Background/Purpose: Rheumatoid arthritis (RA) can improve naturally during pregnancy in a substantial proportion of women (50-75%), while it may worsen or remain unchanged in others. Thus far, there are no biomarkers to predict, at the pre-pregnancy stage, whether a woman with RA will improve or worsen during pregnancy. We examined pre-pregnancy gene expression profiles among women with RA to identify prediction biomarkers for improvement/worsening during pregnancy. We also aimed to identify genes that demonstrated altered expression during pregnancy when RA improved or worsened.

Methods: Blood samples were collected before pregnancy (T0) and at the 3^rd trimester (T3) from 19 women with RA and 14 healthy women enrolled in our prospective pregnancy cohort. RA improvement/worsening during pregnancy was assessed using the Clinical Disease Activity Index (CDAI). Total RNA from whole blood was sequenced to examine gene expression, and differences between groups or time-points were evaluated using differential expression analysis, using FDR < 0.05 and fold-change >=1.5 for significance. Co-expression network analysis and functional enrichment were also performed.

Results: Of the 19 women with RA, 14 improved during pregnancy (RA_improved) and 5 worsened (RA_worsened). At the T0 baseline, although both groups had similar disease activity (CDAI) [RA_improved (mean±S.D.): 16.8±11.5 and RA_worsened: 16.9±7.6; p=0.9], their gene expression profiles were significantly different. The RA_improved T0 gene expression signature showed increased expression of neutrophil-related genes. Additionally, one gene co-expression module related to B cell function was significantly correlated with the worsening of RA during pregnancy (r=0.65, FDR=5E^-5). This module was also significantly enriched (21-fold, FDR=1.7E^-118) in genes differentially expressed between the 2 RA groups at T0. At T3, the expression profile of the RA_improved group became similar to those of the healthy women, and for most (86%) of the genes in the RA_improved T0 RA signature, their T3 expression were no longer associated with the disease. In the RA_worsened group, several genes became newly differentially expressed at T3, including some candidates known to be expressed in the RA synovium. Further, additional candidate genes (e.g. PADI4) previously reported to be involved in RA demonstrated longitudinal expression patterns that were associated with pregnancy, and those associations were influenced by clinical outcome during pregnancy.

Conclusion: Pre-pregnancy gene expression profiles in RA appear to be predictive of the subsequent improvement or worsening of RA during pregnancy, and they suggest that the RA_improved and RA_worsened groups may represent two distinct RA endotypes.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pre-pregnancy-gene-expression-signatures-among-women-with-rheumatoid-arthritis-may-represent-predictive-biomarkers-for-subsequent-improvement-or-worsening-during-pregnancy/