Kathleen M. O'Neil

Neutrophil gelatinase–associated lipocalin is a predictor of the course of global and renal childhood‐onset systemic lupus erythematosus disease activity

OBJECTIVE To determine whether neutrophil gelatinase-associated lipocalin (NGAL) can predict worsening of global and renal disease activity in childhood-onset systemic lupus erythematosus (SLE). METHODS One hundred eleven patients with childhood-onset SLE were enrolled in a longitudinal, prospective study with quarterly study visits and had at least 3 study visits. At each visit, global disease activity was measured using 3 external standards: the numerically converted British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index 2000 update score, and the physicians assessment of global disease activity. 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 enzyme-linked immunosorbent assay, and urinary NGAL levels were standardized to the urinary creatinine concentration. The longitudinal changes in NGAL levels were compared with the changes in SLE disease activity using mixed-effect models. RESULTS Significant increases in standardized urinary NGAL levels of up to 104% were detected up to 3 months before worsening of lupus nephritis (as measured by all 3 external standards). Plasma NGAL levels increased significantly by as much as 26% up to 3 months before worsening of global SLE disease activity as measured by all 3 external standards. Plasma NGAL levels increased significantly by 26% as early as 3 months prior to worsening of lupus nephritis as measured by the BILAG renal score. CONCLUSION Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal childhood-onset SLE disease activity.

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.

EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I: Overall methodology and clinical characterisation

Objectives To report methodology and overall clinical, laboratory and radiographic characteristics for Henoch–Schönlein purpura (HSP), childhood polyarteritis nodosa (c-PAN), c-Wegener granulomatosis (c-WG) and c-Takayasu arteritis (c-TA) classification criteria. Methods The preliminary Vienna 2005 consensus conference, which proposed preliminary criteria for paediatric vasculitides, was followed by a EULAR/PRINTO/PRES - supported validation project divided into three main steps. Step 1: retrospective/prospective web-data collection for HSP, c-PAN, c-WG and c-TA, with age at diagnosis ≤18 years. Step 2: blinded classification by consensus panel of a subgroup of 280 cases (128 difficult cases, 152 randomly selected) enabling expert diagnostic verification. Step 3: Ankara 2008 Consensus Conference and statistical evaluation (sensitivity, specificity, area under the curve, κ-agreement) using as ‘gold standard’ the final consensus classification or original treating physician diagnosis. Results A total of 1183/1398 (85%) samples collected were available for analysis: 827 HSP, 150 c-PAN, 60 c-WG, 87 c-TA and 59 c-other. Prevalence, signs/symptoms, laboratory, biopsy and imaging reports were consistent with the clinical picture of the four c-vasculitides. A representative subgroup of 280 patients was blinded to the treating physician diagnosis and classified by a consensus panel, with a κ-agreement of 0.96 for HSP (95% CI 0.84 to 1), 0.88 for c-WG (95% CI 0.76 to 0.99), 0.84 for c-TA (95% CI 0.73 to 0.96) and 0.73 for c-PAN (95% CI 0.62 to 0.84), with an overall κ of 0.79 (95% CI 0.73 to 0.84). Conclusion EULAR/PRINTO/PRES propose validated classification criteria for HSP, c-PAN, c-WG and c-TA, with substantial/almost perfect agreement with the final consensus classification or original treating physician diagnosis.

The Localized Scleroderma Skin Severity Index and Physician Global Assessment of Disease Activity: A Work in Progress Toward Development of Localized Scleroderma Outcome Measures

Objective. To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments’ clinimetric property and effect on quality of life (QOL). Methods. A 3-phase study was conducted. The first phase involved 15 patients with LS and 14 examiners who assessed LoSSI [surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E)] twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children’s Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined. Results. Interrater reliability was excellent for ER [intraclass correlation coefficient (ICC) 0.71], ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners’ experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman’s rho = 0.71–0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy. Conclusion. mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.

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.

Development of consensus treatment plans for juvenile localized scleroderma: A roadmap toward comparative effectiveness studies in juvenile localized scleroderma

Juvenile localized scleroderma (LS) is a chronic inflammatory skin disorder associated with substantial morbidity and disability. Although a wide range of therapeutic strategies has been reported in the literature, a lack of agreement on treatment specifics and accepted methods for clinical assessment has made it difficult to compare approaches and identify optimal therapy. Our objective was to develop standardized treatment plans, clinical assessments, and response criteria for active, moderate to high severity juvenile LS.

Randomized, Double-Blind, Placebo-Controlled Trial of the Efficacy and Safety of Rilonacept in the Treatment of Systemic Juvenile Idiopathic Arthritis

To assess the efficacy and safety of rilonacept, an interleukin‐1 inhibitor, in a randomized, double‐blind, placebo‐controlled trial.

Treatment of pediatric localized scleroderma: results of a survey of North American pediatric rheumatologists.

Objective. We surveyed pediatric rheumatologists (PR) in North America to learn how they treat pediatric localized scleroderma (LS), a disease associated with significant morbidity for the growing child. Methods. A Web-based survey was sent to the 195 PR members of the pediatric rheumatology research alliance CARRA (Childhood Arthritis and Rheumatology Research Alliance). Members were asked which medications they use to treat LS and which factors modify their treatment strategies. Clinical vignettes were provided to learn the specific treatment regimens used. Results. A total of 158 PR from over 70 clinical centers in the United States and Canada participated in the survey, representing 81% of the CARRA membership. These PR saw over 650 patients with LS in the prior year. Nearly all respondents treated LS with methotrexate (MTX) and corticosteroids; most of them intensify treatment for lesions located on the face or near a joint, and about half intensify treatment for recent disease onset (< 6 months). Most PR reserve topical medications for limited treatment situations. Clinical vignettes showed that PR use a broad range of treatment doses and durations for MTX and corticosteroids. Conclusion. Most PR in North America treat localized scleroderma with a combination of MTX and corticosteroids. However, there is no consensus on specific treatment regimens. There is a need for controlled treatment trials to better determine optimal therapy for this potentially disabling disease.

Gene Expression Profiling in Neutrophils From Children With Polyarticular Juvenile Idiopathic Arthritis

OBJECTIVE We have previously reported a defect in neutrophil activation in children with polyarticular juvenile idiopathic arthritis (JIA). The current study was undertaken to determine whether gene expression abnormalities persist in JIA in remission and to use systems biology analysis to elucidate pathologic pathways in polyarticular JIA. METHODS We performed gene expression profiling on neutrophils from children with polyarticular JIA. Children were grouped according to disease status. We studied 14 children with active disease who were taking medication, 8 children with clinical remission of disease who were taking medication (CRM status), and 6 children with clinical remission of disease who were not taking medication (CR status). We also studied 13 healthy children whose age ranges overlapped those of the patients. RESULTS Neutrophil abnormalities persisted in children with polyarticular JIA even after disease remission was achieved. Children with active disease and those with CRM status showed no differences in expression of specific genes, although they could be separated on cluster analysis. A comparison of children with CR status and healthy control children revealed networks of pro- and antiinflammatory genes that suggested that remission is a state of homeostasis and balance rather than a return to normal immune function. Furthermore, gene overexpression in patients with CR status supports the hypothesis that neutrophils play a role in regulating adaptive immunity in this disease. CONCLUSION Neutrophil gene profiling in polyarticular JIA suggests important roles for neutrophils in disease pathogenesis. These findings suggest the presence of complex interactions between innate and adaptive immunity, that are not easily modeled in conventional, linear, reductionist systems.

Clinically Inactive Disease in a Cohort of Children with New-onset Polyarticular Juvenile Idiopathic Arthritis Treated with Early Aggressive Therapy: Time to Achievement, Total Duration, and Predictors

Objective. To determine the elapsed time while receiving aggressive therapy to the first observation of clinically inactive disease (CID), total duration of CID and potential predictors of this response in a cohort of children with recent onset of polyarticular juvenile idiopathic arthritis (poly-JIA). Methods. Eighty-five children were randomized blindly to methotrexate (MTX), etanercept, and rapidly tapered prednisolone (MEP) or MTX monotherapy and assessed for CID over 1 year of treatment. Patients who failed to achieve intermediary endpoints were switched to open-label MEP treatment. Results. Fifty-eight (68.2%) of the 85 patients achieved CID at 1 or more visits including 18 who received blinded MEP, 11 while receiving MTX monotherapy, and 29 while receiving open-label MEP. Patients starting on MEP achieved CID earlier and had more study days in CID compared to those starting MTX, but the differences were not significantly different. Patients given MEP (more aggressive therapy) earlier in the disease course were statistically more likely to have a higher proportion of followup visits in CID than those with longer disease course at baseline. Those who achieved American College of Rheumatology Pediatric 70 response at 4 months had a significantly greater proportion of followup visits in CID, compared to those who failed to achieve this improvement (p < 0.0001). Of the 32 patients who met criteria for CID and then lost CID status, only 3 fulfilled the definition of disease flare. Conclusion. Shorter disease duration prior to treatment, a robust response at 4 months, and more aggressive therapy result in a higher likelihood and longer duration of CID in patients with poly-JIA. The original trial from which data for this analysis were obtained is registered on www.clinicaltrials.gov NCT 00443430.