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Background:CD30 is a member of the TNF-receptor family and commonly expressed on lymphocytes of Hodgkin lymphoma and anaplastic large cell lymphoma. It has been reported that levels of soluble CD30 in serum and joint fluid is significantly elevated in rheumatoid arthritis (RA). Although RA patients may develop lymphoproliferative disorders (LPD) as a result of immunosuppression by MTX or bDMARDs, safety medications after the regression of LPD for RA have not yet been established.Objectives:To explore the potential of CD30 targeting therapy for RA.Methods:(1) Immuno-histological staining of CD30 was performed for fresh synovial tissues of RA and osteoarthritis (OA). In addition, double immunofluorescence staining of CD30 with CD3, CD20, CD68, CD138 were performed on RA synovial tissue. (2) Brentuximab vedotin (BV) is an anti-CD30 antibody conjugated with monomethyl auristatin E, designed to induce apoptosis of CD30 expressing cells. A multiple myeloma cell line (RPMI8226) was used as a non-lymphoma cell line and plasma cell-like cell line. Immuno-cytological staining for CD30 was performed on RPMI8226. Cells were cultured and harvested on days 0, 1, and 3 to evaluate the effects of BV (50 μl / ml per well). Cytospin specimens were stained by May-Grunwald-Giemsa (MGG) staining for cell counting and by FIFC-terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining for detection of apoptosis. (3) Collagen antibody induced arthritis (CAIA) was induced in DBA/1 mice by arthritogenic cocktail of monoclonal antibodies against type II collagen. BV was administered to the treatment groups (30mg/kg and 70mg/kg n=4 each) and evaluated clinical score, histological findings and levels of SAA, IL-6, and TNFα in serum by ELISA. Student’st-test (two-tailed) was used to determine statistical significance for analysis of synovial tissues and cell line assay. Two way ANOVA with Dunnett’s post hoc analysis was used for multiple comparisons of mice model.Results:(1) The number of CD30-positive cells was significantly higher in RA synovial tissue than in OA synovial tissue (pConclusion:We showed the expression of CD30 on synovial tissue of RA and the expression of CD30 on plasma cells. In addition, the current study provides the first evidence that BV depletion of CD30-positive cells suppressed arthritis and osteochondral destruction in CAIA mice. Our results may provide an important clue for the development of an effective treatment for RA with iatrogenic immunodeficiency-related LPD.Disclosure of Interests:Minami Matsuhashi: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Yoshihisa Nasu: None declared, Ryuichi Nakahara: None declared, Masahito Watanabe: None declared, Yoshifumi Hotta: None declared, Toshifumi Ozaki: None declared

Background:Patient-reported outcomes (PROs) have become widespread in daily clinical evaluation in patients with rheumatoid arthritis (RA). However, there are few reports for the relationship or discordance between the subjective assessment by the physician and the objective assessment by the patient with RA in surgical treatment.Objectives:We examined the relationship or discordance about the PROs in patients with RA who underwent total elbow arthroplasty (TEA).Methods:We retrospectively identified 53 elbows of 48 patients with RA who underwent TEA at Okayama University Hospital, collected from January 2012 to December 2016.We collected clinical data for the grip strength, range of motion, the Mayo Elbow Performance Scale (MEPS) as objective assessments, and the Patient-Related Elbow Evaluation (PREE), Disability of the Arm, Shoulder, and Hand (DASH) Japanese version and Hand20 as subjective assessments.For statistical analysis, we performed t-tests for pre- and post-operative physical findings and subjective evaluations, and Spearman rank correlation to examine the relationship between objective and subjective assessments.Results:The mean age of the patients at the time of arthroplasty was 63 years, the average disease duration was 23 years, and the average postoperative observation period was 32 months. The average DAS28-CRP was 3.01, and biological uses were 18 cases.The range of motion of the elbow joint and the grip strength was significantly improved postoperatively. All outcome assessments improved significantly except for HAQ (see table1).There was significantly correlated PREE with DASH, Hand20, and MEPS preoperatively. Postoperative PREE showed a significant and robust correlation in postoperative DASH, Hand20, whereas not associated with postoperative MEPS (see table2).To investigate the discordance between PREE and MEPS after TEA, we focused on changes in each item of PREE. Pain- and reach-related items improved postoperatively. But, it was difficult to improve in items affected by hand and finger functions, such as “tie shoelaces.”To explore the effects of finger and hand functions on postoperative assessments, we performed multiple regression analyses. Both preoperative grip strength (unstandardized coefficient [Β] =-0.07; 95%CI -0.148 to -0.006, t value=-2.18, P=0.03) and preoperative Hand20 (B = 0.27, 95%CI 0.029 - 0.518, t=2.25, p=0.02) were significant predictors of postoperative PREE.Conclusion:Surprisingly, the PROs of patients and the surgeon’s evaluations correlated well before surgery but resulted in discordance after TEA. We improved elbow functions by TEA, but since rheumatoid arthritis was a polyarticular disorder, improvement of a single joint function did not improve utterly subjective assessment in patients with RA. We found that the upper limb functions after TEA were significantly affected by preoperative finger and hand function. A rheumatologist should consider the dysfunctions of finger and hand when planning for elbow surgery in patients with RA.Table 1.Pre- and postoperative range of motion of elbow and forearm, grip strength, and measurementCharacteristicPreoperativePostoperativeP valueElbow flexion, degree116 ± 19134 ± 9< 0.001- extension-34 ± 21-25 ± 160.005- total arc82 ± 32109 ± 19< 0.001Grip power, mmHg106 ± 66130 ± 740.007DASH50.5 ± 20.535.8 ± 25.4< 0.001Hand2060.4 ± 19.138.9 ± 29.6< 0.001PREE55.6 ± 18.818.5 ± 17.1< 0.001- pain29.7 ± 11.36.5 ± 7.9< 0.001- function25.9 ± 11.512.0 ± 11.9< 0.001- specific function56.9 ± 25.525.4 ± 25.3< 0.001- usual function20.8 ± 11.310.5 ± 11.3< 0.001HAQ-DI1.06 ± 0.701.07 ± 0.800.607MEPS51.3 ± 16.697.9 ± 3.6< 0.001Table 2.Spearman’s correlation coefficients for pre- and postoperative PREE score*QuestionnairePreoperative Correlation estimateP valuePostoperative Correlation estimateP valueDASH0.56< 0.00010.84< 0.0001Hand200.58< 0.00010.84< 0.0001MEPS- 0.39< 0.01-0.27N.S.Disclosure of Interests:ryozo harada: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Yoshihisa Nasu: None declared, Ryuichi Nakahara: None declared

Background:Total management including reconstructive joint surgery and rehabilitation should be needed for further improvements of physical function for long-standing RA patients. In these days, it is very important to evaluate the effectiveness of joint surgery as well as drug therapy based on patient-reported outcome (PRO)Objectives:The purpose of this study is to explore the relationship among depression, clinical variables and other PROs including physical function and to explore whether joint surgery can improve the depression.Methods:Multicenter prospective observational cohort study was conducted among patients who underwent elective joint surgery for RA from April 2012 to March 2016 (Study registration: UMIN000012649). In this study, we collected data at baseline and at 6 or 12 months after the surgery. These data were as follow; age, sex, disease duration, drug therapies, and disease activity (DAS), TUG, and patient-reported outcome [HAQ-DI, EQ-5D (QOL), pain and BDI-II (depression)]. Correlation between BDI-II and other variables were determined using multiple liner regression analysis.Results:Totally, 346 patients before elective joint surgery were analyzed cross-sectionally. Mean age, disease duration, pain VAS, DAS28, HAQ-DI, EQ-5D and BDI-II were 64.2 years, 17.0 years, 36.2 mm, 3.02, 1.11, 0.641 and 13.0, respectively. 52.6% of elective joint surgeries were in upper limbs and 47.4% were in lower limbs. Multiple liner regression analysis showed that HAQ-DI [B:-0.099 (95%CI:-0.117- -0.08) β:-0.48] pain VAS [B:-0.002 (95%CI:-0.002- -0.001) β:-0.26] and BDI-II [B:-0.003 (95%CI:-0.005- -0.002) β:-0.19] had significant impact on EQ-5D. Furthermore, HAQ-DI [B:3.78 (95%CI:2.54- 5.06) β: 0.33] and pain VAS [B: 0.062 (95%CI: 0.023- 0.101) β 0.17] had significant impact on BDI-II. Especially, walking and eating were independent factors for BDI-II in HAQ-DI categories. These results were confirmed in longitudinal analyses using results from joint surgery in lower limbs (LL; n=138) and upper limbs (UL; n=165), respectively. BDI-II was remarkably improved from 12.1 (mean) to 10.5 in LL and from 14.2 (mean) to 11.9 in UL. Change in HAQ-DI had significant impact on that in BDI-II [LL; B:3.183 (95%CI:0.301- 6.065) β:0.229, and UL; B:2.55 (95%CI:0.19- 4.92) β:0.19] while that in painVAS did not. Especially, the improving in walking category by LL [B:1.38 (95%CI:0.06- 2.70) β:0.18] and in hygiene category by UL [B:2.11 (95%CI:0.79- 3.42) β:0.24] were relevant factors for improving of BDI-II.Conclusion:Depression is an important patient-reported outcome for QOL in established RA patients. Improving of physical function with joint surgery in both lower and upper limbs caused improving of depression status. Rheumatologists should take the joint surgery into consideration as effective intervention for treatment of established RA patients with treatment.Acknowledgments:This study was funded by a grant from the Ministry of Health, Labour and Walfare (h2424YN002-00) to Naoki Ishiguro.We thank Drs Tanaka S, Haga N, Yukioka M, Hashimoto J, Miyahara H, Niki Y, Kimura T, Oda H, Funahashi K for their contribution to this study and all medical staff members of each institute for their data collection efforts for their data collection efforts.Disclosure of Interests:Toshihisa Kojima Grant/research support from: Chugai, Eli Lilly, Astellas, Abbvie, and Novartis, Consultant of: AbbVie, Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eli Lilly, Janssen, Mitsubishi Tanabe, Pfizer, and Takeda, Masayo Kojima: None declared, Hajime Ishikawa: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Shuji Asai Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Janssen, Takeda, and UCB Japan, Naoki Ishiguro Grant/research support from: AbbVie, Asahi Kasei, Astellas, Chugai, Daiichi-Sankyo, Eisai, Kaken, Mitsubishi Tanabe, Otsuka, Pfizer, Takeda, and Zimmer Biomet, Consultant of: Ono, Speakers bureau: Astellas, Bristol-Myers Squibb, Daiichi-Sankyo, Eli Lilly, Pfizer, and Taisho Toyama

Background:Several studies demonstrated that total power Doppler (PD) signal can predict radiographic progression as a change in total van der Heijde-modified total Sharp score (mTSS) in rheumatoid arthritis (RA) patients. However, in some studies, radiographic progression was observed in a different joint compared with the site of a positive PD signal at baseline in many cases.Objectives:The aim of this study was to identify the clinical factor of RA patients in association with radiographic progression of hands and wrists and to investigate which joint showed radiographic progression in RA patients. We focused on the correlation of the site of a positive PD signal and the site of radiographic progression.Methods:We examined retrospectively of 70 RA patients (67 women, three men) who underwent ultrasonography (US) examination at 32 regions on bilateral hands and wrists from 2014 to 2016. Radiographs of the hands were taken at baseline and at least one year after US (mean, 19.9 months), and radiographic progression was assessed using mTSS system. We performed multivariate logistic regression analysis to investigate the association between baseline factors and radiographic progression. The relationships between radiographic progression of the individual joint and total/each joint PD score were assessed by ROC analysis and Fisher’s exact test.Results:Nineteen patients (37.3%) experienced progression of mTSS of hands and wrists. DAS28-CRP (P=0.02) and total PD score (P=0.01) were associated with radiographic progression, and total PD score was significantly associated with radiographic progression (OR 1.22; 95% CI 1.04-1.36; P=0.006) by multivariate logistic regression analysis (Table 1).Table 1.Association between the demographic and clinical findings at baseline and radiographic progression over 12 monthsa.univariate analysisNo radiographicprogression(n = 51)Radiographicprogression(n = 19)P-valueAge, years63.4 ± 12.758.1 ± 10.60.61Duration of RA, years24.4 ± 13.620.0 ± 5.00.28Usage of Bio, %42.240.40.57Amount of MTX, mg/week4.8 ± 3.34.5 ± 4.30.77Amount of PSL, mg1.5 ± 2.11.8 ± 2.20.73DAS28-CRP2.5 ± 0.72.9 ± 0.60.02*CRP, mg/dl0.4 ± 0.50.7 ± 0.70.10Total PD score2.4 ± 3.36.6 ± 6.10.01*b.multivariate analysisodds ratio95% CIP-valueDAS28-CRP1.630.72 - 3.710.238Total PD score1.191.04 - 1.360.010*Predictive performance of total PD score was good for radiographic progression of MCP joint (AUC-ROC 0.91) and wrist joint (AUC-ROC 0.85), although poor for PIP joint (AUC-ROC 0.57).PD score of wrist joint, MCP joint, and PIP joint were significantly associated with radiographic progression of each joint (PConclusion:Total PD score of hands and wrists was a strong predictor of radiographic progression, especially in MCP and wrist joint. Evaluation of PD signal in individual joint is a clinically useful method to predict radiographic progression of the same joint, however there are some differences in sensitivity and specificity.References:[1]Brown AK, et al. Arthritis & Rheumatism. 2008;58:2958-2967.[2]McQueen F, et al. Annals of the Rheumatic Diseases. 2011;70:241-244.Disclosure of Interests:Shunji Okita: None declared, Ryuichi Nakahara: None declared, Minami Matsuhashi: None declared, Masahito Watanabe: None declared, Yoshihisa Nasu: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Toshifumi Ozaki: None declared

Background:ADAM12 is a member of a disintegrin and metalloproteinase family and has been reported to participate in the development of a variety of tumors by degrading ECM and shed precursors, thus promoting cell proliferation, invasion, and metastasis1). Additionally, ADAM12 is involved in chondrocyte differentiation from osteoarthritis (OA) patients by regulation of TGFβ1-induced IGF-1 and RUNX-2 expressions2). However, there is no report on the role of ADAM12 for rheumatoid arthritis (RA).Objectives:To investigate the expression and role of ADAM12 in the synovial tissue of RA.Methods:(1) The expression of ADAM12 in synovial tissues from RA (18 cases), OA (5 cases) and healthy control (HC) (3 cases) was examined by immunohistochemistry. The synovial tissues of HC were obtained during surgery of hemiarthroplasty for bone tumors. Three researchers evaluated the positive cell ratio. The samples were scored according to the percentage of positive staining: 0 points (weak positive, positive expression was less than 5%), 1 point (moderate positive, positive expression was between 5% and 50%) and 2 points (strong positive, positive expression was greater than 50%). In addition, the samples were scored according to the staining intensity: 0 points (weak intensity), 1 point (moderate intensity) and 2 points (high intensity). (2) The cultured synovial fibroblasts obtained from RA patients at the surgery (RASF) were stimulated by TNFα (1, 5, 10 ng/mL), TGFβ1 (1, 5, 10 ng/mL), PDGF-BB (1, 5, 10 ng/mL) and TNFα+TGFβ1+PDGF-BB (all 10 ng/mL), and the expression levels of ADAM12 relative mRNA was examined by real-time PCR. (3) siADAM12 was transfected in RASF, and the proliferation was examined by WST-1 assay, and the expression of ADAM12 protein was examined by western blotting.Results:(1) ADAM12 positive cells were found in synovial lining cells, plasma cells, and vascular endothelial cells. ADAM12 was highly expressed in RA synovial tissues. The immunostaining scores of RA, OA, and HC were 3.9±0.01, 1.9±0.27, and 0.8±0.18, respectively. (2) Stimulation by TNFα, TGFβ1, and PDGF-BB resulted in the upregulation of the expression of ADAM12 relative mRNA in RASF, and TGFβ1 stimulation notably tended to increase the expression by about 5 to 6 times. (3) siADAM12 successfully suppressed the expression of ADAM12 protein and simultaneously suppressed the proliferation of RASF.Conclusion:ADAM12 might be involved in the pathogenesis of RA, promoting the cell proliferation of RASF.References:[1] Kyeiborg M, Albrechtsen R, Couchman J, et al., Cellular roles of ADAM12 in health and disease, Int J Biochem Cell Biol, 2008[2] Masahiro H, Keiichiro N, Joe H, et al., Involvement of ADAM12 in Chondrocyte Differentiation by Regulation of TGF-beta1-Induced IGF-1 and RUNX-2 Expressions, Calcif Tissue Int, 2019Disclosure of Interests:Masahito Watanabe: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Yoshihisa Nasu: None declared, Ryuichi Nakahara: None declared, Minami Matsuhashi: None declared, Yoshifumi Hotta: None declared, Toshifumi Ozaki: None declared

Background:It has been suggested that perioperative use of biological disease-modifying anti-rheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) patients carries risks for the surgical-site infection and the delayed wound healing (DWH); however, the risk of DWH with perioperative use of bDMARDs has not reached a general consensus.Objectives:This retrospective study aimed to investigate the risk factors associated with DWH after orthopedic surgery in RA patients treated with bDMARDs.Methods:We reviewed medical records of 277 orthopedic procedures for 188 RA patients treated with bDMARDs between from 2014 to 2017 in Niigata Rheumatic Center. As preoperative nutritional status assessment, we evaluated body mass index (BMI), prognostic nutritional index (PNI), and CONtrolling NUTritional status (CONUT). In addition, we evaluated DAS28-CRP, DAS28-ESR, face scale for pain, global health (GH), and Health Assessment Questionnaire-Disability Index (HAQ-DI) to assess the disease activity. Univariate and multivariate logistic regression analyses were performed to evaluate the risk factor for DWH.Results:The major characteristics of the patients in 277 procedures were mean age of 63.2 years old and mean disease duration of 18.2 years. Surgical site were hand and wrist (145 procedures), foot and ankle (76), hip and knee (31), elbow and shoulder (24), and spine (1). Seventy-four patients were treated with tocilizumab, 62 with etanercept, 55 with golimumab, 49 with abatacept, 16 with infliximab, 15 with adalimumab, and 6 with certolizumab. According to nutritional assessment in PNI and CONUT, 63% (n=175) and 47% (n=130) were normal nourished patients, respectively.In 277 procedures, DWH were identified in 24 patients (8.6%). The following variables were significant in the univariate analyses: disease duration (OR 1.053; 95% CI 1.010–1.099; p=0.016), foot and ankle surgery (OR 7.091; 95% CI 2.130–23.603; p=0.001), tocilizumab (OR 0.286; 95% CI 0.093–0.881; p=0.029) (Table 1). These variables were entered into a multivariate model, and it was revealed that pre-operative use of tocilizumab (OR 0.265; 95% CI 0.074–0.953; p=0.042) and procedures in the foot and ankle (OR 6.915; 95% CI 1.914–24.976; p=0.003) were associated with an increased risk of DWH (Table 1).Conclusion:As previous study on tocilizumab described, the current retrospective study suggested that pre-operative use of tocilizumab and procedures in the foot and ankle were risk factors for DWH. Pre-operative disease activity and nutritional status were not independent risk factors for an increase in the prevalence of DWH.References:[1] Momohara S, Hashimoto J, Tsuboi H et al. Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: Results from the multicentre tocilizumab in perioperative period (TOPP) study. Modern rheumatology. 2013, 23: 440-9.Disclosure of Interests:Shunji Okita: None declared, Hajime Ishikawa: None declared, Asami Abe: None declared, Satoshi Ito Speakers bureau: Abbvie,Eisai, Akira Murasawa: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Toshifumi Ozaki: None declared

Background:In Japan, Methotrexate (MTX) has been approved in 1999, the first biologic DMARD (bDAMRD) in 2003, and the Janus kinase (JAK) inhibitors have been used since 2013. Although it is expected that the recent advancement of drug therapy would contribute the decrease in the incidence of orthopaedic surgeries by preventing structural damages1, 2), we are still facing a considerable number of patients who require surgical interventions3).Objectives:To investigate the recent trends of patient’s background who underwent the orthopaedic surgery for rheumatoid arthritis, number of orthopaedic intervention, and the type of the surgery.Methods:We reviewed the records of 1569 patients with RA who underwent orthopedic surgeries between 2004 and 2019 in our institution. The mean age of patients was 62.8 (22-88) years-old with disease duration of 20.9 (0.5-64) years. Data of these patients such as age, disease duration, medication (Glucocorticoid; GC, MTX, b/tsDMARD), type of surgeries (total joint replacement; TJR, hand surgery, foot surgery, spine surgery, and others), and preoperative serum CRP level were collected. We analyzed the annual change of these demographic and clinical data. Then, we compared them between CRP negative (Results:Among all cases, 426 cases (27.2%) were treated with b/tsDMARDs at the time of operation. MTX and GC were used in 937 cases (59.7%) and 1015 cases (64.7%), respectively. The mean age and disease duration of RA showed an increasing trend, although the CRP level was dramatically decreased during the study period. While the rate of MTX use has not changed significantly (p=0.102), the number of cases treated by b/ts DMARD increased significantly to 46.7% (pConclusion:Along with the increasing use of b/tsDMARD, the preoperative disease control of RA, as well as the type of demanded surgeries have dramatically changed.References:[1] Yamanaka H, Tanaka E, Nakajima A, et al. A large observational cohort study of rheumatoid arthritis, IORRA: Providing context for today’s treatment options.Mod Rheumatol2020;30:1-6.[2] Matsumoto T, Nishino J, Izawa N, et al. Trends in Treatment, Outcomes, and Incidence of Orthopedic Surgery in Patients with Rheumatoid Arthritis: An Observational Cohort Study Using the Japanese National Database of Rheumatic Diseases.J Rheumatol2017;44:1575-82.[3] Momohara S, Tanaka S, Nakamura H, et al. Recent trends in orthopedic surgery performed in Japan for rheumatoid arthritis.Mod Rheumatol2011;21:337-42.Disclosure of Interests:Yoshifumi Hotta: None declared, Yoshihisa Nasu: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Minami Matsuhashi: None declared, Masahito Watanabe: None declared, Ryuichi Nakahara: None declared, Toshifumi Ozaki: None declared

Background:In Japan, Methotrexate (MTX) has been approved in 1999, the first biologic DMARD (bDAMRD) in 2003, and the Janus kinase (JAK) inhibitors have been used since 2013. Although it is expected that the recent advancement of drug therapy would contribute the decrease in the incidence of orthopaedic surgeries by preventing structural damages1, 2), we are still facing a considerable number of patients who require surgical interventions3).Objectives:To investigate the recent trends of patient’s background who underwent the orthopaedic surgery for rheumatoid arthritis, number of orthopaedic intervention, and the type of the surgery.Methods:We reviewed the records of 1569 patients with RA who underwent orthopedic surgeries between 2004 and 2019 in our institution. The mean age of patients was 62.8 (22-88) years-old with disease duration of 20.9 (0.5-64) years. Data of these patients such as age, disease duration, medication (Glucocorticoid; GC, MTX, b/tsDMARD), type of surgeries (total joint replacement; TJR, hand surgery, foot surgery, spine surgery, and others), and preoperative serum CRP level were collected. We analyzed the annual change of these demographic and clinical data. Then, we compared them between CRP negative (Results:Among all cases, 426 cases (27.2%) were treated with b/tsDMARDs at the time of operation. MTX and GC were used in 937 cases (59.7%) and 1015 cases (64.7%), respectively. The mean age and disease duration of RA showed an increasing trend, although the CRP level was dramatically decreased during the study period. While the rate of MTX use has not changed significantly (p=0.102), the number of cases treated by b/ts DMARD increased significantly to 46.7% (pConclusion:Along with the increasing use of b/tsDMARD, the preoperative disease control of RA, as well as the type of demanded surgeries have dramatically changed.References:[1] Yamanaka H, Tanaka E, Nakajima A, et al. A large observational cohort study of rheumatoid arthritis, IORRA: Providing context for today’s treatment options.Mod Rheumatol2020;30:1-6.[2] Matsumoto T, Nishino J, Izawa N, et al. Trends in Treatment, Outcomes, and Incidence of Orthopedic Surgery in Patients with Rheumatoid Arthritis: An Observational Cohort Study Using the Japanese National Database of Rheumatic Diseases.J Rheumatol2017;44:1575-82.[3] Momohara S, Tanaka S, Nakamura H, et al. Recent trends in orthopedic surgery performed in Japan for rheumatoid arthritis.Mod Rheumatol2011;21:337-42.Disclosure of Interests:Yoshifumi Hotta: None declared, Yoshihisa Nasu: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Minami Matsuhashi: None declared, Masahito Watanabe: None declared, Ryuichi Nakahara: None declared, Toshifumi Ozaki: None declared

In patients with osteoarthritis (OA), there is a decrease in both the concentration and molecular size of hyaluronan (HA) in the synovial fluid and cartilage. Cell migration-inducing hyaluronidase 1 (CEMIP), also known as hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), was recently reported as an HA depolymerization-related molecule expressed in the cartilage of patients with OA. However, the underlying mechanism of CEMIP regulation is not well understood. We found that CEMIP expression was transiently increased by interleukine-1&beta, (IL-1&beta, ) stimulation in chondrocytic cells. We also observed that ERK activation and NF-&kappa, B nuclear translocation were involved in the induction of CEMIP by IL-1&beta, In addition, both administration of HA and mechanical strain attenuated the CEMIP induction in IL-1&beta, stimulated chondrocytes. In conclusion, we clarified the regulatory mechanism of CEMIP in chondrocytes by inflammatory cytokines and suggested the potential involvement in osteoarthritis development.

Objectives: eLORETA (exact low-resolution brain electromagnetic tomography) is a technique created by Pascual-Marqui et al. [Int J Psychophysiol. 1994 Oct; 18(1): 49–65] for the 3-dimensional representation of current source density in the brain by electroencephalography (EEG) data. Kurtosis analysis allows for the identification of spiky activity in the brain. In this study, we focused on the evaluation of the reliability of eLORETA kurtosis analysis. For this purpose, the results of eLORETA kurtosis source localization of paroxysmal activity in EEG were compared with those of eLORETA current source density (CSD) analysis of EEG data in 3 epilepsy patients with partial seizures. Methods: EEG was measured using a digital EEG system with 19 channels. We set the bandpass filter at traditional frequency band settings (1–4, 4–8, 8–15, 15–30, and 30–60 Hz) and 5–10 and 20–70 Hz and performed eLORETA kurtosis to compare the source localization of paroxysmal activity with that of visual interpretation of EEG data and CSD analysis of eLORETA in focal epilepsy patients. Results: The eLORETA kurtosis analysis of EEG data preprocessed by bandpass filtering from 20 to 70 Hz and traditional frequency band settings did not show any discrete paroxysmal source activity compatible with the results of CSD analysis of eLORETA. In all 3 cases, eLORETA kurtosis analysis filtered at 5–10 Hz showed paroxysmal activities in the theta band, which were all consistent with the visual inspection results and the CSD analysis results. Discussion: Our findings suggested that eLORETA kurtosis analysis of EEG data might be useful for the identification of spiky paroxysmal activity sources in epilepsy patients. Since EEG is widely used in the clinical practice of epilepsy, eLORETA kurtosis analysis is a promising method that can be applied to epileptic activity mapping.

Background: Abatacept (ABT) is clinically used as the only T-cell modifier available for rheumatoid arthritis treatment and has shown similar efficacy as tumour necrosis factor inhibitors and a safer profile, especially a lower infection ratio in registry data. Latourte et al. recently published the results of perioperative complications of orthopaedic and other types of surgery in patients using ABT. However, they did not compare the complication rates with those in patients who received csDMARDs. It remains unknown whether ABT is associated with more postoperative complications than conventional synthetic DMARDs (csDMARDs). Objectives: The aims of this study were to investigate whether ABT is associated with more adverse events after orthopaedic surgery compared with csDMARDs and, if so, to identify significant risk factors for those events. Methods: A retrospective multicenter nested case–control study was performed in 18 institutions. Patients receiving ABT were matched individually with patients receiving csDMARDs and/or steroid. Serious adverse events were defined as surgical site infection, delayed wound healing, deep vein thrombosis or pulmonary embolism, flare-up, serious infection in other organs. The incidence rates of serious adverse events in both groups were compared with Mantel-Haenzel test. Risk factors for serious adverse events in the ABT group were analyzed by logistic regression model. Results: A total of 3358 cases were collected. After inclusion and exclusion, 2651 patients were selected for matching, and 194 patients in 97 pairs were chosen for subsequent comparative analyses between the ABT and control groups. No between-group differences were detected in the incidence rates of each adverse event or in the combined incidence rate of adverse events. The odds ratio of the history of serious infection for serious adverse events was 12.6 (95%CI 1.12–141, P=0.04) in patients who received ABT and underwent orthopaedic surgery. Conclusions: Compared with csDMARDs and/or steroid without ABT, adding ABT to the treatment does not appear to increase the incidence rates of postoperative adverse events in rheumatoid arthritis patients undergoing orthopaedic surgery. A history of serious infection is a significant risk factor for both infection and other serious adverse events, and such patients should be treated with particular caution. Reference [1]Latourte A, et al. Safety of surgery in patients with rheumatoid arthritis treated by abatacept: data from the French Orencia in Rheumatoid Arthritis Registry. Rheumatology (Oxford)2017Apr 1;56(4):629–637. Disclosure of Interest: H. Ito Grant/research support from: BMS, ONO Pharmaceutical, S. Tsuji: None declared, M. Nakayama: None declared, Y. Mochida: None declared, K. Nishida: None declared, H. Ishikawa: None declared, T. Kojima: None declared, T. Matsumoto: None declared, A. Kubota: None declared, T. Mochizuki: None declared, K. Sakuraba: None declared, I. Matsushita: None declared, A. Nakajima: None declared, R. Hara: None declared, A. Haraguchi: None declared, T. Matsubara: None declared, K. Kanbe: None declared, N. Nakagawa: None declared, M. Haraguchi: None declared, S. Momohara: None declared

Background Total management including reconstructive joint surgery and rehabilitation should be needed for further improvements of physical function for long-standing RA patients. It is very important to set treatment goal for those management. Objectives The purpose of this study is to set treatment target using Timed Up and Go test (TUG) in relation to achievement of HAQ-DI remission (HAQ-DI Methods Multicenter prospective observational cohort study was conducted among patients who underwent elective joint surgery for RA from April 2012 to March 2016 (Study registration: UMIN000012649). In this study, we collected data including age, sex, disease duration, drug therapies, and disease activity (DAS), TUG, and patient-reported outcome [HAQ-DI, EQ-5D (QOL), patient’s global assessment (PtGA) and BDI-II (depression)] at baseline and at 6 or 12 months after the surgery. Association between TUG and achievement of HAQ remission and cut-off values for HAQ remission were also determined using logistic regression analysis with adjustment of age and sex and ROC curve, respectively. Results Totally, 139 patients with elective joint surgery in lower limbs were analysed. Mean age, disease duration, HAQ-DI and TUG were 65.4 years, 17.5 years, 1.022, and 12.7 s, respectively. Performed joint surgeries were total hip arthroplasty; 10.1%, total knee arthroplasty; 33.8%, total ankle arthroplasty or ankle fixation; 10.1%, and forefoot arthroplasty; 46.0%. The surgeries can significantly improve the outcome measures, including TUG, DAS, PtGA, pain, EQ-5D and BDI-II other than HAQ-DI. In this study, 45 of 139 patients (32.4%) had HAQ remission status at baseline. 18 of 94 patients (19.1%) who had HAQ-DI >0.5 can achieve HAQ remission with the surgery. Notably, TUG at last observation was significantly associated with achievement of HAQ remission even after adjustment for age, sex, and DAS (1 s increasing of TUG. OR:0.72, 95% CI: 0.53–0.97). The adjusted-TUG at last observation of patients with achievement of HAQ remission was 9.2 s (95% CI: 5.6–12.8) (figure 1). Cut-off of TUG at observation for achievement of HAQ remission was 9.2 s based on ROC analysis (figure 2). Importantly, We confirmed significant more improving of EQ-5D, HAQ-DI and TUG in patients who achieved TUG 9.2 s at last observation than in patients who did not (figure 3). Conclusions TUG was significantly associated with PRO; HAQ-DI and EQ-5D. The cut-off values of TUG (9.2 s) should be important to achieve good QOL and physical function for patients with joint surgery in lower limbs and could be suitable target for surgical procedure. Acknowledgements This study is supported by grant from the Japanese Ministry of Health, Labour and Welfare Disclosure of Interest None declared

Objective This prospective observational cohort study aimed to set targets for lower limb joint surgery based on the Timed Up and Go test (TUG), an objective functional outcome measure, in patients with established rheumatoid arthritis (RA). Methods We validated TUG as an outcome measure of lower limb joint surgery and compared it with changes in patient-reported outcomes, including the Health Assessment Questionnaire Disability Index (HAQ-DI) and European Quality of life scale with five dimensions (EQ-5D). Changes in these outcomes were compared by performed surgery and by achievement of the minimal clinically important difference (MCID) for EQ-5D using univariate analysis of variance. Associations between TUG and HAQ remission (HAQ-DI ≤0.5) were determined using logistic regression analysis. Cut-off values of TUG at baseline and 6 months after surgery for HAQ remission were determined using receiver operating characteristic curves. Results A total of 126 patients were analyzed. Mean age, HAQ-DI, and TUG were 65.4 years, 1.036, and 12.8 seconds, respectively. After surgery, patients showed improvements in TUG as well as HAQ-DI. TUG at 6 months after surgery was significantly associated with HAQ remission (adjusted OR: 0.78; 95% CI: 0.65-0.93). TUG cut-off values at baseline and 6 months after surgery for achieving HAQ remission were 12.1 and 8.8 seconds, respectively. Significant improvements in TUG (∆TUG, 3.7 seconds) were associated with achievement of the MCID for EQ-5D (≥0.05) at 6 months after surgery. Conclusion Timed Up and Go test is a useful tool for assessing the outcome of lower limb joint surgery in RA patients. We propose that TUG ≤9 seconds could be an objective target for achieving good physical function after lower limb joint surgery.

1.AbstractEEG/MEG neuroimaging consists of estimating the cortical distribution of time varying signals of electric neuronal activity, for the study of functional localization and connectivity. Currently, many different imaging methods are being used, with very different capabilities of correct localization of activity and of correct localization of connectivity. The aim here is to provide a guideline for choosing the best (i.e. least bad) imaging method. This first study is limited to the comparison of the following methods for EEG signals: sLORETA and eLORETA (standardized and exact low resolution electromagnetic tomography), MNE (minimum norm estimate), dSPM (dynamic statistical parametric mapping), and LCMVBs (linearly constrained minimum variance beamformers). These methods are linear, except for the LCMVBs that make use of the quadratic EEG covariances. To achieve a fair comparison, it is assumed here that the generators are independent and widely distributed (i.e. not few in number), giving a well-defined theoretical population EEG covariance matrix for use with the LCMVBs. Measures of localization error, false positive activity, and false positive connectivity are defined and computed under ideal no-noise conditions. It is empirically shown with extensive simulations that: (1) MNE, dSPM, and all LCMVBs are in general incapable of correct localization, while sLORETA and eLORETA have exact (zero-error) localization; (2) the brain volume with false positive activity is significantly larger for MN, dSPM, and all LCMVBs, as compared to sLORETA and eLORETA; and (3) the number of false positive connections is significantly larger for MN, dSPM, all LCMVBs, and sLORETA, as compared to eLORETA. Non-vague and fully detailed equations are given. PASCAL program codes and data files are available. It is noted that the results reported here do not apply to the LCMVBs based on EEG covariance matrices generated from extremely few generators, such as only one or two independent point sources.

Tofacitinib (TOF) is the first small-molecule inhibitor of the JAK1 and JAK3 signalling pathways, and has been reported to effectively suppress the synovial inflammation of rheumatoid arthritis (RA...

1.AbstractThe sharing and the transmission of information between cortical brain regions is carried out by mechanisms that are still not fully understood. A deeper understanding should shed light on how consciousness and cognition are implemented in the brain. Research activity in this field has recently been focusing on the discovery of non-conventional coupling mechanisms, such as all forms of cross-frequency couplings between diverse combinations of amplitudes and phases, applied to measured or estimated cortical signals of electric neuronal activity. However, all coupling measures that involve phase computation have poor statistical properties. In this work, the conventional estimators for the well-known phase-phase (phase synchronization or locking), phase-amplitude, and phaseamplitude-amplitude couplings are generalized by means of the weighted multiple regression model. The choice of appropriate weights produces estimators that bypass the need for computing the complex-valued phase. In addition, a new coupling, denoted as the inhibitory coupling (InhCo), is introduced and defined as the dependence of one complex-valued variable on the inverse and on the conjugate inverse of another complex-valued variable. A weighted version denoted as wInhCo is also introduced, bypassing the need for computing the inverse of a complex variable, which has very poor statistical properties. The importance of this form of inhibitory coupling is that it may capture well- known processes, such as the observed inverse alpha/gamma relation within the same cortical region, or the inverse alpha/alpha relation between distant cortical regions.

Aim This study aimed to validate the Timed Up and Go test (TUG) for measuring objective functional impairment in patients with established rheumatoid arthritis (RA) based on a prospective observational cohort of RA patients undergoing joint surgery. Methods We collected data on demographics, Health Assessment Questionnaire Disability Index (HAQ-DI), and associations between TUG and HAQ-DI and other patient-reported outcomes, including European Quality of life scale (EQ-5D) were determined. Cut-off values of TUG for HAQ remission (HAQ-DI ≤0.5), normal HAQ (HAQ-DI ≤0.25), and the absence of disability in each HAQ-DI category were also determined by age. Results A total of 435 patients were enrolled and analyzed. Mean age was 64.2 years, mean disease duration was 17.1 years, mean HAQ-DI was 1.14, and mean TUG was 11.1 sec. TUG was significantly correlated with aging, EQ-5D, and HAQ-DI categories related to lower limb function (arising, walking, reach and activity). After adjusting for age and sex, mean TUG values were 9.0 sec (95% CI, 7.7-10.3) in patients with HAQ remission and 8.7 sec (7.4-10.4) in those with normal HAQ. By age, mean TUG values for HAQ remission were 7.2 sec (5.9-8.5) in young patients (≤61 years), 9.1 sec (7.6-10.5) in middle-aged patients (62-70 years) and 10.0 sec (5.7-14.2) in old patients (≥71 years). Conclusion TUG was significantly associated with functional impairment and aging in patients with long-standing RA. Thus, TUG could be useful in setting treatment goals for joint surgery and rehabilitation in established RA patients.

IntroductionWe aimed to identify causes of false-positives in ultrasound scanning of synovial/tenosynovial/bursal inflammation and provide corresponding imaging examples.MethodsWe first performed systematic literature review to identify previously reported causes of false-positives. We next determined causes of false-positives and corresponding example images for educational material through Delphi exercises and discussion by 15 experts who were an instructor and/or a lecturer in the 2013 advanced course for musculoskeletal ultrasound organized by Japan College of Rheumatology Committee for the Standardization of Musculoskeletal Ultrasonography (JCR-CoSMUS).ResultsSystematic literature review identified 11 articles relevant to sonographic false-positives of synovial/tenosynovial inflammation. Based on these studies, 21 candidate causes of false-positives were identified in the consensus meeting. Of these items, 11 achieved a pre-defined consensus (≥ 80 %) in Delphi exercise and were classified as follows: I. Gray-scale assessment (A. Non-specific synovial findings, B. Normal anatomical structures which can mimic synovial lesions due to either their low echogenicity or anisotropy); II. Doppler assessment (A. Intra-articular normal vessels, B. Reverberation). Twenty-four corresponding examples with 49 still and 23 video images also achieved consensus.ConclusionsOur study provides a set of representative images that can help sonographers to understand false-positives in ultrasound scanning of synovitis and tenosynovitis.

Background: Alzheimer's disease (AD) is affected by apolipoprotein E (ApoE); however, its effects assessed by means of cognitive tests and by neuroimaging have not been sufficiently studied. Methods: We administered the Alzheimer's Disease Assessment Scale (ADAS) and single-photon emission computed tomography imaging in patients with AD medicated with donepezil at baseline and after 1 year. Patients were classified as with or without ApoE4 and we evaluated the progress of AD. Results: Analysis of covariance showed that cerebral blood flow after 1 year in subjects with ApoE4 is significantly reduced in some areas including the left lenticular nucleus, left thalamus, and right hippocampus compared with subjects without ApoE4. Paired t tests showed significantly reduced blood flow in several regions including the right hippocampus in subjects with ApoE4 and significant deterioration of ideational praxis in subjects without ApoE4. Conclusion: This study provides evidence that supports the notion of ApoE4 playing an important role in the progress of AD.

To retrospectively investigate the clinical and radiographic results of partial arthrodesis for the wrists with rheumatoid arthritis (RA).Forty-one wrists with RA were treated by radiolunate (RL) or radiolunotriquetral (RLT) arthrodesis with ulnar head resection. The average follow-up period after surgery was 7.1 years. Preoperative radiographs of all wrists were classified according to Schulthess classification. We performed RL arthrodesis for all Type II (n = 26) and Type III wrists (n = 7), and RLT arthrodesis for Type III wrists (n = 8). Pre- and postoperative pain score (visual analog scale), grip strength, range of motion, and radiographic parameters were statistically compared.Pain scores in all groups were significantly improved at final follow-up (P0.05). Grip strength increased from 5.9 to 12.4 (kg) significantly in Type II wrists (P0.01), from 7.2 to 9.1 in Type III wrists after RLT arthrodesis, but decreased from 6.9 to 6.0 in Type III wrists after RL arthrodesis. In all groups, the arc of pronation and supination improved significantly (P0.05), and all radiographic parameters improved.RL arthrodesis for Type II wrists showed satisfactory clinical results. RLT arthrodesis would be a reliable method in case of unstable wrist joint.

To describe the process of collecting and evaluating evidence for treating rheumatoid arthritis (RA) for developing clinical practice guidelines (CPGs) for rheumatologists in Japan.The task force comprised rheumatologists, epidemiologists, health economists, and patients. First, the critical outcomes were determined according to a three-round Delphi method, and eight topics with 88 clinical questions (CQs) were formulated. A systematic review of CQs was conducted using the Cochran Database of Systematic Reviews, MEDLINE, and Japana Centra Revvo Medicina (2003-2012). A questionnaire survey and focus group interview were performed to capture the patients' values and preferences. Data from the National Health Insurance drug price list and product information provided by pharmaceutical companies were collected to evaluate drug cost and safety. The GRADE approach was used to describe the evidence quality and determine the strength of recommendations. Recommendations were developed using a modified Delphi method by a multidisciplinary panel including patients.Eight meetings and frequent e-mail communications were conducted to draft a quality assessment of evidence and recommendations. For 88 CQs, recommendation statements were determined.Using the GRADE approach, new CPGs successfully addressed important clinical issues for treating RA patients. Timely updating of recommendations should be routinely considered.

Rheumatoid arthritis (RA) is a chronic inflammatory bone destructive disorder with autoimmune features. It is driven by diverse cellular and humoral immune responses, resulting in bone destruction. Bone loss in RA is caused by osteoclasts (1-3). Osteoclast differentiation is controlled mainly by receptor activator of nuclear factor-κB (RANK) and its ligand, RANKL. RANKL is expressed on osteoblasts and can be expressed by other cells such as fibroblasts and T cells in inflammatory conditions (4-6). In RA, tumor necrosis factor (TNF)-α augments RANKL expression in synovial fibroblasts and subsequently enhances osteoclastogenesis in inflamed joints (4-6). Additionally, TNF-α enhances osteoclastogenesis by acting on osteoclast precursors directly or synergistically with RANKL (7-10). Consequently, excessive osteoclast activity causes local and systemic bone loss (11, 12). Additionally, one of the characteristic features of RA is the presence of autoantibodies, notably rheumatoid factor and anti-citrullinated protein antibodies (3, 13). Autoantibody production by B cells is a major pathogenic mechanism leading to chronic inflammation in RA. SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein, which is expressed primarily in immune cells including T cells, B cells, and macrophages as well as osteoclasts. SH3BP2 interacts with various proteins, including SYK (14), PLCγ (14, 15), and SRC (16, 17), and regulates intracellular signaling pathways in immune and skeletal systems (18-21). Previously we have reported that gain-of-function mutations in SH3BP2 cause a human craniofacial disorder, cherubism (OMIM#118400) (22, 23), characterized by excessive jawbone destruction (24). The cherubism jaw lesions consist mainly of fibroblastoid cells with numerous tartrate-resistant acid phosphatase (TRAP)-positive multinucleated giant cells (24, 25), suggesting that the excessive bone resorption is caused by increased osteoclast formation. We have generated a mouse model of cherubism by knocking-in a P416R SH3BP2 mutation (equivalent to the most common P418R mutation in cherubism patients) (21). Analysis of the mouse model has revealed that heterozygous (Sh3bp2P416R/+) mice exhibit osteopenia due to increased RANKL-induced osteoclastogenesis (21). Unexpectedly, homozygous mutants (Sh3bp2P416R/P416R) spontaneously develop severe arthritis. In SH3BP2-deficient (Sh3bp2–/–) mice, B-cell proliferation and signaling in response to B-cell antigen receptor (BCR) ligation were impaired, although no noticeable abnormalities in T-cell functions were observed (18, 19). Furthermore, SH3BP2 loss of function suppresses RANKL-induced osteoclastogenesis (16, 17, 26). These findings suggest a potential pathological link between SH3BP2 and arthritis through the SH3BP2 modulation of osteoclastogenesis and autoimmune reactions. However, the exact mechanisms by which SH3BP2 regulates arthritis have not been clarified. In this study, we hypothesized that SH3BP2 plays a role in the pathogenesis of bone destructive inflammatory diseases such as RA, in which TNF-α and autoantibody production are critically involved (3). To test this hypothesis, we used two different murine arthritis models, a human TNF-α transgenic (hTNFtg) (27, 28) and a collagen-induced arthritis (CIA) model (29, 30). Here we demonstrate that SH3BP2-deficiency prevents bone loss via impaired osteoclastogenesis in the hTNFtg model and suppresses the induction of arthritis via decreased autoantibody production in the CIA model.

The outcome measures in rheumatology clinical trials (OMERACT) scores are the most mature quantitation system for rheumatoid arthritis (RA) on magnetic resonance imaging (MRI). Direct measuring techniques of synovial volume have been reported with good reproducibility, although few reports have demonstrated the changes of these measures in response to treatment. To assess these clinical responses, we evaluated the correlation of the changes of clinical activity score 28-joints disease activity score (DAS28-CRP) with the changes of OMERACT scores and with synovial volume measurements. Eight RA patients who were treated by biologic agents were examined with MRI of the dominant affected wrist and finger joints before and one year after the treatment. The total OMERACT score was reduced from 48.0 to 41.3, and synovial volume was reduced from 15.4 to 8.8 milliliters. Positive correlations were seen between the changes of DAS28-CRP and the changes of OMERACT synovitis score (r＝0.27), OMERACT total score (r＝0.43) and synovial volume (r＝0.30). Limited to synovium assessment, synovial volume showed a better correlation with DAS28-CRP than the OMERACT synovitis score. On the other hand, the OMERACT total score showed a higher correlation with DAS28-CRP than synovial volume, probably because the OMERACT total score includes scores for bone erosion and bone edema as well.

We aimed to investigate factors predictive of increased serum infliximab (IFX) concentration with improvement of disease activity, as well as better 1-year continuation rate after dose escalation, in patients with rheumatoid arthritis (RA) who showed inadequate response to 3 mg/kg IFX.Among 42 patients allotted to receive 3 mg/kg IFX, 13 patients showed adequate response (DAS28 3.2) and 29 patients required dose escalation to 4.5 or 6 mg/kg after inadequate response (DAS28 ≥ 3.2) to 3 mg/kg IFX. DAS28, mHAQ, serum level of CRP, interleukin (IL)-6, IL-17, anti-infliximab antibody (AIA) titers and IFX concentration before and on average 2.7 months after dose escalation were examined to explore the baseline factors predictive of a clinically beneficial increase of serum IFX concentration and drug survival.One year after IFX dose escalation, 25 patients completed the study protocol, and 16 patients (64%) continued to show a good response for one year, while 9 patients (36%) required switching of biologics because of inadequate response. Multivariate analyses revealed that a serum IL-6 level of less than 4.0 pg/mL at baseline was the only factor predictive of a clinically beneficial increase of serum IFX concentration in patients who required dose escalation. Receiver operating characteristic analysis revealed that 5.16 pg/mL of IL-6 was the cut-off value with sensitivity 0.833 and specificity of 0.769 (95%CI for AUC: 0.712-1.006). In patients with IL-6 levels of less than 5.16 pg/mL at baseline, the serum IFX concentration significantly increased after dose escalation with adequate response. The 1-year drug survival rates of patients with IL-6 levels less than 5.16 pg/mL and in those with levels greater than or equal to 5.16 pg/mL at baseline were 83.3% and 30.8%, respectively (log-rank test, p = .011).The results of our study indicated that a baseline serum level of IL-6 below 5.16 pg/mL might be a predictive factor for a clinically beneficial increase of serum IFX concentration with improvement of disease activity and better 1-year continuation rate after IFX dose escalation.

Hyaluronan (HA) is an extracellular matrix (ECM) component of articular cartilage and has been used to treat patients with osteoarthritis (OA). A disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs) play an important role in cartilage degradation in OA. We have previously reported that ADAMTS4 and ADAMTS9 were induced by cytokine stimulation. However, the effect of HA on the cytokine‐inducible ADAMTS9 has never been investigated. Moreover, it is unclear whether HA protects cartilage by suppressing aggrecan degradation. Here, we examined the effects of HA on ADAMTS expression in vitro and on cartilage degradation in vivo. ADAMTS9 expression was higher than that of the other aggrecanases (ADAMTS4 and 5) in human chondrocytes, chondrocytic cells, and rat cartilage. ADAMTS4 and 9 mRNA levels were upregulated in cytokine‐stimulated chondrocytes and chondrocytic cells. Pre‐incubation with HA significantly inhibited ADAMTS9 mRNA expression in cytokine‐stimulated cells. In a rat OA model, Adamts5 and 9 mRNA levels were transiently increased after surgery; intra‐articular HA injections attenuated the induction of Adamts5 and 9 mRNA. HA also blocked aggrecan cleavage by aggrecanase in OA rats in a molecular size‐dependent manner. These results demonstrate that HA attenuates induced aggrecanases expression in OA and thereby protects articular cartilage degradation by this enzyme. Our findings provide insight into the molecular basis for the beneficial effects of HA in OA. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:3247–3255, 2018.

The problem of interest here is the study of brain functional and effective connectivity based on non-invasive EEG-MEG inverse solution time series. These signals generally have low spatial resolution, such that an estimated signal at any one site is an instantaneous linear mixture of the true, actual, unobserved signals across all cortical sites. False connectivity can result from analysis of these low-resolution signals. Recent efforts toward "unmixing" have been developed, under the name of "leakage correction". One recent noteworthy approach is that by Colclough et al (2015 NeuroImage, 117:439-448), which forces the inverse solution signals to have zero cross-correlation at lag zero. One goal is to show that Colclough's method produces false human connectomes under very broad conditions. The second major goal is to develop a new solution, that appropriately "unmixes" the inverse solution signals, based on innovations orthogonalization. The new method first fits a multivariate autoregression to the inverse solution signals, giving the mixed innovations. Second, the mixed innovations are orthogonalized. Third, the mixed and orthogonalized innovations allow the estimation of the "unmixing" matrix, which is then finally used to "unmix" the inverse solution signals. It is shown that under very broad conditions, the new method produces proper human connectomes, even when the signals are not generated by an autoregressive model., preprint, technical report, under license "Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)", https://creativecommons.org/licenses/by-nc-nd/4.0/

Objective: To explore the characteristics of functional impairment in patients with established rheumatoid arthritis (RA) based on the range of motion (ROM) of joints in a prospective observational study of RA patients undergoing joint surgery. Methods: We collected data on demographics, Health Assessment Questionnaire Disability Index (HAQ-DI), and the ROM of large joints including the shoulder, elbow, wrist, hip, knee, and ankle. Associations between the ROM of each joint and disability in the eight HAQ-DI categories were determined using receiver operating characteristic (ROC) and logistic regression analyses. ROM cut-off values of each joint for the absence of disability in each HAQ-DI category were determined using ROC curves. Results: A total of 460 patients were enrolled and analyzed in this study. Based on ROC analysis, the ROM of each joint was significantly associated with disability in each category. After adjusting for disease activity, age, and sex, shoulder abduction had the highest independent impact on disability in activity [cut-off: 139 degrees (OR: 5.26)], elbow flexion-extension in dressing [121 degrees (OR: 2.22)], wrist flexion-extension in reach [86 degrees (OR: 2.71)], hip flexion-extension in walking [126 degrees (OR: 3.42)], and knee flexion-extension in walking [134 degrees (OR: 2.97)]. Conclusions: Limited ROM of multiple joints was significantly associated with functional impairment in patients with long-standing RA. Motion in daily activity involves multiple joints, and at least two joints were independently involved in disability., Published online: 25 Jul 2017

In a seminal paper by von Stein and Sarnthein (2000), it was hypothesized that "bottom-up" information processing of "content" elicits local, high frequency (beta-gamma) oscillations, whereas "top-down" processing is "contextual", characterized by large scale integration spanning distant cortical regions, and implemented by slower frequency (theta-alpha) oscillations. This corresponds to a mechanism of cortical information transactions, where synchronization of beta-gamma oscillations between distant cortical regions is mediated by widespread theta-alpha oscillations. It is the aim of this paper to express this hypothesis quantitatively, in terms of a model that will allow testing this type of information transaction mechanism. The basic methodology used here corresponds to statistical mediation analysis, originally developed by (Baron and Kenny 1986). We generalize the classical mediator model to the case of multivariate complex-valued data, consisting of the discrete Fourier transform coefficients of signals of electric neuronal activity, at different frequencies, and at different cortical locations. The "mediation effect" is quantified here in a novel way, as the product of "dual frequency RV-coupling coefficients", that were introduced in (Pascual-Marqui et al 2016, http://arxiv.org/abs/1603.05343). Relevant statistical procedures are presented for testing the cross-frequency mediation mechanism in general, and in particular for testing the von Stein & Sarnthein hypothesis., https://doi.org/10.1101/119362 licensed as CC-BY-NC-ND 4.0 International license: http://creativecommons.org/licenses/by-nc-nd/4.0/

Highlights • sLORETA analyses performed on 14 healthy adults at rest and during an arithmetic task. • Theta and alpha directed connectivity revealed ACC and left IPL as hubs during task. • Information flow between left IFG and STG suggested a feedback loop., Objectives The aim of this paper is to investigate cortical electric neuronal activity as an indicator of brain function, in a mental arithmetic task that requires sustained attention, as compared to the resting state condition. The two questions of interest are the cortical localization of different oscillatory activities, and the directional effective flow of oscillatory activity between regions of interest, in the task condition compared to resting state. In particular, theta and alpha activity are of interest here, due to their important role in attention processing. Methods We adapted mental arithmetic as an attention ask in this study. Eyes closed 61-channel EEG was recorded in 14 participants during resting and in a mental arithmetic task (“serial sevens subtraction”). Functional localization and connectivity analyses were based on cortical signals of electric neuronal activity estimated with sLORETA (standardized low resolution electromagnetic tomography). Functional localization was based on the comparison of the cortical distributions of the generators of oscillatory activity between task and resting conditions. Assessment of effective connectivity was based on the iCoh (isolated effective coherence) method, which provides an appropriate frequency decomposition of the directional flow of oscillatory activity between brain regions. Nine regions of interest comprising nodes from the dorsal and ventral attention networks were selected for the connectivity analysis. Results Cortical spectral density distribution comparing task minus rest showed significant activity increase in medial prefrontal areas and decreased activity in left parietal lobe for the theta band, and decreased activity in parietal-occipital regions for the alpha1 band. At a global level, connections among right hemispheric nodes were predominantly decreased during the task condition, while connections among left hemispheric nodes were predominantly increased. At more detailed level, decreased flow from right inferior frontal gyrus to anterior cingulate cortex for theta, and low and high alpha oscillations, and increased feedback (bidirectional flow) between left superior temporal gyrus and left inferior frontal gyrus, were observed during the arithmetic task. Conclusions Task related medial prefrontal increase in theta oscillations possibly corresponds to frontal midline theta, while parietal decreased alpha1 activity indicates the active role of this region in the numerical task. Task related decrease of intracortical right hemispheric connectivity support the notion that these nodes need to disengage from one another in order to not interfere with the ongoing numerical processing. The bidirectional feedback between left frontal-temporal-parietal regions in the arithmetic task is very likely to be related to attention network working memory function. Significance The methods of analysis and the results presented here will hopefully contribute to clarify the roles of the different EEG oscillations during sustained attention, both in terms of their functional localization and in terms of how they integrate brain function by supporting information flow between different cortical regions. The methodology presented here might be clinically relevant in evaluating abnormal attention function.

Objective: To survey the current status and problems of cooperation between clinics and hospitals in Okayama Prefecture, Japan for the treatment of rheumatoid arthritis (RA). Methods: We distributed a questionnaire to 300 of the 983 Okayama Prefecture clinics that had either an internal medicine or orthopedic surgery department, from December 2013 to February 2014. The questionnaire covered practice pattern for RA treatment in clinics, current status of the hospital and clinic cooperation, and acceptance of the biologic therapy. Results: One hundred clinics responded to the questionnaire. Seventy percent of the clinics reported making referrals to rheumatologists before the initiation of RA treatment, and half of the other 30% of the clinics administered methotrexate as the first-line treatment for RA by their own decision. Sixty-six clinics cooperated with flagship hospitals, conducting medical and laboratory examinations, providing prescriptions, and treating common diseases of patients. These clinics expected the cooperating rheumatologists to follow-up patients every 3 to 6 months and to make the diagnosis, make decisions regarding RA treatment changes, and perform surgery. Seventy-one percent of the clinics responded that cooperation with a hospital is possible even for patients who are administered biologics. As reasons for no cooperation with the flagship hospitals, clinics noted the lack of information about rheumatologists in the area and recent trends in the management of RA. Conclusion: The current study reported, for the first time, the actual conditions of management of RA in clinics, as well as future problems of hospital and clinic cooperation in Okayama Prefecture.

We determined mid to long-term results of total elbow arthroplasty (TEA) by use of unlinked elbow prostheses with solid alumina ceramic trochleae, and ceramic ulnar stems (stemmed Kyocera type I; SKC-I) for patients with rheumatoid arthritis.Fifty-four elbows of 39 patients were available for detailed clinical and radiographic review after a follow-up period of at least 5 years. The mean follow-up period was 12.6 years (range 5-22 years). Clinical condition before and after surgery was assessed by use of a modified version of the Mayo Elbow Performance Score (MEPS; 0-100 points) and a Japan Orthopaedic Association Elbow score (JOA score; 0-100 points). The radiographs were reviewed and loosening was defined as a progressive radiolucent line1 mm wide that was completely circumferential around the prosthesis. Clinical records of post-operative events affecting the elbows were used for survival analysis of the prostheses using the Kaplan-Meier method.The average modified MEPS and JOA scores improved significantly from 39.7 ± 14.3 to 44.7 ± 9.4, respectively, pre-operatively, to 89.7 ± 15.4 and 83.1 ± 12.8, respectively, post-operatively (P0.0001). The functional assessment score also improved from 4.9 ± 2.8 to 8.5 ± 3.3 points (P0.0001). With loosening or implant revision defined as end points, the likelihood of survival of the prosthesis for up to 20 years was 92.6% (95% confidence interval (CI), 85.6-100.0) or 86.3 % (95 % CI 75.0-97.6), respectively.Satisfactory clinical results were obtained after TEA using SKC-I prostheses, which provided excellent pain relief and functional range of motion. The results of our study reveal the high reliability over a long period of the cemented SKC-I prosthesis with an alumina ceramic component.

The metatarsophalangeal (MTP) joints are often and predominantly affected in rheumatoid arthritis. The aim of the current study was to describe surgical techniques of shortening oblique osteotomy for lesser metatarsal bone with screw fixation at the osteotomy site, and to investigate the short-term clinical outcomes of our procedure. Twenty-seven feet (78 toes) of 24 RA patients underwent the shortening oblique osteotomy for the correction of deformity at the lesser MTP joints. The average Japanese Society of Surgery of the Foot (JSSF) standard rating system for the RA foot and ankle scale improved significantly from 59.6 points preoperatively to 88.3 points postoperatively (p＜0.001). Twenty-four feet (89% ) were free from metatarsalgia and symptomatic callosities at the lesser MTP joint after surgery. Our present findings showed satisfactory early clinical outcomes of the shortening oblique osteotomy of the metatarsal bone with screw fixation for RA forefoot.

The synovial fluids of patients with osteoarthritis (OA) contain elevated levels of inflammatory cytokines, which induce the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and of the matrix metalloproteinase (MMP) in chondrocytes. Mechanical strain has varying effects on organisms depending on the strength, cycle, and duration of the stressor; however, it is unclear under inflammatory stimulation how mechanical strain act on. Here, we show that mechanical strain attenuates inflammatory cytokine-induced expression of matrix-degrading enzymes. Cyclic tensile strain (CTS), as a mechanical stressor, attenuated interleukin (IL)-1β and tumor necrosis factor (TNF)-α-induced mRNA expression of ADAMTS4, ADAMTS9, and MMP-13 in normal chondrocytes (NHAC-kn) and in a chondrocytic cell line (OUMS-27). This effect was abolished by treating cells with mechano-gated channel inhibitors, such as gadolinium, transient receptor potential (TRP) family inhibitor, ruthenium red, and with pharmacological and small interfering RNA-mediated TRPV1 inhibition. Furthermore, nuclear factor κB (NF-κB) translocation from the cytoplasm to the nucleus resulting from cytokine stimulation was also abolished by CTS. These findings suggest that mechanosensors such as the TRPV protein are potential therapeutic targets in treating OA.

OBJECTIVE: There are relevant links between resting-state fMRI networks, EEG microstate classes and psychopathological alterations in mental disorders associated with frontal lobe dysfunction. We hypothesized that a certain microstate class, labeled C and correlated with the salience network, was impaired early in frontotemporal dementia (FTD), and that microstate class D, correlated with the frontoparietal network, was impaired in schizophrenia. METHODS: We measured resting EEG microstate parameters in patients with mild FTD (n = 18), schizophrenia (n = 20), mild Alzheimer's disease (AD; n = 19) and age-matched controls (old n = 19, young n = 18) to investigate neuronal dynamics at the whole-brain level. RESULTS: The duration of class C was significantly shorter in FTD than in controls and AD, and the duration of class D was significantly shorter in schizophrenia than in controls, FTD and AD. Transition analysis showed a reversed sequence of activation of classes C and D in FTD and schizophrenia patients compared with that in controls, with controls preferring transitions from C to D, and patients preferring D to C. CONCLUSION: The duration and sequence of EEG microstates reflect specific aberrations of frontal lobe functions in FTD and schizophrenia. SIGNIFICANCE: This study highlights the importance of subsecond brain dynamics for understanding of psychiatric disorders.

Objective: To investigate the inhibitory effects and the regulatory mechanisms of histone deacetylase (HDAC) inhibitors on mechanical stress-induced gene expression of runt-related transcription factor (RUNX)-2 and a disintegrin and metalloproteinase with thrombospondin motif (ADAMTS)-5 in human chondrocytes. Methods: Human chondrocytes were seeded in stretch chambers at a concentration of 5 x 10(4) cells/chamber. Cells were pre-incubated with or without HDAC inhibitors (MS-275 or trichostatin A; TSA) for 12 h, followed by uniaxial cyclic tensile strain (CTS) (0.5 Hz, 10% elongation), which was applied for 30 min using the ST-140-10 system (STREX, Osaka, Japan). Total RNA was extracted and the expression of RUNX-2, ADAMTS-5, matrix metalloproteinase (MMP)-3, and MMP-13 at the mRNA and protein levels were examined by real-time polymerase chain reaction (PCR) and immunocytochemistry, respectively. The activation of diverse mitogen-activated protein kinase (MAPK) pathways with or without HDAC inhibitors during CTS was examined by western blotting. Results: HDAC inhibitors (TSA: 10 nM, MS-275: 100 nM) suppressed CTS-induced expression of RUNX-2, ADAMTS-5, and MMP-3 at both the mRNA and protein levels within 1 h. CTS-induced activation of p38 MAPK (p38), extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (INK) MAPKs was downregulated by both HDAC inhibitors. Conclusion: The CTS-induced expression of RUNX-2 and ADAMTS-5 was suppressed by HDAC inhibitors via the inhibition of the MAPK pathway activation in human chondrocytes. The results of the current study suggested a novel therapeutic role for HDAC inhibitors against degenerative joint disease such as osteoarthritis.

The number of cases with rheumatoid arthritis who requires arthroscopic synovectomy is declining, but it is still a useful procedure in combination with effective pharmacologic disease control. For the destruction of glenohumeral joint, total shoulder arthroplasty is effective for pain relief and functional outcome for patients without rotator cuff impairment. The reverse shoulder arthroplasty has been shown favorable short-term results, but need a careful indication for rheumatoid shoulder with poor bone stock and bone quality. Linked or unlinked total elbow arthroplasty are now reliable methods for the reconstruction of rheumatoid elbows with acceptable long-term survival. Joint replacement surgery for proximal interphalangeal joint is a challenging procedure in terms of relatively high complication rate and disappointing improvement in range of motion, whereas achieves good patients' satisfaction for pain relief and improved finger appearances.

The concept of vascular dementia(VaD) has been under discussion for long time. The most widely used guideline is NINDS-AIREN. However, this guideline tends to emphasize memory impairment, which seems very unrealistic in some cases. Although several guidelines have been created in addition to NINDS-AIREN, each of these guidelines has its advantages and disadvantages. With respect to the pathophysiology, there have been recent important findings, particularly about subcortical vascular dementia(SVD). From the therapeutic point of view, there have been high expectations for cholinesterase inhibitors and memantine, but the effectiveness of these drugs has not proved impressive so far. In this manuscript, we summarized the concept of VaD. In addition, we described recent findings related to pathophysiology and medication by cholinesterase inhibitors and memantine.