Polygenic risk score-based phenome-wide association for glaucoma and its impact on disease susceptibility in two large biobanks.

BACKGROUND: Glaucoma is a leading cause of worldwide irreversible blindness. Considerable uncertainty remains regarding the association between a variety of phenotypes and the genetic risk of glaucoma, as well as the impact they exert on the glaucoma development. METHODS: We investigated the associations of genetic liability for primary open angle glaucoma (POAG) with a wide range of potential risk factors and to assess its impact on the risk of incident glaucoma. The phenome-wide association study (PheWAS) approach was applied to determine the association of POAG polygenic risk score (PRS) with a wide range of phenotypes in 377, 852 participants from the UK Biobank study and 43,623 participants from the Penn Medicine Biobank study, all of European ancestry. Participants were stratified into four risk tiers: low, intermediate, high, and very high-risk. Cox proportional hazard models assessed the relationship of POAG PRS and ocular factors with new glaucoma events. RESULTS: In both discovery and replication set in the PheWAS, a higher genetic predisposition to POAG was specifically correlated with ocular disease phenotypes. The POAG PRS exhibited correlations with low corneal hysteresis, refractive error, and ocular hypertension, demonstrating a strong association with the onset of glaucoma. Individuals carrying a high genetic burden exhibited a 9.20-fold, 11.88-fold, and 28.85-fold increase in glaucoma incidence when associated with low corneal hysteresis, high myopia, and elevated intraocular pressure, respectively. CONCLUSION: Genetic susceptibility to POAG primarily influences ocular conditions, with limited systemic associations. Notably, the baseline polygenic risk for POAG robustly associates with new glaucoma events, revealing a large combined effect of genetic and ocular risk factors on glaucoma incidents.

Molecular signature of neutrophil extracellular trap mediating disease module in idiopathic inflammatory myopathy.

The rarity and heterogeneity of idiopathic inflammatory myopathy (IIM) pose challenges for researching IIM in affected individuals. We analyzed integrated transcriptomic datasets obtained using muscle tissues from patients with five distinct IIM subtypes to investigate the shared and distinctive cellular and molecular characteristics. A transcriptomic dataset of muscle tissues from normal controls (n = 105) and patients with dermatomyositis (n = 89), polymyositis (n = 33), inclusion body myositis (n = 121), immune-mediated necrotizing myositis (n = 75), and anti-synthetase syndrome (n = 18) was used for differential gene-expression analysis, functional-enrichment analysis, gene set-enrichment analysis, disease-module identification, and kernel-based diffusion scoring. Damage-associated molecular pattern-associated pathways and neutrophil-mediated immunity were significantly enriched across different IIM subtypes, although their activities varied. Interferons-signaling pathways were differentially activated across all five IIM subtypes. In particular, neutrophil extracellular trap (NET) formation was significantly activated and correlated with Fcγ R-mediated signaling pathways. NET formation-associated genes were key for establishing disease modules, and FCGRs, C1QA, and SERPINE1 markedly perturbed the disease modules. Integrated transcriptomic analysis of muscle tissues identified NETs as key components of neutrophil-mediated immunity involved in the pathogenesis of IIM subtypes and, thus, has therapeutically targetable value.

De novo molecular subtyping of salivary gland tissue in the context of Sjögren's syndrome heterogeneity.

Understanding the mechanistic features and molecular taxonomy of diseases holds promise for the development of more effective treatments, especially for complex heterogeneous diseases. Here, we analyzed transcriptomic datasets of salivary gland tissues from patients with Sjögren's syndrome (SjS) to identify shared and divergent cellular and molecular signatures. Three molecular subtypes of SjS salivary gland tissue were identified: oxidative phosphorylation (OxPhos)-dominant (C1), weak inflammatory with type I interferon signatures (C2), and B cell receptor (BCR) signaling pathway-dominant (C3). C3 had the highest focus score. Type I helper T cells and B cells were the dominant cell types in C1 and C3 tissues, respectively. Metformin and drugs targeting PI3K, BTK, and JAKs were predicted to be effective treatments for C1 and C3 subtypes, respectively. Three subtypes of SjS salivary gland with distinct molecular signatures were identified. The results could contribute to optimal stratification of patients for more effective treatment approaches.

Integrative analysis of lung molecular signatures reveals key drivers of systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: Interstitial lung disease is a significant comorbidity and the leading cause of mortality in patients with systemic sclerosis. Transcriptomic data of systemic sclerosis-associated interstitial lung disease (SSc-ILD) were analysed to evaluate the salient molecular and cellular signatures in comparison with those in related pulmonary diseases and to identify the key driver genes and target molecules in the disease module. METHODS: A transcriptomic dataset of lung tissues from patients with SSc-ILD (n=52), idiopathic pulmonary fibrosis (IPF) (n=549), non-specific interstitial pneumonia (n=49) and pulmonary arterial hypertension (n=81) and from normal healthy controls (n=331) was subjected to filtration of differentially expressed genes, functional enrichment analysis, network-based key driver analysis and kernel-based diffusion scoring. The association of enriched pathways with clinical parameters was evaluated in patients with SSc-ILD. RESULTS: SSc-ILD shared key pathogenic pathways with other fibrosing pulmonary diseases but was distinguishable in some pathological processes. SSc-ILD showed general similarity with IPF in molecular and cellular signatures but stronger signals for myofibroblasts, which in SSc-ILD were in a senescent and apoptosis-resistant state. The p53 signalling pathway was the most enriched signature in lung tissues and lung fibroblasts of SSc-ILD, and was significantly correlated with carbon monoxide diffusing capacity of lung, cellular senescence and apoptosis. EEF2, EFF2K, PHKG2, VCAM1, PRKACB, ITGA4, CDK1, CDK2, FN1 and HDAC1 were key regulators with high diffusion scores in the disease module. CONCLUSIONS: Integrative transcriptomic analysis of lung tissues revealed key signatures of fibrosis in SSc-ILD. A network-based Bayesian approach provides deep insights into key regulatory genes and molecular targets applicable to treating SSc-ILD.

Clinical characteristics and long-term outcomes in patients with mixed Class III/IV + V and pure proliferative lupus nephritis: A single-center experience.

OBJECTIVES: Proliferative lupus nephritis (LN) is a crucial complication in systemic lupus erythematosus (SLE). This study evaluated the clinical implications of coexistence of membranous LN in proliferative LN in terms of clinical characteristics and long-term outcome. METHODS: We retrospectively reviewed the medical records of patients with SLE who underwent renal biopsy between 2005 and 2018. Patients with proliferative LN based on the 2003 International Society of Nephrology/Renal Pathology Society classification were subclassified into pure (Class III or IV only) and mixed (Class III or IV + Class V) proliferative LN. The clinical features at the time of renal biopsy, incidence of end-stage renal disease (ESRD), and all-cause mortality were compared between patients with mixed or pure proliferative LN. RESULTS: Of the 171 patients, 30 and 141 were classified into mixed and pure proliferative LN groups, respectively. Patients with pure proliferative LN showed higher anti-dsDNA antibody and lower hemoglobin, platelet, and complement 3 levels than patients with mixed proliferative LN. The SLE disease activity index was also higher in patients with pure proliferative LN (p = 0.047). The pure proliferative LN group showed a higher proportion of Class IV and higher histologic activity index scores (p < 0.001 and p = 0.004, respectively). During the follow-up period of 58.3 months, 18 patients developed ESRD and 15 patients died. ESRD was exclusively observed in patients with pure proliferative LN, although the incidence of ESRD was not statistically different (p = 0.055). All-cause mortality was comparable between the two groups. CONCLUSION: Pure proliferative LN was associated with higher clinical and histological activities and modestly increased risk of ESRD. Active immunosuppressive treatment would be required to control the renal inflammation in patients with proliferative LN, regardless of the coexistence of membranous LN.

Drug Survival of Biologic Therapy in Elderly Patients With Rheumatoid Arthritis Compared With Nonelderly Patients: Results From the Korean College of Rheumatology Biologics Registry.

OBJECTIVE: Although the proportion of elderly patients with rheumatoid arthritis (RA) is increasing, the persistency of biologic therapy in elderly patients requires additional investigation. This study evaluated the drug survival of biologic therapy and associated factors in elderly compared with nonelderly patients. METHODS: This longitudinal observational study included RA patients who were enrolled in the Korean College of Rheumatology Biologics Registry (NCT01965132, started from January 1, 2013) between 2013 and 2015. We compared the retention rate of biologic therapy between elderly (age ≥70 years) and nonelderly (age <70 years) patients, and investigated the causes and predictors of biologic withdrawal in both groups. RESULTS: Of 682 patients, 122 were aged 70 years or older. The retention rate of biologic therapy at 24 months was 57.8% and 46.5% in nonelderly and elderly patients, respectively (p = 0.027). Biologic withdrawal due to adverse events and inefficacy within 24 months was not significantly different between the 2 groups, although adverse events were more common in elderly patients (20.6% vs 12.8%, p = 0.360). Drug withdrawal due to patient refusal was more common in elderly patients (9.8% vs 1.8%, p < 0.001). In elderly patients, biologic withdrawal was associated with current smoking and older age at disease onset, whereas the use of tumor necrosis factor inhibitors, nonuse of methotrexate, and combination of corticosteroid were important in nonelderly patients. CONCLUSIONS: Elderly RA patients are more likely to discontinue biologic agents within 24 months. To increase the retention rate of biologic therapy, rheumatologists should consider patient characteristics before and during biologic therapy.

Deep phenotyping of synovial molecular signatures by integrative systems analysis in rheumatoid arthritis.

OBJECTIVE: RA encompasses a complex, heterogeneous and dynamic group of diseases arising from molecular and cellular perturbations of synovial tissues. The aim of this study was to decipher this complexity using an integrative systems approach and provide novel insights for designing stratified treatments. METHODS: An RNA sequencing dataset of synovial tissues from 152 RA patients and 28 normal controls was imported and subjected to filtration of differentially expressed genes, functional enrichment and network analysis, non-negative matrix factorization, and key driver analysis. A naïve Bayes classifier was applied to the independent datasets to investigate the factors associated with treatment outcome. RESULTS: A matrix of 1241 upregulated differentially expressed genes from RA samples was classified into three subtypes (C1-C3) with distinct molecular and cellular signatures. C3 with prominent immune cells and proinflammatory signatures had a stronger association with the presence of ACPA and showed a better therapeutic response than C1 and C2, which were enriched with neutrophil and fibroblast signatures, respectively. C2 was more occupied by synovial fibroblasts of destructive phenotype and carried highly expressed key effector molecules of invasion and osteoclastogenesis. CXCR2, JAK3, FYN and LYN were identified as key driver genes in C1 and C3. HDAC, JUN, NFKB1, TNF and TP53 were key regulators modulating fibroblast aggressiveness in C2. CONCLUSIONS: Deep phenotyping of synovial heterogeneity captured comprehensive and discrete pathophysiological attributes of RA regarding clinical features and treatment response. This result could serve as a template for future studies to design stratified approaches for RA patients.

Clinical phenotype with high risk for initiation of biologic therapy in rheumatoid arthritis: a data-driven cluster analysis.

OBJECTIVES: The clinical manifestations and treatment outcome in patients with rheumatoid arthritis (RA) are heterogeneous. We classified RA patients into subgroups with distinct phenotypes through unsupervised clustering and evaluated the utility of this subclassification for evaluation of clinical outcome. METHODS: A total of 1,103 patients with RA were clustered in an unbiased manner using a k-means clustering method, based on their clinical and phenotypic profiles. Initiation of biological disease-modifying anti-rheumatic drugs (bDMARDs) was evaluated in the segregated clusters to investigate the differential clinical course of each cluster. RESULTS: Patients with RA were classified into four clusters, each with distinct phenotypes. The key features for subclassification were sex, smoking, hypertension, and dyslipidaemia. Cluster 1 consisted of male smokers, who were most likely to initiate bDMARDs by 30 months (p=0.04). Multivariate analysis revealed that overweight, smoking, erythrocyte sedimentation rate, autoantibodies of high titre, and disease activity were the independent predictors of bDMARD initiation at 30 months. Cluster 1 was the highest or the second highest for these independent predictors, suggesting that cluster 1 contained a high-risk group for early initiation of bDMARDs. CONCLUSIONS: The unsupervised clustering of RA patients demonstrated the feasibility of the novel subclassification with respect to predicting clinical outcome. Identifying high-risk patients by a combination of clinical parameters may be useful for the management of RA.

Integrative analysis of lung molecular signatures reveals key drivers of idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a high clinical burden. The molecular signatures of IPF were analyzed to distinguish molecular subgroups and identify key driver genes and therapeutic targets. METHODS: Thirteen datasets of lung tissue transcriptomics including 585 IPF patients and 362 normal controls were obtained from the databases and subjected to filtration of differentially expressed genes (DEGs). A functional enrichment analysis, agglomerative hierarchical clustering, network-based key driver analysis, and diffusion scoring were performed, and the association of enriched pathways and clinical parameters was evaluated. RESULTS: A total of 2,967 upregulated DEGs was filtered during the comparison of gene expression profiles of lung tissues between IPF patients and healthy controls. The core molecular network of IPF featured p53 signaling pathway and cellular senescence. IPF patients were classified into two molecular subgroups (C1, C2) via unsupervised clustering. C1 was more enriched in the p53 signaling pathway and ciliated cells and presented a worse prognostic score, while C2 was more enriched for cellular senescence, profibrosing pathways, and alveolar epithelial cells. The p53 signaling pathway was closely correlated with a decline in forced vital capacity and carbon monoxide diffusion capacity and with the activation of cellular senescence. CDK1/2, CKDNA1A, CSNK1A1, HDAC1/2, FN1, VCAM1, and ITGA4 were the key regulators as evidence by high diffusion scores in the disease module. Currently available and investigational drugs showed differential diffusion scores in terms of their target molecules. CONCLUSIONS: An integrative molecular analysis of IPF lungs identified two molecular subgroups with distinct pathobiological characteristics and clinical prognostic scores. Inhibition against CDKs or HDACs showed great promise for controlling lung fibrosis. This approach provided molecular insights to support the prediction of clinical outcomes and the selection of therapeutic targets in IPF patients.

Prevalence of Osteopenia in Drug-Naive Patients With Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Monocentric Study.

OBJECTIVES: To examine the bone mineral density and prevalence of osteoporosis and osteopenia in glucocorticoid- and immunosuppressive drug-naive patients younger than 55 years with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: This was a cross-sectional study. We reviewed the medical records of 35 AAV patients and 35 age-, sex-, and body mass index (BMI)-matched control subjects. We collected clinical data such as AAV-related variables and conventional risk factors for osteoporosis and assessed bone mineral density and the prevalence of osteoporosis and osteopenia in both groups. Categorical and continuous variables were compared between the 2 groups using the χ2 or Fisher exact test and Mann-Whitney U test, respectively. Multivariate logistic regression analysis was used to calculate the odds ratio (OR). RESULTS: There were no statistically significant differences between the demographical data of AAV patients and control subjects. Patients with AAV showed significantly higher frequencies of conventional risk factors for osteoporosis than the control subjects, except for hyperthyroidism. Osteopenia was found more commonly in AAV patients than in control subjects (57.1% vs. 31.4%, p = 0.030). In the univariate logistic regression analysis, BMI (OR, 0.813) and AAV (OR, 2.620) were associated with osteopenia in all participants. In the multivariate analysis, both BMI and AAV were associated with osteopenia, but this was not statistically significant. In contrast, when analyzing AAV patients only, neither conventional risk factors nor AAV-related variables were associated with the prevalence of osteopenia. CONCLUSIONS: Antineutrophil cytoplasmic antibody-associated vasculitis and BMI were both associated with osteopenia.

Spire localization via zinc finger-containing domain is crucial for the asymmetric division of mouse oocyte.

Zinc plays an essential role in mammalian oocyte maturation, fertilization, and early embryogenesis, and depletion of zinc impairs cell cycle control, asymmetric division, and cytokinesis in oocyte. We report that zinc, via the actin nucleator Spire, acts as an essential regulator of the actin cytoskeleton remodeling during mouse oocyte maturation and fertilization. Depletion of zinc in the mouse oocyte impaired cortical and cytoplasmic actin formation. Spire is colocalized with zinc-containing vesicles via its zinc finger-containing Fab1, YOTB, Vac 1, EEA1 (FYVE) domain. Improper localization of Spire by zinc depletion or mutations in the FYVE domain impair cytoplasmic actin mesh formations and asymmetric division and cytokinesis of oocyte. All 3 major domains of the Spire are required for its proper localization and activity. After fertilization or parthenogenetic activation, Spire localization was dramatically altered following zinc release from the oocyte. Collectively, our data reveal novel roles for zinc in the regulation of the actin nucleator Spire by controlling its localization in mammalian oocyte.-Jo, Y.-J., Lee, I.-W., Jung, S.-M., Kwon, J., Kim, N.-H., Namgoong, S. Spire localization via zinc finger-containing domain is crucial for the asymmetric division of mouse oocyte.

Clinical characteristics and long-term outcomes of Libman-Sacks endocarditis in patients with systemic lupus erythematosus.

OBJECTIVE: Treatment of Libman-Sacks (LS) endocarditis in patients with systemic lupus erythematosus (SLE) is challenging due to the lack of data. This study aimed to identify the clinical characteristics of SLE patients and LS endocarditis, and to investigate the treatment and prognosis of LS endocarditis. METHODS: Of all the patients with SLE who underwent echocardiography between 2010 and 2019, 11 and 29 patients with and without LS endocarditis, respectively, were included. We compared the inflammatory and thrombotic profiles between patients with and without LS endocarditis, and investigated the treatment and long-term outcome of LS endocarditis. RESULTS: No significant differences were observed in disease activity, clinical characteristics and inflammatory marker levels between patients with and without LS endocarditis. Patients with LS endocarditis had a significantly higher prevalence of antiphospholipid antibody (aPL) but a lower prevalence of SLE-specific antibody. Triple positivity of aPL was found in 72.7% and 13.8% of patients with and without LS endocarditis, respectively. Of 11 patients with LS endocarditis, six patients received anticoagulation therapy, and five patients received augmented immunosuppressive therapies. One patient who did not receive anticoagulation therapy developed cerebral infarction. Nine (82%) patients with LS endocarditis were classified as having antiphospholipid syndrome (APS). Despite the residual vegetation and valve dysfunction, surgical intervention was not required during the follow-up period of 56.8 months. CONCLUSION: A significant correlation was observed between APS and LS endocarditis. Anticoagulation therapy should be considered to prevent thromboembolic complications in SLE patients with LS endocarditis.

Can antineutrophil cytoplasmic antibody positivity at diagnosis predict the poor outcomes of Sjögren's syndrome?

We investigated the clinical implication of ANCA positivity at diagnosis on the poor outcomes in patients with Sjögren's syndrome. The medical records of 606 Korean patients with Sjögren's syndrome were retrospectively reviewed. The results of perinuclear (P)-ANCA, myeloperoxidase (MPO)-ANCA, cytoplasmic (C)-ANCA, and proteinase 3 (PR3)-ANCA were collected and the frequencies of all-cause mortality, interstitial lung disease (ILD), end-stage renal disease (ESRD), and lymphoma were assessed as the poor outcomes of Sjögren's syndrome. Comparison of the cumulative patient survivals between the two groups was analysed by the Kaplan-Meier survival analysis. Of the 606 patients, ANCA was detected in 10.2% of Sjögren's syndrome patients without AAV. Twenty-one patients (3.5%) died, 99 patients (16.3%) suffered from ILD, and 8 patients had ESRD. Lymphoma occurred in 5 patients (0.8%) during 37.5 months. Sjögren's syndrome patients with ANCA positivity exhibited a lower cumulative ILD-free survival rate than those with ANCA negativity (P = 0.001). Sjögren's syndrome patients with P-ANCA positivity and those with MPO-ANCA (or P-ANCA) positivity showed a lower cumulative ILD-free survival rate than those without (P = 0.012 and P < 0.001). Also, Sjögren's syndrome patients with P-ANCA positivity exhibited a lower cumulative ESRD-free survival rate than those without (P = 0.043). ANCA positivity was associated with neither all-cause mortality nor lymphoma in Sjögren's syndrome patients. ANCA positivity and MPO-ANCA (or P-ANCA) positivity at diagnosis was associated with the development of ILD during follow-up in patients with Sjögren's syndrome.

Hyperuricemia is associated with decreased renal function and occurrence of end-stage renal disease in patients with microscopic polyangiitis and granulomatosis with polyangiitis: a retrospective study.

Current evidence suggests that high uric acid levels are associated with accelerated renal damage. However, the clinical impact of serum uric acid level on patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) is unknown. We aimed to evaluate the impact of hyperuricemia on such patients. A retrospective study was performed to obtain patients' demographic, clinical, and laboratory data from when they were diagnosed with MPA and GPA. Multivariable logistic regression and Cox hazard model analyses were performed to evaluate factors associated with hyperuricemia at diagnosis and predictive factors of end-stage renal disease (ESRD) development. Among 156 patients, 35 (22.4%) had hyperuricemia at baseline. Hyperuricemic patients had renal manifestation and impaired renal function more frequently than non-hyperuricemic patients. Logistic regression analysis revealed that serum creatinine was significantly associated with hyperuricemia at diagnosis [odds ratio 1.995; 95% confidence interval (CI), 1.503-2.648; P < 0.001]. Cox hazard model analysis revealed that body mass index and serum creatinine were significantly associated with ESRD when all variables were included, but hyperuricemia was independently associated with ESRD [hazard ratio (HR), 3.799; 95% CI 1.719-8.222; P < 0.001) when serum creatinine was excluded. Additionally, in a subgroup analysis of patients with decreased glomerular filtration rates (GFRs), serum uric acid was the sole predictor of ESRD (HR, 1.243; 95% CI 1.048-1.475; P = 0.013). Hyperuricemia is associated with renal damage and ESRD occurrence in MPA and GPA patients. Serum uric acid level is associated with ESRD occurrence in patients with decreased GFRs.

Comparison of clinical features and outcomes between patients with early and delayed lupus nephritis.

BACKGROUND: Lupus nephritis is associated with increased risk of end-stage renal disease (ESRD) and all-cause mortality. We evaluated the clinical features and outcomes of patients with early and delayed lupus nephritis. METHODS: The medical records of 171 patients who met the 1997 revised classification criteria for systemic lupus erythematosus (SLE) with pathologic confirmation of lupus nephritis were reviewed. Early lupus nephritis was defined when lupus nephritis was histopathologically confirmed as the first clinical manifestation of SLE, whereas delayed lupus nephritis was defined as lupus nephritis that was identified after the diagnosis of SLE. Clinical and laboratory data, as well as kidney histopathology and medication usage were investigated. Kaplan-Meier and Cox-proportional hazard analysis was performed to compare the outcomes of early and delayed lupus nephritis and evaluate factors associated with ESRD and all-cause mortality. RESULTS: Patients with early lupus nephritis had higher disease activity (median non-renal SLE disease activity index-2000, 6.0 vs. 4.0; p < 0.001) and more frequent skin rash, oral ulcer and serositis; however, the proportion of patients with higher renal chronicity index was greater in the delayed lupus nephritis group (p = 0.007). Nevertheless, no difference was found regarding ESRD and all-cause mortality between the groups. In Cox-proportional hazard analysis, C-reactive protein level, creatinine level and chronicity index were factors associated with ESRD, while age and haemoglobin level were associated with all-cause mortality. CONCLUSIONS: In conclusion, clinical outcomes of early and delayed lupus nephritis are not significantly different. Rigorous adherence to current treatment recommendations is essential for the treatment of lupus nephritis.

Clinical implication of chronic paranasal sinusitis for the classification of microscopic polyangiitis.

BACKGROUND: Chronic paranasal sinusitis (CPS) has been known as a surrogate marker for granulomatosis with polyangiitis (GPA). We investigated whether CPS at diagnosis may have an influence on the classification and outcomes of microscopic polyangiitis (MPA). METHODS: We retrospectively reviewed the medical records of 106 immunosuppressive drug-naïve patients with MPA. We compared variables at diagnosis of MPA patients with CPS with either MPA patients without CPS or 29 GPA patients with CPS. We applied the algorithm for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) proposed by the European Medicine Agency to 22 MPA patients with CPS and reclassify them. Death, relapse and end-stage renal disease were assessed as the poor outcomes. RESULTS: Except for ENT manifestations, only pulmonary manifestation was more frequently observed in MPA patients with CPS than those without (77.3% vs 47.6%). No proteinase 3-ANCA was detected in all MPA patients with CPS. Meanwhile, general (63.6% vs 27.6%) and renal manifestations (81.8% vs 44.8%) more often developed in MPA patients with CPS than GPA patients with CPS. Of 22 MPA patients with CPS, 21 patients underwent biopsies. When CPS was not considered as a surrogate marker for GPA, all patients with CPS were reclassified as MPA. Ground glass opacity and reticulation on high-resolution computed tomography and renal vasculitis were helpful clues supporting the classification of MPA in patients with CPS. CPS at diagnosis was not associated with the outcomes of MPA. CONCLUSION: CPS might not be a sufficient surrogate marker for GPA in the classification of AAV.

Serum Mannose-Binding Lectin Levels Are Correlated with the Disease Activity of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Single-Center Study.

Mannose-binding lectin (MBL) is a soluble pattern-recognition molecule, which plays a crucial role in the innate immune system and the activation of lectin complement pathway. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease affecting the small vasculatures and is characterized by the alteration of innate and adaptive immunity and complement activation. In this study, we investigated whether serum MBL is associated with disease activity of AAV, which was measured by ELISA. Associations between serum MBL and AAV-specific indices, as well as clinical and laboratory data were assessed using Kendall's tau. Among the 80 patients, 42 (52.5%), 21 (26.3), and 17 (21.3%) patients were classified as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), respectively. The median values of erythrocyte sedimentation rate, C-reactive protein, and serum MBL were 36.5 (normal range < 20) mm/h, 2.4 (normal range < 8) mg/dL, and 8.6 ng/mL, respectively. The median serum levels of MBL in MPA, GPA, and EGPA patients were 8.4, 9.3, and 8.2 ng/mL. Correlation analysis showed that serum MBL was associated with Birmingham Vasculitis Activity Score (BVAS) (R = 0.169, p = 0.027), but not with other AAV-specific indices and clinical and laboratory data. In addition, serum MBL was significantly associated with the pulmonary manifestation score based on BVAS (R = 0.247, p = 0.001). In summary, among the AAV-specific indices and clinical and laboratory variables analyzed, serum MBL is correlated with BVAS and pulmonary manifestation score based on the BVAS.

1,25-dihydroxy Vitamin D3 and Interleukin-6 Blockade Synergistically Regulate Rheumatoid Arthritis by Suppressing Interleukin-17 Production and Osteoclastogenesis.

BACKGROUND: Immune cells express the vitamin (vit) D receptor, and vit D is a potent immune-modulator. A negative correlation between serum vit D levels and rheumatoid arthritis (RA) disease activity has been reported. Therefore, we aimed to investigate if the sufficient serum vit D level is helpful to control disease activity in RA patients treated with interleukin (IL)-6 receptor antibody tocilizumab. METHODS: RA patients taking tocilizumab were enrolled, and data were collected retrospectively. Disease activity scores (DAS) 28, serum vit D levels, modified Sharp scores of hand X-ray at the time of tocilizumab initiation, and follow-up data were analysed. Peripheral blood mononuclear cells were differentiated into T-helper (Th) 17 or osteoclasts in the presence of various concentrations of tocilizumab and/or 1,25(OH)2D. Th17 proportions were analysed by fluorescence-activated cell sorting. Supernatant cytokine levels were determined by enzyme-linked immunosorbent assay. RESULTS: Among 98 RA patients taking tocilizumab, 34 (34.7%) had sufficient serum 25(OH)D levels (≥ 30 ng/mL) when tocilizumab was initiated. At 24 weeks, vit D sufficient patients had greater DAS28 reduction (64.6% ± 15.5% vs. 52.7% ± 20.7%, P = 0.004), and lower disease activity (91.2% vs. 70.3%, P = 0.018) or remission (82.4% vs. 57.8%, P = 0.014). These differences in DAS28 reduction and the proportion of patients with remission persisted at 48 weeks. However, there was no significant difference in hand and wrist erosion progression. In vitro, tocilizumab and 1,25(OH)2D treatment synergistically suppressed IL-17 production and osteoclastogenesis. CONCLUSION: RA patients treated with IL-6 antibody show a better response when they have sufficient serum vit D. Tocilizumab and 1,25(OH)2D synergistically suppress IL-17 production and osteoclast differentiation in RA patients.

Distinct roles of Cep192 and Cep152 in acentriolar MTOCs and spindle formation during mouse oocyte maturation.

Mammalian oocytes lack a centriole that acts as a microtubule organization center (MTOC) in most somatic cells. During oocyte maturation, MTOCs undergo remodeling processes, including decondensation, fragmentation, and self-organization. However, the underlying mechanisms of MTOC remodeling in mouse oocytes are not well understood. We showed that two pericentriolar proteins, Cep192 and Cep152, play crucial roles during MTOC remodeling in mouse oocytes. Cep192 is present in MTOCs at all stages of oocyte maturation, and its depletion induces ablation of MTOCs, delay in spindle formation, and abnormal chromosomal alignment in spindles. In the case of Cep152, its localization on MTOCs is limited at the germinal vesicle stage and then disappears from the MTOCs after the germinal vesicle breakdown stage. Cep152 exclusion from MTOCs is involved in the fragmentation of MTOCs, and it is regulated by cyclin-dependent kinase 1 activity. Our results demonstrate the different roles of Cep192 and Cep152 in MTOC remodeling and a novel regulatory mechanism during meiotic spindle formation in mouse oocytes.-Lee, I.-W., Jo, Y.-J., Jung, S.-M., Wang, H.-Y., Kim, N.-H., Namgoong, S. Distinct roles of Cep192 and Cep152 in acentriolar MTOCs and spindle formation during mouse oocyte maturation.

Serum soluble programmed cell death protein 1 could predict the current activity and severity of antineutrophil cytoplasmic antibody-associated vasculitis: a monocentric prospective study.

OBJECTIVES: We investigated whether serum soluble programmed cell death protein 1 (sPD-1) could predict the current activity and severity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) based on Birmingham vasculitis activity score (BVAS) in patients with AAV. METHODS: Fifty-nine patients from a monocentric prospective cohort of AAV were included. On the same visit-day, blood samples were collected and isolated sera were stored, BVAS and other AAV-related parameters were assessed, and laboratory tests were performed. We defined the lower limit of the highest tertile of BVAS as the cut-off for severe AAV (BVAS ≥12). Serum sPD-1 was measured from stored serum samples. RESULTS: The mean age was 59.7 years (38 women). The mean BVAS was 8.9 and 18 patients had severe BVAS. Patients with severe AAV exhibited the higher mean serum sPD-1 than those without (380.7 pg/mL vs. 180.3 pg/mL). Serum sPD-1 (r=0.367), white blood cell count (r=0.288), haemoglobin (r=-0.590), serum albumin (r=-0.670) erythrocyte sedimentation rate (ESR) (r=0.339) and C-reactive protein (CRP) (r=0.450) were significantly correlated with BVAS. Moreover, serum sPD-1 was meaningfully correlated with haemoglobin and serum albumin, but not ESR or CRP. In the multivariable linear regression analysis, only serum sPD-1 was significantly associated with BVAS (standardised ß 0.274, p=0.024). We calculated the optimal cut-off of serum sPD-1 for severe AAV as 70.1 pg/mL. Severe AAV were more frequently identified in patients with serum sPD-1 ≥70.1 pg/mL than those without (RR 13.867). CONCLUSIONS: Serum sPD-1 could predict the current activity and severity of AAV.