Faculty Bibliography

OBJECTIVE:Physical activity can reduce cardiovascular disease and depression risk and improve quality of life in patients with systemic lupus erythematosus (SLE). To facilitate physical activity and achieve health benefits in patients with SLE, it is critical to understand potential barriers to physical activity, including socioeconomic, social, demographic, quality-of-life, or clinical factors. METHODS:We conducted cross-sectional analyses of data from a large, diverse cohort of patients with SLE. All completed the International Physical Activity Questionnaire, recalling the past seven days of vigorous physical activity, moderate activity, or walking. Data included financial insecurity, Everyday Discrimination Scale, education, demographics, lupus-specific disease activity, immunosuppressive medication, Census Block Area Deprivation Index, and patient-reported pain, fatigue, and cognitive function. Multivariable models included logistic regression for dichotomous outcome of "any" moderate/vigorous physical activity and quasi-Poisson model for total combined days of moderate and vigorous activity. RESULTS:Of the 271 participants, 170 (63%) reported any moderate or vigorous activity in the past 7 days (mean = 2.6 days of moderate/vigorous activity). Only 4% reported zero days of physical activity. Logistic regression analysis indicated that active disease was associated with 47% lower odds of engaging in any moderate/vigorous physical activity (P = 0.04) and with a 35% reduction in the mean number of days of moderate to vigorous physical activity (P = 0.04). In contrast, individual- and area-level socioeconomic factors and patient-reported outcomes were not associated with physical activity. CONCLUSION/CONCLUSIONS:Moderate/vigorous physical activity was negatively associated only with disease activity. The current study reinforces the need primarily to control SLE disease activity to promote patients' ability to be physically active, which may improve symptoms.

BACKGROUND/UNASSIGNED:Hydroxychloroquine (HCQ) is a cornerstone of systemic lupus erythematosus (SLE) management. However, the medication can accumulate within organs and cause toxicity including retinopathy. HCQ is usually discontinued once ocular toxicity is diagnosed, but this is not always sufficient to avoid further damage. Whether retinal injury progresses following HCQ cessation, and which patients are at risk, is of great interest. Prior studies examining progression after HCQ discontinuation are sparse and limited by small sample sizes, and none specifically examine patients with SLE. This study aimed to identify predictors of progression of HCQ-induced retinopathy in SLE patients after medication discontinuation. METHODS/UNASSIGNED:We queried the NYU Lupus Cohort to identify patients with documented HCQ-induced retinopathy who discontinued HCQ and had at least one optical coherence tomography (OCT) follow-up to assess for progression. Demographic information, cumulative HCQ dose, duration of therapy, presence of chronic kidney disease or tamoxifen use, SLE disease activity, and ophthalmologic follow-up intervals were collected. Two ophthalmologists independently reviewed OCT and Humphrey visual field data to confirm retinopathy, grade its severity, and determine progression following drug discontinuation. Statistical analysis was performed using Student's t-test or Wilcoxon rank-sum test for continuous variables and Chi-square or Fisher's exact test for categorical variables. RESULTS/UNASSIGNED:Twenty-one patients with confirmed HCQ retinopathy were included. The mean duration of HCQ therapy preceding diagnosis was 16.2 years and the mean cumulative exposure was 1884 g. Retinal toxicity progressed in 6 patients (28.6%) despite HCQ discontinuation. There appeared to be a trend towards a greater likelihood of progression with more severe retinal toxicity at the time of diagnosis. However, there were no differences between progressors and non-progressors with respect to age at diagnosis, duration or cumulative HCQ exposure, SLE disease activity, tamoxifen use, chronic kidney disease, or guideline-concordant care. CONCLUSIONS/UNASSIGNED:Nearly thirty percent of patients with SLE and HCQ retinopathy progressed despite drug discontinuation. No baseline clinical predictors were associated with progression, though there was a descriptive trend toward greater risk with more severe baseline retinopathy. These data emphasize the importance of continued ocular surveillance for progression of toxicity after discontinuation.

OBJECTIVE:Epidemiologic estimates for age of systemic lupus erythematosus (SLE) diagnosis are limited, particularly for men and racial and ethnic subpopulations in the United States. Leveraging the Centers for Disease Control and Prevention (CDC) National Lupus Registry network of population-based SLE registries, meta-analyses were performed estimating age-specific incidence of SLE by sex, race, and ethnicity. METHODS:The CDC network of SLE registries includes five state-based registries, plus a sixth Indian Health Service registry. Incidence periods spanned calendar years 2002-2018. Registries provided age-specific incidence of SLE, fulfilling the American College of Rheumatology (ACR) SLE classification criteria, per 100,000 person-years, stratified by sex, race, and ethnicity for the meta-analyses. RESULTS:Incidence rates among women were highest for those aged 30-39 (12.7, 95%CI: 9.5-16.8), while rates among men were highest for those aged 60-69 (2.1, 95%CI: 1.3-3.4). Black women aged 20-39 had the highest SLE incidence rates (23.6, 95%CI: 20.7-26.8). Among women diagnosed with SLE before age 20, incidence was highest among Asian (6.5, 95%CI: 2.8-15.2) individuals. Among women diagnosed with SLE after age 60, incidence was highest among American Indian/Alaska Native (9.4, 95%CI: 3.4-15.4) individuals. Weighted percentages show 10.0% of those with SLE were diagnosed before age 20, while 15.1% were diagnosed after age 60. The largest proportion of individuals with SLE, 22.1%, were diagnosed between 30-39 years. CONCLUSIONS:This study provides comprehensive sex- and race-specific estimates of age at SLE diagnosis. The substantial later in life SLE incidence among men and disease burden in pediatric and older populations should raise awareness in considering SLE in the differential diagnosis in previously underrecognized groups.

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE), is a heterogeneous disease driven by diverse immune and tissue cell types. We obtained 538,194 single-cell and 142,881 single-nuclear profiles from kidney biopsies of 155 patients with LN and 30 preimplantation transplant biopsy controls, along with 327,326 single-cell blood profiles. We characterized key stromal and immune cell types and cell states; moreover, we distinguished cell states that were tissue specific from those that were also present in the blood. We observed that LN pathological features were associated with particular cell states. For example, after controlling for the effects of chronic tissue damage, we observed that expansion of glomerular and scar-associated macrophage populations correlated with increasing inflammatory disease activity. Scar-associated macrophages appear to drive LN fibrosis and, in active disease, infiltrate the glomeruli more than other myeloid cells. These observations support that therapeutic targeting of myeloid populations may offer a strategy to prevent renal inflammation and ongoing kidney damage in LN.

PURPOSE/UNASSIGNED:To examine the correlation between hydroxychloroquine levels with real body weight and ideal body weight dose and identify patient characteristics at risk for subtherapeutic or supratherapeutic dosing. METHODS/UNASSIGNED:A retrospective chart review of 181 patients with lupus (429 unique hydroxychloroquine whole blood levels) was performed. Hydroxychloroquine levels <100 (indicating medication noncompliance) were excluded (n = 26). Summary statistics, linear regression of hydroxychloroquine level and real body weight/ideal body weight, and odds ratios (ORs) for factors associated with supratherapeutic (>2000 ng/mL) or subtherapeutic (<750 ng/mL) hydroxychloroquine levels were calculated. RESULTS/UNASSIGNED:, respectively. CONCLUSIONS/UNASSIGNED:All dosing schedules show variability in hydroxychloroquine levels. Ideal body weight may correlate more strongly with hydroxychloroquine level than real body weight. Under real body weight-based guidelines, obesity may increase the risk for supratherapeutic hydroxychloroquine levels, and low weight may increase the risk for subtherapeutic levels.

OBJECTIVES/OBJECTIVE:Autoantibodies directed against Telomerase RNA Ro y-RNAs and Vault RNAs Domain Family Member 2 (TROVE2)/Ro60 and Tripartite Motif 21 (TRIM21)/Ro52 are historically related to distinct SSA/Ro autoantigens. However, despite advances facilitating separate testing, these autoantibodies remain frequently confused resulting in a lack of clarity and precision in the literature. We conducted a systematic literature review to inform a Delphi process to achieve consensus on a clearer, harmonised nomenclature. METHODS:The systematic review included primary publications in systemic lupus erythematosus (SLE) and Sjögren disease (SjD) published between January 1, 2000 and May 26, 2025 that mentioned testing for anti-TROVE2/Ro60 and/or anti-TRIM21/Ro52 autoantibodies. This analysis contributed to a Delphi consensus exercise proposing preferred nomenclature by a group of 17 international expert physicians and laboratorians. RESULTS:Eight hundred ninety-one publications were included (301 SLE, 493 SjD, and 97 mixed SLE/SjD). Only 20.9% of studies tested and reported the autoantibodies separately; 75.0% did neither; and 4.2% tested but did not report them separately. There was considerable nomenclatural heterogeneity with 16 different terms used for anti-TROVE2/Ro60 and 11 terms for anti-TRIM21/Ro52 autoantibodies. After 2 rounds of voting, the Delphi panel reached a unanimous consensus on the terms anti-TROVE2/Ro60 and anti-TRIM21/Ro52 autoantibodies. CONCLUSIONS:The distinction of anti-TROVE2/Ro60 and anti-TRIM21/Ro52 autoantibodies was frequently unclear and imprecise throughout the literature. Their clinical associations also lacked clarity and precision. To clarify and strengthen the understanding of the clinical associations of these 2 important autoantibodies, the terms anti-TROVE2/Ro60 and anti-TRIM21/Ro52 are recommended for future studies and publications.

OBJECTIVES/OBJECTIVE:Lupus nephritis (LN) is a common, potentially fatal manifestation of systemic lupus erythematosus. We aimed to gain new insights into the immune responses underlying LN and their relation to the histologic heterogeneity observed in this disease, focusing on myeloid cells. METHODS:We used single-cell RNA-sequencing (scRNA-seq) data of dissociated kidney samples from 156 patients with LN and 30 healthy individuals. We applied spatial transcriptomics (ST), utilising a gene panel designed to capture all myeloid subsets identified in the scRNA-seq data, to profile kidney samples acquired from 6 patients with LN and 2 controls. RESULTS:CD8 T, B, and dendritic cells, with a parallel decrease in the interferon response. In proliferative/mixed LN only, the degree of active inflammation correlates with the expansion of disease-specific macrophage (DMac) subsets, which later contract as the CI increases. Trajectory analysis of the scRNA-seq data suggested that DMacs arise from both infiltrating monocytes and tissue-resident macrophages; this was supported by the ST data, as well as cell cultures. DMacs are implied to interact with parietal epithelial cells, promoting the development of glomerulosclerosis. CONCLUSIONS:We suggest a detailed picture of the changes in the kidney immune mechanisms in LN as this disease progresses.

OBJECTIVE:Kidney survival is the ultimate goal in lupus nephritis (LN) management, but long-term predictors remain inadequately studied, requiring long-term follow-up. This study aimed to identify baseline and early longitudinal predictors of kidney survival in the Accelerating Medicines Partnership LN longitudinal cohort. METHODS:We performed time-to-event analyses of clinical, centrally scored histological, and serological predictors of kidney function loss (sustained ≥ 40% eGFR decline or progression to end-stage kidney disease) in 172 LN patients with a median follow-up of 4.6 years (range 0.5-7.8). RESULTS:Kidney function loss occurred in 57/172 (33%) patients. Baseline lower eGFR, non-first kidney biopsy, and higher NIH Chronicity Index (CI) were associated with eGFR loss. CI was the strongest predictor, but no clear threshold defined higher risk. NIH Activity Index and International Society of Nephrology (ISN) class were not predictive. Proteinuria at 12 months was prognostic, with urine protein to creatinine ratio <0.7 g/g associated with lower risk, though no single threshold ensured protection, and lower levels had better outcomes. Lack of complete clinical response at 3, 6, or 12 months predicted future eGFR loss, while partial response conferred intermediate risk. Serological markers were not associated with eGFR loss. CONCLUSION/CONCLUSIONS:Low baseline eGFR and chronic histologic damage, but not activity or ISN class, predicted eGFR loss. Proteinuria <0.7 g/g at 1 year was associated with better outcomes but did not ensure protection. Since proteinuria does not reflect intrarenal inflammation, these results suggest current response definitions serve better as prognostic indicators than true measures of treatment efficacy, and better biomarkers are needed.

Dendritic cells (DCs) facilitate the maintenance of immunological tolerance in the steady state. We report that transcription factor Etv3 is preferentially expressed in mature DCs, including tissue-derived migratory DCs (migDCs), and facilitates their homeostatic maturation and CCR7-dependent migration. Mice with global or DC-specific deletion of Etv3 manifested the expansion of CD25^low regulatory T (T_reg) cells, spontaneous activation of conventional T cells, and multiorgan T cell infiltration. Etv3 deficiency exacerbated TLR7-driven systemic lupus erythematosus (SLE)-like disease, supporting the reported genetic association of human ETV3 with SLE. Etv3-deficient migDCs up-regulated multiple costimulatory molecules, including OX40 ligand (OX40L/TNFSF4), whose blockade partially rescued the T_reg cell abnormalities. These results identify Etv3 as an essential regulator of the tolerogenic function of DCs and implicate it in the regulation of human autoimmunity.