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PubMed2026

Expression and mutation characteristics of mitochondrial genes in PBMCs of SLE patients: Implications for SLE pathogenesis.

This study aimed to investigate mitochondrial gene mutations and expression in peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients, focusing on MT-ND5, and assess expression changes under lipopolysaccharide (LPS), tumor necrosis factor-α (TNF-α), and dexamethasone stimulation. Peripheral blood was collected from female SLE patients. Mitochondrial DNA (mtDNA) from PBMCs was sequenced using the HiSeq PE150 platform. Quantitative reverse transcription PCR and western blotting were used to evaluate mRNA and protein expression of the most frequently mutated mitochondrial genes. Cultured PBMCs were treated with LPS, TNF-α, or dexamethasone to examine regulatory effects. A total of 589 mtDNA mutation sites were detected in SLE patients. Among 13 protein-coding genes, MT-ND5, MT-CYB, MT-CO1, MT-ND4, and MT-CO3 exhibited the highest mutation frequencies. Expression analysis revealed significantly reduced mRNA and protein levels of these genes in SLE PBMCs compared with controls, with further decreases after stimulation with LPS, TNF-α, or dexamethasone. SLE PBMCs display extensive mitochondrial mutations and downregulation of key genes, particularly MT-ND5. Inflammatory and therapeutic stimuli exacerbate this suppression, suggesting mitochondrial dysfunction contributes to SLE susceptibility and progression.

Humans↗

PubMed2026

Risk of stroke in SLE: a systematic review and meta-analysis.

UNLABELLED: The association between SLE and composite stroke, ischaemic stroke and haemorrhagic stroke remains incompletely understood. This meta-analysis aims to assess the risk of stroke in patients with SLE. METHODS: Data sources included PubMed, Embase, the Cochrane Library and reference lists of included studies. This meta-analysis included cohort studies evaluating whether stroke risk is associated with SLE. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale (NOS). Risk ratios (RRs) with 95% CIs were pooled using a random-effects model, and publication bias was assessed with funnel plots and Egger's test. RESULTS: A total of 25 cohort studies involving 5 220 837 individuals were included in this meta-analysis, which were published between 2001 and 2026. The pooled analysis demonstrated a significantly increased risk of stroke in patients with SLE (RR of 2.60, 95% CI 2.21 to 3.05, I²=97.9%, p<0.001). The risk of composite stroke (RR of 2.83, 95% CI 2.25 to 3.57, I²=98.0%, p<0.001), ischaemic stroke (RR of 2.34, 95% CI 1.75 to 3.12, I²=97.6%, p<0.001) and haemorrhagic stroke (RR of 2.66, 95% CI 1.57 to 4.49, I²=96.2%, p<0.001) was also increased in SLE. Despite the large heterogeneity, the sensitivity analysis indicated that the results were robust, and there was little evidence of publication bias. CONCLUSION: The risk of composite stroke, ischaemic stroke and haemorrhagic stroke is increased in SLE. PROSPERO REGISTRATION NUMBER: CRD420261294082.

Humans↗

PubMed2026

Stigma, discrimination-related events, and determinants among adult people living with systemic lupus erythematosus (SLE): Systematic review and indicator-level meta-analysis.

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease with 0.4 million new cases diagnosed annually. With its wide variety of visible and invisible manifestations, people living with SLE report being exposed to stigmatization, which impacts their personal and professional lives. However, the current literature is unclear on whether healthcare management teams assess this concern during follow-up. This study aims to synthesize existing evidence on the prevalence and determinants of stigma among people living with SLE.MethodsThis systematic review and meta-analysis gathered evidence from observational studies identified from three databases on 16 July 2025. Dual independent screening, data extraction, and risk-of-bias assessment (using the Newcastle-Ottawa Scale) were performed. Results were synthesized using descriptive statistics, narrative synthesis, and indicator-level meta-analyses.ResultsWithin the past two decades, 11 studies comprising 2254 people living with SLE reported and measured stigma- and discrimination-related events using various scales. Stigma was found to be prevalent across its three constructs: interpersonal, perceived, and intrapersonal stigma. This review demonstrated that people living with SLE reported a moderate overall burden of stigma (34.71 [95% CI 26.15, 43.27]), with average stigma scores indicating psychological impact. Additionally, nearly one in two persons (46% [95% CI 28-66%]) experienced at least one form of stigma or discrimination, most commonly social isolation and unfair treatment. Mental health associations were correlated with higher stigma burden.ConclusionThis review demonstrates that stigma and discrimination are not just social challenges but also critical determinants of health. With cautious interpretation, pooled evidence reveals a consistent high prevalence of stigma and discrimination, which act as "toxic" stressors, creating a vicious cycle with psychological stress and psychiatric manifestations and disease activity. There is an urgent clinical need to move beyond a mere biological approach to disease assessment and management and to begin screening for the "invisible" burden of invalidation and discrimination.

Humans↗

PubMed2026

SLE-Associated rs2295613(A) Allele Strengthens a Predicted c-MYC Motif and Enhances SLAMF1 Promoter Reporter Activity in B Cells.

SLAMF1 encodes CD150, an immunoregulatory receptor involved in lymphocyte activation, T-B-cell interactions, and humoral immune responses. The SLAMF1 promoter polymorphism rs2295613(G>A) was previously associated with systemic lupus erythematosus (SLE) susceptibility in a Chinese case-control cohort. Here, we investigated the regulatory activity of rs2295613 in the transformed B-cell lines Raji and MP1 and in primary human CD19+ B cells. The rs2295613(A)-containing reporter showed higher promoter activity than the rs2295613(G)-containing reporter in all three cellular systems. Bioinformatic analysis predicted that the G to A substitution strengthens a pre-existing MYC-compatible motif. Substitutions disrupting the motif-containing region attenuated the rs2295613(A)-associated increase in reporter activity and reduced enrichment of the promoter fragment in anti-c-MYC DNA pull-down assays. Partial siRNA-mediated reduction in MYC mRNA also decreased the activity of the rs2295613(A)-containing reporter in Raji cells. Together, these findings identify rs2295613 as a functional SLAMF1 promoter variant in B-cell reporter systems and support a contribution of c-MYC-associated regulation to the enhanced activity of the rs2295613(A)-containing promoter.

Humans↗

PubMed2026

Dysregulation of U12-Type Splicing in Lupus Neutrophils.

OBJECTIVE: Neutrophil dysfunction is a hallmark of systemic lupus erythematosus (SLE), but its molecular basis remains unclear. This study explores transcriptional and posttranscriptional changes in low-density granulocytes (LDGs), a proinflammatory neutrophil subset expanded in SLE, focusing on NADPH oxidase (Nox) function and minor intron splicing. METHODS: LDGs and normal-density granulocytes (NDGs) were isolated from patients with SLE and healthy controls (HCs). CYBA (p22phox) expression was evaluated at transcript and protein levels. Nox activity was measured using luminol assays. Bulk RNA sequencing (RNA-seq) and rMATS software were used to assess alternative splicing, particularly of U12-type intron-containing genes. RESULTS: CYBA expression was reduced in SLE LDGs (n = 11) compared to SLE and HC NDGs (n = 6), with levels resembling those in chronic granulomatous disease neutrophils. SLE LDGs exhibited impaired Nox activity (n = 7 SLE, n = 12 HC). CYBA is a U12 intron-containing gene, and transcriptomic analysis revealed broad down-regulation of this gene class in SLE LDGs, suggesting minor spliceosome dysfunction. rMATS analysis showed increased U12-type intron retention and widespread splicing defects-including exon skipping and mutually exclusive exon use-in genes such as GBP5, MAEA, and STX10. These abnormalities were validated in an independent long-read RNA-seq data set from SLE peripheral blood mononuclear cells. Importantly, splicing disruptions correlated with disease activity and autoantibody profiles. CONCLUSION: Impaired U12-dependent splicing may contribute to neutrophil dysfunction in SLE, potentially via defective oxidative burst and altered immune regulation. These findings highlight the minor spliceosome as a novel player in lupus pathogenesis.

Humans↗

PubMed2026

Altered reproductive hormone profiles in systemic lupus erythematosus - A systematic review and meta-analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) shows a marked female predominance during reproductive years, possibly suggesting hormonal factors in its pathogenesis. However, evidence regarding reproductive hormone alterations in SLE remains inconsistent. OBJECTIVES: To systematically review studies assessing reproductive hormone levels in adult SLE patients compared with healthy controls and across disease activity states. METHODS: Following PRISMA guidelines and a pre-registered protocol (PROSPERO CRD42024544730), PubMed and Scopus were searched (May 2024). Eligible observational studies reported estradiol, testosterone, progesterone, prolactin, FSH, LH, DHEA-S, DHEA or androstenedione in SLE patients versus controls or by disease activity. Random-effects meta-analyses were conducted. RESULTS: Eighty-three studies were included (5389 individuals for SLE vs. controls; 2067 for active vs. inactive SLE). Prolactin was consistently higher in SLE (MD 8.07 ng/mL; 95% CI 4.69-11.45; p < 0.001) and even more during flare (MD 5.83 ng/mL; 95% CI 3.88-7.78; p < 0.001). Estradiol showed non-significant overall elevations but was significantly higher in women with active disease (MD 8.55 pg/mL; 95% CI 1.37-15.73; p = 0.03). DHEA-S was found to be significantly lower in SLE (MD -1.00 μg/mL; 95% CI -1.5 to -0.50; p = 0.002) but too few studies evaluated its dynamics during flares. FSH and LH were significantly higher in men with SLE. Other hormones were inconsistent. Only three small heterogeneous studies evaluated hormonal changes during flares. CONCLUSIONS: Prolactin excess and androgen deficiency are consistent features of SLE, particularly in women, while elevated gonadotropins are mainly seen in men. Estradiol is higher during active disease but other data are inconsistent. Longitudinal studies are limited, with prolactin the only hormone consistently linked to disease activity and full hormonal profiles during flares are largely unstudied.

Humans↗

PubMed2025

Immunosuppressant use may be a potential mediator in the progression of systemic lupus erythematosus to osteomyelitis: A bidirectional Mendelian randomization study.

The prevalence of osteomyelitis (OM) is elevated in patients with systemic lupus erythematosus (SLE), but the causal direction and proportion of immunosuppressant (IS) use in this relationship is unclear. Therefore, this study used a bidirectional Mendelian randomization (MR) study to investigate the causal relationship between SLE and OM and to quantify the role of IS use as a potential mediator. Genome-wide association study summary-level data were used to obtain genetic instrumental variables for SLE (5201 cases and 9066 controls), OM (1881 cases and 391,037 controls), and IS (3954 cases and 268,648 controls) genetic instrumental variables with no overlap between their participant populations. Causal and total effects of SLE and OM were analyzed using bidirectional MR. Subsequent "2-step" MR was used to assess the direct effect between the 2 and the indirect effect of IS. Inverse variance weighting was used as the primary method of MR, while a series of sensitivity analyses were performed to assess the reliability of the results. Forward MR of inverse variance weighting results demonstrated a positive causal association between SLE and OM (P = .003, odds ratio [OR] = 1.062, 95% confidence interval [Cl]-OR: 1.019-1.107). The reverse MR results indicated no causal effect of OM on SLE was found (P = .503, OR = 0.914, 95% Cl-OR: 0.703-1.188). The direct effect of SLE acting on OM in our study was found to be 19.36% by 2-step analysis, and the indirect effect of OM through IS was found to be 68.11% (proportion mediated: 68.11%; 95% CI = 0.2277331-1.134507). There was no heterogeneity in all MR analyses of causality, except for the MR analysis of SLE causally related to IS. Sensitivity analysis found no evidence of horizontal pleiotropy. The present study found an increased relative risk of OM in SLE. Mediation analysis suggested a potential substantial mediating role for IS; however, this estimate was highly imprecise and requires further validation. In clinical practice, clinicians should remain aware of the potential for IS therapy to influence infection risk, including OM, in SLE patients.

Humans↗

PubMed2026

Longitudinal comparison of treat-to-target states and clinical outcomes in patients with late-onset versus early-onset systemic lupus erythematosus.

OBJECTIVE: We compared demographic and clinical characteristics between patients with late-onset (LO) and early-onset (EO) systemic lupus erythematosus (SLE) and examined their longitudinal associations with treatment targets and long-term outcomes, irreversible organ damage accrual and health-related quality of life (HRQoL). METHODS: We analyzed prospectively collected data from patients enrolled in the Asia Pacific Lupus Collaboration cohort. Patients diagnosed with SLE at age >50 years were classified as LO-SLE and compared with those diagnosed at age ≤50 years (EO-SLE). Longitudinal associations with treatment targets (LLDAS and DORIS remission), organ damage accrual (SLICC/ACR Damage Index), and HRQoL (SF36v2 physical and mental component summary (PCS and MCS) scores) were examined using multivariable multilevel logistic, recurrent-event survival, and linear mixed-effects models, respectively. Disease activity, flares, medication exposure, and other clinical characteristics were also compared between groups. RESULTS: Among 3,917 patients studied, 346 (8.8%) had LO-SLE. Compared with EO-SLE, patients with LO-SLE had lower disease activity, lower glucocorticoid and immunosuppressant exposure, and higher attainment of treatment targets; LO-SLE was associated with higher odds of attaining LLDAS (OR: 2.33 (1.66, 3.28)) and DORIS remission (OR: 2.22 (1.45, 3.38)). However, they were at a greater risk of damage accrual (HR:1.82 (1.50, 2.21)) and lower PCS scores, meaning poorer physical health (regression coefficient (RC) = -3.63 (-4.58, -2.68)) but not MCS (RC= 0.68 (-.50, 1.86)). CONCLUSION: Despite higher attainment of treatment targets, patients with LO-SLE experienced greater damage accrual and poorer physical health, suggesting that disease activity targets alone may not fully capture outcome risk in LO-SLE.

Journal Article↗

PubMed2026

Barriers to physical activity in patients with systemic lupus erythematosus in the UK.

INTRODUCTION: Physical activity (PA) may play an important role as a non-pharmacological addition to the management of SLE for disease control and reduction of cardiovascular risk factors. Those with SLE have been reported to engage in PA less than the general population. OBJECTIVE: To describe PA patterns and patient-reported barriers to PA for people with SLE in the UK. METHODS: An online survey was conducted of adults aged ≥ 18 years. Participants were recruited from posters in outpatient clinics, newsletters and Lupus UK social media platforms. Survey questions included demographic information, perception of disease activity, the International Physical Activity Questionnaire (IPAQ) and specific leisure time questions. RESULTS: Two hundred sixty-eight patients participated, with a median (IQR) age of 51 (39-59) years and SLE disease duration of 10 (4-20) years were included. SLE-diagnosis was collected by self-report. In those with complete IPAQ data, 178/228 (79.1%) were in a moderate/high activity group. Participants in this group were more likely to be in employment and had lower levels of fatigue and pain. Fatigue was the most reported barrier to PA, irrespective of activity levels. Participants in the low PA group were more likely to have SLE-specific barriers such as higher disease activity and higher pain scores. CONCLUSIONS: Perceptions and preferences in relation to PA differ greatly between individuals with SLE. The most common self-reported barrier to PA was fatigue. Exploration of individual perceptions of PA should form part of consultations, to address perceived barriers. Key Points • Some patients with self-reported SLE can meet WHO physical activity targets, especially those who remain in work. • Fatigue is the most frequently reported barrier to physical activity for patients, irrespective of their activity levels. • People are less likely to engage in PA if they believe it will negatively affect their SLE.

Humans↗

PubMed2025

Uncovering potential biomarkers and metabolic pathways in systemic lupus erythematosus and lupus nephritis through integrated microbiome and metabolome analysis.

OBJECTIVE: This study aims to explore the relationship between gut microbiota and fecal metabolomic profiles in patients with systemic lupus erythematosus (SLE), with and without lupus nephritis (LN), in order to identify potentially relevant biomarkers and better understand their association with disease progression. METHODS: Fecal samples from 15 healthy controls (HC) and 36 SLE patients (18 SLE-nonLN and 18 SLE-LN) were analyzed using 16S rRNA gene sequencing and untargeted metabolomics. Differential microbial taxa and metabolites were identified using Linear Discriminant Analysis Effect Size (LEfSe) and Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Receiver Operating Characteristic (ROC) curve analyses were used to assess the potential clinical relevance of selected metabolites. RESULTS: Beta diversity analysis demonstrated distinct microbial clustering between groups (p < 0.05). SLE-LN samples showed an increased relative abundance of Proteobacteria and decreased Firmicutes compared to SLE-nonLN. Metabolomic profiling identified multiple differentially abundant metabolites, with notable enrichment in primary bile acid biosynthesis pathways (e.g., Glycocholic acid, AUC = 0.951). In the SLE-nonLN group, increased Glycoursodeoxycholic acid levels (AUC = 0.922) were observed in pathways related to taurine and hypotaurine metabolism. Correlation analysis indicated a negative association between Escherichia-Shigella and bile acid levels (p < 0.01). CONCLUSION: This integrative analysis suggests that patients with SLE and LN harbor distinct gut microbiota and metabolomic profiles. The identified microbial taxa and metabolites may have potential as non-invasive biomarkers and could contribute to a better understanding of SLE pathogenesis and progression.

Humans↗

PubMed2026

The Multi-Omics Landscape of Enzymatic Alterations in Systemic Lupus Erythematosus.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease closely associated with enzyme dysfunction, yet its underlying molecular mechanisms remain incompletely understood. This study aims to characterize enzyme-network alterations associated with SLE status and disease activity and to identify candidate molecules with potential clinical relevance. METHODS: We integrated proteomic and phosphoproteomic data from peripheral blood mononuclear cells (PBMCs) of 130 SLE patients and 90 healthy controls (HC), along with transcriptomic data from 1461 SLE patients. Through systematic analysis of key enzyme phosphorylation sites, upstream transcription factors (TFs), and computationally prioritized candidate compounds, we sought to characterize enzyme-centered regulatory associations. RESULTS: Integrated proteomic and phosphoproteomic analyses revealed significant metabolic and signaling pathway disturbances, along with distinct phosphorylation patterns in SLE immune cells. Multiple SLE-associated and disease-activity-associated candidate molecules were identified. Regulatory network analysis uncovered an upstream transcription factor cluster centered around STAT1. Computational drug screening identified computationally prioritized candidate compounds with multi-gene DSigDB associations, which require further clinical safety evaluation and experimental validation. CONCLUSIONS: This study constructs a molecular map of SLE, highlighting associations between enzyme-network alterations, catalytic dysregulation, and SLE-related immune molecular signatures, and identifies candidate molecules for future clinical and functional evaluation.

Humans↗

PubMed2026

Variants in the interferon regulatory factor 5 gene confer genetic risk for systemic lupus erythematosus in a Han Chinese population.

BACKGROUND: Interferon regulatory factor 5 (IRF5), integral to interferon signaling pathways, has been identified as a susceptibility locus for systemic lupus erythematosus (SLE). Nevertheless, the relationship between IRF5 variants and SLE risk within the Han Chinese demographic remains inadequately characterized. MATERIALS AND METHODS: Genotyping of two functional single nucleotide variants (SNVs) in IRF5 was conducted in 167 individuals with SLE and 246 healthy controls utilizing sequence-specific primer polymerase chain reaction (PCR-SSP). Chi-square and Fisher's exact tests were employed to assess associations. RESULTS: The rs10954213 variant demonstrated a significant association with SLE susceptibility under the recessive model (GG vs. AG+AA, OR = 2.20, 95% CI: 1.30-3.75, p = 0.003, adjusted p [pc] = 0.030) and homozygous model (GG vs. AA, OR = 2.43, 95% CI: 1.36-4.42, p = 0.003, pc = 0.032). Similarly, the rs2004640 variant was associated with an increased risk of SLE across allelic (T vs. G, OR = 1.66, 95% CI: 1.22-2.26, p = 0.001, pc = 0.011), dominant (TG+TT vs. GG, OR = 1.77, 95% CI: 1.19-2.63, p = 0.005, pc = 0.047), and homozygous models (TT vs. GG, OR = 3.72, 95% CI: 1.58-8.78, p = 0.002, pc = 0.016). Haplotype analysis identified protective haplotype HT1 (A/G, OR = 0.54, 95% CI: 0.41-0.73, p < 0.001) and risk haplotype HT4 (G/T, OR = 2.51, 95% CI: 1.42-4.42, p = 0.001). CONCLUSIONS: These findings indicate that IRF5 gene variants substantially modulate susceptibility to SLE in the Han Chinese population. They hold potential as biomarkers for evaluating SLE risk and offer valuable perspectives into disease pathogenesis.

Adult↗

PubMed2026

Genome-wide methylation profiling identifies signatures of pain, fatigue and health scores in women with systemic lupus erythematosus.

OBJECTIVES: People with systemic lupus erythematosus (SLE) experience high levels of pain and fatigue with poor overall health, which persist in those with low disease activity. By performing epigenome-wide DNA methylation analysis, this study aims to identify epigenetic alterations associated with self-reported scores for pain, fatigue and health in women with SLE. METHODS: Forty-eight women with SLE from the SLEGOT cohort were included. Study participants exhibited low disease activity (median SLEDAI-2K = 0) and minimal damage (median SLICC damage index = 0). An epigenome-wide DNA methylation analysis in whole blood identified 704 237 CpG loci, with 511 673 annotated to known genes. RESULTS: We identified 485, 591 and 577 differentially methylated CpGs linked to pain, fatigue and poor health, respectively. The association of reported pain with CpGs in GPR107, SPHK2, HBA1 and RERE genes suggested a potential role for neuromodulation in pain perception in SLE. For fatigue, enrichment analysis highlighted pathways related to neuronal development, morphogenesis and synaptic signalling. Nine genes, including BDNF and TGIF1, showed strong correlations with all three scores, suggesting a shared epigenetic influence that may underlie pain, fatigue and poor health in SLE. Specific microRNA genes were differentially methylated in relation to pain and fatigue. CONCLUSION: By studying a cohort of women with well-controlled SLE, we identified several CpGs and genes associated with pain, fatigue and general health. Our findings suggest that epigenetic changes in genes involved in neuronal modulation, rather than inflammatory pathways, could be involved in the development of these symptoms in patients with SLE.

Humans↗

PubMed2026

Clinical features and outcomes of patients with anti-neutrophil cytoplasmic antibody-positive systemic lupus erythematosus from a single-center retrospective study.

INTRODUCTION: The role of anti-neutrophil cytoplasmic antibodies (ANCA) in systemic lupus erythematosus (SLE) remains unclear. ANCA positivity has been linked to more severe disease and possible overlap with ANCA-associated vasculitis, but available data are inconsistent. METHODS: We conducted a retrospective single-center study of SLE patients treated at the University Hospital in Kraków (2012-2022). Patients fulfilled the 2019 EULAR/ACR criteria. ANCA positivity (anti-MPO or anti-PR3) was confirmed by ELISA. Clinical features, laboratory findings, treatment, and outcomes were analyzed. RESULTS: Among 1039 SLE patients, 18 (1.73%) were ANCA-positive (anti-MPO, 72.22%; anti-PR3, 27.78%). Most ANCA-positive SLE patients were female (88.89%), with a median age at disease onset of 35.5 years. The most common manifestations in ANCA-positive cases were hematological abnormalities (100%), constitutional symptoms (88.89%), and joint involvement (88.89%). Renal involvement was observed in 72.22% (n = 13) of ANCA-positive SLE patients; however, lupus nephritis was confirmed by kidney biopsy in only seven cases. Vasculitis was rare (5.56%). Anti-dsDNA (61.11%) and anti-SSA (50%) were the most frequent autoantibodies. No significant differences were found between anti-MPO and anti-PR3 subgroups. Most ANCA-positive patients received glucocorticoids (94.44%), cyclophosphamide (61.11%), and antimalarials (61.11%). No statistically significant differences were observed between the ANCA-positive and ANCA-negative groups (p > 0.05 for all parameters). CONCLUSIONS: ANCA positivity in SLE is rare and predominantly associated with anti-MPO antibodies. It is linked to frequent renal involvement but infrequent vasculitis. No differences were observed between ANCA subtypes, suggesting no distinct clinical phenotype. Key Points • ANCA positivity was rare in this systemic lupus erythematosus cohort (1.73%) and was predominantly associated with anti-MPO antibodies rather than anti-PR3 antibodies. • No significant differences in demographic characteristics, clinical manifestations, comorbidities, or autoantibody profiles were observed between ANCA-positive and ANCA-negative patients. Similarly, no significant differences were identified between the anti-PR3-positive and anti-MPO-positive groups. • ANCA-positive SLE was commonly associated with the need for intensive immunosuppressive treatment, highlighting its potential relevance as a marker of severe disease course.

Humans↗

PubMed2026

From human papillomavirus (HPV) infection to HPV-associated cancers in systemic lupus erythematosus: A systematic review and Meta-analysis.

OBJECTIVE: The current cervix-focused screening paradigm in systemic lupus erythematosus (SLE) may underestimate extra-cervical anogenital cancer risk. This meta-analysis aimed to quantify the risk of human papillomavirus (HPV) infection and HPV-associated cancers in SLE patients. METHODS: A comprehensive search was conducted in PubMed (2010), Embase (2010), and Cochrane Library (2010) to August 8, 2025. Odds Ratios (ORs) and Standardized Incidence Ratios (SIRs) with 95% Confidence Intervals (CIs) were calculated. The study protocol was registered with PROSPERO (CRD420251122192). RESULTS: SLE was associated with significantly increased odds of HPV infection (OR = 4.12, 95% CI 2.03, 8.32). We further assessed the risk of HPV-associated malignancies in SLE patients. SLE patients exhibited substantially elevated risks across multiple HPV-associated cancers (SIR = 1.90, 95% CI 1.51, 2.38). The risk of cervical cancer was more than doubled (SIR = 2.25, 95% CI 1.75, 2.89). Notably, even higher risks were observed for extra-cervical anogenital cancers, namely vulvar/vaginal cancers (SIR = 5.60, 95% CI 3.71, 8.43). CONCLUSIONS: SLE is associated with elevated risks of HPV infection and a broad spectrum of HPV-associated cancers. Subgroup analyses suggested that cyclophosphamide use, multiple sexual partners, and Asian populations may constitute higher-risk subgroups. These findings highlight the need for additional prospective evidence to better characterize HPV-associated cancer risks in SLE patients.

Humans↗

PubMed2025

Next generation sequencing analysis reveals complex genetic architecture of childhood-onset systemic lupus erythematosus.

OBJECTIVES: Our current understanding of the genetic architecture of childhood-onset SLE (cSLE) is limited by a dearth of comprehensive genomic studies in cSLE. We have quantified the number of known rare and common SLE risk variants in a diverse cSLE cohort. We characterised type I interferon (IFN) gene expression scores along with genomic data. METHODS: We performed whole genome sequencing on 83 patients with cSLE and 109 unaffected parents and analysed sequences for known common and rare SLE-associated risk variants. Type I IFN gene expression was quantified on a subset of patients. We investigated the relationship between clinical phenotype, genomic profile and type I IFN signatures in this cohort. RESULTS: Patients with cSLE were enriched for common SLE risk variants compared with unaffected parents and controls. We identified rare SLE risk variants in 11% of individuals with cSLE; those with rare variants had earlier disease onset (<12 years) than those without variants. Patients with cSLE had elevated type I IFN gene expression compared with unaffected parents and controls, even though most patients were treated with immunosuppressive therapy. CONCLUSIONS: Patients with cSLE from this ancestrally and geographically diverse cohort are enriched for common cSLE risk variants compared with controls, and 11% carry a rare variant in known monogenic SLE risk genes. The relationship between rare and common risk variant burden is more complex than previously hypothesised. Our findings indicate that studying patients with cSLE is important for understanding genetic contributions to SLE pathogenesis.

Humans↗

PubMed2025

Genetic relationships between systemic lupus erythematosus and a positive antinuclear antibody test in the absence of autoimmune disease.

OBJECTIVE: We defined the genetic factors associated with a positive ANA test (ANA+) in the absence of autoimmune disease and tested the association with SLE. METHODS: Using a case-control design, we performed a genome-wide association study (GWAS) in individuals of European ancestry without an autoimmune disease who had ANA tested as part of clinical care from DNA biobanks linked to de-identified electronic medical records: BioVU and Electronic Medical Records and Genomics. GWAS results were meta-analysed and single nucleotide polymorphism (SNP) heritability was calculated. A polygenic risk score (PRS) for ANA+ and for SLE was constructed and compared in patients with SLE, ANA+ and ANA negative (ANA-) individuals without autoimmune disease and general controls who never had ANA testing performed. RESULTS: A total of 7287 individuals of European ancestry were included in the meta-analyses (2169 ANA+ and 5118 ANA-); an SNP upstream of the TSBP1 in the HLA locus (rs1967688) was associated with ANA+ (p=4.84×10-8). SNP heritability for ANA+ was low (h2 SNP= 0.04), and the PRS for ANA+ was not significantly different in ANA+ and ANA- individuals. In contrast, the PRS for SLE was significantly higher in SLE compared with ANA+ individuals (p<2.2×10-16) but did not differ among ANA+, ANA- and general control groups (p=0.17). CONCLUSIONS: ANA+ occurring in the absence of autoimmune disease has a genetic association with the HLA region, but overall heritability is low. In addition, few SLE-associated SNPs were associated with ANA+, and the PRS for SLE was not associated with ANA+, indicating limited genetic overlap.

Humans↗

PubMed2026

Integrative post-GWAS analysis prioritizes immune regulatory pathways and candidate effector signals in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) has a complex polygenic architecture, but translating genome-wide association signals into biologically interpretable candidates remains challenging. We applied an integrative post-GWAS framework to refine SLE-associated loci and prioritize candidate regulatory mechanisms. METHODS: European-ancestry SLE GWAS summary statistics from FinnGen and Bentham et al. were meta-analysed, comprising 8417 cases and 354,277 controls. After quality filtering, 6,782,131 SNPs were retained. Downstream analyses included LAVA regional prioritization, Bayesian colocalization with GTEx v8 whole-blood and spleen eQTLs, independent replication in the Julià et al. Spanish cohort, pathway enrichment, bivariate LAVA cross-trait local genetic correlation, and therapeutic annotation. RESULTS: The discovery meta-analysis identified 46 genome-wide significant SLE-associated loci, including putative novel signals requiring database/literature qualification. LAVA identified 14 candidate index variants across 12 high-confidence regions, of which nine index variants were retained as the primary prioritized set based on LAVA support and/or convergent regulatory evidence. The strongest association mapped to the chr6p21.3/MHC region (rs389884), where four genes showed colocalization support, including CLIC1 in whole blood and C4A in spleen. Because the chr6p21.3/MHC rs389884 region lead variant was unavailable for replication and no suitable proxy was identified, this signal was interpreted as an emerging candidate for functional validation rather than a replicated causal signal. Seven available variants replicated with concordant effects. An exploratory Roadmap immune chromatin-state overlap analysis placed 15 of 45 non-MHC lead variants (33.3%) directly, and 34 of 45 (75.6%) within ±10 kb, in active immune enhancer/promoter states. Pathway analyses highlighted type I interferon, JAK-STAT signaling, cytokine regulation, and antigen presentation, while bivariate LAVA analyses supported shared local genetic architecture with rheumatoid arthritis, systemic sclerosis, and Sjögren syndrome. CONCLUSIONS: This integrative post-GWAS analysis refines SLE association signals into biologically interpretable candidate regions and supports interferon and JAK-STAT signaling as central genetically supported pathways in SLE.

CLIC1↗