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To investigate whether a healthy lifestyle, defined by a healthy lifestyle index score (HLIS), was associated with rheumatoid arthritis (RA) risk, overall and with seropositive/seronegative subtypes.We analyzed female nurses in the Nurses' Health Study (NHS, 1986-2016) and NHSII (1991-2017). Lifestyle and medical information were collected on biennial questionnaires. Medical records confirmed incident RA and serostatus. The HLIS index includes 5 modifiable components: smoking, alcohol consumption, body mass index, physical activity, and diet. Cox regression, adjusted for confounders, modeled associations between HLIS and incident RA. The population attributable risk estimated the proportion of incident RA preventable if participants adopted ≥4 healthy lifestyle factors.A total of 1,219 incident RA cases (776 seropositive, 443 seronegative) developed in 4,467,751 person-years. Higher (healthier) HLIS was associated with lower overall (hazard ratio [HR] 0.86 [95% confidence interval (95% CI) 0.82-0.90]), seropositive (HR 0.85 [95% CI 0.80-0.91]), and seronegative RA risk (HR 0.87 [95% 0.80-0.94]). Women with 5 healthy lifestyle factors had the lowest risk (HR 0.42 [95% CI 0.22-0.80]). The population attributable risk for adhering to ≥4 lifestyle factors was 34% for RA.In this prospective cohort, healthier lifestyle was associated with a lower RA risk. A substantial proportion of RA may be preventable by a healthy lifestyle.

Objective To investigate passive smoking throughout the life course and the risk of rheumatoid arthritis (RA), while accounting for personal smoking. Methods We analyzed the Nurses' Health Study II prospective cohort, using information collected via biennial questionnaires. We assessed the influence of 1) maternal smoking during pregnancy (in utero exposure), 2) childhood parental smoking, and 3) years lived with smokers since age 18. Incident RA and serostatus were determined by medical record review. Using the marginal structural model framework, we estimated the controlled direct effect of each passive smoking exposure on adult incident RA risk by serologic phenotype, controlling for early-life factors and time-updated adulthood factors including personal smoking. Results Among 90,923 women, we identified 532 incident RA cases (66% seropositive) during a median of 27.7 years of follow-up. Maternal smoking during pregnancy was associated with RA after adjustment for confounders, with a hazard ratio (HR) of 1.25 (95% confidence interval [95% CI] 1.03-1.52), but not after accounting for subsequent smoking exposures. Childhood parental smoking was associated with seropositive RA after adjustment for confounders (HR 1.41 [95% CI 1.08-1.83]). In the controlled direct effect analyses, childhood parental smoking was associated with seropositive RA (HR 1.75 [95% CI 1.03-2.98]) after controlling for adulthood personal smoking, and the association was accentuated among ever smokers (HR 2.18 [95% CI 1.23-3.88]). There was no significant association of adulthood passive smoking with RA (HR 1.30 for ≥20 years of living with a smoker versus none [95% CI 0.97-1.74]). Conclusion We found a potential direct influence of childhood parental smoking on adult-onset incident seropositive RA even after controlling for adulthood personal smoking.

Objective We sought to improve seropositive rheumatoid arthritis (RA) risk prediction using a novel weighted genetic risk score (wGRS) and preclinical plasma metabolites associated with RA risk. Predictive performance was compared to previously validated models including RA-associated environmental factors. Methods This nested case-control study matched incident seropositive RA cases (meeting ACR 1987 or EULAR/ACR 2010 criteria) in the Nurses’ Health Studies (NHS) to two controls on age, blood collection features, and post-menopausal hormone use at pre-RA blood draw. Environmental variables were measured at the questionnaire cycle preceding blood draw. Four models were generated and internally validated using a bootstrapped optimism estimate: (a) base with environmental factors (E), (b) environmental, genetic and gene-environment interaction factors (E + G + GEI), c) environmental and metabolic factors (E + M), and d) all factors (E + G + GEI + M). A fifth model including all factors and interaction terms was fit using ridge regression and cross-validation. Models were compared using area under the receiver operating characteristic curve (AUC). Results 150 pre-RA cases and 455 matched controls were included. The E model yielded an optimism-corrected AUC of 0.622. The E + M model did not show improvement over the E model (corrected AUC 0.620). Including genetic factors increased prediction, producing corrected AUCs of 0.677 in the E + G + GEI model and 0.674 in the E + G + GEI + M model. Similarly, the performance of the cross-validated ridge regression model yielded an AUC of 0.657. Conclusion Addition of wGRS and gene-environment interaction improved seropositive RA risk prediction models. Preclinical metabolite levels did not significantly contribute to prediction.

OBJECTIVE Smoking has been associated with increased systemic lupus erythematosus (SLE) risk, but the biologic basis for this association is unknown. Our objective was to investigate whether women's smoking was positively associated with SLE-associated proinflammatory chemokines/cytokines (stem cell factor [SCF], B lymphocyte stimulator [BLyS], interferon-γ-inducible 10-kd protein [IP-10], and interferon-α); or negatively associated with antiinflammatory cytokine interleukin-10 (IL-10); and whether associations were modified by SLE-related autoantibody status. METHODS The Nurses' Health Study (NHS, n = 121,700) and NHSII (n = 116,429) cohorts were begun in 1976 and 1989. In 1988-1990 (NHS) and 1996-1999 (NHSII), ~25% of participants donated blood samples. We identified 1,177 women without SLE with banked samples, and we tested by enzyme-linked immunoassay (ELISA) for chemokines/cytokines as well as anti-Sm, anti-Ro/SSA, anti-La/SSB, and anti-RNP. Antinuclear antibodies (ANAs) were detected by HEp-2 cell indirect immunofluorescence, and anti-double-stranded DNA antibodies and were assayed by ELISA. Smoking was assessed until blood draw. Separate tobit and linear regression analyses, adjusted for potential confounders, modeled associations between smoking and log-transformed chemokine/cytokine concentrations. Analyses were stratified by autoantibody status. Effect estimates were calculated as ratios of geometric means expressed as percentage differences. RESULTS Among the 15% of current/recent versus 85% of past/never smokers, BLyS levels were 8.7% higher (P < 0.01) and were 24% higher (P < 0.0001) among those who were ANA positive. Current/recent smokers had IL-10 concentrations 46% lower (P < 0.01) than past/never smokers; each 10 pack-years of smoking was associated with a 17% decrease in IL-10 level (P < 0.001). Smoking was not associated with IP-10 or SCF. CONCLUSION Elevated BLyS and lower IL-10 levels among current smokers, particularly among ANA-positive women, may be involved in SLE pathogenesis.

Objective To examine the association of long-term weight change with RA risk in a large prospective cohort study. Methods The Nurses’ Health Study II started in 1989 (baseline); after exclusions, we studied 108 505 women 25–42 years old without RA. Incident RA was reported by participants and confirmed by medical record review. Body weight was reported biennially through 2015. We investigated two time-varying exposures: weight changes from baseline and from age 18; change was divided into five categories. We used a marginal structural model approach to account for time-varying weight change and covariates. Results Over 2 583 266 person-years, with a median follow-up time of 25.3 years, 541 women developed RA. Compared with women with stable weight from baseline, weight change was significantly associated with increased RA risk [weight gain 2–2 kg: RR = 2.05 (95% CI 1.28, 3.28)]. Weight gain of 10 kg or more from age 18 compared with stable weight was also associated with increased RA risk [10–< 20 kg: RR = 2.12 (95% CI 1.37, 3.27), ≥20 kg: RR = 2.31 (95% CI 1.50, 3.56)]. Consistent findings were observed for seropositive and seronegative RA. Conclusion Long-term weight gain was strongly associated with increased RA risk in women, with weight gain of ≥20 kg associated with more than a three-fold increased RA risk. Maintenance of healthy weight may be a strategy to prevent or delay RA.

OBJECTIVE: Ultraviolet radiation (UV) exposure is associated with photosensitivity, rashes, and flares in systemic lupus erythematosus (SLE). However, it is not known whether UV exposure increases risk of developing SLE. We examined UV exposure and SLE risk in a large prospective cohort. METHODS: The Nurses’ Health Study (NHS) enrolled 121,700 U.S. female nurses in 1976; in 1989, 116,429 were enrolled in NHSII. Biennial questionnaires collected lifestyle and medical data. Self-reported incident SLE by American College of Rheumatology classification criteria was confirmed by medical record review. Ambient UV exposure was estimated by linking geocoded residential addresses with a spatiotemporal UV exposure model. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) across tertiles of time-varying cumulative average UV. We examined SLE risk overall and stratified by anti-Ro/La antibodies and by cutaneous manifestations from 1976 through 2014 (NHS)/2015 (NHSII), adjusting for confounders. RESULTS: With 6,054,665 person-years of exposure, we identified 297 incident SLE cases; mean age at diagnosis was 49.8 (10.6) years. At diagnosis, 16.8% of women had +anti-Ro/La, and 80% had either +anti-Ro/La or ≥1 cutaneous manifestation. Compared to the lowest UV exposure tertile, risk of overall SLE was increased, but not significantly (HR 1.28 [95%CI 0.96–1.70]). Women in the highest tertile had increased risk of malar rash (HR 1.62 [95% CI 1.04–2.52]). CONCLUSION: Cumulative UV exposure was not associated with SLE risk. Higher UV exposure, however, was associated with increased risk of malar rash at presentation. UV exposure may trigger SLE onset with malar rash among susceptible women.

Objective.Being overweight or obese increases rheumatoid arthritis (RA) risk among women, particularly among those diagnosed at a younger age. Abdominal obesity may contribute to systemic inflammation more than general obesity; thus, we investigated whether abdominal obesity, compared to general obesity, predicted RA risk in 2 prospective cohorts: the Nurses’ Health Study (NHS) and NHS II.Methods.We followed 50,682 women (1986–2014) in NHS and 47,597 women (1993–2015) in NHS II, without RA at baseline. Waist circumference (WC), BMI, health outcomes, and covariate data were collected through biennial questionnaires. Incident RA cases and serologic status were identified by chart review. We examined the associations of WC and BMI with RA risk using time-varying Cox proportional hazards models. We repeated analyses restricted to age ≤ 55 years.Results.During 28 years of follow-up, we identified 844 incident RA cases (527 NHS, 317 NHS II). Women with WC > 88 cm (35 in) had increased RA risk (HR 1.22, 95% CI 1.06–1.41). A similar association was observed for seropositive RA, which was stronger among young and middle-aged women. Further adjustment for BMI attenuated the association to null. In contrast, BMI was associated with RA (HRBMI ≥ 30 vs < 25 1.33, 95% CI 1.05–1.68) and seropositive RA, even after adjusting for WC, and, as in WC analyses, this association was stronger among young and middle-aged women.Conclusion.Abdominal obesity was associated with increased RA risk, particularly for seropositive RA, among young and middle-aged women; however, it did not independently contribute to RA risk beyond general obesity.

Background Proton pump inhibitors (PPIs) have a significant impact on the gut microbiome, which in turn, might increase the risk of rheumatoid arthritis (RA). Aim To evaluate regular use of PPIs and risk of RA. Methods This is a prospective analysis of the US nurses who reported PPI use data, and were free of RA from the Nurses' Health Study (NHS 2002-2014) and NHS II (2003-2015). The exposure was regular use of PPI in the past 2 years, which was repeatedly evaluated in biennial surveys. RA was confirmed by the 1987 or 2010 American College of Rheumatology criteria. We estimated the hazard ratios (HRs) and confidence interval (CIs) with time-dependent Cox regression adjusting for potential confounders. Results We documented 421 cases of RA over 1 753 879 person-years of follow-up. Regular PPI users had a 44% higher risk of RA as compared with non-regular users (adjusted HR = 1.44; 95%CI, 1.10-1.89). The risk of RA increased with the total duration of PPI use (P-trend = 0.008). Compared with non-regular users, the adjusted HRs were 1.22 (95%CI, 0.93-1.62) for women with >0 to 4 years' use and 1.73 (95% CI, 1.14 to 2.61) for >4 years' use. Conclusions Regular use of PPI was associated with increased risk of RA in women, with a higher risk observed in individuals with a longer duration of PPI use. Due to the observational study design, large prospective trials are still required to confirm our finding.

Objectives Moderate alcohol consumption has been associated with decreased systemic lupus erythematosus risk, but the biologic basis for this association is unknown. We aimed to determine whether moderate alcohol consumption was associated with lower concentrations of systemic lupus erythematosus-associated chemokines/cytokines in an ongoing cohort of female nurses without systemic lupus erythematosus, and whether the association was modified by the presence of systemic lupus erythematosus-related autoantibodies. Methods About 25% of participants from the Nurses’ Health Study ( n = 121,700 women) and Nurses’ Health Study 2 ( n = 116,429) donated a blood sample; of these, 1177 women were without systemic lupus erythematosus at time of donation. Cumulative average and current (within 4 years) intakes of beer, wine or liquor were assessed from pre-blood draw questionnaires. Chemokine/cytokine concentrations (stem cell factor, B-lymphocyte stimulator, interferon-inducible protein-10, interferon-alpha, interleukin-10) and antibodies against dsDNA and extractable nuclear antigens were obtained using enzyme-linked immunosorbent assays. Antinuclear antibodies were detected by indirect immunofluorescence on HEp-2 cells. Results At blood draw, the women’s mean age was 56 years and 22% were antinuclear antibody positive; 36% were African-American. About half (46%) reported consuming 0–5 g/day of alcohol. Stem cell factor levels were 0.5% lower ( p 5 g/day had mean stem cell factor levels 7% lower ( p = 0.002) than non-drinkers. Other cytokines were not significantly associated with alcohol intake. Autoantibody status did not modify observed associations. Conclusion In this study of female nurses, moderate alcohol consumption was associated with lower stem cell factor levels, suggesting a plausible mechanism through which alcohol may lower systemic lupus erythematosus risk might be by decreasing circulating stem cell factor.

While previous studies have demonstrated an association between individual factors related to lifestyle and the risk of systemic lupus erythematosus (SLE), it is unclear how the combination of these factors might affect the risk of incident SLE. This study was undertaken to prospectively evaluate whether a combination of healthy lifestyle factors is associated with a lower risk of incident SLE and its subtypes (anti-double-stranded DNA [anti-dsDNA]-positive and anti-dsDNA-negative SLE).The study included 185,962 women from the Nurses' Health Study (NHS) and NHSII cohorts, among whom there were 203 incident cases of SLE (96 with anti-dsDNA-positive SLE, 107 with anti-dsDNA-negative SLE) during 4,649,477 person-years of follow-up. The Healthy Lifestyle Index Score (HLIS) was calculated at baseline and approximately every 2 years during follow-up, with scores assigned for 5 healthy lifestyle factors: alcohol consumption, body mass index, smoking, diet, and exercise. A time-varying Cox proportional hazards regression model was used to estimate the adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the risk of SLE. In addition, the percentage of partial population attributable risk (PAR%) of SLE development was calculated.A higher HLIS was associated with a lower risk of SLE overall (HR 0.81 [95% CI 0.71-0.94]) and a lower risk of anti-dsDNA-positive SLE (HR 0.78 [95% CI 0.63-0.95]). Women with ≥4 healthy lifestyle factors had the lowest risk of SLE overall (HR 0.42, 95% CI 0.25-0.70) and lowest risk of anti-dsDNA-positive SLE (HR 0.35, 95% CI 0.17-0.75) as compared to women with only 1 healthy behavior or no healthy behaviors. The PAR% of SLE development was 47.7% (95% CI 23.1-66.6%), assuming that the entire population had adhered to at least 4 healthy lifestyle behaviors.These results indicate that the risk of developing SLE, a disease in which significant evidence of genetic involvement has been established, might be reduced by nearly 50% with adherence to modifiable healthy lifestyle behaviors.

Systemic lupus erythematosus (SLE) is a severe multisystem autoimmune disease that predominantly affects women. Its etiology is complex and multifactorial, with several known genetic and environmental risk factors, but accurate risk prediction models are still lacking. We developed SLE risk prediction models, incorporating known genetic, lifestyle and environmental risk factors, and family history.We performed a nested case-control study within the Nurses' Health Study cohorts (NHS). NHS began in 1976 and enrolled 121,700 registered female nurses ages 30-55 from 11 U.S. states; NHSII began in 1989 and enrolled 116,430 registered female nurses ages 25-42 from 14 U.S. states. Participants were asked about lifestyle, reproductive and environmental exposures, as well as medical information, on biennial questionnaires. Incident SLE cases were self-reported and validated by medical record review (Updated 1997 American College of Rheumatology classification criteria). Those with banked blood samples for genotyping (∼25% of each cohort), were selected and matched by age (± 4 years) and race/ethnicity to women who had donated a blood sample but did not develop SLE. Lifestyle and reproductive variables, including smoking, alcohol use, body mass index, sleep, socioeconomic status, U.S. region, menarche age, oral contraceptive use, menopausal status/postmenopausal hormone use, and family history of SLE or rheumatoid arthritis (RA) were assessed through the questionnaire prior to SLE diagnosis questionnaire cycle (or matched index date). Genome-wide genotyping results were used to calculate a SLE weighted genetic risk score (wGRS) using 86 published single nucleotide polymorphisms (SNPs) and 10 classical HLA alleles associated with SLE. We compared four sequential multivariable logistic regression models of SLE risk prediction, each calculating the area under the receiver operating characteristic curve (AUC): 1) SLE wGRS, 2) SLE/RA family history, 3) lifestyle, environmental and reproductive factors and 4) combining model 1-3 factors. Models were internally validated using a bootstrapped estimate of optimism of the AUC. We also examined similar sequential models to predict anti-dsDNA positive SLE risk.We identified and matched 138 women who developed incident SLE to 1136 women who did not. Models 1-4 yielded AUCs 0.63 (95%CI 0.58-0.68), 0.64 (95%CI 0.59-0.68), 0.71(95% CI 0.66-0.75), and 0.76 (95% CI 0.72-0.81). Model 4 based on genetics, family history and eight lifestyle and environmental factors had best discrimination, with an optimism-corrected AUC 0.75. AUCs for similar models predicting anti-dsDNA positive SLE risk, were 0.60, 0.63, 0.81 and 0.82, with optimism corrected AUC of 0.79 for model 4.A final model including SLE weighted genetic risk score, family history and eight lifestyle and environmental SLE risk factors accurately classified future SLE risk with optimism corrected AUC of 0.75. To our knowledge, this is the first SLE prediction model based on known risk factors. It might be feasibly employed in at-risk populations as genetic data are increasingly available and the risk factors easily assessed. The NHS cohorts include few non-White women and mean age at incident SLE was early 50s, calling for further research in younger and more diverse cohorts.

Objective.Exposure to severe stressors may alter immune function and augment inflammation and cytokine release, increasing risk of autoimmune disease. We examined whether childhood abuse was associated with a heightened risk of incident systemic lupus erythematosus (SLE).Methods.Data were drawn from the Nurses’ Health Study II, a cohort of US female nurses enrolled in 1989, followed with biennial questionnaires. We measured childhood physical and emotional abuse with the Physical and Emotional Abuse Subscale of the Childhood Trauma Questionnaire and sexual abuse with the Sexual Maltreatment Scale of the Parent-Child Conflict Tactics Scale, both administered in 2001. We identified incident SLE (≥ 4 American College of Rheumatology 1997 classification criteria) through 2015. We used multivariable Cox regression models to evaluate the association between childhood abuse and SLE, accounting for potential confounders (e.g., parental education, occupation, home ownership) and mediators [e.g., depression, posttraumatic stress disorder (PTSD)].Results.Among 67,516 women, there were 94 cases of incident SLE. In adjusted models, exposure to the highest versus lowest physical and emotional abuse was associated with 2.57 times greater risk of SLE (95% CI 1.30–5.12). We found that 17% (p < 0.0001) of SLE risk associated with abuse could be explained by depression and 23% (p < 0.0001) by PTSD. We did not observe a statistically significant association with sexual abuse (HR 0.84, 95% CI 0.40–1.77, highest vs lowest exposure).Conclusion.We observed significantly increased risk of SLE among women who had experienced childhood physical and emotional abuse compared with women who had not. Exposure to childhood adversity may contribute to development of SLE.

Objective To elucidate how postdiagnosis multimorbidity and lifestyle changes contribute to the excess mortality of rheumatoid arthritis (RA). Methods We performed a matched cohort study among women in the Nurses' Health Study (1976-2018). We identified women with incident RA and matched each by age and year to 10 non-RA comparators at the RA diagnosis index date. Specific causes of death were ascertained via death certificates and medical record review. Lifestyle and morbidity factors were reported biennially; 61 chronic conditions were combined into the Multimorbidity Weighted Index (MWI). After adjusting for baseline confounders, we used inverse probability weighting analysis to examine the mediating influence of postindex MWI scores and lifestyle factors on total, cardiovascular, and respiratory mortality, comparing women with RA to their matched comparators. Results We identified 1,007 patients with incident RA and matched them to 10,070 non-RA comparators. After adjusting for preindex confounders, we found that hazard ratios (HRs) and 95% confidence intervals (95% CIs) were higher for total mortality (HR 1.46 [95% CI 1.32, 1.62]), as well as cardiovascular (HR 1.54 [95% CI 1.22, 1.94]) and respiratory (HR 2.75 [95% CI 2.05, 3.71]) mortality in patients with RA compared to non-RA comparators. Adjusting for postindex lifestyle factors (physical activity, body mass index, diet, smoking) attenuated but did not substantially account for this excess RA mortality. After additional adjustment for postindex MWI scores, patients with RA had HRs of 1.18 (95% CI 1.05, 1.32) for total, 1.19 (95% CI 0.94, 1.51) for cardiovascular, and 1.93 (95% CI 1.42, 2.62) for respiratory mortality. Conclusion We found that MWI scores substantially accounted for the excess total and cardiovascular mortality among women with RA. This finding underscores the importance of monitoring for the total disease burden as a whole in monitoring patients with RA.

OBJECTIVE To investigate the association of depression with subsequent risk of rheumatoid arthritis (RA) by serologic phenotype. METHODS We performed a cohort study using pooled data from the Nurses' Health Study (NHS; 1992-2014) and the NHSII (1993-2015). Depression was defined according to the following composite definition: diagnosis by clinician, regular antidepressant use, or a 5-question Mental Health Inventory score of

Objective: Past studies have reported associations between pesticide exposure and the risk of systemic lupus erythematosus (SLE). Residential pesticide exposure has been less well studied than agricultural exposure. The purpose of this study was to assess SLE risk associated with residential pesticide exposure in an urban population of predominantly African-American women. Methods: Adult women with SLE were identified from six hospital databases and community screening in three neighborhoods in Boston, Massachusetts, USA. Controls were adult women volunteers from the same neighborhoods who were screened for the absence of connective tissue disease and anti-nuclear antibodies. Subjects were considered exposed to pesticides if they had ever had an exterminator for an ant, cockroach, or termite problem prior to SLE diagnosis or corresponding reference age in controls. Risks associated with pesticide exposure were analyzed using multivariable logistic regression models, adjusted for sociodemographic factors. Results: We identified 93 SLE subjects and 170 controls with similar baseline characteristics. Eighty-three per cent were African-American. Pesticide exposure was associated with SLE, after controlling for potential confounders (odds ratio 2.24, 95% confidence interval 1.28–3.93). Conclusion: Residential exposure to pesticides in an urban population of predominantly African-American women was associated with increased SLE risk. Additional studies are needed to corroborate these findings.

Background Obesity is increasingly prevalent and related to increased risk of several autoimmune diseases, likely via generation of inflammatory adipokines. Prior studies have not evaluated obesity in relation to systemic lupus erythematosus (SLE) risk. We prospectively evaluated whether obesity was associated with increased SLE risk among women in the U.S. Nurses' Health Study cohorts. Methods We conducted a prospective cohort study among 238,130 women in the Nurses' Health Studies (NHS, 1976–2012; NHSII, 1989–2013). Incident SLE was confirmed by American College of Rheumatology 1997 criteria and validated through medical record review. Body mass index (BMI, kg/m 2 ) was calculated at baseline and on biennial questionnaires. Cox proportional hazards models estimated HRs (95% CIs) for SLE by cumulative average BMI category {18.5 to Results We identified 153 NHS incident SLE cases and 115 incident NHSII cases during 5,602,653 person-years of follow-up. At baseline, 8.4% of women in NHS and 11.8% in NHSII were obese. Mean age at enrollment was 42.5 (SD 7.2) years in NHS and 34.4 (SD 4.7) years in NHSII. Cumulative average obesity was significantly associated with SLE risk in NHSII [HR = 1.85 (1.17–2.91)], but not in NHS [HR = 1.11 (0.65–1.87)] compared to normal BMI. In the meta-analysis of both cohorts, obesity was not significantly associated with increased risk of SLE [HR = 1.46 (0.88–2.40)]. Simple time-varying BMI and lagging the exposure window by 4 years produced similar findings to the primary analysis. In NHSII, a 4.54 kg gain between age 18 and enrollment slightly increased SLE risk [HR = 1.09 (1.02–1.18)]. In the secondary analysis starting follow-up of both cohorts at similar calendar years, the point estimate for obesity in NHS was higher than the primary analysis [HR = 1.67 (0.81–3.45)]. Conclusion We observed an 85% significantly increased risk of SLE among obese compared to normal BMI women in the more recent NHSII cohort, but no association was observed in the earlier NHS cohort. Secular trends in obesity may account for the differences between the two birth cohorts.

Background Prior studies suggest that fish may be protective for rheumatoid arthritis (RA) risk perhaps through the anti-inflammatory effect of omega-3 fatty acid, but this relationship has not been clearly established. Therefore, we investigated fish intake and RA risk by serologic status, age of onset, and smoking using a prospective cohort study with large sample size, repeated measures of dietary intake, and lengthy follow-up. Methods We studied fish intake and RA risk among 166,013 women in two prospective cohorts, the Nurses’ Health Study (NHS, 1984–2014) and NHSII (1991–2015). Fish intake was assessed using food frequency questionnaires at baseline and every 4 years. Incident RA during follow-up and serologic status were determined by medical record review. Pooled Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for RA (overall and by serologic status and age at diagnosis) for fish intake frequency. We tested for a smoking-fish interaction for RA risk. Results During 3,863,909 person-years of follow-up, we identified 1080 incident RA cases. Increasing fish intake was not associated with all RA (≥4 servings/week: multivariable HR 0.93 [95%CI 0.67–1.28] vs. 55 years old (p for trend = 0.037). Among women ≤55 years old, frequent fish intake (vs. infrequent) had HRs (95%CIs) of: 0.73 (0.52–1.02) for all RA, 0.85 (0.55–1.32) for seropositive RA, and 0.55 (0.32–0.94) for seronegative RA. Ever smokers with infrequent fish intake had highly elevated risk for RA onset ≤55 years (HR 2.59, 95%CI 1.65–4.06), while ever smokers with frequent fish intake had modestly elevated RA risk (HR 1.29, 95%CI 1.07–1.57; vs. never smokers/frequent fish intake; p for smoking-fish interaction = 0.039). Conclusion In this large prospective cohort study, we found no clear protective effect of fish or marine omega-3 fatty acid intake on RA risk, overall or by serologic status. We found that fish intake attenuated the strong association of smoking for RA diagnosed ≤55 years of age, but this requires further study.

IMPORTANCE: It has long been hypothesized that depression may increase the risk of developing autoimmune disease; however, rigorous empirical evidence is sparse. OBJECTIVE: To evaluate whether an association exists between depression and risk of incident systemic lupus erythematosus (SLE), a paradigmatic, systemic autoimmune disease. DESIGN, SETTING, AND PARTICIPANTS: This 20-year prospective, longitudinal cohort study evaluated data collected from 2 cohorts of women participating in the Nurses’ Health Study (1996-2012) and the Nurses’ Health Study II (1993-2013). Data analyses were conducted from August 2017 to May 2018. MAIN OUTCOMES AND MEASURES: Incident SLE with 4 or more American College of Rheumatology criteria was ascertained by self-report and confirmed by medical record review. Depression was assessed repeatedly throughout follow-up according to whether women reported having received a clinician’s diagnosis of depression, regular antidepressant use, or a score of less than 60 on the 5-item Mental Health Inventory (MHI-5). Whether longitudinally assessed health risk factors (eg, cigarette smoking, body mass index, oral contraceptive use, menopause or postmenopausal hormone use, alcohol use, exercise, or diet) accounted for increased SLE risk among women with vs without depression was examined. Cox proportional hazards regression models were used to estimate risk of SLE. In addition, the association of depression lagged by 4 years, and depression status at baseline with incident SLE throughout follow-up was assessed. RESULTS: Data from 194 483 women (28-93 years of age; 93% white) were included. During 20 years of follow-up, 145 cases of SLE occurred. Compared with women with no depression, women with a history of depression had a subsequent increased risk of SLE (HR, 2.67; 95% CI, 1.91-3.75; P

OBJECTIVE: To investigate whether a dietary pattern derived using inflammatory biomarkers is associated with rheumatoid arthritis (RA) risk. METHODS: We prospectively followed 79,988 women in the Nurses’ Health Study (NHS, 1984–2014) and 93,572 women in the NHSII (1991–2013); incident RA was confirmed by medical records. Food frequency questionnaires (FFQ) were completed at baseline and approximately every 4 years. Inflammatory dietary pattern was assessed from FFQ data using the Empirical Dietary Inflammatory Pattern (EDIP), including 18 anti-/pro-inflammatory food/beverage groups weighted by correlations with plasma inflammatory biomarkers (interleukin-6, C-reactive protein, and tumor necrosis factor-α receptor 2). We investigated associations between EDIP and RA using Cox regression. RESULTS: We identified 1,185 incident RA cases over 4,425,434 person-years. EDIP was not associated with overall RA risk (p trend=0.21 across EDIP quartiles). Among women ≤55 years, increasing EDIP was associated with increased overall RA risk; HRs (95%CIs) across EDIP quartiles were: 1.00 (reference), 1.14 (0.86–1.51), 1.35 (1.03–1.77), and 1.38 (1.05–1.83; p for trend=0.01). Adjusting for BMI attenuated this association. Increasing EDIP was associated with increased seropositive RA risk among women ≤55 years (p for trend=0.04). There was no association between EDIP and RA among women >55 years (EDIP-age interaction: p=0.03). CONCLUSION: An inflammatory dietary pattern was associated with increased seropositive RA risk with onset ≤55 years old, and this association may be partially mediated through BMI.

Background Ultraviolet-B radiation (UV-B) exposure may lead to worsened photosensitivity, rashes, and systemic flares among SLE patients. Although UV-B radiation damages keratinocytes and may result in production of novel forms of autoantigens, it remains unknown whether UV-B exposure increases the risk of developing SLE. We aimed to examine the association of UV-B exposure with risk of incident SLE in a large prospective cohort of women, examining SLE risk overall and by subtypes defined by presence of anti-Ro/La antibodies (+anti Ro/La) and/or cutaneous manifestations most associated with UV exposure in SLE patients. Methods The Nurses’ Health Study (NHS) enrolled 121,701 U.S. female nurses in 1976; NHSII enrolled 116,430 in 1989. Biennial questionnaires collected lifestyle, environmental, and medical data. Residential addresses were geocoded. Incident SLE was confirmed by medical record review. National Aeronautics and Space Administration Total Ozone Mapping Spectrometer and Ozone Monitoring Instrument gridded remote sensing images scaled to a 1 km spatial resolution predicted average July noon-time erythemal UV-B (mW/m2) annually starting in 1980. Participants without UV-B data at baseline were excluded. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression models across tertiles of cohort-specific, time-varying cumulative average UV-B through one cycle prior to SLE onset. We examined SLE risk overall and stratified by presence of anti-Ro/La or cutaneous manifestations (malar rash and/or photosensitivity) at diagnosis through 2014 (NHS) or 2013 (NHSII), controlling for potential confounders. We also conducted a ‘lagged’ analysis by ending the exposure window two cycles prior to SLE diagnosis, as SLE symptoms may develop insidiously pre-diagnosis. Results Mean age at SLE diagnosis was 49.3 (10.4) years among 286 SLE cases in NHS/NHSII. At SLE diagnosis, 13% of women had +anti Ro/La whereas 80% had either +anti Ro/La or at least one cutaneous manifestation. Compared to the lowest tertile of UV-B exposure, risk of overall SLE, SLE with +anti Ro/La, or SLE with photosensitivity in the highest UV-B tertile were increased, but not statistically significant in the main analysis (table 1) or in lagged analyses. However, women in the highest UV-B tertile had statistically significantly increased risks of SLE with malar rash (HR 1.68 [95% CI 1.08 to 2.62]) (table 1), but this was no longer significant in the lagged analysis (HR 1.39 [95% CI 0.92 to 2.10]). Conclusions Increasing cumulative UV-B exposure was not associated with risk of developing overall SLE. However, among women at risk for SLE, living in areas with higher UV-B exposure was associated with increased risk of developing SLE presenting with malar rash. Further studies are warranted to determine whether high UV-B exposure may play a role in triggering SLE onset with malar rash.

Objective To examine the association between symptoms of post-traumatic stress disorder (PTSD) and rheumatoid arthritis (RA) risk in a prospective cohort and to characterize the role of smoking in this relationship. Methods A subset (n = 54,224) of the Nurses’ Health Study II, a prospective cohort of female nurses, completed the Brief Trauma Questionnaire and a screen for PTSD symptoms. Participants were categorized based on trauma exposure and number of PTSD symptoms. Incident RA cases (n = 239) from 1989 to 2011 were identified. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) between PTSD symptoms and incident RA. To identify the impact of smoking, secondary and subgroup analyses were performed. In all analyses, PTSD and smoking were lagged 2 years before the development of RA. Results Compared to no history of trauma/PTSD symptoms, the HR for ≥4 PTSD symptoms and incident RA was 1.76 (95% CI 1.16–2.67) in models adjusted for age, race, and socioeconomic status. The risk for RA increased with an increasing number of PTSD symptoms (P = 0.01). When smoking was added to the model, the HR for RA remained elevated (HR 1.60 [95% CI 1.05–2.43]). In a subgroup analysis, excluding women who smoked before PTSD onset, results were unchanged (HR 1.68 [95% CI 1.04–2.70]). Conclusion This study suggests that women with high PTSD symptomatology have an elevated risk for RA, independent of smoking, adding to emerging evidence that stress is an important determinant of physical health.

Objective: To examine monocyte chemotactic protein-1 (MCP-1) concentration and future rheumatoid arthritis (RA) risk, and investigate effect modification by human leukocyte antigen-shared epitope (HLA-SE) and several lifestyle factors. Methods: We conducted a nested case–control study using stored plasma samples from the Nurses' Health Studies. Each pre-RA case was matched to three controls (Ncase= 220, Ncontrol = 675). Odds ratios (OR) for RA associated with MCP-1 concentration and interactions with HLA-SE, smoking, BMI and alcohol intake were estimated. Results: MCP-1 concentration was associated with both seropositive and seronegative RA, in particular

Vitamin D may reduce cell proliferation and tumor growth in breast tissue, and exposure may be most important during adolescence when breast tissue is developing. In the Nurses’ Health Study II, higher recalled adolescent vitamin D intake was associated with a lower risk of benign breast disease (BBD). Our study aimed to assess adolescent vitamin D exposure in relation to BBD in young women. Vitamin D was assessed in 6,593 adolescent girls (9–15 years of age at baseline) in the prospective Growing Up Today Study cohort using the mean energy-adjusted intakes from food frequency questionnaires in 1996, 1997, and 1998. In 1999, 5,286 girls reported skin color, sunscreen use, tanning bed use, and number of sunburns in the past year, and we used state of residence to assess low versus high ultraviolet index. Biopsy-confirmed BBD was reported on questionnaires in 2005, 2007, and 2010 (n = 122). Dietary vitamin D, tanning behaviors, and other sun exposure variables were not significantly associated with BBD in logistic regression models adjusted for age, family history of breast cancer or BBD, age at menarche, nulliparity, alcohol intake, body mass index, and physical activity. The relative risk for the top (>467 IU/day) versus bottom (

ObjectivesSystemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, subtyped according to clinical manifestations and autoantibodies. Evidence concerning cigarette smoking and SLE risk has been conflicting. We investigated smoking and SLE risk, overall and by anti-double stranded DNA (dsDNA) presence, in two prospective cohort studies.MethodsThe Nurses’ Health Study (NHS) enrolled 121 701 US female nurses in 1976; Nurses’ Health Study II (NHSII) enrolled 116 430 in 1989. Lifestyle, environmental and medical data were collected through biennial questionnaires. Incident SLE was confirmed by medical record review. Cox regression models estimated HRs of SLE, overall and by dsDNA subtype, in association with time-varying smoking status and cumulative smoking pack-years through the 2-year cycle prior to diagnosis, controlling for potential confounders.ResultsAmong 286 SLE cases identified (159 in NHS (1978–2012) and 127 in NHSII (1991–2013)), mean age was 49.2 (10.3) years and 42% were dsDNA+ at SLE diagnosis. At baseline, 45% of women had ever smoked, 51% of whom currently smoked. Compared with never smokers, current smokers had increased dsDNA+ SLE risk (HR 1.86 (1.14–3.04)), whereas past smokers did not (HR 1.31 (0.85–2.00)). Women who smoked >10 pack-years (vs never) had an elevated dsDNA+ SLE risk (HR 1.60(95% CI 1.04 to 2.45)) compared with never smokers. No associations were observed between smoking status or pack-years and overall SLE or dsDNA− SLE.ConclusionStrong and specific associations of current smoking and >10 pack-years of smoking with dsDNA+ SLE were observed. This novel finding suggests smoking is involved in dsDNA+ SLE pathogenesis.

Objective We assessed the contributions of familial rheumatoid arthritis (RA) or lupus and environmental factors to the risk of RA. Methods Among 121,700 women in the Nurses' Health Study, 65,457 provided data on familial RA/lupus. Among these, 493 RA cases (301 seropositive and 192 seronegative) were validated. We estimated hazard ratios (HRs) for RA comparing those with and without familial RA/lupus, adjusting for environmental factors (smoking, alcohol, body mass index [BMI], parity, breastfeeding, menopause, hormone use, early menarche, and menstrual regularity) using Cox proportional hazards models. Population attributable risks (PARs) for RA within this cohort were calculated for familial RA/lupus, smoking, alcohol, BMI, parity, and breastfeeding. Results Familial RA/lupus was significantly associated with RA (HR 3.67), seropositive RA (HR 3.90), and seronegative RA (HR 3.95). After adjusting for environmental factors, familial RA/lupus was significantly associated with RA (HR 3.59, 95% confidence interval 2.94–4.37). Smoking >10 pack-years, overweight, BMI, and premenopause status remained significantly associated with RA after adjusting for familial RA/lupus. For RA in this cohort, the PAR for smoking, BMI, alcohol, parity, or breastfeeding collectively was 41%; the PAR due to heredity from familial RA/lupus was 21%. Conclusion In this large, prospective cohort, women with familial RA/lupus had a 4-fold increased risk for RA that remained significant after adjusting for environmental factors. A large proportion of RA risk was attributable to environmental factors, even among those with familial RA/lupus.

To examine the relationship between being overweight or obese and developing rheumatoid arthritis (RA) in two large prospective cohorts, the Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII).We followed 109 896 women enrolled in NHS and 108 727 in NHSII who provided lifestyle, environmental exposure and anthropometric information through biennial questionnaires. We assessed the association between time-varying and cumulative Body Mass Index (BMI) in WHO categories of normal, overweight and obese (18.5-25, 25.0-30, ≥30.0 kg/m(2)) and incident RA meeting the 1987 American College of Rheumatology (ACR) criteria. We estimated HRs for overall RA and serologic subtypes with Cox regression models adjusted for potential confounders. We repeated analyses restricted to RA diagnosed at age 55 years or younger.During 2 765 195 person-years of follow-up (1976-2008) in NHS and 1 934 518 person-years (1989-2009) in NHSII, we validated 1181 incident cases of RA (826 in NHS, 355 in NHSII). There was a trend toward increased risk of all RA among overweight and obese women (HR (95% CI) 1.37 (0.95 to 1.98) and 1.37 (0.91, 2.09), p for trend=0.068). Among RA cases diagnosed at age 55 years or younger, this association appeared stronger (HR 1.45 (1.03 to 2.03) for overweight and 1.65 (1.34 to 2.05) for obese women (p trend0.001)). Ten cumulative years of being obese, conferred a 37% increased risk of RA at younger ages (HR 1.37 (1.11 to 1.69)).Risks of seropositive and seronegative RA were elevated among overweight and obese women, particularly among women diagnosed with RA at earlier ages.

BACKGROUND: Carotenoids may reduce risk of benign breast disease (BBD), an independent risk factor for breast cancer, through antioxidative or antiproliferative mechanisms. Exposure to carotenoids may be most important during adolescence when breast tissue is still developing. We examined adolescent carotenoid intake in relation to BBD in young women. METHODS: In 6593 adolescent girls in the prospective Growing Up Today Study cohort, intakes of α-carotene, β-carotene, β-cryptoxanthin, lutein/zeaxanthin, and lycopene were assessed by using the means from food-frequency questionnaires in 1996, 1997, and 1998. Girls reported biopsy-confirmed BBD on questionnaires in 2005, 2007, and 2010 (n = 122). We conducted logistic regression of energy-adjusted carotenoid intakes in relation to BBD, adjusted for age, family history of breast cancer or BBD, age at menarche, nulliparity, alcohol intake, BMI, and physical activity. RESULTS: Mean (SD) age at baseline was 12.0 (1.6) years. β-Carotene intake was inversely associated with BBD; comparing the highest to lowest quartile, the multivariate-adjusted odds ratio was 0.58 (95% confidence interval: 0.34–1.00; P-trend = .03). α-Carotene and lutein/zeaxanthin were also inversely associated with BBD, but the associations were not statistically significant. CONCLUSIONS: Adolescent carotenoid intake may be associated with lower BBD risk; these findings warrant further study.

Performance of rheumatoid arthritis (RA) classification by the 2010 American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria, compared to the 1987 ACR criteria, has not been assessed in population-based cohorts in which disease identification is by mailed questionnaire. Women followed in the Nurses’ Health Study and Nurses’ Health Study II cohorts self-reported new doctor-diagnosed RA on biennial questionnaires. Two RA experts reviewed medical records of 128 new RA self-reports to obtain individual 1987 and 2010 criteria and arrived at a consensus opinion. We compared agreement in classification by the two criteria sets (kappa), and calculated sensitivity and specificity, with reviewers’ opinion as gold standard. Ninety-eight (77 %) participants were classified as RA by reviewers’ consensus opinion; 98 (77 %) fulfilled 1987 criteria, while 79 (63 %) fulfilled 2010 criteria. Seventy-two (56 %) were classified as RA by both sets, 21 (16 %) by neither, 26 (20 %) by only 1987 criteria, and 9 (7 %) by only 2010 criteria. Kappa for concordance was 0.36 (95 % CI 0.20–0.53). Compared to reviewer’s opinion, sensitivity and specificity were 0.93 and 0.77 for 1987 criteria, and 0.79 and 0.87 for 2010 criteria. Participants fulfilling 1987 criteria only were more likely to be seronegative. In these prospective population-based cohorts, significant discordance between 1987 ACR and 2010 ACR/EULAR criteria for classifying RA exists. Using the 2010 ACR/EULAR criteria alone had decreased sensitivity, and seronegative RA cases would be excluded in particular. Combined use of both will be necessary to maximize inclusion and allow sensitivity analyses.

ObjectivesTo evaluate the association between long-term dietary quality, measured by the 2010 Alternative Healthy Eating Index, and risk of rheumatoid arthritis (RA) in women.MethodsWe prospectively followed 76 597 women in the Nurses' Health Study aged 30–55 years and 93 392 women in the Nurses' Health Study II aged 25–42 years at baseline and free from RA or other connective tissue diseases. The lifestyle, environmental exposure and anthropometric information were collected at baseline and updated biennially. Cumulative follow-up rates were more than 90% for both cohorts. The primary outcome was RA alone with two subtypes of the disease: seropositive and seronegative RA.ResultsDuring 3 678 104 person-years, 1007 RA cases were confirmed. In the multivariable-adjusted model, long-term adherence to healthy eating patterns was marginally associated with reduced RA risk. To assess potential effect modification by age at diagnosis, we stratified by age. Among women aged ≤55 years, better quality diet was associated with lower RA risk (HRQ4 vs Q1: 0.67; 95% CI 0.51 to 0.88; p trend: 0.002), but no significant association was found for women aged >55 years (p interaction: 0.005). When stratifying by serostatus, the inverse association among those aged ≤55 years was strongest for seropositive RA (HRQ4 vs Q1: 0.60; 95% CI 0.42 to 0.86; p trend: 0.003).ConclusionsA healthier diet was associated with a reduced risk of RA occurring at 55 years of age or younger, particularly seropositive RA.

Objective To investigate whether menopausal factors are associated with the development of serologic rheumatoid arthritis (RA) phenotypes. Methods Data were analyzed from the Nurses’ Health Studies (NHS; 1976–2010 and NHSII 1989–2011). A total of 120,700 female nurses ages 30–55 years in the NHS, and a total of 116,430 female nurses ages 25–42 years in the NHSII, were followed via biennial questionnaires on lifestyle and disease outcomes. In total, 1,096 incident RA cases were confirmed by questionnaire and chart review. Seropositive RA was defined as rheumatoid factor positive (RF) or antibodies to citrullinated protein antigen (ACPA) positive, and seronegative RA was defined as RF negative and ACPA negative. We used Cox proportional hazards models to obtain multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) of seropositive/seronegative RA associated with menopausal status, age at menopause, type of menopause, ovulatory years, and postmenopausal hormone therapy (PMH) use. Results Postmenopausal women had a 2-fold increased risk of seronegative RA, compared with premenopausal women (NHS: HR 1.8 [95% CI 1.1–3.0], NHSII: HR 2.4 [95% CI 1.4–3.9], and pooled HR 2.1 [95% CI 1.4–3.0]). Natural menopause at early age (≤44 years) was associated with an increased risk of seronegative RA (pooled HR 2.4 [95% CI 1.5–4.0]). None of the menopausal factors was significantly associated with seropositive RA. We observed no association between PMH use and the risk of seronegative or seropositive RA, except that PMH use of ≥8 years was associated with increased risk of seropositive RA (pooled HR 1.4 [95% CI 1.1–1.9]). Conclusion Postmenopause and natural menopause at an early age were strongly associated with seronegative RA, but only marginally with seropositive RA, suggesting potential differences in the etiology of RA subtypes.

summary scores created from normalized data con-trols for these differences, reduces variance andminimizes the chance of finding false-positiveresults, as fewer variables are analyzed. 27,28 Summary scores are routinely used to analyzeTQNE data. The 20 raw MVIC values are first con-verted to z-scores based on a population mean andstandard deviation for each muscle group derivedfrom a natural history ALS data bank. Two re-gional megascores are then calculated by averagingthe 10 individual leg z-scores (megaleg) and the 10individual arm z-scores (megaarm). This methodplaces all muscles on a ‘‘common yardstick,’’ thusallowing each muscle, regardless of size, to contrib-ute equally to the megascore. Disease progressioncan then be expressed as the slope of the mega-score over time (megaslope). 29 Unfortunately, megascore values are expressedas z-scores and, thus, clinical interpretation is diffi-cult. In addition, megaslope analysis can be mis-leading, because the slopes are often very small frac-tions. Therefore, clinically insignificant changes canresult in a several-fold change in slope (e.g., the dif-ference between a megaslope of 0.001 and a meg-aslope of 0.0001 is not clinically detectable,although, statistically, the difference is tenfold).An improved method for summarizing TQNEdata is to convert raw MVIC values to percent of pre-dicted normal (PPN).

Background: Previous studies convincingly showed an increase in risk of breast cancer associated with current or recent use of oral contraceptives from the 1960s to 1980s. The relation of contemporary oral contraceptive formulations to breast cancer risk is less clear. Methods: We assessed lifetime oral contraceptive use and the specific formulations used among 116,608 female nurses ages 25 to 42 years at enrollment in 1989, and subsequently updated this information every 2 years. We related this information to risk of breast cancer up to June 1, 2001. Results: During 1,246,967 person-years of follow-up, 1,344 cases of invasive breast cancer were diagnosed. Past use of any oral contraceptive was not related to breast cancer risk [multivariate relative risk (RR), 1.12; 95% confidence interval 0.95-1.33]. Current use of any oral contraceptive was related to a marginally significant higher risk (multivariate RR, 1.33; 95% CI, 1.03-1.73). One specific formulation substantially accounted for the excess risk: the RR for current use of triphasic preparations with levonorgestrel as the progestin was 3.05 (95% CI, 2.00-4.66; P < 0.0001). Conclusions: Current use of oral contraceptives carries an excess risk of breast cancer. Levonorgestrel used in triphasic preparations may account for much of this elevation in risk. Impact: Different oral contraceptive formulations might convey different risks of breast cancer; ongoing monitoring of these associations is necessary as oral contraceptive formulations change. Cancer Epidemiol Biomarkers Prev; 19(10); 2496–502. ©2010 AACR.

background: Endometriosis is a prevalent but enigmatic gynecologic disorder for which few modifiable risk factors have been identified. Fish oil consumption has been associated with symptom improvement in studies of women with primary dysmenorrhea and with decreased endometriosis risk in autotransplantation animal studies. methods: To investigate the relation between dietary fat intake and the risk of endometriosis, we analyzed 12 years of prospective data from the Nurses’ Health Study II that began in 1989. Dietary fat was assessed via food frequency questionnaire in 1991, 1995 and 1999. We used Cox proportional hazards models adjusted for total energy intake, parity, race and body mass index at age 18, and assessed cumulatively averaged fat intake across the three diet questionnaires. results: During the 586 153 person-years of follow-up, 1199 cases of laparoscopically confirmed endometriosis were reported. Although total fat consumption was not associated with endometriosis risk, those women in the highest fifth of long-chain omega-3 fatty acid consumption were 22% less likely to be diagnosed with endometriosis compared with those with the lowest fifth of intake [95% confidence interval (CI) ¼ 0.62– 0.99; P-value, test for linear trend (Pt) ¼ 0.03]. In addition, those in the highest quintile of trans-unsaturated fat intake were 48% more likely to be diagnosed with endometriosis (95% CI ¼ 1.17–1.88; Pt ¼ 0.001). conclusion: These data suggest that specific types of dietary fat are associated with the incidence of laparoscopically confirmed endometriosis, and that these relations may indicate modifiable risk. This evidence additionally provides another disease association that supports efforts to remove trans fat from hydrogenated oils from the food supply.

BACKGROUND Studies of the association between physical activity (PA) and weight maintenance have been inconsistent. METHODS We prospectively examined the association between PA patterns and prevention of weight gain among 46,754 healthy premenopausal women, aged 25–43 years in 1989. Participants reported their PA and weight in 1989 and 1997. The primary outcome was gaining >5% of baseline weight by 1997 (62% of the population). RESULTS Compared with women who maintained

The aim of the present study was to examine the associations between circulating carotenoids and future risk of rheumatoid arthritis (RA).We conducted a nested case-control study consisting of 227 incident RA cases and 671 matched controls with prospectively measured plasma carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene and lutein/zeaxanthin) levels in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). Each incident RA case was matched with 3 healthy controls. Serologic phenotype of RA was determined by rheumatoid factor or anti-citrullinated peptide antibody (ACPA) obtained by chart review. Multivariable logistic regressions were used to estimate odds ratios (OR) and 95% confident intervals (95% CI) for RA risk associated with each circulating carotenoid after adjusting for matching factors and other covariates.The median time from blood draw until RA diagnosis was 8.6 years. In the multivariable models, no significant associations were found between any plasma carotenoids and risk of RA. We further examined the associations for two subtypes of RA, and found associations of circulating α-carotene and β-carotene with reduced risk of seronegative RA. After correction for multiple comparisons using the Bonferroni method, the findings did not reach statistical significance.Circulating carotenoids levels are not associated with reduced risk of RA. Further investigations using large prospective cohorts are needed to confirm our findings.

BACKGROUND AND OBJECTIVE: Subjective social status (SSS), a person’s sense of their (or for youth, their family’s) position in the socioeconomic hierarchy, is strongly related to health in adults but not health in adolescence. Understanding this developmental discrepancy requires first understanding the developmental trajectory of SSS. The objective of this study was to identify the number and shape of SSS trajectories as adolescents transition to adulthood and explore if trajectory membership affects health. METHODS: Using data from 7436 assessments from the Princeton School District Study, a decade-long cohort study of non-Hispanic black and white youth, latent class growth models with 3 to 7 SSS trajectories were developed. Model fit, trajectory structure, and shape were used to guide optimal model selection. Using this optimal model, the associations of trajectory membership with BMI and depressive symptoms in young adulthood were explored. RESULTS: The 5-class model was optimal. In this model, trajectories were persistent high (7.8%), mid–high (32.2%), middle (43.4%), low–lower (7.4%), and high–low (9.1%). Non-Hispanic black race/ethnicity, lower household income, and low parent education were associated with membership in this high–low trajectory. High–low trajectory membership was associated with higher BMI and depressive symptoms in non-Hispanic white subjects but was not associated with depressive symptoms. It was associated with lower BMI only after adjustment for BMI in adolescence in non-Hispanic black subjects. CONCLUSIONS: SSS is relatively stable in adolescence and the transition to adulthood, and it generally reflects objective markers of social advantage. However, socially disadvantaged youth with high SSS in early adolescence may be at increased health risk.

Objectives The aetiologies of endometriosis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are all characterised by immune dysfunction. SLE and RA occur more often in women, and reproductive and hormonal factors have been shown to be related to increased risk. However, only one previous study has evaluated the temporal association between endometriosis and SLE or RA. We sought to investigate the association between laparoscopically confirmed endometriosis and subsequently diagnosed SLE and RA. Methods We analysed data from the Nurses’ Health Study II (n=114 453 women) over a 22-year follow-up period. Multivariable, time-varying Cox proportional hazards models were used to calculate HRs and 95% CIs for the association between laparoscopically confirmed endometriosis and confirmed incident SLE or RA. Results From 1989 to 2011, 103 incident cases of SLE and 390 cases of RA were confirmed. Laparoscopically confirmed endometriosis was significantly associated with subsequent SLE diagnosis (HR=2.03; CI 1.17 to 3.51) and RA diagnosis (HR=1.41; CI 1.05 to 1.89). These associations were robust to adjustment for SLE or RA risk factors and for potential confounders; however, adjustment for hysterectomy and oophorectomy attenuated both relations such that they were no longer significant. No significant differences by infertility status or age ( Conclusions Our findings suggest an association between endometriosis and risk of SLE and RA. It remains to be understood whether and how endometriosis itself, or hysterectomy or other factors associated with endometriosis, is related to risk of SLE or RA.

Objective To investigate a previously hypothesized relation between natural hair color and endometriosis. Design Prospective cohort study. Setting Nurses' Health Study II with 10 years of follow-up. Participant(s) A total of 90,065 women, 25–42 years old, who had never been diagnosed with endometriosis, infertility, or cancer at baseline in 1989. Main Outcome Measure(s) Incidence of laparoscopically confirmed endometriosis according to natural hair color. Result(s) During 379,422 person-years of follow-up, 1,130 cases of laparoscopically confirmed endometriosis were reported among women with no past infertility. After adjusting for age, calendar time, parity, race, and body mass index at age 18, we observed no association overall. However, compared with women with any other hair color, we observed an increased rate of endometriosis among women with naturally red hair who had never been infertile (incidence rate=1.3, 95% confidence interval [CI] = 1.0–1.7), but a decreased rate among women with naturally red hair among women who were infertile (incidence rate=0.4, 95% CI=0.2–1.2); P value, test for heterogeneity=.03. Conclusion(s) Overall, we did not observe a significant relation between red hair color and the rate of endometriosis, however this prospective cohort study suggests that the relation may differ by infertility status.

To clarify the temporal complexities of the relation between reproductive factors and endometriosis.We analyzed 10 years of prospective data from the Nurses' Health Study II cohort. Information was obtained through questionnaires sent every 2 years to 116,678 women aged 25-42 years when enrolled in 1989. Cox proportional hazards models were used to adjust for age, calendar time, and confounding variables.During 726,205 woman-years of follow-up, 1,721 cases of laparoscopically confirmed endometriosis were reported among women with no past infertility. Greater incidence was observed among women with an earlier age at menarche (rate ratio of 1.3 comparing menarche at age10 to age 12 years; 95% confidence interval [CI] 1.0-1.8; P value, test for trend.001) and shorter cycle length during late adolescence (rate ratio of 1.3 comparing26 days to 26-31 days; 95% CI 1.1-1.5). Time to cycle regularity was not associated with risk. Among parous women, a linear decrease in risk was observed with number of liveborn children (rate ratio of 0.5 comparing3 with 2 children; 95% CI 0.4-0.7; P value, test for trend.001) and lifetime duration of lactation if time since last birth was less than 5 years (rate ratio of 0.2 comparing23 months with never; 95% CI 0.1-0.4; P value, test for trend.001).Hormonal and anatomical changes associated with menstruation and pregnancy may affect the rate of laparoscopically confirmed endometriosis. Within this cohort, risk was greatest among nulliparous women with earlier age at menarche and shorter menstrual cycles. Among parous women, parity and lifetime duration of lactation were associated with decreased risk.

To examine associations between sexual orientation and breast cancer risk factors, cardiovascular disease (CVD) risk factors, mental health status, and health-related functioning.We compared participants in the Nurses' Health Study II (NHSII) reporting a lesbian or bisexual orientation with those reporting a heterosexual orientation, with heterosexuals serving as the reference group for all comparisons. Prevalence of health behaviors and conditions was adjusted for differences in the distribution of age, ancestry, and region of residence by standardizing to the distribution of the overall cohort. Multivariate prevalence ratios were calculated to compare lesbians and bisexuals with heterosexuals using binomial regression with the log link function. Means of health conditions were measured using continuous scales standardized to the distribution of the overall cohort. Differences in means comparing lesbians and bisexuals with heterosexuals were tested by multivariate linear regression. All comparisons were adjusted for age, ancestry, and region of residence.Based on information from 90,823 women aged 32-51 in 1995, those reporting a sexual orientation of lesbian (n = 694) had a higher prevalence of risk factors for breast cancer, including nulliparity and high daily alcohol intake, compared with heterosexual women. Lesbians also had a higher prevalence of several risk factors for CVD, including higher body mass index (BMI) and elevated prevalence of current smoking. Lesbians were more likely to report depression and the use of antidepressants. Key results for health risk factors were similar for lesbians and bisexual women (n = 317).Lesbian and bisexual women were found to have a higher prevalence of several important risk factors for breast cancer, CVD, and poor mental health and functioning outcomes. Most of these risk factors are modifiable, and appropriate interventions could play an important role in improving the health status of lesbian and bisexual women.

Objective. To assess whether dieting to control weight was associated with weight change among children and adolescents.Methods. A prospective study was conducted of 8203 girls and 6769 boys who were 9 to 14 years of age in 1996, were in an ongoing cohort study, and completed at least 2 annual questionnaires between 1996 and 1999. Dieting to control weight, binge eating, and dietary intake were assessed annually from 1996 through 1998 with instruments designed specifically for children and adolescents. The outcome measure was age- and sex-specific z score of body mass index (BMI).Results. In 1996, 25.0% of the girls and 13.8% of the boys were infrequent dieters and 4.5% of the girls and 2.2% of the boys were frequent dieters. Among the girls, the percentage of dieters increased over the following 2 years. Binge eating was more common among the girls, but in both sexes, it was associated with dieting to control weight (girls: infrequent dieters, odds ratio [OR]: 5.10; frequent dieters, OR: 12.4; boys: infrequent dieters, OR: 3.49; frequent dieters, OR: 7.30). During 3 years of follow-up, dieters gained more weight than nondieters. Among the girls, frequency of dieting was positively associated with increases in age- and sex-specific z scores of BMI (β = 0.05 and β = 0.04 for frequent and infrequent dieters vs nondieters). Among the boys, both frequent and infrequent dieters gained 0.07 z scores of BMI more than nondieters. In addition, boys who engaged in binge eating gained significantly more weight than nondieters.Conclusions. Although medically supervised weight control may be beneficial for overweight youths, our data suggest that for many adolescents, dieting to control weight is not only ineffective, it may actually promote weight gain.

Objective. The aim of this study was to examine the relationship between preclinical circulating 25-hydroxyvitamin D [25(OH)D] and RA in two nested case–control studies within the prospective cohort Nurses’ Health Study (NHS) and NHS II (NHSII). Methods. We included 166 women with RA and blood specimens collected 3 months to 16 years prior to the first RA symptom and 490 matched controls (3:1, matched on age, date of blood draw, hormonal factors). We calculated the odds ratio (OR) and 95% CI for incident RA using conditional logistic regression multivariable adjusted models, including additional covariates for smoking status, parity and breastfeeding, alcohol consumption, BMI, median income and region of residence in the USA. We repeated analyses stratified by time from blood draw to RA diagnosis (3 months to

To assess biobank participants' preferences for disclosure of genetic research results.We conducted a cross-sectional survey of participants in the OurGenes, OurHealth, OurCommunity biobank. Respondents were surveyed about preferences for disclosure, importance of disclosure, communication of results with practitioners, and sharing of results after respondents' death. Multivariate regression analysis was used to assess independent sociodemographic and clinical predictors of disclosure preferences. Data collection occurred from June 6, 2011, to June 25, 2012.Among 1154 biobank participants, 555 (48%) responded. Most thought that research result disclosure was important (90%). Preference for disclosure varied, depending on availability of disease treatment (90% vs 64%, P.001), high vs low disease risk (79% vs 66%, P.001), and serious vs mild disease (83% vs 68%, P.001). More than half of respondents (57%) preferred disclosure even when there is uncertainty about the results' meaning, and 87% preferred disclosure if the disease is highly heritable. Older age was positively associated with interest in disclosure, whereas female sex, nonwhite race, diabetes mellitus, and depression and/or anxiety were negatively associated with disclosure. More than half of respondents (52%) would want their results returned to their nearest biological relative after death.OurGenes biobank participants report strong preferences for disclosure of research results, and most would designate a relative to receive results after death. Participant preferences for serious vs mild disease, high vs low disease risk, and availability of disease treatment differed significantly. Future research should consider family members' preferences for receiving research results from enrolled research participants.

The objective of this work was to develop a psychometrically sound questionnaire for measuring the on-the-job impact of chronic health problems and/or treatment ("work limitations").Three pilot studies (focus groups, cognitive interviews, and an alternate forms test) generated candidate items, dimensions, and response scales. Two field trials tested the psychometric performance of the questionnaire (studies 1 and 2). To test recall error, study 1 subjects were randomly assigned to 2 different questionnaire groups, a questionnaire with a 4-week reporting period completed once or a 2-week version completed twice. Responses were compared with data from concurrent work limitation diaries (the gold standard). To test construct validity, we compared questionnaire scores of patients with those of healthy job-matched control subjects. Study 2 was a cross-sectional mail survey testing scale reliability and construct validity.The study subjects were employed individuals (18-64 years of age) from several chronic condition groups (study 1, n = 48; study 2, n = 121) and, in study 1, 17 healthy matched control subjects.Study 1 included the assigned questionnaires and weekly diaries. Study 2 included the new questionnaire, SF-36, and work productivity loss items.In study 1, questionnaire responses were consistent with diary data but were most highly correlated with the most recent week. Patients had significantly higher (worse) limitation scores than control subjects. In study 2, 4 scales from a 25-item questionnaire achieved Cronbach alphas ofor = 0.90 and correlated with health status and self-reported work productivity in the hypothesized manner (Por = 0.05).With 25 items, 4 dimensions (limitations handling time, physical, mental-interpersonal, and output demands), and a 2-week reporting period, the Work Limitations Questionnaire demonstrated high reliability and validity.

To estimate the total prevalence of health-related work limitations among working people in the United States (US) as well as their condition-specific prevalence.A new questionnaire measuring limitations in ability to perform specific work demands was administered to 940 employed people in a national household survey. The prevalence of specific work limitations is reported as are condition-specific risk estimates (odds ratios) based on logistic regression.In the US, 19.3% of working people (CI = 14.0, 24.6) were limited in their abilities to perform physical work demands; 24.1% (CI = 18.9, 29.2) were limited in performing psychosocial work demands; and 13.8% (CI = 8.3, 19.3) were limited in their abilities to function without difficulty within the ambient work environment. With successive increments in the number of conditions, the odds of having a limitation increased significantly.This study contributes new information concerning the implications of chronic health problems for working people and the significant risks for workers with multiple chronic conditions.