Bracha Shaham

Etanercept therapy in children with treatment-resistant uveitis

OBJECTIVE To evaluate the safety and efficacy of the tumor necrosis factor fusion protein etanercept in children with treatment-resistant uveitis. METHODS Ten children with chronic active uveitis (7 girls and 3 boys, mean age 7.5 years [range 3-12 years]) were enrolled in this prospective study. In 7 children, uveitis was associated with pauciarticular juvenile rheumatoid arthritis. Five children were antinuclear antibody positive. All patients had failed previous therapy with topical steroids and methotrexate and/or cyclosporine. All were treated with etanercept at a dosage of 0.4 mg/kg twice weekly for the first 3 months, and then, if eyes did not improve, with 25 mg twice weekly (mean 1.1 mg/kg) for at least 3 additional months. RESULTS At the beginning of the trial, uveitis affected 18 eyes in the 10 children. Within 3 months, 10 of 16 affected eyes (63%; P = 0.017) showed a rapid decrease in anterior chamber cell density, including remission of uveitis in 4 eyes. In children with visual acuity of less than 20/25, 4 of 10 eyes (40%) improved. An exacerbation of uveitis during etanercept therapy occurred in only 1 child (1 of 14 eyes [7%]). Other ocular outcome parameters, such as intraocular pressure, synechia formation, and lens clarity, remained unchanged. Following a dosage increase to an average of 1.1 mg/kg after 3 months in 7 children, no further improvement was noted. CONCLUSION Our data suggest that etanercept injected subcutaneously twice a week has a beneficial effect on treatment-resistant chronic uveitis in children. Further controlled studies with etanercept in systemic or topical form are necessary to confirm its efficacy and optimal mode of administration.

Consensus treatments for moderate juvenile dermatomyositis: Beyond the first two months. Results of the Second Childhood Arthritis and Rheumatology Research Alliance Consensus Conference

To use consensus methods and the considerable expertise contained within the Childhood Arthritis and Rheumatology Research Alliance (CARRA) organization to extend the 3 previously developed treatment plans for moderate juvenile dermatomyositis (DM) to span the full course of treatment.

B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients

OBJECTIVE To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA). METHODS Blood samples collected from patients with pediatric SLE (n = 56) and patients with JIA (n = 54) at the beginning and end of a 6-month interval were analyzed for plasma BLyS protein levels by enzyme-linked immunosorbent assay and for blood leukocyte full-length BLyS and DeltaBLyS messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (normalized to 18S expression). Healthy siblings (n = 34) of these patients served as controls. RESULTS In pediatric SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels were each significantly elevated, and plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were correlated with disease activity. In contrast, plasma BLyS protein levels were normal in JIA despite blood leukocyte BLyS mRNA levels being elevated to degrees similar to those in pediatric SLE. Among JIA patients, neither BLyS parameter was correlated with disease activity. In both pediatric SLE and JIA, the BLyS expression profiles remained stable at 6 months. CONCLUSION Our findings indicate that, as previously noted in adult SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels are elevated in pediatric SLE. The correlation of plasma BLyS protein levels with disease activity points to BLyS as a candidate therapeutic target in pediatric SLE. Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels. The absence of correlation between either of the BLyS parameters and disease activity in JIA calls for circumspection prior to assigning BLyS as a candidate therapeutic target in this disorder.

High Dose Infliximab in the Treatment of Refractory Uveitis: Does Dose Matter?

Background. Infliximab (INF) has been shown to be beneficial in treating refractory uveitis, however, no data exist on optimal dosing and the efficacy of higher dosing. Objectives. To compare the efficacy of low-dose (LD) (<10 mg/kg), moderate-dose (MD) (≥10–15 mg/kg), and high-dose (HD) INF (≥15–20 mg/kg) in the treatment of uveitis. Methods. Retrospective chart review children with uveitis diagnosed at Childrens Hospital Los Angeles and Millers Childrens Hospital, CA, USA. Results. Of the 34 INF-treated children, 6 patients received LD, 19 received MD, and 9 received HD. Average disease duration prior to therapy was 10.6, 24.6, and 37.1 months each group, respectively. Topical steroids were discontinued after an average of 3 months, 9.5 months, and 10.2 months in the LD, MD, and HD groups, respectively. We found that 66% of patients receiving LD, 42% of MD, and 66% receiving HD INF failed therapy and required either dose escalation or alternate medication for disease control. Conclusions. INF is beneficial in the treatment of uveitis, and dose escalation up to 4 times above the approved dose is often necessary to achieve disease control in patients with uveitis. Doses < 10 mg/kg every 4 weeks may not be sufficient to control disease.

Early Juvenile Idiopathic Arthritis

Early juvenile idiopathic arthritis (JIA) is important to recognize as timely diagnosis and treatment improves prognosis. It is a misconception that complications of JIA arise only from long-standing disease and that children will outgrow it. Early aggressive treatment is the paradigm as early disease activity has long-term consequences. There are predictors of persistent disease and joint erosions that may identify patients at higher risk. Control of disease activity within the first 6 months of onset confers improved clinical course and outcomes. The treatment perspective is thus one of early aggressive treatment for induction of disease control and ultimately remission.

Study of thymic size and function in children and adolescents with treatment refractory systemic sclerosis eligible for immunoablative therapy

Following hematopoietic stem cell transplantation (HSCT), thymic reconstitution of peripheral T lymphocytes is essential to avoid a chronically immunodeficient state and disease recurrence. The purpose of this study was to determine if children and adolescents with treatment refractory SSc, awaiting HSCT, have sufficient thymic function to reconstitute T lymphocyte function after transplantation. Thirteen children with systemic scleroderma were enrolled and assessed by physical exam, chest MRI, measurement of autoantibodies, B and T cell immuno-phenotyping, and quantization of T cell receptor rearrangement excision circles (TREC) as a marker of thymopoiesis. MRI detected thymic tissue in 9/13 children. TREC levels were detectable in all but one child but were significantly reduced (p<0.001) when compared to a control population. SSc patients also had a reduced percentage of naïve (CD45RA+CD31+) CD4+ T lymphocytes, further indicating diminished thymopoiesis. Our data suggest that thymic function in children with SSc might be insufficient for an adequate immunoreconstitution following transplantation in some patients. A thorough evaluation of immune and thymic functions to identify those patients prior to HSCT is recommended.

Association of Anti–3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Autoantibodies With DRB1*07:01 and Severe Myositis in Juvenile Myositis Patients

Autoantibodies recognizing 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) are associated with statin exposure, the HLA allele DRB1*11:01, and necrotizing muscle biopsies in adult myositis patients. The aim of this study was to characterize the features of juvenile anti‐HMGCR‐positive myositis patients.

Pediatric rheumatic disease in the intensive care unit: lessons learned from 15 years of experience in a tertiary care pediatric hospital.

Objective: This study describes the 15-yr experience of a large urban tertiary care children’s hospital in treating critically ill patients with pediatric rheumatic diseases. Design: Retrospective case series. Setting: Children’s Hospital Los Angeles, a large urban tertiary care children’s hospital. Patients: All patients with pediatric rheumatic diseases admitted to the Children’s Hospital Los Angeles pediatric intensive care unit from January 1995 to July 2009. Interventions: None. Measurements and Main Results: An internal database and medical records were reviewed for demographics, diagnoses, treatments, organ dysfunction, interventions, infections, and outcomes. Standardized mortality ratio was calculated based on Pediatric Risk of Mortality III estimated mortality. Factors associated with mortality were identified by univariate analyses. Ninety patients with 122 total admissions were identified. The majority of patients were Hispanic (63%), female (73%), and had systemic lupus erythematosus (62%). Pediatric rheumatic disease-related complications (50%) were the most common reason for admission; 32% of admissions involved multiorgan dysfunction. Eighteen admissions (15%) resulted in mortality. Deaths were most commonly attributed to combined infection and active rheumatic disease (50%), infection only (22%), rheumatic disease only (11%), or other causes (17%). In 30 (25%) admissions, a new rheumatologic diagnosis was established. Standardized mortality ratio was 0.72 (95% confidence interval 0.38-1.25) for pediatric rheumatic disease patients compared to 0.87 (95% confidence interval 0.79-0.96) for all pediatric intensive care unit patients. Factors associated with mortality included use of mechanical ventilation, vasopressors, and renal replacement (continuous venovenous hemodialysis) (all p < .05). Conclusions: Pediatric rheumatic disease-related complications were the principal cause of pediatric intensive care unit admission. Deaths occurred most often from severe infections in patients with active rheumatic disease. Pediatric rheumatology patients admitted to the pediatric intensive care unit had outcomes similar to the global pediatric intensive care unit population when adjusted for severity of illness.

A Child with X-Linked Agammaglobulinemia and Enthesitis-Related Arthritis

X-linked agammaglobulinemia (XLA) is a primary immune deficiency characterized by recurrent bacterial infections and profoundly depressed serum immunoglobulin levels and circulating mature B cells. We describe a 12-year-old boy with XLA and enthesitis-related arthritis (ERA). To date, there has been a paucity of reports of noninfectious inflammatory arthritis in children with XLA. This case illustrates that functional B cells and/or immunoglobulin are not required for ERA pathogenesis. In addition, this case suggests a possible link between immune deficiency, immune dysregulation, and rheumatic illness.

Anti‐3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A Reductase Autoantibodies are Associated with DRB1*07:01 and Severe Myositis in Pediatric Myositis Patients

Autoantibodies recognizing 3‐hydroxy‐3‐methylglutaryl‐coenzyme A reductase (HMGCR) are associated with statin exposure, the HLA allele DRB1*11:01, and necrotizing muscle biopsies in adult myositis patients. The aim of this study was to characterize the features of juvenile anti‐HMGCR‐positive myositis patients.