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Enthesophyte formation plays a crucial role in the development of spinal ankylosis in ankylosing spondylitis (AS). We aimed to investigate the role of platelet-derived growth factor B (PDGFB) in enthesophyte formation of AS using in vitro and in vivo models, and to determine the association between PDGFB and spinal progression in AS. Serum PDGFB levels were measured in AS patients and healthy controls (HC). Human entheseal tissues attached to facet joints or spinous processes were harvested at the time of surgery and investigated for bone-forming activity. The impact of a pharmacological agonist and antagonist of platelet-derived growth factor B receptor (PDGFRB) were investigated respectively in curdlan-treated SKG mice. PDGFB levels were elevated in AS sera and correlated with radiographic progression of AS in the spine. Mature osteoclasts secreting PDGFB proteins were increased in the AS group compared to HC and were observed in bony ankylosis tissues of AS. Expression of PDGFRB was significantly elevated in the spinous enthesis and facet joints of AS compared to controls. Moreover, recombinant PDGFB treatment accelerated bone mineralization of enthesis cells, which was pronounced in AS, whereas PDGFRB inhibition efficiently reduced the PDGFB-induced bone mineralization. Also, PDGFRB inhibition attenuated the severity of arthritis and enthesophyte formation at the joints of curdlan-treated SKG mice. This study suggests that regulating PDGFB/PDGFRB signaling could be a novel therapeutic strategy to block key pathophysiological processes of AS. This article is protected by copyright. All rights reserved.

Summary Objective Although cartilage degeneration and invasion of the subchondral bone plate in entheseal lesion has been considered to consequently lead bony ankylosis in ankylosing spondylitis (AS), no evident mechanisms are known. Design To identify histopathological and physiological changes in enthesitis-related ankylosis in AS, we performed molecular characterization of transcription factors and surface markers, and transcriptome analysis with human tissues. Entheseal tissue containing subchondral bone was obtained from the facet joints of 9 patients with AS and 10 disease controls, and assessed by using differential staining techniques. Enthesis cells were isolated, characterized, stimulated with TNF and/or IL-17A, and analysed by cell-based experimental tools. Results We found diffusely distributed granular tissue and cartilage in the subchondral bone in AS. Co-expression of SOX9, a specific transcription factor in cartilage, and matrix metalloproteinase 13 (MMP13) was found in the granular tissues within the subchondral bone from AS patients. Intriguingly, SOX9 expression was significantly higher in AS enthesis cells than controls and correlated with TNFR1 and IL-17RA expressions, which is important for high reactivity to TNF and IL-17A cytokines. Co-stimulation by TNF and IL-17A resulted in accelerated mineralization/calcification features, and increased OCN expression in AS enthesis cells. Furthermore, SOX9 overexpression in enthesis leads to promoting mineralization feature by TNF and IL-17A stimuli. Finally, OCN expression is elevated in the destructive enthesis of advanced AS. Conclusion These findings provide insight into the links between inflammation and the mineralization of entheseal tissue as the initiation of spinal ankylosis, emphasizing the importance of SOX9+ enthesis cells.

ObjectivesTo identify clinical and genetic factors associated with severe radiographic damage in patients with ankylosing spondylitis (AS).MethodsWe newly generated genome-wide single nucleotide polymorphism data (833K) for 444 patients with AS. The severity of radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). To identify clinical and genetic factors associated with severe radiographic damage, multiple linear regression analyses were performed. Human AS-osteoprogenitor and control-osteoprogenitor cells were used for functional validation.ResultsThe significant clinical factors of final mSASSS were baseline mSASSS (β=0.796, p=3.22×10−75), peripheral joint arthritis (β=−0.246, p=6.85×10−6), uveitis (β=0.157, p=1.95×10−3), and smoking (β=0.130, p=2.72×10−2) after adjusting for sex, age and disease duration. After adjusting significant clinical factors, theRyanodine receptor 3(RYR3) gene was associated with severe radiographic damage (p=1.00×10−6). For pathway analysis, the PI3K-Akt signalling pathway was associated with severe radiographic damage in AS (p=2.21×10−4, false discovery rate=0.040). Treatment with rhodamine B, a ligand of RYR3, dose-dependently induced matrix mineralisation of AS osteoprogenitors. However, the rhodamine B-induced accelerated matrix mineralisation was not definitive in control osteoprogenitors. Knockdown of RYR3 inhibited matrix mineralisation in SaOS2 cell lines.ConclusionsThis study identified clinical and genetic factors that contributed to better understanding of the pathogenesis and biology associated with radiographic damage in AS.

Spondyloarthritis (SpA), a type 3 immunity-mediated inflammatory arthritis, is a systemic rheumatic disease that primarily affects the joints, spine, gut, skin, and eyes. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine, yet MIF's pathological role in SpA is unknown. Here, we observed that the expression of MIF and its receptor CD74 is increased in blood and tissues of curdlan (β-glucan)-treated SKG mice, a mouse model of SpA. We found that neutrophils substantially expanded and produced MIF in curdlan-treated SKG mice and that human neutrophils from SpA patients secreted higher concentrations of MIF compared to healthy individuals. Although genetic deletion of Mif (Mif-/-) substantially suppressed the severity of SpA features, adoptive transfer of inflammatory neutrophils induced SpA pathology in curdlan-treated Mif-/- SKG mice; in contrast, blocking the function of neutrophils with anti-Gr-1 antibody suppressed the curdlan-induced SpA-like phenotype. We also determined that systemic MIF overexpression was sufficient to induce SpA-like clinical features in SKG mice with enhanced type 3 immunity, whereas SKG mice treated with a MIF antagonist prevented or attenuated curdlan-induced SpA manifestations. Mechanistically, we identified that MIF intensifies type 3 immunity by boosting human and mouse T regulatory cell (Treg) acquisition of a TH17 cell-like phenotype, including the up-regulation of interleukin-17 (IL-17) and IL-22 in vitro. Tregs in blood and synovial fluids from SpA patients have a pathologic TH17 phenotype. These results indicate that MIF is a crucial regulator and a potential therapeutic target in type 3 immunity-mediated arthritis.

Study design A retrospective study. Objective To evaluate the psychological changes and employment outcomes following corrective osteotomy in patients with ankylosing spondylitis (AS). Summary of background data To date, no study has investigated the changes in psychological status and subsequent improvement in employment outcome after correction of kyphotic deformities in patients with AS. Methods This study included 48 patients with AS who underwent corrective osteotomy for severe kyphotic deformity. Sagittal alignment was assessed radiographically. Clinical status was evaluated using the Short Form-36 Health Survey, psychological status was evaluated using the Hospital Anxiety and Depression Scale (HADS), and employment outcomes were assessed using the Lam Employment Absence and Productivity Scale (LEAPS). The degree of postoperative sagittal alignment correction was measured, and changes in clinical and employment outcomes and psychological status were evaluated. The relationship between the degree of sagittal alignment correction and each evaluation item was analyzed. Results Following postoperative sagittal alignment correction, all patients could stand erect and look straight. Significant improvements were observed in the clinical and employment outcomes, as well as in patients' psychological status. The degree of sagittal vertical axis correction was significantly correlated with the HADS depression and the LEAPS total scores. The degree of correction of the chin-brow vertical angle was significantly correlated with the Short Form-36 mental health score, the HADS depression and anxiety scores, and the LEAPS total and productivity subscores. Notably, the improvement in the HADS depression score was significantly correlated with the LEAPS total score. Conclusion This study demonstrated the psychological changes and subsequent improvement in employment outcomes after corrective osteotomy in patients with AS. The degree of sagittal alignment correction was correlated with improvements in psychological status and employment outcomes. Level of evidence 4.

Receptor activator of nuclear factor kappa B ligand (RANKL) expression in osteoblasts is regulated by 1,25-dihydroxyvitamin D3 (1,25D3). CCAAT/enhancer-binding protein beta (C/EBPβ) has been proposed to function as a transcription factor and upregulate RANKL expression, but it is still uncertain how C/EBPβ is involved in 1,25D3-induced RANKL expression of osteoblasts. 1,25D3 stimulation increased the expression of RANKL and C/EPBβ genes in osteoblasts and enhanced phosphorylation and stability of these proteins. Moreover, induction of RANKL expression by 1,25D3 in osteoblasts was downregulated upon knockdown of C/EBPβ. In contrast, C/EBPβ overexpression directly upregulated RANKL promoter activity and exhibited a synergistic effect on 1,25D3-induced RANKL expression. In particular, 1,25D3 treatment of osteoblasts increased C/EBPβ protein binding to the RANKL promoter. In conclusion, C/EBPβ is required for induction of RANKL by 1,25D3. [BMB Reports 2019; 52(6): 391-396].

Although risk factors of new adjacent vertebral fracture (AVF) and remote vertebral fracture (RVF) after vertebroplasty may differ, research on this topic is lacking.To determine the natural course of new vertebral fractures after vertebroplasty for osteoporotic vertebral compression fracture (OVCF) and to analyze each risk factor for understanding the incidence of AVF and RVF.Retrospective cohort study.The study subjects included 205 patients who received vertebroplasty for OVCF and were followed-up for at least 1-year.Data on factors that could affect the occurrence of vertebral fractures, such as age, body mass index, and bone density, were collected from the patients' medical records. Fracture pattern, fracture location, sagittal imbalance, degree of segmental kyphosis after vertebroplasty, cement distribution, and cement leakage were radiologically examined.xDuring the follow-up period, any newly developed vertebral fractures were identified. We analyzed whether the time of occurrence differed between AVF and RVF by performing a survival analysis and each risk factor separately.New vertebral fractures occurred in 47 patients (22.9%) after vertebroplasty, AVF occurred in 21 patients (10.2%), and RVF occurred in 26 patients (12.7%). The onset time of AVF was 6.2±1.8 months after vertebroplasty, showing a significant difference from that of RVF, which was 15.2±1.8 months (p.001). In the univariate analysis, the risk factors of AVF included severe osteoporosis (T-score-3.0), vertebroplasty in the thoracolumbar junction, sagittal imbalance, and segmental kyphosis angle15° (p=0.029, p=0.033, p=0.001, and p=0.021, respectively). The risk factors of RVF included severe osteoporosis (T-score-3.0) and sagittal imbalance (p=0.013 and p=0.004). In the multivariate analysis, the risk factors of AVF included vertebroplasty in the thoracolumbar junction and sagittal imbalance (hazard ratio=3.34, p=0.032 and hazard ratio=4.05, p=0.008), and those of RVF included only sagittal imbalance (hazard ratio=2.66, p=0.024).After vertebroplasty for OVCF, a significant difference in the meantime of occurrence was found; it took 6 months for AVF and 15 months for RVF to develop. Vertebroplasty in the thoracolumbar junction was identified as a risk factor for AVF, whereas sagittal imbalance was a risk factor of both AVF and RVF.

Background: While the indications of parathyroid hormone (PTH) in osteoporosis prevention and management have been established, its indications in the treatment of osteoporotic vertebral fractures remain unknown. This study aimed to compare the effects of intervention (percutaneous vertebroplasty followed by anti-resorptive agents) and conservative treatment (PTH administration) in patients with osteoporotic vertebral fractures, as well as to investigate the optimal duration of PTH administration. Methods: A retrospective study was conducted using data of patients treated for osteoporotic vertebral fractures between January 2015 and November 2019. Treatment was selected based on the patient’s age, comorbidities, and patient’s preference after explaining the expected advantages and disadvantages of each treatment. Group C was administered PTH injections once weekly, whereas Group I underwent vertebroplasty followed by the administration of anti-resorptive agents. Radiological and clinical parameters were analyzed between two groups.Results: This study enrolled 58 patients (77 vertebrae). Group C included 24 patients (38 vertebrae) with average age of 77.50 ± 7.19 years (range, 65–85 years), average bone mineral density (BMD) of −3.39 ± 0.86 (range, −2.5 to −5.8), average follow-up period of 27.47 ± 7.60 weeks (range, 12–49 weeks). Group I included 34 patients (39 vertebrae) with an average age of 76.20 ± 8.67 years (range, 65–92 years), average BMD of −3.35 ± 0.91 (range, −2.5 to −5.1), average follow-up period of 30.82 ± 10.95 weeks (range, 16–59 weeks). There was no significant difference between the two groups in initial demographic, clinical and radiographic parameters. Group I showed significantly better clinical and radiological outcome during the last follow-up. Regarding side effects in Group C, two cases of dizziness (8.3%), nausea and vomiting (8.3%) were reported. In Group I, cement leakage was found in 26 vertebrae (66.7%), and cement leakage complications were observed in four patients (11.8%). Conclusion: Conservative treatment using PTH injection demonstrated slower pain relief and lesser suppression of vertebral height loss than vertebroplasty. However, PTH injection demonstrated a lower risk of procedure-related complications. The patient’s age, preference, and general condition with respect to the procedure’s risk should be considered when determining treatment options for osteoporotic vertebral fracture in old age.

Background: Patients with ankylosing spondylitis (AS) have increased levels of protein phosphatase magnesium-dependent 1A (PPM1A) and autoantibodies. We evaluated the usefulness of serum anti-PPM1A antibodies as a biomarker for AS. Methods: Serum samples from 58 AS patients were obtained from a multicenter registry prior to the initiation of anti-TNF agents. The serum levels of anti-PPM1A antibodies were measured using ELISA. Spinal radiographic progression was defined as an increase in the modified stoke ankylosing spondylitis spinal score (mSASSS) by &ge, 2 units or a newly developed syndesmophyte. The role of exogenous PPM1A on bone mineralization was evaluated using primary osteoprogenitors acquired from patients with AS and non-inflammatory controls. Results: The baseline levels of anti-PPM1A antibodies and mSASSS were higher in the radiographic progression group than in the non-progression group. In logistic regression analysis, baseline mSASSS and serum anti-PPM1A antibodies were associated with a higher risk of progression. The level of anti-PPM1A antibodies for predicting progression had an AUC of 0.716 (cut-off value: 43.77 ng/mL). PPM1A stimulation increased matrix mineralization in AS-osteoprogenitors but not in controls. Conclusion: Along with mSASSS, the serum levels of anti-PPM1A antibodies might be useful as a predictor of radiographic progression after treatment with anti-TNF agents.

This study discussed application of a machine learning approach (Support vector machine, SVM) for the automatic cognition of gait changes due to scoliosis using gait measures: kinematic based on gait phase segmentation. The gaits of 18 controls and 24 scoliosis patients were recorded and analyzed using inertial measurement unit (IMU)-based systems during normal walking. Altogether, 72 gait features were extracted for developing gait recognition models. Cross-validation test results indicated that the performance of SVM was 90.5% to recognize scoliosis patients and controls gait patterns. When features were optimally selected, a feature selection algorithm could effectively distinguish the age groups with 95.2% accuracy. Applying the method that the previous test used, the severity of scoliosis was classified after clinician labeled the severity based on the Cobb angle. Test results indicated an accuracy of 81.0% by the SVM to recognize scoliosis severity gait patterns. Optimal selected features could effectively distinguish the scoliosis severity with 85.7% accuracy. When the measured features are ranked in order of high contribution, the abduction and adduction of left hip joint in the single support phase is most important in gait of patients with scoliosis. These results demonstrate considerable potential in applying SVMs in gait classification for medical applications.

Sagittal translation, a potential complication of pedicle subtraction osteotomy (PSO), can result in neurologic damage. However, few studies have been conducted on sagittal translation and its risk factors after PSO in patients with ankylosing spondylitis (AS).We aimed to report cases of sagittal translation that developed after PSO in patients with AS with kyphotic deformity and to analyze risk factors for sagittal translation.A retrospective case-control study was carried out.This study included 53 patients (58 cases) with AS who underwent PSO to correct their kyphotic deformity.The modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) was measured before the surgery. Radiological pelvic and sagittal parameters were also measured before and after surgery. Developments of sagittal translation were confirmed with intraoperative radiograph.The subjects were grouped according to the presence (ST group) and absence (non-ST group) of sagittal translation. The demographic and radiological parameters were compared between two groups. Through multivariate logistic regression analysis, the correlations between sagittal translation and relevant parameters were analyzed for risk factor evaluation.Sagittal translation developed in 16 patients (30.2%) [16 cases (27.6%)]. The mean lumbar lordosis angle and sagittal vertical axis of both ST group and non-ST group were successfully corrected. In a comparison of two groups, the ST group (58.2±13.3) showed a significantly higher mSASSS than the non-ST group (33.9±11.9) (p.001). The ST group (50.4°±7.8°, 16.9°±6.8°) also showed a significantly higher preoperative pelvic incidence and sacral slope than the non-ST group (45.3°±7.2°, 11.0°±7.7°) (p=.026, p=.011). No significant differences were observed between the two groups for the rest of radiological parameters. In multivariate analysis, only mSASSS was positively correlated with sagittal translation (odds ratio 1.16, p=.001).The incidence of sagittal translation after PSO was closely related with severity of ankylosis in patients with AS. Therefore, surgeons must consider sagittal translation, which could induce neurologic complications, when PSO is performed for patients with AS with severe ankylosis.

Background IL-17A has recently emerged as a potential target that regulates the extensive inflammation and abnormal bone formation observed in ankylosing spondylitis (AS). Blocking IL-17A is expected to inhibit bony ankylosis. Here, we investigated the effects of anti IL-17A agents in AS. Methods TNFα, IL-17A, and IL-12/23 p40 levels in serum and synovial fluid from patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), osteoarthritis (OA), or healthy controls (HC) were measured by ELISA. Bone tissue samples were obtained at surgery from the facet joints of ten patients with AS and ten control (Ct) patients with noninflammatory spinal disease. The functional relevance of IL-17A, biological blockades, Janus kinase 2 (JAK2), and non-receptor tyrosine kinase was assessed in vitro with primary bone-derived cells (BdCs) and serum from patients with AS. Results Basal levels of IL-17A and IL-12/23 p40 in body fluids were elevated in patients with AS. JAK2 was also highly expressed in bone tissue and primary BdCs from patients with AS. Furthermore, addition of exogenous IL-17A to primary Ct-BdCs promoted the osteogenic stimulus-induced increase in ALP activity and mineralization. Intriguingly, blocking IL-17A with serum from patients with AS attenuated ALP activity and mineralization in both Ct and AS-BdCs by inhibiting JAK2 phosphorylation and downregulating osteoblast-involved genes. Moreover, JAK2 inhibitors effectively reduced JAK2-driven ALP activity and JAK2-mediated events. Conclusions Our findings indicate that IL-17A regulates osteoblast activity and differentiation via JAK2/STAT3 signaling. They shed light on AS pathogenesis and suggest new rational therapies for clinical AS ankylosis.

Study DesignA noninterventional, multicenter, cross-sectional study.PurposeWe investigated the prevalence of neuropathic pain (NP) and patient-reported outcomes (PROs) of the quality of life (QoL) and functional disability in Korean adults with chronic low back pain (CLBP).Overview of LiteratureAmong patients with CLBP, 20%–55% had NP.MethodsPatients older than 20 years with CLBP lasting for longer than three months, with a visual analog scale (VAS) pain score higher than four, and with pain medications being used for at least four weeks before enrollment were recruited from 27 general hospitals between December 2014 and May 2015. Medical chart reviews were performed to collect demographic/clinical features and diagnosis of NP (douleur neuropathique 4, DN4). The QoL (EuroQoL 5-dimension, EQ-5D; EQ-VAS) and functional disability (Quebec Back Pain Disability Scale, QBPDS) were determined through patient surveys. Multiple linear regression analyses were performed to compare PROs between the NP (DN4≥4) and non-NP (DN4ResultsA total of 1,200 patients (females: 65.7%; mean age: 63.4±13.0 years) were enrolled. The mean scores of EQ-5D, EQ-VAS, and QBPDS were 0.5±0.3, 55.7±19.4, and 40.4±21.1, respectively. Among all patients, 492 (41.0%; 95% confidence interval, 38.2%–43.8%) suffered from NP. The prevalence of NP was higher in male patients (46.8%; pppppppConclusionsNP was highly prevalent in Korean patients with CLBP. Patients with CLBP having NP had a lower QoL and more severe dysfunction than those without NP. To enhance the QoL and functional status of patients with CLBP, this study highlights the importance of appropriately diagnosing and treating NP.

The main aim of this study are to explore the role of bone-derived cells (BdCs) in ankylosing spondylitis (AS) and determine the underlying molecular mechanisms of IL-23 production. Primary BdCs were isolated from diced bone of facet joints obtained during surgery from seven AS patients and seven disease control (Ct) patients. Osteoblastic activity of BdCs was assessed by measuring their alkaline phosphatase activity and by alizarin red staining. Osteoblast and endoplasmic reticulum (ER) stress-related genes were assessed by quantitative PCR, immunoblotting, immunofluorescence, and immunohistochemistry. In addition, expression of IL-23 in response to BIX (selective BIP inducer X)-induced ER stress was evaluated by qPCR and ELISA. Protein interaction and binding to IL-23 promoter were confirmed by Immunoprecipitation and Chromatin immunoprecipitation, respectively. Transcript levels of genes involved in osteoblast function, as well as of the ER stress marker were higher in the AS group than the Ct group, and elevated RUNX2, BiP and IL-23 expression were observed in the BdCs, serum, and bone biopsies from the AS group. BIX-induced ER stress stimulated osteoblastic activity and IL-23 secretion by upregulating RUNX2 expression. Furthermore, in AS BdCs, RUNX2 interacted with C/EBPβ to bind to IL-23 promoter and RUNX2 knockdown suppressed IL-23 secretion. These finding may provide a molecular mechanism involved in sustained ER stress in AS BdCs stimulates the activation of RUNX2 and C/EBPβ genes, leading to IL-23 production.

BACKGROUND This study aimed to evaluate quality of life (QOL) using the EuroQOL-5 dimensions (EQ-5D) index and to examine factors affecting QOL in patients with an osteoporotic vertebral compression fracture (OVCF). METHODS This ambispective study used a questionnaire interview. Patients over 50 years old with an OVCF at least 6 months previously were enrolled. Individual results were used to calculate the EQ-5D index. Statistical analysis was performed, and factors related to QOL were examined. RESULTS Of 196 patients in the study, 84.2% were female, with an average age of 72.7 years. There were 66 (33.7%) patients with multilevel fractures. Conservative management was used in 75.0% of patients, and 56.1% received anti-osteoporosis treatment. The mean EQ-5D index was 0.737±0.221 and was significantly correlated with the Oswestry disability index score (correlation coefficient -0.807, P

Ankylosing spondylitis (AS) is characterized by excessive bone formation with syndesmophytes, leading to bony ankylosis. The contribution of osteoblasts to the pathogenesis of ankylosis is poorly understood. The aim of this study was to determine molecular differences between disease controls (Ct) and AS bone-derived cells (BdCs) during osteogenic differentiation with or without inflammation using AS patient serum. We confirmed osteoblastic differentiation of Ct and AS BdCs under osteogenic medium by observing morphological changes and measuring osteoblastic differentiation markers. Osteoblast differentiation was detected by alkaline phosphatase (ALP) staining and activity, and alizarin red and hydroxyapatite staining. Osteoblast-specific markers were analyzed by quantitative reverse-transcriptase-polymerase chain reaction, immunoblotting, and immunostaining. To examine the effects of inflammation, we added AS and healthy control serum to Ct and AS BdCs, and then analyzed osteoblast-specific markers. AS BdCs showed elevated basal intercellular and extracellular ALP activity compared to Ct. When osteoblast differentiation was induced, AS BdCs exhibited higher expression of osteoblast-specific marker genes and faster mineralization than Ct, indicating that these cells differentiated more rapidly into osteoblasts. ALP activity and mineralization accelerated when serum from AS patients was added to Ct and AS BdCs. Our results revealed that AS BdCs showed significantly increased osteoblastic activity and differentiation capacity by regulating osteoblast-specific transcription factors and proteins compared to Ct BdCs. Active inflammation of AS serum accelerated osteoblastic activity. Our study could provide useful basic data for understanding the molecular mechanism of ankylosis in AS.

Background Ankylosing spondylitis (AS) is characteristically male-predominant, and progressive spinal ankylosis affects male patients more severely; however, the hormonal effects in males with AS are poorly understood. Methods In the present study, the regulatory effects of dutasteride, a 5-α reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone (DHT), were examined in curdlan-administered male SKG mice to determine spinal bone formation, bone metabolism-related markers, and interleukin (IL)-17A cytokine and T cell populations. In addition, the effects of DHT on primary osteoprogenitors from the facet joints of AS patients were assessed based on osteoblast-related parameters. DHT level was measured, and the correlation with modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) was analyzed in AS patients. Results In curdlan-administered SKG mice, dutasteride treatment resulted in an increased accumulation of hydroxyapatite in the spine which was positively correlated with serum IL-17A levels. In the analysis of bone metabolism-related molecules, a decrease in sclerostin levels was observed in the sera in the dutasteride group. Continuous exposure to DHT resulted in fewer calcium deposits in AS osteoprogenitors during osteoblast differentiation. DHT-treated AS osteoprogenitors showed decreased osteocalcin and increased DKK1 and SOST1 mRNA expression, supporting the results of the in vivo experiments. Treatment with dutasteride upregulated bone formation in the spine of curdlan-administered SKG mice and DHT treatment downregulated osteoblast differentiation in vitro. Conclusions Treatment with dutasteride affected the bone formation in the spine of curdlan-treated SKG mice, and DHT treatment attenuated osteoblast differentiation in vitro. Therefore, contrary to what could be expected if osteoblasts contributed to spinal ankylosis, DHT inhibition might increase rather than decrease the progression of spinal ankylosis despite the higher levels of DHT observed in many AS patients.

To compare the radiographic migration profiles of primary cementless total hip arthroplasty (THA) between patients with rheumatoid arthritis (RA) and those with osteoarthritis (OA).A total of 197 patients (215 hips) who underwent cementless THA for RA or OA between January 2001 and January 2013 and followed up for a minimum of 5.5 years were included. Ninety-four RA patients (109 hips) were compared with 103 OA patients (106 hips). Radiological evaluation was performed for acetabular cup loosening, and cup migration was measured using Einzel-Bild-Röntgen-Analyse (EBRA) software. Multiple variables were assessed to identify influencing factors for cup migration.Early cup migration was observed in 13 hips (11.9%) in the RA group and four hips (3.8%) in the OA group, showing a significant difference (p = 0.041). Acetabular cup loosening occurred in three cups (2.8%) in the RA group and in one cup (0.9%) in the OA group, showing no significant difference (p = 0.321). Total cup migration was higher in the RA group (2.62 mm) than in the OA group (1.44 mm, p = 0.005). Total cup migration was significantly higher in patients aged 50 years than in those aged 50 years (p = 0.005). Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody influenced total cup migration. Patients with seropositive RA showed significantly higher total cup migration and early cup migration incidence than those with seronegative RA (p = 0.005, p = 0.038, respectively).Acetabular cups in primary cementless THAs of RA patients were less stable in terms of cup migration compared with that of OA patients.

The efficacy of once-weekly risedronate with and without cholecalciferol in bone mineral density (BMD) in Korean patients with osteoporosis was compared. After 12 months, both spine and hip BMD increased significantly in both groups, but there was no significant difference between two groups. This study investigated the efficacy and safety of once-weekly risedronate with and without cholecalciferol in BMD in Korean patients with osteoporosis. This was a prospective, 12-month, randomized, open-labeled, actively controlled trial involving 41 hospitals. A total of 841 subjects with osteoporosis were randomized to once-weekly risedronate (35 mg) and cholecalciferol (5600 IU) in a single pill (RSD+, n = 642) or once-weekly risedronate (35 mg) alone (RSD, n = 199). BMD was measured via dual-energy X-ray absorptiometry at the lumbar spine and hip, and the serum levels of 25-hydroxy vitamin D (25(OH) D), parathyroid hormone (PTH), and alkaline phosphatase (ALP) were assayed at baseline and after 12 months of treatment. After 12 months, the lumbar spine, femoral neck, and total hip BMD increased significantly in both groups; there was no significant difference between two groups. Women in the RSD+ group exhibited significantly increased lumbar spine BMD, and subjects with previous fracture history in the RSD+ group had significantly increased total hip BMD compared with the RSD group. The serum 25(OH) D level increased significantly in the RSD+ group. The serum PTH level decreased in the RSD+ group but increased in the RSD group. The serum ALP level significantly decreased in both groups; there was no significant difference between two groups. A once-weekly pill containing risedronate and cholecalciferol had the equivalent antiresorptive efficacy on BMD compared with risedronate alone and improved 25(OH) D serum levels after 12 months of treatment without significant adverse events in Korean patients with osteoporosis.

The aim of this study is to determine the relationship between AS and subsequent depression. This study was conducted using a nationwide dataset available in Korean National Health Insurance System (KNHIS). We identified 11,465 newly diagnosed AS patients and 57,325 patients without AS in the ratio of 1:5 matched by sex, age, and index date, between 2010 and 2014. We investigated any latent characteristics in the patients’ demographic information and chronic comorbidities that could trigger a depression when diagnosed with AS. By comparing the cohort data, the hazard ratio of developing subsequent depression in AS patients was calculated and adjusted based on several risk factors. Despite the adjustment of demographic variables and chronic comorbidities, the risk of depression was 2.21 times higher in the AS cohort than in the control group. Multivariate analysis showed that AS patients with female gender, old age and low-income status showed higher risks of developing depression. Additionally, the presence of chronic comorbidities including diabetes mellitus, hypertension, hyperlipidemia, cancer, stroke, and chronic kidney disease increased the patients’ risk of depression. The AS patients with stroke were reported to have the highest risk of depression. This population-based cohort study showed that AS significantly increased the subsequent risk of developing depression. Moreover, the development of a depression is influenced by certain demographic variables and different chronic comorbidities.

BACKGROUND Opioids are recently recommended for those who do not gain adequate pain relief from the use of acetaminophen or nonsteroidal anti-inflammatory drugs. Medical opioids are administered in various routes, and transdermal opioid products that can make up for the weaknesses of the oral or intravenous products have been developed. This study is to evaluate the clinical usefulness of fentanyl matrix in terms of the long-term improvement in pain and physical and mental functions. METHODS This was a multicenter, open, prospective, observational study that was conducted in 54 institutions in Korea. Patients with non-cancerous chronic pain completed questionnaires, and investigators also completed questionnaires. A total of 1,355 subjects participated in this study, and 639 subjects completed the study. Subjects received transdermal fentanyl matrix (12 µg/hr, 25 µg/hr, or 50 µg/hr depending on the patient's response and demand). Subjects visited at 29 ± 7 days, 85 ± 14 days, and 169 ± 14 days after administration, respectively, to receive drug titration and fill out the questionnaires. The results were analyzed using the intention-to-treat (ITT) analysis, full analysis set (FAS), and per-protocol (PP) analysis. The FAS analysis included only 451 participants; the PP analysis, 160 participants; and the ITT analysis, 1,355 participants. RESULTS The intensity of pain measured by the Numeric Rating Scale decreased from 7.07 ± 1.78 to 4.93 ± 2.42. The physical assessment score and mental assessment score of the Short-Form Health Survey 12 improved from 28.94 ± 7.23 to 35.90 ± 10.25 and from 35.80 ± 11.76 to 42.52 ± 10.58, respectively. These differences were significant, and all the other indicators also showed improvement. Adverse events with an incidence of ≥ 1% were nausea, dizziness, vomiting, and pruritus. CONCLUSIONS The long-term administration of fentanyl matrix in patients with non-cancerous pain can reduce the intensity of pain and significantly improves activities of daily living and physical and mental capabilities.

Background Context Although the simultaneous management of neuronal ischemia-related pain and compression-demyelination–related neuropathic pain is considered optimal in treating lumbar spinal stenosis (LSS), the effect of combination therapy with pregabalin and limaprost has not been elucidated. Purpose This study aimed to compare the effects of limaprost and pregabalin individually and in combination for the treatment of LSS. Study Design This is a prospective, double-blind, double-dummy, randomized controlled trial. Patient Sample The sample consists of patients with LSS. Outcome Measures The baseline-adjusted Oswestry Disability Index (ODI) score, visual analog scale (VAS) scores for leg pain, the European Quality of Life-5 dimensions (EQ-5D), and initial claudication distance (ICD). Methods The present study ( ClinicalTrials.gov , number NCT01888536) was a prospective, double-blind, double-dummy, randomized controlled trial designed to determine the efficacy of limaprost in alleviating leg pain, improving disability, and increasing walking distance in persons with degenerative LSS in three different treatment groups: limaprost alone, pregabalin alone, and combined limaprost and pregabalin through 1:1:1 allocation. The primary outcome was the baseline-adjusted ODI score at 8 weeks after treatment. The non-inferior margin of the ODI was set at δ=10 points. Results The baseline-adjusted ODI score (primary outcome) at 8 weeks after treatment in the limaprost group was not inferior to those in the pregabalin and limaprost+pregabalin groups. The overall changes of the baseline-adjusted ODI scores, VAS scores for leg pain, the EQ-5D, and ICD during the follow-up assessments over an 8-week period (secondary end point) were not different among the three groups. The baseline-adjusted ODI scores and VAS scores for leg pain decreasedsignificantly over time after treatment in all three groups. The baseline-adjusted EQ-5D score and ICD also increased significantly over time after treatment in all three groups. Conclusions The efficacy of limaprost for lumbar spinal stenosis was not inferior compared with that of pregabalin or the combination of limaprost and pregabalin in terms of disability. Therefore, combined treatment with limaprost and pregabalin does not provide additional relief in symptoms in patients with LSS compared with monotherapy with limaprost or pregabalin.

Both increased sagittal vertical axis (SVA) and sarcopenia affect performance of daily activities and morbidity in the elderly; however, little is known regarding their relationship. The aim of this study was to analyze the association between sarcopenia and increased SVA. This retrospective study included 71 female patients aged between 60 and 85 years. Entire-spine radiography was used to measure radiological parameters. A bioelectrical impedance analyzer was used to measure the skeletal muscle mass index (SMI). Gait velocity (GV) and hand grip strength (HGS) were examined as well. Lumbar spine magnetic resonance imaging was employed to measure the functional cross-sectional area (FCSA) and fat signal fraction (FSF) of the paraspinal muscle as well. The subjects were divided into two groups according to the SVA (group I; SVA > 50 mm and group II; SVA ≤ 50 mm). The group I showed lower GV, HGS, and SMI than the group II (p

Percutaneous vertebroplasty (PVP) is a minimally invasive surgical treatment for patients with osteoporotic vertebral compression fracture (OVCF) and can rapidly alleviate pain, improve mobility, and stabilize the vertebrae. However, it has the potential to cause complications such as cement embolism. A 55-year-old female presented with pain in the lumbar region as a chief complaint. PVP was performed after diagnosis of acute OVCFs at L4 and L5. No abnormal symptoms were reported after surgery, but a large cement embolism was observed in her right atrium and ventricle. After discussion in a multi-disciplinary team, the large cement embolism was successfully removed by a combination of endovascular procedure and an inferior vena cava exploration. Surgeons must consider the possibility of intra-cardiac cement embolism after PVP. A hybrid approach of an endovascular procedure and a vascular surgery may be a reasonable treatment option to minimize the surgical procedure in cases of a large intra-cardiac cement embolism., Graphical Abstract

Objectives The purpose of present study was to investigate the coincidence rate and risk factors of sacral insufficiency fracture accompanied by compression fracture of thoracolumbar spine. Material and methods The candidates for this study were 945 patients who measured their bone mineral density (BMD) and showed spinal compression fracture on MRI or CT between January 2008 and December 2012. Sacral insufficiency fracture was diagnosed by MRI and the whole body bone scan. We assessed the risk factors of sacral insufficiency fracture which include sex, age, body mass index (BMI), underlying diseases (hypertension, diabetes mellitus, rheumatoid arthritis, and thyroid disease), the number of spinal compression fractures and the presence of osteoporosis. Results Among 945 patients with spinal compression fracture [76 (8%) males and 869 (92%) females], 36 (3.8%) had sacral insufficiency fractures (3 [8.3%] males and 33 [91.7%] females). Age and the presence of osteoporosis among risk factors were significant (p Conclusions The coincidence rate of sacral insufficiency fracture is about 3.8%. The clinicians should evaluate sacral insufficiency fractures more actively in patient with compression fracture of thoracolumbar spine accompanied by risk factors (age, the presence of osteoporosis).

Figure S1. Effect of osteogenic differentiation on both Ct-BdCs and AS-BdCs. Figure S2. Correlation of IL-17 levels in AS patients with ESR, CRP, and BASDAI levels. Figure S3. Correlation of IL-17 levels in RA patients with ESR and CRP levels. Figure S4. Secukinumab inhibits AS serum-induced phosphorylation status of JAK2/STAT3 in Ct-BdCs. Figure S5. Secukinumab suppresses IL-17A dose-dependent ALP activation in Ct-BdCs. Figure S6. Effect of JAK2 inhibitor (AG490) treatment on viability and toxicity of both Ct- and AS-BdCs. Table S1. Primer Sequences for qPCR. Table S2. Primary antibodies used in Immunoblotting (IB), Immunostaining (IF), and Immunohistochemistry (IHC). (DOCX 826 kb)

The aim of this study is to determine the prevalence and incidence of ankylosing spondylitis (AS) in South Korea, 2010–2015. This study was conducted using the Health Insurance Review Agency (HIRA) database, which includes information on every patient diagnosed with AS. The incidence and prevalence of AS were evaluated by age, sex, and income status. The prevalence increased linearly by 7.7% annually, i.e., 31.62 in 2010 to 52.30 in 2015 (per 100,000 persons). During the study period, the incidence was 6.34 per 100,000 person-years. The prevalence peaked for both men and women in the age range 30–39 years. Incidence peaked for men in the age range 20–29 years, but peaked for women between ages 70 and 89. AS was 3.6 times more prevalent in men than in women, and the incidence in men was 2.1 times greater than in women. With respect to income status, the prevalence and incidence of AS were 3 times greater and 5 times greater, respectively, in medical aid recipients compared to individuals with other income levels. The trend of increasing AS prevalence and the observation that 14.3% of all patients newly diagnosed with AS are medical aid recipients have significant implications for healthcare planning.

This study was designed to identify and characterize primary bone-derived cells (BdCs) and investigate the potential role of osteoblast differentiation. Primary BdCs were isolated from surgical bone for comparative analysis with mesenchymal stem cells (MSCs) and fetal osteoblasts (FOBs) and for potential differentiation to mature osteoblasts. Using three different cells, we successfully cultivated human osteoblast differentiation and activity which were evaluated using microarray and biochemical methods. BdCs are more correlated to MSCs in bioinformatics result and similar with FOBs in gene expression. In particular, Osterix, osteoprogenitor marker, was high expressed in BdCs, while the expression in MSCs and FOBs were very low. Furthermore, BdCs exhibited a marked alkaline phosphatase (ALP) expression, early stage of osteogenic marker, and retained osteogenic properties and physiological changes into maturation as in FOBs. BdCs also showed an increase in bone morphogenic protein 2 (BMP2), osteopontin (OPN), and osteocalcin (OCN) mRNA expressions during differentiation. This study suggests that BdCs may be osteoprogenitor cells or undifferentiated preosteoblasts with strong capacity to differentiate toward mature osteoblasts.

Background A prolonged-release formulation of oxycodone/naloxone has been shown to be effective in European populations for the management of chronic moderate to severe pain. However, no clinical data exist for its use in Korean patients. The objective of this study was to assess efficacy and safety of prolonged-release oxycodone/naloxone in Korean patients for management of chronic moderate-to-severe pain. Methods In this multicenter, single-arm, open-label, phase IV study, Korean adults with moderate-to-severe spinal disorder-related pain that was not satisfactorily controlled with weak opioids and nonsteroidal anti-inflammatory drugs received prolonged-release oral oxycodone/naloxone at a starting dose of 10/5 mg/day (maximum 80/40 mg/day) for 8 weeks. Changes in pain intensity and quality of life (QoL) were measured using a numeric rating scale (NRS, 0-10) and the Korean-language EuroQol-five dimensions questionnaire, respectively. Results Among 209 patients assessed for efficacy, the mean NRS pain score was reduced by 25.9% between baseline and week 8 of treatment (p < 0.0001). There was also a significant improvement in QoL from baseline to week 8 (p < 0.0001). The incidence of adverse drug reactions was 27.7%, the most common being nausea, constipation, and dizziness; 77.9% of these adverse drug reactions had resolved or were resolving at the end of the study. Conclusions Prolonged-release oxycodone/naloxone provided significant and clinically relevant reductions in pain intensity and improved QoL in Korean patients with chronic spinal disorders. (ClinicalTrials.gov identifier: NCT01811238).

Background Context The influence of rheumatoid arthritis (RA) on the lumbar spine has received relatively little attention compared with cervical spine, and few studies have been conducted for adjacent segment disease (ASD) after lumbar fusion in patients with RA. Purpose The present study aims to determine the incidence of ASD requiring surgery (ASDrS) after short lumbar fusion and to evaluate risk factors for ASDrS, including RA. Study Design This is a retrospective cohort study. Patient Sample The present study included 479 patients who underwent lumbar spinal fusion of three or fewer levels, with the mean follow-up period of 51.2 (12–132) months. Outcome Measures The development of ASD and consequent revision surgery were reviewed using follow-up data. Methods The ASDrS-free survival rate of adjacent segments was calculated through Kaplan-Meier method. The log-rank test and Cox regression analysis were used to evaluate risk factors comprising RA, age, gender, obesity, osteoporosis, diabetes, smoking, surgical method, and the number of fusion segments. Results After short lumbar fusion, revision surgery for ASD was performed in 37 patients (7.7%). Kaplan-Meier analysis predicted that the ASDrS-free survival rate of adjacent segments was 97.8% at 3 years, 92.7% at 5 years, and 86.8% at 7 years. In risk factor analysis, patients with RA showed a 4.5 times higher risk of ASDrS than patients without RA (p Conclusions Adjacent segment disease requiring surgery was predicted in 13.2% of patients at 7 years after short lumbar fusion. Rheumatoid arthritis and the number of fusion segments were confirmed as risk factors.