In South Korea, belimumab is indicated for patients with systemic lupus erythematosus (SLE), including paediatric patients aged ≥ 5 years, and for adults with lupus nephritis, based on clinical trial evidence; however, real-world data in this population remain limited. To assess the real-world safety and effectiveness of intravenous (IV) belimumab administered in patients with SLE in South Korea. This observational study (GSK Study 216984) enrolled patients with active SLE and patients with lupus nephritis across 18 South Korean institutions (July 2021–February 2023). Patients received on-label IV belimumab plus standard therapy (antimalarials, glucocorticoids and immunosuppressants). Data were collected for a minimum of 48 weeks as part of routine clinical practice (July 2021–March 2024). Safety was assessed by monitoring the incidence of adverse events (AEs), adverse drug reactions (ADRs), serious AEs (SAEs)/ADRs and AEs of special interest (including psychiatric events) and summarised descriptively. Changes in SELENA-SLEDAI scores, laboratory biomarkers and glucocorticoid dosage from baseline to week 24 or 48 were tested using the Wilcoxon signed-rank test. Of 126 enrolled patients, 105 were eligible for the ≥ 48-week safety evaluation (completed ≥ 24 weeks of belimumab treatment). Patients were mostly female (91.4

OBJECTIVE:Using a hydroxychloroquine (HCQ) dose of 5 mg/kg/day in systemic lupus erythematosus (SLE) is associated with a higher risk of flares; HCQ blood level monitoring could be a better way to adjust the HCQ dose. We studied the upper threshold for a reference range of HCQ levels to inform routine monitoring. METHODS:This observational study included patients (N = 2,010) across the Systemic Lupus International Collaborating Clinics, Wisconsin, international, and French studies who underwent HCQ blood level measurements. Using adjusted spline and logistic regression analyses on the cross-sectional data, we first identified an HCQ blood level associated with higher HCQ toxicity. Next, we tested if this upper threshold level was supratherapeutic (no further risk reduction for the Systemic Lupus Erythematosus Disease Activity Index 2000 [score ≥6]). Finally, we examined associations between chronic kidney disease (CKD) stage and supratherapeutic (toxic) HCQ blood levels. RESULTS:Among 1,842 patients (excluding 168 patients with very low HCQ blood levels), 4.9% had HCQ-related toxicity. Odds of toxicity were 2.1-fold higher with blood levels ≥1,150 ng/mL and 1.7-fold higher with the cumulative HCQ dose per 1,000-g increase. Blood levels ≥1,150 ng/mL were associated with a saturation in therapeutic effect, indicating supratherapeutic levels. Patients with CKD stage ≥3 had 2.3-fold higher odds of having supratherapeutic levels (≥1,150 ng/mL). CONCLUSION:The therapeutic reference range for HCQ blood level monitoring is 750 to <1,150 ng/mL. HCQ level monitoring could optimize HCQ use, particularly in patients with CKD stage ≥3. Future longitudinal studies are needed to validate the use of HCQ blood level monitoring in optimizing dosing.

Lupus nephritis (LN) is a common and severe manifestation of systemic lupus erythematosus (SLE). We sought to evaluate treatment patterns, treat-to-target state attainment, and outcomes of patients with active LN on non-biologic, conventional therapy, in a large real-world cohort from the Asia–Pacific region. Adult patients enrolled in a multinational lupus cohort were studied for evidence of active LN, defined based on the SLE Disease Activity Index-2000 (SLEDAI-2K)-proteinuria threshold (> 0.5 g/24 h or > 0.05g/mmol), ≥ 2 visits of data, and no exposure to biologics. The subset of these patients who had kidney biopsy-confirmed LN was retrospectively determined. Attainment of treatment goals, including modified versions of complete renal response (mCRR) and primary efficacy renal response (mPERR), lupus low disease activity state (LLDAS) and DORIS remission (REM), and organ damage accrual, were assessed over time following the first visit with proteinuria. One thousand one hundred eighty patients were studied for a median 2.7 [IQR 1.0, 5.0] years, 435 (37

Genome-wide association studies have identified genetic polymorphisms at 11p15 associated with Systemic Lupus Erythematosus (lupus). Statistical fine mapping prioritizes a highly prevalent coding haplotype within the IRF7 gene. Analysis of ancient DNA confirms that this haplotype has persisted at high frequencies in the global population for millennia. The IRF7 risk haplotype is sufficient to increase nuclear localization of IRF7 and transcriptional activity downstream of pattern recognition receptor pathways. This risk haplotype increases IRF7 DNA binding strength and alters IRF7 DNA sequence specificity, resulting in genotype-dependent increases in IFN-α production in numerous biological systems, including monocytes and airway epithelial cells. CRISPR engineering of a homologous risk variant in mouse Irf7 results in both enhanced innate control of virus infection and increased autoantibody titers in a model of autoimmunity. Altogether, we establish a persistent and prominent genetic IRF7 haplotype that amplifies IRF7 activity in a manner that has immunological risks and benefits. HIGHLIGHTS:Genetic analysis using modern and evolutionary datasets identifies a persistent and highly prevalent lupus-associated coding haplotype in IRF7 at 11p15 The IRF7 lupus risk haplotype increases IFN-α production by monocytes and airway epithelial cells The IRF7 lupus risk haplotype increases IRF7 DNA binding strength and alters DNA sequence specificity A homologous lupus risk variant in mouse Irf7 enhances control of vesicular stomatitis virus and exacerbates autoantibody production.

Systemic lupus erythematosus (SLE) guidelines predominantly focus on common major organ involvement. An international taskforce from three SLE expert groups (European Reference Network on Connective Tissue and Musculoskeletal Diseases, Systemic Lupus International Collaborating Clinics, and the European Lupus Society) previously developed consensus therapeutic strategies for 24 rare SLE manifestations. Here, 77 participants contributed to the development of consensus therapeutic strategies for 22 additional rare SLE manifestations, including diffuse pulmonary haemorrhage, rare cutaneous manifestations (bullous lupus, chilblain lupus, lupus tumidus, erythema multiforme, and toxic epidermal necrolysis-like lupus erythematosus), renal manifestations (interstitial nephritis and lupus podocytopathy), rare neurological manifestations (chorea, small fibre neuropathy, catatonia, and intracranial hypertension), rare gastrointestinal manifestations (protein-losing enteropathy, lupus hepatitis, intestinal pseudo-obstruction, and peritonitis), musculoskeletal manifestations (myositis and Jaccoud's arthropathy), and other rare manifestations such as uveitis, angioedema due to anti-C1 esterase inhibitor antibodies, interstitial cystitis, and lupus mastitis. These expert-based therapeutic strategies provide a framework for guiding therapeutic decisions where evidence-based recommendations might be insufficient.

OBJECTIVE:To evaluate the risk of intrahepatic cholestasis of pregnancy (ICP) in azathioprine (AZA)-exposed versus unexposed systemic lupus erythematosus (SLE) pregnancies within the multicenter prospective Lupus in Pregnancy (LEGACY) cohort. METHODS:LEGACY is conducted at Systemic Lupus International Collaborating Clinics in Canada, South Korea, Peru, and Mexico. Pregnant women with SLE are enrolled before 17 weeks and followed in the second (20-24 weeks) and third (30-34 weeks) trimesters and postpartum (8-12 weeks). Because ICP occurs after 20 weeks, only pregnancies with a second-trimester visit were included. Follow-up began at that visit and continued until delivery. AZA exposure was modeled as time varying. The primary outcome was iatrogenic delivery for ICP or spontaneous preterm birth occurring after ICP diagnosis. Multivariable Cox models with frailties adjusted for relevant covariates. At the Montreal site, thiopurine metabolites and shunting were assessed. RESULTS:Among 127 SLE pregnancies (46 AZA exposed, 81 unexposed), 10 ICP cases occurred (each in a distinct woman): 8 among AZA exposed (17.4%, 95% confidence interval [CI] 9.1-30.7) and 2 among unexposed (2.5%, 95% CI 0.7-8.6). AZA exposure was associated with a substantially increased risk of ICP (adjusted hazard ratio 12.1, 95% CI 2.4-59.7). All ICP cases with metabolite data (4 of 4) showed second-trimester shunting. Among all pregnancies with second-trimester metabolite data (n = 22), 36.4% (95% CI 19.7-57.0) were shunting, and 50.0% (95% CI 21.5-78.5) of these developed ICP. CONCLUSION:We observed that AZA exposure may be strongly associated with ICP in SLE pregnancies. Second-trimester thiopurine shunting may identify women at high risk, supporting the value of metabolite monitoring.

OBJECTIVE:This study attempted to quantify the bias expected due to partly interval-censored (IC) outcomes in the estimated association between hydroxychloroquine (HCQ) taper/cessation and time to disease flare among individuals with systemic lupus erythematosus (SLE). METHODS:Using data-driven simulations, we estimated bias expected due to IC using real-world data from the Systemic Lupus International Collaborating Clinics inception cohort. The time-varying exposure of interest was a binary indicator of HCQ tapering/cessation. The composite outcome was lupus flare, defined as lupus hospitalizations or increases in disease activity or medication dose. The two latter components were IC, as they were recorded only at annual assessment, without a precise date. For the unknown IC event times, a "true" event time was randomly generated from a uniform distribution of the time between two assessments. Each simulated sample was analyzed separately imputing unknown event times (for IC outcomes) either at the midpoint or endpoint of the interval between the two adjacent yearly assessments. Results of multivariable Cox proportional hazards models, adjusted for demographics, drugs, and clinical variables, using either "true" or imputed IC event times were compared. RESULTS:The 1543 SLE patients were followed for a median of 42.2 months. During follow-up, 396 participants tapered/stopped HCQ and 1187 experienced a flare. The adjusted uncorrected hazard ratio was 1.51 (95% confidence interval: 1.30, 1.75) and 1.40 (95% confidence interval: 1.21, 1.62) for midpoint and endpoint imputations, respectively. Data-driven simulations showed that imputation of IC event times resulted in a small but systematic bias toward the null that was consistently larger for endpoint than for midpoint imputation. CONCLUSIONS:IC events induced bias toward the null in the estimated association between HCQ taper/cessation and lupus flares. Data-driven simulations are useful for quantitative bias analyses in complex situations, as they allow accounting for relevant characteristics of a particular real-world dataset.

Objectives Adverse pregnancy outcomes (APO) are a major concern in SLE, particularly with antiphospholipid antibodies. While lupus anticoagulant (LAC) is the strongest predictor of APO, emerging evidence suggests anti-phosphatidylserine/prothrombin antibodies (aPS/PT) may also indicate increased risk. We examined whether aPS/PT predict APO and how they compare to LAC in the multicenter prospective LEGACY cohort. Methods LEGACY includes Systemic Lupus International Collaborating Clinics in Canada, South Korea, Peru, and Mexico. Pregnant SLE women are consecutively enrolled <17 weeks’ gestation and followed at predefined visits throughout pregnancy and postpartum. At enrollment, plasma was tested for aPS/PT, using ELISA (Werfen, San Diego), with positivity cutoffs for IgG and IgM as >30 chemiluminescent units. LAC testing was performed at each site using validated assays. The present analysis includes the first 98 pregnancies with aPS/PT results. APO were a composite outcome of either: (1) fetal death >20 weeks, (2) neonatal death, (3) placenta-mediated preterm delivery <36 weeks, and/or 4) small for gestational age (<5th percentile). We performed multivariable hazards models with frailties and gestational age as the time axis to assess associations between APO and aPS/PT IgG and/or IgM vs LAC. Maternal covariates at enrollment included age, body mass index, prior nephritis, SLE Pregnancy Disease Activity Index, and medications. We used Harrell’s C-index to assess model discrimination. Results Among 98 SLE pregnancies, 9 (9%) were aPS/PT IgG-positive, 25 (26%) were aPS/PT IgM-positive, and 11 (11%) were LAC-positive (Table 1). Eight pregnancies (8%) were positive for both aPS/PT (IgG and/or IgM) and LAC. Thirteen pregnancies (13%) experienced APO, including 5/9 (56%) in the aPS/PT IgG-positive group and 5/11 (46%) in the LAC-positive group. In multivariable analysis, aPS/PT IgG positivity was strongly associated with APO (HR 12.2, 95% CI 1.7-87.2), whereas IgM and/or overall aPS/PT positivity showed nonsignificant trends [HR 1.9 (95% CI 0.3-11.2) and HR 2.2 (95% CI 0.4-11.2), respectively]. LAC positivity was also associated with a substantially higher APO risk (HR 7.8, 95% CI 1.7-35.1), though less strongly than aPS/PT IgG. Discriminative performance was slightly higher for aPS/PT IgG (adjusted C-index 0.80, 95% CI 0.65-0.95) compared with LAC, aPS/PT IgM, and combined aPS/PT IgG and/or IgM models (0.78, 95% CI 0.68-0.89; 0.72, 95% CI 0.59-0.85; and 0.73, 95% CI 0.61-0.86, respectively). Table 1. Maternal characteristics at baseline and pregnancy outcomes (n=98) Conclusion In this preliminary analysis of the LEGACY cohort, aPS/PT IgG demonstrated a stronger independent association with APO and slightly better discriminative performance than LAC. These findings suggest that aPS/PT IgG may outperform LAC in predicting APO and could improve risk stratification in SLE pregnancies. Supported by a CIORA grant.

Objectives Intrahepatic cholestasis of pregnancy (ICP) is linked to adverse maternal and fetal outcomes. Emerging data from IBD cohorts and a 2024 FDA safety report suggest a strong association between thiopurines and ICP.[1] This is concerning as azathioprine (AZA), a thiopurine, is the immunosuppressive of choice in SLE pregnancies. However, evidence in SLE is limited to a 2025 administrative study reporting a 3-fold increased ICP risk with AZA, without considering disease activity or thiopurine metabolites.[2] Thus, we performed a multicenter prospective cohort study to evaluate the risk of ICP in AZA-exposed vs unexposed SLE pregnancies. Methods The Lupus in prEGnAnCY (LEGACY) cohort is conducted at SLICC centers in Canada, South Korea, Peru, and Mexico. Pregnant women with SLE are enrolled before 17 weeks and followed in the second (20–24 weeks), third (30–34 weeks) trimesters, and postpartum (8-12 weeks). Since ICP occurs after 20 weeks, only pregnancies with a second-trimester visit were included. Follow-up began at that visit and continued until delivery. AZA exposure was modeled as time varying. The primary outcome was delivery for ICP and/or early-onset ICP (<28 weeks). Multivariable Cox proportional hazards models with frailties adjusted for maternal demographics, co-morbidities, disease activity, and glucocorticoid use. At the Montreal site, thiopurine metabolites and shunting were assessed, using established cut-offs.[3] Results Of 127 SLE pregnancies, 46 were AZA-exposed and 81 unexposed (Table 1). Ten ICP cases occurred (each in a distinct woman): 8 among AZA-exposed (17.4%, 95% CI 9.1-30.7) and 2 among unexposed (2.5%, 95% CI 0.7-8.6). AZA was continued until and beyond delivery in most (6/8) exposed ICP cases. All ICP cases required delivery except one AZA-exposed case (who stopped AZA at ICP diagnosis). AZA exposure was associated with a substantially increased risk of ICP (unadjusted HR 9.1, 95% CI 1.9-44.5; adjusted HR 11.9, 95% CI 2.2-65.1). Of note, all ICP cases with metabolite data (4/4) exhibited second-trimester shunting. Among all pregnancies with second-trimester metabolite data (n=22), 36.4% (95% CI 19.7-57.0) were shunting, and 50.0% (95% CI 21.5-78.5) of these developed ICP. No ICP occurred with tacrolimus alone (n=14). All ICP pregnancies resulted in live births, although AZA-exposed cases tended to have higher bile acid levels, earlier delivery, and lower birth weight for gestational age vs unexposed cases. Table 1. Characteristics of SLE pregnancies at the second trimester visit according to AZA exposure (n=127) Conclusion We observed that AZA exposure was strongly associated with ICP in SLE pregnancies. Second-trimester thiopurine shunting may identify women at highest risk, supporting the value of metabolite monitoring. References [1.] Joudaki S, Aliment Pharmacol Ther 2025;61:1430-6. [2.] Nguyen NV. Am J Gastroenterol 2025;121:1183-91. [3.] Lambert-Fliszar F, Lupus Sci Med 2021;8:e000519. Supported by a CIORA grant. Best Abstract by a Post-Graduate Research Trainee Award

ObjectiveLupus nephritis (LN) is a major mortality risk factor in patients with systemic lupus erythematosus (SLE). We investigated the predictors of end-stage renal disease (ESRD) and mortality in patients with LN.MethodsWe enrolled 599 Korean patients with biopsy-proven proliferative or membranous LN from a prospective cohort of 1497 patients with SLE. Baseline demographics, serology, histology, disease activity, and organ damage were collected and assessed. Regression models were used to evaluate predictors of renal survival and mortality.ResultsWe followed a total of 599 patients with proliferative LN (class III or IV/±V, N = 509) or membranous LN (class V, N = 90). Among these patients, 42 patients (7.0%) progressed to ESRD and 31 (5.2%) died. In a multivariate logistic regression analysis, antiphospholipid antibody positivity (OR 3.18, p = .023), higher activity and chronicity indices at biopsy (OR 1.14, p = .034; OR 1.33, p = .042), and sustained high disease activity (extra-renal adjusted mean Systemic Lupus Erythematosus Disease Activity Index-2000 [SLEDAI-2K] ≥ 3, OR 4.33, p = .019) significantly influenced progression to ESRD after adjusting for age at LN diagnosis, gender, disease duration, and hypertension. While the 6-month renal response after induction treatment showed no association with ESRD risk, the 12-month treatment response demonstrated a significant association (p < .001). Renal survival was poorer in patients with an activity index ≥6 and in those with a chronicity index ≥4 (p = .013 and p = .002, respectively). Patients who developed ESRD had significantly worse overall survival than those who did not (p = .028). Higher adjusted mean SLEDAI-2K (hazard ratio [HR] 1.43, p < .0001) and higher extra-renal adjusted mean SLEDAI-2K (HR 1.83, p < .0001) were significantly associated with increased overall mortality.ConclusionsOur study indicates that antiphospholipid antibodies, higher histologic activity and chronicity indices, and sustained high disease activity beyond renal items were independently associated with progression to ESRD. Mortality was increased among patients with ESRD and those with persistent high disease activity. These findings emphasize the need for stringent disease activity control and support clinicopathologic stratification to identify patients at high risk of adverse long-term renal outcomes.

OBJECTIVES:To determine the prevalence and predictive correlates of arthritis and joint damage in systemic lupus erythematosus (SLE) patients in the Asia-Pacific Lupus Collaboration (APLC) cohort, and to determine their impact on health-related quality of life (HRQoL). METHODS:SLE patient data (2013-2020) were collected from the prospective multinational APLC cohort. We defined arthritis according to the SLE Disease Assessment Index (SLEDAI-2K) definition of persistent arthritis as arthritis in ≥2 consecutive visits, and joint damage according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) definition (deforming or erosive arthritis). HRQoL was measured by Short Form Survey (SF36). Descriptive statistics, univariable and multivariable Cox hazard models, and Kaplan-Meier analyses were performed. RESULTS:During median 2.5 (1.0-5.1) years of follow-up, 803/4106 (19.6%) patients had arthritis at least once, and 18/3383 (0.53%) accrued joint damage. Patients with arthritis were more likely to be female, Caucasian, current smokers at enrolment, and less like to have tertiary education; they also had higher overall disease activity, and lower physical and mental HRQoL. Kaplan-Meier analysis demonstrated that joint damage was more likely in patients with arthritis. Persistent arthritis and longer follow-up were risk factors for joint damage accrual; being from high-income countries was protective. Patients with joint damage also had worse physical HRQoL. CONCLUSION:Arthritis in the APLC cohort was infrequent compared with other cohorts and was associated with smoking, higher overall disease activity, and damage accrual across multiple domains. Presence of arthritis significantly impacted physical and mental HRQoL. Joint damage was strongly predicted by persistent arthritis.

OBJECTIVE:This study aimed to explore evidence related to long-term health outcomes for patients with connective tissue disease (CTD)-associated pulmonary arterial hypertension (PAH) and any clinical practices associated with screening, early detection, and initiation of treatments. METHODS:We conducted a systematic literature review (SLR) of observational studies and randomised controlled trials of adult patients with confirmed CTD-PAH, including systemic lupus erythematosus (SLE)-PAH, systemic sclerosis (SSc)-PAH, and mixed CTD (MCTD)-PAH. Based on the findings from our SLR, we conducted a Delphi panel to develop recommendations and consensus around early detection and initiation of appropriate treatment for patients with CTD-PAH. RESULTS:Sixty-three publications (54 studies and 9 guidelines) were included in the SLR, with 22 involving Asia-Pacific populations. Combination therapy reduced clinical worsening and mortality versus monotherapy. After three Delphi rounds, consensus was reached on the importance of early PAH screening in CTD, with disease-specific recommendations for SLE, SSc, and MCTD. Consensus was also achieved on appropriate treatments, including endothelin receptor antagonists (ERA), phosphodiesterase-5 (PDE5) inhibitors, and pulmonary vasodilators. However, long-term outcomes remain uncertain due to limited evidence. CONCLUSION:This study highlights the need for early screening and timely treatment initiation in CTD-PAH to potentially reduce adverse long-term outcomes.

OBJECTIVE:This research article aims to describe the prevalence, associations, and health-related quality of life (HRQoL) impact of mucocutaneous features of systemic lupus erythematosus (SLE). METHODS:Data from the Asia-Pacific Lupus Collaboration cohort were analyzed (2013-2021). Mucocutaneous activity (MC-A) items were rash, alopecia, and mucosal ulcers; were defined by the Systemic Lupus Erythematosus Disease Activity Index 2000; and were persistent if present for at least six months. Mucocutaneous damage (MC-D) items were chronic skin ulceration, scarring alopecia, and skin/panniculum scarring and were defined by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. HRQoL was measured by 36-Item Short Form Health Survey (SF-36) surveys. Multivariate logistic generalized estimating equation models were used to determine correlates of MC-A at each visit. Time-varying covariate survival models were used to determine predictors of MC-D. RESULTS:During a median of 2.5 (interquartile range 1.0-5.1) years' follow-up, 1,499 of 4,102 patients (36.5%) had MC-A (rash n = 1,055, alopecia n = 731, mucosal ulcers n = 352) and 606 of 3,655 patients (16.6%) had persistent MC-A. These patients were more likely to record worse mean mental (42.6 vs 44.8; P = 0.014) and physical component (41.1 vs 46.1; P < 0.001) SF-36 scores. Being White, smoking, serologic activity, vasculitis, myositis, serositis, nephritis, and neurologic/psychiatric features were correlates of MC-A. Of 3,647 patients, 157 (4.3%) accrued MC-D (skin/panniculum scarring n = 53, alopecia n = 98, ulceration n = 30). These patients had worse mean physical component (39.8 vs 46.0, P = 0.001) SF-36 scores and were more likely to be White with persistent MC-A. CONCLUSION:All mucocutaneous manifestations were associated with worse HRQoL. MC-A correlated with serologic and systemic disease activity burden in SLE. Persistent MC-A was associated with increased risk of MC-D, emphasizing the importance of early and effective treatment. Both MC-A and MC-D were more likely in White patients, suggesting ethnic and environmental impacts. Smoking was a potentially modifiable correlate of MC-A.

Objectives We aimed to characterise the dynamic transcriptional changes associated with treatment responses in lupus nephritis (LN) through longitudinal single-cell RNA sequencing analysis of peripheral blood mononuclear cells (PBMCs) during standard-of-care induction therapy. Methods We leveraged the Korean Unlimited multi-Dimensional Omics research in Systemic lupus erythematosus cohort, comprising patients with biopsy-proven active proliferative LN. Single-cell RNA sequencing of PBMCs was conducted at baseline and subsequently at 3, 6, and 12 months following initiation of therapy (n = 10). For validation purposes, bulk RNA sequencing of monocytes was performed in an independent patient group at baseline and at 3 months (n = 13). Renal response was classified as complete response or nonresponse at 12 months according to predefined criteria. Results In single-cell RNA sequencing analysis of patients with LN, the myeloid cell population—particularly classical and intermediate monocytes—demonstrated the highest number of differentially expressed genes following induction therapy. Weighted gene coexpression network analysis identified distinct gene modules closely associated with treatment responses. Complete responders exhibited progressive suppression of type I interferon (IFN-I) signalling, whereas nonresponders maintained persistent IFN-I-driven gene expression characterised by sustained inflammatory features. Bulk RNA sequencing of monocytes from an independent group of patients with LN confirmed that 6 IFN-I-responsive genes (IRF7, ISG15, LY6E, IFI44, IFI44L, and IFI6) were significantly downregulated by 3 months in complete responders, but not in nonresponders. This gene signature correlated with both proteinuria and disease activity scores. Conclusions This study demonstrates that persistent IFN-I-driven gene expression in monocytes characterises treatment resistance in LN. Our findings suggest that early transcriptional profiling may enable timely identification of nonresponders and warrant further investigation in larger, independent cohorts.

We conducted the largest-ever cross-ancestry GWAS meta-analysis for SLE with 25,109 cases and 271,084 controls comprising East Asian (EA), Southeast Asians (SEA) and Europeans (EUR). We identified 279 independent non-MHC associations, including 51 unreported SLE associations, among which EA-driven associations were identified at PIK3AP1, FOXK1, UBASH3A, and CTDSP1. We further identified a significant interactive association between FOXK1 and IRF5 variants. Statistical fine-mapping together with SNP-to-gene inference and functional prediction identified plausible causal non-coding variants in PRKD3 and TSPAN32, as well as variants in enhancers for CD83, IL12A, c-MYC, and l-MYC, along with an EA-specific missense variant rs55882956 in TYK2. Transcription factors (TFs) linked to fine-mapped enhancer variants contributed to trans-acting regulatory mechanisms in SLE, with strong heritability enrichment at their binding sites across various immune cell types. These include a disproportionate representation of B cell TFs that are themselves risk genes. MYC protein showed the largest enrichment at its binding sites in B cells. In addition, Prioritizing MYC binding sites of B cells in polygenic risk score improved SLE prediction. We also identified 67 candidate druggable genes, providing mechanistic insights and highlighting opportunities for therapeutic development in SLE.

OBJECTIVE:We compared demographic and clinical characteristics between patients with late-onset (LO) and early-onset (EO) systemic lupus erythematosus (SLE) and examined their longitudinal associations with treatment targets and long-term outcomes, irreversible organ damage accrual and health-related quality of life (HRQoL). METHODS:We analyzed prospectively collected data from patients enrolled in the Asia Pacific Lupus Collaboration cohort. Patients diagnosed with SLE at age >50 years were classified as LO-SLE and compared with those diagnosed at age ≤50 years (EO-SLE). Longitudinal associations with treatment targets (LLDAS and DORIS remission), organ damage accrual (SLICC/ACR Damage Index), and HRQoL (SF36v2 physical and mental component summary (PCS and MCS) scores) were examined using multivariable multilevel logistic, recurrent-event survival, and linear mixed-effects models, respectively. Disease activity, flares, medication exposure, and other clinical characteristics were also compared between groups. RESULTS:Among 3,917 patients studied, 346 (8.8%) had LO-SLE. Compared with EO-SLE, patients with LO-SLE had lower disease activity, lower glucocorticoid and immunosuppressant exposure, and higher attainment of treatment targets; LO-SLE was associated with higher odds of attaining LLDAS (OR: 2.33 (1.66, 3.28)) and DORIS remission (OR: 2.22 (1.45, 3.38)). However, they were at a greater risk of damage accrual (HR:1.82 (1.50, 2.21)) and lower PCS scores, meaning poorer physical health (regression coefficient (RC) = -3.63 (-4.58, -2.68)) but not MCS (RC= 0.68 (-.50, 1.86)). CONCLUSION:Despite higher attainment of treatment targets, patients with LO-SLE experienced greater damage accrual and poorer physical health, suggesting that disease activity targets alone may not fully capture outcome risk in LO-SLE.

Objectives Organ damage in SLE is assessed using the SLICC/ACR Damage Index (SDI), which quantifies damage in 12 organ systems but generally reports a total score. We examined whether the risk factors for overall organ damage accrual captured those associated with domain-specific damage accrual in patients with SLE. Methods Data from a 13-country longitudinal SLE cohort were collected between 2013 and 2020 using standard templates. SDI was used to assess overall and domain-specific organ damage. A series of multi-failure, multivariate models were performed to examine the risk factors associated with overall and domain-specific damage accrual. Results A total of 3449 patients with a median of 2.8 [interquartile range (IQR): 1.1, 5.6] years of follow-up were studied. Twenty-one percent (n = 717) patients accrued damage in at least one domain during the study period (musculoskeletal, 6%; renal and ocular, 5% each, neuropsychiatric, 2.5%; <2%, other domains). Risk factors for damage accrual differed among domains. Older age, cumulative glucocorticoid dose, existing skin damage, and diabetes were strong predictors in multiple but discrete domains. Asian ethnicity conferred greater risk of ocular, musculoskeletal, and diabetic damage accrual but was protective against peripheral vascular damage accrual. Smoking was a significant risk factor for peripheral vascular and skin damage accrual, while male sex was associated with the malignancy domain. Conclusion Risk factors for individual organ system damage accrual were highly varied in patients with SLE. Not all factors associated with domain-specific damage accrual were captured by the risk factors analysed for overall organ damage accrual. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT03138941.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with unknown etiology. To pinpoint new disease-relevant cell states in SLE and their detailed molecular profiles, we applied the deepest investigation strategy for single-cell data, cellular and molecular fine mapping, to the largest-scale multimodal SLE datasets, comprising ∼2.1 million peripheral blood mononuclear cells from 232 SLE cases and 114 healthy controls. Among 123 fine-grained cell states in 27 cell types, we discovered that previously uncharacterized cell states, such as GZMK + GZMH + HLA-DR + effector memory CD8 + T cells (double-positive [DP] EMCD8), FAM13A + CDK6 + naive CD4 + T cells, and ARHGAP15 + FOXO1 + T cells, expanded especially in severe SLE. Based on our new statistical model, which efficiently dissects gene signatures reflecting cell state abundance (quantitative change) and single-cell-level gene dysregulation (qualitative change) within each conventional cell type, we found that key biological processes and genetic risks of SLE were linked to these expanded cell states. Finally, by combining multimodal in-silico analyses, CRISPR perturbations, and cellular function assays, we identified cell-state-specific transcriptional regulators (e.g., FOXO1 in ARHGAP15 + FOXO1 + T cells), key surface proteins (e.g., HLA-DR, CD27, CD38, and CD28 in DP EMCD8), T cell receptor features, and cis-regulatory elements. Notably, we newly revealed that DP EMCD8 cells exhibit chronic antigen exposure signatures and serve as a major source of key cytokines, such as IFN-γ, underscoring this cell state as a central driver of SLE immunopathology. These findings provide new insights into the drug target discovery in SLE.

PV193 / #375 Poster Topic:AS22 - SLE Heterogeneity Systemic lupus erythematosus (SLE) is an autoimmune disease with a broad range of clinical manifestations and a high unmet need across patient populations. Real-world data on SLE are scattered across many registries worldwide, with heterogeneous data collection. The Lupus Federated Data Network (LupusNet) is an interdisciplinary international initiative that aims to combine and harmonize data from existing SLE registries to create a global, federated network of SLE databases with a larger number of patients, greater data consistency, and the potential to address gaps in the understanding of SLE. Data from 5 registries representing > 10,000 patients with SLE from 4 regions contributed to LupusNet: APLC (Asia Pacific), RELESSER (Europe), FORWARD (North America), and Almenara and GLADEL (Central and South America). LupusNet uses a federated data network approach and a privacy-by-design method, where the data remains with the respective registries and the analysis occurs at the local center; only aggregated results are shared. Figure 1 illustrates the schedule of patient visits for clinical assessments (including the Systemic Lupus Erythematosus Disease Activity Index [SLEDAI]) in each registry. Demographic and clinical variables (eg, disease activity/severity, clinical events, biopsies/histology, biomarkers, treatment history, comorbidities, medications, and patient-reported outcomes) were mapped and harmonized to the Observational Medical Outcomes Partnership Common Data Model v5.4. This study describes the baseline demographics, patient characteristics, and disease activity based on the SLEDAI in LupusNet during ± 90 days of registration. Figure 1. Frequency of Patient Visits by Registry A total of 10,267 patients were included and mapped in LupusNet. Of those, 3,908 patients were in Asia Pacific, 1,806 in Europe, 3,066 in North America, and 1,487 in Central and South America. Select baseline demographics and characteristics of patients with SLE are presented in Table 1. Disease activity based on the SLEDAI questionnaire was assessed at registration from 4 registries that collected these data. Across registries, the majority of the patients were females; the duration from SLE diagnosis to the registry entry ranged from 5 to 10 years. Heterogeneity and variability in disease manifestations determined from SLEDAI responses were observed across registries, particularly in relation to arthritis, nephritis (ie, proteinuria, pyuria, hematuria, and urinary casts), increased anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody, and leukopenia. Table 1. Baseline Demographics and Patient Characteristics in LupusNet Mapping patient characteristics from LupusNet allows researchers to analyze a larger population of patients with SLE across different geographical regions. These findings demonstrate a high degree of variability in disease activity measured by SLEDAI across registries, likely due to differences in recruitment strategy, treatment strategy/access, healthcare system, and race/ethnicity. Compared to individual registries, this network of collective SLE databases allows further study to better understand disease heterogeneity, patient populations, and treatment patterns with the goal of improving outcomes for patients with SLE across the globe.