Clinical Aspects of Pregnancy-induced Amelioration of Rheumatoid Arthritis: PARA-study

In this PhD thesis, embedded in the PARA (Pregnancy-induced Amelioration of Rheumatoid Arthritis) study, several clinical aspects of the spontaneously occurring pregnancy-induced improvement of rheumatoid arthritis (RA) are addressed. An overview is given of inflammatory rheumatic diseases and the current knowledge about their disease courses and treatment options during pregnancy and postpartum. This thesis focuses firstly on the description of tools to objectively measure the disease activity and functionality of RA before, during and after pregnancy. Associations with the disease course and patient’s characteristics are subsequently made. The influence on the pregnancy outcome of both disease activity and treatment of RA with prednisone, are assessed regarding pregnancy durations and birth weight. Postpartum however RA tends to flare again. The problems which patients with RA will encounter in parental function, while nursing their babies, are addressed

Immunoglobulin G galactosylation and sialylation are associated with pregnancy-induced improvement of rheumatoid arthritis and the postpartum flare: Results from a large prospective cohort study

Introduction: Improvement of rheumatoid arthritis (RA) during pregnancy has been causatively associated with increased galactosylation of immunoglobulin G (IgG) N-glycans. Since previous studies were small, did not include the postpartum flare and did not study sialylation, these issues were addressed in the present study.Methods: Serum from 148 RA cases and 32 healthy controls was collected at several time points before, during and after pregnancy. Improvement during pregnancy and postpartum flare were determined according to the European League Against Rheumatism (EULAR) response criteria. Galactosylation and sialylation of Immunoglobulin G (IgG) and the presence of bisecting N-acetylglucosamine (GlcNAc) were analyzed by matrix-assisted laser desorption/ionization - time of flight - mass spectrometry (MALDI-TOF-MS).Results: IgG1 and IgG2 galactosylation of the cases and controls increased during pregnancy with a maximum in the third trimester. Galactosylation decreased directly postpartum. IgG galactosylation of controls was at a higher level than cases (P < 0.001 at all time points) and a similar pattern was observed for sialylation. Moreover, there was a good association between galactosylation and sialylation. The increase in galactosylation was significantly more pronounced for cases with improvement than cases without improvement during pregnancy. The reverse was true for deteriorators and non-deteriorators postpartum. The presence of bisecting GlcNAc was not significantly influenced by pregnancy or postpartum for c

Parenting problems postpartum can be detected early in pregnancy in patients with rheumatoid arthritis

OBJECTIVE: To describe parenting disability postpartum in patients with rheumatoid arthritis (RA) using the Parenting Disability Index and to determine early in pregnancy which patients will face parenting problems postpartum. METHODS: Data were collected from a prospective study on pregnancy and RA (Pregnancy induced Amelioration of Rheumatoid Arthritis study). Postpartum visits were performed at 6, 12 and 26 weeks after delivery. Domains causing parenting difficulties were identified. A multivariate logistic regression model to identify which patients develop parenting disabilities postpartum with patient characteristics in the first trimester as covariates was performed. RESULTS: 148 patients were eligible for this study. The domains carrying, hygiene, feeding, getting up and down, and household/shopping were frequently scored as difficult. Maintaining discipline, taking care of the children when sick, listening and having other children over caused the least problems. 30.1% of patients with RA report low parenting disability, 30.9% reports intermediate disability and 39.0% reports high disability. Patients with a low Health Assessment Questionnaire (HAQ)-score in the first trimester (OR 9.2, 95% CI 3.0 to 27.7, p<0.001) and low disease activity in the first trimester (Disease Activity Score 28-joint count C reactive protein<3.2) (OR 4

Glucocorticoid receptor gene polymorphisms and disease activity during pregnancy and the postpartum period in rheumatoid arthritis

Introduction: The mechanism underlying the spontaneous improvement of rheumatoid arthritis (RA) during pregnancy and the subsequent postpartum flare is incompletely understood, and the disease course varies widely between pregnant RA patients. In pregnancy, total and free levels of cortisol increase gradually, followed by a postpartum decrease to prepregnancy values. The glucocorticoid receptor (GR) polymorphisms BclI and N363S are associated with relatively increased glucocorticoid (GC) sensitivity, whereas the 9β and ER22/23EK polymorphisms of the GR gene are associated with a relatively decreased GC sensitivity. We examined the relation between the presence of these GR polymorphisms and level of disease activity and disease course of RA during pregnancy and postpartum.Methods: We studied 147 participants of the PARA study (Pregnancy-Induced Amelioration of Rheumatoid Arthritis study), a prospective study investigating the natural improvement during pregnancy and the postpartum flare in women with RA. Patients were visited, preferably before pregnancy, at each trimester and at three postpartum time points. On all occasions, disease activity was scored by using DAS28. All patients were genotyped for the GR polymorphisms BclI, N363S, 9β, and ER22/23EK and divided in groups harboring either polymorphisms conferring increased GC sensitivity (BclI and N363S; GC-S patients) or polymorphisms conferring decreased GC sensitivity (9β or 9β + ER22/23EK; GC-I patients). Data were analyzed by using a mixed linear model, comparing GC-S patients with GC-I patients with respect to improvement during pregnancy and the postpartum flare. The cumulative disease activity was calculated by using time-integrated values (area under the curve, AUC) of DAS28 in GC-I patients versus GC-S patients. Separate analyses were performed according to the state of GC use.Results: GC-S patients treated with GC had a significantly lower AUC of DAS28 in the postpartum period than did GC-I patients. This difference was not observed in patients who were not treated with GCs. During pregnancy, GC-S and GC-I patients had comparable levels of disease activity and course of disease.Conclusions: Differences i

[Rheumatic diseases need more attention in case of the desire to have children and during pregnancy].

Treatment of rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus and Bechterew's disease is still improving and the number of fertile patients with a wish to conceive will probably increase. New knowledge regarding the course of rheumatic diseases during pregnancy and post partum herald a change in the support of women with rheumatic diseases who desire to have children. Justified use of antirheumatic drugs before, during and after pregnancy is a key issue for a successful pregnancy. The newer agents such as tumour necrosis factor (TNF) alpha blocking agents can also be of use. Specific preconception care should be offered to women with rheumatic diseases to optimize and increase chances of a successful pregnancy

Circulating maternal cytokines influence fetal growth in pregnant women with rheumatoid arthritis

Background High rheumatoid arthritis (RA) disease activity during pregnancy is associated with a lower birth weight. Active RA is characterised by high circulating levels of cytokines, which can mediate placental growth and remodelling. Objectives To assess the influence of maternal serum cytokine levels on birth weight in RA pregnancy. Methods This study is embedded in the PARA Study, a prospective study on RA and pregnancy. In the present study, 161 pregnant women with RA and 32 healthy pregnant women were studied. The main outcome measures were birth weight SD score (birth weight SDS) in relation to maternal serum levels of interleukin-10 (IL10), interleukin-6 (IL-6) and tumour necrosis factor-α (TNFα) at three different time points: preconception and during the first and third trimester. Single-nucleotide polymorphisms (SNPs) in the corresponding cytokine genes were also studied. Results During the first trimester, IL-10 was detectable in 16% of patients wi

Mannose-binding lectin levels during pregnancy: A longitudinal study

Background: Pregnancy is associated with changes in the immune system. Although previous studies have focussed mainly on adaptive immunity, there are indications that components of innate immunity, such as mannose-binding lectin (MBL), are associated with pregnancy outcome. Although this would suggest that pregnancy also involves adaptations in innate immunity, there are few studies in this area. Therefore, we aimed to determine whether MBL concentrations and the following steps in complement pathway activation are influenced by pregnancy. Methods: MBL and Ficolin-2 concentrations, MBL-MBL-associated serine protease (MASP) complex activity, MBL pathway activity and classical complement pathway activity were determined by enzyme-linked immunosorbent assay (ELISA) in sera from pregnant women (n = 32) during each trimester and post-partum. MBL genotyping was performed by PCR. Results: During pregnancy, MBL concentrations increased to 140% [interquartile range (IQR) 116-181%, P < 0.0001]. This increase was already present at 12 weeks of pregnancy and was most pronounced in the high-production AA-gen