Endometriosis and Sjögren's syndrome: Bidirectional associations in population‐based 15‐year retrospective cohorts

Abstract

Introduction

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder affecting salivary and lacrimal glands, while endometriosis involves uterine‐like tissue growth outside the uterus, causing pelvic pain and infertility. Investigating their intricate relationship using real‐world data is crucial due to limited research on their connection.

Material and Methods

This population‐based cohort study included patients with endometriosis and controls without endometriosis. Propensity score matching was used to balance baseline differences in demographic and clinic characteristics between the two groups. Cox proportional hazards model were used to estimate the effect of endometriosis on the risk of new‐onset pSS over time. A symmetrical cohort study, including patients with pSS and propensity score‐matched controls without pSS, was conducted to investigate the effect of pSS on the risk of endometriosis over time. To elaborate on the mechanisms linking endometriosis and pSS, Ingenuity Pathway Analysis was performed to identify activated pathways in eutopic endometrium from patients with endometriosis and parotid tissues from patients with pSS.

Results

A total of 15 947 patients with endometriosis and 15 947 propensity score‐matched controls without endometriosis were included. Patients with endometriosis presented a significantly greater risk of pSS compared to non‐endometriosis controls (adjusted hazard ratio, aHR = 1.57, 95% CI = 1.29–1.91, p < 0.001). In the symmetrical cohort study, which included 4906 pSS patients and 4,906 propensity score‐matched controls without pSS, patients with pSS were found to be at a significantly higher risk of endometriosis compared to non‐pSS controls (aHR = 1.51, 95% CI = 1.12–2.04, p = 0.012). Ingenuity Pathway Analysis showed that the underlying cellular mechanisms involved autoimmune‐related pathways, including activation of dendritic cell maturation, and chronic inflammatory pathways, including the fibrosis signaling pathway.

Conclusions

These findings support a bidirectional association between endometriosis and pSS, which may be driven by dendritic cell maturation and fibrosis signaling pathways.

The bidirectional association between endometriosis and primary Sjögren's syndrome was observed in two population‐based cohort studies. Autoimmune‐related or chronic inflammatory pathologies may drive the link. Studies are needed to investigate whether immunomodulating therapies can attenuate these risk associations.

Abbreviations

aHR

adjusted hazard ratio

DC

dendritic cell

LHID

Longitudinal Health Insurance Database

NHI

National Health Insurance

NSAIDs

nonsteroidal anti‐inflammatory drugs

pSS

primary Sjögren's syndrome

Key message.

The bidirectional association between endometriosis and primary Sjögren's syndrome was observed in two population‐based cohort studies. The link may be driven by autoimmune‐related or chronic inflammatory pathologies. Future studies are needed to investigate whether immunomodulating therapies can attenuate these risk associations.

1. INTRODUCTION

Endometriosis is an estrogen‐dependent disorder seen in up to 10% of women of reproductive age. ¹ It is estimated that 50% to 60% of women experiencing pelvic pain have endometriosis. ² One theory regarding the etiology of endometriosis involves retrograde menstruation, which leads to the implantation of endometrial tissue outside of the uterus. ¹ , ³ Dysfunctions in the immune system may also contribute to this disorder, as endometrial tissues that would typically be eliminated from ectopic sites remain uncleared. ⁴ These theories have led to speculation about a potential link between endometriosis and autoimmune disorders. ⁴

Immunological studies have demonstrated that endometriosis is associated with increased levels of cytokines, ⁵ abnormalities in B and T cell functions, ⁶ and elevated amounts of circulating auto‐antibodies. ⁴ , ⁷ In contrast, epidemiological studies have yielded varying and inconclusive results. A cross‐sectional survey of 3680 women with surgically confirmed endometriosis reported a significantly higher risk of developing multiple sclerosis and systemic lupus erythematosus. ⁸ Other studies based on registry data found a slight increase in the risk of autoimmune disorders among patients with endometriosis. ⁹ , ¹⁰ , ¹¹ , ¹²

Primary Sjögren syndrome (pSS) is an autoimmune disease predominantly affecting young and middle‐aged females, characterized by sicca syndromes and dryness leading to conjunctivitis. ¹³ Earlier studies have reported the risk for pSS in patients with endometriosis, ranging from no significant risk to up to a 24‐fold increased risk. ⁸ , ⁹ , ¹⁴ Due to discrepancies in previous research findings, this long‐term nationwide population‐based cohort study was conducted to investigate: (1) the association between endometriosis and the risk of pSS, (2) the risk of endometriosis in female patients with pSS, and (3) the underlying mechanisms contributing to the possible bidirectional relationship between endometriosis and pSS.

2. MATERIALS AND METHODS

2.1. Data source and study design

A single‐payer National Health Insurance (NHI) program was implemented in Taiwan in 1995, covering approximately 99% of the population by the end of 2008. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ The NHI Research Database (NHIRD) contains data from reimbursement claims under the NHI program. For the present study, we utilized the Longitudinal Health Insurance Database (LHID), a subset of NHIRD that includes the original claims data for 1 million randomly sampled individuals enrolled in the NHI. Using the LHID, we conducted two parallel population‐based cohort studies involving females diagnosed with endometriosis and with pSS between January 1998 and December 2013. Respective controls without endometriosis or without pSS were selected for comparison.

The diagnosis of endometriosis followed the revised American Society for Reproductive Medicine (rASRM) classification, ¹⁹ , ²⁰ which incorporated visually identified ectopic endometrial lesions via laparoscopy in combination, along with histological findings such as hemosiderin‐laden macrophages or endometrial epithelium, glands, or stroma. Diagnosis of pSS adhered to the criteria set by the American College of Rheumatology and the European League Against Rheumatism Consensus Group, ²¹ , ²² , ²³ which included weighted scores for anti‐SSA(Ro) antibody positivity, focal lymphocytic sialadenitis, abnormal ocular staining, Schirmer tests, and unstimulated salivary flow rates. ²⁴ To ensure validity and consistency of diagnostic records, both endometriosis and pSS required confirmation through at least three outpatient visits or one inpatient discharge diagnosis within a 2‐year period, adjudicated by an independent review committee.

2.2. The endometriosis cohort and follow‐up for new‐onset pSS

Participants eligible for the endometriosis cohort were females older than 20 years who were newly diagnosed with endometriosis between 1998 and 2013. The index date for the endometriosis cohort was defined as the year endometriosis was diagnosed. Individuals who were never diagnosed with endometriosis were placed in the control group. Endometriosis patients who had received any diagnosis of pSS before the index date were excluded. The remaining patients were age‐matched (1:6) with control patients without a history of endometriosis. Propensity score matching between patients with endometriosis and controls without endometriosis was then conducted to reduce the effect of potential confounding factors, ²⁵ , ²⁶ including underlying comorbidities and medications. The covariates considered in the propensity score included age, hypertension, hyperlipidemia, chronic liver disease, diabetes, coronary artery disease, autoimmune disease, cancer, corticosteroids, nonsteroidal anti‐inflammatory drugs (NSAIDs), and oral contraceptives (progestin/estrogen). People in the endometriosis cohort were followed up until pSS was diagnosed, loss of follow‐up, death, or the end of 2013, whichever took place first.

2.3. The pSS cohort and follow‐up for new‐onset endometriosis

Likewise, the pSS cohort consisted of females older than 20 years with new‐onset pSS between 1998 and 2013. The index date for the pSS cohort was set as the date when pSS was first diagnosed. After excluding patients who had received a diagnosis of endometriosis before the index date, patients with pSS were age‐matched (1:4) with controls without pSS. Using the same set of variables employed for the propensity score in the endometriosis cohort, patients without pSS were selected as non‐cpSS controls through propensity score matching. Patients with endometriosis prior to the index date were excluded. The included patients were followed up until endometriosis was diagnosed, loss of follow‐up, death, or the end of 2013, whichever occurred first.

2.4. Statistical analyses for the cohort studies

A Cox proportional hazards model was adopted to estimate the crude hazard ratio (HR) and the adjusted hazard ratio (aHR) of pSS in the endometriosis cohort and the risk of endometriosis in the pSS cohort, along with their 95% confidence intervals (CIs). The crude HR was obtained by comparing outcomes among the exposed group and propensity score‐matched controls, while the aHR was calculated after additional adjustment for baseline covariates. A cumulative probability model was applied to assess the effect of endometriosis on pSS over time for the endometriosis cohort and the effect of pSS on endometriosis in the pSS cohort. In the endometriosis cohort, a sensitivity analysis was conducted to confirm the risk of pSS by restricting the criteria for pSS to patients who were prescribed at least 30 days of disease‐modifying anti‐rheumatic drugs. Subgroup analyses based on age and the use of corticosteroids, NSAIDs, and oral contraceptives identified the subpopulations susceptible to pSS. Results with a p ‐value less than 0.05 were considered statistically significant. All analyses were conducted using SPSS version 18.0 (SPSS Inc., Chicago, IL, USA).

2.5. Canonical pathway analysis

Canonical pathway analysis was conducted by comparing differentially expressed RNA‐seq data among endometrial endothelial cells derived from eutopic endometrium from patients (n = 5) with endometriosis in GSE7846, as well as parotid gland tissues from pSS patients (n = 17) in GSE40611 from the Gene Expression Omnibus (GEO), each compared with respective healthy controls. The differentially expressed RNA‐seq data was derived by normalizing the RNA expression level of patient samples to those of healthy controls. RNA‐seq data with values of −log₁₀(p) greater than 1.3 were considered statistically significant, and positive z‐scores indicated upregulation while negative scores indicated downregulation. The canonical pathway analysis was conducted with Ingenuity Pathway Analysis software (QIAGEN, Hilden, Germany).

3. RESULTS

3.1. The effect of endometriosis on the risk of new‐onset pSS

In LHID, a total 486 069 females were identified, among whom 16 214 patients had endometriosis. After excluding patients with a history of pSS prior to the index date, 15 949 patients with endometriosis and 95 694 age‐matched controls remained. From these people, 15 947 eligible patients with endometriosis and 15 947 propensity score‐matched controls were included, with a mean age of 38.9 years (Figure S1 and Table 1). Among them, 240 patients with endometriosis and 171 non‐endometriosis controls developed pSS during the follow‐up. The incidence density of pSS in patients with endometriosis was significantly higher than in non‐endometriosis controls (1.9 vs. 1.2 per 1000 person‐years) (p < 0.001) (Table 2A).

TABLE 1.

Baseline characteristics of patients with endometriosis and controls without endometriosis.

	Before propensity score matching				p‐Value	After propensity score matching				p‐Value
	Endometriosis (N = 15 949)		Controls (N = 95 694)			Endometriosis (N = 15 947)		Controls (N = 15 947)
	N	%	n	%		n	%	n	%
Age
20–55	15 644	98.1	93 864	98.1		15 643	98.1	15 646	98.1	0.902
≧55	305	1.9	1830	1.9		304	1.9	301	1.9
Mean ± SD	38.8 ± 8.8		38.8 ± 8.8		1	38.8 ± 8.8		38.9 ± 8.8		0.309
Hypertension	825	5.2	3577	3.7	<0.001	823	5.2	814	5.1	0.819
Hyperlipidemia	337	2.1	1420	1.5	<0.001	335	2.1	325	2.0	0.694
Chronic hepatitis C	17	0.1	46	0.05	0.004	16	0.1	18	0.1	0.731
Alcoholic liver disease	5	0.03	20	0.02	0.391 a	5	0.03	3	0.02	0.727 a
Diabetes	363	2.3	1680	1.8	<0.001	362	2.3	342	2.1	0.446
Coronary artery disease	169	1.1	580	0.6	<0.001	167	1.0	170	1.1	0.870
Cerebrovascular disease	77	0.5	285	0.3	<0.001	77	0.5	73	0.5	0.743
Autoimmune disease	71	0.4	327	0.3	0.042	71	0.4	66	0.4	0.669
Cancer	363	2.3	897	0.9	<0.001	361	2.3	363	2.3	0.940
Corticosteroids	9387	58.9	41 286	43.1	<0.001	9385	58.9	9382	58.8	0.973
NSAIDs	12 328	77.3	55 960	58.5	<0.001	12 326	77.3	12 332	77.3	0.936
Oral contraceptives	3926	24.6	7038	7.4	<0.001	3924	24.6	3917	24.6	0.927

Note: Bold font represents statistical significance (p < 0.05).

Abbreviation: NSAIDs, nonsteroidal anti‐inflammatory drugs.

^a Fisher's exact test.

TABLE 2.

(A) Risk factors for Sjögren's syndrome in the Cox proportional hazards model. (B) The effect of endometriosis on the risk of new‐onset Sjögren's syndrome in subgroups.

(A)
	Events of Sjögren's syndrome	Observed person‐years	Incidence density (per 1000 person‐years)	Crude HR	95% CI	Adjusted HR a	95% CI
Endometriosis
No	171	137 140	1.2	1		1
Yes	240	124 237	1.9	1.59	1.31–1.94	1.57	1.29–1.91
Age
20–55	397	256 979	1.5	1		1
≧55	14	4399	3.2	2.09	1.23–3.57	1.58	0.89–2.79
Hypertension	25	11 877	2.1	1.39	0.92–2.08	0.87	0.55–1.37
Hyperlipidemia	18	4354	4.1	2.79	1.74–4.48	1.84	1.08–3.14
Alcoholic liver disease	1	56	18.0	11.79	1.66–83.89	6.58	0.87–49.50
Diabetes	24	4971	4.8	3.27	2.16–4.93	2.50	1.57–3.99
Coronary artery disease	8	2664	3.0	1.94	0.96–3.90	1.21	0.58–2.55
Cerebrovascular disease	3	1114	2.7	1.75	0.56–5.44	1.13	0.35–3.62
Autoimmune disease	14	910	15.4	10.35	6.07–17.64	9.45	5.51–16.21
Cancer	11	5009	2.2	1.44	0.79–2.62	1.30	0.71–2.38
Corticosteroids	277	173 920	1.6	0.99	0.81–1.22	1.15	0.91–1.44
NSAIDs	306	221 268	1.4	0.48	0.39–0.61	0.41	0.32–0.53
Oral contraceptives	132	76 421	1.7	1.11	0.90–1.37	1.15	0.93–1.43

(B)
	Endometriosis		Controls		HR	95% CI
	N	Events of Sjögren's syndrome	N	Events of Sjögren's syndrome
Age
20–55	15 643	233	15 646	164	1.59	1.3–1.94
≧55	304	7	301	7	1.16	0.41–3.30
p for interaction = 0.550
Corticosteroids
No	6562	88	6565	46	2.16	1.51–3.08
Yes	9385	152	9382	125	1.33	1.05–1.68
p for interaction = 0.009
NSAIDs
No	3621	63	3615	42	1.73	1.17–2.56
Yes	12 326	177	12 332	129	1.53	1.22–1.92
p for interaction = 0.332
Oral contraceptives
No	12 023	164	12 030	115	1.59	1.26–2.02
Yes	3924	76	3917	56	1.50	1.06–2.12
p for interaction = 0.671

Note: Bold font represents statistical significance (p < 0.05). The hazard ratio (HR) was estimated by a univariate Cox proportional hazards model.

Abbreviation: NSAIDs, nonsteroidal anti‐inflammatory drugs.

^a Adjusted for age, hypertension, hyperlipidemia, alcoholic liver disease, diabetes, coronary artery disease, cerebrovascular disease, autoimmune disease, cancer, corticosteroids, NSAIDs, and oral contraceptives.

Patients with endometriosis had a significantly higher risk of pSS compared to non‐endometriosis controls (aHR = 1.57, 95% CI = 1.29–1.91) after adjustment for baseline covariates (Table 2A). The cumulative probability of pSS was significantly higher in patients with endometriosis over time (log‐rank test, p < 0.001) (Figure 1A). Subgroup analyses showed that the magnitude of the effect of endometriosis on the risk of pSS was lower among those who were exposed to corticosteroids (HR = 1.33, 95% CI = 1.05–1.68 for corticosteroid users vs. HR = 2.16, 95% CI = 1.51 = 3.08 for corticosteroid non‐users, p for interaction = 0.009) (Table 2B).

FIGURE 1.

Bidirectional associations between pSS and endometriosis. (A) Kaplan–Meier curves illustrating the cumulative probability of pSS in patients with and without endometriosis. (B) Kaplan–Meier curves illustrating the cumulative probability of endometriosis in patients with and without pSS.

The observed association between pSS and endometriosis was consistent with findings in the sensitivity analysis, in which patients with endometriosis still had a significantly greater risk of pSS compared to non‐endometriosis controls (aHR = 1.78, 95% CI = 1.28–2.47). Alcoholic liver disease (aHR = 28.66, 95% CI = 3.45–283.32) and autoimmune disease (aHR = 21.95, 95% CI = 11.73–41.08) were independent risk factors for pSS. The use of NSAIDs attenuated the risk of pSS (aHR = 0.48, 95% CI = 0.32–0.73) (Table S1).

3.2. The effect of pSS on the risk of new‐onset endometriosis

A total of 5809 females with pSS were identified from LHID. After excluding patients diagnosed with endometriosis before the index date, 5356 patients and 21 424 age‐matched controls were included. From these individuals, 4906 eligible patients with pSS and 4906 propensity score‐matched controls without pSS were selected (Figure S2). After propensity score matching, there was no statistically significant difference in baseline characteristics between the pSS group and the non‐pSS group (all p > 0.50) (Table 3).

TABLE 3.

Baseline characteristics of patients with Sjögren's syndrome and controls without Sjögren's syndrome.

	Before propensity score matching				p‐Value	After propensity score matching				p‐Value
	Sjögren’s syndrome (N = 5356)		Controls (N = 21 424)			Sjögren’s syndrome (N = 4906)		Controls (N = 4906)
	N	%	n	%		n	%	N	%
Age
20–55	2757	51.5	11 028	51.5	1	2458	50.1	2384	48.6	0.135
≥55	2599	48.5	10 396	48.5		2448	49.9	2522	51.4
Mean ± SD	53.7 ± 15.8		53.7 ± 15.8		1	54.3 ± 15.8		54.5 ± 15.6		0.528
Hypertension	1222	22.8	4594	21.4	0.029	1150	23.4	1169	23.8	0.652
Hyperlipidemia	530	9.9	1705	8.0	<0.001	505	10.3	508	10.4	0.921
Chronic hepatitis C	31	0.6	51	0.24	<0.001	24	0.5	19	0.4	0.445
Alcoholic liver disease	2	0.04	8	0.04	1 a	2	0.04	2	0.04	1 a
Diabetes	475	8.9	2191	10.2	0.003	456	9.3	459	9.4	0.917
Coronary artery disease	379	7.1	1094	5.1	<0.001	363	7.4	360	7.3	0.908
Cerebrovascular disease	207	3.9	716	3.3	0.061	193	3.9	186	3.8	0.714
Autoimmune disease	555	10.4	111	0.5	<0.001	108	2.2	111	2.3	0.838
Cancer	147	2.7	512	2.4	0.134	141	2.9	145	3.0	0.810
Corticosteroids	4494	83.9	10 884	50.8	<0.001	4061	82.8	4058	82.7	0.936
NSAIDs	4351	81.2	13 746	64.2	<0.001	3943	80.4	3958	80.7	0.702
Oral contraceptives	654	12.2	1530	7.1	<0.001	587	12.0	584	11.9	0.926

Abbreviation: NSAIDs, nonsteroidal anti‐inflammatory drugs.

^a Fisher's exact test.

During the follow‐up, 99 patients with pSS and 75 non‐pSS controls developed endometriosis. The incidence density (3.1 vs. 2.1 per 1000 person‐years) and the risk of endometriosis in patients with pSS (aHR = 1.51, 95% CI = 1.12–2.04) were significantly higher than in non‐pSS controls (Table 4A). Kaplan–Meier curves showed that the cumulative probability of endometriosis in patients with pSS was significantly greater than in non‐pSS controls (log‐rank test p = 0.012) (Figure 1B). Subgroup analyses indicated that the magnitude of the effect of pSS on the risk of endometriosis was lower among pSS patients exposed to corticosteroids (HR = 1.06, 95% CI = 0.72–1.54 for corticosteroid users vs. HR = 2.75, 95% CI = 1.62–4.64 for corticosteroid non‐users, p for interaction = 0.002). Likewise, the magnitude of the effect of pSS on the risk of endometriosis was lower among patients with pSS receiving NSAIDs (HR = 1.13, 95% CI = 0.78–1.65 for NSAID users vs. HR = 2.46, 95% CI = 1.46–4.15 for NSAID non‐users, p for interaction = 0.011) or oral contraceptives (HR = 0.52, 95% CI = 0.18–1.52 for oral contraceptive users vs. HR = 1.63, 95% CI = 1.19–2.24 for oral contraceptive non‐users, p for interaction = 0.044) (Table 4B).

TABLE 4.

(A) Risk factors for endometriosis in the Cox proportional hazards model. (B) The effect of endometriosis on the risk of new‐onset endometriosis in subgroups.

(A)
	Events of endometriosis	Observed person‐years	Incidence density (per 1000 person‐years)	Crude HR	95% CI	Adjusted HR a	95% CI
Sjögren's syndrome
No	75	36 270	2.1	1		1
Yes	99	32 259	3.1	1.47	1.09–1.98	1.51	1.12–2.04
Age
20–55	167	36 131	4.6	1		1
≥55	7	32 397	0.2	0.05	0.02–0.10	0.06	0.03–0.13
Hypertension	8	14 204	0.6	0.18	0.09–0.37	0.66	0.30–1.42
Hyperlipidemia	4	5818	0.7	0.25	0.09–0.67	0.85	0.29–2.47
Chronic hepatitis C	1	202	5.0	1.88	0.26–13.42	3.02	0.42–21.64
Diabetes	3	5391	0.6	0.20	0.06–0.63	0.81	0.25–2.67
Coronary artery disease	4	4549	0.9	0.33	0.12–0.88	1.74	0.60–5.00
Cerebrovascular disease	2	2232	0.9	0.34	0.08–1.36	1.32	0.32–5.47
Autoimmune disease	3	1349	2.2	0.87	0.28–2.73	1.23	0.39–3.87
Cancer	3	1446	2.1	0.79	0.25–2.48	1.28	0.41–4.04
Corticosteroids	107	59 602	1.8	0.24	0.18–0.33	0.42	0.30–0.58
NSAIDs	109	59 150	1.8	0.27	0.20–0.36	0.51	0.36–0.72
Oral contraceptives	15	10 767	1.4	0.53	0.31–0.90	0.61	0.36–1.05

(B)
	Sjögren's syndrome		Controls		HR	95% CI
	N	Events of endometriosis	N	Events of endometriosis
Age
20–55	2458	94	2384	73	1.41	1.04–1.92
≥55	2448	5	2522	2	2.70	0.52–13.94
						p for interaction = 0.418
Corticosteroids
No	845	47	848	20	2.75	1.62–4.64
Yes	4061	52	4058	55	1.06	0.72–1.54
						p for interaction = 0.002
NSAIDs
No	963	44	948	21	2.46	1.46–4.15
Yes	3943	55	3958	54	1.13	0.78–1.65
						p for interaction = 0.011
Oral contraceptives
No	4319	94	4322	65	1.63	1.19–2.24
Yes	587	5	584	10	0.52	0.18–1.52
						p for interaction = 0.044

Note: Bold font represented statistical significance (p < 0.05). The hazard ratio (HR) was estimated using a univariate Cox proportional hazards model.

Abbreviation: NSAIDs, nonsteroidal anti‐inflammatory drugs.

^a Adjusted for age, hypertension, hyperlipidemia, chronic hepatitis C, diabetes, coronary artery disease, cerebrovascular disease, autoimmune disease, cancer, corticosteroids, NSAIDs, and oral contraceptives.

3.3. The underlying mechanisms of the bidirectional associations between endometriosis and pSS

Canonical pathway analysis using Ingenuity Pathway Analysis indicated that the mechanisms underlying the correlation between endometriosis and pSS involved multiple inflammatory pathways (Figure 2). Among these pathways, the canonical pathway for dendritic cell (DC) maturation was highly expressed in both endometrium of endometriosis patients (n = 5) and in parotid glands of pSS patients (n = 17), compared to healthy donors (n = 14) (Figure 2). Specifically, the z‐scores were 2.83 for endometriosis and 4.00 for pSS, indicating upregulation in both conditions. The −log₁₀(P) values were 2.29 for endometriosis and 9.57 for pSS, suggesting the statistical significance of the pathway upregulation. These findings highlighted the upregulated pathways involved in the association between endometriosis and SS, particularly implicating DC maturation in initiating adaptive immunity through the antigen‐presenting capabilities of DCs.

FIGURE 2.

Heatmap visualizing canonical pathway enrichment based on z‐scores, generated using RNA‐seq data from endometriosis and pSS patients in Ingenuity Pathway Analysis.

4. DISCUSSION

The study reveals a statistically significant bidirectional association between endometriosis and pSS. Patients with endometriosis exhibit a significantly increased risk of developing pSS, which persists in the sensitivity analyses. At the same time, individuals with pSS are also significantly more likely to develop endometriosis. The underlying mechanisms involve autoimmune‐related pathways, such as DC maturation, and chronic inflammatory pathways including fibrosis signaling. These findings emphasize the interplay between endometriosis and pSS, shedding light on shared immunological pathways and providing valuable insights for understanding and managing these conditions.

While it has been reported that patients with endometriosis are at a high risk of migraine headaches, ²⁷ fibromyalgia, chronic fatigue syndrome, inflammatory arthritis, and irritable bowel syndrome, ⁸ , ²⁸ , ²⁹ the findings in the present study provide evidence of the bidirectional association between endometriosis and pSS as well as its underlying mechanisms. Patients with endometriosis present a higher risk of pSS as compared to those without endometriosis. The use of NSAIDs is associated with a significantly lower risk of pSS in patients with endometriosis. Likewise, patients with pSS are associated with a higher risk of endometriosis compared to those without pSS. Subgroup analysis shows that the use of corticosteroids, NSAIDs, and oral contraceptives is associated with a significantly lower risk of endometriosis in patients with pSS. Chronic inflammatory pathways involving DC maturation for initiating adaptive immunity through the antigen‐presenting capabilities of DCs contributec to the bidirectional associations between endometriosis and pSS.

Previous cross‐sectional survey‐based studies found that endometriosis was associated with immune‐mediated inflammatory diseases ⁸ including systemic lupus erythematosus. ¹² Among all studied autoimmune diseases, a mildly elevated risk of pSS in patients with endometriosis was demonstrated. ⁹ , ¹⁴ A statistically significant association between endometriosis and an increased risk of pSS was reported based on data from the Danish Hospital Discharge Register, which became non‐significant when the criteria for endometriosis were restricted to severe endometriosis requiring laparoscopy or laparotomy. Likewise, another cross‐sectional study reported no statistically significant difference in the prevalence of SS in 22 women with endometriosis, compared to 501 controls. ¹⁴

Findings in the Cox proportional hazards regression in the present study suggested that patients with endometriosis presented with approximately a 57% higher risk of pSS. The risk remained statistically significant even when the criteria of pSS were restricted to more severe cases that required disease‐modifying anti‐rheumatic drugs. Overall, the present study supported the theory that patients with endometriosis had a modestly elevated risk of pSS. In addition to endometriosis, hyperlipidemia and diabetes were as well independent risk factors for pSS, which is consistent with previous studies showing that common comorbidities of pSS include hyperlipidemia and type 2 diabetes. ³⁰ , ³¹

Steroids and NSAIDs are commonly prescribed to relieve symptoms of parotid swelling and arthritis in pSS. ³² The subgroup analysis of the present study reported a significantly lowered risk of pSS by NSAIDs in patients with endometriosis. This finding suggested that steroids or analgesic medications may not only relieve symptoms but also attenuate the risk of pSS in endometriosis patients for their anti‐inflammatory effect, for which steroids and analgesics are known to effectively suppress inflammatory cytokines central to both endometriosis and pSS. ³³ , ³⁴ , ³⁵ Since this finding may allow for primary prevention of comorbidities in patients with endometriosis or pSS using steroids or NSAIDs, further prospective studies that include disease activity as a covariate are warranted to validate the findings.

Immunological evidence supports the link between endometriosis and pSS, in which defective B‐, T‐, and natural killer (NK) cell activity has been observed in patients with endometriosis. ⁴ , ³⁶ Similarly, patients with pSS have been reported to show abnormal B‐ and T‐ cell activity that leads to lymphocytic infiltration and glandular dysfunction. ³⁷ , ³⁸ , ³⁹ Such alterations in humoral responses result in the generation of autoantibodies in both endometriosis and pSS. ⁴⁰ , ⁴¹ Increased pro‐inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α), interleukin‐1 (IL‐1), and interleukin‐6 (IL‐6) in patients with endometriosis ³⁶ , ⁴² , ⁴³ , ⁴⁴ were also observed in the pSS population. ⁴⁵ The current study, along with previous reports, suggests that estrogen signaling may play a role in the development of endometriosis. ⁴⁶ As oral contraceptives, which are often used to manage endometriosis, can downregulate estrogen signaling, the downregulation of the estrogen pathway observed in the heatmap of patients with endometriosis in the present study may be attributed to the use of oral contraceptives among the participants. In the heatmap of the present study, significantly inhibited Rho GDP‐dissociation inhibitor (RhoGDI) signaling was found for both endometriosis and pSS. Cell migration and movement are important factors in the pathogenesis of endometriosis, and RhoGDI has been shown to play a role in these processes. ⁴⁷ Furthermore, RhoGDI is involved in cyclooxygenase 2 (Cox2)‐dependent inflammatory pathways. ⁴⁸ In healthy individuals, immune cells typically remove endometrial cells that have migrated outside the uterus. However, in endometriosis, the downregulation of immune cell migration impairs this mechanism, resulting in the proliferation and migration of endometrial cells outside the uterus. Collectively, the evidence suggests that endometriosis and pSS share a common pathogenic pathway, which echoes our findings that DC maturation ⁴⁹ is responsible for the clinically identified bidirectional relationship.

An increasing number of epidemiological studies have shown that endometriosis is linked to autoimmune disorders. Patients with endometriosis have been found to have increased risks of systemic lupus erythematosus, ⁹ , ¹² multiple sclerosis, ⁹ rheumatoid arthritis, ¹² inflammatory bowel disease, and celiac disease. ¹² These reports support autoimmunity as a possible cause of endometriosis. From a therapeutic standpoint, whether or not endometriosis could be managed as an autoimmune disease by immunomodulation, disparate from conventional medical and surgical modalities for endometriosis, remains unclear. Gonadotropin‐releasing hormone agonists have been shown to exert immunomodulatory effects on endometriosis, particularly by increasing the NK cell counts and T‐cell activity ⁵⁰ ; likewise, progesterone can facilitate the suppression of cytokine release and action. ⁵⁰ More studies are warranted to verify whether immunomodulating therapies may alleviate endometriosis in patients with endometriosis in patients with concomitant immune‐mediated inflammatory diseases.

There are several limitations that should be considered while interpreting our findings. For instance, there could be a lack of diagnosis of endometriosis. Endometriosis may remain undiagnosed in patients who present with pain associated with menstruation and subsequently receive treatments for dysmenorrhea. Therefore, the actual number of cases of endometriosis may be higher than estimated, resulting in an underestimated effect of endometriosis on pSS, as well as the effect of pSS on endometriosis. Prospective studies are needed to investigate the association between pSS and endometriosis among patients with endometriosis requiring surgical treatment for endometriosis. Secondly, the lack of inflammatory biomarkers for endometriosis secreted by endometrial lesions makes it difficult to predict the risk of developing pSS or other autoimmune diseases in patients with endometriosis. As a result, there is a need for further research to identify more accurate diagnostic and predictive biomarkers for these conditions. Thirdly, the effect of healthcare‐seeking behaviors on the observed associations was not assessed. It is conceivable that both participants with pSS and those with endometriosis may be more likely to have healthcare interactions, particularly after their diagnosis, which could potentially lead to easier diagnosis of the other disease. That being said, the major strengths of our study include the fairly larger sample size compared to previous studies. ⁹ , ¹⁴ Additionally, propensity score matching was used to minimize the effect of potential confounders such as underlying comorbidities and comedications. Overall, after adjusting for characteristics including comorbidities, comedications, and socioeconomic status, the present study was able to solidify the association between endometriosis and pSS.

5. CONCLUSION

Bidirectional associations between endometriosis and pSS were observed, with underlying mechanisms involving chronic inflammatory pathways such as DC maturation. The use of corticosteroids, NSAIDs, and oral contraceptives in patients with endometriosis or pSS was associated with a reduced risk of the other disease. Prospective studies are warranted to ascertain the necessity of regular follow‐ups and patient education ⁵¹ for patients with endometriosis or pSS who have developed early signs of the other disease.

AUTHOR CONTRIBUTIONS

Kevin Sheng‐Kai Ma: conceptualization. Kevin Sheng‐Kai Ma, Li‐Tzu Wang, Naoko Sasamoto, and Yu‐Hsun Wang: methodology. Kevin Sheng‐Kai Ma and Li‐Tzu Wang: writing – original draft. Naoko Sasamoto, James Cheng‐Chung Wei, Jon Ivar Einarsson, and Marc R. Laufer: writing, review & editing.

FUNDING INFORMATION

This work was partially funded by the International Team for Implantology (ITI) (research grant fund no. 1577_2021 to K.S.M.), the National Science and Technology Council (NSTC 113‐2314‐B‐038‐021 to L.T.W.), and Taipei Medical University (TMU112‐AE1‐B08 to L.T.W.).

CONFLICT OF INTEREST STATEMENT

None.

ETHICS STATEMENT

The study protocol was approved by the Institutional Review Board of Chung Shan Medical University Hospital (CS15134) on May 4, 2019.

Supporting information

Table S1. Risk factors for Sjögren’s syndrome in the sensitivity analysis.

Ma K‐K, Wang L‐T, Sasamoto N, et al. Endometriosis and Sjögren's syndrome: Bidirectional associations in population‐based 15‐year retrospective cohorts. Acta Obstet Gynecol Scand. 2024;103:2070‐2080. doi: 10.1111/aogs.14909

DATA AVAILABILITY STATEMENT

The data used in this study are available upon reasonable request from the corresponding author.