Posted May 4, 2021
Joan Merrill, M.D., Oklahoma Medical Research Foundation
Disease heterogeneity continues to be one of the greatest obstacles when treating individuals with lupus, and it often coincides with unpredictable prognosis and outcomes. As a result, treating lupus effectively has been challenging, and often patients experience flares with under-treatment or toxic side effects with overtreatment. Clinical trials of promising targeted biologics have yielded disappointing results. This can be attributed to the poor understanding of the underlying mechanisms and variables surrounding heterogeneous patient subsets, as well as the different background medications they are taking, thereby creating a lack of understanding as to which subset of patients will benefit most from specific treatments. In fiscal year 2017, Dr. Joan Merrill at the Oklahoma Medical Research Foundation was awarded a Lupus Research Program (LRP) Impact Award to compare the immune patterns of responders vs. non-responders to methotrexate.
Lupus patients are often prescribed multiple immunomodulatory medications to treat symptoms of the disease. Dr. Merrill’s team is utilizing data collected from previously completed clinical trials to create a database and tease out differences in how various combinations of individual and overlapping treatments impact the immune phenotypes and gene expression levels in patients. Understanding how these specific immune expressions correlate to treatments within a large cohort of lupus patients will allow researchers to find commonalities and create subsets within the heterogeneous population. Positive results of this type of research may create new opportunities for care providers to optimize treatment regimens to the specific immune markers expressed in individual patients for improved therapeutic benefit.
With the support from the LRP, Dr. Merrill’s team was able to retrospectively collect, match, and validate 564 paxgene samples, 543 plasma samples, and complete clinical data (including medication history and disease state) from 154 individual patients from previously completed clinical trials to provide samples from active/inactive disease on no immune suppressants, methotrexate, and other common treatments to use as controls. Using a bioinformatics computational approach to analyze patient RNA, the team was able to evaluate the expression of immune-modulated genes and group patients into similar subpopulations, or clusters, based on their phenotypes expressed. Through this extensive effort, Dr. Merrill was able to reproduce and statistically confirm the preliminary findings to phenotypically group a range of patients with high and low disease activity while taking methotrexate vs. control medications into unique clusters. These initial findings highlight several active immune pathways in lupus for future study. The team will continue to explore the impact of changes in medication and disease activity in the near future to further understand the significance and mechanisms of each subtype.
Dr. Merrill has completed the first step of many to collect and develop a large and complete dataset for study, and she hopes that this tool will be leveraged by other researchers for future studies. In fact, as the Clinical Trial Project Leader, she is currently leveraging results from this work in a clinical trial recently funded by the National Institute of Allergy and Infectious Diseases – Oklahoma Autoimmunity Center of Excellence: Molecular Deconstruction of Autoimmune Disease to Aid Clinical Trial Success (1UM1AI144292; Principal Investigator is Dr. Judith James). Through her work, Dr. Merrill aims to integrate “precision medicine” into lupus trials by understanding the phenotypic subtypes of individuals with lupus and to design better clinical trials for patients who will benefit from the treatment, in hopes of being able to select safer and more effective treatments for lupus patients.
Public and Technical Abstracts: Systemic Lupus: Improving the Rationale for Treatment Choices in a Heterogenous Disease
Last updated Thursday, May 26, 2022