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OBJECTIVE: Renal involvement in systemic lupus erythematosus (SLE) is associated with poor prognosis. Currently available renal biomarkers are relatively insensitive and nonspecific for diagnosing SLE nephritis. Previous research suggests that neutrophil gelatinase-associated lipocalin (NGAL) is a high-quality renal biomarker of acute kidney injury, while its usefulness in SLE is unclear. We undertook this study to determine the relationship between urinary NGAL excretion and SLE disease activity or damage, with a focus on nephritis. METHODS: A cohort of 35 patients diagnosed as having SLE prior to age 16 years (childhood-onset SLE) was assessed for disease activity (using the Systemic Lupus Erythematosus Disease Activity Index 2000 update) and damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology SLE Damage Index) in a double-blind, cross-sectional study. Information on current markers of renal function and disease was obtained and compared with NGAL levels (ng/mg of urinary creatinine) measured by enzyme-linked immunosorbent assay. Eight children with juvenile idiopathic arthritis (JIA) served as controls. RESULTS: NGAL levels did not differ with the age, weight, height, sex, or race of the patients. Patients with childhood-onset SLE had significantly higher NGAL levels than did those with JIA (P < 0.0001). NGAL levels were strongly to moderately correlated with renal disease activity and renal damage (Spearman's r >/= 0.47, P < 0.0001 for both comparisons), but not with extrarenal disease activity or extrarenal damage. NGAL levels of >0.6 ng/mg urinary creatinine were 90% sensitive and 100% specific for identifying childhood-onset SLE patients with biopsy-proven nephritis. CONCLUSION: Urinary NGAL is a promising potential biomarker of childhood-onset SLE nephritis. The results of the current study require validation in a larger cohort to more accurately delineate urinary NGAL excretion in relation to the diverse SLE phenotypes. [ABSTRACT FROM AUTHOR]

The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) is the most commonly used measure of disease activity for children with systemic lupus erythematosus(SLE). For headachesto be scored in the SLEDAI as a symptom of active disease, they have to be nonresponsive to narcotic analgesia. This may affect the overall estimation of disease activity, especially because headaches are common among children with SLE and narcotic analgesia is rarely used for headache therapy in paediatrics. Moreover, the importance of headaches for the development of damage and their relation to other clinical parameters and outcomes has not been well described for children with SLE. We reviewed the medical charts of an inception cohort of children (n = 63) who were newly diagnosed with SLE. Information on headaches and other disease parameters was obtained. Disease activity and damage were measured using the SLEDAI and the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index (SDI), respectively. It has been shown that the accumulated burden of active disease as measured by serial SLEDAI scores over time is one of the best predictors of eventual damage to children with SLE. New-onset or significant increase of severe and/or persistent headaches (LHA) were reportedin 43% of the patients during a mean follow-up of 3.6 years. LHA occurred preferentiallyamong patients with elevated levels of antiphospholipid antibodies (aPL) (P < 0.02) and only 6% of all LHA episodes were treated with narcotics and thus considered for the measurement of disease activity in the SLEDAI. LHA were unrelated to proxy-measures of disease activity, such as the need to intensify therapies. When used in children, the insensitivity of the SLEDAI to capture LHA did not seem to decrease the responsiveness of the SLEDAI to detect clinically important worsening of disease, or negatively impact on its ability to predict damage. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To use a core set of outcome measures to develop preliminary definitions of improvement for adult and juvenile myositis as composite end points for therapeutic trials. METHODS: Twenty-nine experts in the assessment of myositis achieved consensus on 102 adult and 102 juvenile paper patient profiles as clinically improved or not improved. Two hundred twenty-seven candidate definitions of improvement were developed using the experts' consensus ratings as a gold standard and their judgment of clinically meaningful change in the core set of measures. Seventeen additional candidate definitions of improvement were developed from classification and regression tree analysis, a data-mining decision tree tool analysis. Six candidate definitions specifying percentage change or raw change in the core set of measures were developed using logistic regression analysis. Adult and pediatric working groups ranked the 13 top-performing candidate definitions for face validity, clinical sensibility, and ease of use, in which the sensitivity and specificity were >/=75% in adult, pediatric, and combined data sets. Nominal group technique was used to facilitate consensus formation. RESULTS: The definition of improvement (common to the adult and pediatric working groups) that ranked highest was 3 of any 6 of the core set measures improved by >/=20%, with no more than 2 worse by >/=25% (which could not include manual muscle testing to assess strength). Five and 4 additional preliminary definitions of improvement for adult and juvenile myositis, respectively, were also developed, with several definitions common to both groups. Participants also agreed to prospectively test 6 logistic regression definitions of improvement in clinical trials. CONCLUSION: Consensus preliminary definitions of improvement were developed for adult and juvenile myositis, and these incorporate clinically meaningful change in all myositis core set measures in a composite end point. These definitions require prospective validation, but they are now proposed for use as end points in all myositis trials. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To determine whether neutrophil gelatinase-associated lipocalin (NGAL) can predict worsening of global and renal disease activity in childhood-onset systemic lupus erythematosus (SLE). METHODS: One hundred eleven patients with childhood-onset SLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least 3 study visits. At each visit, global disease activity was measured using 3 external standards: the numerically converted British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index 2000 update score, and the physician's assessment of global disease activity. Renal and extrarenal disease activity were measured by the respective domain scores. The disease course over time was categorized at the most recent visit (persistently active, persistently inactive, improved, or worsening). Plasma and urinary NGAL levels were measured by enzyme-linked immunosorbent assay, and urinary NGAL levels were standardized to the urinary creatinine concentration. The longitudinal changes in NGAL levels were compared with the changes in SLE disease activity using mixed-effect models. RESULTS: Significant increases in standardized urinary NGAL levels of up to 104% were detected up to 3 months before worsening of lupus nephritis (as measured by all 3 external standards). Plasma NGAL levels increased significantly by as much as 26% up to 3 months before worsening of global SLE disease activity as measured by all 3 external standards. Plasma NGAL levels increased significantly by 26% as early as 3 months prior to worsening of lupus nephritis as measured by the BILAG renal score. CONCLUSION: Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal childhood-onset SLE disease activity. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate changes in brain activation patterns detected by functional magnetic resonance imaging (FMRI), and the relationship between FMRI activation patterns and results of formal neuropsychological testing, in patients with childhood-onset systemic lupus erythematosus (SLE). METHODS: Ten patients with childhood-onset SLE underwent formal neuropsychological testing and FMRI using 3 paradigms: a continuous performance task (CPT) to evaluate attention, an N-Back task to assess working memory, and verb generation to evaluate language processing. Composite Z maps were generated to summarize the brain activation patterns for each FMRI paradigm in patients with childhood-onset SLE and to compare these patterns with those observed in healthy controls. Between-group comparison Z maps showing differences in activation between childhood-onset SLE patients and controls were generated, using a significance level of P < 0.05 in a general linear model. RESULTS: Compared with the control group, the childhood-onset SLE group showed statistically significant increased activation of brain areas involved in the CPT, N-Back, and verb generation tasks. In contrast, in the absence of active stimulus, e.g., during times of the paradigm control tasks, childhood-onset SLE patients consistently undersuppressed activity in the expected brain areas. Activation in selected cortical areas was found to correlate negatively with results of a subset of individual neuropsychological test scores. CONCLUSION: FMRI abnormalities are present in childhood-onset SLE, manifesting as an imbalance between active and inhibitory responses to an array of stimuli. Differences in brain activation patterns compared with those observed in controls suggest that childhood-onset SLE may be associated with abnormalities in white matter connectivity resulting in neuronal network dysfunction, rather than injury of specific gray matter areas. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Macrophage activation syndrome is characterized by an overwhelming inflammatory reaction driven by excessive expansion of T cells and hemophagocytic macrophages. Levels of soluble interleukin-2 receptor alpha (sIL-2Ralpha) and soluble CD163 (sCD163) may reflect the degree of activation and expansion of T cells and macrophages, respectively. This study was undertaken to assess the value of serum sIL-2Ralpha and sCD163 in diagnosing acute macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (JIA). METHODS: Enzyme-linked immunosorbent assay was used to assess sIL-2Ralpha and sCD163 levels in sera from 7 patients with acute macrophage activation syndrome complicating systemic JIA and 16 patients with untreated new-onset systemic JIA. The results were correlated with clinical features of established macrophage activation syndrome, including ferritin levels. RESULTS: The median level of sIL-2Ralpha in the patients with macrophage activation syndrome was 19,646 pg/ml (interquartile range [IQR] 18,128), compared with 3,787 pg/ml (IQR 3,762) in patients with systemic JIA (P = 0.003). Similarly, the median level of sCD163 in patients with macrophage activation syndrome was 23,000 ng/ml (IQR 14,191), compared with 5,480 ng/ml (IQR 2,635) in patients with systemic JIA (P = 0.017). In 5 of 16 patients with systemic JIA, serum levels of sIL-2Ralpha or sCD163 were comparable with those in patients with acute macrophage activation syndrome. These patients had high inflammatory activity associated with a trend toward lower hemoglobin levels (P = 0.11), lower platelet counts, and significantly higher ferritin levels (P = 0.02). Two of these 5 patients developed overt macrophage activation syndrome several months later. CONCLUSION: Levels of sIL-2Ralpha and sCD163 are promising diagnostic markers for macrophage activation syndrome. They may also help identify patients with subclinical macrophage activation syndrome. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the relationship between the vasculopathy of juvenile dermatomyositis (juvenile DM) and the balance between the angiostatic ELR- and angiogenic ELR+ CXC chemokines in the muscle of patients with the disease. METHODS: The expression of 3 ELR- CXC chemokines (interferon-inducible protein 10 [IP-10], monokine induced by interferon-gamma, and interferon-inducible T cell alpha-chemoattractant) and 2 ELR+ CXC chemokines was quantitated in muscle biopsy samples from 7 patients with juvenile DM and 7 healthy children, by real-time polymerase chain reaction. The findings were correlated with various histopathologic features, with particular emphasis on the degree of vasculopathy. Synovial biopsy specimens from patients with juvenile rheumatoid arthritis (JRA) were used for additional comparison. RESULTS: The angiostatic ELR- chemokines were expressed at high levels, while the angiogenic ELR+ chemokines were barely detectable, in most juvenile DM samples. This contrasted sharply with the findings in both normal muscle biopsy specimens and JRA synovial tissue specimens. The expression of the ELR- chemokines in juvenile DM samples correlated with the intensity of mononuclear cell infiltration. Furthermore, the juvenile DM samples with the highest degree of capillary loss had the highest levels of ELR- CXC chemokines. The presence of IP-10 in juvenile DM muscle specimens was confirmed by immunohistochemistry analysis. In addition, immunohistochemical staining of muscle tissue revealed that CXCR3, a receptor utilized by ELR- CXC chemokines, was expressed in vascular endothelial cells. CONCLUSION: Increased expression of the interferon-induced angiostatic ELR- CXC chemokines is a feature of juvenile DM that parallels the degree of vasculopathy in patients with the disease. Collectively, these findings are consistent with a model in which a subset of inflammatory cells secrete angiostatic ligands, which then contribute to a local atrophying effect on the muscle's vasculature via a receptor-mediated process. [ABSTRACT FROM AUTHOR]