• Our Projects

  • Daniel J. Lovell, MD, MPH, Principal Investigator

    Current treatment approaches for children with JIA result in up to 50 percent of patients demonstrating clinically inactive disease while on treatment. Much of this success is due to the introduction of anti-tumor necrosis factor (anti-TNF) biologic therapies.

    Unfortunately, more than 50 percent of the children with clinically inactive disease for periods of three to 12 months while on treatment will demonstrate an obvious and clinically important worsening of the disease within three to 12 months following treatment withdrawal. In addition, anti-TNF therapy is expensive and has been shown to have short- and medium-term toxicities in children with JIA. Current testing cannot predict which children with JIA will experience disease flares after treatment withdrawal.

    Our study intends to develop a method (or methods) of using biomarkers to accurately identify patients in whom anti-TNF therapy can be effectively stopped. The study has three specific aims:

    • Assess the quantitation of serum level of the protein complex of two calgranulin proteins (S100A8 and S100A9) as a biomarker to predict which children with polyarticular JIA will be able to discontinue anti-TNF biologic therapy without demonstrating a disease flare within eight months.
    • Assess the ability of an in-vivo cytokine capture assay (IVCCA), which quantitates the in-vivo production of TNF, to predict which children with polyarticular JIA will be able to discontinue anti-TNF monoclonal antibody therapy (infliximab or adalimumab) without demonstrating a disease flare within eight months.
    • Use whole-genome gene expression profiling to identify genes in children with polyarticular JIA that show differential expression during anti-TNF treatment and during post-treatment disease flares. This will help us better understand the underlying biology of these clinical states and identify novel markers that associate with induction, maintenance and loss of clinical and biological inactivity.


    This project will use a tiered approach in research design. The first two aims will investigate specific hypotheses about markers that may be used to identify patients in whom anti-TNF therapies can be effectively stopped. Both hypotheses already have strong theoretical support and / or support from preliminary data; consequently, we believe it likely that they will be proven correct.

    The third aim uses a gene expression approach to identify additional markers that may be used to identify candidate genes for stopping therapy. Although this aim is more discovery-oriented than focused on testing a specific hypothesis, we believe it has great potential to identify important new biomarkers.

    If successful, this study will provide better understanding of the effect of TNF antagonist therapy on the biology of JIA, and could allow safer and more cost effective use of these profoundly important new therapies.


    Alexi A. Grom, MD, Principal Investigator

    Macrophage activation syndrome (MAS) is a potentially fatal complication for children with systemic JIA (sJIA). It is characterized by an overwhelming inflammatory reaction driven by excessive expansion of T cells and hemophagocytic macrophages. Complicating matters, the diagnosis is difficult due to the lack of diagnostic criteria.

    This project seeks to understand the pathways leading to the increased incidence of MAS in patients with sJIA, define the MAS risk group, and to develop guidelines for monitoring and treatment of these patients. The project has three specific aims:

    • We will determine whether genetic polymorphisms in the MUNC 13-4 gene are associated with MAS in sJIA and consequently may help identify patients at long-term risk for MAS. Using targeted genetic analysis of a limited number of SNPs, we are examining banked DNA samples from a large cohort of sJIA patients (including those with MAS) and controls for the presence of the MUNC13-4 haplotype. Preliminary evidence suggests that serum levels of soluble IL2 receptor α chain (sIL2Rα) and soluble CD163 (sCD163) may reflect the degree of activation and expansion of T cells and macrophages in MAS, and thus serve as early diagnostic markers.
    • We will determine whether elevated levels of sIL2Ra and sCD163 will distinguish patients with overt and subclinical MAS from patients with conventional sJIA flare.
    • We will determine whether sJIA patients at risk for MAS represent a distinct subtype of sJIA with a distinct course, and these patients can be distinguished at onset of sJIA.

    Related Publications

    2010

    Hinze CH, Fall N, Thornton S, Griffin TA, Thompson SD, Colbert RA, Glass DN, Michael G, Barnes BG, Grom AA. Immature cell populations and an erythropoiesis gene-expression signature in systemic juvenile idiopathic arthritis: implications for pathogenesis. Arthritis Res Ther. 2010.

    2009

    Vastert SJ, Kuis W, Grom AA. Systemic JIA: new developments in the understanding of the pathophysiology and therapy. Best Pract Res Clin Rheumatol 23:655-64. 2009.

    2008

    Hazen MM, Woodward AL, Hofman I, Degar BA, Grom AA, Filipovich AH, Binstadt BA. Mutations of the hemophagocytosis-associated gene UNC13D in a patient with systemic juvenile idiopathic arthritis. Arthritis Rheum. 58:567-70. 2008.

    Zhang K, Biroscak J, Glass DN, Thompson S, Finkel T, Murray P, Binstadt B, Filipovich A, Grom AA. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheum. 58:2892-6. 2008.

    Other Significant Publications

    Bleesing J, Prada E, Siegel DM, Villanueva J, Olson J, Ilowite N, Brunner HI, Griffin T, Graham TB, Sherry DD, Passo MH, Filipovich A, Grom AA. The Diagnostic Significance of soluble CD163 and soluble IL2Rα chains in Macrophage Activation Syndrome and Untreated New Onset Systemic Juvenile Idiopathic Arthritis. Arthritis Rheum. 56:965-71. 2007.


    Hermine Brunner, MD, Principal Investigator

    Although research shows that thinking and memory are affected by lupus, there is currently no way to test for this complication, known as neuropsychiatric lupus (NPSLE), in the clinical setting. This study is employing magnetic resonance imaging to explore how NPSLE affects the nervous system and aims to produce a clinic-useable screening tool for NPSLE.

    This project has three specific aims:

    • We intend to validate the Pediatric Automatic Assessment Metrics (Ped-ANAM) software program as a measure of cognitive function in pediatric lupus. We will use formal neuropsychological testing as the criterion standard.
    • Using formal psychological testing and the Ped-ANAM, we will assess the effects of pediatric lupus on cognitive development during childhood.
    • We will use functional MRI and diffusion tensor imaging to determine the effect of lupus on attention, visuoconstructional ability and working memory in gray and white matter neurological networks.

    Preliminary results from functional MRI scanning show abnormalities even in children with pediatric lupus who do not have NPSLE. Additionally, preliminary testing suggests that Ped-ANAM performance is markedly different in patients with NPSLE versus pediatric lupus patients with normal cognition.


    Michael Seid, PhD, Principal Investigator

    Health-related quality of life (HRQOL), an individual’s perceptions of his or her physical, psychosocial and role functioning with respect to his or her health, is a key outcome in clinical care of, and clinical trials for, children with juvenile idiopathic arthritis (JIA). Implicit in the measurement of HRQOL as a JIA outcome is the notion that medical interventions, such as drug therapies, can affect not only clinical parameters but also more distal outcomes, such as HRQOL. While much research has focused on understanding how biological and physiological variables affect disease outcomes, far less is known about how changes in clinical parameters are related to improvement in HRQOL.

    Our preliminary data suggest that, even with excellent disease control through the use of biologic medications, about half of children with polyarticular arthritis will continue to have a lower quality of life than healthy children. Without a thorough understanding of the determinants of HRQOL and identification of potential modifiers, many children with JIA, even those treated with biologics who have well-controlled arthritis, will continue to experience suboptimal HRQOL. This study’s long-term goal, then, is to improve HRQOL for children with JIA.

    Our central hypothesis is that HRQOL is determined only in part by medical parameters, and that non-medical parameters have both direct and indirect effects on the HRQOL of children with JIA. Preliminary analysis of our data suggests that there is an association between medical parameters and HRQOL in the context of treatment, but there is substantial unexplained variance in HRQOL for children with well-controlled arthritis and for children with polyarticular JIA treated for 12 months with biologics.

    We will perform a prospective longitudinal cohort study to test our central hypothesis. We will recruit current patients in treatment for six months or less, as well as new patients, and will collect survey data semiannually, for a total of three assessments (baseline, six months and 12 months). This research has two specific aims:

    • We will determine the pathways by which medical variables (biological, physiological, clinical and physical function) predict HRQOL in children being treated for JIA.
    • We will determine the extent to which non-medical characteristics of the individual, family and environment explain additional variance, beyond medical factors, in HRQOL in children being treated for JIA.

    This study represents a novel approach to understanding how clinical parameters and treatment affect HRQOL in children with JIA. It is the first prospective study of HRQOL determinants in this population. Our hope is that this project will lead to a thorough understanding of the main medical and non-medical drivers of HRQOL in children with JIA, thus providing foundational knowledge to develop therapeutic interventions aimed at improving HRQOL.

    Related Publications

    Seid M, Opipari L, Huang B, Brunner HI, Lovell DJ. Disease control and health-related quality of life in juvenile idiopathic arthritis. Arthritis Rheum. 61(3):393-9. Mar 15, 2009.