Lupus Science & Medicine最新文献

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.

Objective: Small fibre neuropathy (SFN) is an under-recognised complication of SLE that contributes to chronic pain and reduced quality of life. We assessed the utility of corneal confocal microscopy (CCM) for identifying small fibre damage in SLE in relation to disease activity, neuropathic pain and quality of life.

Methods: Participants with SLE and healthy controls underwent CCM to quantify corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), corneal nerve fibre length (CNFL), corneal nerve fibre tortuosity (CNFT), inferior whorl length (IWL), Douleur Neuropathique 4 (DN4) Score, vibration perception threshold (VPT) and sudomotor function.

Results: Participants with SLE (n=59; age 38.6±9.6 years; mean Systemic Lupus Erythematosus Disease Activity Index Score 3.4±4.2) had significantly lower CNBD (41.5±21.3 vs 72.1±29.4 branches/mm², p=0.0001) and CNFL (18.5±4.3 vs 24.2±4.4 mm/mm², p=0.0001) but comparable CNFD (31.7±7.1 and 34.0±6.9 fibres/mm², respectively, p=0.25), CNFT (15.0±4.0 and 14.3±3.1, respectively, p=0.55), and IWL (38.5±8.0 and 35.6±5.9 mm/mm², respectively, p=0.16) compared with healthy controls (n=17). Patients with SLE had a DN4 Score of 3.5±2.5 and elevated VPT (4.1±3.3 vs 2.8±0.7 V, p<0.01) but comparable sudomotor function of the hands and feet (p=0.28-0.42). Active SLE was associated with a lower CNBD/CNFD ratio (p<0.05). Patients with SLE associated with sustained neuropathic pain (17.2%) had significantly lower CNFD, CNFL and IWL than those with transient (p<0.05-0.0001) and recurrent (p<0.05-0.01) pain but comparable VPT (p=0.27) and sudomotor function (p=0.14). Reduced CNFL was associated with bodily pain, affecting quality of life (p<0.05).

Conclusion: This study demonstrates that CCM detects peripheral neurodegeneration in patients with SLE, which relates to disease activity, sustained neuropathic pain and quality of life. CCM may serve as a rapid non-invasive neuroimaging technique to identify SFN in SLE.

Background: Lupus nephritis (LN) is the most serious complication of SLE. Interstitial fibrosis is the dominant pathological change of renal injury in LN. Enhanced histone deacetylase 3 (HDAC3) positively correlates with renal interstitial fibrosis (RIF). Our study objective was to explore the accurate role and mechanism of HDAC3 in the RIF of LN.

Methods: To knock down HDAC3, Murphy Roths large (MRL)/wt and MRL/MpJ-Faslpr/J (MRL/lpr mice were injected with lentiviral short hairpin RNAs. Human renal proximal tubular epithelial cells (HK-2 cells) were treated with serum from patients with LN to establish an LN cell model. Renal histopathological change was assessed by H&E, Masson and Sirius red staining. Cell viability was determined using Cell Counting Kit-8 (CCK-8) kits. Inflammation cytokine determination was conducted employing ELISA assays. Protein expression was detected by western blot, and immunohistochemical and immunofluorescence staining. Gene densities were analysed by quantitative real-time PCR assays. Co-immunoprecipitation analysis validated the interactions of nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1).

Results: HDAC3 levels were increased in the serum and kidney tissues of patients with SLE and LN, and the LN group posted the highest level. HDAC3 knockdown ameliorated RIF, oxidative stress, inflammation and ferroptosis in kidney tissues of MRL/lpr mice. Moreover, HDAC3 inhibition repressed the inflammatory and oxidative reactions, fibrosis and ferroptosis in LN-serum-induced HK-2 cells. Further, HDAC3 knockdown could inhibit the Keap1-Nrf2 interaction to trigger Nrf2 activation.

Conclusion: HDAC3 inhibition relieved RIF, oxidative stress, inflammation and ferroptosis by upregulating Nrf2 in the mice and cell models of LN.

Objective: To evaluate the effect of early belimumab administration on disease progression in patients with early active SLE.

Methods: This multicentre observational study included patients with early active SLE, defined as being diagnosed ≤12 months from enrolment in the study, displaying ≤2 clinical European Alliance of Associations for Rheumatology (EULAR)/American College of Rheumatology (ACR) 2019 criteria, without major organ involvement but with active serology. Patients were receiving glucocorticoids and hydroxychloroquine as standard of care (SoC) and either belimumab (BEL group) or standard immunosuppression (SoC group). Patients were followed up for 12 months, and accrual of new EULAR/ACR criteria served as a marker of disease progression. Kaplan-Meier survival analysis and log-rank tests were applied to assess differences in criteria-free survival between groups, while Cox regression compared the lag time to criteria accrual.

Results: 69 patients were included (BEL=33 and SoC=36). Patients receiving early BEL accrued fewer events per 100 patient-years compared with SoC (2.78 vs 12.12, p=0.035). Criteria-free survival was longer in the BEL group (log-rank p=0.04), with a mean time-to-event of 11.8±1.07 months versus 10.3±3.33 months in the SoC group (Cox regression, p=0.027). Early BEL was associated with a sixfold higher likelihood of achieving glucocorticoid (GC) discontinuation at 12 months as compared with patients on hydroxychloroquine (HCQ) and GC alone (OR 6.67, p=0.0014).

Conclusions: Early administration of BEL in active SLE significantly delays disease progression and promotes GC withdrawal. These findings are more striking when limiting SoC to HCQ and GC and underscore the potential of early biologic intervention to modify disease course. Further validation in larger, prospective studies is warranted.