7 results on '"Sundel Robert P"'
Search Results
2. A multidisciplinary assessment of pain in juvenile idiopathic arthritis.
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Upadhyay, Jaymin, Lemme, Jordan, Cay, Mariesa, Van Der Heijden, Hanne, Sibai, Diana, Goodlett, Benjamin, Lo, Jeffery, Hoyt, Kacie, Taylor, Maria, Hazen, Melissa M., Halyabar, Olha, Meidan, Esra, Schreiber, Rudy, Chang, Margaret H., Nigrovic, Peter A., Jaimes, Camilo, Henderson, Lauren A., Ecklund, Kirsten, and Sundel, Robert P. more...
- Abstract
• Pain may adversely impact physical and cognitive health in JIA patients. • Pain may persist independent of inflammatory or treatment status. • Structural & functional CNS properties in regions such as the anterior insula suggest neurological correlates of JIA pain. • Altered CNS properties potentially underlie the dissociation between perceived pain and detectable joint pathology in JIA. Pain is prevalent in juvenile idiopathic arthritis (JIA). Unknowns regarding the biological drivers of pain complicate therapeutic targeting. We employed neuroimaging to define pain-related neurobiological features altered in JIA. 16 male and female JIA patients (12.7 ± 2.8 years of age) on active treatment were enrolled, together with age- and sex-matched controls. Patients were assessed using physical examination, clinical questionnaires, musculoskeletal MRI, and structural neuroimaging. In addition, functional magnetic resonance imaging (fMRI) data were collected during the resting-state, hand-motor task performance, and cold stimulation of the hand and knee. Patients with and without pain and with and without inflammation (joint and systemic) were evaluated. Pain severity was associated with more physical stress and poorer cognitive function. Corrected for multiple comparisons, morphological analysis revealed decreased cortical thickness within the insula cortex and a negative correlation between caudate nucleus volume and pain severity. Functional neuroimaging findings suggested alteration within neurocircuitry structures regulating emotional pain processing (anterior insula) in addition to the default-mode and sensorimotor networks. Patients with JIA may exhibit changes in neurobiological circuits related to pain. These preliminary findings suggest mechanisms by which pain could potentially become dissociated from detectable joint pathology and persist independently of inflammation or treatment status. [ABSTRACT FROM AUTHOR] more...
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- 2021
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3. Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis.
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Lee, Pui Y., Schulert, Grant S., Canna, Scott W., Yuelong Huang, Sundel, Jacob, Ying Li, Hoyt, Kacie J., Blaustein, Rachel B., Wactor, Alexandra, Thuy Do, Halyabar, Olha, Chang, Margaret H., Dedeoglu, Fatma, Case, Siobhan M., Meidan, Esra, Lo, Mindy S., Sundel, Robert P., Richardson, Edward T., Newburger, Jane W., and Hershfield, Michael S. more...
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CYTOKINES ,C-reactive protein ,REFERENCE values ,INTERLEUKINS ,MACROPHAGE activation syndrome ,DERMATOMYOSITIS ,GROWTH factors ,FERRITIN ,JUVENILE idiopathic arthritis ,HYDROLASES ,BLOOD sedimentation ,RESEARCH funding ,MUCOCUTANEOUS lymph node syndrome ,SYSTEMIC lupus erythematosus ,DISEASE complications - Abstract
Objective: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS.Methods: We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis.Results: ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes.Conclusions: These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition. [ABSTRACT FROM AUTHOR] more...- Published
- 2020
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4. Next-Generation Sequencing Reveals Restriction and Clonotypic Expansion of Treg Cells in Juvenile Idiopathic Arthritis.
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Henderson, Lauren A., Volpi, Stefano, Frugoni, Francesco, Janssen, Erin, Kim, Susan, Sundel, Robert P., Dedeoglu, Fatma, Lo, Mindy S., Hazen, Melissa M., Beth Son, Mary, Mathieu, Ronald, Zurakowski, David, Yu, Neng, Lebedeva, Tatiana, Fuhlbrigge, Robert C., Walter, Jolan E., Nee Lee, Yu, Nigrovic, Peter A., and Notarangelo, Luigi D. more...
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ANALYSIS of variance ,BIOLOGICAL models ,CELL physiology ,CELL receptors ,GENES ,JUVENILE idiopathic arthritis ,RHEUMATOLOGY ,T cells ,CD4 antigen ,DATA analysis ,CROSS-sectional method ,SEQUENCE analysis ,DIAGNOSIS - Abstract
Objective Treg cell-mediated suppression of Teff cells is impaired in juvenile idiopathic arthritis (JIA); however, the basis for this dysfunction is incompletely understood. Animal models of autoimmunity and immunodeficiency demonstrate that a diverse Treg cell repertoire is essential to maintain Treg cell function. The present study was undertaken to investigate the Treg and Teff cell repertoires in JIA. Methods Treg cells (CD4+CD25+CD127
low ) and Teff cells (CD4+CD25−) were isolated from peripheral blood and synovial fluid obtained from JIA patients, healthy controls, and children with Lyme arthritis. Treg cell function was measured in suppressive assays. The T cell receptor β chain ( TRB) was amplified by multiplex polymerase chain reaction and next-generation sequencing was performed, with amplicons sequenced using an Illumina HiSeq platform. Data were analyzed using ImmunoSEQ, International ImMunoGeneTics system, and the Immunoglobulin Analysis Tools. Results Compared to findings in controls, the JIA peripheral blood Treg cell repertoire was restricted, and clonotypic expansions were found in both blood and synovial fluid Treg cells. Skewed usage and pairing of TRB variable and joining genes, including overuse of gene segments that have been associated with other autoimmune conditions, was observed. JIA patients shared a substantial portion of synovial fluid Treg cell clonotypes that were private to JIA and not identified in Lyme arthritis. Conclusion We identified restriction and clonotypic expansions in the JIA Treg cell repertoire with sharing of Treg cell clonotypes across patients. These findings suggest that abnormalities in the Treg cell repertoire, possibly engendered by shared antigenic triggers, may contribute to disease pathogenesis in JIA. [ABSTRACT FROM AUTHOR] more...- Published
- 2016
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5. Multiple juvenile idiopathic arthritis subtypes demonstrate proinflammatory IgG glycosylation.
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Ercan, Altan, Barnes, Michael G., Hazen, Melissa, Tory, Heather, Henderson, Lauren, Dedeoglu, Fatma, Fuhlbrigge, Robert C., Grom, Alexei, Holm, Ingrid A., Kellogg, Mark, Kim, Susan, Adamczyk, Barbara, Rudd, Pauline M., Son, Mary Beth, Sundel, Robert P., Foell, Dirk, Glass, David N., Thompson, Susan D., and Nigrovic, Peter A. more...
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AGE distribution ,ENZYME-linked immunosorbent assay ,GLYCOSYLATION ,HIGH performance liquid chromatography ,IMMUNOGLOBULINS ,INFLAMMATION ,MEDICAL cooperation ,REGRESSION analysis ,RESEARCH ,RESEARCH funding ,JUVENILE idiopathic arthritis ,STATISTICS ,T-test (Statistics) ,DATA analysis ,EQUIPMENT & supplies - Abstract
Objective Rheumatoid arthritis is associated with an excess of agalactosylated (G0) IgG that is considered relatively proinflammatory. Assessment of this association in juvenile idiopathic arthritis (JIA) is complicated by age-dependent IgG glycan variation. The aim of this study was to conduct the first large-scale survey of IgG glycans in healthy children and patients with JIA, with a focus on early childhood, the time of peak JIA incidence. Methods IgG glycans from healthy children and disease-modifying antirheumatic drug-naive patients with JIA were characterized using high-performance liquid chromatography. Agalactosylated glycans were quantitated with reference to monogalactosylated (G1) species. Associations were sought between the G0:G1 ratio and disease characteristics. Results Among healthy children ages 9 months to 16 years (n = 165), the G0:G1 ratio was highly age dependent, with the ratio peaking to 1.19 in children younger than age 3 years and declining to a nadir of 0.83 after age 10 years (Spearman's ρ = 0.60, P < 0.0001). In patients with JIA (n = 141), the G0:G1 ratio was elevated compared with that in control subjects (1.32 versus 1.02; P < 0.0001). The G0:G1 ratio corrected for age was abnormally high in all JIA subtypes (enthesitis-related arthritis was not assessed), most strikingly in systemic JIA. Glycosylation aberrancy was comparable in patients with and those without antinuclear antibodies and in both early- and late-onset disease and exhibited at most a weak correlation with markers of inflammation. Conclusion IgG glycosylation is skewed toward proinflammatory G0 variants in healthy children, in particular during the first few years of life. This deviation is exaggerated in patients with JIA. The role for IgG glycan variation in immune function in children, including the predilection of JIA for early childhood, remains to be defined. [ABSTRACT FROM AUTHOR] more...
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- 2012
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6. Trial of early aggressive therapy in polyarticular juvenile idiopathic arthritis.
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Wallace, Carol A., Giannini, Edward H., Spalding, Steven J., Hashkes, Philip J., O'Neil, Kathleen M., Zeft, Andrew S., Szer, Ilona S., Ringold, Sarah, Brunner, Hermine I., Schanberg, Laura E., Sundel, Robert P., Milojevic, Diana, Punaro, Marilynn G., Chira, Peter, Gottlieb, Beth S., Higgins, Gloria C., Ilowite, Norman T., Kimura, Yukiko, Hamilton, Stephanie, and Johnson, Anne more...
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BLOOD testing ,CHI-squared test ,CONFIDENCE intervals ,EPIDEMIOLOGY ,FISHER exact test ,LONGITUDINAL method ,MEDICAL cooperation ,METHOTREXATE ,PLACEBOS ,RESEARCH ,RESEARCH funding ,JUVENILE idiopathic arthritis ,LOGISTIC regression analysis ,DATA analysis ,ETANERCEPT ,RANDOMIZED controlled trials ,BLIND experiment ,EARLY medical intervention ,DESCRIPTIVE statistics ,PREDNISOLONE - Abstract
Objective To determine whether aggressive treatment initiated early in the course of rheumatoid factor (RF)-positive or RF-negative polyarticular juvenile idiopathic arthritis (JIA) can induce clinical inactive disease within 6 months. Methods Between May 2007 and October 2010, a multicenter, prospective, randomized, double-blind, placebo-controlled trial of 2 aggressive treatments was conducted in 85 children ages 2-16 years with polyarticular JIA of <12 months' duration. Patients received either methotrexate (MTX) 0.5 mg/kg/week (maximum 40 mg) subcutaneously, etanercept 0.8 mg/kg/week (maximum 50 mg), and prednisolone 0.5 mg/kg/day (maximum 60 mg) tapered to 0 by 17 weeks (arm 1), or MTX (same dosage as arm 1), etanercept placebo, and prednisolone placebo (arm 2). The primary outcome measure was clinical inactive disease at 6 months. An exploratory phase determined the rate of clinical remission on medication (6 months of continuous clinical inactive disease) at 12 months. Results By 6 months, clinical inactive disease had been achieved in 17 (40%) of 42 patients in arm 1 and 10 (23%) of 43 patients in arm 2 (χ
2 = 2.91, P = 0.088). After 12 months, clinical remission on medication was achieved in 9 patients in arm 1 and 3 patients in arm 2 ( P = 0.053). There were no significant interarm differences in adverse events. Conclusion Although this study did not meet its primary end point, early aggressive therapy in this cohort of children with recent-onset polyarticular JIA resulted in clinical inactive disease by 6 months and clinical remission on medication within 12 months of treatment in substantial proportions of patients in both arms. [ABSTRACT FROM AUTHOR] more...- Published
- 2012
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7. A119: Deep Sequencing Analysis of the T Regulatory and T Effector Repertoire in Juvenile Idiopathic Arthritis.
- Author
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Henderson, Lauren A., Volpi, Stefano, Frugoni, Francesco, Kim, Susan, Janssen, Erin, Sundel, Robert P., Dedeoglu, Fatma, Lo, Mindy S., Hazen, Melissa M., Mathieu, Ronald, Fuhlbrigge, Robert C., Lee, Yu Nee, Nigrovic, Peter A., and Notarangelo, Luigi D. more...
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DNA analysis ,HUMAN genome ,POLYMERASE chain reaction ,JUVENILE idiopathic arthritis ,T cells ,DESCRIPTIVE statistics ,SEQUENCE analysis ,IN vitro studies - Abstract
Background/Purpose: T regulatory (Treg) function has been shown to be impaired in juvenile idiopathic arthritis (JIA) as synovial fluid (SF) Tregs are unable to suppress T effector cells (Teffs) found in the joint. The cause of this breach in immunologic tolerance is not fully understood, meriting the further study of Tregs and Teffs in JIA. The T cell receptor (TCR) endows T lymphocytes with antigen specificity and mediates interactions between T cells and their environment. Yet, little is known about the comparative specificities, clonality, and diversity of Tregs and Teffs in JIA. Further, the Treg repertoire has not been studied in adult or pediatric inflammatory arthritis. Therefore, we endeavored to characterize these TCR repertoires in JIA through deep sequencing technology. Methods: Mononuclear cells were isolated by Ficoll gradient centrifugation from paired peripheral blood (PB) and SF samples. Tregs (CD4
+ CD25+ CD127low ) and Teffs (CD4+ CD25− ) were sorted by flow cytometry. The TCRβ chain was amplified by multiplex PCR with genomic DNA serving as the template and then deep sequenced (ImmunoSEQ™). Sequences were aligned to the reference International ImMunoGeneTics information system. Further analysis utilizing Immunoglobulin Analysis Tool software was done to assess clonality, diversity, and variable (V), diversity (D), and joining (J) usage. Statistical analysis was completed with paired/unpaired Wilcoxon signed-rank and Kruskal-Wallis tests. Results: Three girls and 2 boys with oligoarticular (n = 2), extended oligoarticular (n = 2), and psoriatic (n = 1) arthritis were studied. Patients were similar in age (7-12 yrs) and ANA status (negative n = 4). Treatment consisted of NSAIDs (n = 2), methotrexate (n = 1), leflunomide (n = 1), and leflunomide with etanercept (n = 1). Tregs, measured as % of CD4+ cells, were enriched in the SF compared to PB (mean ± SEM: SF Tregs 13.2 ± 1.8; PB Tregs 5.1 ± 0.6). SF Teff repertoire was less diverse (p = 0.008) and more clonal (p = 0.008) than PB Teffs. In SF Teffs, a single complementarity determining region 3 (CDR3) was shared across all patients, though different V and J genes were used to create this CDR3, suggesting antigen selection. SF Tregs had the largest clonal expansions compared to PB Tregs (p = 0.016), PB Teffs (p = 0.008) and SF Teffs (p = 0.032). The degree of SF Treg clonality correlated with the active joint count. V gene usage, particularly Vβ29, in unique clonotypes was skewed in SF Tregs compared to PB Teffs, PB Tregs, and SF Teffs (p = 0.022); Vβ29 gene overuse was most prominent in patients with more active joints. Conclusion: We report on the first deep sequencing analysis of T cells in JIA. An antigen-driven process was suggested by the clonality and shared CDR3 clonotypes in SF Teffs. This study is the first to demonstrate abnormalities in the Treg repertoire in inflammatory arthritis. The SF Treg repertoire had the most pronounced clonality and skewing of V gene usage, and these abnormalities correlated with disease severity. These results suggest that Treg insufficiency in JIA may be partially due to an aberrant Treg repertoire in the arthritic joint. Studies of additional patients with functional correlates are needed to augment these findings. [ABSTRACT FROM AUTHOR] more...- Published
- 2014
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