Altered DNA methylation in children born to mothers with rheumatoid arthritis during pregnancy.

OBJECTIVES: The main objective of this study was to determine whether the DNA methylation profile of children born to mothers with rheumatoid arthritis (RA) is different from that of children born to mothers from the general population. In addition, we aimed to determine whether any differences in methylation are associated with maternal RA disease activity or medication use during pregnancy. METHODS: For this study, genome-wide DNA methylation was measured at cytosine-phosphate-guanine (CpG) sites, using the Infinium Illumina HumanMethylation 450K BeadChip, in 80 blood samples from children (mean age=6.8 years) born to mothers with RA. As controls, blood samples from 354 children (mean age=6.0 years) from the population-based Generation R Study were used. Linear mixed models were performed to investigate differential methylation between the groups, corrected for relevant confounders. RESULTS: A total of 147 CpGs were differentially methylated between blood samples of children born to mothers with RA and the control blood samples. The five most significantly associated CpGs were cg06642177, cg08867893, cg06778273, cg07786668 and cg20116574. The differences in methylation were not associated with maternal RA disease activity or medication use during pregnancy. CONCLUSIONS: DNA methylation at 147 CpGs differed between children born to mothers with RA and children born to mothers from the general population. It remains unknown whether the identified associations are causal, and if so whether they are caused by the disease or treatment. More research, including replication of these results, is necessary in order to strengthen the relevance of our findings for the later-life health of children born to mothers with RA.

Associations between antenatal prednisone exposure and long-term cortisol and cortisone concentrations in children born to women with rheumatoid arthritis: results from a nationwide prospective cohort study.

Objectives: To identify whether children with antenatal prednisone exposure have chronically elevated cortisol and cortisone concentrations, an altered body composition or higher blood pressure. In addition, to identify whether maternal rheumatoid arthritis disease (RA) activity is associated with these alterations. Methods: In this prospective study, 56 children (mean age=10.0 years) with and 61 children (mean age=9.6 years) without antenatal prednisone exposure, born to women with RA, were included. Hair cortisol and cortisone were analysed using liquid chromatography-tandem mass spectrometry. Linear regression models were built to analyse differences between the two groups, corrected for relevant covariates. Hair cortisol concentrations were also compared between the study population and an age-matched healthy reference group(n=150 children, mean age=9.8 years). Results: Hair cortisol and cortisone concentrations were similar in children with and without antenatal prednisone exposure (median cortisol 1.14 pg/mg (IQR 0.67-1.75) and 1.15 pg/mg (IQR 0.65-2.21) and median cortisone 6.76 pg/mg (IQR 5.42-8.86) and 7.40 pg/mg (IQR 5.39-10.73), respectively). Antenatal prednisone exposure and maternal RA disease activity were also not associated with body composition or blood pressure. Hair cortisol concentrations were not different in children born to mothers with RA compared with children from the reference group. Conclusion: This, in its kind, large and unique long-term prospective study demonstrates that low-dose antenatal prednisone exposure and maternal RA disease activity are not associated with negative consequences in prepubertal childhood. The findings of this study are reassuring and support the assumption that low-dose maternal prednisone use during pregnancy is safe for the offspring, at least until the age of approximately 10 years.

Breastfeeding among Women with Rheumatoid Arthritis Compared with the General Population: Results from a Nationwide Prospective Cohort Study.

OBJECTIVE: The World Health Organization recommends that infants be exclusively breastfed until the age of 6 months. The first objective was to compare breastfeeding frequencies and time of cessation between women with rheumatoid arthritis (RA) and the general population. The second objective was to identify why patients with RA discontinue breastfeeding. METHODS: This study was embedded in the Pregnancy-induced Amelioration of Rheumatoid Arthritis (PARA) study, a nationwide prospective cohort study. From 2002 to 2008, a total of 249 pregnancies were followed from pregnancy until 6 months postpartum. Data on lactation and medication use were collected. Proportion tests were used to compare percentages of breastfeeding between the study population and the general/reference population. RESULTS: At 4-6, 12, and 26 weeks postpartum, 43%, 26%, and 9% of the RA patients breastfed their offspring, respectively, compared with 63%, 46%, and 41% in the general population, respectively (p < 0.001). The main reason for women to discontinue breastfeeding was the restart of medication (n = 129, 57.8%). Nevertheless, more than 40% of these patients restarted medication that was considered compatible with breastfeeding. CONCLUSION: This large prospective study demonstrates that RA is associated with lower proportions of women breastfeeding their offspring and earlier cessation compared with the general population. A considerable number of patients discontinued breastfeeding so that they could start medication, even though many of the medications are considered safe to use during lactation. Using the results of this study, intervention strategies supporting RA patients who wish to breastfeed may be developed.

Identifying Clinical Factors Associated With Low Disease Activity and Remission of Rheumatoid Arthritis During Pregnancy.

OBJECTIVE: To identify a combination of clinical factors associated with low disease activity and remission in the third trimester during pregnancy in women with rheumatoid arthritis (RA). METHODS: This study is embedded in the Pregnancy-Induced Amelioration of Rheumatoid Arthritis study, a prospective cohort study. There were data available on 190 pregnancies from first trimester until delivery. Multivariate regression analyses were performed on the disease activity (Disease Activity Score in 28 joints [DAS28] using the C-reactive protein [CRP] level) in the third trimester. Independent covariates were the DAS28-CRP-3 in first trimester, prednisone and sulfasalazine use in the first trimester, parity, methotrexate use in the past, autoantibody status, the presence of erosions, and RA disease duration. RESULTS: In multivariate regression models, the DAS28-CRP-3, use of prednisone in the first trimester, and the presence of autoantibodies were negatively associated with low disease activity (DAS28-CRP-3 <3.2) in the third trimester (P < 0.05), and the DAS28-CRP-3 and presence of autoantibodies were also associated with remission (DAS28-CRP-3 <2.6) (P < 0.001). Subgroup analysis revealed that the associations of prednisone use and presence of autoantibodies were only present in patients with moderate-to-high disease activity (DAS28-CRP-3 ≥3.2) in the first trimester. CONCLUSION: RA patients who have a low DAS28-CRP-3 in the first trimester (irrespective of autoantibody status or prednisone use) are likely to have low disease activity or remission in the third trimester. Also, women with higher disease activity who are not taking prednisone and who express no autoantibodies still have a fair chance of low disease activity in the last trimester.

Is Disease Activity in Rheumatoid Arthritis during Pregnancy and after Delivery Predictive for Disease Activity in a Subsequent Pregnancy?

OBJECTIVE: To determine whether disease activity in women with rheumatoid arthritis (RA) in 1 pregnancy is predictive for disease activity in a subsequent pregnancy. METHODS: In the Pregnancy-induced Amelioration of Rheumatoid Arthritis study, there are prospective data on 27 patients who participated twice. Improvement and deterioration is determined by changes in the Disease Activity Score in 28 joints. RESULTS: Only 4 patients (14.8%) had comparable disease courses in both pregnancies, whereas treatment remained mostly similar. In contrast, a flare postpartum after the first pregnancy was predictive for a flare after the second pregnancy (p = 0.003). CONCLUSION: RA disease course in following pregnancies cannot be predicted based upon previous pregnancies. However, a flare postpartum seems to predict subsequent flares.

Pregnancy and rheumatoid arthritis.

Fertility is impaired in female patients with rheumatoid arthritis (RA), which is related to disease activity and the use of certain medication. During pregnancy, disease activity usually improves, but less than previously thought. Especially in women with high disease activity, the pregnancy outcome is also impaired. All of this underscores the importance of strict control of disease activity in RA patients who wish to conceive. Management of RA disease activity during pregnancy might be a challenge as the treatment options are limited. Evidence is accumulating that tumor necrosis factor (TNF) blockers can be safely used during pregnancy, particularly during the first trimester and the beginning of the second trimester. Far less is known about the problems faced by male RA patients who wish to conceive, in terms of not only fertility and pregnancy outcome but also the safety of medication. In this paper, the fertility issues in patients with RA, the pregnancy-associated improvement of RA, the pregnancy outcomes, including the long-term effects on the offspring, and treatment options, including those during lactation and for male patients wishing to conceive, will be reviewed.