Background Soluble urokinase plasminogen activator receptor (suPAR) is linked to organ damage in systemic lupus erythematosus (SLE). We investigated whether serum suPAR associates with histological activity and chronicity in diagnostic and 12-month repeat kidney biopsies in lupus nephritis (LN). Methods suPAR levels were determined using ELISA in serum samples from 23 LN patients (19 incident) before and 12 months after initiation of immunosuppressive therapy, and from 15 age- and sex-matched healthy controls. Correlations with NIH activity index (AI) and chronicity index (CI) scores were assessed using Spearman’s rank correlation coefficient. Results suPAR levels were higher at active LN than in controls (5.37±0.93 ng/mL versus 2.64±0.97 ng/mL; p<0.001), decreased by month 12 (3.77±0.94 ng/mL; p=0.005), but remained elevated compared with controls (p<0.001). Baseline suPAR did not correlate with AI at baseline (rho=0.202; p=0.368) or month 12 (rho=0.332; p=0.165), whereas month-12 suPAR correlated with month-12 AI (rho=0.595; p=0.007). Baseline suPAR correlated with CI at baseline (rho=0.541; p=0.008) and month 12 (rho=0.554; p=0.017). Month-12 suPAR showed a trend towards a correlation with month-12 CI (rho=0.440; p=0.066). Baseline suPAR correlated with baseline interstitial fibrosis (rho=0.422; p=0.044) and predicted month-12 glomerular sclerosis (rho=0.580; p=0.011) and tubular atrophy (rho=0.477; p=0.045). Month-12 suPAR correlated with month-12 glomerular sclerosis (rho=0.572; p=0.013). Conclusions Serum suPAR levels were elevated in active LN and, despite a decline, after 12 months of treatment compared with healthy individuals. suPAR levels correlated with intrarenal chronicity and predicted post-treatment glomerular sclerosis and tubular atrophy, suggesting suPAR as a potential biomarker of kidney damage in LN.

In systemic lupus erythematosus (SLE) and other autoimmune diseases, B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play critical roles through three receptors, i.e., BAFF-Receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI), and B-cell maturation antigen (BCMA), promoting the survival of self-reactive B cells and supporting their differentiation into antibody-producing cells. Several biologic therapies with anti-BAFF and anti-BAFF/APRIL agents induce profound suppression of immunoglobulin production and B-cell survival with variable safety profiles. While belimumab has demonstrated significant improvement of overall disease activity in clinical trials, some cases of de novo lupus nephritis have been reported suggesting a potential lack of protection in certain cases. The sustained reduction in B cell populations expressing regulatory markers, alongside a rapid decline in IL-10 levels following belimumab initiation, suggests that BAFF may have a previously underappreciated role in supporting the development or function of regulatory B cells (Bregs). Given the complex receptor interactions of BAFF and APRIL, as well as the heterogeneous phenotype of regulatory B cells and their different mechanisms for regulating the immune response, the involvement of BAFF in regulatory immune responses remains difficult to fully elucidate. This review explores the current evidence on the anti-BAFF/APRIL therapies and examines the unresolved question of whether BAFF exerts a context-dependent role in supporting regulatory B cell function.

Background In the American College of Rheumatology/European Alliance of Rheumatology Associations 2010 classification criteria for rheumatoid arthritis (RA), rheumatoid factor (RF) and anti-citrullinated protein/peptide antibodies (ACPA) are assigned the same weight, although ACPA have proven more specific than RF. We aimed to refine the serological weight factors for RA classification.Materials and methods Diagnostic samples from 398 patients with RA and 448 diseased controls (DC) were evaluated with RF and ACPA assays from five different manufacturers. A grid search was conducted across all possible integer score pairs for RF and ACPA to identify the weighting combination that optimised the specificity of RA classification. This combination was applied in a refined scoring system (RSS) for three confirmatory cohorts comprising, respectively, 67, 157 and 132 patients with RA and 441, 153 and 193 DC.Findings In the investigative cohort, the optimal combination of weighting scores was characterised by higher scores for ACPA, higher antibody levels and double RF/ACPA positivity.Applying the optimal combination of weighting scores decreased misclassification compared with the 2010 RA classification criteria, minimally affecting sensitivity. For seropositive patients, RSS significantly lowered misclassification from 38.3–55.8% to 15.0–26.9%.The improved specificity of RSS (compared with the 2010 criteria) was validated in the confirmatory cohorts. Considering only seropositive patients, the RSS significantly decreased RA misclassification (8.6–36.8% vs 20.0–78.9%), minimally affecting the sensitivity (86.7–97.3% vs 86.7–96.0%).Interpretation Serological weight factors for RA classification can be improved by taking into account the antibody type, the antibody levels and single or combined positivity. The application of an RSS reduced the number of RA misclassifications.

Objectives Patients with Systemic lupus erythematosus (SLE) who carry a high genetic burden often experience more severe disease. To understand the molecular consequences of polygenic risk, we analyzed single-cell gene expression profiles in SLE patients stratified by genetic risk. Methods Single-cell RNA sequencing (scRNA-seq) was performed on fresh peripheral blood mononuclear cells (PBMCs) from 16 female SLE patients, stratified by a weighted polygenic risk score (PRS), and 6 healthy controls (HCs). All patients were in low disease activity (LLDAS) and treated with antimalarials only. We assessed differential gene expression, interferon (IFN) signatures, transcription factor (TF) activity, and pathway enrichment across groups. Results Patients with High-PRS had significantly elevated IFN scores compared to HCs (p < 0.001), whereas no significant difference was observed between Low-PRS patients and HCs (p > 0.05) This pattern held across multiple immune cell types, including T cells, NK cells, and monocytes. Notable genes with increased expression in High-PRS patients included ISG15 and USP18 in plasmacytoid dendritic cells (pDCs), and IFI27 and RSAD2 in monocytes. IFN-related pathways were enriched in pDCs and monocytes in High-PRS patients, and only in monocytes in Low-PRS patients. TF analysis identified IRF7 and BATF3 as key candidate regulators in High-PRS of both cell types. Conclusions High polygenic risk in SLE is associated with persistent activation of IFN signaling pathways, indicating that antimalarial treatment alone is insufficient to fully suppress IFN activity, even during remission or low disease activity.

Abstract Objectives The aetiopathogenesis of SLE encompasses genetic, environmental and epigenetic factors. We investigated associations between an SLE methylation risk score (MRS), HLA-DRB1*03:01, a non-HLA polygenic risk score (PRS) and clinical and immunological phenotypes. Methods DNA methylation in whole blood from patients fulfilling ≥4 ACR-82 criteria and controls were investigated using the Illumina HM450K array. The discovery cohort included 311 patients and 400 controls, and the replication cohort comprised 175 patients and 187 controls. Seventeen independent, top differentially methylated CpG sites (Δβ of ≥0.1) from case-control comparisons, were used to calculate the MRS. Genotyping was performed using the Immunochip, and the PRS included 57 non-HLA SLE SNVs. Clinical data were collected from patient charts, and serum IFN-α2 was measured using Simoa. Results Higher MRS was strongly associated with serum IFN-α2 levels (p=1.04×10 −14 ). In both cohorts, higher MRS associated with discoid lupus, immunologic involvement, and anti-SSA/SSB/RNP/Sm autoantibodies (all p<0.05), and with higher disease activity in the discovery cohort (p=1.50×10⁻⁴). MRS was also elevated in patients with multiple autoantibodies (p<1.0×10 -15 ) and in HLA-DRB1*03:01 carriers (p<1.0×10 -3 ). In contrast, higher PRS was associated with nephritis, anti-dsDNA positivity, and lower prevalence of anti-SSB antibodies (all p<0.05). No correlation was observed between the MRS and the PRS (p=0.35). Conclusion The MRS defines an interferon-high, HLA-DRB1*03:01-linked SLE subset with multiple autoantibodies, partly distinct from PRS-associated nephritis risk, highlighting potentially divergent pathogenic pathways. These findings underscore the value of integrating genetic and epigenetic data to better understand underlying disease mechanisms in SLE. Key Messages Higher MRS, but not PRS, correlated with increased levels of serum IFN-α. The MRS was associated with discoid rash, hematologic disorder, hypocomplementemia, antibodies including anti-SSA and HLA-DRB1*03:01. Higher PRS was linked to nephritis and anti-dsDNA positivity, and did not associate with the MRS.

OBJECTIVE:To examine B cell-activating factor (BAFF) and type I interferon (IFN) activity at the transcriptional and protein levels in blood and placental tissue in SLE compared with healthy pregnancies to assess their relationship and to determine whether BAFF levels are associated with pregnancy outcomes in SLE. METHODS:In the SLE-Placenta study, we followed women with SLE (n=83) and healthy controls (n=67) throughout pregnancy. Blood samples were collected in all trimesters and at delivery from peripheral blood, placental intervillous blood and cord blood. Postpartum blood samples were obtained from a subset of women with SLE. Bulk messenger RNA (mRNA) sequencing was performed on peripheral blood mononuclear cells (PBMCs) and placental tissue from a subgroup of women with SLE and healthy controls. BAFF concentrations were measured by ELISA and IFNα protein levels by single-molecule array (Simoa). RESULTS:Women with SLE had upregulated BAFF (TNFSF13B) and IFN-stimulated gene expression in PBMCs and placenta compared with controls. BAFF blood levels were consistently and significantly higher in SLE throughout pregnancy and inversely correlated with circulating B cell numbers. SLE pregnancies with IF-ANA or anti-dsDNA positivity displayed higher BAFF levels than antibody-negative pregnancies but BAFF showed no association with disease activity. Both BAFF and IFNα concentrations were higher in placental than peripheral blood in SLE, whereas only BAFF showed additional accumulation in cord blood. Finally, elevated BAFF levels were associated with shorter pregnancy duration in SLE but not in healthy pregnancy. CONCLUSIONS:Pregnant women with SLE exhibited persistently elevated BAFF levels, which were associated with lower B cell numbers, SLE-related autoantibody positivity and shorter pregnancy duration. Together with a disease-specific placental enrichment of IFNα, these findings support the presence of an inflammatory and potentially pathogenic IFN-BAFF signature in SLE pregnancy. Further studies are needed to determine the functional consequences of these immunological alterations on maternal-fetal health in SLE.

OBJECTIVES:The aetiopathogenesis of SLE encompasses genetic, environmental and epigenetic factors. We investigated associations between an SLE methylation risk score (MRS), HLA-DRB1*03:01, a non-HLA polygenic risk score (PRS), and clinical and immunological phenotypes. METHODS:DNA methylation in whole blood from patients fulfilling ≥4 ACR-82 criteria and from controls was investigated using the Illumina HM450K array. The discovery cohort included 311 patients and 400 controls, and the replication cohort comprised 175 patients and 187 controls. Seventeen independent, top differentially methylated CpG sites (Δβ of ≥0.1) from case-control comparisons were used to calculate the MRS. Genotyping was performed using the Immunochip, and the PRS included 57 non-HLA SLE single-nucleotide variants. Clinical data were collected from patient charts, and serum IFN-α2 was measured using Simoa. RESULTS:Higher MRS was strongly associated with serum IFN-α2 levels (P = 1.04 × 10-14). In both cohorts, higher MRS was associated with DLE, immunologic involvement, and anti-SSA/SSB/RNP/Sm autoantibodies (all P < 0.05), and with higher disease activity in the discovery cohort (P = 1.50 × 10-4). MRS was also elevated in patients with multiple autoantibodies (P < 1.0 × 10-15) and in HLA-DRB1*03:01 carriers (P < 1.0 × 10-3). In contrast, higher PRS was associated with nephritis, anti-dsDNA positivity, and lower prevalence of anti-SSB antibodies (all P < 0.05). No correlation was observed between the MRS and the PRS (P = 0.35). CONCLUSION:The MRS defines an IFN-high, HLA-DRB1*03:01-linked SLE subset with multiple autoantibodies, partly distinct from PRS-associated nephritis risk, highlighting potentially divergent pathogenic pathways. These findings underscore the value of integrating genetic and epigenetic data to better understand underlying disease mechanisms in SLE.

ObjectiveAnti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are chronic, relapsing inflammatory diseases, yet reliable biomarkers for detecting relapse and organ involvement remain limited. This study aimed to identify plasma protein biomarkers that distinguish active disease from remission and to explore markers associated with lung and kidney involvement.MethodsPlasma samples from 113 patients with granulomatosis with polyangiitis or microscopic polyangiitis (68 active disease and 45 remission) were profiled using a proximity extension assay targeting 181 inflammation- and cardiovascular-related proteins. Clinical data, including CRP and Birmingham vasculitis activity score (BVAS), were collected at sampling. Differential protein expression was assessed using ANOVA, with top candidates validated in independent sample cohorts (plasma samples, n = 74; serum samples, n = 34). Correlations with BVAS and CRP and discriminatory performance (AUC) were evaluated. Associations with chest- and kidney-specific BVAS were also examined.ResultsA total of 57 proteins were differentially expressed between active disease and remission. Seven proteins (ST2, OPN, IL-2RA, CCL23, IL-6, Flt3L, and SCF) were validated in independent cohorts and showed strong associations with disease activity. Several demonstrated high discriminatory ability (AUC ≥ 0.80) between active disease and remission. Multiple proteins correlated with organ-specific BVAS scores: seven for chest involvement and 16 for kidney involvement, after adjustment for kidney function-related protein variation.ConclusionThis study identifies a robust panel of plasma proteins that differentiate active AAV from remission and correlate with global and organ-specific disease activity. These biomarkers may enhance non-invasive disease monitoring and support earlier recognition of relapse and organ involvement in AAV.

Objectives Belimumab is an approved biologic therapy for active, autoantibody-positive SLE that has been shown to reduce disease activity, flare frequency, and glucocorticoid use, thereby preventing organ damage.[1] It is typically reserved for refractory disease but emerging evidence suggests earlier initiation of belimumab may lead to higher response rates, greater achievement of remission or low disease activity, and further reduction in glucocortoid use.[2] This cost-utility analysis evaluates the economic and health impacts of early vs delayed belimumab initiation for biologic-naïve adult patients with clinically active SLE, comparing direct medical costs and quality-adjusted life-years (QALYs). Methods A Markov model was developed to simulate disease progression over 5 years with monthly cycles from the U.S. payer perspective. Costs included drug acquisition, hospitalizations, outpatient care, and emergency visits, updated to 2024 USD. Transition probabilities, Euro-QoL-5D utility values, and healthcare resource utilization were derived from a targeted literature review. Patients began in a pre-treatment state and transitioned monthly between 4 health states: complete response (assessed by SLE Responder Index-4; SRI-4), partial response, non-response (did not meet SRI-4 and experienced a flare or treatment-emergent adverse event), and death. Patients in the early group had higher disease activity (3-point higher SLEDAI-2K) and higher glucocorticoid use (10mg/day more prednisone) at baseline relative to the delayed group. Early belimumab was defined as initiation within 2 years of diagnosis and delayed initiation followed failure of standard immunosuppressants. Results Early belimumab initiation provided an additional 0.09 QALYs at a cost savings of USD$8,639.48 per patient relative to delayed belimumab, yielding a favorable incremental cost-effectiveness ratio (ICER) of −USD$93,092.98/QALY, making it the dominant strategy. Sensitivity analyses identified utility values, flare rates, and SRI-4 response rates as key drivers (Figure 1). Early belimumab retained dominance across most parameter variations, though cost-effectiveness was attenuated in parameter extremes favoring delayed initiation. Conclusion Early initiation of belimumab in biologic-naïve adults with clinically active SLE is both clinically and economically advantageous, offering greater health benefits at a lower cost compared to delayed initiation. These findings support timely adoption of belimumab in appropriate patients and highlight the need to reform reimbursement policies that delay access. As mounting evidence across immune-mediated diseases supports early biologic intervention as disease-modifying, frameworks must evolve to recognize treatment timing as a critical driver of long-term outcomes.[3] This model highlights the potential of early belimumab to reduce morbidity, mitigate irreversible organ damage, and generate sustained value for patients and health systems. References [1.] Urowitz M. Arthritis Care Res (Hoboken) 2022;74:1822-8. [2.] Zhao Y. Rheumatology (Oxford) 2025;64:106-16. [3.] Mease P. ACR Open Rheumatol 2025;7:e70019.

OBJECTIVE:Lupus nephritis (LN) is a potentially severe manifestation of SLE, often resulting in permanent kidney damage. We investigated whether polygenic and/or epigenetic risk is associated with time to LN relapse and whether this association differs by initial therapy. METHODS:Caucasian patients with biopsy-verified LN between 1974 and 2022 (n=149) were genotyped using the Illumina Global Screening Array, and DNA methylation was assessed with the Illumina HumanMethylation450k BeadChip. A weighted Polygenic Risk Score (PRS) based on 55 non-Human leukocyte antigen (HLA) SLE risk gene variants and a Methylation Risk Score (MRS) based on the 17 most differentially methylated cytosine-phosphate-guanine sites identified in SLE-control comparison were calculated. Time to LN relapse was analysed using Cox proportional hazards models, adjusted for centre, sex and year of the first LN. RESULTS:Neither PRS nor MRS was associated with time to LN relapse in the overall cohort, irrespective of treatment (PRS: HR=1.00 (0.77-1.30); p=0.99; MRS: HR=1.01 (1.00-1.02); p=0.21). No associations were observed among cyclophosphamide (CYC)-treated patients (PRS: HR=0.81 (0.55-1.20); p=0.29; MRS: HR=1.00 (0.99-1.02); p=0.89). In non-CYC-treated patients, PRS showed a non-significant trend towards shorter time to LN relapse (HR=1.26 (0.88-1.81); p=0.21), with a similar trend for MRS (HR=1.02 (1.00-1.03); p=0.066). Adding MRS to the PRS model improved performance in this subgroup (likelihood ratio test, p=0.028), with significant associations for MRS (PRS: HR=1.56 (0.97-2.50); p=0.066; MRS: HR=1.02 (1.00-1.04); p=0.037). CONCLUSIONS:Genetic and epigenetic susceptibility appears to influence LN relapse risk in a treatment-dependent manner. The absence of an association among patients receiving CYC suggests that initial treatment with CYC may attenuate the impact of genetic and epigenetic predisposition on relapse. These findings support the potential of genetic and epigenetic profiling at LN diagnosis to improve relapse risk stratification and individualise selection of treatment.

INTRODUCTION:Systemic lupus erythematosus (SLE) is a prototypical autoimmune disorder characterized by production of autoantibodies targeting self-antigens. These autoantibodies form immune-complexes that deposit in various tissues, leading to complement activation, inflammation, and, ultimately, organ damage. The detection of specific autoantibodies is crucial for diagnosing SLE and for assessing disease activity. AREAS COVERED:A variety of autoantibodies are employed in clinical practice to assess the risk of different SLE manifestations and other systemic inflammatory diseases. These autoantibody specificities are integral to clinical decision-making procedures. Herein, we examine the most commonly evaluated autoantibodies and their associations with disease phenotypes. In addition, we discuss recent findings of novel autoantibodies in SLE and their clinical relevance and potential utility. EXPERT OPINION:In addition to the well-established autoantibody specificities routinely assessed in clinical practice for patients with a diagnosis of - or clinically suspected - SLE, recent studies have identified several new autoantibodies with potential clinical relevance. If these findings are validated through further research and accessible diagnostic assays are developed, these emerging autoantibodies could narrow the gap between first symptoms and classifiable disease and significantly enhance patient management by providing critical insights into the risk of specific SLE manifestations, thereby facilitating more timely and personalized interventions.

The hallmark of HIV-1 (HIV) infection is the progressive development of multicellular and systemic immune dysfunction, culminating in AIDS. Dendritic cells (DCs) play a pivotal role in HIV dissemination to CD4 + T cells, which are subsequently depleted by the virus leading to HIV disease progression. Type I interferons (IFNs) are critical for host defense during acute infection but contribute to chronic immune activation during the later stages of HIV disease. This persistent activation leads to immune cell exhaustion. HIV can activate type I IFN responses via several pathways, including the STING pathway, which is activated by, e.g., virus-derived oligonucleotides. Here, we investigated the underlying mechanisms creating HIV-mediated immune dysfunction and role of type I IFNs using a DC and T cell co-culture model. HIV exposure in the DC-T cell co-culture promoted the expansion of suppressive T cells with diminished proliferation and effector functions. The impairment required type I IFNs and subsequent IFNα/β receptor signaling, and our data indicate that this was initiated by HIV-derived ssDNA activation of IFI16/cGAS followed by STING signaling in the DCs. Targeting IFNAR1 with anifrolumab restored the immune functions of both DCs and T cells, as well as T cell proliferation and T cell effector functions, including their secretion of IL-2, IFNγ, and granzyme B. Our findings support that the immune impairments existing in untreated or antiretroviral therapy (ART) treated HIV-infected individuals are mediated, if not fully in part by type I IFN's negative effect on DC and T cells. Therapeutics targeting IFNα/β receptors, such as anifrolumab, hold potential as combination treatment alongside ART, to achieve a more complete immune restoration and contribute to improved quality of life among people living with HIV.

Antibodies against the Dense Fine Speckled 70 kDa protein (anti-DFS70), associated with the anti-cell 2 (AC-2) pattern on immunofluorescence HEp-2 cells, represent a frequent finding in antinuclear antibody (ANA) testing, particularly among healthy individuals, and have been proposed as an exclusion marker for systemic autoimmune rheumatic diseases (SARDs). In systemic lupus erythematosus (SLE), however, their interpretation is more complex. Anti-DFS70 antibodies are uncommon, rarely monospecific, and are not consistently associated with global disease activity, although selective associations with musculoskeletal and mucocutaneous manifestations have been reported. In lupus nephritis (LN), evidence from a single dedicated cohort suggests that anti-DFS70 antibodies are enriched compared with healthy controls and patients with non-lupus chronic kidney disease (CKD), while within biopsy-proven LN they may associate with proliferative histological subtypes and intrarenal inflammatory activity. In this narrative review, we provide a critical overview of the epidemiological, serological, clinical, and experimental evidence on anti-DFS70 antibodies, with a particular focus on SLE and LN. Overall, current evidence supports a context-dependent interpretation of anti-DFS70 antibodies across health, systemic autoimmunity, and organ-specific inflammation.

Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease with heterogeneous clinical manifestations and immune dysregulation. Disease course and clinical phenotypes vary considerably between patients, and to improve disease monitoring, novel biomarkers must be sought. Extracellular vesicles (EVs) are emerging as mediators of immune activation, emphasizing their potential role as biomarkers. We enriched circulating EVs from sera of 10 healthy donors and 14 patients at the time point of SLE diagnosis prior to exposure to immunosuppressive therapy, and profiled their size, abundance, and protein content. The patients showed significantly higher circulating EV concentrations than age- and sex-matched healthy donors, showing a positive correlation with disease activity score assessed by SLE disease activity-2000 (SLEDAI-2K) (p = 0.00092). Stratification by disease activity revealed greater proteomic dysregulation in patients with high SLEDAI-2K scores (> 6), with 59 differently abundant proteins versus healthy donors, compared to 30 proteins in patients with low SLEDAI-2K scores (≤ 6). High disease activity was associated with enrichment of innate immune, neutrophil, platelet, and perturbed homeostasis pathways, as well as immune cell and tissue signatures. In patients with a SLEDAI-2K score > 6, the highest expressed proteins in EVs were complement C9 and TNFRSF17, suggesting their potential role as soluble biomarkers of putative treatment response to emerging BAFFR and BCMA-targeting therapies.

Importance:Belimumab is a biologic therapy for active, autoantibody-positive systemic lupus erythematosus (SLE) that has been shown to reduce disease activity, flare frequency, and glucocorticoid use, thereby preventing organ damage. Belimumab is typically reserved for refractory disease, but emerging evidence suggests earlier initiation may lead to higher response rates, greater achievement of remission or low disease activity, and further reduction in glucocorticoid use. Objective:To evaluate the economic and health-related outcomes of early vs delayed belimumab initiation for biologic-naive patients with clinically active SLE, comparing medical costs and quality-adjusted life-years (QALYs). Design, Setting, and Participants:This economic evaluation using cost-utility analysis from a US payer perspective was conducted with a Markov model with monthly cycles over a 15-year horizon and was informed by studies published from 2013 to 2025, identified through a targeted literature review. Biologic-naive adult SLE patients with active disease (SLE Disease Activity Index 2000 score >0) were included. Patients began in a pretreatment state and transitioned monthly between 5 health states: complete response (per SLE Responder Index-4 [SRI-4]), partial response, nonresponse (failure to meet SRI-4 accompanied by flare or treatment-emergent adverse event), no treatment (standard of care), and death. Exposure:Early (≤2 years of disease duration) or delayed (after failure of standard therapy) initiation of intravenous belimumab. Main Outcomes and Measures:Primary outcomes included total direct medical costs, QALYs, incremental cost-effectiveness ratio (ICER), and incremental net monetary benefit (INMB). The 95% uncertainty intervals (UIs) for incremental costs, QALYs, and INMB were calculated from the 2.5 and 97.5 percentiles of the probabilistic sensitivity analyses. Results:The modeled cohort included 1000 adults (912 female [91.2%]) with a mean (SD) age of 41 (11) years at belimumab initiation. Early initiation provided an additional 0.30 (95% UI, -0.42 to 1.39) QALYs at an incremental cost of -$126 337.12 (95% UI, -$910 010.39 to $168 383.94) per patient relative to delayed initiation, yielding a favorable ICER of -$421 123.73 per QALY. At a $50 000 per QALY threshold, the mean INMB was $141 337.12 (95% UI, -$157 997.53 to $925 019.51), with early initiation preferred in 81.3% of simulations (8125 of 10 000 simulations). Deterministic sensitivity analyses identified time horizon (INMB range, $6351.07 for a 1-year horizon to $156 497.12 for a lifetime horizon) and SRI-4 response odds ratio (INMB range, $69 741.68 for an odds ratio of 1.08 to $209 591.09 for an odds ratio of 3.47) as the most influential parameters. Conclusions and Relevance:In this economic evaluation of early vs delayed belimumab in biologic-naive patients with active SLE, early initiation was associated with improved health outcomes and reduced costs. These findings support earlier clinical adoption and reconsideration of reimbursement criteria to reflect long-term value.

Renal dysfunction increases cardiovascular (CV) risk. We compared cystatin C-based estimated glomerular filtration rate (eGFRcys), creatinine-based eGFR (eGFRcr), and their ratio (eGFRcys/eGFRcr) in relation to major adverse cardiovascular events (MACE) and all-cause mortality in chronic coronary syndrome, assessing the added prognostic value of the eGFRratio. In this post hoc analysis of 14,513 Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy trial patients, we investigated associations between baseline eGFRcys, eGFRcr, their ratio, and MACE and all-cause death using Cox regression models, unadjusted and adjusted for eGFRcys, eGFRcr, and their combination. Discrimination was assessed using Harrell's C -index; added value by the fraction of new information (FNI). Median age was 65 years; 82% were male. Median eGFRcys was 77 (interquartile range [IQR]: 61–94) and eGFRcr 79 (IQR: 65–91) mL/min/1.73 m 2 . Over 3.7 years, 1449 MACE and 1063 deaths occurred. Lower eGFR values and eGFRratio were associated with increased MACE risk, primarily driven by CV death. For eGFRcys 60 versus 90, the hazard ratio (HR) for MACE adjusted for eGFRcr was 1.77 (95% CI: 1.49–2.09, FNI 54%). In contrast, eGFRcr adjusted for eGFRcys showed no positive association (HR 0.82, 95% CI: 0.68–0.97, FNI 3%). A lower eGFRratio was linked to higher MACE risk (HR 1.99, 95% CI: 1.80–2.21), which remained after eGFRcr adjustment (HR 1.89, 95% CI: 1.70–2.10, FNI 54%) but was attenuated after eGFRcys adjustment (HR 1.29, 95% CI: 1.13–1.46, FNI 5%). In chronic coronary syndrome, lower eGFRcys, eGFRcr, and eGFRratio were associated with higher MACE and mortality risk. eGFRcys had the strongest association; eGFRcr and eGFRratio added limited incremental value.

Background SLE is a systemic autoimmune disease with a large number of common risk gene variants, but several rare gene variants can cause monogenic SLE. The relationship between common and rare variants in SLE is unclear. We therefore investigated the occurrence of rare deleterious variants in patients with childhood-onset SLE (cSLE) and adult-onset SLE (aSLE) and compared the frequency of these variants with their individual SLE polygenic risk score (PRS).Materials and methods Targeted sequencing of 1832 gene regions, including coding regions of 31 genes associated with monogenic SLE, was performed in 958 patients with SLE and 1026 healthy individuals. A total of 116 patients with SLE had disease onset before the age of 18 (cSLE). An SLE common variant PRS was created from 37 SLE genome-wide association study single nucleotide variants (SNVs).Results Rare coding deleterious SNVs (RD SNVs) were observed in 23 of the monogenic SLE-associated genes. Six per cent of patients with cSLE, compared with 3.2% of controls and 4.6% of patients with aSLE, carried rare deleterious alleles. In cSLE, RD SNVs were observed in the C1S, DDX58, IFIH1, IKZF1, RNASEH2A and C8A genes. A PRS analysis showed that patients with cSLE with any of these gene variants had a similar average PRS as control individuals.Conclusion RD SNVs were observed in a small proportion of cSLE and carriers of these RD SNVs had a PRS similar to healthy individuals, suggesting the importance of rare coding heterozygous variants in driving disease risk in a subset of children with SLE.