Background/Purpose: Pregnancy can induce a natural improvement of rheumatoid arthritis (RA) in 50-75% of women with the disease, while others may worsen or remain unchanged. Since the mechanism(s) underlying this phenomenon remains unknown, we sought to identify longitudinal gene expression changes associated with RA improvement or worsening during pregnancy in our unique prospective pregnancy cohort of RA and healthy women from Denmark.

Methods: Blood samples were collected before pregnancy (T0) and at each trimester (T1, T2, T3) from 19 RA and 14 healthy women. RA improvement/worsening during pregnancy was assessed using the Clinical Disease Activity Index (CDAI). Gene expression levels at each timepoint were evaluated using bulk RNA-sequencing. Longitudinal Generalized Estimating Equation (GEE) models were fitted to identify genes whose expression patterns were associated with pregnancy when RA improved or worsened. An interaction term (pregnancy status x improved/worsened) was included to determine whether improvement/worsening during pregnancy significantly modified that association. Fold-changes in expression between timepoints or groups were assessed by differential expression analysis. 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). When compared to healthy women, both groups demonstrated significant differential expression at the T0 baseline. However, as RA improved during pregnancy, gene expression profiles of the RA_improved women became more similar to those of the healthy women, with most (86%) of the genes differentially expressed (DE) [vs healthy] at T0 being no longer DE at T3. On the other hand, when RA worsened, several genes became newly DE in the RA_worsened group at T3 [vs healthy], including candidates (e.g. TUBB2B) previously reported to be over-expressed in the RA synovium or associated with angiogenesis. In the longitudinal GEE models, among the RA_improved women, numerous genes showing pregnancy-associated expression from T1 or T2 remained significant until T3, with their expression increasing with each trimester. These included several genes with neutrophil-related functions. In the RA_worsened women, patterns of expression associated with each pregnancy trimester differed from those in the RA_improved women, with an enrichment in GO terms related to neutrophil and B cell function. Additionally, some candidate genes previously implicated in RA had longitudinal expression patterns associated with pregnancy, and those associations differed between the RA_improved and RA_worsened groups (significant interaction term in GEE model). Expression levels of some of these genes (e.g. PADI4) increased significantly with advancing pregnancy when RA worsened, but not when RA improved.

Conclusion: Our data suggest that the candidate genes with significant pregnancy-associated associations that differed between the RA_improved and RA_worsened groups may play a role in modulating RA disease activity during pregnancy. These results warrant further investigations in a larger cohort.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-the-natural-improvement-of-rheumatoid-arthritis-during-pregnancy/