Association of endometriosis with Sjögren's syndrome: Genetic insights (Review)

Sjögren's syndrome (SS) is a rare chronic and systemic autoimmune disorder, primarily characterized by lymphocytic infiltrations and autoimmune exocrinopathy and epithelitis as well as a female predominance (9:1 female-to-male predisposition ratio primarily in perimenopausal women) ( 1 ). The characteristic lymphocytic infiltration consists of activated T and B lymphocytes that affect exocrine glands and autoantibody production. SS occurs in 0.5-1% of the population, and the spectrum of the manifestations of the disorder may extend from organ-specific to systemic ones, including xerostomia, dry eyes, arthralgias/arthritis, rash, keratoconjunctivitis sicca, primary liver cirrhosis, lymphoma and lung involvement ( 2 , 3 ). The disorder is also characterized by hypergammaglobulinemia and autoantibody production, mainly against the ribonucleoproteins SS-A/Ro and SS-B/La characteristic of SS and identified in the serum of the patients ( 4 ). The increased levels of various cytokines such as interferon (IFN)-γ, interleukin (IL)-6 and IL-10 found in patients with SS have suggested their notable role in the pathogenesis of the disease ( 5 , 6 ). SS has a complex pathogenesis, involving interacting genetic, epigenetic, hormonal and environmental factors. Furthermore, additional activators of the disease include specific viruses, such as Epstein-Barr virus, human T-lymphotropic virus, retroviruses and Coxsackie virus ( 7 - 9 ). No effective treatment for SS has been developed so far. Current medical treatments focus on the alleviation of the symptoms of the disease as well as the decrease of inflammatory events ( 10 ). Endometriosis is an enigmatic, multifactorial disorder, representing one of the most common gynecological diseases affecting 3-10% of women in their reproductive years, and it can be a debilitating disease leading to poor quality of life ( 11 ). Despite the frequent occurrence, its etiology and pathogenesis are poorly understood and the exact cause is unknown ( 12 - 14 ). Multiple genetic and epigenetic factors, in combination with interacting environmental factors, including pollution agents and toxins, lead to the development of this condition ( 15 ). It is characterized by ectopic localization of endometrial cells and, therefore, the occurrence of endometrial tissue outside the uterine cavity on other organs ( 16 , 17 ). Endometriosis can appear as ovarian endometriotic cysts, peritoneal lesions, fibrosis and deeply infiltrative endometriosis ( 15 ). It is associated with chronic pelvic pain, dysmenorrhea, irregular menstrual bleeding, deep dyspareunia and urinary tract symptoms, while ~30% of patients with endometriosis also suffer from infertility ( 18 - 20 ). Considering that all endometriosis cases cannot be explained by a uniform theory, apart from the favorable and most accepted theory of Sampson ( 21 ) based on retrograde menstruation hypothesis, more pathways and cellular processes have been considered, including angiogenesis, chronic inflammation, increased oxidative stress and endothelial dysfunction ( 22 , 23 ). Clinical presentation varies widely, ranging from asymptomatic to severe, and no diagnostic biomarkers have been approved for routine clinical diagnosis of endometriosis ( 24 ). Notably, the type and severity of symptoms depend on the extent of the disease and the location of the involved organ(s). Advances in the past years have shown that female patients with endometriosis are at higher risk of developing chronic diseases as systemic comorbidities, such as cancer ( 25 ), cardiovascular diseases ( 26 , 27 ), asthma ( 25 ), hypothyroidism ( 25 ) and psychiatric disorders ( 28 ). Most importantly, epidemiological studies demonstrated that patients with endometriosis were associated with an increased risk of developing a number of autoimmune diseases compared with unaffected controls due to notable changes in immune-related parameters. The autoimmune diseases included in this category include rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), ulcerative colitis, Crohn's disease, coeliac disease, ankylosing spondylitis and autoimmune thyroid disorder ( 29 - 33 ). However, it is unclear whether autoimmune diseases represent a risk factor of endometriosis, or these two types of diseases share similar pathogenetic mediators. Previous and recent epidemiological studies have suggested that endometriosis can increase the susceptibility to SS in these females compared with unaffected controls ( 29 , 34 - 36 ). Although the pathogenesis of SS has not been elucidated, there has been strong evidence pointing out the important role of genetics in the development of this disease. Moreover, current research has demonstrated substantial deregulation of the immune system of female patients with endometriosis and epidemiological studies have presented evidence for a link between endometriosis and an increased risk of developing SS ( 29 , 34 - 36 ). The etiology of this co-occurrence remains poorly defined. It is possible that the immunological alterations and chronic inflammation characterizing endometriosis may lead to SS. These similarities between molecular and cellular pathways of endometriosis and SS may implicate a partially shared genetic background. Thus, in the current review, an overview of the shared genetic factors known thus far that are associated with an increased susceptibility for both disorders are presented, while the review did not focus on the plausible clinical basis and relevant aspects regarding the co-occurrence of both diseases.

The present review is a first attempt at searching the literature and analyzing the genetic and epigenetic factors that are involved in the co-occurrence of endometriosis and SS, aiming to shed a light in some shared mechanisms involved in both conditions while also pointing to the delineation of the relevant biochemical and molecular pathways. In the present review, the clinical basis underlying the co-occurrence of both diseases was not investigated. As presented already in the current review, the influence of autoimmunity, inflammation, tissue remodeling and angiogenesis in the underlying biochemical, cellular and pathophysiological mechanisms leading to the reported association between endometriosis and SS has been documented. Although it was beyond the scope of the present review to discuss all these processes in detail, some aspects regarding their role in the development of SS and endometriosis were clearly shown in previous sections. The role of autoimmunity in endometriosis has been hypothesized and/or established considering that a series of anti-nuclear, anti-phospholipid and anti-endometrial antibodies are present in this condition, in combination with elevated levels of inflammatory cytokines and various immune cell-mediated abnormalities ( 74 , 78 ). Aiming to unravel the aforementioned mechanisms, different explanations can be given, including the putative role of chronic inflammation and immune dysregulation appearing in endometriosis when it co-occurs with SS. The development of ectopic endometrial cells and lesions may provoke an increased immune response, which may be combined with pathological causes leading to SS. Furthermore, the hypothesis that endometriosis should be considered an autoimmune disease has been strengthened by the beneficial effects of danazol and GnRH agonists as part of endometriosis treatment, likely due to their immunomodulatory action ( 259 ) as well as the increased number of peritoneal macrophages, high T and B lymphocyte counts ( 260 ) and the increased levels of circulating anti-endometrial antibodies ( 261 ). However, the putative mechanisms leading to endometriosis in female patients with SS remain largely uncertain, given that studies from different countries examining this relationship have not yet reached a consensus. Together, the possible role of SS in the etiology of endometriosis or the occurrence of SS as a secondary response to endometriosis needs further exploration from a genetic and biological aspect ( 36 ). It is known that understanding the genetic basis of complex diseases may provide a unique window into human disease pathogenesis, which will facilitate the development of improved diagnostic and therapeutic strategies and enable personalized medicine. However, apart from the substantial contribution of various GWAS to the identification of a number of SNPs associated with an increased risk of endometriosis or SS development, only a small number of these associations have been analyzed in depth from a functional aspect, thus minimizing the potential of these SNPs to be considered as putative therapeutic targets. Therefore, despite the efforts to analyze the biochemical pathways leading to endometriosis, it remains an emerging public health problem of reproductive-age women and the pathogenesis remains elusive. It has been reported that the prevalence rate of endometriosis in women with chronic pelvic pain is >33%, and in patients with SS the prevalence rate is 6.3% ( 262 ). In the same study ( 262 ), it was reported that patients with endometriosis were more likely to also have SS compared with controls ( 262 ). The risk of endometriosis has been strongly linked to ethnicity but the main differences between population groups have not been well defined ( 263 ). A nine-fold increase in the risk of developing endometriosis among females from the East Asian population was found compared with European or American female populations ( 263 ). It is noteworthy that various studies are currently trying to delineate how disease risk variation is linked to ethnicity, and to identify minor differences in SNP variation and differences in autoimmune disease risk variants reported across different continental populations ( 263 ). The worldwide range of prevalence of SS is 0.05-4.8% with an overall 9:1 female-to-male ratio, which appears highest in Asian females ( 36 ). However, a limitation of this type of studies is the lack of information on the patient's socioeconomic status, personal health behaviors or toxic habits, with all of them representing confounding factors of the association between endometriosis and SS ( 36 ). Taking into account that endometriosis has been associated with various autoimmune diseases, this condition may be considered a risk factor for SS, which requires specific counseling and medical management. Immune and inflammatory dysfunctions are considered challenging therapeutic targets for endometriosis and SS. The ultimate task of this type of study is the development of either novel therapeutic alternative by using the in depth understanding of the role of the associated shared genetic factors or the use of some miRNAs, a class of agents considered possible immunomodulators, considering that miRNAs exhibiting a deregulation in both endometriosis and SS have been identified. Thus, translation of recent discoveries based on miRNAs may allow the development of novel therapeutics for endometriosis and SS in the near future, considering that it has been shown that this type of drugs provide specificity and reduced toxicity compared with other therapeutic agents ( 264 , 265 ). The human miRNAome has been recently analyzed to define a saliva-based diagnostic miRNA signature for patients with endometriosis, based on their expression profile, and the results of this study may contribute to the early diagnosis of this condition ( 266 ). The treatment of complex diseases has undergone substantial change over the last few years and novel, promising therapies have been developed. As presented in the current review, two SNPs of the STAT4 gene, a member of the JAK/STAT pathway playing a pivotal role in IFN signaling related to immunological processes promoting chronic inflammation, are associated with both endometriosis and SS. As a consequence, a promising therapeutic option may be JAK inhibitors that interrupt the transduction of the aforementioned JAK/STAT pathway ( 267 , 268 ). Accumulated results suggest that the JAK inhibitor tofacitinib, a signal transducer associated with inflammation, can be used as an anti-inflammatory agent in patients with SS ( 269 ). The JAK/STAT pathway, especially STAT3 phosphorylation, is upregulated in the utopic endometrium of female patients with endometriosis ( 270 ), and it has been reported that inhibition of JAK/STAT signaling using tofacitinib may be a viable method for the treatment of endometriosis as well ( 271 ). One of the genes that are activated by STAT3 is HIF1α , which is associated with both diseases ( 64 , 127 ). The SNP rs1800629 of the TNF-α gene is associated with both endometriosis and SS ( Table I ). The targeting of the inflammatory cytokine TNF-α expressed at high levels in the peripheral blood or tissue of patients with SS ( 126 , 181 ) may represent another beneficial therapeutic option for a large percentage of affected patients. In this context, it has already been shown that TNF-α also stimulates proliferation of endometriotic stromal cells, thus playing the role of an essential factor for the pathogenesis of endometriosis ( 272 ). This cytokine was found at high levels in female patients with endometriosis ( 273 ). Etanercept, a TNF-α blocker that can neutralize the activity of TNF and is currently used to alleviate the symptoms of autoimmune diseases clinically ( 274 ), has been shown to block the ability of the PF in endometriosis to enhance the proliferation of utopic or ectopic endometrial cells ( 275 ). However, the efficacy of etanercept in the treatment of SS has not been addressed. When it was used for a prolonged treatment of patients with SS, it did not appear to reduce the main symptoms of the patients, being beneficial in a small subgroup of patients with severe fatigue only ( 276 ), while Sankar et al ( 277 ) did not find any evidence suggesting that treatment with etanercept is clinically efficient in patients with SS ( 277 ). Consistently, Moutsopoulos et al ( 278 ) also presented data indicating that etanercept is an ineffective therapeutic agent in SS, thus suggesting that TNF-α may not be a pivotal cytokine in the pathogenesis of SS ( 278 ). In addition, infliximab, another anti-TNF-α agent, failed to demonstrate any beneficial effect in SS ( 279 ) and endometriosis ( 280 ). Clinicians should always keep in mind that patients with endometriosis may also have additional autoimmune diseases, including SS, while the possible co-occurrence of endometriosis in patients with SS should not be underestimated. Thus, female patients with endometriosis, apart from their reference for follow-up with the gynecologist have to be alerted if they have any symptoms characterizing SS, such as xerophthalmia, xerostomia, fatigue, vaginal dryness, myalgia or arthralgia, and report it immediately to the rheumatologist. It has been reported that female patients with endometriosis have a higher risk of developing SS within the first 5 years ( 36 ). Thus, a suitable medication must be provided to these female patients by clinicians. In this framework, Bardi et al ( 281 ) presented the new concept of 'holism' for endometriosis, which leads physicians to evaluate this disorder in a complex and global way, considering its increased risk to co-occur with various autoimmune diseases. This combined, global approach is expected to result in beneficial patient management, taking into account the heterogeneous character of these diseases. In conclusion, information that can be derived by analyzing the intersection between autoimmunity, inflammation and angiogenesis, and the identified shared genetic factors may be of high value in understanding the underlying biochemical and cellular mechanisms of the association between endometriosis and SS, thus contributing to the development of novel therapeutic alternatives for both disorders.