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Background: Overall survival of systemic lupus erythematosus (SLE) patients significantly increased in recent decades, however, the relative risk of mortality is still high. Long-term survival outcome of pediatric SLE remains unclear. This study aims to explore the long-term survival rate and its predictors in patients with systemic lupus erythematosus (SLE)., Methods: A retrospective, hospital-based cohort study was performed between 2004 and 2018 in a tertiary referral medical center in Taiwan. Data on comorbidities, medications, and causes of admission were collected for risk factor analysis using time-dependent multivariate Cox proportional hazards models., Results: A total of 2392 adults and 115 pediatric SLE patients were enrolled (female, n = 2157 and 95, respectively). The 10-year survival rates were 93.2%, 90.2%, 98.9%, and 100% in adult women, adult men, girls, and boys with SLE, respectively. The overall mortality rate was 2.09 case/100 patient-years (PY) for male SLE and 1.39 case/100 PY for female SLE patients. Male SLE patients did not have a statistically significantly higher mortality rate than female SLE patients in each age stratification. Infectious disease (n = 119), heart failure (n = 21), and cerebrovascular accident (n = 14) were the leading causes of death in adult SLE patients. Advanced age (hazard ratio [HR]: 1.04, 95% confidence interval [CI]: 1.03-1.05), treatment with mean dosage of systemic glucocorticoid equivalent to >10 mg/d of prednisolone (HR: 1.71, 95% CI: 1.14-2.57), comorbidities with malignancy (HR: 1.94, 95% CI: 1.22-3.09), chronic kidney disease (HR: 1.86, 95% CI: 1.25-2.77), hypertension (HR: 1.42, 95% CI: 1.01-1.98), and admission due to bacterial pneumonia (HR: 1.92, 95% CI: 1.12-3.31) and sepsis (HR: 2.78, 95% CI: 1.51-5.13) were independent risk factors for mortality in SLE patients., Conclusion: SLE patients with advanced age, malignancy, chronic kidney disease, hypertension, treated with a higher average dosage of glucocorticoids, and admission due to bacterial pneumonia and sepsis have an increased risk of mortality., Competing Interests: Conflicts of interest: Dr. Chang-Youh Tsai and Dr. Deh-Ming Chang, editorial board members at Journal of the Chinese Medical Association, have no roles in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Objective: Deletion of Deltex1 (DTX1) in mice caused hyperactivation of T cells and lupus-like autoimmune syndromes, however, the association of DTX1 with human autoimmune diseases is totally unknown. This study investigated the role of DTX1 in human T cell functions and its correlation with disease activity in patients with SLE., Methods: The influence of DTX1 on T cell function was evaluated using human primary cells. DTX1 expression in peripheral blood mononuclear cells (PBMCs) from healthy controls and SLE patients was measured by quantitative real-time PCR and the SLEDAI was used to assess disease activity., Results: After stimulation with anti-CD3 and anti-CD28, silencing of DTX1 expression enhanced IFN-γ secretion by human T cells. The expression of DTX1 in PBMCs was significantly lower in 100 SLE patients than in 50 age- and sex-matched healthy controls (DTX1/glyceraldehyde 3-phosphate dehydrogenase, 0.452 vs 1.269, P < 0.001). The area under the receiver operator characteristics curve of the model was 0.737 (95% CI 0.658, 0.815). Intriguingly, a low DTX1 level in T cells led to high IFN-γ production in SLE patients and had a correlation with severe disease activity. In addition, low DTX1 expression in SLE patients was associated with active LN, lung involvement or hypocomplementaemia., Conclusion: Knockdown DTX1 expression in human T cells reduced IFN-γ secretion. DTX1 expression in the PBMCs was significantly lower in SLE patients and had an inverse correlation with disease activity, indicating that the DTX1 level may be a good disease marker of SLE., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We evaluated plasma glutamine levels and basal mitochondrial oxygen consumption rate (mOCR B ) and basal extracellular acidification rate (ECAR B ) of peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematous (SLE) patients and healthy controls (HCs). Lower plasma glutamine levels correlated with higher SLE disease activity indexes (p=0.025). Incubated in DMEM containing 100mg/dL glucose, SLE-PBMCs displayed lower mOCR B (p=0.018) but similar ECAR B (p=0.467) to those of HC-PBMCs, and their mOCR B got elevated (p<0.001) without altering ECAR B (p=0.239) by supplementation with 2 or 4mM glutamine. We conclude that impaired mitochondrial respiration of SLE-PBMCs could be improved by glutamine under euglycemic condition., (Copyright © 2018. Published by Elsevier B.V.)

We evaluated plasma IL-10, IFN-alpha, IL-23, IFN-gamma, IP-10, MCP-1, 8-OHdG, leukocyte mtDNA, serum anti-dsDNA antibodies and disease activity index (SLEDAI) in SLE patients. 93 patients (35 nephritis, 4 under dialysis, 5 under rituximab) and 50 healthy controls were recruited. Compared with healthy controls, SLE patients had higher IL-10, IFN-alpha, IL-23, IFN-gamma, IP-10 and MCP-1 ( p <0.05). High IFN-alpha ( p =0.031) and IP-10 ( p =0.026) correlated with high SLEDAI; high IFN-alpha ( p< 0.001), IL-23 ( p =0.023) and IP-10 ( p< 0.001) correlated with high anti-dsDNA. High IL-10 ( p =0.014), IL-23 ( p< 0.001), IFN-gamma ( p< 0.001) and MCP-1 ( p =0.002) correlated with high 8-OHdG and high IL-23 ( p <0.001), INF-gamma ( p <0.001), IP-10 ( p =0.023) and MCP-1 ( p =0.002) correlated with low leukocyte mtDNA. mtDNA 4977 deletion correlated with high mtDNA ( p =0.011) and low IL-10 ( p =0.009). MCP-1 ( p =0.043) decreased after rituximab therapy. 54 SLE patients without nephritis, 35 with nephritis but without dialysis, and 4 with nephritis under dialysis exhibited stepwise increases in IL-23 ( p =0.009) and MCP-1 ( p =0.015). These data suggest that oxidative DNA and mtDNA alterations and coordinate changes in cytokines/chemokines are implicated in progression of SLE and rituximab in amelioration of SLE.

Objectives: Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150 kb flanking regions containing NMNAT2 and SMG7 in a 15 292 case-control multi-ancestry population and tested functions of identified variants., Methods: We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA., Results: We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 -8 , OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10 -3 and 6.8×10 -8 , respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=-0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10 -5 and 2.0×10 -4 , respectively)., Conclusion: We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis., Competing Interests: Conflicts of Interest: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

SLE is characterized by an increased production of detrimental autoantigens, exaggerated effects of pro-inflammatory cytokines, dysregulated functioning of immunocompetent cells including lymphocytes and leukocytes, and devastating tissue and organ damage. All of these derangements can be potentiated or attenuated by the abnormal energy expenditure and overproduction of reactive oxygen species (ROS). Mitochondrial heteroplasmy or dysfunction has been recognized to play a role in these abnormalities. Abnormal redox reaction, decreased functioning of biogenesis-related enzymes, increased NETosis, harmful cytokine effects, and aberrant lymphocyte behavior have been shown to be associated with the pathological state of mitochondria. There is accumulating data which support the importance of abnormal oxygen metabolism and mitochondrial disorders in the immunopathogenesis of SLE. Further laboratory as well as clinical data are required to expand our understanding of SLE pathogenesis., (Copyright © 2016 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Leptin is abnormally elevated in the plasma of patients with systemic lupus erythematosus (SLE), where it is thought to promote and/or sustain pro-inflammatory responses. Whether this association could reflect an increased genetic susceptibility to develop SLE is not known, and studies of genetic associations with leptin-related polymorphisms in SLE patients have been so far inconclusive. Here we genotyped DNA samples from 15,706 SLE patients and healthy matched controls from four different ancestral groups, to correlate polymorphisms of genes of the leptin pathway to risk for SLE. It was found that although several SNPs showed weak associations, those associations did not remain significant after correction for multiple testing. These data do not support associations between defined leptin-related polymorphisms and increased susceptibility to develop SLE., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The Xq28 region containing IRAK1 and MECP2 has been identified as a risk locus for systemic lupus erythematosus (SLE) in previous genetic association studies. However, due to the strong linkage disequilibrium between IRAK1 and MECP2, it remains unclear which gene is affected by the underlying causal variant(s) conferring risk of SLE., Methods: We fine-mapped ≥136 SNPs in a ∼227 kb region on Xq28, containing IRAK1, MECP2 and seven adjacent genes (L1CAM, AVPR2, ARHGAP4, NAA10, RENBP, HCFC1 and TMEM187), for association with SLE in 15 783 case-control subjects derived from four different ancestral groups., Results: Multiple SNPs showed strong association with SLE in European Americans, Asians and Hispanics at p<5×10(-8) with consistent association in subjects with African ancestry. Of these, six SNPs located in the TMEM187-IRAK1-MECP2 region captured the underlying causal variant(s) residing in a common risk haplotype shared by all four ancestral groups. Among them, rs1059702 best explained the Xq28 association signals in conditional testings and exhibited the strongest p value in transancestral meta-analysis (p(meta )= 1.3×10(-27), OR=1.43), and thus was considered to be the most likely causal variant. The risk allele of rs1059702 results in the amino acid substitution S196F in IRAK1 and had previously been shown to increase NF-κB activity in vitro. We also found that the homozygous risk genotype of rs1059702 was associated with lower mRNA levels of MECP2, but not IRAK1, in SLE patients (p=0.0012) and healthy controls (p=0.0064)., Conclusions: These data suggest contributions of both IRAK1 and MECP2 to SLE susceptibility.

Objective: The increased risk of thrombosis in systemic lupus erythematosus (SLE) may be partially explained by interrelated genetic pathways for thrombosis and SLE. The present study was undertaken to investigate whether 33 established and novel single-nucleotide polymorphisms (SNPs) in 20 genes involved in hemostasis pathways that have been associated with deep venous thrombosis (DVT) in the general population are risk factors for SLE among Asian subjects., Methods: Patients in the discovery cohort were enrolled in 1 of 2 North American SLE cohorts. Patients in the replication cohort were enrolled in 1 of 4 Asian or 2 North American cohorts. We first genotyped 263 Asian patients with SLE and 357 healthy Asian control subjects for 33 SNPs in the discovery phase, and then genotyped 5 SNPs in up to an additional 1,496 patients and 993 controls in the replication phase. Patients were compared to controls for bivariate association with minor alleles. Principal components analysis was used to control for intra-Asian ancestry in the replication cohort., Results: Two genetic variants in the gene VKORC1 were highly significant in both the discovery and replication cohorts: rs9934438 (in the discovery cohort, odds ratio [OR] 2.45, P=2×10(-9); in the replication cohort, OR 1.54, P=4×10(-6)) and rs9923231 (in the discovery cohort, OR 2.40, P=6×10(-9); in the replication cohort, OR 1.53, P=5×10(-6)). These associations were significant in the replication cohort after adjustment for intra-Asian ancestry: for rs9934438, OR 1.34, P=0.0029; for rs9923231, OR 1.34, P=0.0032., Conclusion: Genetic variants in VKORC1, which are involved in vitamin K reduction and associated with DVT, correlate with SLE development in Asian subjects. These results suggest that there may be intersecting genetic pathways for the development of SLE and thrombosis., (Copyright © 2013 by the American College of Rheumatology.)

Immunoregulatory cytokine interleukin-10 (IL-10) is elevated in sera from patients with systemic lupus erythematosus (SLE) correlating with disease activity. The established association of IL10 with SLE and other autoimmune diseases led us to fine map causal variant(s) and to explore underlying mechanisms. We assessed 19 tag SNPs, covering the IL10 gene cluster including IL19, IL20 and IL24, for association with SLE in 15,533 case and control subjects from four ancestries. The previously reported IL10 variant, rs3024505 located at 1 kb downstream of IL10, exhibited the strongest association signal and was confirmed for association with SLE in European American (EA) (P = 2.7×10⁻⁸, OR = 1.30), but not in non-EA ancestries. SNP imputation conducted in EA dataset identified three additional SLE-associated SNPs tagged by rs3024505 (rs3122605, rs3024493 and rs3024495 located at 9.2 kb upstream, intron 3 and 4 of IL10, respectively), and SLE-risk alleles of these SNPs were dose-dependently associated with elevated levels of IL10 mRNA in PBMCs and circulating IL-10 protein in SLE patients and controls. Using nuclear extracts of peripheral blood cells from SLE patients for electrophoretic mobility shift assays, we identified specific binding of transcription factor Elk-1 to oligodeoxynucleotides containing the risk (G) allele of rs3122605, suggesting rs3122605 as the most likely causal variant regulating IL10 expression. Elk-1 is known to be activated by phosphorylation and nuclear localization to induce transcription. Of interest, phosphorylated Elk-1 (p-Elk-1) detected only in nuclear extracts of SLE PBMCs appeared to increase with disease activity. Co-expression levels of p-Elk-1 and IL-10 were elevated in SLE T, B cells and monocytes, associated with increased disease activity in SLE B cells, and were best downregulated by ERK inhibitor. Taken together, our data suggest that preferential binding of activated Elk-1 to the IL10 rs3122605-G allele upregulates IL10 expression and confers increased risk for SLE in European Americans., Competing Interests: The authors have declared that no competing interests exist.

Systemic lupus erythematosus (SLE) is a chronic heterogeneous autoimmune disorder characterized by the loss of tolerance to self-antigens and dysregulated interferon responses. The etiology of SLE is complex, involving both heritable and environmental factors. Candidate-gene studies and genome-wide association (GWA) scans have been successful in identifying new loci that contribute to disease susceptibility; however, much of the heritable risk has yet to be identified. In this study, we sought to replicate 1,580 variants showing suggestive association with SLE in a previously published GWA scan of European Americans; we tested a multiethnic population consisting of 7,998 SLE cases and 7,492 controls of European, African American, Asian, Hispanic, Gullah, and Amerindian ancestry to find association with the disease. Several genes relevant to immunological pathways showed association with SLE. Three loci exceeded the genome-wide significance threshold: interferon regulatory factor 8 (IRF8; rs11644034; p(meta-Euro) = 2.08 × 10(-10)), transmembrane protein 39A (TMEM39A; rs1132200; p(meta-all) = 8.62 × 10(-9)), and 17q21 (rs1453560; p(meta-all) = 3.48 × 10(-10)) between IKAROS family of zinc finger 3 (AIOLOS; IKZF3) and zona pellucida binding protein 2 (ZPBP2). Fine mapping, resequencing, imputation, and haplotype analysis of IRF8 indicated that three independent effects tagged by rs8046526, rs450443, and rs4843869, respectively, were required for risk in individuals of European ancestry. Eleven additional replicated effects (5 × 10(-8) < p(meta-Euro) < 9.99 × 10(-5)) were observed with CFHR1, CADM2, LOC730109/IL12A, LPP, LOC63920, SLU7, ADAMTSL1, C10orf64, OR8D4, FAM19A2, and STXBP6. The results of this study increase the number of confirmed SLE risk loci and identify others warranting further investigation., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with complex immunological and clinical manifestations. Multiple organ failure in SLE can be caused by immune dysfunction and deposition of autoantibodies. Studies of SLE-susceptible loci and the cellular and humoral immune responses reveal variable aberrations associated with this systemic disease. Invariant natural killer T (iNKT) cells are a unique subset of lymphocytes that control peripheral tolerance. Mounting evidence showing reductions in the proportion and activity of iNKT cells in SLE patients suggests the suppressive role of iNKT cells. Studies using murine lupus models demonstrate that iNKT cells participate in SLE progression by sensing apoptotic cells, regulating immunoglobulin production, and altering the cytokine profile upon activation. However, the dichotomy of iNKT cell actions in murine models implies complicated interactions within the body's milieu. Therefore, application of potential therapy for SLE using glycolipids to regulate iNKT cells should be undertaken cautiously.

Objective: T cells from patients with systemic lupus erythematosus (SLE) express increased amounts of PP2Ac, which contributes to decreased production of interleukin-2 (IL-2). Because IL-2 is important in the regulation of several aspects of the immune response, it has been proposed that PP2Ac contributes to the expression of SLE. This study was designed to determine whether genetic variants of PPP2AC are linked to the expression of SLE and specific clinical manifestations and account for the increased expression of PP2Ac., Methods: We conducted a trans-ethnic study of 8,695 SLE cases and 7,308 controls of 4 different ancestries. Eighteen single-nucleotide polymorphisms (SNPs) across PPP2CA were genotyped using an Illumina custom array. PPP2CA expression in SLE and control T cells was analyzed by real-time polymerase chain reaction., Results: A 32-kb haplotype comprising multiple SNPs of PPP2CA showed significant association with SLE in Hispanic Americans, European Americans, and Asians, but not in African Americans. Conditional analyses revealed that SNP rs7704116 in intron 1 showed consistently strong association with SLE across Asian, European American, and Hispanic American populations (odds ratio 1.3 [95% confidence interval 1.14-1.31], meta-analysis P=3.8×10(-7)). In European Americans, the largest ethnic data set studied, the risk A allele of rs7704116 was associated with the presence of renal disease, anti-double-stranded DNA, and anti-RNP antibodies. PPP2CA expression was ∼2-fold higher in SLE patients carrying the rs7704116 AG genotype than those carrying the GG genotype (P=0.007)., Conclusion: Our data provide the first evidence of an association between PPP2CA polymorphisms and elevated PP2Ac transcript levels in T cells, which implicates a new molecular pathway for SLE susceptibility in European Americans, Hispanic Americans, and Asians., (Copyright © 2011 by the American College of Rheumatology.)

Systemic lupus erythematosus (SLE), a complex polygenic autoimmune disease, is associated with increased complement activation. Variants of genes encoding complement regulator factor H (CFH) and five CFH-related proteins (CFHR1-CFHR5) within the chromosome 1q32 locus linked to SLE, have been associated with multiple human diseases and may contribute to dysregulated complement activation predisposing to SLE. We assessed 60 SNPs covering the CFH-CFHRs region for association with SLE in 15,864 case-control subjects derived from four ethnic groups. Significant allelic associations with SLE were detected in European Americans (EA) and African Americans (AA), which could be attributed to an intronic CFH SNP (rs6677604, in intron 11, P(meta) = 6.6×10(-8), OR = 1.18) and an intergenic SNP between CFHR1 and CFHR4 (rs16840639, P(meta) = 2.9×10(-7), OR = 1.17) rather than to previously identified disease-associated CFH exonic SNPs, including I62V, Y402H, A474A, and D936E. In addition, allelic association of rs6677604 with SLE was subsequently confirmed in Asians (AS). Haplotype analysis revealed that the underlying causal variant, tagged by rs6677604 and rs16840639, was localized to a ~146 kb block extending from intron 9 of CFH to downstream of CFHR1. Within this block, the deletion of CFHR3 and CFHR1 (CFHR3-1Δ), a likely causal variant measured using multiplex ligation-dependent probe amplification, was tagged by rs6677604 in EA and AS and rs16840639 in AA, respectively. Deduced from genotypic associations of tag SNPs in EA, AA, and AS, homozygous deletion of CFHR3-1Δ (P(meta) = 3.2×10(-7), OR = 1.47) conferred a higher risk of SLE than heterozygous deletion (P(meta) = 3.5×10(-4), OR = 1.14). These results suggested that the CFHR3-1Δ deletion within the SLE-associated block, but not the previously described exonic SNPs of CFH, might contribute to the development of SLE in EA, AA, and AS, providing new insights into the role of complement regulators in the pathogenesis of SLE., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To determine the safety of and immunogenicity induced by A/H1N1 influenza vaccination in patients with systemic lupus erythematosus (SLE)., Research Design and Methods: The study population comprised 21 SLE patients and 15 healthy control subjects who underwent split-virion, inactivated monovalent A/H1N1 vaccination between December 2009 and January 2010. Sera were obtained before, three weeks after, and six months after vaccination. SLE disease activity index (SLEDAI) scores and autoantibodies were measured at every visit in SLE patients. Haemagglutination inhibition and the serum immunoglobulin G (IgG) level were calculated using the World Health Organization (WHO) procedure to evaluate the antibody responses. We also recorded current medications and past seasonal influenza vaccinations to analyse the interactions between vaccinations and the autoimmunity of SLE patients., Results: The mean age of the enrolled population was 34.3 years for SLE patients and 39.4 years for control subjects. The average SLEDAI score for SLE patients was 4.1 at vaccination, 4.5 at three weeks, and 4.3 at six months. The seroprotection rate at three weeks was 76.2% in SLE patients and 80.0% in healthy control subjects; by six months, the seroprotection rate was 66.7% in SLE patients and 60% in healthy control subjects. The seroconversion rate was 76.2% in SLE patients and 80% in healthy controls at three weeks; by six months, the seroconversion rate was 52.4% in SLE patients and 53.3% in healthy controls. The response in SLE patients met the criteria of the European Committee for Proprietary Medicinal Products guidelines at three weeks, while the percentage of seroprotection did not at six months. The clinical disease activity and SLEDAI scores did not differ significantly from before to after vaccination in SLE patients, although the level of anticardiolipin IgG increased at three weeks after vaccination, but with no apparent clinical manifestations., Conclusions: The A/H1N1 influenza vaccine is safe and effective in SLE patients and has no obvious adverse clinical effects. Treatment with a single immunosuppressive agent or combination therapy also leads to effective humoral immunity in these patients., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Systemic lupus erythematosus (SLE) is considered to be the prototypic autoimmune disease, with a complex genetic architecture influenced by environmental factors. We sought to replicate a putative association at 11p13 not yet exceeding genome-wide significance (p < 5 × 10(-8)) identified in a genome-wide association study (GWAS). Our GWA scan identified two intergenic SNPs located between PDHX and CD44 showing suggestive evidence of association with SLE in cases of European descent (rs2732552, p = 0.004, odds ratio [OR] = 0.78; rs387619, p = 0.003, OR = 0.78). The replication cohort consisted of >15,000 subjects, including 3562 SLE cases and 3491 controls of European ancestry, 1527 cases and 1811 controls of African American (AA) descent, and 1265 cases and 1260 controls of Asian origin. We observed robust association at both rs2732552 (p = 9.03 × 10(-8), OR = 0.83) and rs387619 (p = 7.7 × 10(-7), OR = 0.83) in the European samples with p(meta) = 1.82 × 10(-9) for rs2732552. The AA and Asian SLE cases also demonstrated association at rs2732552 (p = 5 × 10(-3), OR = 0.81 and p = 4.3 × 10(-4), OR = 0.80, respectively). A meta-analysis of rs2732552 for all racial and ethnic groups studied produced p(meta) = 2.36 × 10(-13). This locus contains multiple regulatory sites that could potentially affect expression and functions of CD44, a cell-surface glycoprotein influencing immunologic, inflammatory, and oncologic phenotypes, or PDHX, a subunit of the pyruvate dehydrogenase complex.

Purpose: To distinguish lupus flare-up from infection in systemic lupus erythematosus (SLE), we analyze the expression of circulating CD27(high) plasma cells in SLE patients with and without infection, in comparison to non-SLE patients with infection., Materials and Methods: The percentage of circulating CD27(high) plasma cells was measured by flow cytometry in the following four groups: 36 SLE patients without infection, 23 SLE patients with infection, eight non-SLE patients with infection, and 26 healthy controls., Results: The frequency of CD27(high) plasma cells had a correlation with the SLE disease activity index (SLEDAI) (r = 0.866, p < 0.05), level of anti-dsDNA (r = 0.886, p < 0.05), C3 (r = - 0.392, p < 0.05), and C4 (r = - 0.337, p < 0.05) in SLE patients without infection, but there was no correlation with disease activity in SLE patients with infection. Among three groups in particular-SLE without infection, SLE with infection, and non-SLE with infection- the percentages of CD27(high) plasma cells were elevated. The percentage of CD27(high) plasma cells was higher in SLE patients with infection, when compared to SLE patients without infection., Conclusion: The percentage of CD27(high) plasma cells is a biomarker for disease activity of SLE without infection, under correlation with SLEDAI, anti-dsDNA, and C3 and C4 level. However, when the SLE patients have an infection, the percentage of CD27(high) plasma cells is not an adequate biomarker for the survey of disease activity. The percentage of CD27(high) plasma cells may serve as a potential parameter to distinguish a lupus flare-up from infection.

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that predominantly affects women. Previous findings that duplicated Toll-like receptor 7 (Tlr7) promotes lupus-like disease in male BXSB mice prompted us to evaluate TLR7 in human SLE. By using a candidate gene approach, we identified and replicated association of a TLR7 3'UTR SNP, rs3853839 (G/C), with SLE in 9,274 Eastern Asians (P(combined) = 6.5 x 10(-10)), with a stronger effect in male than female subjects [odds ratio, male vs. female = 2.33 (95% CI = 1.64-3.30) vs. 1.24 (95% CI = 1.14-1.34); P = 4.1 x 10(-4)]. G-allele carriers had increased TLR7 transcripts and more pronounced IFN signature than C-allele carriers; heterozygotes had 2.7-fold higher transcripts of G-allele than C-allele. These data established a functional polymorphism in type I IFN pathway gene TLR7 predisposing to SLE, especially in Chinese and Japanese male subjects.

Objective: SLE is an autoimmune disorder characterized by abnormal complement activation. Numerous new biomarkers have recently been used to diagnose or monitor disease activity in patients with SLE. We checked the levels of erythrocyte-bound C4d (E-C4d), an activation-derived fragment of C4 that is deposited on the erythrocytes, under different conditions of SLE in order to correlate these levels with disease activity., Methods: We conducted a cross-sectional investigation of three groups of patients: (i) 63 patients with SLE; (ii) 43 patients with other diseases; and (iii) 26 healthy controls. Erythrocytes were analysed by flow cytometry to determine the levels of E-C4d., Results: We found a significant elevation in the mean levels of E-C4d in SLE patients compared with patients with other diseases or healthy controls. In SLE patients, the levels of E-C4d were correlated with the SLEDAI and inversely correlated with serum C3/C4 levels. In the subgroup of SLE patients with haemolytic anaemia (HA), a significantly higher level of E-C4d was observed than that in SLE patients without HA. However, in SLE patients with HA, there was no correlation between the levels of E-C4d and other markers of disease activity, including SLEDAI and levels of anti-dsDNA, C3 and C4., Conclusion: E-C4d levels are useful diagnostic markers for SLE and can serve as biomarkers of disease activity in patients with SLE. However, E-C4d is of limited value in monitoring disease activity in SLE patients with HA.

A genomic region on distal mouse chromosome 1 and its syntenic human counterpart 1q23-42 show strong evidence of harboring lupus susceptibility genes. We found evidence of linkage at 1q32.2 in a targeted genome scan of 1q21-43 in 126 lupus multiplex families containing 151 affected sibpairs (nonparametric linkage score 2.52, P = 0.006). A positional candidate gene at 1q32.2, complement receptor 2 (CR2), is also a candidate in the murine Sle1c lupus susceptibility locus. To explore its role in human disease, we analyzed 1,416 individuals from 258 Caucasian and 142 Chinese lupus simplex families and demonstrated that a common three-single-nucleotide polymorphism CR2 haplotype (rs3813946, rs1048971, rs17615) was associated with lupus susceptibility (P = 0.00001) with a 1.54-fold increased risk for the development of disease. Single-nucleotide polymorphism 1 (rs3813946), located in the 5' untranslated region of the CR2 gene, altered transcriptional activity, suggesting a potential mechanism by which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility gene for human lupus at 1q32.2, extending previous studies suggesting that CR2 participates in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) and autoimmune hepatitis are distinct clinical disorders, which rarely occur, in the same patient. We describe a 59-year-old woman with coexistence of both conditions. Photosensitivity, arthritis, positive ANA, and extreme elevation of anti-dsDNA concluded the diagnosis of SLE. Hyperbilirubinemia, high serum value of liver function, and elevation of alpha-fetoprotein were also prominent. By a review of pertinent literature, clinical investigation, calculation of autoimmune hepatitis score, and pathology of liver biopsy specimen, we were in favor of autoimmune hepatitis. Awareness of this rare presentation may be beneficial to clinicians in identifying and treating patients with both SLE and autoimmune hepatitis.

Histiocytic necrotizing lymphadenitis, called Kikuchi-Fujimoto's disease (KFD), is an idiopathic, self-limited condition rarely associated with systemic lupus erythematosus (SLE). The cause of concomitant KFD and SLE is still unknown. We describe a 19-year-old man simultaneously diagnosed with both KFD and SLE complicated with deep vein thrombosis (DVT). To the best of our knowledge, this is the first case report of KFD associated with SLE complicated with antiphospholipid antibody syndrome (APS). Our patient was successfully treated with intravenous pulse methylprednisolone, anticoagulation with heparin, oral hydroxychloroquine, azathioprine, and low-dose aspirin.

Transverse myelitis is a rare and serious complication of systemic lupus erythematosus (SLE). A longitudinal involvement of the spinal cord with lupus-related transverse myelitis is more unusual. Only 7 cases have been reported. We describe a 53-year-old woman presenting with short-term paraplegia as an initial manifestation of SLE with longitudinal myelitis. She had a partial response to treatment with pulse cyclophosphamide and high-dose corticosteroids after follow-up more than 2 years. To the best of our knowledge, this is the first case report of "longitudinal" myelitis as an initial presentation of SLE. Magnetic resonance imaging typically shows increased signal intensity in T2-weighted images, cord swelling, and contrast enhancement over several spinal segments. The possibility of SLE should be kept in mind in women presenting with paraplegia with no apparent cause.

Objective: To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE)., Methods: In a multicenter randomized, double-blind, placebo-controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24., Results: The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA -2.6 +/- 3.4 versus placebo -2.0 +/- 3.8, mean +/- SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA-treated patients versus 33.9% of placebo-treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA -5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA-treated patients compared with placebo-treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life-threatening reactions or serious safety issues were identified during this study., Conclusion: The overall results confirm that DHEA treatment was well-tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.