Pregnancy Genes May Help Rheumatoid Arthritis

Type I interferons (IFNs) may play a role in the natural amelioration of rheumatoid arthritis (RA) during pregnancy, a new pilot study suggests.

For women living with RA who become pregnant, little is known about the biology of pregnancy in terms of the overall systemic changes it induces, how they may differ between women with RA and healthy women, and how pregnancy-induced changes may have an impact on RA.

However, it is well documented that pregnancy can produce significant changes in RA disease activity. Between 50% and 75% of women with RA may experience a natural improvement in disease activity while pregnant, whereas other women may worsen or show no change.

Led by Damini Jawaheer, PhD, of the UCSF Benioff Children’s Hospital in Oakland, California, researchers hypothesized that pregnancy-induced changes in gene expressions among women with RA who improve during pregnancy may overlap substantially with those observed among healthy women and may differ from changes among women with RA who worsen during pregnancy.

They reported their findings in Arthritis Research & Therapy.

The study

The study established a cohort of women with RA and healthy women of Danish descent, who were enrolled prior to pregnancy and followed prospectively through pregnancy. Using state-of-the-art RNA sequencing technology, the researchers examined systemic global gene expression in peripheral blood from a subset of 11 women with RA and 5 healthy women as a pilot.

Women with RA fulfilled the 1987 revised American College of Rheumatology criteria for RA. Disease activity was assessed using the Disease Activity Score based on 28 joints and 4 variables (DAS28-CRP4). Change in DAS28 score from pre-pregnancy to the third trimester was calculated, separating the women with RA into 2 subsets. Women with a decrease in DAS28 scores were considered “improved” during pregnancy; those with an increase in DAS28 scores were considered “worsened.” Disease activity categories (remission, low, moderate, or high) were assessed using previously defined criteria.

The researchers performed differential gene expression analysis, which compared normalized gene-level counts between the third trimester and pre-pregnancy time points within each group of women (improved, worsened, and healthy). Comparisons between groups (improved vs worsened and improved vs healthy) also were performed. This analysis allowed for further investigation of pregnancy-induced gene expression patterns and fold-changes within the pilot dataset.

The findings

Of the 11 women with RA, 8 fell into the improved group and 3 were in the worsened group. In the improved group, a total of 1296 genes showed significant differential expression between the third trimester and pre-pregnancy time points. Of these, 161 genes displayed 2-fold or more change in expression. A large proportion of the 161 genes were also differentially expressed among healthy women. Some (n=31) were differentially expressed among worsened women.

The remaining 130 genes that were differentially expressed in the data among the improved women, but not among the worsened women, were significantly enriched in several immune-related processes, such as immune system process, defense response, immune response, and innate immune response.

A comparison of the fold-changes in expression from pre-pregnancy to the third trimester within each of the RA subsets revealed a small cluster of genes that were significantly overexpressed at the third trimester among improved women and underexpressed among worsened women.

“Interestingly, all of the genes in this cluster were type I interferon (IFN)-inducible,” the researchers observed. All of these genes “belong to a common functional network, as shown by known and predicted protein interactions from the STRING database.”

Implications

These findings are novel in that gene expression changes that accompany improvement or worsening of RA disease activity during pregnancy have not previously been investigated relative to a pre-pregnancy baseline. However, the significance of the type I IFN signature in the improved subset is not entirely clear.

Type I IFNs appear to have conflicting roles in autoimmune diseases, correlating with an alleviation of symptoms in multiple sclerosis and associated with active disease in lupus. Studies suggest that type I IFN most likely has a protective role in RA, although translation of these findings from animal models to treating humans with RA has thus far not been successful.

Still, the observations from this study support the idea that increased levels of the IFN-inducible genes identified in the pilot data may help shift the immunomodulatory balance to an anti-inflammatory state during pregnancy. The researchers speculated that specific levels of these gene products may be crucial to maintaining a healthy pregnancy, which would explain why expression levels at the third trimester among improved women were comparable to those of healthy women.

This study has some limitations. The sample size was quite small, especially for the women who worsened during pregnancy, though the availability of data from the same women before and during pregnancy and the ethnic homogeneity of the study population alleviate some of the limitations of a small sample size.

Still, observations specifically relating to the worsened subset should be interpreted with caution until they can be replicated in a larger sample. There’s also a possibility that anti–tumor necrosis factor or other medications may have influenced the results, but a lack in variation in medication use within each subset of women with RA precluded researchers from determining whether this was the case.

Overall, the results suggest that genes demonstrating significant changes in expression during pregnancy in the improved women, but not the worsened women, could be involved in the natural amelioration of RA.

“These findings warrant further investigation into expression of these genes in RA pregnancy and their potential role in modulation of disease activity,” the researchers concluded.

References:

Goin DE, Smed MK, Pachter L, et al. “Pregnancy-induced gene expressions changes in vivo among women with rheumatoid arthritis: a pilot study.” Arthritis Res Ther. 2017;19:104. doi: 10.1186/s13075-017-1312-2.