Endometriosis is a common estrogen-dependent gynecologic disorder. Individuals with endometriosis have a high rate of infertility. As an inflammatory disease that depends on estrogen, endometriosis impacts about 5-10% of women in their reproductive years (1) and prevalence about 20-30% in infertile women (2). According to the report of Eisenberg (3), the prevalence of diagnosed endometriosis was 10% of premenopausal women worldwide. Endometriosis is the endometrium present outside the ovaries and the pelvic peritoneum. Approximately 8.9% of the women have endometriosis in Taiwan (4). Nevertheless, little is known regarding the pathophysiology of endometriosis. Endometriosis has been reported to be associated with immune dysfunctions, such as the evasion of endometrial tissues from natural killer (NK) cell-mediated clearance, inflammation in the peritoneal microenvironment, and upregulation of interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α, which promote the proliferation of endometrial cells and neovascularization (5–7). Although the immune system appears to play a role in the pathogenesis of endometriosis, the association between endometriosis and autoimmune diseases is still being argued with little and conflicting evidence (8). It is not clear whether autoimmune diseases are a risk factor of endometriosis or whether these two types of diseases share similar pathological mediators. It has been indicated that autoimmune disorders could occur more often among those with endometriosis. However, endometriosis’s actual mechanism and genetic etiology are unknown (9).

As a chronic systemic autoimmune disease, Sjögren’s syndrome is characterized by xerostomia (dry mouth), keratoconjunctivitis sicca (eye dryness), and other systemic conditions (10). Sjögren’s syndrome is classified as primary Sjögren’s syndrome or second Sjögren’s syndrome. Primary Sjögren’s syndrome occurs in the absence of another rheumatic disorder. On the other hand, secondary Sjögren’s syndrome is mainly associated with autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, and Graves’ disease (11). The hallmark of primary Sjögren’s syndrome is lymphocytic infiltration of the lacrimal and salivary glands (12). The prevalence of primary Sjögren’s syndrome is around 0.05% to 4.8% of the world population, with a 9:1 female to male ratio and is highest in Asian women (13, 14). Taiwan’s incidence of Sjögren’s syndrome was 4.98 to 8.86 of 100,000 per year (15). A complicated mechanism moderates the pathogenesis of Sjögren’s syndrome: the infiltration of lymphocytes (mainly T and B cells) in target organs within the dysregulated adaptive immunity system (16). Sjögren’s syndrome characteristics include an exacerbated T cell infiltration in exocrine glands, which is related to its inflammatory feature and disease progression (17, 18). Previous studies have revealed that autoimmune diseases such as Sjögren’s syndrome, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and inflammatory bowel disease were more prevalent in patients with endometriosis (19). Those with endometriosis are also more at risk of having rheumatoid arthritis, according to a retrospective cohort study (20). In a systematic review of 26 case-control cohort and cross-sectional studies, endometriosis was proposed to be related to autoimmune diseases, including Sjögren’s syndrome (21). In contrast, epidemiological research explored that women with endometriosis do not have an increased prevalence of Sjögren’s syndrome (22). In addition, a nationwide cohort-based study does not provide evidence to back up prior claims of endometriosis patients being significantly more likely of getting Sjögren’s syndrome (23). Although conflicting evidence demonstrates relationships between women with endometriosis and autoimmune diseases, it requires more clinical supporting evidence for their relevance. Therefore, we evaluated the prevalence and risk of Sjögren’s syndrome in a nationwide Taiwan cohort among endometriosis patients.

A total of 73,665 individuals were included in this study. 14,733 were in the endometriosis group, and the remaining 58,932 people were in the comparison group. As a result of a successful incidence density sampling program, no significant difference was found between patients with endometriosis and the matched comparison cohort in the distributions of observation age groups, according to Table 1 . The mean ages (SD) of the study subjects were 38.9 ( ± 10.3) and 38.9 ( ± 10.4) years old among patients with endometriosis and matched comparison cohort (Student’s t-test, p >0.99). Among the subjects, patients between 20 and 39 years old were dominant. The mean follow-up (SD) time is 7.27 (0.03) years in patients with endometriosis and 7.25 (0.01) years in the matched comparison cohort.

However, several demographic data(comorbidities) were significantly more frequent in patients with endometriosis than in matched comparison cohort; these included hypertension (11.1%), hyperlipidemia (9.67%), coronary artery disease (4.47%), obesity (1.53%), and stroke (4%). Urbanization level was defined as the categorization of residential areas’ population density: level 1 is the most urbanized whereas level 4 is the least urbanized. Urbanization levels and the amount of monthly income were also found to be significantly associated with endometriosis (p<0.01).

Sjögren’s syndrome incidence density rate was higher in endometriosis patients than those in the matched comparison cohort group (2.84 and 1.93 per 1,000 person-years), as shown in Table 2 . The results revealed that patients with endometriosis had 1.45 times the risk (95% CI=1.27-1.65) of developing Sjögren’s syndrome compared to individuals without endometriosis. Advanced age between 40 and 64 years, over 65 years, hyperlipidemia, and monthly income of more than 30,000 NT dollars showed a significantly positive association with Sjögren’s syndrome. Compared with patients of urbanization 1, patients of urbanization 2,3 and 4 had an adjusted HR of 0.96 (95%CI=0.83-1.11),0.97 and 1.03, respectively, but the difference did not show significance. The risk of Sjögren’s syndrome was 1.60-fold and 2.33-fold more significant in patients of the age of 40-64 and more than 65 years old compared to that in patients of less than 40 years old (95% CI=1.40-1.82 and 95% CI=1.59-3.43, p<0.001), respectively. Among various types of comorbidities, the significantly elevated risk appeared in those with hyperlipidemia (adjusted HR=1.25, 95% CI=1.01-1.54) and those with a monthly income of more than 30,000 NT dollars (adjusted HR=1.19, 95% CI=1.00-1.42). However, the association between comorbidities such as diabetes mellitus, hypertension, coronary artery disease, congestive heart failure, obesity, stroke, chronic kidney disease, and urbanization level was statistically insignificant.

Supplementary Table 1 . shows the results of Cox regression analyses of primary and secondary Sjögren’s syndrome in patients with endometriosis. Among the 305 endometriosis patients, there were 56 (18.36%) patients with primary Sjögren’s syndrome and 249 (81.64%) patients with secondary Sjögren’s syndrome. The incidence density rate of primary Sjögren’s syndrome was higher than secondary Sjögren’s syndrome (2.84 and 2.32 per 1,000 person-years, respectively). The risk of primary Sjögren’s syndrome was 1.40-fold (95%CI=1.21-1.62, p<0.001) in patients with endometriosis, whereas those with secondary Sjögren’s syndrome had an adjusted HR of 1.73 (95%CI=1.26-2.38, p<0.001).

Table 3 shows the results of Cox regression stratified by age and various comorbidities. The study results revealed that among the 1,131 patients with endometriosis, 305 of them developed subsequent Sjögren’s syndrome. After adjusting for age and multiple comorbidities, patients with endometriosis were at a significantly higher risk of getting Sjögren’s syndrome than matched cohorts in the age of 20-39 years old (adjusted HR=1.53, 95% CI=1.25-1.88), in the age of 40-64 years old (adjusted HR=1.41, 95% CI=1.18-1.68), in diabetes mellitus (adjusted

HR=2.54, 95% CI=1.26-5.09), and hyperlipidemia (adjusted HR=1.54, 95% CI=1.09-2.18). Among women with coronary artery disease, endometriosis was not related to an increased risk of Sjögren’s syndrome (adjusted HR 0.91, 95% CI=0.50-1.65). Likewise, endometriosis was not associated with an increased risk of Sjögren’s syndrome among women with congestive heart failure, obesity, stroke, and chronic kidney diseases.

Table 4 presents Cox regression analyses of Sjögren’s syndrome in patients with endometriosis stratified by follow-up time. Compared to the cohort without endometriosis, the risk of Sjögren’s syndrome among endometriosis patients with a follow-up time of fewer than 5 years (adjusted HR=1.57, 95% CI=1.32-1.87) was significantly higher.

Figure 1 shows that the Kaplan-Meier analysis for the cumulative incidence of Sjögren’s syndrome reveals differences between endometriosis patients and the matched comparison cohort (p<0.0001) as being statistically significant in Sjögren’s syndrome.

This study was the first retrospective cohort study that evaluated the relationship between endometriosis and the risk of developing subsequent Sjögren’s syndrome through nationwide population-based data. The results demonstrated that patients with endometriosis are associated with an increased risk of 1.45 times (95% CI=1.27-1.65) of developing Sjögren’s syndrome, as compared to those non-endometriosis comparison group. Moreover, women diagnosed with endometriosis have a higher risk of developing Sjögren’s syndrome within the first 5 years.

Our study results echoed former research and provided information analysis for patients with comorbidities by comparing cumulative incidence and Kaplan-Meier. According to a survey analysis (26), women who were diagnosed with endometriosis were found to be at a significantly (p < 0.001) higher risk of developing autoimmune diseases such as SLE, RA, and multiple sclerosis. According to new research from Fan et al. (2021), demonstrated an increased risk of SLE (adjusted HR= 2.37, 95% CI=1.35-4.14) compared to the non-endometriosis patients (27). In addition, another study suggested that women with endometriosis were significantly associated with rheumatoid arthritis (20). An immunological and inflammatory etiology has been speculated, as indicated by increased concentrations of activated macrophages, cytokines, T cells, and B cells (28). A study pointed out that endometriosis patients can be differentiated from those without by measuring their relative serum IL-6 and PF TNF-α levels (29). Many studies suggest that women with endometriosis may have a hormonal imbalance and be prone to other immune surveillance-related imbalances such as suppressed cell-mediated immunity (high T, B, and NK cell counts, but lessened activity) and increased antibody-mediated immune response (high serum levels of immunoglobulin IgA, IgG, IgM, and anti-endometrial antibodies) (30). In addition, inflammatory cytokine concentrations like IL-1, IL-6, and TNF-α were elevated among endometriosis patients (20). Patients with endometriosis also present with other chronic inflammatory diseases, chronic inflammation, and increased oxidative stress (31). As one of the most prevalent autoimmune diseases, Sjögren’s syndrome predominantly affects the lacrimal and salivary glands and thus, results in sicca symptoms (25). The possible mechanisms of endometriosis in Sjögren’s syndrome remain largely uncertain. While various other studies from different countries have examined the relationship between endometriosis and Sjögren’s syndrome risk, the studies have not yet reached a consensus. Whether Sjögren’s syndrome is a part of etiology in endometriosis or a secondary response to endometriosis deserves further genetic and biological studies for exploration.

Women aged 40-64 and women more than 65 years old have a 1.60-fold and 2.33-fold risk of having Sjögren’s syndrome compared to patients less than 40 years old, respectively. A systematic review on the epidemiology of primary Sjögren’s syndrome revealed that the mean age was 56.16 years (32). According to a 2014 population-based study in Taiwan by Yu et al, the percentage of patients with primary Sjögren’s syndrome was 73.1% and that of patients with secondary Sjögren’s syndrome was 20.3% (11). Our study cohort showed a higher percentage of secondary Sjögren’s syndrome in endometriosis patients may be association between underlying diseases, such as rheumatoid arthritis, systemic lupus erythematosus, or other autoimmune diseases. Research from Ma (33) used the Cox proportional hazard regression model analysis to show that patients with endometriosis have a significant risk of Sjögren’s syndrome (adjusted HR=1.5, 95% CI=1.27-1.77; p<0.05) than non-endometriosis. Our result is in agreement with these findings. Among various comorbidities, the risk of Sjögren’s syndrome was significantly higher only in patients with hyperlipidemia. In addition, a monthly income of more than 30,000 NT dollars was significantly associated with an increased risk of Sjögren’s syndrome. However, the association between other comorbidities, including diabetes mellitus, hypertension, coronary artery disease, congestive heart failure, obesity, stroke, and chronic kidney disease was not statistically significant. Furthermore, when the patients were stratified by comorbidities, we found that the risk of Sjögren’s syndrome was significantly increased in women with endometriosis only among those with hyperlipidemia and diabetes. In contrast, the risk of Sjögren’s syndrome was not significantly increased in women with other comorbidities, including coronary artery disease, congestive heart failure, obesity, stroke, and chronic kidney disease.

This study is noteworthy because of the large sample size from a nationwide population-based cohort and its long-term follow up for 13 years.

Nevertheless, several limitations ought to be granted attention in our study. Since the diagnosis with ICD-9 CM was confirmed by different physicians, referral bias might exist. However, we did apply a strict diagnostic definition in this study to minimize this potential problem. The other limitation is that Taiwan NHIRD does not have information on the patient’s socioeconomic status, personal health behaviors, toxic habits data, family history, and inflammatory biomarkers. Because of these confounding factors, the association between Sjögren’s syndrome and endometriosis could be biased. Since we adjusted for various comorbidities and stratified analysis and regression modeling, unmeasured confounding factors may be lessened in the results.

This study demonstrated that those with a history of endometriosis increased the risk of developing subsequent Sjögren’s syndrome. Such a development was mainly observed during the first five years of patients’ endometriosis diagnosis. Future research needs to consider using the underlying biological mechanisms of these correlations. Therefore, clinicians are advised to monitor individuals with endometriosis or Sjögren’s syndrome appropriately.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

Y-HC drafted the manuscript. J-CW revised the manuscript critically. All authors approved the final version of the manuscript, contributed to the conception, design, and interpretation of the work substantially.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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