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Objective.To investigate whether abatacept (ABA) causes more adverse events (AE) than conventional synthetic disease-modifying antirheumatic drugs (csDMARD) after orthopedic surgery in patients with rheumatoid arthritis (RA).Methods.A retrospective multicenter nested case–control study was performed in 18 institutions. Patients receiving ABA (ABA group) were matched individually with patients receiving csDMARD and/or steroids (control group). Postoperative AE included surgical site infection, delayed wound healing, deep vein thrombosis or pulmonary embolism, flare, and death. The incidence rates of the AE in both groups were compared with the Mantel-Haenszel test. Risk factors for AE 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 ABA and control groups. No between-group differences were detected in the incidence rates of each AE or in the incidence rates of total AE (control vs ABA: 15.5% vs 20.7% in total, 5.2% vs 3.1% in death).Conclusion.Compared with csDMARD and/or steroids without ABA, adding ABA to the treatment does not appear to increase the incidence rates of postoperative AE in patients with RA undergoing orthopedic surgery. Large cohort studies should be performed to add evidence for the perioperative safety profile of ABA.

The objective of this study is to investigate the inhibitory effect of golimumab on large joint destruction in patients with rheumatoid arthritis.We recruited 45 patients with rheumatoid arthritis and evaluated the radiographic severity of large joint destruction using the assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging (ARASHI) score. We evaluated 450 large joints including the elbow, shoulder, hip, knee, and ankle at baseline and 52 weeks after treatment with golimumab. Rapid radiographic progression (RRP) and rapid radiographic improvement (RRI) were calculated and the correlation between large joint destruction and clinical factors was analyzed.The mean age of the study population was 61.29 ± 14.71 years old, and most patients (91.1%) were female. The mean disease duration was 12.6 ± 12.48 years. The cohort included patients in all clinical stages of disease as defined by the Steinbroker criteria (I:7, II:10, III:9, IV:19) as well as clinical classes 2 (n = 18), 3 (n = 26), and 4 (n = 1) and the mean disease activity score-CRP (DAS28-CRP) was 4.431 ± 1.044. Patients were treated with methotrexate (mean dose 6.44 ± 1.78 mg/week), prednisolone (PSL) (mean dose 1.078 ± 1.871 mg/d), and golimumab (44.4% of 100 mg). RRP was evident in 20% of the large joints treated with golimumab, and, therefore, golimumab was effective at inhibiting large joint destruction in 80% of joints. RRI was evident in 33.3% of large joints following golimumab treatment. We also observed that EULAR response criteria significantly correlated with the ARASHI change score at 52 weeks after treatment. The total ARASHI status score significantly correlated with the Sharp-van der Heijde score, but not with the delta total sharp score. Multiple regression analyses revealed that the total ARASHI change score was only correlated with EULAR response criteria significantly.Golimumab therapy was effective at inhibiting large joint destruction of RA patients who have good clinical response, including higher improvement of the shoulder and ankle joints than other large joints.

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

Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for treatment of RA in Japan in 1999 at the recommended dose of 6-8 mg/week; it was approved as first-line drug with the maximum dose of 16 mg/week in February 2011. However, more than half of Japanese patients with RA are unable to tolerate a dose of 16 mg/week of MTX. Moreover, some serious adverse events during the treatment with MTX, such as pneumocystis pneumonia (PCP) and lymphoproliferative disorders (LPD) have been observed much more frequently in Japan than in other countries. Therefore, this article, an abridged English translation summarizing the 2016 update of the Japan College of Rheumatology (JCR) guideline for the use of MTX in Japanese patients with RA, is not intended to be valid for global use; however, it is helpful for the Japanese community of rheumatology and its understanding might be useful to the global community of rheumatology.

The aim of this study was to determine whether the levels of stromal cell-derived factor (SDF)-1 and its receptor C-X-C chemokine receptor 4 (CXCR4) in synovium were correlated with clinical outcome and bone and joint destruction in rheumatoid arthritis (RA) patients being treated with golimumab.Synovial tissues were obtained from 15 golimumab-treated patients and were assessed for SDF-1 and CXCR4 using a new immunohistological scoring system (IH score). The IH score was used to assess correlations between synovial SDF-1 or CXCR4 and the disease activity score (DAS28 CRP), Rooney score, tumor necrosis factor alpha, interleukin-6 (IL-6), CD4, CD20, CD68 and the Assessment of RA by Scoring of Large-Joint Destruction and Healing in Radiographic Imaging (ARASHI) score. Receiver-operating characteristic (ROC) curves were used to predict ARASHI scores from the CXCR4 IH scores.SDF-1 strongly correlated with the DAS28 CRP and serum IL-6. CXCR4 correlated with synovial CD4 and the ARASHI score. ROC analysis of CXCR4 and ARASHI scores 10 indicated a cutoff of 12 points on the IH score for predicting joint destruction during treatment.Synovial SDF-1 correlated with disease activity, and its receptor CXCR4 was related to joint destruction in RA patients treated with golimumab.

Background The purpose of this study was to investigate the long-term clinical outcome and its related factors regarding the severity of adhesion of CH ligament over long head of biceps (LHB) after shoulder arthroscopic capsular release for frozen shoulder with technical points in 255 patients. Methods We performed arthroscopic capsular release for frozen shoulder in 267 shoulders of 255 patients, 112 males and 143 females, with mean age of 56.39 years, mean disease duration periods of 0.934 years for conservative treatment, and mean follow-up periods of 5.6 years. The frozen shoulders were divided based on the severity of adhesion between CH ligament over LHB: those with slight degree of synovitis, no adhesion by obtuse rod, and slight thickness of the released capsule (type A), those with moderate degree of synovitis, moderate adhesion of the LHB by obtuse rod, and moderate thickness of the released capsule (type B), and those with severe degree of synovitis, severe adhesion of the LHB by obtuse rod, and severe thickness of the released capsule adhesion and a flatly shaped LHB (type C). We assessed the clinical factors related to the scoring of the shoulders by the criteria of the American Shoulder and Elbow Surgeons (ASES) and the relationship with severity of LHB adhesion. Results The ASES scores improved at 5 years postoperatively in all three groups significantly. The range of motion also significantly improved in all three groups significantly. The severity of the LHB adhesion over the CH ligament was confirmed to influence the ASES scores before and after the arthroscopic capsular release. There was a significant difference between type A and type B (p

Objectives. This study aimed to analyze the relationship between the expression of tumor necrosis factor alpha (TNF-α) or interleukin-6 (IL-6) in synovium and the disease activity score (DAS) 28 (C-reactive protein, CRP) in treatment of infliximab for rheumatoid arthritis (RA).Methods. Synovial tissues were obtained from 16 infliximab-treated patients and assessed for TNF-α and IL-6 with a new immunohistology (IH) scoring system. The validation of IH score was performed and applied for the analysis of correlation between synovial TNF-α or IL-6 and DAS28 (CRP) in addition to Rooney score.Results. The IH score had high internal validity; the IH score of TNF-α strongly correlated with serum CRP and matrix metalloprotease-3 (MMP-3), as well as DAS28 (CRP) and the Rooney score. IL-6 did not correlate with DAS28 (CRP).Conclusions. This study indicates that the IH score is useful as a new procedure to assess the cytokine expression easily and TNF-α in synovium correlates with disease activity in patients...

To evaluate perioperative changes in rheumatoid arthritis (RA) patients treated with tocilizumab.We collected RA cases with tocilizumab and orthopaedic surgery from 1999 to 2010. Incidences of postoperative infections, delayed wound healing, and RA symptom flare-ups were extracted from the data for comparison with patients without these postoperative events. We also evaluated the changes in C-reactive protein (CRP) and body temperature in patients without postoperative complications with normal CRP before surgery, i.e., patients without postoperative events in whom the tocilizumab level was maintained, for each duration to discontinuation before surgery.A total of 161 cases (n = 122) were collected. The patients had mean age of 56.9 years, and mean disease duration of 12.8 years at operation. Joint replacement surgery was performed in 89 cases. Three patients had postoperative infections (two superficial and one organ/space surgical-site infection), 20 had delayed wound healing, and 36 had RA symptom flare-ups. Delayed wound healing occurred most commonly in patients who underwent spinal surgery (P = 0.0061, versus patients without delayed wound healing). CRP levels were high when tocilizumab was restarted in patients with RA symptom flare-ups (P = 0.0010, versus patients without RA symptom flare-ups). Increased postoperative CRP was observed in patients without postoperative events when the duration from final tocilizumab infusion to surgery was long. The changes in body temperature showed a similar trend to CRP.Although it has been demonstrated that infection rates in patients treated with tocilizumab are by no means high, incidence of delayed wound healing was significantly higher in cases with surgical interventions such as foot and spinal surgeries. Many patients treated with tocilizumab remained in a normal range of CRP even during the perioperative period. For prevention of perioperative complications, observation of postoperative conditions and surgical wounds, and subjective symptoms of patients are considered important.

An artificial patch can be used in open and arthroscopic surgery in a massive rotator cuff tear but there is no evidence of biological attachment between the artificial patch and the cuff or bone tissue. We used an artificial polytetrafluoroethylene (PTFE) patch for the arthroscopic treatment for a massive rotator cuff tear. One year after surgery, we could undertake second-look arthroscopy to evaluate whether the PTFE patch was attached to cuff tissue and humeral bone with regard to histological features. We found a tight connection between the PTFE patch and bone, and also recognized smooth attachment to cuff tissue without proliferation of inflammatory cells in the synovium. We assessed the outcome of surgery using the American Shoulder and Elbow Surgeons (ASES) scale and range of motion before and after surgery: A score of 24 before surgery improved to 75 after surgery. MRI after surgery showed continuous low intensity from the PTFE patch to cuff and bone. This is the first report to describe the histological findings of PTFE patch reconstruction of massive rotator cuff tear after 1 year: A major biological reaction was not observed in this respect.

The aim of this study was to investigate the histological changes following the treatment with abatacept compared with methotrexate (MTX) by an immunohistological examination of synovial tissue for eleven different molecules to detect the expression patterns of cytokines. We histologically assessed the synovial tissues from 10 methotrexate (MTX)-treated RA patients as controls and 5 abatacept plus MTX-treated RA patients. The synovium samples from both group were assessed by hematoxylin and eosin (HE) staining and analyzed for their expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD20, CD68, vascular endothelial growth factor (VEGF), CD4, CD8, CD28, CD80, and CD86 by an immunohistological examination. HE staining showed that there was a decrease in cell proliferation in the synovium of the RA patients who received abatacept compared with the controls. TNF-α, IL-6, and VEGF were not significantly different in either of the groups. On the other hand, MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 were significantly decreased in the abatacept group compared with the control (P < 0.05). Based on the histological analysis of the synovium, it appears that the efficacy of the treatment with abatacept may involve the inhibition of cell proliferation, with decreases in the expression of MMP-3, CD68, CD4, CD8, CD20, CD80, and CD86 in the synovium. These findings indicate inhibition of not only T cells but also B cells and macrophages, which likely plays a role in the efficacy of abatacept in RA patients.

To investigate the histological changes of mitogen-activated protein kinase (MAPK) in synovium with tocilizumab in rheumatoid arthritis (RA), synovial tissue samples were assessed from ten methotrexate (MTX)-treated RA patients for control and ten tocilizumab with MTX-treated RA patients. The synovium was observed using hematoxylin and eosin (HE) stain and analyzed immunohistochemically for the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD4 (T cell), CD20 (B cell), CD68 (macrophage), vascular endothelial growth factor (VEGF), CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK [extracellular signal-regulated kinase (ERK) 1/ERK2], and phospho-c-Jun N-terminal kinase (JNK). HE staining showed that there is a significant difference of cell proliferation; however, there is no change of hypervascularity in the synovium between both groups. An immunohistochemical examination showed that the decrease of CD29 (β-1 integrin) and JNK was found significant, while ERK was increased in the tocilizumab group. CD20, B-lymphocyte, was decreased in the tocilizumab group compared with the MTX group significantly. IL-6 was completely blocked in the patients who received tocilizumab. TNF-α was similarly expressed in the interstitial cells of synovium of patients in both groups. MMP-3 and CD68 were similarly expressed on the surface of synovium. VEGF was less expressed in both groups. These findings indicate that the inhibition of CD20, CD29, and JNK in MAPK may be involved in the efficacy of tocilizumab compared with MTX treatment in RA.

Aims: In order to investigate the histological change in the secondary non-responder cases of adalimumab compared with methotrexate (MTX) treatment, we performed immunohistochemical examination of synovial tissue by seven different molecules to detect expression patterns of cytokines. Methods: We histologically assessed synovial tissues from five MTX-treated rheumatoid arthritis (RA) patients as controls and five adalimumab plus MTX-treated RA patients after arthroscopic synovectomy in the knee joints. The synovium of both groups were assessed by hematoxylin and eosin (H&E) and analyzed the positive expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell precursor and mature B-cell transmembrane protein, CD20, macrophage marker, CD68, vascular endothelial growth factor (VEGF), receptor activator of nuclear (kappa) B ligand (RANKL) by immunohistochemical examination. Results: H&E staining showed the increase of vascular and cell proliferations in the synovium of the RA patients who received adalimumab compared with the controls. TNF-α, IL-6 and CD20 were not significantly different in either group. On the other hand, MMP-3 and CD68 showed a significant decrease in the adalimumab group compared with controls (P

The aim of this study was to investigate histological changes of bone marrow in response to tocilizumab for rheumatoid arthritis (RA). After tocilizumab therapy, bone marrow tissues were extracted from ten RA patients at the time of total knee arthroplasty (TKA). Control samples were obtained from ten RA patients who underwent MTX mono-therapy. Histological examination of structural differences between the tocilizumab and control groups in bone marrow was performed using hematoxylin and eosin (H&E) to evaluate differences. In immunohistochemical examination, the expression of seven molecules including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), CD68, osteoprotegerin (OPG), receptor activator of nuclear kappa B ligand (RANKL), CD4 and osteopontin (OPN) were compared between two groups. NTx was significantly low at 44.5 ± 2 nM BCE/mM Cr compared with control at 73.2 ± 8 nM BCE/mM Cr. Immunohistochemical examination revealed that the bone marrow tissues of the RA patients who underwent tocilizumab therapy demonstrated significant positive OPG as compared with the control. However, immunohistochemical examinations after tocilizumab revealed that TNF-α, IL-6, CD68, CD4, OPN and RANKL were not significantly different with control of MTX in bone marrow. Therefore, treatment with tocilizumab increased the expression of OPG as the histological changes with respect to inhibit RANKL-related bone resorption of bone marrow in RA.

Objective.The aim of the Efficacy and Safety of Etanercept on Active Rheumatoid Arthritis Despite Methotrexate Therapy in Japan (JESMR) study is to compare the efficacy of continuation versus discontinuation of methotrexate (MTX) when starting etanercept (ETN) in patients with active rheumatoid arthritis (RA).Methods.In total, 151 patients with active RA who had been taking MTX were randomized to either ETN 25 mg twice a week with 6–8 mg/week MTX (the E+M group), or ETN alone (the E group). The primary endpoint at Week 52 was the radiographic progression assessed by van der Heijde-modified Sharp score.Results.The mean progression in total score at Week 52 was not significantly different, statistically, between the E+M group and the E group (0.8 vs 3.6, respectively; p = 0.06). However, a significant difference was observed in radiographic progression between Weeks 24 and 52 (0.3 vs 2.5; p = 0.03), and the mean progression of the erosion score was negative in the E+M group, which was significantly better than the E group at Week 52 (–0.2 vs 1.8; p = 0.02). Clinically, the cumulative probability plot of the American College of Rheumatology (ACR)-N values at Week 52 clearly demonstrated a superior response in the E+M group than in the E group. ACR20, 50, and 70 response rates at Week 52 in the E+M group (86.3%, 76.7%, and 50.7%) were significantly greater than those in the E group (63.8%; p = 0.003, 43.5%; p < 0.0001 and 29.0%; p = 0.01, respectively).Conclusion.MTX should be continued when starting ETN in patients with active RA. (ClinicalTrials.gov: NCT00688103)

Aims: To determine what clinical factors relating to efficacy besides complications of orthopedic surgery for patients treated with anti-tumor necrosis factor (TNF)-α therapy (infliximab), we analyzed the clinical data of 52 cases of orthopedic surgery, such as total hip arthroplasy (THA), total knee arthroplasty (TKA), total shoulder arthroplasy (TSA), total elbow arthroplasty (TEA), arthroscopic synovectomy, foot arthroplasty, spine surgery, hand surgery and fracture. Methods: We analyzed clinical factors including age, disease duration, preoperative C-reactive protein (CRP), disease activity score (DAS)-28, matrix metalloproteinase (MMP)-3, and rheumatoid arthritis particle-agglutination (RAPA) in 52 cases of rheumatoid arthritis (RA) undergoing orthopedic surgery. For complications of orthopedic surgery, signs of postoperative infection were recorded, including rubor, discharge, systemic infection and frequencies of wound dehiscence, as well as the incidence of any surgical complication requiring a secondary revision procedure were measured. Results: Signs of infection or surgical complications occurred in two of 52 patients (3.8%). There is significant correlation between RAPA and improvement of CRP 3 months after surgery; however, there is no correlation between infection and clinical factors including age, disease duration, preoperative CRP, MMP-3, RAPA and the period until surgery after infliximab infusion. Conclusion: Infliximab did not increase the risk of either infections or surgical complications occurring in patients with RA within 1 year of orthopedic surgery. Improvement of CRP after surgery is likely to be due to infliximab for high RAPA in RA patients.

To investigate the histological changes of synovium in cases of effect attenuation occurring after the use of infliximab in the treatment of rheumatoid arthritis (RA), we histologically assessed synovial tissue from ten methotrexate-treated RA patients and 12 infliximab-treated RA patients after arthroscopic synovectomy. The synovium was observed using hematoxylin and eosin (H&E) stain and analyzed immunohistochemically for expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell transmembrane protein, cluster of differentiation 20 (CD20), nuclear factor kappa B (NFkB), bromodeoxyuridine (BrdU), and vascular endothelial growth factor (VEGF). H&E staining showed significant vascular proliferation in the synovium of the RA patients in the infliximab group (p

肩関節拘縮26 例26 肩に対して肩関節鏡視下授動術に肩峰下徐圧術（ASD）を追加した群としなかった群での長期成績（平均14 カ月）の差と，術後1 カ月の時点で，外旋運動を中心とした外来リハビリテーション訓練回数による可動域の差を検討した．肩関節鏡視下授動術にASDを併用したA群14 例は，男性7 例，女性7 例で，手術時年齢，平均53.7 歳で，ASD併用なしB群12 例は，男性5 例，女性7 例で，手術時年齢平均58.2 歳であった．術後14 カ月時に肩関節可動域は自動，他動ともA群でB群にくらべて大幅に改善し，日本整形外科学会肩関節疾患治療成績評価基準でも有意に改善した．またA群B群それぞれの中で，リハビリテーションを週3 回以上施行した群は週2 回以下の群にくらべ術後1カ月時の可動域改善が大きかった．以上より肩関節拘縮における肩関節鏡視下授動術では肩峰下徐圧術と術後リハビリテーションの重要性を認めた．

Matrilin-1 (Matn1), a cartilage-specific peri-cellular and extracellular matrix (ECM) protein, has been hypothesized to regulate ECM interactions and transmit mechanical signals in cartilage. Since Matn1 knock-out (Matn1-/-) mice exhibit a normal skeleton, its function in vivo is unclear. In this study, we found that the anabolic Acan and Col2a transcript levels were significantly higher in wildtype (Matn1+/+) mouse cartilage than that of MATN1-/- mice in vivo. However, such difference was not observed between Matn1+/+ and MATN1-/- chondrocytes cultured under stationary conditions in vitro. Cyclic loading significantly stimulated Acan and Col2a transcript levels in Matn1+/+ but not in MATN1-/- chondrocytes. This suggests that, while Matn1+/+ chondrocytes increase their anabolic gene expression in response to mechanical loading, the MATN1-/- chondrocytes fail to do so because of the deficiency in mechanotransduction. We also found that altered elastic modulus of cartilage matrix in Matn1-/- mice, suggesting the mechanotransduction has changed due to the deficiency of Matn1. To understand the impact of such deficiency on joint disease, mechanical loading was altered in vivo by destabilization of medial meniscus. While Matn1+/+ mice exhibited superficial fissures and clefts consistent with mechanical damage to the articular joint, Matn1-/- mice presented more severe cartilage lesions characterized by proteoglycan loss and disorganization of cells and ECM. This suggests that Matn1 deficiency affects pathogenesis of post-traumatic osteoarthritis by failing to up-regulate anabolic gene expression. This is the first demonstration of Matn1 function in vivo, which suggests its protective role in cartilage degeneration under altered mechanical environment.

Pericellular matrix is at the ideal location to be involved in transmitting mechanical signals from the microenvironment to a cell. We found that changes of the content of matrilins that link various pericellular molecules surrounding chondrocytes affect mechanical stimulation of chondrocyte proliferation and gene expression. Thus, pericellular matrilins may play a role in chondrocyte mechanotransduction. Introduction: Chondrocytes reside in a capsule of pericellular matrix (chondron), which has been hypothesized to play a critical role in transducing mechanical signals to the cell. In this study, we test the hypothesis that the levels of matrilin (MATN)-1 and -3, major components of the chondrocyte pericellular matrix network, regulate activation of chondrocyte proliferation and differentiation by cyclic load–induced matrix deformation. Materials and Methods: Functional matrilins were decreased by expressing a dominant negative mini-MATN in primary chondrocytes or by using MATN1-null chondrocytes. The abundance of matrilins was also increased by expressing a wildtype MATN1 or MATN3 in chondrocytes. Chondrocytes were cultured in a 3D sponge subjected to cyclic deformation at 1 Hz. Chondrocyte gene expression was quantified by real-time RT-PCR and by Western blot analysis. Matrilin pericellular matrix assembly was examined by immunocytochemistry. Results: Elimination of functional matrilins from pericellular matrix abrogated mechanical activation of Indian hedgehog signaling and abolished mechanical stimulation of chondrocyte proliferation and differentiation. Excessive or reduced matrilin content decreased mechanical response of chondrocytes. Conclusions: Normal content of matrilins is essential to optimal activation of chondrocytes by mechanical signals. Our data suggest that the sensitivity of chondrocytes to the changes in the microenvironment can be adjusted by altering the content of matrilins in pericellular matrix. This finding supports a critical role of pericellular matrix in chondrocyte mechano-transduction and has important implications in cartilage tissue engineering and mechanical adaptation.

The chondrocytes of cartilage have so far been reported to include three mechanoresponsive genes: cartilage matrix protein (CMP, matrilin-1), type X collagen, and Indian hedgehog (Ihh). In fact, all of the genes identified in these chondrocytes are associated solely with mechanical stress. In this study we examined the how mechanical stress influenced the patterns of gene expression of chondrocytes in three-dimensional (3D) sponges in order to better understand the mechanisms that control the chondrocyte phenotype during the development of osteoarthritis. We cultured mouse chondrocytes in 3D sponge as a model of mechanical stress and isolated total RNA for a large-scale DNA microarray analysis covering 12,000 genes. We analyzed the pattern of gene expression in relation to gene localization in cellular components such as the cytoplasm, cytoskeleton, and nucleus. Immunoblotting of osteoarthritis cartilage were performed using polyclonal anti-clock antibody. The biological rhythm of mRNA of clock and clock-related genes was analyzed by real-time polymerase chain reaction (PCR). Clock gene was confirmed by real-time PCR to validate the microarray data. Other clock-related genes such as Per1 and Per2 were also expressed in chondrocytes, exhibiting biological rhythm after serum shock. The large-scale DNA microarray indicated that clock and other genes functionally associated with mechanical stress play an essential role in regulating the biological rhythm of chondrocyte metabolism in osteoarthritis cartilage.

Aims: The aim of this study was to determine which matrix metalloproteinases (MMPs) are involved with C-reactive protein (CRP) and which stage of rheumatoid arthritis (RA) correlated with MMP-9 or MMP-13 level. Methods: In the present clinical trial, we analysed MMP-9 activity and MMP-13 activity in 53 RA patients. We examined the presence of MMP-9 and MMP-13 in the synovium tissue and articular cartilage in RA patients by immunohistochemistry. In addition, we compared these factors and clinical Steinbrocker staging. Results: We found that MMP-9 in blood serum correlates significantly with CRP. MMP-13 also correlates with CRP but the coefficiency with CRP is much higher in MMP-9 (r = 0.6694) than in MMP-13 (r = 0.4037). MMP-9 and MMP-13 did not correlated with rheumatoid factor (RF). MMP-9 level is increased in stages II and III in RA. On the other hand, MMP-13 is increased in stages III and IV. Our results indicated that early stage RA shows high MMP-9 release in serum while late stage RA shows high MMP-13 release. Conclusion: MMP-9 activity may correlate with synovium proliferation with vascularization, and serum MMP-13 activity may correlate with the grade of joint destruction in rheumatoid arthritis.

Aims: To investigate the efficacy and safety of leflunomide, including the side-effects, we assessed 84 rheumatoid arthritis (RA) patients who received leflunomide treatment. Methods: We analyzed the C-reactive protein (CRP), white blood cell count (WBC), KL-6, and visual analogue scale (VAS) scores, modified Stanford Health Assessment Questionnaire (MHAQ) score, American Rheumatism Association score (ACR20 and ACR50) within a time course after treatment with leflunomide. We treated 84 RA patients, 12 male and 72 female from 28 to 81-years-old, with an average age of 63.5 years. The patients were divided into three groups: a group consisting of 38 patients who received 100 mg/day of leflunomide for 3 days followed by 20 mg/day thereafter; a second group of 11 patients who received a no-loading dose of 10 mg/day; and a third group of 35 patients who received a no loading dose of 20 mg/day. Results: The 50% decrease of CRP seen in 2 weeks was 52% of the total of 84 patients. The WBC score did not change significantly after the medication was given. The KL-6 score did not change significantly, either. The VAS pain score improved 4 weeks later, and then further improved 8 weeks later. Therefore, RA patients using leflunomide obtained pain relief 4 weeks after commencing medication. The MHAQ score did not change significantly until 8 weeks after the patients started the medication. ACR20 was 62% and ACR50 was 38% at 8 weeks after treatment. The side-effects of leflunomide observed in our patients were rash, respiratory infection, diarrhea, nausea, alopecia, muscle pain, headache, dizziness and general fatigue. Twenty-three out of 84 patients experienced side-effects (27%), and 48/84 (57%) experienced withdrawal. In our hospital, there were no patients who developed severe interstitial pneumonia (IP) or who died after taking leflunomide; however, the incidence of side-effects of the 100 mg/day loading dose (42.1%) was 2.5 times higher than in the patients who received 20 mg/day (17.1%) of a no-loading dose. Conclusion: Because of this, it is possible that a 100 mg/day loading dose is a relatively high risk dose in terms of causing side-effects, especially for severely ill RA patients with a high CRP level.

In terms of the relationship between synovial inflammation and radiographic changes, including both joint damage repair and progression,1 in rheumatoid arthritis (RA), pre-existing joint damage and persistent synovitis may promote joint destruction, while in the absence of synovitis, damaged joints may heal.2 ,3 Although presentation of radiographic results using cumulative probability plots has substantially improved understanding of clinical trial data,4 the effects of treatments on radiographic progression and improvement (regression) in individual RA patients has not yet been fully explained. In the JESMR study,5 ,6 151 active RA patients unresponsive to treatment with methotrexate (MTX) were randomised into 1 of 2 treatment groups: etanercept (ETN) 50 mg/week with 6–8 mg/week of MTX (the E+M group), or ETN alone (the E group). Radiographs of the hands and feet before ETN (baseline) and during the first year of treatment were available from 53 (72%) and 68 (88%) patients in the E and E+M groups, respectively. Baseline characteristics of patients were comparable between those with and without available radiographic data in each treatment group (data not shown). However, most patients without data did not complete the study up to Week 52 as per protocol, chiefly due to lack of efficacy in the E group.6 The mean baseline total Sharp-van der Heijde score (TSS)7 was 114.5 in the E group and 113.1 in the E+M …

In order to investigate the predictive factors related to clinical efficacy and radiographic progression at 24 weeks by looking at the serum levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 including baseline characteristics in patients with rheumatoid arthritis (RA) treated with golimumab, serum concentrations of TNF-α and IL-6 were analyzed every 4 weeks up to 24 weeks in 47 patients treated with golimumab. Baseline levels of the Disease Activity Score 28 C-reactive protein (DAS28-CRP) and Simplified Disease Activity Index (SDAI) scores were also assessed. Radiographic progression using the van der Heijde-modified Sharp (vdH-S) score was assessed in 29 patients. Multiple regression analyses related to the DAS28-CRP score and delta total sharp score at 24 weeks was undertaken using the baseline characteristics of patients and serum concentrations of matrix metalloproteinase (MMP)-3, TNF-α, and IL–6. The DAS28-CRP score and SDAI decreased significantly at 4 weeks up to 24 weeks compared with baseline. Serum levels of TNF-α were not changed significantly up to 24 weeks compared with baseline, but those of IL-6 decreased significantly at 4 weeks up to 8 weeks. Multiple regression analyses showed that disease duration and serum levels of MMP-3 were related significantly to the DAS28-CRP score at 24 weeks. Radiographic progression was related significantly to disease duration with regard to joint space narrowing and bone erosion. However, serum levels of TNF-α and IL-6 were not correlated significantly with the DAS28-CRP score and radiographic progression. These data suggest that decreasing serum levels of IL-6 significantly, MMP-3, and disease duration are predictive factors for RA activity in patients taking golimumab.

Objective The chemokine family of secreted proteins regulates cellular activities through interaction with G protein-coupled chemokine receptors. The aim of this study was to analyze the role of a chemokine stromal cell-derived factor 1 (SDF-1) and its receptor CXCR4 in rheumatoid arthritis (RA) and osteoarthritis (OA) by examining their gene expression in joint cartilage and synovium and by determining the effect of their interaction on the release of matrix metalloproteases (MMPs) from chondrocytes. Methods SDF-1 protein levels in synovial fluid from the knee joints of 58 RA patients, 55 OA patients, and 60 control patients without arthritis were quantified by enzyme-linked immunosorbent assay. SDF-1 and CXCR4 messenger RNA (mRNA) levels in chondrocytes and synovial fibroblasts were determined by reverse transcriptase-polymerase chain reaction. Isolated human chondrocytes were stimulated with 100 ng/ml of SDF-1, and the response was analyzed by quantifying the release of MMPs 1 and 3. Results We found that the concentration of SDF-1 in synovial fluid increased 3.57-fold in OA patients and 10.71-fold in RA patients compared with normal controls. The source of SDF-1 in synovial fluid was synovium, since SDF-1 mRNA was synthesized by synovial fibroblasts but not by chondrocytes. Conversely, CXCR4 was expressed by chondrocytes but not by synovial fibroblasts. The interaction of SDF-1, which was abundant in synovial fluid from RA and OA patients, with CXCR4-positive chondrocytes resulted in a specific elevation of the release of the cartilage matrix-degrading enzyme MMP-3 (stromelysin 1). Conclusion Our findings suggest a novel mechanism by which synovial cells induce degradation of cartilage matrix through SDF-1 signaling in RA and OA.

Shoulder synovectomy is a well-known surgical treatment for rheumatoid arthritis. However, synovectomy alone is insufficient for improving range of motion clinically. We investigated the clinical factors related to the efficacy of shoulder synovectomy performed with capsular release in patients with rheumatoid arthritis. Fifty-four shoulders of 54 patients (12 males, 42 females; mean age 53.3 years) with rheumatoid arthritis were treated by synovectomy plus capsular release. The patients had a mean disease duration of 8.33 years, a mean follow-up period of 5.02 years, and 66.7% received biological treatment. The disease activity score 28 using C-reactive protein, range of motion of the shoulder, and Japanese Orthopaedic Association (JOA) score assessment were used to investigate clinical factors, analyzed by multiple regression analysis, associated with improved outcome. The average disease activity score 28 using C-reactive protein and JOA score improved significantly from 4.29 and 36.7 to 3.11 and 84.6, respectively, with the restoration of range of motion. Multiple regression analysis showed that disease duration and prednisolone were significantly associated with flexion degree and JOA score. Larsen grade and JOA score were not correlated significantly. There was no significant difference in the JOA score between the groups with or without biological medicinal treatment. Shoulder arthroscopic synovectomy performed with capsular release with or without biological treatment effectively improved function. Short disease duration and low prednisolone dose in rheumatoid arthritis were important for prediction of efficacy.

Background The chemokine receptors (CKRs), mainly CCR5 and CXCR4 function as major coreceptors in infections caused by human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). Approximately 20 G protein-coupled receptors (GPCRs) have been identified as minor coreceptors, alike CCR6 that we reported recently. Since CKR-L3 is indentified as a natural isoform of CCR6, we attempted in this study to explore the coreceptor function of CKR-L3. Methods NP-2 cells transduced with CD4-receptor (NP-2/CD4) normally remain resistant to HIV or SIV infection. However, the introduction of functional coreceptors can make these cells susceptible to these viruses. NP-2/CD4/CKR-L3 cells were produced to examine the coreceptor activity of CKR-L3. Likely, CCR6-isoform and the major coreceptors, CCR5 and CXCR4 were also examined in parallel. Presence of viral antigen in infected NP-2/CD4/coreceptor cells was detected by indirect immunofluorescence assay (IFA). The results were validated by detection of syncytia, proviral DNA and by measuring reverse transcriptase (RT) activities. Results HIV-2MIR and SIVsmE660 were found to infect NP-2/CD4/CKR-L3 cells, indicative of the coreceptor function of CKR-L3. Viral antigens appeared faster in NP-2/CD4/CKR-L3 cells than in NP-2/CD4/CCR6, indicating that CKR-L3 is a more efficient coreceptor. Moreover, syncytia formation was more rapid and RT release evidenced earlier and at higher levels with CKR-L3 than with CCR6. Sequence analysis in the C2-V3 envelope region of HIV-2MIR replicated through CKR-L3 and CCR6 coreceptor showed two and three amino acid substitutions respectively, in the C2 region compared to the CCR5-variant. The SIVsmE660-CKRL3 variant showed three amino acid substitutions in the V1 region, one change in the V2 and two changes in the C2 region. The SIVsmE660-CCR6 variant produced two changes in the V1 region, and three in the C2 region. Conclusions Isoform CKR-L3 exhibited coreceptor activity for limited primary HIV and SIV isolates with better efficiency than the parent CCR6-isoform. Amino acid substitutions in the envelope region of these viruses may confer selective pressure towards CKR-L3-use. CKR-L3 with other minor coreceptors may contribute to HIV and SIV pathogenesis including dissemination, trafficking and latency especially when major coreceptors become compromised. However, further works will be required to determine its clinical significance in HIV and SIV infection.

More than 10 G protein-coupled receptors (GPCRs) have been shown to act as coreceptors for infection of human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus (SIV). We have isolated HIV-1 variants infectious to primary brain-derived CD4-positive cells (BT-3 and BT-20/N) and U87/CD4 glioma cells that are resistant to T-cell line-tropic (T-tropic), macrophage-tropic (M-tropic), and T- and M-tropic (dualtropic) (X4, R5, and R5X4) HIV-1 strains. These primary brain-derived cells were also highly susceptible to HIV-2 ROD , HIV-2 SBL6669 , and SIV mndGB-1 . A factor or coreceptor that determines the susceptibility of these brain-derived cells to these HIV and SIV strains has not been fully identified. To identify this coreceptor, we examined amino acid sequences of all known HIV and SIV coreceptors and noticed that tyrosine residues are well conserved in their extracellular amino-terminal domains. By this criterion, we selected 18 GPCRs as candidates of coreceptors for HIV and SIV strains infectious to these brain-derived cells. mRNA expression of an orphan GPCR, RDC1, was detected in the brain-derived cells, the C8166 T-cell line, and peripheral blood lymphocytes, all of which are susceptible to HIV-1 variants, but not in macrophages, which are resistant to them. When a CD4-expressing cell line, NP-2/CD4, which shows strict resistance to infection not only with HIV-1 but also with HIV-2 or SIV, was transduced with the RDC1 gene, the cells became highly susceptible to HIV-2 and SIV mnd strains but to neither M- nor T-tropic HIV-1 strains. The cells also acquired a low susceptibility to the HIV-1 variants. These findings indicate that RDC1 is a novel coreceptor for several HIV-1, HIV-2, and SIV strains which infect brain-derived cells.

This case report describes arthroscopic findings of the effect on articular distraction of ankle joint by means of external fixator for the patient with chondrolysis. Arthroscopy showed fibrocartilage tissue lying between the talus and tibia to protect damaged articular surfaces although apparent repair of surface cartilage failed to find.

Objective To investigate the long-term efficacy of rehabilitation following arthroscopic synovectomy in patients with rheumatoid arthritis treated with biologic agents. Methods Arthroscopic synovectomy was performed in 29 joints of 17 patients, which were divided into two groups. Group 1 included arthroscopic synovectomy plus rehabilitation for 19 joints in 10 patients, and group 2 included arthroscopic synovectomy without rehabilitation for 10 joints in 7 patients. The Disease Activity Score C-reactive protein (DAS28-CRP), Health Assessment Questionnaire-Disability Index (HAQ-DI), and Functional Independence Measure (FIM) values (motor subscale) at 9.7 years after arthroscopic synovectomy were evaluated to identify the clinical factors related to outcomes. Results The increase in FIM score was significant in group 1 (p=0.05). HAQ-DI at 9 years was significantly decreased in group 1 (p=0.02). Therefore, arthroscopic synovectomy with rehabilitation was significant in improving FIM and HAQ-DI scores over a long period. Multiple regression analysis of FIM scores at 9 years indicated that rehabilitation (p=0.03) and disease duration (p=0.02) were significantly related to outcomes. FIM score at 9 years was significantly negatively correlated with disease duration (p=0.01, r=-0.58, Y=88.89-0.21X). Conclusion Rehabilitation following arthroscopic synovectomy was effective in achieving high FIM scores over time in patients with rheumatoid arthritis.

Background There is no investigation of large joint destruction treated with golimumab in rheumatoid arthritis. Especially what clinical factors related to the inhibition of large joint destruction was not reported so far. Objectives In order to investigate the inhibition of large joint destruction for rherumatoid arthritis in treated with golimumab, 450 large joints were assessed at baseline and 52 weeks after treatment with golimumab. Methods 450 large joints from 45 patients including elbow, shoulder, hip, knee and ankle by using ARASHI (Assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging) scoring system (1) at baseline and 52 weeks after treatment with golimumab. Baseline data were mean age of 61.29±14.71 years, 91.1% of female, mean disease duration of 12.6±12.48 years, stage/class of I:7,II:10,III:9:,IV:19/2:18,3:26,4:1, mean MTX of 6.44±1.78 mg/weeks, mean PSL of 1.078±1.871 mg/day, 44.4% of 100 mg for golimumab, mean DAS28 (CRP) of 4.431±1.044. Rapid radiographic progression (RRP) and rapid radiographic improvement (RRI) were calculated and analysis of correlation for large joint destruction and clinical factors between baseline and 52 weeks. Results RRP was 21.9% in 450 large joints treated with golimumab. Therefore 78.1% were inhibited large joint destruction treated with goimumab in RA. RRI was 35.7% showing large joint improvement were obtained by golimumab. In clinical factors, baseline CRP affects ARASHI change score of knee at 52 weeks after treatment of golimumab. Conclusions Inhibition of large joint destruction were obtained in 78.1% for the patients treated with golimumab in RA. References Kaneko A, et al. Development and validation of a new radiographic scoring system to evaluate bone and cartilage destruction and healing of large joints with rheumatoid arthritis: ARASHI (Assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging) study. Modern Rheumatology 23:1053–62, 2013. Disclosure of Interest None declared

To assess the reliability and sensitivity of a novel scoring method to evaluate the radiographic appearance of and longitudinal changes including joint remodeling in large joints with early and established rheumatoid arthritis (RA).The ARASHI study group devised new radiographic scoring systems (Status score; range 0-16 points, and Change score; range -11 to 12 points) for evaluation of large joints with RA. Radiographs showing anterior/posterior views of large joints (shoulder, elbow, hip, knee, and ankle joints) taken at two time points (mean interval 2.3 years) were collected from 25 patients with established RA (5 patients for each of the 5 joints, 50 films in total), and an additional 5 films of each joint with severe joint destruction were collected from 5 different sets of RA patients. After consensus on the definition of each component and reader training, images were evaluated using the Larsen's grading system and the ARASHI Status and Change score by 9 independent senior orthopedic surgeons. The reliability was estimated by intra-class correlation coefficients (ICCs) and measurement error by 95% confidence intervals of minimum detectable change (MDC95).ARASHI Status score and Change score significantly correlated with Larsen's grade (r = 0.89, P0.0001) and follow-up-baseline differences in Larsen's grade (r = 0.83, P0.0001), respectively. Inter-reader ICCs were very high for both Status score (0.88, 95% confidence interval [CI], 0.83-0.92, P0.001) and Change score (0.92, 95% CI, 0.87-0.96, P0.001). Intra-reader ICCs were also very high for both Status score (0.92, 95% CI, 0.71-0.98, P0.001) and Change score (0.97, 95% CI, 0.91-0.99, P0.001). The MDC95 for inter-reader agreement were 4.18 (25% of maximum obtainable score, MOS) and 4.99 (21% of MOS) for Status score and Change score, respectively. The MDC95 for intra-reader agreement was acceptable with 2.82 (17% of MOS) and 3.02 (13% of MOS) for Status score and Change score, respectively.The ARASHI scoring method showed good inter-/intra-reader reliability with high ICCs and acceptable MDC95 with respect to each large joint and the components of both Status and Change scores. The results suggest that the ARASHI scoring method might be useful for the assessment of status, as well as longitudinal monitoring of destruction and remodeling of large joints with RA.

The aim of this study was to investigate immunohistological changes in mitogen-activated protein kinases (MAPKs) in the synovium following treatment with golimumab, compared with methotrexate (MTX). We assessed synovial tissues for 13 different molecules to detect cytokine levels histologically from 10 methotrexate (MTX)-treated rheumatoid arthritis (RA) patients as controls and 10 golimumab plus MTX-treated RA patients. Synovium samples from both groups were assessed by hematoxylin and eosin (HE) staining and analyzed for expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), CD4 (T cells), CD8 (T cells), CD20 (B cells), CD68 (macrophages), receptor activator of nuclear (kappa) B ligand (RANKL), bromodeoxyuridine (BrdU), CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK (ERK1/ERK2), and phospho-c-Jun N-terminal kinase (JNK), by an immunohistological examination. HE staining showed that there was a significant decrease in cell proliferation in the synovium in RA patients who received golimumab compared with the controls. TNF-α, IL-6, MMP3, BrdU, p38, and ERK were not seen at significant levels in either group. On the other hand, CD4, CD8, CD20, CD29, CD68, RANKL, and JNK were significantly decreased in the golimumab group compared with the control. Based on a histological analysis of the synovium, it appears that the efficacy of the treatment with golimumab may involve the inhibition of cell proliferation, with decreases in T cells, B cells, macrophages, β-1 integrin, RANKL, and JNK in the synovium, compared with MTX treatment, in RA.

Preincubation of Dunn osteosarcoma cells for 1 h with both 100 nM of staurosporine and 10 μg/ml of genistein resulted in a significant decrease in the motility stimulated by autocrine motility factor (AMF), whereas these reagents did not affect the basal motility and proliferation at these concentrations. The effect of the agents on the stimulated motility was both dose- and time-dependent. The motility stimulated by the anti-AMF receptor mAb was also inhibited. In contrast, H-8 had a negligible effect upon the stimulated motility. These data suggest that both kinase C and tyrosine kinase play a role in AMF-stimulated cell motility, while protein kinase A, which is selectively associated with the adenylate cyclase pathway, may not be required for the stimulation.

To determine what clinical factors relating to efficacy besides complications of orthopedic surgery for patients treated with anti-tumor necrosis factor (TNF)-α therapy (infliximab), we analyzed the clinical data of 52 cases of orthopedic surgery, such as total hip arthroplasy (THA), total knee arthroplasty (TKA), total shoulder arthroplasy (TSA), total elbow arthroplasty (TEA), arthroscopic synovectomy, foot arthroplasty, spine surgery, hand surgery and fracture.We analyzed clinical factors including age, disease duration, preoperative C-reactive protein (CRP), disease activity score (DAS)-28, matrix metalloproteinase (MMP)-3, and rheumatoid arthritis particle-agglutination (RAPA) in 52 cases of rheumatoid arthritis (RA) undergoing orthopedic surgery. For complications of orthopedic surgery, signs of postoperative infection were recorded, including rubor, discharge, systemic infection and frequencies of wound dehiscence, as well as the incidence of any surgical complication requiring a secondary revision procedure were measured.Signs of infection or surgical complications occurred in two of 52 patients (3.8%). There is significant correlation between RAPA and improvement of CRP 3 months after surgery; however, there is no correlation between infection and clinical factors including age, disease duration, preoperative CRP, MMP-3, RAPA and the period until surgery after infliximab infusion.Infliximab did not increase the risk of either infections or surgical complications occurring in patients with RA within 1 year of orthopedic surgery. Improvement of CRP after surgery is likely to be due to infliximab for high RAPA in RA patients.

Aims: In order to investigate the histological change in effect attenuation cases of etanercept compared with methotrexate (MTX), we performed immunohistochemical examination by seven different molecules. Methods: We histologically assessed synovial tissue from five MTX-treated rheumatoid arthritis (RA) patients as control and six etanercept and MTX-treated RA patients after synovectomy by arthroscopy. The synovium of both groups were assessed by hematoxylin and eosin (HE) and we also analysed the expression of tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), matrix metalloproteinase-3 (MMP-3), B-cell precursors and mature B-cell transmembrane protein, CD20, macrophage marker, CD68, bromodeoxyuridine (BrdU) and vascular endothelial growth factor (VEGF) by immunohistochemistry. Results: HE staining showed vascular and cell proliferations of the synovium of the RA patients who received etanercept compared with the control MTX group. TNF-α and IL-6 were expressed in both groups.MMP-3 and CD68 expressed less significantly in the etanercept group compared with the control (P

Mitogen-activated protein (MAP) kinases are well-known molecules that play key roles in mechanical stress signals during skeletal development. To test our hypothesis that the synovium in frozen shoulders is induced by MAP kinases, immunohistochemical analyses for detecting expression and signal transduction of MAP kinases were performed in synovial tissue obtained from the rotator interval (RI) in frozen shoulders.Synovial tissues were examined from 10 frozen shoulder patients with a mean age of 55.4 years (46-62 years). Synovial tissues between the long head of the biceps tendon (LHB) and the RI in frozen shoulders were stained with hematoxylin and eosin (HE) and then examined with immunohistochemical staining. Extracellular signal-regulated (ERK), the Jun N-terminal (JNK), and p38 mitogen-activated protein (MAP) kinases, nuclear factor kappaB (NF-kappaB), p50, CD29 (beta(1)-integrin), matrix metalloproteinase (MMP)-3, interleukin-6 (IL-6), CD56, CD68, S-100, and vascular endothelial growth factor (VEGF) were analyzed to detect expression patterns.HE showed vascular proliferation with fibrin and fibrous tissue in the synovium of frozen shoulders. ERK was expressed in the epithelial cells of vascular tissue, and JNK was expressed strongly in the interstitial cells around vascular tissue; p38 MAPK was not expressed. NF-kappaB was expressed in vascular tissue, and IL-6 was expressed around vascular tissue. CD29 (beta1-integrin) was expressed in vascular tissue and in superficial cells of synovial tissue. MMP-3 and VEGF were expressed on the surface layer of synovial tissue and vascular tissue, and CD68 was expressed on the surface layer. Nerve-related proteins, CD56 and S-100, were expressed weakly.Mechanical stress on the LHB and RI in the shoulder may induce ERK and JNK to express NF-kappaB by CD29 to develop capsule contracture, producing MMP-3, IL-6, and VEGF.

Background Tight control of severe rheumatoid arthritis (RA) in patients with high disease activity, even when using biologics, is sometimes difficult using a treat-to-target strategy. Switching from one biologic to another is associated with lower efficacy than that in treatment-naive cases. We developed the K-method that involves simultaneous treatment with golimumab and intra-articular joint injection of triamcinolone acetonide (TA) in patients undergoing switching of biologics. We performed this retrospective case–control study to investigate the efficacy of achieving an immediate treatment response using the K-method. Methods This study involved 20 patients with RA (control group, 10 patients; K-method group, 10 patients). Patients in the control group were switched to golimumab from other biologics without intra-articular injection of TA. The K-method involved injection of 1 mL of TA (40 mg/mL) and 2 mL of 1% lidocaine hydrochloride into swollen or painful joints on the same day as golimumab treatment. A quick response one day after treatment was compared between the two groups according to the disease activity score 28 based on C-reactive protein (DAS28 CRP), clinical disease activity index (CDAI), simplified disease activity index (SDAI), European League Against Rheumatism (EULAR) response, and remission rate. These parameters were investigated for 24 weeks. Results The K-method group showed significant improvements in DAS28 CRP, CDAI, and SDAI at one day, 12 weeks, and 24 weeks compared with the control group. The number of swollen and tender joints and the patient and doctor global visual analog scale scores were also significantly different between the two groups. The remission rates based on DAS28 CRP were 30% at one day, 50% at 12 weeks, and 60% at 24 weeks in the K-method group. The EULAR good/moderate response rates were 80% at one day, 90% at 12 weeks, and 90% at 24 weeks in the K-method group; however, these rates were only 10%, 40%, and 40%, respectively, in the control group. No adverse events occurred in either group. Conclusion Simultaneous treatment with biologics and intra-articular injection of TA is useful for cases involving switching of biologics for RA. This strategy is safe and practical for RA treatment.

The aim of this study was to analyze the histological changes related to mitogen-activated protein (MAP) kinases in bone and cartilage treated with abatacept for rheumatoid arthritis (RA). A total of 20 patients of bone and cartilage were assessed: 10 abatacept with methotrexate (MTX)-treated RA patients were compared with 10 MTX-treated RA patients (control). The histology of bone and cartilage was observed by staining with hematoxylin and eosin and analyzed immunohistochemically for the expression of tumor necrosis factor-α, interleukin-6, CD4 (T cell), CD68 (macrophage), receptor activator of nuclear kappa-B ligand, osteoprotegerin, osteopontin, CD29 (β-1 integrin), phospho-p38 MAPK (Tyr180/Tyr182), phospho-p44/42 MAPK (extracellular signal-regulated kinase, ERK1/ERK2), and phosphor-c-Jun N-terminal kinase. The expressions of CD29 known as mechanoreceptor and ERK known as mechanotransduction signal protein in MAP kinases in the bone and cartilage of patients treated with abatacept were significantly different from those of control. These findings suggest that increases in CD29 and ERK in MAP kinases may change the metabolism of bone and cartilage in RA patients treated with abatacept.

The von Willebrand Factor A (vWF A) domain is one of the most widely distributed structural modules in cell-matrix adhesive molecules such as intergrins and extracellular matrix proteins. Mutations in the vWF A domain of matrilin-3 cause multiple epiphyseal dysplasia (MED), however the pathological mechanism remains to be determined. Previously we showed that the vWF A domain in matrilin-1 mediates formation of a filamentous matrix network through metal-ion dependent adhesion sites in the domain. Here we show two new functions of the vWF A domain in cartilage-specific matrilins (1 and 3). First, vWF A domain regulates oligomerization of matrilins. Insertion of a vWF A domain into matrilin-3 converts the formation of a mixture of matrilin-3 tetramer, trimer, and dimer into a tetramer only, while deletion of a vWF A domain from matrilin-1 converts the formation of the native matrilin-1 trimer into a mixture of trimer and dimer. Second, the vWF A domain protects matrilin-1 from proteolysis. We identified a latent proteolytic site next to the vWF A2 domain in matrilin-1, which is sensitive to the inhibitors of matrix proteases. Deletion of the abutting vWF A domain results in degradation of matrilin-1, presumably by exposing the adjacent proteolytic site. In addition, we also confirmed the vWF A domain is vital for the secretion of matrilin-3. Secretion of the mutant matrilin-3 harbouring a point mutation within the vWF A domain, as occurred in MED patients, is markedly reduced and delayed, resulting from intracellular retention of the mutant matrilin-3. Taken together, our data suggest that different mutations/deletions of the vWF A domain in matrilins may lead to distinct pathological mechanisms due to the multiple functions of the vWF A domain.

To investigate histological evidence of bone remodeling in response to infliximab for rheumatoid arthritis (RA), bone marrow tissues were extracted from ten RA patients at the time of total knee arthroplasty after treatment of infliximab for an average of 16 months (range, 8-24 months). The patients had a mean age of 65.3 years (range, 57-76 years) with 4.8 mg/week of methotrexate (MTX; 4-6 mg) and 3.8 mg/day of prednisolone (2-5 mg). Control samples were obtained from ten RA patients who did not undergo infliximab therapy. These patients had an average age of 67.6 years (range, 59-78 years) and received 5.2 mg/week of MTX (4-6 mg) and 4.0 mg/day of prednisolone (2-5 mg). Histological examination of structural differences between the infliximab and control groups in bone marrow was performed using hematoxylin and eosin (HE) to evaluate differences. In immunohistochemical examination, the expressions of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), receptor activator of nuclear (kappa) B ligand (RANKL), osteoprotegerin (OPG), and osteopontin (OPN) were compared between both groups. HE staining revealed that the bone marrow tissues of the RA patients who underwent infliximab therapy demonstrated newly formed thickness of interstitial septum among the trabeculae as compared with the control group. Moreover, immunohistochemical examinations revealed that TNF-alpha, IL-6, RANKL, OPG, and OPN were expressed in this newly formed bone after infliximab therapy. Therefore, treatment with infliximab improved the histological changes with respect to bone metabolism in the newly formed bone marrow tissues.

Repair of bone and articular destruction in rheumatoid arthritis (RA) is major problem to treat RA patients recently. However bone destruction starts in early phase of disease duration in RA. Histological meta-analysis of synovium is one of a key to solve the problem in RA. We investigated synovial histology about five factors including synovial proliferation, pillonodular synovium, vascular proliferation, and fibrin deposit and lymphocyte infiltration. Disease duration and pilonodular synovium has significant correlation by multiple regression analysis (p = 0.018). Therefore pillonodular synovium is important to decrease bone destruction in RA. It is possible that biological treatment for RA is effective to bone and cartilage metabolism, however some cases do not improve bone metabolism. Further investigation needs to analyze the factors of efficacy of bone and cartilage metabolism.

The joint dysfunction caused by bone and articular destruction is the most important pathology in rheumatoid arthritis (RA) patients. The progression of bone and articular destruction starts within five years from disease onset, however depending each case inflammation. Quality of life (QOL) of RA patients needs early stage treatment to prevent joint destruction. We recognized villonodular synovial proliferation is significantly correlated with early stage RA. Therefore to decrease those synovium leads to prevent joint destruction. Biological therapy itself can not inhibit villonodular synovial proliferation in effect attenuation cases. Arthroscopical synovectomy is effective to remove those synovium and restore the effect of biological therapy. It is needed that detail analysis of improvement of joint destruction by biological therapy near future to lead the improvement QOL of RA patients.

Background Health Assessment Questionnaire (HAQ) is often used to assess functional disabilities, and is closely associated with disease activity and radiographic joint damage in patients with rheumatoid arthritis (RA) 1 . Joint range of motion (ROM) is also affected by inflammation and joint destruction in RA. However, the relationship between HAQ and large joint ROM still remains. Objectives To examine the association of HAQ with clinical parameters including ROM of large joints in patients with RA. Methods We have examined 62 patients with RA that were resistant to disease-modifying anti-rheumatic drugs (DMARDs). The mean age was 58.7 years and mean disease duration was 10.2 years. We measured ROM of cervical spine and large joints (bilateral shoulder, elbow, hip, knee and ankle joints), CRP, MMP-3 DAS28-ESR, SDAI, CDAI, degree of large joint damage (ARASHI status score 2 and HAQ. Correlations of parameters were estimated by Spearman9s rank correlation coefficient. Differences were considered significant if two-sided P-values were Results HAQ was well correlated with DAS28-ESR, SDAI and CDAI as expected. HAQ was not correlated with total ARASHI status score. However, HAQ was significantly correlated with shoulder flexion (r=0.38, P Conclusions We showed that HAQ was associated with ROM of large joint in patients with RA. Specifically, shoulder, elbow and ankle plantar flexion were important determinants of HAQ and, therefore, should be monitored to guide treatment. References Drossaers-Bal KW, et al. Arthritis Rheum. 1999; 42; 1854-1860. Kaneko A, Matsushita I, et al. Mod Rheumatol. 2013; 23; 1053-1062. Disclosure of Interest None declared