Long-term weight changes and risk of rheumatoid arthritis among women in a prospective cohort: a marginal structural model approach.

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-<10 kg: RR = 1.98 (95% CI 1.38, 2.85); 10-<20 kg: RR = 3.28 (95% CI 2.20, 4.89); ≥20 kg: RR = 3.81 (95% CI 2.39, 6.07); and weight loss >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.

Associations between daily alcohol consumption and systemic lupus erythematosus-related cytokines and chemokines among US female nurses without SLE.

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 < 0.0001) for every gram per day increase in cumulative average alcohol consumption. Women who consumed >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.

Association of fish intake and smoking with risk of rheumatoid arthritis and age of onset: a prospective cohort study.

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. < 1 serving/month; p for trend = 0.42), seropositive RA (p for trend = 0.66), or seronegative RA (p for trend = 0.45), but had increased risk for RA diagnosed > 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.

Cigarette smoking and the risk of systemic lupus erythematosus, overall and by anti-double stranded DNA antibody subtype, in the Nurses' Health Study cohorts.

OBJECTIVES: Systemic 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. METHODS: The 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. RESULTS: Among 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. CONCLUSION: Strong 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.

Long-term dietary quality and risk of developing rheumatoid arthritis in women.

OBJECTIVES: To evaluate the association between long-term dietary quality, measured by the 2010 Alternative Healthy Eating Index, and risk of rheumatoid arthritis (RA) in women. METHODS: We 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. RESULTS: During 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). CONCLUSIONS: A healthier diet was associated with a reduced risk of RA occurring at 55 years of age or younger, particularly seropositive RA.

Circulating carotenoids and subsequent risk of rheumatoid arthritis in women.

OBJECTIVES: The aim of the present study was to examine the associations between circulating carotenoids and future risk of rheumatoid arthritis (RA). METHODS: We conducted a nested case-control study consisting of 227 incident RA cases and 671 matched controls with prospectively measured plasma carotenoids (α-carotene, ß-carotene, ß-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. RESULTS: 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 ß-carotene with reduced risk of seronegative RA. After correction for multiple comparisons using the Bonferroni method, the findings did not reach statistical significance. CONCLUSIONS: Circulating carotenoids levels are not associated with reduced risk of RA. Further investigations using large prospective cohorts are needed to confirm our findings.

Endometriosis and the risks of systemic lupus erythematosus and rheumatoid arthritis in the Nurses' Health Study II.

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 (<45 years) were observed. 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.

Adolescent dietary vitamin D and sun exposure in relation to benign breast disease.

PURPOSE: 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. METHODS: 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). RESULTS: 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 (<243 IU/day) quartile of vitamin D intake was 0.76 (95 % CI 0.47, 1.23). CONCLUSIONS: Sun exposure was not significantly associated with BBD in this prospective cohort. However, a suggestive inverse association between dietary vitamin D and BBD was observed that merits further study.

Improved performance of epidemiologic and genetic risk models for rheumatoid arthritis serologic phenotypes using family history.

OBJECTIVE: To develop and validate rheumatoid arthritis (RA) risk models based on family history, epidemiologic factors and known genetic risk factors. METHODS: We developed and validated models for RA based on known RA risk factors, among women in two cohorts: the Nurses' Health Study (NHS, 381 RA cases and 410 controls) and the Epidemiological Investigation of RA (EIRA, 1244 RA cases and 971 controls). Model discrimination was evaluated using the area under the receiver operating characteristic curve (AUC) in logistic regression models for the study population and for those with positive family history. The joint effect of family history with genetics, smoking and body mass index (BMI) was evaluated using logistic regression models to estimate ORs for RA. RESULTS: The complete model including family history, epidemiologic risk factors and genetics demonstrated AUCs of 0.74 for seropositive RA in NHS and 0.77 for anti-citrullinated protein antibody (ACPA)-positive RA in EIRA. Among women with positive family history, discrimination was excellent for complete models for seropositive RA in NHS (AUC 0.82) and ACPA-positive RA in EIRA (AUC 0.83). Positive family history, high genetic susceptibility, smoking and increased BMI had an OR of 21.73 for ACPA-positive RA. CONCLUSIONS: We developed models for seropositive and seronegative RA phenotypes based on family history, epidemiological and genetic factors. Among those with positive family history, models using epidemiologic and genetic factors were highly discriminatory for seropositive and seronegative RA. Assessing epidemiological and genetic factors among those with positive family history may identify individuals suitable for RA prevention strategies.

Being overweight or obese and risk of developing rheumatoid arthritis among women: a prospective cohort study.

OBJECTIVES: 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). METHODS: 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. RESULTS: 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 trend <0.001)). Ten cumulative years of being obese, conferred a 37% increased risk of RA at younger ages (HR 1.37 (1.11 to 1.69)). CONCLUSIONS: Risks of seropositive and seronegative RA were elevated among overweight and obese women, particularly among women diagnosed with RA at earlier ages.

Circulating 25-hydroxyvitamin D level and risk of developing rheumatoid arthritis.

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 <4 years or ≥4 years) and meta-analysed estimates from the two cohorts using fixed effects models. RESULTS: Incident RA was confirmed in 120 NHS [mean age 63.8 years (s.d. 8.2)] and 46 NHSII participants [mean age 48.5 years (s.d. 4.7)]. Mean time from blood draw to RA diagnosis was 7.8 years (s.d. 4.2) for NHS and 4.2 years (s.d. 2.0) for NHSII participants. Meta-analysis of crude and multivariable-adjusted conditional logistic models did not show significant associations between circulating 25(OH)D and RA. However, among NHSII women with blood drawn between 3 months and <4 years prior to RA diagnosis, there was a 20% decreased risk of RA associated with each 1 ng/ml increase in 25(OH)D [OR 0.80 (95% CI 0.64, 0.99)]. CONCLUSION: We did not observe a significant association between circulating 25(OH)D levels and RA, except for among a small subset of NHSII women with levels measured closest to RA diagnosis.

Comparison of the 1987 American College of Rheumatology and the 2010 American College of Rheumatology/European League against Rheumatism criteria for classification of rheumatoid arthritis in the Nurses' Health Study cohorts.

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.

Ultraprocessed Food Intake and Risk of Systemic Lupus Erythematosus Among Women Observed in the Nurses' Health Study Cohorts.

OBJECTIVE: We assessed ultraprocessed food (UPF) intake and systemic lupus erythematosus (SLE) incidence within the prospective Nurses' Health Study (NHS) cohorts. METHODS: A total of 204,175 women were observed (NHS 1984-2016; NHSII 1991-2017). Semiquantitative food frequency questionnaires were completed every two to four years. UPF intake was determined as per the Nova classification. Nurses self-reported new doctor-diagnosed SLE, confirmed by medical records. Time-varying Cox regressions estimated hazard ratios (HRs; 95% confidence intervals [CIs]) for patients with incident SLE and SLE by anti-double-stranded DNA (dsDNA) antibody at diagnosis, according to cumulatively updated daily (a) UPF servings, (b) total intake (in grams and milliliters), and (c) percentage of total intake. Analyses adjusted for age, race, cohort, caloric and alcohol intakes, household income, smoking, body mass index (BMI), physical activity, menarchal age, and oral contraceptive use. We tested for interaction with BMI and examined UPF categories. RESULTS: Mean baseline age was ~50 years (NHS) and ~36 years (NHSII); 93% self-reported White race. A total of 212 patients with incident SLE were identified. SLE risk was higher in the third versus first UPF tertile (servings per day pooled multivariable [MV] HR 1.56, 95% CI 1.04-2.32; P = 0.03). Results were stronger for dsDNA antibody in patients with SLE (servings per day pooled MV HR 2.05, 95% CI 1.15-3.65; P = 0.01) and for absolute (servings or total) than percentage of total intake. Sugar-sweetened/artificially sweetened beverages were associated with SLE risk (third vs first tertile MV HR 1.45, 95% CI 1.01-2.09). No BMI interactions were observed. CONCLUSION: Higher cumulative average daily UPF intake was associated with >50% increased SLE risk and with doubled risk for anti-dsDNA antibody in patients with SLE. Many deleterious effects on systemic inflammation and immunity are postulated.

Dairy-food, calcium, magnesium, and vitamin D intake and endometriosis: a prospective cohort study.

The etiology of endometriosis is poorly understood, and few modifiable risk factors have been identified. Dairy foods and some nutrients can modulate inflammatory and immune factors, which are altered in women with endometriosis. We investigated whether intake of dairy foods, nutrients concentrated in dairy foods, and predicted plasma 25-hydroxyvitamin D (25(OH)D) levels were associated with incident laparoscopically confirmed endometriosis among 70,556 US women in Nurses' Health Study II. Diet was assessed via food frequency questionnaire. A score for predicted 25(OH)D level was calculated for each participant. During 737,712 person-years of follow-up over a 14-year period (1991-2005), 1,385 cases of incident laparoscopically confirmed endometriosis were reported. Intakes of total and low-fat dairy foods were associated with a lower risk of endometriosis. Women consuming more than 3 servings of total dairy foods per day were 18% less likely to be diagnosed with endometriosis than those reporting 2 servings per day (rate ratio = 0.82, 95% confidence interval: 0.71, 0.95; P(trend) = 0.03). In addition, predicted plasma 25(OH)D level was inversely associated with endometriosis. Women in the highest quintile of predicted vitamin D level had a 24% lower risk of endometriosis than women in the lowest quintile (rate ratio = 0.76, 95% confidence interval: 0.60, 0.97; P(trend) = 0.004). Our findings suggest that greater predicted plasma 25(OH)D levels and higher intake of dairy foods are associated with a decreased risk of endometriosis.

Developing normalized strength scores for neuromuscular research.

INTRODUCTION: The Accurate Test of Limb Isometric Strength (ATLIS) device can reliably measure the strength of 12 muscle groups using a fixed load cell. The purpose of this study was to analyze ATLIS data from healthy adults to calculate an individual's predicted strength scores. METHODS: ATLIS data were collected from 432 healthy adults. Linear regression models were developed to predict each muscle group's strength. The R-squared statistic assessed variability accounted for by the models. RESULTS: Simple main effects models stratified by gender were used to establish regression equations for each muscle using factors of age, weight, and height. CONCLUSIONS: Normalizing raw strength scores controls for biometric factors, thus enabling meaningful comparisons between subjects and allowing each muscle to contribute equally to a summary score. Normalized scores are easily interpreted for broad clinical uses, and derived summary scores establish individuals' disease progression rates using a common scale, allowing for more efficient clinical trials.

Association of Sleep Deprivation and the Risk of Developing Systemic Lupus Erythematosus Among Women.

OBJECTIVE: Sleep deprivation has been associated with risk of autoimmune diseases. Using the Nurses' Health Study (NHS) (1986-2016) and NHSII (1989-2017) cohorts, we aimed in the present study to investigate whether sleep deprivation was associated with risk of developing systemic lupus erythematosus (SLE). METHODS: Average sleep duration in a 24-hour period was reported in the NHS (1986-2014) and NHSII (1989-2009). Lifestyle, exposure, and medical information was collected on biennial questionnaires. Adjusted Cox regression analyses modeled associations between cumulative average sleep duration (categorical variables) and incident SLE. Interactions between sleep duration and shiftwork, bodily pain (using the Short Form 36 [SF-36] questionnaire), and depression were examined. RESULTS: We included 186,072 women with 187 incident SLE cases during 4,246,094 person-years of follow-up. Chronic low sleep duration (≤5 hours/night versus reference >7-8 hours) was associated with increased SLE risk (adjusted hazard ratio [HRadj ] 2.47 [95% confidence interval (95% CI) 1.29, 4.75]), which persisted after the analysis was lagged (4 years; HRadj 3.14 [95% CI 1.57, 6.29]) and adjusted for shiftwork, bodily pain, and depression (HRadj 2.13 [95% CI 1.11, 4.10]). We detected additive interactions between low sleep duration and high bodily pain (SF-36 score <75) with an attributable proportion (AP) of 64% (95% CI 40%, 87%) and an HR for SLE of 2.97 (95% CI 1.86, 4.75) for those with both risk factors compared to those with neither. Similarly, there was an interaction between low sleep duration and depression, with an AP of 68% (95% CI 49%, 88%) and an HR for SLE of 2.82 (95% CI 1.64, 4.85). CONCLUSION: Chronic low sleep duration was associated with higher SLE risk, with stronger effects among those with bodily pain and depression, highlighting the potential role of adequate sleep in disease prevention.

Association of Ultraviolet B Radiation and Risk of Systemic Lupus Erythematosus Among Women in the Nurses' Health Studies.

OBJECTIVE: Ultraviolet (UV) radiation 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 US female nurses in 1976; in 1989, 116,429 nurses were enrolled in NHS II. 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 (95% 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 (NHS II), adjusting for confounders. RESULTS: With 6,054,665 person-years of exposure, we identified 297 incident SLE cases; the mean ± SD 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 with 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.

Risk prediction models for incident systemic lupus erythematosus among women in the Nurses' health study cohorts using genetics, family history, and lifestyle and environmental factors.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Association of Healthy Lifestyle Behaviors and the Risk of Developing Rheumatoid Arthritis Among Women.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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 RA risk (hazard ratio [HR] 0.86 [95% confidence interval (95% CI) 0.82-0.90]), seropositive RA risk (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. CONCLUSION: 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.

Determinants of plasma 25-hydroxyvitamin D and development of prediction models in three US cohorts.

Epidemiological and other evidence suggests that vitamin D may be protective against several chronic diseases. Assessing vitamin D status in epidemiological studies, however, is challenging given finite resources and limitations of commonly used approaches. Using multivariable linear regression, we derived predicted 25-hydroxyvitamin D (25(OH)D) scores based on known determinants of circulating 25(OH)D, including age, race, UV-B radiation flux at residence, dietary and supplementary vitamin D intakes, BMI, physical activity, alcohol intake, post-menopausal hormone use (women only) and season of blood draw, in three nationwide cohorts: the Nurses' Health Study, Nurses' Health Study II and the Health Professionals Follow-up Study. The model r 2 for each cohort ranged from 0·25 to 0·33. We validated the prediction models in independent samples of participants from these studies. Mean measured 25(OH)D levels rose with increasing decile of predicted 25(OH)D score, such that the differences in mean measured 25(OH)D between the extreme deciles of predicted 25(OH)D were in the range 8·7-12·3 ng/ml. Substituting predicted 25(OH)D scores for measured 25(OH)D in a previously published case-control analysis of colorectal cancer yielded similar effect estimates with OR of approximately 0·8 for a 10 ng/ml difference in either plasma or predicted 25(OH)D. We conclude that these data provide reasonable evidence that a predicted 25(OH)D score is an acceptable marker for ranking individuals by long-term vitamin D status and may be particularly useful in research settings where biomarkers are not available for the majority of a study population.