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Objective Epidemiologic data on systemic lupus erythematosus (SLE) are limited, particularly for racial/ethnic subpopulations in the US. This meta-analysis leveraged data from the Centers for Disease Control and Prevention (CDC) National Lupus Registry network of population-based SLE registries to estimate the overall prevalence of SLE in the US. Methods The CDC National Lupus Registry network includes 4 registries from unique states and a fifth registry from the Indian Health Service. All registries defined cases of SLE according to the American College of Rheumatology (ACR) 1997 revised classification criteria for SLE. Case findings spanned either 2002-2004 or 2007-2009. Given the heterogeneity across sites, a random-effects model was used to calculate the pooled prevalence of SLE. An estimate of the number of SLE cases in the US was generated by applying sex/race-stratified estimates to the 2018 US Census population. Results In total, 5,417 cases were identified as fulfilling the ACR SLE classification criteria. The pooled prevalence of SLE from the 4 state-specific registries was 72.8 per 100,000 person-years (95% confidence interval [95% CI] 65.3-81.0). The prevalence estimate was 9 times higher among females than among males (128.7 versus 14.6 per 100,000), and highest among Black females (230.9 per 100,000), followed by Hispanic females (120.7 per 100,000), White females (84.7 per 100,000), and Asian/Pacific Islander females (84.4 per 100,000). Among males, the prevalence of SLE was highest in Black males (26.7 per 100,000), followed by Hispanic males (18.0 per 100,000), Asian/Pacific Islander males (11.2 per 100,000), and White males (8.9 per 100,000). The American Indian/Alaska Native population had the highest race-specific SLE estimates, both among females (270.6 per 100,000) and among males (53.8 per 100,000). In 2018, an estimated 204,295 individuals (95% CI 160,902-261,725) in the US fulfilled the ACR classification criteria for SLE. Conclusion A coordinated network of population-based SLE registries provides more accurate estimates of the prevalence of SLE and the numbers of individuals affected with SLE in the US in 2018.

ObjectiveHealth-related quality of life (HRQoL) is reduced in systemic lupus erythematosus (SLE), partly driven by comorbid depression. Among patients with SLE, the association between major depression and HRQoL, measured using the NIH's Patient-Reported Outcomes Measurement Information System (PROMIS), is not well characterized. The objective was to determine an association between major depression and HRQoL as measured by PROMIS.MethodsCross-sectional data were obtained from the California Lupus Epidemiology Study, a cohort of adults in the San Francisco Bay Area with SLE. We studied the association between major depression (score ≥10 on the Patient Health Questionnaire 8 depression scale) and T scores (scaled to population mean ± SD of 50 ± 10) on 12 PROMIS domains representing physical, mental, and social health. Mean T scores in depressed and nondepressed individuals were compared using multiple linear regression models adjusting for age, sex, race/ethnicity, disease activity, damage, body mass index, and household income.ResultsMean age of the 326 participants was 45 years; ~89% were women, 29% White, 23% Hispanic, 10% African American, and 36% Asian. One-fourth met the criteria for major depression. In multivariable analyses, major depression was independently associated with worse T scores on all 12 PROMIS domains (P < 0.001); compared with those without major depression, depressed individuals scored >10 points (1 SD) worse on fatigue, sleep impairment, negative psychosocial impact of illness, satisfaction in discretionary social activities, and satisfaction in social roles.ConclusionIn individuals with SLE, major depression is associated with markedly worse PROMIS scores in physical, mental, and social domains. Diagnosing and treating depression may help improve HRQoL in individuals with SLE.

Objective To assess the safety, mechanism of action, and preliminary efficacy of rituximab followed by belimumab in the treatment of refractory lupus nephritis (LN). Methods In a multicenter, randomized, open-label clinical trial, 43 patients with recurrent or refractory LN were treated with rituximab, cyclophosphamide (CYC), and glucocorticoids followed by weekly belimumab infusions until week 48 (RCB group), or treated with rituximab and CYC but no belimumab infusions (RC group). Patients were followed up until week 96. Percentages of total and autoreactive B cell subsets in the patients' peripheral blood were analyzed by flow cytometry. Results Treatment with belimumab did not increase the incidence of adverse events in patients with refractory LN. At week 48, a complete or partial renal response occurred in 11 (52%) of 21 patients receiving belimumab, compared to 9 (41%) of 22 patients in the RC group who did not receive belimumab (P = 0.452). Lack of improvement in or worsening of LN was the major reason for treatment failure. B cell depletion occurred in both groups, but the percentage of B cells remained lower in those receiving belimumab (geometric mean number of B cells at week 60, 53 cells/μl in the RCB group versus 11 cells/μl in the RC group; P = 0.0012). Percentages of total and autoreactive transitional B cells increased from baseline to week 48 in both groups. However, percentages of total and autoreactive naive B cells decreased from baseline to week 48 in the belimumab group compared to the no belimumab RC group (P = 0.0349), a finding that is consistent with the observed impaired maturation of naive B cells and enhanced censoring of autoreactive B cells. Conclusion The addition of belimumab to a treatment regimen with rituximab and CYC was safe in patients with refractory LN. This regimen diminished maturation of transitional to naive B cells during B cell reconstitution, and enhanced the negative selection of autoreactive B cells. Clinical efficacy was not improved with rituximab and CYC in combination with belimumab when compared to a therapeutic strategy of B cell depletion alone in patients with LN.

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.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.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 × 10In 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.

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. INTRODUCTION: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with elevated prevalence in women and individuals of Asian, African, and Hispanic ancestry. Bulk transcriptomic profiling has implicated increased type 1 interferon signaling, dysregulated lymphocyte activation, and failure of apoptotic clearance as hallmarks of disease. Many genes participating in these processes are proximal to the ~100 loci associated with SLE. Despite this progress, a comprehensive census of circulating immune cells in SLE remains incomplete, and annotating the cell types and contexts that mediate genetic associations remains challenging. RATIONALE: Historically, flow cytometry and bulk transcriptomic analyses were used to profile the composition and gene expression of circulating immune cells in SLE. However, flow cytometry is biased by its use of a limited set of known markers, whereas bulk transcriptomic profiling does not have sufficient power to detect cell type–specific expression differences. Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) holds potential as a comprehensive and unbiased approach to simultaneously profile the composition and transcriptional states of circulating immune cells. However, application of scRNA-seq to population cohorts has been limited by sample throughput, cost, and susceptibility to technical variability. To overcome these limitations, we previously developed multiplexed scRNA-seq (mux-seq) to enable systematic and cost-effective scRNA-seq of population cohorts. RESULTS: We used mux-seq to profile more than 1.2 million PBMCs from 162 SLE cases and 99 healthy controls of either Asian or European ancestry. SLE cases exhibited differences in both the composition and state of PBMCs. Analysis of lymphocyte composition revealed a reduction in naïve CD4(+) T cells and an increase in repertoire-restricted GZMH(+) CD8(+) T cells. Analysis of transcriptomic profiles across eight cell types revealed that classical monocytes expressed the highest levels of both pan–cell type and myeloid-specific type 1 interferon-stimulated genes (ISGs). The expression of ISGs in monocytes was inversely correlated with naïve CD4(+) T cell abundance. Cell type–specific expression features accurately predicted case-control status and stratified patients into molecular subtypes. By integrating genotyping data and using a novel matrix decomposition method, we mapped shared and cell type–specific cis–expression quantitative trait loci (cis-eQTLs) across eight cell types. Cell type–specific cis-eQTLs were enriched for regions of open chromatin specific to the same or related cell types. Joint analysis of cis-eQTLs and genome-wide association study results enabled identification of cell types relevant to immune-mediated diseases, fine-mapping of disease-associated loci, and discovery of novel SLE associations. Interaction analysis identified variants whose effects on gene expression are further modified by interferon activation across patients. CONCLUSION: SLE remains challenging to diagnose and treat. The heterogeneity of disease manifestations and treatment response highlight the need for improved molecular characterization. In a large multiethnic cohort, we demonstrate mux-seq as a systematic approach to characterize cellular composition, identify cell type–specific transcriptomic signatures, and annotate genetic variants associated with SLE.

Author(s): Almaani, Salem; Bhatt, Udayan; Arriens, Cristina; Bonfa, Eloisa; Dall'Era, Maria; Houssiau, Frederic; Kalunian, Kenneth; Mackay, Megan; Sanchez-Guerrero, Jorge; Solomons, Neil; Rovin, Brad H

Objective The California Lupus Surveillance Project (CLSP) is a population-based registry of individuals with systemic lupus erythematosus (SLE) residing in San Francisco County, California from 2007 to 2009, with a special focus on Asian/Pacific Islander and Hispanic patients. We used retrospective CLSP data to analyze racial and ethnic differences in lupus manifestations and in the timing and risk of developing severe manifestations. Methods A total of 724 patients with SLE were retrospectively identified. Prevalence ratios (PRs) of SLE manifestations were calculated using Poisson regression models stratified by race/ethnicity and adjusted for sex, age at SLE diagnosis, and disease duration. We studied onset of severe SLE manifestations after SLE diagnosis using Kaplan-Meier methods to examine time-to-event and Cox proportional hazards regression models to estimate hazard ratios (HRs). White patients were the referent group in all analyses. Results African Americans, Asian/Pacific Islanders, and Hispanic patients had increased prevalence of renal manifestations (PR 1.74 [95% confidence interval (95% CI) 1.40-2.16], PR 1.68 [95% CI 1.38-2.05], and PR 1.35 [95% CI 1.05-1.74], respectively). Furthermore, African Americans had increased prevalence of neurologic manifestations (PR 1.49 [95% CI 1.12-1.98]), and both African Americans (PR 1.09 [95% CI 1.04-1.15]) and Asian/Pacific Islanders (PR 1.07 [95% CI 1.01-1.13]) had increased prevalence of hematologic manifestations. African Americans, Asian/Pacific Islanders, and Hispanic patients, respectively, had higher risk of developing lupus nephritis (HR 2.4 [95% CI 1.6-3.8], HR 4.3 [95% CI 2.9-6.4], and HR 2.3 [95% CI 1.4-3.8]) and thrombocytopenia (HR 2.3 [95% CI 1.1-4.4], HR 2.3 [95% CI 1.3-4.2], and HR 2.2 [95% CI 1.1-4.7]). Asian/Pacific Islander and Hispanic patients had higher risk of developing antiphospholipid syndrome (HR 2.5 [95% CI 1.4-4.4] and HR 2.6 [95% CI 1.3-5.1], respectively). Conclusion This is the first epidemiologic study comparing lupus manifestations among 4 major racial and ethnic groups. We found substantial differences in the prevalence of several clinical SLE manifestations among racial/ethnic groups and discovered that African Americans, Asian/Pacific Islanders, and Hispanic patients are at increased risk of developing several severe manifestations following a diagnosis of SLE.

Objective Adverse childhood experiences (ACEs) are associated with poor adult health and immune dysregulation. The impact of ACEs on patients with autoimmune disease is unknown. The present study was undertaken to compare the prevalence of ACEs in patients with systemic lupus erythematosus (SLE) to a population-based survey estimate and to investigate relationships between ACEs and SLE outcomes. Methods Data derived from the California Lupus Epidemiology Study (CLUES), a sample of adult patients with SLE. Participants completed a 10-item ACE questionnaire covering 3 domains (abuse, neglect, household challenges). We estimated ACE prevalence in 269 CLUES participants compared to geographically matched respondents from the 2015 California Behavioral Risk Factor Surveillance System (BRFSS), which was standardized to CLUES participant characteristics (age, sex, race/ethnicity). We examined associations of patient-reported and physician-assessed health status measures with overall ACE levels and domains using multivariable linear regression, controlling for sociodemographics, nephritis, and juvenile-onset SLE. Results Although specific domains varied, overall ACE levels were similar for CLUES and BRFSS respondents. Among SLE patients, 63.2% had ≥1 ACE, and 19.3% had ≥4. ACEs were more prevalent in those who were older, women, Latino or African American, and without college degrees, but not in those with lupus nephritis. In adjusted models, higher ACE levels and ACE domains were associated with worse patient-reported SLE activity, depression, and health status but were not significantly associated with physician-assessed SLE activity, damage, or severity. Conclusion Given the association between ACE levels and important patient-reported outcomes in SLE, our study reinforces the need for prevention of ACEs in childhood and for clinical interventions to promote resilience among adults who have experienced ACEs.

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.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).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.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.

Disease modification has become a well-established concept in several therapeutic areas; however, no widely accepted definition of disease modification exists for SLE.We reviewed established definitions of disease modification in other conditions and identified a meaningful effect on ‘disease manifestations’ (ie, signs, symptoms and patient-reported outcomes) and on ‘disease outcomes’ (eg, long-term remission or progression of damage) as the key principles of disease modification, indicating a positive effect on the natural course of the disease. Based on these findings and the treatment goals and outcome measures for SLE, including lupus nephritis, we suggest a definition of disease modification based on disease activity indices and organ damage outcomes, with the latter as a key anchor. A set of evaluation criteria is also suggested.Establishing a definition of disease modification in SLE will clarify which treatments can be considered disease modifying, provide an opportunity to harmonise future clinical trial outcomes and enable comparison between therapies, all of which could ultimately help to improve patient outcomes. This publication seeks to catalyse further discussion and provide a framework to develop an accepted definition of disease modification in SLE.

Objective Delayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. Methods A total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. Results At biopsy, 54 patients had UPCR Conclusion In this prospective study, three-quarters of patients with UPCR

ObjectiveTo estimate the annual incidence rate of SLE in the USA.MethodsA meta-analysis used sex/race/ethnicity-specific data spanning 2002–2009 from the Centers for Disease Control and Prevention network of four population-based state registries to estimate the incidence rates. SLE was defined as fulfilling the 1997 revised American College of Rheumatology classification criteria. Given heterogeneity across sites, a random effects model was employed. Applying sex/race/ethnicity-stratified rates, including data from the Indian Health Service registry, to the 2018 US Census population generated estimates of newly diagnosed SLE cases.ResultsThe pooled incidence rate per 100 000 person-years was 5.1 (95% CI 4.6 to 5.6), higher in females than in males (8.7 vs 1.2), and highest among black females (15.9), followed by Asian/Pacific Islander (7.6), Hispanic (6.8) and white (5.7) females. Male incidence was highest in black males (2.4), followed by Hispanic (0.9), white (0.8) and Asian/Pacific Islander (0.4) males. The American Indian/Alaska Native population had the second highest race-specific SLE estimates for females (10.4 per 100 000) and highest for males (3.8 per 100 000). In 2018, an estimated 14 263 persons (95% CI 11 563 to 17 735) were newly diagnosed with SLE in the USA.ConclusionsA network of population-based SLE registries provided estimates of SLE incidence rates and numbers diagnosed in the USA.

Lupus nephritis is the most common organ-threatening manifestation of systemic lupus erythematosus. The current standard of care for patients is treatment with a combination of steroids plus either mycophenolate mofetil (MMF) or cyclophosphamide. However, these medications are associated with considerable toxicity and suboptimal efficacy. This retrospective propensity analysis of data from 63 matched patients enrolled in two of the largest active lupus nephritis controlled trials, ALMS and AURA, suggests that the high dose regimen of MMF and steroids as described in the 2012 American College of Rheumatology lupus nephritis guidelines may not be necessary in all lupus nephritis patients. A lower dose regimen may result in better long-term safety, including a reduction in lymphoproliferative disorders, skin cancers and steroid related side effects, without compromising efficacy. An ongoing randomized controlled double-blind phase 3 study, AURORA (NCT03021499), is investigating renal response in 358 patients randomized to receive a low dose regimen containing voclosporin, MMF and steroid therapy as used in the AURA trial. It is anticipated that the AURORA study and its blinded two-year extension will provide important long-term outcome data.

Author(s): Dall'Era, Maria; Pauli, Mariela L; Remedios, Kelly; Taravati, Keyon; Sandova, Priscila M; Putnam, Amy L; Lares, Angela; Haemel, Anna; Tang, Qizhi; Hellerstein, Marc; Fitch, Marc; McNamara, James; Welch, Beverly; Bluestone, Jeffrey A; Wofsy, David; Rosenblum, Michael D; Autoimmunity Centers of Excellence | Abstract: ObjectiveAdoptive Treg cell therapy has great potential to treat autoimmune disease. Currently, very little is known about how these cells impact inflamed tissues. This study was undertaken to elucidate how autologous Treg cell therapy influences tissue inflammation in human autoimmune disease.MethodsWe describe a systemic lupus erythematosus (SLE) patient with active skin disease who received adoptive Treg therapy. We comprehensively quantified Treg cells and immune activation in peripheral blood and skin, with data obtained at multiple time points posttreatment.ResultsDeuterium tracking of infused Treg cells revealed the transient presence of cells in peripheral blood, accompanied by increased percentages of highly activated Treg cells in diseased skin. Flow cytometric analysis and whole transcriptome RNA sequencing revealed that Treg cell accumulation in skin was associated with a marked attenuation of the interferon-γ pathway and a reciprocal augmentation of the interleukin-17 (IL-17) pathway. This phenomenon was more pronounced in skin relative to peripheral blood. To validate these findings, we investigated Treg cell adoptive transfer of skin inflammation in a murine model and found that it also resulted in a pronounced skewing away from Th1 immunity and toward IL-17 production.ConclusionWe report the first case of a patient with SLE treated with autologous adoptive Treg cell therapy. Taken together, our results suggest that this treatment leads to increased activated Treg cells in inflamed skin, with a dynamic shift from Th1 to Th17 responses.

Background and Aims Voclosporin is a novel calcineurin inhibitor with a favorable metabolic profile and a consistent dose-concentration relationship, potentially eliminating the need for therapeutic drug monitoring. We have previously reported the primary endpoint of the Phase 3 AURORA trial showing the addition of voclosporin to mycophenolate mofetil (MMF) and a low-dose glucocorticoid regimen results in significantly higher renal response (RR) rates at one year of treatment compared to MMF and low-dose glucocorticoids alone in patients with lupus nephritis (LN). For the primary endpoint, RR was defined as ≤0.5 mg/mg UPCR with stable renal function in the presence of low-dose glucocorticoids and no use of rescue medication. Several studies have demonstrated that proteinuria represents the best single predictor for long-term renal outcomes.1,2 Given the efficacy of voclosporin in terms of proteinuria reduction, we conducted a sensitivity analysis evaluating RR with additional UPCR targets. Method A total of 179 participants in the voclosporin (23.7 mg BID) arm and 178 participants in the control arm from the AURORA trial were included in this analysis. All participants received MMF (target 1 g BID) and low-dose oral glucocorticoids (initiated at 20-25 mg/day and tapered to 2.5 mg/day at 16 weeks). For this post hoc analysis, the UPCR component of RR was revised to include UPCR targets at 0.2 mg/mg intervals above and below the original ≤0.5 target used for the primary endpoint in AURORA (i.e., ≤0.7 mg/mg or ≤0.3 mg/mg, respectively). Odds ratios for RR at six months and one year of treatment were analyzed using a logistic regression model with terms for treatment, baseline UPCR, biopsy class, and MMF use at baseline and region. Results RR with UPCR ≤0.7 mg/mg was achieved by 46.9% of participants in the voclosporin arm vs 32.0% of participants in the control arm at one year of treatment (OR 2.07, p Conclusion Participants treated with voclosporin in addition to MMF and low-dose glucocorticoids achieved statistically significantly increased renal response rates regardless of the level of UPCR used, including at an even more stringent ≤0.3 mg/mg target. This analysis further supports the efficacy observed with voclosporin in the Phase 3 AURORA and the prior Phase 2 AURA-LV global trials.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with manifestations that vary widely in severity. Although minority populations are at higher risk for SLE and have more severe outcomes (1), population-based estimates of mortality by race and ethnicity are often lacking, particularly for Asian and Hispanic/Latino persons. Among 812 patients in the California Lupus Surveillance Project (CLSP) during 2007-2009 (2,3), who were matched to the 2007-2017 National Death Index (NDI), 16.6% had died by 2017. This proportion included persons of White (14.4%), Black (25%), Asian (15.3%), and Hispanic/Latino (15.5%) race/ethnicity. Standardized mortality ratios (SMRs) of observed-to-expected deaths among persons with SLE within each racial/ethnic group were 2.3, 2.0, 3.8, and 3.9, respectively. These findings provide the first population-based estimates of mortality among Asian and Hispanic/Latino persons with SLE. Coordination of robust care models between primary care providers and rheumatologists could ensure that persons with SLE receive a timely diagnosis and appropriate treatments that might help address SLE-associated mortality.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. The aim of this study is to leverage large-scale transcriptomic data from diverse populations to better sub-classify SLE patients into more clinically actionable 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 analytical approach to identify SLE subgroups within this multiethnic cohort: unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning. K-means clustering on the individual cell type data resulted in three clusters for CD4 and CD14, and two clusters for B cells and NK cells. Correlation analysis revealed significant positive associations between the transcriptomic clusters of each immune cell and clinical parameters including disease activity and ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across the four cell types were involved in SLE or other autoimmune related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Samples were grouped into White-high, Asians-high (high disease activity defined by SLEDAI score >=6) and White-low, Asians-low (SLEDAI < 6). Random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4+ T cells in White. The results from these analyses will help stratify patients based on their gene expression signatures to enable precision medicine for SLE.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. The aim of this study is to leverage large-scale transcriptomic data from diverse populations to better sub-classify SLE patients into more clinically actionable 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 analytical approach to identify SLE subgroups within this multiethnic cohort: unsupervised clustering, differential expression analyses, gene co-expression analyses, and machine learning. K-means clustering on the individual cell type data resulted in three clusters for CD4 and CD14, and two clusters for B cells and NK cells. Correlation analysis revealed significant positive associations between the transcriptomic clusters of each immune cell and clinical parameters including disease activity and ethnicity. We then explored differentially expressed genes between Asian and White groups for each cell-type. The shared differentially expressed genes across the four cell types were involved in SLE or other autoimmune related pathways. Co-expression analysis identified similarly regulated genes across samples and grouped these genes into modules. Samples were grouped into White-high, Asians-high (high disease activity defined by SLEDAI score >=6) and White-low, Asians-low (SLEDAI < 6). Random forest classification of disease activity in the White and Asian cohorts showed the best classification in CD4+ T cells in White. The results from these analyses will help stratify patients based on their gene expression signatures to enable precision medicine for SLE.

Objective We examined quality measures for screening, diagnosis, and treatment of lupus nephritis (LN) among participants of the California Lupus Epidemiology Study across 25 different clinical sites to identify gaps in quality of care. Methods Data from 250 participants with lupus were analyzed across 3 sources (medical records, physician examination, and patient interviews). Overall performance on 8 quality measures was calculated separately for participants with and without LN. We used generalized estimating equations in which the outcome was performance on measures, adjusting for participant demographics, lupus disease severity, and practice characteristics. Results Of 148 patients without LN, 42% underwent screening laboratory tests for nephritis, 38% underwent lupus activity serum studies, and 81% had their blood pressure checked every 6 months. Of 102 LN patients, 67% had a timely kidney biopsy, at least 81% had appropriate treatment, and 78% achieved target blood pressure within 1 year of diagnosis. Overall performance in participants across quality measures was 54% (no LN) and 80% (LN). Significantly higher overall performance for screening measures for LN was seen at academic (63.4-73%) versus community clinics (37.9-38.4%). Similarly, among those with LN, higher performance in academic (84.1-85.2%) versus community clinics (54.8-60.2%) was observed for treatment measures. Conclusion In this quality-of-care analysis across 25 diverse clinical settings, we found relatively high performance on measures for management of LN. However, future work should focus on bridging the gaps in lupus quality of care for patients without nephritis, particularly in community settings.

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.

Objective. To develop and evaluate a mobile learning module to support knowledge construction between medical and pharmacy students through structured dialogue prompts. Methods. Rheumatologists and pharmacists collaboratively developed a two-week, case-based, asynchronous interprofessional learning module that was delivered via a mobile app and focused on collaborative medication management of a complex case involving a patient with systemic lupus erythematosus. The clinical case evolved over three phases: diagnosis, initial treatment, and medication-related complications. Dialogue prompts were incorporated in each phase as a mechanism to support knowledge construction among learners. Pharmacy and medical student pairs were randomized to receive either high guidance or low guidance prompts for collaborative learning. The student pairs worked together, asynchronously, online, to develop three collaborative care plans. The evaluation of the learning module to support knowledge construction included: analysis of text-based dialogue coded for knowledge construction phases; the accuracy and completeness of the three collaborative care plans; and quantitative and qualitative participant feedback. Results. Sixteen pairs of medical and pharmacy students (n=32) participated. Pairs who received high guidance engaged in all phases of knowledge construction more often than pairs who received low guidance. Guidance phase did not differentially impact collaborative care plan scores. Ninety-eight percent of students agreed or strongly agreed that the module improved their clinical reasoning, interprofessional communication, and knowledge of systemic lupus erythematosus. Conclusion. The knowledge construction framework can guide the design and evaluation of educational interventions such as a mobile learning module to support knowledge construction among health professionals.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author(s): Katz, Patricia; Pedro, Sofia; Alemao, Evo; Yazdany, Jinoos; Dall'Era, Maria; Trupin, Laura; Rush, Stephanie; Michaud, Kaleb | Abstract: OBJECTIVE:Examinations of Patient-Reported Outcomes Measurement Information System (PROMIS) measures in adult systemic lupus erythematosus (SLE) have provided support for their cross-sectional validity in SLE. We estimated responsiveness to change, meaningful changes (minimally important differences [MIDs]), and the patient acceptable symptom state (PASS) for five PROMIS short forms to facilitate longitudinal use and interpretation of PROMIS scales in SLE. METHODS:Data from five administrations of PROMIS short forms in the FORWARD SLE cohorts were used. Pearson correlation coefficients were used to assess associations between changes in PROMIS measures and changes in anchor measures for responsiveness analyses. Worse, same, or better groups were defined for each anchor. Differences in PROMIS scores were calculated for each consecutive PROMIS administration; mean changes in PROMIS scores of individuals in the worse, same, and better groups were calculated. Both anchor-based and distribution-based methods were used to estimate MIDs. PASS was defined as the 75th-percentile positive score among those who considered their health to be acceptable or who were somewhat or very satisfied with their health. RESULTS:All PROMIS short forms showed adequate responsiveness to changes in related patient-reported outcomes. However, only the fatigue and pain interference scales were responsive to self-reported SLE activity. Taking into account all methods, we estimated MIDs for each scale to be approximately two points. All PASS values were better than the population mean T-score of 50. CONCLUSION:These results support use and further study of PROMIS short forms in SLE and should facilitate interpretation of PROMIS scores and changes.

Objective We examined psychometric performance of Patient-Reported Outcomes Measurement Information System (PROMIS) measures in a racially/ethnically and linguistically diverse cohort with systemic lupus erythematosus (SLE). Methods Data were from the California Lupus Epidemiology Study, a multiracial/multiethnic cohort of individuals with physician-confirmed SLE. The majority (n = 332) attended in-person research visits that included interviews conducted in English, Spanish, Cantonese, or Mandarin. Up to 12 PROMIS short forms were administered (depending on language availability). An additional 99 individuals completed the interview by phone only. Internal consistency was examined with Cronbach's alpha and item-total correlations. Correlations with the Short Form 36 subscales and both self-reported and physician-assessed disease activity assessed convergent validity. All analyses were repeated within each racial/ethnic group. Differences in scores by race/ethnicity were examined in bivariate analyses and by multiple regression analyses controlling for age, sex, disease duration, and disease damage and activity. Results The total sample was 30.0% white, 22.3% Hispanic, 10.9% African American, 33.7% Asian, and 3.0% other race/ethnicity. Seventy-seven percent of interviews were conducted in-person. Non-English interviews were conducted in 26.0% of the Hispanic subjects and 18.6% of the Asian subjects. Each scale demonstrated adequate reliability and validity overall and within racial/ethnic groups. Minimal floor effects were observed, but ceiling effects were noted. Missing item responses were minimal for most scales, except for items related to work. No differences were noted by mode of administration or by language of administration among Hispanics and Asians. After accounting for differences in disease status, age, and sex, few differences in mean scores between whites and other racial/ethnic groups were noted. Conclusion PROMIS measures appear reliable and valid in persons with lupus across racial/ethnic groups.

Background and objectives Incomplete peripheral blood B cell depletion after rituximab in lupus nephritis might correlate with inability to reduce tubulointerstitial lymphoid aggregates in the kidney, which together could be responsible for inadequate response to treatment. We utilized data from the Lupus Nephritis Assessment with Rituximab (LUNAR) study to characterize the variability of peripheral blood B cell depletion after rituximab and assess its association with complete response in patients with lupus nephritis. Design, setting, participants, & measurements We analyzed 68 participants treated with rituximab. Peripheral blood B cell depletion was defined as 0 cells/µl, termed “complete peripheral depletion,” assessed over 78 weeks. Logistic regression was used to estimate the association between characteristics of complete peripheral depletion and complete response (defined as urine protein-to-creatinine ratio Results A total of 53 (78%) participants achieved complete peripheral depletion (0 cells/µl) in a median time of 182 days (interquartile range, 80–339).The median duration of complete peripheral depletion was 71 days (interquartile range, 14–158). Twenty-five (47%) participants with complete peripheral depletion achieved complete response, compared with two (13%) without. Complete peripheral depletion was associated with complete response (unadjusted odds ratio [OR], 5.8; 95% confidence interval [95% CI], 1.2 to 28; P=0.03). Longer time to achieving complete peripheral depletion was associated with a lower likelihood of complete response (unadjusted OR, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Complete peripheral depletion lasting >71 days (the median) was associated with complete response (unadjusted OR, 4.1; 95% CI, 1.5 to 11; P=0.008). Conclusions There was substantial variability in peripheral blood B cell depletion in patients with lupus nephritis treated with rituximab from the LUNAR trial. Achievement of complete peripheral depletion, as well as the rapidity and duration of complete peripheral depletion, were associated with complete response at week 78. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_09_06_CJASNPodcast_18_10_.mp3

The management of lupus nephritis (LN) and concomitant thrombotic microangiopathy (TMA), with or without antiphospholipid antibodies (aPL), remains controversial, and few studies are available to inform clinical management.1–4 The purpose of this multicentre retrospective study was to analyse the impact of anticoagulation (vitamin K antagonists (VKAs) and/or heparins) in addition to conventional immunosuppression on kidney outcomes (assessed at 12 months, according to the Kidney Disease: Improving Global Outcomes-KDIGOguidelines5) in patients with biopsy-proven LN and concomitant TMA. Data source, population and statistical analysis are detailed in the online supplementary material 1. Anticoagulation was considered if given for at least three consecutive months after TMA diagnosis.### Supplementary data [annrheumdis-2018-214559supp002.docx] We retrospectively identified 97 patients with biopsy-proven LN and TMA (2007–2017). See online supplementary table 1 for clinical and demographic characteristics. Laboratory parameters were collected at the time of the biopsy. The mean age of patients was 38.9±15.2 years (13–69) and 85 females (87.6%). Most had proliferative LN (class …

Lupus nephritis is a potentially fatal autoimmune disease for which the current treatment is ineffective and often toxic. To develop mechanistic hypotheses of disease, we analyzed kidney samples from patients with lupus nephritis and from healthy control subjects using single-cell RNA sequencing. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid cells, T cells, natural killer cells and B cells that demonstrated both pro-inflammatory responses and inflammation-resolving responses. We found evidence of local activation of B cells correlated with an age-associated B-cell signature and evidence of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, implying a potentially central role in cell trafficking. Gene expression of immune cells in urine and kidney was highly correlated, which would suggest that urine might serve as a surrogate for kidney biopsies.

Background Medication decision-making is challenging in lupus. No validated, effective decision-aids are available to assist patients with medication decision-making. Objectives Our objective was to assess the effectiveness of an individualized, culturally-tailored, computerized decision-aid for immunosuppressive medications for lupus nephritis. Methods In a multicenter, randomized controlled trial, diverse adult women with lupus nephritis, largely racial/ethnic minorities with low socio-economic status, were randomized to decision-aid vs. American College of Rheumatology lupus pamphlet (1:1 ratio). Co-primary outcomes were change in decisional conflict and informed choice regarding immunosuppressive medications. Results Of 301 randomized women, 47% were African-American, 26% were Hispanic, and 15% White. Mean age (standard deviation [SD]) was 37 (12) years, 57% had annual income of Conclusion An individualized decision-aid was effective in reducing decisional conflict for immunosuppressive medications in diverse women with lupus nephritis. Disclosure of Interests jasvinder singh Shareholder of: Amarin pharmaceuticals and Viking therapeutics, Consultant for: Crealta/Horizon, Fidia, UBM LLC, Medscape, WebMD, the National Institutes of Health and the American College of Rheumatology, Liana Fraenkel: None declared, Candace Green: None declared, Graciela S Alarcon: None declared, Jennifer Barton: None declared, Kenneth Saag Grant/research support from: Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda, Consultant for: Abbvie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin, Leslie Hanrahan: None declared, Sandra Raymond: None declared, Robert Kimberly: None declared, Amye Leong: None declared, Elyse Reyes: None declared, Richard Street: None declared, Maria Suarez-Almazor : None declared, Guy Eakin: None declared, Laura Marrow: None declared, Charity Morgan: None declared, Brennda Caro: None declared, Jeffrey Sloan: None declared, Bochra Jandali: None declared, Salvador Garcia: None declared, Jennifer Grossman: None declared, Kevin Winthrop Consultant for: Gilead, Galapagos, Eli Lilly and Company, Abbvie, Pfizer, GSK, Laura Trupin: None declared, Maria Dall’Era Grant/research support from: University has received funds to serve as a site on this clinical study, Consultant for: On Data Monitoring Committee for Janssen, Biogen, and Genentech; on Steering Committee for EMD Serono., Alexa Meara: None declared, Tara Rizvi: None declared, Winn Chatham: None declared, Jinoos Yazdany Grant/research support from: Pfizer, Consultant for: AstraZeneca

Background Nonspecific proteasome inhibitors, e.g., bortezomib (BTZ), target both the constitutive and immuno- proteasomes and are standard of care for multiple myeloma. While BTZ has been used to treat refractory systemic lupus erythematosus (SLE) and lupus nephritis (LN), it is associated with adverse events (AEs) that limit its broad use. KZR-616, a first-in-class selective inhibitor of the immunoproteasome, is highly active and well tolerated in murine SLE1. In a Phase (Ph) 1 healthy volunteer (HV) study, KZR-616 subcutaneously (SC) at 30 and 45 mg weekly (QW) was shown to be safe, be well tolerated and achieve the target level of immunoproteasome inhibition2. We report here the preliminary safety and efficacy of KZR-616 in the Ph 1b portion of Study KZR–616–002 in active SLE patients (pts) (NCT03393013). Objectives The 1° objective of this first-in-patient study is to assess the safety and tolerability of KZR–616. The 2° objectives are to evaluate pharmacokinetics (PK) and determine the KZR-616 doses for the Ph 2 portion of the study. Pharmacodynamics (PD) and efficacy are also being assessed. Methods This open-label multicenter dose escalation trial enrolled SLE pts (per Systemic Lupus International Collaborating Clinics Classification Criteria) with SLE Disease Activity Index (SLEDAI) ≥4 despite stable background immunosuppressant, antimalarial, and/or corticosteroid (≤20 mg prednisone equivalent) therapy. Patients received KZR-616 at 45 mg (Cohort 1) or 60 mg (Cohort 2) SC QW through Week 13 (W13) with 12 weeks of follow up. Cohort 2a is currently enrolling pts using intrapatient dose escalation from 30 to 60 mg. Safety data include AEs, vitals, electrocardiograms and laboratory tests. Efficacy measures include the SLEDAI, Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), 28 tender (T) and swollen (S) joint counts (JC), Physician Global Assessment (PhGA), and Patient Global Assessment (PtGA) in evaluable pts (receive ≥1 month of KZR-616; non-evaluable pts can be replaced). Results We enrolled 13 pts: 8 in Cohort 1, 5 in Cohort 2. The pts were 100% female; Baseline (BL) median SLEDAI was 10.0. All pts received at least 1 dose of KZR-616. In each cohort, 3 pts withdrew due to withdrawal of consent prior to W13. Overall, the 45 mg dose was well tolerated with no SAEs; all AEs were mild in intensity. The most common AEs were injection site erythema (62.5%), nausea (25%), and injection site pruritus (25%).Cohort 2 (60 mg) enrollment was halted, as all pts experienced vomiting within ∼8-24 hours (h) of their first dose, which typically resolved within 24 h. One pt had an SAE of thrombotic microangiopathy. Two pts permanently reduced their dose to 45 mg. After 2 doses at 45 mg, another pt successfully re-escalated to 60 mg. In Cohort 2a (n=5 to date), there has been 1 SAE of localized herpes zoster. In pts, PK and PD were similar to that achieved for the same doses in HV1. Efficacy data for evaluable pts are shown in the table. Two (33%) and 2 (67%) evaluable pts in Cohorts 1 and 2, respectively, had a SLEDAI improvement of ≥4 points from BL at W13. Conclusion KZR-616 dosed at 45 mg SC QW appears to be safe and well tolerated and showed evidence of disease suppression at W13 in active SLE pts on stable background therapy. The Ph 2 doses in the first randomized placebo-controlled trial with KZR-616 in active LN pts on mycophenolate and prednisone will be 30 and 45 mg. Efforts are ongoing to evaluate KZR–616 doses ≥60 mg using step–up dosing. References [1] Muchamuel, et al. ARD 2018. 77:A685. [2] Lickliter, et al. ARD 2018. 77:A1413. Disclosure of Interests Richard Furie Grant/research support from: Biogen, UCB Pharma, but not in the last 12 months, Consultant for: Biogen, UCB Pharma, but not in the last 12 months, Darrin Bomba Shareholder of: Stockholder in Kezar Life Sciences, Employee of: Employee of Kezar Life Sciences, Maria Dall’Era Grant/research support from: University has received funds to serve as a site on this clinical study, Consultant for: On Data Monitoring Committee for Janssen, Biogen, and Genentech; on Steering Committee for EMD Serono., Massiel Prieto Grant/research support from: Site has received funds to conduct this clinical trial, Janet Anderl Shareholder of: Stockholder in Kezar Life Sciences, Employee of: Employee of Kezar Life Sciences, Jinhai Wang Shareholder of: Shareholder in Kezar Life Sciences, Employee of: Employee of Kezar Life Sciences, Christopher Kirk Shareholder of: Shareholder and option holder in Kezar Life Sciences, Consultant for: Consultant for Amgen, Employee of: Employee of Kezar Life Sciences, Niti Goel Shareholder of: Own stock options in Kezar Life Sciences., Employee of: Corporate officer of Kezar Life Sciences.

Background Treatment decision-making regarding immunosuppressive therapy is challenging for individuals with lupus. We assessed the effectiveness of a decision aid for immunosuppressive therapy in lupus nephritis. Methods and findings In a United States multicenter, open-label, randomized controlled trial (RCT), adult women with lupus nephritis, mostly from racial/ethnic minority backgrounds with low socioeconomic status (SES), seen in in- or outpatient settings, were randomized to an individualized, culturally tailored, computerized decision aid versus American College of Rheumatology (ACR) lupus pamphlet (1:1 ratio), using computer-generated randomization. We hypothesized that the co-primary outcomes of decisional conflict and informed choice regarding immunosuppressive medications would improve more in the decision aid group. Of 301 randomized women, 298 were analyzed; 47% were African-American, 26% Hispanic, and 15% white. Mean age (standard deviation [SD]) was 37 (12) years, 57% had annual income of, Jasvinder Singh and colleagues reveal how a decision aid helps women with lupus to make decisions about immunosuppressive therapy., Author summary Why was this study done? Lupus kidney disease is a serious immune system condition that can lead to kidney failure and dialysis in young women, if not treated appropriately. Effective treatment with immune-blocking medicines is available, but patients report difficulty making informed decisions that weigh benefits and risks, such as side effects. No patient decision aids are available for lupus medication decision-making. The research team made an online decision aid for women with lupus kidney disease, with extensive input from individuals with lupus. The aid can be individualized to help patients make informed decisions about immune-blocking medicines for lupus. What did the researchers do and find? In 301 women with lupus kidney disease across four centers, researchers assessed whether an online decision aid improved lupus treatment decisions, compared with the use of a paper pamphlet on lupus kidney disease from the American College of Rheumatology. Compared with women who received the lupus pamphlet, women who used the decision aid reported feeling less doubt about their medication choice. More women who used the online decision aid said that the information source was easy to use, compared with women who used the lupus pamphlet. What do these findings mean? This study provides evidence that a decision aid for women with kidney disease may help patients feel more confident in their treatment choices.

Background Systemic Lupus Erythematous (SLE) is a chronic autoimmune disease with heterogeneous disease manifestations and outcomes. Previous work has found associations between DNA methylation at specific CpG sites and lupus nephritis, serologies, and SLEDAI score. However, these methods examine single CpGs and do not capture the full biological complexity. Using an integrative network-based approach, we aim to define how DNA methylation and genetic variation underlie this clinical heterogeneity in a well-phenotyped multiethnic cohort of SLE patients. Methods 333 SLE participants from diverse ethnic backgrounds were recruited as part of this study. From peripheral blood, DNA methylation was measured using the Illumina EPIC Beadchip and single nucleotide polymorphism (SNP) genotype data was generated on the Affymetrix LAT1 World Array. Weighted gene correlation network analysis (WGCNA) was applied to the DNA methylation data. The resulting CpG networks were associated with relevant SLE clinical features ina multivariate linear regression model adjusting for population stratification, cell composition, sex, smoking history, medications. Results We identified one WGCNA CpG module significantly associated with SLEDAI score, anti-Sm, and anti-dsDNA serologies (FDR Conclusions Overall, we performed a network-based analysis of DNA methylation and identified a network of CpGs significantly associated with SLE serologies and SLEDAI score. Our approach identifies large-scale epigenetic remodeling that drives SLE pathology rather than single CpG associations as in previous studies that may be influenced by stochastic variation. By applying an integrative computational approach, our method serves to reveal the epigenetic and genetic role of the Type I interferon pathway in SLE. Funding Source(s): This study was funded through the following grants: P30 AR070155 (MS, IP, LC), P60AR053308 (LC), K01LM012381 (MS), F32 AR070585 NIAMS (MG), U01DP005120 CDC (LC, CL, JY, MD, LT, PK), the Rheumatology Research Foundation 128849A (CL), and the Lupus Research Alliance (LC).

Background SLE is a chronic disease that affects many organ systems and can cause permanent damage. We sought to determine if there are differences in patterns of SLE organ system damage among racial/ethnic groups. Methods Data derive from the baseline visit of the California Lupus Epidemiology Study (CLUES), an ongoing cohort of patients in the San Francisco Bay Area with confirmed SLE diagnoses. Participants provided access to medical records and had a visit with a study rheumatologist. Race/ethnicity (White, African American, Hispanic of any race, and Asian) was determined by patient report. Due to the small sample size, patients from other racial groups were excluded from this analysis (n=5). Disease damage was measured using the SLICC/ACR Damage Index (SDI), calculated at the study visit. We examined damage at the organ system level, using items from the SDI, and defined glucocorticoid-related damage as avascular necrosis, diabetes, cataracts, and osteoporosis. Logistic regression was used to estimate the prevalence of damage in each organ system and the prevalence of glucocorticoid-related damage by race/ethnicity controlling for current age. We ranked the prevalence of damage in each organ system that comprises the SDI for each racial/ethnic group. Results Among 323 participants, 89% were female, 39% Asian, 11% African American, 22% Hispanic of any race, and 29% White. Mean age was 45±14; mean age at diagnosis 29±12. SDI ranged from 0 to 10 points, mean 1.8±2.0; 70% of the cohort had SDI>0. There were no differences in mean SDI by race/ethnicity (p=0.4; see Table). Musculoskeletal and ocular damage were among the five most common systems for all groups. African Americans were significantly (p=0.02) more likely to have skin damage than the other racial/ethnic groups. Non-Hispanic whites were the only group that had malignancy in their top five systems of SDI damage. Renal damage was most prevalent among Hispanics and least prevalent among whites. Glucocorticoid-related damage was more prevalent among African Americans in comparison to whites, although this difference was not statistically significant. Conclusions There are differences in prevalence of damage by organ system among racial/ethnic groups, with blacks significantly more likely to have skin manifestations and whites more likely to have a history of cancer. There is also evidence of higher glucocorticoid-related damage among blacks. Further research is required to explain what leads to these differences; they could be related to quality and access to care and treatment, or to differential disease biology or environmental exposures. Funding Source(s): CDC (U01 DP005120)

Background Earlier age of SLE onset is associated with greater disease damage, even after taking into account the effects of current age and disease duration. We sought to determine if this association was consistent across racial and ethnic groups, given the differences in disease severity among these groups. Methods Data derive from the baseline visit of the California Lupus Epidemiology Study (CLUES), an ongoing cohort of patients in the San Francisco Bay Area with confirmed SLE diagnoses, drawn from a variety of clinical sources and prior SLE studies. Participants provided access to medical records and had a visit with a study physician in which clinical labs were drawn. Disease damage was measured using the SLICC/ACR Damage Index (SDI), calculated at the study visit. Age of diagnosis was ascertained by the study physician or from the medical records. Race/ethnicity (White, African American, Hispanic of any race, and Asian) and educational attainment (high school or less, some college, college graduate) were determined by patient report. Due to the small sample size, patients from other racial groups were excluded from this analysis (n=5). Using multiple linear regression, we estimated a model of SDI as a function of race/ethnicity and age of diagnosis, plus terms for interaction between the variables. The model controlled for sex, current age, and education. Results Among 323 participants, 89% were female, 39% Asian, 11% African American, 22% Hispanic of any race, and 29% White. Mean age was 45±14; mean age at diagnosis 29±12. Nearly half of respondents had a college degree. SDI at the baseline study visit ranged from 0 to 10 points, mean 1.8±2.0; 70% of the cohort had SDI>0. The regression model showed strong evidence (p=0.01) for interaction of age of diagnosis with race/ethnicity. As seen in the figure 1, SDI scores in racial/ethnic minorities were much higher among those diagnosed at younger ages; this relationship was not seen among whites. Conclusions In this multi-ethnic cohort of SLE patients, the association of diagnosis age and disease damage varied according to race/ethnicity, with whites diagnosed at younger ages accumulating less damage than those in other racial/ethnic groups diagnosed at comparable ages. Future research should examine if these differences are due to phenotypic differences among the groups, diagnostic delays, or other access to care issues. Funding Source(s): Centers for Disease Control and Prevention (U01 DP005120)

Background Despite case series suggesting efficacy, controlled trials of anti-CD20 in lupus and lupus nephritis (LN) have not meet their primary endpoints (Arthritis Rheum 2012;64:1215 and 2013;65:2368). A potential explanation is the observation that serum BAFF levels are elevated after treatment with rituximab and may lead to disease flare by facilitating maturation of and re-population with autoreactive B cells. The CALIBRATE study (NCT 02260934) was designed to test this hypothesis, to determine whether addition of anti-BAFF (belimumab) could enhance the clinical effects of anti-CD20 (rituximab), and assess safety of the combination. Methods Forty-three patients with active LN despite conventional treatment were enrolled in a prospective randomized open-label trial that compared two therapeutic strategies. All subjects received iv rituximab (1000 mg), CTX (750 mg), and methylprednisolone (100 mg) at wks 0 and 2, followed by 40 mg/d prednisone with taper to 10 mg/d by wk 12. At wk 4, subjects were randomized to belimumab (10 mg/kg iv at wks 4, 6, 8 and then every 4 wks) plus prednisone (n=21) (RCB) or prednisone alone (RC) (n=22). Complete response (CR) was defined as: (i) urine protein:creatinine ratio (UPCR) 80% of screening; and (iii) prednisone dose of 10 mg/d. Partial response (PR) differed only in the UPCR criterion (>50% reduction). Results The clinical outcome at wk 48 was similar in both groups: CR was 38% in the belimumab group (RCB) and 32% in the control group (RC). The frequency of subjects with serious infections was also similar between groups. B cell depletion occurred in both groups by wk 12, but the pace of repopulation was delayed in the RCB group. However, median IgG levels remained within the normal range in both groups. Mechanistic analyses of circulating B cells at week 48 showed differences in the relative proportions of B cell subpopulations between RC and RCB groups and fewer ANA +B cells in the RCB group (figure 1). Conclusions Treatment with anti-BAFF following anti-CD20 did not improve clinical outcome at week 48; (ii) anti-BAFF delayed blood B cell reconstitution following B cell depletion; (iii) anti-BAFF following anti-CD20 was not associated with hypogammaglobulinemia or an increase in serious infections and (iv) the reconstituted B cell populations differed between the RCB and RC groups. Further analyses at 96 weeks will address how anti-BAFF therapy affects quantitative and qualitative recovery of B cells as well as long-term clinical outcome. Funding Source(s): Conducted by ITN with support from NIAID (UM1AI109565) and Genentech.

Systemic lupus erythematous (SLE) is a heterogeneous autoimmune disease in which outcomes vary among different racial groups. Here, we aim to identify SLE subgroups within a multiethnic cohort using an unsupervised clustering approach based on the American College of Rheumatology (ACR) classification criteria. We identify three patient clusters that vary according to disease severity. Methylation association analysis identifies a set of 256 differentially methylated CpGs across clusters, including 101 CpGs in genes in the Type I Interferon pathway, and we validate these associations in an external cohort. A cis-methylation quantitative trait loci analysis identifies 744 significant CpG-SNP pairs. The methylation signature is enriched for ethnic-associated CpGs suggesting that genetic and non-genetic factors may drive outcomes and ethnic-associated methylation differences. Our computational approach highlights molecular differences associated with clusters rather than single outcome measures. This work demonstrates the utility of applying integrative methods to address clinical heterogeneity in multifactorial multi-ethnic disease settings., Systemic lupus erythematosus (SLE) is an autoimmune disease of substantial phenotypic heterogeneity in different ethnic groups. Here, using data from a multi-ethnic cohort, the authors describe an approach based on clinical and molecular data to subtype SLE patients into three clusters of severity.

This chapter describes the terminology and classification criteria associated with systemic lupus erythematosus (SLE) and the related disorders of drug induced lupus, chronic cutaneous lupus, mixed connective tissue disease (MCTD), undifferentiated connective tissue disease (UCTD), overlap syndromes, antiphospholipid antibody syndrome (APS), and neonatal lupus. Classification criteria are designed for the purpose of categorizing patients into relatively homogeneous groups to ensure appropriate enrollment in clinical studies. However, these criteria also serve to remind trainees and the practicing clinician about the key clinical and serological features of each of these diseases. Importantly, these criteria should never be used to definitively diagnose an individual patient in the clinical setting. Classification criteria evolve over the course of time, as understanding of the clinical and biological features of these diseases continue to improve through research.

Background:Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus (SLE) affecting 50% of SLE patients and leading to end-stage kidney disease (ESKD) in up to 30% of patients with LN.1 Previous studies have reported higher healthcare costs in patients with SLE that develop LN compared to patients without LN.2-5 These studies captured overall treatment costs associated with LN, regardless of disease activity or severity, and were conducted in small patient populations.Objectives:The aim of this study was to assess the real-world economic implications of achieving low disease activity compared to active disease or ESKD in a large LN population.Methods:This study was a retrospective observational analysis of patients with LN within Optum’s health plan identified with ICD9 or ICD10 codes to have LN between January 1, 2015, and December 31, 2019. Patients were ≥18 years of age and had ≥2 months of follow-up data available. Patients were followed until death, loss to follow-up, or December 31, 2019. Low disease activity was defined by evidence of glucocorticoid doses ≤5 mg/day, evidence of mycophenolate mofetil (MMF) doses ≤2 g/day, and no use of cyclophosphamide for ≥6 consecutive months. Follow-up time that could not be defined as low disease activity was defined as active disease periods, except for periods with evidence of ESKD. Healthcare payer costs for medical and pharmacy services were compared between periods of low disease activity, active disease, and ESKD. A univariate generalized estimating equation model accounting for interdependence was used to compare differences in costs between periods of active and low disease activity.Results:A total of 21,251 patients with LN met study criteria with a mean follow-up time of 31.0 months. The mean age was 60.3 years; 86.9% of patients were female and 35.2% of patients were non-White race. Low disease activity was evident in 51.3% of patients with a mean duration of 27.5 months. Mean monthly medical costs were $2,523 during periods of low disease activity and $4,777 during periods of active disease. After factoring in pharmacy costs, mean monthly total costs were $3,584 during periods of low activity and $6,612 during periods of active disease (PConclusion:Achieving low disease activity in patients with LN is associated with reduced economic burden to healthcare payers, with monthly medical costs averaging $2,254 less and total monthly costs averaging $3,028 less than costs during periods of active disease.References:[1]Parikh SV et al. Update on Lupus Nephritis: Core Curriculum 2020. Am J Kidney Dis. 2020;76(2):265-281.[2]Bartels-Peculis L et al. Treatment patterns and health care costs of lupus nephritis in a United States payer population. Open Access Rheumatol. 2020;12:117-124.[3]Furst DE et al. Medical costs and healthcare resource use in patients with lupus nephritis and neuropsychiatric lupus in an insured population. J Med Econ. 2013;16(4):500-509.[4]Li T et al. Long-term medical costs and resource utilization in systemic lupus erythematosus and lupus nephritis: a five-year analysis of a large Medicaid population. Arthritis Rheum. 2009;61(6):755-763.[5]Pelletier EM et al. Economic outcomes in patients diagnosed with systemic lupus erythematosus with versus without nephritis: results from an analysis of data from a US claims database. Clin Ther. 2009;31(11):2653-2664.Disclosure of Interests:Maria Dall’Era Speakers bureau: Consulting agreement with Aurinia for Advisory Boards and educational lectures, Tim Hermes Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc., Michael Eaddy Consultant of: Aurinia Pharmaceuticals Inc., Augustina Ogbonnaya Consultant of: Aurinia Pharmaceuticals Inc., Eileen Farrelly Consultant of: Aurinia Pharmaceuticals Inc., Paola Mina-Osorio Shareholder of: Aurinia Pharmaceuticals Inc., Employee of: Aurinia Pharmaceuticals Inc.

Objective Numerous factors can impede or facilitate patients’ medication decision-making and adherence to physicians’ recommendations. Little is known about how patients and physicians jointly view issues that affect the decision-making process. Our objective was to derive an empirical framework of patient-identified facilitators to lupus medication decision-making from key stakeholders (including 15 physicians, 5 patients/patient advocates, and 8 medical professionals) using a patient-centered cognitive mapping approach. Methods We used nominal group patient panels to identify facilitators to lupus treatment decision-making. Stakeholders independently sorted the identified facilitators (n = 98) based on their similarities and rated the importance of each facilitator in patient decision-making. Data were analyzed using multidimensional scaling and hierarchical cluster analysis. Results A cognitive map was derived that represents an empirical framework of facilitators for lupus treatment decisions from multiple stakeholders’ perspectives. The facilitator clusters were 1) hope for a normal/healthy life, 2) understand benefits and effectiveness of taking medications, 3) desire to minimize side effects, 4) medication-related data, 5) medication effectiveness for “me,” 6) family focus, 7) confidence in physician, 8) medication research, 9) reassurance about medication, and 10) medication economics. Conclusion Consideration of how different stakeholders perceive the relative importance of lupus medication decision-making clusters is an important step toward improving patient-physician communication and effective shared decision-making. The empirically derived framework of medication decision-making facilitators can be used as a guide to develop a lupus decision aid that focuses on improving physician-patient communication.

The loss of tolerance and the presence of circulating autoantibodies directed against nuclear Ags is the hallmark of systemic lupus erythematosus (SLE). Many of these Ags are complexed with short, noncoding RNAs, such as U1 and Y1. The amount of U1 and Y1 RNA complexed with SLE patient Abs and immune complexes was measured in a cross-section of 228 SLE patients to evaluate the role of these RNA molecules within the known biochemical framework of SLE. The study revealed that SLE patients had significantly elevated levels of circulating U1 and/or Y1 RNA compared with healthy volunteers. In addition, the blood-borne RNA molecules were correlated with SLE disease activity and increased expression of IFN-inducible genes. To our knowledge, this study provides the first systematic examination of the role of circulating RNA in a large group of SLE patients and provides an important link with IFN dysregulation.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a considerable impact on patients’ quality of life. Despite the plethora of clinical trials for SLE since the turn of the millennium, only one new treatment has been approved for the condition, and the overall pace of successful drug development remains slow. Nevertheless, the myriad of clinical studies has yielded insights that have informed and refined our understanding of eligibility criteria, outcome measures and trial design in SLE. In this review, we highlight the achievements of clinical trials as well as the major pitfalls that have been identified in drug development for SLE and, in doing so, identify areas where collaboration and consensus will be important to facilitate progress.

Background Systemic Lupus Erythematous (SLE) is chronic autoimmune disease with heterogeneous disease manifestations and outcomes. We aimed to define how molecular differences underlie this clinical heterogeneity through an integrative approach leveraging methylation, genetic and phenotypic data from a well characterized multiethnic cohort of SLE patients. Methods 274 participants were studied. We defined our phenotypic outcomes by clustering analyses. We performed principal component analysis on the ACR clinical criteria and used the top 2 eigenvectors as input for K-means clustering. We identified stable clusters based on a stability score >0.8 determined by a bootstrap resampling method. Our predictors were DNA methylation and genetic variation. DNA extracted from blood was analyzed on the illumina EPIC Beadchip. Single nucleotide polymorphism (SNP) genotype data was generated on the Affymetrix LAT1 World Array. Multivariate linear regression adjusting for population stratification, cell composition, sex, smoking history, and age was used to identify differentially methylated CpGs across clinical ACR criteria. We then investigated whether the differentially methylated CpG were under genetic control in a methylation quantitative trait loci analyses (cis-meQTLs). Results We identified three stable clusters based on ACR criteria. Cluster 1 was characterized by a higher proportion of participants of white ethnicity with malar rash, photosensitivity, serositis, arthritis, oral ulcers and fewer subserologies. Cluster 2 was characterized by a higher proportion of lupus nephritis and anti-dsDNA antibodies. Cluster 3 was characterized by higher proportion of hematologic manifestations, lupus nephritis, anti-dsDNA and anti-Sm antibodies. We identified 196 CpGs in 107 genomic regions that were differentially methylated between the clusters (FDR Conclusion Overall, we identified three clinical relevant clusters in a multiethnic SLE cohort. The three clusters could be differentiated by 196 CpGs of which 97 were under genetic control and enriched for IFN-gamma and IFN-alpha responsive genes. This work helps to elucidate the epigenetic and genetic mechanism behind the role of Type 1 interferon in SLE pathology.

Lupus nephritis is a potentially fatal autoimmune disease, whose current treatment is ineffective and often toxic. To gain insights into disease mechanisms, we analyzed kidney samples from lupus nephritis patients and healthy controls using single-cell RNA-seq. Our analysis revealed 21 subsets of leukocytes active in disease, including multiple populations of myeloid, T, NK and B cells, demonstrating both pro-inflammatory and resolving responses. We found evidence of local activation of B cells correlated with an age-associated B cell signature, and of progressive stages of monocyte differentiation within the kidney. A clear interferon response was observed in most cells. Two chemokine receptors, CXCR4 and CX3CR1, were broadly expressed, pointing to potential therapeutic targets. Gene expression of immune cells in urine and kidney was highly correlated, suggesting urine may be a surrogate for kidney biopsies. Our results provide a first comprehensive view of the complex network of leukocytes active in lupus nephritis kidneys.

Background In addition to glomerular lesions, renal vascular involvement is an important prognostic marker of lupus nephritis (LN). Among patients with various vascular changes, individuals with thromboticmicroangiopathy (TMA) present with severe clinical manifestations and have a high mortality. Objectives We sought to assess renalout comes and response to anti-thrombotic treatmentsin addition to conventional immunosuppression in patients with biopsy proven LN and TMA. Methods Clinical and renal histopathological data for 97 patients with biopsy-proven LN and TMA were retrospectively analysed. Antibody profiles, induction and maintenance therapies for LN, and anti-thrombotic treatments were collected. TMA lesions were classified into acute and chronic (table 1). A complete renal response (CR) was defined as proteinuria Results The mean age of the patients was 38.9±15.2 years (range, 13–69 years). The study included 85 females (87.6%) and 12 males (12.4%). The clinical presentations were nephrotic syndrome, nephritic syndrome, and asymptomatic urinary abnormalitiesin 38 (39.2%), 20 (20.6%), 39 (40.2%) patients, respectively. Nine patients were classified Class III (9.3%, including 2 as ClassIII +V), 82 as Class IV (84.5%, 10 as Class IV-segmental(IV-S) (10.3%) and 72 as Class IV-global (IV-G) (74.2%),including 4 as Class IV-G+V) and 6 as Class V (6.2%). Forty-two(43%) patients presented with acute and 55 (57%) with features of chronic TMA. All patients had received treatment with standard immunosuppressants (55% mycophenolate, 39% cyclophosphamide, 6% other regimen) and steroids. At 12 months, CR was observed in 37 patients (38.1%), PR in 22 (22.6%) and no response in 38 (39.1%). Sixty-one patients (62.9%) were antiphospholipid positive (aPL) and 37 (38.1%) received anticoagulation with vitamin-K antagonist (VKA) and/or heparins. Presence of aPLs(OR, 2.4; 95% confidence interval-CI-, 1.2–7.3; p=0.03), anti-DNA positivity (OR, 12.8; 95% CI: 3.0 to 71.3; p=0.002), and chronic features of TMA (OR, 3.0; 95% CI: 1.2 to 17.5; p=0.04) were all found to be associated with no response. When limiting the analysis to aPL positive patients, after adjusting for type of immunosuppressant therapy and LN class on biopsy, variables that were significantly associated with CR +PR were features of acute TMA rather than chronic (OR, 8.62; 95% CI: 1.4 to 97.1; p=0.03) and the use of VKA/heparins(OR, 2.1; 95% CI, 1.02–16.2; p=0.046) Conclusions In patients with concomitant LN and TMA, the presence of aPL and chronic features of TMA were associated with poorer renal outcomes. In patients with aPL, the use of anticoagulation appeared protective and warrants further investigation as a therapeutic tool, especially in the setting of acute TMA. Disclosure of Interest None declared

Background Despite case series suggesting efficacy, controlled trials of anti-CD20 in lupus nephritis (LN) did not confirm benefit;Arthritis Rheum 201264:1215 and 2013;65:2368). Objectives One possible explanation for this failure stems from the fact that B cell depletion stimulates production of B cell activating factor (BAFF) which, in turn, facilitates maturation of autoreactive B cells in lymphoid organs or during B cell repopulation. The CALIBRATE study (NCT 02260934) was designed to test this hypothesis, to determine whether addition of anti-BAFF could enhance the clinical effects of anti-CD20, and to assess safety of the combination. Methods Forty-three patients with active LN despite conventional treatment enrolled in a prospective randomised open-label trial that compared two treatment strategies. All subjects received iv rituximab (1000 mg), CTX (750 mg), and methylprednisolone (100 mg) at wks 0 and 2, followed by 40 mg/d prednisone tapered to 10 mg/d by wk 12. At wk 4, subjects received either belimumab (10 mg/kg iv at wks 4, 6, 8 and then every 4 wks) plus prednisone (n=21) or prednisone alone (n=22). Complete response (CR) was defined as: (i) urine protein:creatinine ratio (UPCR) 80% of screening; and (iii) prednisone tapered to 10 mg/d. The definiton of partial response (PR) differed only in the UPCR criterion (>50% reduction). Results The clinical outcome at wk 24 was similar in both groups (table 1). The CR rate was 24% in the belimumab group (RCB) and 23% in the control group (RC). Three subjects in each group withdrew (WD) prior to wk 24 (two withdrawals in each group due either to progressive nephritis or an infusion reaction, and one in each group for reasons unrelated to SLE or its treatment). B cell depletion from blood was virtually absolute in both groups at wk 12, but the pace of recovery differed. Six subjects experienced serious adverse events between wks 0 and 24; three subjects in the RC group (pneumonia followed by LN flare; deep vein thrombosis; SLE flare); and three subjects in the RCB group (anti-CD20 infusion reaction; soft-tissue abscesses prior to anti-BAFF treatment; quadriceps tendon rupture). Median B Cell Count Median IgG Level CR PR NR WD Wk 0 Wk 12 Wk 24 Wk 0 Wk 24 RC Group 23%–23% 41%–14% 105 1 31 1050 1100 RCB Group 24% 24% 38% 14% 143 1 3 984 837 Conclusions An interim analysis of data from CALIBRATE shows: (i) anti-BAFF following anti-CD20 for LN did not improve clinical outcome at week 24; (ii) anti-BAFF delayed blood B cell reconstitution following B cell depletion; and (iii) anti-BAFF following anti-CD20 was not associated with hypogammaglobulinemia or an increase in serious infections. Further analyses at 48 weeks and beyond will address how anti-BAFF therapy affects quantitative and qualitative recovery of B cells as well as long-term clinical outcome. Acknowledgements Conducted by ITN with support from NIAID (UM1AI109565) and Genentech. Disclosure of Interest C. Aranow Grant/research support from: GlaxoSmithKline, Consultant for: GlaxoSmithKline, M. Dall’Era Consultant for: Genentech, M. Byron: None declared, L. Ding: None declared, D. Smilek: None declared, B. Diamond: None declared, D. Wofsy Consultant for: GlaxoSmithKline, Celgene, Novartis, UCB, Sanofi

Formidable impediments stand in the way of treatment development for lupus. These include the unwieldy size of current trials, international competition for scarce patients, complex outcome measures and a poor understanding of these outcomes in the world at large. The heterogeneity of the disease itself coupled to superimposition of variegated background polypharmacy has created enough immunological noise to virtually ensure the failure of lupus treatment trials, leaving an understandable suspicion that at least some of the results in testing failed drugs over the years may not have been negative, but merely uninterpretable. The authors have consulted with many clinical trial investigators, biopharmaceutical developers and stakeholders from government and voluntary sectors. This paper examines the available evidence that supports workable trial designs and proposes approaches to improve the odds of completing interpretable treatment development programs for lupus.

Objective Vitamin D modulates the immune response and blocks induction of an interferon signature by SLE sera. We investigated the effects of vitamin D supplementation on the IFN signature in SLE patients.