Lupus Science & Medicine最新文献

Background: Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterised by thrombosis, pregnancy complications and other non-thrombotic manifestations in the presence of antiphospholipid antibodies (aPL). Since its identification in 1983, research on APS has progressed, but no targeted therapies other than anticoagulation are yet available, with a mortality rate of 9.3% after a 10-year follow-up.

Objective: The aim of the current systematic literature reviews (SLRs) is to identify and compare upregulated proteins in patients with thrombotic APS (tAPS) and non-aPL thrombosis, thereby providing useful insights into APS pathogenesis.

Methods: We conducted two SLRs in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to identify proteins upregulated in tAPS and non-aPL-related thrombosis. Eligible studies included observational controlled research and focused on proteomics. Gene Ontology (GO) enrichment and network analyses were performed on the identified proteins.

Results: Of 108 and 209 records identified, seven and 13 were included in the SLR for tAPS and non-aPL thrombosis, respectively. The review identified 118 upregulated proteins in tAPS and 319 in non-aPL-related thrombosis. GO analysis revealed distinct biological process enrichment: platelet aggregation, platelet activation and blood coagulation were predominant in tAPS, while haemostasis, coagulation and wound healing were central in non-aPL-related thrombosis. Molecular functions in tAPS centred on receptor and protein complex binding, while enzymatic activities dominated in non-aPL thrombosis.

Conclusion: Our findings highlight the central role of platelet-related processes in tAPS pathogenesis, distinguishing it from non-aPL thrombosis. By elucidating the unique proteomic and functional characteristics of tAPS, this study provides a foundation for future research into targeted therapies that address platelet involvement in APS pathogenesis.

Objective: The left atrial stiffness index (LASI) has been proven to be a promising marker for assessing left atrial (LA) and left ventricular diastolic functions. This study aimed to evaluate the implication of LASI in diagnosing left ventricular diastolic dysfunction (LVDD) in patients with SLE.

Methods: 145 patients diagnosed with SLE were enrolled and subdivided into two groups based on the absence of concomitant lupus nephritis (LN). Additionally, a control group comprising 57 healthy volunteers was recruited. Speckle tracking echocardiography (STE) was performed in all participants. Conventional parameters and the LA strains were obtained, and LASI was calculated.

Results: (1) Patients with SLE presented significantly increased LA size and reduced function, with a significant increase in LASI, especially in those with concomitant LN. (2) LASI was positively correlated with age, interventricular end-diastolic septal thickness (IVSd) and E/e' (mitral E peak velocity to e' peak velocity) average, and negatively correlated with LA total emptying fraction (LATEF), LA passive emptying fraction (LAPEF), glomerular filtration rate (GFR), LA reservoir strain (LASr) and LA conduit strain (LAScd). Multivariate analysis showed that age, IVSd, maximum LA size and SLE activity index were independent determinants of LASI. (3) LASI demonstrated superior diagnostic performance for LVDD compared with E/e' average, LATEF, LASr and LAScd, with an area under the curve of 0.919.

Conclusions: LASI can effectively reflect changes in LA function in patients with SLE and provide superior diagnostic accuracy compared with other parameters and LA strains for LVDD. Therefore, LASI could be a potential marker for the early detection of LVDD in patients with SLE.

Objectives: Neuropsychiatric SLE (NPSLE) lacks evidence-based treatment strategies. This study compared the effectiveness and safety profiles of obinutuzumab (OBZ) and rituximab (RTX) in patients with NPSLE.

Methods: Patients with new-onset NPSLE meeting British Isles Lupus Assessment Group grade A criteria who received either OBZ or RTX between 2018 and 2024 at Renji Hospital, Shanghai Jiao Tong University School of Medicine (with ≥12 months follow-up) were included. Propensity score matching (1:2 ratio) based on age, sex and SLE Disease Activity Index (SLEDAI) was performed. The primary outcome was complete or partial response at 12 months. Kaplan-Meier curves compared therapeutic effectiveness. Safety profiles of OBZ and RTX were recorded.

Results: 27 patients with new-onset NPSLE were included in this retrospective study, with 9 patients receiving OBZ and 18 patients receiving RTX. At 12 months, the primary outcome was achieved in 8 of 9 patients in the OBZ group and 13 of 18 patients in the RTX group (88.9% vs 72.2%; OR: 3.08, 95% CI 0.30 to 31.33; p=0.34). Compared with the RTX group, the OBZ group demonstrated higher lupus low disease activity state attainment (74.1% vs 52.3%; p=0.049), lower SLEDAI-2000 Scores (median (IQR): 2 (1-2) vs 4 (2-4.25); p=0.04) and a trend towards higher B cell depletion rates at 12 months (57.1% vs 20.0%; p=0.08). OBZ treatment significantly shortened hospitalisation by 7 days (14.7±5.4 vs 21.9±11.9 days; p=0.04) and achieved a deeper B cell depletion at 6 months (median CD19+B cells: 0.4 (0-1.4) vs 3.5 (2-19.3) cells/µL; p=0.01), compared with the RTX group. Safety profiles were comparable between groups, with both treatments well tolerated. No deaths occurred.

Conclusion: These findings suggest OBZ may induce superior clinical responses in NPSLE through enhanced B cell depletion, with acceptable safety at 12 months, calling for further exploration.

Objective: To investigate the pharmacokinetics, effectiveness, safety and tolerability of tofacitinib in young adults with active mucocutaneous (MC) SLE manifestations.

Methods: Patients with SLE and Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) Activity (CLASI-A) Scores >8 newly received open-label tofacitinib from baseline to week (week) 72. Intensive pharmacokinetics sampling was done at the end of week 1, and safety was assessed throughout the study. The primary effectiveness endpoint was partial response of MC activity defined as <20% improvement of the CLASI-A Score from baseline (CLASI-PR) at week 8 in intention-to-treat analysis; secondary and other endpoints included MC complete response (CLASI-CR; CLASI-A=0) and quality of life (QoL) as measured by Skindex-29.

Results: Subjects were 11 patients (female patients: 10, mean±SD age: 23.0±5.87 years) with moderate to severe MC manifestations (CLASI-A=16.6±8.03). The pharmacokinetics of tofacitinib was comparable to that seen in juvenile and adult arthritis. During 629 patient-weeks of follow-up, 73 adverse events (AEs) were reported, none of which were considered severe or led to study discontinuation. There were three serious AEs (pelvic inflammatory disease, appendicitis and migraine with aura) but no major cardiovascular events, malignancies or death. In intention-to-treat analysis, at week 8 CLASI-PR was achieved in 73% (8/11) of subjects, in 82% at week 24 and 100% at week 72, respectively. Although CLASI-A Scores significantly decreased from baseline (baseline/week 8/week 24/week 72=16.55±8.03/8.64±7.8/8.82+7 .9/7+9.7; p<0.001), CLASI-CR was achieved by only <10% (1/11), starting week 8. Skindex-29 Scores improved significantly as early as week 4 (baseline/week 4/week 24/week 72= 37.6±24.16/26.1±23.58/24.3±28.67/25.5±30.71; p=0.009).

Conclusion: Tofacitinib in patients with SLE with active MC manifestations showed good effectiveness by week 4 as well as tolerability at exposure comparable to those with other rheumatic diseases. Tofacitinib was associated with significant improvement of QoL due to rapid improvement of MC inflammation. Observed safety and pharmacokinetics were comparable to observations in juvenile and adult arthritis.

Objective: To investigate the effects of Qihuang Jianpi Zishen Granules (QJZG) on renal injury in SLE mice, focusing on macrophage M1/M2 polarisation mediated by the AMPK/ULK1 signalling pathway.

Methods: Parameters of renal function and proteinuria were assessed. Pathological changes in the kidney were examined using H&E, periodic acid-Schiff and Masson's trichrome staining. Serum inflammatory factor levels were quantified using ELISA. The expression levels of the glycolysis rate-limiting enzymes hexokinase 2 (HK2) and glucose transporter 1 (GLUT1) were determined, and the transcriptional levels of AMPK/ULK1 pathway components were measured using quantitative PCR. The abundance of proteins associated with AMPK/ULK1 signalling was assessed via immunoblotting. Flow cytometry was used to quantify CD86+ M1 type and CD206+ M2 type macrophage populations. Dual immunofluorescence staining was employed to visualise F4/80+CD86+ and F4/80+CD206+ coexpression patterns.

Results: Compared with the Untreated group, mice in the PRED (prednisone acetate), QJZG and 2-Deoxy-D-glucose groups exhibited improved renal histopathology, reduced levels of creatinine, blood urea nitrogen, 24-hour RRO (24-hour urinary protein), ACR (Albumin-to-Creatinine Ratio), TPCR (Urine Total Protein-to-Creatinine Ratio), tumour necrosis factor alpha, interleukin (IL)-1β, IL-12, IL-23, IL-27, HK2, GLUT1, mTOR, CD86 and iNOS messenger RNA (mRNA), CD86 and iNOS proteins, M1 macrophages, M1/M2 macrophages and F4/80+CD86 expression (p<0.05). They also displayed increased expression of transforming growth factor-beta, IL-4, IL-10, C-C motif chemokine ligand 18, AMPK, ULK1, Atg13, CD206 and Arg-1 mRNA, AMPK, ULK1, CD206 and Arg-1 proteins, M2 macrophages and F4/80+CD206 (p<0.05).

Conclusion: QJZG effectively improved renal injury in SLE by reducing inflammation and modulating the AMPK/ULK1 signalling pathway to suppress M1 macrophage polarisation.

Objective: To determine whether subclinical brain dysfunction in SLE can be detected by disrupted interhemispheric connectivity and assess its modulation by immunosuppressive regimens.

Methods: 234 subjects (140 patients with SLE and 94 healthy controls (HCs)) were included. Through stratified analysis, patients with SLE were divided into treatment-naïve group (n=22), glucocorticoid monotherapy group (GC group, n=30) and GC combined with cyclophosphamide (CTX) and/or hydroxychloroquine (HCQ) treatment group (n=50) to assess the differences in voxel-mirrored homotopic connectivity (VMHC) between groups.

Results: SLE group showed lower VMHC than the HC group in bilateral superior temporal gyrus, medial superior frontal gyrus, calcarine fissure and surrounding cortex and middle occipital cortices (Gaussian random field corrected: voxel p<0.005, cluster p<0.01). The VMHC in the bilateral superior temporal gyrus (r_s=-0.250, p=0.024) and medial superior frontal gyrus (r_s=-0.246, p=0.026) was negatively correlated with the depression score, while the VMHC in the medial superior frontal gyrus was negatively correlated with the anxiety score (r_s=-0.239, p=0.031). Three SLE subgroups and HCs had different VMHC in the postcentral/precentral gyrus (F=8.942) and anterior cingulate/paracingulate gyrus (F=9.868). Post hoc analysis found that compared with the HC group, VMHC in the treatment-naïve group was decreased in the bilateral posterior central gyrus (t=-2.953), while in the GC monotherapy group, it decreased in the posterior central gyrus (t=-2.999) and anterior cingulate/paracingulate gyrus (t=-2.999). Compared with GC combined with CTX and/or HCQ group, VMHC in GC monotherapy group was decreased in the postcentral gyrus (t=-2.999).

Conclusion: Even without overt neuropsychiatric symptoms, patients with SLE exhibit impaired interhemispheric functional synergy that is partially reversed by combination immunosuppression, suggesting an early targetable brain pathway.

Background: Anti-C1q autoantibodies can disrupt normal complement function, contributing to the formation of pathogenic immune complexes and end-organ damage. Although their role in SLE is well-established, their detection rate and clinical relevance across a broader spectrum of diseases remain insufficiently characterised. This study aimed to investigate the distribution of abnormal anti-C1q levels in the population and examine their associations with age, sex and specific clinical subtypes.

Methods: This retrospective study included patients who underwent anti-C1q testing at our hospital between September 2020 and September 2023. The primary outcome was the detection rate of abnormal anti-C1q levels (>10 U/mL) categorised by patient sex, age and disease diagnosis. One-way and two-way fixed-effect models were used to assess associations between odds of abnormal antibody levels and demographic factors. Multivariate logistic regression was performed to identify disease-specific correlates.

Results: Among 15 363 patients (median (IQR) age, 38 (28-53) years; 79.02% female; 52.19% aged <40 years) representing 67 distinct diagnoses, 7.88% showed abnormal anti-C1q levels. Female sex and younger age showed higher median anti-C1q levels and a greater proportion of abnormal results. SLE subtypes showed the highest detection rate of abnormal anti-C1q levels, with SLE without severe complications (853 of 3760, 22.69%) and lupus nephritis (88 of 294, 29.93%) being the most obvious. Lupus haematological and encephalopathic manifestations were associated with elevated antibody levels. Additionally, autoimmune cirrhosis (7 of 59, 11.86%) and systemic sclerosis (19 of 165, 11.52%) also showed high detection rates of abnormal anti-C1q levels. Both univariate and multivariate analyses indicated that male sex and younger age were significantly associated with increased odds of abnormal anti-C1q levels.

Conclusion: Elevations in anti-C1q levels extend beyond SLE and are influenced by both demographic factors and specific disease phenotypes. Male sex and younger age emerged as significant predictors of abnormal anti-C1q status. Our findings underscore the potential utility of anti-C1q testing for improving diagnostic precision and risk stratification across a wide range of clinical conditions.

Objective: To evaluate multiple-ascending doses of enpatoran, a selective toll-like receptor 7/8 (TLR7/8) inhibitor with the potential to modulate processes central to lupus pathophysiology, in patients with systemic and cutaneous lupus erythematosus (SLE/CLE).

Methods: In this randomised, double-blind, placebo-controlled phase Ib trial (NCT04647708), patients with active SLE/CLE were randomised 3:1 to enpatoran or placebo across four cohorts. Treatment duration was 12/24 weeks. All patients had a 2-week safety follow-up. The primary endpoint was safety and tolerability. Secondary endpoints included pharmacokinetics (PK) and clinical response. Change in lupus biomarkers, including interferon gene signature (IFN-GS), was an exploratory endpoint.

Results: 25 patients received placebo (n=6) or enpatoran (n=19); 80% were female, all were white, and the median age was 44 years. By week 12, treatment-emergent adverse events (TEAEs) were reported by 42% of patients across the four enpatoran dose groups and 33% of placebo-treated patients. Enpatoran remained well tolerated to week 24. Most TEAEs (96%) were mild or moderate in severity. There were no serious TEAEs. Enpatoran PK was dose proportional, with peak concentration reached 1-2 hours postdose and an apparent half-life of 6-10 hours across doses. Greater reductions in Systemic Lupus Erythematosus Disease Activity Index 2000, Physician's Global Assessment and 28-joint count were observed at week 24 with enpatoran versus placebo. Rapid, dose-dependent and reversible suppression of IFN-GS was observed.

Conclusions: Enpatoran was well tolerated and demonstrated favourable safety and PK profiles in patients with SLE and CLE. Although preliminary, the SLE disease activity and biomarker results support the therapeutic targeting of TLR7/8 for lupus.

Trial registration number: NCT04647708.