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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]

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]

Objective: Cerebral atrophy is a prominent feature in adults with systemic lupus erythematosus (SLE). We assessed cerebral and cerebellar volume loss on clinically acquired brain magnetic resonance imaging (MRI) scans of children and adolescents with SLE., Methods: We abstracted information on disease course for patients who underwent clinical brain MRI during the period 2002-2008. We completed qualitative assessments of volume loss and measured corpus callosum thickness and ventricular enlargement for patients with lupus and controls., Results: Forty-nine children underwent brain MRI during the review period due to clinical indications. The lupus cohort was predominantly female and ethnically diverse. Mean age at imaging was 15.3 +/- 2.6 years and mean disease duration was 30.6 +/- 33.3 months. Findings suggestive of cerebral and cerebellar volume loss were seen respectively in 89.8% and 91.8% of lupus patients. Cerebral volume loss was moderate or severe in 26.5% of children. Cerebellar volume loss was moderate in 20.4% of these patients. Linear measurement means reflected corpus callosum thinning and ventricular enlargement in lupus patients. Volume loss was observed in newly diagnosed patients prior to corticosteroid use. Disease duration and corticosteroid use did not predict the severity of volume loss. There were statistically significant differences in linear imaging measurements comparing lupus patients to 14 similar-age controls., Conclusion: Regional volume loss was observed in most adolescents with lupus undergoing clinical brain MRI scans. As in other pediatric conditions with inflammatory or vascular etiologies, these findings may be reflecting disease-associated neuronal loss and not solely the effects of corticosteroid.

The disease course of a complete C4-deficient patient in the U.S. was followed for 18 years. The patient experienced multiple episodes of infection, and he was diagnosed with systemic lupus erythematosus at age 9 years. The disease progressed to WHO class III mild lupus nephritis and to fatal CNS vasculitis at age 23 years. Immunochemical experiments showed that the patient and his sibling had complete absence of C4A and C4B proteins and were negative for the Rodgers and Chido blood group Ags. Segregation and definitive RFLP analyses demonstrated that the patient and his sibling inherited two identical haplotypes, HLA A2 B12 DR6, each of which carries a defective long C4A gene and a defective short C4B gene. PCR and DNA sequencing revealed that the mutant C4A contained a 2-bp insertion in exon 29 at the sequence for codon 1213. The identical mutation was absent in the mutant C4B. The C4B mutant gene was selectively amplified by long range PCR, and its 41 exons were completely sequenced. The C4B mutant had a novel single C nucleotide deletion at the sequence for codon 522 in exon 13, leading to frame-shift mutation and premature termination. Thus, a multiplex PCR is designed by which known mutations in C4A and C4B can be elucidated conveniently. Among the 28 individuals reported with complete C4 deficiency, 75-96% of the subjects (dependent on the inclusion criteria) were afflicted with autoimmune or immune complex disorders. Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus.