Randomized, double-blind, dose-escalation trial of triptorelin for ovary protection in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To determine the dose of triptorelin that is sufficient to maintain complete ovarian suppression in female patients with childhood-onset systemic lupus erythematosus (SLE) who require cyclophosphamide therapy, to determine the length of time needed to achieve ovarian suppression after initiation of triptorelin treatment, and to investigate the safety of triptorelin. METHODS: In this randomized, double-blind, placebo-controlled, dose-escalation study, female patients ages <21 years were randomized 4:1 to receive triptorelin (n = 25) or placebo (n = 6). The starting doses of triptorelin were 25, 50, 75, and 100 µg/kg, and the dose was escalated until complete ovarian suppression was maintained. The primary outcome was the weight-adjusted dose of triptorelin that provided complete ovarian suppression in at least 90% of the patients, as determined by gonadotropin-releasing hormone agonist stimulation testing. The secondary outcome was the period of time required to achieve ovarian suppression, as measured by unstimulated follicle-stimulating hormone and luteinizing hormone levels after the initiation of triptorelin treatment. RESULTS: Treatment with triptorelin at a weight-adjusted dose of 120 µg/kg body weight provided sustained complete ovarian suppression in 90% of the patients. After administration of the initial dose of triptorelin, 22 days were required to achieve complete ovarian suppression. The rates of adverse events (AEs) and serious adverse events (SAEs) per 100 patient-months of followup were not higher in the triptorelin group compared with the placebo group (for AEs, 189 versus 362; for SAEs, 2.1 versus 8.5). CONCLUSION: High doses of triptorelin are needed to achieve and maintain complete ovarian suppression, but such doses appear to be well tolerated in adolescent female patients with childhood-onset SLE. Our data suggest that a lag time of 22 days after initiation of triptorelin treatment is required before cyclophosphamide therapy is started or continued.

Value of questionnaire-based screening as a proxy for neurocognitive testing in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To investigate the utility of questionnaire-based assessment of cognitive function and behavioral/emotional symptoms to screen for neurocognitive dysfunction in childhood-onset systemic lupus erythematosus (cSLE). METHODS: Forty children with cSLE and 24 healthy controls ages 10­16 years were enrolled. Formal neurocognitive testing (FNCT) was done to determine cognitive performance in 4 key areas that appear to be sensitive to the adverse effects of cSLE: attention, working memory, psychomotor speed, and visuoconstructional ability. Paper and pencil questionnaires sampling cognitive functioning and behavioral/emotional symptoms were also completed: the Subjective Awareness of Neuropsychological Deficits for Children (SAND-C) questionnaire by patients, and the Child Behavioral Checklist and the Behavior Rating Inventory of Executive Function (BRIEF) by parents. RESULTS: Domain and summary scores of the BRIEF and SAND-C correlated modestly with participants' performance on FNCT. Questionnaire ratings did not discriminate subjects with different levels of cognitive ability as measured by FNCT. CONCLUSION: Contrary to some reports in adults with SLE, self-administered questionnaires of cognitive functioning and parent ratings of executive functioning do not appear well suited to replace FNCT in screening for neurocognitive impairment of children and adolescents with cSLE. However, they may provide information that is complementary to FNCT and therefore play a useful role in clinical followup.

Validation of the systemic lupus erythematosus responder index for use in juvenile-onset systemic lupus erythematosus.

OBJECTIVES: This study tested the concurrent validity of the systemic lupus erythematosus responder index (SRI) in assessing improvement in juvenile-onset systemic lupus erythematosus (jSLE). METHODS: The SRI considers changes in the SELENA-SLEDAI, BILAG and a 3-cm visual analogue scale of physician-rated disease activity (PGA) to determine patient improvement. Using prospectively collected data from 760 unique follow-up visit intervals of 274 jSLE patients, we assessed the sensitivity and specificity of the SRI using these external standards: physician-rated improvement (MD-change), patient/parent-rated major improvement of wellbeing (patient-change) and decrease in prescribed systemic corticosteroids (steroid-change). Modifications of the SRI that considered different thresholds for the SELENA-SLEDAI, BILAG and 10-cm PGA were explored and agreement with the American College of Rheumatology/PRINTO provisional criteria for improvement of jSLE (PCI) was examined. RESULTS: The sensitivity/specificity in capturing major improvement by the MD-change were 78%/76% for the SRI and 83%/78% for the PCI, respectively. There was fair agreement between the SRI and PCI (kappa=0.35, 95% CI 0.02 to 0.73) in capturing major improvement by the MD-change. Select modified versions of the SRI had improved accuracy overall. All improvement criteria tested had lower sensitivity when considering patient-change and steroid-change as external standards compared to MD-change. CONCLUSIONS: The SRI and its modified versions based on meaningful changes in jSLE have high specificity but at most modest sensitivity for capturing jSLE improvement. When used as an endpoint of clinical trials in jSLE, the SRI will provide a conservative estimate regarding the efficacy of the therapeutic agent under investigation.

Validation of the Pediatric Automated Neuropsychological Assessment Metrics in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To evaluate the reproducibility and validity of the Pediatric Automated Neuropsychological Assessment Metrics (Ped-ANAM) when used in childhood-onset systemic lupus erythematosus (cSLE). METHODS: 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 followup; overall cognitive performance and domain-specific cognition (attention, working memory, processing speed, and visuoconstructional ability) were measured and categorized as 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. RESULTS: 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 versus 18 months; Spearman's correlation coefficient >0.4, P < 0.05; n = 24). CONCLUSION: 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 outstanding accuracy of the Ped-ANAM in identifying cognitive impairment, as well as its usefulness in detecting clinically relevant changes in cognition over time.

Academic outcomes in childhood-onset systemic lupus erythematosus.

OBJECTIVE: 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. METHODS: 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 of the participants received formal neurocognitive testing and were also rated on standardized scales of behavioral/emotional adjustment and executive functioning. RESULTS: 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. CONCLUSION: 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 that distinguish children with cSLE from their demographically-matched peers appear to be mediated by SLE disease activity and treatment.

Inactive disease and remission in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To define inactive disease (ID) and clinical remission (CR) and to delineate variables that can be used to measure ID/CR in childhood-onset systemic lupus erythematosus (cSLE). METHODS: 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 with ID and 31 children with minimally active lupus (MAL). RESULTS: 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 nonlimiting symptoms (i.e., fatigue, arthralgia, headaches, or myalgia) but not Raynaud's phenomenon, chest pain, or objective physical signs of cSLE; antinuclear antibody positivity and erythrocyte sedimentation rate elevation can be present. Complete blood count, 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. CONCLUSION: 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.

Usefulness of cellular text messaging for improving adherence among adolescents and young adults with systemic lupus erythematosus.

OBJECTIVE: In a cohort of 70 patients with childhood-onset systemic lupus erythematosus (cSLE): to determine the baseline adherence to medications and visits; to investigate the effects of cellular text messaging reminders (CTMR) on adherence to clinic visits; and to study the influence of CTMR on adherence to use of hydroxychloroquine (HCQ). METHODS: CTMR were sent to 70 patients prior to clinic visits for 14 months. A subgroup of patients were evaluated for medication adherence to HCQ: 19 patients receiving CTMR prior to each scheduled HCQ dose were compared to 22 patients randomized to standard of care education about HCQ. Visit adherence was measured using administrative databases. Pharmacy refill information, self-report of adherence, and HCQ blood levels were utilized to monitor medication adherence to HCQ. Sufficient adherence to visits or HCQ was defined as estimates > 80%. Disease activity was primarily monitored with the Systemic Lupus Erythematosus Disease Activity Index. RESULTS: At baseline, 32% of patients were sufficiently adherent to HCQ, and 81% to clinic visits. Visit adherence improved significantly by > 80% among those who were nonadherent to clinic visits at the baseline CTMR (p = 0.01). CTMR did not influence adherence to HCQ over time. CONCLUSION: Patients with cSLE were only modestly adherent to HCQ and clinic visits. CTMR may be effective for improving visit adherence among adolescents and young adults with cSLE, but it does not improve adherence to HCQ.

Identification of urinary metabolites that distinguish membranous lupus nephritis from proliferative lupus nephritis and focal segmental glomerulosclerosis.

INTRODUCTION: Systemic lupus erythematosus (SLE or lupus) is a chronic autoimmune disease, and kidney involvement with SLE, a.k.a. lupus nephritis (LN), is a frequent and severe complication of SLE that increases patient morbidity and mortality. About 50% of patients with SLE encounter renal abnormalities which, if left untreated, can lead to end-stage renal disease. Kidney biopsy is considered the criterion standard for diagnosis and staging of LN using the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, which was developed to help predict renal outcomes and assist with medical decision-making. However, kidney biopsy-based classification of LN is highly invasive and impractical for real-time monitoring of LN status. Here, nuclear magnetic resonance (NMR) spectroscopy-based metabolic profiling was used to identify urinary metabolites that discriminated between proliferative and pure membranous LN as defined by the ISN/RPS classification, and between LN and primary focal segmental glomerulosclerosis (FSGS). METHODS: Metabolic profiling was conducted using urine samples of patients with proliferative LN without membranous features (Class III/IV; n = 7) or pure membranous LN (Class V; n = 7). Patients with primary FSGS and proteinuria (n = 10) served as disease controls. For each patient, demographic information and clinical data was obtained and a random urine sample collected to measure NMR spectra. Data and sample collection for patients with LN occurred around the time of kidney biopsy. Metabolic profiling analysis was done by visual inspection and principal component analysis. RESULTS: Urinary citrate levels were 8-fold lower in Class V LN compared to Class III/IV patients, who had normal levels of urinary citrate (P < 0.05). Class III/IV LN patients had > 10-fold lower levels of urinary taurine compared to Class V patients, who had mostly normal levels (P < 0.01). Class V LN patients had normal urinary hippurate levels compared to FSGS patients, who completely lacked urinary hippurate (P < 0.001). CONCLUSIONS: This pilot study indicated differences in urinary metabolites between proliferative LN and pure membranous LN patients, and between LN and FSGS patients. If confirmed in larger studies, these urine metabolites may serve as biomarkers to help discriminate between different classes of LN, and between LN and FSGS.

Pharmacokinetics and pharmacodynamics of mycophenolic acid and their relation to response to therapy of childhood-onset systemic lupus erythematosus.

OBJECTIVES: 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. METHODS: MPA-PK [area under the curve from 0-12 hours (AUC(0-12))] 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 Assessment Group (BILAG) index. RESULTS: A total of 19 AUC(0-12) and 10 IMPDH activity profiles were included in the analysis. Large interpatient variability in MPA exposure (AUC(0-12)) was observed (mean ± SE: 32 ± 4.2 mg h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC(0-12) and weight-adjusted MMF dosing were only moderately correlated (r = 0.56, P = 0.01). An AUC(0-12) of ≥30 mg h/L was associated with decreased BILAG scores while on MMF therapy (P = 0.002). CONCLUSION: 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 immunologic suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC(0-12) of at least 30 mg h/L is required for cSLE improvement.

Functional magnetic resonance imaging assessment of cognitive function in childhood-onset systemic lupus erythematosus: a pilot study.

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.

Initial validation of the Pediatric Automated Neuropsychological Assessment Metrics for childhood-onset systemic lupus erythematosus.

OBJECTIVE: To evaluate the concurrent validity and diagnostic accuracy of the pediatric Automated Neuropsychological Assessment Metrics (Ped-ANAM) when used in childhood-onset systemic lupus erythematosus (SLE). METHODS: Formal neuropsychological testing and the Ped-ANAM were performed on 27 children with SLE who had not been previously diagnosed with neuropsychiatric SLE. Performance when completing the 10 Ped-ANAM tests was based on accuracy (AC), mean time to correct response, coefficient of variation of the time required for a correct response (CVc), and throughput. Formal neuropsychological testing was used as a criterion standard for diagnosing neurocognitive dysfunction (NCD; yes/no). RESULTS: NCD was common and present in 16 (59%) of 27 participants. Ped-ANAM performance parameters were often moderately correlated with the Z scores on formal neuropsychological testing. The NCD group differed significantly (P < 0.05) from the normal cognition group in 3 Ped-ANAM tests: CVc with mathematical processing (MTH-CVc), AC with continuous performance test (CPT-AC), and CVc with spatial processing (SPD-CVc). Areas under the receiver operating curves (AUCs) ranged between 0.75 and 0.84 when each of these parameters (CPT-AC, MTH-CVc, SPD-CVc) was used to identify NCD independently. The AUC was improved to 0.96 for the combined assessment. CONCLUSION: The Ped-ANAM has concurrent validity when used in children with SLE. Initial validation suggests that the Ped-ANAM could be a useful screening tool for NCD in children with SLE.

Identification of a urinary proteomic signature for lupus nephritis in children.

The quest for reliable biomarkers of systemic lupus erythematosus (SLE) nephritis is an area of intense contemporary research. In this study, surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) technology was used for urinary proteomic profiling of patients with SLE nephritis. Clinical, laboratory, and kidney biopsy data from pediatric patients with SLE (n = 32) were analyzed. Children with juvenile idiopathic arthritis (n = 11) served as controls. SELDI-TOF-MS was performed using ProteinChips with different chromatographic surfaces. The resulting spectra were analyzed with Bio-Rad Biomarker Wizard software. A consistent urinary proteomic signature for SLE nephritis was found, comprising eight biomarker proteins with peaks at m/z of 2.7, 22, 23, 44, 56, 79, 100, and 133 kDa. The peak intensities of these biomarkers were significantly greater in patients with SLE nephritis compared with controls and SLE patients without nephritis. These biomarkers were strongly correlated with renal disease activity and moderately with renal damage. For the diagnosis of active nephritis, the area under the receiver operating characteristic curve was > or =0.90 for 22, 23, 44, 79, and 100 kDa biomarkers. Thus, SELDI-TOF-MS has identified a urine proteomic signature strongly associated with SLE renal involvement and active SLE nephritis.

Central venous catheter occlusion: a prospective, controlled trial examining the impact of a positive-pressure valve device.

BACKGROUND: Central venous catheter (CVC) occlusion occurs frequently in children. This problem is often associated with disruption of intravascular therapy and monitoring. Multiple factors may predispose to catheter occlusion, but reflux of blood into the catheter lumen is a common factor. We hypothesized that use of a positive pressure valve device would reduce the incidence of catheter occlusion. METHODS: In phase I of this sequential study design, newly placed CVCs were capped with a standard device. In Phase II, CVCs were capped with a positive-pressure valve device. Data collected included patient demographics, type of catheter, infusate, catheter duration, and complications. Partial and complete catheter occlusions were delineated. A user satisfaction survey was conducted. RESULTS: There were 153 children (mean age 48.0 +/- 7.7 months) with 312 CVC lumens enrolled in the study. Mean catheter duration was 9.4 +/- 0.9 days. There were fewer complete occlusions in CVCs capped with the positive pressure valve device than with the standard device [6/161 (3.7%) vs 18/151 (11.9%) occlusions, respectively; p = .012)]. There were no significant differences in partial occlusions, phlebitis, or catheter-related bloodstream infection between the 2 groups. CONCLUSIONS: CVCs with a positive-pressure valve cap device have a lower incidence of complete catheter occlusion than those with a standard cap device.