Induction of pulmonary thromboembolism by neutrophil elastase in collagen-induced arthritis mice and effect of recombinant human soluble thrombomodulin.

We previously reported that during total knee arthroplasty in rheumatoid arthritis (RA) patients, the use of tourniquet might promote local release of neutrophil elastase (NE) from neutrophils, which may contribute to the development of pulmonary thromboembolism (PTE) and tissue injury. The aim of this study was to develop PTE by the use of NE in a mouse model of collagen-induced arthritis (CIA) and investigate the relationship between thrombus and endothelial cells as well as the effect of recombinant human soluble thrombomodulin (rhs-TM) in reducing the risk of PTE. Male DBA/1J mice were injected intracutaneously at several sites with an emulsion containing bovine collagen and later a booster shot to produce CIA mice. Subsequently, NE was injected intravenously 2 times a day for 3 days and after a further 4 days, mice were sacrificed. A group of mice received rhs-TM injections prior to NE injections. We divided the mice into four groups of normal, CIA control, CIA + NE, and CIA + rhs-TM + NE mice and evaluated thrombus formation status. All CIA + NE mice developed PTE. In contrast, no thrombosis was found in normal control, CIA control and CIA + rhs-TM + NE mice. Plasma thrombin level, fibrinogen expression and neutrophil count were increased in CIA + NE mice. Double staining for anticoagulant TM and procoagulant von Willebrand factor (vWF) in pulmonary endothelial cells in normal mice showed a TM-dominant expression while in both CIA control and CIA + NE mice a vWF-dominant expression compatible with coagulant status was observed. Injection of rhs-TM into CIA + NE mice resulted in a phenotypic conversion of endothelial cells from vWF-dominant to TM-dominant expression and a reduction in fibrinogen deposition. These findings demonstrate that by repeated use of NE in CIA mice, it is feasible to produce PTE and to study its pathogenesis and that rhs-TM reduces the risk of PTE. We suggest that in surgical operations of upper and lower extremities in RA patients, the use of a tourniquet should be avoided as it may trigger NE release.

Rapid destruction of the hip joint associated with enlarged iliopsoas bursa in a patient with refractory rheumatoid arthritis.

A case of refractory rheumatoid arthritis with a rapid destruction of the hip joint and an enlarged iliopsoas bursa is presented. Rapidly destructive coxarthrosis, chondrocalcinosis, suppurative arthritis, and pigmented villonodular synovitis were the differential diagnoses. Radiological examination showed that rheumatoid arthritis was most likely diagnosis. The patient was treated with total hip arthroplasty and etanercept, with good results.

Postoperative results and complications of total elbow arthroplasty in patients with rheumatoid arthritis: three types of nonconstrained arthroplasty.

Postoperative results and complications of total elbow arthroplasty (TEA) conducted for rheumatoid arthritis (RA) patients at our institute were studied. Primary TEAs were performed in 72 patients. The mean follow-up period was 3.5 years. Three types of prostheses were implanted: JACE prosthesis in 34 elbows, STABLE prosthesis in 13 elbows, and KUDO prosthesis (type 5) in 32 elbows. The outcome was evaluated by the change in the range of motion and the Japanese Orthopaedic Association functional evaluation score for the elbow joint (JOA score). The arc of motion and the JOA score at discharge and at final examination significantly improved in patients with the three types of prosthesis. The loosening rates for the JACE, STABLE and KUDO prostheses were 15, 23, and 0%, respectively, although the follow-up periods were different. The loosening rate decreased to 2.5% when the humeral component was fixed with cement. Intraoperative fractures occurred in eight (10.1%) elbows and ulnar nerve palsy in six. Deep infection developed in three (4.8%) elbows and was treated by removing the prosthesis. Although there were considerable complications, the marked improvements in pain and function favor TEA in patients with rheumatoid elbow.

Critical roles of capillary endothelial cells for alveolar remodeling in nonspecific and usual interstitial pneumonias.

To characterize the relationship between angiogenesis factors and alveolar remodeling in interstitial lung diseases, we examined alveolar capillary endothelial cells in the normal lung (n=5) and in lungs with nonspecific interstitial pneumonia (NSIP) (n=4) or usual interstitial pneumonia (UIP) (n=6) using immunofluorescence staining for thrombmodulin and von Willebrand factor (vWF). With three-dimensional images of alveolar capillaries, the diameter of capillary tubes and their branching frequency per unit length were determined to define rearrangement of the capillary meshwork. Alveolar capillary endothelial cells in normal lungs expressed surface thrombomodulin, and those in lungs with cellular NSIP often showed coexpression of surface thrombmodulin and cytoplasmic vWF. In the alveolar septa of fibrotic NSIP and UIP, capillary endothelial cells demonstrated vWF in only the cytoplasm. Capillary branching frequencies in NSIP and UIP were decreased to 45% and 22%, respectively, of the normal level (p<0.002). Compared with normal lungs, in NSIP and UIP lungs alveolar capillaries containing TUNEL-positive endothelial cells (p<0.05) showed increases of 3.6-fold and 4.3-fold, respectively, indicating a close correlation between endothelial cell apoptosis and remodeling of alveolar capillary frameworks. The analysis of mRNA expression of vascular endothelial growth factors (VEGF) and their receptors (VEGFR1 and VEGFR2) showed a significant decrease in each VEGF isoform and in VEGFR2 mRNA in representative alveolar wall tissues microdissected from the normal, NSIP, and UIP lungs. These results suggest that decreased expression of VEGF mRNA is associated with a reduction in the number of capillary tubes via endothelial cell apoptosis that possibly results in alveolar remodeling in NSIP and UIP. However, whether VEGF is related to fibroblastic activation in the interstitial matrix remains unclear.

Modeling and cost-effectiveness analysis of etanercept in adults with rheumatoid arthritis in Japan: a preliminary analysis.

The tumor necrosis factor (TNF) antagonist etanercept is an antirheumatic agent which was approved by Japanese regulatory authorities in January 2005. In Japan, the cost-effectiveness of this therapy for patients with rheumatoid arthritis (RA) has not previously been evaluated. This study models the cost-utility of etanercept in comparison with standard therapy with disease-modifying antirheumatic drugs (DMARDs) among adult Japanese RA patients who have failed a previous course of the DMARD bucillamine. A Markov model with 6-month cycles was constructed to compare two therapeutic strategies: etanercept versus standard therapy. For each cycle, one of three options was possible: a patient could (i) remain on current therapy if American College of Rheumatology criteria for 20% clinical improvement (ACR20) were achieved, (ii) switch to another drug in the therapeutic pathway if ACR20 was not achieved or if side effects severe enough to cause treatment discontinuation occurred, or (iii) they could die. The therapeutic pathway for the etanercept strategy was etanercept, methotrexate (MTX), sulfasalazine (SSZ), combination therapy (MTX + SSZ) and, finally, no DMARD. The pathway for standard therapy was identical except the initial therapy was MTX (etanercept was excluded). Results from clinical trials in U.S. and European patient populations were used to derive model probabilities for disease progression, response to drug therapy, and relationships between ACR20 response and functional improvement as measured by the Health Assessment Questionnaire (HAQ) disability index. An equation was developed to predict utility from HAQ scores of Japanese patients. Costs for drugs and medical services in Japan were obtained for April 2003. Analysis was conducted from a societal perspective, including lost productivity costs due to RA disability and premature mortality. Costs were discounted at 6% annually, and quality-adjusted life years (QALYs) at 1.5% annually. Model parameters were varied by 20% above and below base-case values in sensitivity analyses. Compared to standard therapy, the etanercept strategy was yen6.39 million more costly per patient but yielded an additional 2.56 QALYs. The incremental cost-utility ratio was yen 2.50 million/QALY. Sensitivity analyses revealed that cost-utility was most strongly influenced by the acquisition cost of etanercept and the percentage of etanercept recipients who achieved ACR20. Using commonly applied thresholds for acceptable cost-effectiveness in the United States ($50 000 = yen 5.5 million/QALY) and the United Kingdom (pound 30 000 = yen 5.7 million/QALY), etanercept therapy in Japan can be considered cost-effective. Cost-utility ratios did not exceed these thresholds in any sensitivity analysis. Further analyses should be conducted once clinical and epidemiologic data for Japanese patients become available.

Follow-up study of ankle arthrodesis in severe hind foot deformity in patients with rheumatoid arthritis using an intramedullary nail with fins.

We report herein a retrospective study of 25 cases of ankle arthrodesis performed in 23 patients with rheumatoid arthritis (RA) using an intramedullary nail with fins, developed in 1994. Surgical treatment, postoperative management, and clinical evaluation are described. Clinical evaluation, at an average follow-up period of 7 years 1 month, was based on foot disease scores from the Japanese Orthopedic Association; we compared these scores pre- and postoperatively, and during follow-up. These parameters showed a significant difference between preoperation and the follow-up period. However, instability only significantly improved when compared between pre- and postoperation. Arthrodesis using an intramedullary nail with fins was effective for the treatment of severe deformity of the hind foot. Nonunion was not observed and no remarkable changes of the Chopart joint were recognized between preoperation and the follow-up period. In our series, delayed wound healing was recognized in 6 of 25 joints. However, infection or neuropathy and other complications were not found. Arthrodesis using an intramedullary nail with fins is a viable treatment option for severe deformity of the hind foot in RA patients, because nonunion was not recognized and the clinical results over an average 7-year follow-up period were good or satisfactory.

Study of the mechanism involved in angiogenesis and synovial cell proliferation in human synovial tissues of patients with rheumatoid arthritis using SCID mice.

To examine whether synovial cell proliferation is due to angiogenesis, we studied the relationship between the inhibition of synovial cell proliferation and an angiogenesis inhibitor, TNP-470, in human synovial tissues. Human synovial tissues were implanted into the back of SCID mice (SCID-HuAg mice). Sixteen mice were divided into two groups of eight mice each: the untreated group (vehicle group) and the TNP-470-treated group that received a dose of 10 mg/kg body weight by subcutaneous injection. The number of blood vessels and synovial lining cells clearly increased in the vehicle group, but the number of synovial lining cells clearly decreased and the blood vessels were hardly detected in the TNP-470 group. Immunohistochemically, cells that stained positively for the anti-proliferating cell nuclear antigen (PCNA) mAb were abundant in synovial lining cells and endothelial cells in synovial tissues. Cells that stained positively for the anti-CD34 polyclonal antibody were abundant in the endothelial cells in the vehicle group, but these positively stained cells were hardly detected in the TNP-470 group. The PCNA positivity ratio in the vehicle group was 0.64 +/- 0.019, whereas that in the TNP-470 group was 0.199 +/- 0.007. The numbers of cells that stained positively for anti-CD34 polyclonal antibody were 242 +/- 13.4 in the vehicle group and 153 +/- 6.73 in the TNP-470 group per 10 microscopic fields. Cells that stained positively for anti-mouse CD31 mAb were mainly localized in the synovial lining, but invaded the subsynovial lining layer in human synovial tissues. On the other hand, cells that stained positively for anti-human CD31 mAb were mainly localized in the subsynovial lining layer. We found that endothelial cell proliferation is dependent on angiogenesis based on the result that angiogenesis and synovial cell proliferation were inhibited by treatment with TNP-470.