Katherine Marzan

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.

Treatment of Pediatric Takayasu arteritis with infliximab and cyclophosphamide: experience from an American-Brazilian cohort study.

BackgroundPediatric Takayasu arteritis (pTA) is difficult to treat and can lead to significant morbidity and mortality. ObjectivesThe objective of this study was to describe clinical characteristics for pTA and determine the safety and efficacy of cyclophosphamide (CYC) and infliximab (IFX) in pTA. MethodsThis was a retrospective analysis of 23 pTA patients seen at Children’s Hospital Los Angeles and Universidade Federal de São Paulo–Brazil from 1990 to 2011. All patients fulfilled the 1990 American College of Rheumatology criteria for Takayasu arteritis. Disease activity was assessed using a modified National Institutes of Health score. ResultsTwenty-three patients (14 female and 9 male patients), mean age of 15.7 ± 6.0 years, were included. Cyclophosphamide was used before IFX treatment in 17 of 23 and IFX before CYC in 2 of 23 patients. The average time from disease onset to treatment initiation was 2.6 ± 2.4 years for CYC and 4.1 ± 2.4 years for IFX. Nine (60%) of 15 patients failed CYC, and of these 6 were changed to IFX with subsequent clinical stabilization in 5 (83%) of 6. Two patients initially treated with IFX were switched to CYC because of lack of appropriate response: 1 patient later worsened, and the other was lost to follow-up. Five opportunistic infections requiring hospitalization occurred in the CYC group, whereas none were observed in the IFX group. Patients in the IFX group were more likely to decrease or stop their corticosteroids when compared with the CYC patients. ConclusionsCyclophosphamide is often used as initial treatment but has many adverse effects. In this retrospective case series, IFX was equivalent to CYC with fewer adverse effects, making IFX an alternative therapeutic option for pTA.

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.

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.

Adalimumab in juvenile rheumatoid arthritis/juvenile idiopathic arthritis.

Chronic arthritis in childhood is the most common pediatric rheumatic disease and can lead to significant short- and long-term disability. TNF-a is a cytokine involved in joint inflammation and destruction. It has been suggested that early and aggressive treatment leads to improved outcomes by ameliorating clinical signs and symptoms, inhibiting joint destruction and improving functional disability. The early and aggressive use of disease-modifying antirheumatic drugs and biologic response modifiers are key to achieving this goal. Anti-TNF agents are effective biologic modifiers that have had a major impact on the clinical course of arthritis. Adalimumab, a recombinant monoclonal antibody to TNF-α, is emerging as a valuable new therapy for juvenile arthritis.

FRI0353 Infliximab vs cyclophosphamide in pediatric takayasu’s arteritis

Background Pediatric Takayasu’s Arteritis (pTA) is a rare granulomatous vasculitis that affects the aorta and its branches. Though cyclophosphamide (CYC) is often used as first line therapy there are few studies proving its efficacy (2). Recently, several case series have reported beneficial results with Infliximab (INF) treating adult and pediatric patients with TA (1). Objectives To describe the treatment response to CYC and INF in an American and Brazilian cohort of pTA patients. Methods Retrospective analysis of 23 pediatric Takayasu’s Arteritis patients seen at Children’s Hospital Los Angeles (CHLA) and Universidade Federal de São Paulo – Brazil (Unifesp) from 1990 to 2011. All patients fulfilled the 1990 American College of Rheumatology criteria for TA. Disease activity was assessed by angiographic imaging, markers of inflammation, and clinical findings. Outcome was assessed using a scoring system (-1 = worse, 0 = unchanged, 1 = improved) that was applied to imaging and clinical findings. Results 23 pts (14F:9M), mean age at disease onset 9.0±3.8 yrs were included: 3 patients presented with type IIa, 2 with type IIb, 3 with type III, 2 with type IV, and 13 with type V (1994 International TA Conference criteria). There was a significantly longer time between disease onset and diagnosis in the Unifesp cohort (2.7±2.1 yrs) compared to the CHLA cohort (1.0±4.6 yrs) (p-value 0.027). CYC was used as initial treatment in 17/23 and INF in 2/23 patients. Average time from disease onset to initiation of CYC was 2.6±2.4 yrs and INF 4.1±2.4 yrs. 9/17 patients initially treated with CYC were changed to INF due to disease progression (7) or partial response (2). 7/9 of these patients subsequently clinically improved on INF. The 2 patients initially treated with INF were changed to CYC due to lack of appropriate response. 1 patient worsened on CYC and the other was lost to follow-up. Of the remaining 4 patients who did not receive CYC or INF 1 patient improved on methotrexate, 1 patient was treated with corticosteroids, methotrexate, and cyclosporine, and 2 patients died. The 2 fatalities were Unifesp patients who died prior to treatment with any immunosuppressant medications except corticosteroids. No differences were detected between the inflammatory markers or angiographic progression in the 2 treatment groups at 6, 12, 24, and 48 months. One serious adverse event occurred during CYC (sepsis) but none during treatment with INF. Conclusions Pediatric Takayasu’s Arteritis is difficult to treat and can lead to significant morbidity or mortality. CYC is often used in the treatment of pTA but has many potential side effects. INF was non-inferior to CYC in our study although patient numbers were too low to detect meaningful statistical differences. Use of INF may be an alternative therapeutic option in pediatric patients with TA. References Hoffman GS, et al. Anti-tumor necrosis factor therapy in patients with difficult to treat Takayasu’s arteritis. Arthritis Rheum 2004; 50:2296-304. Ozen S, et al. Takayasu arteritis in children: Preliminary experience with cyclophosphamide induction and corticosteroids followed by methotrexate. J Pediatr 2007; 150:72-6. Disclosure of Interest S. Stern: None Declared, G. Clemente Consultant for: Novartis, A. Reiff Consultant for: Immunex, Wyeth, Amgen, Merck, Abbott, Pfizer, Novartis, & Genentech, M. Ramos: None Declared, K. Marzan: None Declared, M. T. Terreri Consultant for: Novartis, Pfizer, Johnson & Johnsons, & Abbott

Role of adalimumab in the management of children and adolescents with juvenile idiopathic arthritis and other rheumatic conditions.

Treatment of children and adolescents with juvenile idiopathic arthritis and other pediatric rheumatic diseases has evolved. Where once there was only a limited arsenal of medications, with significant side effects and inadequate efficacy, today, with an increased understanding of the pathogenesis of these diseases, there is a wider variety of more targeted and effective treatments. TNF-α is a cytokine involved in a number of inflammatory pathways in pediatric rheumatic diseases. The emergence of biologic modifiers that target TNF-α has been pivotal in providing the ability to deliver early and aggressive treatment. Adalimumab, a recombinant monoclonal antibody to TNF-α, is an important therapeutic option, which affords children and adolescents with chronic illnesses an improved quality of life.

Do pedometers with or without education on exercise increase functional walking capacity and physical activity level in adolescents with juvenile idiopathic arthritis

ABSTRACT To evaluate the impact of pedometer use on the physical activity (PA) and functional walking capacity (FWC) of adolescents with juvenile idiopathic arthritis (JIA) and lower extremity (LE) involvement. Twenty-seven adolescents, aged 11–19 years with JIA and LE involvement, participated in the three-phase pedometer study that introduced the use of a pedometer and an education seminar at 6 weeks. Measurements were taken at the baseline first visit and at weeks 6, 12, and 20. The primary outcome measure was the 6-minute walk test (6MWT). Thirteen completed the study. Six-minute walk distance (6MWD) significantly increased from baseline (458.0 ± 70.8 m) to the end of phase 1 (501.4 ± 59.8 m) (p = 0.035), prior to receiving the pedometer; and from baseline to the end of study (p = 0.0037). No significant changes in 6MWD were found between weeks 6 and 12 (intervention) (p = 0.77) or between weeks 12 and 20 (follow through phase) (p = 0.27). In adolescents with LE JIA, consistent guidance and support by rheumatology professionals appears to positively influence PA and measures of FWC as seen through improved 6MWD. There was insufficient evidence to show that pedometers further increased FWC or PA.