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New Predictors of SLE Disease Activity
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New Predictors of SLE Disease Activity
PI: Virginia Pascual
Funding Organization: Alliance for Lupus Research
Project Start: April 1, 2006
Project End: March 31, 2008
 
Abstract:

Systemic Lupus Erythematosus (SLE) is a disease characterized by flares of high morbidity for which we have no predictors. Assessment of disease activity relies on time-consuming indices requiring evaluation of 7-9 organs/domains. The aims of our project, funded during the past 18 months by the ALR, were i) to establish an objective disease activity index based on blood leukocyte transcriptional profiles and ii) to develop robust laboratory assays to monitor disease activity and response to therapy. To accomplish this, we extended earlier findings in a larger set of pediatric SLE patients and on a genome-wide scale. We confirmed the presence of type-I IFN-; neutrophil-; immunoglobulin- (Ig); and lymphopenia-related signatures. A fifth signature of genes encoding ribosomal proteins was also identified. These signatures were found in adult SLE patients, but not in anti-nuclear antibody positive fibromyalgia patients. Expression of several genes correlated with disease activity, as measured by SLEDAI, in untreated patients. However, the performance of individual genes as indicators of disease activity lacked consistency in patients undergoing treatment. Data derived from modules of coordinately expressed genes representative of each transcriptional signature were used in an innovative multivariate analysis based on U-statistics. Excellent correlations were obtained between the genomic U-score and disease activity, according to SLEDAI (R2=0.82 and R2=0.71, p<0.0001 for untreated and treated patients, respectively). Furthermore, a longitudinal study demonstrated the value of this genomic score for the long term follow-up of patients. These studies also allowed us to identify sets of genes whose expression may predict the development of lupus nephritis, the most common form of end organ involvement in children.

The primary objectives for the renewal of this application are 1) to validate predictive blood transcriptional markers of lupus nephritis in a large scale multi-centric study and 2) to establish a reference database for the assessment of SLE disease activity by genomic scoring. We have developed collaborations with Pediatric Rheumatology Centers across the country which are members of the Childhood Alliance for Arthritis and Rheumatism Research (CARRA). Through this collaborative network, we will recruit more than 200 patients/year and follow them longitudinally for the two years of award. Sets of validated blood transcriptional markers used to assess disease activity and risk of nephritis will be incorporated in the design of an inexpensive focused "lupus microarray" for monitoring patients in the clinical setting. The ultimate goal of this project is the establishment of a nationwide repository of gene expression profiles that will be used as a reference for the assessment of SLE patients.