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1.  Blood-based candidate biomarkers of the presence of neuropsychiatric systemic lupus erythematosus in children 
Lupus Science & Medicine  2014;1(1):e000038.
To examine select brain-reactive proteins for their usefulness to serve as blood-based biomarkers in the screening for neurocognitive deficits in childhood-onset systemic lupus erythematosus (cSLE-NCD).
Patients withcSLE (n=40) were studied longitudinally (month 1; month 18): working memory, psychomotor speed and visuoconstructional ability were assessed using formal neurocognitive testing to determine the presence of cSLE-NCD. Patients also completed the computerised Paediatric Automated Neuropsychological Assessment Metrics. The following brain-reactive proteins were measured in the blood: neutrophil gelatinase associated lipocalin (NGAL), S100B, S100A8/9, antibodies to NR2 glutamate receptor (aNR2-AB), ribosomal-P (aP-AB), glycoprotein-1 (aGP1-AB), and lupus anticoagulant.
cSLE-NCD was present in 6 of 40 patients at baseline and 4 of 27 patients with 18-month information. aP-AB positivity was more commonly present with cSLE-NCD than without (p=0.05). aP-ABs were negatively associated with performance on tests assessing working memory, psychomotor speed and visuoconstructional ability in using formal neurocognitive testing. There were also significant negative associations between aP-AB, S100A8/9, aNR2-AB, aGP1-AB, and lupus anticoagulant and accuracy rates on select Paediatric Automated Neuropsychological Assessment Metrics subtests (p<0.05). Over time, decline in cognitive performance was more pronounced among patients with higher NGAL and aNR2-AB levels. Combinations of serum levels of S100A8/9, S100B, NGAL, aNR2-AB and aP-AB were able to identify cSLE-NCD (sensitivity: 100%; specificity 76%) in exploratory analysis.
Select brain-reactive proteins in the blood are associated with cognitive performance and the presence of cSLE-NCD, cross-sectionally and over time. This raises the possibility that testing of these proteins may assist with the screening of cSLE-NCD.
PMCID: PMC4225735  PMID: 25396068
Childhood/paediatric lupus; Inflammation; Psychology; NPSLE
2.  Clinical features of childhood granulomatosis with polyangiitis (wegener’s granulomatosis) 
Granulomatosis with polyangiitis (GPA), formerly known as Wegener’s granulomatosis (WG), belongs to the group of ANCA-associated necrotizing vasculitides. This study describes the clinical picture of the disease in a large cohort of GPA paediatric patients.
Children with age at diagnosis ≤ 18 years, fulfilling the EULAR/PRINTO/PRES GPA/WG classification criteria were extracted from the PRINTO vasculitis database. The clinical signs/symptoms and laboratory features were analysed before or at the time of diagnosis and at least 3 months thereafter and compared with other paediatric and adult case series (>50 patients) derived from the literature.
The 56 children with GPA/WG were predominantly females (68%) and Caucasians (82%) with a median age at disease onset of 11.7 years, and a median delay in diagnosis of 4.2 months. The most frequent organ systems involved before/at the time of diagnosis were ears, nose, throat (91%), constitutional (malaise, fever, weight loss) (89%), respiratory (79%), mucosa and skin (64%), musculoskeletal (59%), and eye (35%), 67% were ANCA-PR3 positive, while haematuria/proteinuria was present in > 50% of the children. In adult series, the frequency of female involvement ranged from 29% to 50% with lower frequencies of constitutional (fever, weight loss), ears, nose, throat (oral/nasal ulceration, otitis/aural discharge), respiratory (tracheal/endobronchial stenosis/obstruction), laboratory involvement and higher frequency of conductive hearing loss than in this paediatric series.
Paediatric patients compared to adults with GPA/WG have similar pattern of clinical manifestations but different frequencies of organ involvement.
PMCID: PMC4041043  PMID: 24891844
Wegener’s granulomatosis; Granulomatosis with polyangiitis; Clinical study; Clinical picture of disease; Comparison with literature
Arthritis care & research  2013;65(3):372-381.
To evaluate the reproducibility and validity of the Pediatric Automated Neuropsychological Assessment Metrics (Ped-ANAM) when used in childhood-onset systemic lupus erythematosus (cSLE).
Forty children with cSLE and 40 matched controls were followed for up to 18 months. Formal neuropsychological testing at baseline was repeated after 18 months of follow-up; overall cognitive performance and domain-specific cognition (attention, working memory, processing speed and visuoconstructional ability) were measured and categorized as having normal cognition, mild/moderate or moderate/severe impairment. The 10 Ped-ANAM subtests were completed every 6 months and twice at baseline. Ped-ANAM performance was based on accuracy (AC), mean time to correct response (MNc), throughput, and coefficient of variation of the time required for a correct response (CVc) as a measure of response consistency.
Particularly MNc scores demonstrated moderate to substantial reproducibility (intraclass correlation coefficients: 0.47-0.80). Means of select Ped-ANAM scores (MNc, AC, CVc) differed significantly between children with different levels of cognitive performance and allowed for the detection of moderate or severe cognitive impairment with 100% sensitivity and 86% specificity. Six Ped-ANAM subtests significantly correlated with the change in overall cognitive function in cSLE (baseline vs. 18 month; Spearman correlation coefficient > ±0.4; p<0.05, n=24).
The Ped-ANAM has moderate to substantial reproducibility, criterion and construct validity and may be responsive to change in cSLE. Additional research is required to confirm the Ped-ANAM's outstanding accuracy in identifying cognitive impairment and its usefulness in detecting clinically relevant changes in cognition over time.
PMCID: PMC3519977  PMID: 22933364
SLE; cognitive dysfunction; SLE; children; Ped-ANAM; ANAM
Arthritis care & research  2012;64(8):1167-1174.
To explore academic outcomes in childhood-onset systemic lupus erythematosus (cSLE) and their relationship to variables such as demographic and socioeconomic status, neurocognitive functioning, behavioral/emotional adjustment, and cSLE disease status.
Forty pairs of children diagnosed with cSLE and healthy best-friend controls were rated by parents on a standardized scale of school competence. Information about participants’ demographic and socioeconomic status was obtained, along with measures of cSLE disease activity and damage. All participants received formal neurocognitive testing and were also rated on standardized scales of behavioral/emotional adjustment and executive functioning.
Compared to healthy controls, school competence was rated as lower in the cSLE group, although the groups did not differ significantly on indices of cognitive, behavioral, emotional, or executive functioning. School competence ratings were correlated with reading and mathematics achievement test scores in both groups, and with ratings of mental self-regulation in the cSLE group. School competence ratings were correlated with measures of cSLE disease activity and treatment intensity.
cSLE is associated with inferior parent-rated academic outcomes compared to those noted in demographically-matched peers, despite similar neurocognitive function. The adverse academic outcomes which distinguish children with cSLE from their demographically-matched peers appear to be mediated by SLE disease activity and treatment.
PMCID: PMC3409290  PMID: 22807373
SLE; Children; cognition; NPSLE
5.  Inactive Disease and Remission in Childhood-onset Systemic Lupus Erythematosus 
Arthritis care & research  2012;64(5):683-693.
To define inactive disease (ID) and clinical remission (CR), and delineate variables that can be used to measure ID/CR in childhood-onset systemic lupus erythematosus (cSLE).
Delphi questionnaires were sent to an international group of pediatric rheumatologists. Respondents provided information about variables to be used in future algorithms to measure ID/CR. The usefulness of these variables was assessed in 35 children in ID and 31 children with minimally active lupus (MAL).
While ID reflects cSLE status at a specific point in time, CR requires the presence of ID for ≥ 6 months and considers treatment. There was consensus that patients in ID/CR can have ≤ 2 mild non-limiting symptoms (i.e. fatigue, arthralgia, headaches or myalgia) but not Raynaud’s phenomenon, chest pain, or objective physical signs of cSLE; ANA positivity and ESR elevation can be present. CBC, renal function testing, and complement C3 all must be within the normal range. Based on consensus, only damage-related laboratory or clinical findings of cSLE are permissible with ID. The above parameters were suitable to differentiate children with ID/CR from those with MAL (area under the receiver operating characteristic curve > 0.85). Disease activity scores with or without the physician global assessment of disease activity and patient symptoms were well suited to differentiate children with ID from those with MAL.
Consensus has been reached on common definitions of ID/CR with cSLE and relevant patient characteristics with ID/CR. Further studies must assess the usefulness of the data-driven candidate criteria for ID in cSLE.
PMCID: PMC3336032  PMID: 22238253
lupus; childhood-onset SLE; SLE; pediatric SLE; juvenile SLE; remission; inactive disease; children; cSLE
6.  Functional neuronal network activity differs with cognitive dysfunction in childhood-onset systemic lupus erythematosus 
Neuropsychiatric manifestations are common in childhood-onset systemic lupus erythematosus (cSLE) and often include neurocognitive dysfunction (NCD). Functional magnetic resonance imaging (fMRI) can measure brain activation during tasks that invoke domains of cognitive function impaired by cSLE. This study investigates specific changes in brain function attributable to NCD in cSLE that have potential to serve as imaging biomarkers.
Formal neuropsychological testing was done to measure cognitive ability and to identify NCD. Participants performed fMRI tasks probing three cognitive domains impacted by cSLE: visuoconstructional ability (VCA), working memory, and attention. Imaging data, collected on 3-Tesla scanners, included a high-resolution T1-weighted anatomic reference image followed by a T2*-weighted whole-brain echo planar image series for each fMRI task. Brain activation using blood oxygenation level-dependent contrast was compared between cSLE patients with NCD (NCD-group, n = 7) vs. without NCD (noNCD-group, n = 14) using voxel-wise and region of interest-based analyses. The relationship of brain activation during fMRI tasks and performance in formal neuropsychological testing was assessed.
Greater brain activation was observed in the noNCD-group vs. NCD-group during VCA and working memory fMRI tasks. Conversely, compared to the noNCD-group, the NCD-group showed more brain activation during the attention fMRI task. In region of interest analysis, brain activity during VCA and working memory fMRI tasks was positively associated with the participants' neuropsychological test performance. In contrast, brain activation during the attention fMRI task was negatively correlated with neuropsychological test performance. While the NCD group performed worse than the noNCD group during VCA and working memory tasks, the attention task was performed equally well by both groups.
NCD in patients with cSLE is characterized by differential activation of functional neuronal networks during fMRI tasks probing working memory, VCA, and attention. Results suggest a compensatory mechanism allows maintenance of attentional performance under NCD. This mechanism appears to break down for the VCA and working memory challenges presented in this study. The observation that neuronal network activation is related to the formal neuropsychological testing performance makes fMRI a candidate imaging biomarker for cSLE-associated NCD.
PMCID: PMC3672728  PMID: 23497727
Arthritis care & research  2012;64(3):375-383.
To formulate consensus treatment plans (CTPs) for induction therapy of newly-diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (jSLE).
A structured consensus formation process was employed by the members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) after considering the existing medical evidence and current treatment approaches.
After an initial Delphi survey (response rate 70%), a 2-day consensus conference, and two follow-up Delphi surveys (response rates 63–79%), consensus was achieved for a limited set of CTPs addressing the induction therapy of proliferative LN. These CTPs were developed for prototypic patients defined by eligibility characteristics, and included immunosuppressive therapy with either mycophenolic acid orally twice per day, or intravenous cyclophosphamide once per month at standardized doses for six months. Additionally, the CTPs describe three options for standardized use of glucocorticoids; including a primarily oral, a mixed oral/intravenous, and a primarily intravenous regimen. There was consensus on measures of effectiveness and safety of the CTPs. The CTPs were well accepted by the pediatric rheumatology providers treating children with LN, and up to 300 children per year in North America are expected to be candidates for the treatment with the CTPs.
CTPs for induction therapy of proliferative LN in jSLE based on the available scientific evidence and pediatric rheumatology group experience have been developed. Consistent use of the CTPs may improve the prognosis of proliferative LN, and support the conduct of comparative effectiveness studies aimed at optimizing therapeutic strategies for proliferative LN in jSLE.
PMCID: PMC3457803  PMID: 22162255
children; SLE; lupus nephritis; induction therapy; consensus
8.  Preliminary Criteria for Global Flares in Childhood-Onset Systemic Lupus Erythematosus 
Arthritis care & research  2011;63(9):1213-1223.
To develop widely acceptable preliminary criteria of global flare for childhood-onset SLE (cSLE).
Pediatric rheumatologists (n=138) rated a total of 358 unique patient profiles (PP) with information about the cSLE flare descriptors (cSLE-FD) from two consecutive visits: patient global assessment of well-being, physician global assessment of disease activity (MD-global), health-related quality of life, anti-dsDNA antibodies, disease activity index score, protein/creatinine (P/C) ratio, complement levels and ESR. Based on 2996 rater responses about the course of cSLE (baseline vs. follow-up) the accuracy (sensitivity, specificity, area under the receiver operating characteristic curve) of candidate flare criteria was assessed. An international consensus conference was held to rank these candidate flare criteria as per the ACR-recommendations for the development and validation of criteria sets.
The highest ranked candidate criteria considered absolute changes (Δ) of the SLEDAI or BILAG, MD-global, P/C ratio, and ESR; Flare scores can be calculated [0.5 × ΔSLEDAI + 0.45 × ΔP/C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR], where values ≥ 1.04 are reflective of a flare. Similarly, BILAG-based flare scores [0.4 × ΔBILAG + 0.65 × ΔP/C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR] of ≥ 1.15 were diagnostic of a flare. Flare scores increase with flare severity.
Consensus has been reached on preliminary criteria for global flares in cSLE. Further validation studies are needed to confirm the usefulness of the cSLE flare criteria in research and for clinical care.
PMCID: PMC3167979  PMID: 21618452
lupus; childhood-onset SLE; SLE; pediatric SLE; juvenile SLE; flare; criteria; children; cSLE
Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF) which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity.
MPA-PK [area under the curve from 0 to 12 hours (AUC0-12)] and MPA-PD [inosine-monophosphate dehydrogenase (IMPDH) activity] were evaluated in cSLE patients on stable MMF dosing. Change in SLE disease activity while on MMF therapy was measured using the British Isles Lupus Activity Group (BILAG) index.
A total of 19 AUC0-12 and 10 IMPDH activity profiles were included in the analysis. Large inter-patient variability in MPA exposure (AUC0-12) was observed (mean ± SE: 32 ± 4.2 mg*h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC0-12 and weight-adjusted MMF dosing were only moderately correlated (r= 0.56, p=0.01). An AUC0-12 of ≥ 30 mg*h/L was associated with decreased BILAG scores while on MMF therapy (p= 0.002).
Weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to biologically active MPA in cSLE. Individualized dosing considering MPA-PK appears warranted as this allows for better estimation of immunological suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC0-12 of at least 30 mg*h/L is required for cSLE improvement.
PMCID: PMC3021770  PMID: 20655577
systemic lupus erythematosus; mycophenolic acid; pharmacokinetics; pharmacodynamics; inosine 5’-monophosphate dehydrogenase (IMPDH)
11.  Serum Neopterin Levels as a Diagnostic Marker of Hemophagocytic Lymphohistiocytosis Syndrome ▿ 
The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients.
PMCID: PMC3122569  PMID: 21270283
14.  Minimal Clinically Important Differences of Disease Activity Indices in Childhood-onset Systemic Lupus Erythematosus 
Arthritis care & research  2010;62(7):950-959.
To determine the minimal clinically important differences (MCID) of validated measures of SLE disease activity in childhood-onset systemic lupus erythematosus (cSLE).
cSLE patients (n=98) were followed every 3 months for up to 7 visits (total number of visits 623). Disease activity measures (ECLAM, SLEDAI, SLAM, BILAG, RIFLE) were completed at the time of each visit. Physician-rated changes in the disease course (clinically relevant improvement, no change, clinically relevant worsening) between visits served as the criterion standard.
MCID defined by mean change scores with improvement and worsening, or those based on the standard error of measurement with stable disease were both small and did not discriminate well between disease courses (detection rates for improvement or worsening were all < 55%). MCID based on discriminant and classification analyses yielded similar results. Alternative MCID, defined by a 70% predicted probability of improvement or worsening as per discrimination analysis, were larger but underestimated the proportion of patients with change. The RIFLE only correctly identified 26% and 8% episodes of clinically important worsening and improvement of cSLE, respectively.
The MCID of cSLE disease activity measures are often small but similar to those reported for adults with SLE. Thus even small changes in disease activity scores can be clinically relevant. Low correct detection rates of these MCID thresholds for changes in disease course support the notion that worsening and improvement with cSLE, or its response to therapy, is unlikely to be captured adequately by validated measures of disease activity alone.
PMCID: PMC2916727  PMID: 20589695
MID; MCID; quality of life; HRQoL; lupus
Arthritis care & research  2010;62(7):1029-1033.
To develop and propose a standardized battery of neuropsychological tests for the assessment of cognitive functioning of children and adolescents with pediatric systemic lupus erythematosus (pSLE).
A committee of health care professionals involved in the assessment of pSLE patients reviewed the literature to identify cognitive domains most commonly affected in pSLE and in adult SLE. They then reviewed the standardized tests available for children and adolescents that assess the cognitive domains identified. Through a structured consensus formation process the committee considered psychometric characteristics and duration of the tests.
A test battery was developed that appears suitable to provide a comprehensive assessment of cognitive domains commonly affected by pSLE with a 2.5 hour period.
It is hoped that the consistent use of this reliable and efficient battery increases the practicality of routine evaluations in pSLE, enabling between cohort comparisons and facilitating the longitudinal assessment of individual patients over time.
PMCID: PMC2936487  PMID: 20589693
cognition; lupus; children; neuropsychological testing
16.  Towards the Development of Criteria for Global Flares in Juvenile Systemic Lupus Erythematosus 
Arthritis care & research  2010;62(6):811-820.
To develop a definition of global flare in jSLE and derive candidate criteria for measuring jSLE flares.
Pediatric rheumatologists answered two Delphi questionnaires to achieve consensus on a common definition of jSLE flare and identify variables for use in candidate flare criteria. The diagnostic accuracy of these candidate flare criteria was tested with data from jSLE patients (n=98; 623 visits total). Physician-rated change in the jSLE course (worsening yes/no) between visits served as the criterion standard.
There was 96% consensus that a “a flare is a measurable worsening of jSLE disease activity in at least one organ system, involving new or worse signs of disease that may be accompanied by new or worse SLE symptoms. Depending on the severity of the flare, more intensive therapy may be required”. Variables suggested for use in flare criteria were: physician-rated disease activity (V1), patient well-being, protein:creatinine ratio, validated disease activity index (V2), Child Health Questionnaire physical summary score (V3), anti-dsDNA antibodies, ESR, and complement levels. Using multiple logistic regression, several candidate flare criteria were derived with area under the receiver operating characteristic curve (AUC) as high as 0.92 (sensitivity≥ 85%; specificity≥ 85%); CART analysis suggested that V1, V2 and V3 suffice to identify jSLE flares (AUC = 0.81; sensitivity = 64%; specificity = 86%).
Consensus about a definition of global disease flare with jSLE has been obtained and promising candidate flare criteria have been developed. These will need further assessment of their ease-of-use and accuracy in prospective study.
PMCID: PMC3049164  PMID: 20535792
jSLE; cSLE; children; flare criteria; flare; lupus
17.  Physician assessment of disease activity in JIA subtypes. Analysis of data extracted from electronic medical records 
Although electronic medical records (EMRs) have facilitated care for children with juvenile idiopathic arthritis (JIA), analyses of treatment outcomes have required paper based or manually re-entered data. We have started EMR discrete data entry for JIA patient visits, including joint examination and global assessment, by physician and patient. In this preliminary study, we extracted data from the EMR to Xenobase™ (TransMed Systems, Inc., Cupertino, CA), an application permitting cohort analyses of the relationship between global assessment to joint examination and subtype.
During clinic visits, data were entered into discrete fields in ambulatory visit forms in the EMR (EpicCare™, Epic Systems, Verona, WI). Data were extracted using Clarity Reports, then de-identified and uploaded for analyses to Xenobase™. Parameters included joint examination, ILAR diagnostic classification, physician global assessment, patient global assessment, and patient pain score. Data for a single visit for each of 160 patients over a 2 month period, beginning March, 2010, were analyzed.
In systemic JIA patients, strong correlations for physician global assessment were found with pain score, joint count and patient assessment. In contrast, physician assessment for patients with persistent oligoarticular and rheumatoid factor negative patients showed strong correlation with joint counts, but only moderate correlation with pain scores and patient global assessment. Conversely, for enthesitis patients, physician assessment correlated strongly with pain scores, and moderately with joint count and patient global assessment. Rheumatoid factor positive patients, the smallest group studied, showed moderate correlation for all three measures. Patient global assessment for systemic patients showed strong correlations with pain scores and joint count, similar to data for physician assessment. For polyarticular and enthesitis patients, correlation of patient global assessment with pain scores was strong. Moderate correlations were found between patient global assessment and joint count in oligoarticular and polyarticular patients.
Data extraction from the EMR is feasible and useful to evaluate JIA patients for indicators of treatment responsiveness. In this pilot study, we found correlates for physician global assessment of arthritis differed, according to disease subtype. Further data extraction and analyses will determine if these findings can be confirmed, and will assess other outcome measures, compare longitudinal responses to treatment, and export extracted data to multi-center databases.
PMCID: PMC3089777  PMID: 21492466
18.  Neutrophil Gelatinase-associated Lipocalin Anticipates the Course of Global and Renal Childhood-Onset Systemic Lupus Erythematosus Disease Activity 
Arthritis and rheumatism  2009;60(9):2772-2781.
The goal of the study was to determine the predictive validity of neutrophil gelatinase-associated lipocalin (NGAL) in anticipating worsening of global and renal childhood-onset SLE (cSLE) disease activity.
111 patients with cSLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least three study visits. At each visit global disease activity was measured using three external standards: numerically converted BILAG index, SLEDAI-2K and physician assessment score. 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 ELISA, and urinary NGAL was standardized to urinary creatinine. The longitudinal changes in NGAL levels were compared to the changes in SLE disease activity using mixed effects models.
Significant increases in standardized urinary NGAL levels of up to 104% were detected up to three months before worsening of lupus nephritis (as measured by all three external standards). Plasma NGAL levels increased significantly by as much as 20% up to three months before worsening of global SLE disease activity as measured by all three external standards. Plasma NGAL levels increased significantly by 26% as early as three months prior to worsening of lupus nephritis as measured by the renal BILAG domain score.
Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal cSLE disease activity.
PMCID: PMC3064260  PMID: 19714584
Childhood-onset systemic lupus erythematosus; lupus nephritis; neutrophil gelatinase-associated lipocalin (NGAL); renal biomarker
19.  Prospective Validation of the Provisional Criteria for the Evaluation of Response to Therapy in Childhood-onset Systemic Lupus Erythematosus (cSLE) 
Arthritis care & research  2010;62(3):335-344.
To prospectively validate the provisional criteria for the evaluation of response to therapy in children with systemic lupus erythematosus (cSLE).
In this multi-center study cSLE patients (n=98; F: M = 81:17; 50% white; 88% non-Hispanic) were followed every 3 months for up to 7 visits (total number of visits 623). The five cSLE core response variables were obtained at the time of each visit: (1) physician assessment of overall disease activity; (2) parent assessment of patient well-being; (3) Child Health Questionnaire; (4) proteinuria; and (5) global disease activity measure score as measured by the ECLAM, SLEDAI, or SLAM. Physician-rated relevant changes in the disease course (clinically relevant improvement; no change in disease, or worsening) between visits served as the criterion standard. Mixed models were used to assess the diagnostic accuracy of the four highest-ranked provisional definitions of response to therapy.
There were 89 episodes of clinically relevant improvement between two consecutive visits, and 448 episodes without improvement. Irrespective of the choice of the global disease activity measure (ECLAM, SLAM, SLEDAI), sensitivities of all four highest-ranked definitions were low (all ≤ 31%), while their specificities were excellent (all > 88%). Using logistic models, alternative definitions can be developed with both 80% sensitivity and specificity.
The provisional criteria of response to therapy in cSLE may have considerably lower sensitivity than previously reported. Additional validation in clinical trials is necessary to further evaluate the measurement properties of the provisional PRINTO/ACR Criteria for Response to Therapy in cSLE.
PMCID: PMC2946212  PMID: 20391479
Criteria; validation; improvement; pediatric SLE; childhood-onset SLE; JSLE
20.  Initial Validation of a Novel Protein Biomarker Panel for Active Pediatric Lupus Nephritis 
Pediatric research  2009;65(5):530-536.
Lupus nephritis (LN) is among the main determinants of poor prognosis in systemic lupus erythematosus (SLE). The objective of this study was to 1) isolate and identify proteins contained in the LN urinary protein signature (PS) of children with SLE; 2) assess the usefulness of the PS-proteins for detecting activity of LN over time. Using surface-enhanced or matrix assisted laser desorption/ionization time of flight mass spectrometry, the proteins contained in the LN urinary PS were identified. They were transferrin (Tf), ceruloplasmin (Cp), α1-acid-glycoprotein (AGP), lipocalin-type prostaglandin-D synthetase (L-PGDS), albumin and albumin-related fragments. Serial plasma and urine samples were analyzed using immunonephelometry or ELISA in 98 children with SLE (78% African-American) and 30 controls with juvenile idiopathic arthritis. All urinary PS-proteins were significantly higher with active versus inactive LN or in patients without LN (all p<0.005), and their combined area under the receiver operating characteristic curve was 0.85. As early as 3 months before a clinical diagnosis of worsening LN, significant increases of urinary Tf, AGP (both p < 0.0001) and L-PGDS (p < 0.01) occurred, indicating that these PS-proteins are biomarkers of LN activity and may help anticipate the future course of LN.
PMCID: PMC2737257  PMID: 19218887
21.  High density genotyping of STAT4 gene reveals multiple haplotypic associations with Systemic Lupus Erythematosus in different racial groups 
Arthritis and rheumatism  2009;60(4):1085-1095.
Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.
Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.
We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.
Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.
PMCID: PMC2776081  PMID: 19333953
22.  Brain Morphometric Changes Associated With Childhood-Onset Systemic Lupus Erythematosus and Neurocognitive Deficit 
Arthritis and Rheumatism  2013;65(8):2190-2200.
ObjectiveTo use structural magnetic resonance imaging (MRI) to characterize changes in gray matter and white matter volumes between patients with childhood-onset systemic lupus erythematosus (SLE) and matched controls, between patients with childhood-onset SLE with and those without neurocognitive deficit, and in relation to disease duration and treatment with steroids.
MethodsTwenty-two patients with childhood-onset SLE and 19 healthy controls underwent high-resolution structural MRI. Probability density maps for gray matter and white matter were compared between groups.
ResultsNeuropsychological testing confirmed the presence of neurocognitive deficit in 8 patients with childhood-onset SLE. Multiple brain regions had reduced gray matter volume in the patients with childhood- onset SLE with neurocognitive deficit versus controls or patients with childhood-onset SLE without neurocognitive deficit. Neither disease duration nor cumulative oral or intravenous steroid doses accounted for decreases in gray matter. White matter volume was also reduced in patients with childhood-onset SLE with neurocognitive deficit, and the reduction was positively associated with both disease duration and cumulative oral steroid dose. Conversely, higher cumulative intravenous steroid doses were associated with higher white matter volumes.
ConclusionNeurocognitive deficit in patients with childhood-onset SLE is associated with multifocal decreases in both gray and white matter volumes. Since only white matter volume changes are related to disease duration and cumulative oral steroid use, this may suggest that gray and white matter alterations relate to different underlying mechanisms. Further work is needed to understand the relationship between gray and white matter alterations in childhood-onset SLE, whether the underlying mechanisms relate to immunologic, vascular, or other causes, and whether the changes are reversible or preventable. Likewise, the protective properties of intravenous steroids in maintaining white matter volumes require confirmation in larger cohorts.
PMCID: PMC3840703  PMID: 23666759

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