Objective To study the impact of parity history on the risk of antibodies to citrullinated peptide antigens (ACPA) positive and ACPA-negative rheumatoid arthritis (RA), in different age-groups.
Method Data from a population-based case-control study of female incident RA cases were analysed (2035 cases and 2911 controls, aged 18–70 years ). Parity history was assessed through a questionnaire. Parous women were compared with nulliparous, by calculating odds ratios (ORs) with 95% confidence interval (CI).
Results Parity was associated with an increased risk of ACPA-negative RA in women aged 18–44 years (OR=2.1, 95% CI 1.4 to 3.2), but not in those aged 45–70 years (OR=0.9, 95% CI 0.7 to 1.3). Among young women, an increased risk of ACPA-negative RA was found in those who gave birth during the year of symptom onset (OR=2.6, 95% CI 1.4 to 4.8) and who were at a young age at first birth (<23) (OR=2.5, 95% CI 1.5 to 4.1). Parity and the postpartum period were not associated with ACPA-positive RA, but older age at first birth was weakly associated with a decreased risk.
Conclusions The increased risk of ACPA-negative RA in parous women of reproductive age seemed to be associated with an increased postpartum risk and with young age at first birth. Further research is needed to explore the biological mechanisms behind our findings.
- Rheumatoid Arthritis
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The gender difference in rheumatoid arthritis (RA) incidence is higher at reproductive ages,1 ,2 which might reflect a possible aetiological role of hormonal factors at younger but not at older ages. A reduction in RA incidence during pregnancy but an increase after delivery has been described, suggesting the involvement of reproductive factors in the aetiology. The increased risk has been observed during the first 3 months up to 2 years post partum,3–6 whereas parous women in the long run seem to have no increased risk7–10 or even a reduced risk of RA.11–13 For other reproductive factors, such as number of children7–9 ,11 ,13 ,14 and age at first birth,7–9 ,11 ,12 the reported results are inconclusive. Notably, previous studies have been conducted without studying the two subsets of RA, which are characterised by the presence/absence of antibodies to citrullinated peptide antigens (ACPA), separately.
Against this background, we aimed to study the impact of parity history, age at first birth and the postpartum period on the risk of ACPA-positive and ACPA-negative RA, by using data from a large population-based case–control study including incident cases in Sweden.
This study is based on the Swedish Epidemiological Investigation of Rheumatoid Arthritis (EIRA), comprising women aged 18–70 years living in defined geographical parts of Sweden, between 1996 and 2009. The general design of EIRA has been described in detail elsewhere.15 Briefly, incident cases of RA were included and diagnosed by rheumatologists according to the American College of Rheumatology 1987 criteria for RA.16 Controls were randomly selected from the national population register and matched to the cases by age, gender and residential area. One control (two controls from 2006) was selected per case. At the start of the EIRA, cases were included that did not fulfil the American College of Rheumatology criteria. These cases were later excluded from the analyses but their controls were kept for analysis.
Cases and controls answered an extensive questionnaire, in order to collect information about lifestyle and environmental exposures, including parity, number of delivered children and year(s) when the children were born. A second version of the questionnaire was used from 2006, adding information on breast feeding and age of menarche. In total, 2171 cases and 3635 controls were identified of which 2063 cases (95%) and 2911 controls (80%) answered the questionnaire. Blood samples were taken from participating cases.
The blood samples were assayed for ACPA status using the Immunoscan-RA Mark2 ELISA test (Euro-Diagnostica, Malmö, Sweden).17 The cut-off was set to 25 U/mL for ACPA-positive RA. Twenty-eight cases lacked information on ACPA status.
For each case, the year when the first symptoms of RA occurred was defined as the index year; the same index year was used for the corresponding controls. Since we only had information on which year the participants had given birth, parous women were defined as those who had biological offspring before or during the index year. Women who had not given birth before or during the index year were considered to be nulliparous. The postpartum period was defined as 0 years (during the index year), 1 year and 2 years between the most recently delivered child and the index year. Age at first birth for women aged 18–44 years was categorised according to the quartiles among the controls (≤22, 23–26, 27–30 and ≥31 years). The number of children was categorised as 1, 2, 3 and ≥4.
All participants gave written informed consent, and ethical approval was obtained from the relevant ethical committees.
Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for ACPA-positive and ACPA-negative RA, associated with overall parity, number of children, age at first birth and postpartum period. Nulliparous women were used as the reference group. We performed unmatched/matched analyses (unconditional/conditional logistic regression). We only present unmatched results, as these were in close agreement with the matched results but had higher precision.
We adjusted for the matching variables (age and residential area). All analyses were carried out using the Statistical Analysis System (SAS) v.9.2.
In total, 2035 cases and 2911 controls were included in the analyses, of which 603 cases and 906 controls were aged 18–44 years. In all, 64% of the cases were ACPA-positive and the mean time period between symptom onset and diagnosis was 10 months for ACPA-positive RA and ACPA-negative RA cases (see online supplementary table S1). Furthermore, 80% of the cases had a symptom duration of less than 1 year.
Parity and the risk of ACPA-positive and ACPA-negative RA
Parous women had an increased risk of developing ACPA-negative RA compared with nulliparous women in the young age-group (18–44 years) (OR=2.1, 95% CI 1.4 to 3.2), but not in the older age-group (45–70 years) (OR=0.9, 95% CI 0.7 to 1.3). There was no association between parity and the risk of developing ACPA-positive RA in any age-group (table 1), nor did we find any differences according to the number of children and the risk of ACPA-positive and ACPA-negative RA (see online supplementary table S2).
The postpartum period and the risk of ACPA-positive and ACPA-negative RA
An increased risk of ACPA-negative RA was found in women aged 18–44 years who had their last child in the same year as index year (OR=2.6, 95% CI 1.4 to 4.8). The OR was lower among those with deliveries within 1 year before the index year (OR=1.8, 95% CI 0.9 to 3.6) and reached the null value within 2 years before disease onset (table 2). After adjustments for age at first birth, the estimates decreased.
Age at first birth and the risk of ACPA-positive and ACPA-negative RA
Among women aged 18–44 years, the OR of ACPA-negative RA was 2.5 (95% CI 1.5 to 4.1) in those who had their first child before 23 years of age. The OR decreased by increasing age at first birth. A moderately decreased risk of ACPA-positive RA was found among women who had their first child after 30 years of age (OR=0.7, 95% CI 0.4 to 1.0) (table 3). Adjustment for the postpartum period increased the estimates for ACPA-negative RA and decreased the estimates for ACPA-positive RA.
Our data demonstrate an increased risk of ACPA-negative RA in parous women of reproductive age (18–44 years) but not at older ages (45–70 years). The increased risk was attributable to an elevated risk during the postpartum period, and to a young age at first birth. Parity and the postpartum period were not associated with risk of ACPA-positive RA, but older age at first birth seemed to be associated with a decreased risk in this subgroup.
Our study is a large population-based case-control study that includes incident cases. This, in combination with a high participation proportion among both cases and controls, reduced the risk of selection bias. However, in the postpartum analysis, misclassification of the postpartum period during index year might have occurred, since we only had information on the year(s) of delivery. This misclassification is probably non-differential (generally leading to a dilution of the results), which is supported by the different results for ACPA-negative and ACPA-positive RA.
From previous literature, parity seems to increase the risk of RA close after delivery3–6 (with one exception showing no association11) but this risk is attenuated after some years.7–13 Our results extend these findings by demonstrating that the increased postpartum risk was only found in ACPA-negative RA. For other reproductive factors, such as age at first birth7–9 ,11 ,12 and number of children,7–9 ,11 ,13 ,14 previous results have been inconclusive. The disparate findings might be explained by methodological issues (prevalent cases,13 inclusion of non-population-based controls12–13) or relatively few cases (less than 300 in most of the studies).9–13 Notably, no previous study has investigated parity history separately for ACPA-positive and ACPA-negative RA. The different result observed in ACPA-positive RA remains to be elucidated.
Emerging evidence demonstrates that environmental risk factors (eg, smoking), and genetic risk factors (eg, HLA-DRB1 shared epitope alleles) act differently in the development of ACPA-positive and ACPA-negative RA.18 Our findings of different impact of parity history on these two subgroups thus add further evidence to the notion that RA comprises two different disease entities with different aetiology.
In pregnant women, high concentrations of hormones (eg, cortisol, oestrogen, norepinephrine and progesterone) provide a Th2 pathway predominance and an immunosuppressive milieu, which might explain the lower RA incidence during pregnancy.19 Levels of prolactin (a proposed pro-inflammatory hormone) are also high during pregnancy. After delivery, the drastic fall in immunosuppressive hormonal levels, in combination with continued high prolactin levels during breast feeding, might be a potential explanation of the increased postpartum risk.14 ,20 However, published data on the impact of breast feeding on RA development are conflicting8 ,10 ,14 and our results were not substantially altered after adjustment for breast feeding (possibly due to having only a few observations, which did not allow for finer grading of that variable). Finally, why these potential mechanisms would act differently in the two subgroups of RA remains to be elucidated.
In summary, we found an increased risk of ACPA-negative RA in parous women of reproductive age. The increased risk was mainly due to an increased risk in the postpartum period and young age at first birth. Further research is needed in order to explore the biological mechanisms behind our findings but the effect of hormonal/reproductive factors such as the postpartum period might partly explain this notoriously higher incidence of RA in women.
First, we express our sincere gratitude to Prof. Lars Klareskog, who (together with Prof. Lars Alfredsson) is one of the principal investigators and founders of the EIRA study. We thank Marie-Louise Serra and Lena Nise for excellent assistance in collection of the data. We also thank all the cases and controls who participated in the study as well as the clinicians and nurses in the Epidemiological Investigation of Rheumatoid Arthritis study group: Göran Lindahl, Danderyd Hospital; Berit Sverdrup, Eskilstuna Hospital; Helena Hellström, Falu Lasarett; Tomas Weitoft, Gävle Hospital; Bengt Lindell, Kalmar Hospital; Birgitta Nordmark, Johan Bratt and Ingiäld Hafström, Karolinska University Hospital; Ido Leden, Kristianstad Hospital; Björn Löfström, Katrineholm Hospital; Ann Bengtsson and Thomas Skogh, Linköping Hospital; Elisabeth Lindqvist, Lund University Hospital; Lennart Jacobsson, Malmö University Hospital; Kjell Huddénius, Rheumatology Clinic in Stockholm City; Christin Lindström, Sophiahemmet; Annika Teleman, Spenshult Hospital; Eva Baecklund and Ann Knight, Uppsala University Hospital; Olle Svernell, Västervik Hospital; and Patrik Stolt, Västerås Hospital.
Handling editor Tore K Kvien
Contributors CO was responsible for the statistical analysis, interpreting the results and writing the paper. CB initiated the study and was responsible for the analysis, interpreting the results and revising the manuscript. SW and MH contributed with interpreting the results from a clinical perspective. HK was responsible for guiding the statistical/epidemiological results. EWK contributed to interpreting the results and guiding the analyses. LA is one of the principal investigators of EIRA and contributed to the interpretation of the results and guidance of the analyses. All authors contributed to the writing of the final article.
Funding This study was supported by grants from the Swedish Medical Research Council, the Swedish Council for Working Life and Social Research, King Gustav V's 80-year Foundation, the Swedish Rheumatic Foundation, the Stockholm County Council, the Insurance Company AFA, the Innovative Medicines Initiative-supported BTCure project, the Controlling Chronic Inflammatory Diseases with Combined Efforts project and the National Institutes of Health (NIH, AR047782).
Competing interests None.
Patient consent Obtained.
Ethics approval Ethical Committee Karolinska Institutet.
Provenance and peer review Not commissioned; externally peer reviewed.