Peripheral Blood Lymphocyte Subsets and Heterogeneity of B Cell Subsets in Patients of Idiopathic Inflammatory Myositis with Different Myositis-specific Autoantibodies.

Idiopathic inflammatory myopathies (IIM) are a group of myopathies that present with muscle weakness and multiple extra-muscular manifestations, in which lymphocytes play central roles in myositis pathogenesis. This study aimed to explore the clinical characteristics of lymphocyte subsets, especially B cell subsets, in patients with IIM. Our study included 176 patients with active IIM and 210 gender/age-matched healthy controls (HCs). Compared to HCs, patients have reduced counts of T cells, B cells, and natural killer cells. In addition, B cell subsets from 153 patients with IIM and 92 HCs were characterized. Patients had a lower percentage of memory B cells and translational memory B cells, while those patients were with an elevated percentage of CD19+ B cells, plasmablast and naïve B cells compared with HCs. Moreover, to further explore the heterogeneity of B cells in IIM, patients were categorized into three clusters based on clustering analysis. Cluster 1 was dominated by CD19+ B cells, Bregs and naïve B cells, cluster 3 was dominated by memory B cells and plasmablast, and cluster 2 had the highest proportion of translational memory B cells. Notably, patients in cluster 1 presented with higher CK levels, indicating muscle damage, whereas patients in cluster 3 showed a higher incidence of chest tightness. Our study indicated that lymphopenia is a common manifestation in patients with IIM. B cell subsets are abnormally expressed and showed high heterogeneity in patients with IIM. The patients with IIM were divided into three different clusters with different percentages of chest tightness and distinct CK levels.

Comparison of clinical characteristics between patients with axial spondyloarthritis with and without acute anterior uveitis: a multicentre study of the Chinese Spondyloarthritis Registry.

OBJECTIVES: This study explores the clinical characteristics associated with the occurrence of acute anterior uveitis (AAU) in patients with axial spondyloarthritis (axSpA) within a large, multicentre database. METHODS: This observational, cross-sectional study of patients with axSpA used data from the Chinese Spondyloarthritis Registry between August 1, 2018, and March 31, 2020. The demographic and clinical features of patients with and without AAU were compared. Univariate and multivariate analyses were performed to determine the association between variables and uveitis. RESULTS: A total of 4304 patients were included in this study. The prevalence of AAU in patients with axSpA was 10.59%. Multivariate logistic regression analysis revealed a positive correlation between AAU and age at diagnosis (odds ratio [OR], 1.026; p<0.001), disease duration (OR, 2.117; p<0.001), current or past Achilles tendinitis (OR, 1.692; p<0.001), current or past dactylitis (OR, 1.687; p=0.002), current or past psoriasis (OR, 3.932; p<0.001), presence of human leukocyte antigen-B27 (HLA-B27) (OR, 2.787; p<0.001), and a good response to non-steroidal anti-inflammatory drugs (NSAIDs) (OR, 1.343; p=0.027). CONCLUSIONS: AAU was the most common extra-articular manifestation in the Chinese Spondyloarthritis Registry. In Chinese patients with axSpA, older age at diagnosis, longer disease duration, presence of HLA-B27, current or past Achilles tendinitis, current or past dactylitis, current or past psoriasis, and a good response to NSAIDs were positively associated with AAU.

Changes in metabolic parameters and serum YKL-40 levels in Chinese rheumatoid arthritis patients during tocilizumab therapy.

OBJECTIVE: To investigate the metabolic changes during therapy of tocilizumab (TCZ) and methotrexate (MTX) in non-diabetic rheumatoid arthritis (RA) patients and for the first time explore the associations between metabolic parameters and serum YKL-40 (sYKL-40) levels. METHODS: We enrolled active non-diabetic RA patients who were refractory to MTX. Patients received intravenous TCZ (8 mg/kg) once every 4 weeks combined with MTX for 24 weeks. Metabolic parameters and sYKL-40 levels were measured before TCZ infusion at baseline, week 4, week 12, and week 24. Correlations were assessed by the Spearman's rank correlation analysis. RESULTS: A total of 91 non-diabetic RA patients were enrolled in this study. At week 24, we observed a significant elevation in body mass index (BMI), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels. In contrast, there was a significant decrease in TC/HDL­C ratio. No apparent changes in insulin resistance were found. Additionally, we detected a significant reduction in sYKL-40 levels during the study. At week 24, changes in sYKL-40 levels showed a significant negative correlation (r = -0.334, p = 0.002) with changes in TC levels. CONCLUSION: The combined therapy of TCZ and MTX resulted in a significant increase in BMI and lipid levels, while an evident decrease in the TC/HDL­C ratio and sYKL-40 levels in RA patients. Additionally, there was a significant correlation between the decrease in sYKL-40 levels and the increase in TC levels during treatment with TCZ and MTX. Key Points • Lipid levels elevated significantly and sYKL-40 levels decreased obviously after therapy of TCZ combined with MTX in Chinese RA patients. • There was a significant correlation between the increase in TC levels and the decrease in sYKL-40 levels during treatment with TCZ and MTX in RA patients.

Arenethiolate-Catalyzed 1,5-HAT of Aryl Halides: Synthesis of γ-Spirolactams.

γ-Spirolactam is a privileged building block that is found in a wide range of natural products and bioactive compounds. Herein, we report an arenethiolate-catalyzed 1,5-HAT of aryl halides to obtain γ-spirolactams through a SET reduction/intramolecular 1,5-HAT/cyclization/HAT process. This protocol features metal-free conditions and a broad substrate scope, furnishing the γ-spirolactams in moderate to excellent yields. Notably, aryl bromides, aryl chlorides and even aryl fluorides are well tolerated in this transformation. A mechanism involving arenethiolate as a SET catalyst is proposed based on DFT calculation.

Anemia and Low Body Mass Index in Axial Spondyloarthritis: Results from ChinaSpA, the Chinese Spondyloarthritis Registry.

INTRODUCTION: Anemia and malnutrition are recognized indicators of suboptimal physical condition in chronic inflammatory diseases. This study aimed to examine the association between anemia, low body mass index (BMI), and clinical outcomes in axial spondyloarthritis (axSpA). METHOD: This cross-sectional analysis utilized data from the multicenter ChinaSpA cohort. A total of 4146 participants with axSpA were categorized into four groups based on BMI and hemoglobin levels: those with both anemia and low BMI, those with anemia only, those with low BMI only, and those with neither condition. Logistic regression analyses were performed to analyze the association between anemia, low BMI, inflammation status, functional impairment, and disease activity. RESULTS: Anemia was present in 13.94%, low BMI in 11.99%, and both conditions in 2.15% of axSpA participants. Those with both anemia and low BMI showed significantly higher levels of inflammation (hypersensitive C-reactive protein [hsCRP] 30.60 mg/L vs. 8.44 mg/L), functional impairment (Bath Ankylosing Spondylitis Functional Index [BASFI] 3.80 vs. 2.10), and disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI] 4.52 ± 2.04 vs. 3.67 ± 2.21; Ankylosing Spondylitis Disease Activity Score calculated with C-reactive protein [ASDAS_CRP] 3.51 ± 1.10 vs. 2.62 ± 1.21) compared to those without these conditions. After adjusting for sex and age, significant associations were observed between elevated hsCRP levels and the presence of low BMI (odds ratio [OR] 1.44, 95% CI 1.17-1.78), anemia (OR 1.91, 95% CI 1.56-2.32), and their concurrent presence (OR 3.59, 95% CI 2.22-5.80). Similarly, increased BASFI was significantly associated with low BMI (OR 1.57, 95% CI 1.25-1.97), anemia (OR 1.47, 95% CI 1.19-1.80), and their combination (OR 3.11, 95% CI 2.02-4.78). CONCLUSION: All-cause anemia and low BMI are prevalent complications in patients with axSpA, exhibiting a significant correlation with elevated inflammation status and functional impairment. The simultaneous occurrence of anemia and low BMI particularly exacerbates clinical outcomes, emphasizing the critical role of comprehensive nutritional assessment and management in the therapeutic strategy for axSpA.

Comparing tocilizumab biosimilar BAT1806/BIIB800 with reference tocilizumab in patients with moderate-to-severe rheumatoid arthritis with an inadequate response to methotrexate: a phase 3, randomised, multicentre, double-blind, active-controlled clinical trial.

BACKGROUND: Biosimilars provide an opportunity to address unmet medical need by expanding access to biological treatments. This study aimed to show equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles of a proposed tocilizumab biosimilar BAT1806/BIIB800, to reference tocilizumab, in participants with rheumatoid arthritis with an inadequate response to methotrexate. METHODS: This phase 3, multicentre, randomised, double-blind, active-controlled, equivalence study comprised a 24-week initial treatment period (results reported here) and a 24-week secondary treatment period. Participants were recruited at 54 centres across five countries (China, Ukraine, Poland, Georgia, and Bulgaria). Patients with active rheumatoid arthritis with an inadequate response to methotrexate were randomly assigned (1:1:2) to receive reference tocilizumab up to week 48, or reference tocilizumab up to week 24 followed by BAT1806/BIIB800 up to week 48 (the two reference tocilizumab groups were analysed as a single group in this analysis), or BAT1806/BIIB800 up to week 48 (the BAT1806/BIIB800 group), administered by intravenous infusion once every 4 weeks at a starting dose of 8 mg/kg. The primary endpoint was the proportion of participants who had a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 (for the European Medicines Agency [EMA]) or week 24 (for the US Food and Drug Administration [FDA] and China National Medical Products Administration [NMPA]) using prespecified equivalence margins (95% CI -14·5 to +14·5 [EMA], 90% CI -12·0 to +15·0 [FDA], and 95% CI -13·6 to +13·6 [NMPA]). The International Council for Harmonisation E9(R1) estimand framework, with strategies for addressing intercurrent events, was implemented for the efficacy evaluations with expected differences as per the predefined equivalence margins. This trial is registered at ClinicalTrials.gov (NCT03830203) and EudraCT (2018-002202-31), and is closed to new participants. FINDINGS: Between Dec 19, 2018, and Jan 5, 2021, we randomly assigned 621 participants: 309 to the reference tocilizumab group and 312 to the BAT1806/BIIB800 group. The mean age was 50·5 years (SD 12·0), 534 (86%) were women, 87 (14%) were men, and 368 (59%) were White. For the primary estimands, estimated ACR20 response rates were 64·8% in the reference tocilizumab group and 69·0% in the BAT1806/BIIB800 group (treatment difference 4·1% [95% CI -3·6 to 11·9]) at week 12, and 67·9% in the reference tocilizumab group and 69·9% in the BAT1806/BIIB800 group (treatment difference 1·9% [90% CI -4·0 to 7·9; 95% CI -5·2 to 9·1]) at week 24. All confidence intervals were contained within the predefined equivalence margins. Comparable pharmacokinetic and immunogenicity profiles were observed for the reference tocilizumab and BAT1806/BIIB800 groups. Adverse events were reported by 201 (65%) participants in the reference tocilizumab group and 206 (66%) in the BAT1806/BIIB800 group; 196 (63%) participants in the reference tocilizumab group and 201 (64%) participants in the BAT1806/BIIB800 group reported a treatment-emergent adverse event. Five participants had a fatal event (reference tocilizumab n=1; BAT1806/BIIB800 n=4). INTERPRETATION: BAT1806/BIIB800 showed equivalent efficacy, and comparable safety, immunogenicity, and pharmacokinetic profiles as reference tocilizumab. FUNDING: Bio-Thera Solutions and Biogen.

Predictors of mortality for dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 and optimal treatment.

OBJECTIVES: To explore the risk factors of early death in dermatomyositis patients positive with anti-melanoma differentiation-related gene 5 antibody (anti-MDA5-DM). To explore the optimal treatment regimen for patients with anti-MDA5-DM. METHODS: Patients with newly onset anti-MDA5-DM from June 2018 to October 2021 in our centre were retrospectively reviewed for 6 months. Patients were divided into five groups based on initial treatments. The major outcome was mortality in 6 months. Secondary outcomes included remission and severe infection. RESULTS: A total of 214 patients were included in the study. During 6 month follow-up, 63 patients (30.14%) died, 112 patients (53.59%) achieved remission, 52 patients (24.88%) experienced serious infection and 5 patients (2.34%) were lost. Independent risk factors of mortality in the first 6 months after diagnosis were as follows: age> 53 years, skin ulcer, peripheral blood lymphocyte count (LYMP)≤ 0.6×109/L, lactate dehydrogenase (LDH) > 500 U/L, C reactive protein (CRP) > 5mg/L, anti-Ro52 antibody and ground-glass opacity (GGO) score> 2. On the contrary, prophylactic use of the compound sulfamethoxazole (SMZ Co) was independent protective factor. The five-category treatment was not an independent influencing factor of early death, but subgroup analysis found that patients with rapidly progressive interstitial lung disease (RPILD) responded better to a triple combination of high-dose glucocorticoids (GC), calcineurin inhibitors (CNI) and cyclophosphamide (CYC) or a triple combibation of GC, CNI and tofacitinib (TOF). CONCLUSIONS: Advanced age, skin ulcer, lymphopenia, anti-Ro52 antibody and higher levels of LDH, CRP and GGO score increase the risk of early death for MDA5-DM, while prophylactic use of SMZ Co is protective. Aggressive therapy with combined immunosuppressants may improve the short-term prognosis of anti-MDA5-DM with RPILD.

Clinical features of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with macrophage activation syndrome.

OBJECTIVES: This study aimed to describe the clinical features of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5) antibody-positive dermatomyositis (DM) who had macrophage activation syndrome (MAS). METHODS: We retrospectively examined 44 patients with anti-MDA5-positive DM and compared the clinical features between patients with MAS (n = 11) and those without (n=33). Patients without MAS were selected randomly in the same year as those with MAS at a ratio of 3:1. Among patients with MAS, we compared the features between non-survivors and survivors. We used Fisher's exact test, Student's t test, the Mann-Whitney U test and the log-rank test for statistical analysis. RESULTS: Patients complicated with MAS had a significantly higher incidence of infection, heliotrope sign, Gottron's papule, V-neck sign, and higher serum levels of ferritin, aspartate aminotransferase (AST), lactic dehydrogenase (LDH), and creatine kinase (CK) than those without MAS (p<0.05). Among the 11 patients with MAS, 4 (36.4%) died after intensive treatment. Deceased patients were older, given more combination therapy with tofacitinib (TOF) and had a higher incidence of rapid progressive interstitial lung disease, infection, heart failure and renal impairment than those who survived (p<0.05). CONCLUSIONS: Among anti-MDA5-positive DM, Infection, DM typical rashes, and higher serum levels of ferritin, AST, LDH, and CK were more common in patients complicated with MAS. The mortality of patients with MAS was high, particularly among patients who were older, given more combination therapy with TOF, and had RP-ILD, infection, heart failure and renal impairment.

An Integration Framework of Secure Multiparty Computation and Deep Neural Network for Improving Drug-Drug Interaction Predictions.

Drug-drug interaction (DDI) is a key concern in drug development and pharmacovigilance. It is important to improve DDI predictions by integrating multisource data from various pharmaceutical companies. Unfortunately, the data privacy and financial interest issues seriously influence the interinstitutional collaborations for DDI predictions. We propose multiparty computation DDI (MPCDDI), a secure MPC-based deep learning framework for DDI predictions. MPCDDI leverages the secret sharing technologies to incorporate the drug-related feature data from multiple institutions and develops a deep learning model for DDI predictions. In MPCDDI, all data transmission and deep learning operations are integrated into secure MPC frameworks to enable high-quality collaboration among pharmaceutical institutions without divulging private drug-related information. The results suggest that MPCDDI is superior to other eight baselines and achieves the similar performance to that of the corresponding plaintext collaborations. More interestingly, MPCDDI significantly outperforms methods that use private data from the single institution. In summary, MPCDDI is an effective framework for promoting collaborative and privacy-preserving drug discovery.

Consensus on targeted drug therapy for spondyloarthritis.

Spondyloarthritis (SpA) is a group of chronic inflammatory diseases that predominantly involve the spine and/or peripheral joints. The clinical manifestations of SpA are highly heterogenous and complicated with various comorbidities. SpA is a disabling disease and adversely affects the quality of life of patients. Many new medications that target cytokines or pathways specific for the pathogenesis of SpA have been developed and they are becoming increasingly important in the treatment of SpA. However, identifying the target patient population and standardizing the usage of these drugs are critical issues in the clinical application of these "targeted therapeutic drugs". Under the leadership of National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), managed by Peking Union Medical College Hospital, the "Consensus on targeted drug therapy for spondyloarthritis" has been developed in collaboration with the Rheumatology and Immunology Physicians Committee, Chinese Medical Doctors Association, Rheumatology and Immunology Professional Committee, Chinese Association of Rehabilitation Medicine, and Chinese Research Hospital Association Rheumatology and Immunology Professional Committee. This consensus has been developed with evidence-based methodology and has followed the international standard for consensus development.

Ground-glass opacity score predicts the prognosis of anti-MDA5 positive dermatomyositis: a single-centre cohort study.

OBJECTIVE: Dermatomyositis (DM) positive with anti-melanoma differentiation-associated gene 5 (anti-MDA5-DM) is a systemic autoimmune disease with high mortality. This study aimed to explore the risk factors of death in anti-MDA5-DM and validate a prediction model for all-cause mortality in anti-MDA5-DM. METHOD: We conducted a retrospective study using a single-centre cohort of patients with newly onset anti-MDA5-DM from June 1, 2018 to August 31, 2021. Patients were divided into four groups according to baseline ground-glass opacity (GGO) score: Group A, GGO ≤ 1; Group B, 1 < GGO ≤ 2; Group C, 2 < GGO ≤ 3; Group D, GGO > 3. The primary outcome was death during the follow-up. Secondary outcomes included death within 3, 6, 12 months, severe infection, and remission during the first 12 months. RESULTS: A total of 200 patients were included in the study. Based on multivariable Cox regression, the prognostic factors at baseline were identified as CRP > 5 mg/L, serum ferritin (SF) > 600ng/ml, positive anti-Ro52 antibody, prophylactic use of compound sulfamethoxazole (SMZ Co), four-category GGO score: GGO ≤ 1, 1 < GGO ≤ 2, 2 < GGO ≤ 3, GGO > 3. The final mortality of four groups was 16.4, 22.2, 48.5, 92.0%, respectively. Compared with Group A, the Hazards Ratio (HR) of Group B was 1.408, (p = 0.408), HR of Group C was 3.433 (p = 0.005), HR of Group D was 4.376 (p = 0.001). CONCLUSIONS: GGO score is a reliable predictor for risk stratification in anti-MDA5-DM and may provide guidance for individualized managements of patients.

Research on the purification enhancement of ecological ponds: Integrating water cycle optimization and plants layout.

The hydrodynamic conditions of ponds are generally poor, which seriously affects the long-term water quality guarantee. In this research, the numerical simulation method was used to establish an integrated model of hydrodynamics and water quality for the simulation of the plant purification effect in ponds. Based on the flushing time using the tracer method, the purification rate of plants was introduced to consider the purification effect of plants on water quality. In-situ monitoring was carried out at the Luxihe pond in Chengdu, and the model parameters such as the purification rate of typical plants were calibrated. The degradation coefficient of NH3-N in the non-vegetated area was 0.014 d-1 in August and 0.010 d-1 in November. In areas with vegetation, the purification rate of NH3-N was 0.10-0.20 g/(m2·d) in August and 0.06-0.12 g/(m2·d) in November. The comparison of the results in August and November showed that due to the higher temperature in August, the plant growth effect was better, and the degradation rate of pollutants and the purification rate of pollutants by plants were higher. The flushing time distribution of the proposed Baihedao pond under the conditions of terrain reconstruction, water replenishment, and plant layout was simulated, and the frequency distribution curve of flushing time was used to evaluate the results. Terrain reconstruction and water replenishment can significantly improve the water exchange capacity of ponds. The reasonable planting of plants can reduce the variability of the water exchange capacity. Based on this combined with the purification effect of plants on NH3-N, the layout plan of Canna, Cattails, and Thalia in ponds was proposed.

Type 1 interferon signature in peripheral blood mononuclear cells and monocytes of idiopathic inflammatory myopathy patients with different myositis-specific autoantibodies.

Background: Myositis-specific autoantibodies (MSAs) are clinically used to diagnose and define idiopathic inflammatory myopathy (IIM) subsets. However, the underlying pathogenic mechanisms of patients with different MSAs remain unclear. Methods: A total of 158 Chinese patients with IIM and 167 gender- and age-matched healthy controls (HCs) were enrolled. Transcriptome sequencing (RNA-Seq) was performed with peripheral blood mononuclear cells (PBMCs), followed by the identification of differentially expressed genes (DEGs) and analysis of gene set enrichment analysis, immune cell infiltration, and WGCNA. Monocyte subsets and related cytokines/chemokines were quantified. The expressions of interferon (IFN)-related genes were validated using qRT-PCR and Western blot in both PBMCs and monocytes. We also performed correlation analysis and ROC analysis to explore the potential clinical significance of the IFN-related genes. Results: There were 1,364 genes altered in patients with IIM, including 952 upregulated and 412 downregulated genes. The type I interferon (IFN-I) pathway was remarkably activated in patients with IIM. Compared with patients with other MSAs, IFN-I signatures were significantly activated in patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies. In total, 1,288 hub genes associated with IIM onset were identified using WGCNA, including 29 key DEGs associated with IFN signaling. The patients had more CD14brightCD16- classical, CD14brightCD16+ intermediate, and fewer CD14dimCD16+ non-classical monocyte subsets. Plasma cytokines like IL-6 and TNF and chemokines including CCL3 and MCPs increased. The validation of IFN-I-related gene expressions was consistent with the findings from RNA-Seq. The IFN-related genes were correlated with laboratory parameters and helpful for IIM diagnosis. Conclusion: Gene expressions were remarkably altered in the PBMCs of IIM patients. Anti-MDA5+ IIM patients had a more pronounced activated IFN signature than others. Monocytes exhibited a proinflammatory feature and contributed to the IFN signature of IIM patients.

Radial growth responses of three coniferous species to climate change on the southern slope of Funiu Mountains, China.

Funiu Mountains are located in a transition region between warm temperate zone and northern subtropical region, where a variety of plant species are distributed with sensitive response to climate change. Their response characteristics to climate change are still unclear. We developed the basal area increment (BAI) index chronologies of Pinus tabuliformis, P. armandii, and P. massoniana in the Funiu Mountains to examine their growth trend and their sensitivity to climatic change. The results showed that the BAI chronologies gave a clue that the three conife-rous species had similar radial growth rate. The large Gleichlufigkeit (GLK) indices among the three BAI chronologies also indicated that the three species had a similar growth trend. Results of correlation analysis showed that the three species also had similar response to climatic change to a certain extent. Radial growth of all the three species was significantly positively correlated with the total monthly precipitation in December of previous year and June of the current year, but negatively correlated with the precipitation in September and the mean monthly temperature in June of the current year. There were some differences in the responses of the three coniferous to climate change. P. massoniana had a significant negative correlation with the mean temperature in March, and a significant positive correlation with the precipitation in March, while P. armandii and P. massoniana were affected negatively by the maximum temperature in August. Results of the moving correlation analysis showed that the three coniferous species had some similar sensitivity to climate change. Their positive responses to precipitation in previous December consistently increased, as well as the negative correlation with precipitation in current September. As to P. masso-niana, they had a relatively stronger climatic sensitivity and higher stability than the other two species. It would be more suitable for P. massoniana trees on the southern slope of the Funiu Mountains under global warming.

Plasma proteomic profiling reveals KRT19 could be a potential biomarker in patients with anti-MDA5+ dermatomyositis.

OBJECTIVE: To investigate the immune response-related protein profiling in plasma of patients with idiopathic inflammatory myopathies (IIMs), especially in anti-MDA5+ dermatomyositis (DM). METHODS: A total of 166 IIM patients and 107 healthy controls (HCs) were enrolled in our study. Ninety-two plasma immune response-related proteins were detected by Olink proteomics in 36 IIM patients and 25 HCs. The expression of plasma KRT19 was validated in another 130 IIM patients, 82 HCs, and 55 other rheumatic diseases. RESULTS: A total of 46 differentially expressed proteins were detected, including 12 upregulated proteins and 34 downregulated proteins in IIM patients compared with HCs. Pathway analysis revealed lactoferrin danger signal response pathway, TLR4 signaling and tolerance, infection, and IL-10 signaling pathway were activated. The immune response-related protein profiling significantly altered in anti-MDA5+ DM patients, with LAMP3, HSD11B1, and KRT19 significantly increased, while SH2D1A, ITGA11, TRIM21, CD28, ITGB6, and HEXIM1 tremendously decreased. In addition, KRT19 was significantly increased in IIM patients, especially in anti-MDA5+ DM patients with the diagnostic value of a significant area under the ROC curve of 0.881. CONCLUSION: Immune response-related proteins are significantly altered in patients with anti-MDA5+ DM patients. KRT19 could be a potential biomarker for anti-MDA5+ DM patients. Key Points • What is already known on this topic? Anti-MDA5+ DM is a distinctive subtype of IIM. Plasma immune response-related proteins panel needs to be investigated. • What this study adds? Plasma protein profiling of immune response-related proteins significantly altered in patients with idiopathic inflammatory myopathies (IIM), especially in anti-MDA5+ DM patients. • How this study might affect research, practice, or policy? KRT19 could be a potential biomarker in patients with anti-MDA5+ dermatomyositis.

Latent Tuberculosis Infection and Associated Factors in Patients with Systemic Lupus Erythematosus: a Multicenter, Cross-Sectional Study.

The objectives of this study were to screen for latent tuberculosis infection (LTBI) among patients with systemic lupus erythematosus (SLE) using the T-SPOT.TB assay and to identify factors affecting the assay results. SLE patients were enrolled from 13 tertiary hospitals in eastern, central, and western China from September 2014 to March 2016 and were screened using the T-SPOT.TB assay to detect LTBI. Basic information about the subjects was collected, including gender, age, body mass index (BMI), course of disease, evidence of previous tuberculosis, Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, and the use of glucocorticoids and immunosuppressants. Univariate analysis and multivariable logistic regression were performed to identify factors affecting the results of the T-SPOT.TB assay. In all, 2,229 SLE patients were screened using the T-SPOT.TB assay, of whom 334 patients tested positive, yielding a positivity rate of 15% (95% confidence interval [CI], 13.5% to 16.5%). The positivity rate was higher in male than female patients and had an increasing trend with age. Multivariable logistic regression analysis showed that patients over 40 (odds ratio [OR], 1.65; 95% CI, 1.29 to 2.10) and with evidence of previous tuberculosis (OR, 4.43; 95% CI, 2.81 to 6.99) were more likely to have positive T-SPOT.TB results, while patients with a SLEDAI-2K score of ≥10 (OR, 0.61; 95% CI, 0.43 to 0.88), a glucocorticoid dose of ≥60 mg/d (OR, 0.62; 95% CI, 0.39 to 0.98), leflunomide (LEF) treatment (OR, 0.51; 95% CI, 0.29 to 0.88), or tacrolimus (FK506) treatment (OR, 0.40; 95% CI, 0.16 to 1.00) were more likely to have negative T-SPOT.TB results. The frequencies of CFP-10-specific gamma interferon (IFN-γ)-secreting T cells were significantly lower in SLE patients with severe disease activity or high-dose glucocorticoids (P < 0.05). The positivity rate of the T-SPOT.TB assay was 15% among SLE patients. Severe, active SLE disease and the use of high-dose glucocorticoids and some types of immunosuppressants are likely to result in negative T-SPOT.TB results. For SLE patients with the above conditions, diagnosing LTBI based on a positive T-SPOT.TB result may lead to underestimation of the prevalence. IMPORTANCE The burden of tuberculosis and systemic lupus erythematosus in China ranks among the top three in the world. Therefore, active screening for LTBI and preventive intervention in SLE patients are of great significance in China. In view of the lack of relevant data in a large sample, we conducted a multicenter, cross-sectional study using T-SPOT.TB as a screening method for LTBI, to investigate the prevalence of LTBI and analyze the factors affecting the results of the T-SPOT.TB assay in SLE patients. Our study showed that the overall positivity rate of the T-SPOT.TB assay in SLE patients was 15.0%, which was lower than the estimated LTBI prevalence in the general population in China (~20%). For SLE patients with severe, active disease, high-dose glucocorticoids, and some types of immunosuppressants, a diagnosis of LTBI based on only positive T-SPOT.TB results may lead to underestimation of the prevalence.

Efficacy and Safety of CMAB008 Compared with Innovator Infliximab in Patients with Moderate-to-Severe Rheumatoid Arthritis Receiving Concomitant Methotrexate: A Randomized, Double-blind, Multi-center, Phase III Non-inferiority Study.

OBJECTIVES: The aim of this work is to verify the non-inferior efficacy and safety of CMAB008 compared with innovator infliximab in rheumatoid arthritis patients combined with methotrexate. METHODS: We conducted a randomized, double-blinded, parallel, positive control design, multicenter study, with a stable dose of methotrexate. Patients were enrolled randomly with a ratio of 1:1 to receive intravenously CMAB008 3 mg/kg or innovator infliximab 3 mg/kg at weeks 0, 2, 6, 14, 22 and 30. The primary efficacy endpoint was American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 30. The non-inferiority was established if the lower limit of the one-sided 97.5% confidence interval (CI) for the difference was more than - 15% and the equivalence was established if the two-sided 95% CI was within ± 15% in an exploratory equivalence analysis. The secondary endpoints included other efficacy assessment parameters, as well as immunogenicity, safety, and pharmacokinetics. RESULTS: In the full analysis population (FAS), 110 (57.6%) of 191 patients in the CMAB008 group and 120 (62.2%) of 193 patients in the innovator infliximab group reached the primary outcome of ACR20 at week 30. The differences of the rates were - 4.6% and the lower limit of one-sided 97.5% confidence interval was - 14.29%, not less than the lower limit of the non-inferiority margin (- 15%); so CMAB008 was non-inferior to innovator infliximab. Further, CMAB008 was equivalent to innovator infliximab both in FAS (difference - 4.6%, 95% CI - 14.29% to 5.12%) and PPS (difference - 3.3%, 95% CI - 13.18% to 6.62%). The efficacy, safety, immunogenicity, and pharmacokinetics are highly similar between CMAB008 and innovator infliximab. CONCLUSIONS: Non-inferior efficacy of CMAB008 to innovator infliximab is illustrated with similar early and lasting therapeutic effects, and the equivalence is further demonstrated. CMAB008 is well tolerated and has semblable safety compared with the innovator infliximab. TRIAL REGISTRATION NUMBER: NCT03478111.

Age- and sex-specific differences in the association of serum osteocalcin and cardiometabolic risk factors in type 2 diabetes.

BACKGROUND: Serum osteocalcin levels are closely related to metabolic syndrome and cardiovascular disease. This study aimed to investigate the relationship between serum osteocalcin levels and cardiometabolic risk factors in patients with type 2 diabetes (T2D) according to age and sex. METHODS: This cross-sectional study included 1500 patients with T2D (991 men and 509 women) aged ≥ 18 years old. The age- and sex-specific disparities in glycemic and lipid control, as well as cardiometabolic risk factors were evaluated. RESULTS: The levels of serum osteocalcin were significantly higher in women aged > 50 years compared with women aged ≤ 50 years (15.6 ± 6.5 ng/mL vs. 11.3 ± 4.5 ng/mL, p < 0.0001). However, this was lower in men aged > 50 years than men aged ≤ 50 years (12.2 ± 4.2 ng/mL vs. 12.9 ± 4.3 ng/mL, p = 0.0081). We performed correlation analyses of serum osteocalcin and cardiometabolic parameters. Serum osteocalcin concentrations were negative associated with FBG and HbA1c levels in women and men ≤ 50 years old, but not in men aged > 50 years old. Serum osteocalcin were negatively correlated with TG and positively correlated with HDL-C and LDL-C only in men aged ≤ 50 years. In binary logistic regression analysis, serum osteocalcin levels were associated with multiple cardiovascular risk factors, as follows: overweight/obese (odds ratio [OR], 0.944; 95% confidence interval [CI], 0.9-0.991, p = 0.02) in men aged > 50 years; high HbA1C and high FBG in women and men aged ≤ 50 years, but not in men aged > 50 years; after adjustment for confounding factors, high TG (OR, 0.905; 95% CI 0.865-0.947, p < 0.0001), metabolic syndrome (OR, 0.914; 95% CI 0.874-0.956, p < 0.0001), and low high-density lipoprotein cholesterol (OR, 0.933; 95% CI, 0.893-0.975, p = 0.002) were seen in men aged ≤ 50 years only. CONCLUSIONS: Serum osteocalcin level has significant relationships with cardiometabolic risk factors and several age- and sex-related differences in patients with T2D. Decreased serum osteocalcin levels are associated with a worse cardiometabolic risk profile.

Alterations in the human oral microbiota in systemic lupus erythematosus.

BACKGROUND: Alterations in oral microbiota in patients with systemic lupus erythematosus (SLE) is less evaluated. The aim of this study was to compare the characteristics of the oral microbiome in SLE patients and healthy controls, and construct an SLE classifier based on the oral microbiota. METHODS: We sequenced tongue-coating samples of individuals in treatment-naïve SLE (n = 182) and matched healthy controls (n = 280). We characterized the oral microbiome and constructed a microbial classifier in the derivation cohort and validated the results in the validation cohorts. Furthermore, the oral microbiome of posttreatment SLE (n = 73) was characterized. RESULTS: The oral microbial diversity of SLE was increased, and the microbial community was different between SLE and healthy controls. The genera Prevotella and Veillonella were enriched, while Streptococcus and Porphyromonas were reduced in SLE. In addition, an increase was noted in 27 predicted microbial functions, while a decrease was noted in 34 other functions. Thirty-nine operational taxonomy units (OTUs) were identified to be related with seven clinical indicators. Two OTUs were identified to construct a classifier, which yielded area under the curve values of 0.9166 (95% CI 0.8848-0.9483, p < 0.0001), 0.8422 (95% CI 0.7687-0.9157, p < 0.0001), and 0.8406 (95% CI 0.7677-0.9135, p < 0.0001) in the derivation, validation, and cross-regional validation groups, respectively. Moreover, as disease activity increased, Abiotrophia and Lactobacillales increased, while Phyllobacterium and unclassified Micrococcusaceae decreased. Finally, nine OTUs were selected to construct a classifier distinguishing posttreatment SLE patients from healthy controls, which achieved a diagnostic efficacy of 0.9942 (95% CI 0.9884-1, p < 0.0001). CONCLUSIONS: Our study comprehensively characterizes the oral microbiome of SLE and shows the potential of the oral microbiota as a non-invasive diagnostic biomarker in SLE.