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Antiphospholipid syndrome (APS) is a multisystem autoimmune condition characterized by vascular thromboses associated with persistently positive antiphospholipid antibodies. There is currently a paucity of data (incidence, prevalence, thrombosis risk, and effective treatment) in pediatric APS. The purpose of this report is to review the current literature on APS in children and neonates, identify the gaps in current knowledge, and suggest avenues for studies to fill those gaps. [ABSTRACT FROM AUTHOR]

Objective To investigate the impact of tocilizumab treatment on growth and growth-related laboratory parameters in patients with systemic juvenile idiopathic arthritis (JIA) enrolled in a phase III clinical trial. Methods Patients with systemic JIA ages 2-17 years (n = 112) received tocilizumab in a 12-week, randomized, placebo-controlled period and a long-term open-label extension. Height velocity and standard deviation (SD) score; levels of insulin-like growth factor 1 (IGF-1), osteocalcin (OC), and C-telopeptide of type I collagen (CTX-I); and Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71) were measured in a post hoc analysis of 83 patients who never received growth hormone and did not reach Tanner stage 5 by the end of the first year of treatment. Results Patients had stunted growth at baseline (mean height SD score −2.2). During tocilizumab treatment, males (73%) and females (83%) experienced above-normal mean height velocities of 6.6 cm/year ( P < 0.0001 versus World Health Organization norms). Mean height SD score increases during year 1 (0.29) and year 2 (0.31) were significant (both P < 0.0001). The mean SD score for IGF-1 levels increased significantly (−0.2 for year 1 and −0.1 for year 2 versus −1.0 at baseline; both P < 0.0001). Mean OC and CTX-I levels (both P < 0.0001) and the OC:CTX-I ratio ( P = 0.014) significantly increased from baseline to year 2. In multiple regression analysis, first-year height velocity had a significant inverse relationship to JADAS-71 at year 1, age, mean glucocorticoid dosage during the year, and height SD score at baseline. Conclusion Our findings indicate that during treatment with tocilizumab, patients with systemic JIA experience significant catch-up growth, normalization of IGF-1 levels, and bone balance improvement favoring bone formation. [ABSTRACT FROM AUTHOR]

Severe manifestations of systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), and thrombotic thrombocytopenic purpura (TTP) are characterized by multiorgan thrombotic microangiopathy. We describe reduction of ADAMTS13 activity and the development of systemic autoimmunity in all 8 children initially diagnosed with acquired noncongenital TTP during an 8.5-year period. Median age at diagnosis was 12.0 years (range, 2.6-17.3 years). ADAMTS13 activity was absent (<5%) in 6 patients; 3 patients had a detected inhibitor. SLE was diagnosed concurrently in 3 patients, and 4 patients were diagnosed within 5 years. Six of the children diagnosed with SLE had absent ADAMTS13 activity at diagnosis. In 6 patients with SLE, immune-mediated nephritis developed by 46 months. All surviving patients with SLE developed antiphospholipid antibodies, including some with a lupus anticoagulant. Patients with SLE did not have TTP recurrences once daily immunosuppressive regimens were started. An evaluation for SLE/APS is warranted in children and adolescents with reduced ADAMTS13 activity and thrombotic microangiopathy. [ABSTRACT FROM AUTHOR]

Thrombotic events that occur in children are relatively rare and are mostly associated with indwelling catheters, infectious processes, surgical procedures, or genetic defects or deficiencies. However, case reports, case series, and registries continue to report children who exhibit the clinical features often associated with the antiphospholipid syndrome. Many of these cases are well-documented and also meet the published research criteria for the antiphospholipid syndrome. Children with antiphospholipid antibodies generally do not experience a high rate of thrombotic events. This is in part related to developmental differences in levels of coagulation proteins and to the relative health of the vascular endothelium compared with that of adults. Therapeutic issues in children may be oriented more toward identifying risk factors and providing preventive health, as well as more short-term treatment of transient events. [ABSTRACT FROM AUTHOR]

Endothelial damage, hypertension and cytotoxic medications may serve as risk factors for the posterior reversible encephalopathy syndrome (PRES) in systemic lupus erythematosus. There have been few case reports of these findings in pediatric lupus patients. We describe clinical and neuroimaging findings in children and adolescents with lupus and a PRES diagnosis. We identified all clinically acquired brain MRIs of lupus patients at a tertiary care pediatric hospital (2002–2008). We reviewed clinical features, conventional MRI and diffusion-weighted imaging (DWI) findings of patients with gray- and white-matter changes suggestive of vasogenic edema and PRES. Six pediatric lupus patients presenting with seizures and altered mental status had MRI findings suggestive of PRES. In five children clinical and imaging changes were seen in conjunction with hypertension and active renal disease. MRI abnormalities were diffuse and involved frontal regions in five children. DWI changes reflected increased apparent diffusivity coefficient (unrestricted diffusion in all patients). Clinical and imaging changes significantly improved with antihypertensive and fluid management. MRI changes suggestive of vasogenic edema and PRES may be seen in children with active lupus and hypertension. The differential diagnosis of seizures and altered mental status should include PRES in children, as it does in adults. [ABSTRACT FROM AUTHOR]

A combined forward and reverse genetic approach was undertaken to test the candidacy of IRAK1 (interleukin-1 receptor associated kinase-1) as an X chromosome-encoded risk factor for systemic lupus erythematosus (SLE). In studying ≈5,000 subjects and healthy controls, 5 SNPs spanning the IR.4K1 gene showed disease association (P values reaching 10[sup-10], odds ratio >1.5) in both adultand childhoodonset SLE, in 4 different ethnic groups, with a 4 SNP haplotype (GGGG) being strongly associated with the disease. The functional role of IRAK1 was next examined by using congenic mouse models bearing the disease loci: S/el or S1e3. IRAK1 deficiency abrogated all lupusassociated phenotypes, including 1gM and lgG autoantibodies, lymphocytic activation, and renal disease in both models. In addition, the absence of IRAK1 reversed the dendritic cell "hyperactivity" associated with S!e3. Collectively, the forward genetic studies in human SLE and the mechanistic studies in mouse models establish IRAK1 as a disease gene in lupus, capable of modulating at least 2 key checkpoints in disease development. This demonstration of an X chromosome gene as a disease susceptibility factor in human SLE raises the possibility that the gender difference in SLE may in part be attributed to sex chromosome genes. [ABSTRACT FROM AUTHOR]

The article focuses on the genotyping of STAT4 which reveals multiple haplotypic associations with systematic lupus erythematosus (SLE). SLE is a prototypical systematic autoimmune disorder with complex etiology and strong genetic component. STAT-1 and STAT-4 are transcription factors that play a key role in the interferon and Th1 signalling pathways. An additional haplotypic association across STAT4 was identified to have common risk haplotype found in multiple racial groups.

The article presents a study which identified susceptibility genes contributing to systemic lupus erythematosus (SLE), using a novel candidate gene pathway microarray platform. A platform of single-nucleotide polymorphisms (SNPs) from genes was designed and validated. The authors said the overall findings demonstrate that the platform used provides an novel and powerful approach which is applicable to determining genetic foundations of complex diseases.

Outcomes in children with proliferate lupus nephritis (PLN) show 9–15% progress to end-stage renal disease (ESRD) at 5 years. Immunosuppression improves outcome, but significant side effects are possible. Clinical and laboratory analyses are poor predictors of class and progression in PLN. We describe 28 patients with systemic lupus erythematosus (SLE), between 1990 and 2005, whose initial biopsy (Bx1) showed PLN and who received nine monthly doses of intravenously administered cyclophosphamide (CYP) (500–750 mg/m2 up to 1 g to maintain their absolute neutrophil count (ANC) > 3,000). Continued therapy with additional quarterly intravenous (i.v). administration of CYP was dictated by repeat renal biopsy (Bx2). Bx1 was done 1 ± 1.6 years after diagnosis of SLE. Bx2 showed histological improvement by WHO classification in 20/25 children; 3/25 were unchanged, 1/25 was categorized as new class V, and 1/25 was worse. Four patients (14%) had infectious complications requiring hospitalization (one of these died). Mean follow-up (f/u) after Bx2 was 3.5 ± 2.3 years. At last follow-up, 26 patients had normal glomerular filtration rate (GFR), with a mean of 126 ± 42.8 ml/min per 1.73 m2 body surface area, one non-compliant patient had ESRD, and one had chronic renal failure. At last follow-up, most patients had minimal to no proteinuria. Clinical and biopsy results greatly improved after 9 monthly intravenously administered CYP pulses in most children with class IV PLN. Those who did not improve are at risk for flares and progression of disease. The tailoring of therapies based on findings from a biopsy after induction may improve outcomes. [ABSTRACT FROM AUTHOR]

Human B and T lymphoblastoid cell lines were shown to synthesize C5. C5 synthesis was quantitated with an enzyme-linked immunosorbent assay (ELISA) that utilized a pool of C5-specific monoclonal antibodies (mAbs). Some level of C5 synthesis was detected in all eight of the B and T cell lines examined. In three of the cell lines, C5 was detected in both culture supernatants and whole cell detergent lysates, whereas in the other five cell lines, C5 was detected only in the cell lysates. Lymphoblastoid cells with both distributions of C5 were shown to synthesis a messenger RNA that was similar in size to the C5 mRNA expressed by the HepG2 hepatoma cell line. Estimates of the concentration of the C5 transcript in poly(A) RNA from lymphoblastoid and HepG2 cells suggested that C5 mRNA levels in the lymphoblastoid cell lines were comparable and about one-tenth of the levels in HepG2 cells. Lymphoblastoid C5, isolated by immunoaffinity chromatography from the supernatants of S-labeled cultures, had the same subunit composition as plasma-derived C5, but an α subunit of slightly smaller relative mass. [ABSTRACT FROM AUTHOR]

Background/Purpose: In the phase 3 TENDER trial of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (sJIA), decreases in neutrophil count were commonly observed. The purpose of this study was to determine whether neutropenia was associated with increased risk for infection and to investigate variables associated with the development of neutropenia in patients treated with TCZ for up to 2 years in TENDER. Methods: One hundred twelve children with active, persistent sJIA were randomly assigned 2:1 to receive TCZ based on body weight (12 mg/kg <30 kg or 8 mg/kg ≥30 kg) or placebo intravenously every 2 weeks for 12 weeks and continued in an ongoing, TCZ openlabel extension (). Worst Common Toxicity Criteria (CTC) neutropenia grade (grade 1, ≥1.5 and <2.0 × 109/L; grade 2, ≥;1.0 and <1.5 × 109/L; grade 3, ≥0.5 and <1.0 × 109/L; grade 4, <0.5 × 109/L) and lowest observed neutrophil count (109/L) were identified for each patient. Univariate linear regression analysis was performed to investigate the association of patient characteristics with lowest observed neutrophil count. Rates of infection and serious infection (per 100 patient-years [PY]) in periods ±15 days around grade 1-2 neutropenia (22.9 PY) and around grade 3-4 neutropenia (5.5 PY) were compared with corresponding rates in periods with normal neutrophil count (173.6 PY). Results: Up to week 104, 64 of 112 patients (57.1%) had at least 1 episode of grade 1-4 neutropenia; worst grade: 1 (n = 2), 2 (n = 34), 3 (n = 26), and 4 (n = 2). Rates of infection and serious infection during periods of normal neutrophil counts (276.5/100 PY [95% CI: 252.3, 302.3] and 11.5/100 PY [95% CI: 7.0, 17.8], respectively) were comparable with those observed ±15 days around grade 1-2 neutropenia (226.7/100 PY [95% CI: 169.3, 297.3]; 8.7/100 PY [95% CI: 1.1, 31.5]) and grade 3-4 neutropenia (292.5/100 PY [95% CI: 167.2, 475.0]; 0/100 PY), with no trend toward increased risk with higher grade neutropenia. Methotrexate use (Yes/No) was significantly associated with lowest observed neutrophil count (difference: −0.575 [95% CI: −1.02, −0.13], p = 0.012), with 62% of 77 patients receiving methotrexate versus 46% of 35 patients not receiving methotrexate having grade 1-4 neutropenia. Younger age was borderline associated with lowest observed neutrophil count (β = 0.04661; p = 0.047). Concurrent use of glucocorticoids and TCZ exposure were not associated with lowest observed neutrophil count (p > 0.3). Conclusion: No trend for association between neutropenia and increased risk for infection was observed in the TENDER trial. Background methotrexate, and somewhat younger age, was associated with increased risk for neutropenia, whereas TCZ exposure and concurrent glucocorticoid use were not. [ABSTRACT FROM AUTHOR]

The article focuses on new developed alternative bioinformatics-driven method to decrease the test needed in analyzing genetic disease. It says an applied methodology is used to discover genes associated with systematic lupus erythematosus (SLE). Results show that a single identified mutation in neutrophil cytosolic factor (NCF2) contributes to the reduction of reactive oxygen species (ROS) production and that NCF2 plays a significant function in predisposition to SLE.