Childhood and adolescent residential and farm pesticide exposures and inflammatory bowel disease incidence in a U.S. cohort of women.

BACKGROUND AND AIMS: There are few known risk factors for inflammatory bowel disease (IBD), an autoimmune disease characterized by chronic intestinal inflammation. Use of specific pesticides has been associated with higher incidence of IBD among pesticide applicators and their spouses, but no study has examined pesticide exposure in early life, a period where the human immune system undergoes rapid changes. We evaluated pesticide use during childhood and adolescence and incidence of IBD among US women enrolled in the Sister Study. METHODS: Incident IBD diagnoses between enrollment (2003-2009) and 2021 were identified and validated with medication use and colectomy/colostomy surgery. We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for the relationship of childhood/adolescent residential and farm pesticide exposures with IBD incidence using Cox models, accounting for age, race and ethnicity, education, smoking, and birth year. RESULTS: We identified 277 incident IBD cases among 48,382 eligible participants. IBD hazard was elevated among those whose childhood residence was regularly treated with pesticides, especially among those who ever personally applied pesticides (HR = 1.39, 95%CI: 0.65, 2.99). We observed a positive association between IBD and exposure to broadcast pesticide sprays before DDT was banned (>6 times vs. never HR = 1.56, 95%CI: 1.06, 2.31). Among participants who lived on a farm during childhood/adolescence for ≥1 year (N = 9162), IBD hazards were higher among those who were in crop fields during pesticide application (HR = 2.06, 95%CI: 0.94, 4.51) and who ever personally applied pesticides on crops (HR = 1.85, 95%CI: 0.81, 4.18) or livestock (HR = 2.58, 95%CI: 1.14, 5.83). CONCLUSION: Early-life pesticide exposure may be a novel risk factor for IBD. Practices that reduce pesticide exposure during early life may help reduce the burden of this disease.

Early life socioeconomic position contributes to adult obesity independent of adult socioeconomic factors: Findings from the sister study cohort.

Low socioeconomic position (SEP) has been associated with obesity within life stages; however, life course SEP may also alter downstream obesity risk. Research is needed to understand the impact of childhood SEP, independent of adult SEP, as well as SEP trajectories over the life course on adult obesity risk. We use data from the Sister Study, a prospective U.S. cohort of women aged 35-74 years (N = 50,884; enrollment: 2003-2009). Relative risks (RR) for adult obesity associated with childhood SEP (latent variable) and five latent life course SEP profiles were estimated in overall and race and ethnicity-stratified log binomial regression models. We estimated the direct effect of childhood SEP on adult obesity and mediation by adult SEP. Lower childhood SEP was associated with greater obesity risk (RR = 1.16, 95% CI: 1.15-1.17). In stratified models, RRs were elevated across groups though lower for Black and Hispanic/Latina participants, despite greater prevalence of obesity among Black participants. The direct effect of childhood SEP on adult obesity persisted in mediation models independent of adult SEP (RR = 1.10, 95% CI: 1.08-1.12) with adult SEP mediating approximately 40% of the total effect of childhood SEP on adult obesity. Furthermore, adult obesity risk was elevated for all life course SEP profiles compared to persistent high advantage. Life course SEP profiles indicating greater advantage in adulthood than childhood were not associated with reduced adult obesity risk among those experiencing less than high advantage in childhood. In conclusion, lower childhood SEP, independent of adult SEP, may be an important risk factor for adult obesity.

Opportunities, challenges, and future directions for simulation modeling the effects of structural racism on cancer mortality in the United States: a scoping review.

PURPOSE: Structural racism could contribute to racial and ethnic disparities in cancer mortality via its broad effects on housing, economic opportunities, and health care. However, there has been limited focus on incorporating structural racism into simulation models designed to identify practice and policy strategies to support health equity. We reviewed studies evaluating structural racism and cancer mortality disparities to highlight opportunities, challenges, and future directions to capture this broad concept in simulation modeling research. METHODS: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Scoping Review Extension guidelines. Articles published between 2018 and 2023 were searched including terms related to race, ethnicity, cancer-specific and all-cause mortality, and structural racism. We included studies evaluating the effects of structural racism on racial and ethnic disparities in cancer mortality in the United States. RESULTS: A total of 8345 articles were identified, and 183 articles were included. Studies used different measures, data sources, and methods. For example, in 20 studies, racial residential segregation, one component of structural racism, was measured by indices of dissimilarity, concentration at the extremes, redlining, or isolation. Data sources included cancer registries, claims, or institutional data linked to area-level metrics from the US census or historical mortgage data. Segregation was associated with worse survival. Nine studies were location specific, and the segregation measures were developed for Black, Hispanic, and White residents. CONCLUSIONS: A range of measures and data sources are available to capture the effects of structural racism. We provide a set of recommendations for best practices for modelers to consider when incorporating the effects of structural racism into simulation models.

Dietary patterns, socioeconomic disparities, and risk of type 2 diabetes in the Sister Study.

AIMS: We investigated the role of socioeconomic disparities in the association between diet and risk of type 2 diabetes (T2D). METHODS: We used prospective data from 40,243 Sister Study participants aged 35 to 74 years who were enrolled in 2003-2009. Scores for healthy eating indices (alternate Mediterranean diet, Dietary Approaches to Stop Hypertension, alternative Healthy Eating Index, and Healthy Eating Index 2015 (HEI-2015)) were calculated using data from a 110-item food frequency questionnaire completed at enrollment. Incident T2D was defined based on self-reported physician's diagnosis or use of anti-diabetic medications. Multivariable-adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. RESULTS: We observed inverse associations between all four dietary indices and incident T2D after multivariable adjustment. These associations were most pronounced among women with higher educational attainment, higher income, and lower area deprivation index (ADI) (e.g., for the HEI-2015: low ADI, aHRQ4vsQ1: 0.44, 95% CI: 0.35, 0.56 vs high ADI, aHRQ4vsQ1: 0.75, 95% CI: 0.63, 0.90; pinteraction: 0.0007). CONCLUSIONS: Weaker associations among women with lower socioeconomic status and higher neighborhood deprivation suggests that other factors play a larger role in T2D incidence than diet quality among individuals with low SES.

Association between prenatal socioeconomic disadvantage, adverse birth outcomes, and inflammatory response at birth.

Prenatal socioeconomic disadvantage is associated with inflammation in mid- to late-life, yet whether a pro-inflammatory phenotype is present at birth and the role of adverse birth outcomes in this pathway remains unclear. We utilized data on prenatal socioeconomic disadvantage at the individual- (i.e., mother's and father's education level, insurance type, marital status, and Women, Infants, and Children benefit receipt) and census-tract level as well as preterm (< 37 weeks gestation) and small-for-gestational-age (SGA) (i.e., < 10th percentile of sex-specific birth weight for gestational age) birth status, and assessed inflammatory markers (i.e., C-reactive protein, serum amyloid p, haptoglobin, and α-2 macroglobulin) in archived neonatal bloodspots from a Michigan population-based cohort of 1000 neonates. Continuous latent variables measuring individual- and combined individual- and neighborhood-level prenatal socioeconomic disadvantage were constructed and latent profile analysis was used to create a categorical inflammatory response variable (high versus low) based on continuous inflammatory marker levels. Structural equation models were used to estimate the total and direct effect of prenatal socioeconomic disadvantage on the inflammatory response at birth as well as indirect effect via preterm or SGA birth (among term neonates only), adjusting for mother's age, race/ethnicity, body mass index, smoking status, comorbidities, and antibiotic use/infection as well as grandmother's education level. There was a statistically significant total effect of both individual- and combined individual- and neighborhood-level prenatal socioeconomic disadvantage on high inflammatory response among all neonates as well as among term neonates only, and a positive but not statistically significant direct effect in both groups. The indirect effects via preterm and SGA birth were both negative, but not statistically significant. Our findings suggest prenatal socioeconomic disadvantage contributes to elevated neonatal inflammatory response, but via pathways outside of these adverse birth outcomes.

Health Equity Implications of Missing Data Among Youths With Childhood-Onset Systemic Lupus Erythematosus: A Proof-of-Concept Study in the Childhood Arthritis and Rheumatology Research Alliance Registry.

OBJECTIVE: Health disparities in childhood-onset systemic lupus erythematosus (SLE) disproportionately impact marginalized populations. Socioeconomically patterned missing data can magnify existing health inequities by supporting inferences that may misrepresent populations of interest. Our objective was to assess missing data and subsequent health equity implications among participants with childhood-onset SLE enrolled in a large pediatric rheumatology registry. METHODS: We evaluated co-missingness of 12 variables representing demographics, socioeconomic position, and clinical factors (e.g., disease-related indices) using Childhood Arthritis and Rheumatology Research Alliance Registry childhood-onset SLE enrollment data (2015-2022; n = 766). We performed logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) for missing disease-related indices at enrollment (Systemic Lupus Erythematosus Disease Activity Index 2000 [SLEDAI-2K] and/or Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]) associated with data missingness. We used linear regression to assess the association between socioeconomic factors and SLEDAI-2K at enrollment using 3 analytic methods for missing data: complete case analysis, multiple imputation, and nonprobabilistic bias analyses, with missing values imputed to represent extreme low or high disadvantage. RESULTS: On average, participants were missing 6.2% of data, with over 50% of participants missing at least 1 variable. Missing data correlated most closely with variables within data categories (i.e., demographic). Government-assisted health insurance was associated with missing SLEDAI-2K and/or SDI scores compared to private health insurance (OR 2.04 [95% CI 1.22, 3.41]). The different analytic approaches resulted in varying analytic sample sizes and fundamentally conflicting estimated associations. CONCLUSION: Our results support intentional evaluation of missing data to inform effect estimate interpretation and critical assessment of causal statements that might otherwise misrepresent health inequities.

Racial/Ethnic Differences in Associations Between Traumatic Childhood Experiences and Both Metabolic Syndrome Prevalence and Type 2 Diabetes Risk Among a Cohort of U.S. Women.

OBJECTIVE: Childhood adversity has been associated with metabolic syndrome (MetS) and type 2 diabetes risk in adulthood. However, studies have yet to investigate traumatic childhood experiences (TCEs) beyond abuse and neglect (e.g., natural disaster) while considering potential racial/ethnic differences. RESEARCH DESIGN AND METHODS: To investigate race/ethnicity as a potential modifier of the association between TCEs, MetS, and type 2 diabetes, we used prospectively collected data from 42,173 eligible non-Hispanic White (NHW; 88%), Black/African American (BAA; 7%), and Hispanic/Latina (4%) Sister Study participants (aged 35-74 years) enrolled from 2003 to 2009. A modified Brief Betrayal Trauma Survey captured TCEs. At least three prevalent metabolic abnormalities defined MetS, and self-report of a new diagnosis during the study period defined type 2 diabetes. We used adjusted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CIs for type 2 diabetes over a mean ± SD follow-up of 11.1 ± 2.7 years, overall and by race/ethnicity. We also tested for modification and mediation by MetS. RESULTS: Incident cases of type 2 diabetes were reported (n = 2,479 among NHW, 461 among BAA, and 281 among Latina participants). Reporting any TCEs (50% among NHW, 53% among BAA, and 51% among Latina participants) was associated with a 13% higher risk of type 2 diabetes (HR 1.13; 95% CI 1.04-1.22). Associations were strongest among Latina participants (HR 1.64 [95% CI 1.21-2.22] vs. 1.09 for BAA and NHW). MetS was not a modifier but mediated (indirect effect, HR 1.01 [95% CI 1.00-1.01]; P = 0.02) the overall association. CONCLUSIONS: TCE and type 2 diabetes associations varied by race/ethnicity and were partially explained by MetS.

Systemic Lupus Erythematosus Risk: The Role of Environmental Factors.

Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease. The etiology of SLE is multifactorial and includes potential environmental triggers, which may occur sequentially (the "multi-hit" hypothesis). This review focuses on SLE risk potentially associated with environmental factors including infections, the microbiome, diet, respirable exposures (eg, crystalline silica, smoking, air pollution), organic pollutants, heavy metals, and ultraviolet radiation.

Early life trauma and adult leucocyte telomere length.

BACKGROUND: Telomere length, a biomarker of cell division and cellular aging, has been associated with multiple chronic disease endpoints. Experienced trauma over the life course may contribute to telomere shortening via mechanisms of stress embodiment. However, it is unclear how patterns of co-occurring trauma during sensitive periods (e.g., early life) throughout the life course may influence telomere shortening. We examine the relationship between co-occurring early life trauma on adult telomere length and the extent to which adulthood trauma, socioeconomic position, and health and lifestyle factors may mediate this relationship. METHODS: We use data from a sample of participants in the Sister Study (N = 740, analytic sample: n = 602), a prospective cohort of U.S. self-identified females aged 35-74 years at enrollment (2003-2009) for whom leukocyte telomere length was measured in baseline blood samples. Participants reported their experience of 20 different types of trauma, from which we identified patterns of co-occurring early life trauma (before age 18) using latent class analysis. We estimated the direct and indirect effects of early life trauma on leukocyte telomere length using structural equation modeling, allowing for mediating adult pathways. RESULTS: Approximately 47 % of participants reported early life trauma. High early life trauma was associated with shorter telomere length compared to low early life trauma (ß = -0.11; 95 % CI: -0.22, -0.004) after adjusting for age and childhood socioeconomic position. The inverse association between early life trauma and adult leukocyte telomere length was largely attributable to the direct effect of early life trauma on telomere length (ß = -0.12; 95 %CI: -0.23, -0.01). Mediating indirect pathways via adult trauma, socioeconomic position, and health metrics did not substantively contribute the overall association. CONCLUSIONS: These findings highlight the role of patterns of co-occurring early life trauma on shortened telomere length independent of adult pathways.

Prenatal Socioeconomic Disadvantage and Epigenetic Alterations at Birth Among Children Born to White British and Pakistani Mothers in the Born in Bradford Study.

Prenatal socioeconomic disadvantage (SD) has been linked to DNA methylation (DNAm) in adulthood, but whether such epigenetic alterations are present at birth remains unclear. We carried out an epigenome-wide analysis of the association between several measures of individual- and area-level prenatal SD and DNAm assessed in neonatal cord blood via the Infinium EpicBeadChip among offspring born to mothers of White British (N = 455) and Pakistani (N = 493) origin in the Born in Bradford Study. Models were adjusted for mother's age, ethnicity, and education level as well as cell-type fractions and then for maternal health behaviours and neonate characteristics, and last, stratified by mother's ethnicity. P-values were corrected for multiple testing and a permutation-based approach was used to account for small cell sizes. Among all children, housing tenure (owning versus renting) as well as father's occupation (manual versus non-manual) were each associated with DNAm of one CpG site and index of multiple deprivation (IMD) was associated with DNAm of 11 CpG sites. Among children born to White British mothers, father's occupation (student or unemployed versus non-manual) was associated with DNAm of 1 CpG site and IMD with DNAm of 3 CpG sites. Among children born to Pakistani mothers, IMD was associated with DNAm of 1 CpG site. Associations were largely unchanged after further adjustment for maternal health behaviours or neonate characteristics and remained statistically significant. Our findings suggest that individual- and area-level prenatal SD may shape alterations to the neonatal epigenome, but associations vary across ethnic groups.

Latent Class Models of Early-life Trauma and Incident Breast Cancer.

BACKGROUND: Psychosocial trauma has been hypothesized to influence breast cancer risk, but little is known about how co-occurring traumas-particularly during early life-may impact incidence. We examine the relationship between multiple measures of early-life trauma and incident breast cancer. METHODS: The Sister Study is a prospective cohort study of US women (n = 50,884; enrollment 2003-2009; ages 35-74). Of 45,961 eligible participants, 3,070 developed invasive breast cancer or ductal carcinoma in situ through 2017. We assessed trauma before age 18 using previously studied measures (cumulative score, individual trauma type, and substantive domain) and a six-class latent variable to evaluate co-occurring traumas. We accounted for missing data using multiple imputation and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional-hazards models. RESULTS: Approximately 49% of participants reported early-life trauma. Using the latent class variable approach, breast cancer hazard was higher among participants who had sexual trauma or household dysfunction (HR = 1.1; CI = 0.93, 1.3) or moderate (HR = 1.2; CI = 0.99, 1.4) but not high trauma (HR = 0.66; CI = 0.44, 0.99) compared to low trauma. Breast cancer HRs associated with sexual early-life trauma or household dysfunction were elevated for pre- and postmenopausal breast cancer and by estrogen receptor status. We found no effect modification by race-ethnicity. Estimated effects were attenuated with report of constant childhood social support. CONCLUSIONS: Breast cancer incidence varied by latent patterns of co-occurring early-life trauma. Models capturing childhood social support and trauma patterning, rather than cumulative or discrete indicators, may be more meaningful in breast cancer risk assessment.

The role of environmental exposures and gene-environment interactions in the etiology of systemic lupus erythematous.

Systemic lupus erythematosus (SLE) is a complex, chronic autoimmune disease, whose etiology includes both genetic and environmental factors. Individual genetic risk factors likely only account for about one-third of observed heritability among individuals with a family history of SLE. A large portion of the remaining risk may be attributable to environmental exposures and gene-environment interactions. This review focuses on SLE risk associated with environmental factors, ranging from chemical and physical environmental exposures to lifestyle behaviors, with the weight of evidence supporting positive associations between SLE and occupational exposure to crystalline silica, current smoking, and exogenous estrogens (e.g., oral contraceptives and postmenopausal hormones). Other risk factors may include lifestyle behaviors (e.g., dietary intake and sleep) and other exposures (e.g., ultraviolet [UV] radiation, air pollution, solvents, pesticides, vaccines and medications, and infections). Alcohol use may be associated with decreased SLE risk. We also describe the more limited body of knowledge on gene-environment interactions and SLE risk, including IL-10, ESR1, IL-33, ITGAM, and NAT2 and observed interactions with smoking, UV exposure, and alcohol. Understanding genetic and environmental risk factors for SLE, and how they may interact, can help to elucidate SLE pathogenesis and its clinical heterogeneity. Ultimately, this knowledge may facilitate the development of preventive interventions that address modifiable risk factors in susceptible individuals and vulnerable populations.

Disparities in Pediatric Rheumatic Diseases.

Health and health care disparities in pediatric rheumatology are prevalent among socially disadvantaged and marginalized populations based on race/ethnicity, socioeconomic position, and geographic region. These groups are more likely to experience greater disease severity, morbidity, mortality, decreased quality of life, and poor mental health outcomes, which are in part due to persistent structural and institutional barriers, including decreased access to quality health care. Most of the research on health and health care disparities in pediatric rheumatology focuses on juvenile idiopathic arthritis and childhood-onset systemic lupus erythematosus; there are significant gaps in the literature assessing disparities associated with other pediatric rheumatic diseases. Understanding the underlying causes of health care disparities will ultimately inform the development and implementation of innovative policies and interventions on a federal, local, and individual level.

Prioritized Agenda for Mental Health Research in Pediatric Rheumatology from the Childhood Arthritis and Rheumatology Research Alliance Mental Health Workgroup.

OBJECTIVE: Mental health problems are prevalent in youth with rheumatologic disease. Gaps in knowledge exist regarding their effect, as well as strategies for detection and effective treatment. To address these gaps, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Mental Health Workgroup developed and prioritized an agenda of research topics. METHODS: We systematically reviewed the literature and identified 5 major research domains in further need of study: (A) mental health burden and relationship to pediatric rheumatologic disease, (B) effect of mental health disorders on outcomes, (C) mental health awareness and education, (D) mental health screening, and (E) mental health treatment. Research topics within these areas were developed by workgroup leaders and refined by the workgroup. Members were surveyed to prioritize the topics by importance, feasibility of study, and actionability. RESULTS: Fifty-nine members (57%) completed the survey. Among the proposed research topics, 31/33 were rated as highly important and 4/33 were rated highly for importance, feasibility, and actionability. Topics rated most important related to (A) mental health burden and relationship to rheumatologic disease, and (B) the effect of mental health on outcomes. Topics rated most feasible and actionable were related to (D) mental health screening. CONCLUSION: Addressing gaps in knowledge regarding mental health in youth with rheumatologic disease is essential for improving care. We have identified high priority research topics regarding mental health of pediatric rheumatology patients in need of further investigation that are feasible to study and believed to lead to actionable results in patient care.

Measurements of the radiographic cardiac silhouette of ospreys (Pandion haliaetus).

OBJECTIVE: To evaluate and report measurements of the radiographic cardiac silhouette of healthy juvenile and adult ospreys (Pandion haliaetus). ANIMALS: 54 ospreys (22 adults, 19 juveniles, and 13 birds of undetermined age) without clinical signs of cardiac disease and with adequate ventrodorsal radiographic images for cardiac silhouette assessment. PROCEDURES: Radiographs of ospreys were assessed to determine cardiac width at the widest point as well as sternal width and thoracic width at the same level. Two-way mixed-effects models were used to evaluate interrater reliability for mean rating. Multivariable linear regression analysis was used to create predictive models of cardiac width and to establish a theoretical reference range for healthy ospreys. RESULTS: Cardiac width of healthy ospreys was approximately 90% to 92% of sternal width and 67% to 69% of thoracic width. Both sternal width and thoracic width were significant predictors of cardiac width in independent predictive models as well as in a combined model after controlling for age. Thirty-four of 41 (83%) measured cardiac widths were within the theoretical reference range. CONCLUSIONS AND CLINICAL RELEVANCE: Ospreys are sentinels used in monitoring environmental health. Environmental factors may have an impact on the cardiac health of ospreys, but reference values for healthy ospreys have not been established for use in assessing cardiomegaly in this species. The radiographic ratios and predictive model obtained in this study may be useful for objective evaluation of cardiomegaly in ospreys.

Gaps in Mental Health Care for Youth With Rheumatologic Conditions: A Mixed Methods Study of Perspectives From Behavioral Health Providers.

OBJECTIVE: To identify behavioral health provider perspectives on gaps in mental health care for youth with rheumatologic conditions. METHODS: Social workers (n = 34) and psychologists (n = 8) at pediatric rheumatology centers in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) completed an online survey assessing current practices and mental health care needs of youth with rheumatologic conditions. Responses were compared to a published survey of CARRA rheumatologists (n = 119). Thematic analysis of 20 semi-structured interviews with behavioral health providers was performed. RESULTS: One-third of CARRA centers (n = 100) had no affiliated social worker or psychologist. Only 1 behavioral health provider reported current universal mental health screening at their rheumatology clinic, yet routine depression screening was supported by >85% of behavioral health providers and rheumatologists. Support for anxiety screening was higher among behavioral health providers (90% versus 65%; P < 0.01). Interviews illustrated a need for interventions addressing illness-related anxiety, adjustment/coping/distress, transition, parent/caregiver mental health, and peer support. Limited resources, lack of protocols, and patient cost/time burden were the most frequent barriers to intervention. Inadequate follow-up of mental health referrals was indicated by 52% of providers. More behavioral health providers than rheumatologists favored mental health services in rheumatology settings (55% versus 19%; P < 0.01). Only 7 social workers (21%) provided counseling/therapy, and interviews indicated their perceived underutilization of these services. CONCLUSION: Behavioral health providers indicated an unmet need for mental health interventions that address illness-related issues affecting youth with rheumatologic conditions. Implementation of mental health protocols and optimizing utilization of social workers may improve mental health care for these youth.

46-Year Trends in Systemic Lupus Erythematosus Mortality in the United States, 1968 to 2013: A Nationwide Population-Based Study.

BACKGROUND: No large population-based studies have been done on systemic lupus erythematosus (SLE) mortality trends in the United States. OBJECTIVE: To identify secular trends and population characteristics associated with SLE mortality. DESIGN: Population-based study using a national mortality database and census data. SETTING: United States. PARTICIPANTS: All U.S. residents, 1968 through 2013. MEASUREMENTS: Joinpoint trend analysis of annual age-standardized mortality rates (ASMRs) for SLE and non-SLE causes by sex, race/ethnicity, and geographic region; multiple logistic regression analysis to determine independent associations of demographic variables and period with SLE mortality. RESULTS: There were 50 249 SLE deaths and 100 851 288 non-SLE deaths from 1968 through 2013. Over this period, the SLE ASMR decreased less than the non-SLE ASMR, with a 34.6% cumulative increase in the ratio of the former to the latter. The non-SLE ASMR decreased every year starting in 1968, whereas the SLE ASMR decreased between 1968 and 1975, increased between 1975 and 1999, and decreased thereafter. Similar patterns were seen in both sexes, among black persons, and in the South. However, statistically significant increases in the SLE ASMR did not occur among white persons over the 46-year period. Females, black persons, and residents of the South had higher SLE ASMRs and larger cumulative increases in the ratio of the SLE to the non-SLE ASMR (31.4%, 62.5%, and 58.6%, respectively) than males, other racial/ethnic groups, and residents of other regions, respectively. Multiple logistic regression showed independent associations of sex, race, and region with SLE mortality risk and revealed significant racial/ethnic differences in associations of SLE mortality with sex and region. LIMITATIONS: Underreporting of SLE on death certificates may have resulted in underestimates of SLE ASMRs. Accuracy of coding on death certificates is difficult to ascertain. CONCLUSION: Rates of SLE mortality have decreased since 1968 but remain high relative to non-SLE mortality, and significant sex, racial, and regional disparities persist. PRIMARY FUNDING SOURCE: None.

CD3Z hypermethylation is associated with severe clinical manifestations in systemic lupus erythematosus and reduces CD3ζ-chain expression in T cells.

Objective: The importance of hypomethylation in SLE is well recognized; however, the significance of hypermethylation has not been well characterized. We screened hypermethylated marks in SLE and investigated their possible implications. Methods: DNA methylation marks were screened in SLE whole-blood DNA by microarray, and two marks ( CD3Z and VHL hypermethylations) were confirmed by a methylation single-base extension method in two independent ethnic cohorts consisting of 207 SLE patients and 151 controls. The correlation with clinical manifestations and the genetic influence on those epigenetic marks were analysed. Results: Two epigenetic marks, CD3Z and VHL hypermethylation, were significantly correlated with SLE: CD3Z hypermethylation (odds ratio = 7.76; P = 1.71 × 10 -13 ) and VHL hypermethylation (odds ratio = 3.77; P = 3.20 × 10 -8 ), and the increased CD3Z methylation was correlated with downregulation of the CD3ζ-chain in SLE T cells. In addition, less genetic influence on CD3Z methylation relative to VHL methylation was found in analyses of longitudinal and twin samples. Furthermore, a higher CD3Z methylation level was significantly correlated with a higher SLE disease activity index and more severe clinical manifestations, such as proteinuria, haemolytic anaemia and thrombocytopenia, whereas VHL hypermethylation was not. Conclusion: CD3Z hypermethylation is an SLE risk factor that can be modified by environmental factors and is associated with more severe SLE clinical manifestations, which are related to deranged T cell function by downregulating the CD3ζ-chain.

Biological agents in polyarticular juvenile idiopathic arthritis: A meta-analysis of randomized withdrawal trials.

BACKGROUND AND OBJECTIVE: Although various biological agents are in use for polyarticular juvenile idiopathic arthritis (pJIA), head-to-head trials comparing the efficacy and safety among them are lacking. We aimed to compare the efficacy and safety of biological agents in pJIA using all currently available randomized withdrawal trials (wRCTs). METHODS: A systematic search of MEDLINE, EMBASE, CENTRAL, and clinicaltrials.gov was performed. Eligible wRCTs: patients with pJIA where a biological agent was compared with another biological agent or placebo. Efficacy was evaluated using disease flare as a measure. Adverse events (AEs) and serious AEs were evaluated. Network meta-analysis compared biological agents based on a (empirical Bayes) mixed-effects logistic regression model that combines statistical inference from both direct and indirect comparisons of the treatment effects between biological agents. RESULTS: Of 496 references identified, five wRCTs were included-abatacept, adalimumab, anakinra, etanercept, and tocilizumab, one trial each, all vs. placebo. There were no differences in efficacy among biological agents and most showed statistically significant efficacy compared with placebo (nearly all exceptions were in agreement with the original study data). Serious AEs occurred very infrequently (0-8%) and an analysis was not possible. There were no differences for AEs when compared among biological agents or to placebo. CONCLUSION: There were no statistical differences among biological agents for efficacy or safety. Overall, biological agents were effective and safe when compared to placebo. Based on these data, other considerations such as price and availability may need to be used to decide among biological agents when treating pJIA patients.

Agreements and Discrepancies between FDA Reports and Journal Papers on Biologic Agents Approved for Rheumatoid Arthritis: A Meta-Research Project.

BACKGROUND: Sponsors that seek to commercialize new drugs apply to the Food and Drug Administration (FDA) which independently analyzes the raw data and reports the results on its website. OBJECTIVES: This study sought to determine if there are differences between the FDA assessments and journal reports on biologic agents developed for the treatment of rheumatoid arthritis. METHODS: Available data on FDA-approved drugs were extracted from the website, and a systematic literature search was conducted to identify matching studies in peer-reviewed medical journals. Outcome measures were the American College of Rheumatology response criteria ACR20 (efficacy) and withdrawal due to adverse events (safety). As effect size odds ratios were estimated for each active trial arm vs. control arm (i.e. for both sources: FDA and journal report), followed by calculation of the ratios of the FDA and journal report odds ratios. A ratio of odds ratios not equal to 1 was categorized as a discrepancy. RESULTS: FDA reports were available for 8 of 9 FDA-approved biologic agents for rheumatoid arthritis; all identified trials (34) except one were published in peer-reviewed journals. Overall, discrepancies were noted for 20 of the 33 evaluated trials. Differences in the apparent benefit reporting were found in 39% (24/61) pairwise comparisons and in 11 cases these were statistically significant; the FDA report showed greater benefit than the journal publication in 15 comparisons and lesser benefit in 9. Differences in the reported harms were found in 51% (28/55) pairwise comparisons and were statistically significant in 5. The "signal" in FDA reports showed a less harmful effect than the journal publication in 17 comparisons whereas a more harmful effect in 11. The differences were attributed to differences in analytic approach, patient inclusion, rounding effect, and counting discrepancies. However, no differences were categorized as critical. CONCLUSION: There was no empirical evidence to suggest biased estimates between the two sources. Increased and detailed transparency in publications would improve the understanding and credibility of published results. Further, the FDA report was found to be a useful source when data are missing in the published report (i.e. reporting bias).