Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome.

Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases.

IL-6 inhibitors and JAK inhibitors as favourable treatment options for patients with anaemia and rheumatoid arthritis: ANSWER cohort study.

OBJECTIVES: Anaemia, a common comorbidity of RA, is related to high disease activity and poor prognosis. It is unknown which biologic/targeted synthetic (b/ts)-DMARDs are optimal for patients with anaemia and RA in regulating anaemia and controlling disease activity. METHODS: We investigated the change in haemoglobin (Hb) levels, drug retention rates and disease activities after the administration of b/ts-DMARDs with different modes of action [TNF inhibitors (TNFis), immunoglobulin fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), IL-6 receptor inhibitors (IL-6Ris) and Janus kinase inhibitors (JAKis)] in patients with RA stratified by baseline Hb levels using the multicentre observational registry for patients with RA in Japan (ANSWER cohort). RESULTS: A total of 2093 patients with RA were classified into three groups based on tertiles of the baseline Hb levels (Hblow, anaemic; Hbint, intermediate; Hbhigh, non-anaemic). IL-6Ri increased Hb levels in all groups (the mean change at 12 months in Hblow was +1.5 g/dl, Hbint +0.7 g/dl and Hbhigh +0.1 g/dl). JAKis increased the Hb level in patients with anaemia and RA and retained or decreased the Hb level in non-anaemic patients (the mean change at 12 months in Hblow was +0.6 g/dl, Hbint 0 g/dl and Hbhigh -0.3 g/dl). In patients with anaemia and RA, overall adjusted 3-year drug retention rates were higher in JAKi followed by IL-6Ri, CTLA4-Ig and TNFi (78.6%, 67.9%, 61.8% and 50.8%, respectively). Change of disease activity at 12 months was not different among different b/ts-DMARDs treatments. CONCLUSION: IL-6Ri and JAKi can effectively treat patients with anaemia and RA in a real-world setting.

The proliferative activity levels of each immune cell population evaluated by mass cytometry are linked to the clinical phenotypes of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, and many peripheral immune cell populations (ICPs) are thought to be altered according to the course of the disease. However, it is unclear which ICPs are associated with the clinical phenotypes of SLE. We analyzed peripheral blood mononuclear cells (PBMCs) of 28 SLE patients using mass cytometry and identified 30 ICPs. We determined the proliferative activity of ICPs by measuring the proportion of cells expressing specific markers and Ki-67 among CD45+ cells (Ki-67+ proportion). We observed an increased Ki-67+ proportion for many ICPs of SLE patients and examined the association between their Ki-67+ proportions and clinical findings. The Ki-67+ proportions of five ICPs [classical monocyte (cMo), effector memory CD8+ T cell (CD8Tem), CXCR5- naive B cell (CXCR5- nB), and CXCR5- IgD-CD27- B cell (CXCR5- DNB)] were identified as clinically important factors. The SLE Disease Activity Index (SLEDAI) was positively correlated with cMo and plasma cells (PC). The titer of anti-DNA antibodies was positively correlated with cMo, CXCR5- nB, and CXCR5- DNB. The C4 level was negatively correlated with CXCR5- DNB. The bioactivity of type I interferon was also positively correlated with these ICPs. Fever and renal involvement were associated with cMo. Rash was associated with CD8Tem and CXCR5- DNB. On the basis of the proliferative activity among five ICPs, SLE patients can be classified into five clusters showing different SLE phenotypes. Evaluation of the proliferative activity in each ICP can be linked to the clinical phenotypes of individual SLE patients and help in the treatment strategy.

Usefulness of the spectral shaping dual-source computed tomography imaging technique in posterior corrective fusion for adolescent idiopathic scoliosis.

PURPOSE: Since childhood exposure to radiation has been demonstrated to increase cancer risk with increase in radiation dose, reduced radiation exposure during computed tomography (CT) evaluation is desired for adolescent idiopathic scoliosis (AIS). Therefore, this retrospective study aimed to investigate the radiation dose of dual-source CT using a spectral shaping technique and the accuracy of the thoracic pedicle screw (TPS) placement for posterior spinal fusion (PSF) in patients with AIS. METHODS: Fifty-nine female patients with thoracic AIS who underwent PSF using CT-guided TPSs were included and divided into two groups comprised of 23 patients who underwent dual-source CT (DSCT) with a tin filter (DSCT group) and 36 who underwent conventional multislice CT (MSCT group). We assessed the CT radiation dose using the CT dose index (CTDIvol), effective dose (ED), and accuracy of TPS insertion according to the established Neo's classification. RESULTS: The DSCT and MSCT groups differed significantly (p < 0.001) in the mean CTDIvol (0.76 vs. 3.31 mGy, respectively) and ED (0.77 vs. 3.47 mSv, respectively). Although the correction rate of the main thoracic curve in the DSCT group was lower (65.7% vs. 71.2%) (p = 0.0126), the TPS accuracy (Grades 0-1) was similar in both groups (381 screws [88.8%] vs. 600 screws [88.4%], respectively) (p = 0.8133). No patient required replacement of malpositioned screws. CONCLUSION: Spectral shaping DSCT with a tube-based tin filter allowed a 75% radiation dose reduction while achieving TPS insertion accuracy similar to procedures based on conventional CT without spectral shaping.

Neck and shoulder pain in thoracic adolescent idiopathic scoliosis 10 years after posterior spinal fusion.

PURPOSE: We aimed to determine the clinical significance of neck and shoulder pain (NSP) 10 years after posterior spinal fusion (PSF) for thoracic adolescent idiopathic scoliosis (AIS) and the relationship between radiographic parameters and NSP. METHODS: Of 72 patients who underwent PSF for thoracic AIS (Lenke 1 or 2) between 2000 and 2013, we included 52 (46 females; Lenke type 1 in 34 patients and type 2 in 18; mean age, 25.6 years) who underwent NSP evaluation using visual analog scale (VAS, 10 cm) 10 years postoperatively (follow-up rate, 72.2%). Correlation analyses were performed using Spearman's rank correlation coefficient (r). RESULTS: The VAS for NSP was 2.6 cm in median and 3.4 cm in mean at 10 years. The VAS had significant negative correlations with several SRS-22 domain scores (rs = - 0.348 for pain, - 0.347 for function, - 0.308 for mental health, and - 0.372 for total) (p < 0.05). In addition, the VAS score was significantly correlated with cervical lordosis (CL) (rs = 0.296), lumbar lordosis (rs = - 0.299), and sacral slope (rs = 0.362) (p < 0.05). Furthermore, at the 10-year follow-up, CL was significantly negatively correlated with T1 slope (rs = - 0.763) and thoracic kyphosis (TK) (- 0.554 for T1-12 and - 0.344 for T5-12) (p < 0.02). CONCLUSION: NSP was associated with deterioration in SRS-22 scores, indicating that NSP is a clinically significant long-term issue in PSF for thoracic AIS. Restoring or maintaining the TK and T1 slopes, which are controllable factors during PSF, may improve cervical lordosis and alleviate NSP at 10-year follow-up.

[Usefulness of Preoperative Simulation: Skull Base Approach].

Preoperative simulation images creates an accurate visualization of a surgical field. The anatomical relationship of the cranial nerves, arteries, brainstem, and related bony protrusions is important in skull base surgery. However, an operator's intention is unclear for a less experienced neurosurgeon. Three-dimensional(3D)fusion images of computed tomography and magnetic resonance imaging created using a workstation aids precise surgical planning and safety management. Since the simulation images allows to perform virtual surgery, a déjà vu effect for the surgeon can be obtained. Additionally, since 3D surgical images can be used for preoperative consideration and postoperative verification, discussion among the team members is effective from the perspective of surgical education for residents and medical students. Significance of preoperative simulation images will increase eventually.

SLE stratification based on BAFF and IFN-I bioactivity for biologics and implications of BAFF produced by glomeruli in lupus nephritis.

OBJECTIVE: B-cell activating factor (BAFF) is implicated in SLE pathogenesis. Blocking BAFF signalling has contributed to reducing glucocorticoid dosage and preventing organ damage. However, clinical characteristics of patients who may benefit from this therapy are not yet fully elucidated. Therefore, we identified patients with high BAFF-bioactivity to investigate their clinical characteristics and BAFF-producing cells. METHODS: We established the reporter cell for BAFF and investigated the clinical characteristics of SLE patients with high BAFF-bioactivity. We identified BAFF-expressing kidney cells using publicly available scRNA-seq data and immunohistological analysis. SLE patients were stratified based on the bioactivity of BAFF and type-I IFN (IFN-I) to identify associated characteristic clinical manifestations. RESULTS: SLE patients, especially patients with LN, had significantly higher serum BAFF-bioactivity than healthy controls (HC) and non-LN patients. Additionally, single-cell-RNA-seq data and immunohistological analysis of kidney samples from LN patients revealed that BAFF is expressed in glomerular macrophages and mesangial cells. Notably, BAFF bioactivity was elevated in the urine of LN patients compared with that of non-LN patients, while no IFN-I bioactivity was detected in the urine. Furthermore, SLE stratification based on bioactivities of serum BAFF and IFN-I revealed the clinical characteristics of patients: high BAFF represented patients with LN and high IFN-I represented patients with blood and skin manifestations. CONCLUSIONS: Monitoring urinary BAFF-bioactivity may be valuable in diagnosing LN. Furthermore, stratification based on serum BAFF and IFN-I bioactivities may allow the identification of appropriate patients for biologics targeting BAFF and IFN-I.

Predictive biomarkers of ossification progression and bone metabolism dynamics in patients with cervical ossification of the posterior longitudinal ligament.

PURPOSE: This study aimed to establish biomarkers to predict the progression of ossification by examining ossification volume and bone metabolism dynamics in patients with ossification of the posterior longitudinal ligament (OPLL). METHODS: We assessed OPLL progression using computed tomography-based three-dimensional (3D) image analysis and examined bone metabolism dynamics in 107 patients with OPLL (men, 72; women, 35; mean age, 63.6 years). The volume of OPLL was calculated twice during the follow-up period, and OPLL progression was evaluated by the annual rate of ossification increase. Bone metabolism dynamics were assessed by routine blood tests and analysis of various serum biomarkers (including 25-hydroxyvitamin D, intact parathyroid hormone, fibroblast growth factor 23, intact N-terminal propeptide of type 1, tartrate-resistant acid phosphatase isoform 5b, sclerostin, and Dickkopf-1) and bone mineral density (BMD). Patients were classified into the progression (P) or non-progression (NP) group according to the annual rate of increase in previous 3D image analyses, and associated factors between these groups were compared. RESULTS: The P and NP groups consisted of 29 patients (23 men and 6 women) and 78 patients (49 men and 29 women), respectively. Univariate analysis revealed significant differences in terms of age, body mass index, serum phosphorus, serum sclerostin, and BMD. In multivariate analysis, age, serum phosphorus, and serum sclerostin were identified as independent factors associated with OPLL progression. CONCLUSION: Younger age, hypophosphatemia, and high serum sclerostin are risk factors for OPLL progression. Serum phosphorus and sclerostin could serve as important biomarkers for predicting ossification progression.

Evaluating flexibility and predicting curve correction using fulcrum-bending radiographs in Lenke type 2 adolescent idiopathic scoliosis.

BACKGROUND: Fulcrum-bending (FB) correction is considered to provide the best estimation of main thoracic (MT) curve flexibility and postoperative correction in surgical treatment for adolescent idiopathic scoliosis (AIS). However, few studies evaluated the usefulness of FB radiographs for proximal thoracic (PT) curve. We aimed to perform flexibility assessments using both active side-bending (SB) and FB radiographs and evaluate surgical outcomes after posterior spinal fusion (PSF) for Lenke type 2 AIS. METHODS: This study included 38 consecutive patients with Lenke type 2 AIS who underwent PSF using a pedicle screw construct with a minimum 2-year follow-up. Radiographic parameters, including correction rate, SB and FB flexibility, and FB correction index (FBCI: [correction rate/FB flexibility] × 100), were evaluated preoperatively, immediately after surgery, and at the 2-year follow-up. The clinical outcomes were preoperatively evaluated using the Scoliosis Research Outcomes Instrument-22 and at the follow-up. RESULTS: All scoliosis curves significantly improved and shoulder balance shifted toward left shoulder elevation (all comparisons, p < 0.0001). There were significant differences between the SB and FB corrections in the PT and MT curves (p < 0.0001). The magnitudes of the discrepancies between the SB and FB corrections in the PT and MT curves were 11.2° ± 5.2° and 11.6° ± 7.2°, respectively. FB correction did not differ from postoperative Cobb angles correction immediately after surgery or at the 2-year follow-up; the mean FBCIs in the PT and MT curves were 98.8% and 105.5%, respectively. The self-image domain SRS-22 scores had significantly increased at the 2-year follow-up (p < 0.0001). CONCLUSIONS: There were significant differences between the SB and FB corrections, and FB correction tended to approximate the postoperative curve correction (FBCI = 100%) for PT and MT curves in patients with Lenke type 2 AIS. FB flexibility is more reliable than SB flexibility in evaluating actual curve flexibility even for the PT curve.

Association of success of brace treatment and various aspects of in-brace correction in patients with adolescent idiopathic scoliosis.

BACKGROUND: Although skeletal maturity and brace wear time contribute to the success of brace treatment in adolescent idiopathic scoliosis (AIS), the extent of initial in-brace correction for ensuring successful outcomes remains unclear. We hypothesized that the degree of initial in-brace correction correlates with brace success in patients with AIS. METHOD: The study included 135 AIS patients with a major Cobb angle of 20°-40° treated with a thoracic lumbosacral orthosis for at least one year and followed up for skeletal maturity. The subjects were divided into two groups: the skeletally immature group (group I, n = 72), who met the Bracing in Adolescent Idiopathic Scoliosis Trial study protocol at the start of brace treatment, and the skeletally mature group (group M, n = 63). Treatment success was defined as not needing surgical treatment and a major Cobb angle <40° at the end of brace treatment. RESULTS: In both groups, the mean major Cobb angles before treatment, while wearing the brace, and at the end of brace treatment were 30.6°/31.7°, 22.9°/24.2°, and 38.8°/33.9° (p < 0.05), respectively, and the treatment success rate was 56.9% and 77.8%, respectively (p < 0.05). Univariate regression analysis revealed the following risk factors: Risser grade 0 in group I, major Cobb angles before treatment, initial in-brace major Cobb angle, and in-brace correction rate in both groups. Cutoff values of in-brace major Cobb angle for treatment success calculated by ROC curve in groups I and M were 24° and 29°, respectively. CONCLUSIONS: In-brace major scoliosis correction of <25° in patients with immature skeletal status and <30° in patients with mature skeletal structure should be aimed at to achieve significant brace treatment success.

Characteristics of back pain in patients with adolescent idiopathic scoliosis: Considerations in candidates for corrective surgery.

BACKGROUND: Previous studies have demonstrated that the point prevalence of back pain ranges from 12 % to 33 % and that the lifetime prevalence of back pain ranges from 28 % to 51 % in adolescents. However, few studies on back pain in patients with Adolescent idiopathic scoliosis (AIS) have been conducted, and these studies had significant limitations, including a lack of comparative controls and detailed information about scoliotic deformity or pain location. This study aimed to determine whether adolescents with AIS experience back pain in specific regions. METHODS: This retrospective case-control study included 189 female adolescents with AIS who underwent corrective fusion from 2008 to 2020. Questionnaires on back pain and health-related quality of life (HRQOL) using the Scoliosis Research Society Outcomes Instrument-22 (SRS-22) were conducted preoperatively. The control group included 2909 general female adolescents. RESULTS: The mean Cobb angles in the main thoracic and thoracolumbar/lumbar curves were 51.4 ± 15.3° and 40.4 ± 12.9°. Back pain characteristics included higher point prevalence (25.9 %) and lifetime prevalence (64.6 %) compared to healthy controls. Adolescents with back pain showed lower scores in the pain and mental health domains of the SRS-22. Adolescents with major thoracic AIS showed more back pain in the upper and middle right back compared to adolescents with major thoracolumbar/lumbar AIS. CONCLUSION: The point and lifetime prevalence of back pain were definitely higher in patients with AIS, which affected their HRQOL. There was a relationship between pain around the right scapula and the right major thoracic curve with a rib hump deformity.

Usefulness and limitations of intraoperative pathological diagnosis using frozen sections for spinal cord tumors.

BACKGROUND: Intraoperative pathological diagnosis has a major influence on the intra- and postoperative management of spinal cord tumors. Thus, the aim of this study was to assess the reliability of intraoperative pathological diagnosis for spinal cord lesions by comparing it with the final pathological diagnosis and to determine its usefulness and limitations. METHOD: Three-hundred and three consecutive patients (mean age, 53.9 years) with neoplastic spinal cord lesions who underwent initial surgery between 2000 and 2021 were included. The anatomical locations of the spinal cord tumors and the implementation rate of intraoperative pathological diagnosis in each tumor type were evaluated. As the primary outcome, we determined the concordance rates between the intraoperative pathological diagnosis and the final diagnosis. When the intraoperative pathological diagnosis and final diagnosis were the same, the diagnosis was defined as a "match." Otherwise, the diagnosis was defined as a "mismatch." RESULTS: The overall implementation rate of intraoperative pathological diagnosis was 53%, with implementation rates of 71%, 45%, 47%, and 50% for intramedullary, intradural extramedullary, extradural, and dumbbell tumors, respectively. The overall concordance rate was 87.6%, with concordance rates of 80%, 95%, 75%, and 90% for intramedullary, intradural extramedullary, extradural, and dumbbell tumors, respectively (p < 0.05). The diagnoses of ependymomas, low-grade astrocytomas, and high-grade astrocytomas was occasionally difficult among intramedullary tumors. Among intradural extramedullary tumors, differentiation between grade 1 meningioma and high-grade meningioma was difficult using intraoperative pathological diagnosis. CONCLUSIONS: Surgeons must recognize the lower accuracy of intraoperative pathological diagnosis for intramedullary and extradural lesions and make a final decision by considering the intraoperative gross findings, preoperative clinical course, and imaging.

Prognostic Factors Affecting Death in Patients with Rheumatoid Arthritis Complicated by Pneumocystis jirovecii Pneumonia and One-Year Clinical Course: The ANSWER Cohort Study.

This multicenter retrospective study aimed to clarify the prognostic factors for mortality and changes in treatment modalities and disease activities after the onset of Pneumocystis jirovecii pneumonia (PCP) in patients with rheumatoid arthritis (RA). Data regarding the clinical background, treatment modalities, and disease activity indicators of RA at the onset of PCP (baseline), and 6 months and 12 months after treatment were extracted. Of the 37 patients with RA-PCP (median age, 69 years; 73% female), chemical prophylaxis was administered to 8.1%. Six patients died during PCP treatment. The serum C-reactive protein (CRP) levels and the prednisolone (PDN) dose at baseline in the PCP death group were significantly higher than those in the survivor group. Multivariate analysis using a Cox regression model showed that PDN dose at baseline was a predictor of death from PCP in patients with RA. During the 12 months from baseline, the RA disease activity significantly decreased. A high dose of corticosteroids for RA may result in a poor prognosis when PCP is complicated. In the future, preventive administration techniques must be established for patients with RA who need PCP prevention.

Add-on effectiveness of methotrexate or iguratimod in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors: The ANSWER cohort study.

OBJECTIVES: This multicenter, retrospective study evaluated the effectiveness of add-on methotrexate (MTX) or iguratimod (IGU) in patients with rheumatoid arthritis exhibiting an inadequate response to Janus kinase inhibitors (JAKis). METHODS: Forty-five patients were treated with new additional MTX (n = 22) or IGU (n = 23) and followed for 6 months. Patients' background is as follows: age, 59.2 years; disease activity score of 28 joints with C-reactive protein (DAS28-CRP), 3.4; clinical disease activity index, 15.7; biological disease-modifying antirheumatic drug (DMARD)-switched cases, 77.8%; first JAKi cases, 95.6%; and JAKi treatment: tofacitinib (n = 25), baricitinib (n = 17), upadacitinib (n = 2), and peficitinib (n = 1) for 9.6 months. RESULTS: Thirty-five patients continued the combination therapy for 6 months without a significant change in concomitant glucocorticoid or other conventional synthetic DMARDs. DAS28-CRP (MTX, 3.6 to 2.6, p < 0.05; IGU, 3.3 to 2.1, p < 0.001) and clinical disease activity index (MTX, 16.7 to 8.8, p < 0.05; IGU, 14.6 to 6.5, p < 0.01) improved significantly from baseline. Using the 2019 European League Against Rheumatism criteria, 45.4% (MTX) and 39.1% (IGU) achieved moderate or good response and 40.9% (MTX) and 39.1% (IGU) achieved American College of Rheumatology 20% improvement criteria. CONCLUSIONS: Adding MTX or IGU to inadequate responders of JAKi can be considered as a complementary treatment.

Prognostic factors affecting respiratory-related death in patients with rheumatoid arthritis complicated by interstitial lung disease: An ANSWER cohort study.

The aim of this multi-centre retrospective study was to clarify the prognostic factors for respiratory-related death in patients with interstitial lung disease (ILD) complicated rheumatoid arthritis (RA). Patient background data, treatment regimen, and disease activity indicators of RA and ILD at baseline, 6 months after the diagnosis of ILD, and at the last follow-up visit were extracted. A total of 312 patients with RA-ILD (17 patients who died from respiratory-related causes and 295 survivors) were included. Patients who died from respiratory-related causes had an older median age, a higher proportion of being male, and a higher anti-cyclic citrullinated peptide antibody positivity rate than survivors (p = .0001, .038, and .016, respectively); they also had significantly higher baseline serum levels of Krebs von den Lungen-6 (KL-6) than survivors (p = .013). Patients who died from respiratory-related causes showed significantly greater changes in serum KL-6 levels between the 6-month time point and the last visit [ΔKL-6 (6 months - last)] than survivors (p = .011). Multivariate analysis showed that the ΔKL-6 (6 months - last) corrected by disease duration was a predictor of respiratory-disease-related death in patients with RA-ILD (p < .0001). Long-term increase in serum KL-6 levels is associated with respiratory-disease related death in patients with RA-ILD.

Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies.

Intracellular proteins are often targeted by autoantibodies in autoimmune diseases; however, the mechanism through which intracellular molecules are targeted remains unknown. We previously found that several intracellular misfolded proteins are transported to the cell surface by HLA class II molecules and are recognized by autoantibodies in some autoimmune diseases, such as rheumatoid arthritis, antiphospholipid syndrome, and microscopic polyangiitis. Ro52 is an intracellular Fc receptor that is a target antigen for myositis-associated autoantibodies. We analyzed the role of HLA class II molecules in the autoantibody recognition of Ro52. Ro52 alone was not transported to the cell surface by HLA class II molecules; however, it was transported to the cell surface in the presence of both IgG heavy chain and HLA class II molecules to form a Ro52/IgG/HLA-DR complex. The Ro52/IgG/HLA-DR complex was specifically recognized by autoantibodies from some patients with inflammatory myopathies. We then evaluated 120 patients with inflammatory myopathies with four types of myositis-specific antibodies and analyzed the autoantibodies against the Ro52/IgG/HLA-DR complex. The specific antibodies against the Ro52/IgG/HLA-DR complex were detected in 90% and 93% of patients who were positive for anti-MDA5 and anti-ARS antibodies, respectively. In individual patients with these two inflammatory myopathies, changes in serum titers of anti-Ro52/IgG/HLA-DR-specific antibodies were correlated with the levels of KL-6 (R = 0.51 in anti-MDA5 antibody-positive DM patients, R = 0.67 in anti-ARS antibody-positive PM/DM patients with respiratory symptoms) and CK (R = 0.63 in anti-ARS antibody-positive PM/DM patients with muscle symptoms) over time. These results suggest that antibodies against Ro52/IgG/HLA-DR expressed on the cell surface could be involved in the pathogenesis of inflammatory myopathy subgroups.

Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 µg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

Predictors for quality of life improvement after acute osteoporotic vertebral fracture: results of post hoc analysis of a prospective randomized study.

PURPOSE: No study has investigated the clinical and radiographic risk factors for the deterioration of quality of life (QOL) beyond 6 months after osteoporotic vertebral fractures (OVF). The purpose of this study was to identify the predictors associated with poor QOL improvement after OVF. METHODS: This post hoc analysis included 166 women aged 65-85 years with acute 1-level OVFs. For the patient-reported outcome measures, scores on the European Quality of Life-5 Dimensions (EQ-5D) scale, and visual analogue scale (VAS) for low back pain were used. Lateral radiography at 0, 12, and 48 weeks and magnetic resonance imaging (MRI) at enrollment and at 48 weeks were performed. The associations between baseline variables with change scores for EQ-5D were investigated using a multiple linear regression model. RESULTS: Univariate analysis showed that time since fracture, EQ-5D score, and VAS for low back pain at 0 week showed significant association with increased EQ-5D score from 0 to 48 weeks. According to the multiple regression analysis, the following equation was obtained: increased EQ-5D score from 0 to 48 weeks = 1.305 - 0.978 × EQ-5D at 0 week - 0.021 × VAS for low back pain at 0 week - 0.006 × age + (fluid-intensity T2-weighted MR image patterns: - 0.037, except for fluid-intensity T2-weighted MR image patterns: + 0.037). CONCLUSION: In conclusion, older patients with severe low back pain and fluid-intensity T2-weighted MR image patterns were more likely to have lower QOL improvements after OVFs and may therefore need extra support to improve QOL.

Comparison of efficacy between anti-IL-6 receptor antibody and other biological disease-modifying antirheumatic drugs in the patients with rheumatoid arthritis who have knee joint involvement: the ANSWER cohort, retrospective study.

OBJECTIVE: We aimed to investigate the efficacy of anti-IL-6 receptor antibody (aIL-6) and other biologic disease-modifying antirheumatic drugs (bDMARDs), such as TNF inhibitor and CTLA4-Ig in the treatment of rheumatoid arthritis (RA) in patients with knee joint involvement. METHODS: We retrospectively analyzed 1059 treatment courses of patients with RA who visited our hospitals and were treated with bDMARDs. We categorized them into two groups, with or without knee joint involvement. We investigated the clinical disease activity index (CDAI) at baseline and 12 weeks after the initiation of bDMARDs. We compared the improvement of the markers between aIL-6 and other bDMARDs. RESULTS: Treatment with aIL-6 significantly increased ΔCDAI (n = 91, 15.4 ± 1.1; mean ± SEM) in patients with knee joint involvement, compared to other bDMARDs (n = 232, 11.0 ± 0.7) at 12 weeks (P = 0.006). Following the multivariate analysis adjusted by the CDAI levels at baseline, age, gender, concomitant use of methotrexate, and the first use of bDMARDs, ΔCDAI levels were significantly higher in aIL-6, compared to other bDMARDs (P = 0.02). However, there was no significant difference in ΔCDAI improvement between aIL-6 (n = 162, 5.9 ± 0.6) and other bDMARDs (n = 573, 6.2 ± 0.4) in patients without swollen knee joints. ΔCDAI levels were equally increased in patients with shoulder and elbow joint involvement. CONCLUSION: aIL-6 was more effective in the patients with RA and knee joint involvement, compared to other bDMARDs.

Risk factors for subsequent vertebral fracture after acute osteoporotic vertebral fractures.

PURPOSE: To investigate the incidence and characteristics of subsequent vertebral fracture after osteoporotic vertebral fractures (OVFs) and identify risk factors for subsequent vertebral fractures. METHODS: This post-hoc analysis from a prospective randomized multicenter trial included 225 patients with a 48-week follow-up period. Differences between the subsequent and non-subsequent fracture groups were analyzed. RESULTS: Of the 225 patients, 15 (6.7%) had a subsequent fracture during the 48-week follow-up. The annual incidence of subsequent vertebral fracture after fresh OVFs in women aged 65-85 years was 68.8 per 1000 person-years. Most patients (73.3%) experienced subsequent vertebral fractures within 6 months. At 48 weeks, European Quality of Life-5 Dimensions, the Japanese Orthopedic Association Back Pain Evaluation Questionnaire pain-related disorder, walking ability, social life function, and lumbar function scores were significantly lower, while the visual analog scale (VAS) for low back pain was higher in patients with subsequent fracture. Cox proportional hazards analysis showed that a VAS score ≥ 70 at 0 weeks was an independent predictor of subsequent vertebral fracture. After adjustment for history of previous fracture, there was a ~ 67% reduction in the risk of subsequent vertebral fracture at the rigid-brace treatment. CONCLUSION: Women with a fresh OVF were at higher risk for subsequent vertebral fracture within the next year. Severe low back pain and use of soft braces were associated with higher risk of subsequent vertebral fractures. Therefore, when treating patients after OVFs with these risk factors, more attention may be needed for the occurrence of subsequent vertebral fractures. LEVEL OF EVIDENCE: III.