Junji Chiba

Isolation and characterization of wear particles generated in patients who have had failure of a hip arthroplasty without cement.

Wear particles from thirty-five membranes obtained during revision hip-replacement operations were studied after digestion of the soft tissue with papain. The particles were isolated and were characterized with use of light and scanning electron microscopic techniques, x-ray microanalysis, and an automated particle analyzer. The mean size of the polyethylene particles was 0.5 micrometer, and the metal particles were a mean of 0.7 micrometer, as determined with scanning electron microscopy. The automated particle analyzer revealed a mean particle diameter of 0.63 micrometer (more than 90 per cent of all particles were less than 0.95 micrometer) and a mean of 1.7 billion particles per gram of tissue, compared with only 143 million per gram of tissue for the control samples. X-ray microanalysis revealed metal debris in sixteen (46 per cent) of the thirty-five membranes after digestion. Thirteen (50 per cent) of the twenty-six membranes surrounding a titanium-alloy stem contained metal particles, compared with three of the nine membranes surrounding a chromium-cobalt stem. Metal debris was present in only one of the twelve membranes surrounding a titanium-alloy stem without a porous coating, compared with twelve of the fourteen membranes surrounding a titanium-alloy stem with a porous coating. This tenfold difference in prevalence was significant (p < 0.005). On the average, the total number of particles (expressed in millions per gram of tissue) associated with the bipolar acetabular components was twice that associated with the fixed acetabular components. In addition, there was a trend toward a larger mean size of the polyethylene particles in association with the bipolar cups. Our data indicate that particulate prosthetic debris in the tissues around failed femoral components that have been inserted without cement constitutes a class of particles that are predominantly less than one micrometer in size and are present in amounts of more than one billion particles per gram of tissue. Routine histological methods did not detect this class of wear debris and led to a gross underestimation of the amount of debris in these membranes.

Interleukin–6 and interleukin–8 levels in serum and synovial fluid of patients with osteoarthritis

Concentrations of interleukin (IL)-6 and IL-8 in serum and synovial fluid obtained from patients with osteoarthritis (OA) of the knee were determined by the chemiluminescence-ELISA (CL-ELISA) method, the sensitivity of which is 100-1,000 times greater than that of the conventional ELISA method. The results were compared with those obtained from patients with rheumatoid arthritis (RA) and from healthy subjects. The mean IL-6 and IL-8 levels in synovial fluid indicated higher concentrations in RA than in OA. The IL-6 and IL-8 levels in serum were significantly higher in RA and OA relative to controls. Among OA patients in whom remarkable improvement was noted in hydrarthrosis, the synovial fluid IL-6 and IL-8 levels at the initial examination were relatively higher, and were markedly decreased after treatment with sodium hyaluronate (NaHA). Among those in whom no improvement was noted in hydrarthrosis, the synovial fluid IL-6 and IL-8 levels at the time of initial examination were relatively lower, and hydrarthrosis was not significantly improved even after treatment with NaHA. In addition, there was a tendency for the synovial fluid IL-6 and IL-8 levels to decrease as HA levels increased. Evaluation of X-ray findings revealed that the IL-6 levels in synovial fluid at the initial examination in low-grade cases tended to be significantly higher than in high-grade cases. In low-grade cases, as determined by X-ray findings, there was a significant decrease in IL-6 levels in synovial fluid after treatment with NaHA.

A biochemical, histologic, and immunohistologic analysis of membranes obtained from failed cemented and cementless total knee arthroplasty.

Biochemical, histologic, and immunohistochemical analyses were performed on 34 interface membranes obtained from 33 patients during revision total knee arthroplasty. The membranes had surrounded components of cementless (n=11) and cemented (n=23) knee prostheses that were aseptically loose. None of these implant failures was caused by catastrophic polyethylene erosion leading to metal-to-metal contact. The histologic findings were similar in the membranes from cemented and cementless knee components: small polyethylene debris within macrophages and large birefringent polyethylene debris within foreign-body giant cells. Metallic debris was seen in membranes from both groups, but cemented membranes had more polymethylmethacrylate particles and more hyalinization

Hypoxia upregulates the expression of angiopoietin-like-4 in human articular chondrocytes: role of angiopoietin-like-4 in the expression of matrix metalloproteinases and cartilage degradation.

The objective of this article was to investigate the role and expression of a novel adipocytokine, angiopoietin‐like‐4 (ANGPTL4), in arthropathy. Human chondrocytes were obtained from articular cartilage of patients with rheumatoid arthritis (RA) and osteoarthritis (OA), who underwent total knee or hip arthroplasty. Isolated chondrocytes were cultured under hypoxic (95% N2, 5% CO2) or normoxic conditions. The effects of hypoxia on ANGPTL4 expression were determined by real‐time reverse transcription polymerase chain reaction and Western blot analysis. We examined the role of ANGPTL4 using small interference RNA or by stimulating chondrocytes with recombinant ANGPTL4 protein. ANGPTL4 expression in the articular cartilage specimens was examined by immunohistochemistry. Hypoxia induced a significant increase in ANGPTL4 production (p < 0.05). Incubation of chondrocytes in vitro with recombinant ANGPTL4 enhanced the expression of matrix metalloproteinase (MMP)‐1 and MMP‐3. Downregulation of ANGPTL4 mRNA expression by siRNA diminished the expression of MMP‐1, but not that of MMP‐3, suggesting that each proteinase has a distinct response to ANGPTL4. Although the in vitro responses of chondrocytes to hypoxia were similar between RA and OA samples, the in vivo expression of ANGPTL4 had unique disease‐specific patterns, suggesting differences in oxygen tension in vivo. Human chondrocytes expressed ANGPTL4 and the expression was enhanced by hypoxia. ANGPTL4 might modulate cartilage metabolism by regulating MMPs.

Clinical factors related to the efficacy and complications of orthopedic surgery for rheumatoid arthritis with infliximab

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.

Decrease of CD68 and MMP-3 expression in synovium by treatment of adalimumab for rheumatoid arthritis

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.

Histological analysis of synovium by treatment of etanercept for rheumatoid arthritis

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.

Application of a new immunohistology scoring system (IH score): analysis of TNF-α in synovium related to disease activity score in infliximab-treated patients with rheumatoid arthritis.

Abstract 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 with RA treated with infliximab.

Predictive Factors Related to the Efficacy of Golimumab in Patients with Rheumatoid Arthritis

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.

SDF-1 and CXCR4 in synovium are associated with disease activity and bone and joint destruction in patients with rheumatoid arthritis treated with golimumab

Abstract Objectives: 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. Methods: 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. Results: 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. Conclusions: Synovial SDF-1 correlated with disease activity, and its receptor CXCR4 was related to joint destruction in RA patients treated with golimumab.