{"paper_id":"77f8736a-a509-428e-badd-8def23aebf93","body_text":"Received\n 05/28/2022 \nReview began\n 05/22/2023 \nReview ended\n 07/16/2023 \nPublished\n 07/24/2023\n© Copyright \n2023\nHamouda et al. This is an open access\narticle distributed under the terms of the\nCreative Commons Attribution License CC-\nBY 4.0., which permits unrestricted use,\ndistribution, and reproduction in any\nmedium, provided the original author and\nsource are credited.\nThe Comorbidity of Endometriosis and Systemic\nLupus Erythematosus: A Systematic Review\nRanim K. Hamouda \n \n, \nHadia \nArzoun \n \n \n, \nIsra \nSahib \n \n, \nLisbeth Escudero Mendez \n \n, \nMirra Srinivasan \n \n,\nShoukrie I. Shoukrie \n \n, \nRavneet \nK. Dhanoa \n \n, \nRamaneshwar Selvaraj \n \n, \nJyothirmai Malla \n \n, \nTharun Yadhav\nSelvamani \n \n, \nAnam \nZahra \n \n, \nSathish Venugopal \n \n, \nLubna Mohammed \n1.\n Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA \n2.\n Internal\nMedicine, St. Bernards Medical Center, Jonesboro, USA \n3.\n Pathology, California Institute of Behavioral Neurosciences\nand Psychology, Fairfield, USA \n4.\n Orthopedics and Traumatology, California Institute of Behavioral Neurosciences and\nPsychology, Fairfield, USA \n5.\n Internal Medicine/Family Medicine/General Surgery, California Institute of Behavioral\nNeurosciences and Psychology, Fairfield, USA \n6.\n Internal Medicine/Family Medicine, California Institute of Behavioral\nNeurosciences and Psychology, Fairfield, USA \n7.\n General Surgery, California Institute of Behavioral Neurosciences and\nPsychology, Fairfield, USA \n8.\n Surgery, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA\n9.\n Neurology, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA\nCorresponding author: \nRanim K. Hamouda, \nraneem.khaled.hamouda1999@gmail.com\nAbstract\nAutoimmune diseases manifest in genetically predisposed individuals exposed to certain triggers that\naggravate immune dysfunction and result in an exacerbated immune response in the form of hyperactivity\nto both the humoral and cell-mediated response. The devastating reality apart from the severity of the\ndisease is that multiple immune diseases could co-occur, increasing the patient's physical, psychological,\nand financial burden. Autoimmune diseases are utterly deranging. One of the dreadful autoimmune diseases\nis systemic lupus erythematosus (SLE). SLE is a rheumatological disease that affects multiple systems, and\nthere are no predictors to know which system will be affected in the future. It could affect the\nmucocutaneous system. It could also present with hematological, rheumatological, neuronal, renal,\npulmonary, and cardiac manifestations. SLE is prevalent in females, predominantly in the childbearing age\ngroup. The pharmacological therapy and bombarding pathophysiology of the disease lead to obstetrical and\ngynecological complications such as infertility, abortion, miscarriage, and stillbirth.\nOver the past decade, the autoimmune disease comorbidity increased eminently. One of the common\nassociations is rheumatological diseases (like rheumatoid arthritis, Sjogren syndrome, and SLE) with\ngynecological diseases (e.g., endometriosis and uterine fibroids). SLE and endometriosis have strong\nassociations, and the prevalence of each condition is relatively high among the female population.\nEndometriosis\n is a chronic disease triggered by inflammation, hormonal milieu, and other predisposing\nfactors that lead to the fibrous tissue that lines the uterus (endometrial tissue) to be implanted at sites other\nthan the uterus, commonly in the peritoneum and mesentery. The pathogenesis of this association remains\nunexplained. The approved theory is that their immune dysfunction is summarized by the elevated humoral\nand cell-mediated response, which leads to an attack to the epithelium, mesothelium, and Serosa and leads\nto fibrous tissue deposition in different sites other than the uterus. Statistical evaluations have shown a\nremarkable association between autoimmune diseases and both gynecological and nongynecological\ndiseases.\nCategories:\n Obstetrics/Gynecology, Allergy/Immunology, Rheumatology\nKeywords:\n multisystem involvement, rheumatology & autoimmune diseases, auto immune disease, systemic lupus\nerythematosus, general gynecology\nIntroduction And Background\nSystemic lupus erythematosus (SLE) is a multisystem chronic autoimmune disease. SLE is a chronic\ninflammatory disease with the autoactivation of T-cells and B-cells with the production of autoantibodies\nand with the production of the inflammatory cytokine infiltrating multiple systems, primarily the kidney,\nresulting in nephritis with the deposition of the immune complex in the glomerular tissue. Skin, joints,\nbrain, lungs, and blood vessels can be affected as well. Therefore, SLE can be classified as a multisystem\ninflammatory disease. This disease is characterized by its clinical variability \n[1]\n. Its presentation ranges from\nmild-moderate mucocutaneous symptoms to a systemic involvement, including profound, severe\nmanifestations in the central nervous system (CNS). The etiology behind this disease is unknown. However,\nit has been established that genetic predisposition, environmental triggers, hormonal milieu, and\nsocioeconomic status levels all interact to cause the disorder \n[2]\n. The disease is more common in women of\nAfrican American ethnicity \n[3]\n. It is predominant in the younger age group. However, it can still be present at\n50 years old or more, and this has been clinically presented in 20% of this age group \n[4]\n. The disease is\ncharacterized by occurring in bouts as it has a remitting and a relapsing period \n[5]\n. Diagnosis would be based\non laboratory and clinical investigations, and the management would be system-directed and symptom-\n1\n2,\n1\n1\n3\n1\n4\n1\n5\n6\n7\n8\n9\n1\n \n Open Access Review\nArticle\n \nDOI:\n 10.7759/cureus.42362\nHow to cite this article\nHamouda R K, Arzoun H, Sahib I, et al. (July 24, 2023) The Comorbidity of Endometriosis and Systemic Lupus Erythematosus: A Systematic\nReview . Cureus 15(7): e42362. \nDOI 10.7759/cureus.42362\n\noriented. The guidelines state that sunscreen, a healthy diet, regular exercise, and the avoidance of the risk\nfactors that aggravate the disease, like smoking with the administration of an immunosuppressive and anti-\ninflammatory drug, would help control the disease \n[6]\n.\nEndometriosis is a chronic inflammatory disease and is diagnosed based on the presence of endometrial\ntissue beyond the uterine lining \n[7]\n. Endometriosis would remain the most puzzling disease in gynecology as\nits etiology is unknown and affects about 5% to 10% of women \n[8]\n. It is the third most common gynecological\ncause of hospitalization \n[7]\n. It presents with severe pelvic pain, especially menarche, during menstruation\nand intercourse. Moreover, the patient would present with back pain and nausea. Infertility is a common\nsymptom manifested with endometriosis \n[8]\n. A cross-sectional study concluded that 41% of the patients in\nthe study were affected by infertility, and 99% had pelvic pain \n[9]\n. The diagnosis is confirmed only\nlaparoscopically. The current treatment is analgesic for ovulatory pain. Surgery has successfully improved\npregnancy rates and is the first choice for infertility treatment \n[8]\n. Even though the etiology of SLE and\nendometriosis is unknown, the incidence of endometriosis is high in patients with SLE. The lupus attacks\nbecome more intense and recurrent than those who did not present with endometriosis. The high incidence\nof autoimmune diseases and the interlink between the diseases should increase the physician's awareness\nabout the possibility of other illnesses that might affect the quality of life \n[10]\n. Figure \n1\n illustrates the\nclinical features in a systemic pattern that could potentially emerge in a patient with SLE \n[8]\n. \nFIGURE\n 1: Clinical features in a systemic pattern that could potentially\nemerge in a patient with systemic lupus erythematosus.\nThis figure was created with BioRender.com and approval was received for publishing the figure.\nThis study reviews the prevalence of endometriosis in patients with SLE. It compares the prevalence of\nendometriosis in patients with SLE to endometriosis in females without SLE. It presents the constitutional\nsymptoms presented along with the current manifestations and future treatment regimens to improve the\npatient's quality of life. Current plans for the treatment of endometriosis associated with SLE include in\nvitro fertilization (IVF) implantation. They have shown successful results of a 30-week live birth and no\ncomplications recorded in the follow-up regarding lupus flare reaction, thrombosis, or ovaries\nhyperstimulation syndrome \n[11]\n. Furthermore, interventions were prescribed for patients with SLE, including\nhydroxychloroquine. It proved to be a safe drug to be administered during pregnancy to decrease the\nautoimmune reaction and the bouts of the lupus attack, thrombus caused by the antiphospholipid\nantibodies, in addition to the reduced need for steroid usage \n[12]\n. However, there is not any established\nmethod to prevent the development of endometriosis among patients with SLE.\nMethodology\nThe method used for this systematic review followed the guidelines of Preferred Reporting Items for\nSystematic Reviews and Meta-Analyses (PRISMA) \n[13]\n.\nInclusion and exclusion criteria\n2023 Hamouda et al. Cureus 15(7): e42362. DOI 10.7759/cureus.42362\n2\n of \n10\n\nThe criteria specified for this review included case-control, cohort, clinical trial, systematic review, and\ncross-sectional studies. The studies included were those published from 2011 to 2021. The papers that have\nbeen chosen are those written in the English language. The population group selected was female, after\npuberty up to postmenopausal (12-60 years). The population group should answer the research question\nthrough the patient/population, intervention, comparison, and outcomes (PICO) format. Papers that were\npublished in any language other than English, outside the age group, and included confounding factors that\nmay affect the result of the review were excluded.\nInformation sources and search strategy\nThe database used were PubMed, PubMed Central (PMC), Google Scholar, Web of Science, Cochrane, and\nBase. The studies included in this review were based on keywords that created the Medical Subject Heading\n(MeSH) strategy in PubMed and applied a set of keywords in other databases. The relevant articles were then\nfinalized by filtering records according to the titles and abstracts, after which a thorough analysis was done\non all the subheadings of the articles. \nKeywords\nThe keywords that were included in the search study were endometriosis or endometrioma or adenomyosis,\nautoimmune, genetics, diagnostic imaging, immunology, pathophysiology, systemic lupus erythematosus,\nchronic lupus erythematosus, cutaneous lupus erythematosus or discoid lupus erythematosus or primary\nimmunodeficiency or autoantibodies, lupus erythematosus classification, drug therapy, diet therapy,\nprevention and control, rehabilitation. Moreover, these keywords were also incorporated into the MeSH\nstrategy in PubMed.\nData extraction and selection process\nThe quality appraisal tools were used primarily to ensure the studies' validity and check if the selected\narticles satisfied the inclusion criteria. Two writers have worked individually to extract the data following\nthe specified criteria. Certain disagreements arose during the process. Those disagreements were resolved\nsimultaneously. The data extraction was based on the gender (female), age group (mainly pubertal,\nchildbearing period, and postmenopausal), and the association with other rheumatological and autoimmune\ndiseases.\nQuality assessment\nThe following studies have undergone an assessment for quality. The following reports were selected\naccording to the PRISMA tool (a systematic review) and Newcastle-Ottawa (case-control and cohort study).\nA total of nine studies were assessed. Table \n1\n summarizes the type of study and the quality appraisal tools\nused for each study analyzed in this review. \nType of study\nTools used\nNumber of studies\nSystematic review\nPRISMA\n2\nCase-control\nNewcastle-Ottawa\n2\nCohort\nNewcastle-Ottawa\n5\nTABLE\n 1: Type of study and the quality appraisal tools used for each study analyzed in this\nreview.\nPRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses\nResults\nThe search strategy was fulfilled through the following five databases: PubMed, PMC, Cochrane, Google\nScholar, and Base. The limit set for selecting the articles was more than 70%. The initial search yielded 438\npublished articles, which were brought down to 164. This is due to the presence of 218 duplicate articles, and\n56 were removed for other reasons. The remaining 164 records were further filtered to a total of 65 after\nscreening and removed 99 records that did not match our research question or the stated inclusion or\nexclusion criteria. The remaining 65 articles were further condensed to 25 articles as 40 articles were not\nretrievable. The 25 articles came down to a final nine articles that were included in our systematic review.\nOut of the 16 articles that were removed, 10 were excluded because they were published outside the desired\npublishing period, three articles measured different outcomes, three articles were deemed irrelevant to the\nstudy, and nine articles were ultimately included for analysis. Figure \n2\n depicts the search strategy used in\n2023 Hamouda et al. Cureus 15(7): e42362. DOI 10.7759/cureus.42362\n3\n of \n10\n\nthis review in the form of a PRISMA flow diagram \n[13]\n. \nFIGURE\n 2: \nDepicts the search strategy used in this review in the form of\na PRISMA flow diagram.\nPRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses\nTable \n2\n presents a summary of the results of all the studies included in this review.\n2023 Hamouda et al. Cureus 15(7): e42362. DOI 10.7759/cureus.42362\n4\n of \n10\n\nAuthor\nYear\nTitle\nMethod\nSubject\nConclusion\nNielsen et al. \n[14]\n2001\nThe Co-occurrence of\nEndometriosis with Multiple\nSclerosis, Systemic Lupus\nErythematosus and Sjogren\nSyndrome\nCohort Study\n37,661\nThis study concluded that women with\nsystemic lupus, multiple sclerosis, and\nSjogren syndrome are more likely to\ndevelop endometriosis and other\nautoimmune diseases.\nMuthuppalaniappan\net al. \n[15]\n2016\nSilent Obstruction in a Young\nWoman with Systemic Lupus\nErythematosus: A Case Report\nand Literature Review on Kidney\nInjury from Ureteral\nEndometriosis\nCase Report\n1\nPatients with systemic lupus\nerythematosus and more likely to\ndevelop ureteral endometriosis.\nHarris et al. \n[16]\n2016\nEndometriosis and the Risk of\nSystemic Lupus Erythematous\nand Rheumatoid Arthritis in the\nNurses’ Health Study II\nCohort Study\n16,578\nThere is a strong etiological correlation\nbetween endometriosis and the likelihood\nof developing systemic lupus\nerythematosus and rheumatoid arthritis.\nHarris et al. \n[17]\n2016\nEndometriosis and Systemic\nLupus Erythematous: A\nPopulation-Based-Case-Control\nStudy\nCase-Control\nStudy\n2,834 cases\nand 14,164\ncontrol cases\nThere is a significant correlation between\nSLE and endometriosis. Endometriosis\ncould be a risk factor predisposing to\nsystemic lupus erythematosus\npathogenesis, or a certain etiology could\nbe common between both diseases.\nMatalliotaki et al.\n[18]\n2018\nCo-existence of Endometriosis\nwith 13 Non-gynecological Co-\nmorbidities: Mutation Analysis by\nWhole Exome Sequencing\nCohort Study\n1,000\nGene sequencing is considered a vital\npredictor technique, showing a\ncompelling association between\nendometriosis with systemic lupus\nerythematosus and other autoimmune\ndiseases.\nShigesi et al. \n[11]\n2019\nThe Association Between\nEndometriosis and Autoimmune\nDiseases: A Systematic Review\nand Meta-Analysis\nSystematic\nReview and\nMeta-\nAnalysis\nStudy\nN/A\nVarious study types have concluded a\nstrong correlation between endometriosis\nand rheumatological autoimmune\ndisease.\nFarland and Harris\n[19]\n2020\nLong-Term Health\nConsequences of Endometriosis\n– Pathways and Mediation by\nTreatment\nSystematic\nReview\nNA\nThe knowledge behind the mechanism of\nassociation between endometriosis and\nother autoimmune diseases/ chronic\ndiseases is limited.\nFan et al. \n[20]\n2021\nAssociation Between\nEndometriosis and    Risk of\nSystemic Lupus Erythematosus\nRetrospective\nCohort Study\n16,758 with\nendometriosis\nand 16,758\nwithout\nendometriosis\nMultiple etiological factors contribute to\nthe comorbidity.\nCozier et al. \n[21]\n2021\nA Prospective Study of\nReproductive Factors in Relation\nto Risk of Systemic Lupus\nErythematosus Among Black\nWomen\nCohort\n125\nThe late menstrual age or breastfeeding\nfor more than or equal six months would\nincrease the likelihood of systemic lupus\nerythematosus.\nTABLE\n 2: Summary of results for all the studies in this review.\nReview\nDiscussion\nIn this section, the etiology, pathophysiology of SLE, and endometriosis, along with a statistical evaluation,\nare discussed. A note on the treatment and prevention strategy and the limitations of this study are also\nenumerated. \n2023 Hamouda et al. Cureus 15(7): e42362. DOI 10.7759/cureus.42362\n5\n of \n10\n\nEtiology\nThe etiology of autoimmune diseases and their comorbidity remain unknown. The main etiological\ncomponent is the hereditary and genetic factors. According to previous statistical surveillance, 66% of the\ncases of SLE patients had a positive family history. A specific study illustrated a pathway explaining the\ncorrelation between endometriosis development and how it influences other diseases to be encountered.\nEndometriosis is induced via an altered environment in terms of inflammatory, immunological, or hormonal\nchanges, in addition to shared risk factors, which could be genetic, ethnic, or other environmental factors\nsupporting these risk factors. Furthermore, the treatment prescribed to treat endometriosis could be the\nleading cause of chronic disease, including autoimmune diseases like SLE and rheumatoid arthritis. These\ntreatment methods that trigger other conditions include oral contraceptive pills (OCPs), hysterectomy, and\noophorectomy. These treatment methods initiate an inflammatory cascade, immune dysregulation, and\nhormonal dysfunction \n[19]\n.\nPrimarily, the diagnosis of endometriosis will be confirmed based on an investigation of the discharge\nsample. However, it was observed that the women who tested positive for endometriosis and reported SLE\nlater was the same magnitude as women who performed laparotomy for endometriosis diagnosis. Ironically,\nthe age of both groups was similar. However, the strongest association was among women who completed a\nprevious hysterectomy. It was found that symptoms would be more profoundly severe than those who did\nnot perform the procedure \n[17]\n. Identification of endometriosis along with connective tissue diseases like\nSLE and rheumatoid arthritis will be demonstrated in a two-stage procedure in a case-control study.\nTo begin with, women who tested positive for endometriosis filled out a screening questionnaire. Women at\nrisk for testing positive for connective tissue diseases filled out a screening questionnaire every other year\nguided by the Connective Tissue Disease Screening Questionnaire (CSQ). Women who screened positive will\nbe asked to consent for their medical file to be reviewed by a rheumatologist, preferably two\nrheumatologists. This incident case report was done by two board-certified rheumatologists who followed\nthe American College of Rheumatology (ACR) diagnostic criteria for SLE. The cases were confirmed by both\ndoctors via the ACR criteria. The guaranteed case rate for comorbidity of endometriosis along with SLE was\n69%. At the time of the report, there was 7% of the cases diagnosed positive for SLE. The screening results\nwere similar in another prospective cohort study (The Iowa Women Health Study). Those two studies\nhighlighted the risk of CSQ disease occurrence at the time diagnosed with endometriosis. Incident reports\nwere not exclusively positive for the patients at the time of the depiction of CSQ \n[16]\n.\nSpecific confounders were found to be profoundly associated with endometriosis and autoimmune diseases\ncomorbidity. Those confounders are classified into nonmodifiable factors (risk traits) and modifiable factors\n(social characteristics). The risk factors include menarche age, the average duration of the menstrual cycle,\nthe number of pregnancies, the ratio of parity to total breastfeeding time, infertility, hysterectomy,\noophorectomy, and last but not least, race and ethnicity. The social factors include body mass index,\nphysical activity, smoking, usage of OCPs, post-menopausal hormones, and routine excessive consumption\nof analgesics \n[16]\n.\nStatistical evaluation\nThe US Endometriosis Association Female Membership proposed the results from a survey that stated that\nwomen diagnosed with endometriosis had a higher risk than other women in terms of developing SLE and\nother autoimmune diseases, and this was supported by the prevalence odds ratio for SLE over 20 cases in\ncomparison with a female control group from the general population in a case-control study \n[17]\n. A\nsystematic review reported that the prevalence was relatively high, especially in women under 45 years old,\nwith a hazard ratio equivalent to 2.11 and a confidence interval between 1.06 and 4.19. Also, the history of\ninfertility poses a hazard ratio of 2.41 and a confidence interval of 2.11 to 5.24. However, those factors seem\nstatistically insignificant as the \nP\n-values were 0.86 and 0.44 for both factors, respectively \n[16]\n.\nIn a prospective study, 954,476 individuals and 125 cases were diagnosed as SLE after follow-up. Those cases\nshared late menarche and prolonged breastfeeding period. Regarding the age of menarche, it was\nstatistically evaluated to show a hazard risk of 2.31 and a confidence interval lying within 1.30 to 4.11 at or\nmore than 15 years in comparison with 12 years. Moreover, the hazard risk for the breastfeeding duration\nwas 1.73, and the confidence interval was between 1.01 and 2.94 if the course was more than six months.\nThis study denied any relation between the number of parities, age of first parity, hysterectomy, or the\ncurrent menstruation status with comorbidity of SLE and endometriosis \n[21]\n.\nA cross-sectional study was performed on women diagnosed with endometriosis from the nation's\nendometriosis support organization compared with controls from the US general population. The study\nconcluded that the prevalence odds ratio for SLE was 20.7; the confidence interval was between 14.3 and\n29.9 \n[16]\n. The most recent study was a retrospective cohort study in Denmark, which stated that the risk of\nSLE in women diagnosed with endometriosis is significantly higher than in the general population. The\nincidence ratio was 1.6, with a confidence interval between 1.2 and 2.1, and this study also confirmed the\nfact that risk could be attenuated when endometriosis is treated properly via the modified surgical procedure\n[16]\n.\n2023 Hamouda et al. Cureus 15(7): e42362. DOI 10.7759/cureus.42362\n6\n of \n10\n\nA systematic review published in 2019 reported that a cross-sectional study showed that women diagnosed\nwith SLE are at a higher risk for endometriosis than the general female population. The prevalence was 20.7,\nwith a confidence interval of 14.3 to 29.9, and it was clinically significant at the \nP\n-value <0.01. The high\nprevalence rate reported was mainly due to the self-consciousness of the patients, as most of the patients\nwere recruited from the Endometriosis Patient Association \n[18]\n. A case-control study was performed to\nconfirm that the association between endometriosis and SLE is different from the prevalence rate between\nuterine fibroids and SLE. The prevalence was significantly higher; the 9% prevalence rate of SLE in\nendometriosis-positive females versus the 0% prevalence rate in the case of having uterine fibroids.\nHowever, this study could have been biased as the study group was pretty small \n[18]\n. In 2011, a study\nanalyzed that 9,191 females were diagnosed with endometriosis via the gold standard\nlaparoscopy/laparotomy procedure. It stated that the association with autoimmune diseases like multiple\nsclerosis (MS) is significantly higher than with SLE \n[14]\n.\nCertain diseases increase the risk of endometriosis. Those diseases could be hypertension, dyslipidemia,\nhepatic diseases, cardiovascular diseases, pulmonary disease, and certain medication intake, which include\nhormones, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroid usage. According to this\nstudy, those factors increase the association between endometriosis and chronic diseases, and this was a\nstatistically significant association as the \nP\n-value <0.05 \n[20]\n.\nPathophysiology\nWomen diagnosed with endometriosis have shown a decline in natural killer cell cytotoxicity and elevation\nin both the number and activation of macrophages. Endometriosis-positive women have shown diminished\ncell-mediated response and elevated humoral response compared to women without endometriosis. Those\nimmune disturbances play a role in the initiation of diverse autoimmune diseases. These are multiple\ntheories explaining the pathophysiology of endometriosis. The two accepted theories include Sampson's\ntheory of retrograde menstruation, which states the endometrial tissue would be implanted on the\nextrauterine tissue, and the plaque theory that says the ovarian epithelium in particular, or the mesothelium\nof the pelvic peritoneum. The primary key to the pathophysiology's hypotheses is inflammation; the\ncoelomic metaplasia pathway is still unexplained. After endometriosis has occurred, a cascade of\ninflammation would be initiated, leading to adhesions and scar formation on top of the peritoneal tissue\nsurfaces. This would result in the elevated release of prostaglandins, cytokines, and other inflammatory\nproducts like metalloproteinases, chemokines, etc. These products would result in the deposition of fibrin\nand further scarring and adhesions. The excessive inflammation imbalance and immune instability enhance\nthe extra-endometrial tissue to survive and the development of other immune conditions, including SLE,\nMS, Sjogren syndrome, and rheumatoid arthritis \n[19]\n.\nFurthermore, other studies have correlated endometriosis with other autoimmune conditions with elevated\nsynergic circulating hormones, mainly steroids. Case reports have proposed the hypothesis of the\ndevelopment of endometriosis with SLE that further proves the theory of the imbalance of humoral and cell-\nmediated immune response. Immune surveillance was performed on women with endometriosis that\nconcluded that elevated immunoglobulins (Ig) like IgG, IgM, IgA autoantibodies, and anti-endometrial auto-\nantibodies depressed cell-mediated immunity in terms of cellular activity. However, according to this\nstudy's result, the number of T-cells, B-cells, and natural killer cells was elevated \n[16]\n.\nMoreover, a specific antibody was observed in comorbidity of SLE and endometriosis, known as the anti-\nnuclear auto-antibody. The immune surveillance found that particular cytokines are dominant in this case.\nThe dominant inflammatory cytokines are interleukin 1, interleukin 6, and tumor necrosis factor. This\nimmune response heightens the chance of developing the extrauterine endometrial tissue, further\naggravating the immunological disease, mainly SLE \n[16]\n. The association of endometriosis with\nnongynecological, autoimmune diseases like SLE was found in individuals with susceptible gene loci\nconfirmed via several case-control studies and by the genome-wide association studies (GWAS) \n[18]\n. Figure \n3\ndemonstrates the pathophysiology of endometriosis and other nongynecological chronic autoimmune\ndisease\n2023 Hamouda et al. Cureus 15(7): e42362. DOI 10.7759/cureus.42362\n7\n of \n10\n\nFIGURE\n 3: Pathophysiology of endometriosis and other\nnongynecological chronic autoimmune disease.\nThis figure was created with BioRender.com and approval was received for publishing the figure.\nMMP, matrix metalloproteinase; TNF, tumor necrosis factor; IL, interleukin\nA prospective follow-up with the future generation's gene sequence allows a broad perspective on the\nprimary gene susceptibility loci that increase the risk of comorbidity incidence. This study was performed on\nthree generations diagnosed with endometriosis via a surgical confirmation and then consented to a whole-\ngenome sequence and found that they were at risk for 13 diseases; those diseases were mainly\nnongynecological \n[18]\n.\nThe gene sequencing detected that risk groups are homozygous for the T allele for SLE on the protein\ntyrosine phosphatase, non-receptor type 22 (PTPN22) gene, which codes for the tyrosine phosphatase\nprotein. This protein stimulates the PTPN22 gene, which leads to the simulation and modification of the T\ncell's adverse selection on the thymus and inhibition of the auto-active T cells in the systemic circulation.\nThe association is yet not clear. However, females diagnosed with endometriosis had common gene\nsequencing risk loci. Positive autoimmune individuals presented with a heterozygous gene were more likely\nto show SLE as a nongynecological autoimmune disease \n[18]\n.\nPrevention and treatment strategies\nIt was noted that the association could be attenuated if there was an appropriate modification in the\nhysterectomy/oophorectomy procedures \n[16]\n. Hysterectomy is the first line for treating severe\nendometriosis, and in certain conditions, endometriosis is diagnosed during the procedure. Hence, the risk\nof comorbidity would remain present but could only be attenuated in the situation where the procedure\nmodifications were followed \n[17]\n. Furthermore, women diagnosed with endometriosis would most probably\nhave a hysterectomy earlier than other women. This will result in surgical menopause, and the early\nhormonal imbalance would lead to autoimmune disease induction or aggravation to an excessive disease\n[16]\n. Moreover, endometriosis's first-line treatment is OCPs, which pose an immediate risk for SLE\nincidence. Theoretically, the cessation of OCP usage would alter the association. However, clinically, there\nwere no significant observed changes in drug cessation \n[16]\n.\nA systematic review stated that the central generally accepted hypothesis is the theory of retrograde\nmenstruation. This theory proposes that the endometrial cells will be disseminated and expressed through\nthe uterine tubes. This phenomenon occurs in a significant proportion of females. However, few individuals\nwill be diagnosed with endometriosis except those with identifiable risk factors, immune dysregulation, and\nimbalanced hormonal milieu. Immune dysregulation and imbalanced hormonal milieu result in excessive\nendometrial tissue deposition into ectopic sites. Further dysregulation in the immune system leads to the\ndevelopment of autoimmune disease (almost 13 nongynecological autoimmune diseases could develop) \n[18]\n.\n2023 Hamouda et al. Cureus 15(7): e42362. DOI 10.7759/cureus.42362\n8\n of \n10\n\nFurthermore, multiple pathways initiate autoimmune disease as these endometrial cells escape the immune\nsurveillance. Endometrial cells will be widely spread beyond the uterine wall and into the peritoneum. The\nimmune cells analysis showed that the neutrophils and macrophages of the peritoneum are widely elevated\nwith a declined function of the cytotoxic cells, killer cells, and elevated autoantibodies. Certain blood and\nurinary biomarkers were found to be specific for endometriosis, mainly the endometrial autoantibodies and\ninterleukin 6. Moreover, proving the hereditary involvement was the gene sequencing that was performed.\nThe risk gene was PTPN22, which showed a significant association with the disease comorbidity \n[18]\n.\nLimitations\nThere are profound limitations to this research question. To begin with, the explanation of the disease\netiology and pathophysiology is based mainly upon hypothesis. The fact that SLE is a vast disease regarding\nits manifestation makes it harder to investigate significantly. The definitions of the disease itself may differ\nregarding a previous laparoscopic procedure or hysterectomy. Furthermore, there is a lack of prestigious and\ntrustworthy studies that have extensively addressed this issue. In addition, there is a significant degree of\nbias and inadequate follow-up with the cases. Moreover, certain published articles have exhibited poor\nquality in terms of the quality assessment analysis. This can be attributed to the small sample size and the\ninability of researchers to determine the chronological occurrence of simultaneous diseases, as well as the\nsimilarity or dissimilarity in disease etiology or pathophysiology between the conditions.\nConclusions\nAutoimmune diseases are very diverse and can occur spontaneously without known pathogenesis or specific\netiology. Autoimmune diseases occur in individuals with inherited, genetic predispositions, which cause\nimmunological dysfunction. Different factors initiate and aggregate the illness and increase the association.\nSLE occurs in females aged 40 years. However, clinically, SLE is observed throughout the childbearing\nperiod. Endometriosis occurs as well in the same age group. Both diseases result in significant difficulty\nregarding pregnancy as it is very likely for abortion, miscarriage, and stillbirth.\nSLE and endometriosis are very prevalent in the female population, and there is excellent comorbidity\nbetween both diseases. Endometriosis is diagnosed laparoscopically and is highly common in females who\nhave undergone hysterectomy. However, adequately modified hysterectomy decreases postoperative\ninflammation, immune irritation, and fibrosis, leading to autoimmune diseases in susceptible individuals.\nSpecific therapies are being proposed to limit the disease, which can be modified hysterectomy as a surgical\ntherapy and anti-inflammatory like corticosteroids and NSAIDs to limit the disease progression.\nAdditional Information\nDisclosures\nConflicts of interest:\n In compliance with the ICMJE uniform disclosure form, all authors declare the\nfollowing: \nPayment/services info:\n All authors have declared that no financial support was received from\nany organization for the submitted work. \nFinancial relationships:\n All authors have declared that they have\nno financial relationships at present or within the previous three years with any organizations that might\nhave an interest in the submitted work. \nOther relationships:\n All authors have declared that there are no\nother relationships or activities that could appear to have influenced the submitted work.\nReferences\n1\n. \nFava A, Petri M: \nSystemic lupus erythematosus: diagnosis and clinical management\n. 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