The Impact of Lifestyle on Cardiovascular Risk in Patients with Gout: a Population-based Cohort Study.

AIMS: Gout is associated with a significant burden of cardiovascular disease. The aim of this study was to evaluate the impact of a favorable lifestyle on incident cardiovascular events in patients with gout. METHODS: We identified 9 110 patients with gout from the UK Biobank cohort based on self-report and/or hospital diagnostic codes. Lifestyle behaviors, including smoking status, physical activity, obesity, and diet, were categorized into three patterns: favorable (3-4 healthy factors), intermediate (2 healthy factors), and unfavorable (0-1 healthy factor). The cardiovascular risk of participants with and without gout was estimated based on their serum uric acid levels and lifestyle patterns. RESULTS: Among 9 110 patients with gout and 457 596 participants without gout, the median follow-up duration was 8.9 years. The incidence rate of cardiovascular disease was significantly higher in the gout population than in the non-gout population (11.38 vs 5.49 per 1000 person-years). The gout population consistently exhibited a high cardiovascular risk, irrespective of uric acid levels, whereas a positive correlation was observed between uric acid levels and cardiovascular risk in the non-gout population. Adopting a favorable lifestyle pattern was associated with a lower risk of cardiovascular disease in both gout and non-gout populations. Across all categories of uric acid, a favorable lifestyle was found to reduce cardiovascular risk in patients with gout. CONCLUSION: Patients with gout remain at high risk of developing cardiovascular disease despite having normal uric acid levels. Lifestyle modifications may represent an effective and cost-efficient therapeutic approach for preventing cardiovascular events in this population.

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.

Quantitative prediction of radiographic progression in patients with axial spondyloarthritis using neural network model in a real-world setting.

BACKGROUND: Predicting radiographic progression in axial spondyloarthritis (axSpA) remains limited because of the complex interaction between multiple associated factors and individual variability in real-world settings. Hence, we tested the feasibility of artificial neural network (ANN) models to predict radiographic progression in axSpA. METHODS: In total, 555 patients with axSpA were split into training and testing datasets at a 3:1 ratio. A generalized linear model (GLM) and ANN models were fitted based on the baseline clinical characteristics and treatment-dependent variables for the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) of the radiographs at follow-up time points. The mSASSS prediction was evaluated, and explainable machine learning methods were used to provide insights into the model outcome or prediction. RESULTS: The R2 values of the fitted models were in the range of 0.90-0.95 and ANN with an input of mSASSS as the number of each score performed better (root mean squared error (RMSE) = 2.83) than GLM or input of mSASSS as a total score (RMSE = 2.99-3.57). The ANN also effectively captured complex interactions among variables and their contributions to the transition of mSASSS over time in the fitted models. Structural changes constituting the mSASSS scoring systems were the most important contributing factors, and no detectable structural abnormalities at baseline were the most significant factors suppressing mSASSS change. CONCLUSIONS: Clinical and radiographic data-driven ANN allows precise mSASSS prediction in real-world settings. Correct evaluation and prediction of spinal structural changes could be beneficial for monitoring patients with axSpA and developing a treatment plan.

Costovertebral joint involvement in patients with axial spondyloarthritis.

OBJECTIVES: To evaluate costovertebral joint involvement in patients with axial spondyloarthritis (axSpA) and to assess its association with disease features. METHODS: We included 150 patients from the Incheon Saint Mary's axSpA observational cohort who underwent whole spine low-dose computed tomography (ldCT). Costovertebral joint abnormalities were scored by two readers on a scale of 0-48 based on the presence or absence of erosion, syndesmophyte, and ankylosis. The interobserver reliability of costovertebral joint abnormalities was assessed using intraclass correlation coefficients (ICCs). Associations between costovertebral joint abnormality scores and clinical variables were evaluated using a generalized linear model. RESULTS: Two independent readers found costovertebral joint abnormalities in 74 (49%) patients and 108 (72%) patients. The ICCs of scores for erosion, syndesmophyte, ankylosis, and total abnormality were 0.85, 0.77, 0.93, and 0.95, respectively. For both readers, total abnormality score was correlated with age, symptom duration, Ankylosing Spondylitis Disease Activity Score (ASDAS), Bath AS functional index (BASFI), CT syndesmophyte score (CTSS), and number of bridging spines. Multivariate analyses showed age, ASDAS, CTSS to be independently associated with total abnormality scores in both readers. The frequency of ankylosed costovertebral joint was 10.2% (reader 1) and 17.0% (reader 2) in patients without radiographic syndesmophytes (n=62), and 10.3% (reader 1) and 17.2% (reader 2) in patients without radiographic sacroiliitis (n=29). CONCLUSIONS: Costovertebral joint involvement was common in patients with axSpA, even in the absence of radiographic damage. LdCT is recommended for evaluating structural damage in patients with clinically suspected costovertebral joint involvement.

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.

Comparison of developing tuberculosis following tumor necrosis factor inhibition and interleukin-6 inhibition in patients with rheumatoid arthritis: a nationwide observational study in South Korea, 2013-2018.

BACKGROUND: Tumor necrosis factor (TNF) inhibitors increase the risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA). This study compared the incidence of TB after treatment with TNF inhibitors and tocilizumab in patients with RA, separately in those who were treated for latent tuberculosis infection (LTBI) and those without evidence of LTBI. METHODS: This study included patients with RA who initiated TNF inhibitors and tocilizumab between December 2013 and August 2018. Patient data were collected from the nationwide database of the Health Insurance Review and Assessment service in South Korea. The incidence of TB was compared among different biologic drugs in patients with or without LTBI treatment. RESULTS: Of 4736 patients, 1168 were treated for LTBI and 48 developed TB (554.9 per 100,000 person-years). When compared based on etanercept, infliximab showed a higher risk of TB (adjusted incidence rate ratio 2.71, 95% confidence interval 1.05-7.01), especially in patients without evidence of LTBI. Other TNF inhibitors and tocilizumab showed a comparable incidence of TB, regardless of treatment for LTBI. There was no significant difference in TB incidence after biologic therapy between patients with and without LTBI treatment (627.9/100,000 vs. 529.5/100,000 person-years). In patients treated for LTBI, no differential risk of TB was observed among biologic drugs. CONCLUSIONS: The incidence of TB was not significantly different among biologic drugs in the current era, except for infliximab in patients who were not treated for LTBI. Treatment of LTBI might alleviate the drug-specific risk of TB in patients with RA.

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.

Targeted Immunotherapy for Autoimmune Disease.

In the past few decades, biological drugs and small molecule inhibitors targeting inflammatory cytokines, immune cells, and intracellular kinases have become the standard-of-care to treat autoimmune diseases. Inhibition of TNF, IL-6, IL-17, and IL-23 has revolutionized the treatment of autoimmune diseases, such as rheumatoid arthritis, ankylosing spondylitis, and psoriasis. B cell depletion therapy using anti-CD20 mAbs has shown promising results in patients with neuroinflammatory diseases, and inhibition of B cell survival factors is approved for treatment of systemic lupus erythematosus. Targeting co-stimulatory molecules expressed on Ag-presenting cells and T cells is also expected to have therapeutic potential in autoimmune diseases by modulating T cell function. Recently, small molecule kinase inhibitors targeting the JAK family, which is responsible for signal transduction from multiple receptors, have garnered great interest in the field of autoimmune and hematologic diseases. However, there are still unmet medical needs in terms of therapeutic efficacy and safety profiles. Emerging therapies aim to induce immune tolerance without compromising immune function, using advanced molecular engineering techniques.

Clinical Implications of Shared Epitope and Anti-citrullinated Peptide Antibody in Patients With Rheumatoid Arthritis.

Objective: The shared epitope (SE) and anti-citrullinated peptide antibody (ACPA) are involved in the pathogenesis of rheumatoid arthritis (RA). This study evaluated the clinical implications of SE and ACPA in terms of disease manifestation and response to biologic disease modifying anti-rheumatic drugs (DMARDs). Methods: Patients with identified human leukocyte antigen (HLA)-DRB1 alleles were included to compare the clinical characteristics and drug survival rate of tumor necrosis factor (TNF) inhibitors or abatacept based on the presence of SE and ACPA. Results: Of the 533 patients with identified HLA-DRB1 alleles, 329 patients (61.7%) with SE alleles showed higher disease activity and erosive changes compared to patients without SE alleles. SE-positive patients were more likely to start biologic (b-) or targeted synthetic DMARDs (tsDMARDs) within the first 5 years (p=0.020). The presence of SE, smoking, dyslipidemia, and higher erythrocyte sedimentation rate were independently associated with the initiation of b- or tsDMARDs (p=0.016, 0.028, 0.031, and 0.001, respectively). The presence of SE and ACPA did not affect the drug survival rate of TNF inhibitors, whereas the abatacept retention rate was higher in ACPA-positive patients (p=0.024). Conclusion: The presence of SE affected disease characteristics and prognosis in Korean patients with RA without a significant impact on drug survival rate of TNF inhibitors and abatacept. ACPA positivity was associated with abatacept drug retention, suggesting that abatacept may be helpful in ACPA-positive patients than in ACPA-negative patients.

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.

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.

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.

Characterization of Early-Onset Finger Osteoarthritis-Like Condition Using Patient-Derived Induced Pluripotent Stem Cells.

Early osteoarthritis (OA)-like symptoms are difficult to study owing to the lack of disease samples and animal models. In this study, we generated induced pluripotent stem cell (iPSC) lines from a patient with a radiographic early-onset finger osteoarthritis (efOA)-like condition in the distal interphalangeal joint and her healthy sibling. We differentiated those cells with similar genetic backgrounds into chondrogenic pellets (CPs) to confirm efOA. CPs generated from efOA-hiPSCs (efOA-CPs) showed lower levels of COL2A1, which is a key marker of hyaline cartilage after complete differentiation, for 21 days. Increase in pellet size and vacuole-like morphologies within the pellets were observed in the efOA-CPs. To analyze the changes occurred during the development of vacuole-like morphology and the increase in pellet size in efOA-CPs, we analyzed the expression of OA-related markers on day 7 of differentiation and showed an increase in the levels of COL1A1, RUNX2, VEGFA, and AQP1 in efOA-CPs. IL-6, MMP1, and MMP10 levels were also increased in the efOA-CPs. Taken together, we present proof-of-concept regarding disease modeling of a unique patient who showed OA-like symptoms.

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.

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.

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.

Reclassification of Korean patients with polymyositis and dermatomyositis based on the Bohan and Peter criteria by the 2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies.

BACKGROUND/AIMS: We investigated the concordance rate of the classification of polymyositis (PM) and dermatomyositis (DM) between the Bohan and Peter criteria and the 2017 European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies (IIMs) (the 2017 EULAR/ACR criteria) in Korean patients. METHODS: We retrospectively reviewed the medical records of 137 patients with PM and DM. We finally included 72 PM patients and 49 DM patients who fulfilled the Bohan and Peter criteria for PM and DM and reclassified them by the 2017 EULAR/ ACR criteria. RESULTS: Three patients (4.2%) with probable PM were newly reclassified as non-IIM due to a total score of 5.3 or smaller. Meanwhile, one patient with possible PM was newly reclassified as probable PM due to the presence of dysphagia. In addition, eight patients (16.3%) with possible DM with DM-specific typical skin rash were newly reclassified as amyopathic DM (ADM) due to the absence of proximal muscle weakness. The concordance rate of the classification between the Bohan and Peter criteria and the 2017 EULAR/ACR criteria was 95.8% for PM patients and 83.7% for DM patients. CONCLUSION: The Bohan and Peter criteria were comparable to the 2017 EULAR/ ACR criteria for classifying PM and DM in Korean patients. Considering the convenience of the Bohan and Peter criteria in the real clinical settings, we suggest that the old criteria should be preferentially applied and then performing muscle biopsy should be considered in a patient suspected of PM without antihistidyl tRNA synthetase (anti-Jo-1). Moreover, we suggest that ADM could also clinically be classified by the old criteria.

Clinical and imaging findings suggestive of histopathological immunoglobulin G4-related disease: a single-center retrospective study.

OBJECTIVE: To investigate the clinical and imaging features predicting the histopathological diagnosis of immunoglobulin G4 (IgG4)-related disease (IgG4RD) in patients with suspected IgG4RD on computed tomography (CT). METHODS: We retrospectively reviewed the medical records of 178 patients with CT findings suspicious of IgG4RD from January 2015 to December 2017. Patients who underwent tissue biopsy were included to evaluate the association between patient characteristics and histopathological diagnosis of IgG4RD. The histopathological diagnosis was classified into IgG4RD and non-IgG4RD. Clinical, laboratory, and imaging features were compared between patients with IgG4RD and non-IgG4RD, and logistic regression analysis was performed to identify the predictors for histopathologically confirmed IgG4RD. RESULTS: Of the 103 patients with histopathologically proven diseases, 46 and 57 patients were classified as IgG4RD and non-IgG4RD, respectively. The median age was 64 years; 65% of patients were male. There were significant differences in sex (P = 0.035), fever (P = 0.039), serum IgG4 level (P < 0.001), renal involvement (P = 0.036), lacrimal or salivary glands involvement (P = 0.050), swelling pattern on CT (P = 0.001), and positron emission tomography (PET)-CT findings (P < 0.001) between patients with IgG4RD and non-IgG4RD. Multivariate analysis revealed elevated IgG4 level > 135 mg/dL (odds ratio [OR] = 5.418, P < 0.001), kidney involvement (OR = 6.170, P = 0.044), and the swelling feature on CT (OR = 4.301, P = 0.012) to be independent factors for histopathological diagnosis of IgG4RD. CONCLUSION: This study suggests that elevated IgG4 level, renal involvement, and swelling pattern on CT are associated with histopathological diagnosis of IgG4RD. The clinical and imaging features might help to decide further evaluation in patients with clinically suspected IgG4RD. Key Points • Computed tomography (CT) is not sufficient to discriminate between IgG4-related disease (IgG4RD) and non-IgG4RD conditions. • Histopathological diagnosis of IgG4RD is associated with elevated IgG4 level, renal involvement, and swelling pattern on CT. • Positron emission tomography-CT may be a useful diagnostic tool in patients with clinically suspected IgG4RD. >.