Alterations in peripheral T- and B-cell subsets in patients with systemic sclerosis.

OBJECTIVES: To determine the alteration of peripheral T and B cell subsets in patients with systemic sclerosis (SSc) and to evaluate their correlation with the progression of SSc. METHODS: We recruited 47 SSc patients and 45 healthy controls (HCs) in this study. Demographic and clinical data were then collected. Flow cytometry was used to detect the proportions of 44 different T and B cell subsets in circulating blood. RESULTS: The proportion of total B cells (p = .043) decreased in SSc patients, together with similar frequencies of total T cells, CD4+ T cells, and CD8+ T cells in both groups. Several subsets of T and B cells differed significantly between these two groups. Follicular helper T cells-1 (Tfh1) (p < .001), helper T cells-1 (Th1) (p = .001), regulatory T cells (Treg) (p = .004), effector memory CD8+ T cells (p = .041), and cytotoxic T cells-17 (Tc17) (p = .01) were decreased in SSc patients. Follicular helper T cells-2 (Tfh2) (p = .001) and, helper T cells-2 (Th2) (p = .001) levels increased in the SSc group. Regulatory B cells (Breg) (p = .015) were lower in the SSc group, together with marginal zone (MZ) B cells (p < .001), memory B cells (p = .001), and non-switched B cells (p = .005). The modified Rodnan skin score (mRSS) correlated with helper T cells-17 (Th17) (r = -.410, p = .004), Tfh1 (r = -.321, p = .028), peripheral helper T cells (Tph) (r = -.364, p = .012) and plasma cells (r = -.312, p = .033). CONCLUSIONS: The alterations in T and B cells implied immune dysfunction, which may play an essential role in systemic sclerosis.

Safety and efficacy of peficitinib in Asian patients with rheumatoid arthritis who had an inadequate response or intolerance to methotrexate: results of a multicenter, randomized, double-blind, placebo-controlled phase 3 study.

Background: The efficacy and safety of the oral Janus kinase inhibitor peficitinib were investigated in Asian patients with rheumatoid arthritis (RA). Methods: In this double-blind, phase 3 study, patients from mainland China, Korea, and Taiwan with RA and an inadequate response/intolerance to methotrexate were randomized (1:1:1) to once-daily placebo (N = 128), peficitinib 100 mg (N = 129), or 150 mg (N = 128) in combination with non-biologic DMARDs. At Week 24, patients receiving placebo switched to peficitinib 100 mg or 150 mg. American College of Rheumatology (ACR) 20 response at Week 24/early termination (ET) was the primary endpoint. Adverse events (AEs) were assessed. The study was registered at ClinicalTrials (NCT03660059). Findings: 385 patients were included in the analysis. ACR20 responses were statistically significantly higher in both peficitinib 100 mg (56.6%) and 150 mg (56.3%) groups versus placebo (24.2%); Odds Ratio (95% confidence interval, CI) 4.14 (2.42, 7.08) and 4.07 (2.38, 6.96), respectively (both P < 0.001) at Week 24/ET. The incidence rate of herpes zoster related disease (herpes zoster and varicella) was higher in patients who received peficitinib versus placebo, but no dose dependency was observed (incidence rate/100 patient-years (95% CI): peficitinib 6.7 (4.32, 10.37); placebo 3.7 (0.93, 14.88). Interpretation: In Asian patients with RA and an inadequate response/intolerance to methotrexate, peficitinib 100 mg and 150 mg demonstrated superiority to placebo in the reduction of RA symptoms and was well tolerated. No additional benefit was observed with use of the higher peficitinib dose in this study population of predominantly Chinese patients. Funding: Astellas Pharma.

Association between asymptomatic hyperuricemia and risk of arthritis, findings from a US National Survey 2007-2018.

BACKGROUND: Arthritis is thought to be closely related to serum uric acid. The study aims to assess the association between asymptomatic hyperuricemia (AH) and arthritis. METHODS: A multistage, stratified cluster was used to conduct a cross-sectional study of adult US civilians aged≥20 years from the 2007-2018 National Health and Nutrition Examination Survey. Participants with hyperuricemia and without hyperuricemia prior to gout were included. A questionnaire was used to determine whether participants had arthritis and the type of arthritis. Logistic regression was used to investigate the association between hyperuricemia and arthritis. RESULT: During the past 12 years, the percentage of participants with arthritis changed from 25.95% (22.53%-29.36%) to 25.53% (21.62%-29.44%). The prevalence of osteoarthritis (OA) increased from 8.70% (95% CI: 6.56% to 10.85%) to 12.44% (95% CI: 9.32% to 15.55%), the prevalence of AH changed from 16.35% (95% CI: 14.01% to 18.40%) to 16.39% (95% CI: 13.47% to 19.30%). Participants with AH were associated with onset of arthritis (OR=1.34, 95% CI: 1.07 to 1.69), but the association was muted after adjusting demographic and socioeconomic factors. For participants aged 40-49 years, AH is associated with incident arthritis (OR=1.96, 95% CI: 1.23 to 2.99) and the relationship remained after adjusting for education level, income to poverty ratio, body mass index, diabetes, hypertension and smoking (OR=2.00, 95% CI: 1.94 to 3.36). Compared with male, female participants with AH are more likely to develop arthritis, especially in OA (OR=1.35, 95% CI: 1.14 to 1.60). CONCLUSION: Our data identified AH as the risk factor for incident arthritis, especially for OA, which might be exaggerated in aged population and female population.

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.

Diagnostic delay and its associated factors in Chinese axial spondyloarthritis: A single-center study of 1295 patients.

AIM: To delineate the landscape of diagnostic delay in Chinese axial spondyloarthritis (axSpA), investigate its associated factors, and explore its potential impact on medication modalities. METHODS: A total of 1295 patients fulfilling the ASAS classification criteria were obtained. Demographic and clinical data were collected through face-to-face interviews, based on predesigned questionnaires and available medical records. Logistic regression analyses under univariate and multivariable model were performed, using the median of diagnostic delay as the cut-off point for group classification. Differences between early- and late-diagnosed groups were subsequently compared by the Pearson chi-square test or Mann-Whitney U test. RESULTS: Of 1295 axSpA patients, 80.3% were male and the median of disease duration was 8.0 years. The median (IQR) diagnostic delay in Chinese axSpA was 3.0 (1.0 ~ 7.0) years and 24.8% of them reported a history of misdiagnosis. Older age at onset (OR = 0.97, p < .001) and higher education attainment (p = .001) were correlated with early diagnosis of axSpA, whereas coming from less developed areas (p = .002), a history of peripheral arthritis at the time of diagnosis (OR = 1.58, p = .002) and history of misdiagnosis (OR = 1.98, p < .001) increased the risk of diagnostic delay. Oral medication modalities were similar between two groups, but the proportion with no medication ever was higher in the late-diagnosed group (26.5% vs. 20.7%, p = .02). CONCLUSION: Our findings depicted a detailed spectrum of diagnostic delay in Chinese axSpA, verified five associated factors that may help facilitate timely diagnosis of axSpA, and pinpointed that timely medication was unsatisfying, especially in the late diagnosis group.

Evaluation of causal associations between interleukin-18 levels and immune-mediated inflammatory diseases: a Mendelian randomization study.

BACKGROUND: Altered interleukin (IL)-18 levels are associated with immune-mediated inflammatory diseases (IMIDs), but no studies have investigated their causal relationship. This study aimed to examine the causal associations between IL-18 and IMIDs. METHODS: We performed a two-sample Mendelian randomization (MR) analysis. Genetic variants were selected from genome-wide association study datasets following stringent assessments. We then used these variants as instrumental variables to estimate the causal effects of IL-18 levels on the risk of developing five common IMIDs: rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), ankylosing spondylitis (AS), and psoriasis. We used the inverse variance-weighted (IVW) method as the primary analysis, with sensitivity analyses performed to avoid potential bias. Reverse-direction MR analyses were performed to rule out the possibility of reverse associations. RESULTS: We found that genetically determined higher circulating IL-18 levels were causally associated with a higher risk for SLE (PIVW = 0.009; OR, 1.214; 95% CI, 1.049 - 1.404) and IBD (PIVW < 0.001; OR, 1.142; 95% CI, 1.062 - 1.228), but found no significant associations of IL-18 with RA (PIVW = 0.496; OR, 1.044; 95% CI, 0.923 - 1.180), AS (PIVW = 0.021; OR, 1.181; 95% CI, 1.025 - 1.361), or psoriasis (PIVW = 0.232; OR, 1.198; 95% CI, 0.891 - 1.611). In the reverse direction, no causal relationship existed between SLE or IBD and IL-18 levels. Globally, sensitivity studies using alternative MR methods supported the results that were robust and reliable. The Cochran's Q test, MR-Egger intercept, and MR-Pleiotropy RESidual Sum and Outlier excluded the influence of heterogeneity, horizontal pleiotropy, and outliers. CONCLUSIONS: We have demonstrated that elevated IL-18 levels increase the risk of SLE and IBD but not RA, AS, or psoriasis. The results enhanced our understanding of IL-18 in the pathology of IMIDs.

Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

The diagnostic value of morphological features of fat deposition of sacroiliac joint steatosis in axial spondyloarthritis.

Background: Findings of fatty lesions in the context of other imaging manifestations, especially bone marrow edema and erosions can effectively assist in the diagnosis of axSpA. Chemical shift-encoded MRI is a sequence which allows for the quantification of fat signal and has been applied in the imaging evaluation of the SIJ in axSpA. The objective of this study was to investigate the diagnostic performance of morphological features of fatty lesions visualized by CSE-MRI in the imaging evaluation of SIJ in axSpA. Methods: Fatty lesions with morphological features (subchondral, homogeneity and distinct border) were assessed and recorded as a binary variable in each quadrant of the SIJ. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for different morphological features as well as the anatomical distribution in patients with nr-axSpA and r-axSpA. T1-weighted images and CSE-MRI fat fraction maps were directly compared in the recognition of different morphological features. Results: Eighty-two patients [non-SpA (n = 21), nr-axSpA (n = 23), r-axSpA (n = 38)] with lower back pain (LBP) were enrolled. Presence of the three morphological features of fatty lesions had a specificity of 90.48% in axSpA. The sensitivities of being subchondral, homogeneity and distinct border were 52.17, 39.13 and 39.13% in nr-axSpA on T1-weighted images. For patients with r-axSpA, the sensitivities reached 86.84, 76.32 and 57.89%. No significant difference was found in the distribution of fatty lesions between T1-weighted images and CSE-MRI. However, CSE-MRI fat fraction maps could detect significantly more fatty lesions with homogeneity (p = 0.0412) and distinct border (p = 0.0159) than T1-weighted images in the sacroiliac joint, but not subchondral lesions (p = 0.6831). Conclusion: The homogeneity and distinct border are more relevant for the diagnosis of axSpA. Moreover, CSE-MRI could detect more typical morphological features of fatty lesions than T1-weighted images in showing these two features. The presence of all three features was more likely to be indicative of axSpA.

Safety and Effectiveness of Baricitinib in Chinese Patients with Moderate-to-Severe Rheumatoid Arthritis: 24-Week Results from a Post-Marketing Safety Study.

INTRODUCTION: Baricitinib, a JAK1/JAK2 inhibitor, is approved for treatment of moderate-to-severe rheumatoid arthritis (RA) in China. This single-arm, prospective, multi-center, post-marketing safety study (PMSS) evaluated the safety and effectiveness of baricitinib in Chinese patients. METHODS: This study included adult patients with moderate-to-severe active RA who received baricitinib over periods of approximately 12 and 24 weeks. The primary endpoint was safety, defined as week 12 adverse event (AE)/serious AE incidence. Secondary endpoints were week 24 safety and effectiveness (disease activity score with 28 joints/C-reactive protein [DAS28-CRP] and simplified/Clinical Disease Activity Index [SDAI/CDAI]). RESULTS: Safety analyses included 667 patients (female, 82.3%; mean age, 53.3 years; mean RA duration, 86.9 months); 106/667 (15.9%) were 65-74 years old and 19/667 (2.8%) were ≥ 75 years old; 87.0% received baricitinib 2 mg QD. Total exposure was 262.1 patient-years (PY). At week 12, AEs had occurred in 214 (32.1%; exposure-adjusted incidence rate [EAIR], 172.5 per 100 PY) patients (serious AEs: 22 [3.3%; EAIR, 15.0]). At week 24, AEs had occurred in 250 (37.5%; EAIR, 125.9) patients (serious AEs: 28 [4.2%; EAIR, 10.9]). Two patients (0.3%) died (of pneumonia and unknown cause); EAIR for death, 0.77. Serious infection occurred in 1.2% of patients (EAIR, 3.1). Hepatotoxicity occurred in 3.4% of patients (EAIR, 9.0). No patients met potential Hy's law laboratory criteria (alanine/aspartate aminotransferases ≥ 3 × upper limit of normal (ULN) and total bilirubin ≥ 2 × ULN). Malignancy occurred in one patient. No patients experienced venous thromboembolism (VTE) or major adverse cardiovascular events (MACE). At week 24, 52.4%, 27.5%, and 27.6% of patients achieved remission per DAS28-CRP, SDAI, and CDAI, respectively. CONCLUSIONS: This PMSS investigated the safety and effectiveness of baricitinib in clinical practice in China. No VTE/MACE or new safety signals were reported and there was promising effectiveness, supporting the use of baricitinib in Chinese patients with moderate-to-severe active RA. TRIAL REGISTRATION: EU PAS Register: EUPAS34213.

A prognostic model for systemic lupus erythematosus-associated pulmonary arterial hypertension: CSTAR-PAH cohort study.

BACKGROUND: Pulmonary arterial hypertension is a major cause of death in systemic lupus erythematosus, but there are no tools specialized for predicting survival in systemic lupus erythematosus-associated pulmonary arterial hypertension. RESEARCH QUESTION: To develop a practical model for predicting long-term prognosis in patients with systemic lupus erythematosus-associated pulmonary arterial hypertension. METHODS: A prognostic model was developed from a multicenter, longitudinal national cohort of consecutively evaluated patients with systemic lupus erythematosus-associated pulmonary arterial hypertension. The study was conducted between November 2006 and February 2020. All-cause death was defined as the endpoint. Cox regression and least absolute shrinkage and selection operators were used to fit the model. Internal validation of the model was assessed by discrimination and calibration using bootstrapping. RESULTS: Of 310 patients included in the study, 81 (26.1%) died within a median follow-up of 5.94 years (interquartile range 4.67-7.46). The final prognostic model included eight variables: modified World Health Organization functional class, 6-min walking distance, pulmonary vascular resistance, estimated glomerular filtration rate, thrombocytopenia, mild interstitial lung disease, N-terminal pro-brain natriuretic peptide/brain natriuretic peptide level, and direct bilirubin level. A 5-year death probability predictive algorithm was established and validated using the C-index (0.77) and a satisfactory calibration curve. Risk stratification was performed based on the predicted probability to improve clinical decision-making. CONCLUSIONS: This new risk stratification model for systemic lupus erythematosus-associated pulmonary arterial hypertension may provide individualized prognostic probability using readily obtained clinical risk factors. External validation is required to demonstrate the accuracy of this model's predictions in diverse patient populations.

Peripheral CD4+ /CD8+ T cell composition distinct from healthy individuals is shared by ankylosing spondylitis and rheumatoid arthritis.

OBJECTIVE: Ankylosing spondylitis (AS) and rheumatoid arthritis (RA) are chronic inflammatory joint diseases, linking to the alterations of immune cells. We attempted to assess whether the alterations in the composition of CD4+ /CD8+ T cells are different between AS and RA and identify the characteristic cells between male and female patients. METHODS: The proportions of CD3+ or double positive T cells, 6 CD4+ T subsets and 9 CD8+ T cell subsets were detected by flow cytometry and compared in 30 healthy individuals, 42 AS patients and 45 RA patients. The differentially altered cells were individually analyzed for associations with disease activity parameters. In addition, their proportions were compared between different genders in the 3 groups. RESULTS: The proportions of CD4+ T cells, naive CD4+ T cells and central memory CD4+ T cells were lower in AS patients (P = 0.001, P = 0.002 and P = 0.007, respectively) and RA patients (P = 0.032, P < 0.001 and P = 0.016, respectively), but the proportion of effector memory ones was higher when compared with healthy populations (both P < 0.001), as were the decrease of naive/central memory CD8+ T cells in AS (P = 0.003 and P = 0.016, respectively) and RA (P < 0.001 and P = 0.006, respectively), and the increased tendency of terminally differentiated CD8+ T cells. However, these above-mentioned cells, regulatory T (Treg) cells and CD8+ T cells with different CD127 expressions between AS and RA were similar in proportion. Furthermore, naive CD4+ T cells were positively associated with C-reactive protein (CRP) in AS, whereas CD4+ T cells and terminally differentiated CD8+ T of RA patients were associated with CRP in RA. The gender-related alterations predominantly displayed the overexpressions of Treg cells and naive CD8+ T cells in female patients with AS and RA, respectively. CONCLUSIONS: AS patients and RA patients have some similar peripheral CD4+ /CD8+ T cell subsets but are distinct from healthy individuals, which may contribute to disease severity. Females are respectively characterized by the up-regulation of Treg cells and naive CD8+ T cells in AS patients and RA patients. The study offers an in-depth understanding of the role of T cell subsets in the similarities of the disorders and helps us to monitor disease changes and may offer a theoretical basis of developing novel therapies against common targets.

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.

The study of the effect of HLA-B27 on THP-1 monocytic cells survival and its mechanism.

OBJECTIVE: Previous studies have shown that human leukocyte antigen (HLA)-B27 induces the accumulation of unfolded proteins in the endoplasmic reticulum (ER) to cause ER stress, resulting in the unfold protein response (UPR), apoptosis and autophagy. However, it is still unknown whether it affects the survival of monocytes. In this study, we attempted to examine the effect of HLA-B27 gene knockout on the proliferation and apoptosis of THP-1 monocytic cell line and its potential mechanism. METHODS: HLA-B27 gene knockout THP-1 cell line was constructed by lentivirus infection, and knockout efficiency was detected by immunofluorescence, quantitative reverse transcription - polymerase chain reaction (qRT-PCR) and western blot. Cell Counting Kit-8 (CCK-8) method and Annexin-V/PI double staining were used to detect the proliferation and apoptosis of the constructed THP-1 cell line, respectively. qRT-PCR was used to detect the effect of HLA-B27 inhibition on the expressions of ER molecular chaperone binding immunoglobulin protein (BiP) and genes about the UPR pathway. The proliferation rate of human BiP protein-stimulated THP-1 cells was detected by CCK-8 method. RESULTS: HLA-B27 gene knockout THP-1 cells were successfully constructed by lentivirus infection. Knockout of HLA-B27 effectively promoted the proliferation of THP-1 cells and inhibited the apoptosis induced by cisplatin. qRT-PCR showed that BiP was synchronously increased, while activation of UPR pathway was inhibited. Stimulation with human BiP promoted the proliferation of THP-1 cells in a concentration-dependent manner. CONCLUSIONS: HLA-B27 inhibition can promote the proliferation and inhibit the apoptosis of THP-1 cells. The inhibition function may be achieved through promotion of BiP and inhibition of UPR pathway activation.

Zero echo time MRI improved detection of erosions and sclerosis in the sacroiliac joint in comparison with LAVA-flex.

Background: T1-weighted spoiled 3D Gradient Recalled Echo pulse sequences, exemplified by Liver Acquisition with Volume Acceleration-flexible MRI (LAVA-Flex), are currently the preferred MR sequence for detecting erosions of the sacroiliac joint (SIJ). However, zero echo time MRI (ZTE) is recently reported to provide excellent visualization of the cortical bone. Purpose: To directly compare the diagnostic accuracy of ZTE and LAVA-Flex in the detection of structural lesions of the SIJ, including erosions, sclerosis and joint space changes. Materials and methods: Two readers independently reviewed the ldCT, ZTE and LAVA-Flex images of 53 patients diagnosed as axSpA and scored the erosions, sclerosis and joint space changes. Sensitivity, specificity and Cohen's kappa (κ) of ZTE and LAVA-Flex were calculated, while McNemar's test was employed to compare the two sequences for the positivity of detecting the structural lesions. Results: Analysis of diagnostic accuracy showed a higher sensitivity of ZTE in comparison with LAVA-Flex in the depiction of erosions (92.5% vs 81.5%, p<0.001), especially first-degree erosions (p<0.001) and second-degree erosions (p<0.001), as well as sclerosis (90.6% vs 71.2%, p<0.001), but not joint space changes (95.2% vs 93.8%, p=0.332). Agreement with ldCT was also higher in ZTE in the detection of erosions than LAVA-Flex as indicated by the κ values (0.73 vs 0.47), as well as in the detection of sclerosis (0.92 vs 0.22). Conclusion: With ldCT as the reference standard, ZTE could improve diagnostic accuracy of erosions and sclerosis of the SIJ in patients suspected of axSpA, in comparison with LAVA-Flex.

PKM2 promotes proinflammatory macrophage activation in ankylosing spondylitis.

Macrophages play a critical role in ankylosing spondylitis by promoting autoimmune tissue inflammation through various effector functions. The inflammatory potential of macrophages is highly influenced by their metabolic environment. Here, we demonstrate that glycolysis is linked to the proinflammatory activation of human blood monocyte-derived macrophages in ankylosing spondylitis. Specifically, ankylosing spondylitis macrophages produced excessive inflammation, including TNFα, IL1ß, and IL23, and displayed an overactive status by exhibiting stronger costimulatory signals, such as CD80, CD86, and HLA-DR. Moreover, we found that patient-derived monocyte-derived M1-type macrophages (M1 macrophages) exhibited intensified glycolysis, as evidenced by a higher extracellular acidification rate. Upregulation of PKM2 and GLUT1 was observed in ankylosing spondylitis-derived monocytes and monocyte-derived macrophages, especially in M1 macrophages, indicating glucose metabolic alteration in ankylosing spondylitis macrophages. To investigate the impact of glycolysis on macrophage inflammatory ability, we treated ankylosing spondylitis M1 macrophages with 2 inhibitors: 2-deoxy-D-glucose, a glycolysis inhibitor, and shikonin, a PKM2 inhibitor. Both inhibitors reduced proinflammatory function and reversed the overactive status of ankylosing spondylitis macrophages, suggesting their potential utility in treating the disease. These data place PKM2 at the crosstalk between glucose metabolic changes and the activation of inflammatory macrophages in patients with ankylosing spondylitis.

Overexpressed RAD51 promoted osteogenic differentiation by activating IGF1R/PI3K/AKT pathway in osteoblasts.

BACKGROUND: Osteoporosis (OP) is a skeleton disease induced by imbalance between osteoblast and osteoclast. Osteogenic differentiation of osteoblasts is of great importance, and the regulatory mechanisms are urgent to be studied. METHODS: Differentially expressed genes were screened from microarray profile related to OP patients. The dexamethasone (Dex) was used to induce osteogenic differentiation of MC3T3-E1 cells. MC3T3-E1 cells were exposed to microgravity environment to mimic OP model cells. Alizarin Red staining and alkaline phosphatase (ALP) staining were used to evaluate the role of RAD51 in osteogenic differentiation of OP model cells. Furthermore, qRT-PCR and western blot were applied to determine expression levels of genes and proteins. RESULTS: RAD51 expression was suppressed in OP patients and model cells. Alizarin Red staining and ALP staining intensity, the expression of osteogenesis-related proteins including runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and collagen type I alpha1 (COL1A1) were increased by over-expressed RAD51. Furthermore, RAD51 related genes were enriched in IGF1 pathway, and up-regulated RAD51 activated IGF1 pathway. The effects of oe-RAD51 on osteogenic differentiation and IGF1 pathway were attenuated by IGF1R inhibitor BMS754807. CONCLUSIONS: Overexpressed RAD51 promoted osteogenic differentiation by activating IGF1R/PI3K/AKT signaling pathway in OP. RAD51 could be a potential therapeutic marker for OP.

Temporal trend of population structure, burden of diseases, healthcare resources and expenditure in China, 2000-2019.

OBJECTIVES: To explore the evolutionary trend of population structure, disease burden, healthcare resources and expenditure in China, and to identify key domains that are most in need of intervention. DESIGN: A cross-sectional and longitudinal analysis. DATA SOURCE: Population and healthcare data from China Statistical Yearbook, and disease burden attributable to causes and risk factors from the Global Burden of Diseases between 2000 and 2019. MEASURES AND METHODS: We used the Joinpoint Regression Program to measure trends in population composition, population change, dependency ratio, healthcare institution, personnel, expenditure and disease burden from 2000 to 2019. RESULTS: Regarding the population in China between 2000 and 2019, a decreasing trend was observed among youth aged 0-14 years (average annual percent change (AAPC): -1.17), a slow rising trend was observed among individuals aged 15-64 years (AAPC: 1.10) and a rapidly increasing trend was observed among individuals older than 65 years (AAPC: 3.67). Astonishing increasing trends in healthcare institutions (AAPC: 3.97), medical personnel (AAPC: 3.26) and healthcare expenditures (AAPC: 15.28) were also observed. Among individuals younger than 70 years, neoplasms (AAPC: 0.54) and cardiovascular diseases (AAPC: 0.67) remained among the top three causes, while tobacco (AAPC: 0.22) remained a top three risk factor. However, while musculoskeletal disorders (AAPC: 1.88) were not a top three cause in 2000, they are a top three cause in 2019. CONCLUSION: Comprehensive age/cause/risk factor-specific strategies are key to reconcile the tension among the triad of population ageing, disease burden and healthcare expenditure. The disease burden from cardiometabolic diseases, neoplasms and musculoskeletal disorders was identified as key domains that require intervention to reduce an increasing disease burden among individuals currently older than 70 years, as well as those approaching this age group.

Efficacy of belimumab in patients with systemic lupus erythematosus from North East Asia: Results of exploratory subgroup analyses.

OBJECTIVES: To assess belimumab efficacy in patients from North East Asia (NEA) with systemic lupus erythematosus (SLE) in baseline demographic/disease characteristic subgroups. METHODS: This analysis of patient subgroups from BLISS-NEA (GSK Study 113750; NCT01345253) studied adults with SLE randomized to belimumab (10 mg/kg intravenous) or placebo. Primary endpoint, SLE Responder Index 4 (SRI-4) response rate at Week 52, was analysed in subgroups defined by gender, country, prednisone-equivalent dose, concomitant medications, Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score, complement (C) levels, anti-double-stranded deoxyribonucleic acid (dsDNA) positivity, Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index score. RESULTS: Patients (overall population: N = 677; belimumab: n = 451, placebo: n = 226) were from China (76.4%), Korea (14.8%), and Japan (8.9%). The mean age was 32.1 years; 92.9% were female. In the overall population, more belimumab (53.8%) than placebo (40.1%) patients were SRI-4 Week 52 responders (p = .0001). SRI-4 response rates by subgroups were generally consistent with the overall population. A greater response with belimumab was seen in patients with a baseline SELENA-SLEDAI score ≥10 versus ≤9 and patients with low C3/C4 levels and anti-dsDNA positive at baseline versus those 'NOT' (low C3 and/or C4 and anti-dsDNA positive). CONCLUSIONS: These findings continue to support the efficacy of belimumab in SLE.