Background/Purpose: Women with Rheumatoid arthritis (RA) tend to have a predictable flare of disease activity in the months after childbirth. The mechanism(s) underlying this post-partum flare are as yet unknown. Using our pregnancy cohort, we (a) examined gene expression changes associated with a flare of RA disease activity post-partum, (b) determined how those changes compare to post-partum changes observed among healthy women, and (c) examined whether expression profiles by 3 months post-partum differed from those before pregnancy.

Methods: Ten women with RA and five healthy women were enrolled in our pregnancy cohort and prospectively followed. Data on joint counts and global scores were collected from the women with RA before pregnancy (T0), at the third trimester (T3) and every 3 months post-partum (PP), and used to assess disease activity. Blood samples were drawn from all women at each time-point. Total RNA was isolated and used for RNA sequencing (RNA-seq). Pseudo-alignment and quantification of the raw RNA-seq reads were performed using kallisto. Differentially expressed (DE) genes were identified with edgeR using a significance threshold of q≤0.05 and fold-change≥2. Longitudinal mixed linear models were also used to test for associations between gene expression and disease activity post-partum. Functional analyses were performed using Cytoscape and ClueGO.

Results: Among the women with RA, 133 genes were DE between T3 and 3 months PP, when there was a flare of disease activity. These included genes encoding cell surface receptors CD24, CD177 and PD-L1, defensins, immunoglobulin receptors, S100 calcium binding proteins, and TRIM proteins. Functionally, these genes were enriched in the Gene Ontology (GO) terms neutrophil activation (q=1.1e-16) and antimicrobial humoral response (q=1.4e-5). Of the 133 DE genes, 118 were also DE among healthy women between T3 and 3 months PP, with expression changing in the same direction in both RA and healthy women. Similar results were obtained when the PP time-point with maximal disease activity during the flare was used (instead of 3 months PP). In the mixed linear model, 64 genes had expression patterns significantly associated with RA disease activity post-partum; these were enriched in various immune-related pathways including complement and coagulation cascades and systemic lupus erythematosus.  At 3 months PP, the gene expression profile among the women with RA differed from that at T0, with 61 genes DE between the 2 time-points. Among healthy women, however, there were no statistically significant changes in gene expression between T0 and 3 months PP, although some immune-related genes (n=24) were under-expressed by at least two-fold at 3 months PP compared to T0.

Conclusion: The large majority of gene expression changes between 3^rd trimester and 3 months post-partum in RA reflect normal post-partum changes also seen among healthy women. Nonetheless, there are a set of immune-related genes whose expression appear to be influencing disease activity during the post-partum flare. Further, our results show that the RA expression profile at 3 months post-partum is distinct from that before pregnancy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-the-post-partum-flare-in-rheumatoid-arthritis-using-transcriptome-analysis/