The Pregnancy Transcriptome in Rheumatoid Arthritis - Renewal

Northwestern University At Chicago, Evanston IL

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Abstract

PROJECT SUMMARY Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that leads to significant disability and is thus far incurable. Although the introduction of biologic therapies revolutionized RA treatment, these are ineffective in a substantial proportion of patients and are often associated with serious side effects. Thus, RA continues to contribute significantly to the global burden of disease. Intriguingly though, 50-75% of women with RA who get pregnant experience a natural improvement of the disease, while others either experience no change or they may worsen during pregnancy. The mechanism(s) underlying these natural pregnancy-induced improvement or worsening of RA remain unknown. Furthermore, since it is currently not possible to predict who will improve during pregnancy, women are given indiscriminate treatment during pregnancy, even though many might have improved naturally. Thus, there are two major unmet needs to be addressed: biomarkers are needed at the pre-pregnancy stage so that treatment can be targeted only to women who are expected to worsen during pregnancy; and how pregnancy induces an improvement or worsening of RA needs to be elucidated. This will help uncover novel therapeutic targets, leading to development of improved therapies to mimic the natural improvement of RA, without side effects. We propose an innovative approach, applying state-of-the-art omics tools to address these unmet needs. In the last cycle of this grant, we established a unique prospective pregnancy cohort of RA and healthy women followed from a pre-pregnancy baseline. Using that cohort, we already demonstrated that women who improved during pregnancy and those who worsened had different RA- associated gene expression signatures when compared to healthy women before pregnancy. Within each group, these transcriptional signatures were enriched in neutrophil and B cell related genes. Further, we found several candidate genes exhibiting temporal expression changes during pregnancy that were also influenced by whether RA was improving or worsening. In this proposal, we will use our existing cohort and a new cohort being established at Northwestern University to test our hypothesis that there is a difference in pre-pregnancy transcriptional profiles of specific cell subsets between the women who improve during pregnancy and those who worsen. We will also test whether, during pregnancy, changes in transcriptional states of specific cell subsets may be associated with the improvement or worsening of RA. We expect that our investigations will provide pre-pregnancy prediction biomarkers associated with the subsequent improvement/worsening of RA. Additionally, there is a high potential that the proposed work will uncover novel therapeutic targets modeled on the natural pregnancy-induced improvement of RA, and will also provide novel targets to pre-empt worsening among the women who worsen during pregnancy.