To examine B cell-activating factor (BAFF) and type I interferon (IFN) activity at the transcriptional and protein levels in blood and placental tissue in SLE compared with healthy pregnancies to assess their relationship and to determine whether BAFF levels are associated with pregnancy outcomes in SLE. In the SLE-Placenta study, we followed women with SLE (n=83) and healthy controls (n=67) throughout pregnancy. Blood samples were collected in all trimesters and at delivery from peripheral blood, placental intervillous blood and cord blood. Postpartum blood samples were obtained from a subset of women with SLE. Bulk messenger RNA (mRNA) sequencing was performed on peripheral blood mononuclear cells (PBMCs) and placental tissue from a subgroup of women with SLE and healthy controls. BAFF concentrations were measured by ELISA and IFNα protein levels by single-molecule array (Simoa). Women with SLE had upregulated BAFF (TNFSF13B) and IFN-stimulated gene expression in PBMCs and placenta compared with controls. BAFF blood levels were consistently and significantly higher in SLE throughout pregnancy and inversely correlated with circulating B cell numbers. SLE pregnancies with IF-ANA or anti-dsDNA positivity displayed higher BAFF levels than antibody-negative pregnancies but BAFF showed no association with disease activity. Both BAFF and IFNα concentrations were higher in placental than peripheral blood in SLE, whereas only BAFF showed additional accumulation in cord blood. Finally, elevated BAFF levels were associated with shorter pregnancy duration in SLE but not in healthy pregnancy. Pregnant women with SLE exhibited persistently elevated BAFF levels, which were associated with lower B cell numbers, SLE-related autoantibody positivity and shorter pregnancy duration. Together with a disease-specific placental enrichment of IFNα, these findings support the presence of an inflammatory and potentially pathogenic IFN-BAFF signature in SLE pregnancy. Further studies are needed to determine the functional consequences of these immunological alterations on maternal-fetal health in SLE.

Combined-isotype anticardiolipin (aCL) and anti-β2-glycoprotein I (anti-β2GPI) immunoglobulin A, G and M (IgAGM) assays are used in current laboratory practice, but their disease relevance and clinical interpretation remain incompletely defined. This study aimed to establish 99th-percentile reference intervals for aCL IgAGM and anti-β2GPI IgAGM in a large general healthy population and to provide a basis for future disease-oriented evaluation. A total of 7846 eligible individuals who underwent health inspection were included in the analysis. Plasma aCL IgAGM and anti-β2GPI IgAGM were measured by ELISA. A physiologically normal reference subgroup was defined by excluding predefined laboratory abnormalities at the retained index visit (n=989). Retrospective contextual analyses were also performed in systemic lupus erythematosus (SLE) and coronary heart disease (CHD) populations with historical IgAGM results. Among 7846 individuals (5170 male and 2676 female; age 15-90 years), the 99th percentiles were 35.4 relative units (RU)/mL for aCL and 51.7 RU/mL for anti-β2GPI. In the physiologically normal reference subgroup, the corresponding values were 23.33 RU/mL and 46.25 RU/mL. Sex differences were significant for both antibodies in the overall population and in the physiologically normal subgroup, and aCL showed age-related increases at the upper tail. In retrospective analyses, SLE showed higher proportions above all four cut-offs than CHD, with significance for anti-β2GPI at both the general health participant cut-off (11.4% vs 4.5%, p=0.0425) and the physiologically normal cut-off (12.3% vs 4.5%, p=0.0200). Exploratory analyses linked antibody levels to triglyceride-related profiles. Assay-specific 99th-percentile reference intervals for aCL IgAGM and anti-β2GPI IgAGM were established in a large health-inspection population and a physiologically normal reference subgroup. These findings provide a practical interpretive framework for combined-isotype assays and support future disease-oriented evaluation.

Women with systemic lupus erythematosus (SLE) have increased prevalence of precancer cervical squamous intraepithelial lesions (SIL). This study aimed to compare human papillomavirus (HPV) seroprevalence, cervical HPV-DNA detection and HPV-related cervical lesions between SLE and immunocompetent women. In this cross-sectional study, women aged 18-45 years with SLE receiving immunosuppressive or disease-modifying antirheumatic drugs were compared with immunocompetent women, selected from the same hospital in Sao Paulo, Brazil. Eligible participants had no self-reported history of genital warts or any other HPV-related cervical, vaginal or vulvar lesions, nor received prior HPV vaccination. Cervical samples were tested for HPV-DNA using PapilloCheck and for SIL lesions by liquid-based cytology. A multiplex pseudovirion-based serology assay (PsV-Luminex) measured serum antibodies against eight of the HPV types targeted by non-valent (9vHPV) HPV vaccine. A total of 122 women with SLE and 132 immunocompetent women (mean age 34.3 and 32.5 years, respectively) were enrolled. Compared with immunocompetent women, SLE participants had higher prevalence of HPV-related cervical lesions (low-grade and high-grade SIL combined, 11.3% vs 2.4%, p=0.009), higher prevalence of at least one cervical HPV type (38.8% vs 20.2%, p=0.003), non-significantly higher prevalence of cervical high-risk HPV types (23.5% vs 14.9% p=0.286) and higher HPV seroprevalence to eight HPV types included in the 9vHPV vaccine (80.4% vs 59.7%, p=0.001). Our findings underscore the importance of tailored cervical cancer screening and HPV vaccination of SLE women at young age.

Systemic lupus erythematosus (SLE) primarily affects women of reproductive age, necessitating complex conversations surrounding pregnancy and contraception use. Hispanic women in the USA bear a disproportionate and severe burden of SLE, facing language and cultural barriers to care, and higher rates of unplanned pregnancy and under-representation in reproductive health research. This study explores patient-reported barriers and facilitators to reproductive health conversations as well as their attitudes and perceptions on how these conversations can be improved. We conducted 30 semistructured interviews in both English and Spanish with Hispanic women aged 18-45 with SLE. Participants were recruited from Los Angeles General Medical Center and Lupus LA. Eligible participants were heterosexually active or considering pregnancy within 3 years. Interviews were analysed using grounded theory to identify themes related to barriers and facilitators in clinical reproductive health interactions. Three major themes emerged: (1) barriers to reproductive health conversations were often driven by competing clinical priorities as well as discomfort discussing sensitive topics; (2) facilitators to reproductive health conversations included the presence of genuine clinician-patient rapport, well-controlled disease activity and patient proactiveness; (3) areas of improvement included both a more encompassing and thorough data-driven approach to reproductive health discussions throughout disease course. Findings reported herein underscore the importance of early, individualised reproductive health counselling for women with SLE. Enhanced clinician communication with sensitive topics, refined patient education and frequent interdisciplinary collaboration can help address the emotional, medical and informational needs of Hispanic women with SLE navigating reproductive decisions.

Patients with SLE have increased risk of both clinical cardiovascular disease (CVD) and subclinical atherosclerosis. Reports have shown that controlling CVD risk factors reduces subclinical plaque progression in patients with SLE. We investigated whether this finding was confirmed in our ethnically diverse cohort of patients, measuring total plaque area (TPA) as well as the number of plaques. 69 patients with SLE underwent ultrasound scans of the carotid and common femoral arterial bifurcations on two occasions (mean 63 months apart). Clinical, demographic, CVD risk and treatment factors were recorded for each patient. Change in plaque number and increase in TPA between scans were the outcome measures. 31 patients had plaque at the second scan. 13 had unchanged number of plaques while 18 had increased plaque numbers including six who were initially free of plaque. All 31 patients had increased TPA with median increase 4.59 mm2/year (IQR 2.4-7.33) and these patients were subdivided into two groups with change in TPA above or below the median. Factors associated with both increased plaque number and above-median TPA increase at the second scan compared with the first were age at baseline, positive lupus anticoagulant, negative anti-La and failure to attain at least three CVD risk targets within the follow-up period between scans. We found no associations with disease activity or medication. In this ethnically diverse (40% non-Caucasian) population, we confirmed earlier findings that better control of CVD risk targets reduces progression of atherosclerotic plaque. Anti-La positivity was associated with less plaque progression, which was unexpected.

SLE is a multifaceted chronic inflammatory disorder characterised by a dysregulated immune response that involves various organ systems, with significant implications stemming from the type I interferon (IFN) signalling pathway in its pathogenesis. This study aimed to elucidate the contributory role of the IFN-induced protein 44-like (IFI44L) gene in SLE progression and to investigate its transcriptional regulatory mechanisms. We quantified IFI44L expression in peripheral blood mononuclear cells of patients with SLE through quantitative PCR (qPCR), and established an in vitro THP-1 cell model overexpressing IFI44L to assess its impact under IFN-α exposure using Cell Counting Kit-8 assays and flow cytometry. Additionally, we generated Ifi44l knockout mice and Pristane-induced lupus mice to evaluate the influence of IFI44L on immune phenotypes and organ functionality. Our findings demonstrated that IFI44L is significantly expressed in CD3+ and CD14+ lymphocytes in patients with SLE, and under heightened IFN conditions, it plays a role in promoting cell proliferation while inhibiting apoptosis. Importantly, Ifi44l knockout mice exhibited ameliorated clinicopathological features of lupus, showing reduced haematological and renal damage. Furthermore, we identified c-Jun as a transcriptional factor that directly targets the IFI44L promoter, specifically activated by IFN-α in CD14+ lymphocytes. Our research indicates that IFN-α enhances IFI44L expression via c-Jun, underscoring its critical role in the pathogenesis of SLE and suggesting potential pathways for therapeutic intervention.

ObjectivePosterior reversible encephalopathy syndrome (PRES) is a clinicoradiological diagnosis that can be associated with SLE. The clinical presentation, risk factors and outcomes of PRES in patients with SLE remain insufficiently described.MethodsWe conducted a multicentre cohort study at the Mayo Clinic and performed a systematic literature review (SLR) of patients with incident PRES and SLE. We described the clinical features, treatments and outcomes. Across both the cohort study and SLR, we assessed neurological sequelae, recurrence and survival. Within the cohort study, we examined PRES risk factors and discontinuation of antiseizure medications (ASMs). We used logistic regression to evaluate factors associated with neurological sequelae and Cox regression to assess predictors of recurrence. Kaplan-Meier methods estimated the rates of recurrence, survival and ASMs discontinuation.Results550 cases (53 from the cohort study) were included, of whom 92% were female. Across both cohort and SLR, the most common symptom was seizure, occurring in 80%. PRES was the first manifestation of SLE in 13% of cases. In the adjusted analysis, older age was associated with neurological sequelae (OR 1.63 per 10-year increase; 95% CI 1.12 to 2.39). After 5 years of follow-up, 11.5% (95% CI 2.3 to 19.9%) of patients had a recurrent PRES episode. 30-day and 180-day survival following PRES was observed in 96.3% (95% CI 93.5 to 99.1%) and 93.7% (95% CI 89.8 to 97.7%) patients, respectively. In the Mayo Clinic cohort, 81% of PRES cases were attributed to hypertension in the context of lupus nephritis (LN), and by the fifth year of follow-up, 78.1% (95% CI 58.7 to 88.4%) of patients had discontinued ASMs.ConclusionsIn this cohort, most of the incident PRES episodes were preceded by hypertension and occurred in patients with LN. Although short-term and long-term prognoses are favourable, older patients more frequently experienced neurological sequelae.

BackgroundThe interaction between fine particulate matter (PM2.5) and genetic factors can lead to epigenetic modifications, potentially increasing the risk of SLE development. However, the impact of PM2.5 on incident SLE development remains unelucidated. This study investigated the effects of year-to-year variations in PM2.5 exposure on incident SLE risk in Taiwanese adults.MethodsIn this longitudinal study, we followed up 268 254 adults from the Taiwan MJ cohort (2005–2017) for 9.8 years to identify incident SLE cases, ascertained from patients’ clinical and laboratory reports. Residential address-specific annual PM2.5 concentrations were obtained from Taiwan Air Quality-Monitoring sites. We employed a time-dependent Cox regression model, considering death as a competing risk, to assess the impact of year-to-year variations of PM2.5 exposure on SLE development.ResultsDuring 2 628 889 person-years of follow-up, 151 (0.1%) individuals developed new-onset SLE. Participants with higher levels of PM2.5 exposure (per 5 μg/m3 increase) had significantly higher risk of incident SLE (adjusted HR 3.35; 95% CI 2.94 to 3.82). We observed a significant positive linear relation between increasing level of PM2.5 exposure and higher risk of incident SLE in all individual subgroups after stratifying study subjects by age and sex (p<0.001).ConclusionPM2.5 exposure emerged as a risk factor for incident SLE. Air pollution mitigation strategies should be considered as a preventive measure for SLE.

ObjectiveMacrophage activation syndrome (MAS), a subtype of secondary haemophagocytic lymphohistiocytosis (HLH), is a rare and life-threatening complication of rheumatoid diseases. However, the prognostic factors in adult MAS patients are still not fully elucidated, which need further investigation.MethodsWe conducted a retrospective study of adult MAS inpatients between January 2016 and January 2024. In accordance with HLH-2004 criteria, 116 patients were eventually enrolled in this study. Clinical manifestations, laboratory data, treatments and outcomes had been recorded. Influence factors associated with prognosis were analysed using logistic regression models.ResultsSeventeen of 116 (14.7%) patients died during hospitalisation. Further multivariate analysis suggested that admission ferritin <1350 ng/mL (OR=5.387, 95% CI 1.203 to 24.127, p=0.034), platelets (PLT) ≤30×109/L (OR=5.387, 95% CI 1.203 to 24.127, p=0.028), alanine aminotransferase (ALT) ≥275 U/L (OR=5.732, 95% CI 1.167 to 28.167, p=0.032), central nervous system (CNS) involvement (OR=11.268, 95% CI 1.353 to 93.851, p=0.025) and procalcitonin (PCT) >0.9 ng/mL (OR=11.224, 95% CI 2.019 to 62.381, p=0.006) were potential prognostic factors for mortality of adult MAS patients.ConclusionOur results indicated that adult MAS patients with lower ferritin levels at admission, lower PLT counts, elevated ALT, CNS involvement and more active infection were associated with an unfavourable prognosis.

ObjectiveDelivery of a small for gestational age (SGA) infant is a common pregnancy complication among women with SLE. Although disease activity and autoantibodies such as anti-Smith and anti-ribonucleoprotein associate with SGA, underlying pathological mechanisms remain unclear and reliable predictors are lacking. To address this, we applied a proteomic approach to identify proteins associated with SGA in SLE.MethodsPlasma samples were collected repeatedly during pregnancy, at delivery and from placental intervillous blood in women with SLE (n=83) and healthy controls (n=67) enrolled in the prospective SLE-Placenta study. Postpartum samples (≥6 months) from a subset of women with SLE (n=19) served as non-pregnant controls. Mass spectrometry was performed on a discovery cohort comprising six healthy uncomplicated pregnancies, eight uncomplicated SLE pregnancies and eight SLE pregnancies complicated by SGA (SLE-SGA). Differential protein abundance analysis was performed in R. Candidate proteins were quantified by ELISA in the full cohort.ResultsDiscovery proteomics identified four proteins with increased abundance in SLE-SGA compared with uncomplicated SLE pregnancies: endostatin (Padj=0.0003), angiogenin (Padj=0.03), insulin-like growth factor-binding protein 5 (Padj=0.03) and complement factor H-related protein 5 (Padj=0.004). In the full cohort, ELISA quantification did not confirm increased levels of these proteins in SLE-SGA but suggested elevated levels of the angiogenesis-related proteins endostatin and angiogenin in women with SLE who later developed pre-eclampsia. Endostatin levels were consistently higher in SLE compared with controls across all trimesters (p≤0.0001). Endostatin, but not angiogenin, was enriched in placental blood.ConclusionOur study did not validate the differentially abundant proteins as markers for SLE-SGA but suggested a link between the antiangiogenic and proangiogenic proteins, endostatin and angiogenin, respectively, and pre-eclampsia in SLE. Given the consistent elevation of endostatin throughout pregnancy in SLE compared with controls, its potential effects on placental development in SLE warrant further investigation.