Lupus Science & Medicine最新文献

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.

Objective: Lupus nephritis (LN) is a major cause of morbidity and mortality, affecting up to 60% of patients with systemic lupus erythematosus (SLE). The perspectives of patients with SLE have been explored; however, little is known of the lived experiences of patients with LN.

Methods: Patients aged ≥18 years with biopsy-proven pure or mixed International Society of Nephrology/Renal Pathology Society Class III, IV or V LN were purposefully recruited from a Canadian lupus cohort to participate in a photovoice (visual-narrative participatory research method) exercise. Participants took photos of what LN means to them, impacts on daily life and factors impacting LN management. Photos were shared and discussed in focus groups.

Results: 13 individuals with LN participated (92.3% were female; mean (SD) age was 41.7 (14.0) years). The mean (SD) number of photos shared per participant was 4.2 (0.9). Photos (n=54) depicted activities/settings that contribute to well-being (n=15), the participants themselves (n=13), healthcare experiences (n=10), home (n=4), community (n=2), friends (n=2), work (n=2) and other challenges (n=6). All participants described physical and psychosocial impacts of living with LN. Although 12 mentioned activities/settings that contribute to well-being (eg, time in natural environments), participants were consistently reminded of limitations imposed by LN due to physical symptoms, challenges presented by the physical environment and the altered life trajectories experienced. Participants discussed the dual burden of LN and the associated medication journey; side effects and medication-related financial challenges were highlighted by ten and five participants, respectively.

Conclusions: Participants reported a substantial psychosocial burden associated with altered life trajectories, the dual burden of LN and the associated medication journey, and the conflicting role of the physical environment. The need for flexibility (ie, from employers, themselves) is an essential component of navigating altered life trajectories.

Objective: Hydroxychloroquine (HCQ) is an antimalarial drug employed in the treatment of systemic lupus erythematosus (SLE). Prior studies reported inconsistent results regarding the association between HCQ use during pregnancy and adverse pregnancy outcomes. This study aimed to evaluate the impact of HCQ on pregnancy-related outcomes in women with SLE.

Methods: We conducted a systematic search for studies associating pregnancy outcomes with HCQ use in PubMed, EMBASE, Cochrane Library, Web of Science, CNKI, Wanfang database and VIP from inception to 22 September 2022. Random or fixed effect models were used to estimate the pooled effect based on I² measurement of heterogeneity.

Results: Twenty-one studies were included, encompassing 929 and 1031 patients in HCQ and non-HCQ groups, respectively. We found that HCQ use was significantly associated with reduced risks of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (second trimester: mean difference (MD) -1.80, 95% CI -2.46 to -1.13; third trimester: MD -2.30, 95% CI -3.31 to -1.29), flare (OR 0.57, 95% CI 0.33 to 0.97), preterm birth (OR 0.57, 95% CI 0.46 to 0.72), intrauterine growth retardation (IUGR) (OR 0.48, 95% CI 0.31 to 0.72), gestational hypertension (OR 0.19, 95% CI 0.08 to 0.42), pre-eclampsia (OR 0.46, 95% CI 0.29 to 0.72). In contrast, a positive correlation was observed between full-term birth and HCQ use (OR 2.01, 95% CI 1.52 to 2.65). However, the result for disease flare exhibited high heterogeneity (p=0.01, I²=59%). In addition, publication bias was detected in the meta-analysis of full-term birth using the Egger's test.

Conclusions: This meta-analysis offers a comprehensive assessment of the relationship between disease activity, pregnancy-related outcomes and HCQ use, providing supportive evidence for the therapeutic effectiveness of HCQ in pregnant women with SLE.

Prospero registration number: CRD42022374468.

Background: Mental health (MH) conditions are prevalent in adolescents with childhood-onset SLE (cSLE). Early identification is crucial in preventing poor patient outcomes; however, MH screening rates remain low.

Local problem: From July 2021-January 2022, only 15% of adolescents in a paediatric tertiary care cSLE clinic were being screened for depression and anxiety. By November 2023, we aimed to increase the percentage of patients with cSLE (≥12-18 years) screened for depression (Patient Health Questionnaire: PHQ-9) and anxiety (Generalised Anxiety Disorder-7: GAD-7) from 15% to 80%.

Methods: This quality improvement project employed the Model for Improvement framework. Stakeholders included the clinic team, patients and families, and MH providers. Statistical process control charts were used to analyse the outcome measure for percentage of screened patients with cSLE. Patient and caregiver satisfaction surveys were conducted at baseline and after screening as a balancing measure.

Interventions: MH screening workflow with a referral algorithm was developed with stakeholders. Additional interventions included two MH training workshops for healthcare providers and a preclinic reminder of eligible patients for screening.

Results: Over 21 months, 146 patients with cSLE completed 270 MH screens, increasing the screening rate from 15%, peaking at 100%, to a median of 56%. Sixty-six individuals (45%) reported symptoms of depression and/or anxiety on their initial screen. Of 270 screens, 44 individuals (17%) reported moderate to severe symptoms meeting the screening workflow criteria for referral to a MH service; 10% of patients screened were referred and seen by the MH service within 2-12 weeks. Patients and caregivers reported satisfaction with the MH screening process and quality of MH follow-up.

Conclusion: Despite not sustainably meeting the target, MH screening rates increased in the cSLE clinic by nearly fourfold, demonstrating feasibility and acceptability. Patients expressed satisfaction with their mental health follow-up, emphasising its importance in their care.

Objective: This study aimed to validate claims-based algorithms for identifying SLE and lupus nephritis (LN) in Medicare data, enhancing the use of the Lupus Index for geospatial research on SLE prevalence and outcomes.

Methods: We retrospectively evaluated the performance of rule-based algorithms using the International Classification of Diseases, 10th Revision (ICD-10) codes to identify SLE and LN in a well-defined prospective longitudinal cohort of patients with and without SLE from a South Carolina registry and rheumatology outpatient clinics. The analysis included comparison of algorithms based on Medicare fee-for-service claims data to these rigorously phenotyped populations. The primary classification for SLE cases was based on the American College of Rheumatology and Systemic Lupus Erythematosus International Collaborating Clinics criteria for SLE and LN. Algorithms were based on the number of ICD-10 codes with and without a 30-day separation in the observation period, including all of 2016-2018.

Results: The algorithm using two ICD-10 codes for SLE, with or without a 30-day separation, showed the best overall performance. For LN, specific ICD-10 codes outperformed combinations of SLE and renal/proteinuria codes that were found in ICD-9.

Conclusions: The findings of this study highlight the performance of specific ICD-10 code algorithms in identifying SLE and LN cases within Medicare data, providing a valuable tool for informing use of the Lupus Index. This index allows for improved geographical targeting of clinical resources, health disparity studies and clinical trial site selection. The study underscores the importance of algorithm selection based on research objectives, recommending more specific algorithms for precise tasks like clinical trial site identification and less specific ones for broader applications such as health disparities research.

Objective: We report on the clinical characteristics, treatments and outcomes of Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyradiculoneuritis (CIDP) associated with SLE.

Methods: Patients treated at Peking Union Medical College Hospital between January 2004 and November 2021 who fulfilled the diagnostic criteria for SLE and GBS/CIDP (n=9) were included. Clinical presentations, lab results, treatment regimens and prognoses were retrieved and analysed.

Results: Six patients were diagnosed with SLE and GBS, while three were diagnosed with SLE and CIDP, with the average age at diagnosis of 38.6±18.2 years. SLE disease duration ranges from 1 week to 36 years, and the courses of GBS and CIDP range from 1 week to 2 months and from 2 months to 15 months, respectively. All patients exhibited either or both limb paresthesia and weakness, other neurological symptoms include dysphagia, peripheral facial nerve palsy and respiratory and cardiac arrest. The median cerebral spinal fluid white blood cell count and protein level were 0.002×10⁹/L (0-0.006×10⁹/L) and 0.79 g/L (0.57-7.09 g/L), respectively. All patients received glucocorticoid and immunoglobulin therapy. Seven patients received cyclophosphamide, and seven patients received intrathecal injections of methotrexate and dexamethasone. Two patients had complete resolution, five experienced marked improvements and two failed to improve with treatments.

Conclusion: SLE-associated GBS/CIDP may manifest regardless of disease systemic activity. Clinical features may differ from that of pure GBS/CIDP, and treatment often requires immunosuppressants, making differential diagnosis crucial, especially for patients with GBS/CIDP presenting as the first manifestation of SLE.

Introduction: DNA hypomethylation in patients with systemic lupus erythematosus (SLE) has been recently documented in the literature. Low levels of DNA methylation have been observed globally and in genes associated with immune and inflammatory pathways in SLE's CD4+T lymphocytes. Given that certain micronutrients can either donate methyl groups within one-carbon metabolism pathways or serve as cofactors for enzymes involved in the DNA methylation process, this randomised, double-blind, placebo-controlled trial aims to investigate whether a 3-month supplementation of folic acid and vitamin B₁₂ will modulate the DNA methylation profile in subcutaneous adipose tissue (primary outcome) of women with SLE and normal weight or excess body weight. As secondary objectives, we will assess gene expression, telomere length and phenotypic characteristics (ie, clinical parameters, body weight and composition, abdominal circumference, food intake and disordered eating attitude, physical activity, lipid profile, serum concentrations of leptin, adiponectin, and cytokines).

Methods and analysis: Patients will be classified according to their nutritional status by body mass index in normal weight or excess body weight. Subsequently, patients in each group will be randomly assigned to either a placebo or an intervention group (folic acid (400 mcg) and vitamin B₁₂ (2000 mcg) supplementation). Endpoint evaluations will be conducted using both intention-to-treat and per-protocol analyses. This study has the potential to design new personalised nutritional approaches as adjunctive therapy for patients with SLE.

Ethics and dissemination: This study has been reviewed and approved by the Ethical Committee from Clinical Hospital of the School of Medicine of the University of Sao Paulo, Brazil (CAAE.: 47317521.8.0000.0068).

Trial registration number: NCT05097365 (first version).

Background: SLE is a complex autoimmune disease with heterogeneous manifestations and unpredictable outcomes. Early diagnosis is challenging due to non-specific symptoms, and current treatments only manage symptoms. Epigenetic alternations, including 5-Hydroxymethylome (5hmC) modifications, are important contributors to SLE pathogenesis. However, the 5hmC modification status in circulating cell-free DNA (cfDNA) of patients with SLE remains largely unexplored. We investigated the distribution of 5hmC in cfDNA of patients with SLE and healthy controls (HCs), and explored its potential as an SLE diagnosis marker.

Methods: We used 5hmC-Seal to generate genome-wide 5hmC profiles of plasma cfDNA and bioinformatics analysis to screen differentially hydroxymethylated regions (DhMRs). In vitro mechanistic exploration was conducted to investigate the regulatory effect of CCCTC-binding factor (CTCF) in 5hmC candidate biomarkers.

Results: We found distinct differences in genomic regions and 5hmC modification motif patterns between patients with SLE and HCs, varying with disease progression. Increased 5hmC modification enrichment was detected in SLE. Additionally, we screened 151 genes with hyper-5hmC, which are significantly involved in SLE-related processes, and 5hmC-modified BCL2, CD83, ETS1 and GZMB as SLE biomarkers. Our findings suggest that CTCF regulates 5hmC modification of these genes by recruiting TET (ten-eleven translocation) protein, and CTCF knockdown affected the protein expression of these genes in vitro.

Conclusions: Our findings demonstrate the increased 5hmC distribution in plasma cfDNA in different disease activity in patients with SLE compared with HCs and relating DhMRs involved in SLE-associated pathways. Furthermore, we identified a panel of SLE relevant biomarkers, and these viewpoints could provide insight into the pathogenesis of SLE.

Objectives: Chorea, characterised by involuntary, irregular movements, is a rare neurological manifestation of antiphospholipid syndrome (APS). The specific clinical features remain unclear. This study aimed to summarise the available evidence on antiphospholipid antibody (aPL)-associated chorea.

Methods: We used a mixed-methods approach, combining data from patients with chorea with aPL positivity admitted to Peking Union Medical College Hospital (PUMCH) from 2014 to 2024, with cases identified in public databases since 1983. We collected and analysed clinical, laboratory, and imaging results, along with their treatments and outcomes.

Results: A total of 180 patients with incident aPL-associated chorea were included (13 from PUMCH and 167 from the literature). The majority (81.7%) were female, with a mean age of chorea onset 22.8 years (SD=16.0). Chorea was the initial symptom in 87.9% of cases and often occurred as a single episode (67%), involving bilateral limbs (58.8%) and both upper and lower limbs (87.2%). 43.3% met the 2023 American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) APS classification criteria. Thrombocytopenia (30.0%) and arterial thrombosis (29.1%) were the most common manifestations. Lupus anticoagulant was positive in 84.2% of patients, anticardiolipin IgG in 70.8%, and anti-β2 glycoprotein I IgG in 52.9%. Among those who had results available for the three tests, 57.6% were triple-positive. ANAs were positive in 63.6%. MRI revealed basal ganglia lesions in only 14.8% of patients, whereas all positron emission tomography (PET) scans showed contralateral striatal hypermetabolism. Treatment varied, with most receiving combination therapies of neuroleptics, anticoagulants, antiplatelets, steroids and immunosuppressants. Chorea completely or partially improved in 95.5% of patients.

Conclusion: Chorea is a significant but under-recognised manifestation of APS, predominantly affecting young women and often presenting as the initial symptom. Characteristic PET findings of contralateral striatal hypermetabolism can assist in diagnosis. Treatments with glucocorticoids and immunosuppressive therapies appear beneficial. Further research is needed to understand the pathophysiology and optimise management strategies for aPL-associated chorea.

Objective: COVID-19 induces the development of autoimmune diseases, including SLE, which are characterised by inflammation, autoantibodies and thrombosis. However, the effects of COVID-19 on SLE remain unclear.

Methods: We investigated the effects of COVID-19 on SLE development and progression in three animal models. Plasmids encoding SARS-CoV-2 spike protein and ACE2 receptor were injected into R848-induced BALB/C lupus mice, R848-induced IL-1 receptor antagonist knockout (KO) lupus mice and MRL/lpr mice. Serum levels of albumin and autoantibodies, lymphocyte phenotypes and tissue histology were evaluated.

Results: In R848-induced BALB/C lupus mice, the SARS-CoV-2 spike protein increased autoantibody and albumin levels compared with vehicle and mock treatments. These mice also exhibited splenomegaly, which was further exacerbated by the spike protein. Flow cytometric analysis revealed elevated T helper 1 cell counts, and histological analysis indicated increased levels of the fibrosis marker protein α-smooth muscle actin. In KO mice, the spike protein induced splenomegaly, severe kidney damage and pronounced lung fibrosis. In the MRL/lpr group, spike protein increased the serum levels of autoantibodies, albumin and the thrombosis marker chemokine (C-X-C motif) ligand 4.

Conclusion: COVID-19 accelerated the development and progression of lupus by inducing autoantibody production, fibrosis and thrombosis.