Lupus Science & Medicine最新文献

Objective: Delivery of a small for gestational age (SGA) infant is a common pregnancy complication among women with SLE. Although disease activity and autoantibodies such as anti-Smith and anti-ribonucleoprotein associate with SGA, underlying pathological mechanisms remain unclear and reliable predictors are lacking. To address this, we applied a proteomic approach to identify proteins associated with SGA in SLE.

Methods: Plasma samples were collected repeatedly during pregnancy, at delivery and from placental intervillous blood in women with SLE (n=83) and healthy controls (n=67) enrolled in the prospective SLE-Placenta study. Postpartum samples (≥6 months) from a subset of women with SLE (n=19) served as non-pregnant controls. Mass spectrometry was performed on a discovery cohort comprising six healthy uncomplicated pregnancies, eight uncomplicated SLE pregnancies and eight SLE pregnancies complicated by SGA (SLE-SGA). Differential protein abundance analysis was performed in R. Candidate proteins were quantified by ELISA in the full cohort.

Results: Discovery proteomics identified four proteins with increased abundance in SLE-SGA compared with uncomplicated SLE pregnancies: endostatin (P _adj =0.0003), angiogenin (P _adj =0.03), insulin-like growth factor-binding protein 5 (P _adj =0.03) and complement factor H-related protein 5 (P _adj =0.004). In the full cohort, ELISA quantification did not confirm increased levels of these proteins in SLE-SGA but suggested elevated levels of the angiogenesis-related proteins endostatin and angiogenin in women with SLE who later developed pre-eclampsia. Endostatin levels were consistently higher in SLE compared with controls across all trimesters (p≤0.0001). Endostatin, but not angiogenin, was enriched in placental blood.

Conclusion: Our study did not validate the differentially abundant proteins as markers for SLE-SGA but suggested a link between the antiangiogenic and proangiogenic proteins, endostatin and angiogenin, respectively, and pre-eclampsia in SLE. Given the consistent elevation of endostatin throughout pregnancy in SLE compared with controls, its potential effects on placental development in SLE warrant further investigation.

The Lupus Research Alliance formed the Lupus Accelerating Breakthroughs Consortium (Lupus ABC) in 2023 as a public-private partnership with investigators, pharmaceutical companies, the Food and Drug Administration, National Institutes of Health, patient-focused non-profits and professional societies with the goals of developing initiatives to accelerate lupus drug development in a precompetitive setting, and ensuring that perspectives of people with lived experience of lupus are included into the drug development process. Patient-reported outcome (PRO) measures are a top area of focus for the Lupus ABC. To support future work in the area of PROs, a public meeting was held on 16-17 October 2024 with the objectives of (1) assessing the current state of PROs used in lupus clinical trials, (2) developing a roadmap to advance the use of PROs in lupus clinical trials and (3) identifying and setting priorities for efforts to be pursued by a Lupus ABC PRO Working Group. After a series of presentations, small groups addressed what PRO domains to measure, the questionnaire burden for trial participants, how PROs should be selected for trials and what efforts are needed to advance use of PROs in lupus clinical trials.Meeting participants concluded that although PROs are being collected in most lupus clinical trials, they may be underused as primary or secondary/exploratory endpoints. A strong desire to change the focus in trials from disease activity and signs to include PROs, as a way of highlighting patients' voices, was noted. The group concluded that the specific steps needed are to identify PRO measures appropriate for the target populations of interest, incorporate PROs into endpoints for regulatory decision-making, ensure PRO data are publicly available and accessible to researchers and involve people living with lupus in selection of PRO domains, measures and trial design. For these actions, collaborations among industry, researchers, regulators, payors and patients are needed.

Objectives: Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Significant morbidity and early mortality necessitate early intervention. This study harnessed SLE-associated immune dysregulation to create a Lupus Classification Risk Index (LCRII) and Lupus Disease Activity Immune Index (LDAII) that identified individuals at risk for SLE classification and disease activity.

Methods: The LCRII was developed from 84 military personnel who developed classified SLE (≥4 American College of Rheumatology criteria) versus matched healthy controls, which was confirmed in 56 lupus blood relatives who developed SLE versus 154 matched unaffected relatives and 77 unrelated controls. The LDAII was informed by SLE patient visits with low (n=132) or active (n=179) disease and 48 matched controls. Data from blood samples assessed for circulating SLE-associated autoantibody specificities and soluble immune mediators informed the LCRII and LDAII. Random forest modelling guided the selection of informative analytes.

Results: An LCRII informed by 32 or 17 log-transformed/standardised mediators, weighted by their correlation to SLE-associated autoantibodies, differentiated pre-SLE individuals before reaching disease classification (area under the curve (AUC) ≥0.79, p<0.0001; effect size ≥1.1), even before the appearance of clinical criteria (AUC ≥0.74, p<0.0001; effect size ≥0.9). The LCRII-32, LCRII-17 and select mediators, MCP-3/CCL7, TNFRII, stem cell factor (SCF), IL-1α, IP-10/CXCL10 and TGF-β differentiated renal and serositis classification criteria (p<0.05). An LDAII informed by 26 or 13 log-transformed/standardised mediators, weighted by their correlation to SLE-associated autoantibodies or disease activity (hybrid Systemic Lupus Erythematosus Disease Activity Index; hSLEDAI), differentiated SLE patients with low (hSLEDAI <4) or active (hSLEDAI ≥4) disease (AUC >0.6, p ≤0.002, effect size ≥0.4), including clinical/serologic active versus quiescent disease (AUC ≥0.7, p<0.0001, effect size ≥0.6). The LDAII-26, LDAII-13 and select mediators MCP-1/CCL2, TNFRII, SCF, IL-2Rα, IL-10 and TGF-β differentiated renal and serositis manifestations.

Conclusions: We have conceptualised two immune mediator-informed indexes, the LCRII that predicts SLE from months to years before clinical presentation, and the LDAII that analogously predicts active disease in SLE to distinguish patients who would benefit from early intervention.

Objective: The question of sustained remission in SLE has been highlighted recently following data published on the use of chimeric antigen receptor-T cell therapy in SLE. With the review, we wanted to investigate the prevalence of sustained remission of 2 years or more in SLE with the current available treatments and to assess the predictive factors associated with this state.

Methods: A systematic review of Embase via Ovid and Medline via Ovid was performed. We considered articles of adult patients with SLE that report the prevalence and/or the predictive factors of sustained remission in SLE. We considered that the latter state is sustained if it was for 2 years or more.

Results: 20 studies were included for final review. The definition of remission was different between studies, and most authors considered different types of remission based on the serological activity and the current therapy. The prevalence of long-term remission was different across studies depending on the definition used. It ranged from 0.3% to 63%. Older age at diagnosis, lower disease activity at baseline and the absence of renal disease involvement were the most commonly found factors likely associated with sustained remission.

Conclusion: Long-term remission is an achievable state in SLE with current treatment. Studies report a striking heterogeneity in the current prevalences. This is likely to be caused by the lack of objective measures to confirm the state of sustained remission in SLE.

Background: Interstitial fibrosis in lupus nephritis (LN) is often infiltrated by immune cells but typically regarded as non-specific 'scar reaction'. This study aimed to investigate the relationship between inflammatory fibrosis and kidney disease progression in LN.

Methods: Interstitial fibrosis and tubular atrophy (IFTA) were scored in 124 LN kidney biopsies. Inflammation in areas of IFTA (i-IFTA) was graded 0-3 according to the Banff Classification of Allograft Pathology. Significant glomerular filtration rate (GFR) loss was defined as a decline of >15 mL/min at 3 years from biopsy. Immune cell phenotype was defined by serial immunohistochemistry (13-plex).

Results: IFTA was observed in 88/124 (71%) biopsies, and i-IFTA was identified in 76/88 (86%) cases. The distribution of i-IFTA grades was heterogeneous across all IFTA grades. In patients with moderate-to-severe IFTA (>25%), the degree of i-IFTA was associated with a higher risk of significant GFR loss: 0/1 (0%), 0/3 (%), 3/4 (75%) and 7/9 (78%) for i-IFTA grades 0, 1, 2 and 3, respectively (p=0.015). Multiplexed histology revealed that i-IFTA was mostly composed of CD163+ macrophages and CD4 T cells, followed by CD8 T cells and granulocytes.

Conclusion: I-IFTA is frequently observed in LN and is dominated by macrophages and T cells. For patients with baseline IFTA >25%, the degree of i-IFTA emerged as a predictor of GFR loss. These data support the routine scoring of i-IFTA in LN due to its prognostic implications and nominate i-IFTA as a potential therapeutic target.

Background: SLE is a chronic autoimmune disease with heterogeneous manifestations. This study evaluated the discriminative value of complete blood count-derived biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), eosinophil-to-lymphocyte ratio (ELR), basophil-to-lymphocyte ratio (BLR), mean platelet volume and red cell distribution width (RDW), in identifying lupus flares.

Methods: This cross-sectional study was conducted over 10 years in the internal medicine department of Sahloul Hospital. SLE patients were classified by disease activity using Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K): flare (SLEDAI-2K >6) or remission (SLEDAI-2K ≤6). A matched group of healthy controls was included. Comparisons were made between flare/remission and flare/controls. Discriminative performance of biomarkers was evaluated using receiver operating characteristic analysis, with sensitivity (Se), specificity (Sp) and area under the curve (AUC) determined for the optimal cut-off values.

Results: The study included 83 SLE patients (40 flares, 43 remission) and 85 controls, median age of 32 years and a sex ratio of 0.16. Compared with remission, flares had significantly higher NLR and RDW and lower ELR. The most discriminative biomarkers were RDW (AUC=0.708, cutoff ≥14.65, Se =75.9%, Sp =60.6%), NLR (AUC =0.636, cutoff ≥2.63, Se =72.4%, Sp =51.5%) and ELR (AUC =0.647, cutoff ≤0.0076, Se =74.4%, Sp =65%). Compared with controls, flares showed higher NLR, PLR, MLR, RDW and lower ELR and BLR. Best performances were RDW (AUC =0.864, cutoff ≥13.85, Se =89.7%, Sp =75.3%), NLR (AUC =0.822, cutoff ≥2.28, Se =79.3%, Sp =76.5%) and ELR (AUC =0.775, cutoff ≤0.029, Se =87.1%, Sp =70.3%). SLEDAI-2K correlated positively with NLR (r =0.228), PLR (r =0.238), RDW (r =0.303) and negatively with ELR (r =-0.317).

Conclusions: These biomarkers may serve as simple, accessible and cost-effective tools for detecting lupus flares, particularly in resource-limited settings.

Introduction: SLE is a chronic autoimmune disease that is influenced by both genetic and environmental factors, one of which is diet. Dietary intervention plays a role in the management of SLE, and precision nutrition based on genetic data may enhance its effectiveness. The human leukocyte antigen (HLA)-DQ2 and DQ8 genotypes are strongly associated with coeliac disease (CD), and emerging evidence suggests a possible link between SLE and CD. However, no published studies have explored the use of HLA-DQ2 and DQ8 genotyping to guide dietary intervention in patients with SLE. This study aims to investigate the impact of dietary intervention, tailored to HLA-DQ2 and DQ8 genotyping, on disease activity and quality of life of patients with SLE.

Methods and analysis: 90 patients with SLE with positive HLA-DQ2 or DQ8 genotyping will be randomised in a 1:1 ratio to either the intervention group or a control group. Participants in the intervention group will receive intervention in the form of a low-gluten dietary modification for 12 weeks. Participants in both groups will continue their usual SLE medications. During three research visits (weeks 0, 4 and 12), all participants will complete a clinical interview, blood sample collection, dietary assessment and a questionnaire. Disease activity and quality of life will be assessed by the Mexican Systemic Lupus Erythematosus Disease Activity Index score and Lupus Quality of Life questionnaire. Other secondary outcomes that will also be assessed are fatigue score, sleep quality, anxiety and depression, and physical activity.

Ethics and dissemination: This study has obtained ethical approval from the Ethics Committee of the Faculty of Medicine, University of Indonesia-Cipto Mangunkusumo Hospital (KET948/UN2F1/ETIK/PPM0002/2025). Findings will be published in peer-reviewed journals and submitted for intellectual property rights.

Trial registration number: NCT07183007.

Objective: To evaluate the safety and efficacy of CD19 chimeric antigen receptor (CAR) T cell therapy in a patient with refractory lupus nephritis who experienced severe disease flare during immunosuppressive washout, and to assess whether pulse corticosteroid intervention affects CAR T cell therapeutic outcomes.

Methods: We report a single case of a 22-year-old woman with SLE and lupus podocytopathy refractory to multiple therapies including rituximab, belimumab and obinutuzumab. The patient was treated under single-patient IND (#30146) with autologous CD19 CAR T cells (KYV-101). During the preinfusion washout period, she developed severe lupus flare requiring pulse intravenous methylprednisolone. Clinical outcomes, CAR T cell expansion, B cell depletion and laboratory parameters were monitored before and after therapy.

Results: Despite experiencing severe lupus flare (fever, rash, arthritis, anti-dsDNA elevation, hypocomplementaemia) during washout, pulse methylprednisolone (250 mg intravenous, rapidly tapered) successfully controlled symptoms without compromising subsequent CAR T cell expansion (peak 15.5 cells/µL on day 7). The patient achieved sustained clinical remission with SLE Disease Activity Index Score decreasing from 17 prior to leukapheresis to 4 by week 17. At 12 months postinfusion, she remained in drug-free remission with stable kidney function and had returned to full-time work.

Conclusion: This case report illustrates that targeted pulse corticosteroids during CAR T cell therapy washout can effectively manage severe lupus flares without impairing therapeutic efficacy.

Objective: Lupus nephritis (LN) is a prevalent renal manifestation in patients with SLE, with kidney biopsy remaining the gold standard for evaluating disease activity. However, the invasive nature of biopsy and associated risks highlight the need for a non-invasive predictive tool. This study aimed to construct and validate predictive models for the activity index (AI) and tubulointerstitial lesions (TIL) in patients with LN as an alternative tool to assist clinicians in decision-making when kidney biopsy is not feasible.

Methods: We enrolled 266 patients with LN diagnosed by kidney biopsy from three centres, divided into a training cohort (n=213) and a validation cohort (n=53). Patients were stratified by AI and TIL scores: high AI (AI >4), low AI (AI ≤4), high TIL (TIL >4) and low TIL (TIL ≤4). Clinicopathological data were systematically collected. Multivariate logistic regression was employed to identify significant risk factors for high AI and TIL, and nomograms for individualised assessment were constructed. Model performance was evaluated using receiver operating characteristic curves, decision curve analysis, calibration plots and the Hosmer-Lemeshow test.

Results: The key independent risk factors for high AI included lymphocyte count, haematuria, albumin, serum creatinine, complement 4 and antihistone antibodies. For high TIL, the risk factors included age, haemoglobin, platelet count, blood urea nitrogen and antiribosomal P antibodies. Both nomograms demonstrated favourable performance in terms of discrimination and calibration across both cohorts.

Conclusion: The developed nomograms provide reliable, non-invasive tools for identifying patients with LN with high AI and TIL, which can improve clinical risk assessment and help guide more personalised management strategies.

Objectives: To identify antiphospholipid antibody-associated thrombocytopenia (aPLs-TP) phenotypes and assess their clinical outcomes.

Methods: This single-centre, prospective cohort study (January 2012 to April 2024) consecutively enrolled patients with aPLs-TP from Peking Union Medical College Hospital. Inclusion required persistent aPL positivity (≥12 weeks apart) and platelet (PLT) count <100×10⁹/L twice, excluding secondary causes. Demographic aPL profiles and clinical outcomes (thrombosis, pregnancy morbidity, microangiopathy and valve disease) were analysed. Hierarchical clustering and Kaplan-Meier survival analysis were performed.

Results: A total of 123 patients (65.9% female, mean age 36.0 years) were consecutively enrolled in the study. Median PLT count was 50.0×10⁹/L. Three clusters were identified: cluster 1 (n=35, all male, median PLT 67.0×10⁹/L) consisted of men with smoking history, hyperhomocysteinaemia and diabetes, demonstrating the highest rate of atherothrombotic and valvular events; cluster 2 (n=51, all female, median PLT 60.0×10⁹/L) included females with recurrent pregnancy morbidity and mild anaemia; and cluster 3 (n=37, 81.1% female, median PLT 27.0×10⁹/L) comprised patients with isolated severe thrombocytopenia with the lowest rate of complete remission. Analysis of event-free survival for key clinical outcomes differed significantly among clusters at 5 years (p=0.026): cluster 1 at 66.9% (95% CI 52.50 to 85.24), cluster 2 at 45.85% (95% CI 32.41 to 64.86) and cluster 3 at 88.68% (95% CI 78.80 to 99.80).

Conclusions: Significant heterogeneity exists in patients with aPLs-TP, thus making PLT count alone an inadequate predictor of clinical phenotypes and prognosis. Subgroup analysis leveraging distinct clinical features is essential to develop individualised treatment strategies and improve outcomes.