Lupus Risk Variant Increases pSTAT1 Binding and Decreases ETS1 Expression.

Genetic variants at chromosomal region 11q23.3, near the gene ETS1, have been associated with systemic lupus erythematosus (SLE), or lupus, in independent cohorts of Asian ancestry. Several recent studies have implicated ETS1 as a critical driver of immune cell function and differentiation, and mice deficient in ETS1 develop an SLE-like autoimmunity. We performed a fine-mapping study of 14,551 subjects from multi-ancestral cohorts by starting with genotyped variants and imputing to all common variants spanning ETS1. By constructing genetic models via frequentist and Bayesian association methods, we identified 16 variants that are statistically likely to be causal. We functionally assessed each of these variants on the basis of their likelihood of affecting transcription factor binding, miRNA binding, or chromatin state. Of the four variants that we experimentally examined, only rs6590330 differentially binds lysate from B cells. Using mass spectrometry, we found more binding of the transcription factor signal transducer and activator of transcription 1 (STAT1) to DNA near the risk allele of rs6590330 than near the non-risk allele. Immunoblot analysis and chromatin immunoprecipitation of pSTAT1 in B cells heterozygous for rs6590330 confirmed that the risk allele increased binding to the active form of STAT1. Analysis with expression quantitative trait loci indicated that the risk allele of rs6590330 is associated with decreased ETS1 expression in Han Chinese, but not other ancestral cohorts. We propose a model in which the risk allele of rs6590330 is associated with decreased ETS1 expression and increases SLE risk by enhancing the binding of pSTAT1.

Comparative effectiveness of JAK inhibitors and biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

BACKGROUND/AIMS: We aimed to compare the effectiveness and safety of Janus kinase inhibitors (JAKi) vs. biologic disease- modifying antirheumatic drugs (bDMARD) in Korean patients with rheumatoid arthritis (RA) who had an inadequate response to conventional synthetic DMARDs. METHODS: A quasi-experimental, multi-center, prospective, non-randomized study was conducted to compare response rates between JAKi and bDMARDs in patients with RA naïve to targeted therapy. An interim analysis was performed to estimate the proportion of patients achieving low disease activity (LDA) based on disease activity score (DAS)-28- erythroid sedimentation rate (ESR) (DAS28-ESR) at 24 weeks after treatment initiation and to evaluate the development of adverse events (AEs). RESULTS: Among 506 patients enrolled from 17 institutions between April 2020 and August 2022, 346 (196 JAKi group and 150 bDMARD group) were included in the analysis. After 24 weeks of treatment, 49.0% of JAKi users and 48.7% of bDMARD users achieved LDA (p = 0.954). DAS28-ESR remission rates were also comparable between JAKi and bDMARD users (30.1% and 31.3%, respectively; p = 0.806). The frequency of AEs reported in the JAKi group was numerically higher than that in the bDMARDs group, but the frequencies of serious and severe AEs were comparable between the groups. CONCLUSION: Our interim findings reveal JAKi have comparable effectiveness and safety to bDMARDs at 24 weeks after treatment initiation.

Unintended cannulation of the subclavian artery in a 65-year-old-female for temporary hemodialysis vascular access: management and prevention.

Ultrasound-guided cannulation of a large-bore catheter into the internal jugular vein was performed to provide temporary hemodialysis vascular access for uremia in a 65-yr-old woman with acute renal failure and sepsis superimposed on chronic renal failure. Despite the absence of any clinical evidence such as bleeding or hematoma during the procedure, a chest x-ray and computed tomographic angiogram of the neck showed that the catheter had inadvertently been inserted into the subclavian artery. Without immediately removing the catheter and applying manual external compression, the arterial misplacement of the hemodialysis catheter was successfully managed by open surgical repair. The present case suggests that attention needs to be paid to preventing iatrogenic arterial cannulation during central vein catheterization with a large-bore catheter and to the management of its potentially devastating complications, since central vein catheterization is frequently performed by nephrologists as a common clinical procedure to provide temporary hemodialysis vascular access.

Clinical characteristics and outcomes of diffuse alveolar hemorrhage in patients with systemic lupus erythematosus.

OBJECTIVE: To identify the clinical characteristics of diffuse alveolar hemorrhage (DAH) compared to other types of acute diffuse lung infiltration in SLE patients, and the factors associated with mortality in these patients. METHODS: We studied a retrospective cohort including SLE patients with acute diffuse lung infiltration on thoracic CT between January 2004 and August 2014. We divided them into 2 groups, a DAH and a non-DAH group, and compared the clinical characteristics and outcomes in the 2 groups. We also evaluated the risk factors for mortality in SLE patients with diffuse lung infiltration. RESULTS: Of 47 patients with diffuse lung infiltration, 24 patients (51.1%) satisfied the criteria for DAH and the remaining 23 patients (48.9%) were assigned to the non-DAH group. There were no significant differences between the demographic features of the 2 groups. However, decreased hemoglobin (OR = 3.46; 95% CI: 1.38-8.67; p < 0.01) and C4 (OR = 1.21; 95% CI: 1.03-1.42; p = 0.02) levels, and presence of hypoxia (OR = 23.09; 95% CI: 1.47-365.34; p = 0.03) at the time of diagnosis were associated with SLE-DAH. In addition, severe conditions requiring mechanical ventilation (OR = 64.61; 95% CI: 1.98-2112.02; p = 0.02) were associated with increased mortality, whereas DAH did not increase mortality compared with non-DAH in SLE patients with diffuse lung infiltration. CONCLUSIONS: In SLE patients with acute diffuse lung infiltration, it is important to promptly evaluate the DAH when patients have low levels of hemoglobin or C4, and symptoms of hypoxia. Mortality is associated with severe conditions requiring mechanical ventilation rather than with DAH in patients with diffuse lung infiltration.

Brief Report: Influence of HLA-DRB1 Susceptibility Alleles on the Clinical Subphenotypes of Systemic Lupus Erythematosus in Koreans.

OBJECTIVE: To investigate the association between HLA-DRB1 alleles and systemic lupus erythematosus (SLE) susceptibility and features of SLE, such as clinical manifestations and autoantibody profiles, in a Korean population. METHODS: We tested the genetic associations between HLA-DRB1 alleles and SLE susceptibility and clinical subphenotypes in 1,089 patients with SLE and 2,161 control subjects, including a discovery set (475 patients and 1,119 controls) and a replication set (614 patients and 1,042 controls). We used a relative predispositional effects (RPEs) method to examine the independent effect of each allele associated with SLE or its subphenotypes. RESULTS: We identified 4 HLA-DRB1 alleles that were associated with increased susceptibility to SLE, 2 of which had been detected previously (*15:01; P for RPE = 1.11 × 10(-13) , odds ratio [OR] 1.88) and *09:01 (P for RPE = 1.59 × 10(-5) , OR 1.46), and 2 of which were novel alleles (*08:03 [P for RPE = 8.80 × 10(-8) , OR 1.62]) and *07:01 (P for RPE = 1.14 × 10(-6) , OR 1.57)]. In addition, protective effects on the development of SLE were observed for 2 novel alleles (HLA-DRB1*12:02 [P for RPE = 6.35 × 10(-4) , OR 0.49]) and *11:01 [P for RPE = 1.24 × 10(-3) , OR 0.59]). The SLE risk alleles had an additive genetic effect, as demonstrated by the finding that double copies of these alleles (OR 3.38) had larger risk effects size compared with single copies (OR 1.95) and no copy (OR 1 [reference]). In a subphenotype analysis, various HLA-DRB1 alleles (including SLE risk alleles) were observed to have significant predispositional effects on diverse clinical manifestations. In particular, HLA-DRB1*15:01 (OR 2.30), *09:01 (OR 2.46), *07:01 (OR 2.61), and *08:03 (OR 2.97) were strongly associated with the risk of anti-Sm antibody production. CONCLUSION: We detected 6 HLA-DRB1 alleles that were associated with SLE in Koreans. The SLE risk alleles promoted the production of autoantibodies, including anti-Sm, and diverse clinical manifestations.

Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans.

OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population. METHODS: A total of 1,174 SLE cases and 4,246 population controls from Korea were genotyped and analyzed with a GWA scan to identify single-nucleotide polymorphisms (SNPs) significantly associated with SLE, after strict quality control measures were applied. For select variants, replication of SLE risk loci was tested in an independent data set of 1,416 SLE cases and 1,145 population controls from Korea and China. RESULTS: Eleven regions outside the HLA exceeded the genome-wide significance level (P = 5 × 10(-8) ). A novel SNP-SLE association was identified between FCHSD2 and P2RY2, peaking at rs11235667 (P = 1.03 × 10(-8) , odds ratio [OR] 0.59) on a 33-kb haplotype upstream of ATG16L2. In the independent replication data set, the SNP rs11235667 continued to show a significant association with SLE (replication meta-analysis P = 0.001, overall meta-analysis P = 6.67 × 10(-11) ; OR 0.63). Within the HLA region, the SNP-SLE association peaked in the class II region at rs116727542, with multiple independent effects observed in this region. Classic HLA allele imputation analysis identified HLA-DRB1*1501 and HLA-DQB1*0602, each highly correlated with one another, as most strongly associated with SLE. Ten previously established SLE risk loci were replicated: STAT1-STAT4, TNFSF4, TNFAIP3, IKZF1, HIP1, IRF5, BLK, WDFY4, ETS1, and IRAK1-MECP2. Of these loci, previously unreported, independent second risk effects of SNPs in TNFAIP3 and TNFSF4, as well as differences in the association with a putative causal variant in the WDFY4 region, were identified. CONCLUSION: Further studies are needed to identify true SLE risk effects in other loci suggestive of a significant association, and to identify the causal variants in the regions of ATG16L2, FCHSD2, and P2RY2.

Lupus risk variants in the PXK locus alter B-cell receptor internalization.

Genome wide association studies have identified variants in PXK that confer risk for humoral autoimmune diseases, including systemic lupus erythematosus (SLE or lupus), rheumatoid arthritis and more recently systemic sclerosis. While PXK is involved in trafficking of epidermal growth factor Receptor (EGFR) in COS-7 cells, mechanisms linking PXK to lupus pathophysiology have remained undefined. In an effort to uncover the mechanism at this locus that increases lupus-risk, we undertook a fine-mapping analysis in a large multi-ancestral study of lupus patients and controls. We define a large (257kb) common haplotype marking a single causal variant that confers lupus risk detected only in European ancestral populations and spans the promoter through the 3' UTR of PXK. The strongest association was found at rs6445972 with P < 4.62 × 10(-10), OR 0.81 (0.75-0.86). Using stepwise logistic regression analysis, we demonstrate that one signal drives the genetic association in the region. Bayesian analysis confirms our results, identifying a 95% credible set consisting of 172 variants spanning 202 kb. Functionally, we found that PXK operates on the B-cell antigen receptor (BCR); we confirmed that PXK influenced the rate of BCR internalization. Furthermore, we demonstrate that individuals carrying the risk haplotype exhibited a decreased rate of BCR internalization, a process known to impact B cell survival and cell fate. Taken together, these data define a new candidate mechanism for the genetic association of variants around PXK with lupus risk and highlight the regulation of intracellular trafficking as a genetically regulated pathway mediating human autoimmunity.

Heart rate variability and metabolic syndrome in hospitalized patients with schizophrenia.

PURPOSE: Reduced heart rate variability significantly increases cardiovascular mortality. Metabolic syndrome increases the cardiac autonomic dysfunction. Recently, increasing cardiovascular mortality has been reported in patients with schizophrenia. This study was done to compare heart rate variability between adults with and without schizophrenia and to compare the relationship of heart rate variability to metabolic syndrome in hospitalized patients with schizophrenia. METHODS: This was a descriptive and correlational study in which 719 adults without schizophrenia and 308 adults with schizophrenia took part between May and June 2008. We measured the following: five-minute heart rate variability; high-frequency, low-frequency, the ratio of low-frequency to high-frequency, and the Standard Deviation of all the normal RR intervals. Data was also collected on metabolic syndrome, abdominal obesity, triglycerides, HDL cholesterol, blood pressure and fasting glucose. RESULTS: The Standard Deviation of all the normal RR intervals values of heart rate variability indices were 1.53±0.18. The low-frequency and high-frequency values of heart rate variability indices were significantly higher in hospitalized patients with schizophrenia (3.89±1.36; 3.80±1.20) than those in the healthy participants (2.20±0.46; 2.10±0.46). There were no significant differences between the schizophrenic patients with and without metabolic syndrome. CONCLUSION: The results of this study indicate that schizophrenia patients have significantly lower cardiac autonomic control, but they have significantly higher low-frequency and high-frequency values than those of healthy adults. Use of antipsychotic drug may affect the autonomic nervous system in schizophrenic patients. Metabolic syndrome was not associated with cardiac autonomic control in schizophrenia patients.

Local steroid injection via the cricothyroid membrane in patients with a vocal nodule.

OBJECTIVE: To analyze the usefulness and safety of a steroid injection into vocal nodules via the cricothyroid membrane. Local administration of steroid directly into the larynx has been reported in many laryngeal diseases with different methods. DESIGN: Prospective case series at an academic tertiary care hospital. PATIENTS: Eighty patients with vocal nodules were enrolled between December 2008 and May 2010. INTERVENTIONS: Triamcinolone acetonide was injected through the cricothyroid membrane with a transnasal flexible laryngoscope to patients in a sitting position. MAIN OUTCOME MEASURES: Vocal nodules were evaluated before and 2 and 4 weeks after the injection; improvement was assessed both objectively and subjectively. RESULTS: The nodules disappeared in 35 patients by the fourth week after the injection (44%), and 39 patients showed improvement (49%). Jitter, shimmer, maximum phonation time, and mean voice handicap index also improved significantly after the steroid injection (P < .05 for all). Six patients with voice-related occupations showed improvement at the second week (8%), but the nodules had recurred after 4 weeks. Four patients experienced mild vocal fold atrophy, and 2 patients showed a white plaque formation on the vocal fold that resolved spontaneously 1 to 2 months after the injection. CONCLUSIONS: A local steroid injection via the cricothyroid membrane is a useful and safe treatment option for vocal nodules. However, vocal nodules are caused mainly by excessive voice use; therefore, nodules can recur unless the voice use pattern changes. Further study of this treatment technique, including long-term follow-up, is needed.