Clinical Focus

  • Pediatric Rheumatology

Academic Appointments

Administrative Appointments

  • Fellowship Director, Pedatric Rheumatology (2008 - Present)
  • Clinical Service Chief, Pediatric Rheumatology (2007 - Present)
  • Short Stay Unit Medical Director, Lucile Packard Children's Hospital at Stanford (2009 - Present)
  • Physician Lead, Ambulatory Automation, Information Services (2011 - Present)

Professional Education

  • Board Certification: Pediatrics, American Board of Pediatrics (2000)
  • Fellowship:Stanford University School of Medicine (2003) CA
  • Residency:Stanford University School of Medicine (2000) CA
  • Medical Education:Stanford University School of Medicine (1997) CA
  • Internship:Stanford University School of Medicine (1998) CA
  • Board Certification: Pediatric Rheumatology, American Board of Pediatrics (2004)
  • MD, Stanford University, Medicine (1997)

Research & Scholarship

Clinical Trials

  • Observational Study of Pediatric Rheumatic Diseases: The CARRA Registry Recruiting

    Continuation of the CARRA Registry as described in the protocol will support data collection on patients with pediatric-onset rheumatic diseases. The CARRA Registry will form the basis for future CARRA studies. In particular, this observational registry will be used to answer pressing questions about therapeutics used to treat pediatric rheumatic diseases, including safety questions.

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2017-18 Courses

Stanford Advisees


All Publications

  • 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


    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

  • 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


    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


    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


    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


    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

  • 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


    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


    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


    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 9?wk) 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

  • 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


    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


    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

  • 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


    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


    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

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