Validation and incorporation of digital entheses into a preliminary GLobal OMERACT Ultrasound DActylitis Score (GLOUDAS) in psoriatic arthritis.

OBJECTIVES: The main objective was to generate a GLobal OMERACT Ultrasound DActylitis Score (GLOUDAS) in psoriatic arthritis and to test its reliability. To this end, we assessed the validity, feasibility and applicability of ultrasound assessment of finger entheses to incorporate them into the scoring system. METHODS: The study consisted of a stepwise process. First, in cadaveric specimens, we identified enthesis sites of the fingers by ultrasound and gross anatomy, and then verified presence of entheseal tissue in histological samples. We then selected the entheses to be incorporated into a dactylitis scoring system through a Delphi consensus process among international experts. Next, we established and defined the ultrasound components of dactylitis and their scoring systems using Delphi methodology. Finally, we tested the interobserver and intraobserver reliability of the consensus- based scoring systemin patients with psoriatic dactylitis. RESULTS: 32 entheses were identified in cadaveric fingers. The presence of entheseal tissues was confirmed in all cadaveric samples. Of these, following the consensus process, 12 entheses were selected for inclusion in GLOUDAS. Ultrasound components of GLOUDAS agreed on through the Delphi process were synovitis, tenosynovitis, enthesitis, subcutaneous tissue inflammation and periextensor tendon inflammation. The scoring system for each component was also agreed on. Interobserver reliability was fair to good (κ 0.39-0.71) and intraobserver reliability good to excellent (κ 0.80-0.88) for dactylitis components. Interobserver and intraobserver agreement for the total B-mode and Doppler mode scores (sum of the scores of the individual abnormalities) were excellent (interobserver intraclass correlation coefficient (ICC) 0.98 for B-mode and 0.99 for Doppler mode; intraobserver ICC 0.98 for both modes). CONCLUSIONS: We have produced a consensus-driven ultrasound dactylitis scoring system that has shown acceptable interobserver reliability and excellent intraobserver reliability. Through anatomical knowledge, small entheses of the fingers were identified and histologically validated.

ChatGPT4's Proficiency in Addressing Patients' Questions on Systemic Lupus Erythematosus: A Blinded Comparative Study with Specialists.

OBJECTIVES: The efficacy of artificial intelligence (AI)-driven chatbots like ChatGPT4 in specialized medical consultations, particularly in rheumatology, remains underexplored. This study compares the proficiency of ChatGPT4' responses with practicing rheumatologists to inquiries from patients with systemic lupus erythematosus (SLE). METHODS: In this cross-sectional study, we curated 95 frequently asked questions (FAQs), including 55 in Chinese and 40 in English. Responses for FAQs from ChatGPT4 and 5 rheumatologists were scored separately by a panel of rheumatologists and a group of patients with SLE across 6 domains (scientific validity, logical consistency, comprehensibility, completeness, satisfaction level, and empathy) on a 0-10 scale (a score of 0 indicates entirely incorrect responses, while 10 indicates accurate and comprehensive answers). RESULTS: Rheumatologists' scoring revealed that ChatGPT4-generated responses outperformed those from rheumatologists in satisfaction level and empathy, with mean differences of 0.537 (95% CI, 0.252-0.823; p < 0.01) and 0.460 (95% CI, 0.227-0.693 p < 0.01), respectively. From the SLE patients' perspective, ChatGPT4-generated responses were comparable to the rheumatologist-provided answers in all 6 domains. Subgroup analysis revealed ChatGPT4 responses were more logically consistent and complete regardless of language, and exhibited greater comprehensibility, satisfaction, and empathy in Chinese. However, ChatGPT4 responses were inferior in comprehensibility for English FAQs. CONCLUSION: ChatGPT4 demonstrated comparable, possibly better in certain domains, to address FAQs from patients with SLE, when compared with the answers provided by specialists. This study showed the potential of applying ChatGPT4 to improve consultation in SLE patients.

Plasma DNA Profile Associated with DNASE1L3 Gene Mutations: Clinical Observations, Relationships to Nuclease Substrate Preference, and In Vivo Correction.

Plasma DNA fragmentomics is an emerging area in cell-free DNA diagnostics and research. In murine models, it has been shown that the extracellular DNase, DNASE1L3, plays a role in the fragmentation of plasma DNA. In humans, DNASE1L3 deficiency causes familial monogenic systemic lupus erythematosus with childhood onset and anti-dsDNA reactivity. In this study, we found that human patients with DNASE1L3 disease-associated gene variations showed aberrations in size and a reduction of a "CC" end motif of plasma DNA. Furthermore, we demonstrated that DNA from DNASE1L3-digested cell nuclei showed a median length of 153 bp with CC motif frequencies resembling plasma DNA from healthy individuals. Adeno-associated virus-based transduction of Dnase1l3 into Dnase1l3-deficient mice restored the end motif profiles to those seen in the plasma DNA of wild-type mice. Our findings demonstrate that DNASE1L3 is an important player in the fragmentation of plasma DNA, which appears to act in a cell-extrinsic manner to regulate plasma DNA size and motif frequency.

Management of chronic rheumatic diseases in women 18-45 years of age in Asia Pacific: insights from patient and clinician surveys.

OBJECTIVE: Perspectives of women aged 18-45 years with chronic rheumatic diseases (CRD), and clinicians, in the Asia-Pacific (APAC) region are reported. METHODS: Online surveys were completed by women, pregnant in the past 2-5 years, with moderate to severe rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), and rheumatologists, obstetricians, orthopaedic surgeons who medically manage CRDs. RESULTS: Among 210 (RA 122, PsA 48, axSpA 40) patients, 52% (n = 109/210) delayed their decision to have children, most commonly due to concerns of passing on disease to offspring. 33% (n = 70/210) discussed family planning with a healthcare professional at diagnosis. Patients most often initiated discussions. 94% (n = 193/205) stopped treatment around pregnancy due to fear of fetal harm. 66% (n = 139/210) of patients felt they did not receive all relevant information on the impact of CRDs and treatment on pregnancy. Among 335 clinicians who participated, 82% (n = 143/174) of rheumatologists, 86% (n = 72/84) of obstetricians and 43% (n = 33/77) of orthopaedic surgeons agreed good disease control during pregnancy was their primary goal. 69% (n = 120/174) of rheumatologists were 'very comfortable' with prescribing tumour necrosis factor inhibitors (TNFi) for women aged 18-45 years. Comfort levels generally decreased with the onset of family planning. More obstetricians and orthopaedic surgeons supported avoiding TNFi during pregnancy than rheumatologists (40% [n = 34/84]/38% [n = 29/77] versus 16% [n = 28/174]). Access to more TNFi safety data during pregnancy was considered paramount for increasing clinician comfort. CONCLUSIONS: Patients and physicians need current information and multidisciplinary discussions for improved management of CRD in women in APAC.

Jagged Ends on Multinucleosomal Cell-Free DNA Serve as a Biomarker for Nuclease Activity and Systemic Lupus Erythematosus.

BACKGROUND: Jagged ends of plasma DNA are a recently recognized class of fragmentomic markers for cell-free DNA, reflecting the activity of nucleases. A number of recent studies have also highlighted the importance of jagged ends in the context of pregnancy and oncology. However, knowledge regarding the generation of jagged ends is incomplete. METHODS: Jaggedness of plasma DNA was analyzed based on Jag-seq, which utilized the differential methylation signals introduced by the DNA end-repair process. We investigated the jagged ends in plasma DNA using mouse models by deleting the deoxyribonuclease 1 (Dnase1), DNA fragmentation factor subunit beta (Dffb), or deoxyribonuclease 1 like 3 (Dnase1l3) gene. RESULTS: Aberrations in the profile of plasma DNA jagged ends correlated with the type of nuclease that had been genetically deleted, depending on nucleosomal structures. The deletion of Dnase1l3 led to a significant reduction of jaggedness for those plasma DNA molecules involving more than 1 nucleosome (e.g., size ranges 240-290 bp, 330-380 bp, and 420-470 bp). However, less significant effects of Dnase1 and Dffb deletions were observed regarding different sizes of DNA fragments. Interestingly, the aberration in plasma DNA jagged ends related to multinucleosomes was observed in human subjects with familial systemic lupus erythematosus with Dnase1l3 deficiency and human subjects with sporadic systemic lupus erythematosus. CONCLUSIONS: Detailed understanding of the relationship between nuclease and plasma DNA jaggedness has opened up avenues for biomarker development.

Predictors of rapidly progressive interstitial lung disease and mortality in patients with autoantibodies against melanoma differentiation-associated protein 5 dermatomyositis.

OBJECTIVE: Anti-melanoma differentiation-associated protein 5 (MDA5)-positive DM is associated with rapidly progressive interstitial lung disease (RP-ILD) and high mortality. This multicentre retrospective study aimed to identify predictors of mortality and RP-ILD. METHODS: Anti-MDA5-positive DM patients were identified from the Hong Kong Myositis Registry and the Clinical Data Analysis and Reporting System. Clinical characteristics were reviewed. Risk factors for mortality and RP-ILD were identified. RESULTS: Among the 116 recruited patients, 100 (86.2%) had ILD, 47 (40.5%) had RP-ILD and 44 (37.9%) patients died. Cox regression analysis revealed RP-ILD [hazard ratio (HR) 9.735 (95% CI 3.905, 24.272)], age >52 years [HR 4.750 (95% CI 1.692, 13.333)], ferritin level >2800 pmol/l [HR 3.042 (95% CI 1.323, 6.997)] and lactate dehydrogenase (LDH) >400 IU/l [HR 2.290 (95% CI 1.009, 5.198)] were independent predictors of mortality. With regard to RP-ILD, analyses showed that potential predictors at baseline included age >50 years [HR 2.640 (95% CI 1.277, 5.455)], LDH >300 IU/l [HR 3.189 (95% CI 1.469, 6.918)], fever [HR 1.903 (95% CI 0.956, 3.790)] and neutrophil:lymphocyte ratio >7.0 [HR 1.967 (95% CI 0.942, 4.107)]. We proposed a prediction model based on fever, LDH, age and white cell count (FLAW) to stratify the risk of development of RP-ILD. The probability of RP-ILD in a patient with a score of 4 was 100%. A small internal validation cohort showed the odds of RP-ILD with FLAW scores of 0, 1, 2 and 3 were 0%, 0%, 42.9% and 75%, respectively. CONCLUSIONS: Anti-MDA5-associated RP-ILD is significantly associated with poor survival rates. The FLAW model maybe useful to predict the development of RP-ILD.

The Genesis of Sjögren.

Henrik Sjögren was a Swedish ophthalmologist who wrote a dissertation (in German) consisting of a 131-page long monograph on patients who exhibited a constellation of keratitis sicca, xerostomia and arthritis. This article highlights several key moments of his life and work leading to the delineation of a new syndrome.

Pattern and trend of five major musculoskeletal disorders in China from 1990 to 2017: findings from the Global Burden of Disease Study 2017.

BACKGROUND: With increasing life expectancy in China, no large population-based studies have been done on the trend for musculoskeletal disorders in China. We have investigated the pattern and trend of five major musculoskeletal disorders in China from the Global Burden of Disease Study 2017 and its association with sociodemographic index (SDI). METHODS: The main outcome measures were incidence, prevalence, and disability-adjusted life years (DALYs) for rheumatoid arthritis, osteoarthritis, low back pain, neck pain, and gout. Average annual percent change (AAPC) and annual percent change (APC) between 1990 and 2017 were analyzed with Joinpoint regression. RESULTS: The age-standardized rate of incidence, prevalence, and DALYs for the five major musculoskeletal disorders increased with age. For SDI, the age-standardized rate of DALYs was zigzagged increasing for rheumatoid arthritis and curvilinear increasing for gout, curvilinear decreasing for low back pain, and reaching to the highest point for osteoarthritis and neck pain with an SDI value of 0.61. The AAPC in age-standardized rate of DALYs indicated an increasing trend for rheumatoid arthritis (0.20, 95% CI 0.07, 0.34), osteoarthritis (0.26, 95% CI 0.20, 0.31), neck pain (0.09, 95% CI 0.07, 0.12), and gout (0.25, 95% CI 0.23, 0.27), but a decreasing trend for low back pain (- 0.96, 95% CI - 0.98, - 0.93). The AAPC of risk factors indicated a decreasing trend in smoking (- 0.14, 95% CI - 0.24, - 0.04) for rheumatoid arthritis, smoking (- 0.22, 95% CI - 0.24, - 0.19) and occupational ergonomic factors (- 1.25, 95% CI - 1.29, - 1.21) for low back pain, and impaired kidney function (- 0.95, 95% CI - 1.00, - 0.90) for gout, but an increasing trend in high body-mass index for osteoarthritis (3.10, 95% CI 3.03, 3.17), low back pain (3.07, 95% CI 2.99, 3.14), and gout (3.12, 95% CI 3.04, 3.20). Comparing the burden of five musculoskeletal diseases in China with the 19 countries of G20, China ranked first to second in the number of DALYs, and 12th to 16th in age-standardized rate of DALYs. CONCLUSION: There are remarkably complex temporal patterns in disease burden and risk factors for five major musculoskeletal disorders across past three decades. Population-wide initiatives targeting high body-mass index may mitigate the burden of musculoskeletal disorders.

The causal effect of interleukin-17 on the risk of psoriatic arthritis: a Mendelian randomization study.

OBJECTIVE: To determine causal associations between genetically predicted TNF-α, IL-12p70 and IL-17 levels and risk of PsA. METHODS: The publicly available summary-level findings from genome-wide association studies (GWAS) was used to identify loci influencing normal physiological concentrations of TNF-α, IL-12p70 and IL-17 (n = 8293) among healthy individuals as exposure and a GWAS for PsA from the UK Biobank (PsA = 900, control = 462 033) as the outcome. A two-sample Mendelian randomization (MR) analysis was performed using the inverse-variance weighted (IVW), weighted median and MR-Egger regression methods. Sensitivity analysis and MR-Egger regression analysis were performed to evaluate the heterogeneity and pleiotropic effects of each variant. RESULTS: Single-nucleotide polymorphisms (SNPs) at genome-wide significance from GWASs on TNF-α, IL-12p70 and IL-17 were identified as the instrumental variables. The IVW method indicated a causal association between increased IL-17 level and risk of PsA (ß = -0.00186 per allele, s.e. = 0.00043, P = 0.002). Results were consistent in the weighted median method (ß = -0.00145 per allele, s.e. = 0.00059, P = 0.014) although the MR-Egger method suggested a non-significant association (ß = -0.00133 per allele, s.e. = 0.00087; P = 0.087). Single SNP MR results revealed that the C allele of rs117556572 was robustly associated with risk of PsA (ß = 0.00210, s.e. = 0.00069, P = 0.002). However, no evidence for a causal effect was observed between TNF-α, IL-12p70, decreased IL-17 levels and risk of PsA. CONCLUSION: Our findings provide preliminary evidence that genetic variants predisposing to higher physiological IL-17 level are associated with decreased risk of PsA.

Psychiatric disorders and suicidal behavior in patients with acne prescribed oral antibiotics versus isotretinoin: Analysis of a large commercial insurance claims database.

BACKGROUND: The association between isotretinoin and psychiatric disturbance, including depression and suicidal behavior, is controversial. OBJECTIVE: To investigate whether acne patients prescribed isotretinoin or antibiotics were more likely to have psychiatric disorders and/or engage in suicidal behavior. METHODS: Retrospective cohort study using the IBM MarketScan Research Databases, which contain commercial insurance claims in the United States, to identify acne patients who were prescribed isotretinoin or oral antibiotics between 2011 and 2017 and who were diagnosed with psychiatric disorders or suicidal behavior. RESULTS: A total of 72,555 patients were included in the study. Patients in the general population were 1.47 times more likely to be diagnosed with suicidal ideation or attempt compared to acne patients prescribed isotretinoin (adjusted odds ratio [OR] 1.47; confidence interval [95% CI], 1.27, 1.70; P < .0001). The general population (adjusted OR 0.87; 95% CI, 0.84, 0.89; P < .0001) and acne patients prescribed antibiotics (adjusted OR 0.88; 95% CI, 0.85, 0.91; P < .0001) were less likely to have a psychiatric diagnosis compared to acne patients prescribed isotretinoin. The prevalence of suicidal behavior during isotretinoin treatment was lower (0.10%; P = .082) than in the year prior to isotretinoin treatment (0.22%) and in the year following treatment (0.34%; P = .004). LIMITATIONS: The study excluded individuals with public insurance and those who were uninsured, and the data in the study relied on the accuracy of the medical coding. CONCLUSIONS: Compared to the general population, acne patients prescribed isotretinoin were less likely to engage in suicidal behavior. Further exploration into the slight increase in suicidal behavior seen in isotretinoin patients 1 year after therapy is warranted.

DAPSA, carotid plaque and cardiovascular events in psoriatic arthritis: a longitudinal study.

OBJECTIVE: To examine whether Disease Activity in Psoriatic Arthritis (DAPSA) reflecting the inflammatory component of psoriatic arthritis (PsA) can predict cardiovascular (CV) events independent of traditional CV risk factors and subclinical carotid atherosclerosis. METHODS: A cohort analysis was performed in patients with PsA who had been followed since 2006. The outcome of interest was first CV event. Four different CV disease (CVD) risk scores and DAPSA were computed at baseline. The presence of carotid plaque (CP) and carotid intima-media thickness (CIMT) was also determined in a subgroup of patients using high-resolution ultrasound. The association between DAPSA, CVD risk scores, CP, CIMT and the occurrence of CV events was assessed using Cox proportional hazard models. RESULTS: 189 patients with PsA (mean age: 48.9 years; male: 104 (55.0%)) were recruited. After a median follow-up of 9.9 years, 27 (14.3%) patients developed a CV event. Higher DAPSA was significantly associated with an increased risk of developing CV events (HR: 1.04, 95% CI (1.01 to 1.08), p=0.009). The association remained significant after adjusting for all CV risk scores in the multivariable models. In the subgroup analysis, 154 patients underwent carotid ultrasound assessment and 23 (14.9%) of them experienced a CV event. CP was associated with increased risk of developing CV events after adjusting for three CV risk scores and DAPSA, with HR ranging from 2.35 to 3.42. CONCLUSION: Higher DAPSA and the presence of CP could independently predict CVD events in addition to traditional CV risk scores in patients with PsA.

Effect of biologics on radiographic progression of peripheral joint in patients with psoriatic arthritis: meta-analysis.

OBJECTIVES: To determine the efficacy of biologics in preventing radiographic progression in peripheral joints of PsA patients. METHODS: Studies were searched in MEDLINE, Web of Science, and abstracts from the last three EULAR and ACR meetings up to 31 December 2019. Primary and secondary endpoints were the proportion of patients without radiographic progression and the mean change in total radiographic score at week 24. RESULTS: Eleven studies, involving 5382 patients, 9 drugs and 18 treatments, were included. Patients receiving biologics were more likely to achieve radiographic non-progression compared with placebo [odds ratio: pooled: 2.40, 95% CI: 2.00, 2.87; TNF inhibitors (TNFi): 2.94, 95% CI: 2.38, 3.63; IL inhibitors (ILi): 2.15, 95% CI: 1.69, 2.74; abatacept: 1.54, 95% CI: 1.03, 2.28] and have significantly lower radiographic progression [standardized mean difference (SMD): pooled: -2.16, 95% CI: -2.91, -1.41; TNFi: -2.82, 95% CI: -4.31, -1.33; ILi: -1.60, 95% CI: -2.49, -0.72; abatacept: -0.40, 95% CI: -0.59, -0.21]. Concomitant MTX therapy was not superior to monotherapy (SMD: pooled: 0.01, 95% CI: -0.07, 0.08; biologics: 0.01, 95% CI: -0.09, 0.11; placebo: -0.01, 95% CI: -0.13, 0.12). The effect of ustekinumab and secukinumab on radiographic progression was not influenced by prior anti-TNF therapy (SMD: -0.08, 95% CI: -0.25, 0.10). CONCLUSION: Biologic agents may retard radiographic progression in PsA patients in terms of bone erosion and joint space narrowing compared with placebo. MTX seems to have no added effect. Prior anti-TNF therapy seems to not influence the radiographic efficacy of IL blockers.

Treat to target and prevention of subclinical atherosclerosis in psoriatic arthritis-which target should we choose?

OBJECTIVE: PsA patients who achieved sustained minimal disease activity (sMDA) had less subclinical atherosclerosis progression. The vascular effects of achieving other potential treatment targets, including the PsA Disease Activity Score (PASDAS) and the Disease Activity in PsA (DAPSA) score, remained uncertain. This study aimed to compare the vascular effects of achieving different treatment targets in PsA patients. METHOD: This is a post hoc analysis of a 2 year treat-to-target study aimed at MDA. A total of 101 consecutive PsA patients without overt cardiovascular disease were recruited. High-resolution carotid ultrasound and arterial stiffness markers were assessed annually. Low disease activity (LDA) was defined as MDA, DAPSA ≤14 or PASDAS ≤3.2. Sustained disease control was defined as achieving these targets at each visit from month 12 until month 24. RESULTS: Ninety patients [52 male (57.8%), age 50 years (s.d. 11)] who completed 24 months of follow-up were included in this analysis. A total of 44%, 48% and 45% of patients achieved sustained DAPSA LDA (sDAPDA-LDA), sustained PASDAS LDA (sPASDAS-LDA) and sMDA, respectively. Patients who achieved sMDA had significantly less progression of carotid intima-media thickness than those who did not (P = 0.031). Using multivariate analysis, achieving sMDA and sPASDAS-LDA had a protective effect on plaque progression, less increase in total plaque area, reduced mean intima-media thickness and reduced augmentation index after adjusting for covariates. In contrast, no significant differences in the progression of vascular parameters were demonstrated between patients who did or did not achieve sDAPSA-LDA. CONCLUSION: Achieving sMDA/sDASPAS-LDA, but not sDAPSA-LDA, was associated with a protective effect in subclinical atherosclerosis and arterial stiffness progression. A multidimensional domain of disease control might be better in minimizing cardiovascular risk in PsA.

Race and socioeconomic status in pediatric allogeneic hematopoietic cell transplantation for nonmalignant conditions.

BACKGROUND: Survival disparities by race/ethnicity and socioeconomic status (SES) are observed in a wide range of pediatric treatment settings including oncology and solid organ transplantation. To date, few studies have examined the effects of race and SES on outcomes in pediatric allogeneic hematopoietic cell transplantation (HCT). We explored whether survival differed by race/ethnicity or SES in children receiving HCT for nonmalignant conditions at a single institution serving a diverse patient population. PROCEDURES: The Kaplan-Meier method was used to estimate overall survival (OS) with the log-rank test for between-group comparisons. Cox proportional hazards models were used to identify risk factors for OS, adjusting for treatment- and disease-related factors. RESULTS: Of 133 subjects, 0 to 21 years, 19% were non-Hispanic (NH) white, 34% were NH black, 40% were Hispanic, and 7% were Asian. Sixty-seven percent of the subjects had public insurance; 49% lived in neighborhoods with poverty rate ≥20%. Primary diagnoses included hemoglobinopathies (56%), bone marrow failure (22%), and other conditions (22%). Median follow-up was 5.8 years (range 0.1-14.5). Analysis revealed no difference in OS by race, insurance type, or neighborhood SES. CONCLUSIONS: Findings from this single-institution study suggest that in pediatric patients undergoing HCT for nonmalignant conditions, treatment at a tertiary care center with a multidisciplinary approach may mitigate drivers of disparities observed in other settings. Additional studies are now needed to further elucidate the complex interrelationships among race, SES, and clinical outcomes for children undergoing HCT.

Chd1 is essential for the high transcriptional output and rapid growth of the mouse epiblast.

The pluripotent mammalian epiblast undergoes unusually fast cell proliferation. This rapid growth is expected to generate a high transcriptional demand, but the underlying mechanisms remain unknown. We show here that the chromatin remodeler Chd1 is required for transcriptional output and development of the mouse epiblast. Chd1(-/-) embryos exhibit proliferation defects and increased apoptosis, are smaller than controls by E5.5 and fail to grow, to become patterned or to gastrulate. Removal of p53 allows progression of Chd1(-/-) mutants only to E7.0-8.0, highlighting the crucial requirement for Chd1 during early post-implantation development. Chd1(-/-) embryonic stem cells (ESCs) have a self-renewal defect and a genome-wide reduction in transcriptional output at both known mRNAs and intergenic transcripts. These transcriptional defects were only uncovered when cell number-normalized approaches were used, and correlate with a lower engagement of RNAP II with transcribed genes in Chd1(-/-) ESCs. We further show that Chd1 directly binds to ribosomal DNA, and that both Chd1(-/-) epiblast cells in vivo and ESCs in vitro express significantly lower levels of ribosomal RNA. In agreement with these findings, mutant cells in vivo and in vitro exhibit smaller and more elongated nucleoli. Thus, the RNA output by both Pol I and II is reduced in Chd1(-/-) cells. Our data indicate that Chd1 promotes a globally elevated transcriptional output required to sustain the distinctly rapid growth of the mouse epiblast.

Clinical presentation, treatment and outcome of Takayasu's arteritis in southern Chinese: a multicenter retrospective study.

To study the clinical presentation, treatment and outcome of southern Chinese patients with Takayasu's arteritis (TA). This is a retrospective chart review study of 78 patients managed in 14 public hospitals in Hong Kong between the years 2000 and 2010. Patients were identified from the hospital registry using the ICD-10 diagnostic code of the disease. The classification of TA was based on the American College of Rheumatology (ACR) or modified Ichikawa's criteria. Demographic data, clinical presentation, angiographic findings, pattern of vascular involvement (Numano's classification), treatment and outcome of these patients were presented. 78 patients were studied (82% women, age at presentation 34.2 ± 14 years). The estimated point prevalence of TA was 11/million population. The commonest initial manifestations were hypertension (62%) and vascular ischemic symptoms (38%). Systemic symptoms occurred in nine (12%) patients only. The proportion of patients fulfilling the angiographic subtypes of the Numano's classification was: types I (13%), IIa (4%), IIb (12%), III (12%), IV (20%) and V (39%), respectively. Thirty-two patients (41%) were treated with high-dose glucocorticoids (GCs) and 22 patients (28%) received additional non-GC immunosuppressive drugs. Vascular complications occurred in 26 (33%) patients and revascularization surgery was performed in 23(29%) patients. Three (4%) patients died of vascular complication at a median of 8 years after disease onset. TA is rare in southern Chinese patients of Hong Kong. Most patients present with ischemic symptoms during the stenotic phase of the disease. Although mortality is low, a significant proportion of patients developed vascular stenosis that required surgical interventions. More awareness of TA as a differential diagnosis of non-specific systemic symptoms with elevated inflammatory markers in younger patients is needed for earlier diagnosis.

Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription.

Lineage specification during development involves reprogramming of transcriptional states, but little is known about how this is regulated in vivo. The chromatin remodeler chomodomain helicase DNA-binding protein 1 (Chd1) promotes an elevated transcriptional output in mouse embryonic stem cells. Here we report that endothelial-specific deletion of Chd1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E)15.5. Mutant embryos contain normal numbers of E10.5 intraaortic hematopoietic clusters that express Runx1 and Kit, but these clusters undergo apoptosis and fail to mature into blood lineages in vivo and in vitro. Hematopoietic progenitors emerging from the aorta have an elevated transcriptional output relative to structural endothelium, and this elevation is Chd1-dependent. In contrast, hematopoietic-specific deletion of Chd1 using Vav-Cre has no apparent phenotype. Our results reveal a new paradigm of regulation of a developmental transition by elevation of global transcriptional output that is critical for hemogenesis and may play roles in other contexts.

Increased prevalence of coronary plaque in patients with psoriatic arthritis without prior diagnosis of coronary artery disease.

OBJECTIVES: To evaluate coronary atherosclerosis in patients with psoriatic arthritis (PsA) and control subjects using coronary CT angiography (CCTA). METHODS: Ninety consecutive patients with PsA (male: 56(62.2%); 50.3±11.1 years) were recruited. 240 controls (male: 137(57.1%); 49.6±10.7 years) without known cardiovascular (CV) diseases who underwent CCTA due to chest pain and/or multiple CV risk factors were recruited for comparison. RESULTS: Patients with PsA and controls were matched in age, gender and traditional CV risk factors (all p>0.2). The prevalence of overall plaque (54(60%)/84(35%), p<0.001), calcified plaque (CP) (29(32%)/40(17%), p=0.002), mixed plaque (MP) (20(22%)/18(8%), p<0.001), non-calcified plaque (NCP) (39(43%)/53(22%), p<0.001) and combined MP/NCP (46(51%)/62(26%), p<0.001) were all significantly higher in patients with PsA. Three-vessel disease was diagnosed in 12(13%) patients with PsA and 7(3%) controls (p<0.001), while obstructive plaques (>50% stenosis) were observed in 8(9%) patients with PsA and 7(3%) controls (p=0.033). After adjusting for traditional CV risk factors, PsA remained an independent explanatory variable for all types of coronary plaques (OR: 2.730 to 4.064, all p<0.001). PsA was also an independent explanatory variable for three-vessel disease (OR: 10.798, p<0.001) and obstructive plaque (3.939, p=0.024). In patients with PsA, disease duration was the only disease-specific characteristic associated with more vulnerable plaques (MP/NCP) in multivariate analysis (1.063, p=0.031). The other independent explanatory variables were age ≥55 years (5.636, p=0.005) and male gender (8.197, p=0.001). CONCLUSIONS: Patients with PsA have increased prevalence, burden and severity of coronary atherosclerosis as documented by CCTA. Longer disease duration was independently associated with the presence of vulnerable MP/NCP plaques in patients with PsA. TRIAL REGISTRATION NUMBER: NCT02232321.

Plasma DNA aberrations in systemic lupus erythematosus revealed by genomic and methylomic sequencing.

We performed a high-resolution analysis of the biological characteristics of plasma DNA in systemic lupus erythematosus (SLE) patients using massively parallel genomic and methylomic sequencing. A number of plasma DNA abnormalities were found. First, aberrations in measured genomic representations (MGRs) were identified in the plasma DNA of SLE patients. The extent of the aberrations in MGRs correlated with anti-double-stranded DNA (anti-dsDNA) antibody level. Second, the plasma DNA of active SLE patients exhibited skewed molecular size-distribution profiles with a significantly increased proportion of short DNA fragments. The extent of plasma DNA shortening in SLE patients correlated with the SLE disease activity index (SLEDAI) and anti-dsDNA antibody level. Third, the plasma DNA of active SLE patients showed decreased methylation densities. The extent of hypomethylation correlated with SLEDAI and anti-dsDNA antibody level. To explore the impact of anti-dsDNA antibody on plasma DNA in SLE, a column-based protein G capture approach was used to fractionate the IgG-bound and non-IgG-bound DNA in plasma. Compared with healthy individuals, SLE patients had higher concentrations of IgG-bound DNA in plasma. More IgG binding occurs at genomic locations showing increased MGRs. Furthermore, the IgG-bound plasma DNA was shorter in size and more hypomethylated than the non-IgG-bound plasma DNA. These observations have enhanced our understanding of the spectrum of plasma DNA aberrations in SLE and may provide new molecular markers for SLE. Our results also suggest that caution should be exercised when interpreting plasma DNA-based noninvasive prenatal testing and cancer testing conducted for SLE patients.