RESUMEN
OBJECTIVE: To ascertain the mortality rate and causes of death in patients with systemic lupus erythematosus (SLE) within a defined region in southern Sweden during the time period 1981-2014 and determine whether these have changed over time. METHODS: In 1981, a prospective observation study of patients with SLE was initiated in southern Sweden. All incident SLE patients within a defined geographic area were identified using previously validated methods including diagnosis and immunology registers. Patients with a confirmed SLE diagnosis were then followed prospectively at the Department of Rheumatology in Lund. Clinical data was collected at regular visits. Patients were recruited from 1981 to 2006 and followed until 2014. The patient cohort was split into two groups based on the year of diagnosis to determine secular trends. Causes of death were retrieved from medical records and from the cause of death registry at The National Board of Health and Welfare in Sweden. RESULTS: In all, 175 patients were diagnosed with SLE during the study period. A total of 60 deaths occurred during a total of 3053 years of follow-up. In the first half of the study inclusion period 46 patients died, compared with 14 in the latter. The majority of patients (51.7%) died of cardiovascular disease. Infections caused 15% of the deaths and malignancy was the cause of death in 13.3% of patients. SLE was the main cause of death for 6.7% of the patients and a contributing factor for half of the patients. Standardized mortality ratio was increased in patients by a factor of 2.5 compared with the general population. Deaths occurred at an even rate throughout the whole observation period. No significant difference in standardized mortality ratio was observed between genders but was increased in older female patients. Furthermore, secular mortality trends were not identified. CONCLUSIONS: In this long-term epidemiologic follow-up study of incident SLE, we report a substantially raised mortality rate amongst SLE patients compared with the general population. The mortality rates have not changed significantly during the observation period that spanned three decades. The main cause of death was cardiovascular disease and this finding was consistent over time.
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Enfermedades Cardiovasculares/mortalidad , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/mortalidad , Neoplasias/mortalidad , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Cardiovasculares/epidemiología , Causas de Muerte/tendencias , Femenino , Estudios de Seguimiento , Humanos , Incidencia , Infecciones/epidemiología , Infecciones/mortalidad , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Mortalidad , Neoplasias/epidemiología , Estudios Prospectivos , Sistema de Registros , Tasa de Supervivencia , Suecia/epidemiologíaRESUMEN
OBJECTIVE: To study whether serum levels of tumour necrosis factor-α (TNF-α), free or bound to etanercept, in biological-naïve adults with rheumatoid arthritis (RA) could predict the long-term efficacy of etanercept, measured as drug survival. METHOD: We identified 145 biological-naïve patients with RA starting treatment with etanercept at the Department of Rheumatology, Skåne University Hospital (1999-2008), of whom 16 had seronegative and 129 seropositive RA. TNF-α in serum was quantified using enzyme-linked immunosorbent assay in samples from the onset of treatment and at 6 week follow-up. Drug survival time was used to evaluate the long-term efficacy of etanercept. RESULTS: Levels of TNF-α were significantly increased at follow-up compared to at the start. At the 6 week follow-up, circulating TNF-α mainly comprised TNF-α in complex with etanercept. Longer drug survival time correlated with increased TNF-α at 6 week follow-up in the patients with seronegative RA, but not in the seropositive patients. CONCLUSION: We demonstrated that levels of circulating TNF-α increased in almost all individuals after initiation of treatment with etanercept and that this increase mainly comprised TNF-α in complex with etanercept. More importantly, this increase may predict drug survival in adults with seronegative, but not seropositive, RA and suggests that measuring TNF-α/etanercept complexes in serum may be relevant in patients with seronegative RA.
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Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Etanercept/sangre , Factor de Necrosis Tumoral alfa/sangre , Adulto , Artritis Reumatoide/sangre , Ensayo de Inmunoadsorción Enzimática , Etanercept/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Systemic lupus erythematosus (SLE) has a complex clinical picture, and a number of defects in the immune system have been described in patients with the disease. Most organs can be involved in SLE, and in addition to the typical major organ manifestations (e.g. from kidneys and the central nervous system), early cardiovascular disease is a major determinant of prognosis. Several important findings during the last decade have increased the understanding of the mechanisms behind the disease characteristics and the underlying autoimmune process. Amongst, these are defects in the handling of apoptotic cells, increased expression of type I interferon-regulated genes and activation of autoreactive B cells, with both the type I interferon system and the B lymphocyte stimulator (BLyS) having key roles. In addition, a large number of genes have been identified that contribute to these abnormalities. It has also become clear that certain SLE risk genes are associated with some organ manifestations, such as STAT4 with nephritis and IRF8 with myocardial infarction. Furthermore, environmental factors that can induce SLE or trigger a disease flare have been identified. As a consequence of this increased knowledge, new treatments for SLE have been developed. The most recently approved drug for SLE is belimumab, which blocks BLyS, and several new therapies and therapeutic strategies are in the pipeline for clinical application.
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Lupus Eritematoso Sistémico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Factor Activador de Células B/antagonistas & inhibidores , Ambiente , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunologíaRESUMEN
Objectives Systemic lupus erythematosus (SLE) is associated with elevated levels of S100A8/A9, pro-inflammatory proteins mainly secreted by activated polymorphonuclear neutrophils (PMNs). The underlying mechanisms for increased S100A8/A9 levels and their relation to the clinical phenotype have not been carefully investigated. We assessed S100A8/A9 and S100A12 levels in SLE patient sera in relation to disease activity, clinical phenotype, presence of anti-dsDNA antibodies and ability to promote phagocytosis of necrotic cells (NCs) by PMNs. Methods Serum levels of S100A8/A9 and S100A12 were measured by ELISA in paired samples of 100 SLE patients at time points of higher and lower disease activity. Serum-mediated phagocytosis of NCs by PMNs was analysed by flow cytometry. Clinical data were recorded at time points of blood sampling. Results Serum levels of S100A8/A9 and S100A12 were increased in SLE patients with high disease activity compared to paired samples at low disease activity ( p = 0.01 and p = 0.008, respectively). Elevated levels of S100A8/A9 were particularly seen in patients with anti-dsDNA antibodies ( p = 0.01) and glomerulonephritis before treatment ( p = 0.02). Immunosuppressive therapy was associated with a reduction of S100A8/A9 serum levels ( p = 0.002). The ability of serum to support phagocytosis of NCs by PMNs was related to increased S100A8/A9 levels ( p = 0.01). Conclusions Elevated serum levels of S100A8/A9 may be used to monitor disease activity and response to treatment in SLE patients, especially in patients with glomerulonephritis. S100A12 may be a marker of disease activity in SLE. Increased S100A8/A9 levels may reflect immune-pathological processes involving phagocytosis of immune complexes by PMNs.
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Anticuerpos Antinucleares/sangre , ADN/inmunología , Mediadores de Inflamación/sangre , Lupus Eritematoso Sistémico/sangre , Nefritis Lúpica/sangre , Proteínas S100/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Calgranulina A/sangre , Calgranulina B/sangre , Femenino , Humanos , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/inmunología , Nefritis Lúpica/diagnóstico , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Masculino , Persona de Mediana Edad , Neutrófilos/inmunología , Fagocitosis , Proteína S100A12/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
Systemic lupus erythematosus (SLE) is a severe chronic inflammatory autoimmune connective tissue disease. Despite major efforts, SLE remains a poorly understood disease with unpredictable course, unknown etiology and complex pathogenesis. Apoptosis combined with deficiency in clearing apoptotic cells is an important etiopathogenic event in SLE, which could contribute to the increased load of potential autoantigen(s); however, the lack of disease-specific protein signatures deciphering SLE and the underlying biological processes is striking and represents a key limitation. In this retrospective pilot study, we explored the immune system as a specific sensor for disease, in order to advance our understanding of SLE. To this end, we determined multiplexed serum protein expression profiles of crude SLE serum samples, using antibody microarrays. The aim was to identify differential immunoprofiles, or snapshots of the immune response modulated by the disease, reflecting apoptosis, a key process in the etiology of SLE and disease activity. The results showed that multiplexed panels of SLE-associated serum biomarkers could be decoded, in particular reflecting disease activity, but potentially the apoptosis process as well. While the former biomarkers could display a potential future use for prognosis, the latter biomarkers might help shed further light on the apoptosis process taking place in SLE.
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Proteínas Sanguíneas/metabolismo , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Adulto , Anciano , Anticuerpos/inmunología , Apoptosis/fisiología , Biomarcadores/sangre , Femenino , Humanos , Lupus Eritematoso Sistémico/patología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Análisis por Matrices de Proteínas/métodos , Estudios RetrospectivosRESUMEN
Background/purpose The objective of this study was to explore the impact of systemic lupus erythematosus and belimumab given in addition to standard of care therapy on 13-valent conjugated pneumococcal vaccine (PCV13) response. Methods Forty-seven systemic lupus erythematosus patients and 21 healthy controls were immunized with a single dose of 13-valent conjugated pneumococcal vaccine. Forty systemic lupus erythematosus patients were treated with traditional disease-modifying anti rheumatic drugs, 11 of those received belimumab in addition, and 32 patients were treated with concomitant prednisolone. Quantification of serotype specific IgG levels to 12 pneumococcal capsular polysaccharides was performed in serum taken before and four to six weeks after vaccination using multiplex fluorescent microsphere immunoassay. IgG levels against serotypes 23F and 6B were also analyzed using standard enzyme-linked immunosorbent assays. Opsonophagocytic assay was performed on serotype 23F to evaluate the functionality of the antibodies. Pre- and post-vaccination log transformed antibody levels were compared to determine the impact of systemic lupus erythematosus diagnosis and different treatments on antibody response. Results Systemic lupus erythematosus patients as a group showed lower post-vaccination antibody levels and lower fold increase of antibody levels after vaccination compared to controls ( p = 0.02 and p = 0.009, respectively). Systemic lupus erythematosus patients treated with belimumab in addition to standard of care therapy or with only hydroxychloroquine did not differ compared to controls, whereas the other treatment groups had significantly lower fold increase of post-vaccination antibody levels. Higher age was associated with lower post-vaccination antibody levels among systemic lupus erythematosus patients. Conclusion Belimumab given in addition to traditional disease-modifying anti rheumatic drugs or prednisolone did not further impair antibody response to 13-valent conjugated pneumococcal vaccine.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunosupresores/uso terapéutico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Vacunas Neumococicas/administración & dosificación , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Formación de Anticuerpos/inmunología , Antirreumáticos/uso terapéutico , Estudios de Casos y Controles , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/inmunología , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Vacunas Neumococicas/inmunología , Prednisolona/uso terapéutico , Vacunación , Adulto JovenRESUMEN
OBJECTIVES: To explore differences in body structure and function in systemic lupus erythematosus (SLE) patients and controls, with particular reference to joint hypermobility, and to evaluate the usefulness of the Brighton criteria for diagnosing joint hypermobility syndrome (JHS) in SLE. METHOD: Female SLE patients were, according to age group, consecutively invited to participate in the study. Controls were healthy females matched for age. All individuals were examined by a physician according to the Brighton criteria, and by an occupational therapist and a physiotherapist to obtain the Beighton scores, overall joint mobility, and manifestations in body structure and function. RESULTS: Sixteen (23%) SLE patients and 19 (27%) controls had a Beighton score ≥ 4 (non-significant, ns), and 39 (55%) individuals in the SLE group and 22 (31%) in the control group satisfied the Brighton criteria for JHS (p < 0.01). Many individuals in both groups exceeded the normative values for joint mobility in joints other than those included in the Beighton score. Stratifying for a Beighton score ≥ 4 vs. < 4, there were no significant differences in body structure or body function constituting JHS either in the SLE patients or in the controls. CONCLUSIONS: Although the presence of joint hypermobility in SLE patients was frequent, we could not verify that this caused excess manifestations in addition to the SLE symptoms.
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Inestabilidad de la Articulación/congénito , Articulaciones/fisiopatología , Lupus Eritematoso Sistémico/fisiopatología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Inestabilidad de la Articulación/complicaciones , Inestabilidad de la Articulación/diagnóstico , Inestabilidad de la Articulación/etiología , Lupus Eritematoso Sistémico/complicaciones , Persona de Mediana EdadRESUMEN
OBJECTIVE: The epidemiology of systemic lupus erythematosus (SLE) within a defined region in southern Sweden was studied during the time period 1981-2006. Furthermore, whether the phenotypic expression of SLE changed during the study period was investigated. METHODS: Patients with suspected SLE were retrieved from diagnosis registries, hospital records and central laboratory databases. All new cases of SLE in this region were identified using validated retrieval methods and observed prospectively in a structured follow-up program. SLE disease manifestations, including classification criteria, were followed over time. RESULTS: A total of 174 cases were diagnosed with SLE during 1981-2006. In the first period of the study, from 1981 to 1993, the incidence of SLE was 5.0/100,000 inhabitants and in the second period of the study, 1994-2006, the annual incidence decreased to 2.8/100,000. During the first period the highest incidence was among females between the ages of 45 and 54 years; 15.1/100,000 inhabitants, which was reduced in the second period to 3.8/100,000. During the second period the highest age and sex specific incidence was among women between 25 and 34 years (6.6/100,000 inhabitants). The point prevalence of SLE on 31 December 1993 was 55/100,000 inhabitants compared with 31 December 2006, when it was 65/100,000 inhabitants. The phenotype of the disease did not vary significantly during the study period. CONCLUSION: The incidence rate of SLE in younger females remained stable from 1981 to 2006. However, in middle-aged women the incidence was substantially reduced in the latter half of the study period.
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Lupus Eritematoso Sistémico/epidemiología , Adolescente , Adulto , Distribución por Edad , Anciano , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Sistema de Registros , Distribución por Sexo , Suecia/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: To study the annual direct and indirect costs in systemic lupus erythematosus (SLE) and how age, disease manifestations, disease activity, and organ damage influence total costs and predicted costs for SLE. METHODS: Clinical data on all patients with a diagnosis of SLE living in a defined area in southern Sweden during eight years were linked to health authority registries and the social insurance system which contain data on cost. Cost data on four matched population controls for each patient were also extracted. The controls were matched for age, sex, and area of residence. RESULTS: Data from 127 patients with SLE and 508 population controls were extracted. The mean annual total cost for SLE patients was SEK 180,520 ($30,093); the highest costs were found in the subgroup with nephritis SEK 229,423 ($38,246). The total costs for the patient group were significantly higher (p < 0.05) compared to the population controls of SEK 59,985 ($10,000). Of the total costs, 72% were due to indirect costs, 3% to SLE-specific pharmaceuticals, and the remaining 25% were in- and outpatient related costs. During the study period, inpatient days decreased by 60%, while outpatient contacts increased by 25%. Age (inverse relation), increasing disease activity, and acquired organ damage were significant predictors of total costs (all p < 0.05). CONCLUSION: The total annual costs for unselected SLE patients were found to be three times those for matched population controls. Important predictors of total costs were found.
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Artritis/economía , Costo de Enfermedad , Lupus Eritematoso Sistémico/complicaciones , Lupus Eritematoso Sistémico/economía , Nefritis/economía , Enfermedades de la Piel/economía , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Artritis/complicaciones , Niño , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Nefritis/complicaciones , Enfermedades de la Piel/complicaciones , Suecia , Población Blanca , Adulto JovenRESUMEN
This clinical study was performed to investigate hand problems in individuals with systemic lupus erythematosus (SLE) in comparison with healthy controls, and to explore problems in the performance of daily activities related to these hand problems, in order to objectify findings from a previous mail survey. We also investigated whether a simple hand test could detect hand problems in SLE. All individuals, 71 with SLE and 71 healthy controls, were examined for manifestations in body structures and body functions of the hands with a study-specific protocol. The simple hand test was performed by all the individuals and the arthritis impact measurement scale (AIMS 2) questionnaire was completed by the SLE individuals. In the SLE group, 58% had some kind of difficulty in the simple hand test, compared with 8% in the control group. Fifty percent of the SLE individuals experienced problems in performing daily activities due to hand deficits. Pain in the hands, reduced strength and dexterity, Raynaud's phenomenon and trigger finger were the most prominent body functions affecting the performance of daily activities. Deficits in hand function are common in SLE and affect the performance of daily activities. The simple hand test may be a useful tool in detecting hand problems.
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Actividades Cotidianas , Mano/fisiopatología , Lupus Eritematoso Sistémico/complicaciones , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Dolor , Enfermedad de Raynaud , Encuestas y CuestionariosRESUMEN
The type I interferon system genes IKBKE and IFIH1 are associated with the risk of systemic lupus erythematosus (SLE). To identify the sequence variants that are able to account for the disease association, we resequenced the genes IKBKE and IFIH1. Eighty-six single-nucleotide variants (SNVs) with potentially functional effect or differences in allele frequencies between patients and controls determined by sequencing were further genotyped in 1140 SLE patients and 2060 controls. In addition, 108 imputed sequence variants in IKBKE and IFIH1 were included in the association analysis. Ten IKBKE SNVs and three IFIH1 SNVs were associated with SLE. The SNVs rs1539241 and rs12142086 tagged two independent association signals in IKBKE, and the haplotype carrying their risk alleles showed an odds ratio of 1.68 (P-value=1.0 × 10(-5)). The risk allele of rs12142086 affects the binding of splicing factor 1 in vitro and could thus influence its transcriptional regulatory function. Two independent association signals were also detected in IFIH1, which were tagged by a low-frequency SNV rs78456138 and a missense SNV rs3747517. Their joint effect is protective against SLE (odds ratio=0.56; P-value=6.6 × 10(-3)). In conclusion, we have identified new SLE-associated sequence variants in IKBKE and IFIH1, and proposed functional hypotheses for the association signals.
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ARN Helicasas DEAD-box/genética , Predisposición Genética a la Enfermedad , Quinasa I-kappa B/genética , Lupus Eritematoso Sistémico/genética , Polimorfismo de Nucleótido Simple , Estudios de Casos y Controles , Proteínas de Unión al ADN/metabolismo , Frecuencia de los Genes , Estudios de Asociación Genética , Haplotipos , Humanos , Quinasa I-kappa B/metabolismo , Helicasa Inducida por Interferón IFIH1 , Unión Proteica , Factores de Empalme de ARN , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVE: To study serum type I interferon (IFN) activity in patients with early systemic sclerosis (SSc). METHOD: Serum type I IFN activity was measured in 33 consecutive patients with SSc and a disease duration of < 2 years and in 13 healthy individuals by calculating a type I IFN score according to the induction of six IFN-α regulated genes in a reporter cell line. RESULTS: Twenty-seven per cent of the SSc patients had an increased type I IFN score compared to none of the healthy individuals (p < 0.05). The clinical SSc phenotype associated with high serum type I IFN activity did not differ from patients with low serum type I IFN activity regarding the presence of skin or lung fibrosis, pulmonary hypertension, or digital complications. Patients with high serum type I IFN activity were younger (p < 0.01) and had a lower frequency of cardiac involvement (p = 0.053), lower leucocyte count (p < 0.001), higher immunoglobulin (Ig)G levels (p < 0.05), and a higher amount of antibodies against extractable nuclear antigens (p < 0.01) than patients with low serum type I IFN activity. The presence of antibodies against topoisomerase I, Sjögren's syndrome antigen, and nuclear ribonucleoprotein antigens was associated with higher type I IFN activity (p < 0.05 for all comparisons). CONCLUSIONS: Our study indicates that increased serum type I IFN activity in early SSc patients is associated with an antibody and laboratory profile that may reflect a subclinical overlap of SSc with other type I IFN-driven connective tissue diseases (CTDs).
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Autoanticuerpos/sangre , Interferón Tipo I/sangre , Esclerodermia Sistémica/inmunología , Adulto , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ribonucleoproteínas/inmunología , Esclerodermia Sistémica/sangre , Síndrome de Sjögren/inmunologíaRESUMEN
OBJECTIVES: To test the utility of the World Health Organization (WHO) and International Society of Nephrology/Renal Pathology Society (ISN/RPS) criteria for lupus nephritis (LN) in systemic lupus erythematosus (SLE) and the American College of Rheumatology renal response criteria (ACR-RRC) for renal follow-up in an observational cohort. METHOD: All 52 biopsy-verified cases of LN during 19 years were identified, and glomerular filtration rate (GFR), serum creatinine, proteinuria, haematuria, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and complement were retrieved at diagnosis of nephritis, after 6 and 12 months, and at the latest visit. Forty-five renal biopsies were available for re-evaluation with the ISN/RPS criteria. Outcome was defined by the ACR-RRC and the final GFR. RESULTS: The mean follow-up time was 9 years; complete renal response (CRR) was achieved in 11 cases, end-stage renal disease (ESRD) in four, and nephrotic syndrome (NS) in one. The final GFR decreased with increasing age at biopsy (p < 0.01) and with interstitial manifestations added to the ISN/RPS classification (p < 0.05). The final GFR correlated with the decrease of proteinuria or casts and actual serum creatinine after 6 months of treatment (all p < 0.05). The outcome defined by ACR-RRC correlated with the nephrological components of SLEDAI-2K after 6 months of therapy (p < 0.01) and with the presence of antibodies to C1q at biopsy (p < 0.05). CONCLUSIONS: Renal outcome is correlated with the response to treatment after 6 months and with the addition of interstitial changes to the ISN/RPS classification, which might add useful information for prediction. The ACR-RRC offers a defined alternative to categorize renal response.
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Fallo Renal Crónico/patología , Riñón/patología , Nefritis Lúpica/patología , Síndrome Nefrótico/patología , Guías de Práctica Clínica como Asunto , Adolescente , Adulto , Anciano , Biopsia , Niño , Estudios de Cohortes , Femenino , Tasa de Filtración Glomerular , Humanos , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/terapia , Nefritis Lúpica/mortalidad , Nefritis Lúpica/terapia , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/mortalidad , Síndrome Nefrótico/fisiopatología , Pronóstico , Proteinuria , Inducción de Remisión , Índice de Severidad de la Enfermedad , Tasa de Supervivencia , Suecia/epidemiología , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVES: To verify the diagnostic accuracy of anti-double-stranded DNA (anti-dsDNA) antibodies detected by the Crithidia luciliae immunofluorescence test (CLIFT) in a cohort of unselected patients, referred to a rheumatologist due to recent onset of rheumatic symptoms. METHOD: A total of 1073 consecutive patients were screened for anti-nuclear antibodies (ANAs). Serum samples from 292 ANA-positive and 292 matching ANA-negative patients were tested three times for anti-dsDNA antibodies, using two different CLIFT kits (ImmunoConcepts(®) and Euroimmun(®)). An initial clinical diagnosis was made by rheumatologists unaware of the results. The diagnoses were updated after a median follow-up of 4.8 years. RESULTS: CLIFT was positive at least once in 60 patients but only 23 patients were CLIFT positive in all of the assays. Diagnosis of systemic lupus erythematosus (SLE) was made initially in 65 patients, of whom 24 (37%) were CLIFT positive. Many other diagnoses were observed among the CLIFT-positive patients. Overall, 16 (5.5%) ANA-negative patients were CLIFT positive. After approximately 5 years, the diagnosis of SLE remained unchanged in 63 patients (23 CLIFT positive) and altered in only two (one CLIFT positive). Among the 36 CLIFT-positive patients who were not diagnosed with SLE at study entry, only one developed SLE during the follow-up period. CONCLUSIONS: CLIFT was not reliable as a diagnostic tool in unselected patients with rheumatic symptoms. ANAs were of little value as a screening test before the CLIFT analysis. CLIFT had surprisingly low positive predictive value (PPV) for the diagnosis of SLE despite its high specificity. For non-SLE patients, being CLIFT positive poses little risk of developing SLE within 5 years.
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Anticuerpos Antinucleares/sangre , Lupus Eritematoso Sistémico/sangre , Enfermedades Reumáticas/sangre , Enfermedades Reumáticas/diagnóstico , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Anciano , Anciano de 80 o más Años , Anticuerpos Antinucleares/inmunología , Biomarcadores/metabolismo , Estudios de Cohortes , Diagnóstico Precoz , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Estudios de Seguimiento , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/epidemiología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Enfermedades Reumáticas/epidemiología , Medición de Riesgo , Países Escandinavos y Nórdicos , Índice de Severidad de la Enfermedad , Factores Sexuales , Factores de Tiempo , Adulto JovenRESUMEN
OBJECTIVE: Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) has previously shown alterations in cerebral perfusion in patients with systemic lupus erythematosus (SLE). However, the results have been inconsistent, in particular regarding neuropsychiatric (NP) SLE. Thus, we investigated perfusion-based measures in different brain regions in SLE patients with and without NP involvement, and additionally, in white matter hyperintensities (WMHs), the most common MRI pathology in SLE patients. MATERIALS AND METHODS: We included 3 T MRI images (conventional and DSC) from 64 female SLE patients and 19 healthy controls (HC). Three different NPSLE attribution models were used: the Systemic Lupus International Collaborating Clinics (SLICC) A model (13 patients), the SLICC B model (19 patients), and the American College of Rheumatology (ACR) case definitions for NPSLE (38 patients). Normalized cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) were calculated in 26 manually drawn regions of interest and compared between SLE patients and HC, and between NPSLE and non-NPSLE patients. Additionally, normalized CBF, CBV and MTT, as well as absolute values of the blood-brain barrier leakage parameter (K2) were investigated in WMHs compared to normal appearing white matter (NAWM) in the SLE patients. RESULTS: After correction for multiple comparisons, the most prevalent finding was a bilateral significant decrease in MTT in SLE patients compared to HC in the hypothalamus, putamen, right posterior thalamus and right anterior insula. Significant decreases in SLE compared to HC were also found for CBF in the pons, and for CBV in the bilateral putamen and posterior thalamus. Significant increases were found for CBF in the posterior corpus callosum and for CBV in the anterior corpus callosum. Similar patterns were found for both NPSLE and non-NPSLE patients for all attributional models compared to HC. However, no significant perfusion differences were revealed between NPSLE and non-NPSLE patients regardless of attribution model. The WMHs in SLE patients showed a significant increase in all perfusion-based metrics (CBF, CBV, MTT and K2) compared to NAWM. CONCLUSION: Our study revealed perfusion differences in several brain regions in SLE patients compared to HC, independently of NP involvement. Furthermore, increased K2 in WMHs compared to NAWM may indicate blood-brain barrier dysfunction in SLE patients. We conclude that our results show a robust cerebral perfusion, independent from the different NP attribution models, and provide insight into potential BBB dysfunction and altered vascular properties of WMHs in female SLE patients. Despite SLE being most prevalent in females, a generalization of our conclusions should be avoided, and future studies including all sexes are needed.
Asunto(s)
Lupus Eritematoso Sistémico , Vasculitis por Lupus del Sistema Nervioso Central , Humanos , Femenino , Barrera Hematoencefálica/diagnóstico por imagen , Lupus Eritematoso Sistémico/diagnóstico por imagen , Lupus Eritematoso Sistémico/patología , Angiografía por Resonancia Magnética/métodos , Imagen por Resonancia Magnética/métodos , Vasculitis por Lupus del Sistema Nervioso Central/patología , PerfusiónRESUMEN
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). It is not known why ANCA develop, but it has been shown that they participate in pathogenesis by activating polymorphonuclear neutrophils (PMNs). In this study we hypothesize that dysregulation of phagocytosis in AAV leads to the accumulation of apoptotic neutrophils seen in association with blood vessels in AAV. These cells progress into secondary necrosis, contributing to tissue damage and autoantibody formation. Peripheral blood cells were counted, and phagocytosis was investigated using monocyte-derived macrophages (MØ) and PMNs from healthy blood donors (HBD), AAV patients and systemic lupus erythematosus (SLE) patients. Furthermore, the effect of serum was assessed. Phagocytosis was measured using flow cytometry. The results showed no deviation in monocyte subpopulations for AAV patients compared to HBDs, although there was a decrease in lymphocyte and pDC (plasmacytoid dendritic cell) populations (4·2 × 10(6) cells/l versus 10·4 × 10(6) cells/l, P < 0·001). The number of neutrophils was increased (6·0 × 10(9) cells/l versus 3·8 × 10(9) cells/l, P < 0·001). There were no differences found in the ability of MØs to engulf apoptotic cells, nor when comparing apoptotic PMNs to become engulfed. However, serum from AAV donors tended to decrease the phagocytosis ability of MØs (36%) compared to serum from HBDs (43%). In conclusion, there is no intrinsic dysfunction in the MØs or in the PMNs that have an effect on phagocytic activity, but ANCA may play a role by decreasing phagocytic ability.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Anticuerpos Anticitoplasma de Neutrófilos/inmunología , Apoptosis/inmunología , Neutrófilos/patología , Fagocitosis/inmunología , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/patología , Anticuerpos Anticitoplasma de Neutrófilos/metabolismo , Estudios de Casos y Controles , Células Dendríticas/inmunología , Células Dendríticas/patología , Citometría de Flujo , Humanos , Lupus Eritematoso Sistémico/inmunología , Lupus Eritematoso Sistémico/patología , Linfocitos/inmunología , Linfocitos/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Poliangitis Microscópica/inmunología , Poliangitis Microscópica/patología , Persona de Mediana Edad , Necrosis/inmunología , Neutrófilos/inmunologíaRESUMEN
OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have an increased risk of developing vascular diseases (VD) such as myocardial infarction, stroke and venous thrombosis, which can only partly be explained by traditional risk factors. The role of platelets in this process has not been extensively studied. Platelet activation supports complement binding to the platelet surface, and increased C4d has been seen on platelets in SLE patients as well as in non-rheumatic patients with stroke. In this study we investigated in vivo platelet deposition of the classical complement pathway components C1q, C4d and C3d in relation to VD in SLE patients. Furthermore, the ability of serum to support in vitro complement deposition on fixed heterologous platelets was analyzed. METHODS: Blood from 69 SLE patients and age- and sex-matched healthy individuals was collected in sodium-citrate tubes and platelets isolated by centrifugation. Complement deposition on platelets was detected by flow cytometry. RESULTS: We could demonstrate that SLE patients had increased C1q, C3d and C4d deposition on platelets as compared to healthy controls (p < 0.0001). SLE patients with a history of venous thrombosis had increased complement deposition on platelets as compared to SLE patients without this manifestation (p < 0.05). In vitro studies demonstrated that serum from patients with lupus anticoagulant, venous thrombosis or antiphospholipid antibody syndrome supported increased platelet C4d deposition in vitro as compared to SLE patients without these manifestations (p < 0.05). Our data support the hypothesis that platelet activation and the subsequent complement deposition on platelets are central in the development of venous thrombosis in SLE. CONCLUSIONS: Altogether we suggest that complement deposition on platelets could reflect important pathogenetic events related to the development of venous thrombosis in SLE and might be used as a marker for venous thrombosis in SLE.
Asunto(s)
Plaquetas/inmunología , Complemento C1q/análisis , Complemento C3d/análisis , Complemento C4b/análisis , Lupus Eritematoso Sistémico/complicaciones , Fragmentos de Péptidos/análisis , Trombosis de la Vena/etiología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Estudios de Casos y Controles , Vía Clásica del Complemento , Femenino , Citometría de Flujo , Humanos , Inhibidor de Coagulación del Lupus/sangre , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Activación Plaquetaria , Factores de Riesgo , Regulación hacia Arriba , Trombosis de la Vena/sangre , Trombosis de la Vena/inmunología , Adulto JovenRESUMEN
Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177-mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/enzimología , Membrana Celular/metabolismo , Isoantígenos/fisiología , Glicoproteínas de Membrana/fisiología , Mieloblastina/biosíntesis , Neutrófilos/enzimología , Receptores de Superficie Celular/fisiología , Adulto , Anciano , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/sangre , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/inmunología , Artritis Reumatoide/sangre , Artritis Reumatoide/enzimología , Artritis Reumatoide/inmunología , Donantes de Sangre , Inducción Enzimática , Femenino , Proteínas Ligadas a GPI , Regulación de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos/sangre , Factor Estimulante de Colonias de Granulocitos y Macrófagos/sangre , Hemoglobinuria Paroxística/sangre , Hemoglobinuria Paroxística/enzimología , Hemoglobinuria Paroxística/inmunología , Humanos , Isoantígenos/biosíntesis , Isoantígenos/genética , Trasplante de Riñón , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/enzimología , Lupus Eritematoso Sistémico/inmunología , Masculino , Glicoproteínas de Membrana/biosíntesis , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Mieloblastina/genética , Mieloblastina/farmacología , Neutrófilos/inmunología , ARN Mensajero/biosíntesis , ARN Mensajero/sangre , Receptores de Superficie Celular/biosíntesis , Receptores de Superficie Celular/genética , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Transcripción Genética , Células U937/efectos de los fármacos , Células U937/enzimologíaRESUMEN
Inherited deficiencies in components of the classical complement pathway are strong disease susceptibility factors for the development of systemic lupus erythematosus (SLE) and there is a hierarchy among deficiency states, the strongest association being with C1q deficiency. We investigated the relative importance of the different complement pathways regarding clearance of apoptotic cells. Phagocytosis of labelled apoptotic Jurkat cells by monocyte-derived macrophages in the presence of sera from individuals with complement deficiencies was studied, as well as C3 deposition on apoptotic cells using flow cytometry. Sera from individuals deficient in C1q, C4, C2 or C3 all showed decreased phagocytosis. Mannose binding lectin (MBL) and the alternative pathway did not influence phagocytosis. Notably, the components of the complement classical pathway, including C1q, were equally important in clearance of apoptotic cells. This indicates that deposition of C3 fragments is of major significance; we therefore studied C3 deposition on apoptotic cells. Experiments with MBL-deficient serum depleted of C1q or factor D confirmed the predominance of the classical pathway. At low dilution, sera deficient of C1q, C4 or C2 supported C3 fragment deposition demonstrating alternative pathway activation. In conclusion, we have found that complement-mediated opsonization and phagocytosis of apoptotic cells, particularly those undergoing secondary necrosis, are dependent mainly upon an intact classical pathway. The alternative pathway is less important, but may play a role in some conditions. C1q was not more important than other classical pathway components, suggesting a role in additional pathogenetic processes in SLE other than clearance of apoptotic cells.
Asunto(s)
Vía Clásica del Complemento/fisiología , Macrófagos/fisiología , Fagocitosis/inmunología , Apoptosis , Estudios de Casos y Controles , Activación de Complemento , Complemento C1q/deficiencia , Complemento C2/deficiencia , Complemento C3/deficiencia , Complemento C4/deficiencia , Humanos , Células Jurkat , NecrosisRESUMEN
Psychological stress is thought to be an important trigger of cardiovascular events, yet the involved pathways and mediators are largely unknown. Elevated systemic levels of the pro-inflammatory alarmin S100A8/A9 correlate with poor prognosis in coronary artery disease (CAD) patients. Here, we investigated the links between S100A8/A9 release and parameters of anti-inflammatory glucocorticoid secretion in two different cohorts subjected to a psychological stress test. In the first cohort of 60 CAD patients, psychological stress induced a rapid increase of circulating S100A8/A9. This rapid S100A8/A9 response strongly correlated with elevated evening saliva cortisol levels, suggesting an association with a dysregulated hypothalamic-pituitary-adrenal (HPA) axis. In the second cohort of 27 CAD patients and 28 controls, elevated S100A8/A9 levels were still detectable 24 h after stress in 40% of patients and 36% of controls, with a tendency for higher levels in patients. The sustained S100A8/A9 response was associated with a poor rapid cortisol release after stress in patients, but not in the control group. Our findings reveal for the first time that acute psychological stress induces elevated levels of S100A8/A9. We also provide hypothesis-generating evidence that dysregulated cortisol secretion in CAD patients might be associated with an exaggerated pro-inflammatory S100A8/A9 response.