Lupus Science & Medicine最新文献

Objective: To characterise the changing trends in the pharmacological management of SLE in the USA between 2007 and 2023 as new treatment options emerged.

Methods: In a retrospective cohort study using data from OptumLabs Data Warehouse, we characterised the annual prevalent (ie, all) and incident (ie, new) use of antimalarials, glucocorticoids and immunosuppressive medications among patients with SLE from 2007 to 2023 and assessed for changing trends over time.

Results: We identified 19 122 adults with SLE; they were 51.2 (SD 16.1) years of age, 89% were female, 61.3% were White, 18.5% were Black and 13.1% were Hispanic. The proportion of prevalent users of antimalarials has decreased from 79.4% in 2007 to 77.2% in 2023 (p=0.0055), while the proportion of incident users fluctuated between a lowest 5.8% in 2021 and a highest 8.1% in 2008 (p=0.008). The proportion of prevalent users of glucocorticoids increased from 64.6% in 2007 to 66.7% in 2023 (p=0.0132), as did the proportion of incident users (12.4% in 2007 to 21.7% in 2023; p<0.0001). The use of cyclophosphamide (2.0% in 2007 to 0.4% in 2023, p<0.0001) has decreased; the use of mycophenolate mofetil (7.7% in 2007 to 10.3% in 2023, p<0.0001), rituximab (1.4% in 2007 to 2.1% in 2023, p<0.0001) and belimumab (0.8% in 2011 to 6.1% in 2023, p=0.0001) has increased.

Conclusions: Despite increasing availability of alternative treatment options, patients with SLE in the USA increasingly rely on glucocorticoid-based therapy. Efforts to improve the use of antimalarials and steroid-sparing immunosuppressants are needed.

Objective: To determine if serum interferon (IFN)-α levels at the time of a lupus nephritis (LN) flare are associated with renal outcomes.

Methods: Patients with an LN flare who had a preflare estimated glomerular filtration rate (eGFR) ≥60 mL/min were included in the study. The following outcomes were ascertained: (1) Time to first and second LN flares during follow-up, (2) Time to a sustained decline in eGFR by 30% and 50%, and progression to end-stage renal disease (ESRD, <15 mL/min), and (3) Time to an adverse renal event (≥2 renal flares and/or at least a 30% sustained decline in eGFR during follow-up). Serum IFN-α was measured by Simoa.

Results: 92 patients with active LN were included in the study. Elevated serum baseline levels of IFN-α predicted poor renal outcomes. Patients with higher baseline IFN-α had a greater risk of having two or more subsequent LN flares (HR: 1.31 (1.08-1.59), p=0.006), sustained 30% decline in eGFR (HR: 1.27 (1.14-1.40), p<0.001), 50% decline in eGFR (HR: 1.27 (1.12-1.33), p<0.001) and progressing to ESRD (HR: 1.29 (1.14-1.47), p<0.001). Receiver operating characteristic analysis identified an IFN-α cut-off, 0.6 pg/ml, for predicting an adverse renal event.

Conclusions: Elevated serum IFN-α levels measured at the time of an LN flare are associated with poor renal outcomes, including the development of ≥2 LN flares, and a clinically meaningful decline in kidney function.

Objective: To evaluate modified versions of the Belimumab International Study in Lupus Nephritis (BLISS-LN) belimumab study primary efficacy renal response (mPERR) and complete renal response (mCRR) criteria (excluding mandatory corticosteroid tapering) as predictors of real-world, long-term renal outcomes among patients with lupus nephritis (LN).

Methods: This retrospective, observational study (GSK Study 212866) used deidentified data between 1970 and 2015 from the University of Toronto Lupus Cohort from adults diagnosed with systemic lupus erythematosus and biopsy-proven Class III±V, IV±V or V LN. At 24 months postbiopsy, patients were retrospectively indexed as responders/non-responders based on mPERR (estimated glomerular filtration rate (eGFR) ≤20% below biopsy value/≥60 mL/min/1.73 m² and urine protein:creatinine ratio (uPCR) ≤0.7 g/day) or mCRR (eGFR ≤10% below biopsy value/≥90 mL/min/1.73 m² and uPCR ≤0.5 g/day) criteria. The association between index mPERR (primary outcome) or mCRR (secondary outcome) status and long-term (up to 25 years, until censoring or death) renal survival (no progression to end-stage kidney disease (eGFR <30 mL/min/1.73 m², dialysis or transplant) or death) was assessed.

Results: Overall, 179 patients were included in the analysis (mPERR responders, n=128; non-mPERR responders, n=51). Most patients were female (87.2%); the mean (SD) age was 34.1 (11.3) years.Long-term renal survival was attained for 78.9% of mPERR responders and 60.8% of non-mPERR responders; achieving mPERR was associated with an increased likelihood of long-term renal survival versus not achieving mPERR (log-rank p=0.0119). Overall, 102 patients were mCRR responders, and 77 were non-mCRR responders. Long-term renal survival was attained for 80.4% of mCRR responders and 64.9% of non-mCRR responders; achieving mCRR was associated with an increased likelihood of long-term renal survival than not achieving mCRR (log-rank p=0.0259).

Conclusions: Achieving mPERR or mCRR was associated with improved long-term renal survival, highlighting that these statuses are suitable predictors of long-term renal outcomes in patients with LN.

Objective: The current study aims to elucidate the critical function of hepatocyte nuclear factor 1-beta (HNF1-β) in lupus nephritis (LN) by investigating its modulation of the Derlin-1/valosin-containing protein (VCP)/VCP-interacting membrane selenoprotein (VIMP) complex, endoplasmic reticulum (ER) stress and podocyte apoptosis.

Methods: In vitro and in vivo models of LN were established using glomerular podocytes treated with LN serum and MRL/lpr mice, respectively. The expression levels of HNF1-β were analysed in kidney tissues from patients with LN and MRL/lpr mice. To assess the effects of HNF1-β inhibition, an adeno-associated virus vector carrying HNF1-β short hairpin was administered to MRL/lpr mice. In vitro, glomerular podocytes were transfected with HNF1-β small interfering RNA (siRNA) or HNF1-β overexpression plasmids to explore their regulatory effects on the Derlin-1/VCP/VIMP complex and podocyte apoptosis. Dual-luciferase reporter assays and chromatin immunoprecipitation (ChIP) assays were performed to investigate the transcriptional activation of Derlin-1 and VCP promoters by HNF1-β.

Results: A significant decrease in HNF1-β levels was observed in kidney tissues from patients with LN while MRL/lpr mice exhibited an initial compensatory increase followed by a subsequent decrease in renal HNF1-β expression. Overexpression of HNF1-β transcriptionally upregulated Derlin-1 and VCP mitigating LN serum-induced ER stress and podocyte apoptosis. In contrast, HNF1-β inhibition exacerbated renal dysfunction and structural damage in MRL/lpr mice. Interestingly, HNF1-β inhibition transcriptionally repressed ERP44, leading to calcium ions (Ca²⁺) release-mediated disruption and inactivation of the Derlin-1/VCP/VIMP complex. This finding suggests that HNF1-β not only regulates the expression of key proteins in the Derlin-1/VCP/VIMP complex but also influences their assembly through Ca²⁺ release regulation.

Conclusion: This study provides novel insights into the regulatory mechanisms of HNF1-β in LN emphasising its impact on the Derlin-1/VCP/VIMP complex, ER stress and podocyte apoptosis. These findings have the potential to inform the development of new diagnostic tools and therapeutic strategies for LN.

Objective: Previous studies have revealed functional changes within the cerebral hemispheres of patients with SLE; however the changes between cerebral hemispheres are still unknown. The present study aimed to explore the functional and structural changes between bilateral hemispheres using functional MRI and find their relationship with cognition in patients with SLE.

Methods: 54 patients with SLE and 32 age-matched and sex-matched healthy controls (HCs) underwent MRI scanning and neuropsychological testing, and clinical data was collected in patients with SLE. Voxel-mirrored homotopic connectivity (VMHC) values and grey matter volume were calculated for all subjects. Correlation analysis was established to determine the relationship between VMHC values, grey matter volume and cognitive scores, blood biochemical markers in patients with SLE.

Results: Compared with HCs, patients with SLE showed increased VMHC values in the insula and parahippocampal gyrus, while grey matter volume were reduced in these regions. Correlation analysis demonstrated that the increased VMHC values in insula was negatively correlated with decreased orientation function and positively correlated with decreased attention function. The grey matter volume in insula was negatively correlated with decreased attention and abstraction. The VMHC values and grey matter volume in insula and parahippocampal gyrus were negatively associated with lupus-specific antibodies.

Conclusion: The structural and functional changes of insula and parahippocampal gyrus might be potential neuroimaging markers, and specific antibodies associated with lupus might be involved in the pathophysiological mechanisms of brain dysfunction.

Trial registration number: NCT06226324.

Introduction: Lupus nephritis (LN) is a frequent complication of SLE, occurring in up to 60% of adult patients and ultimately progressing from acute inflammation to chronicity with fibrosis and end-stage kidney failure in 10%-30% of patients. Racial/ethnic minority patients with lupus have worse long-term outcomes, including progression to end-stage renal disease and overall mortality. A major challenge in the management of patients with SLE is delayed identification of early kidney disease, which ultimately leads to a greater burden on both patients and the health system.

Methods and analysis: Using a mixed methods approach, this study will develop, adapt and evaluate a home urine sampling protocol with a text-messaging reminder and data capture system for patients at elevated risk of de novo LN or relapse. First, a feasibility pilot using a single-group trial design (n=18) will be implemented, with a feasibility assessment and qualitative, debriefing interviews with patients to further refine the intervention. The second phase is a comparative effectiveness trial of the intervention (n=160) with the primary outcome of biopsy eligibility, that is, the participant has a clinical indication for a kidney biopsy (urine protein-creatinine ratio≥0.5), whether or not the patient actually undergoes the biopsy procedure. The randomised trial includes an economic evaluation of the adapted home urinalysis protocol.

Discussion and dissemination: It is unknown whether weekly home-based urine sampling can identify proteinuria sooner than standard care; if found sooner, kidney problems could be diagnosed earlier, hopefully leading to earlier care for less-involved disease and subsequent reduced morbidity. The data collected in this trial will inform future feasibility and effectiveness of text-messaging-based home urine sampling interventions.

Trial registration number: The randomised trial will be registered with ClincialTrials.gov prior to enrolment start.

Objectives: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown aetiology that can affect almost any organ in the body. Although there are no specific guidelines for the use of intravenous immunoglobulin (IG) in the treatment of patients with SLE, it is thought to be an effective treatment. Our study aimed to evaluate the effectiveness and safety of intravenous IG and to describe the possible profile of patients with SLE who are candidates for intravenous IG treatment.

Methods: This study was designed to retrospectively analyse patients with SLE treated with 2 g/kg/month of intravenous IG (divided across 5 consecutive days). We collected demographic, clinical, laboratory and treatment data from the patient files. The side effects of the intravenous IG treatment, changes in the immunosuppressive therapy used and changes in the clinical and laboratory parameters after the intravenous IG treatment were evaluated.

Results: This study included 31 patients with SLE. The main indication for intravenous IG treatment was haematological involvement (20, 64.5%) and thrombocytopenia in particular (8, 25.8%). Intravenous IG was initiated mainly for refractory disease. At the end of the treatment, the acute phase values, proteinuria, complement levels and anti-double-stranded DNA decreased significantly (p<0.001). In most cases, the side effects were mild and usually manifested as myalgia or a fever.

Conclusion: Despite its high cost, intravenous IG has demonstrated effectiveness in treating refractory SLE, especially when there is haematological involvement. Specific clinical features at baseline may identify the patients who are more likely to respond to this therapy.

Objectives: This study aimed to evaluate cardiac function using Myocardial Performance Index (MPI) in autoimmune connective tissue disease (ACTD) patients without cardiovascular abnormalities.

Methods: A systematic search of databases including Medline, Google Scholar, ProQuest, Scopus and Cochrane Library was conducted to identify relevant studies on ACTD and MPI from 1995 to 2023. ACTD included in the search were rheumatoid arthritis (RA), systemic sclerosis (SSc), systemic lupus erythematosus (SLE), Sjögren syndrome (SjD), polymyositis and dermatomyositis. Quality assessment was performed using the Newcastle-Ottawa Scale, followed by meta-analysis computation of mean differences (MDs) of MPI using Review Manager V.5.4.

Results: A total of 22 studies for qualitative and 19 for quantitative synthesis were included. We found six studies on RA, eight studies on SSc, five studies on SLE, two studies on SjD and one on mixed connective tissue disorder. Conventional echocardiography and tissue Doppler imaging (TDI) were used to assess the MPI. Both conventional MPI and tissue Doppler MPI values were elevated compared with healthy control (MD=0.11, 95% CI 0.08 to 0.14, p value<0.00001 and MD=0.06, 95% CI 0.03 to 0.10, p value=0.00001, respectively).

Conclusions: We found elevated MPI values in patients with ACTD compared with healthy controls. MPI assessment has the potential for early detection and management of cardiac dysfunction in patients with ACTD, but further studies are required to corroborate these findings.

Prospero registration number: CRD42023490643.

Objective: Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by a loss of immune tolerance, affecting multiple organs and significantly impairing patients' health and quality of life. While hereditary elements are essential in the onset of SLE, external environmental influences are also significant. Currently, there are few predictive models for SLE that takes into account the impact of occupational and living environmental exposures. Therefore, we collected basic information, occupational background and living environmental exposure data from patients with SLE to construct a predictive model that facilitates easier intervention.

Methods: We conducted a study comparing 316 individuals diagnosed with SLE and 851 healthy volunteers in a case-control design, collecting their basic information, occupational exposure history and environmental exposure data. Subjects were randomly allocated into training and validation groups using a 70/30 split. Using three-feature selection methods, we constructed four predictive models with multivariate logistic regression. Model performance and clinical utility were evaluated via receiver operating characteristic, calibration and decision curves. Leave-one-out cross-validation further validated the models. The best model was used to create a dynamic nomogram, visually representing the predicted relative risk of SLE onset.

Results: The ForestMDG model demonstrated strong predictive ability, with an area under the curve of 0.903 (95% CI 0.880 to 0.925) in the training set and 0.851 (95% CI 0.809 to 0.894) in the validation set, as indicated by model performance evaluation. Calibration and decision curves demonstrated accurate results along with practical clinical value. Leave-one-out cross-validation confirmed that the ForestMDG model had the best accuracy (0.8338). Finally, we developed a dynamic nomogram for practical use, which is accessible via the following link: https://yingzhang99321.shinyapps.io/dynnomapp/.

Conclusion: We created a user-friendly dynamic nomogram for predicting the relative risk of SLE onset based on occupational and living environmental exposures.

Trial registration number: ChiCTR2000038187.

Introduction: High-dose glucocorticoid (GC)-based dual immunosuppressive treatment regimens are still frequently used in active lupus nephritis (LN) despite their known association with dose-dependent toxicities and incomplete efficacy. We hypothesised that the addition of voclosporin to low-dose GCs and mycophenolate mofetil (MMF) would reduce exposure to the toxicities of high-dose GC-based dual immunosuppressive therapy regimens, resulting in an improved safety profile without compromising efficacy.

Methods: Propensity score matching generated two groups of matched participants from the voclosporin arms (in combination with MMF (2 g/day) and low-dose GCs) of the Phase 2 AURA-LV and Phase 3 AURORA 1 studies and the MMF (3 g/day) and intravenous cyclophosphamide (IVC) arms (both in combination with high-dose GCs) of the Aspreva Lupus Management Study (ALMS) induction study. Safety and efficacy outcomes were assessed over 6 months.

Results: There were 179 matched participants identified between the AURA-LV/AURORA 1 studies and ALMS. The overall incidence of adverse events (AEs) was higher in IVC- and MMF-treated participants of ALMS; more voclosporin-treated participants reported AEs by preferred term of glomerular filtration rate decreased, hypertension and anaemia. The incidence of serious AEs was similar across treatments. There were four (2.2%) deaths in IVC- and MMF-treated participants of ALMS compared with seven (3.9%) deaths in voclosporin-treated participants. Significantly more voclosporin-treated participants achieved a ≥25% reduction in urine protein creatinine ratio (UPCR) from baseline at 3 months and ≥50% reduction in UPCR from baseline at 6 months.

Conclusions: Compared with the high-dose GC-based regimens used in ALMS, voclosporin-based triple immunosuppressive therapy resulted in fewer AEs overall and greater and earlier reductions in proteinuria over the first 6 months of treatment. These data reinforce the feasibility of using low doses of GCs and MMF to treat LN when combined with voclosporin as a third agent.