Rheumatoid arthritis patients harbour aberrant enteric bacteriophages with autoimmunity-provoking potential: a paired sibling study.

OBJECTIVES: Viruses have been considered as important participants in the development of rheumatoid arthritis (RA). However, the profile of enteric virome and its role in RA remains elusive. This study aimed to investigate the atlas and involvement of virome in RA pathogenesis. METHODS: Faecal samples from 30 pairs of RA and healthy siblings that minimise genetic interferences were collected for metagenomic sequencing. The α and ß diversity of the virome and the virome-bacteriome interaction were analysed. The differential bacteriophages were identified, and their correlations with clinical and immunological features of RA were analysed. The potential involvement of these differential bacteriophages in RA pathogenesis was further investigated by auxiliary metabolic gene annotation and molecular mimicry study. The responses of CD4+ T cells and B cells to the mimotopes derived from the differential bacteriophages were systemically studied. RESULTS: The composition of the enteric bacteriophageome was distorted in RA. The differentially presented bacteriophages correlated with the immunological features of RA, including anti-CCP autoantibody and HLA-DR shared epitope. Intriguingly, the glycerolipid and purine metabolic genes were highly active in the bacteriophages from RA. Moreover, peptides of RA-enriched phages, in particular Prevotella phage and Oscillibacter phage could provoke the autoimmune responses in CD4+ T cells and plasma cells via molecular mimicry of the disease-associated autoantigen epitopes, especially those of Bip. CONCLUSIONS: This study provides new insights into enteric bacteriophageome in RA development. In particular, the aberrant bacteriophages demonstrated autoimmunity-provoking potential that would promote the occurrence of the disease.

Proinflammatory phenotype of B10 and B10pro cells elicited by TNF-α in rheumatoid arthritis.

OBJECTIVES: B10 and B10pro cells suppress immune responses via secreting interleukin (IL)-10. However, their regulators and underlying mechanisms, especially in human autoimmune diseases, are elusive. This study aimed to address these questions in rheumatoid arthritis (RA), one of the most common highly disabling autoimmune diseases. METHODS: The frequencies and functions of B10 and B10pro cells in healthy individuals and patients with RA were first analysed. The effects of proinflammatory cytokines, particularly tumour necrosis factor (TNF)-α on the quantity, stability and pathogenic phenotype of these cells, were then assessed in patients with RA before and after anti-TNF therapy. The underlying mechanisms were further investigated by scRNA-seq database reanalysis, transcriptome sequencing, TNF-α-/- and B cell-specific SHIP-1-/- mouse disease model studies. RESULTS: TNF-α was a key determinant for B10 cells. TNF-α elicited the proinflammatory feature of B10 and B10pro cells by downregulating IL-10, and upregulating interferon-γ and IL-17A. In patients with RA, B10 and B10pro cells were impaired with exacerbated proinflammatory phenotype, while anti-TNF therapy potently restored their frequencies and immunosuppressive functions, consistent with the increased B10 cells in TNF-α-/- mice. Mechanistically, TNF-α diminished B10 and B10pro cells by inhibiting their glycolysis and proliferation. TNF-α also regulated the phosphatidylinositol phosphate signalling of B10 and B10pro cells and dampened the expression of SHIP-1, a dominant phosphatidylinositol phosphatase regulator of these cells. CONCLUSIONS: TNF-α provoked the proinflammatory phenotype of B10 and B10pro cells by disturbing SHIP-1 in RA, contributing to the disease development. Reinstating the immunosuppressive property of B10 and B10pro cells might represent novel therapeutic approaches for RA.

Elevated serum soluble CD27 levels are associated with both disease activity and humoral immune activity in patients with rheumatoid arthritis.

OBJECTIVES: To investigate the serum level of soluble CD27 (sCD27) and its potential clinical significance in rheumatoid arthritis (RA). METHODS: Serum sCD27 levels in RA patients, idiopathic inflammatory myopathy (IIM) patients, systemic lupus erythematosus (SLE) patients and healthy controls (HCs) were detected by enzyme-linked immunosorbent assay. The medical information and laboratory data of the patients were collected. Serum sCD27 levels in RA patients with different clinical features were analysed, as was the correlation between the clinical data and serum sCD27 levels. Independent samples t test, the Mann-Whitney U-test or Wilcoxon signed-rank test, and Spearman correlation were used for statistical analysis. RESULTS: Levels of sCD27 were elevated in RA patients (3898 [2525, 5834] pg/mL) compared with IIM patients (2467 [1939, 3324] pg/mL) or HCs (1659 ± 648 pg/mL) (p 0.001). In addition, serum sCD27 levels correlated with age, erythrocyte sedimentation rate, C-reactive protein (CRP), rheumatoid factor (RF), immunoglobulin A, immunoglobulin G, complement 4 and disease activity score in 28 joints in RA patients. Levels of sCD27 were higher in RF-positive RA patients (6054 ± 5842 pg/mL) than in RF-negative patients (3902 ± 2098 pg/mL), and a similar finding was also observed in anti-cyclic citrullinated peptide (anti-CCP) antibody-positive (5810 ± 5671 pg/mL) and anti-CCP-negative (4183 ± 2187 pg/mL) RA patients. Serum ESR, RF, IgA, IgG levels and DAS28-CRP were elevated in RA patients with higher sCD27 levels than in those with lower sCD27 levels (p<0.01). CONCLUSIONS: Serum sCD27 might be a promising biomarker that reflects both disease activity and humoral immunity activity in RA.

The GOUT-36 prediction rule for inpatient gout flare in people with comorbid gout: derivation and external validation.

OBJECTIVES: To develop and validate a gout flare risk stratification tool for people with gout hospitalized for non-gout conditions. METHODS: The prediction rule for inpatient gout flare was derived from a cohort of 625 hospitalized people with comorbid gout from New Zealand. The rule had four items: no pre-admission gout flare prophylaxis, no pre-admission urate-lowering therapy, tophus and pre-admission serum urate >0.36 mmol/l within the previous year (GOUT-36 rule). Two or more items are required for the classification of high risk for developing inpatient gout flares. The GOUT-36 rule was validated in a prospective cohort of 284 hospitalized people with comorbid gout from Thailand and China. RESULTS: The GOUT-36 rule had a sensitivity of 75%, specificity of 67% and area under the curve of 0.71 for classifying people at high risk for developing inpatient gout flares. Four risk groups were developed: low (no items), moderate (one item), high (two items) and very high risk (three or four items). In a population with frequent (overall 34%) in-hospital gout flares, 80% of people with very high risk developed inpatient flares while 11% with low risk had inpatient flares. CONCLUSION: The GOUT-36 rule is simple and sensitive for classifying people with high risk for inpatient gout flares. The rule may help inform clinical decisions and future research on the prevention of inpatient gout flares.

Nomogram to predict dermatomyositis prognosis: a population-based study of 457 cases.

OBJECTIVES: Dermatomyositis (DM) is a systemic autoimmune disease, which typically affects the striated muscle with a variable involvement of the skin and other organs. Clinically amyopathic DM (CADM) is a combination of hypomyopathic DM (HDM) and amyopathic DM (ADM), with a characteristic of skin-predominant lesions. To date, large-scale studies on the prognostic factors of DM/CADM have been limited. The aim of this study is to evaluate the prognostic values of clinical manifestations in DM/CADM and to develop a prognostic nomogram for DM/CADM. METHODS: A development cohort (n=239), an internal validation cohort (n=128) and an external validation cohort (n=90) were included in this study. Overall survival (OS) was estimated by the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards regression analyses were performed. Cox proportional hazards model and forward stepwise selection with the Akaike information criterion were used for multivariate analysis of prognostic factors. The concordance index (C-index) and calibration curve were calculated to evaluate the predictive accuracy of the proposed nomogram. RESULTS: Rapidly progressive interstitial lung disease (RP-ILD) and erythrocyte sedimentation rate (ESR) were identified as risk independent prognostic factors, with antinuclear antibodies (ANA) was identified as protective independent prognostic factors, for DM/CADM. A prognostic nomogram was formulated based on these three predictors. The C-index of the proposed nomogram in the development cohort was 0.874 (95%CI, 0.819-0.929). The predictive accuracy of the proposed nomogram was further validated in the internal validation cohort, with a C-index of 0.799 (95%CI, 0.681-0.917). Furthermore, the C-index was 0.864 (95%CI, 0.699-1.000) in the external validation cohort, indicating a good calibration ability. This proposed nomogram showed a promising predictive accuracy on the prognosis of DM/CADM. CONCLUSIONS: RP-ILD, ANA and ESR are prognostic factors for DM/CADM. The proposed nomogram based on these three factors could accurately predict the 10-year OS probabilities of patients with DM/CADM.

Endoplasmic reticulum stress perpetuated toll-like receptor signalling-mediated inflammation in rheumatoid arthritis via X-box-binding protein-1.

OBJECTIVES: Multiple physiological and pathological conditions interfere with the function of the endoplasmic reticulum (ER). However, much remains unknown regarding the impact of ER stress on toll-like receptors (TLRs) -induced inflammatory responses in rheumatoid arthritis (RA). The aim of this study was to reveal the effects of ER stress and its regulator, X-box-binding protein-1 (XBP-1), on the inflammatory response of RA synovial fibroblasts (RASF) to different TLRs ligands. METHODS: ER stress was induced in RASF by incubating with thapsigargin (Tg). TLR2 ligand Pam3CSK4, TLR3 ligand PolyIC, TLR4 ligand LPS were used to stimulate the cells. Effects of ER stress on TLRs-induced inflammatory mediators were determined by using RT-PCR, qPCR and ELISA analysis. Western blots analysis was used to detected the signalling pathways in this process. For gene silencing experiment, control scrambled or XBP-1 specific siRNA were transfected into RASF. T helper (Th)1/Th17 cells expansion was determined by flow cytometry analysis, and IFN-γ/IL-17A production in supernatants were collected for ELISA assay. RESULTS: ER stress potentiated the expression of inflammatory cytokines, MMPs and VEGF in RASF stimulated by different TLRs ligands, which was companied with enhanced the activation of NF-κB and MAPKs signalling pathways. Silencing XBP-1 in RASF could dampen TLRs signalling-simulated inflammatory response under ER stress. Moreover, blockade of XBP-1 reduced the generation of Th1 and Th17 cells mediated by RASF, and suppressed the production of IFN-γ and IL-17A. CONCLUSIONS: Our findings suggest that ER stress and XBP-1 may function in conjunction with TLRs to drive the inflammation of RASF, and this pathway may serve as a therapeutic target for the disease.

Distribution of abnormal IgG glycosylation patterns from rheumatoid arthritis and osteoarthritis patients by MALDI-TOF-MSn.

Glycosylation is a post-translational modification essential for maintaining the structure and function of proteins. Abnormal N-glycan patterns have been found in various diseases compared to healthy controls. A decrease in terminal galactosylated N-glycans of serum IgG in rheumatoid arthritis (RA) and osteoarthritis (OA) may be involved in their immunopathogenesis. However, how glycan patterns differ between RA and OA remains unclear. Here, we identified 15 glycan forms of serum IgG from RA and OA using MALDI-TOF MS. We found that IgG galactosylation represented a suitable candidate for differentiating RA from healthy controls (AUC > 0.9). Then, we performed binary logistic regression to screen out three bisecting N-acetylglucosamine (GlcNAc) glycoforms for distinguishing between OA and RA. Combined ROC analysis of the selected glycans yielded an AUC of 0.81 between OA and RA and an AUC of 0.79 between OA and RF/ACPA negative RA. Similar results were found in the validation set. In conclusion, our analysis demonstrates that RA and OA are distinguished on the basis of their different IgG glycan patterns, which thus serve as suitable candidates as biomarkers for reliably identifying clinical conditions such as RA and OA.

Hypoxia-inducible factor-1α perpetuates synovial fibroblast interactions with T cells and B cells in rheumatoid arthritis.

Synovial fibroblast hyperplasia, T-cell hyperactivity, B-cell overactivation, and the self-perpetuating interactions among these cell types are major characteristics of rheumatoid arthritis (RA). The inflamed joints of RA patients are hypoxic, with upregulated expression of hypoxia-inducible factor-1α (HIF-1α) in RA synovial fibroblasts (RASFs). It remains unknown whether HIF-1α regulates interactions between RASFs and T cells and B cells. We report here that HIF-1α promotes the expression of inflammatory cytokines IL-6, IL-8, TNF-α, and IL-1ß, and cell-cell contact mediators IL-15, vascular cell adhesion molecule (VCAM)-1, thrombospondin (TSP)-1, and stromal cell-derived factor (SDF)-1 in RASFs. Furthermore, HIF-1α perpetuates RASF-mediated inflammatory Th1- and Th17-cell expansion while differentially inhibiting regulatory B10 and innate-like B cells, leading to increased IFN-γ, IL-17, and IgG production and decreased protective natural IgM secretion. Our findings suggest that HIF-1α perpetuates the interactions between RASFs and T cells and B cells to induce inflammatory cytokine and autoantibody production, thus exacerbating the severity of RA. Targeting HIF-1α may provide new therapeutic strategies for overcoming this persistent disease.

Pathogenic conversion of regulatory B10 cells into osteoclast-priming cells in rheumatoid arthritis.

Regulatory B10 cells were functionally impaired in rheumatoid arthritis (RA), yet the mechanisms were unclear. B cells are recently recognized as important participants in osteoclastogenesis by producing RANKL. In this study, we investigated whether regulatory B10 cells could convert into RANKL-producing cells, thus impairing their immunosuppressive functions in RA and exacerbating the disease progression. Our results showed that human regulatory B10 cells could ectopically express RANKL. Under RA circumstance, RANKL-producing B10 cells expanded dramatically, partially induced by TNF-α. The frequencies of these cells were positively correlated with RA patient disease activities and tender joint counts, but negatively correlated with the frequencies of regulatory B10 cells. Strikingly, RANKL-producing B10 cells from RA patients, but not healthy individuals significantly promoted osteoclast differentiation and bone erosion in a paracrine and cell-cell contact-dependent manner. Moreover, these pathogenic RANKL-producing B10 cells declined while regulatory IL-10-producing B10 cells increased in RA patients with disease remission after therapy. Collectively, these results showed that in RA, regulatory B10 cells demonstrated the potential of converting into RANKL-producing cells, thus exacerbating osteoclast formation, bone destruction and disease progression. Modulating the status of B10 cells might provide novel therapeutic strategies for RA.

Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis.

OBJECTIVES: Although myeloid-derived suppressor cells (MDSCs) have been linked to T cell tolerance, their role in autoimmune rheumatoid arthritis (RA) remains elusive. Here we investigate the potential association of MDSCs with the disease pathogenesis using a preclinical model of RA and specimen collected from patients with RA. METHODS: The frequency of MDSCs in blood, lymphoid tissues, inflamed paws or synovial fluid and their association with disease severity, tissue inflammation and the levels of pathogenic T helper (Th) 17 cells were examined in arthritic mice or in patients with RA (n=35) and osteoarthritis (n=15). The MDSCs in arthritic mice were also characterised for their phenotype, inflammation status, T cell suppressive activity and their capacity of pro-Th17 cell differentiation. The involvement of MDSCs in the disease pathology and a Th17 response was examined by adoptive transfer or antibody depletion of MDSCs in arthritic mice or by coculturing mouse or human MDSCs with naïve CD4+ T cells under Th17-polarising conditions. RESULTS: MDSCs significantly expanded in arthritic mice and in patients with RA, which correlated positively with disease severity and an inflammatory Th17 response. While displaying T cell suppressive activity, MDSCs from arthritic mice produced high levels of inflammatory cytokines (eg, interleukin (IL)-1ß, TNF-α). Mouse and human MDSCs promoted Th17 cell polarisation ex vivo. Transfer of MDSCs facilitated disease progression, whereas their elimination in arthritic mice ameliorated disease symptoms concomitant with reduction of IL-17A/Th17 cells. CONCLUSIONS: Our studies suggest that proinflammatory MDSCs with their capacity to drive Th17 cell differentiation may be a critical pathogenic factor in autoimmune arthritis.

[CCL19/IL-1beta positive feedback loop involved in the progress of inflammation in rheumatoid arthritis].

OBJECTIVE: To explore the function and mechanism of CCL19 in the pathogenesis of rheumatoid arthritis. METHODS: Synovial fibroblasts were collected from 5 cases of rheumatoid arthritis. Peripheral blood mononuclear cells (PBMCs) were obtained from 5 healthy people by Ficoll-Hypaque density gradien centrifugation. The cells were stimulated with IL-1beta, TNF-alpha, IL-17 and other cytokines, and then the expression of CCL19 was detected by RT-PCR. The cells also were treated with different concentration of CCL19, then the expressions of IL-1beta, TNF-alpha were detected by RT-PCR, the expressions of p-ERK, p-p38 were detected by western blot. RESULTS: IL-1beta promoted the CCL19/CCR7 expression in both synovial fibroblasts and PBMCs. CCL19 upregulated the expression of IL-10 in both synovial fibroblasts and PBMCs. The stimulation of CCL19 also increased its receptor CCR7 expression. CCL19 activated p-ERK and p-p38 in PBMCs. CONCLUSION: The positive feedback loop between CCL19 and IL-1 participate in the development of rheumatoid arthritis.

Hypoxia and hypoxia-inducible factor-1α provoke toll-like receptor signalling-induced inflammation in rheumatoid arthritis.

OBJECTIVES: Hyperplasia of synovial fibroblasts, infiltration with lymphocytes and tissue hypoxia are major characteristics of rheumatoid arthritis (RA). Extensive data support a key role for toll-like receptors (TLRs) in RA. Little is known regarding the impact of hypoxia on TLR-induced inflammation in RA. The aim of this study was to reveal the effects of hypoxia and its regulator, hypoxia-inducible factor-1α (HIF-1α), on the inflammatory response of RA synovial fibroblasts (RASF) to TLR ligands. METHODS: Hypoxia was induced in RASF by incubation with Na2S2O4. TLR3 ligand polyIC, TLR2 ligand peptidoglycan, TLR4 ligand LPS and TLR9 ligand CpG were used to stimulate the cells. Effects of hypoxia on TLR-induced inflammatory mediators were determined by RT-PCR, qPCR and ELISA. Overexpression of HIF-1α as well as knocking-down its expression was used to reveal its fundamental role. RASF-induced inflammatory T cell expansion was determined by flow cytometry analysis of T helper (Th)1/Th17 cells, and IFN-γ/IL-17 production by ELISA after RASF/T cell coculture. RESULTS: Hypoxia potentiated the expression of inflammatory cytokines, metalloproteinases and VEGF in RASF stimulated by different TLR ligands, especially polyIC, a synthetic mimic of dsRNA from viruses or apoptotic cells. HIF-1α played a fundamental role in this synergy. Moreover, HIF-1α overexpression enhanced RASF-mediated expansion of inflammatory Th1 and Th17 cells, leading to proinflammatory IFN-γ and IL-17 production. CONCLUSIONS: Our findings suggest that hypoxia and HIF-1α may function in conjunction with TLR-stimulated innate immune responses to drive inflammation in RA. This pathway may serve as a therapeutic target for the disease.

Increased human neutrophil lipocalin and its clinical relevance in adult-onset Still's disease.

BACKGROUND: Human neutrophil lipocalin (HNL) has been used extensively to differentiate acute bacterial infection from febrile diseases as a biomarker to reflect the activation of the neutrophil. The serum HNL levels in the adult-onset Still's disease (AOSD) patients with and without infection, as well as the healthy controls (HCs), were analyzed statistically in this study to evaluate the value of HNL for the diagnosis of AOSD. METHODS: A total of 129 AOSD patients were enrolled, from whom blood samples were drawn and the AOSD diagnosis was confirmed through the review of the medical records, where the systemic score, demographic characteristics, clinical manifestations, and laboratory parameters were also collected for the patients; in addition, a total of 40 HCs were recruited among the blood donors from the healthcare center with the relevant information collected. The HNL test was done for the blood samples with the enzyme-linked immunosorbent assay and the analyses were done for the correlations of HNL with clinical manifestations and diagnostic effectiveness. RESULTS: The serum HNL increased significantly in the patients with only AOSD as compared with that in the HCs (139.76 ±â€Š8.99 ng/mL vs . 55.92 ±â€Š6.12 ng/mL; P  < 0.001). The serum HNL level was correlated with the white blood cell (WBC) count ( r  = 0.335, P  < 0.001), neutrophil count ( r  = 0.334, P  < 0.001), erythrocyte sedimentation rate ( r  = 0.241, P  = 0.022), C-reactive protein ( r  = 0.442, P  < 0.0001), and systemic score ( r  = 0.343, P  < 0.0001) in the AOSD patients significantly. Patients with fever, leukocytosis ≥15,000/mm 3 , and myalgia in the HNL-positive group were observed relatively more than those in the HNL-negative group ( P  = 0.009, P  = 0.023, and P  = 0.007, respectively). HNL was a more sensitive indicator than ferritin and C-reactive protein (CRP) to differentiate the AOSD patients with bacterial infection from AOSD-only patients, and the Youden index was 0.6 for HNL and 0.29 for CRP. CONCLUSION: Serum HNL can be used as a biomarker for the diagnosis of the AOSD, and HNL is also observed to be associated with the disease activity.

Intestinal butyrate-metabolizing species contribute to autoantibody production and bone erosion in rheumatoid arthritis.

The imbalance between pathogenic and beneficial species of the intestinal microbiome and metabolism in rheumatoid arthritis (RA) remains unclarified. Here, using shotgun-based metagenome sequencing for a treatment-naïve patient cohort and a "quasi-paired cohort" method, we observed a deficiency of butyrate-producing species and an overwhelming number of butyrate consumers in RA patients. These outcomes mainly occurred in patients with positive ACPA, with a mean AUC of 0.94. This panel was also validated in established RA with an AUC of 0.986 in those with joint deformity. In addition, we showed that butyrate promoted Tregs, while suppressing Tconvs and osteoclasts, due to potentiation of the reduction in HDAC expression and down-regulation of proinflammatory cytokine genes. Dietary butyrate supplementation conferred anti-inflammatory benefits in a mouse model by rebalancing TFH cells and Tregs, as well as reducing antibody production. These findings reveal the critical role of butyrate-metabolizing species and suggest the potential of butyrate-based therapies for RA patients.

Comparison of short interval and low dose (SILD) with high dose of cyclophosphamide in the susceptibility to infection in SLE: a multicentrereal-world study.

OBJECTIVE: Infection is a major cause of death in patients with SLE. This study aimed to explore the infection rate in patients with SLE receiving a low dose of intravenous cyclophosphamide (IV-CYC). METHODS: Clinical parameters of 1022 patients with SLE from 24 hospitals in China were collected. Patients were divided into the short-interval and lower-dose (SILD, 400 mg every 2 weeks) IV-CYC group and the high-dose (HD, 500 mg/m2 of body surface area every month) IV-CYC group. The clinical data and infection rate between the two groups were compared. RESULTS: Compared with HD IV-CYC, the infection rate of the SILD IV-CYC group was significantly lower (13.04% vs 22.27%, p=0.001). Respiratory tract infection (10.28% vs 15.23%, p=0.046) and skin/soft tissue infection (1.78% vs 4.3%, p=0.040) were significantly decreased in the SILD IV-CYC group. Moreover, infections occurred most likely in patients with SLE with leucopenia (OR 2.266, 95% CI 1.322 to 3.887, p=0.003), pulmonary arterial hypertension (OR 2.756, 95% CI 1.249 to 6.080, p=0.012) and >15 mg/day of glucocorticoid (OR 2.220, 95% CI 1.097 to 4.489, p=0.027). CONCLUSIONS: SILD IV-CYC showed a lower frequency of infection events than high-dose IV-CYC in patients with SLE.

Dickkopf-1 perpetuated synovial fibroblast activation and synovial angiogenesis in rheumatoid arthritis.

OBJECTIVE: Dickkopf-1 (Dkk-1), a regulatory molecule of the Wnt pathway, is elevated and leads to bone resorption in patients with RA. This study is aimed to investigate the contribution of Dkk-1 to synovial inflammation and synovial fibroblast-mediated angiogenesis in RA. METHODS: The expression of Dkk-1 in RA synovial fibroblasts (RASF) and osteoarthritis synovial fibroblasts (OASF) was detected by real-time PCR and ELISA, respectively. RASF were stimulated with different pro-inflammatory factors. The expression of angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF was analyzed by real-time PCR when Dkk-1 was inhibited or overexpressed. Meanwhile, the concentrations of MCP-1, IL-6, IL-8, and MMP-3 in the cell culture supernatant were assessed by ELISA. The effects of Dkk-1 on the MAPK signaling pathway were evaluated by western blot. Matrigel tube formation assay was employed to reveal the direct and indirect effects of Dkk-1 on synovial angiogenesis. RESULTS: Dkk-1 expression was elevated in synovial fluids and synovial fibroblasts of RA patients. Treatment with various pro-inflammatory cytokines significantly promoted DKK-1 expression in RASF. The production of potent angiogenic factors, pro-inflammatory cytokines, and MMPs in RASF was elevated, whereas the reverse results were found in the inhibitor groups. Silenced Dkk-1expression in RASF dampened capillary tube organization in both direct and indirect manners, resulting in restrained ERK, JNK, and p38 signaling pathway activation. CONCLUSION: We concluded that Dkk-1 exacerbated the inflammation, cartilage erosion, and angiogenesis mediated by synovial fibroblasts in RA. Modulation of DKK-1 expression may facilitate development of novel strategies to control RA. Key points • Dkk-1 expression was elevated in synovial fluids and synovial fibroblasts of RA patients. • Treatment with various pro-inflammatory cytokines significantly promoted DKK-1 expression. • Silenced Dkk-1expression in RASF dampened capillary tube organization.

A Clinical Risk Model to Predict Rapidly Progressive Interstitial Lung Disease Incidence in Dermatomyositis.

Background: Rapidly progressive interstitial lung disease (RP-ILD) is a fatal complication of dermatomyositis (DM) and clinically amyopathic DM (CADM). The objective of this study was to evaluate risk markers associated with RP-ILD incidence in patients with DM/CADM and to develop a RP-ILD risk prediction (RRP) model. Methods: The clinical records of 229 patients with DM/CADM from Peking University People's Hospital, and 97 patients from four other independent clinical centers were retrospectively reviewed. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors associated with later RP-ILD incidence to build a risk score model. The concordance index (C-index) and calibration curve were calculated to evaluate the predictive accuracy of the RRP model. Results: A multiparametric RRP model was established based on weighted clinical features, including fever (yes, 5; no, 0), periungual erythema (yes, 6; no, 0), elevated CRP (yes, 5; no, 0), anti-MDA5 antibody (positive, 8; negative, 0), and anti-Ro-52 antibody (positive, 6; negative, 0). Patients were divided into three risk groups according to the RRP total score: low, 0-9; medium, 10-19; high, 20-30. The C-index and calibration curve of the RRP model showed a promising predictive accuracy on the incidence of RP-ILD. Conclusion: The RRP model might promisingly predict the incidence of RP-ILD in DM/CADM patients to guide early individual treatment and further improve the prognosis of DM/CADM patients.

Risk factors for cancer-associated myositis: A large-scale multicenter cohort study.

AIM: The aim of this study was to identify the risk factors and prognosis of patients with cancer-associated myositis (CAM). METHOD: Four hundred and eighty-seven patients with dermatomyositis (DM), clinical amyopathic dermatomyositis (CADM) and polymyositis (PM) from 3 clinical centers were enrolled retrospectively in this study. Clinical and laboratory data of CAM and non-CAM patients were compared. Logistic regression analysis was used to identify risk factors of CAM. RESULTS: Out of the 487 patients with DM/CADM/PM, 7.0% (34/487) of patients were classified as CAM. Older age (53.91 ± 13.32 vs. 48.76 ± 14.34 years), heliotrope rash (61.8% vs. 41.9%), shawl sign (41.2% vs. 22.1%), V sign (58.8% vs. 38.6%) were observed significantly more commonly in patients with CAM than those without CAM (all P < .05). Fever (17.7% vs. 37.8%), arthralgia/arthritis (23.5% vs. 45.7%), interstitial lung disease (ILD, 38.2% vs 68.9%) were significantly less common in the CAM group than the non-CAM group. Age at onset (odds ratio [OR] 1.036, 95% CI 1.001-1.072, P = .042), shawl sign (OR 2.748, 95% CI 1.107-6.822, P = .029), anti-transition initiation factor (TIF)-1γ antibody (OR 4.012, 95% CI 1.268-12.687, P = .018) were identified as the initial risk factors for the onset of CAM, and ILD was identified as a protective factor for CAM (OR 0.292, 95% CI 0.115-0.739, P = .009). All-cause mortality was significantly higher in CAM patients compared with non-CAM patients (P = .001). CONCLUSION: The mortality of patients with CAM was higher than DM/CADM/PM patients without cancer. Malignancy should be screened in DM/CADM/PM patients especially with risk factors, including older age, shawl sign, anti-TIF-1γ antibody, and lack of ILD.