Karen Onel

Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis.

There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies.

Neutrophil gelatinase-associated lipocalin as a biomarker of disease activity in pediatric lupus nephritis

We hypothesized that neutrophil gelatinase-associated lipocalin (NGAL) is an early predictive biomarker of disease activity in lupus nephritis. NGAL in serial plasma (PNGAL) and urine (UNGAL) samples was measured by enzyme-linked immunosorbent assay (ELISA) in 85 participants with pediatric systemic lupus erythematosus (pSLE), healthy children (n = 50), and children with juvenile idiopathic arthritis (JIA) (n = 30). Disease activity was measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Plasma and urinary NGAL were significantly increased in subjects with pSLE compared with those with JIA or with healthy controls (all p < 0.03), and unrelated to subjects’ age, weight, or height. Plasma and urinary NGAL were stable in pSLE subjects with unchanged disease activity. The pSLE subjects with worsening global or renal disease activity had a mean ± standard error (SE) increase of UNGAL (in ng/ml) of 11.5 ± 6.4 or 36.6 ± 12.1 (p < 0.01), corresponding to a 156% or 380% increase, respectively. PNGAL increased with worsening disease but to a much lesser degree than UNGAL [global disease activity (mean ± SE): 7.3 ± 6.2 or 21%; renal disease activity: 20.2 ± 6.0 or 51%; both p = not significant]. In conclusion, NGAL in urine but not in plasma represents a novel biomarker for renal disease activity in pSLE.

Initial validation of a novel protein biomarker panel for active pediatric lupus nephritis.

Lupus nephritis (LN) is among the main determinants of poor prognosis in systemic lupus erythematosus (SLE). The objective of this study was to 1) isolate and identify proteins contained in the LN urinary protein signature (PS) of children with SLE; 2) assess the usefulness of the PS proteins for detecting activity of LN over time. Using surface-enhanced or matrix-assisted laser desorption/ionization time of flight mass spectrometry, the proteins contained in the LN urinary PS were identified. They were transferrin (Tf), ceruloplasmin (Cp), α1-acid-glycoprotein (AGP), lipocalin-type prostaglandin-D synthetase (L-PGDS), albumin, and albumin-related fragments. Serial plasma and urine samples were analyzed using immunonephelometry or ELISA in 98 children with SLE (78% African American) and 30 controls with juvenile idiopathic arthritis. All urinary PS proteins were significantly higher with active vs. inactive LN or in patients without LN (all p < 0.005), and their combined area under the receiver operating characteristic curve was 0.85. As early as 3 mo before a clinical diagnosis of worsening LN, significant increases of urinary Tf, AGP (both p < 0.0001), and L-PGDS (p < 0.01) occurred, indicating that these PS proteins are biomarkers of LN activity and may help anticipate the future course of LN.

Long-term safety and efficacy of rilonacept in patients with systemic juvenile idiopathic arthritis.

OBJECTIVE To determine the long-term safety and efficacy of rilonacept, an anti-interleukin-1 fusion protein, in patients with active systemic juvenile idiopathic arthritis (JIA). METHODS In patients with systemic JIA, ages 4-20 years, the efficacy of rilonacept was evaluated using 30%, 50%, and 70% levels of improvement according to the adapted American College of Rheumatology (ACR) Pediatric 30, 50, and 70 response criteria, respectively. Efficacy and safety were evaluated during 23 months of open-label treatment (3 phases) after a 4-week, double-blind, placebo-controlled phase. Following double-blind treatment with 2.2 mg/kg or 4.4 mg/kg of rilonacept, patients were eligible to receive open-label treatment at their prior dose, with adjustments. Reductions in the median daily dose of oral prednisone and improvements in laboratory parameters of disease activity (i.e., decreased levels of D-dimer and myeloid-related proteins [MRPs]) were also evaluated. RESULTS Twenty-four patients entered the double-blind study and 23 entered the open-label period. Patients were predominantly white and female, and had a median age of 14.0 years at baseline. No significant differences in efficacy were observed between the rilonacept- and placebo-treated patients during the double-blind phase, but fever and rash completely resolved by month 3 in all patients during the open-label treatment period and did not recur. Adapted ACR Pediatric 30, 50, and 70 response rates at 3 months from the start of the study were 78.3%, 60.9%, and 34.8%, respectively; these responses were generally maintained over the study duration. Levels of D-dimer and MRP-8/MRP-14 dramatically improved during the study, and in 22 of 23 patients, the prednisone dose was decreased or prednisone therapy was discontinued. No serious treatment-related adverse events were observed. CONCLUSION Sustained improvements in clinical and laboratory measures of the articular and systemic manifestations of systemic JIA were achieved in >50% of rilonacept-treated patients over 2 years. Treatment with rilonacept had a substantial steroid-sparing effect and was generally well-tolerated.

Childhood Arthritis and Rheumatology Research Alliance consensus treatment plans for new-onset polyarticular juvenile idiopathic arthritis.

There is no standardized approach to the initial treatment of polyarticular juvenile idiopathic arthritis (JIA) among pediatric rheumatologists. Understanding the comparative effectiveness of the diverse therapeutic options available will result in better health outcomes for polyarticular JIA. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for use in clinical practice to facilitate such studies.

Pulmonary Hypertension and Other Potentially Fatal Pulmonary Complications in Systemic Juvenile Idiopathic Arthritis

Systemic juvenile idiopathic arthritis (JIA) is characterized by fevers, rash, and arthritis, for which interleukin‐1 (IL‐1) and IL‐6 inhibitors appear to be effective treatments. Pulmonary arterial hypertension (PAH), interstitial lung disease (ILD), and alveolar proteinosis (AP) have recently been reported with increased frequency in systemic JIA patients. Our aim was to characterize and compare systemic JIA patients with these complications to a larger cohort of systemic JIA patients.

Health-related Quality of Life and Its Relationship to Patient Disease Course in Childhood-onset Systemic Lupus Erythematosus

Objective. To (1) estimate the health-related quality of life (HRQOL) of children with childhood-onset systemic lupus erythematosus (cSLE) and compare it to that of normative cohorts; (2) assess the relationship of HRQOL with cSLE disease activity and damage; and (3) determine the effects of changes of disease activity on HRQOL. Methods. Patients with cSLE (n = 98) followed every 3 months completed HRQOL measures, the Pediatric Quality of Life Inventory Generic Core scale (PedsQL-GC), the Rheumatology Module (PedsQL-RM), and the Child Health Questionnaire (CHQ). The British Isles Lupus Activity Group Index (BILAG) was used to measure organ-system-specific disease activity. Physicians rated the course of cSLE between visits. Results. At baseline, mean (standard deviation, SD) score [parent report] of the PedsQL-GC and the PedsQL-RM was 75 (17) and 79 (14), respectively; the mean (SD) of the CHQ physical summary score (CHQ-PHS) was 49 (7) and that of the CHQ psychological summary score was 42 (12). Higher BILAG scores, especially in the general, musculoskeletal, neurological, and vascular, but not the mucocutaneous, renal, cardiovascular, or hematological BILAG domains, were associated with a significantly lower HRQOL. Patients with damage had lower HRQOL than those without damage. All HRQOL measures included were at most modestly responsive to clinically important changes with cSLE. Conclusion. HRQOL with cSLE is significantly lower than that reported in healthy populations. Organ-specific involvement with cSLE has a differential effect on HRQOL. Higher disease activity and damage are associated with significantly lower HRQOL as measured by the PedsQL-RM and the CHQ-PHS, and worsening of cSLE leads to a further decline.

Efficacy and safety of rituximab in pediatric neuromyelitis optica.

Neuromyelitis optica is a central nervous system disease characterized by optic neuritis and transverse myelitis. It is a devastating illness, and early treatment may prevent future relapses and severe disability. However, there is much variability in protocols used for treatment. In limited studies, rituximab has shown efficacy in adult neuromyelitis optica patients. There is a paucity of literature on the efficacy and tolerability of rituximab in the pediatric population. The authors report the use of rituximab in 2 pediatric patients with neuromyelitis optica, demonstrating its efficacy, dosing, and tolerability. This report may be a useful guide for administering rituximab safely in pediatric neuromyelitis optica patients.

Physical function assessment tools in pediatric rheumatology

Pediatric rheumatic diseases with predominant musculoskeletal involvement such as juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis(JDM) can cause considerable physical functional impairment and significantly affect the childrens quality of life (QOL). Physical function, QOL, health-related QOL (HRQOL) and health status are personal constructs used as outcomes to estimate the impact of these diseases and often used as proxies for each other. The chronic, fluctuating nature of these diseases differs within and between patients, and complicates the measurement of these outcomes. In children, their growing needs and expectations, limited use of age-specific questionnaires, and the use of proxy respondents further influences this evaluation. This article will briefly review the different constructs inclusive of and related to physical function, and the scales used for measuring them. An understanding of these instruments will enable assessment of functional outcome in clinical studies of children with rheumatic diseases, measure the impact of the disease and treatments on their lives, and guide us in formulating appropriate interventions.

Adding Canakinumab to the Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans for Systemic Juvenile Idiopathic Arthritis: Comment on the Article by DeWitt et al

The Childhood Arthritis and Rheumatology Research Alliance (CARRA) previously published an article in Arthritis Care & Research describing the consensus treatment plans (CTPs) for new-onset systemic juvenile idiopathic arthritis (JIA) (1). Since its publication, canakinumab, an interleukin-1 (IL-1) beta monoclonal antibody, was approved for use by US and European regulatory authorities following the publication of studies demonstrating its efficacy and safety in this disease (2). The CARRA systemic JIA workgroup had previously decided that new medications that become commonly available for this disease would be added to the CTPs. The CTPs are meant to be used when treating new-onset systemic JIA patients so that the comparative effectiveness of the CTPs can be studied through data entered into the CARRA registry. Once canakinumab became available for systemic JIA patients, the workgroup decided to revise the IL-1 inhibitor CTP to include this medication so that the patient may start either IL-1 inhibitor (anakinra or canakinumab) at any point during the course of the CTP (Figure 1). This revised IL-1 inhibitor CTP was then circulated via an electronic survey to all CARRA JIA Disease Committee members (n 188) to ensure acceptability. Of these members, 98 responded (52%), of whom 6 were not clinicians and were excluded. Of the remaining 92 members, 90 (98%) agreed with the IL-1 inhibitor CTP as presented and would use it when treating new-onset systemic JIA patients. We anticipate that this new IL-1 inhibitor CTP that allows the use of canakinumab or anakinra will be considered going forward by pediatric rheumatologists for new-onset systemic JIA patients when it is decided that an IL-1 inhibitor is indicated. A pilot study funded by the Arthritis Foundation is currently under way in a limited number of sites to assess the feasibility of using the systemic JIA CTPs in daily practice. In the future, we anticipate that, by widely disseminating the use of these CTPs to all CARRA sites and collecting the resulting data through the CARRA registry, their comparative effectiveness in patients with this disease will be able to be studied. Supported by the Childhood Arthritis and Rheumatology Research Alliance, the Arthritis Foundation, the Wasie Foundation, and Friends of the Childhood Arthritis and Rheumatology Re-