
==== Front
Rheumatology (Oxford)
Rheumatology (Oxford)
brheum
Rheumatology (Oxford, England)
1462-0324
1462-0332
Oxford University Press

37773999
10.1093/rheumatology/kead513
kead513
Clinical Science
Editor's Choice
AcademicSubjects/MED00360
Effects of oral contraceptives and menopausal hormone therapy on the risk of rheumatoid arthritis: a prospective cohort study
https://orcid.org/0000-0002-9855-7610
Hadizadeh Fatemeh Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Johansson Therese Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

https://orcid.org/0000-0002-2915-4498
Johansson Åsa Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

https://orcid.org/0000-0001-8095-6149
Karlsson Torgny Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Ek Weronica E Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

Correspondence to: Fatemeh Hadizadeh, Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala 75108, Sweden. E-mail: fatemeh.hadizadeh@igp.uu.se
8 2024
29 9 2023
29 9 2023
63 8 21012108
23 5 2023
11 9 2023
28 10 2023
© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.
2023
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

Abstract

Objectives

Oral contraceptives (OC) and menopausal hormone therapy (MHT) contain exogenous sex hormones and are used by millions of women around the world. However, their effect on the development of rheumatoid arthritis (RA) is still debated and the current literature suggests that they may exert opposite effects on the risk of RA. The present study aimed to estimate the effects of exogenous hormones on the development of RA, both during the reproductive lifespan and later in life.

Methods

The association between OC and RA, as well as between MHT and late-onset RA (LORA), was investigated using time-dependent Cox regression modelling in white British women from the UK Biobank (n = 236 602 and n = 102 466, respectively) and replicated in women from all ethnic groups.

Results

OC use was associated with a decreased risk of RA in ever-users [hazard ratio (HR) = 0.89; 95% CI = 0.82–0.96], as well as in current (HR = 0.81; 0.73–0.91) and former users (HR = 0.92; 0.84 –1.00), compared with never-users. In contrast, MHT use was associated with an increased risk of LORA in ever-users (HR = 1.16; 1.06–1.26) as well as in former users (HR = 1.13; 1.03–1.24) compared with never-users.

Conclusion

OC use appears to protect against RA, while MHT may increase the risk of LORA. This study provides new insights into the possible inverse effect of exposure to different exogenous sex hormones on the risk of RA.

Rheumatoid Arthritis
Late-Onset RA
Oral Contraceptive
Menopausal Hormone Therapy
A and M Rudbergs Foundation Åke Wiberg Foundation 10.13039/100007435 Marcus Borgström Foundation K and OF Hedströms Foundation Swedish Research Council 10.13039/501100004359 2019–01497 Uppsala University Center for Women’s Mental Health During Reproductive Lifespan
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pmcRheumatology key messages This investigation confirms a previously identified protective effect of OC use on rheumatoid arthritis.

This study identified that MHT use could be a risk factor for late-onset rheumatoid arthritis.

Introduction

Rheumatoid arthritis (RA) is a widely prevalent rheumatic disease known for its potential to cause joint destruction, deformity, irreversible disability and increased mortality rates [1–3]. Multiple studies have suggested a significant role for sex hormones in the development of RA. The female-to-male ratio of RA is significantly higher in patients under 50 years of age [3, 4], and the incidence peaks during menopausal transition which coincides with decreased ovarian function. Furthermore, variations in disease activity have been observed during hormonal transitional periods like pregnancy, post-partum and breastfeeding [3]. This has prompted investigations into the influences of endogenous sex hormones but also the effects of exogenous hormone exposures, particularly oral contraceptives (OC) and menopausal hormone therapy (MHT) on RA development.

Some studies have proposed that OC use may have a protective effect against RA, potentially by delaying disease onset [5–7]. Swedish [8] and French [9] cohort studies have reported protective effects for combined OC and contraceptives containing only progestin, respectively. However, contrasting outcomes were observed in a Chinese Biobank cohort study [10] and a Korean nationwide cross-sectional study [11], which suggested an increased risk of RA in previous OC users. Inconsistent findings may stem from heterogeneities in disease definition [12] or lack of power in many prior studies. Notably, due to teratogenicity concerns, some autoimmune disorder patients, like those with RA, are commonly advised to use contraceptives [13]. This opens up a reversed causal pathway between OC use and RA which cannot be addressed in case-control studies, where OC use timing and disease onset are uncertain.

Regarding the impact of MHT on RA risk, fewer publications are available. Current literature suggests MHT might either show a trend towards increased RA risk [14, 15] or exert a potential protective effect [16, 17].

Considering the age demographics of OC and MHT use, it seems that they might elicit different impacts on the disease initiation. OCs are predominantly used by women of reproductive age, influencing the likelihood of RA development, which is most commonly diagnosed between 30 and 50 years old. In contrast, MHTs are typically prescribed to women aged 45–55 [16], a demographic that falls after the disease’s peak age. Consequently, given the required time for genesis of the disease and manifestation of its characteristics, the potential impact of MHT on RA development might be limited.

However, there is another type of RA that affects older people above age 60, known as elderly-onset or late-onset RA (LORA) [18, 19]. Considering the timing of MHT use, this medication could conceivably hold a role in the development of this type of RA. LORA is represented by a more acute onset, has a worse prognosis, and affects patients’ quality of life more dramatically [16, 18]. As the result of population aging, the global prevalence of LORA is growing [19, 20], which underscores the importance of more targeted investigations on this condition. To date, the largest investigation carried out on postmenopausal women is a Korean nationwide cohort of ∼1.36 million women including 6056 RA patients. In this study, 5 years of exposure to MHT was identified as a risk factor for RA (HR = 1.25; 95% CI, 1.09–1.44) [2]. This result is supported by the outcomes of another study performed on older women (55–69 years) from a prospective cohort of 31 336 Iowa women, which showed a positive association between RA and MHT in former users (RR = 1.47; 95% CI, 1.04–2.06) [21].

The effect of exogenous hormones on RA is yet not well established. In this study, we investigated (i) the lifelong effect of OC use on development of RA, and (ii) the effect of MHT use on the development of LORA in the UK Biobank.

A number of hormone-related and non-hormonal factors, considered as study covariates, are not constant over time, but may change during the follow-up period. Although this type of confounding variable is a critical potential source of bias in the analysis of non-randomized longitudinal data [22], it has been neglected in most previous studies. Here, we applied time-dependent Cox regression, which can be exploited to adjust for both time-varying covariates and time-varying exposures [23].

Materials and methods

Study population

Data from the UK Biobank (UKB) has been exploited for this prospective cohort investigation (see Supplementary Data S1, available at Rheumatology online). To obtain a more homogeneous sample and reduce potential confounding due to ethnicity, study participants were primarily women who reported themselves as ‘white British’ (n = 239 785), given that white British women make up the majority of the UKB (88%). However, importantly, to make the results more generalizable, all the main analyses were repeated by including women from all different ethnic groups (n = 257 194).

Assessment of outcome, exposure and covariates

Events of RA were identified according to the International Classification of Diseases (ICD)-9/ICD-10 codes for RA diagnosis (ICD-10 codes: M05, M06 and ICD-9 code: 7140) or self-reported data. The majority of data were generated from hospital admission of patients. Information on using OC and MHT, as well as age at starting and stopping using them were obtained from the touchscreen questionnaire during the initial visit to the assessment center. Information about previous and current exposures and covariates were assessed between 2006–2010, while RA diagnoses were identified in the registers up to year 2020.

We used the directed acyclic graph approach to identify potential confounders and select proper covariates available in the UKB (Supplementary Fig. S1, available at Rheumatology online). A number of covariates were fixed throughout the study such as Townsend Deprivation Index (TDI), as a proxy for socioeconomic status and number of live birth (Supplementary Data S1 and Table S1, available at Rheumatology online). Age was used as primary time scale in the Cox regression (see method section below), thereby, its effect was effectively controlled for.

Other covariates that were not fixed during the follow-up period (smoking, menopause, hysterectomy, bilateral oophorectomy and OC/MHT use), were modelled as time-varying covariates (Supplementary Fig. S2, available at Rheumatology online). Also, to account for the possible exposure to MHT in investigating the effect of OC on RA and history of exposure to OC in studying LORA, using MHT and OC were included, as time-varying covariates in each study, respectively. Body mass index (BMI) was included when investigating the association between MHT and LORA, while it was not included when examining the effect of OC, as BMI was measured at the end of the follow-up for the latter analysis, and may not reflect the participants’ BMI during follow-up. Nevertheless, we performed a sensitivity analysis to investigate the possible confounding effect of BMI. A recent Mendelian randomization study reported that age at menarche was not significantly associated with RA [24]. Therefore, its effect was investigated in a sensitivity analysis as a time-constant covariate.

Regarding the association between OC and RA, a sensitivity analysis was performed to account for the potential impact of menopausal status, where women who entered menopause during the follow-up period were censored at age of menopause. To investigate the possible confounding effect of polycystic ovary syndrome (PCOS) on the association between MHT and LORA, we performed an additional sensitivity analysis where ovarian dysfunction, including PCOS, was added as a time-varying covariate.

Statistical analysis

Start of studies was the year of birth, i.e. age was considered as the primary time scale, as described in more detail previously [25]. For investigating the effect of OC on RA, participants were followed until they were diagnosed with RA or received the first visit at the assessment center, whichever came first. Due to the age distribution in the UKB, a small number of women were still using OC at time of recruitment (n = 4197), for which, age at discontinuation of OC was imputed by age at the first visit at assessment center. Also, age at discontinuation of smoking and MHT when the participants were still using them (n = 19 569 and n = 13 817, respectively) were imputed by age at first visit at the assessment center.

When investigating the risk of LORA associated with MHT, RA was categorized as LORA in patients who were diagnosed with RA at 60 years old or older (according to the clinical definition of LORA [17]), and women with an RA diagnosis prior to this age were excluded. In contrast to OC, many women were still using MHT during enrolment in the UKB, and many were at an age when it is likely that they started using MHT after the recruitment. As information about MHT use was only collected at the recruitment, we imposed several criteria to avoid misclassification of the exposure in the statistical analyses. For instance, only women with an age of 60 years or older at the assessment were included because at this age it is less likely that unexposed women start to use MHT [26]. Also, when performing the second model (analysing current/former use compared with never use, see below) exposed women with missing information on age of MHT initiation or cessation were excluded. In addition, women who reported still using MHT at the age at assessment (n = 4802) were also excluded from the analyses.

However, to check for the possible selection bias introduced by this exclusion, we performed a sensitivity analysis by also including women who still were using MHT at assessment and filled in their attributed age at discontinuation of MHT by age at assessment. For women who reported that they were still using OC (n = 19), age at assessment was used as the age at discontinuation of OC use and for 6137 current smokers, age at cessation of smoking was filled by age at the end of follow-up (year 2020). End of follow-up was defined as age at RA diagnosis in patients and year 2020 in event-free women.

For both OC and MHT, RA events that occurred at the same age as hormone initiation were considered as an event during exposure. The exposure was modelled as a time-varying variable, following the counting process approach [27, 28]. To avoid immortal time bias [29], hormone users were coded as ‘unexposed’ from birth until they became ‘exposed’ to exogenous hormones and were recoded accordingly. The association between exposure to exogenous hormones and risk of RA development was estimated by the hazard rate ratio (HR) using two different models that were applied to both the OC and MHT exposures by use of the ‘Survival’ R package.

First model: risk of RA in ever-users of exogenous hormones vs never-users

In the first model, the exposure variable could have two values: exposed (ever-users) and unexposed (never-users; reference group) to exogenous hormones. Both groups were coded as unexposed from birth. However, when ever-users started to use, they were considered as exposed during the remaining follow-up period. HRs of RA onset for ever-users compared with never-users were calculated.

Second model: time-dependent effects during and after use of exogenous hormones on risk of RA

To investigate the effect during and after the exposure, ever-users were coded as (i) ‘unexposed’ before initiating hormones; (ii) ‘current users’ from initiating use of hormones till up to one year after discontinuation (to minimize the risk of reversed causation); and (iii) ‘former users’ from more than one year after discontinuation of the studied therapies until the end of follow-up. Never-users were coded as ‘unexposed’ during the entire follow-up. HRs of RA emergence for current users and former users were calculated, with never-users as reference.

Ethics

Performance of this study was approved by UKB (application #41143) and the Swedish Ethical Review Authority (dnr: 2020–04415). Data used for this study are available from the UKB upon application.

Results

A total of 239 785 white British women were included in the study. After including all the variables, in total, 191 288 women had a history of using OC or were still using it, of whom 184 669 (82%) women had recorded age at starting to take OC and year of receiving an RA diagnosis and were included as ever-users and 40 655 (%18) women had never used OC and were labelled as never-users (this information has been summarized in a flowchart presented as Fig. 1).

Figure 1. Flowchart of UK Biobank women included in the study. Right panel illustrates women included in the study to investigate the effect of oral contraceptive (OC) use on rheumatoid arthritis (RA). After exclusion of women who were diagnosed with RA after age at assessment (N = 3164) and those who did not report the year of receiving a RA diagnosis (N = 19), a total of 236 602 women were included in this study of whom 231 943 had information for all the study variables and were subject to analyses. Of women who had reported having ever used OC, 6619 individuals did not report age at initiating OC and were excluded from both models. Therefore, 184 669 women were included in the study as ever-users of OC. Of those, 14 392 individuals did not report age at discontinuation of OC use and were excluded from the second model of the study. Left panel summarized the information of participant in the study of the effect of menopausal hormone therapy (MHT) on late-onset RA (LORA). After considering women ≥60 years of age at first visit to an assessment center as the inclusion criteria and age ≥60 years as definition of LORA and exclusion of RA women without year at diagnosis (N = 14), 102 466 individuals were included in the study of whom 99 681 had information for all study variables. Of those who reported having ever used MHT, 7311 did not report age at starting MHT, therefore, 51 120 women were included as ever-users of MHT. Also, 1614 women did not record the age when they discontinued MHT use and 4802 women were still using MHT which were excluded from the main analyses. A total of 44 704 women were eligible to include in the second model as current and former users. *Variables included in main models: year of birth, Townsend deprivation index (TDI), number of live births, body mass index (only when investigating the effect of MHT on LORA), smoking status, menopausal status, hysterectomy, bilateral oophorectomy and HRT/OC use. The durations when each group were followed up in the studies are presented as person-years (PY)

For estimating MHT effects, a total of 102 466 women, who were at age 60 or older at the recruitment and had no history of RA diagnosis prior to this age, were included and were followed up, of whom 2320 women received an RA diagnose which was considered as LORA. The number of never-users in the MHT analyses (i.e. women who were 60 or older at the initial visit at the assessment center and had not been exposed to MHT before that) was 41 250 (45%), while 51 120 (55%) women, after exclusion of missing values, were included as ever-users (Fig. 1). Of MHT ever-users, 193 women (0.38%) started MHT at or after age 60. A comparison of the characteristics of the ever and never-users of OC and MHT is reported in Table 1.

Table 1. Distribution of general characteristics in ever-users and never-users of OC and MHT

	Oral contraceptives (OC)	Menopausal hormone therapy (MHT)	
Ever-users	Never-users	P-value	Ever-users	Never-users	P-value	
Number (%)	184 669	40 655	—	51 120	41 250	—	
Year of birth, median (full range)	1952 (1936–1970)	1946 (1936–1970)	<0.001	1944 (1936–1950)	1944 (1936–1950)	0.009	
BMI, median (Q1–Q3)	25.95 (23.36–29.47)	26.46 (23.68–30.08)	<0.001	26.40 (23.87–29.63)	26.54 (23.85–30.00)	<0.001	
Age, median (Q1–Q3)	56 (49–62)	63 (58–66)	<0.001	64 (62–66)	64 (61–66)	<0.001	
TDI, median (Q1–Q3)	–2.36 (–3.73–0.001)	–2.30 (–3.68–0.14)	<0.001	–2.48 (–3.80 – –0.26)	–2.45 (–3.77 – –0.24)	0.12	
Age at menarche, median (Q1–Q3)	13 (12–14)	13 (12–14)	0.02	13 (12–14)	13 (12–14)	0.26	
Age at menopause, median (Q1–Q3)	50 (45–52)	50 (46–53)	<0.001	50 (45–53)	51(48–54)	<0.001	
Post-menopausal – Yes, N (%)	107 695 (58%)	29 934 (74%)	<0.001	41 344 (81%)	38 035 (92%)	<0.001	
Post-menopausal – No, N (%)	48 117 (26%)	5114 (13%)	<0.001	211 (0.4%)	293 (0.7%)	<0.001	
Post-menopausal – Not sure hysterectomy, N (%)	20 221 (11%)	4768 (11%)	<0.001	9233 (18%)	2790 (7%)	<0.001	
Post-menopausal – Not sure other, N (%)	8636 (5%)	839 (2%)	<0.001	332 (0.6%)	132 (0.3%)	<0.001	
Had hysterectomy, N (%)	11 177 (0.07)	4043 (0.11)	<0.001	7607 (0.18)	3100 (0.08)	<0.001	
Age at hysterectomy, median (Q1–Q3)	43 (38–49)	45 (40–50)	<0.001	45 (40–50)	45 (40–54)	<0.001	
Had bilateral oophorectomy, N (%)	14 160 (0.08)	4153(0.10)	<0.001	8523 (0.17)	1997 (0.05)	<0.001	
Age at bilateral oophorectomy, median (Q1–Q3)	47 (42–52)	49 (44–55)	<0.001	49 (45–53)	55 (48–59)	<0.001	
Had polycystic ovary syndrome (PCOS), N (%)	—	—	—	217 (0.004)	110 (0.003)	<0.001	
Age at diagnosis PCOS, median (Q1–Q3)	—	—	—	46.50 (39–56)	51.50 (35–60.75)	0.22	
Smoking–Ever, N (%)	77  925 (0.42)	13 502 (0.33)	<0.001	23 635 (0.46)	15 784 (0.38)	<0.001	
Age when initiated smoking, median (Q1–Q3)	17 (15–19)	17 (16–20)	<0.001	18 (16–20)	18 (16–20)	0.004	
Age when discontinued smoking, median (Q1–Q3)	43 (32–53)	48 (35–59)	<0.001	48 (35–61)	48 (34–63)	0.46	
No of live birth, median (Q1–Q3)	2 (1–2)	2 (1–3)	<0.001	2 (2–3)	2 (2–3)	0.42	
MHT use, N (%)	70 242 (38)	16 181 (40)	<0.001	—	—	—	
OC use, N (%)	—	—	—	38 997 (0.76)	26 662 (0.65)	<0.001	
Age when initiated MHT, median (Q1–Q3)	48 (45–50)	49 (45–52)	<0.001	49 (45–52)	—	—	
Age when discontinued MHT, median (Q1–Q3)	55 (59–58)	56 (52–60)	<0.001	56 (52–60)	—	—	
Duration of menopausal hormone therapy, median (Q1–Q3)	6 (2–10)	7 (3–11)	<0.001	6.34 (3–10)	—	—	
Age when initiated OCs, median (Q1–Q3)	21 (18–24)	—	—	24 (21–27)	24 (21–27)	0.21	
Age when discontinued OCs median (Q1– Q3)	30 (26–37)	—	—	32 (28–38)	31 (27–36)	<0.001	
Duration of OC use, median (Q1–Q3)	9 (4–15)	—	—	8 (3–13)	6 (2–12)	<0.001	
Q1 = first quartile, Q3 = third quartile, N = Number, % = percentage.

OC: oral contraceptive; MHT: menopausal hormone therapy; BMI: body mass index; TDI: Townsend deprivation index.

First model: risk of RA in ever-users of exogenous hormones vs never-users

Comparing ever-users of OC with never-users, we observed that exposure to OC was associated with a decreased risk of incident RA (HR=0.89; 95% CI, 0.82–0.96) in British women as well as when including all ethnicities (HR = 0.92; 95% CI, 0.85–0.99).

When censoring women at age at menopause in British women, the results did not change significantly (HR=0.90; 95% CI, 0.83–0.98). Including BMI in the model did not demonstrate any significant difference either (HR = 0.91; 95% CI, 0.84–0.98).

Contrarily, MHT use increased the hazard rate of LORA compared with never use in British women (HR = 1.16; 95% CI, 1.06–1.26) as well as when including all ethnicities (HR = 1.15; 1.06–1.25). Adding PCOS to the model did not change the result (HR = 1.15; 95% CI, 1.05–1.26).

Second model: time-dependent effects during and after use of exogenous hormones on risk of RA development

We had access to start and stop years of OC use from a total of 170 277 British women and 40 655 never-users were included in the second study as the reference. The average duration of OC use was 10.75 years (median: 9 years; 1st–3rd quartile, 4–15) and the interval between discontinuation of OC and end of follow-up (age at first visit at assessment center) was on average 23.1 years (median: 25 years; 1st–3rd quartile, 16–31).

Compared with never-users, we observed a decreased hazard of RA in current users (HR = 0.81; 95% CI, 0.73–0.91) as well as in former users of OC (HR = 0.92; 95% CI, 0.84 –1.00; P-value = 0.043). When including women from all ethnicities, we observed a decreased hazard rate of RA among current OC users (HR = 0.86; 95% CI, 0.78–0.96). However, the result was not significant in former users (HR = 0.94; 95% CI, 0.87–1.02). Considering age at menopause as end of follow-up, the effects looked similar, but with lower HR in the current users of OC compared with never-users (HR = 0.78; 95% CI, 0.70–0.86). However, after discontinuation, OC use was not significantly associated with the risk of RA development (HR = 0.97; 95% CI, 0.89–1.05). Adding BMI to this model did not change the results significantly neither in current users (HR = 0.83; 95% CI 0.74–0.93) nor in former users (HR = 0.93; 95% CI, 0.86–1.01).

For MHT, a total of 85 954 individuals were included in the second analysis, of which 44 704 (52%) had been exposed to MHT and 41 250 (48%) had never used MHT. The mean duration of use was 7.18 years (median: 7 years; 1st–3rd quartile, 3–10) and the mean duration between discontinuation of MHT and age at 2020 (end of follow-up) was 20.24 years (median 19 years; 1st–3rd quartile, 17–23).

Current exposure to MHT was not significantly associated with LORA development compared with never-users (HR = 1.19; 95% CI, 0.88–1.63). However, the rate of LORA development was significantly increased in former MHT users (HR = 1.13; 95% CI, 1.03–1.24) compared with never users. The trend was similar when including all ethnicities (current exposure: 1.17; 0.87–1.58, former exposure: 1.12; 1.02–1.22). Including the women still on MHT at age at assessment did not change the results significantly either in current users (HR = 1.26; 95% CI, 0.95–1.69) or in former users (HR = 1.14; 95% CI, 1.04–1.24). Also, adding PCOS to this model did not change the results (current exposure: 1.19; 0.88–1.63, former exposure: 1.13; 1.03–1.24).

Age at menarche was not included in the main models. However, a possible effect was investigated in a series of sensitivity analyses which did not reflect any significant changes in the results (Supplementary Table S2, available at Rheumatology online). Main results are summarized in Fig. 2.

Figure 2. Hazard ratios (squares) for oral contraceptive use on development of rheumatoid arthritis and hormone replacement therapy for development of rheumatoid arthritis are shown, relative to neverusers. Error bars represent 95% CI. OC: oral contraceptives; MHT: menopausal hormone therapy; RA: rheumatoid arthritis; LORA: late-onset rheumatoid arthritis

Discussion

In this study, we showed that OC use is associated with a decreased risk of RA, with the strongest effect identified during use. We also showed a possible association between MHT use and an increased risk of LORA. The observed presence of two distinct effects of exposure to exogenous hormones on risk of RA could be related to differences in the hormones’ functions in the body, variations in the response to hormones in different reproductive statuses, or heterogeneity between early-onset RA and LORA. We have performed one of the most inclusive studies so far and explored the possible associations during use, as well as after discontinuation of exogenous hormones. Compared with most previous studies, we have utilized a larger sample size with a considerably longer follow-up time. In addition, we defined a distinct group of LORA patients to investigate the association of MHT with RA in a more precise target group.

Various mechanisms have been proposed to justify the detected association between female sex hormones and RA. Estrogen could directly modulate the immune system and can, therefore, in a receptor- and dosage-dependent manner, contribute to development of RA [30]. Moreover, estrogen may have the capacity of influencing the production of antibodies by changing their glycosylation process [31]. B-cell activating factor (BAFF) is a ligand that is necessary for the survival and homeostasis of peripheral B cells [32]. It has been shown that the presence of estrogen is associated with a 5-fold higher expression of BAFF [33] and a higher concentration of BAFF has been detected in the serum of RA patients compared with controls [34].

Before menopause, ovaries produce three types of estrogens: estradiol, estrone and estriol [35]. In contrast to the anti-inflammatory effect of estradiol, estrone is a proinflammatory hormone that, in collaboration with TNF-α, activates the NF-κB signalling pathway [36], a well-recognized key player in the development of RA [37].

Aging is associated with a number of variations in the immune system, which to some degree could result in increased auto reactivity [17]. On the other hand, after menopause the total estrogen levels decrease, the estrone to estradiol ratio increases and estrone becomes the principal estrogen of the body [36, 38]. This results in an imbalance in anti to pro-inflammatory function of estrogen in favor of the pro-inflammatory effect. This effect could be even intensified as estrone may also play an antagonistic role against estradiol [39]. The decrease in the levels of endogenous estrogens and the dominancy of estrone in aged women could represent a plausible mechanistic foundation for the development of LORA. One explanation for the present observation could be that women with the lowest natural levels of estrogen more often use MHT due to stronger symptoms. Another explanation, however, is related to the direct effect of MHT on the production of estrone. While the synthetic ethinylestradiol in OCs is quickly absorbed and does not convert into estrone [40] (it even suppresses the endogenous production of estrone), oral MHT estradiol is known to generate a large amount of circulating estrone through the first hepatic passage [39, 41]. This may partly explain the observed opposite direction of effects of OC and MHT on the development of RA.

This study has several limitations that may affect the outcome or hinder the generalizability of our results. First, UKB consists of a healthier population compared with the general population of the United Kingdom and is therefore subject to selection bias [42]. Second, information on first occurrence of RA diagnosis is partly based on self-reported data and may therefore be less accurate and subject to recall bias. Third, we did not have access to information related to different formulations such as types of progestogens, estrogen doses and routes of administration of studied exogenous hormones. This could potentially limit the generalizability of our results beyond the specific birth-year distribution of the study population. In addition, the study population included majorly white European women residing in the UK, that could also mitigate the generalisability of our findings to other ethnic and geographically distinct populations. Last, the number of women with a history of ovarian dysfunction in our data set was probably underreported (Table 1), considering the high prevalence of PCOS in the UK (5%–10%) [43].

In summary, we carried out a series of analyses to estimate the possible association of exogenous hormones with the incidence of two types of rheumatoid arthritis and showed that OC use could play a protective effect against typical RA while MHT may be a risk factor for late-onset RA. Such findings could eventually contribute to the development of more informed recommendations in clinical guidelines.

Supplementary Material

kead513_Supplementary_Data

Acknowledgements

The computations and data handling were enabled by resources in project sens 2017538 provided by the Swedish National Infrastructure for Computing (SNIC) at Uppsala Multidisciplinary Centre for Advanced Computational Science (UPPMAX), partially funded by the Swedish Research Council through grant agreement no. 2018–05973.

Supplementary material

Supplementary material is available at Rheumatology online.

Data availability

The data utilized for this project is available to legitimate researchers through an application to the UK Biobank (http://www.ukbiobank.ac.uk/about-biobank-uk/).

Funding

This work was funded by A and M Rudbergs Foundation, the Åke Wiberg Foundation (M21-0037), the Marcus Borgström Foundation, K and OF Hedströms Foundation, the Swedish Research Council (2019–01497) and the Uppsala University Center for Women’s Mental Health During the Reproductive Lifespan (WOMHER).

Disclosure statement: The authors have declared no conflicts of interest.
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