American College of Rheumatology White Paper: The Effects of Climate Change on Rheumatic Conditions-An Evolving Landscape and a Path Forward.

OBJECTIVE: Increases in global temperatures and extreme weather events associated with climate change have complex yet poorly understood detrimental impacts on human health. We reviewed the current published literature on climate change-related effects and rheumatic conditions. METHODS: To summarize our current understanding of the likely effects of climate change, including increased air pollution, on rheumatic disease, we searched the published, peer-reviewed English-language literature from January 2000 to December 2022. Articles were reviewed by a team of rheumatologists and clinical and translational science researchers. Systematic review articles were not included but informed additional literature searches. RESULTS: After extensive examination and adjudication, 88 articles met inclusion criteria and were selected for review. Much of the epidemiologic investigations assessed associations between air pollution and increased risk of development of rheumatoid arthritis, anti-citrullinated protein antibodies, flares of gout, and hospitalizations for systemic lupus erythematosus. Increased heat vulnerability was associated with higher odds of recurrent hospitalizations across rheumatic conditions. Mechanisms for observed associations are poorly understood but could include the effects of epigenetic changes, oxidative stress, and inflammatory cytokines. Studies had limitations, including restricted geography and populations studied without focus on historically marginalized communities at highest risk for adverse effects from pollution and climate change, the relative lack of mechanistic evaluations, and most with only indirect links to climate change. CONCLUSION: To date, the published literature lacks studies that directly examine effects of climate change on rheumatic diseases. Collaborative translational and epidemiologic research is needed to enhance our understanding and awareness in this area.

Positive psychosocial factors may protect against perceived stress in people with systemic lupus erythematosus with and without trauma history.

OBJECTIVE: Trauma history is associated with SLE onset and worse patient-reported outcomes; perceived stress is associated with greater SLE disease activity. Stress perceptions vary in response to life events and may be influenced by psychosocial factors. In an SLE cohort, we examined whether stressful events associated with perceived stress, whether psychosocial factors affected perceived stress, and whether these relationships varied by prior trauma exposure. METHODS: This is a cross-sectional analysis of data from the California Lupus Epidemiology Study, an adult SLE cohort. Multivariable linear regression analyses controlling for age, gender, educational attainment, income, SLE damage, comorbid conditions, glucocorticoids ≥7.5 mg/day and depression examined associations of recent stressful events (Life Events Inventory) and positive (resilience, self-efficacy, emotional support) and negative (social isolation) psychosocial factors with perceived stress. Analyses were stratified by lifetime trauma history (Brief Trauma Questionnaire (BTQ)) and by adverse childhood experiences (ACEs) in a subset. RESULTS: Among 242 individuals with SLE, a greater number of recent stressful events was associated with greater perceived stress (beta (95% CI)=0.20 (0.07 to 0.33), p=0.003). Positive psychosocial factor score representing resilience, self-efficacy and emotional support was associated with lower perceived stress when accounting for number of stressful events (-0.67 (-0.94 to -0.40), p<0.0001); social isolation was associated with higher stress (0.20 (0.14 to 0.25), p<0.0001). In analyses stratified by BTQ trauma and ACEs, associations of psychosocial factors and perceived stress were similar between groups. However, the number of recent stressful events was significantly associated with perceived stress only for people with BTQ trauma (0.17 (0.05 to 0.29), p=0.0077) and ACEs (0.37 (0.15 to 0.58), p=0.0011). CONCLUSION: Enhancing positive and lessening negative psychosocial factors may mitigate deleterious perceived stress, which may improve outcomes in SLE, even among individuals with a history of prior trauma who may be more vulnerable to recent stressful events.

Economic insecurities and patient-reported outcomes in patients with systemic lupus erythematosus in the USA: a cross-sectional analysis of data from the California Lupus Epidemiology Study.

BACKGROUND: Social determinants of health are consistently associated with systemic lupus erythematosus (SLE) outcomes. However, social determinants of health are typically measured with conventional socioeconomic status factors such as income or education. We assessed the association of economic insecurities (ie, food, housing, health care, and financial insecurity) with patient-reported outcomes in a cohort of patients with SLE. METHODS: In this cross-sectional analysis, data were derived from the California Lupus Epidemiology Study based in the San Francisco Bay Area, CA, USA. Participants were recruited between Feb 25, 2015, and Jan 10, 2018, from rheumatology clinics. Inclusion criteria were Bay Area residency; oral fluency in English, Spanish, Cantonese, or Mandarin; 18 years or older; ability to provide informed consent; and a physician confirmed SLE diagnosis. Food, housing, health care, and financial economic insecurities were assessed by validated screening tools. Patient-reported outcomes were obtained using PROMIS, Quality of Life in Neurological Disorders (known as Neuro-QoL) Cognitive Function short form, Patient Health Questionnaire (PHQ)-8, and General Anxiety Disorder (GAD)-7 instruments. Poverty was defined as household income of 125% or less of the federal poverty limit. Lower education was defined as less than college-graduate education. The association of economic insecurities with patient-reported outcomes was assessed by multivariable linear regression models adjusting for demographics, SLE disease characteristics, and comorbidities. We tested for interactions of insecurities with poverty and education. FINDINGS: The final cohort included 252 participants. Mean age was 49·7 (SD 13·4) years, 228 (90%) of 252 were women and 24 (10%) were men. 80 (32%) individuals self-identified as Asian, 26 (10%) as Black, 101 (40%) as White, eight (3%) as mixed race, and 37 (15%) as other race; 59 (23%) self-identified as Hispanic. 135 (54%) individuals had at least one insecurity. Insecurities were highly prevalent, and more common in those with poverty and lower education. Adjusted multivariate analyses revealed that participants with any insecurity had significantly worse scores across all measured patient-reported outcomes. For physical function, no insecurity had an adjusted mean score of 48·9 (95% CI 47·5-50·3) and any insecurity had 45·7 (44·3-47·0; p=0·0017). For pain interference, no insecurity was 52·0 (50·5-53·5) and any insecurity was 54·4 (53·0-55·8; p=0·031). For fatigue, no insecurity was 50·5 (48·8-52·3) and any insecurity was 54·9 (53·3-56·5; p=0·0005). For sleep disturbance, no insecurity was 49·9 (48·3-51·6) and any insecurity was 52·9 (51·4-54·5; p=0·012). For cognitive function, no insecurity was 49·3 (47·7-50·9) and any insecurity was 45·6 (44·1-47·0; p=0·0011). For PHQ-8, no insecurity was 4·4 (3·6-5·1) and any insecurity was 6·1 (5·4-6·8; p=0·0013). For GAD-7, no insecurity was 3·3 (2·6-4·1) and any insecurity was 5·2 (4·5-5·9; p=0·0008). Individuals with more insecurities had worse patient-reported outcomes. There were no statistically significant interactions between insecurities and poverty or education. INTERPRETATION: Having any economic insecurity was associated with worse outcomes for people with SLE regardless of poverty or education. The findings of this study provide insight into the relationship between economic insecurities and SLE outcomes and underscore the need to assess whether interventions that directly address these insecurities can reduce health disparities in SLE. FUNDING: US Centers for Disease Control, Rheumatology Research Foundation, and National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Local Ancestry at the Major Histocompatibility Complex Region is Not a Major Contributor to Disease Heterogeneity in a Multiethnic Lupus Cohort.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may shed light on the underlying mechanisms contributing to these disparities, including increased prevalence of lupus nephritis, younger age of symptom onset, and presence of autoantibodies. METHODS: A total of 1,139 European, African American, and Mestizos patients with SLE were genotyped using the Affymetrix LAT1 World array. Global ancestry proportions were estimated using ADMIXTURE, and local ancestry was estimated using RFMIXv2.0. We investigated associations between lupus nephritis, age at onset, and autoantibody status with both global and local ancestry proportions within the Major Histocompatibility Complex region. RESULTS: Our results showed small effect sizes that did not meet the threshold for statistical significance for global or local ancestry proportions in either African American or Mestizo patients with SLE who presented with the clinical manifestations of interest compared with those who did not. CONCLUSION: These findings suggest that local genetic ancestry within the Major Histocompatibility Complex region is not a major contributor to these SLE manifestations among patients with SLE from admixed populations.

Screening of Environmental Chemicals to Characterize Exposures in Participants With Systemic Lupus Erythematosus.

OBJECTIVE: There is a need to characterize exposures associated with the pathogenesis of systemic lupus erythematosus (SLE). In this pilot study, we explore a hypothesis-free approach that can measure thousands of exogenous chemicals in blood ("exposome") in patients with SLE and unaffected controls. METHODS: This cross-sectional study analyzed a cohort of patients with prevalent SLE (n = 285) and controls (n = 106). Plasma was analyzed by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF/MS). Mass spectrometry features present in at least 25% of all samples were selected for association analysis (n = 2,737). Features were matched to potential chemicals using available databases. Association analysis of abundances of features with SLE status was performed, adjusting for age and sex. We also explored features associated with SLE phenotypes, sociodemographic factors, and current medication use. RESULTS: We found 30 features significantly associated with SLE status (Bonferroni P < 0.05). Of these, seven matched chemical names based on databases. These seven features included phthalate metabolites, a formetanate metabolite, and eugenol. The abundance of acid pesticides differed between patients with SLE and controls (Bonferroni P < 0.05). Two unmatched features were associated with a history of lupus nephritis, and one with anti-double-stranded DNA antibody production (Bonferroni P < 0.05). Seventeen features varied by self-reported race and ethnicity, including a polyfluoroalkyl substance (analysis of variance P < 1.69 × 10-5). Eleven features correlated with antimalarials, 6 with mycophenolate mofetil, and 29 with prednisone use. CONCLUSION: This proof-of-concept study demonstrates that LC-QTOF/MS is a powerful tool that agnostically detects circulating exogenous compounds. These analyses can generate hypotheses of disease-related exposures for future prospective, longitudinal studies.

Cell-Specific Transposable Element Gene Expression Analysis Identifies Associations with Systemic Lupus Erythematosus Phenotypes.

There is an established yet unexplained link between interferon (IFN) and systemic lupus erythematosus (SLE). The expression of sequences derived from transposable elements (TEs) may contribute to production of type I IFNs and generation of autoantibodies. We profiled cell-sorted RNA-seq data (CD4+ T cells, CD14+ monocytes, CD19+ B cells, and NK cells) from PBMCs of 120 SLE patients and quantified TE expression identifying 27,135 TEs. We tested for differential TE expression across 10 SLE phenotypes including autoantibody production and disease activity and discovered 731 differentially expressed (DE) TEs whose effects were mostly cell-specific and phenotype-specific. DE TEs were enriched for specific families and viral genes encoded in TE sequences. Increased expression of DE TEs was associated with genes involved in antiviral activity such as LY6E, ISG15, TRIM22 and pathways such as interferon signaling. These findings suggest that expression of TEs contributes to activation of SLE-related mechanisms in a cell-specific manner, which can impact disease diagnostics and therapeutics.

Reframing health disparities in SLE: A critical reassessment of racial and ethnic differences in lupus disease outcomes.

Health disparities in the prevalence and outcomes of systemic lupus erythematosus (SLE) are well documented across racial and ethnic groups. Similar to other chronic diseases, differences in disease severity among individuals with SLE are likely influenced by both genetic predisposition and multiple social determinants of health. However, research in SLE that jointly examines the genetic and environmental contributions to the disease course is limited, resulting in an incomplete understanding of the biologic and social mechanisms that underly health disparities. While research on health disparities can reveal inequalities and inform resource allocation to improve outcomes, research that relies on racial and ethnic categories to describe diverse groups of people can pose challenges. Additionally, results from research comparing outcomes across socially constructed groups without considering other contributing factors can be misleading. We herein comprehensively examine existing literature on health disparities in SLE, including both clinical studies that examine the relationship between self-reported race and ethnicity and disease outcomes and studies that explore the relationships between genomics and lupus outcomes. Having surveyed this body of research, we propose a framework for research examining health disparities in SLE, including ways to mitigate bias in future studies.

Medication Cost Concerns and Disparities in Patient-Reported Outcomes Among a Multiethnic Cohort of Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Concerns about the affordability of medications are common in systemic lupus erythematosus (SLE), but the relationship between medication cost concerns and health outcomes is poorly understood. We assessed the association of self-reported medication cost concerns and patient-reported outcomes (PROs) in a multiethnic SLE cohort. METHODS: The California Lupus Epidemiology Study is a cohort of individuals with physician-confirmed SLE. Medication cost concerns were defined as having difficulties affording SLE medications, skipping doses, delaying refills, requesting lower-cost alternatives, purchasing medications outside the United States, or applying for patient assistance programs. Linear regression and mixed effects models assessed the cross-sectional and longitudinal association of medication cost concerns and PROs, respectively, adjusting for age, sex, race and ethnicity, income, principal insurance, immunomodulatory medications, and organ damage. RESULTS: Of 334 participants, medication cost concerns were reported by 91 (27%). Medication cost concerns were associated with worse Systemic Lupus Activity Questionnaire (SLAQ; beta coefficient [ß] 5.9, 95% CI 4.3-7.6; P < 0.001), 8-item Patient Health Questionnaire depression scale (PHQ-8; ß 2.7, 95% CI 1.4-4.0; P < 0.001), and Patient-Reported Outcomes Measurement Information System (PROMIS; ß for physical function -4.6, 95% CI -6.7 to -2.4; P < 0.001) scores after adjusting for covariates. Medication cost concerns were not associated with significant changes in PROs over 2-year follow-up. CONCLUSION: More than a quarter of participants reported at least 1 medication cost concern, which was associated with worse PROs. Our results reveal a potentially modifiable risk factor for poor outcomes rooted in the unaffordability of SLE care.

Race, Ethnicity, and Disparities in the Risk of End-Organ Lupus Manifestations Following a Systemic Lupus Erythematosus Diagnosis in a Multiethnic Cohort.

OBJECTIVE: Data on the onset of lupus manifestations across multiple organ domains and in diverse populations are limited. The objective was to analyze racial and ethnic differences in the risk of end-organ lupus manifestations following systemic lupus erythematosus (SLE) diagnosis in a multiethnic cohort. METHODS: The California Lupus Epidemiology Study (CLUES) is a longitudinal study of SLE. Data on major end-organ lupus manifestations were collected and categorized by organ system: renal, hematologic, neurologic, cardiovascular, and pulmonary. Multiorgan disease was defined as manifestations in ≥2 of these distinct organ systems. Kaplan-Meier curves assessed end-organ disease-free survival, and Cox proportional hazards regression estimated the rate of end-organ disease following SLE diagnosis, adjusting for age at diagnosis, sex, and self-reported race and ethnicity (White, Hispanic, Black, and Asian). RESULTS: Of 326 participants, 89% were female; the mean age was 45 years. Self-reported race and ethnicity were 30% White, 23% Hispanic, 11% Black, and 36% Asian. Multiorgan disease occurred in 29%. Compared to White participants, Hispanic and Asian participants had higher rates, respectively, of renal (hazard ratio [HR] 2.9 [95% confidence interval (95% CI) 1.8-4.7], HR 2.9 [95% CI 1.9-4.6]); hematologic (HR 2.7 [95% CI 1.3-5.7], HR 2.1 [95% CI 1.0-4.2]); and multiorgan disease (HR 3.3 [95% CI 1.8-5.9], HR 2.5 [95% CI 1.4-4.4]) following SLE diagnosis. CONCLUSION: We found heightened risks of developing renal, hematologic, and multiorgan disease following SLE diagnosis among Hispanic and Asian patients with SLE, as well as a high burden of multiorgan disease among CLUES participants.

Perceived Stress and Prediction of Worse Disease Activity and Symptoms in a Multiracial, Multiethnic Systemic Lupus Erythematosus Cohort.

OBJECTIVE: Studies have suggested a potential link between traumatic experiences, psychological stress, and autoimmunity, but the impact of stress on disease activity and symptom severity in systemic lupus erythematosus (SLE) remains unclear. The present study was undertaken to examine whether increases in perceived stress independently associate with worse SLE disease outcomes over 3 years of follow-up. METHODS: Participants were drawn from the California Lupus Epidemiology Study (CLUES). Stress was measured annually using the 4-item Perceived Stress Scale (PSS). Participants with increases of ≥0.5 SD in PSS score were defined as having an increase in stress. Four outcomes were measured at the year 3 follow-up visit: physician-assessed disease activity (Systemic Lupus Erythematosus Disease Activity Index); patient-reported disease activity (Systemic Lupus Activity Questionnaire); pain (Patient-Reported Outcomes Measurement Information System [PROMIS] pain interference scale); and fatigue (PROMIS fatigue scale). Multivariable linear regression evaluated longitudinal associations of increase in stress with all 4 outcomes while controlling for potential confounders. RESULTS: The sample (n = 260) was 91% female, 36% Asian, 30% White, 22% Hispanic, and 11% African American; the mean ± SD age was 46 ± 14 years. In adjusted longitudinal analyses, increase in stress was independently associated with greater physician-assessed disease activity (P = 0.015), greater self-reported disease activity (P < 0.001), more pain (P = 0.019), and more fatigue (P < 0.001). CONCLUSION: In a racially diverse sample of individuals with SLE, those who experienced an increase in stress had significantly worse disease activity and greater symptom burden at follow-up compared to those with stress levels that remained stable or declined. Findings underscore the need for interventions to bolster stress resilience and support effective coping strategies among individuals living with lupus.

The association of trauma with self-reported flares and disease activity in systemic lupus erythematosus (SLE).

OBJECTIVES: Trauma has been linked to incident SLE, but its relationship with SLE disease activity is unknown. This analysis examines associations between trauma exposures and patient-reported SLE disease activity and flares. METHODS: Data were from the California Lupus Epidemiology Study (CLUES). Flares were self-reported as any flare and, of those, flares accompanied by medical care (hospitalization or physician contact). The Systemic Lupus Activity Questionnaire (SLAQ) assessed disease activity. The Brief Trauma Questionnaire (BTQ) assessed all historical trauma exposures. The Adverse Childhood Experiences (ACEs) questionnaire was available for a subset. Multivariable regression analyses (n = 252) examined whether trauma exposure was associated with flares or SLAQ controlling for age, sex, poverty, race/ethnicity, comorbidities, perceived stress, disease duration and self-reported disease damage. RESULTS: Excluding exposure to serious illness, 63.4% reported ≥1 trauma exposure. Any traumatic event, excluding illness, doubled the odds of a flare [OR 2.27 (95% CI 1.24, 4.17)] and was associated with significantly higher SLAQ scores [ß 2.31 (0.86, 3.76)]. Adjusted odds of any flare and flare with medical care were significantly elevated for those with both BTQ and ACE exposures [5.91 (2.21, 15.82) and 4.69 (1.56, 14.07), respectively]. SLAQ scores were also higher for those with both exposures [ß 5.22 (3.00, 7.44)]. CONCLUSION: In this cohort, those with a history of trauma reported more flares and greater disease activity. Identifying mechanisms of associations between trauma and disease activity and flares, as well as interventions to mitigate the effects of trauma exposures is critical, given the high rates of trauma exposures.

Mer-tyrosine kinase: a novel susceptibility gene for SLE related end-stage renal disease.

OBJECTIVE: Lupus nephritis (LN) is a common and severe manifestation of SLE. The genetic risk for nephritis and progression to end-stage renal disease (ESRD) in patients with LN remains unclear. Herein, we aimed to identify novel genetic associations with LN, focusing on subphenotypes and ESRD. METHODS: We analysed genomic data on 958 patients with SLE (discovery cohort: LN=338) with targeted sequencing data from 1832 immunological pathway genes. We used an independent multiethnic cohort comprising 1226 patients with SLE (LN=603) as a replication dataset. Detailed functional annotation and functional epigenomic enrichment analyses were applied to predict functional effects of the candidate variants. RESULTS: A genetic variant (rs56097910) within the MERTK gene was associated with ESRD in both cohorts, meta-analysis OR=5.4 (2.8 to 10.6); p=1.0×10-6. We observed decreased methylation levels in peripheral blood cells from SLE patients with ESRD, compared with patients without renal SLE (p=2.7×10-4), at one CpG site (cg16333401) in close vicinity to the transcription start site of MERTK and located in a DNAse hypersensitivity region in T and B cells. Rs56097910 is linked to altered MERTK expression in kidney tissue in public eQTL databases. Two loci were replicated for association with proliferative LN: PRDM1 (rs6924535, pmeta=1.6×10-5, OR=0.58) and APOA1BP (NAXE) (rs942960, pmeta=1.2×10-5, OR=2.64). CONCLUSION: We identified a novel genetic risk locus, MERTK, associated with SLE-ESRD using the data from two large SLE cohorts. Through DNA methylation analysis and functional annotation, we showed that the risk could be mediated through regulation of gene expression. Our results suggest that variants in the MERTK gene are important for the risk of developing SLE-ESRD and suggest a role for PRDM1 and APOA1BP in proliferative LN.

Dynamics of Methylation of CpG Sites Associated With Systemic Lupus Erythematosus Subtypes in a Longitudinal Cohort.

OBJECTIVE: Findings from cross-sectional studies have revealed associations between DNA methylation and systemic lupus erythematosus (SLE) outcomes. This study was undertaken to investigate the dynamics of DNA methylation by examining participants from an SLE longitudinal cohort using samples collected at 2 time points. METHODS: A total of 101 participants from the California Lupus Epidemiology Study were included in our analysis. DNA was extracted from blood samples collected at the time of enrolment in the cohort and samples collected after 2 years and was analyzed using Illumina EPIC BeadChip kit. Paired t-tests were used to identify genome-wide changes which included 256 CpG sites previously found to be associated with SLE subtypes. Linear mixed models were developed to understand the relationship between DNA methylation and disease activity, medication use, and sample cell-type proportions, adjusted for age, sex, and genetic principal components. RESULTS: The majority of CpGs that were previously determined to be associated with SLE subtypes remained stable over 2 years (185 CpGs [72.3%]; t-test false discovery rate >0.05). Compared to background genome-wide methylation, there was an enrichment of SLE subtype-associated CpGs that changed over time (27.7% versus 0.34%). Changes in cell-type proportions were associated with changes at 67 CpGs (P < 2.70 × 10-5 ), and 15 CpGs had at least 1 significant association with immunosuppressant use. CONCLUSION: In this longitudinal SLE cohort, we identified a subset of SLE subtype-associated CpGs that remained stable over time and may be useful as biomarkers of disease subtypes. Another subset of SLE subtype-associated CpGs changed at a higher proportion compared to the genome-wide methylome. Additional studies are needed to understand the etiology and impact of these changes on methylation of SLE-associated CpGs.

Single-cell RNA-seq reveals cell type-specific molecular and genetic associations to lupus.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Knowledge of circulating immune cell types and states associated with SLE remains incomplete. We profiled more than 1.2 million peripheral blood mononuclear cells (162 cases, 99 controls) with multiplexed single-cell RNA sequencing (mux-seq). Cases exhibited elevated expression of type 1 interferon-stimulated genes (ISGs) in monocytes, reduction of naïve CD4+ T cells that correlated with monocyte ISG expression, and expansion of repertoire-restricted cytotoxic GZMH+ CD8+ T cells. Cell type-specific expression features predicted case-control status and stratified patients into two molecular subtypes. We integrated dense genotyping data to map cell type-specific cis-expression quantitative trait loci and to link SLE-associated variants to cell type-specific expression. These results demonstrate mux-seq as a systematic approach to characterize cellular composition, identify transcriptional signatures, and annotate genetic variants associated with SLE.

Physical Inactivity and Incident Depression in a Multiracial, Multiethnic Systemic Lupus Erythematosus Cohort.

OBJECTIVE: Physical activity is known to improve depressive symptoms. The present study was undertaken to examine physical inactivity as a predictor of incident depression in systemic lupus erythematosus (SLE). METHODS: Data derive from the California Lupus Epidemiology Study (CLUES), a longitudinal cohort with confirmed SLE diagnoses. Physical inactivity was assessed from a single item, "I rarely or never do any physical activities," and depressive symptoms by the 8-item Patient Health Questionnaire (PHQ-8). Analysis included those not depressed at baseline (PHQ-8 score <10) who completed an in-person baseline assessment and at least 1 follow-up visit (n = 225). Incident depression was defined as a PHQ-8 score of ≥10 at follow-up. Cox proportional hazards regression modeled incident depression over 2 years as a function of baseline physical inactivity, controlling for age, sex, race, income, comorbidities, disease activity, and disease damage. RESULTS: At baseline, the mean ± SD age of the participants was 45 ± 15 years, 88% were female, and 70% identified as non-White. Mean PHQ scores for those without depression at baseline did not differ by activity status, but those who were inactive at baseline were significantly more likely to develop depression over the next 2 years (hazard ratio [HR] 2.89 [95% confidence interval (95% CI) 1.46-5.71]). After adjusting for covariates, the association remained strong, including a >3-fold increased risk of incident depression among the sedentary group (HR 3.88 [95% CI 1.67-9.03]). CONCLUSION: In this diverse SLE cohort, a simple question about physical inactivity was highly predictive of incident depression over the subsequent 2 years. Results suggest an urgent need for approaches to reduce sedentary behavior in this high-risk population.

High Disease Severity Among Asian Patients in a US Multiethnic Cohort of Individuals With Systemic Lupus Erythematosus.

OBJECTIVE: Knowledge about systemic lupus erythematosus (SLE) outcomes among US Asian patients is lacking. The present study was undertaken to examine SLE disease activity, severity, and damage among Asian patients of primarily Chinese and Filipino descent in a multiethnic cohort. METHODS: California Lupus Epidemiology Study (n = 328) data were analyzed. Data were collected in English, Cantonese, Mandarin, or Spanish using validated instruments for disease activity (Systemic Lupus Erythematosus Disease Activity Index), disease severity (Lupus Severity Index [LSI]), and disease damage (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). We assessed differences in SLE outcomes among racial/ethnic groups using multivariable linear regression including interaction terms for age at diagnosis and race/ethnicity. RESULTS: Asian was the largest racial/ethnic group (38% [Chinese = 22%; Filipino = 9%; Other = 7%]). Average age at diagnosis was younger among Asian patients (27.9 years), particularly Filipino patients (22.2 years), compared with White (29.4 years) and Black patients (34.0 years). After adjustment, disease activity and damage were not significantly different across groups. Disease severity among Asian patients was significantly higher than among White patients (LSI score 7.1 versus 6.5; P < 0.05) but similar among Black and Hispanic patients. Early age at diagnosis was associated with greater organ damage among Asian, Black, and Hispanic patients, but not White patients. CONCLUSION: SLE was more severe among US Asian patients compared to White patients. Filipinos were affected at strikingly young ages. Asian patients and non-White groups with younger age at diagnosis had greater organ damage than White patients. Such racial/ethnic distinctions suggest the need for heightened clinical awareness to improve health outcomes among Asian patients with SLE. Further study of SLE outcomes across a range of US Asian subgroups is important.

The Contribution of Genetics and Epigenetics to Our Understanding of Health Disparities in Rheumatic Diseases.

Socioeconomic determinants of health are associated with worse outcomes in the rheumatic diseases and contribute significantly to health disparities. However, genetic and epigenetic risk factors may affect different populations disproportionally and further exacerbate health disparities. We discuss the role of genetics and epigenetics to the health disparities observed in rheumatic diseases. We review concepts of population genetics and natural selection, current genome-wide genetic and epigenetic studies of several autoimmune diseases, and environmental exposures associated with disease risk in different populations. To understand how genomics influence health disparities in the rheumatic diseases, further studies in different populations worldwide are needed.

Transcriptomic analysis of immune cells in a multi-ethnic cohort of systemic lupus erythematosus patients identifies ethnicity- and disease-specific expression signatures.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which outcomes vary among different racial groups. We leverage cell-sorted RNA-seq data (CD14+ monocytes, B cells, CD4+ T cells, and NK cells) from 120 SLE patients (63 Asian and 57 White individuals) and apply a four-tier approach including unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning to identify SLE subgroups within this multiethnic cohort. K-means clustering on each cell-type resulted in three clusters for CD4 and CD14, and two for B and NK cells. To understand the identified clusters, correlation analysis revealed significant positive associations between the clusters and clinical parameters including disease activity as well as ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across cells were involved in SLE or other autoimmune-related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Finally, random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4+ T cells in White individuals. The results from these analyses will help stratify patients based on their gene expression signatures to enable SLE precision medicine.

Concomitant Guillain-Barre syndrome with COVID-19: a case report.

BACKGROUND: During the Coronavirus disease 2019 (COVID-19) pandemic, different neurological manifestations have been observed. However, only a few cases of Guillain-Barre syndrome (GBS) and COVID-19 have been reported. Therefore, the aim of this study is to investigate a case of concomitant GBS with COVID-19 in Colombia. CASE PRESENTATION: A 39-year-old woman was admitted to a teaching hospital in Barranquilla, Colombia with a history of progressive general weakness with lower limb dominance. Previous symptoms such as ageusia, anosmia and intense headache were reported. Upon admission, facial diplegia, quadriparesis with lower extremity predominance and Medical Research Council muscular strength of 2/5 in the lower limbs and 4/5 in the upper limbs were reported. During clinical evolution, due to general areflexia, hypertensive emergency and progressive diaphragmatic weakness, the patient was admitted to an intensive care unit. The cerebrospinal fluid analysis showed protein-cytological dissociation and the GBS diagnosis was confirmed via a nerve conduction and electromyography test. With regard to the symptoms before hospitalisation, SARS-CoV-2 diagnostic testing was performed with positive results in the second test. The patient was managed with supportive care and was discharged after 20 days of hospitalization with clinical improvement. CONCLUSIONS: Only a few cases of COVID-19 with GBS have been reported. Different subtypes have been previously identified, such as Miller-Fisher syndrome and dysautonomic GBS with SARS-CoV-2 infection. This study investigated the first confirmed case of COVID-19 with concomitant GBS in Colombia. In patients with GBS, several viral and bacterial pathogens have been found in case-control studies but the factors that induce the immune-mediated destruction of the nerve tissues have not been determined. Further studies are needed to determine the possible association between COVID-19 exposure and GBS.

Impact of Limited Health Literacy on Patient-Reported Outcomes in Systemic Lupus Erythematosus.

OBJECTIVE: Health disparities in patient-reported outcomes by income and education are well documented; however, the impact of health literacy on patient-reported outcomes has received less attention. We examined independent effects of income, education, and health literacy on patient-reported outcomes in systemic lupus erythematosus (SLE). METHODS: Data from the California Lupus Epidemiology Study (n = 323 participants) were used. Health literacy was assessed with a validated 3-item measure (ability to understand written information, reliance on others to understand written information, confidence in completing written forms). Patient-reported outcomes were administered by interview in English, Spanish, Cantonese, or Mandarin. Generic and disease-specific patient-reported outcomes were examined using the following: 10 Patient-Reported Outcomes Measurement Information System (PROMIS) short forms; the 8 Short Form 36 (SF-36) health survey subscales; and 3 patient-reported SLE disease activity and damage measures. We conducted 2 sets of multivariable analyses: the first examined education, income, or health literacy individually; the second included all 3 simultaneously. All multivariable models included age, sex, race/ethnicity, language, disease duration, and physician-assessed disease activity and damage. RESULTS: More than one-third of participants (38%) had limited health literacy (LHL), including >25% with greater than high school education. In multivariable analyses simultaneously considering education, income, and health literacy, LHL was associated with significantly worse scores on all patient-reported outcomes except disease damage. In contrast, disparities by income were seen in only 3 PROMIS scales, 3 SF-36 subscales, and 1 disease activity measure. No disparities by education level were noted. CONCLUSION: We found significantly worse patient-reported outcome scores among individuals with LHL, even after controlling for disease activity and damage. Whether disparities are due to actual differences in health or measurement issues requires further study.