Defining Lupus Immunologic Variation in Effective Response

Systemic lupus erythematosus (SLE) is a complex autoimmune disease where the immune system mistakenly attacks healthy tissues, affecting people differently. While several medications are available to treat SLE, predicting which treatment will be effective remains a challenge. There are currently no biomarker tests available to help predict which medication is most likely to help each patient.

Drs. Rao and Villani and their team aim to understand how common SLE medications alter immune cell activity by analyzing blood and tissue samples before and after treatment using cutting-edge technologies. Specifically: Project 1 will use blood samples to examine how three different SLE medications affect immune cells in the blood, seeking biomarkers that predict treatment response. Project 2 will focus on skin samples from people with cutaneous lupus, analyzing how a specific drug changes the skin’s immune response, and identifying signatures associated with a good response. Project 3 will integrate data from blood cells, skin, and blood proteins to create a comprehensive view of immune responses, aiming to develop simple tools for predicting treatment success.

What this means for people with lupus:

Ultimately, this study aims to develop tests that could be used in clinical practice to enable providers to personalize SLE treatment, improving the likelihood that people receive the most effective medication for their condition.

SLE is clinically and immunologically heterogenous, with patients displaying varied disease manifestations and differing levels of activation of specific arms of the immune system. While multiple, mechanistically distinct disease-modifying anti-rheumatic drug (DMARD) therapies are available, SLE patients’ treatment responses vary dramatically, and the field lacks predictive biomarkers to help select the right DMARD for each patient. This project seeks to define quantitative changes in SLE patients’ immune cell activation induced by commonly used DMARDs and their relationship to clinical response using single cell multi-omics profiling of paired pre-treatment and post-treatment blood and tissue samples. The project involves an experienced and highly collaborative team with expertise in clinical assessment of systemic lupus, evaluation of cutaneous lupus, cellular immunopathology of lupus, high dimensional genomic studies of patient samples, and multi-modal data integration. In Project 1, we use single cell RNA-seq analyses to define changes in the circulating immune system induced by 3 mechanistically distinct DMARDs and identify cellular signatures associated with clinical response to treatment with different DMARDs. In Project 2, we use spatial transcriptomics of skin from patients with cutaneous lupus, including both early disease and refractory disease treated with anifrolumab, along with paired blood samples, to interrogate changes in tissue composition following treatment and signatures associated with clinical response. In Project 3, we employ multi-modal data integration, incorporating serum proteomics as well, to identify immunologic patterns associated with response across different disease manifestations, and we aim to derive simple metrics to predict treatment response from high-dimensional data. Leveraging both existing datasets and samples, and new analyses of prospectively collected samples, this study has the potential to nominate biomarkers that can be rapidly translated into clinically actionable tests.