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Tzielan Lee, MD

  • Tzielan Lee

Specialties

Rheumatology

Work and Education

Professional Education

Stanford University School of Medicine, Stanford, CA, 1997

Internship

Stanford University School of Medicine, Stanford, CA, 1998

Residency

Stanford University School of Medicine, Stanford, CA, 2000

Fellowship

Stanford University School of Medicine, Stanford, CA, 2003

Board Certifications

Clinical Informatics, American Board of Preventive Medicine

Pediatric Rheumatology, American Board of Pediatrics

Pediatrics, American Board of Pediatrics

All Publications

Barriers to Adherence in Juvenile Idiopathic Arthritis: A Multicenter Collaborative Experience and Preliminary Results JOURNAL OF RHEUMATOLOGY Favier, L. A., Taylor, J., Rich, K., Jones, K. B., Vora, S. S., Harris, J. G., Gottlieb, B. S., Robbins, L., Lai, J. T., Lee, T., Kohlheim, M., Gill, J., Bouslaugh, L., Young, A., Griffin, N., Morgan, E. M., Modi, A. C. 2018; 45 (5): 69096

Abstract

Nonadherence is currently an underrecognized and potentially modifiable obstacle to care in juvenile idiopathic arthritis (JIA). The purpose of our study was to design and implement a standardized approach to identifying adherence barriers for youth with JIA across 7 pediatric rheumatology clinics through the Pediatric Rheumatology Care and Outcomes Improvement Network (PR-COIN) and to assess the frequency of adherence barriers in patients and their caregivers across treatment modalities.An iterative process using coproduction among parents and providers of patients with JIA was used to design the Barriers Assessment Tool to screen for adherence barriers across 4 treatment modalities (i.e., oral medications, injectable medications, infusions, and physical/occupational therapy). This tool was implemented in 7 rheumatology clinics across the United States and patient responses were collected for analysis.Data were collected from 578 parents and 99 patients (n = 44 parent-child dyads). Seventy-seven percent (n = 444) of caregivers and 70% (n = 69) of patients reported at least 1 adherence barrier across all treatment components. The most commonly reported adherence barriers included worry about future consequences of therapy, pain, forgetting, side effects, and embarrassment related to the therapy. There was no significant difference between endorsement of barriers between parents and adolescents.Implementing a standardized tool assessing adherence barriers in the JIA population across multiple clinical settings is feasible. Systematic screening sheds light on the factors that make adherence difficult in JIA and identifies targets for future adherence interventions in clinical practice.

View details for DOI 10.3899/jrheum.171087

View details for Web of Science ID 000431278800016

View details for PubMedID 29419467

View details for PubMedCentralID PMC5932234

Determinants of Anti-Tumor Necrosis Factor Drug Use in Juvenile Spondyloarthropathy and Impact on Clinical Disease Outcomes Oliver, M., Simard, J. F., Gerstbacher, D., Lee, T., Sandborg, C. WILEY. 2017
Resilience and Transition Readiness in Pediatric SLE Patients Lai, J., Nelson, L., Balboni, I., Lee, T., Hsu, J. WILEY. 2017
Pediatric Rheumatology Care and Outcomes Improvement Network Demonstrates Improvement on Quality Measures for Children with Juvenile Idiopathic Arthritis Bingham, C., Pratt, J., Yildirim-Toruner, C., Laxer, R., Gottlieb, B., Weiss, J., Lee, T., Vora, S. S., Burnham, J., Harris, J., Olson, J. C., Passo, M., Batthish, M., Shishov, M., Ferraro, K., Levy, D. M., O'Brien, C., Whitney-Mahoney, K., Griffin, N., Paul, A., Morgan, E. WILEY. 2017: 56
Designing An Individualized EHR Learning Plan For Providers APPLIED CLINICAL INFORMATICS Stevens, L. A., DiAngi, Y. T., Schremp, J. D., Martorana, M. J., Miller, R. E., Lee, T. C., Pageler, N. M. 2017; 8 (3): 92435

View details for DOI 10.4338/040054

View details for Web of Science ID 000413010400013

Novel Metrics for Improving Professional Fulfillment. Annals of internal medicine DiAngi, Y. T., Lee, T. C., Sinsky, C. A., Bohman, B. D., Sharp, C. D. 2017; 167 (10): 74041

View details for DOI 10.7326/M17-0658

View details for PubMedID 29052698

Pediatric Rheumatology Care and Outcomes Improvement Network Demonstrates Improvement on Quality Measures for Children with Juvenile Idiopathic Arthritis Bingham, C., Pratt, J., Yildirim-Toruner, C., Laxer, R., Gottlieb, B., Weiss, J. E., Lee, T., Vora, S. S., Burnham, J. M., Harris, J., Olson, J. C., Passo, M., Batthish, M., Shishov, M., Ferraro, K., Levy, D. M., O'Brien, C., Whitney-Mahoney, K., Griffin, N., Paul, A., Morgan, E. WILEY. 2016
Discordance Between Physician, Patient, and Parent Disease Assessment Scores in Juvenile Idiopathic Arthritis Fox, E., Hsu, J., Lee, T., Sandborg, C., Simard, J. F. WILEY. 2016
Comparing Presenting Clinical Features in 48 Children With Microscopic Polyangiitis to 183 Children Who Have Granulomatosis With Polyangiitis (Wegener's): An ARChiVe Cohort Study ARTHRITIS & RHEUMATOLOGY Cabral, D. A., Canter, D. L., Muscal, E., Nanda, K., Wahezi, D. M., Spalding, S. J., Twilt, M., Benseler, S. M., Campillo, S., Charuvanij, S., Dancey, P., Eberhard, B. A., Elder, M. E., Hersh, A., Higgins, G. C., Huber, A. M., Khubchandani, R., Kim, S., Klein-Gitelman, M., Kostik, M. M., Lawson, E. F., Lee, T., Lubieniecka, J. M., McCurdy, D., Moorthy, L. N., Morishita, K. A., Nielsen, S. M., O'Neil, K. M., Reiff, A., Ristic, G., Robinson, A. B., Sarmiento, A., Shenoi, S., Toth, M. B., Van Mater, H. A., Wagner-Weiner, L., Weiss, J. E., White, A. J., Yeung, R. S. 2016; 68 (10): 2514-2526

Abstract

To uniquely classify children with microscopic polyangiitis (MPA), to describe their demographic characteristics, presenting clinical features, and initial treatments in comparison to patients with granulomatosis with polyangiitis (Wegener's) (GPA).The European Medicines Agency (EMA) classification algorithm was applied by computation to categorical data from patients recruited to the ARChiVe (A Registry for Childhood Vasculitis: e-entry) cohort, with the data censored to November 2015. The EMA algorithm was used to uniquely distinguish children with MPA from children with GPA, whose diagnoses had been classified according to both adult- and pediatric-specific criteria. Descriptive statistics were used for comparisons.In total, 231 of 440 patients (64% female) fulfilled the classification criteria for either MPA (n=48) or GPA (n=183). The median time to diagnosis was 1.6 months in the MPA group and 2.1 months in the GPA group (ranging to 39 and 73 months, respectively). Patients with MPA were significantly younger than those with GPA (median age 11 years versus 14 years). Constitutional features were equally common between the groups. In patients with MPA compared to those with GPA, pulmonary manifestations were less frequent (44% versus 74%) and less severe (primarily, hemorrhage, requirement for supplemental oxygen, and pulmonary failure). Renal pathologic features were frequently found in both groups (75% of patients with MPA versus 83% of patients with GPA) but tended toward greater severity in those with MPA (primarily, nephrotic-range proteinuria, requirement for dialysis, and end-stage renal disease). Airway/eye involvement was absent among patients with MPA, because these GPA-defining features preclude a diagnosis of MPA within the EMA algorithm. Similar proportions of patients with MPA and those with GPA received combination therapy with corticosteroids plus cyclophosphamide (69% and 78%, respectively) or both drugs in combination with plasmapheresis (19% and 22%, respectively). Other treatments administered, ranging in decreasing frequency from 13% to 3%, were rituximab, methotrexate, azathioprine, and mycophenolate mofetil.Younger age at disease onset and, perhaps, both gastrointestinal manifestations and more severe kidney disease seem to characterize the clinical profile in children with MPA compared to those with GPA. Delay in diagnosis suggests that recognition of these systemic vasculitides is suboptimal. Compared with adults, initial treatment regimens in children were comparable, but the complete reversal of female-to-male disease prevalence ratios is a provocative finding.

View details for DOI 10.1002/art.39729

View details for Web of Science ID 000384819400020

View details for PubMedID 27111558

Altered signaling in systemic juvenile idiopathic arthritis monocytes CLINICAL IMMUNOLOGY Macaubas, C., Wong, E., Zhang, Y., Nguyen, K. D., Lee, J., Milojevic, D., Shenoi, S., Stevens, A. M., Ilowite, N., Saper, V., Lee, T., Mellins, E. D. 2016; 163: 66-74

Abstract

Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFN) and type II (IFN) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002 and 2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011 and 2014), monocytes of patients with recent disease onset were IFN hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFN. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology.

View details for DOI 10.1016/j.clim.2015.12.011

View details for Web of Science ID 000370585600010

View details for PubMedID 26747737

Increasing Rates of Remission in Juvenile Idiopathic Arthritis through a Quality Improvement Learning Network - the Pediatric Rheumatology Care and Outcomes Improvement Network DeWitt, E., Ardoin, S. P., Bingham, C., Gottlieb, B. S., Laxer, R. M., Griffin, N., Pratt, J., Paul, A., Lovell, D., Olson, J. C., Passo, M. H., Weiss, J. E., Lee, T. C., Vora, S. S., Hazen, M. M., Margolis, P. WILEY-BLACKWELL. 2014: S1012
Childhood Arthritis and Rheumatology Research Alliance Consensus Treatment Plans for New-Onset Polyarticular Juvenile Idiopathic Arthritis ARTHRITIS CARE & RESEARCH Ringold, S., Weiss, P. F., Colbert, R. A., DeWitt, E. M., Lee, T., Onel, K., Prahalad, S., Schneider, R., Shenoi, S., Vehe, R. K., Kimura, Y. 2014; 66 (7): 1063-1072

Abstract

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.A case-based survey was administered to CARRA members to identify the common treatment approaches for new-onset polyarticular JIA. Two face-to-face consensus conferences employed modified nominal group technique to identify treatment strategies, operational case definition, end points, and data elements to be collected. A core workgroup reviewed the relevant literature, refined plans, and developed medication dosing and monitoring recommendations.The initial case-based survey identified significant variability among treatment approaches for new-onset polyarticular JIA. We developed 3 CTPs based on treatment strategies for the first 12 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The CTPs include a step-up plan (nonbiologic disease-modifying antirheumatic drug [DMARD] followed by a biologic DMARD), an early combination plan (nonbiologic and biologic DMARD combined within a month of treatment initiation), and a biologic only plan. This approach was approved by 96% of the CARRA JIA Research Committee members attending the 2013 CARRA face-to-face meeting.Three standardized CTPs were developed for new-onset polyarticular JIA. Coupled with data collection at defined intervals, use of these CTPs will enable the study of their comparative effectiveness in an observational setting to optimize initial management of polyarticular JIA.

View details for DOI 10.1002/acr.22259

View details for Web of Science ID 000337976700013

View details for PubMedCentralID PMC4467832

Pulmonary Hypertension and Other Potentially Fatal Pulmonary Complications in Systemic Juvenile Idiopathic Arthritis ARTHRITIS CARE & RESEARCH Kimura, Y., Weiss, J. E., Haroldson, K. L., Lee, T., Punaro, M., Oliveira, S., Rabinovich, E., Riebschleger, M., Anton, J., Blier, P. R., Gerloni, V., Hazen, M. M., Kessler, E., Onel, K., Passo, M. H., Rennebohm, R. M., Wallace, C. A., Woo, P., Wulffraat, N. 2013; 65 (5): 745-752

Abstract

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.Systemic JIA patients who developed PAH, ILD, and/or AP were identified through an electronic Listserv and their demographic, systemic JIA, and pulmonary disease characteristics as well as their medication exposure information were collected. Patients with these features were compared to a cohort of systemic JIA patients enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry.The patients (n = 25) were significantly (P < 0.05) more likely than the CARRA registry cohort (n = 389) to be female; have more systemic features; and have been exposed to an IL-1 inhibitor, tocilizumab, corticosteroids, intravenous immunoglobulin, cyclosporine, and cyclophosphamide. Twenty patients (80%) were diagnosed with pulmonary disease after 2004. Twenty patients (80%) had macrophage activation syndrome (MAS) during their disease course and 15 patients (60%) had MAS at pulmonary diagnosis. Sixteen patients had PAH, 5 had AP, and 7 had ILD. Seventeen patients (68%) were taking or recently discontinued (<1 month) a biologic agent at pulmonary symptom onset; 12 patients (48%) were taking anti-IL-1 therapy (primarily anakinra). Seventeen patients (68%) died at a mean of 10.2 months from the diagnosis of pulmonary complications.PAH, AP, and ILD are underrecognized complications of systemic JIA that are frequently fatal. These complications may be the result of severe uncontrolled systemic disease activity and may be influenced by medication exposure.

View details for DOI 10.1002/acr.21889

View details for Web of Science ID 000318114700011

View details for PubMedID 23139240

Correlation analyses of clinical and molecular findings identify candidate biological pathways in systemic juvenile idiopathic arthritis BMC MEDICINE Ling, X. B., Macaubas, C., Alexander, H. C., Wen, Q., Chen, E., Peng, S., Sun, Y., Deshpande, C., Pan, K., Lin, R., Lih, C., Chang, S. P., Lee, T., Sandborg, C., Begovich, A. B., Cohen, S. N., Mellins, E. D. 2012; 10

Abstract

Clinicians have long appreciated the distinct phenotype of systemic juvenile idiopathic arthritis (SJIA) compared to polyarticular juvenile idiopathic arthritis (POLY). We hypothesized that gene expression profiles of peripheral blood mononuclear cells (PBMC) from children with each disease would reveal distinct biological pathways when analyzed for significant associations with elevations in two markers of JIA activity, erythrocyte sedimentation rate (ESR) and number of affected joints (joint count, JC).PBMC RNA from SJIA and POLY patients was profiled by kinetic PCR to analyze expression of 181 genes, selected for relevance to immune response pathways. Pearson correlation and Student's t-test analyses were performed to identify transcripts significantly associated with clinical parameters (ESR and JC) in SJIA or POLY samples. These transcripts were used to find related biological pathways.Combining Pearson and t-test analyses, we found 91 ESR-related and 92 JC-related genes in SJIA. For POLY, 20 ESR-related and 0 JC-related genes were found. Using Ingenuity Systems Pathways Analysis, we identified SJIA ESR-related and JC-related pathways. The two sets of pathways are strongly correlated. In contrast, there is a weaker correlation between SJIA and POLY ESR-related pathways. Notably, distinct biological processes were found to correlate with JC in samples from the earlier systemic plus arthritic phase (SAF) of SJIA compared to samples from the later arthritis-predominant phase (AF). Within the SJIA SAF group, IL-10 expression was related to JC, whereas lack of IL-4 appeared to characterize the chronic arthritis (AF) subgroup.The strong correlation between pathways implicated in elevations of both ESR and JC in SJIA argues that the systemic and arthritic components of the disease are related mechanistically. Inflammatory pathways in SJIA are distinct from those in POLY course JIA, consistent with differences in clinically appreciated target organs. The limited number of ESR-related SJIA genes that also are associated with elevations of ESR in POLY implies that the SJIA associations are specific for SJIA, at least to some degree. The distinct pathways associated with arthritis in early and late SJIA raise the possibility that different immunobiology underlies arthritis over the course of SJIA.

View details for DOI 10.1186/1741-7015-10-125

View details for Web of Science ID 000312394300001

View details for PubMedID 23092393

View details for PubMedCentralID PMC3523070

Do Adult Disease Severity Subclassifications Predict Use of Cyclophosphamide in Children with ANCA-associated Vasculitis? An Analysis of ARChiVe Study Treatment Decisions JOURNAL OF RHEUMATOLOGY Morishita, K., Guzman, J., Chira, P., Muscal, E., Zeft, A., Klein-Gitelman, M., Uribe, A. G., Abramson, L., Benseler, S. M., Eberhard, A., Ede, K., Hashkes, P. J., Hersh, A. O., Higgins, G., Imundo, L. F., Jung, L., Kim, S., Kingsbury, D. J., Lawson, E. F., Lee, T., Li, S. C., Lovell, D. J., Mason, T., McCurdy, D., O'Neil, K. M., Punaro, M., Ramsey, S. E., Reiff, A., Rosenkranz, M., Schikler, K. N., Scuccimarri, R., Singer, N. G., Stevens, A. M., Van Mater, H., Wahezi, D. M., White, A. J., Cabral, D. A. 2012; 39 (10): 2012-2020

Abstract

To determine whether adult disease severity subclassification systems for antineutrophil cytoplasmic antibody-associated vasculitis (AAV) are concordant with the decision to treat pediatric patients with cyclophosphamide (CYC).We applied the European Vasculitis Study (EUVAS) and Wegener's Granulomatosis Etanercept Trial (WGET) disease severity subclassification systems to pediatric patients with AAV in A Registry for Childhood Vasculitis (ARChiVe). Modifications were made to the EUVAS and WGET systems to enable their application to this cohort of children. Treatment was categorized into 2 groups, "cyclophosphamide" and "no cyclophosphamide." Pearson's chi-square and Kendall's rank correlation coefficient statistical analyses were used to determine the relationship between disease severity subgroup and treatment at the time of diagnosis.In total, 125 children with AAV were studied. Severity subgroup was associated with treatment group in both the EUVAS (chi-square 45.14, p < 0.001, Kendall's tau-b 0.601, p < 0.001) and WGET (chi-square 59.33, p < 0.001, Kendall's tau-b 0.689, p < 0.001) systems; however, 7 children classified by both systems as having less severe disease received CYC, and 6 children classified as having severe disease by both systems did not receive CYC.In this pediatric AAV cohort, the EUVAS and WGET adult severity subclassification systems had strong correlation with physician choice of treatment. However, a proportion of patients received treatment that was not concordant with their assigned severity subclass.

View details for DOI 10.3899/jrheum.120299

View details for Web of Science ID 000310256100017

View details for PubMedID 22859342

Assessing the Performance of the Birmingham Vasculitis Activity Score at Diagnosis for Children with Antineutrophil Cytoplasmic Antibody-associated Vasculitis in A Registry for Childhood Vasculitis (ARChiVe) JOURNAL OF RHEUMATOLOGY Morishita, K., Li, S. C., Muscal, E., Spalding, S., Guzman, J., Uribe, A., Abramson, L., Baszis, K., Benseler, S., Bowyer, S., Campillo, S., Chira, P., Hersh, A. O., Higgins, G., Eberhard, A., Ede, K., Imundo, L., Jung, L., Kim, S., Kingsbury, D. J., Klein-Gitelman, M., Lawson, E. F., Lovell, D. J., Mason, T., McCurdy, D., Nanda, K., Nassi, L., O'Neil, K. M., Rabinovich, E., Ramsey, S. E., Reiff, A., Rosenkranz, M., Schikler, K., Stevens, A., Wahezi, D., Cabral, D. A. 2012; 39 (5): 1088-1094

Abstract

There are no validated tools for measuring disease activity in pediatric vasculitis. The Birmingham Vasculitis Activity Score (BVAS) is a valid disease activity tool in adult vasculitis. Version 3 (BVAS v.3) correlates well with physician's global assessment (PGA), treatment decision, and C-reactive protein in adults. The utility of BVAS v.3 in pediatric vasculitis is not known. We assessed the association of BVAS v.3 scores with PGA, treatment decision, and erythrocyte sedimentation rate (ESR) at diagnosis in pediatric antineutrophil cytoplasmic antibody-associated vasculitis (AAV).Children with AAV diagnosed between 2004 and 2010 at all ARChiVe centers were eligible. BVAS v.3 scores were calculated with a standardized online tool (www.vasculitis.org). Spearman's rank correlation coefficient (r(s)) was used to test the strength of association between BVAS v.3 and PGA, treatment decision, and ESR.A total of 152 patients were included. The physician diagnosis of these patients was predominantly granulomatosis with polyangiitis (n = 99). The median BVAS v.3 score was 18.0 (range 0-40). The BVAS v.3 correlations were r(s) = 0.379 (95% CI 0.233 to 0.509) with PGA, r(s) = 0.521 (95% CI 0.393 to 0.629) with treatment decision, and r(s) = 0.403 (95% CI 0.253 to 0.533) with ESR.Applied to children with AAV, BVAS v.3 had a weak correlation with PGA and moderate correlation with both ESR and treatment decision. Prospective evaluation of BVAS v.3 and/or pediatric-specific modifications to BVAS v.3 may be required before it can be formalized as a disease activity assessment tool in pediatric AAV.

View details for DOI 10.3899/jrheum.111030

View details for Web of Science ID 000303975300034

View details for PubMedID 22337238

Alternative activation in systemic juvenile idiopathic arthritis monocytes CLINICAL IMMUNOLOGY Macaubas, C., Nguyen, K. D., Peck, A., Buckingham, J., Deshpande, C., Wong, E., Alexander, H. C., Chang, S., Begovich, A., Sun, Y., Park, J. L., Pan, K., Lin, R., Lih, C., Augustine, E. M., Phillips, C., Hadjinicolaou, A. V., Lee, T., Mellins, E. D. 2012; 142 (3): 362-372

Abstract

Systemic juvenile idiopathic arthritis (SJIA) is a chronic autoinflammatory condition. The association with macrophage activation syndrome, and the therapeutic efficacy of inhibiting monocyte-derived cytokines, has implicated these cells in SJIA pathogenesis. To characterize the activation state (classical/M1 vs. alternative/M2) of SJIA monocytes, we immunophenotyped monocytes using several approaches. Monocyte transcripts were analyzed by microarray and quantitative PCR. Surface proteins were measured at the single cell level using flow cytometry. Cytokine production was evaluated by intracellular staining and ELISA. CD14(++)CD16(-) and CD14(+)CD16(+) monocyte subsets are activated in SJIA. A mixed M1/M2 activation phenotype is apparent at the single cell level, especially during flare. Consistent with an M2 phenotype, SJIA monocytes produce IL-1 after LPS exposure, but do not secrete it. Despite the inflammatory nature of active SJIA, circulating monocytes demonstrate significant anti-inflammatory features. The persistence of some of these phenotypes during clinically inactive disease argues that this state reflects compensated inflammation.

View details for DOI 10.1016/j.clim.2011.12.008

View details for Web of Science ID 000301036700016

View details for PubMedID 22281427

View details for PubMedCentralID PMC3288602

Serum amyloid A overrides T-reg anergy via monocyte-dependent and T-reg-intrinsic, SOCS3-associated pathways BLOOD Nguyen, K. D., Macaubas, C., Nadeau, K. C., Phi Truong, T., Yoon, T., Lee, T., Park, J. L., Mellins, E. D. 2011; 117 (14): 3793-3798

Abstract

The acute phase protein serum amyloid A (SAA) has been well characterized as an indicator of inflammation. Nevertheless, its functions in pro versus anti-inflammatory processes remain obscure. Here we provide unexpected evidences that SAA induces the proliferation of the tolerogenic subset of regulatory T cells (T(reg)). Intriguingly, SAA reverses T(reg) anergy via its interaction with monocytes to activate distinct mitogenic pathways in T(reg) but not effector T cells. This selective responsiveness of T(reg) correlates with their diminished expression of SOCS3 and is antagonized by T(reg)-specific induction of this regulator of cytokine signaling. Collectively, these evidences suggest a novel anti-inflammatory role of SAA in the induction of a micro-environment that supports T(reg) expansion at sites of infection or tissue injury, likely to curb (auto)-inflammatory responses.

View details for DOI 10.1182/blood-2010-11-318832

View details for Web of Science ID 000289265500014

View details for PubMedID 21325601

View details for PubMedCentralID PMC3296631

Plasma profiles in active systemic juvenile idiopathic arthritis: Biomarkers and biological implications PROTEOMICS Ling, X. B., Park, J. L., Carroll, T., Nguyen, K. D., Lau, K., Macaubas, C., Chen, E., Lee, T., Sandborg, C., Milojevic, D., Kanegaye, J. T., Gao, S., Burns, J., Schilling, J., Mellins, E. D. 2010; 10 (24): 4415-4430

Abstract

Systemic juvenile idiopathic arthritis (SJIA) is a chronic arthritis of children characterized by a combination of arthritis and systemic inflammation. There is usually non-specific laboratory evidence of inflammation at diagnosis but no diagnostic test. Normalized volumes from 89/889 2-D protein spots representing 26 proteins revealed a plasma pattern that distinguishes SJIA flare from quiescence. Highly discriminating spots derived from 15 proteins constitute a robust SJIA flare signature and show specificity for SJIA flare in comparison to active polyarticular juvenile idiopathic arthritis or acute febrile illness. We used 7 available ELISA assays, including one to the complex of S100A8/S100A9, to measure levels of 8 of the15 proteins. Validating our DIGE results, this ELISA panel correctly classified independent SJIA flare samples, and distinguished them from acute febrile illness. Notably, data using the panel suggest its ability to improve on erythrocyte sedimentation rate or C-reactive protein or S100A8/S100A9, either alone or in combination in SJIA F/Q discriminations. Our results also support the panel's potential clinical utility as a predictor of incipient flare (within 9wk) in SJIA subjects with clinically inactive disease. Pathway analyses of the 15 proteins in the SJIA flare versus quiescence signature corroborate growing evidence for a key role for IL-1 at disease flare.

View details for DOI 10.1002/pmic.201000298

View details for Web of Science ID 000285882200008

View details for PubMedID 21136595

View details for PubMedCentralID PMC3517169

Laboratory markers of cardiovascular risk in pediatric SLE: the APPLE baseline cohort LUPUS Ardoin, S. P., Schanberg, L. E., Sandborg, C., Yow, E., Barnhart, H. X., Mieszkalski, K. L., Ilowite, N. T., von Scheven, E., Eberhard, A., Levy, D. M., Kimura, Y., Silverman, E., Bowyer, S. L., Punaro, L., Singer, N. G., Sherry, D. D., McCurdy, D., Klein-Gitelman, M., Wallace, C., Silver, R., Wagner-Weiner, L., Higgins, G. C., Brunner, H. I., Jung, L. K., Imundo, L., Soep, J. B., Reed, A. M. 2010; 19 (11): 1315-1325

Abstract

As part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Trial, a prospective multicenter cohort of 221 children and adolescents with systemic lupus erythematosus (SLE) (mean age 15.7 years, 83% female) underwent baseline measurement of markers of cardiovascular risk, including fasting levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), lipoprotein A (Lpa), homocysteine and high-sensitivity C-reactive protein (hs-CRP). A cross-sectional analysis of the baseline laboratory values and clinical characteristics of this cohort was performed. Univariable relationships between the cardiovascular markers of interest and clinical variables were assessed, followed by multivariable linear regression modeling. Mean levels of LDL, HDL, Lpa, TG, hs-CRP and homocysteine were in the normal or borderline ranges. In multivariable analysis, increased Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), prednisone dose, and hypertension (HTN) were independently associated with higher LDL levels. Higher hs-CRP and creatinine clearance were independently related to lower HDL levels. Higher body mass index (BMI), prednisone dose, and homocysteine levels were independently associated with higher TG levels. Only Hispanic or non-White status predicted higher Lpa levels. Proteinuria, higher TG and lower creatinine clearance were independently associated with higher homocysteine levels, while use of multivitamin with folate predicted lower homocysteine levels. Higher BMI, lower HDL, and longer SLE disease duration, but not SLEDAI, were independently associated with higher hs-CRP levels. The R(2) for these models ranged from 7% to 23%. SLE disease activity as measured by the SLEDAI was associated only with higher LDL levels and not with hs-CRP. Markers of renal injury (HTN, proteinuria, and creatinine clearance) were independently associated with levels of LDL, HDL, and homocysteine, highlighting the importance of renal status in the cardiovascular health of children and adolescents with SLE. Future longitudinal analysis of the APPLE cohort is needed to further examine these relationships.

View details for DOI 10.1177/0961203310373937

View details for Web of Science ID 000282090700007

View details for PubMedID 20861207

Monocytes are resistant to apoptosis in systemic juvenile idiopathic arthritis CLINICAL IMMUNOLOGY Srivastava, S., Macaubas, C., Deshpande, C., Alexander, H. C., Chang, S., Sun, Y., Park, J. L., Lee, T., Begovich, A., Mellins, E. D. 2010; 136 (2): 257-268

Abstract

We investigated whether circulating monocytes from patients with systemic juvenile idiopathic arthritis (SJIA) are resistant to apoptosis and which apoptotic pathway(s) may mediate this resistance. A microarray analysis of peripheral blood mononuclear cells (PBMC) of SJIA samples and RT-PCR analysis of isolated monocytes showed that monocytes from active SJIA patients express transcripts that imply resistance to apoptosis. SJIA monocytes incubated in low serum show reduced annexin binding and diminished FasL up-regulation compared to controls. SJIA monocytes are less susceptible to anti-Fas-induced apoptosis and, upon activation of the mitochondrial pathway with staurosporine, show diminished Bid cleavage and Bcl-w down-regulation compared to controls. Exposure to SJIA plasma reduces responses to apoptotic triggers in normal monocytes. Thus, SJIA monocytes are resistant to apoptosis due to alterations in both the extrinsic and intrinsic apoptosis pathways, and circulating factors associated with active SJIA may confer this phenotype.

View details for DOI 10.1016/j.clim.2010.04.003

View details for Web of Science ID 000280222200012

View details for PubMedID 20462799

View details for PubMedCentralID PMC2902595

Neonatal Legionellosis The Tip of the Iceberg for Pediatric Hospital-Acquired Pneumonia? PEDIATRIC INFECTIOUS DISEASE JOURNAL Yu, V. L., Lee, T. C. 2010; 29 (3): 282-284

View details for DOI 10.1097/INF.0b013e3181d1dfda

View details for Web of Science ID 000275136000024

View details for PubMedID 20190615

Distribution of circulating cells in systemic juvenile idiopathic arthritis across disease activity states CLINICAL IMMUNOLOGY Macaubas, C., Nguyen, K., Deshpande, C., Phillips, C., Peck, A., Lee, T., Park, J. L., Sandborg, C., Mellins, E. D. 2010; 134 (2): 206-216

Abstract

Juvenile idiopathic arthritis (JIA) encompasses a group of chronic childhood arthritides of unknown etiology. One subtype, systemic JIA (SJIA), is characterized by a combination of arthritis and systemic inflammation. Its systemic nature suggests that clues to SJIA pathogenesis may be found in examination of peripheral blood cells. To determine the immunophenotypic profiles of circulating mononuclear cells in SJIA patients with different degrees of disease activity, we studied PBMC from 31 SJIA patients, 20 polyarticular JIA patients (similar to adult rheumatoid arthritis), and 31 age-matched controls. During SJIA disease flare, blood monocyte numbers were increased, whereas levels of myeloid dendritic cells (DC) and gammadelta T cells were reduced. At both flare and quiescence, increased levels of CD14 and CD16 were found on SJIA monocytes. Levels of CD16-DC were elevated at SJIA quiescence compared both to healthy controls and to SJIA subjects with active disease. Overall, our findings suggest dysregulation of innate immunity in SJIA and raise the possibility that quiescence represents a state of compensated inflammation.

View details for DOI 10.1016/j.clim.2009.09.010

View details for Web of Science ID 000273701800013

View details for PubMedID 19879195

View details for PubMedCentralID PMC2818241

Classification, Presentation, and Initial Treatment of Wegener's Granulomatosis in Childhood ARTHRITIS AND RHEUMATISM Cabral, D. A., Uribe, A. G., Benseler, S., O'Neil, K. M., Hashkes, P. J., Higgins, G., Zeft, A. S., Lovell, D. J., Kingsbury, D. J., Stevens, A., McCurdy, D., Chira, P., Abramson, L., Arkachaisri, T., Campillo, S., Eberhard, A., Hersh, A. O., Huber, A. M., Kim, S., Klein-Gitelman, M., Levy, D. M., Li, S. C., Mason, T., DeWitt, E. M., Muscal, E., Nassi, L., Reiff, A., Schikler, K., Singer, N. G., Wahezi, D., Woodward, A. 2009; 60 (11): 3413-3424

Abstract

To compare the criteria for Wegener's granulomatosis (WG) of the American College of Rheumatology (ACR) with those of the European League Against Rheumatism/Pediatric Rheumatology European Society (EULAR/PRES) in a cohort of children with WG and other antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs), and to describe the interval to diagnosis, presenting features, and initial treatment for WG.Eligible patients had been diagnosed by site rheumatologists (termed the "MD diagnosis") since 2004. This diagnosis was used as a reference standard for sensitivity and specificity testing of the 2 WG classification criteria. Descriptive analyses were confined to ACR-classified WG patients.MD diagnoses of 117 patients (82 of whom were female) were WG (n = 76), microscopic polyangiitis (n = 17), ANCA-positive pauci-immune glomerulonephritis (n = 5), Churg-Strauss syndrome (n = 2), and unclassified vasculitis (n = 17). The sensitivities of the ACR and EULAR/PRES classification criteria for WG among the spectrum of AAVs were 68.4% and 73.6%, respectively, and the specificities were 68.3% and 73.2%, respectively. Two more children were identified as having WG by the EULAR/PRES criteria than by the ACR criteria. For the 65 ACR-classified WG patients, the median age at diagnosis was 14.2 years (range 4-17 years), and the median interval from symptom onset to diagnosis was 2.7 months (range 0-49 months). The most frequent presenting features by organ system were constitutional (89.2%), pulmonary (80.0%), ear, nose, and throat (80.0%), and renal (75.4%). Fifty-four patients (83.1%) commenced treatment with the combination of corticosteroids and cyclophosphamide, with widely varying regimens; the remainder received methotrexate alone (n = 1), corticosteroids alone (n = 4), or a combination (n = 6).The EULAR/PRES criteria minimally improved diagnostic sensitivity and specificity for WG among a narrow spectrum of children with AAVs. Diagnostic delays may result from poor characterization of childhood WG. Initial therapy varied considerably among participating centers.

View details for DOI 10.1002/art.24876

View details for Web of Science ID 000271781400031

View details for PubMedID 19877069

Premature Atherosclerosis in Pediatric Systemic Lupus Erythematosus ARTHRITIS AND RHEUMATISM Schanberg, L. E., Sandborg, C., Barnhart, H. X., Ardoin, S. P., Yow, E., Evans, G. W., Mieszkalski, K. L., Ilowite, N. T., Eberhard, A., Levy, D. M., Kimura, Y., von Scheven, E., Silverman, E., Bowyer, S. L., Punaro, L., Singer, N. G., Sherry, D. D., McCurdy, D., Klein-Gitelman, M., Wallace, C., Silver, R., Wagner-Weiner, L., Higgins, G. C., Brunner, H. I., Jung, L., Soep, J. B., Reed, A. 2009; 60 (5): 1496-1507

Abstract

To evaluate risk factors for subclinical atherosclerosis in a population of patients with pediatric systemic lupus erythematosus (SLE).In a prospective multicenter study, a cohort of 221 patients underwent baseline measurements of carotid intima-media thickness (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess the thickness of the bilateral common carotid arteries and the mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT, which were examined in multivariable linear regression modeling.Based on the mean-mean common or the mean-max CIMT as the dependent variable, univariable analysis showed significant associations of the following variables with increased CIMT: increasing age, longer SLE duration, minority status, higher body mass index (BMI), male sex, increased creatinine clearance, higher lipoprotein(a) level, proteinuria, azathioprine treatment, and prednisone dose. In multivariable modeling, both azathioprine use (P=0.005 for the mean-mean model and P=0.102 for the mean-max model) and male sex (P<0.001) were associated with increases in the mean-max CIMT. A moderate dosage of prednisone (0.15-0.4 mg/kg/day) was associated with decreases in the mean-max CIMT (P=0.024), while high-dose and low-dose prednisone were associated with increases in the mean-mean common CIMT (P=0.021) and the mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031) remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing lipoprotein(a) level (P=0.005) were associated with increased mean-max CIMT.Traditional as well as nontraditional risk factors were associated with increased CIMT in this cohort of patients in the APPLE trial. Azathioprine treatment was associated with increased CIMT. The relationship between CIMT and prednisone dose may not be linear.

View details for DOI 10.1002/art.24469

View details for Web of Science ID 000266071700036

View details for PubMedID 19404953

View details for PubMedCentralID PMC2770725

Problem pathogens: paediatric legionellosis - implications for improved diagnosis LANCET INFECTIOUS DISEASES Greenberg, D., Chiou, C. C., Famigilleti, R., Lee, T. C., Yu, V. L. 2006; 6 (8): 529-535

Abstract

Legionnaires' disease is an established and frequent cause of pneumonia in adults but is thought to be a rare cause in children. We reviewed the medical literature for cases of Legionnaires' disease in children and analysed the epidemiology, clinical characteristics, and treatment. 76 cases of legionella infection in children were identified. In 56%, diagnosis was made with culture methodology. 46% were community-acquired infections. 51.5% were under 2 years of age. 78% of the patients had an underlying condition such as malignancy. Fever, cough, and tachypnoea were the most common symptoms. The overall mortality rate was 33% and was higher in immunosuppressed children and in children younger than the age of 1 year. Patients who were treated empirically with anti-legionella therapy had a notably lower mortality rate compared with patients on inappropriate therapy (23%vs 70%). In 88% of hospital-acquired cases, an environmental link to potable water colonised with legionella was identified. We found no clinical features unique to Legionnaires' disease in children that would allow differentiation from pneumonia due to other respiratory pathogens. Awareness of legionella as a potential cause of paediatric pneumonia is particularly important because infection can be severe and life threatening and antimicrobial therapy often used for empirical therapy in children is not effective against legionella. In any case of pneumonia unresponsive to antibiotics, Legionnaires' disease should be considered and specific diagnostic tests to verify this diagnosis should be done. As legionella diagnostic tests become more widely applied, we predict that legionellosis may appear as an emerging infectious disease in children.

View details for Web of Science ID 000239341300024

View details for PubMedID 16870531

J Rheum Sandborg, Lee 2006
Systemic lupus erythematosus and antiphospholipid syndrome in children and adolescents CURRENT OPINION IN RHEUMATOLOGY Lee, T., von Scheven, E., Sandborg, C. 2001; 13 (5): 415-421

Abstract

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) can be associated with significant morbidity in children and adolescents. Renal involvement in SLE appears to be more severe and more frequent in the pediatric age group, with the major predictors for poor outcome being the severity of histopathologic lesions, severity of renal impairment at diagnosis, and hypertension. In addition to currently recognized cardiovascular and pulmonary involvement, accelerated atherosclerosis is of increasing concern in young individuals with SLE, because of both disease effects and medication usage. Neuropsychiatric SLE seen in childhood ranges from subtle cognitive dysfunction to severe central nervous system involvement; however, there is controversy over the value of different diagnostic studies. APS in children may be associated with SLE, idiopathic, or associated with viral infections. Systemic anticoagulation is recommended for patients with thrombotic events, but long-term management has not been well studied in children.

View details for Web of Science ID 000171262000013

View details for PubMedID 11604598