Abstract
Objective
To investigate whether menopausal factors are associated with development of serologic rheumatoid arthritis (RA) phenotypes.
Methods
Data were analyzed from Nurses’ Health Studies (NHS, 1976–2010; NHSII 1989–2011). In NHS 120,700 female nurses aged 30–55 and in NHSII 116,430 female nurses aged 25–42 were followed via biennial questionnaires on lifestyle and disease outcomes. In total, 1,096 incident RA cases were confirmed by questionnaire and chart review. Seropositive RA was defined as +RF or ACPA+; seronegative RA as –RF and ACPA−. We used Cox proportional hazards models to obtain multivariable adjusted hazard ratios (HR) with 95% confidence intervals (CI) of seropositive/-negative RA associated with menopausal status, age at menopause, type of menopause, ovulatory years and postmenopausal hormone therapy (PMH) use.
Results
Postmenopausal women had a two-fold increased risk of seronegative RA, compared with premenopausal women (NHS: HR 1.8, 95% CI 1.1–3.0; NHSII: HR 2.4, 95% CI 1.4–3.9; pooled HR 2.1, 95% CI 1.4–3.0). Natural menopause at early age (≤ 44) was associated with an increased risk of seronegative RA (pooled HR 2.4, 95% CI 1.5–4.0). None of the menopausal factors was significantly associated with seropositive RA. We observed no association between PMH use and the risk of seronegative or seropositive RA, except that PMH use of ≥8 years was associated with increased risk of seropositive RA (pooled HR 1.4, 95% CI 1.1–1.9).
Conclusion
Postmenopause and natural menopause at early age were strongly associated with seronegative RA, but only marginally with seropositive RA, suggesting potential differences in the etiology of RA subtypes.
Several environmental and genetic risk factors (e.g. smoking and HLA-DRB1 shared epitope alleles) have been associated with the seropositive subgroup of rheumatoid arthritis (RA) (i.e. antibodies to citrullinated peptides (ACPA) or rheumatoid factor (RF) positive RA), [1–5] but specific factors associated with the development of seronegative RA are less understood [6].
RA is more frequent among women than men at all ages, but the gender difference seems to be highest before menopause with a peak incidence among women at 45–64 years of age in most of previous reports,[7–10] except from one Swedish study in which the RA incidence peaked at 70–79 years of age [11]. It has been hypothesized that changes in female hormonal levels at the time of menopause might be involved in RA pathogenesis. Oral contraceptive (OC) use has been associated with a decreased risk, especially in early years when OC preparations contained higher doses of estrogens [12]. Several studies have shown no association of low-dose estrogen OCs with RA including an analysis of the Nurses’ Healthy Study Cohorts [13,14]. During the postpartum period, with rapid falls in endogenous estrogen levels, the risk of RA is increased [15–17] and it has been suggested that this elevated risk might be confined only to seronegative RA [18]. Although the literature is scarce, it appears that the menopausal transition may be related to an increased risk of RA [19]. Early menopause (< age 45) has been associated with both an increased risk of RA, as well as RF positivity in early arthritis. A previous case-control study nested within a community-based health survey reported that early menopause was associated with an increased risk of RA, and that the risk of RF negative RA was much more pronounced (OR 5.0, 95% CI 1.72–14.51) than the risk of RF positive RA (OR 1.98, 94% CI 0.91–4.31 [20]. In a Canadian cohort of early RA cases, early age at menopause (<45 years) was associated with RF positivity with an OR of 2.2 (1.3–3.8) [21]. If increased RA risk at the time of menopause is due to hormonal fluctuation, then postmenopausal hormone therapy (PMH) could theoretically reduce RA risk. In a recent study, we observed PMH use reduced the risk of ACPA-positive RA in post-menopausal women over 50 years of age, but not of ACPA-negative RA [22]. However, past studies of the association between PMH use and later development of RA have had conflicting results [12,14,23–28–27].
Emerging evidence suggests that several environmental and genetic factors have different impact on the risk of seropositive and seronegative RA [1–6]. Menopausal factors may also associate differently with the two subgroups of disease [20,22], but most prior studies were performed without stratification into seronegative and seropositive RA disease phenotypes. Our aim was to investigate menopausal factors and risk of RA, and serologic phenotypes of RA (seropositive/negative RA), among women followed in two large prospective cohorts. We hypothesized that menopausal status and PMH use would be differently associated with the 2 distinct RA phenotypes
MATERIALS AND METHODS
Study population
The Nurses’ Health Study (NHS) is a prospective cohort in the US which started in 1976 when 121,700 female nurses, aged 30–55 years, born between 1921 and 1946, completed a baseline questionnaire on their lifestyles, medical histories, disease diagnosis and environmental exposures. In 1989 a second cohort began, the Nurses’ Health Study II (NHSII), which included younger nurses at baseline (116,430 women aged 25–42 years, born between 1947 and 1964). Since the start of both cohorts, the women have answered questionnaires biennially and the participation rate has been high with only 5% of person-time lost to follow-up [30]. All participants gave written informed consent and ethical approval was obtained from the Partners HealthCare Institutional Review Board.
The study period for the current report started at baseline in each cohort, and women were censored at RA diagnosis, self-report of RA or other connective tissue disease not confirmed as RA, loss to follow-up, death or end of analytic follow-up (NHS: 2010, NHSII: 2011).Women reporting RA at baseline (i.e. prevalent cases) were excluded. Since different cancer forms might alter the immune system as well as hormonal balance and treatments during menopause, we censored women at the date of self-report of cancer (except non-melanomatous skin cancer) and censored at the reported date of menopause due to radiation. In NHS, 109,443 women were included in the analysis. In NHSII, 112,523 women were included in the analysis.
Identification of RA
The identification RA of cases has previously been described in detail [14]. Briefly, case identification was a two-stage procedure where a Connective Tissue Disease Screening Questionnaire (CSQ) [31] was sent to those who self-reported a physician’s diagnosis of RA. Two board-certified rheumatologists reviewed the medical records of those that screened positive in order to confirm RA according to the 1987 American College of Rheumatology classification criteria [32]. All RA cases included in the study were confirmed as incident RA with information on serologic status (RF and/or ACPA). Charts were reviewed for presence of RF throughout follow-up and ACPA (since the availability in the early 1990s) test results. If results were not found, these were recorded as negative. Seropositive RA was defined as +RF or ACPA+; seronegative RA was defined as –RF and ACPA−. Women were excluded if they had RA at baseline (NHS 33, NHSII 0), if they denied the RA diagnosis after self-report (NHS 2990, NHSII 807), denied permission for medical record review (NHS 1156, NHSII 466), or if the CSQ was negative (NHS 3231, NHSII 1477). In total, 1,096 incident RA cases (729 in NHS, 367 in NHSII) were included in the analyses.
Menopausal factors
Information on menopausal factors was gathered through self-administered questionnaires which were mailed to the participants biennially since 1976 in the NHS and since 1989 in the NHSII. In both cohorts, participants were asked on each questionnaire (until 2002 in NHS) whether their menstrual periods had ceased permanently and, if so, at what age and the type of menopause (natural, radiation, or surgery). In the analyses, menopausal status was categorized into premenopausal, postmenopausal or unclear. Women with hysterectomy and bilateral oophorectomy were classified as menopausal at the date of surgery. Women with hysterectomy and unilateral oophorectomy were classified as menopausal based on average age at menopause according to smoking status and cohort, but were considered unsure menopausal status at earlier ages. Age at menopause was categorized as premenopausal, ≤44 years, 45–49 years, ≥50 years, and missing age at menopause. We further stratified type of menopause at different ages and the categories as premenopausal, natural ≤44, natural ≥ 45, surgical ≤44, surgical ≥ 45, and missing. Finally, after excluding women with hysterectomy and one ovary removed (as their chemical age at menopause is unknown), we calculated total ovulatory years as the age at natural menopause or age at surgical menopause (if both ovaries removed), subtracting age at menarche, number of childbirths (12 months each) and years of oral contraceptive use. Ovulatory years were then categorized as <24 years, 24–29 years, 30–34 years, ≥35 years, or missing.
In each cohort, information on PMH use was collected at baseline and at each biennial questionnaire. In the analyses of PMH, we studied never/past/current PMH use, age at initiation (never, ≤44 years, ≥45–49 years, ≥50 years, missing), and total duration of PMH use (never, <4 years, 4≤ years <8, ≥8 years, missing). We analyzed PMH use among only postmenopausal women.
Since the majority of the women were pre-menopausal at baseline in both cohorts, basic characteristics were analyzed ten years later (1986 in NHS, 1999 in NHSII). Pre-menopausal factors were reported in NHS and NHS2 by Karlson et. al. [14] which showed no association between oral contraceptive use and RA risk in this cohort, but demonstrated a protective effect of breast feeding, and increased risk from early menarche.
Potential confounding factors
Based on previous findings in these cohorts, we considered several factors as potential confounders [14,33]. Data on these covariates were assessed on the biennial questionnaires in both NHS and NHSII, and updated when appropriate every second year and treated as time-varying. The covariates included were: age (updated at each cycle), questionnaire cycle, median household income in quintiles, BMI (<25, 25-<30, ≥30), pack-years of cigarette smoking (never to ≤10, >10-<20, ≥20), and parity/breastfeeding (nulliparous, none-<1mo, 1–11mo, ≥12mo).
Additional variables, including alcohol consumption (5-<10 g/day, ≥10 g/day), oral contraceptive use (ever/never), age at menarche (<12 years, ≥12 years), and irregular menses (irregular/regular), were considered as potential confounders, but since they did not substantially alter the estimates they were not included in the final models.
Statistical analyses
We analyzed age and the relative risk of three outcomes: seropositive and seronegative RA phenotypes as well as overall RA by calculating the incidence rate ratios in different age-groups compared with women aged 25–44 years.
We used Cox proportional hazards models to obtain hazard ratios (HR) with 95% confidence intervals (CI) of seropositive or seronegative RA associated with each factor in separate models including: menopausal status, age at menopause, type of menopause, and ovulatory years. We censored women at first self-report of cancer, RA or other connective tissue disease if not confirmed as RA, as well as RA diagnosis or death, whichever came first. The reference group was premenopausal women, except for in the analysis of ovulatory years, in which the reference group was <24 years. We calculated crude HRs adjusted by age and questionnaire cycle as well as multivariate HRs adjusted by age, income, BMI, smoking, breast-feeding, and parity. The primary exposure was menopausal status as a time-varying variable. We excluded women who were missing data on menopausal status. To ensure that models were performed among the same set of women, we included a missing indicator for other exposure variables. We further analyzed risk of RA according to PMH factors among only postmenopausal women in separate models including current/past PMH use, age at initiation and duration of PMH use, where never users were the reference category. As in the above mentioned analyses, we calculated crude HRs and multivariate HRs, adjusting for age, income, BMI, smoking, parity and breast-feeding.
The analyses were performed separately for NHS and NHSII and pooled by meta-analysis using DerSimonian and Laird random effects methods [34]. Two-sided p-values <0.05 were considered statistically significant. All analyses were performed using the Statistical Analysis System (SAS) version 9.3.
RESULTS
The study population of the present study was 109,443 women contributing 2,498,323 person-years in NHS from 1976–2010, and 112,523 women contributing 1,987,756 person-years in NHSII from 1989–2011. In total, 1,096 cases were included in the analyses (401 seronegative cases; 695 seropositive cases).
The characteristics of the participants in NHS in 1986 and NHSII in 1999 by menopausal status are provided in Table 1. Among both pre- and postmenopausal women, parity was lower in NHSII than in NHS, but longer duration of breastfeeding was more common in NHSII as well as OC use. Heavy smoking was more prevalent among postmenopausal women in both cohorts, however heavy smoking was substantially lower in NHSII. The distribution of other variables in pre- and postmenopausal women was similar in the two cohorts.
Table 1.
Age-standardized characteristics of subjects in NHS and NHSII according to menopausal status
| NHS, 19861 | NHSII, 19991 | |||||
|---|---|---|---|---|---|---|
| Characteristic | Premenopausal | Postmenopausal | Unclear | Premenopausal | Postmenopausal | Unclear |
| n=27992 | n=47520 | n=6597 | n=73345 | n=14680 | n=5769 | |
| Age, years, mean(sd) | 45.3(3.8) | 57.4(5.1) | 51.3(2.4) | 43.0(4.2) | 48.3(3.5) | 49.2(2.7) |
| Body mass index, kg/m2,mean(sd) |
25.4(5.1) | 25.3(4.8) | 25.6(4.7) | 26.4(6.1) | 27.4(6.4) | 27.2(6.7) |
| Median household income, USD | 66,623(26,288) | 63,314(25,326) | 60,394(17,339) | 65,806(24,119) | 60,750(22,188) | 63,601(23,539) |
| Nonwhite, % | 3 | 3 | 19 | 8 | 7 | 7 |
| Cigarette smoking, pack years % | ||||||
| Never | 48 | 41 | 72 | 67 | 61 | 60 |
| 1–10 | 21 | 16 | 9 | 18 | 15 | 17 |
| 11–19 | 9 | 10 | 5 | 8 | 10 | 11 |
| ≥20 | 21 | 30 | 13 | 7 | 13 | 11 |
| Alcohol intake, g/day, % | ||||||
| 0-<5 | 39 | 37 | 33 | 78 | 81 | 75 |
| 5-<10 | 14 | 12 | 6 | 13 | 11 | 15 |
| ≥10 | 22 | 20 | 26 | 9 | 8 | 10 |
| Age at menarche, years | ||||||
| <12 | 20 | 23 | 29 | 23 | 28 | 27 |
| ≥12 | 80 | 77 | 71 | 76 | 71 | 73 |
| Menstrual periods, % | ||||||
| Regular | 77 | 71 | 63 | 77 | 48 | 60 |
| Irregular | 14 | 14 | 25 | 7 | 11 | 10 |
| Parity/breast feeding, % | ||||||
| Nulliparous | 4 | 7 | 2 | 16 | 22 | 21 |
| Parous/ no breast feeding | 42 | 42 | 70 | 13 | 17 | 17 |
| 1–11 months | 32 | 29 | 15 | 24 | 26 | 26 |
| ≥12 months | 21 | 14 | 8 | 36 | 26 | 27 |
| Oral contraceptive use, % | ||||||
| Never | 44 | 56 | 57 | 13 | 10 | 6 |
| Ever | 56 | 44 | 43 | 86 | 90 | 93 |
Values are means (SD) or percentages and are standardized to the age distribution of the study population.
Since the majority of the women were pre-menopausal at baseline in both cohorts, the characteristics were analyzed ten years later
Age and risk of RA
Women aged 45 years or older had an increased risk of RA in all age-groups, compared with women aged 25–44, with peak HR at 55–59. For all RA, the pooled HR at ages 45–49 was 1.5 (95% CI 1.2–1.9); at ages 50–54 was 2.0 (95% CI 1.6–2.5); at ages 55–59 was 2.3 (95% CI 1.7–3.2), and at ages 60–64 was 1.9 (95% CI 1.4–2.6). (Table 2). There were no large differences between NHS and NHSII; however there were very few cases aged 60 years or greater in NHSII. (Table 2) For seronegative RA, the pattern was similar, with a peak HR at ages 55–59 in the pooled analysis. Women aged 50 or more had an increased risk of seropositive RA, with peak HR at ages 55–59.
Table 2.
Age and relative risk of in the NHS (1976–2008) and NHSII (1989–2009) cohorts
| NHS | NHSII | Pooled (NHS+NHSII) |
|||||
|---|---|---|---|---|---|---|---|
| Age, years |
Cases | Person- years |
RR (95% CI) |
Cases | Person- years |
RR (95% CI) |
RR (95% CI) |
| RA | |||||||
| 25–44 | 85 | 462,886 | 1.0 | 143 | 1,125,559 | 1.0 | 1.0 |
| 45–49 | 86 | 311,812 | 1.5 (1.1–2.1) | 86 | 407,473 | 1.5 (1.1–2.1) | 1.5 (1.2–1.9) |
| 50–54 | 140 | 384,407 | 2.1 (1.5–2.7) | 77 | 287,458 | 2.0 (1.3–2.9) | 2.0 (1.6–2.5) |
| 55–59 | 135 | 389,003 | 2.0 (1.5–2.7) | 56 | 139,421 | 2.8 (1.8–4.4) | 2.3 (1.7–3.2) |
| 60–64 | 111 | 345,588 | 2.0 (1.4–2.8) | 5 | 27,845 | 1.3 (0.5–3.5) | 1.9 (1.4–2.6) |
| ≥65 | 172 | 604,628 | 1.9 (1.4–2.7) | - | - | - | - |
| Total | 729 | 2,498,323 | - | 367 | 1,987,756 | - | - |
| Seronegative RA | |||||||
| 25–44 | 28 | 459,452 | 1.0 | 50 | 1,122,095 | 1.0 | 1.0 |
| 45–49 | 39 | 309,696 | 2.2 (1.3–3.5) | 36 | 406,518 | 2.0 (1.2–3.4) | 2.1 (1.5–3.0) |
| 50–54 | 41 | 382,172 | 1.8 (1.1–3.0) | 23 | 286,971 | 2.2 (1.2–4.4) | 2.0 (1.3–3.0) |
| 55–59 | 45 | 387,208 | 2.1 (1.2–3.5) | 20 | 139,311 | 4.2 (1.9–9.0) | 2.7 (1.4–5.4) |
| 60–64 | 45 | 344,415 | 2.4 (1.4–4.2) | 3 | 27,844 | 3.1 (0.8–12.0) | 2.5 (1.5–4.2) |
| ≥65 | 71 | 603,449 | 2.4 (1.3–4.3) | - | - | - | - |
| Total | 269 | 2,486,392 | - | 132 | 1,982,738 | - | - |
| Seropositive RA | |||||||
| 25–44 | 57 | 455,915 | 1.0 | 93 | 1,093,795 | 1.0 | 1.0 |
| 45–49 | 47 | 307,365 | 1.2 (0.8–1.8) | 50 | 399,484 | 1.3 (0.8–1.9) | 1.2 (0.9–1.7) |
| 50–54 | 99 | 379,513 | 2.2 (1.5–3.0) | 54 | 283,838 | 1.8 (1.1–2.9) | 2.0 (1.5–2.7) |
| 55–59 | 90 | 385,127 | 2.0 (1.4–2.9) | 36 | 138,447 | 2.3 (1.3–4.0) | 2.1 (1.5–2.8) |
| 60–64 | 66 | 343,171 | 1.8 (1.2–2.7) | 2 | 27,742 | 0.7 (0.2–3.0) | 1.4 (0.6–3.2) |
| ≥65 | 101 | 602,647 | 1.7 (1.1–2.6) | - | - | - | - |
| Total | 460 | 2,473,737 | - | 235 | 1,943,306 | - | - |
Menopausal factors and risk of seropositive/seronegative RA
Postmenopausal women had an increased risk of seronegative RA, compared with premenopausal women, after adjusting for age, questionnaire cycle, median household income, BMI, pack-years of smoking, breastfeeding and parity (NHS: HR 1.8, 95% CI 1.1–3.0; NHSII: HR 2.4, 95% CI 1.4–3.9; pooled HR 2.1, 95% CI 1.4–.0) (Table 3). Any age at menopause was associated with an increased risk of seronegative RA, with the highest HR observed among women with natural menopause at early age (≤44 years) (NHS: HR 2.7, 95% CI 1.4–5.3; NHSII: HR 2.6, 95% CI 1.1–6.2; pooled HR 2.4, 95% CI 1.5–4.0). Longer duration of ovulatory years appeared to be associated with a decreased risk, at least in NHSII. None of the menopausal factors were significantly associated with seropositive RA (HR for postmenopausal women compared with premenopausal women were: NHS: HR 1.3, 95% CI 0.9–1.9; NHSII: HR 1.1, 95% CI 0.7–1.7; pooled HR 1.2, 95% CI 0.9–1.6).
Table 3.
Menopausal status and the relative risk of seropositive RA and seronegative RA in the NHS (1976–2010) and NHSII (1989–2011) cohorts
| Seronegative RA | |||||||
|---|---|---|---|---|---|---|---|
| NHS | NHSII | Pooled (NHS+NHSII) |
|||||
| Factors | Cases | Person-years | HR 95%CI1 | Cases | Person-years | HR 95%CI1 | HR 95%CI1 |
| Menopausal status | |||||||
| Pre-menopausal | 52 | 755,275 | 1.0 | 71 | 1479200 | 1.0 | 1.0 |
| Post | 201 | 1,600,561 | 1.8 (1.1–3.0) | 53 | 423261 | 2.4 (1.4–3.9) | 2.1 (1.4–3.0) |
| Unclear3 | 16 | 130,556 | 1.5 (0.8–2.9) | 8 | 80277 | 2.1 (1.0–4.8) | 1.7 (1.0–2.9) |
| Type of menopause | |||||||
| Pre-menopausal | 52 | 755,275 | 1.0 | 71 | 1479200 | 1.0 | 1.0 |
| Natural | 165 | 1,281,514 | 2.0 (1.2–3.4) | 30 | 281384 | 1.9 (1.0–3.6) | 2.0 (1.3–2.9) |
| Surgical | 36 | 319,046 | 1.6 (0.9–2.8) | 23 | 141876 | 2.7 (1.6–4.7) | 2.1 (1.2–3.5) |
| Age at menopause | |||||||
| Pre-menopausal | 52 | 755,275 | 1.0 | 71 | 1479200 | 1.0 | 1.0 |
| ≤44 years | 33 | 223,806 | 1.9 (1.1–3.2) | 18 | 132428 | 2.4 (1.3–4.2) | 2.1 (1.4–3.1) |
| 45–49 years | 55 | 412,947 | 1.7 (1.0–3.0) | 11 | 125915 | 1.8 (0.8–3.8) | 1.7 (1.1–2.7) |
| ≥ 50 years | 77 | 658,661 | 1.7 (1.0–2.9) | 18 | 138738 | 2.7 (1.2–6.1) | 2.0 (1.2–3.1) |
| Type of/age at menopause | |||||||
| Pre-menopausal | 52 | 755,275 | 1.0 | 71 | 1,479,200 | 1.0 | 1.0 |
| Natural≤44 | 15 | 74.935 | 2.7 (1.4–5.3) | 6 | 41,718 | 2.6 (1.1–6.2) | 2.4 (1.5–4.0) |
| Natural≥45 | 116 | 919,120 | 1.8 (1.1–3.1) | 23 | 222,463 | 2.0 (1.0–4.0) | 1.8 (1.2–2.8) |
| Surgical≤44 | 18 | 148,871 | 1.6 (0.8–2.9) | 12 | 90,711 | 2.2 (1.1–4.2) | 1.8 (1.0–3.0) |
| Surgical≥45 | 16 | 152,488 | 1.4 (0.7–2.8) | 6 | 42,190 | 2.6 (1.0–6.8) | 1.6 (0.9–2.9) |
| Ovulatory years | |||||||
| < 24 years | 42 | 465,671 | 1.0 | 25 | 505367 | 1.0 | 1.0 |
| 24–29 years | 53 | 518,520 | 0.9 (0.6–1.4) | 27 | 545347 | 0.4 (0.2–0.8) | 0.6 (0.2–1.5) |
| 30–34 years | 57 | 589,439 | 0.7 (0.5–1.1) | 35 | 415482 | 0.4 (0.1–0.9) | 0.6 (0.3–1.1) |
| ≥ 35 years | 47 | 412,547 | 0.8 (0.5–1.3) | 21 | 228713 | 0.4 (0.1–1.1) | 0.7 (0.3–1.3) |
| Seropositive RA | |||||||
| NHS | NHSII | Pooled (NHS+NHSII) | |||||
| Factors | Cases | Person-years | HR 95%CI1 | Cases | Person-years | HR 95%CI1 | HR 95%CI1 |
| Menopausal status | |||||||
| Pre-menopausal | 101 | 750,055 | 1.0 | 141 | 1,447,465 | 1.0 | 1.0 |
| Post | 327 | 1,594,188 | 1.3 (0.9–1.9) | 83 | 417,058 | 1.1 (0.7–1.7) | 1.2 (0.9–1.6) |
| Unclear2 | 32 | 129,495 | 1.3 (0.8–2.1) | 11 | 78,782 | 0.8 (0.4–1.6) | 1.3 (0.9–1.8) |
| Type of menopause | |||||||
| Pre-menopausal | 101 | 750,055 | 1.0 | 141 | 1,447,465 | 1.0 | 1.0 |
| Natural | 265 | 1,277,316 | 1.3 (0.9–2.0) | 53 | 278,836 | 1.0 (0.6–1.6) | 1.2 (0.9–1.6) |
| Surgical | 62 | 316,872 | 1.3 (0.8–1.9) | 30 | 138,222 | 1.3 (0.8–2.0) | 1.3 (0.9–1.7) |
| Age at menopause | |||||||
| Pre-menopausal | 101 | 750,055 | 1.0 | 141 | 1,447,465 | 1.0 | 1.0 |
| ≤44 years | 51 | 222,262 | 1.4 (0.9–2.1) | 19 | 128,843 | 0.9 (0.6–1.6) | 1.2 (0.9–1.7) |
| 45–49 years | 87 | 411,303 | 1.2 (0.8–1.9) | 26 | 124,646 | 1.1 (0.7–1.9) | 1.2 (0.9–1.7) |
| ≥ 50 years | 126 | 656,583 | 1.2 (0.8–1.9) | 30 | 137,833 | 1.1 (0.6–2.0) | 1.2 (0.9–1.7) |
| Type of/age at menopause |
|||||||
| Pre-menopausal | 101 | 750,055 | 1.0 | 141 | 1,447,465 | 1.0 | 1.0 |
| Natural≤44 | 21 | 74,559 | 1.6 (1.0–2.8) | 5 | 40,939 | 0.8 (0.3–1.9) | 1.4 (0.9–2.3) |
| Natural≥45 | 184 | 916,366 | 1.3 (0.8–1.9) | 44 | 220,848 | 1.0 (0.6–1.7) | 1.1 (0.8–1.6) |
| Surgical<45 | 30 | 147,703 | 1.2 (0.8–2.0) | 14 | 87,904 | 1.0 (0.6–1.8) | 1.1 (0.8–1.7) |
| Surgical≥45 | 29 | 151,519 | 1.3 (0.8–2.1) | 12 | 41,631 | 1.6 (0.8–3.1) | 1.4 (0.9–2.1) |
| Ovulatory years | |||||||
| < 24 years | 67 | 462,049 | 1.0 | 34 | 493,200 | 1.0 | 1.0 |
| 24–29 years | 88 | 516,119 | 0.9 (0.6–1.3) | 51 | 531,987 | 1.1 (0.6–2.2) | 1.1 (0.8–1.5) |
| 30–34 years | 121 | 586,979 | 1.0 (0.7–1.4) | 62 | 408,867 | 1.5 (0.7–3.3) | 1.1 (0.8–1.5) |
| ≥ 35 years | 75 | 410,846 | 0.9 (0.6–1.3) | 42 | 226,651 | 1.4 (0.6–3.2) | 1.2 (0.8–1.7) |
Cox proportional hazards models adjusted for age, questionnaire cycle, median household income, BMI, smoking pack-years, breast-feeding, parity Reference category is premenopausal women for menopausal variables
Unclear includes women whose date of menopause is unclear due to hysterectomy with unilateral oophorectomy, or menopause due to radiation
Missings for each model (cases/person years):
Seronegative, Type of menopause NHS 16/130,556, NHSII 8/80,277, Age at menopause NHS 52/435,703, NHSII 14/106,456 Type of/age at menopause NHS 52/435,703 NHSII 14/106,456 Ovulatory years NHS 70/500,215 NHSII 24/287,830
Seropositive, Type of menopause NHS 32/129,495 NHSII 11/78,782 Age at menopause NHS 95/433,535 NHSII 19/104,518 Type of/age at menopause NHS 95/433,535 NHSII 19/104,518 Ovulatory years NHS 109/497,745 NHSII 46/282,600
Postmenopausal hormone use and risk of seropositive/seronegative RA
Current PMH use was not associated with risk of seronegative RA (NHS HR 1.3, 95% CI 0.9–1.9; NHSII: HR 1.3, 95% CI 0.6–2.9; pooled HR 1.3, 95% CI 0.9–1.8), (Table 4). Long duration of PMH use (≥8 years) was not associated with risk of seronegative RA (NHS HR 1.4, 95% CI 0.9–2.0; NHSII: 1.8, 95% CI 0.8–4.2; pooled HR 1.4, 95% CI 1.0–2.0). Past PMH use, age at PMH initiation or time since last use did not associate with this sub-group of disease.
Table 4.
Postmenopausal hormones among post-menopausal women and the relative risk of seronegative RA and seropositive RA in the NHS cohort 1978–2008, NHSII cohort, 1989–2009
| Seronegative RA | |||||||
|---|---|---|---|---|---|---|---|
| NHS | NHSII | Pooled (NHS+NHSII) |
|||||
| Factors | Cases | Person- years |
HR 95%CI2 | Cases | Person- years |
HR 95%CI2 | HR 95%CI2 |
| PMH use | |||||||
| Never users | 54 | 436,538 | 1.0 | 9 | 78,189 | 1.0 | 1.0 |
| Current users | 86 | 568,618 | 1.3 (0.9–1.9) | 26 | 166,600 | 1.3 (0.6–2.9) | 1.3 (0.9–1.8) |
| Past users | 44 | 431,407 | 0.9 (0.6–1.4) | 17 | 149,182 | 0.9 (0.4–2.1) | 0.9 (0.6–1.4) |
| Age at PMH initiation | |||||||
| Never users | 54 | 436,538 | 1.0 | 9 | 78,189 | 1.0 | 1.0 |
| ≤44 years | 24 | 181,501 | 1.1 (0.7–1.9) | 23 | 151,186 | 1.2 (0.5–2.7) | 1.2 (0.8–1.8) |
| 45–49 years | 38 | 231,166 | 1.4 (0.9–2.1) | 7 | 82,527 | 0.6 (0.2–1.8) | 1.1 (0.5–2.2) |
| ≥ 50 years | 63 | 563,017 | 1.0 (0.7–1.5) | 10 | 52,732 | 1.8 (0.7–4.7) | 1.1 (0.8–1.7) |
| PMH duration | |||||||
| Never use | 54 | 436,538 | 1.0 | 9 | 78,189 | 1.0 | 1.0 |
| < 4 years | 35 | 347,583 | 0.9 (0.6–1.3) | 18 | 145,873 | 1.0 (0.4–2.2) | 0.9 (0.6–1.3) |
| 4 ≤ years < 8 | 35 | 217,216 | 1.5 (1.0–2.3) | 8 | 88,551 | 0.7 (0.2–1.8) | 1.1 (0.5–2.5) |
| ≥ 8 years | 58 | 408,625 | 1.4 (0.9–2.0) | 17 | 77,942 | 1.8 (0.8–4.2) | 1.4 (1.0–2.0) |
| Seropositive RA | |||||||
| NHS | NHSII | Pooled (NHS+NHSII) |
|||||
| Factors | Cases | Person- years |
HR 95%CI1 | Cases | Person- years |
HR 95%CI1 | HR 95%CI1 |
| PMH use | |||||||
| Never users | 80 | 435,113 | 1.0 | 19 | 77,600 | 1.0 | 1.0 |
| Current users | 132 | 565,905 | 1.4 (1.1–1.9) | 30 | 162,813 | 0.9 (0.5–1.7) | 1.3 (0.9–1.8) |
| Past users | 83 | 429,953 | 1.2 (0.9–1.7) | 29 | 147,514 | 0.8 (0.5–1.5) | 1.1 (0.8–1.5) |
| Age at PMH initiation | |||||||
| Never users | 80 | 435,113 | 1.0 | 19 | 77,600 | 1.0 | 1.0 |
| ≤44 years | 40 | 180,250 | 1.3 (0.9–2.0) | 33 | 147,501 | 1.1 (0.6–1.9) | 1.2 (0.9–1.7) |
| 45–49 years | 52 | 230,105 | 1.4 (0.9–1.9) | 13 | 81,571 | 0.7 (0.3–1.4) | 1.0 (0.5–2.0) |
| >49 years | 117 | 561,322 | 1.3 (1.0–1.8) | 9 | 52,389 | 0.8 (0.4–1.8) | 1.2 (0.8–1.8) |
| PMH duration | |||||||
| Never users | 80 | 435,113 | 1.0 | 19 | 77,600 | 1.0 | 1.0 |
| < 4 years | 86 | 345,971 | 1.4 (1.0–1.9) | 26 | 143,365 | 0.8 (0.4–1.5) | 1.2 (0.7–2.0) |
| 4 ≤ years < 8 | 34 | 216,085 | 0.9 (0.6–1.4) | 13 | 86,945 | 0.7 (0.3–1.5) | 0.9 (0.6–1.3) |
| ≥ 8 years | 89 | 407,352 | 1.5 (1.1–2.0) | 20 | 76,644 | 1.2 (0.6–2.2) | 1.4 (1.1–1.9) |
Cox proportional hazards models adjusted for age, questionnaire cycle, median household income, BMI, smoking pack-years, breast-feeding, parity Reference category is premenopausal women for menopausal variables
Unclear includes women whose date of menopause is unclear due to hysterectomy with unilateral oophorectomy, or menopause due to radiation
Missings for each model (cases/person years):
Seronegative, Type of menopause NHS 16/130,556, NHSII 8/80,277, Age at menopause NHS 52/435,703, NHSII 14/106,456 Type of/age at menopause NHS 52/435,703 NHSII 14/106,456 Ovulatory years NHS 70/500,215 NHSII 24/287,830
Seropositive, Type of menopause NHS 32/129,495 NHSII 11/78,782 Age at menopause NHS 95/433,535 NHSII 19/104,518 Type of/age at menopause NHS 95/433,535 NHSII 19/104,518 Ovulatory years NHS 109/497,745 NHSII 46/282,600
Regarding seropositive RA, current PMH users had an increased risk only in NHS (HR 1.4, 95% CI 1.1–1.9), but not in NHSII (HR 0.9, 95% CI 0.5–1.7) with a pooled HR of 1.3, 95% CI 0.9–1.8. There was no association with past PMH use in either cohort. Long duration of PMH use (≥8 years) was significantly associated with risk of seropositive RA (NHS HR 1.5, 95% CI 1.1–2.0; NHSII: 1.2, 95% CI 0.6–2.2; pooled HR 1.4, 95% CI 1.1–1.9). However, age at initiation of PMH was not associated with either type of RA.
DISCUSSION
In these large prospective cohorts of women, menopausal factors were strongly associated with risk of seronegative, but only marginally of seropositive, RA. Postmenopausal women had more than a doubled risk of seronegative disease, compared with premenopausal women. The highest risk of seronegative disease was observed among those with natural menopause at early age (≤44 years of age) with a HR of 2.4. We found no particular associations between PMH use and the risk of either serologic phenotype of RA, with the exception of an increased risk of seropositive RA among those with a long PMH duration. In addition, the peak risk of developing RA, both seropositive and seronegative, was observed at ages 55–59, which is after the menopausal transition in most women.
To our knowledge, our study is the first to demonstrate that menopausal factors, menopause and early age at menopause (≤44 ) are primarily associated with seronegative RA in two large prospective cohorts. Adult women experience three phases of substantial endogenous hormonal shifts in life; pregnancy, postpartum and menopause. It has been observed that the incidence of RA is lower during pregnancy, which might be explained by high concentrations of different circulating hormones (e.g. cortisol, estrogen, progesterone) [35]. Three to 24 months after delivery, the risk of RA seems to be increased [15–18], possibly due to drastic fall in hormonal levels in combination with increased prolactin levels during breastfeeding. The third hormonal shift is during menopause, when estrogen levels decrease. It has been hypothesized that the menopausal transition is related to an increased risk of RA, but the literature has been scarce [19–20], Early menopause (≤44 ) was previously associated with RF negative RA in one study [20] but with RF positivity in study of a group of women with early RA [21]. The disparity between our study and the study by Wong et al [21] could be due to different study designs. We studied the risk of developing RA among women in two large prospective cohort studies adjusting for time-varying confounders including cumulative pack-years of smoking, whereas Wong et al used a cross-sectional case-only design including postmenopausal women with early arthritis, and studied the association between early menopause and RF positivity vs, RF negativity adusting for current smoking, and current PMH use. Our study suggests that postmenopausal women are at an increased risk of developing RA where the comparison group is non-RA, but that this risk was confined to the seronegative RA phenotype. Furthermore, we found that natural menopause at early age was related to an increased risk mainly for seronegative RA, which is in agreement with a small nested case-control study within a prospective study by Pikwer, et al [20].
Environmental (e.g. smoking) and genetic (e.g. HLA-DRB1 shared epitope alleles) factors have been associated with seropositive RA [1–5], but knowledge concerning risk factors for seronegative RA is scarce [6]. One study has suggested that the increased postpartum risk is restricted only to ACPA-negative RA [18]. Taken together, this study and ours suggest that menopausal transition may influence the development of seronegative RA. Our findings add to the growing literature supporting the idea that seronegative and seropositive RA may have different epidemiologic risk factors.. [1–6].
Whether the menopausal RA risk is increased due to falling estrogen or progesterone levels, remains to be elucidated. However, there is an immunomodulatory effect given by the natural hormone progesterone, which has been suggested to differ from the one from estrogens and androgens [36–38]. Moreover, as progesterone might decrease RA disease activity in the pregnant state, through inhibition of Th1 and Th17 pathways and induction of anti-inflammatory molecules [37], progesterone might also be important during the menopausal phase. We could not confirm any association between PMH and the risk of seronegative or seropositive RA, which is in accordance with several previous studies [12,14,24–29]. However, the results differed between NHS and NHSII especially for seropositive RA which might reflect that different PMH treatment strategies during the decades have different influence on disease development [22]. Finally, there could be other factors related to menopause, other than estrogen loss that increase the risk of RA. Alternatively, perhaps low dose estrogen therapy does not completely abrogate the effect of estrogen loss on the immune system. Alternatively, mechanisms other than estrogen loss could play a role in seronegative RA pathogenesis.
The peak overall RA incidence among women has previously been reported to occur at ages 45–64 [7–10], except from in one Swedish study in which the RA incidence peaked at 70–79 years of age [11]. To our knowledge, our study demonstrates for the first time that the risk of both serologic RA phenotypes is elevated (mainly seronegative RA) during the early menopausal age years, and peaking at ages 55–59, later than the mean age of menopause in these cohorts (age 51–52). RA risk was attenuated after age 60, but only for seropositive RA. Our findings suggest that menopausal factors are involved in subsequent development of RA, particularly seronegative RA, but that other factors may contribute to the peak incidence after menopause. Interestingly, in the age-group 45–49 the risk was higher for seronegative RA (HR 2.1) and only non-significantly associated with seropositive RA (HR 1.2) which reflects the results that natural menopause at early age is mainly associated with seronegative disease.
The current study does have some limitations. Although the process to identify cases was very thorough, there is a potential risk that RA cases could have been misclassified as non-cases, as we relied upon medical record documentation rather than physical examination. Therefore, if a RA diagnosis could not be confirmed by medical records, we censored those with self-reported RA or other CTDs at the date of first report. An additional limitation is the self-reported exposure data, which might lead to misclassification of the menopausal factors. However, since the data were collected prospectively this potential misclassification of exposure would be non-differential and the results would be diluted. Furthermore, there was also a possibility of unmeasured confounding especially for seronegative RA. Less is known regarding risk factors for this subtype of disease and there might be unknown confounders that could contribute the observed associations. One potential explanation for the association of early menopause with seronegative RA, could be occurrence of arthralgias in the peri-menopausal period that leads to physician visits, evaluation for potential RA, and a diagnosis of seronegative RA (eg. surveillance bias) among women whose antibody tests are negative. We ran a sensitivity analysis, adjusting for recent physician visits (as a marker for health care utilization and potential surveillance bias) in the multivariable models, however, the results were unchanged, suggestion that perhaps the earlier onset of seronegative RA is a biologic phenomenon. However the biologic mechanism is unknown. ACPA was not available for women diagnosed with RA in the 1980s and early 1990’s, prior to its clinical availability. Thus there is potential for misclassification of ACPA+ RA cases as seronegative cases, which would underestimate the associations between menopausal factors and the risk of seronegative RA. For RA cases diagnosed before 2003, we have chart review findings for RF, and ACPA assays measured among a subset of pre-RA cases who provided blood samples in 1989. Stratifying by RF/ACPA categories and 2003 diagnosis year, the subset RF-/ACPA+ included 19 (2%) RA cases diagnosed before 2003, and 13 (4%) in 2003 or later. Thus, among cases classified as seronegative RA (N=293), we estimate that 2% (6 cases) are misclassified as seronegative before 2003. Using available data on ACPA status, we restricted the analysis to ACPA+ RA outcomes (N=174), and censored other RA cases at date of diagnosis. Although underpowered, the results were essentially unchanged, suggesting that menopausal status was not associated with risk of ACPA+ RA or seropositive RA and PMH use was not associated with risk of ACPA RA or seropositive RA.
The strengths of our study include the lrge number of incident RA cases, the repeated assessment of most exposures/confounders, the prospective assessment of most exposures/confounders, the possibility to adjust for several confounders (including BMI, smoking, alcohol, income, parity and breast-feeding) and the long follow-up period. Results of analyses of most menopausal factors were similar between the two cohorts, strengthening the conclusion that these factors are involved in the development of seronegative RA.
In conclusion, postmenopausal status and natural menopause at early age, are strongly associated with seronegative RA, but only marginally with seropositive RA, suggesting differences in disease etiology according to serotype.
SIGNIFANCE AND INNOVATIONS.
-
-
To our knowledge, this is the first prospective study to observe that postmenopausal women had an increased risk of seronegative RA, but only marginally of seropositive RA.
-
-
Early age of natural menopause (≤ 44) was more closely associated with seronegative RA.
-
-
Our findings suggest potential differences in the etiology of RA subtypes, and also hormonal influences in the development of the disease.
Acknowledgments
Funding: The NHS was supported by National Institutes of Health (NIH) grants AR049880, AR052403, AR059073, AR066109, CA186107, and CA176726.
Swedish Council for Working Life and Social Research 2010–0674, The Swedish Rheumatism Association R-158031 and Börje Dahlin fond (Bengtsson)
We would like to thank all participants for their contribution to this study.
Footnotes
Competing interest: None
Contributors: SM conducted statistical analyses; EK, CB initiated the study and were responsible for the analysis, interpreting the results and revising the manuscript; EK contributed to study design; CB, EK, SM, JS, CO contributed to data interpretation and critical revision of the manuscript for important intellectual content. All authors have read and approved the final manuscript. All authors had full access to all of the data (including statistical reports and tables) and can take responsibility for the integrity of the data and the accuracy of the data analysis.
REFERENCES
- 1.Karlson EW, Deane K. Environmental and gene-environment interactions and risk of rheumatoid arthritis. Rheum Dis Clin North Am. 2012;38:405–426. doi: 10.1016/j.rdc.2012.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Raychaudhuri S. Recent advances in the genetics of rheumatoid arthritis. Curr Opin Rheumatol. 2010;22:109–118. doi: 10.1097/BOR.0b013e328336474d. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54:38–46. doi: 10.1002/art.21575. [DOI] [PubMed] [Google Scholar]
- 4.Kallberg H, Ding B, Padyukov L, Bengtsson C, Rönnelid J, Klareskog L, et al. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 2011;70:508–511. doi: 10.1136/ard.2009.120899. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Padyukov L, Seielstad M, Ong RT, Ding B, Rönnelid J, Seddighzadeh M, et al. A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann Rheum Dis. 2011;70:259–265. doi: 10.1136/ard.2009.126821. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009;373:659–672. doi: 10.1016/S0140-6736(09)60008-8. [DOI] [PubMed] [Google Scholar]
- 7.Humphreys JH, Verstappen SM, Hyrich KL, Chipping JR, Marshall T, Symmons DP. The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria the 1987 ACRclassification criteria. Results from the Norfolk Arthritis Register. Ann Rheum Dis. 2013;72:1315–1320. doi: 10.1136/annrheumdis-2012-201960. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Kvien TK, Uhlig T, Odegard S, Heiberg MS. Epidemiological aspects of rheumatoid arthritis: the sex ratio. Ann N Y Acad Sci. 2006;1069:212–212. doi: 10.1196/annals.1351.019. [DOI] [PubMed] [Google Scholar]
- 9.Doran MF, Pond GR, Crowson CS, O’Fallon WM, Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum. 2002;46:625–631. doi: 10.1002/art.509. [DOI] [PubMed] [Google Scholar]
- 10.Dugowson CE, Koepsell TD, Voigt LF, Bley L, Nelson JL, Daling JR. Rheumatoid arthritis in women: incidence rates in Group Health Cooperative, Seattle, Washington, 1987–1989. Arthritis Rheum. 1991;34:1502–1507. doi: 10.1002/art.1780341205. [DOI] [PubMed] [Google Scholar]
- 11.Eriksson JK, Neovius M, Ernestam S, Lindblad S, Simard JF, Askling J. Incidence of rheumatoid arthritis in Sweden: a nationwide population-based assessment of incidence, its determinants, and treatment penetration. Arthritis Care Res (Hoboken) 2013;65:870–878. doi: 10.1002/acr.21900. [DOI] [PubMed] [Google Scholar]
- 12.Doran MF, Crowson CS, O’Fallon WM, Gabriel SE. The effect of oral contraceptives and estrogen replacement therapy on the risk of rheumatoid arthritis: a population based study. J Rheumatol. 2004;31:207–213. [PubMed] [Google Scholar]
- 13.Pikwer M, Bergstrom U, Nilsson JA, Jacobsson L, Berglund G, Turesson C. Breast feeding, but not use of oral contraceptives, is associated with a reduced risk of rheumatoid arthritis. Ann Rheum Dis. 2009;68:526–530. doi: 10.1136/ard.2007.084707. [DOI] [PubMed] [Google Scholar]
- 14.Karlson EW, Mandl LA, Hankinson SE, Grodstein F. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses’ Health Study. Arthritis Rheum. 2004;50:3458–3467. doi: 10.1002/art.20621. [DOI] [PubMed] [Google Scholar]
- 15.Wallenius M, Skomsvoll JF, Irgens LM, Salvesen KA, Koldingsnes W, Mikkelsen K. 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. doi: 10.1136/ard.2009.115964. [DOI] [PubMed] [Google Scholar]
- 16.Silman A, Kay A, Brennan P. Timing of pregnancy in relation to the onset of rheumatoid arthritis. Arthritis Rheum. 1992;35:152–155. doi: 10.1002/art.1780350205. [DOI] [PubMed] [Google Scholar]
- 17.Lansink M, de Boer A, Dijkmans BA, Vandenbrouke JP, Hazes JM. The onset of rheumatoid arthritis in relation to pregnancy and childbirth. Clin Exp Rheumatol. 1993;11:171–174. [PubMed] [Google Scholar]
- 18.Orellana C, Wedrén S, Källberg H, Holmqvist M, Karlson EW, Alfredsson L, et al. Parity and the risk of developing rheumatoid arthritis: results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study. Ann Rheum Dis. 2014;73:752–755. doi: 10.1136/annrheumdis-2013-203567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Goemaere S, Ackerman C, Goethals K, De Keyser F, Van der Straeten C, Verbruggen G. Onset of symptoms of rheumatoid arthritis in relation to age, sex and menopausal transition. J Rheumatol. 1990;17:1620–1622. [PubMed] [Google Scholar]
- 20.Pikwer M, Bergstrom U, Nilsson JA, Jacobsson L, Turesson C. Early menopause is an independent predictor of rheumatoid arthritis. Ann Rheum Dis. 2012;71:378–381. doi: 10.1136/ard.2011.200059. [DOI] [PubMed] [Google Scholar]
- 21.Wong LE, Huang WT, Pope JE, Haraoui B, Boire G, Thome JC. Canadian Early Arthritis Cohort Investigators. Effect of age at menopause on disease presentation in early rheumatoid arthritis: results from the Canadian Early Arthritis Cohort. Arthritis Care Res (Hoboken) 2015;67:616–623. doi: 10.1002/acr.22494. [DOI] [PubMed] [Google Scholar]
- 22.Orellana C, Saevarsdottir S, Klareskog L, Karlson EW, Alfredsson L, Bengtsson C. Postmenopausal hormone therapy and the risk of rheumatoid arthritis: results from the Swedish EIRA population-based case-control study. Eur J Epidemiol. 2015;30:449–457. doi: 10.1007/s10654-015-0004-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Vandenbroucke JP, Witteman JC, Valkenburg HA, Boersma JW, Cats A, Festen JJ, et al. Noncontraceptive hormones and rheumatoid arthritis in perimenopausal and postmenopausal women. JAMA. 1986;255:1299–1303. [PubMed] [Google Scholar]
- 24.Rodriguez LA, Tolosa LB, Ruigomez A, Johansson S, Wallander MA. Rheumatoid arthritis in UK primary care: incidence and prior morbidity. Scand J Rheumatol. 2009;38:173–177. doi: 10.1080/03009740802448825. [DOI] [PubMed] [Google Scholar]
- 25.Walitt B, Pettinger M, Weinstein A, Katz J, Torner J, Wasko MC, et al. Effects of postmenopausal hormone therapy on rheumatoid arthritis: the women’s health initiative randomized controlled trials. Arthritis Rheum. 2008;59:302–310. doi: 10.1002/art.23325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Merlino LA, Cerhan JR, Criswell LA, Mikuls TR, Saag KG. Estrogen and other female reproductive risk factors are not strongly associated with the development of rheumatoid arthritis in elderly women. Semin Arthritis Rheum. 2003;33:72–82. doi: 10.1016/s0049-0172(03)00084-2. [DOI] [PubMed] [Google Scholar]
- 27.Spector TD, Brennan P, Harris P, Studd JW, Silman AJ. Does estrogen replacement therapy protect against rheumatoid arthritis? J Rheumatol. 1991;18:1473–1476. [PubMed] [Google Scholar]
- 28.Hernandez-Avila M, Liang MH, Willett WC, Stampfer MJ, Colditz GA, Rosner B, et al. Exogenous sex hormones and the risk of rheumatoid arthritis. Arthritis Rheum. 1990;33:947–953. doi: 10.1002/art.1780330705. [DOI] [PubMed] [Google Scholar]
- 29.Carette S, Marcoux S, Gingras S. Postmenopausal hormones and the incidence of rheumatoid arthritis. J Rheumatol. 1989;16:911–913. [PubMed] [Google Scholar]
- 30.Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA. 2011;306:1884–1890. doi: 10.1001/jama.2011.1590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Karlson EW, Sanchez-Guerrero J, Wright EA, Lew RA, Daltroy LH, Katz JN, et al. A connective tissue disease screening questionnaire for population studies. Ann Epidemiol. 1995;5:297–302. doi: 10.1016/1047-2797(94)00096-c. [DOI] [PubMed] [Google Scholar]
- 32.Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–324. doi: 10.1002/art.1780310302. [DOI] [PubMed] [Google Scholar]
- 33.Costenbader KH, Feskanich D, Mandl LA, Karlson EW. Smoking intensity, duration, andcessation, and the risk of rheumatoid arthritis in women. Am J Med. 2006;119:503, e1–e9. doi: 10.1016/j.amjmed.2005.09.053. [DOI] [PubMed] [Google Scholar]
- 34.DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188. doi: 10.1016/0197-2456(86)90046-2. [DOI] [PubMed] [Google Scholar]
- 35.Straub RH, Buttgereit F, Cutolo M. Benefit of pregnancy in inflammatory arthritis. Ann Rheum Dis. 2005;64:801–803. doi: 10.1136/ard.2005.037580. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Tibbetts TA, Conneely OM, O’Malley BW. Progesterone via its receptor antagonizes the pro-inflammatory activity of estrogen in the mouse uterus. Biol Reprod. 1999;60:1158–1165. doi: 10.1095/biolreprod60.5.1158. [DOI] [PubMed] [Google Scholar]
- 37.Hughes GC, Martin D, Zhang K, Hudkins HL, Alpers CL, Clark EA, et al. Decrease in glomerulonephritis and Th1-associated autoantibody production after progesterone treatment in NZB/NZW mice. Arthritis Rheum. 2009;60:1775–1784. doi: 10.1002/art.24548. [DOI] [PubMed] [Google Scholar]
- 38.Hughes GC, Clark EA. Regulation of dendritic cells by female sex steroids: relevance to imunity and autoimmunity. Autoimmunity. 2007;40:470–481. doi: 10.1080/08916930701464764. [DOI] [PubMed] [Google Scholar]