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Claas H Hinze,
Michiko Suzuki,
Marisa Klein-Gitelman,
Murray H Passo, Judyann Olson,
Nora G Singer,
Kathleen A Haines,
Karen Onel,
Kathleen O'Neil,
Earl D Silverman,
Lori Tucker,
Jun Ying,
Prasad Devarajan,
Hermine I Brunner
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ABSTRACT: To determine whether neutrophil gelatinase-associated lipocalin (NGAL) can predict worsening of global and renal disease activity in childhood-onset systemic lupus erythematosus (SLE).
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 physician's 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.
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.
Serial measurement of urinary and plasma NGAL levels may be valuable in predicting impending worsening of global and renal childhood-onset SLE disease activity.
Arthritis & Rheumatism 09/2009; 60(9):2772-81. · 7.87 Impact Factor
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Michiko Suzuki,
Kristina Wiers,
Elizabeth B Brooks,
Kenneth D Greis,
Kathleen Haines,
Marisa S Klein-Gitelman, Judyann Olson,
Karen Onel,
Kathleen M O'Neil,
Earl D Silverman,
Lori Tucker,
Jun Ying,
Prasad Devarajan,
Hermine I Brunner
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ABSTRACT: 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), alpha1-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.
Pediatric Research 02/2009; 65(5):530-6. · 2.70 Impact Factor
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Michiko Suzuki,
Kristina M Wiers,
Marisa S Klein-Gitelman,
Kathleen A Haines, Judyann Olson,
Karen B Onel,
Kathleen O'Neil,
Murray H Passo,
Nora G Singer,
Lori Tucker,
Jun Ying,
Prasad Devarajan,
Hermine I Brunner
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ABSTRACT: 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.
Pediatric Nephrology 04/2008; 23(3):403-12. · 2.52 Impact Factor
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Ndate Fall,
Michael Barnes,
Sherry Thornton,
Lorie Luyrink, Judyann Olson,
Norman T Ilowite,
Beth S Gottlieb,
Thomas Griffin,
David D Sherry,
Susan Thompson,
David N Glass,
Robert A Colbert,
Alexei A Grom
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ABSTRACT: Systemic juvenile idiopathic arthritis (JIA) is frequently associated with the development of macrophage activation syndrome. This study was undertaken to better understand the relationship between systemic JIA and macrophage activation syndrome.
Gene expression profiles were examined in 17 patients with untreated new-onset systemic JIA, 5 of whom showed evidence of subclinical macrophage activation syndrome (of whom 2 eventually developed overt macrophage activation syndrome). Peripheral blood mononuclear cells (PBMCs) were separated on Ficoll gradients, and purified RNA was analyzed using Affymetrix GeneChip expression arrays. A fraction of the PBMCs were used for flow cytometry to define the cellular composition of the samples.
Two hundred twenty-five differentially expressed genes (P < 0.05) that distinguished patients with systemic JIA from healthy controls (n = 30) were identified. Clustering analysis indicated that expression patterns correlated with serum ferritin levels. Three main clusters distinguished systemic JIA patients with highly elevated ferritin levels (including those with subclinical macrophage activation syndrome) from those with normal or only moderately elevated ferritin levels. The first cluster comprised genes involved in the synthesis of hemoglobins and structural proteins of erythrocytes. This transcriptional profile was consistent with immature nucleated red blood cells, likely reflective of high red blood cell turnover. Also included were transcripts indicating immature granulocytes. The second cluster was enriched for genes involved in cell cycle regulation. The third cluster was enriched for genes involved in innate immune responses, including those involved in the negative regulation of Toll-like receptor/interleukin-1 receptor-triggered inflammatory cascades and markers of the alternative pathway of macrophage differentiation. Additional differentially expressed genes of interest were those involved in the cytolytic pathway, including SH2D1A and Rab27a.
These data indicate that gene expression profiling can be a useful tool for identifying early macrophage activation syndrome in patients with systemic JIA.
Arthritis & Rheumatism 11/2007; 56(11):3793-804. · 7.87 Impact Factor
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Jack Bleesing,
Anne Prada,
David M Siegel,
Joyce Villanueva, Judyann Olson,
Norman T Ilowite,
Hermine I Brunner,
Thomas Griffin,
Thomas B Graham,
David D Sherry,
Murray H Passo,
Athimalaipet V Ramanan,
Alexandra Filipovich,
Alexei A Grom
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ABSTRACT: Macrophage activation syndrome is characterized by an overwhelming inflammatory reaction driven by excessive expansion of T cells and hemophagocytic macrophages. Levels of soluble interleukin-2 receptor alpha (sIL-2Ralpha) and soluble CD163 (sCD163) may reflect the degree of activation and expansion of T cells and macrophages, respectively. This study was undertaken to assess the value of serum sIL-2Ralpha and sCD163 in diagnosing acute macrophage activation syndrome complicating systemic juvenile idiopathic arthritis (JIA).
Enzyme-linked immunosorbent assay was used to assess sIL-2Ralpha and sCD163 levels in sera from 7 patients with acute macrophage activation syndrome complicating systemic JIA and 16 patients with untreated new-onset systemic JIA. The results were correlated with clinical features of established macrophage activation syndrome, including ferritin levels.
The median level of sIL-2Ralpha in the patients with macrophage activation syndrome was 19,646 pg/ml (interquartile range [IQR] 18,128), compared with 3,787 pg/ml (IQR 3,762) in patients with systemic JIA (P = 0.003). Similarly, the median level of sCD163 in patients with macrophage activation syndrome was 23,000 ng/ml (IQR 14,191), compared with 5,480 ng/ml (IQR 2,635) in patients with systemic JIA (P = 0.017). In 5 of 16 patients with systemic JIA, serum levels of sIL-2Ralpha or sCD163 were comparable with those in patients with acute macrophage activation syndrome. These patients had high inflammatory activity associated with a trend toward lower hemoglobin levels (P = 0.11), lower platelet counts, and significantly higher ferritin levels (P = 0.02). Two of these 5 patients developed overt macrophage activation syndrome several months later.
Levels of sIL-2Ralpha and sCD163 are promising diagnostic markers for macrophage activation syndrome. They may also help identify patients with subclinical macrophage activation syndrome.
Arthritis & Rheumatism 04/2007; 56(3):965-71. · 7.87 Impact Factor
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ABSTRACT: Two children with chronic and asymmetric skin indurations are presented. The clinical and pathologic features are suggestive of asymmetric childhood scleredema and stiff skin syndrome. The key features of scleredema and stiff skin syndrome are discussed.
Pediatric Dermatology 20(4):350-5. · 1.07 Impact Factor
