Risk Of Systemic Lupus Erythematosus Research Articles

Environmental triggers of autoimmunity: The association between bisphenol analogues and systemic lupus erythematosus

The aim of this research was to examine the correlation between the exposure to bisphenol analogues (BPs), such as bisphenol A (BPA), bisphenol F (BPF), and bisphenol S (BPS), and the risk of developing systemic lupus erythematosus (SLE). Ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was utilized to measure the levels of BPA, BPF, and BPS in the urine of 168 female participants diagnosed with SLE and 175 female participants who were deemed healthy controls. Logistic regression models were utilized to assess the connections between levels of bisphenol and the risk of SLE. The findings indicated that levels of BPA and BPF in the urine of individuals with SLE were markedly elevated compared to those in the control group. Higher exposure to BPA and BPF exhibited positive dose-response relationships with increased SLE risk. No significant associations were identified between BPS and the risk of SLE. These findings suggest exposure to BPA and BPF may be implicated as novel environmental triggers in the development of autoimmunity such as SLE. The significantly increased levels of these bisphenol analogues detected in SLE patients versus healthy controls, along with the associations between higher exposures and elevated SLE risk, which offers crucial hints for comprehending how endocrine-disrupting substances contribute to the genesis of autoimmune illnesses. Further research using robust longitudinal assessments of bisphenol analogue exposures is warranted to corroborate these epidemiological findings. Overall, this study highlights potential environmental risk factors for SLE while calling for additional investigation into the impact of bisphenol exposures on autoimmunity development.

Assessing the causality of interferon‐γ and its receptor 1/2 with systemic lupus erythematosus risk using genetic data

AbstractBackgroundThe interferon‐γ (IFN‐γ) signaling pathway is activated in systemic lupus erythematosus (SLE). This study aimed to assess the causal association between IFN‐γ, IFN‐γ receptor 1 (IFN‐γR1), and IFN‐γR2 and SLE using a bidirectional Mendelian randomization (MR) design.MethodsGenetic instruments for exposure to IFN‐γ, IFN‐γR1, and IFN‐γR2 were derived from a large genome‐wide association study (GWAS) that included a sample size of 3301 participants. Instrumental variables for SLE were selected from another independent GWAS analysis comprising 5201 cases and 6099 controls with European ancestry. Bidirectional two‐sample MR was performed using inverse variance weighting, MR‐Egger regression, and weighted median methods. A series of sensitivity analyses were conducted to assess the robustness of the results.ResultsThe inverse variance weighting showed that IFN‐γ had a positive causal association with the risk of SLE (odd ratio [OR] = 1.24, 95% confidence interval [CI]: 1.03–1.47, p = 0.018). IFN‐γR2 levels were not associated with SLE risk after adjustment for multiple comparisons (OR = 0.85, 95% CI: 0.73–0.99, p = 0.034). No genetic association was also detected between IFN‐γR1 and SLE (OR = 0.97, 95% CI: 0.79–1.19, p = 0.768). Evidence from bidirectional MR did not support reverse causality. The weighted median regression also showed directionally similar estimates.ConclusionHigher levels of IFN‐γ are significantly associated with an increased risk of SLE, providing insights into the pathogenesis of SLE.

Mental health conditions in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

The reported prevalence of mental health conditions (MHCs) in people with systemic lupus erythematosus (SLE) ranges widely. Whether MHCs are associated with increased risk of SLE or the outcomes of the disease is unclear. This paper aimed to conduct an umbrella and updated meta-analysis of MHCs in people with SLE and to identify whether MHCs are associated with the risk of SLE or patient outcomes. We comprehensively searched PubMed, Web of Science, and Embase databases to identify relevant studies published before June 2023. Random-effect models were used to calculate the pooled prevalence and risk ratios for each MHC. 203 studies with 1485094 individuals were included. The most MHCs observed in patients with SLE were sleep disturbance (59.7% [95% CI, 52.4%-66.8%]) among adults and cognitive dysfunction (63.4% [95% CI, 46.9%-77.9%]) among children. We found that depressive disorders (RR = 2.30, 95% CI = 1.94-2.75) and posttraumatic stress disorder (RR = 1.93, 95% CI = 1.61-2.31) in the general population were significantly associated with an increased likelihood of developing SLE. Furthermore, concurrent MHCs were linked to unfavorable outcomes in patients with SLE, such as decreased quality of life, increased risk of unemployment, and other somatic comorbidities. Our study demonstrated a high prevalence of MHCs among patients with SLE. Individuals with pre-existing mental disorders exhibited an elevated susceptibility to developing SLE, and patients presenting with MHCs were at increased risk of experiencing suboptimal health and functional outcomes. Therefore, evaluating and preventing MHCs should be considered as an integral component of the comprehensive treatment strategy for SLE.

Incidence and risk factors of systemic lupus erythematosus in patients with primary immune thrombocytopenia: a systematic review and meta-analysis.

Immune disorders and autoantibodies has been noted in both primary immune thrombocytopenia (ITP) and systemic lupus erythematosus (SLE). Whether the two disorders are correlated is unclear. The lack of evidence on the incidence of and risk factors for SLE in primary ITP patients poses a challenge for prediction in clinical practice. Therefore, we conducted this study. The protocol was registered with PROSPERO (CRD42023403665). Web of Science, Cochrane, PubMed, and EMBASE were searched for articles published from inception to 30 September 2023 on patients who were first diagnosed with primary ITP and subsequently developed into SLE. Furthermore, the risk factors were analyzed. Study quality was estimated using the Newcastle-Ottawa Scale. The statistical process was implemented using the R language. This systematic review included eight articles. The incidence of SLE during the follow-up after ITP diagnosis was 2.7% (95% CI [1.3-4.4%]), with an incidence of 4.6% (95% CI [1.6-8.6%]) in females and 0 (95% CI [0.00-0.4%]) in males. Older age (OR = 6.31; 95% CI [1.11-34.91]), positive antinuclear antibody (ANA) (OR = 6.64; 95% CI [1.40-31.50]), hypocomplementemia (OR = 8.33; 95% CI [1.62-42.91]), chronic ITP (OR = 24.67; 95% CI [3.14-100.00]), organ bleeding (OR = 13.67; 95% CI [2.44-76.69]), and female (OR = 20.50; 95% CI [4.94-84.90]) were risk factors for subsequent SLE in ITP patients. Patients with primary ITP are at higher risk of SLE. Specific follow-up and prevention strategies should be tailored especially for older females with positive ANA, hypocomplementemia, or chronic ITP. In subsequent studies, we need to further investigate the risk factors and try to construct corresponding risk prediction models to develop specific prediction strategies for SLE.

Hormone and reproductive factors and risk of systemic lupus erythematosus: a Mendelian randomized study.

Systemic lupus erythematosus (SLE) is an autoimmune and inflammatory disease with a risk associated with hormonal and reproductive factors. However, the potential causal effects between these factors and SLE remain unclear. A two-sample Mendelian randomization study was conducted using the published summary data from the genome-wide association study database. Five independent genetic variants associated with hormonal and reproductive factors were selected as instrumental variables: age at menarche, age at natural menopause, estradiol, testosterone, and follistatin. To estimate the causal relationship between these exposure factors and disease outcome, we employed the inverse-variance weighted, weighted median, and MR-Egger methods. In addition, we carried out multiple sensitivity analyses to validate model assumptions. Inverse variance weighted showed that there was a causal association between circulating follistatin and SLE risk (OR = 1.38, 95% CI 1.03 to 1.86, P = 0.033). However, no evidence was found that correlation between AAM (OR = 1.04, 95% CI 0.77 to 1.40, P = 0.798), ANM (OR = 0.99, 95% CI 0.92 to 1.06, P = 0.721), E2 (OR = 1.40, 95% CI 0.14 to 13.56, P = 0.772), T (OR = 1.25, 95% CI 0.70 to 2.28, P = 0.459), and SLE risk. Our study revealed that elevated circulating follistatin associates with an increased risk of SLE. This finding suggests that the regulatory signals mediated by circulating follistatin may provide a potential mechanism relevant to the treatment of SLE.

Association between genetically proxied PCSK9 inhibition and systemic lupus erythematosus risk: A mendelian randomization study.

Preclinical and epidemiological studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) had a potential effect on the development of SLE, but it was unclear whether a causal relationship exists. We aimed to investigate the association between genetically proxied inhibition of PCSK9 and the risk of SLE using a two-sample Mendelian randomization (MR) approach. Single nucleotide polymorphisms (SNPs) associated with PCSK9 were extracted from pooled data obtained from the Global Lipid Genetics Consortium (GLGC) Genome-wide Association Study (GWAS) related to LDL-c levels, which was used as a proxy for PCSK9 inhibition. Pooled statistics for SLE were obtained from an independent GWAS dataset including 5201 SLE patients and 9066 controls. Inverse variance-weighted random-effects models were used to examine the association between genetically proxied inhibition of PCSK9 and the risk of SLE. MR-Egger, weighted median, weighted mode, Simple mode, and co-location analyses were used as sensitivity analyses to test the robustness of the analyses. Genetically proxied inhibition of PCSK9 was associated with a reduced risk of SLE (OR = 0.51, 95% CI = 0.34 to 0.77, p = .001). This finding was replicated in an earlier GLGC GWAS analysis (OR = 0.59, 95% CI = 0.40 to 0.87, p = .007). Sensitivity analysis ensured that the results were robust. Co-localization analysis did not find evidence of shared causal variation between PCSK9 and SLE. This Mendelian randomization study showed that PCSK9 was associated with SLE pathogenesis, and its inhibition was associated with a reduced risk of SLE. This study has offered a prospective therapeutic avenue for intervening in the progression of SLE by inhibiting PCSK9 levels.

Causal association between air pollution and autoimmune diseases: a two-sample Mendelian randomization study.

In recent years, an increasing number of observational studies have reported the impact of air pollution on autoimmune diseases (ADs). However, no Mendelian randomization (MR) studies have been conducted to investigate the causal relationships. To enhance our understanding of causality, we examined the causal relationships between particulate matter (PM) and nitrogen oxides (NOx) and ADs. We utilized genome-wide association study (GWAS) data on PM and NOx from the UK Biobank in European and East Asian populations. We also extracted integrated GWAS data from the Finnish consortium and the Japanese Biobank for two-sample MR analysis. We employed inverse variance weighted (IVW) analysis to assess the causal relationship between PM and NOx exposure and ADs. Additionally, we conducted supplementary analyses using four methods, including IVW (fixed effects), weighted median, weighted mode, and simple mode, to further investigate this relationship. In the European population, the results of MR analysis suggested a statistically significant association between PM2.5 and psoriasis only (OR = 3.86; 95% CI: 1.89-7.88; PIVW < 0.00625), while a potential association exists between PM2.5-10 and vitiligo (OR = 7.42; 95% CI: 1.02-53.94; PIVW < 0.05), as well as between PM2.5 and systemic lupus erythematosus (OR = 68.17; 95% CI: 2.17-2.1e+03; PIVW < 0.05). In East Asian populations, no causal relationship was found between air pollutants and the risk of systemic lupus erythematosus and rheumatoid arthritis (PIVW > 0.025). There was no pleiotropy in the results. Our results suggest a causal association between PM2.5 and psoriasis in European populations. With the help of air pollution prevention and control, the harmful progression of psoriasis may be slowed.

Low heterozygosity for rs3811050, a 5 prime untranslated region variant of the gene encoding interleukin-38 (IL1F10), is associated with a reduced risk of systemic lupus erythematosus

BackgroundInterleukin-38 (IL-38), an inflammatory cytokine discovered in recent years, has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). IL-38 is encoded by the IL1F10 (interleukin 1 family member 10) gene. Genetic variants of this gene have been associated with susceptibility to a number of autoimmune and inflammatory diseases, while their association with SLE risk has not been explored. In this case–control study, two novel variants of the 5 prime untranslated region (5′UTR) of the IL1F10 gene, rs3811050 C/T and rs3811051 T/G, were investigated in 120 women with SLE and 120 age-matched control women. The TaqMan allelic discrimination assay was used for genotyping of rs3811050 and rs3811051.ResultsThe frequency of the rs3811050 CT genotype was significantly lower in SLE patients compared to controls (30.8 vs. 50.0%; odds ratio = 0.49; 95% confidence interval = 0.28–0.86; corrected probability = 0.045). The rs3811051 genotype frequencies did not show significant differences between patients and controls. Rs3811050 and rs3811051 showed weak linkage disequilibrium (LD) as indicated by the estimated LD coefficient and correlation coefficient values (0.32 and 0.05, respectively), and two-locus haplotype analysis revealed no significant differences between patients and controls. The frequencies of the rs3811050 T allele (38.8 vs. 20.6%; probability = 0.029) and the rs3811051 G allele (56.3 vs. 38.2%; probability = 0.038) were significantly higher in patients with mild/moderate disease activity than in patients with high disease activity, but significance was not maintained after applying Bonferroni correction (corrected probability = 0.058 and 0.076, respectively). Serum IL-38 concentrations (median and interquartile range) were significantly decreased in patients compared with controls (69.5 [64.1–74.8] vs. 73.5 [66.1–82.9] pg/mL; probability = 0.03), but were not influenced by SNP genotypes.ConclusionsThe heterozygous genotype of rs3811050, a 5'UTR variant, of the IL-38 encoding gene, IL1F10, is associated with a reduced risk of SLE among women. Furthermore, the rs3811050 T and rs3811051 G alleles may influence disease activity. In addition, serum IL-38 concentrations were down-regulated in SLE patients but were not affected by the rs3811050 and rs3811051 genotypes.

An update on cardiovascular disorders in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a complex multifactorial etiology that develops as a result of autoimmune processes, leading to widespread inflammation and malfunction of multiple tissues and organs, and, as a consequence, triggers arterial hypertension, conduction disorders, valvular heart disease, pulmonary hypertension (PH), and venous thromboembolism events (VTE), contributing to increased mortality. Moreover, autoimmune abnormalities can accelerate atherogenesis and lead to many SLE manifestations, including coronary artery disease (CAD) and cerebrovascular events. The current review aimed to systematize existing data from the latest works and summarize published guidelines and recommendations. In particular, the prevalence of cardiovascular disorders in SLE patients, advances in diagnostics (including imaging methods and biomarker laboratory testing), the possible future direction of therapy, and the latest European Alliance of Associations for Rheumatology (EULAR) guidelines for optimal management of cardiovascular risk in SLE were overviewed.

Comparison of the SLE Risk Probability Index (SLERPI) scale against the European League Against Rheumatism/American College of Rheumatology (ACR/EULAR) and Systemic Lupus International Collaborating Clinics (SLICC) criteria.

Timely diagnosis and proper recognition of Systemic Lupus Erythematosus (SLE) is essential to establish early management in inpatients and outpatients. There are different classification scales to identify SLE, which include various clinical and serological aspects. In 2021, the SLE Risk Probability Index (SLERPI) was published, which focuses predominantly on the clinical characteristics of patients with suspected SLE and uses a simple algorithm for early recognition of the disease. The aim of this study is to compare the European League Against Rheumatism/American College of Rheumatology (ACR/EULAR) classification criteria, the Systemic Lupus International Collaborating Clinics (SLICC) criteria, and the SLERPI criteria in a cohort of Colombian patients with SLE and to analyze the correlations observed between their absolute scores. A registry of SLE patients from two referral hospitals in Bogotá, Colombia, was used. 2021 SLERPI, 2019 ACR/EULAR, and 2012 SLICC scores were calculated for each patient and the correlations found between the scales were analyzed. The sensitivities of each were compared, and frequency analyses were conducted among different clinical and laboratory variables. Between 2016 and 2019, 146 patients diagnosed with SLE were registered, including inpatients and outpatients. The median age was 36years (interquartile range 26-51), and 82.2% were women. According to the SLERPI criteria, a high prevalence of antinuclear antibodies (92%), immunological disorders (71%), and arthritis (64%) were observed. The most used treatments were corticosteroids (87.6%) and chloroquine (67.8%). A Spearman evaluation analysis was performed, with a moderately strong correlation of 0.76 (p = .000) between the SLERPI and ACR/EULAR scales and very strong correlation of 0.80 (p = .000) between the SLERPI and SLICC. Patients classified with SLE according to the SLERPI scale exhibited a higher incidence of hematological compromise, along with elevated levels of serological markers such as anti-DNA antibodies. Additionally, this group more commonly received treatments involving corticosteroids and azathioprine, and displayed a higher prevalence of hypertension. The SLERPI scale could be useful in the diagnosis of SLE, especially in early stages, given its good correlation with other classification scales and its good sensitivity.

Associations of toll-like receptor polymorphisms with systemic lupus erythematosus: A meta-analysis

ObjectiveThe objective of this study was to examine whether polymorphisms in toll-like receptors 7 and 4 (TLR7 and 4) contribute to vulnerability to systemic lupus erythematosus (SLE). MethodsWe searched MEDLINE, Embase, and Web of Science for relevant articles and performed a meta-analysis to investigate the relationship between TLR7 rs179008, rs3853839, rs1790010, TLR4 rs4986791, and rs798690 polymorphisms and SLE. ResultsEighteen studies and 16 papers including 8022 patients with SLE and 9822 healthy controls were retrieved. Meta-analysis revealed that the TLR7 rs179008 T variant was not associated with SLE (OR = 1.008, 95% CI = 0.849–1.394, P = 0.504). Ethnic classification revealed no association between the TLR7 rs179008 T gene and SLE in either European or Latin American groups. Additionally, homozygous comparison, recessive, and dominant models revealed no association between the TLR7 rs179008 variant and SLE. In contrast, a significant association between SLE and the TLR7 rsrs3853839 GG + GA allele (OR = 2.135, 95% CI = 1.502–3.035, <0.001; OR = 23.20, 95% CI = 14.13–38.08, <0.001) was observed in the Arab and Asian groups. The T variant of TLR7 rsrs179010 was also associated with SLE in Asians (OR = 1.177, 95% CI = 1.048–1.321, P = 0.006). In contrast, the TLR4 rs4986791 variant was not associated with SLE in Europeans when allele, homozygous comparison, recessive, and dominant models were used. Furthermore, no association between the TLR4 rs4986790 variant and SLE risk in Europeans was found using any genomic model. ConclusionsMeta-analysis revealed that the TLR7 rs3853839 variant is associated with SLE risk in Asians and Arabs and that TLR7 rs179010 is associated with SLE in Asians. However, TLR7 rs179008, TLR4 rs4986791, and TLR rs798690 polymorphisms were not associated with SLE risk.

Basal Cell Carcinoma in a Case of Systemic Lupus Erythematosus – A Case Report

Systemic lupus erythematosus (SLE) is a chronic, systemic autoimmune with autoantibody production, complementactivation, and immune complex deposition. SLE patients have higher mortality rates as compared to the general populationEven though there have been improvements in finding and treating diseases, cancer is still a major reason for death in this group.The most common type of cancer is Basal cell carcinoma, and it is widespread. The risk of malignancy in SLE is of considerableinterest because the immune and genetic pathways underlying the pathogenesis of SLE and the immunosuppressant drugs (ISDs)used in its management may mediate this altered risk. Here, we present a case of long-standing SLE in an elderly female who wason treatment for the same. She presented with a chronic ulcer over her scalp. She got checked, and a biopsy showed she hadBasal Cell Carcinoma on her scalp. Doctors removed it with surgery and covered the open area with skin from another part ofher body. At her first checkup, everything looked good, and the new skin was healing well. Even though skin cancers are knownto happen in people with certain skin conditions, getting Basal Cell Carcinoma with lupus is very uncommon. In various cohortstudies of adults with SLE and overall risk of malignancy, ranging from 1992 to 2017, it was found that though cutaneousmalignancies did occur, not a single study reported Basal Cell Carcinoma.

Antiphospholipid Antibodies Are Major Risk Factors for Non-Thrombotic Cardiac Complications in Systemic Lupus Erythematosus.

In systemic lupus erythematosus (SLE), cardiovascular complications are among the leading causes of death. Cardiovascular risk in SLE is even higher in the presence of antiphospholipid antibodies or secondary antiphospholipid syndrome (APS). The aim of this retrospective, single-center study was to investigate the occurrence of antiphospholipid antibodies and non-thrombotic cardiac manifestations in 369 SLE patients. We also assessed the clinical and laboratory characteristics of the patients to reveal the risk factors for cardiac manifestations. Patients were divided into two groups based on the presence of antiphospholipid antibodies (APA); 258 (69.9%) patients were APA positive, and 111 (30.1%) patients were APA negative. Mitral and tricuspid insufficiency, aortic stenosis and pulmonary arterial hypertension were more common in APA-positive patients. Anticardiolipin IgG showed the strongest correlation with any non-thrombotic cardiac manifestations. Based on our results, the adjusted global antiphospholipid syndrome score (aGAPSS) above 8.5 is predictive of valvulopathies and ischemic heart disease, while aGAPSS above 9.5 is predictive of cardiomyopathies. The presence of antiphospholipid antibodies may affect the development of cardiac manifestations in SLE. Periodic cardiological and echocardiographic screening of patients without cardiac complaints, as well as regular monitoring of antiphospholipid antibodies, have great importance during the treatment of SLE patients.

Genetically predicted circulating interleukin-18 levels are associated with risk of systemic lupus erythematosus and type 1 diabetes.

Interleukin-18 (IL-18) is a proinflammatory cytokine. This study aims to determine whether there is a causal relationship between circulating IL-18 concentrations and the risk of inflammatory and autoimmune diseases. We collected significant single nucleotide polymorphisms (SNPs) associated with circulating IL-18 levels (p < 5 × 10-8) as instrumental variables (IVs) from a genome-wide association study (GWAS) involving 21,758 individuals of European descent. We mainly employed the inverse-variance weighed (IVW) method of two-sample Mendelian randomization (TSMR) analysis to estimate the causality of circulating IL-18 levels on inflammatory and autoimmune diseases. The IVW method results showed evidence of a causal relationship between IL-18 and the risk of systemic lupus erythematosus (SLE) (OR = 1.32; 95% CI 1.15, 1.50; p < .001) and type 1 diabetes (T1D) (OR = 1.22; 95% CI 1.06, 1.42; p = .007) in individuals of European ancestry. No significant heterogeneity or horizontal pleiotropy for SLE and T1D was detected. The sensitivity analysis, which involved removing confounding SNP, produced similar results for SLE and T1D. The results of sensitivity analysis using leave-one-out method indicated no single SNP significantly influenced the analysis results. However, we did not find any significant findings for multiple sclerosis, psoriasis, asthma, and osteoarthritis. Our analyses suggest that circulating IL-18 is significantly related to SLE and T1D and may serve as a potential target for the treatment of these diseases.

Optimizing Warfarin use in Egyptian patients with Autoimmune Diseases – Genetic and Clinical Related Factors

Introduction: Over the last Century, Thousands of studies were conducted to highlight the factors affecting warfarin efficacy and toxicity. Many of these studies had major limitations because they focused only on one or a few factors. Objectives: to determine the effect of 14 different clinical and genetic factors on the clinical outcomes (efficacy and toxicity) of warfarin in Egyptian patients with autoimmune diseases. The secondary objective was detecting the association between genetic polymorphisms of VKORC1 (rs 9923231) and systemic lupus erythematosus (SLE) susceptibility in the Egyptian population. Methods: after signing a consent form, 150 patients were included in the study from Kasr Aleiny Hospital, Cairo University. All medical records were reviewed to extract the effect of age, sex, diagnoses, genotypes, warfarin-drug interactions, and all patients' comorbidities on warfarin's efficacy and toxicity. The average warfarin doses, INR, (No. of times)/total times of INR within the therapeutic range, differences between the maximum and minimum INR values, the addition of enoxaparin and discontinuing warfarin and shifting to Rivaroxaban, and bleeding episodes were determined. Results: all the studied factors had clinical and statistical significance on the clinical outcomes. The T allele was associated with treatment failure and a shift to rivaroxaban, a higher risk of bleeding and SLE. Conclusions: Awareness of the effect of the factors addressed in this study is mandatory for the assessment of warfarin efficacy and toxicity for each patient. Further studies are essential in other specialties because different warfarin-drug interactions may be detected, with other comorbidities and on different genes.

KLF2 enhancer variant rs4808485 increases lupus risk by modulating inflammasome machinery and cellular homoeostasis

ObjectiveA recent genome-wide association study linked KLF2 as a novel Asian-specific locus for systemic lupus erythematosus (SLE) susceptibility. However, the underlying causal functional variant(s), cognate target gene(s) and genetic mechanisms...

Classifying systemic lupus erythematosus using laboratory items alone: a preliminary study.

To explore the performance of laboratory items alone in systemic lupus erythematosus (SLE) classification. Our cohort consisted of 352 and 385 (control) patients with and without SLE. This study evaluated the performance of the American College of Rheumatology (ACR)-1997, Systemic Lupus International Collaborating Clinics (SLICC)-2012, European League Against Rheumatism (EULAR)/ACR-2019, and Systemic Lupus Erythematosus Risk Probability Index (SLERPI) using laboratory items alone, including blood and urine test results. The median ratio of laboratory items/total items was 66.7%, 75.0%, 60.4%, and 77.4% in ACR-1997, SLICC-2012, EULAR/ACR-2019, and SLERPI, respectively. After including laboratory items alone, the sensitivity of ACR-1997, SLICC-2012, EULAR/ACR-2019, and SLERPI was 31.3% (95% confidence interval [CI]: 26.4%-36.4%), 79.8% (95% CI: 75.3%-83.9%), 75.9% (95% CI: 71.0%-80.2%), and 85.2% (95% CI: 81.1%-88.8%), respectively. We referenced the SLERPI and removed the additional restrictions, i.e., SLICC-2012 criteria only needs to fulfill at least four items (mSLICC-2012) and EULAR/ACR-2019 criteria needs to have ≥ 10 points (mEULAR/ACR-2019) to qualify for SLE classification. The mSLICC-2012 and mEULAR/ACR-2019 criteria, including laboratory items alone, newly identified 13 and 25 patients, respectively. Based on laboratory items alone, the combination of mSLICC-2012, mEULAR/ACR-2019, and SLERPI identified 348 patients with an improved sensitivity of 90.6% (95% CI: 87.1%-93.5%). Patients, who were classified according to the mEULAR/ACR-2019 criteria, all met the other criteria. Incorporating laboratory items alone was clinically feasible to help identify SLE. SLERPI and SLICC-2012, using laboratory items alone, were more worthwhile to promote in the clinic compared with EULAR/ACR-2019. Key Points • Laboratory items play a crucial role in the SLE classification criteria, and incorporating laboratory items alone was clinically feasible to help in the identification of SLE. • The SLERPI and SLICC-2012, using laboratory items alone, were more worthwhile to promote in the clinic compared with EULAR/ACR-2019, and the combination of the two could further improve the sensitivity. • The relative simplicity of evaluating laboratory indices may help nonrheumatologists and inexperienced rheumatologists to identify SLE more quickly, thereby reducing the risk of delayed diagnosis in patients.

Genetic link between primary biliary cholangitis and connective tissue diseases in European populations: A two-sample Mendelian randomization study.

An association between primary biliary cholangitis (PBC) and connective tissue diseases (CTDs) [rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), systemic sclerosis (SSc)] has been found in observational studies. However, the direction causality is unclear. The aim of this study was to assess the causality between PBC and CTDs and to promote early screening, pre-emptive therapy, and accurate stratification. A two-sample Mendelian randomization (MR) analysis was performed to assess the causal relationship between PBC [Genome-Wide Association Study (GWAS) meta-analysis, 8021 cases/16498 controls], and SLE (GWAS meta-analysis, 8021 cases/16489 controls), RA(FinnGen, 6236 cases/14727 controls), SS(FinnGen, 2495 cases/365533 controls), SSc (FinnGen, 302 cases/213145 controls). Inverse variance weighting (IVW) was used as the primary analysis method, supplemented by four sensitivity analyses to assess the robustness of the results. The IVW revealed that genetically predicted PBC increased the risk of SLE [odd's ratio (OR) = 1.43, 95% confidence interval (CI) 1.30-1.58, P < 0.001]), RA (OR = 1.09, 95%CI1.04-1.14, P<0.001), and SS (OR = 1.18, 95%CI1.12-1.24, P<0.001), but not that of SSc. In addition, no association was observed between CTDs as an exposure and PBC. Sensitivity analyses did not reveal horizontal pleiotropy. Our study provided new genetic evidence for a causal relationship between PBC and CTDs. PBC increased the risk of SLE, RA, and SS. Our findings highlighted the importance of active screening and intervention for CTDs in patients with PBC.

Causal association between systemic lupus erythematosus and the risk of migraine: A Mendelian randomization study.

Numerous studies have found that patients with systemic lupus erythematosus (SLE) often have comorbid headache, especially migraine. However, the causal relationship between genetically determined SLE and migraine risk remains unclear. Therefore, we conducted a Mendelian randomization (MR) study to explore this causal association. Genome-wide association studies (GWAS) provided the instrumental variables. We selected summary data from GWAS of SLE as exposure (5201 SLE patients and 9066 controls). Both outcome GWAS data were from the Finnish Gene GWAS, including migraine with aura, migraine with aura and triptan purchases, and migraine without aura. The main MR approach was inverse-variance weighted. Pleiotropy and heterogeneity were detected using the MR pleiotropy residual sum and outlier, MR-Egger intercept test, leave-one-out analysis, and Cochran's Q test. There was a significant association between genetically predicted SLE susceptibility and increased risk of migraine with aura [odds ratio (OR)=1.05, 95% confidence interval (CI)=1.02-1.08, p=.001]. The result was consistent when the outcome was migraine with aura and triptan purchases [OR=1.05, 95% CI=1.02-1.08, p=.001]. However, we found no association between SLE and migraine without aura. Our MR study showed no pleiotropy or heterogeneity. Our study indicates that genetic susceptibility to SLE increases the incidence of migraine with aura but not migraine without aura. It is necessary for the routine evaluation and early recognition of migraine in patients with SLE in clinical settings.

A survey of ficolin-3 activity in Systemic Lupus Erythematosus reveals a link to hematological disease manifestations and autoantibody profile

The complement system plays a central role in the pathogenesis of Systemic Lupus Erythematosus (SLE), but most studies have focused on the classical pathway. Ficolin-3 is the main initiator of the lectin pathway of complement in humans, but its role in systemic autoimmune disease has not been conclusively determined. Here, we combined biochemical and genetic approaches to assess the contribution of ficolin-3 to SLE risk and disease manifestations. Ficolin-3 activity was measured by a functional assay in serum or plasma samples from Swedish SLE patients (n = 786) and controls matched for age and sex (n = 566). Genetic variants in an extended 300 kb genomic region spanning the FCN3 locus were analyzed for their association with ficolin-3 activity and SLE manifestations in a Swedish multicenter cohort (n = 985). Patients with ficolin-3 activity in the highest tertile showed a strong enrichment in an SLE cluster defined by anti-Sm/DNA/nucleosome antibodies (OR 3.0, p < 0.001) and had increased rates of hematological disease (OR 1.4, p = 0.078) and lymphopenia (OR = 1.6, p = 0.039). Genetic variants associated with low ficolin-3 activity mapped to an extended haplotype in high linkage disequilibrium upstream of the FCN3 gene. Patients carrying the lead genetic variant associated with low ficolin-3 activity had a lower frequency of hematological disease (OR 0.67, p = 0.018) and lymphopenia (OR 0.63, p = 0.031) and fewer autoantibodies (p = 0.0019). Loss-of-function variants in the FCN3 gene were not associated with SLE, but four (0.5 %) SLE patients developed acquired ficolin-3 deficiency where ficolin-3 activity in serum was depleted following diagnosis of SLE.Taken together, our results provide genetic and biochemical evidence that implicate the lectin pathway in hematological SLE manifestations. We also identify lectin pathway activation through ficolin-3 as a factor that contributes to the autoantibody response in SLE.