Skip to content

Advertisement

  • Research article
  • Open Access

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

  • 1Email author,
  • 2,
  • 1,
  • 1,
  • 3,
  • 1,
  • 2,
  • 2 and
  • 1
Arthritis Research & Therapy201214:R183

https://doi.org/10.1186/ar4014

©  Quax et al.; licensee BioMed Central Ltd. 2012

  • Received: 6 April 2012
  • Accepted: 13 August 2012
  • Published:

Abstract

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 in relative GC sensitivity, as determined by GR polymorphisms, are associated with the level of disease activity in the postpartum period in GC-treated patients, but they do not seem to influence the course of the disease per se.

Keywords

  • Rheumatoid Arthritis
  • Glucocorticoid Receptor
  • Postpartum Period
  • Grave Ophthalmopathy
  • Rheumatoid Arthritis Study

Introduction

Rheumatoid arthritis (RA) is a systemic inflammatory disorder characterized by chronic synovitis leading to joint destruction. During pregnancy, spontaneous reduction of disease activity in RA is common, a phenomenon that is also observed in other autoimmune disorders [1–5]. After birth, however, RA deteriorates in the majority of women [3, 4, 6]. Pregnancy is supposed to have immunomodulatory effects, but the exact mechanisms underlying the spontaneous amelioration during pregnancy and the subsequent postpartum flare have still not been elucidated. Several hypotheses have, however, been put forward, including the beneficial effect of maternal-fetal HLA-incompatibility [7, 8] and of increased galactosylation of immunoglobulin G [9–11]. Shifts in T-cell cytokine secretion profiles also have been proposed as a potential mechanism underlying the improvement of RA during pregnancy and the postpartum deterioration [12–15].

In healthy pregnancy, total and free levels of cortisol increase progressively, reaching a peak in the second and third trimesters [16–18]. The improvement in RA starts in the first trimester, and almost half of patients have at least low disease activity (DAS28 <3.2) in the third trimester [4]. Nevertheless, prospectively studied cohorts of pregnant RA patients concurrently evaluating reduction of disease activity with accompanying (free) cortisol levels on an individual basis are lacking. It is known from daily clinical practice, however, that interindividual differences in the degree of pregnancy-induced remission and the postpartum deterioration do exist, with some women reaching complete remission during pregnancy, whereas others have persistent active disease. This discrepancy was already noticed in two early case series in which a cortisol metabolite (that is, 17-hydroxycorticosteroid (17-OHCS)) was measured in pregnant RA women. High levels of 17-OHCS related to improvement of disease activity in only a subset of patients [19, 20]. This variation in clinical responses does not depend solely on the absolute levels of cortisol but might also be explained by differences in individual GC sensitivity.

In the healthy population, a considerable variation in GC sensitivity has been demonstrated by low-dose (0.25 mg) dexamethasone suppression tests and functional in vitro assays [21, 22]. In diseased states, these differences in GC sensitivity are reflected by a wide spectrum of GC therapy efficacy, which may partly be explained by four functional single nucleotide polymorphisms (SNPs) in the glucocorticoid receptor (GR) gene. The minor alleles of the polymorphisms N363S (rs6195) and BclI (rs41423247) are associated with a relative hypersensitivity to GC, whereas the ER22/23EK (rs6189 and rs6190) and 9β (rs6198) SNPs are associated with a relatively decreased GC sensitivity [23]. Previously, we demonstrated that carriers of the ER22/23EK variant more often had erosive disease and more frequently needed tumor necrosis factor-alpha (TNF-α) blocking therapy [24]. Similarly, these GR polymorphisms could explain differences in disease course during pregnancy and postpartum in RA.

Therefore, the aim of our study was to investigate the association between GR gene polymorphisms and level of disease activity and disease course during pregnancy and in the postpartum period in RA patients.

Materials and methods

Patients

All patients were participants of the PARA study (Pregnancy-Induced Amelioration of Rheumatoid Arthritis study), a nationwide prospective study investigating the natural improvement of RA during pregnancy and the postpartum flare [4]. If possible, patients were visited before conception. Patients were visited at their home address at each trimester and at 6 weeks, 12 weeks, and 26 weeks after delivery. In the present study, women who had a miscarriage were excluded from further analysis, and no woman was included twice.

Data collection

Trained research nurses or physicians examined all patients by using a standardized 28-joint count for swelling and pain. Disease activity was calculated by using the disease activity score (DAS28) with three variables (swollen joint count, tender joint count and C-reactive protein (CRP) level) [25], because this variant of the DAS has been shown to reflect disease activity most reliably during pregnancy [26]. Current medication use at each visit was recorded. All mothers provided information on breastfeeding, because this may interfere with resumption of methotrexate (MTX) therapy after delivery.

Improvement of disease activity during pregnancy was defined according to the EULAR criteria as responders (moderate and good response combined) versus nonresponders and could, in accordance with the EULAR criteria, be applied only to those patients with a baseline DAS28 ≥3.2 at the first trimester (n = 71) [25]. The "reversed" EULAR criteria were used to define a very early flare (deterioration between the visits at the third trimester and at 6 weeks postpartum), early flare (deterioration between the visits at 6 weeks and at 3 months postpartum), and late flare (deterioration between the visits at 6 weeks and at 6 months postpartum), as described previously [4], with minor modifications (see Additional file 1, Table S1).

Glucocorticoid-receptor polymorphisms

All patients were genotyped for four functional polymorphisms of the GR gene (ER22/23EK, rs6189 and rs6190; N363S, rs6195; BclI, rs41423247 and 9β, rs6198), by using DNA extracted from samples of peripheral venous blood. Genotyping was performed by using Taqman allelic discrimination assays (Applied Biosystems, Nieuwerkerk a/d IJssel, The Netherlands), following protocols described by the supplier. Results were analyzed by using the sequence detection system 2.2 software (Applied Biosystems).

Data and statistical analysis

Mann-Whitney U tests and χ2 tests were used to determine differences in baseline characteristics.

We estimated DAS28 in patients who used GCs versus patients who did not use GCs by using a linear mixed model (LMM). With this model, we compared the area under the curve (AUC) of DAS28 in the two groups on the whole trajectory, during pregnancy, and in the postpartum period. We used the DAS28 score as the response, and Time and the Use of glucocorticoid × Time interaction as covariates. Time is used as a categoric variable denoting one of the seven measurement occasions. Similarly, we then estimated separate linear mixed models for each individual polymorphism, by using Time and the interaction of Time × Carriage of minor alleles as covariates. Because of the low frequencies of the N363S (4.1%) and the ER22/23EK (7.5%) carriers, no AUC of DAS28 could be calculated for these models. Subjects were therefore further analyzed as carriers of a polymorphism associated with increased sensitivity for GCs (BclI and/or N363S, referred to as the GC-S group) versus carriers of a polymorphism associated with reduced sensitivity to GCs (9β or 9β + ER22/23EK, referred to as the GC-I group). Patients who were heterozygous for both the BclI and 9β polymorphisms or the N363S and 9β variants were excluded from the GC-S/GC-I groups. In this final model, we again tested whether the average DAS28 was equal between the GC-S and GC-I groups on the whole profile, during pregnancy and postpartum. In all models, we used a person-specific intercept and assumed that the residual covariance structure was autoregressive heteroskedastic.

χ2 analysis was applied to compare rates of response during pregnancy and the presence of a very early, early, or late flare. All previously mentioned analyses were performed in patients who used GCs and in patients who did not use GCs separately. Patients were designated as GC-users when patients used GCs during pregnancy and used GCs at the time of at least two of three postpartum visits. No correction for multiple comparisons was applied. Differences in the median daily dosage of prednisone given during pregnancy and postpartum were calculated by using the Mann-Whitney test. Statistical analysis was performed by using the SPSS version 17.0 and SAS version 9.2. We considered differences statistically significant if P ≤ 0.05 (two-sided).

Ethical approval

All subjects signed informed consent, and the study was approved by the medical ethics committee of the Erasmus Medical Center. This study is in compliance with the Declaration of Helsinki.

Results

Baseline characteristics

In total, 147 patients participating in the PARA study were enrolled in the current study. More than 60% of patients had active disease in the first trimester of their pregnancy, and all women fulfilled the ACR 1987 revised criteria for RA (Table 1).
Table 1

Patient characteristics

 

n= 147

Age at delivery in years, mean (SD)

32.4 (3.8)

Disease duration in years, median (range)

5.5 (0.1-28.4)

Gestational age at delivery in weeks, mean (SD)

39.3 (1.9)

Anti-CCP positive, n (%)

87 (59.2)

Rheumatoid factor (IgM) positive, n (%)

110 (74.8)

Presence of erosions, n (%)

105 (71.4)

Number of DMARDs before conception, median (range)

2 (0-6)

Breastfeeding (6 weeks postpartum), n (%)

60 (40.8)

DAS28-CRP3 ≥3.2 in first trimester, n (%)a

71 (61.7)

Moderate/good response during pregnancy, n (%)b

32 (45.1)

Very early flare, N (%)c

29 (21.5)

Early flare, n (%)d

29 (22.0)

Late flare, n (%)e

37 (30.1)

aIn 115 patients, DAS28 in the first trimester was available. bAccording to EULAR response criteria, DAS28 ≥3.2 in the first trimester is required. Data were available in c135 , d132, and e123 patients, respectively, according to reversed EULAR response criteria. Very early flare, deterioration between the visit at the third trimester and at 6 weeks postpartum; early flare, deterioration between visits at 6 weeks and at 3 months postpartum; late flare, deterioration between visits at 6 weeks and at 6 months postpartum; anti-CCP, anti-cyclic citrullinated protein. DMARDs, Disease-modifying antirheumatic drugs, including prednisone.

As shown previously, sulfasalazine and prednisone were the most frequently used treatment regimens during pregnancy [4]. Approximately 40% of patients did not use any antirheumatic drug (see Additional file 2, Table S2). Disease activity scores were available in 69, 115, 133, 142, 140, 137, and 131 women at the seven different study visits before conception, during pregnancy, and postpartum, respectively.

In general, patients treated with GCs (n = 57) had significantly higher disease activity than did patients not treated with GCs (n = 90; Figure 1). Patients who used GCs had a significantly shorter duration of gestation and had erosions more frequently (Table 2). Analyses were therefore performed separately according to the state of GC use.
Figure 1
Figure 1

Disease activity (DAS28 ± SEM) among pregnant women with ( n = 57) and without ( n = 90) use of glucocorticoids.

Table 2

Patient characteristics stratified according to use of glucocorticoids

 

Use of GCs (n= 57)

No use of GCs (n= 90)

Age at delivery in years, mean (SD)

33.15 (3.80)

31.93 (3.67)

Disease duration in years, median (range)

6.07 (0.22-28.57)

5.18 (0.14-28.54)

Gestational age at delivery in weeks, mean (SD)

38.44 (2.30)

39.85 (1.27)f

Anti-CCP positive, n (%)

39 (68.4)

51 (56.7)

Rheumatoid factor (IgM) positive, n (%)

47 (82.5)

63 (70.0)

Presence of erosions, n (%)

49 (86)

56 (62.2)f

Dosage of prednisone (mg/day), median (range)

7.5 (2.5-20)

-

Number of DMARDs before conception, median (range)

2 (0-5)

1 (0-4)f

Breastfeeding (6 weeks postpartum), n (%)

13 (22.8)

47 (52.2)f

DAS28 ≥3.2 in first trimester, n (%)a

33 (70.2)

38 (55.9)

Moderate/good response during pregnancy, n (%)b

15 (45.5)

17 (43.6)

Very early flare, n (%)c

9 (17.3)

18 (21.7)

Early flare, n (%)d

9 (18.0)

20 (24.4)

Late flare, n (%)e

10 (21.3)

27 (35.5)

aIn 115 patients, DAS28 in the first trimester was available. bAccording to EULAR response criteria, DAS28 ≥3.2 in the first trimester is required, n = 71 of 115. cData were available in 135 patients, d132 patients, and e123 patients, according to reversed EULAR response criteria. fP < 0.05 as compared with patients using GCs. Anti-CCP, anti-cyclic citrullinated protein.

DMARDs, Disease-modifying antirheumatic drugs, excluding prednisone.

Glucocorticoid receptor polymorphisms and disease course during gestation and postpartum

We found 84 (57.1%) patients who were heterozygous or homozygous carriers of the BclI polymorphism. The 9β polymorphism was present in 48 (32.7%) patients.

Analysis of the level of disease activity in carriers versus noncarriers of these polymorphisms showed that 9β carriers did not differ significantly in AUC of DAS28 compared with noncarriers (Figure 2A). BclI carriers treated with GC had a near-significant lower AUC of DAS28 postpartum compared with noncarriers (P = 0.056; Figure 2B, right panel). No differences in the AUCs of DAS28 postpartum were observed in non-GCtreated patients.
Figure 2
Figure 2

Disease activity according to carriage of GR polymorphisms. (A) Disease activity in carriers of 9β (n = 29) versus noncarriers (n = 61) in patients not using glucocorticoids (GCs) (left panel). Of patients using GCs, 19 were carriers of the 9β polymorphism, and 37 were noncarriers (right panel). In one patient, the 9β-genotype could not be determined. (B) Disease activity in carriers of BclI (n = 55) versus noncarriers (n = 34) in patients not using GCs (left panel). In one patient, the BclI-genotype could not be determined. Of patients using GCs, 29 were carriers of the BclI polymorphism, and 28 were WT carriers (right panel). (C) Disease activity in carriers of polymorphisms conferring increased GC sensitivity (n = 44; GC-S group) versus patients carrying polymorphisms conferring decreased GC sensitivity (n = 15; GC-I group) not using GC (left panel). Of patients using GC, 24 were in the GC-S group, and 13, in the GC-I group (right panel). Disease activity is presented as DAS28 ± SEM.

Nineteen (12.9%) patients were heterozygous carriers of both the BclI and 9β polymorphisms or the N363S and 9β variants. These patients were excluded in the final analysis to allow an appropriate comparison between patients carrying a polymorphism associated with increased sensitivity to GCs (BclI and/or N363S, GC-S group) and patients harboring a genetic variant associated with reduced sensitivity to GCs (9β or 9β + ER22/23EK, GC-I group). The results of this analysis, shown in Figure 2C, indicate that GC treated patients in the GC-I group had a significantly higher AUC of DAS28 in the whole postpartum period (that is, up to 26 weeks), than did patients in the GC-S group (P = 0.046). In patients not treated with GCs, these differences did not exist.

The AUC of DAS28 during pregnancy, the course of the disease, EULAR response during pregnancy, and the presence of a very early flare, early flare, or late flare with reversed EULAR response criteria, were not associated with any GR genotype, although the DAS28 was lower in the GC-S group than in the GC-I group at all time points in GC treated patients (Figure 2C).

The GR genotypes were equally distributed among GC users and non-GC users. The clinical characteristics between GC-S and GC-I patients, stratified according to the use of GCs, did not differ, except for the more frequent use of nonsteroidal antiinflammatory drugs (NSAIDs) in the GC-I group (P = 0.01; Table 3). The median daily dosage of prednisone given during pregnancy, taking the highest dosage needed at any time during pregnancy, tended to be higher in GC-I patients (8.75 mg daily versus 6.25 mg daily; P = 0.157). GC-S patients could more frequently reduce the daily needed GC dose during pregnancy than could the GC-I patients, possibly reflecting higher GC sensitivity to the pregnancy-related increase in cortisol in GC-S patients, although this was not statistically significant (n = 7, 29.2% versus n = 1, 7.7%; P = 0.130). In the postpartum period, prednisone daily dosages did not differ between GC-S and GC-I patients.
Table 3

Clinical characteristics of patients in the GC-S and GC-I groups according to the use of glucocorticoids

 

Use of GCs

 

No use of GCs

 
 

GC-S (n= 24)

GC-I (n= 13)

GC-S (n= 44)

GC-I (n= 15)

Age at delivery in years, mean (SD)

34.1 (3.1)

34.1 (3.6)

31.6 (3.9)

31.2 (3.0)

Disease duration in years, median (range)

4.6 (0.2-28.6)

6.8 (1.0-22.7)

5.3 (0.1-28.5)

2.4 (0.2-28.4)

Gestational age at delivery in weeks, mean (SD)

39.0 (1.9)A

37.4 (2.2)

39.8 (1.3)

39.9 (1.3)

Anti-CCP positive, n (%)

16 (66.7)

8 (61.5)

24 (54.5)

6 (40%)

Rheumatoid factor (IgM) positive, n (%)

17 (70.8)

10 (76.9)

31 (70.5)

9 (60.0)

Presence of erosions, n (%)

22 (91.7)

13 (100)

28 (63.6)

8 (53.3)

Dosage of prednisone (pregnancy; mg/day), median (range)

6.25 (2.5-15)

8.75 (5-20)

-

-

Dosage of prednisone (postpartum; mg/day), median (range)

8.75 (2.5-15)

10.0 (5-15)

-

-

Number of DMARDs before conception, median (range)

2 (0-4)

2 (1-5)

2 (0-4)

2 (0-3)

Moderate/good response during pregnancy, n (%)

5/11 (45.5)

4/9 (44.4)

8/16 (50)

5/11 (45.5)

Very early flare, N/Ntotal (%)

5/21 (23.8)

3/13 (23.1)

10/41 (24.4)

5/13 (38.5)

Early flare, N/Ntotal (%)

4/21 (19.0)

2/12 (16.7)

12/40 (30.0)

3/13 (23.1)

Late flare, N/Ntotal (%)

4/19 (21.1)

4/13 (30.8)

15/37 (40.5)

4/12 (33.3)

Breastfeeding (6 weeks postpartum), n (%)

8 (33.3)

1 (7.7)

20 (45.5)

8 (53.3)

Use of NSAIDs at 6 months postpartum,a N/Ntotal (%)

7/22 (31.8)b

10/13 (76.9)

13/40 (32.5)

6/13 (46.2)

Use of MTX at 6 months postpartum,a N/Ntotal (%)

11/22 (50.0)

9/13 (69.2)

10/40 (25.0)

5/13 (38.5)

Use of sulfasalazine at 6 months postpartum,a N/Ntotal (%)

6/22 (27.3)

2/13 (15.4)

17/40 (42.5)

6/13 (46.2)

Use of anti-TNF-α at 6 months postpartum,a N/Ntotal (%)

3/22 (13.6)

3/13 (23.1)

2/40 (5.0)

0/13 (0)

Data concerning response during pregnancy, very early flare, early flare, and late flare were present in 47, 88, 86, and 81 patients, respectively. aAvailable in 88 patients. bP < 0.05 compared with GC-I, use of GC. Anti-CCP, anti-cyclic citrullinated protein; TNF-α, tumor necrosis factor-alpha.

Discussion

In this nationwide prospective study including 147 pregnant RA patients, we examined for the first time whether GR polymorphisms that modulate GC sensitivity are associated with the level of disease activity and disease course during pregnancy and the postpartum period. We show that GC treated patients in the GC-S group (that is, those with the BclI or N363S or both polymorphisms, associated with relatively increased GC sensitivity) have a significantly lower disease activity in the postpartum period than do patients in the GC-I group (9β or 9β + ER22/23EK, associated with relatively decreased GC sensitivity), as measured by the AUC of the DAS28. In patients not treated with GC, the level of disease activity and disease course during pregnancy or in the postpartum period does not seem to be influenced by differences in GR genotype.

Gestational-induced remission of RA has been recognized for a long time [27] and may in part be attributed to the increase in cortisol production that in turn enhances endogenous immunosuppression. Pregnancy is indeed considered to be a natural variant of hypercortisolism [28, 29] and serum (free) cortisol, urinary free cortisol, salivary cortisol, and cortisol content in hair all have been demonstrated to increase progressively during gestation, followed by a rapid postpartum decrease in cortisol levels [17, 18, 30–37].

Apart from cortisol availability, the ultimate biologic effects of GCs also depend on GC sensitivity, which is modulated by GR polymorphisms [23].

Based on the course of cortisol levels during pregnancy and after delivery, we hypothesized that differences in glucocorticoid sensitivity might in part explain why the beneficial effect of pregnancy on RA disease activity does not occur in all RA patients.

Polymorphisms of the GR gene have been demonstrated to influence disease course in several inflammatory disorders, including Graves ophthalmopathy [38], Crohn disease [39], and multiple sclerosis [40]. We recently demonstrated that the minor alleles of BclI and 9β were associated, respectively, with decreased and increased susceptibility to develop RA. In addition, ER22/23EK carriers had a worse disease phenotype and needed more frequent TNF-α blocking therapy [24]. We extend these data by demonstrating higher levels of disease activity in the postpartum period in GC treated patients in the GC-I group, despite the more frequent use of NSAIDs.

Interestingly, the differences in disease activity between carriers of GC-sensitive and GC-resistant polymorphisms were observed only in women treated with GCs. The GC treated patients involve a subgroup of women with high disease activity, as reflected by observed higher DAS28. Our observations may imply that in the postpartum phase, when endogenous cortisol levels decrease, patients with polymorphisms associated with increased GC sensitivity have more benefit from GC therapy. Therefore, in states of relative glucocorticoid deficiency, differences in GC sensitivity due to genetic variability may in part determine variations in disease activity. Conversely, in patients with low disease activity, as characterized by the absence of glucocorticoid therapy in our cohort, endogenous levels of cortisol apparently can prevent uncontrolled inflammatory processes independent of genetic variations of the GR gene, although we did not measure cortisol levels in our patients.

This concept of a "relative glucocorticoid deficiency" might also explain why the observed variation in disease activity seems to be restricted to the postpartum period, because Magiakou and co-workers [41] showed that hypothalamic CRH secretion in healthy pregnant women is transiently suppressed at 3 and 6 weeks, recovering only at 12 weeks postpartum. This suppression of the hypothalamic-pituitary-adrenal (HPA) axis in the postpartum period, which could be even more pronounced in RA in which a preexisting blunted HPA axis is described in nonpregnant states [42], might even further attenuate the ability of the HPA axis to produce sufficient levels of cortisol.

The clinical relevance of this blunted HPA axis in the first 3 months after childbirth is illustrated by a higher incidence or exacerbation of several autoimmune diseases, including postpartum depression, autoimmune thyroid disease, and rheumatoid arthritis itself [41, 43–46]. The lack of differences between GC-I and GC-S patients in disease activity during pregnancy could also be explained by altering levels of glucocorticoid sensitivity, as was suggested by Majzoub and co-workers [47, 48]. Alternatively, patients in the GC-I group tended to need higher daily dosages of GCs during pregnancy, which could have masked a higher level of disease activity in this subgroup of patients. Although we focused on glucocorticoids, absolute levels of estrogens and progesterone also increase progressively during gestation. Both estrogens and progesterone possess antiinflammatory properties and are therefore likely to have substantially influenced the disease course [49]. Similar to differences in GC sensitivity, one could speculate that variation in sensitivity to the immunosuppressing effects of estrogens and progesterone might also contribute to the wide clinical spectrum of changes in disease activity observed in pregnancy and after delivery in RA.

Interestingly, the difference in disease activity between GC-I and GC-S patients persisted during the entire postpartum follow-up period (that is, up to 26 weeks). Future studies should examine at which time points disease activity patterns of both groups converge to prepregnancy levels.

It should be noted that our study also has some limitations. First, genetic-association studies usually require larger numbers of patients. Although this is the largest prospectively studied cohort of pregnant RA patients, additional studies are needed to validate our findings. Second, the presented data are based on Caucasian patients only, who may differ from patients from other geographic areas with different genetic and environmental backgrounds. Third, parameters of HPA axis activity, not measured in this study, could have provided additional information in the non-GC treated patients.

Although the pattern of cortisol levels in pregnancy and after delivery has been extensively documented [17, 18, 30–37], large prospective studies evaluating cortisol levels along with clinical responses during pregnancy and postpartum in RA are currently lacking. Together with new insights in the past two decades supporting a blunted HPA axis in RA, this justifies renewed interest in the precise role of GC in pregnant RA patients and the course of disease [42, 50]. In this context, long-term indices of HPA axis activity, as measured by means of cortisol in hair, together with dynamic functional assays to assess GC sensitivity (that is, GR number, affinity of the GR receptor, and GR-mediated gene transcription) are promising techniques to unravel further the role of GCs and the precise contribution to pregnancy-associated alterations in disease activity in RA.

Conclusions

We demonstrate that differences in GC sensitivity, as determined by GR polymorphisms, might influence the level of disease activity in the postpartum period in GC treated women. The course of the disease itself does not seem to be associated with polymorphisms of the GR. In the light of the relatively small numbers of patients in each genotype group, however, our data should be regarded as an interesting new hypothesis possibly adding to the elucidation of the multifactorial mechanisms underlying pregnancy-induced amelioration and the postpartum flare, but the data do not necessarily prove the genetic association. Therefore, future (larger) studies should validate our hypothesis and examine both parameters of glucocorticoid availability and parameters of glucocorticoid sensitivity in relation to individual disease courses of pregnant RA patients.

Abbreviations

AUC: 

area under the curve

GC: 

glucocorticoid

GR: 

glucocorticoid receptor

HPA axis: 

hypothalamic-pituitary-adrenal axis

LMM: 

linear mixed model

MTX: 

methotrexate

NSAIDs: 

nonsteroidal antiinflammatory drugs

PARA study: 

Pregnancy-Induced Amelioration of Rheumatoid Arthritis study

RA: 

rheumatoid arthritis

SNPs: 

single-nucleotide polymorphisms

TNF-α: 

tumor necrosis factor-alpha.

Declarations

Acknowledgements

The authors thank all patients and rheumatologists for their contribution to the PARA study. We are grateful to all research assistants for their help in data collection. This study was supported by the Dutch Arthritis Association.

Authors’ Affiliations

(1)
Department of Internal Medicine, Erasmus MC, University Medical Center, 's-Gravendijkwal 230, Rotterdam, 3015, CE, The Netherlands
(2)
Department of Rheumatology, Erasmus MC, University Medical Center, 's-Gravendijkwal 230, Rotterdam, 3015, CE, The Netherlands
(3)
Department of Epidemiology and Biostatistics, Erasmus MC, University Medical Center, 's-Gravendijkwal 230, Rotterdam, 3015, CE, The Netherlands

References

  1. Straub RH, Buttgereit F, Cutolo M: Benefit of pregnancy in inflammatory arthritis. Ann Rheum Dis. 2005, 64: 801-803. 10.1136/ard.2005.037580.PubMed CentralView ArticlePubMedGoogle Scholar
  2. Ostensen M, Villiger PM: The remission of rheumatoid arthritis during pregnancy. Semin Immunopathol. 2007, 29: 185-191. 10.1007/s00281-007-0072-5.View ArticlePubMedGoogle Scholar
  3. Barrett JH, Brennan P, Fiddler M, Silman AJ: Does rheumatoid arthritis remit during pregnancy and relapse postpartum? Results from a nationwide study in the United Kingdom performed prospectively from late pregnancy. Arthritis Rheum. 1999, 42: 1219-1227. 10.1002/1529-0131(199906)42:6<1219::AID-ANR19>3.0.CO;2-G.View ArticlePubMedGoogle Scholar
  4. de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM: Disease activity of rheumatoid arthritis during pregnancy: results from a nationwide prospective study. Arthritis Rheum. 2008, 59: 1241-1248. 10.1002/art.24003.View ArticlePubMedGoogle Scholar
  5. Confavreux C, Hutchinson M, Hours MM, Cortinovis-Tourniaire P, Moreau T: Rate of pregnancy-related relapse in multiple sclerosis: Pregnancy in Multiple Sclerosis Group. N Engl J Med. 1998, 339: 285-291. 10.1056/NEJM199807303390501.View ArticlePubMedGoogle Scholar
  6. Nelson JL, Ostensen M: Pregnancy and rheumatoid arthritis. Rheum Dis Clin North Am. 1997, 23: 195-212. 10.1016/S0889-857X(05)70323-9.View ArticlePubMedGoogle Scholar
  7. Hunt JS: Stranger in a strange land. Immunol Rev. 2006, 213: 36-47. 10.1111/j.1600-065X.2006.00436.x.PubMed CentralView ArticlePubMedGoogle Scholar
  8. Nelson JL, Hughes KA, Smith AG, Nisperos BB, Branchaud AM, Hansen JA: Maternal-fetal disparity in HLA class II alloantigens and the pregnancy-induced amelioration of rheumatoid arthritis. N Engl J Med. 1993, 329: 466-471. 10.1056/NEJM199308123290704.View ArticlePubMedGoogle Scholar
  9. Forger F, Ostensen M: Is IgG galactosylation the relevant factor for pregnancy-induced remission of rheumatoid arthritis?. Arthritis Res Ther. 2010, 12: 108-10.1186/ar2919.PubMed CentralView ArticlePubMedGoogle Scholar
  10. van de Geijn FE, Wuhrer M, Selman MH, Willemsen SP, de Man YA, Deelder AM, Hazes JM, Dolhain RJ: 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. Arthritis Res Ther. 2009, 11: R193-10.1186/ar2892.PubMed CentralView ArticlePubMedGoogle Scholar
  11. Alavi A, Arden N, Spector TD, Axford JS: Immunoglobulin G glycosylation and clinical outcome in rheumatoid arthritis during pregnancy. J Rheumatol. 2000, 27: 1379-1385.PubMedGoogle Scholar
  12. Wegmann TG, Lin H, Guilbert L, Mosmann TR: Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon?. Immunol Today. 1993, 14: 353-356. 10.1016/0167-5699(93)90235-D.View ArticlePubMedGoogle Scholar
  13. Forger F, Marcoli N, Gadola S, Moller B, Villiger PM, Ostensen M: Pregnancy induces numerical and functional changes of CD4+CD25 high regulatory T cells in patients with rheumatoid arthritis. Ann Rheum Dis. 2008, 67: 984-990.View ArticlePubMedGoogle Scholar
  14. Elenkov IJ, Hoffman J, Wilder RL: Does differential neuroendocrine control of cytokine production govern the expression of autoimmune diseases in pregnancy and the postpartum period?. Mol Med Today. 1997, 3: 379-383. 10.1016/S1357-4310(97)01089-7.View ArticlePubMedGoogle Scholar
  15. Russell AS, Johnston C, Chew C, Maksymowych WP: Evidence for reduced Th1 function in normal pregnancy: a hypothesis for the remission of rheumatoid arthritis. J Rheumatol. 1997, 24: 1045-1050.PubMedGoogle Scholar
  16. Mastorakos G, Ilias I: Maternal and fetal hypothalamic-pituitary-adrenal axes during pregnancy and postpartum. Ann N Y Acad Sci. 2003, 997: 136-149. 10.1196/annals.1290.016.View ArticlePubMedGoogle Scholar
  17. Abou-Samra AB, Pugeat M, Dechaud H, Nachury L, Bouchareb B, Fevre-Montange M, Tourniaire J: Increased plasma concentration of N-terminal beta-lipotrophin and unbound cortisol during pregnancy. Clin Endocrinol (Oxf). 1984, 20: 221-228. 10.1111/j.1365-2265.1984.tb00077.x.View ArticleGoogle Scholar
  18. D'Anna-Hernandez KL, Ross RG, Natvig CL, Laudenslager ML: Hair cortisol levels as a retrospective marker of hypothalamic-pituitary axis activity throughout pregnancy: comparison to salivary cortisol. Physiol Behav. 2011, 104: 348-353. 10.1016/j.physbeh.2011.02.041.PubMed CentralView ArticlePubMedGoogle Scholar
  19. Smith WD, West HF: Pregnancy and rheumatoid arthritis. Acta Rheum Scand. 1960, 6: 189-201. 10.3109/03009746009165037.View ArticleGoogle Scholar
  20. Oka M: Activity of rheumatoid arthritis and plasma 17-hydroxycorticosteroids during pregnancy and following parturition: report on two cases. Acta Rheumatol Scand. 1958, 4: 243-248.View ArticlePubMedGoogle Scholar
  21. Huizenga NA, Koper JW, de Lange P, Pols HA, Stolk RP, Grobbee DE, de Jong FH, Lamberts SW: Interperson variability but intraperson stability of baseline plasma cortisol concentrations, and its relation to feedback sensitivity of the hypothalamo-pituitary-adrenal axis to a low dose of dexamethasone in elderly individuals. J Clin Endocrinol Metab. 1998, 83: 47-54. 10.1210/jc.83.1.47.PubMedGoogle Scholar
  22. Hearing SD, Norman M, Smyth C, Foy C, Dayan CM: Wide variation in lymphocyte steroid sensitivity among healthy human volunteers. J Clin Endocrinol Metab. 1999, 84: 4149-4154. 10.1210/jc.84.11.4149.PubMedGoogle Scholar
  23. Manenschijn L, van den Akker EL, Lamberts SW, van Rossum EF: Clinical features associated with glucocorticoid receptor polymorphisms: an overview. Ann N Y Acad Sci. 2009, 1179: 179-198. 10.1111/j.1749-6632.2009.05013.x.View ArticlePubMedGoogle Scholar
  24. van Oosten MJ, Dolhain RJ, Koper JW, van Rossum EF, Emonts M, Han KH, Wouters JM, Hazes JM, Lamberts SW, Feelders RA: Polymorphisms in the glucocorticoid receptor gene that modulate glucocorticoid sensitivity are associated with rheumatoid arthritis. Arthritis Res Ther. 2010, 12: R159-10.1186/ar3118.PubMed CentralView ArticlePubMedGoogle Scholar
  25. Van Riel PL, van Gestel AM, Scott DG: Interpreting disease course. EULAR Handbook of Clinical Assessments of Disease Activity in Rheumatoid Arthritis. Edited by: van Riel PL, van Gestel AM, Scott DG. 2000, Alphen aan den Rijn: van Zuiden Communications, 39-43.Google Scholar
  26. de Man YA, Hazes JM, van de Geijn FE, Krommenhoek C, Dolhain RJ: Measuring disease activity and functionality during pregnancy in patients with rheumatoid arthritis. Arthritis Rheum. 2007, 57: 716-722. 10.1002/art.22773.View ArticlePubMedGoogle Scholar
  27. Hench PS: The amelioration effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrosis, and intermittent hydrarthrosis. Mayo Clinic Proc. 1938, 13: 161-167.Google Scholar
  28. Goland RS, Jozak S, Conwell I: Placental corticotropin-releasing hormone and the hypercortisolism of pregnancy. Am J Obstet Gynecol. 1994, 171: 1287-1291.View ArticlePubMedGoogle Scholar
  29. Magiakou MA, Mastorakos G, Rabin D, Margioris AN, Dubbert B, Calogero AE, Tsigos C, Munson PJ, Chrousos GP: The maternal hypothalamic-pituitary-adrenal axis in the third trimester of human pregnancy. Clin Endocrinol (Oxf). 1996, 44: 419-428. 10.1046/j.1365-2265.1996.683505.x.View ArticleGoogle Scholar
  30. Elenkov IJ, Wilder RL, Bakalov VK, Link AA, Dimitrov MA, Fisher S, Crane M, Kanik KS, Chrousos GP: IL-12, TNF-alpha, and hormonal changes during late pregnancy and early postpartum: implications for autoimmune disease activity during these times. J Clin Endocrinol Metab. 2001, 86: 4933-4938. 10.1210/jc.86.10.4933.PubMedGoogle Scholar
  31. Obel C, Hedegaard M, Henriksen TB, Secher NJ, Olsen J, Levine S: Stress and salivary cortisol during pregnancy. Psychoneuroendocrinology. 2005, 30: 647-656. 10.1016/j.psyneuen.2004.11.006.View ArticlePubMedGoogle Scholar
  32. Harville EW, Savitz DA, Dole N, Herring AH, Thorp JM, Light KC: Patterns of salivary cortisol secretion in pregnancy and implications for assessment protocols. Biol Psychol. 2007, 74: 85-91. 10.1016/j.biopsycho.2006.07.005.View ArticlePubMedGoogle Scholar
  33. Kirschbaum C, Tietze A, Skoluda N, Dettenborn L: Hair as a retrospective calendar of cortisol production-Increased cortisol incorporation into hair in the third trimester of pregnancy. Psychoneuroendocrinology. 2009, 34: 32-37. 10.1016/j.psyneuen.2008.08.024.View ArticlePubMedGoogle Scholar
  34. Nolten WE, Rueckert PA: Elevated free cortisol index in pregnancy: possible regulatory mechanisms. Am J Obstet Gynecol. 1981, 139: 492-498.View ArticlePubMedGoogle Scholar
  35. Carr BR, Parker CR, Madden JD, MacDonald PC, Porter JC: Maternal plasma adrenocorticotropin and cortisol relationships throughout human pregnancy. Am J Obstet Gynecol. 1981, 139: 416-422.View ArticlePubMedGoogle Scholar
  36. Cohen M, Stiefel M, Reddy WJ, Laidlaw JC: The secretion and disposition of cortisol during pregnancy. J Clin Endocrinol Metab. 1958, 18: 1076-1092. 10.1210/jcem-18-10-1076.View ArticlePubMedGoogle Scholar
  37. Fleming AS, Ruble D, Krieger H, Wong PY: Hormonal and experiential correlates of maternal responsiveness during pregnancy and the puerperium in human mothers. Horm Behav. 1997, 31: 145-158. 10.1006/hbeh.1997.1376.View ArticlePubMedGoogle Scholar
  38. Boyle B, Koranyi K, Patocs A, Liko I, Szappanos A, Bertalan R, Racz K, Balazs C: Polymorphisms of the glucocorticoid receptor gene in Graves ophthalmopathy. Br J Ophthalmol. 2008, 92: 131-134. 10.1136/bjo.2007.126789.View ArticlePubMedGoogle Scholar
  39. De Iudicibus S, Stocco G, Martelossi S, Drigo I, Norbedo S, Lionetti P, Pozzi E, Barabino A, Decorti G, Bartoli F, Ventura A: Association of BclI polymorphism of the glucocorticoid receptor gene locus with response to glucocorticoids in inflammatory bowel disease. Gut. 2007, 56: 1319-1320.PubMed CentralView ArticlePubMedGoogle Scholar
  40. van Winsen LM, Manenschijn L, van Rossum EF, Crusius JB, Koper JW, Polman CH, Uitdehaag BM: A glucocorticoid receptor gene haplotype (TthIII1/ER22/23EK/9beta) is associated with a more aggressive disease course in multiple sclerosis. J Clin Endocrinol Metab. 2009, 94: 2110-2114. 10.1210/jc.2008-2194.View ArticlePubMedGoogle Scholar
  41. Magiakou MA, Mastorakos G, Rabin D, Dubbert B, Gold PW, Chrousos GP: Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab. 1996, 81: 1912-1917. 10.1210/jc.81.5.1912.PubMedGoogle Scholar
  42. Straub RH, Paimela L, Peltomaa R, Scholmerich J, Leirisalo-Repo M: Inadequately low serum levels of steroid hormones in relation to interleukin-6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis. Arthritis Rheum. 2002, 46: 654-662. 10.1002/art.10177.View ArticlePubMedGoogle Scholar
  43. Oka M: Effect of pregnancy on the onset and course of rheumatoid arthritis. Ann Rheum Dis. 1953, 12: 227-229. 10.1136/ard.12.3.227.PubMed CentralView ArticlePubMedGoogle Scholar
  44. Weetman AP: Immunity, thyroid function and pregnancy: molecular mechanisms. Nat Rev Endocrinol. 2010, 6: 311-318. 10.1038/nrendo.2010.46.View ArticlePubMedGoogle Scholar
  45. Silman A, Kay A, Brennan P: Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis Rheum. 1992, 35: 152-155. 10.1002/art.1780350205.View ArticlePubMedGoogle Scholar
  46. Wallenius M, Skomsvoll JF, Irgens LM, Salvesen KA, Koldingsnes W, Mikkelsen K, Kaufmann C, Kvien TK: Postpartum onset of rheumatoid arthritis and other chronic arthritides: results from a patient register linked to a medical birth registry. Ann Rheum Dis. 2010, 69: 332-336. 10.1136/ard.2009.115964.View ArticlePubMedGoogle Scholar
  47. Majzoub JA, Karalis KP: Placental corticotropin-releasing hormone: function and regulation. Am J Obstet Gynecol. 1999, 180: S242-246. 10.1016/S0002-9378(99)70708-8.View ArticlePubMedGoogle Scholar
  48. Karalis K, Goodwin G, Majzoub JA: Cortisol blockade of progesterone: a possible molecular mechanism involved in the initiation of human labor. Nat Med. 1996, 2: 556-560. 10.1038/nm0596-556.View ArticlePubMedGoogle Scholar
  49. Straub RH: The complex role of estrogens in inflammation. Endocr Rev. 2007, 28: 521-574. 10.1210/er.2007-0001.View ArticlePubMedGoogle Scholar
  50. Harbuz MS, Jessop DS: Is there a defect in cortisol production in rheumatoid arthritis?. Rheumatology (Oxford). 1999, 38: 298-302. 10.1093/rheumatology/38.4.298.View ArticleGoogle Scholar

Copyright

© Quax et al.; licensee BioMed Central Ltd. 2012

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement

Arthritis Research & Therapy

ISSN: 1478-6362

Contact us