Background/Purpose: Pregnancy is known to induce a natural improvement of  Rheumatoid Arthritis (RA) symptoms in 50-75% of patients as gestation progresses. However, the underlying mechanisms are not well understood. In this study, we aimed to identify genes that demonstrate altered expression in RA during pregnancy through analysis of transcriptome profiles before pregnancy and at the third trimester from women with RA who show pregnancy-induced improvement in Clinical Disease Activity Index (CDAI) scores, and from healthy women (controls).

Methods: Blood was drawn from 7 women fulfilling the 1987 ACR criteria for RA and from 5 healthy women, before conception and at the third trimester. Total RNA was isolated and used to prepare cDNA libraries which were sequenced on an Illumina HiSeq2500 instrument at an average depth of 60 million reads (100bp). The raw RNA sequencing (RNA-seq) data was pre-processed and aligned to the reference Human transcriptome using Bowtie2. Gene expression levels were quantified using eXpress. Genes differentially expressed between groups (between RA cases and controls or between time-points) were identified with edgeR using a fold-change cutoff of 2 and significance threshold p<0.05 (FDR corrected). Functional category enrichment analysis was performed using the DAVID bioinformatics resource.

Results: Before pregnancy, 1,311 genes were differentially expressed in RA cases (CDAI: 11.1 ± 8.9) vs controls. In contrast, in the third trimester of pregnancy when there was improvement in RA disease activity (CDAI: 3.0 ± 2.4), differential expression between RA cases and controls was limited to only 38 genes, showing a dilution of the pre-pregnancy RA gene expression signature. Among the genes demonstrating RA-associated expression before pregnancy, those showing differential expression among healthy women in the third trimester vs before pregnancy – i.e. genes with expression levels modulated by pregnancy in the absence of RA – were found to be enriched in biological processes such as translational elongation, inflammatory response, immune response and leukocyte activation. Interestingly, in the third trimester, a subset of these pregnancy-modulated genes no longer displayed differential expression between cases and controls, even though they were over-expressed in RA cases compared to controls before pregnancy. These included genes such as CEACAM8, OLFM4, CAMP, ELOF1 and SLPI, some of which have been implicated in RA and some in pregnancy.

Conclusion: These pre-pregnancy and third trimester transcriptional signatures in RA suggest that the set of genes that show altered expression among cases during pregnancy may have a role in the pregnancy-induced changes in RA disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-the-ameliorating-effect-of-pregnancy-on-rheumatoid-arthritis-using-whole-transcriptome-analysis/