend toward a higher risk of severe neurological events (HR = 7.7; p = 0.08) compared to nonclassical males. Our simple, rapid and clinically-relevant FFABRY score gave concordant results with the validated MSSI. CONCLUSION: Acroparesthesia and cornea verticillata are simple clinical criteria that efficiently stratify Fabry patients, defining 3 different groups: females and males with nonclassical and classical phenotypes of significantly different severity. The FFABRY score allows severity stratification of Fabry patients.
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Enfermedad de Fabry/clasificación , Adulto , Estudios de Cohortes , Córnea/diagnóstico por imagen , Enfermedad de Fabry/complicaciones , Enfermedad de Fabry/diagnóstico por imagen , Femenino , Francia , Humanos , Persona de Mediana Edad , Parestesia/etiología , Fenotipo , Estudios Prospectivos , Sistema de Registros , Adulto JovenRESUMEN
BACKGROUND: Age at onset of large-vessel vasculitis (LVV) is commonly used to distinguish giant cell arteritis (GCA) and Takayasu arteritis (TA). However, LVV between age 50 and 60â¯years may be difficult to classify. METHODS: We conducted a retrospective study including LVV aged between 50 and 60â¯years at onset (LVV50-60, cases) and compared them to LVV aged over 60â¯years (LVV>60, controls). LVV was defined histologically and/or morphologically. Controls fulfilled ACR 1990 criteria for GCA or presented isolated aortitis. RESULTS: We included 183 LVV50-60 and 183 gender-matched LVV>60. LVV50-60 had more frequent peripheral limb manifestations (23 vs. 5%), and less frequent cephalic (73 vs. 90%) and ocular signs (17 vs. 27%) than LVV>60. Compared to LVV>60, CT angiography and PET/CT scan were more frequently abnormal in LVV50-60 (74 vs. 38%, and 90 vs. 72%, respectively), with aorta being more frequently involved (78 vs. 47%). By multivariate analysis, absence of cephalic symptoms, presence of peripheral limb ischemia and aorta involvement, and increased CRP level were significantly associated with LVV50-60 presentation compared to LVV>60. At last follow-up, compared to LVV>60, LVV50-60 received significantly more lines of treatment (2 vs. 1), more frequent biologics (12 vs. 3%), had more surgery (10 vs. 0%), and had higher prednisone dose (8.8 vs. 6.5â¯mg/d) at last follow-up, CONCLUSION: LVV onset between 50 and 60â¯years identifies a subset of patients with more frequent aorta and peripheral vascular involvement and more refractory disease compared to patients with LVV onset after 60.
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Arteritis de Células Gigantes/epidemiología , Edad de Inicio , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Arteritis de Células Gigantes/diagnóstico , Arteritis de Células Gigantes/terapia , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Fabry disease (OMIM #301500) is an X-linked disorder caused by alpha-galactosidase A deficiency with two major clinical phenotypes: classic and non-classic of different prognosis. From 2001, enzyme replacement therapies (ERT) have been available. We aimed to determine the epidemiology and the functional characteristics of anti-drug antibodies. Patients from the French multicenter cohort FFABRY (n = 103 patients, 53 males) were prospectively screened for total anti-agalsidase IgG and IgG subclasses with a home-made enzyme-linked immunosorbent assay (ELISA), enzyme-inhibition assessed with neutralization assays and lysoGb3 plasma levels, and compared for clinical outcomes. RESULTS: Among the patients exposed to agalsidase, 40% of men (n = 18/45) and 8% of women (n = 2/25) had antibodies with a complete cross-reactivity towards both ERTs. Antibodies developed preferentially in men with non-missense GLA mutations (relative risk 2.88, p = 0.006) and classic phenotype (58.6% (17/29) vs 6.7% (1/16), p = 0.0005). Specific anti-agalsidase IgG1 were the most frequently observed (16/18 men), but the highest concentrations were observed for IgG4 (median 1.89 µg/ml, interquartile range (IQR) [0.41-12.24]). In the men exposed to agalsidase, inhibition was correlated with the total IgG titer (r = 0.67, p < 0.0001), especially IgG4 (r = 0.75, p = 0.0005) and IgG2 (r = 0.72, p = 0.001). Inhibition was confirmed intracellularly in Fabry patient leucocytes cultured with IgG-positive versus negative serum (median: 42.0 vs 75.6%, p = 0.04), which was correlated with IgG2 (r = 0.67, p = 0.017, n = 12) and IgG4 levels (r = 0.59, p = 0.041, n = 12). Plasma LysoGb3 levels were correlated with total IgG (r = 0.66, p = 0.001), IgG2 (r = 0.72, p = 0.004), IgG4 (r = 0.58, p = 0.03) and IgG1 (r = 0.55, p = 0.04) titers. Within the classic group, no clinical difference was observed but lysoGb3 levels were higher in antibody-positive patients (median 33.2 ng/ml [IQR 20.6-55.6] vs 12.5 [10.1-24.0], p = 0.005). CONCLUSION: Anti-agalsidase antibodies preferentially develop in the severe classic Fabry phenotype. They are frequently associated with enzyme inhibition and higher lysoGb3 levels. As such, they could be considered as a hallmark of severity associated with the classic phenotype. The distinction of the clinical phenotypes should now be mandatory in studies dealing with Fabry disease and its current and future therapies.
Asunto(s)
Anticuerpos/sangre , Enfermedad de Fabry/inmunología , Enfermedad de Fabry/patología , alfa-Galactosidasa/antagonistas & inhibidores , Adulto , Terapia de Reemplazo Enzimático , Ensayo de Inmunoadsorción Enzimática , Enfermedad de Fabry/sangre , Enfermedad de Fabry/tratamiento farmacológico , Femenino , Glucolípidos/sangre , Humanos , Inmunoglobulina G/sangre , Enfermedades por Almacenamiento Lisosomal/sangre , Enfermedades por Almacenamiento Lisosomal/tratamiento farmacológico , Enfermedades por Almacenamiento Lisosomal/inmunología , Enfermedades por Almacenamiento Lisosomal/patología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Esfingolípidos/sangre , alfa-Galactosidasa/inmunologíaRESUMEN
Noninfectious inflammatory diseases (connective tissue diseases, vasculitis syndromes, granulomatous diseases) emerged as the most frequent cause of fever of unknown origin in western countries. Among these diseases, giant cell arteritis and polymyalgia rheumatica are the most frequent specific diagnosis in the elderly and adult-onset Still's disease the most frequent in younger patients. This article focuses on noninfectious inflammatory diseases as a cause of classic fever of unknown origin (mainly rheumatic diseases, such as vasculitis and connective tissue diseases).
Asunto(s)
Fiebre de Origen Desconocido/etiología , Enfermedades Reumáticas/diagnóstico , Enfermedades del Tejido Conjuntivo/diagnóstico , Enfermedad Granulomatosa Crónica/diagnóstico , Humanos , Vasculitis/diagnósticoRESUMEN
BACKGROUND: Although peripheral nervous system involvement is common in eosinophilic granulomatosis with polyangiitis (EGPA), central nervous system (CNS) manifestations are poorly described. This study aimed to describe CNS involvement in EGPA. PATIENTS AND METHODS: This retrospective, observational, multicenter study included patients with EGPA and CNS involvement affecting cranial nerves, brain and/or spinal cord. We also undertook a systematic literature review. RESULTS: We analyzed 26 personal cases and 62 previously reported cases. At EGPA diagnosis, asthma was noted in 97%, eosinophilia in 98%, peripheral neuropathy in 55% and cardiac involvement in 41%. 38/71 (54%) were ANCA-positive, with a perinuclear-labeling pattern and/or anti-MPO specificity. CNS was involved in 86% at EGPA diagnosis, preceded EGPA in 2%, and occurred during follow-up in 12% after a median of 24months. Main neurological manifestations were ischemic cerebrovascular lesions in 46 (52%), intracerebral hemorrhage and/or subarachnoid hemorrhage in 21 (24%), loss of visual acuity in 28 (33%) (15 with optic neuritis, 9 with central retinal artery occlusion, 4 with cortical blindness), and cranial nerves palsies in 18 (21%), with 25 patients having ≥1 of these clinical CNS manifestations. Among the 81 patients with assessable neurological responses, 43% had complete responses without sequelae, 43% had partial responses with long-term sequelae and 14% refractory disease. After a mean follow-up of 36months, 11 patients died including 5 from intracerebral hemorrhages. CONCLUSION: EGPA-related CNS manifestations form 4 distinct neurological pictures: ischemic lesions, intracerebral hemorrhages, cranial nerve palsies and loss of visual acuity. Such manifestation should prompt practitioners to consider EGPA in such conditions. Long-term neurological sequelae were common, and intracerebral hemorrhages had the worst prognostic impact.
Asunto(s)
Encéfalo/patología , Eosinofilia/patología , Granulomatosis con Poliangitis/patología , Adulto , Anciano , Asma/diagnóstico por imagen , Asma/patología , Encéfalo/diagnóstico por imagen , Eosinofilia/diagnóstico por imagen , Eosinofilia/tratamiento farmacológico , Femenino , Granulomatosis con Poliangitis/diagnóstico por imagen , Granulomatosis con Poliangitis/tratamiento farmacológico , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Oclusión de la Arteria Retiniana/diagnóstico por imagen , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Cogan syndrome is mainly treated with steroids. We aimed to determine the place of DMARDs and biologic-targeted treatments. PATIENTS AND METHODS: We conducted a French nationwide retrospective study of patients with Cogan syndrome (n=40) and a literature review of cases (n=22) and analyzed the efficacy of disease-modifying anti-rheumatic drugs (DMARDs) and tumor necrosis factor α (TNF-α) antagonists. RESULTS: We included 62 patients (31 females) (median age 37years [range 2-76]. At diagnosis, 61 patients (98%) had vestibulo-auditory symptoms, particularly bilateral hearing loss in 41% and deafness in 31%. Ocular signs were present in 57 patients (92%), with interstitial keratitis in 31 (51%). The first-line treatment consisted of steroids alone (n=43; 70%) or associated with other immunosuppressive drugs (n=18; 30%). Overall, 13/43 (30%) and 4/18 (22%) patients with steroids alone and with associated immunosuppressive drugs, respectively (p=0.8), showed vestibulo-auditory response; 32/39 (82%) and 15/19 (79%) ocular response; and 23/28 (82%) and 10/14 (71%) general response. Overall 61 patients had used a total of 126 lines of treatment, consisting of steroids alone (n=51 lines), steroids with DMARDs (n=65) and infliximab (n=10). Vestibulo-auditory response was significantly more frequent with infliximab than DMARDs or steroids alone (80% vs 39% and 35%, respectively), whereas ocular, systemic and acute-phase reactant response rates were similar. Infliximab was the only significant predictor of vestibulo-auditory improvement (odds ratio 20.7 [95% confidence interval 1.65; 260], p=0.019). CONCLUSION: Infliximab could lead to vestibulo-auditory response in DMARDS and steroid-refractory Cogan syndrome, but prospective studies are necessary.