{"paper_id":"dec1a2e5-18a1-4cab-82b2-e0b633db0309","body_text":"Explor Immunol. 2022;2:25–31 | https://doi.org/10.37349/ei.2022.00034 Page 25\nEndometriosis and autoimmunity\nNoémie Abisror1, Kamila Kolanska 2,3       , Meryem Cheloufi 4, Lise Selleret 2,3       , Emmanuelle d’ Argent2,3, \nGilles Kayem4     , Arsene Mekinian1*\n1Sorbonne Université, AP-HP , Hôpital Saint-Antoine, service de Médecine Interne and Inflammation-(DMU i3), 75012 \nParis, France\n2Sorbonne Université, AP-HP , Hôpital Tenon, service de Gynécologie-Obstétrique et Médecine de la Reproduction, Université \nParis 06, UMRS-938, 75020 Paris, France\n3GRC-6 Centre Expert En Endométriose (C3E), Sorbonne Université, UMRS-938, 75020 Paris, France\n4Sorbonne Université, AP-HP , Hôpital Trousseau, service d’Obstétrique, Université Paris 06, 75012 Paris, France\n*Correspondence: Arsene Mekinian, Sorbonne Université, AP-HP , Hôpital Saint-Antoine, service de Médecine Interne and \nInflammation-(DMU i3), 75012 Paris, France. arsene.mekinian@aphp.fr\nAcademic Editor: Satish Kumar Gupta, Indian Council of Medical Research, India\nReceived: August 10, 2021  Accepted: December 13, 2021  Published: February 16, 2022\nCite this article:  Abisror N, Kolanska K, Cheloufi M, Selleret L, d’ Argent E, Kayem G, et al. Endometriosis and autoimmunity. \nExplor Immunol. 2022;2:25–31. https://doi.org/10.37349/ei.2022.00034\nAbstract\nEndometriosis is an inflammatory oestrogen-dependent chronic disease and is mainly expressed by pain and \nincreased infertility. Several studies showed an increased prevalence of autoimmune systemic diseases and \nvarious autoantibodies in endometriosis. The association of these autoimmune markers and diseases could \nraise the fact that endometriosis is an authentic autoimmune or inflammatory disease and thus could argue \nfor the use of immunomodulatory therapies. Usually, it is considered that the autoantibodies did not directly \nact in endometrium implants growth, and could be rather implicated in endometriosis-related infertility. The \nuse of immunomodulatory strategies could be an important alternative or additional strategy to the use of \nhormones and surgery but need prospective well-designed trials.\nKeywords\nEndometriosis, autoimmune diseases, immunomodulation\nIntroduction\nEndometriosis is an inflammatory oestrogen-dependent disease characterized by extra-uterine infiltration \nof endometrial glands and stroma [1]. Endometriosis prevalence is from 5–10% in women with pelvic pain, \ndyspareunia, and dysmenorrhea. About 30% of patients with endometriosis also suffer from infertility [2 ]. \nMany women remain asymptomatic, but some of them complain with a variety of symptoms and pain with \nsevere impact on the quality of life and fertility [3]. Endometriosis is a particularly original multifaceted disease, \nwith physiopathological aspects including not only hormonal but also immunological and inflammatory \naspects. Different causes could reduce the fertility in endometriosis women, such as adhesions, chronic \nperitoneal inflammation, disturbed folliculogenesis, and hormonal disturbance. Various immunological \nOpen Access   Perspective\n© The Author(s) 2022. This is an Open Access article licensed under a Creative Commons Attribution 4.0 International \nLicense (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution \nand reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the \noriginal author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nExploration of Immunology\n\n\nExplor Immunol. 2022;2:25–31 | https://doi.org/10.37349/ei.2022.00034 Page 26\nfactors, such as increased inflammatory factors and immune antibodies mediated disturbances could be also \ninvolved in the fertility of endometriosis women. The management actually includes the hormonal therapies \n(oral contraceptives, progestins, and gonadotropin-releasing hormone agonists), and surgery could be \nproposed in some refractory cases. These therapies are not sufficient in most cases of endometriosis-related \ninfertility and complementary strategies should be developed.\nThe frequency of associated autoimmune diseases, of autoantibodies, and the increase of various \npro-inflammatory markers should consider the endometriosis as an autoimmune or inflammatory \ndisease. These statements argue for the use of immunomodulatory therapies in the management of \nendometriosis-related infertility. Despite these arguments, the use of immunomodulation is actually limited \nin the routine management of endometriosis. Usually, it is considered that autoantibodies do not directly act \nin endometrium implants growth, which could be rather implicated in endometriosis-related infertility, and \nrepresents markers of immune mechanisms. This review aims to describe the prevalence of autoimmune \ndiseases associated with endometriosis, the prevalence of various autoantibodies, and the perspectives of \nimmunomodulatory therapies.\nEndometriosis and autoimmune diseases\nThe prevalence of several autoimmune diseases is increased in women with endometriosis. Among them, \nsystemic lupus erythematosus (SLE), rheumatoid arthritis (RA), celiac disease, inflammatory bowel \ndisease, Sjogren’s syndrome (SS), and autoimmune thyroiditis are particularly involved. A case-control \nstudy of 150 women with endometriosis, SLE, celiac disease, inflammatory bowel disease, and autoimmune \nthyroiditis was more frequent in those with endometriosis [4 ]. Another case-control study demonstrated \nan increasing number of immune-mediated conditions and co-occurring endometriosis [5 ]. A nationwide \npopulation-based study showed an increased risk of RA in patients with endometriosis during more than \n10-year follow-up [6]. A population-based, retrospective cohort study from Taiwan including endometriosis \n(n = 16,758) and non-endometriosis (n  = 16,758) women showed a significantly higher incidence rate in \nwomen with endometriosis (0.3 vs.  0.1 per 1,000 person-years) and hazard ratio (HR) for SLE [adjusted \nHR (aHR), 2.37; 95% confidence interval (CI) 1.35–4.14] as compared to the non-endometriosis group [7 ]. \nAnother retrospective study from Taiwan with a total of 17,779 patients with endometriosis and 17,779 \ncontrols without endometriosis showed an increased risk of SLE in those with endometriosis (0.85 vs.  0.57 \nper 1,000 person-years, HR = 1.86; 95% CI 1.36–2.53) as compared to those without endometriosis [8 ]. \nIn a Swedish study of women with endometriosis from 1964 to 2011, including 2,834 cases of SLE and \n14,164 controls, a significant association between endometriosis and subsequent SLE was noted with an \nodds ratio of 1.39 (95% CI 1.09–1.78) [9 ]. Among 114,453 women from the Nurses’ Health Study II study \nfollowed since 22 years, 103 incident cases of SLE and 390 cases of RA were confirmed and endometriosis \nwas significantly associated with SLE (HR = 2.03; CI 1.17–3.51) and RA diagnosis (HR = 1.41; 95% CI \n1.05–1.89) [10]. In a case-control study of 58 primary SS (pSS)-patients and 157 controls, endometriosis \nwas reported in 8.5% of pSS patients vs.  2.1% of those without pSS [11]. Celiac disease was diagnosed in 5 \nof 223 (2.2%) women with endometriosis and in 2 of 246 (0.8%) controls (P  = 0.265) [12]. Among 11,097 \nwomen with celiac disease, 118 patients with celiac disease developed endometriosis in comparison \nwith 399 controls without celiac disease among 54,992 age-matched control women [13]. Among 37,661 \nwomen with endometriosis from Danish Hospital Discharge Register (1977 to 2007), 13,054 and 86 cases \nof multiple sclerosis (MS), SLE and SS were noted, respectively, with standardized incidence ratios (SIR) \nat an odds ratio of 1.2 (95% CI 1.05–1.5) for MS, odds ratio 1.6 (95% CI 1.2–2.1) for SLE and odds ratio \n1.6 (95% CI 1.3–2.0) for pSS [14]. When the analysis was restricted to 9,191 women with laparoscopy or \nlaparotomy confirmed endometriosis, associations were significant for MS (SIR = 1.4; 95% CI 1.04–1.9), \nbut not for SLE (SIR = 1.1; 95% CI 0.6–2.1) and pSS (SIR = 1.4; 95% CI 0.9–2.3). Thus, endometriosis \ncould be associated with various autoimmune diseases, even if the force of this demonstration of these \nassociations remains low due to the study biases.\n\nExplor Immunol. 2022;2:25–31 | https://doi.org/10.37349/ei.2022.00034 Page 27\nAutoantibodies in endometriosis\nVarious autoantibodies in blood and peritoneal fluids have been studied in endometriosis women, and \ntheir prevalence could be increased even in the absence of any autoimmune disease [15 , 16]. The list of \nautoantibodies that have been detected in endometriosis is very large, and includes antinuclear antibodies \n(ANAs), antiphospholipids (aPLs), antithyroid, anti-endometrial, anti-α-enolase, anti-PDIK1L, anti-survivin, \nanti-laminin-1, anti-carbonic anhydrase, anti-granulocyte macrophage-colony stimulating factor \n(anti-GM-CSF) autoantibodies, etc.\nFor instance, studies showed that anti-endometrial antibodies are more frequent in sera of \nwomen with endometriosis and that they are directed against the cytoplasm of glandular and surface \nepithelium [17 ]. In women with endometriosis, ANAs, anti-Sjogren’s-syndrome-related antigen A \n(anti-SSA/Ro), and aPL autoantibodies were also more commonly detected usually in the absence of any \nclinical autoimmune disease [18]. In 323 various stage endometriosis women, anti-cardiolipin antibodies and \nanti-sperm antibodies were both found to be more frequent in sera and peritoneal fluids [19]. Both levels and \nprevalence of anti-laminin-1 autoantibodies were increased in endometriosis-associated infertility, but these \nautoantibodies failed to predict in vitro fertilization (IVF) failure [20, 21]. Other rare autoantibodies, such as \nanti-ovary, anti-theca, anti-granulosa cells, and anti-endometrium autoantibodies have been more frequent in \ninfertile endometriosis women [22]. Among 23 women with endometriosis-associated infertility, aPL except \nfor lupus anticoagulant (LAC), and ANAs were significantly more frequent in women with endometrioses than \ncontrols with tubal infertility [23]. Anti-GM-CSF antibodies levels in 106 sera of endometriosis women were \nincreased in patients with endometriosis and with the levels correlated to the severity of the disease [24]. The \nclinical value and the predictive impact of these various autoantibodies, the correlation of the endometriosis \nstage, and the value in patients with endometriosis-related infertility remain unclear. Among 35 IVF cycles \nwith at least one aPL or ANA, 8 (23%) women became pregnant, vs.  16 (46%) in autoantibodies-negative \nones (P = 0.04) [25]. The levels of anti-alpha enolase antibodies have been found to be increased from stages \nI to III, but not in stage IV [26]. Anti-PDIK1L and anti-survivin antibodies have not been found to be correlated \nwith the stage of endometriosis [27 , 28]. The relevance of these factors thus seems to be limited in clinical \npractice, and probably reflects more an immunological overall disturbance (Table 1).\nTable 1. Immune factors associated with endometriosis-related infertility\nAuto-immune diseases, in particular\n- SLE\n- Celiac disease\n- Inflammatory bowel disease\n- Rheumatoid arthritis\n- Autoimmune thyroiditis\nVarious autoantibodies, in particular\n- ANAs\n- aPLs\n- Antithyroid\n- Anti-endometrial\n- Anti-α-enolase\n- Anti-PDIK1L\n- Anti-survivin\n- Anti-laminin-1\n- Anti-carbonic anhydrase\n- Anti-GM-CSF antibodies\n- Anti-syntaxin 5\n- Anti-PEP\nProinflammatory factors (blood, peritoneum)\nanti-PEP: anti-peptide\n\nExplor Immunol. 2022;2:25–31 | https://doi.org/10.37349/ei.2022.00034 Page 28\nImmunomodulatory therapies\nThis probable immunological origin of endometriosis, the increased prevalence of various autoimmune \nbiomarkers and autoimmune systemic disorders could raise the interest in immunomodulatory strategies. \nIn particular, in patients with chronic pain resistant to hormonal therapies and surgery, and women with \nendometriosis-related infertility, alternative strategies are urgently needed. Despite this evidence, the \navailable data about these strategies are extremely scarce.\nIn a murine embryo assay, the addition of dexamethasone with endometriotic peritoneal fluid significantly \nimproved the rates of blastocyst expansion [29]. Steroids used in 21 patients with endometriosis before IVF, \nat 10 mg/day from the third day of the cycle until the day of oocyte retrieval [30 ] allowed an increase of \nclinical pregnancies rates at 42.6% in the steroid-treated women vs.  22.8% without steroids (P < 0.05). The \nclinical pregnancy rates were higher in the steroid-treated group with positive autoantibodies as compared \nto the non-treated group (40.9% vs. 14.8%; P < 0.05). In 84 infertile women with endometriosis which \nreceived steroids during the IVF cycle or 5 days before embryo transfer, steroid use during the IVF cycle in \n35 autoantibodies-positives patients was associated with clinical pregnancy in 8/10 cases vs. 0/25 in those \nwithout steroid treatment (80% vs. 0%; P < 0.05) [25].\nSeveral studies demonstrated increased levels of pro-inflammatory cytokines, such as tumor necrosis \nfactor-α (TNF-α), interleukin-6 (IL-6), transforming growth factor-β (TGF-β) and IL-1β, both in sera \nand peritoneal fluids of women with endometriosis [31 ]. In a rat/baboon model of endometriosis, the \nneutralization of TNF-α activity with recombinant TNF binding protein 1 decreased the endometriotic \nlesions [15, 16, 32–34]. TNF-α induced peritoneal endometriosis was significantly reduced under anti-TNF-α \nin endometriosis baboons [35]. Female rats were randomized to receive either etanercept (0.4 mg/kg body \nweight) subcutaneously or placebo once weekly during 4 weeks in a randomized placebo-controlled \nstudy using rat endometriosis model [36 ]. The volume and extension of endometrial implants were \nsignificantly reduced in female rats under etanercept. Infliximab is a monoclonal antibody targeting soluble \nTNF-α and is usually used in several autoimmune and inflammatory diseases, such as RA, Crohn’s disease, \netc. In a randomized trial of women with endometriosis-related pain, the pain severity decreased in 30% \nof infliximab-treated women and was not significantly different from women who received a placebo [37 ]. \nNineteen women with endometrioma received etanercept 50 mg on the second day of the menstrual cycle \npreceding IVF cycle with higher clinical pregnancy rate in patients who received etanercept: odds ratio 4.17 \n(95% CI 1.23–14.14) [38 ]. In the rat model of endometriosis, a humanized monoclonal antibody against \nIL-6 receptor, tocilizumab significantly suppressed the volume of endometriotic lesions and the ectopic \nendometrial-like epithelium: in 42.8% of treated rats vs. 0% in the control group [39, 40].\nConclusions\nEndometriosis is associated with an increased prevalence of various autoimmune markers and autoimmune \ndiseases. The use of immunomodulatory strategies could be an important alternative or additional strategy \nto the use of hormones and surgery but need prospective well-designed trials.\nAbbreviations\nANAs: antinuclear antibodies\nanti-GM-CSF: anti-granulocyte macrophage-colony stimulating factor\naPLs: antiphospholipids\nCI: confidence interval\nHR: hazard ratio\nIL-6: interleukin-6 \nIVF: in vitro fertilization\nMS: multiple sclerosis\n\nExplor Immunol. 2022;2:25–31 | https://doi.org/10.37349/ei.2022.00034 Page 29\npSS: primary Sjogren’s syndrome\nRA: rheumatoid arthritis\nSIR: standardized incidence ratios\nSLE: systemic lupus erythematosus\nTNF-α: tumor necrosis factor-α \nDeclarations\nAuthor contributions\nNA, GK and AM contributed conception and design of the study; NA and AM wrote the first draft of the \nmanuscript; KK, MC, LS, EA, GK wrote sections of the manuscript. All authors contributed to manuscript \nrevision, read and approved the submitted version.\nConflicts of interest\nAM is an investigator of CELGENE, ROCHE, CHUGAI founded trials with APHP and Hospital 15–20 promotion; \nAM received several fees for congress travels and experts’ use from LFB, SANOFI, SHIRE, and CELGENE.\nEthical approval\nNot applicable.\nConsent to participate\nNot applicable.\nConsent to publication\nNot applicable.\nAvailability of data and materials\nNot applicable.\nFunding\nNot applicable.\nCopyright\n© The Author(s) 2022.\nReferences\n1. Bulun SE. Endometriosis. N Engl J Med. 2009;360:268–79.\n2. de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. \nLancet. 2010;376:730–8.\n3. Zhang T , De Carolis C, Man GCW, Wang CC. The link between immunity, autoimmunity and endometriosis: \na literature update. Autoimmun Rev. 2018;17:945–55.\n4. 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