Highlights from CARRA Studies

The Childhood Arthritis & Rheumatology Research Alliance (CARRA) is a national organization of pediatric rheumatologists who have joined together to answer critical clinical research questions. Each year, the Arthritis Foundation provides monetary support to CARRA so it can continue to bring scientists together in their common goal of finding the cause of, the cure for and the best possible treatment options for childhood arthritis. In March, members of CARRA gathered together to discuss the group’s strategic plans for future studies and investigations. Immediately following the CARRA meeting, the American College of Rheumatology hosted its Keystone Pediatric Rheumatology Symposium. At that meeting, preliminary results of several CARRA-related projects were presented.

Here, we give you some highlights of those presentations. 


Interim Report of the TREAT Study

What Is the Problem Being Studied?

It has been established that early aggressive therapy for adults with rheumatoid arthritis results in superior outcomes, but whether or not the same is true for children with juvenile idiopathic arthritis (JIA, also commonly called juvenile rheumatoid arthritis) is not known. A team of scientists from Children’s Hospital and Medical Center in Seattle, Wash., and Cincinnati Children’s Hospital Medical Center in Ohio are using the CARRA network to pool together enough children with JIA to test the hypothesis that “aggressive treatment initiated within the first six months of the onset of signs and symptoms of polyarticular JIA can induce inactive disease within six months of beginning such therapy and clinical remission on medication (inactive disease for six months on medication) within 12 months.”

What Is Being Done in the Study?

The TRial of Early Aggressive Therapy (TREAT) Study is a 12-month, double-blind clinical trial of 86 children with polyarticular JIA funded by the National Institutes of Health (NIH). All participants will enter the study within six months of disease onset and will be randomly assigned to one of two treatment arms: methotrexate plus etanercept plus prednisolone or methotrexate plus etanercept placebo plus prednisolone placebo. After four months of that treatment, those participants who do not achieve at least a 70 percent improvement in their symptoms will be lifted from the “blinding” and receive un-blinded etanercept and prednisolone in addition to methotrexate. After six months’ treatment, those who do not achieve inactive disease will also receive additional un-blinded medications. Participants will be evaluated for up to 12 months to determine if they achieve inactive disease and clinical remission while taking medication.

What Are the Study Results So Far?

By early February, 13 children ages 5 to 16 years have enrolled in the study. At the baseline visit, the active joint counts ranged from 6 to 54 (median 21), Physician Global Assessment of Disease Activity ranged from 4 to 10 (median 7; where 0 = no activity, 10 = worst activity), Parent Global Assessment of Overall Well-Being ranged from 2 to 9 (median 4; where 0 = very well, 10 = very poor), sedimentation rate ranged from 6 to 84 mm/hour (median 47) and 4 of 13 were rheumatoid factor positive.

What Does This Mean for the Study?

Dr. Wallace concluded in her presentation, “At this interim time, early aggressive therapy of subjects with polyarticular JIA appears to be feasible with the enrolled subjects having significant disease activity.”

Wallace CA, Lovell DJ, Giannini EH, Hamilton SW, Johnson AL. Interim Report of the TRial of Early Aggressive Therapy (TREAT) in JIA Study.


Predictors of Atherosclerosis in Pediatric Lupus

What Problem Was Studied?

Cardiovascular disease is a common and serious complication of systemic lupus erythematosus (SLE; lupus). CARRA researchers came together to create a study to help prevent cardiovascular disease in children with lupus: the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) study. One goal of the study is to identify predictors of subclinical atherosclerosis (hardening of the arteries) in children with lupus.

What Was Done in the Study?

Anatomy Basics

CIMT: The carotid intima medial thickness is tested by taking an ultrasound picture of the carotid arteries (the arteries leading from the heart to the head and neck). The earliest stages of athersclerosis cause the thickness of the walls of these arteries to increase. Thus, this test can be used to detect the earliest stages of atherosclerosis.

To accomplish the goal of finding predictors of atherosclerosis, scientists from Duke University Medical Center in Durham, N.C., and Stanford University in Palo Alto, Calif., compiled a group of 221 young people with lupus. Each participant underwent a baseline carotid intima medial thickness (CIMT) measurement as part of the APPLE trial. Clinical and laboratory parameters, disease activity, organ damage, medication use and traditional risk factors for atherosclerosis were assessed.

What Were the Study Results?

Based on the data gathered, the following predictors were found to be significantly associated with increased CIMT: age, longer duration of lupus, minority ethnicity (defined as Hispanic or non-Caucasian), higher body mass index, male gender, increased creatinine clearance (a measure of kidney function), proteinuria (increased protein in the urine, a sign of kidney damage), current azathioprine use and current prednisone dosage.

What Does This Mean for Children with Lupus?

In children with lupus, both traditional and nontraditional risk factors predict CIMT. Of note, the use of azathioprine was associated with increased CIMT and the effect of prednisone was dependent on dosage. Additional analysis of data from the APPLE study will help clarify the role of azathioprine and other medications in the premature atherosclerosis and cardiovascular disease associated with lupus.

Schanberg LE, Sandborg C, Ardoin SP, et al. Predictors of Increased Carotid Intima Medial Thickness (CIMT) in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Cohort.


Pediatric Wegener’s Granulomatosis: Preliminary Data

What Problem Is Being Studied?

The vasculitides are a group of inflammatory diseases in which the blood vessels become inflamed. Rare among adults, these diseases are even more uncommon in children. As a CARRA initiative, investigators from more than 40 pediatric health centers in Canada and the United States established A Registry of Childhood Vasculitis: e-entry (ARChiVe) to facilitate the study of these rare disorders, specifically Wegener’s granulomatosis (WG) and related diseases. One goal of this registry and study is to compare the classification criteria for adult WG with pediatric-specific criteria. The research team also plans to record presenting features of the disease, the time from symptom onset to diagnosis and initial treatment for WG.

What Is Being Done in the Study?

Children with chronic vasculitis diagnosed since 2004 are eligible to be included in ARChiVe. Data being collected from the patients’ medical records includes presenting and diagnostic features of disease; time from symptom onset to diagnosis; diagnostic imaging and laboratory results; and initial therapy.

What Are the Study Results To Date?

So far, 62 young people (45 girls and 17 boys) from 32 different health centers have agreed to participate. Mean age at diagnosis was 13.5 years and mean time from symptom onset to diagnosis was 8.1 months (although half of the patients were diagnosed within three months). Results indicated most children received intensive treatment with corticosteroids and cyclophosphamide as initial therapy, although different centers administered them according to different protocols. Some presenting features at disease onset differed between children and adults with WG. For example, the frequency of WG among girls compared with boys is higher than it is among women compared with men. Also, children’s disease symptoms were more generalized. The pediatric-specific classification criteria performed somewhat better than the adult criteria in classifying pediatric WG, although it must be remembered that these classification systems are primarily used for research purposes.

Cabral DA, O’Neil KM, Higgins G, et al. Pediatric Wegener’s granulomatosis (WG): Preliminary data from a US/Canadian registry of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis.



Associations Between Race and Clinical Features of Lupus

What Problem Was Studied?

Members of the CARRA research alliance sought to determine whether clinical features of systemic lupus erythematosus (SLE; lupus) correlated with race or ethnicity. To do this, scientists from Duke University Medical Center in Durham, N.C., and Stanford University in Palo Alto, Calif., used data from the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) study to compare clinical features of disease by race and ethnicity.

What Was Done in the Study?

A group of 221 children with lupus enrolled in the APPLE trial were categorized into four groups based on self-reported race and ethnicity: Caucasian/non-Hispanic, African-American/non-Hispanic, Hispanic and other. Statistical tests for differences by race/ethnicity were performed for sex, historical clinical features including organ involvement, high blood pressure, kidney function, immunosuppressive use and various measures of disease activity.

What Were the Study Results?

This study revealed statistically significant differences in clinical characteristics between groups. Non-Hispanic Caucasians showed increased skin/mucous membrane and neuropsychiatric symptoms, whereas kidney involvement was increased in Hispanic and African-American groups. African-Americans may be at increased risk of cardiovascular disease with younger age at diagnosis, increased carotid artery wall thickness (an early predictor of cardiovascular disease) and increased inflammatory markers.

What Does This Mean for Children With Lupus?

Understanding which clinical features are most common among different ethnic groups can help physicians customize the monitoring and treatment of their patients with lupus.

Schanberg LE, Sandborg C, Barnhart H, et al. Associations Between Race/Ethnicity and Clinical SLE Features in the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) Cohort


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