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Abstract Background Systemic lupus erythematosus (SLE) has numerous symptoms across organs and an unpredictable flare-remittance pattern. This has made it challenging to understand drivers of long-term SLE outcomes. Our objective was to identify whether changes in DNA methylation over time, in an actively flaring SLE cohort, were associated with remission and whether these changes meaningfully subtype SLE patients. Methods Fifty-nine multi-ethnic SLE patients had clinical visits and DNA methylation profiles at a flare and approximately 3 months later. Methylation was measured using the Illumina EPIC array. We identified sites where methylation change between visits was associated with remission at the follow-up visit using limma package and a time x remission interaction term. Models adjusted for batch, age at diagnosis, time between visits, age at flare, sex, medications, and cell-type proportions. Separately, a paired T-test identified Bonferroni significant methylation sites with ≥ 3% change between visits (n = 546). Methylation changes at these sites were used for unsupervised consensus hierarchical clustering. Associations between clusters and patient features were assessed. Results Nineteen patients fully remitted at the follow-up visit. For 1,953 CpG sites, methylation changed differently for remitters vs. non-remitters (Bonferroni p

Objective 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 SLE phenotypes, specifically production of type I IFNs and generation of autoantibodies. Methods We profiled cell‐sorted RNA‐sequencing data (CD4+ T cells, CD14+ monocytes, CD19+ B cells, and natural killer cells) from peripheral blood mononuclear cells of 120 patients with SLE and quantified TE expression identifying 27,135 TEs. We tested for differential TE expression across 10 SLE phenotypes, including autoantibody production and disease activity. Results We found 731 differentially expressed (DE) TEs across all SLE phenotypes that were mostly cell specific and phenotype specific. DE TEs were enriched for specific families and open reading frames of viral genes encoded in TE sequences. Increased expression of DE TEs was associated with genes involved in antiviral activity, such as LY6E, ISG15, and TRIM22, and pathways such as IFN signaling. Conclusion 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.

Summary: Background: Physical activity is an adjunctive therapy that improves symptoms in people living with systemic lupus erythematosus (SLE), yet the mechanisms underlying this benefit remain unclear. Methods: We carried out a cohort study of 123 patients with SLE enrolled in the California Lupus Epidemiology Study (CLUES). The primary predictor variable was self-reported physical activity, which was measured using a previously validated instrument. We analyzed peripheral blood mononuclear cell (PBMC) single-cell RNA sequencing (scRNA-seq) data available from the cohort. From the scRNA-seq data, we compared immune cell frequencies, cell-specific gene expression, biological signalling pathways, and upstream cytokine activation states between physically active and inactive patients, adjusting for age, sex and race. Findings: We found that physical activity influenced immune cell frequencies, with sedentary patients most notably demonstrating greater CD4+ T cell lymphopenia (Padj = 0.028). Differential gene expression analysis identified a transcriptional signature of physical inactivity across five cell types. In CD4+ and CD8+ T cells, this signature was characterized by 686 and 445 differentially expressed genes (Padj

Introduction High-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy.Methods Propensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months.Results There were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months.Conclusions Compared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.

Abstract Background Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis. Methods Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day. Results Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (ORadj = 3.71 [95%CI = 1.34–10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (ORadj = 2.61 [95%CI = 1.07–6.41]; p = 0.036), lower chronicity index (ORadj = 1.33 per unit decrease [95%CI = 1.10–1.62]; p = 0.003), and positive anti-dsDNA antibody (ORadj = 2.61 [95%CI = 0.93–7.33]; p = 0.069). Conclusions CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.

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

Abstract Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including increased renal involvement and tissue damage. However, the mechanisms underlying elevated severity in the AsA population remain unclear. Here, we utilized available gene expression data and genotype data based on all non-HLA SNP associations in EA and AsA SLE patients detected using the Immunochip genotyping array. We identified 2778 ancestry-specific and 327 trans-ancestry SLE-risk polymorphisms. Genetic associations were examined using connectivity mapping and gene signatures based on predicted biological pathways and were used to interrogate gene expression datasets. SLE-associated pathways in AsA patients included elevated oxidative stress, altered metabolism and mitochondrial dysfunction, whereas SLE-associated pathways in EA patients included a robust interferon response (type I and II) related to enhanced cytosolic nucleic acid sensing and signaling. An independent dataset derived from summary genome-wide association data in an AsA cohort was interrogated and identified similar molecular pathways. Finally, gene expression data from AsA SLE patients corroborated the molecular pathways predicted by SNP associations. Identifying ancestry-related molecular pathways predicted by genetic SLE risk may help to disentangle the population differences in clinical severity that impact AsA and EA individuals with SLE.

Objective Evobrutinib is a highly selective, orally administered Bruton's tyrosine kinase (BTK) inhibitor. The objective of this phase II, multicenter, randomized, double‐blind, placebo‐controlled trial was to evaluate the efficacy and safety of evobrutinib in patients with active autoantibody‐positive systemic lupus erythematosus (SLE). Methods Patients were diagnosed with SLE by either the Systemic Lupus International Collaborating Clinics criteria or at least four American College of Rheumatology criteria 6 months or more prior to screening, had an SLE Disease Activity Index‐2000 score of 6 or more, were autoantibody‐positive and on standard‐of‐care therapy. Randomization was 1:1:1:1 to oral evobrutinib 25 mg once daily (QD), 75 mg QD, 50 mg twice daily, or placebo. Primary efficacy endpoints were SLE responder index (SRI)‐4 response at week 52 and SRI‐6 response at week 52 in the high disease activity subpopulation. Safety endpoints included treatment‐emergent adverse events (TEAEs). Results A total of 469 patients were randomized and received at least one dose of evobrutinib or placebo at the time of primary analysis. Mean (SD) age at baseline was 40.7 (±12.3) years; 94.9% of patients were female. Neither primary efficacy endpoint was met. All doses of evobrutinib were well tolerated, and there was no clear dose effect on the incidence of reported TEAEs, or serious TEAEs, including severe infections. Conclusion This phase II, dose‐ranging trial in SLE failed to show a treatment effect of evobrutinib versus placebo at any dose. Evobrutinib was generally well tolerated, with no dose effect observed for TEAEs. These results suggest that BTK inhibition does not appear to be an effective therapeutic intervention for patients with SLE.

Objective There is a lack of data on the use of telemedicine (TM) in SLE. SLE outcome measures remain complex, and clinicians and clinical trialists have raised concerns about the accuracy of virtual disease activity measures. This study evaluates the level of agreement between virtual SLE outcome measures and face-to-face (F2F) encounter. Here, we describe the study design, virtual physical examination protocol and demographics for the first 50 patients evaluated.Methods and analysis This is an observational, longitudinal study of 200 patients with SLE with varying levels of disease activity from 4 academic lupus centres serving diverse populations. Each study participant will be evaluated at a baseline and a follow-up visit. At each visit, participants are evaluated by the same physician first via a videoconference-based TM and then a F2F encounter. For this protocol, virtual physical examination guidelines relying on physician-directed patient self-examination were established. SLE disease activity measures will be completed immediately after the TM encounter and repeated after the F2F encounter for each visit. The degree of agreement between TM and F2F disease activity measures will be analysed using the Bland-Altman method. An interim analysis is planned after the enrolment of the first 50 participants.Ethics and dissemination This study has been reviewed by the Columbia University Medical Center Institutional Review Board (IRB Protocol #: AAAT6574). The full results of this study will be published after the final data analysis of 200 patients. The abrupt shift to TM visits due to the COVID-19 pandemic disrupted clinical practice and clinical trials. Establishing a high level of agreement between SLE disease activity measures obtained with videoconference TM and F2F at the same time point, will allow for improved assessment of disease activity when F2F data cannot be acquired. This information may guide both medical decision-making and provide reliable outcome measures for clinical research.

Objectives Type I interferon (IFN) plays a role in the pathogenesis of systemic lupus erythematosus (SLE), but insufficient attention has been directed to the differences in IFN responses between ancestral populations. Here, we explored the expression of the interferon gene signatures (IGSs) in SLE patients of European ancestry (EA) and Asian ancestry (AsA).Methods We used gene set variation analysis with multiple IGS encompassing the response to both type 1 and type 2 IFN in isolated CD14+ monocytes, CD19+B cells, CD4+T cells and Natural Killer (NK) cells from patients with SLE stratified by self-identified ancestry. The expression of genes upstream of the IGS and influenced by lupus-associated risk alleles was also examined. Lastly, we employed machine learning (ML) models to assess the most important features classifying patients by disease activity.Results AsA patients with SLE exhibited greater enrichment in the IFN core and IFNA2 IGS compared with EA patients in all cell types examined and, in the presence and absence of autoantibodies. Overall, AsA patients with SLE demonstrated higher expression of genes upstream of the IGS than EA counterparts. ML with feature importance analysis indicated that IGS expression in NK cells, anti-dsDNA, complement levels and AsA status contributed to disease activity.Conclusions AsA patients with SLE exhibited higher IGS than EA patients in all cell types regardless of autoantibody status, with enhanced expression of genetically associated genes upstream of the IGS potentially contributing. AsA, along with the IGS in NK cells, anti-dsDNA and complement, independently influenced SLE disease activity.

Gaia Andreoletti et al. leverage cell-sorted RNA-seq data and machine learning to investigate gene expression patterns in immune cell subtypes purified from Asian and White patients with a medical diagnosis of systemic lupus erythematosus (SLE). They report distinct clinical subtypes of SLE and identify ethnicity- and disease-specific gene clusters, potentially contributing toward the future development of personalized therapeutic strategies for patients with SLE.

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.

BackgroundThe pandemic disrupted the care of patients with rheumatic diseases; difficulties in access to care and its psychological impact affected quality of life. Telemedicine as an alternative to traditional face-to-face office visits has the potential to mitigate this impact.ObjectiveTo evaluate patient and provider experience with telemedicine and its effect on care.MethodsWe surveyed patients with rheumatic diseases and their rheumatology providers. The surveys were conducted in 2020 and repeated in 2021. We assessed data on quality of care and health-related quality of life.ResultsHundred patients and 17 providers responded to the survey. Patients reported higher satisfaction with telemedicine in 2021 compared to 2020 (94 vs. 84%), felt more comfortable with (96 vs. 86%), expressed a stronger preference for (22 vs. 16%), and higher intention to use telemedicine in the future (83 vs. 77%); patients thought physicians were able to address their concerns. While providers' satisfaction with telemedicine increased (18–76%), 14/17 providers believed that telemedicine visits were worse than in-person visits. There were no differences in annualized office visits and admissions. Mean EQ-5D score was 0.74, lower than general population (0.87) but equivalent to a subset of patients with SLE (0.74).ConclusionOur data showed a high level of satisfaction with telemedicine. The lower rheumatology provider satisfaction raises concern if telemedicine constitutes an acceptable alternative to in-person care. The stable number of office visits, admissions, and the similar quality of life to pre-pandemic level suggest effective management of rheumatic diseases using telemedicine/in-person hybrid care.

This viewpoint article on a forecast of clinically meaningful changes in the management of systemic lupus erythematosus (SLE) in the next 10 years is based on a review of the current state of the art. The groundwork has been laid by a robust series of classification criteria and treatment recommendations that have all been published since 2019. Building on this strong foundation, SLE management predictably will take significant steps forward. Assessment for lupus arthritis will presumably include musculoskeletal sonography. Large-scale polyomics studies are likely to unravel more of the central immune mechanisms of the disease. Biomarkers predictive of therapeutic success may enter the field; the type I interferon signature, as a companion for use of anifrolumab, an antibody against the common type I interferon receptor, is one serious candidate. Besides anifrolumab for nonrenal SLE and the new calcineurin inhibitor voclosporin in lupus nephritis, both of which are already approved in the United States and likely to become available in the European Union in 2022, several other approaches are in advanced clinical trials. These include advanced B cell depletion, inhibition of costimulation via CD40 and CD40 ligand (CD40L), and Janus kinase 1 (Jak1) and Tyrosine kinase 2 (Tyk2) inhibition. At the same time, essentially all of our conventional therapeutic armamentarium will continue to be used. The ability of patients to have successful SLE pregnancies, which has become much better in the last decades, should further improve, with approaches including tumor necrosis factor blockade and self-monitoring of fetal heart rates. While we hope that the COVID-19 pandemic will soon be controlled, it has highlighted the risk of severe viral infections in SLE, with increased risk tied to certain therapies. Although there are some data that a cure might be achievable, this likely will remain a challenge beyond 10 years from now.

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.

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.

Objective To estimate the annual incidence rate of SLE in the USA.Methods A 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.Results The 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.Conclusions A network of population-based SLE registries provided estimates of SLE incidence rates and numbers diagnosed in the USA.

Objectives In lupus nephritis the pathological diagnosis from tissue retrieved during kidney biopsy drives treatment and management. Despite recent approval of new drugs, complete remission rates remain well under aspirational levels, necessitating identification of new therapeutic targets by greater dissection of the pathways to tissue inflammation and injury. This study assessed the safety of kidney biopsies in patients with SLE enrolled in the Accelerating Medicines Partnership, a consortium formed to molecularly deconstruct nephritis.Methods 475 patients with SLE across 15 clinical sites in the USA consented to obtain tissue for research purposes during a clinically indicated kidney biopsy. Adverse events (AEs) were documented for 30 days following the procedure and were determined to be related or unrelated by all site investigators. Serious AEs were defined according to the National Institutes of Health reporting guidelines.Results 34 patients (7.2%) experienced a procedure-related AE: 30 with haematoma, 2 with jets, 1 with pain and 1 with an arteriovenous fistula. Eighteen (3.8%) experienced a serious AE requiring hospitalisation; four patients (0.8%) required a blood transfusion related to the kidney biopsy. At one site where the number of cores retrieved during the biopsy was recorded, the mean was 3.4 for those who experienced a related AE (n=9) and 3.07 for those who did not experience any AE (n=140). All related AEs resolved.Conclusions Procurement of research tissue should be considered feasible, accompanied by a complication risk likely no greater than that incurred for standard clinical purposes. In the quest for targeted treatments personalised based on molecular findings, enhanced diagnostics beyond histology will likely be required.

Objective The outcome of participants with nephrotic syndrome in clinical trials of lupus nephritis has not been studied in detail.Methods Collated data from two randomised controlled trials in lupus nephritis, Lupus Nephritis Assessment of Rituximab (LUNAR) and A Study to Evaluate Ocrelizumab in Patients With Nephritis due to Systemic Lupus Erythematosus (BELONG) were analysed. Nephrotic syndrome was defined as albumin

BackgroundTreatment 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 findingsIn 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 ConclusionsAn individualized decision aid was more effective than usual care in reducing decisional conflict for choice of immunosuppressive medications in women with lupus nephritis.Trial registrationClinicaltrials.gov, NCT02319525.

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