Single-Cell Profiling of Bone Marrow B Cells and Early B Cell Developmental Disorders Associated With Systemic Lupus Erythematosus.

OBJECTIVE: The peripheral B cell compartment is heavily disturbed in systemic lupus erythematosus (SLE), but whether B cells develop aberrantly in the bone marrow (BM) is largely unknown. METHODS: We performed single-cell RNA/B cell receptor (BCR) sequencing and immune profiling of BM B cells and classified patients with SLE into two groups: early B cell (Pro-B and Pre-B) normal (EBnor) and EB defective/low (EBlo) groups. RESULTS: The SLE-EBlo group exhibited more severe disease activity and proinflammatory status, overaction of type I interferon signaling and metabolic pathways within the B cell compartment, and aberrant BCR repertoires compared with the SLE-EBnor group. Moreover, in one patient with SLE who was initially classified in the SLE-EBlo group, early B cell deficiency and associated abnormalities were largely rectified in a second BM sample at the remission phase. CONCLUSION: In summary, this study suggests that early B cell loss in BM defines a unique pathological state in a subset of patients with SLE that may play an active role in the dysregulated autoimmune responses.

Serum urate goal attainment and associated factors in Chinese gout patients.

We conducted a cross-sectional study with 350 gout patients to investigate serum urate acid (sUA) goal attainment (sUA < 360 µmol/L) and associated factors in Chinese gout patients in the Affiliated Hospital of Nantong University from August 2015 to September 2017. Descriptive statistics, health assessment questionnaire, global visual analog scale for general health and Gout Knowledge Questionnaire were calculated comparing patients at sUA goal or not at sUA goal. Univariate analysis and logistic regression models were applied to analyze data. The proportion of urate-lowering therapy (ULT) use was 61.2% (211/350). The mean ± standard deviation sUA of the participants was 475.07 ± 121.53 µmol/L. Only 17.4% of gout patients attain the serum urate goal, which also means 289(82.6%) patients cannot keep their sUA below the target of 360 µmol/L. The factors associated with sUA goal attainment including age, education level and ULT use. Among these, age, waist hip ratio, ULT, family history of cardiovascular disease was the predictor of sUA goal attainment. In conclusion, more than 80% of gout patients did not achieve sUA goal. Younger and fatter patients were more difficult to control the serum urate level.

Gout and risk of diabetes mellitus: meta-analysis of observational studies.

To determine the prevalence of diabetes mellitus (DM) in people with gout, and investigate the relationship between gout and the occurrence of DM. Systematic review and meta-analysis of epidemiological studies. Data sources: MEDLINE, Web of Science, EMBASE and CINAHL databases, hand-searched reference lists, citation history and contact with authors. Eligibility criteria: cohort, case-control or cross-sectional studies which examined the occurrence of DM amongst adults with gout (with or without gout group) in primary care or general population samples. Prevalence and risk estimate meta-analyses were performed using a random-effects model. A total of 23 identified studies matched the inclusion criteria, reporting on a total of 575 284 gout patients. Meta-analyses revealed that the prevalence of DM in gout patients was 16% (95% CI, 14-18%, I2 = 99.8%) according to clinical interviews. In the subgroup analysis, the prevalence of DM was higher in the female population (18%, 95%CI 2.7-33.3%) than the male population (12.6%, 95%CI 8.2-17.1%). As age increased, the incidence of diabetes in gout population increased. DM is commonly found among patients with gout. Patients with gout should be actively screened for DM and its consequences.

The correlations of socioeconomic status, disease activity, quality of life, and depression/anxiety in Chinese patients with rheumatoid arthritis.

This study aimed (i) to investigate the relationships among socioeconomic status, disease activity, quality of life, and the psychological status in Chinese rheumatoid arthritis (RA) patients; (ii) to explore the possible risk factors of anxiety and depression. A total of 160 RA patients underwent standardized laboratory examinations and completed several questionnaires. Independent samples t-tests, χ2 analyses, and logistic regression modeling were used to analyze the data. We found 30.6% RA patients were anxiety, and 27.5% had depression, which were significantly higher than the control group (7.8 and 11.7%, respectively). And there were significant correlations among education, pain, disease activity, medication adherence, functional capacity, quality of life, and anxiety/depression. Meanwhile, logistic regression analysis revealed that poor quality of life and low education level were significantly associated with anxiety/depression in RA patients. In conclusion, there were significant relationships among education, quality of life, and anxiety/depression in Chinese RA patients.

Sleep quality in Chinese patients with rheumatoid arthritis: contributing factors and effects on health-related quality of life.

BACKGROUND: Poor sleep quality is common in rheumatoid arthritis (RA) patients and may lead to disease aggravation and decreased health-related quality of life (HRQoL). The increasing prevalence of poor sleep in RA patients is associated with adverse demographic, clinical, and psychological characteristics. However, there are currently no known reported studies related to the effects of sleep quality on HRQoL in RA patients from China. This cross-sectional study aims to evaluate the contributors of poor sleep and the effects of sleep quality on HRQoL in Chinese RA patients. METHODS: A self-report survey was administered to 131 RA patients and 104 healthy individuals using the Pittsburgh Sleep Quality Index (PSQI) for sleep quality. RA patients completed the Hospital Anxiety and Depression Scale for anxiety and depression, the 28-joint Disease Activity Score for disease activity, the 10 cm Visual Analog Scale for pain, the Health Assessment Questionnaire-Disability Index for functional capacity and the Short Form 36 health survey for HRQoL. Blood samples were taken to gain some biochemical indicators (e.g., erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and anti-cyclic citrullinated peptide). Independent samples t-tests, Chi square analysis, logistic regression modeling and linear regression were used to analyze these data. RESULTS: Our results found that the prevalence of poor sleep (PSQI ≥ 5) was 78.6% and the mean global score of PSQI was 7.93 (SD 3.98) in patients, which were significantly higher than the controls (18.7% and 3.88 (SD 1.89), respectively). There were significant correlations among synthetic disease-modifying antirheumatic drugs, erythrocyte sedimentation rate, pain, disease activity, functional capacity, anxiety/depression and sleep quality in RA patients. Meanwhile, logistic regression models identified disease activity and depression as predictors of poor sleep quality. Poor RA sleepers had impaired HRQoL than good RA sleepers, and sleep quality was independently and significantly associated with social function and mental components summary. CONCLUSIONS: The majority of Chinese RA patients suffered from poor sleep, which significantly impairs their HRQoL. The data suggested the need for holistic assessment and management of RA patients and the importance of objective interventions to improve their sleep quality and finally to improve their HRQoL.

Treatment adherence to disease-modifying antirheumatic drugs in Chinese patients with rheumatoid arthritis.

OBJECTIVE: Nonadherence in rheumatoid arthritis (RA) patients using disease-modifying antirheumatic drugs (DMARDs) may lead to joint damage and function loss. The aim of this cross-sectional study was to explore Chinese RA patients' adherence rates and investigate potential risk factors for nonadherence. METHODS: A total of 122 RA patients were recruited from the Affiliated Hospital of Nantong University from January 2014 to April 2015. Patients were asked to complete a set of standardized self-report questionnaires (Compliance Questionnaire on Rheumatology, Health Assessment Questionnaire, Short Form-36 questionnaire, 28-joint Disease Activity Score, Hospital Anxiety and Depression Scale, and Visual Analog Scale). Independent samples t-tests, chi-square analyses, and logistic regression modeling were used to analyze these data. RESULTS: Based on Compliance Questionnaire on Rheumatology, 38% of the patients adhered to DMARDs. Adherence was associated with education, income, depression, and the total number of DMARDs. Other demographic and clinical characteristics were not associated with adherence. Logistic regression models identified income, depression, and the total number of DMARDs as predictors of medication nonadherence. CONCLUSION: In this study, 62% of patients with RA were not adherent to their DMARD prescription. Education, income, depression, and the total number of DMARDs were associated with medication adherence, and income, depression, and the total number of DMARDs were independent predictors of medication adherence in patients with RA. These findings could help medical personnel develop helpful interventions to improve adherence in RA patients by paying more attention to the patients with these accompanying risk factors and, finally, improve RA patients' quality of life.

Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway.

We have shown that bone marrow (BM)-derived mesenchymal stem cells (BM-MSCs) from SLE patients exhibit senescent behavior and are involved in the pathogenesis of SLE. The aim of this study was to investigate the effects of rapamycin (RAPA) on the senescences and immunoregulatory ability of MSCs of MRL/lpr mice and SLE patients and the underlying mechanisms. Cell morphology, senescence associated ß-galactosidase (SA-ß-gal) staining, F-actin staining were used to detect the senescence of cells. BM-MSCs and purified CD4+ T cells were co-cultured indirectly. Flow cytometry was used to inspect the proportion of regulatory T (Treg) /T helper type 17 (Th17). We used small interfering RNA (siRNA) to interfere the expression of mTOR, and detect the effects by RT-PCR, WB and immunofluorescence. Finally, 1x106 of SLE BM-MSCs treated with RAPA were transplanted to cure the 8 MRL/lpr mice aged 16 weeks for 12 weeks. We demonstrated that RAPA alleviated the clinical symptoms of lupus nephritis and prolonged survival in MRL/lpr mice. RAPA reversed the senescent phenotype and improved immunoregulation of MSCs from MRL/lpr mice and SLE patients through inhibition of the mTOR signaling pathway. Marked therapeutic effects were observed in MRL/lpr mice following transplantation of BM-MSCs from SLE patients pretreated with RAPA.

Involvement of autophagy in the procedure of endoplasmic reticulum stress introduced apoptosis in bone marrow mesenchymal stem cells from nonobese diabetic mice.

Recent studies showed that bone marrow mesenchymal stem cells (BM-MSCs) from nonobese diabetic (NOD) mice exhibited the phenomenon of apoptosis. However, the mechanisms of apoptosis remained largely unknown. In this study, endoplasmic reticulum (ER) stress and autophagy were evidenced in BM-MSCs from NOD mice for the first time. We found the ER stress-mediated apoptosis was supported by the up-regulation of ER stress markers including augmented phosphorylation of phosphorylated protein kinase RNA-like ER kinase and eukaryotic translation initiator factor 2α as well as cleavage of caspase-3. Evidence of autophagy included the formation of the acidic vesicular organelles and increase of LC3 accumulation. Intriguingly, blockage of ER stress could reduce the apoptosis of BM-MSCs from NOD mice and alleviated accumulation of LC3, which indicated that ER stress induced apoptosis and autophagy. Furthermore, our results showed that the mechanism of ER stress-induced autophagy was associated with the decrease of p-S6 (a marker of mTOR activity). Here, we demonstrated that ER stress-induced cell death was mediated by autophagy that was partly attributed to the inactivation of the mammalian target of rapamycin. SIGNIFICANCE PARAGRAPH: We report for the first time that endoplasmic reticulum (ER) stress mediated apoptosis of bone marrow mesenchymal stem cells (BM-MSCs) from nonobese diabetic (NOD) mice. The evidence of autophagy was also found in BM-MSCs from NOD mice, included the formation of the acidic vesicular organelles and increase of LC3 accumulation. Furthermore, we demonstrated that ER stress-induced cell death was mediated by autophagy that was partly attributed to the inactivation of the mammalian target of rapamycin. Deciphering the mechanisms of ER stress signalling involved in the apoptosis of BM-MSCs from NOD mice will help improve transplantation efficacy of BM-MSCs in type 1 diabetes patients.

Induction of Apoptosis Coupled to Endoplasmic Reticulum Stress through Regulation of CHOP and JNK in Bone Marrow Mesenchymal Stem Cells from Patients with Systemic Lupus Erythematosus.

Previous studies indicated that bone marrow mesenchymal stem cells (BM-MSCs) from patients with systemic lupus erythematosus (SLE) exhibited the phenomenon of apoptosis. In this study, we aimed to investigate whether apoptosis of BM-MSCs from SLE patients were dysregulated. In this paper, endoplasmic reticulum stress (ERS) was evidenced by increased expression of phosphorylated protein kinase RNA-like ER kinase (PERK) and inositol-requiring protein-1 (IRE-1). We also found the activation of downstream target eukaryotic translation initiator factor 2α (eIF 2α) and CCAAT/enhancer-binding protein- (C/EBP-) homologous protein (CHOP) in BM-MSCs from SLE patients. Interestingly, we discovered that 4-phenylbutyric acid (4-PBA), a selective inhibitor of ERS, blocked the apoptosis of BM-MSCs from SLE patients and alleviated the level of Jun N-terminal kinase1/2 (JNK1/2) and CHOP. Furthermore, blockage of PERK signaling expression by siRNA not only significantly reduced the expression of CHOP, but also activated the anti-apoptotic regulator B-cell lymphoma-2 (Bcl-2). Blockage of IRE-1 or JNK1/2 by siRNA resulted in the decreased expression of JNK1/2 and proapoptosis protein Bcl-2 associated protein X (BAX). These results implicated that ERS-mediated apoptosis was a critical determinant of BM-MSCs from SLE patients.

Endoplasmic reticulum stress participates in the progress of senescence of bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus.

Previous studies suggested that the senescence of bone marrow mesenchymal stem cells (BM-MSCs) played an important role in the pathological process of systemic lupus erythematosus (SLE). However, the molecular mechanisms that govern this phenomenon have not been fully elucidated. Recent studies reported the activation of endoplasmic reticulum stress (ERS) participated in the growth arrest in G1 phase of cell cycle. In this study, we aimed to investigate whether ERS would induce the senescence of BM-MSCs from SLE patients. We found that there was increased expression of Glucose Regulated Protein 78 (GRP 78) in BM-MSCs from SLE patients, which indicated the activation of ERS in BM-MSCs from SLE patients. Accumulation of p27 was also found in BM-MSCs from SLE patients. Interestingly, as a chemical chaperone helping the correct folding of proteins, 4-phenylbutyric acid (4-PBA) partly rescued the senescence of BM-MSCs from SLE patients and alleviated the level of p27. These results implicated ERS-mediated senescence as a critical determinant of BM-MSCs from SLE patients.