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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.

Objective: To determine early predictors of 6-month outcomes in a prospective cohort of patients with juvenile idiopathic arthritis (JIA)., Methods: Patients selected were those enrolled in an inception cohort study of JIA, the Research in Arthritis in Canadian Children Emphasizing Outcomes Study, within 6 months after diagnosis. The juvenile rheumatoid arthritis core criteria set and quality of life measures were collected at enrollment and 6 months later. Outcomes evaluated included inactive disease, Juvenile Arthritis Quality of Life Questionnaire (JAQQ) scores, and Childhood Health Assessment Questionnaire (C-HAQ) scores at 6 months., Results: Thirty-three percent of patients had inactive disease at 6 months. Onset subtype and most baseline core criteria set measures correlated with all 3 outcomes. Relative to oligoarticular JIA, the risks of inactive disease were lower for enthesitis-related arthritis, polyarthritis rheumatoid factor (RF)-negative JIA, and polyarthritis RF-positive JIA, and were similar for psoriatic arthritis. In multiple regression analyses, the baseline JAQQ score was an independent predictor of all 3 outcomes. Other independent baseline predictors included polyarthritis RF-negative and systemic JIA for inactive disease; C-HAQ score and polyarthritis RF-positive JIA for the 6-month C-HAQ score; and active joint count, pain, and time to diagnosis for the 6-month JAQQ score., Conclusion: Clinical measures soon after diagnosis predict short-term outcomes for patients with JIA. The JAQQ is a predictor of multiple outcomes. Time to diagnosis affects quality of life in the short term.

Objective: To evaluate risk factors for subclinical atherosclerosis in a population of patients with pediatric systemic lupus erythematosus (SLE)., Methods: In a prospective multicenter study, a cohort of 221 patients underwent baseline measurements of carotid intima-media thickness (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess the thickness of the bilateral common carotid arteries and the mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT, which were examined in multivariable linear regression modeling., Results: Based on the mean-mean common or the mean-max CIMT as the dependent variable, univariable analysis showed significant associations of the following variables with increased CIMT: increasing age, longer SLE duration, minority status, higher body mass index (BMI), male sex, increased creatinine clearance, higher lipoprotein(a) level, proteinuria, azathioprine treatment, and prednisone dose. In multivariable modeling, both azathioprine use (P=0.005 for the mean-mean model and P=0.102 for the mean-max model) and male sex (P<0.001) were associated with increases in the mean-max CIMT. A moderate dosage of prednisone (0.15-0.4 mg/kg/day) was associated with decreases in the mean-max CIMT (P=0.024), while high-dose and low-dose prednisone were associated with increases in the mean-mean common CIMT (P=0.021) and the mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031) remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing lipoprotein(a) level (P=0.005) were associated with increased mean-max CIMT., Conclusion: Traditional as well as nontraditional risk factors were associated with increased CIMT in this cohort of patients in the APPLE trial. Azathioprine treatment was associated with increased CIMT. The relationship between CIMT and prednisone dose may not be linear.

Objective: Systemic lupus erythematosus (SLE) is the prototypical 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 terms of the pathogenesis of SLE. STAT-1 and STAT-4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for involvement in SLE susceptibility., Methods: Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 on chromosome 2 were genotyped using the Illumina platform, as part of an extensive association study in a large collection of 9,923 lupus patients and control subjects from different racial groups. DNA samples were obtained from the peripheral blood of patients with SLE and control subjects. Principal components analyses and population-based case-control association analyses were performed, and the P values, false discovery rate q values, and odds ratios with 95% confidence intervals were calculated., Results: We observed strong genetic associations with SLE and multiple SNPs located within STAT4 in different ethnic groups (Fisher's combined P = 7.02 x 10(-25)). In addition to strongly confirming the previously reported association in the third intronic region of this gene, we identified additional haplotypic association across STAT4 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 its proximity to STAT4., Conclusion: Our findings indicate that STAT4 is likely to be a crucial component in SLE pathogenesis in multiple racial groups. Knowledge of the functional effects of this association, when they are revealed, might improve our understanding of the disease and provide new therapeutic targets.

Objective: To determine the feasibility of conducting a randomized controlled trial of a 12-week exercise intervention in children with fibromyalgia (FM) and to explore the effectiveness of aerobic exercise on physical fitness, function, pain, FM symptoms, and quality of life (QOL)., Methods: FM patients ages 8-18 years were randomized to a 12-week exercise intervention of either aerobics or qigong. Both groups participated in 3 weekly training sessions. Program adherence and safety were monitored at each session. Data were collected at 3 testing sessions, 2 prior to and 1 after the intervention, and included FM symptoms, function, pain, QOL, and fitness measures., Results: Thirty patients participated in the trial. Twenty-four patients completed the program; 4 patients dropped out prior to training and 2 dropped out of the aerobics program. Better adherence was reported in the aerobics group than in the qigong group (67% versus 61%). Significant improvements in physical function, functional capacity, QOL, and fatigue were observed in the aerobics group. Anaerobic function, tender point count, pain, and symptom severity improved similarly in both groups., Conclusion: It is feasible to conduct an exercise intervention trial in children with FM. Children with FM tolerate moderate-intensity exercise without exacerbation of their disease. Significant improvements in physical function, FM symptoms, QOL, and pain were demonstrated in both exercise groups; the aerobics group performed better in several measures compared with the qigong group. Future studies may need larger sample sizes to confirm clinical improvement and to detect differences in fitness in childhood FM.

Objective: To determine the prevalence of anticardiolipin antibodies (aCL), anti-beta(2)-glycoprotein I (anti-beta(2)GPI) antibodies, and lupus anticoagulant (LAC) in a large cohort of children with systemic lupus erythematosus (SLE), and to evaluate the associations with neuropsychiatric manifestations., Methods: A single-center retrospective cohort study with longitudinal followup of antiphospholipid antibodies (aPL) in 137 children with SLE (25 boys and 112 girls, mean age at diagnosis 13.0 years) was performed. Patients were followed up for a mean of 31 months., Results: At the time of diagnosis, 65% of the children were aCL positive, 41% had anti-beta(2)GPI antibodies, and 26% were LAC positive. Analysis of the association between presence of aPL and individual neuropsychiatric manifestations at diagnosis showed a statistically significant association of positive LAC with cerebrovascular disease (5 patients; P = 0.015). A persistently positive aCL was observed in 50%, anti-beta(2)GPI antibodies in 29%, and LAC in 16% of children over time. The prevalence of anti-beta(2)GPI antibodies, but not aCL and LAC, was found to be statistically significantly higher in children with neuropsychiatric disease compared with those without (P = 0.02). Comparison for specific neuropsychiatric manifestations showed a statistically significant association between a persistently positive LAC and chorea (2 patients; P = 0.02)., Conclusion: The prevalence of anti-beta(2)GPI antibodies was found to be higher in the group of SLE patients with neuropsychiatric disease compared with those without. Our data suggest an association between LAC and cerebrovascular disease at the time of SLE diagnosis and chorea over the disease course, but not between aPL and other neuropsychiatric manifestations.

Objective: To investigate potential differences between childhood-onset and adult-onset systemic lupus erythematosus (SLE)., Methods: An inception cohort with childhood-onset SLE (n = 67) was compared with an inception cohort with adult-onset SLE (n = 131), each of whom was diagnosed between 1990 and 1998 and followed up until February 1999. Prospective information included data on medications, laboratory markers, and disease activity and damage as measured by the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI), respectively., Results: Eighty-five percent of patients with childhood-onset SLE and 88% of patients with adult-onset SLE were female; the mean duration of followup was 3.2 and 3.5 years, respectively. On average, the children had more-active disease than did the adults at the time of diagnosis and during followup. There was a higher incidence of renal disease in those with childhood-onset SLE (78% versus 52% in adults; P = 0.0005), and the adjusted mean SLEDAI renal score was higher in the children than in the adults (2.37 versus 0.82; P < 0.0001). Treatment with steroids (97% versus 72%; P < 0.0001) and immunosuppressive drugs (66% versus 37%; P = 0.0001) was used significantly more often in children with SLE. Four adult patients with SLE, but none of the children, died during the followup. At the end of the followup, the mean SDI scores in those with childhood-onset SLE were higher than those with adult-onset SLE (1.70 versus 0.76; P = 0.008)., Conclusion: Children with childhood-onset SLE have more active disease at presentation and over time than do adults with SLE, especially active renal disease. Compared with adults with SLE, children receive more intensive drug therapy and accrue more damage, often related to steroid toxicity.

Objective: To determine the reliability of formal exercise testing and the reliability of functional and activity questionnaires in children with juvenile idiopathic arthritis (JIA)., Methods: Children with JIA of any subtype ages 8-16 years who were recruited to a randomized trial comparing different exercise therapies participated in 2 preintervention sessions of exercise testing 2-6 weeks apart. Exercise testing included 1) submaximal oxygen uptake (VO(2submax)), 2) peak VO(2) (VO(2peak)), and 3) anaerobic power using modified Wingate tests (W(ant)). Two physical function questionnaires (the Childhood Health Assessment Questionnaire [C-HAQ] and Revised Activity Scale for Kids [ASK]) and 1 daily physical activity questionnaire (the Habitual Activity Estimation Scale [HAES]) were also completed at these times. Test-retest reliability was assessed using type 3, intrarater intraclass correlation coefficient (ICC(3,1)) and Bland and Altman plots were used to determine limits of agreement., Results: Data were available for 74 patients (58 girls). VO(2submax), VO(2peak), and W(ant) demonstrated high reliability (ICC(3,1) 0.82, 0.91, and 0.94, respectively). C-HAQ and ASK questionnaires also had very high reliability (ICC(3,1) 0.82 and 0.91, respectively). The HAES demonstrated low reliability for total activity score (ICC(3,1) 0.15) and moderate reliability when the number of very active hours was analyzed separately (ICC(3,1) 0.59)., Conclusion: Results of this investigation suggest that exercise testing and functional questionnaires in children with JIA are consistent and reliable. Reliability of the HAES total score was poor, but moderate when the very active hours subscale score was used.

Objective: Childhood-onset systemic lupus erythematosus (SLE) presents a unique subgroup of patients for genetic study. The present study was undertaken to identify susceptibility genes contributing to SLE, using a novel candidate gene pathway microarray platform to investigate gene expression in patients with childhood-onset SLE and both of their parents., Methods: Utilizing bioinformatic tools, a platform of 9,412 single-nucleotide polymorphisms (SNPs) from 1,204 genes was designed and validated. Molecular inversion probes and high-throughput SNP technologies were used for assay development. Seven hundred fifty three subjects, corresponding to 251 full trios of childhood-onset SLE families, were genotyped and analyzed using transmission disequilibrium testing (TDT) and multitest corrections., Results: Family-based TDT showed a significant association of SLE with a N673S polymorphism in the P-selectin gene (SELP) (P = 5.74 x 10(-6)) and a C203S polymorphism in the interleukin-1 receptor-associated kinase 1 gene (IRAK1) (P = 9.58 x 10(-6)). These 2 SNPs had a false discovery rate for multitest correction of <0.05, and therefore a >95% probability of being considered as proven. Furthermore, 7 additional SNPs showed q values of <0.5, suggesting association with SLE and providing a direction for followup studies. These additional genes notably included TNFRSF6 (Fas) and IRF5, supporting previous findings of their association with SLE pathogenesis., Conclusion: SELP and IRAK1 were identified as novel SLE-associated genes with a high degree of significance, suggesting new directions in understanding the pathogenesis of SLE. The overall design and results of this study demonstrate that the candidate gene pathway microarray platform used provides a novel and powerful approach that is generally applicable in identifying genetic foundations of complex diseases.

Objective: To examine the effectiveness of high-intensity aerobic training compared with low-intensity training in terms of energy cost of locomotion, peak oxygen uptake, peak power, and self-reported physical function in children with juvenile idiopathic arthritis (JIA)., Methods: Eighty children with JIA, ages 8-16 years, were enrolled in a randomized, single-blind controlled trial. Both groups participated in a 12-week, 3-times-weekly training program consisting of high-intensity aerobics in the experimental group and qigong in the control group. Subjects underwent exercise testing measuring submaximal oxygen uptake at 3 km/hour (VO(2submax)) as the primary outcome, maximal oxygen uptake, and peak power at the beginning and end of the program. Physical function was measured using the Child Health Assessment Questionnaire (C-HAQ)., Results: The exercise program was well tolerated in both groups. There was no difference in VO(2submax) or any other exercise testing measures between the groups through the study period and no indication of improvement. Both groups showed significant improvements in C-HAQ with no difference between the groups. Adherence was higher in the control group than the experimental group., Conclusion: Our findings suggest that activity programs with or without an aerobic training component are safe and may result in an important improvement in physical function. The intensity of aerobic training did not seem to provide any additional benefits, but higher adherence in the qigong program may suggest that less intensive regimens are easier for children with JIA to comply with, and provide a degree of benefit equivalent to more intensive programs.

Objective: To evaluate the safety and efficacy of infliximab in the treatment of juvenile rheumatoid arthritis (JRA)., Methods: This was an international, multicenter, randomized, placebo-controlled, double-blind study. One hundred twenty-two children with persistent polyarticular JRA despite prior methotrexate (MTX) therapy were randomized to receive infliximab or placebo for 14 weeks, after which all children received infliximab through week 44. Patients received MTX plus infliximab 3 mg/kg through week 44, or MTX plus placebo for 14 weeks followed by MTX plus infliximab 6 mg/kg through week 44., Results: Although a higher proportion of patients in the 3 mg/kg infliximab group than in the placebo group had achieved responses according to the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement at week 14 (63.8% and 49.2%, respectively), the between-group difference in this primary efficacy end point was not statistically significant (P = 0.12). By week 16, after the crossover from placebo to infliximab 6 mg/kg when all patients were receiving infliximab, an ACR Pedi 30 response was achieved in 73.2% of all patients. By week 52, ACR Pedi 50 and ACR Pedi 70 responses had been reached in 69.6% and 51.8%, respectively, of patients. Infliximab was generally well tolerated, but the safety profile of infliximab 3 mg/kg appeared less favorable than that of infliximab 6 mg/kg, with more frequent occurrences of serious adverse events, infusion reactions, antibodies to infliximab, and newly induced antinuclear antibodies and antibodies to double-stranded DNA observed with the 3 mg/kg dose., Conclusion: While infliximab at 3 mg/kg and 6 mg/kg showed durable efficacy at 1 year, achievement of the primary efficacy end point at 3 months did not differ significantly between infliximab-treated and placebo-treated patients. Safety data indicated that the 6-mg/kg dose may provide a more favorable risk/benefit profile. These results warrant further investigation in children with JRA.

Objective: Studies of adults with systemic lupus erythematosus (SLE) have frequently demonstrated the presence of decreased bone mineral density (BMD). However, there have been few investigations in pediatric patients to date. This study was undertaken to determine the prevalence of low BMD in patients with juvenile SLE and to identify associated risk factors., Methods: We studied 64 consecutive patients with juvenile SLE in whom routine dual x-ray absorptiometry (DXA) scanning was performed. Lumbar spine osteopenia was defined as a BMD Z score of < -1 and > or = -2.5, and osteoporosis as a BMD Z score of < -2.5. Decreased hip BMD was defined as a value of < 80%. Data on disease activity, quality of life, disease-related damage, sex, ethnicity, body mass index, age at diagnosis, age at DXA, medication use and duration, clinical features, and puberty status were collected at the time of DXA., Results: Lumbar spine osteopenia was seen in 24 patients (37.5%) and osteoporosis in 13 (20.3%). Decreased hip BMD was present in 12 patients (18.8%). By univariate analysis, osteopenia was significantly correlated with age, disease duration, duration of corticosteroid use, cumulative corticosteroid dose, azathioprine use, cyclophosphamide use, lupus nephritis, and damage. Two additional variables, mycophenolate mofetil use and class III-IV nephritis, were associated with osteoporosis. Abnormal hip BMD was associated with disease duration, duration of corticosteroid use, and cumulative corticosteroid dose. By multivariate analysis, only disease duration remained in the model for osteoporosis and abnormal hip BMD, while cumulative corticosteroid dose was the variable associated with osteopenia., Conclusion: These results indicate that osteopenia and osteoporosis are common in juvenile SLE and are associated more closely with increased disease duration than with cumulative corticosteroid dose.

Objective: Neurologic involvement has been reported to occur in infants with neonatal lupus erythematosus (NLE), although the significance of these findings is unknown. The purpose of this study was to determine if hydrocephalus/macrocephaly is a manifestation of NLE., Methods: Infants from the Hospital for Sick Children in Toronto, Canada whose mothers had anti-Ro antibodies were followed prospectively. A total of 87 infants were seen in the study period (1999-2004). The maternal autoantibody status of all infants was documented, and all infants underwent full clinical examination at each visit., Results: Of the 87 infants, 47 had NLE. Five of the 47 infants with NLE and 2 of the healthy infants had hydrocephalus, resulting in a prevalence of 8.0% (95% confidence interval 4.0-15.0%) in the entire cohort. This is significantly higher than the prevalence in the general population of 0.048-0.081%. Head circumference measurements of infants in the Toronto cohort were largest between 12-24 months of age (Z score difference = 0.71, P = 0.008)., Conclusion: We suggest that hydrocephalus and macrocephaly are manifestations of NLE and that infants born to mothers with anti-Ro antibodies should be carefully monitored for hydrocephalus as part of their routine physical examination.

Objective: Lipid abnormalities in patients with systemic lupus erythematosus (SLE) are common and are likely to be one of the causes of premature atherosclerosis in these patients. This study was undertaken to serially examine the lipid profile in pediatric patients with SLE to determine the roles of active disease and therapy in altering lipid levels., Methods: Serial lipid measurements were obtained in an inception cohort of 139 pediatric patients with SLE at the time of treatment with either a constant dose or differing doses of prednisone, and annually. The levels of cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were correlated with measures of disease activity and prednisone dose., Results: At the time of SLE diagnosis in this pediatric cohort, the mean values for all lipids were abnormal. With each reduction in prednisone dose, there was a statistically significant decrease in cholesterol and triglyceride levels (P < 0.001) but not HDL or LDL levels. Nephrotic-range proteinuria was associated with altered cholesterol, triglyceride, and LDL levels, whereas changes in HDL were more commonly associated with active nephritis. In the absence of nephrotic-range proteinuria, increases in prednisone dose were associated with increased levels of all lipids, including HDL., Conclusion: Active SLE leads to a proatherogenic lipid profile. Levels of cholesterol and LDL were mainly associated with the dose of prednisone, and were abnormal only during very high disease activity. Triglyceride levels were mainly associated with proteinuria, while changes in HDL were associated with active SLE and a high dose of prednisone. Our results suggest that the lipid profile in pediatric SLE is the result of a complex interaction of disease manifestations and the effects of prednisone therapy.

Objective: Primary angiitis of the central nervous system (PACNS) is a severe and ill-defined neurologic disease. The goal of this study was to characterize the presenting features, treatment, and neurologic outcome of PACNS in children (cPACNS) and to define the predictors of disease progression in order to identify high-risk patients with cPACNS., Methods: The cohort comprised consecutive patients diagnosed as having cPACNS based on clinical and vascular imaging findings, including identification of arterial stenosis on conventional angiography or magnetic resonance (MR) angiography. Disease progression was defined angiographically at >3 months after initial angiography. Clinical data obtained in prospectively collected standardized assessments and results of laboratory tests, including detection of cerebrospinal fluid abnormalities, were noted, and neuroimaging studies were reanalyzed. Predictors of progression were identified and tested in multivariate regression models., Results: Sixty-two consecutive patients with cPACNS (38 male, 24 female, median age 7.2 years) were included. Two distinct subgroups were identified, those with progressive disease and those with nonprogressive disease. Progressive cPACNS was found in 20 of 62 children and was predicted by a clinical presentation of neurocognitive dysfunction, multifocal parenchymal lesions on MR imaging, and evidence of distal stenoses on angiography., Conclusion: The spectrum of PACNS in children includes both progressive and nonprogressive forms. Characteristic features at diagnosis can be used to predict later progression, to identify a distinct high-risk cPACNS cohort, and to help guide selection of patients for immunosuppressive therapy.

Objective: To determine the prevalence of lipid abnormalities at different times and to determine the influence of both the disease and corticosteroid therapy on lipid abnormalities in pediatric patients with systemic lupus erythematosus (SLE)., Methods: Lipid measurements were obtained in an inception cohort of 139 pediatric patients with SLE (114 females). Fasting levels of total cholesterol, triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol in the SLE patients were compared with those in age- and sex-matched control subjects. Disease activity levels and medication dosages were obtained at the time of lipid measurements., Results: At the time of diagnosis, the mean levels of total cholesterol, LDL cholesterol, and triglycerides were highest, whereas the mean levels of HDL cholesterol were lowest. The percentage of patients with abnormal triglyceride values was highest at diagnosis, decreased at year 1, and then remained relatively constant thereafter. The mean total cholesterol and LDL cholesterol levels decreased at year 1 as compared with the time of diagnosis and then remained relatively constant. The lowest mean HDL cholesterol levels were found at the time of diagnosis, and these values rose with time. Comparison of lipid levels at different prednisone dosages and disease activity levels revealed that changes in triglyceride levels were mainly associated with changes in disease activity, changes in both total cholesterol and LDL cholesterol levels were associated with changes in the prednisone dosage and not disease activity, and low levels of HDL cholesterol were associated with active SLE, whereas the prednisone dosage was associated with increased levels of HDL cholesterol., Conclusion: Factors intrinsic to SLE appear to alter lipid levels. Control of SLE may be the most important factor in improving abnormal lipid profiles, and paradoxically, prednisone therapy may improve abnormal lipid levels.

The X;Y translocation break point sequence in an XX male patient with prepubertal systemic lupus erythematosus (SLE) was characterized with the intention of identifying a predisposing gene(s) for SLE. Spectral karyotyping of the patient's metaphase chromosomes showed normal autosomes and 2 X chromosomes, one of which displayed a small portion of the Y chromosome. Using a Y chromosome polymerase chain reaction (PCR) walking strategy and inverse PCR, we found that the abnormal recombination occurred between retroviral long terminal repeats located at Xp22.33 (position 0.95 Mb; inside the pseudoautosomal regions) and Yp11.2 (4.20 Mb) downstream of the sex-determining region Y (SRY) gene. The complete DNA sequence of the break point was determined, revealing a partial duplication of the pseudoautosomal region 1 (PAR1) in the derivative X chromosome and causing a partial trisomy of the 12 known genes located between the interleukin-3 receptor alpha (IL3RA; position 1.1 Mb on the X and Y chromosomes) and CD99 (position 2.2 Mb) genes inclusively. All other X chromosome genes were present as 2 copies. Real-time quantitative PCR confirmed the presence of 3 copies of each of the 12 genes in the patient's genomic DNA. We also found that RNA for 1 of the candidate genes was indeed overexpressed in the patient's blood as compared with normal subjects. Taken together, the uniqueness of the translocation, the rarity of severe prepubertal SLE in males, and the presence of SLE in some patients with Klinefelter's syndrome (who have a triplication of the 2 PAR regions) point to a possible relationship between the partial triplication of the PAR1 region and the development of SLE.

Inflammatory central nervous system (CNS) diseases in childhood comprise a wide spectrum of heterogeneous conditions. We studied 4 children with primary CNS vasculitis in whom results of magnetic resonance imaging studies were abnormal but results of conventional angiography were normal. We determined that angiography-negative, biopsy-confirmed primary small-vessel CNS vasculitis is a previously unrecognized distinct disease entity in children. The diagnosis must be considered in a child with a progressive, acquired diffuse or focal neurologic deficit, even if the results of conventional angiography are normal. A lesional brain biopsy is required to confirm the diagnosis. Use of immunosuppressive therapy plus aspirin leads to an excellent neurologic outcome.

Objective: To obtain preliminary data regarding the efficacy and long-term safety of leflunomide in patients with refractory polyarticular-course juvenile rheumatoid arthritis (JRA)., Methods: Twenty-seven patients were entered into the initial 26-week open-label study of leflunomide therapy; 17 entered the extension phase (maximum 107 weeks). Mean disease duration at study entry was 7.0 years. All patients had >or=5 joints with active arthritis and had received methotrexate for a mean of 36.0 months. Following a loading dose, patients initially received leflunomide at a dosage of 10 mg/1.73 m(2)/day, which could be increased to 20 mg/1.73 m(2)/day (maximum 20 mg/day) beginning at week 8. The primary efficacy outcome was the American College of Rheumatology (ACR) Pediatric 30 (Pedi 30) criteria for improvement. Last observation carried forward (LOCF) analysis was used, and all patients were entered into an intent-to-treat analysis. Intraarticular corticosteroids (maximum of 2 in the initial 26 weeks) were allowed, but no new disease-modifying antirheumatic drug or change in nonsteroidal antiinflammatory drug was allowed throughout the study., Results: Seventeen of the 27 patients (63%) completed the initial 26-week study. Fourteen patients (52%) met the ACR Pedi 30 response criteria at week 26. Seventeen patients entered into the extension phase (13 who met response criteria and 4 who failed to meet response criteria but decided to continue). Nine of the 17 patients (53%) who entered the extension phase either completed all 30 months of study or the study ended prior to the month 30 visit. Five patients withdrew because of failure to maintain efficacy, 2 withdrew their consent, and 1 withdrew because of an adverse event. Using LOCF analysis, 65% of patients met ACR Pedi 30 response criteria at 1 year and 2 years (weeks 50 and 106, respectively) and 53% at the end of the study. Good response rates were also seen using ACR Pedi 50 and ACR Pedi 70 criteria (47% and 24% at week 106, respectively)., Conclusion: In this open-label study of JRA patients who either failed to respond to, or were intolerant of, methotrexate, the majority met the ACR Pedi 30 response criteria at week 26. The response was durable, since 53% of patients who entered into the extension phase (maximum 30 months) responded at the end of this phase. Our findings support the further study of the role of leflunomide in the treatment of polyarticular-course JRA.

Objectives: To evaluate the European Consensus Lupus Activity Measurement (ECLAM) for responsiveness to change in disease activity when used in childhood-onset systemic lupus erythematosus (cSLE). To confirm the construct validity and to characterize the measurement properties of the ECLAM by assessing its ability to predict damage and steroid requirements., Methods: The disease courses of 66 newly diagnosed cSLE patients were reviewed. The ECLAM and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were scored for all clinic visits and hospitalizations. Damage was assessed at the end of the followup period using the Systemic Lupus International Collaboration Clinics/American College of Rheumatology Damage Index. Disease activity at the time of diagnosis, 6 months after diagnosis, at the time of first flare, and 6 months after first flare was used to estimate responsiveness of the measures. Responsiveness was measured by the effect size, the effect size index, the standardized response mean, and the relative efficiency index (REI). The measurement properties of the ECLAM and SLEDAI over time were examined by comparing the ability of both measures to predict damage and oral steroid requirement., Results: The ECLAM and SLEDAI are both responsive to change in disease activity irrespective of the statistic used. The ECLAM is more sensitive than the SLEDAI using the REI (all >1.9). Cumulative disease activity as measured by the SLEDAI or the ECLAM are important predictors of damage. There are no statistically important differences between the 2 measures with regard to their ability to predict steroid requirements., Conclusions: The ECLAM has construct validity in cSLE and, like the SLEDAI, is highly sensitive to clinically important change in disease activity. The ECLAM may be more responsive. The quantitative properties of the 2 measures are very similar. The SLEDAI likely remains the preferable disease activity measure for cSLE given its overall measurement properties and ease of use.

Objective: The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index measures damage in adult patients with systemic lupus erythematosus (SLE), but its usefulness in patients with childhood-onset SLE has not been examined. This study was conducted to evaluate the sensibility of the SLICC/ACR Damage Index, to investigate how cumulative disease activity is related to damage in childhood-onset SLE, and to identify other risk factors for damage in childhood-onset SLE., Methods: Disease activity and damage in 66 patients with newly diagnosed childhood-onset SLE were assessed retrospectively, and information on potential risk factors for damage (age, race, sex, medications, duration of disease, hypertension, body mass index, antiphospholipid antibodies, kidney disease, acute thrombocytopenia) was obtained. In addition, a group of physicians was surveyed to establish the sensibility of the SLICC/ACR Damage Index in childhood-onset SLE., Results: The SLICC/ACR Damage Index was found to have face, content, and construct validity when used in children. The mean SLICC/ACR Damage Index score of the patients was 1.76 (mean followup 3.3 years). Cumulative disease activity over time was the single best predictor of damage (R(2) = 0.30). Other, possibly important risk factors for damage were corticosteroid treatment, the presence of antiphospholipid antibodies, and acute thrombocytopenia. It was determined that immunosuppressive agents may be protective., Conclusion: The SLICC/ACR Damage Index, though useful in childhood-onset SLE, may benefit from the introduction of weightings and redefinition of some of the items. Ongoing disease activity leads to disease damage, and treatment should be prompt. Prolonged use of high-dose corticosteroids may further increase damage, but use of immunosuppressive agents may protect against disease damage; this latter finding may have potential implications for the treatment of childhood-onset SLE and deserves further study. The relationship between disease activity and concomitant use of medication also requires further investigation.