A clinical practice guideline for the screening and assessment of enthesitis in patients with spondyloarthritis.

Objective: The aim of this review is to provide guidance on the selection of approaches to the screening and assessment of enthesitis in patients with spondyloarthritis (SpA). Methods: Twenty-four questions regarding the approaches to the screening and assessment of enthesitis and the implementation details were devised, followed by a systemic literature review. The Grading of Recommendations Assessment, Development, and Evaluation methodology was employed in the development of this guideline, with modifications to evaluate non-interventional approaches under comprehensive consideration of costs, accessibility, and evidence strength. A consensus from the voting panel was required for the inclusion of the final recommendations and the strength of each recommendation. Results: Seventeen recommendations (including five strong recommendations) were included in this guideline. The voting panel expressed unequivocal support for the necessity of screening and assessment of enthesitis in patients with SpA. It was agreed unanimously that symptom evaluation and physical examination should serve as the initial steps to the recognition of enthesitis, whereas Maastricht Ankylosing Spondylitis Enthesitis Score is a reliable tool in both clinical trials and daily medical practice. Ultrasound examination is another reliable tool, with power Doppler ultrasound as an informative addition. Notwithstanding its high resolution, MRI is limited by the costs and relatively low accessibility, whereas radiographs had low sensitivity and therefore should be rendered obsolete in the assessment of enthesitis. PET/CT was strongly opposed in the detection of enthesitis. Conclusion: This guideline provides clinicians with information regarding the screening and assessment of enthesitis in patients with SpA. However, this guideline does not intend on dictating choices, and the ultimate decisions should be made in light of the actual circumstances of the facilities.

KLF4 downregulates FGF21 to activate inflammatory injury and oxidative stress of LPS­induced ATDC5 cells via SIRT1/NF­κB/p53 signaling.

Ankylosing spondylitis (AS) is a chronic inflammatory disease. Transcriptional regulation of fibroblast growth factor 21 (FGF21) by the transcription factor Krüppel­like factor 4 (KLF4) serves an important role in chronic inflammatory disease. However, to the best of our knowledge, the role of both these factors in AS has not been previously reported. In the present study, ATDC5 cells were induced by lipopolysaccharide (LPS) to establish an AS inflammatory injury model. The expression levels of FGF21 and KLF4 were detected using reverse transcription­quantitative PCR and western blotting. Cell transfection was performed to alter the expression levels of KLF4 and FGF21. Subsequently, the regulatory effects and mechanisms underlying KLF4 and FGF21 on oxidative stress and inflammation in AS were investigated by performing Cell Counting Kit­8 assays, ELISAs, TUNEL staining and western blotting. Moreover, the expression levels of sirtuin 1 (SIRT1)/NF­κB/p53 pathway­related proteins were detected via western blotting. FGF21 overexpression promoted LPS­induced viability on ATDC5 cells, inhibited LPS­induced apoptosis, and decreased the LPS­induced inflammatory response and oxidative stress levels of ATDC5 cells. Overexpression of the transcription factor KLF4 reversed the protective effect of FGF21 overexpression on LPS­induced inflammatory injury in ATDC5 cells. The results suggested that this process may be achieved via regulating the SIRT1/NF­κB/p53 signaling pathway. Overall, the present study demonstrated that KLF4 downregulates FGF21 to activate inflammatory injury and oxidative stress of LPS­induced ATDC5 cells via SIRT1/NF­κB/p53 signaling.

A Nomogram for Predicting the Residual Back Pain after Percutaneous Vertebroplasty for Osteoporotic Vertebral Compression Fractures.

OBJECTIVE: Current findings suggest that percutaneous vertebroplasty (PVP) is a suitable therapeutic approach for osteoporotic vertebral compression fractures (OVCFs). However, a significant minority of patients still experience residual back pain after PVP. The present retrospective study was designed to determine the risk factors for residual back pain after PVP and provides a nomogram for predicting the residual back pain after PVP. METHODS: We retrospectively reviewed the medical records of patients with single-segment OVCFs who underwent bilateral percutaneous vertebroplasty. Patients were divided into group N and group R according to the postoperative VAS score. Group R is described as the VAS score of residual back pain ≥ 4. Pre- and postoperative factors that may affect back pain relief were evaluated between two groups. Univariate and multivariate logistic regression analysis were performed to identify risk factors affecting residual back pain after PVP. We provided a nomogram for predicting the residual back pain and used the receiver operating characteristic curve (ROC), concordance index (C-index), calibration curve, and decision curve analyses (DCA) to evaluate the prognostic performance. RESULTS: Among 268 patients treated with PVP, 37 (13.81%) patients were classified postoperative residual back pain. The results of the multivariate logistical regression analysis showed that the presence of an intravertebral vacuum cleft (IVC) (OR 3.790, P=0.026), posterior fascia oedema (OR 3.965, P=0.022), severe paraspinal muscle degeneration (OR 5.804, P=0.01; OR 13.767, P < 0.001), and blocky cement distribution (OR 2.225, P=0.041) were independent risk factors for residual back pain after PVP. The AUC value was 0.780, suggesting that the predictive ability was excellent. The prediction nomogram presented good discrimination, with a C-index of 0.774 (0.696∼0.852) and was validated to be 0.752 through bootstrapping validation. The calibration curve of the nomogram demonstrated a good consistency between the probabilities predicted by the nomogram and the actual probabilities. The nomogram showed net benefits in the range from 0.06 to 0.66 in DCA. CONCLUSIONS: The presence of IVC, posterior fascia oedema, blocky cement distribution, and severe paraspinal muscle degeneration were significant risk factors for residual back pain after PVP for OVCFs. Patients with OVCFs after PVP who have these risk factors should be carefully monitored for the possible development of residual back pain. We provide a nomogram for predicting the residual back pain after PVP.

Development and validation of a nomogram for predicting the probability of new vertebral compression fractures after vertebral augmentation of osteoporotic vertebral compression fractures.

INTRODUCTION: New vertebral compression fractures (NVCFs) are adverse events after vertebral augmentation of osteoporotic vertebral compression fractures (OVCFs). Predicting the risk of vertebral compression fractures (VCFs) accurately after surgery is still a significant challenge for spinal surgeons. The aim of our study was to identify risk factors of NCVFs after vertebral augmentation of OVCFs and develop a nomogram. METHODS: We retrospectively reviewed the medical records of patients with OVCFs who underwent percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP). Patients were divided into the NVCFs group and control group, base on the patients with or without NVCFs within 2 years follow-up period after surgery. A training cohort of 403 patients diagnosed in our hospital from June 2014 to December 2016 was used for model development. The independent predictive factors of postoperative VCFs were determined by least absolute shrinkage and selection operator (LASSO) logistic regression, univariate analysis and multivariate logistic regression analysis. We provided a nomogram for predicting the risk of NVCFs based on independent predictive factors and used the receiver operating characteristic curve (ROC), calibration curve, and decision curve analyses (DCA) to evaluated the prognostic performance. After internal validation, the nomogram was further evaluated in a validation cohort of 159 patients included between January 2017 and June 2018. RESULTS: Of the 403 patients in the training cohort, 49(12.16%) were NVCFs at an average of 16.7 (1 to 23) months within the 2 years follow-up period. Of the 159 patients in the validation cohort, 17(10.69%) were NVCFs at an average of 8.7 (1 to 15) months within the 2 years follow-up period. In the training cohort, the proportions of elderly patients older than 80 years were 32.65 and 13.56% in the NVCFs and control group, respectively (p = 0.003). The percentages of patients with previous fracture history were 26.53 and 12.71% in the NVCFs and control group, respectively (p = 0.010). The volume of bone cement were 4.43 ± 0.88 mL and 4.02 ± 1.13 mL in the NVCFs and Control group, respectively (p = 0.014). The differences have statistical significance in the bone cement leakage, bone cement dispersion, contact with endplate, anti-osteoporotic treatment, post-op Cobb angle and Cobb angle restoration characteristics between the two groups. The model was established by multivariate logistic regression analysis to obtain independent predictors. In the training and validation cohort, the AUC of the nomogram were 0.882 (95% confidence interval (CI), 0.824-0.940) and 0.869 (95% CI: 0.811-0.927), respectively. The C index of the nomogram was 0.886 in the training cohort and 0.893 in the validation cohort, demonstrating good discrimination. In the training and validation cohort, the optimal calibration curves demonstrated the coincidence between prediction and actual status, and the decision curve analysis demonstrated that the full model had the highest clinical net benefit across the entire range of threshold probabilities. CONCLUSION: A nomogram for predicting NVCFs after vertebral augmentation was established and validated. For patients evaluated by this model with predictive high risk of developing postoperative VCFs, postoperative management strategies such as enhance osteoporosis-related health education and management should be considered.

Clinical observation of two bone cement distribution modes after percutaneous vertebroplasty for osteoporotic vertebral compression fractures.

BACKGROUND: Current findings suggest that percutaneous vertebroplasty(PVP) is a suitable therapeutic approach for osteoporotic vertebral compression fractures (OVCFs). The present retrospective study aimed to investigate the differences in clinical efficacy and related complications between the two bone cement distribution modes. METHODS: We retrospectively reviewed the medical records of the patients with single-segment OVCFs who underwent bilateral percutaneous vertebroplasty. Patients were divided into blocky and spongy group according to the type of postoperative bone cement distribution. Clinical efficacy and related complications was compared between the two bone cement distribution modes on 24 h after the operation and last follow-up. RESULTS: A total of 329 patients with an average follow up time of 17.54 months were included. The blocky group included 131 patients, 109 females(83.2 %) and 22 males(16.8 %) with a median age of 72.69 ± 7.76 years, while the Spongy group was made up of 198 patients, 38 females(19.2 %) and 160 males(80.8 %) with a median age of 71.11 ± 7.36 years. The VAS and ODI after operation improved significantly in both two groups. The VAS and ODI in the spongy group was significantly lower than that in the blocky group, 24 h postoperatively, and at the last follow-up. There were 42 cases (12.8 %) of adjacent vertebral fractures, 26 cases (19.8 %) in the blocky group and 16 cases (8.1 %) in the spongy group. There were 57 cases (17.3 %) of bone cement leakage, 18 cases (13.7 %) in blocky group and 39 cases (19.7 %) in the spongy group. At 24 h postoperatively and at the last follow-up, local kyphosis and anterior vertebral height were significantly corrected in both groups, but gradually decreased over time, and the degree of correction was significantly higher in the spongy group than in the block group. The change of local kyphosis and loss of vertebral body height were also less severe in the spongy group at the last follow-up. CONCLUSIONS: Compared with blocky group, spongy group can better maintain the height of the vertebral body, correct local kyphosis, reduce the risk of the vertebral body recompression, long-term pain and restore functions.

Study of miRNA interactome in active rheumatoid arthritis patients reveals key pathogenic roles of dysbiosis in the infection-immune network.

OBJECTIVES: To characterize serum microRNA (miR) and the miR interactome of active RA patients in RA aetiology and pathogenesis. METHODS: The differentially expressed miRs (DEmiRs) in serum of naïve active RA patients (NARAPs, n = 9, into three pools) vs healthy controls (HCs, n = 15, into five pools) were identified with Agilent human miR microarray analysis. Candidate driver genes in epigenetic and pathogenic signalling pathway modules for RA were analysed using miRTarBase and a molecular complex detection algorithm. The interactome of these DEmiRs in RA pathogenesis were further characterized with gene ontology and Kyoto Encyclopaedia of Genes and Genomes. RESULTS: Three upregulated DEmiRs (hsa-miR-187-5p, -4532, -4516) and eight downregulated DEmiRs (hsa-miR-125a-3p, -575, -191-3p, -6865-3p, -197-3p, -6886-3p, -1237-3p, -4436b-5p) were identified in NARAPs. Interactomic analysis from heterogeneous experimentally validated sources yielded 1719 miR-target interactions containing 5.67% strong and 94.33% less strong experimental evidence. Gene ontology and Kyoto Encyclopaedia of Genes and Genomes analyses allocated the upregulated DEmiRs in the infection modules and the downregulated DEmiRs in the immune signalling pathways. Specifically, these DEmiRs revealed the significant contributions of the intestinal microbiome dysbiosis in the infection-inflammation-immune network for activation of T cells, immune pathways of IL-17, Toll-like receptor, TNF, Janus kinase-signal transducer and activator of transcription, osteoclast cell differentiation pathway and IgA production to the active RA pathogenesis. CONCLUSIONS: Our experiment-based interactomic study of DEmiRs in serum of NARAPs revealed novel clinically relevant miRs interactomes in the infection-inflammation-immune network of RA. These results provide valuable resources for understanding the integrated function of the miR network in RA pathogenesis and the application of circulating miRs as biomarkers for early aetiologic RA diagnosis.

MiR-27a targets sFRP1 in hFOB cells to regulate proliferation, apoptosis and differentiation.

MicroRNAs (miRNAs) play a key role in the regulation of almost all the physiological and pathological processes, including bone metabolism. Recent studies have suggested that miR-27 might play a key role in osteoblast differentiation and bone formation. Increasing evidence indicates that the canonical Wnt signaling pathway contributes to different stages of bone formation. In this study, we identify miR-27a can promote osteoblast differentiation by repressing a new target, secreted frizzled-related proteins 1 (sFRP1) expression at the transcriptional level. Here, 21 candidate targets of miR-27a involved in canonical Wnt/ß-catenin signaling were predicted, and a significant decrease in sFRP1 luciferase activity was observed both in 293T and MG63 cells co-transfected with the matched luciferase reporter constructs and miR-27a mimic. Furthermore, the presence of exogenous miR-27a significantly decreased sFRP1 mRNA and protein expression in hFOB1.19 cells during both proliferation and osteogenic differentiation. The over-expression of miR-27a or knockdown sFRP1 significantly increased the percentage of apoptotic hFOBs, the percentage of cells in the G2-M phase of the cell cycle and the expression of key osteoblastic markers, including ALP, SPP1, RUNX2 and ALP activity. Over-expression of miR-27a or knockdown of endogenous sFRP1 led to an accumulation of ß-catenin in hFOBs. In the present study, we demonstrate that miR-27a induced gene silencing effect is a vital mechanism contributing to bone metabolism in hFOB cells in vitro, which is partly affected by the post-transcriptional regulation of sFRP1, during osteoblast proliferation, apoptosis and differentiation.