RESEARCH COMMITTEES: SLE

Overview

Systemic Lupus Erythematosus (SLE)is a disease that affects many internal organs in the body. SLE most often harms the heart, joints, skin, lungs, blood vessels, liver, kidneys, and nervous system. The course of the disease is unpredictable, with periods of illness and remission. Lupus affects women more frequently than men, and often begins or worsens at puberty.

Leadership

 

Stacy Ardoin, MD

Stacy Ardoin, MD SLE Chair

Aimee Hersh, MD SLE Vice Chair

 

SLE Workgroups

The SLE Nephritis Work Group, led by Drs. Tasha Ruth and Emily von Scheven, represents a collaboration between CARRA and Midwest Pediatric Nephrology Consortium (MWPNC) and currently has over 30 members.  Ongoing projects include developing consensus treatment plans for refractory proliferative nephritis and membranous lupus nephritis.  A recent publication from this group: Pediatr Rheumatol Online J. 2015 Jun 19;13:26. Practice patterns and approach to kidney biopsy in lupus: a collaboration of the Midwest Pediatric Nephrology Consortium and the Childhood Arthritis and Rheumatology Research Alliance (http://www.ncbi.nlm.nih.gov/pubmed/26087651).

The SLE Dermatology Work Group, led by Drs. Marisa Klein-Gitelman, Emily von Scheven and Lisa Arkin, represents collaboration between CARRA and Pediatric Dermatology Association (PeDRA). Ongoing projects include survey of pediatric rheumatologist and dermatologists regarding current management of discoid lupus, development of a retrospective discoid lupus cohort study.

The SLE Mental Health Work Group, led by Andrea Knight and Emily von Scheven, has completed a survey assessing pediatric rheumatology providers’ practices concerning screening and management of mental health in children and adolescents with SLE.  Next steps include surveys of patients, parents regarding their emotional and social health needs and of pediatric behavioral health providers regarding their roles in mental health intervention for youth with lupus.

The Antiphospholipid Syndrome (APS) Work Group, led by Dr. Barry Myones, is a new work group that is partnering with the multidisciplinary Pediatric APS International Task Force. This group’s initial work is approaching standardization of data and sample collection for APS and will have its first face to face meeting at spring 2016 CARRA Meeting.

The SLE Translational Research Work Group, led by Drs. Anne Stevens and Rebecca Kunder, is a new group representing collaboration with the CARRA TRTC.  This group aims to help with standardizing and facilitating biosample collection for SLE studies.

The SLE Registry/Database Work Group, led by Dr. Deb Levy, is in the process of finalizing case report forms for the CARRA SLE Registry.

All SLE Work Groups welcome additional volunteers. Please contact the group leaders if you are interested in joining or learning more.

SLE Projects

Nitric oxide metabolism in statin-treated pediatric SLE

Principal Investigator: Marc Levesque, PhD, Duke University, Durham, NC

Patients with systemic lupus erythematosus (SLE) develop atherosclerosis or hardening of the arteries faster than healthy people.  Accelerated atherosclerosis in SLE patients may be caused by overproduction of chemicals such as nitric oxide that cause inflammation of the blood vessels.  Nitric oxide normally acts to keep blood vessels open but when nitric oxide is overproduced it may cause inflammation and destruction of blood vessels.  We will be measuring nitric oxide levels in the blood of pediatric SLE patients enrolled in the APPLE trial.  The APPLE trial is sponsored by the National Institutes of Health (NIH) and is testing whether cholesterol-lowering drugs will slow atherosclerosis in SLE patients.  Our goal is to determine whether the cholesterol lowering drug atorvastatin can reduce inflammation and overproduction of nitric oxide in SLE patients.  We also plan to study the genetic reasons for overproduction of nitric oxide in SLE patients.  The APPLE trial has been enrolling patients and we will begin analyzing blood and genetic samples from SLE patients enrolled in the APPLE trial during the next few months.

Meaningful outcome measures for pediatric lupus trials

Principal Investigator: Hermine Brunner, MD, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Standardized high-quality surrogate markers to verify the effects of new drugs within the short time frames usually used in randomized controlled trials (RCT) in children with SLE are critical in order to assess treatment responses of children with SLE. This multi-center study will:

  1. Assess the proposed American College of Rheumatology Ad-hoc Committee criteria for minimal important differences in disease activity of adults with SLE for their validity when used in cSLE.
  2. Prospectively validate the preliminary definitions of improvement for cSLE that have been proposed by the Pediatric Rheumatology International Trial Organization (PRINTO) and the Prediatric Rheuamtology Collaborative Study Group (PRCSG).
  3. Develop preliminary criteria of disease flare in cSLE based on the set of cSLE core response variables that have been previously developed by PRINTO/PRCSG.

The expectations are that this study will provide validated surrogate markers of changes in global diseases to be used as primary response parameters of future cSLE RCTs. We will identify within a short period of time urgently required RCT outcome parameters to directly measure the effects of cSLE treatments. Validated surrogate markers will simplify the measurement of drug effects and provide standards to uniformly judge the effects of study medications on the course of cSLE. Specifically, we will test whether these parameters can be used for adults and children with SLE, possibly being able to confirm that both groups can be studied in future. drug trials concurrenlty based on the validity of similar response parameters. This would facilitate SLE RCTs in general and further promote cSLE research in particular.

Effects of puberty on childhood onset systemic lupus erythematosus and the development of antiphospholipid antibodies

Principal Investigator: Kathleen O’Neil, MD, Children’s Hospital of Oklahoma, Oklahoma City, OK

This study is currently recruiting patients.

Sponsors: The Presbyterian Health Research Foundation, The University of Oklahoma College of Medicine Alumni Association

Condition: Systemic Lupus Erythematosus (SLE)

Study Type: Observational, multi-center pilot study.

Purpose: Lupus affects women more frequently than men, and often begins or worsens at puberty. This implies that female sex hormones are important in SLE, but women with SLE who take estrogen supplements only have mild worsening in disease activity. This study will examine disease activity in children whose SLE began before puberty, to define which hormone(s) is important in exacerbating disease activity during puberty, and what the immune effects of hormone changes in puberty are.

Expected total enrollment: 50 (during the pilot phase) girls with SLE age 8-12.

Start of Study: November 1, 2004

Most children who develop SLE do so during the adolescent years, but children with early onset SLE (before puberty) have more active disease during the time they go through puberty. Adult women with SLE outnumber men 9:1. Estrogen treatment increases the risk of mild-to-moderate flares in women with SLE, but the increase is modest, and so estrogen may not be the only hormone that is responsible for the dramatic increase in lupus in girls during the teen years. Several other hormones change during puberty, and may account for the immune activation seen in lupus.

This study will measure disease activity in girls with SLE that began before the onset of puberty, watching them closely for a three-year time period that includes the onset of puberty. Hormone levels will be tested in urine and blood, and changes in autoantibodies and complement will also be measured serially during the study, to correlate changes in hormone production with disease activity measures and with immunologic changes.

We will examine standard lupus-associated autoantibodies, and will study anti-phospholipid antibodies in particular. These antibodies are associated with low platelet counts, and can contribute to many of the clotting and blood vessel problems that complicate SLE. If a hormone trigger to autoimmunity is identified, it may be possible to modify hormone activity in children when their disease is particularly active, perhaps decreasing the toxicity of the strong medications needed to control very active SLE.

Eligibility: Girls between their 8th and 13th birthdays who have not begun puberty, or are very early in the development process, who have systemic lupus erythematosus. They should not have other significant diseases (e.g., diabetes, severe asthma) unrelated to SLE, and should have serum creatinine <2.5 mg/dl. They should be able to complete self-report questionnaires in English or Spanish.

Location and Contact Information:

Coordinating Center : University of Oklahoma Health Science Center
Participating Centers : (Cincinnati, OH) Children’s Hospital Medical Center
(Dallas, TX) Texas Scottish Rite Children’s Hospital and Univ. Texas Southwestern
(Hackensack, NJ) Hackensack University Medical Center
(Houston, TX) Texas Children’s Hospital, Baylor College of Medicine
(Indianapolis, IN) Riley Children’s Hospital, University of Indiana
(Oklahoma City, OK) Children’s Hospital at OU Medical Center, University of  OK
(Salt Lake City, UT) Health Sciences Center, University of Utah

Towards improved biological markers for lupus renal disease

Principal Investigator: Hermine Brunner, MD, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

The central hypothesis to be tested is that especially urinary NGAL is elevated with SLE nephritis and that a decrease predicts renal response to therapy. Thus we will pursue the following 2 specific aims:

  1. To determine the relationship of NGAL levels to the presence, severity and future development of SLE renal disease
  2. To screen for additional RBM of SLE using proteomics.

SMILEY (Simple measure of impact of lupus erythematosus in youngsters) questionnaire for SLE patients

Principal Investigator: L. Nandini Moorthy, MD, MS, Robert Wood Johnson Medical School, New Brunswick, NJ

Brief Summary and Invitation to Collaborate: Dr. Moorthy developed an instrument for measuring health-related quality of life (HRQOL) in children with lupus called Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY). The U.S.-English version of the SMILEY (child and parent reports) has been found to be valid and reliable.1 The 26-item SMILEY has parallel child and parent reports with 5-face scales for responses and takes <10 minutes to complete. Scores are reported as percentages and higher scores indicate better HRQOL. The first two questions relate to global HRQOL and SLE status. SMILEY has been organized to four domains: effect on self, limitations (physical, fatigue, school), social, and burden of SLE. Scoring takes less than 10 minutes.

We are inviting sites to collaborate on the following two projects:

1. Cross-Cultural Validation of US-English SMILEY

We are conducting cross-cultural validation of SMILEY. Translation, adaption to the required language, and validation will be conducted. Responsiveness to change in disease activity will be determined (see below for procedure).

SMILEY child and parent reports are currently available in the following languages:

  • Danish
  • Dutch
  • English for US (validated)
  • French for France Hebrew for Israel
  • Hindi
  • Italian
  • Portuguese for Brazil Slovene
  • Spanish for Argentina
  • Spanish for Spain
  • Spanish for US and Puerto Rico
  • Turkish

Translation and adaption are in progress for the following languages:

  • Arabic
  • Chinese (Mandarin)
  • Czech
  • English for UK
  • French for Canada
  • German for Austria
  • German for Germany
  • German for Switzerland
  • Greek
  • Japanese
  • Polish
  • Romanian
  • Serbian
  • Spanish for Colombia
  • Spanish for Costa Rica
  • Spanish for Mexico
  • Spanish for Peru

2. Determine responsiveness of the U.S.-English SMILEY to change in disease activity

We are expanding the sample to determine the responsiveness of SMILEY to change in disease activity. Patients, 2-18 years of age, with SLE and their legal guardians will be administered a series of questionnaires that will collect baseline historical data, demographic, psychosocial, medication, and SLE-specific information. Additionally, gold standard questionnaires will be used for validation. Data on HRQOL and disease status will be collected on the patients every 2-4 months, at 4-6 time points.

Recruitment Status:  Recruiting

Eligibility Criteria: The inclusion criteria for child-subjects are as follows: (a) Age 2-18 years; (b) SLE defined by the 1982 ACR criteria (c) For children < 18 years, one legal guardian willing to sign consent.  The inclusion criteria for parents/legal guardians are as follows: (a) Have a child with SLE that meets eligibility criteria for the study.  The exclusion criteria for children and parents are as follows: (a) Not able to speak the language in which the adaptation and validation will be conducted; (b) Subjects not well enough to complete the questionnaires; (c) Physical or mental disabilities which would seriously affect the individual’s ability to understand the informed consent and/ or study questionnaires.

Data analysis and storage:  My center will be responsible for scoring all the questionnaires, data organization, entry and management.

CONTACT:
L. Nandini Moorthy, MD, MS
Assistant Professor of Pediatrics
Chief, Division of Pediatric Rheumatology
University of Medicine and Dentistry of New Jersey
Robert Wood Johnson Medical School
89 French Street/ CHINJ/ 1st Floor
New Brunswick, NJ 08901
E-mail: [email protected]

FOR ADDITIONAL INFORMATION OR TO JOIN THE COLLABORATION CONTACT:
Maria J. Baratelli
Research Assistant, Pediatric Rheumatology
Tel: 732.235.6555
Fax: 732.235.5002
E-mail: [email protected]

Relevant References:
1. Moorthy LN, Peterson MG, Baratelli M, Harrison MJ, Onel KB, Chalom EC, Haines K, Hashkes PJ, Lehman TJ. Multicenter validation of a new quality of life measure in pediatric lupus. Arthritis Rheum. 57(7):1165-73, 2007 Oct 15

[Updated as of 13 November 2008]

Completed Projects: APPLE Substudies

Formal requests

1) Title: Efficacy Measures for Ped Lupus Clinical Trials
PI: Hermine Brunner, MD, Cincinnati Medical Center

2) Title:SLE Nephritis and Ethnicity
PI: Joyce Hsu, MD, Jennifer Frankovich, MD and Christy Sandborg, MD, Stanford University

3) NPSLE Manifestations in the APPLE Cohort
PI: Stacy Ardoin, MD, Nationwide Children’s Hospital

4) Vitamin D Deficiency and Response to Atorvastatin in Pediatric Systemic Lupus Erythematosus
PI: Angela Robinson, Rainbow Babies and Children’s Hospital
Evaluation of the effect of vitamin D deficiency on response to atorvastatin in cardiovascular risk and development of long-term morbidities in systemic lupus erythematosus, as well as the response of vitamin D levels to treatment with atorvastatin.

Projects related to initial study aims

1) Title : Predictors of lipids & Homocysteine
PI: Stacy Ardoin, MD, Duke University

2) Title: Predictors of IMT
PI: Laura Schanberg, MD and Stacy Ardoin, MD, Duke University

3) Title: Baseline data by minority status
PI: Laura Schanberg, MD, Duke University

4) Title: IMT methods paper-baseline data
PI: Greg Evans,  Wake Forest University

Completed Project: The role of maternal microchimerism in pediatric systemic lupus erythematosus

Principal Investigator: Anne Stevens, MD, PhD, University of Washington, Seattle, WA

Specific Aims

The overall objective of this proposal is to test a functional model for involvement of maternal microchimerism (MMC) in systemic lupus erythematosus (SLE).

Maternal cells transported to the fetus during pregnancy can persist in their offspring for decades, creating a state of MMC and implying a state of tolerance to maternal antigens. A murine chimerism model suggests that parental cell infusion can lead to SLE. The principal investigator (PI) has demonstrated that chimeric maternal cells in her progeny can differentiate into tissue-specific phenotypes, including cardiac myocytes, renal tubular cells and hepatocytes. The PI’s preliminary data also suggests increased MMC in peripheral blood from SLE patients compared to controls and suggests maternal/fetal HLA compatibility is an SLE risk factor. Thus the proposed studies will test the hypothesis that maternal cells interact with host cells in the pathogenesis of SLE, either as target cells in tissues or effector cells in blood.

Hypothesis: MMC in SLE nephritis kidneys correlates with disease activity.
Aim 1. To investigate the prevalence, frequency and phenotype of MMC in the kidney for correlation with the severity of SLE nephritis.
Female (maternal) cells in renal biopsies from males will be identified, quantified, and phenotyped by fluorescence in situ hybridization (FISH) for X- and Y-chromosomes with simultaneous immunohistochemistry. Three groups will be studied: 1) SLE nephritis, 2) normal kidney to control for baseline MMC, and 3) renal allograft rejection as a control for chronic inflammation. The prevalence, levels, and phenotypes of MMC will be assessed for correlation with severity of SLE nephritis, as determined by WHO morphological classes. Comparisons will also be made between the three groups.

Hypothesis: MMC in the blood in pediatric SLE correlates with disease activity.
Aim 2. To investigate the level of MMC in the blood for correlation with SLE disease severity.
MMC will be assayed by real-time quantitative PCR (Q-PCR) for non-shared maternal HLA sequences. Disease activity will be measured using the SLE Disease Activity Index (SLEDAI). The levels of MMC will be assessed for correlation with disease in 1) SLE vs. controls and 2) severity (SLEDAI score).

Hypothesis: Allogeneic maternal cells are targets for autoimmunity in SLE.
Aim 3: To compare the frequency and character of T lymphocyte alloreactivity to MMC in pediatric SLE patients vs. controls.
Peripheral blood lymphocytes from patients and controls will be stimulated with maternal antigen presenting cells (APC). Cytokine production (interferon (IFN)-g, IL-4, IL-10, and TGF-b) in subsets of T lymphocyte early responders (CD69 expression), and proliferating responders (CFSE) will be quantified by flow cytometry. Responders will be compared to T lymphocytes stimulated with APCs from fathers and unrelated donors (URD).

Completed Project: Efficacy measures for pediatric lupus clinical trials

Principal Investigator: Hermine Brunner, MD, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

The central hypothesis to be tested is that especially urinary NGAL is elevated with SLE nephritis and that a decrease predicts renal response to therapy. Thus we will pursue the following 2 specific aims: 1) To determine the relationship of NGAL levels to the presence, severity and future development of SLE renal disease; 2) To screen for additional RBM of SLE using proteomics.

Completed Project: Towards evidence-based practice guidelines for use of steroids in children with SLE

Principal Investigator: Hermine Brunner, MD, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH

Steroids are the mainstay of therapy for childhood SLE (cSLE), but often contribute to the development of permanent damage. There is considerable practice variation in the use of steroids among pediatric rheumatologists treating cSLE. These differences in treatment approach may have an impact on patient outcomes. Further, there are no published guidelines of the best treatment for cSLE, especially for the use of steroids or when to introduce steroid-sparing medications. This multi-center pilot investigation will document treatment patterns of pediatric rheumatologists for patients with cSLE in order:

a) To identify key factor that prompt physicians to choose a certain steroid dose and document the factors that make physicians change a given dose of steroids;

b) To identify the key variables that prompt physicians to introduce of immunosuppressive therapies for patients diagnosed with cSLE.

c) To measure quality of life and specific outcomes (damage, costs) associated with the treatment of children and adolescents diagnosed with cSLE.

The proposed pilot study will provide information regarding physician treatment patterns, cost of cSLE and patient quality of life. Data will be collected to support that there are important differences in the approach to cSLE therapy that have a significant impact on patient outcomes. Results of the study will be used to generate hypotheses towards improved treatment approaches for cSLE. The proposed study constitutes a first step towards the development of evidence-based guidelines for treatment of this disease.