Objective

To formulate consensus treatment plans (CTPs) for induction therapy of newly-diagnosed proliferative lupus nephritis (LN) in juvenile systemic lupus erythematosus (jSLE).

Methods

A structured consensus formation process was employed by the members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) after considering the existing medical evidence and current treatment approaches.

Results

After an initial Delphi survey (response rate 70%), a 2-day consensus conference, and two follow-up Delphi surveys (response rates 63–79%), consensus was achieved for a limited set of CTPs addressing the induction therapy of proliferative LN. These CTPs were developed for prototypic patients defined by eligibility characteristics, and included immunosuppressive therapy with either mycophenolic acid orally twice per day, or intravenous cyclophosphamide once per month at standardized doses for six months. Additionally, the CTPs describe three options for standardized use of glucocorticoids; including a primarily oral, a mixed oral/intravenous, and a primarily intravenous regimen. There was consensus on measures of effectiveness and safety of the CTPs. The CTPs were well accepted by the pediatric rheumatology providers treating children with LN, and up to 300 children per year in North America are expected to be candidates for the treatment with the CTPs.

Conclusion

CTPs for induction therapy of proliferative LN in jSLE based on the available scientific evidence and pediatric rheumatology group experience have been developed. Consistent use of the CTPs may improve the prognosis of proliferative LN, and support the conduct of comparative effectiveness studies aimed at optimizing therapeutic strategies for proliferative LN in jSLE.

Objectives

To develop widely acceptable preliminary criteria of global flare for childhood-onset SLE (cSLE).

Methods

Pediatric rheumatologists (n=138) rated a total of 358 unique patient profiles (PP) with information about the cSLE flare descriptors (cSLE-FD) from two consecutive visits: patient global assessment of well-being, physician global assessment of disease activity (MD-global), health-related quality of life, anti-dsDNA antibodies, disease activity index score, protein/creatinine (P/C) ratio, complement levels and ESR. Based on 2996 rater responses about the course of cSLE (baseline vs. follow-up) the accuracy (sensitivity, specificity, area under the receiver operating characteristic curve) of candidate flare criteria was assessed. An international consensus conference was held to rank these candidate flare criteria as per the ACR-recommendations for the development and validation of criteria sets.

Results

The highest ranked candidate criteria considered absolute changes (Δ) of the SLEDAI or BILAG, MD-global, P/C ratio, and ESR; Flare scores can be calculated [0.5 × ΔSLEDAI + 0.45 × ΔP/C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR], where values ≥ 1.04 are reflective of a flare. Similarly, BILAG-based flare scores [0.4 × ΔBILAG + 0.65 × ΔP/C ratio + 0.5 × ΔMD-global + 0.02 × ΔESR] of ≥ 1.15 were diagnostic of a flare. Flare scores increase with flare severity.

Conclusions

Consensus has been reached on preliminary criteria for global flares in cSLE. Further validation studies are needed to confirm the usefulness of the cSLE flare criteria in research and for clinical care.

Background

Mycophenolic acid (MPA) is the active form of mycophenolate mofetil (MMF) which is currently used off-label as immunosuppressive therapy in childhood-onset SLE (cSLE). The objectives of this study were to (1) characterize the pharmacokinetics (MPA-PK) and pharmacodynamics (MPA-PD) of MPA and (2) explore the relationship between MPA-PK and cSLE disease activity.

Methods

MPA-PK [area under the curve from 0 to 12 hours (AUC0-12)] and MPA-PD [inosine-monophosphate dehydrogenase (IMPDH) activity] were evaluated in cSLE patients on stable MMF dosing. Change in SLE disease activity while on MMF therapy was measured using the British Isles Lupus Activity Group (BILAG) index.

Results

A total of 19 AUC0-12 and 10 IMPDH activity profiles were included in the analysis. Large inter-patient variability in MPA exposure (AUC0-12) was observed (mean ± SE: 32 ± 4.2 mg*h/L; coefficient of variation: 57%). Maximum MPA serum concentrations coincided with maximum IMPDH inhibition. AUC0-12 and weight-adjusted MMF dosing were only moderately correlated (r= 0.56, p=0.01). An AUC0-12 of ≥ 30 mg*h/L was associated with decreased BILAG scores while on MMF therapy (p= 0.002).

Conclusion

Weight-adjusted MMF dosing alone does not reliably allow for the prediction of exposure to biologically active MPA in cSLE. Individualized dosing considering MPA-PK appears warranted as this allows for better estimation of immunological suppression (IMPDH activity). Additional controlled studies are necessary to confirm that an MPA AUC0-12 of at least 30 mg*h/L is required for cSLE improvement.

The objective of this study was to retrospectively evaluate the utility of serum neopterin as a diagnostic marker of hemophagocytic lymphohistiocytosis (HLH). The medical records of patients diagnosed with HLH (familial and secondary) between January 2000 and May 2009 were reviewed retrospectively, and clinical and laboratory information related to HLH criteria, in addition to neopterin levels, was recorded. A group of 50 patients with active juvenile dermatomyositis (JDM) (who routinely have neopterin levels assessed) served as controls for the assessment of the accuracy, sensitivity, and specificity of neopterin as a diagnostic test for HLH. The Pearson correlation was used to measure the association between serum neopterin levels and established HLH-related laboratory data. Serum neopterin levels were measured using a competitive enzyme immunoassay. During the time frame of the study, 3 patients with familial HLH and 18 patients with secondary HLH were identified as having had serum neopterin measured (all HLH patients were grouped together). The mean neopterin levels were 84.9 nmol/liter (standard deviation [SD], 83.4 nmol/liter) for patients with HLH and 21.5 nmol/liter (SD, 10.13 nmol/liter) for patients with JDM. A cutoff value of 38.9 nmol/liter was 70% sensitive and 95% specific for HLH. For HLH patients, neopterin levels correlated significantly with ferritin levels (r = 0.76, P = 0.0007). In comparison to the level in a control group of JDM patients, elevated serum neopterin was a sensitive and specific marker for HLH. Serum neopterin has value as a diagnostic marker of HLH, and prospective studies are under way to further evaluate its role as a marker for early diagnosis and management of patients.

Objective

To determine the minimal clinically important differences (MCID) of validated measures of SLE disease activity in childhood-onset systemic lupus erythematosus (cSLE).

Methods

cSLE patients (n=98) were followed every 3 months for up to 7 visits (total number of visits 623). Disease activity measures (ECLAM, SLEDAI, SLAM, BILAG, RIFLE) were completed at the time of each visit. Physician-rated changes in the disease course (clinically relevant improvement, no change, clinically relevant worsening) between visits served as the criterion standard.

Results

MCID defined by mean change scores with improvement and worsening, or those based on the standard error of measurement with stable disease were both small and did not discriminate well between disease courses (detection rates for improvement or worsening were all < 55%). MCID based on discriminant and classification analyses yielded similar results. Alternative MCID, defined by a 70% predicted probability of improvement or worsening as per discrimination analysis, were larger but underestimated the proportion of patients with change. The RIFLE only correctly identified 26% and 8% episodes of clinically important worsening and improvement of cSLE, respectively.

Conclusions

The MCID of cSLE disease activity measures are often small but similar to those reported for adults with SLE. Thus even small changes in disease activity scores can be clinically relevant. Low correct detection rates of these MCID thresholds for changes in disease course support the notion that worsening and improvement with cSLE, or its response to therapy, is unlikely to be captured adequately by validated measures of disease activity alone.

Objectives

To develop and propose a standardized battery of neuropsychological tests for the assessment of cognitive functioning of children and adolescents with pediatric systemic lupus erythematosus (pSLE).

Methods

A committee of health care professionals involved in the assessment of pSLE patients reviewed the literature to identify cognitive domains most commonly affected in pSLE and in adult SLE. They then reviewed the standardized tests available for children and adolescents that assess the cognitive domains identified. Through a structured consensus formation process the committee considered psychometric characteristics and duration of the tests.

Results

A test battery was developed that appears suitable to provide a comprehensive assessment of cognitive domains commonly affected by pSLE with a 2.5 hour period.

Conclusion

It is hoped that the consistent use of this reliable and efficient battery increases the practicality of routine evaluations in pSLE, enabling between cohort comparisons and facilitating the longitudinal assessment of individual patients over time.

Objective

To develop a definition of global flare in jSLE and derive candidate criteria for measuring jSLE flares.

Methods

Pediatric rheumatologists answered two Delphi questionnaires to achieve consensus on a common definition of jSLE flare and identify variables for use in candidate flare criteria. The diagnostic accuracy of these candidate flare criteria was tested with data from jSLE patients (n=98; 623 visits total). Physician-rated change in the jSLE course (worsening yes/no) between visits served as the criterion standard.

Results

There was 96% consensus that a “a flare is a measurable worsening of jSLE disease activity in at least one organ system, involving new or worse signs of disease that may be accompanied by new or worse SLE symptoms. Depending on the severity of the flare, more intensive therapy may be required”. Variables suggested for use in flare criteria were: physician-rated disease activity (V1), patient well-being, protein:creatinine ratio, validated disease activity index (V2), Child Health Questionnaire physical summary score (V3), anti-dsDNA antibodies, ESR, and complement levels. Using multiple logistic regression, several candidate flare criteria were derived with area under the receiver operating characteristic curve (AUC) as high as 0.92 (sensitivity≥ 85%; specificity≥ 85%); CART analysis suggested that V1, V2 and V3 suffice to identify jSLE flares (AUC = 0.81; sensitivity = 64%; specificity = 86%).

Conclusions

Consensus about a definition of global disease flare with jSLE has been obtained and promising candidate flare criteria have been developed. These will need further assessment of their ease-of-use and accuracy in prospective study.

Objective

Although electronic medical records (EMRs) have facilitated care for children with juvenile idiopathic arthritis (JIA), analyses of treatment outcomes have required paper based or manually re-entered data. We have started EMR discrete data entry for JIA patient visits, including joint examination and global assessment, by physician and patient. In this preliminary study, we extracted data from the EMR to Xenobase™ (TransMed Systems, Inc., Cupertino, CA), an application permitting cohort analyses of the relationship between global assessment to joint examination and subtype.

Methods

During clinic visits, data were entered into discrete fields in ambulatory visit forms in the EMR (EpicCare™, Epic Systems, Verona, WI). Data were extracted using Clarity Reports, then de-identified and uploaded for analyses to Xenobase™. Parameters included joint examination, ILAR diagnostic classification, physician global assessment, patient global assessment, and patient pain score. Data for a single visit for each of 160 patients over a 2 month period, beginning March, 2010, were analyzed.

Results

In systemic JIA patients, strong correlations for physician global assessment were found with pain score, joint count and patient assessment. In contrast, physician assessment for patients with persistent oligoarticular and rheumatoid factor negative patients showed strong correlation with joint counts, but only moderate correlation with pain scores and patient global assessment. Conversely, for enthesitis patients, physician assessment correlated strongly with pain scores, and moderately with joint count and patient global assessment. Rheumatoid factor positive patients, the smallest group studied, showed moderate correlation for all three measures. Patient global assessment for systemic patients showed strong correlations with pain scores and joint count, similar to data for physician assessment. For polyarticular and enthesitis patients, correlation of patient global assessment with pain scores was strong. Moderate correlations were found between patient global assessment and joint count in oligoarticular and polyarticular patients.

Conclusion

Data extraction from the EMR is feasible and useful to evaluate JIA patients for indicators of treatment responsiveness. In this pilot study, we found correlates for physician global assessment of arthritis differed, according to disease subtype. Further data extraction and analyses will determine if these findings can be confirmed, and will assess other outcome measures, compare longitudinal responses to treatment, and export extracted data to multi-center databases.

Objective

The goal of the study was to determine the predictive validity of neutrophil gelatinase-associated lipocalin (NGAL) in anticipating worsening of global and renal childhood-onset SLE (cSLE) disease activity.

Methods

111 patients with cSLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least three study visits. At each visit global disease activity was measured using three external standards: numerically converted BILAG index, SLEDAI-2K and physician assessment score. Renal and extrarenal disease activity were measured by the respective domain scores. The disease course over time was categorized at the most recent visit (persistently active, persistently inactive, improved or worsening). Plasma and urinary NGAL levels were measured by ELISA, and urinary NGAL was standardized to urinary creatinine. The longitudinal changes in NGAL levels were compared to the changes in SLE disease activity using mixed effects models.

Results

Significant increases in standardized urinary NGAL levels of up to 104% were detected up to three months before worsening of lupus nephritis (as measured by all three external standards). Plasma NGAL levels increased significantly by as much as 20% up to three months before worsening of global SLE disease activity as measured by all three external standards. Plasma NGAL levels increased significantly by 26% as early as three months prior to worsening of lupus nephritis as measured by the renal BILAG domain score.

Conclusion

Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal cSLE disease activity.

Objective

To prospectively validate the provisional criteria for the evaluation of response to therapy in children with systemic lupus erythematosus (cSLE).

Methods

In this multi-center study cSLE patients (n=98; F: M = 81:17; 50% white; 88% non-Hispanic) were followed every 3 months for up to 7 visits (total number of visits 623). The five cSLE core response variables were obtained at the time of each visit: (1) physician assessment of overall disease activity; (2) parent assessment of patient well-being; (3) Child Health Questionnaire; (4) proteinuria; and (5) global disease activity measure score as measured by the ECLAM, SLEDAI, or SLAM. Physician-rated relevant changes in the disease course (clinically relevant improvement; no change in disease, or worsening) between visits served as the criterion standard. Mixed models were used to assess the diagnostic accuracy of the four highest-ranked provisional definitions of response to therapy.

Results

There were 89 episodes of clinically relevant improvement between two consecutive visits, and 448 episodes without improvement. Irrespective of the choice of the global disease activity measure (ECLAM, SLAM, SLEDAI), sensitivities of all four highest-ranked definitions were low (all ≤ 31%), while their specificities were excellent (all > 88%). Using logistic models, alternative definitions can be developed with both 80% sensitivity and specificity.

Conclusions

The provisional criteria of response to therapy in cSLE may have considerably lower sensitivity than previously reported. Additional validation in clinical trials is necessary to further evaluate the measurement properties of the provisional PRINTO/ACR Criteria for Response to Therapy in cSLE.

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 versus 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 months 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.

Objective

Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disorder with complex etiology and a strong genetic component. Recently, gene products involved in the interferon pathway have been under intense investigation in SLE pathogenesis. STAT1 and STAT4 are transcription factors that play key roles in the interferon and Th1 signaling pathways, making them attractive candidates for SLE susceptibility.

Methods

Fifty-six single-nucleotide polymorphisms (SNPs) across STAT1 and STAT4 genes on chromosome 2 were genotyped using Illumina platform as a part of extensive association study in a large collection of 9923 lupus cases and controls from different racial groups. DNA from patients and controls was obtained from peripheral blood. Principal component analyses and population based case-control association analyses were performed and the p values, FDR q values and Odds ratios with 95% confidence intervals (95% CIs) were calculated.

Results

We observed strong genetic associations with SLE and multiple SNPs located within the STAT4 gene in different ethnicities (Fisher combined p= 7.02×10−25). In addition to strong confirmation of the association in the 3rd intronic region of this gene reported previously, we identified additional haplotypic association across STAT4 gene and in particular a common risk haplotype that is found in multiple racial groups. In contrast, only a relatively weak suggestive association was observed with STAT1, probably due to the proximity to STAT4.

Conclusion

Our findings indicate that the STAT4 gene is likely to be a crucial component in SLE pathogenesis among multiple racial groups. The functional effects of this association, when revealed, might improve our understanding of the disease and provide new therapeutic targets.