Lupus Science & Medicine最新文献

Background: Lupus nephritis (LN) is a severe and prevalent complication of SLE. Compound Muniziqi granule (CMG), a traditional remedy, is commonly used to treat immune system-related disorders. However, its efficacy in treating LN remains unassessed. This study aims to evaluate the therapeutic potential of CMG for LN and to explore its molecular mechanisms.

Methods: CMG was evaluated for therapeutic effects on LN in Murphy Roths Large (MRL)/lymphoproliferation (lpr) mice. Renal tissues from mice in the Control, Model and CMG treatment groups were collected for transcriptomic analysis to identify the potential pathways involved in CMG's action in LN. We then examined the effects of CMG on inflammatory cell infiltration, complement system activation and B-cell accumulation in the renal tissues of MRL/lpr mice. Additionally, we assessed the impact of CMG on the cluster of differentiation 40 (CD40)/Nuclear Factor-kappa B p65 (NF-κB p65) signalling pathway in these tissues.

Results: CMG treatment reduced the spleen index in MRL/lpr mice, decreased serum levels of antibodies and inflammatory cytokines and improved renal function markers. It also alleviated renal pathological damage and inflammatory infiltration. Transcriptomic analysis indicated that CMG's therapeutic effects may be linked to 'SLE' and the 'NF-κB signalling pathway'. Further investigation revealed that CMG downregulated a wide array of complement-related and inflammation-associated genes. Notably, CMG reduced the gene expression of CD40 and CD40L. In addition, CMG decreased inflammatory cytokine levels. Preliminary immunofluorescence analysis indicated that CMG reduced immune complex deposition and diminished B-cell infiltration in the renal tissues of MRL/lpr mice. Preliminary western blot analysis indicated that CMG downregulated B Lymphocyte-Induced Maturation Protein 1 (BLIMP1), CD40 and tumour necrosis factor (TNF) receptor-associated factor 6 (TRAF6) expression, as well as the phosphorylation of NF-κB p65.

Conclusion: CMG effectively mitigates inflammatory infiltration and renal damage in MRL/lpr mice. Preliminary evidence indicates that this protective effect may be associated with reduced activity of the CD40/NF-κB p65 signalling pathway, along with decreased B-cell activation and complement system activation.

Objective: To investigate sex-related differences in clinical and immunological features across lupus erythematosus (LE) subtypes.

Methods: This cross-sectional analysis, based on the Lupus Erythematosus Multicenter Case-Control Study in Chinese populations (ChiCTR2100048939), included patients with SLE and major cutaneous LE (CLE) subtypes. Sex-specific comparisons were performed using R V.4.4.2.

Results: In 2097 patients (1865 SLE, 1648 CLE), female predominance was observed in all subtypes, with female-to-male ratios ranging from 11.3:1 (acute CLE, ACLE) to 2.1:1 (isolated CLE, iCLE). Except for ACLE, females had earlier or similar onset than males in all other subtypes. ACLE lesions were most common in females (67%). In male patients with LE, the proportion of discoid LE (DLE) lesions was higher than female patients (31% vs 12%). Compared with males, females exhibited higher frequencies of arthritis in SLE, ACLE, DLE and chilblain LE (CHLE). In DLE, renal involvement, haematological abnormalities and serositis were more frequently observed in females. In subacute CLE (SCLE), haematological abnormalities were significantly more common in females. Additionally, non-scarring alopecia was more common in females than in males. Females had higher autoantibody positivity in iCLE and chronic CLE, with significant differences in anti-double-stranded DNA, anti-Smith, anti-U1-nuclear ribonucleoprotein and anti-ribosomal P antibodies.

Conclusions: Across the subtypes, several clinical manifestations show a consistent sex distribution: ACLE lesions, arthritis, non-scarring alopecia, Raynaud's phenomenon and autoantibodies occur more frequently in women with LE, whereas the proportions of DLE and SCLE lesions are higher in men with LE. In addition, certain features exhibit subtype-specific sex differences: among patients with SCLE, DLE and CHLE, women show a greater propensity for systemic involvement, whereas in those with SLE and ACLE, men demonstrate a higher tendency toward systemic disease.

Trial registration number: ChiCTR2100048939.

Objective: To determine if the levels of five urinary biomarkers (UBs), including cluster of differentiation 163 (CD163), monocyte chemoattractant protein-1 (MCP-1), adiponectin, soluble vascular cell adhesion molecule and platelet factor 4 (PF4), measured 24 months after a lupus nephritis (LN) flare are associated with adverse long-term outcomes.

Methods: We included patients with an LN flare who had a preflare estimated glomerular filtration rate (eGFR) ≥60 mL/min and stored urine 24±3 months after the flare. The following outcomes were then examined: (1) time to a subsequent LN flare and (2) time to 30% sustained decline in eGFR. UBs were measured by ELISA 24±3 months after the LN flare. The results were normalised to urine creatinine and expressed as pg per mmol of urine creatinine.

Results: 69 patients with LN were included, the median (IQR) follow-up time after their 24-month urinary sample collection was 129 (97.5-150) months. 50 patients achieved a primary efficacy renal response 24 months after the LN flare. This subcohort of patients had significantly lower UB levels. In this subcohort, 27 (54%) experienced a subsequent LN flare with a median time to flare (IQR) of 3.5 (1.67-6.87) years, and 10 (20%) had a 30% decline in eGFR at a median time of 4.38 (3.73-5.33) years after their 24-month urinary sample collection. Elevated levels of MCP-1 (HR 1.40 (1.11-1.76), p=0.004) and CD163 (HR 1.14 (1.00-1.38), p=0.01) predicted a subsequent LN flare. While CD163 (HR 1.16 (1.02-1.32), p=0.02), MCP-1 (HR 1.33 (1.01-1.74), p=0.04), adiponectin (HR 2.67 (1.68-2.46), p<0.001) and PF4 (HR 1.14 (1.04-1.25), p=0.002) predicted a 30% decline in eGFR.

Conclusion: UBs measured 24±3 months after an LN flare were associated with subsequent flares and a clinically meaningful decline in kidney function.

Objective: The objective of this study was to investigate the effects of rituximab (RTX) intrathecal injection on antibody levels in serum and cerebrospinal fluid (CSF), hippocampal tissue and neuronal injury and the behaviour of central neuropsychological lupus erythematosus (cNPSLE) model mice and to further explore the effects of RTX on microglia (MG) polarisation and related signalling pathways.

Methods: Female MRL/lpr mice received intrathecal RTX, with C57BL/6 and MRL/mpj mice as controls. Behavioural performance was evaluated using the open field test, novel object recognition and Porsolt swim task. Autoantibody levels in serum and CSF were measured by ELISA. Hippocampal pathology was assessed by H&E and Nissl staining. M1-type MG activation (Iba-1⁺/CD32⁺), CD20⁺ B-cell infiltration and immunoglobulin G (IgG) deposition were examined via immunohistochemistry and immunofluorescence. Immune transcriptome sequencing and in vitro polarisation assays were used to identify regulatory pathways.

Results: Intrathecal injection of RTX reduced the levels of antibodies in the serum and CSF of MRL/lpr mice and alleviated brain tissue injury and neuronal injury. Moreover, hippocampal MG M1 polarisation was inhibited, and the number of CD20⁺ B cells and expression of IgG were reduced. Transcriptome sequencing revealed that the cAMP-dependent protein kinase A (cAMP/PKA) pathway may be involved in the activation of M1-type MG in the hippocampus. In vitro cell experiments demonstrated that RTX could reduce the expression of kinase cAMP-activated catalytic subunit alpha and phosphorylated-cAMP response element-binding protein/cAMP response element-binding protein through the suppression of the cAMP/PKA pathway, thus inhibiting M1-type MG activation.

Conclusion: The data in this study revealed that the intrathecal injection of RTX can attenuate M1-type MG activation-mediated inflammatory neuronal injury in cNPSLE model mice.

Objective: Although treatment guidelines recommend pulse steroids, induction treatment of lupus nephritis (LN) varies significantly among providers. This paper aims to explore evidence that intravenous pulse provides pharmacological benefits along with improved clinical efficacy without greater toxicity compared with high-dose oral glucocorticoids justifying inclusion for all active LN.

Methods: We conducted a systematic literature review (SLR) using the term 'pulse glucocorticoids in LN' in order to identify studies that summarise the pharmacologic mechanisms of glucocorticoids, reviewed the historical use of glucocorticoids in SLE, and compared pulse therapy with high-dose oral treatment related to their efficacy and toxicities.

Results: SLR demonstrated that non-genomic mechanisms of action are more associated with pulse than oral steroids. Some observational studies reported improved renal responses with pulse steroids but in exchange for more adverse metabolic bone disease effects (eg, osteoporosis and avascular necrosis) as well as infections and, importantly, mortality.

Conclusions: Current guidelines promoting pulse therapy for all forms of proliferative LN (and in the case of American College of Rheumatology 2024 treatment guidelines, even isolated class V membranous LN) rely on structured evidence grading processes, including expert consensus and observational data, but are not based on head-to-head randomised controlled trial comparisons. Therefore, there can be an ongoing debate regarding the best approach. The SLR identifies a distinct pharmacological benefit unique to pulse treatment, though without direct evidence necessary for the treatment of LN; includes observational studies with evidence of superior efficacy, but not consistently; and identifies a higher risk of adverse effects. In our opinion, the data advocates for a more selective approach to treatment, foregoing universal treatment with pulse steroids, based on a toxicity versus benefit assessment that patients with mild disease do not require the additional risks.

Objective: Dyslipidaemia in systemic lupus erythematosus (SLE) contributes to pathogenesis and cardiovascular risk. The effect of statin therapy on SLE disease activity remains controversial. This meta-analysis systematically evaluates the impact of statins on SLE activity and inflammatory markers.

Methods: This study adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. A systematic literature search across multiple databases was conducted up to 13 November 2024. Study selection, data extraction and quality assessment were performed independently by two reviewers. Meta-analysis was conducted using R software, evaluating outcomes including SLE Disease Activity Index (SLEDAI), C-reactive protein (CRP), interleukin-6 (IL-6) and erythrocyte sedimentation rate (ESR).

Results: From 3596 identified records, 12 studies were included. Statins significantly reduced SLEDAI in controlled before-after studies (weighted mean difference (WMD)=-0.70, 95% CI -1.16 to -0.23; p=0.0037), but not in parallel controlled trials (WMD=-0.58, 95% CI -1.74 to 0.59; p=0.330; I² = 81.1%). Subgroup analysis showed a pronounced reduction in patients with a mean age <40 years (WMD=-1.60, 95% CI -1.98 to -1.22; p<0.001). Statins lowered CRP in both controlled before-after studies (standardised mean difference (SMD)=-0.38, 95% CI -0.73 to -0.03; p=0.032) and parallel controlled trials (SMD=-1.45, 95% CI -2.84 to -0.07; p=0.040). After excluding an outlier, the reduction in IL-6 became significant (SMD=-0.32, 95% CI -0.63 to -0.00; p=0.048). ESR was also reduced (SMD=-1.81, 95% CI -3.54 to -0.08; p=0.0406). No significant publication bias was detected.

Conclusion: Statin therapy may reduce disease activity and inflammation in SLE, with a consistent benefit observed in patients with a mean age <40 years. Significant heterogeneity underscores the need for future rigorously designed, age-stratified randomised trials to confirm these findings and define the target patient population.

Prospero registration number: CRD42025630267.

Background: Current diagnosis of antiphospholipid syndrome (APS) relies on antiphospholipid antibodies (aPL) testing, but false-positive aPL results and asymptomatic aPL carriers pose significant clinical challenges. The importance of S100A8 in thrombosis has been demonstrated, yet its potential role in APS has received little attention. This study aimed to assess serum S100A8 for APS diagnosis and risk stratification among aPL carriers.

Methods: Serum S100A8 levels were measured by ELISA in healthy controls (HCs), aPL carriers without manifestation and patients with APS. Receiver operating characteristic curves were used to evaluate the diagnostic performance of APS. Logistic regression was performed to identify independent variables associated with obstetric morbidity among female aPL carriers.

Results: The study enrolled 120 HCs, 57 aPL carriers and 114 patients with APS. Serum S100A8 levels were significantly higher in aPL carriers (median 44.3 (IQR 35.6-75.4) ng/mL, p<0.001) and patients with APS (52.8 (37.2-79.2) ng/mL, p<0.001) compared with HCs (25 (21.6-31.1) ng/mL). S100A8 showed good diagnostic accuracy for APS (area under the curve (AUC)=0.854, 95% CI 0.803 to 0.907, p<0.001), with similar performance for thrombotic APS (AUC=0.819, 95% CI 0.747 to 0.891, p<0.001) and obstetric APS (AUC=0.874, 95% CI 0.821 to 0.926, p<0.001). Multivariate logistic regression revealed that S100A8 positivity was independently associated with increased obstetric APS risk among aPL carriers (OR 3.335, 95% CI 1.010 to 11.012, p=0.048).

Conclusion: S100A8 may serve as a complementary biomarker for the diagnosis and risk stratification of APS, especially in female aPL carriers at risk of obstetric morbidity. These findings support further investigation into its clinical and mechanistic role in APS pathogenesis.

Objective: Skeletal fragility is a major comorbidity in systemic lupus erythematosus (SLE), yet the accuracy of fracture risk algorithms in this population remains uncertain. We compared the discriminative ability of Fracture Risk Assessment Tool (FRAX) and the Italian FRAX-derived tool (DeFRA) for fractures in SLE.

Methods: This is a secondary analysis of the multicentre osteoporosis and FRagility fracture Among SLE patients (FRAIL - NCT05590390) cohort that included patients with SLE who underwent dual-energy X-ray absorptiometry with vertebral fracture assessment (VFA). Vertebral fractures were confirmed by radiography. For each patient, 10-year major osteoporotic fracture probability was calculated using FRAX and DeFRA. Discrimination was assessed with receiver operating characteristic curves and DeLong's test. Operational thresholds (FRAX ≥20%, DeFRA ≥20% and 15%) were evaluated for sensitivity, specificity, predictive values and number needed to scan (NNS=1/positive predictive value). Robustness of estimates was tested using 2000 bootstrap resamples with out-of-bag evaluation.

Results: 106 patients with SLE were included in the study. Mean age was 53.6 years, 88.7% were female and 41.5% were on glucocorticoids. Morphometric vertebral fractures were identified in 23 patients (21.7%), including 15 previously unrecognised. For newly detected fractures, area under the curve (AUC) was higher for DeFRA (0.834, 95% CI 0.725 to 0.944) than FRAX (0.681, 95% CI 0.495 to 0.867; p=0.022). Similar results were observed when considering any vertebral fracture (AUC 0.902 vs 0.770; p=0.013). At operational thresholds, DeFRA ≥20% identified 9/15 new fractures (NNS=1.78) versus 7 with FRAX ≥20%, while lowering the cut-off to DeFRA ≥15% increased sensitivity (10/15 fractures, NNS=2.0) without loss of specificity. Bootstrap validation confirmed the robustness of rank ordering.

Conclusion: In SLE, DeFRA outperforms FRAX in detecting vertebral fractures and offers a clinically efficient threshold for guiding targeted VFA, with potential implications for optimising imaging strategies and glucocorticoid management.