Endometriosis, Psoriasis, and Psoriatic Arthritis: A Prospective Cohort Study

Endometriosis, psoriasis, and psoriatic arthritis (PsA) are chronic inflammatory disorders whose etiologies remain poorly understood but may be correlated, as endometriosis has been associated with other inflammatory disorders. We investigated the bidirectional associations between laparoscopically confirmed endometriosis and physician-diagnosed psoriasis and PsA in the Nurses’ Health Study II cohort (n = 116,429, United States, 1991–2013). We confirmed 4,112 incident cases of laparoscopically confirmed endometriosis (mean age at diagnosis = 40.3 years) and 697 validated physician-diagnosed cases of psoriasis (mean age at diagnosis = 43.6 years), 110 of which presented with concomitant PsA. A history of psoriasis with concomitant PsA was associated with a 2-fold higher risk of endometriosis (hazard ratio (HR) = 2.01, 95% CI: 1.23, 3.30); however, no association was observed between psoriasis without PsA and endometriosis risk (HR = 0.93, 95% CI: 0.68, 1.26). When endometriosis was the exposure, it was not associated with a risk of subsequent psoriasis (HR = 1.28, 95% CI: 0.95, 1.72). The risk of psoriasis with PsA was notably higher; however, the sample size was small and the confidence intervals wide (HR = 1.77, 95% CI: 0.89, 3.52). Our findings suggest that psoriasis with concomitant PsA is associated with greater risk of laparoscopically confirmed endometriosis. In addition, there was a suggestive association between endometriosis diagnosis and subsequent risk of psoriasis with PsA.

cohort study, endometriosis, psoriasis, psoriatic arthritis Abbreviations - BMI body mass index - CI confidence interval - CVD cardiovascular disease - HR hazard ratio - MET metabolic equivalent of task - NHSII Nurses’ Health Study II - PsA psoriatic arthritis - PST Psoriasis Screening Tool - T2D type 2 diabetes Endometriosis is an estrogen-dependent inflammatory disorder affecting approximately 10% of women during their reproductive years (1–12). Symptoms include chronic pelvic pain, dysmenorrhea, and reduced fertility (13). The disorder is characterized by the implantation of endometrial-like tissue outside the uterus, believed to be in part due to a defect in immune surveillance, which would otherwise have eliminated the ectopic endometrium (13). In light of the postulated underlying immune mechanisms, endometriosis has been demonstrated to be associated with other immune-mediated disorders (e.g., systemic lupus erythematosus) (14) in case reports (15) and in cross-sectional (16, 17) and prospective (18–20) studies. Psoriasis is an immune-mediated inflammatory skin disease that affects 2%–4% of the population and is characterized by scaly, red, and well-demarcated skin plaques (21). Psoriasis is sometimes associated with an inflammatory psoriatic arthritis (PsA). PsA affects up to 30% of people that have psoriasis and causes joint pain, stiffness, and swelling that can be disabling and develop into a deforming erosive arthropathy in some patients (22–26). Previous reports have suggested a possible overlap in pathogenic mechanisms between psoriasis and endometriosis (27–29); however, to our knowledge, only one published study has reported on this association. A registry-based study in Denmark examined the lifetime prevalence of 31 autoimmune diseases and co-occurring conditions, reporting a nonsignificant odds ratio of 1.3 for the co-occurrence of endometriosis and psoriasis vulgaris (30). Given the overlapping age-incidence curves of these conditions and the potential for shared underlying immunological and inflammatory dysfunction (18, 31), we sought to quantify the bidirectional association between endometriosis and psoriasis and PsA within the prospective Nurses’ Health Study II over 22 years of follow-up.

Study population The Nurses’ Health Study II (NHSII) is an ongoing prospective cohort established in 1989 when 116,429 female registered nurses aged 25–42 years completed a baseline questionnaire about their health, medical history, and lifestyle factors. Subsequent biennial questionnaires have collected information on incident diseases and lifestyle factors. The response rates have been at least 90% throughout follow-up cycles. Further details have been provided elsewhere (32, 33). The institutional review boards of Brigham and Women’s Hospital and Harvard T. H. Chan School of Public Health approved this study. Completion and return of the study questionnaires was considered implied consent. Follow-up for the current analyses began in 1991 and closed in June 2013 (Figure 1). Ascertainment of endometriosis Starting in 1993, women were asked on each biennial questionnaire whether they had ever had physician-diagnosed endometriosis, and if so, the date of the diagnosis and whether it had been confirmed by laparoscopy, the gold standard for endometriosis diagnosis (34). To assess the validity of self-reported endometriosis, supplementary questionnaires were mailed in 1994 to 200 women randomly selected from cases who had reported an incident diagnosis in 1993 (155 of these 200 women (77.5%) had reported laparoscopic confirmation). Of the 184 women who responded (92%), 78.3% had reported laparoscopic confirmation (n = 144/184). Among the nonresponders, 68.5% had reported a laparoscopy (n = 11/16). A total of 148 (77.2%) of the responders gave permission for review of their clinical and surgical records, of which 88.5% (n = 131) were received. A record of performance of laparoscopy was confirmed for all of those who had reported having had a laparoscopy. A diagnosis of endometriosis was confirmed in 96% of the women by review of their laparoscopic reports (n = 101/105). Among those women who did not report a laparoscopic confirmation, no record of a laparoscopy was found, and evidence of a clinical diagnosis was found for only 53.8% (n = 14/26) (35). As the occurrence of newly diagnosed endometriosis is rare after menopause, we censored follow-up at report of hysterectomy or menopause. Ascertainment of psoriasis and psoriatic arthritis In 2005, 2009, and 2013, participants were asked whether they had been diagnosed with psoriasis by a clinician and, if so, the date of the diagnosis by year since 1991. Self-reported psoriasis diagnoses were confirmed using the previously validated Psoriasis Screening Tool (PST) questionnaire, which inquired about the type of clinician making the diagnosis and their psoriasis phenotypic details. A pilot study validating the PST questionnaire reached 99% sensitivity and 94% specificity for psoriasis screening (36). Participants completing the PST were asked whether they had been diagnosed with PsA. A reported diagnosis of concomitant PsA was confirmed by using the Psoriatic Arthritis Screening and Evaluation questionnaire, which has a reported 82% sensitivity and 73% specificity (37). Details of the instrument design and pilot studies have been described previously (37, 38). In a recent study conducted in the NHSII using the PST self-administered questionnaire the validation rate of psoriasis was 90% (1,243 validated cases/1,382 completed PST questionnaires) (39). Only validated cases of psoriasis and PsA were included in these analyses. Statistical analysis At baseline, participants were excluded if they had an unknown birth year, were postmenopausal, had reported a hysterectomy, had unconfirmed endometriosis or psoriasis/PsA, or had a previous cancer diagnosis (Figure 1). Participants then contributed person-time from return of the 1991 questionnaire until report of the outcome of interest: 1) confirmed psoriasis/PsA or 2) laparoscopically confirmed endometriosis, diagnosis of any cancer (except nonmelanoma skin cancer), hysterectomy or menopause, death, loss to follow-up, or end of follow-up (June 2013), whichever occurred first. Cox proportional hazards models with age and questionnaire period as the timescale were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between 1) psoriasis/PsA (exposure) and incident endometriosis (outcome), and 2) endometriosis (exposure) and incident confirmed psoriasis/PsA (outcome). Exposures and covariates were time-varying—updated throughout the follow-up whenever new information was available from the biennial questionnaires. We defined potential confounders as factors potentially associated with endometriosis and/or psoriasis risk that could have preceded both exposure and outcome. These included body mass index (BMI), physical activity, smoking, alcohol, age at menarche, menstrual cycle length, parity, oral contraceptive use, and infertility. Covariates that could be confounders and/or intermediates of the associations (occurring between the exposure and outcome) were added to multivariable models in a separate step and included hypertension, type 2 diabetes (T2D), cardiovascular disease (CVD), hypercholesterolemia, and use of acetaminophen, aspirin, or ibuprofen ≥2 days/week. As these variables could be both confounders and intermediates we did not conduct a formal mediation analyses but instead chose to adjust for them in separate models. Missing data were handled with the missing indicator method, with categories created for missing data included in the regression model. When endometriosis was the outcome, 2 multivariable models were applied. Model 1 adjusted for potential confounders (1): BMI (calculated as weight (kg)/height (m)2: <18.5, 18.5–22.4, 22.5–24.9, 25–29.9, 30–34.9, 35–39.9, ≥40), physical activity (metabolic equivalent of task (MET)-hours/week), alcohol consumption (g/day: none, 0.1–4.9, 5.0–9.9, 10.0–19.9, ≥20.0), smoking status (never, past, current smoker 1–14 cigarettes/day, current smoker 15–24 cigarettes/day, current smoker ≥25 cigarettes/day), age at menarche (years: >12, 12–13, ≥14), menstrual cycle length at ages 18–22 years (days: <31, 21–25, 26–31, 32–39, ≥40), oral contraceptive use (never, past, current), parity (nulliparous, 1, 2, 3, ≥4), and infertility (yes, no). Model 2 further adjusted for the following disease variables that could be intermediates: hypertension, T2D, CVD, and hypercholesterolemia. When psoriasis was the outcome, 3 different multivariable models were applied. Model 1 adjusted for potential confounders (40): BMI, physical activity, smoking, and alcohol. Model 2 further adjusted for the following disease variables that could be intermediates: hypertension, T2D, CVD, and hypercholesterolemia. Model 3 additionally adjusted for medications that were considered potential intermediates because they have been hypothesized to increase risk of psoriasis and are commonly used among women with endometriosis (acetaminophen, aspirin, or ibuprofen use ≥2 days/week). We conducted additional analyses including age at menarche, menstrual cycle length, parity, oral contraceptive use, and infertility in all psoriasis outcome models and as results were similar we present the more parsimonious models described above. Analyses were conducted with SAS, version 9.4 (SAS Institute, Inc., Cary, North Carolina). All tests for statistical significance were 2-sided.

Psoriasis and subsequent risk of endometriosis diagnosis A total of 87,860 participants were included in the population for analyses with psoriasis as the exposure and endometriosis as the outcome, with 4,112 incident cases of laparoscopically confirmed endometriosis identified over the 22 years of follow-up with a mean age of diagnosis of 40.3 years. Diagnosis of endometriosis occurred a median of 6.5 years after psoriasis diagnosis. At start of follow-up (1991), participants with psoriasis (n = 767) were more likely to have ever smoked cigarettes (41.9% versus 33.5%) and reported slightly less physical activity (19.2 versus 21.0 MET-hours/week) than those who did not have psoriasis (Table 1). Participants who had psoriasis with PsA (n = 140 from among the 767 with psoriasis) had a higher mean BMI (28.8 versus 24.5), reported less physical activity (16.4 versus 21.0 MET hours/week), were more likely to report having experienced infertility (10.0% versus 5.5%), and were much more likely to use over-the-counter analgesics ≥2 days/week (23.8% aspirin to 44.5% acetaminophen versus 12.0%–23.4%) than participants without psoriasis. Table 1. | No Psoriasis(n = 86,953) | Psoriasis(n = 767) | Psoriasis With Psoriatic Arthritis (n = 140) | |||| |---|---|---|---|---|---|---| | Participant Characteristic | Mean (SD) | % | Mean (SD) | % | Mean (SD) | % | | Age, yearsb | 36.3 (4.6) | 36.4 (4.4) | 37.0 (2.7) | ||| | White race/ethnicity, % | 95.7 | 97.6 | 97.7 | ||| | BMIc, age 18 years | 21.2 (3.3) | 21.1 (3.2) | 22.9 (3.2) | ||| | BMIc | 24.5 (5.2) | 24.8 (5.0) | 28.8 (5.4) | 5.4 | || | Physical activity, MET-hours/weekd | 21.0 (27.1) | 19.2 (29.3) | 16.4 (15.0) | ||| | Cigarette smoking, % | |||||| | Never | 66.5 | 58.1 | 65.3 | ||| | Past | 22.1 | 27.5 | 20.7 | ||| | Current | 11.4 | 14.4 | 14.0 | ||| | Alcohol intake, g/day | 3.1 (6.0) | 3.8 (6.3) | 2.4 (3.5) | ||| | Age at menarche, yearsb | 12.4 (1.4) | 12.4 (1.5) | 12.2 (1.6) | ||| | Menstrual cycle length of 26–31 days, % | 66.2 | 62.9 | 62.5 | ||| | Ever use of oral contraceptives, % | 83.9 | 85.4 | 80.8 | ||| | Nulliparity, % | 25.7 | 25.5 | 26.2 | ||| | Age at first birth, years | 26.0 (4.1) | 25.8 (4.3) | 25.5 (4.3) | ||| | Infertility, % | 5.5 | 4.9 | 10.0 | ||| | Aspirin use (≥2 days/week), % | 12.0 | 12.8 | 23.8 | ||| | Ibuprofen use (≥2 days/week), % | 20.3 | 20.7 | 40.8 | ||| | Acetaminophen use (≥2 days/week), % | 23.4 | 24.1 | 44.5 | Abbreviations: BMI, body mass index; MET, metabolic equivalent of task; SD, standard deviation. a Values are expressed as mean (SD) or percentage and are standardized to the age distribution of the study population. b Value is not age-adjusted. c BMI is calculated as weight (kg)/height (m)2. d From recreational and leisure-time activities. A history of psoriasis was not associated with endometriosis risk (HR for psoriasis with or without PsA = 1.09, 95% CI: 0.84, 1.42, and HR for psoriasis without PsA = 0.93, 95% CI: 0.68, 1.26) (Table 2). However, psoriasis with concomitant PsA was associated with a 2-fold greater risk of subsequent endometriosis diagnosis (HR = 2.01, 95% CI: 1.23, 3.30). After additionally adjusting for potential intermediate morbidities along the pathway from PsA to endometriosis (hypertension, hypercholesterolemia, T2D, and CVD) the association was slightly attenuated but remained 2-fold in magnitude (HR = 1.94, 95% CI: 1.18, 3.18). Table 2. | Exposure | No. of Endometriosis Cases | Person-Years | Age-Adjusted Model | Model 1 a | Model 2 b | ||| |---|---|---|---|---|---|---|---|---| | HR | 95% CI | HR | 95% CI | HR | 95% CI | ||| | No psoriasis | 4,055 | 1,107,489 | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | | Psoriasis | 57 | 15,640 | 1.11 | 0.86, 1.45 | 1.09 | 0.84, 1.42 | 1.08 | 0.83, 1.40 | | Psoriasis without PsA | 41 | 13,377 | 0.94 | 0.69, 1.28 | 0.93 | 0.68, 1.26 | 0.92 | 0.67, 1.25 | | Psoriasis with PsA | 16 | 2,246 | 2.13 | 1.30, 3.49 | 2.01 | 1.23, 3.30 | 1.94 | 1.18, 3.18 | Abbreviations: CI, confidence interval; HR, hazard ratio; MET, metabolic equivalent of task; PsA, psoriatic arthritis. a Model 1: multivariable Cox proportional hazards regression model adjusting for age (years), body mass index (calculated as weight (kg)/height (m)2: <18.5, 18.5–22.4, 22.5–24.9, 25–29.9, 30–34.9, 35–39.9, ≥40), physical activity (MET-hours/week), alcohol consumption (g/day: none, 0.1–4.9, 5.0–9.9, 10.0–19.9, ≥20.0), and smoking status (never, past, current smoker 1–14 cigarettes/day, current smoker 15–24 cigarettes/day, current smoker ≥25 cigarettes/day), age at menarche (years: >12, 12–13, ≥14), menstrual cycle length at ages 18–22 years (days: <31, 21–25, 26–31, 32–39, ≥40), oral contraceptive use (never, past, current), parity (nulliparous, 1, 2, 3, ≥4), and infertility (yes, no). b Model 2 additionally adjusted for potential intermediate comorbidities (yes, no): hypertension, type 2 diabetes, cardiovascular disease, and hypercholesterolemia. Endometriosis and risk of subsequent confirmed psoriasis and psoriatic arthritis A total of 91,380 participants were included in the population for analysis with endometriosis as the exposure and psoriasis as the outcome, with 697 incident cases of psoriasis identified over 22 years of follow-up with a mean age of diagnosis of 43.6 years (n = 110 of whom had psoriasis with PsA, mean age of diagnosis of 43.4 years). At start of follow-up (1991), participants with laparoscopically confirmed endometriosis (n = 3,915) were slightly more likely to have ever used oral contraceptives (89.1% versus 83.9%), more likely to be nulliparous (40.2% versus 25.7%), much more likely to report having experienced infertility (29.2% versus 5.5%), and slightly more likely to use ibuprofen (29.5% versus 20.3%) or acetaminophen ≥2 days/week (29.4% versus 23.4%) compared with participants without endometriosis (Table 3). Table 3. | No Endometriosis (n = 87,465) | Endometriosis (n = 3,915) | ||| |---|---|---|---|---| | Participant Characteristic | Mean (SD) | % | Mean (SD) | % | | Age, yearsb | 36.3 (4.6) | 36.6 (4.2) | 4.2 | | | White, % | 95.7 | 97.1 | || | BMIc at age 18 years | 21.2 (3.3) | 20.7 (2.9) | || | BMIc | 24.5 (5.3) | 24.0 (4.7) | || | Physical activity, MET-hours/weekd | 20.9 (27.0) | 20.5 (26.4) | || | Cigarette smoking, % | |||| | Never | 66.4 | 66.3 | || | Past | 22.1 | 22.5 | || | Current | 11.4 | 11.1 | || | Alcohol intake, g/day | 3.1 (6.0) | 3.0 (5.9) | || | Age at menarche, yearsb | 12.4 (1.4) | 12.3 (1.4) | || | Menstrual cycle length of 26–31 days, % | 66.2 | 67.5 | || | Ever use of oral contraceptives, % | 83.9 | 89.1 | || | Nulliparity, % | 25.7 | 40.2 | || | Age at first birth, years | 26.0 (4.1) | 27.4 (4.8) | || | Infertility, % | 5.5 | 29.2 | || | Aspirin use (≥2 days/week), % | 12.0 | 12.7 | || | Ibuprofen use (≥2 days/week), % | 20.3 | 29.5 | || | Acetaminophen use (≥ 2 days/week), % | 23.4 | 29.4 | Abbreviations: BMI, body mass index; MET, metabolic equivalent of task; SD, standard deviation. a Values are means (standard deviations) or percentages and are standardized to the age distribution of the study population. b Value is not age-adjusted c BMI calculated as weight (kg)/height (m)2. d From recreational and leisure-time activities. Endometriosis was not associated with a higher risk of incident psoriasis when all psoriasis cases were considered (HR = 1.28, 95% CI: 0.95, 1.72) or when restricted to psoriasis without PsA (HR = 1.27, 95% CI: 0.92, 1.76) (Table 4). Endometriosis was suggestively associated with a nearly 2-fold greater risk of psoriasis with PsA (HR = 1.77, 95% CI: 0.89, 3.52), although this relationship was driven by just 9 incident PsA cases, and thus confidence intervals were wide. For all 3 case definitions (all psoriasis, psoriasis without PsA, psoriasis with PsA) and among all multivariable models, further adjustment for potential intermediate disease variables (hypertension, hypercholesterolemia, type 2 diabetes, and CVD) and for medication use (acetaminophen, aspirin, or ibuprofen use ≥2 days/week) suggested little to no change in hazard ratio estimates, with marginal attenuation (HR = 1.69, 95% CI: 0.85, 3.38). Table 4. | Laparoscopically Confirmed Endometriosis | No. of Psoriasis Cases | Person-Years | Age-Adjusted Model | Model 1 a | Model 2 b | Model 3 c | |||| |---|---|---|---|---|---|---|---|---|---|---| | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | ||| | Psoriasis | |||||||||| | No | 649 | 1,133,663 | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | | Yes | 48 | 67,880 | 1.24 | 0.92, 1.67 | 1.28 | 0.95, 1.72 | 1.27 | 0.95, 1.71 | 1.27 | 0.95, 1.71 | | Psoriasis Without PsA | |||||||||| | No | 537 | 1,133,779 | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | | Yes | 40 | 67,888 | 1.24 | 0.90, 1.72 | 1.27 | 0.92, 1.76 | 1.27 | 0.92, 1.75 | 1.27 | 0.92, 1.75 | | Psoriasis With PsA | |||||||||| | No | 101 | 1,134,239 | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | 1.00 | Referent | | Yes | 9 | 67,920 | 1.57 | 0.79, 3.12 | 1.77 | 0.89, 3.52 | 1.68 | 0.84, 3.36 | 1.69 | 0.85, 3.38 | Abbreviations: CI, confidence interval; HR, hazard ratio; MET, metabolic equivalent of task; PsA, psoriatic arthritis. a Model 1: multivariable Cox proportional hazards regression model adjusting for age (years), body mass index (calculated as weight (kg)/height (m)2: <18.5, 18.5–22.4, 22.5–24.9, 25–29.9, 30–34.9, 35–39.9, ≥40), physical activity (MET-hours/week), alcohol consumption (g/day: none, 0.1–4.9, 5.0–9.9, 10.0–19.9, ≥20.0), and smoking status (never, past, current smoker 1–14 cigarettes/day, current smoker 15–24 cigarettes/day, current smoker ≥25 cigarettes/day). b Model 2 additionally adjusted for potential intermediate comorbidities (yes, no): hypertension, type 2 diabetes, cardiovascular disease, and hypercholesterolemia. c Model 3 additionally adjusted for medications that have been hypothesized to increase risk of psoriasis and are commonly used among women with endometriosis: regular use (≥2 days/week) of acetaminophen, aspirin, and ibuprofen.

In this prospective cohort, we examined the temporally bidirectional association between psoriasis, PsA, and endometriosis. We observed a greater risk of subsequent laparoscopically confirmed endometriosis (HR = 2.01, 95% CI: 1.23, 3.30) among women with psoriasis with PsA. In addition, when the temporality was flipped and endometriosis was examined as the exposure, we observed a greater risk of subsequent psoriasis with PsA of similar but slightly smaller magnitude (HR = 1.77, 95% CI: 0.89, 3.52), although this analysis yielded wide confidence intervals, demonstrating limited statistical power (n = 9 psoriasis with PsA cases among women with endometriosis) and should be interpreted with caution. No clear associations were observed between psoriasis without PsA and endometriosis regardless of the temporality of the 2 disease diagnoses. To our knowledge, this is the first prospective study to comprehensively examine the association between endometriosis, psoriasis, and PsA. One prior study using Danish registry data examined multiple autoimmune disease and calculated a nonsignificant odds ratio of 1.3 for having a history of endometriosis and a history of psoriasis vulgaris (30). Additional studies have reported that other autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis) co-occur with endometriosis (14). Psoriasis and endometriosis share some comorbidities that have been associated independently with an increased risk of their development including hypercholesterolemia (41–46), hypertension (41, 47, 48), and cutaneous melanoma (49–55). Often comorbidities appear to be related to common pathogenetic pathways. In contrast to syndromes, which comprise symptoms that appear synchronously, comorbidities reflect seemingly unrelated secondary diseases involving the same or additional organs (56). Comorbidities tend to arise in complex disorders, they are frequently multigenic and multifactorial, and to date there is greater demonstration of comorbidities among diseases with a chronic or hyperinflammatory pathophysiologic component (57). Both local and systemic inflammation is hypothesized to play an important role in endometriosis (2, 58, 59). Inflammatory factors have been found to be elevated in the peritoneal fluid and in the peripheral blood of women with endometriosis compared with those without endometriosis (2, 31, 60–63). Psoriasis is also caused by the complex interaction of genetic, environmental, and immunological factors (64) and is associated with a chronic inflammatory state (65). Among those with psoriasis, patients with PsA usually present with more severe skin manifestations (66) in addition to arthritis. It is further hypothesized that those with psoriasis alone may be earlier in the disease course, as most cases of PsA occur 8–10 years after the onset of clinically evident psoriasis skin manifestation (23), and thus psoriasis alone versus psoriasis with concomitant PsA may represent points along a disease continuum or disease progression with higher inflammatory burden. If this continuum/progression is true, then our results suggest that women with endometriosis may not be at greater risk of developing psoriasis, but once psoriasis is present, women with endometriosis may be more likely to progress to PsA compared with women without endometriosis. Consistent with these results, previous studies have shown PsA to be more strongly associated with other conditions (i.e., gout (67), hypercholesteremia (46), gallstones (68), and depression (69)) than psoriasis without PsA. Both psoriasis and endometriosis patients have increased serum levels of unspecific inflammation markers such as C-reactive protein (70, 71) and proinflammatory cytokines such as interleukin (IL)-6 (72, 73), IL-8, and TNF-α (72, 74). Recently the IL-23 pathway has been associated with both psoriasis and endometriosis (75, 76). Increased levels of IL-23 in the serum and in the cutaneous lesions of psoriasis patients has been observed (77), as well as identified in the peritoneal fluid of infertile women with endometriosis (76). Blauvelt et al. (78) have demonstrated that IL-23 stimulates survival and proliferation of Th17 cells and induces the secretion of a characteristic set of cytokines, thus serving as a key cytokine regulator in autoimmune inflammatory diseases. Both endometriosis and psoriasis are well-recognized for having a strong autoimmune component, for which Th17 cells have been implicated as playing a role in sustaining chronic inflammation (79–81). This aberrant inflammatory background coupled with immune dysfunction could explain a pathophysiologic pathway underlying the association observed between endometriosis and PsA. Shared genetics may be another physiologic pathway connecting endometriosis and PsA. In a case-control study with 17 endometriosis cases and 21 controls, Gentilini et al. (29) demonstrated that endometriosis induces the expression of genes in peripheral blood mononuclear cells previously identified in psoriasis. The authors compared blood samples from patients with severe endometriosis obtained a few days before the surgical intervention and 6 months later. Five genes up-regulated in diseased stage (FBJ Murine osteosarcoma viral oncogene homolog (FOS) gene, dual specificity phosphatase 1, pre-B-cell colony enhancing factor 1, adrenomedullin, and S100 calcium binding protein P) were identical to those shown to be up-regulated in peripheral leukocytes of psoriasis patients in the active disease stage when compared with the peripheral leukocytes in the same patients following treatment who were in the “cured” stage (82). Another potential shared pathway may be through killer cell immunoglobulin-like receptors (KIRs). KIRs are a family of cell surface receptors that exert inhibitory or stimulatory functions and are expressed by natural killer cells and a subset of T cells (83). Killer immunoglobulin-like 2-domain short-tail receptor 5 (KIR2DS5) is a member of a large KIR family of cell-surface receptors expressed on natural killer cells and subpopulations of T lymphocytes. Nowak et al. (28) suggested a protective effect of the presence of KIR2DS5 in endometriosis and this protective effect of KIR2DS5 has previously been described in relation to the susceptibility of psoriasis vulgaris (84, 85). It is important to consider the strengths and limitations of this longitudinal study. The present study design avoids the potential recall and selection biases that are inherent in case-control studies that collect data after diagnosis of the disease of interest. In addition, the large sample size and long follow-up period allow for valid exploration of uni- and bidirectional temporal relationships between the 2 diseases. Unfortunately, the small samples sizes in the analysis of endometriosis to subsequent diagnosis of PsA demonstrate that future studies to replicate these findings must be at least as large as or, ideally, larger than this large cohort with 22 years of follow-up. In addition, there is an estimated 7-year delay from endometriosis symptom onset to surgical diagnosis in the general population (86) and a shorter but still 5-year delay in this cohort of nurses, making the establishment of temporality in incidence of these diseases difficult. PsA may also have a delayed diagnosis (25, 26), while psoriasis does not have a clearly established diagnostic delay. However, we observed similar magnitude of associations between endometriosis and PsA regardless of directionality. Endometriosis, psoriasis, and PsA diagnosis were self-reported, which is time- and cost-efficient, to take advantage of the benefits of large population-based cohorts, but could result in some unidentified cases in the unexposed groups. Under the assumption that this misclassification is nondifferential with respect to the outcome(s), associations would likely be biased towards the null. In addition, given the large size of the unexposed groups, the impact of any misclassified cases would be diluted. While this would suggest that our estimates may be spuriously conservative, validation of both endometriosis and psoriasis/PsA reported within this specific cohort of medical professionals suggest very accurate reporting (96% of laparoscopic cases confirmed with medical records for endometriosis (35), 90% for psoriasis (39)). In regard to generalizability, this cohort represents the demographics of US women who were registered nurses at the time of their enrollment in 1989. Therefore, they are predominantly White women, and certainly they are women with at least 2 years of post-high-school education. In addition, the mean age of incident endometriosis diagnosis was 40.3 years, which is older than estimates from general population studies (3). This older age at endometriosis diagnosis is due to the overall age distribution of the NHSII cohort at baseline (25–42 years) and in part due to the time-to-event analysis, in which any endometriosis diagnosed prior to psoriasis diagnosis was censored when endometriosis was considered as the outcome. Thus, these results may not be generalizable to cases diagnosed at earlier ages, other racial/ethnic groups, and those with differing education. Both endometriosis and psoriasis are less likely to be diagnosed among Black women (35, 66), although whether this is due to biases, discrimination, or disparities within the medical system versus true race/ethnicity-related differences in incidence is not clear. Further, while we were able to adjust for known and potential risk factors for both conditions, applying robust time-varying methods, we cannot rule out the possibility of residual or unmeasured confounding. However, the multivariable adjustment for several known risk factors suggested no confounding in either of the bidirectional analyses, and an unmeasured or unknown confounder would have to exert a greater effect than those known factors that were accounted for (87). Additionally, we explored the impact of potential intermediates (88) along the pathway between the diseases in both temporal directions, by adjusting for specific medications (i.e., oral contraceptives, acetaminophen, aspirin, and ibuprofen) and other comorbidities (i.e., CVD, T2D, hypercholesterolemia, and hypertension). Evidence of a mediating pathway attributable to these factors was not observed. However, we lacked information on noncontraceptive hormonal treatments for endometriosis, such as danazol (a synthetic androgen) and leuprolide (a gonadotropin-releasing hormone analog) to assess to what extent the association between endometriosis and PsA could have been explained by these hormonal treatments, and also about systemic psoriasis treatments, such as methotrexate, acitretin, and biologics. Previous studies have documented that prescriptions of certain drugs (e.g., β-blockers, angiotensin-converting enzyme inhibitors) may increase the risk of psoriasis or make it more severe (89–91). Our inability to explore these potential mediators has no impact on the primary observed relationship between endometriosis and PsA; however, it does leave unexplored these potential mediating pathophysiologic pathways that could be addressed in future replicating studies. Given that our time-varying adjustment for oral contraceptives, acetaminophen, aspirin, and ibuprofen yielded no suggestion of confounding or mediation, the physiologic pathways mediated by these other drug types and classes would need to be unique to exist. Despite these limitations, this study provided us with a unique opportunity to prospectively examine the temporally bidirectional associations between endometriosis, psoriasis, and PsA, while simultaneously adjusting for time-varying risk factors. Our findings within this cohort suggest that while endometriosis and psoriasis overall are not associated, women with endometriosis have twice the risk of subsequent PsA. The mechanisms underlying the endometriosis-PsA association remain to be elucidated, but there are hints regarding inflammatory and genetic pathways within the small existing literature. Future studies are needed to replicate these findings and, in particular, explore whether PsA is a more advanced stage or a distinct subset of progression among those with psoriasis; it may be that women with endometriosis are not at higher risk of psoriasis but at higher risk of its progression to this more inflammatory, painful, and higher-impact stage or form of psoriasis. These results, their replication, and additional biologic elucidation would confirm that gynecologists and dermatologists should recognize the potential association between endometriosis and PsA and work together to screen for and coordinate treatment of these conditions when they co-exist. Earlier diagnosis and treatment of the index condition may help to avoid or minimize the systemic inflammation that influences the emergence of subsequent comorbidities ultimately decreasing the negative life impact and improving the quality of life of patients. ACKNOWLEDGMENTS Author affiliations: Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States (Holly R. Harris); Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, United States (Holly R. Harris); Gynecologic Division, Hospital das Clınicas da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil (Karen Moreno Nascimento Korkes, Luiz Fernando Carvalho, Mauricio Abrao); Department of Dermatology, Warren Alpert Medical School, Brown University, Providence, Rhode Island, United States (Tricia Li, Eunyoung Cho, Abrar A. Qureshi); Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States (Tricia Li, Eunyoung Cho, Abrar A. Qureshi); Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Inserm, Gustave Roussy, “Exposome and Heredity” Team, CESP, 94805, Villejuif, France (Marina Kvaskoff); Department of Epidemiology, Brown University School of Public Health, Providence, Rhode Island, United States (Eunyoung Cho); Department of Dermatology, Rhode Island Hospital, Providence, Rhode Island, United States (Abrar A. Qureshi); Gynecologic Division, BP-A Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Brazil (Mauricio Abrao); Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, United States (Stacey A. Missmer); and Department of Obstetrics, Gynecology, and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, United States (Stacey A. Missmer). This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (grant U01 CA176726, and grants HD57210 and HD096033). H.R.H. was supported by the National Cancer Institute (grant K22 CA193860). Further information including the procedures to obtain and access data from the Nurses’ Health Study II is described at https://www.nurseshealthstudy.org/researchers (contact e-mail: [email protected]). Presented as a poster at the 14th World Congress on Endometriosis (online), March 6–10, 2021; and the Society for Epidemiologic Research Annual Meeting (online), December 16–17, 2020. The study funders had no involvement in the study design, data collection, data analysis or manuscript preparation. Conflict of interest: none declared.

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