Katsumitsu Arai

Risk factors for vertebral fracture in menopausal or postmenopausal Japanese women with rheumatoid arthritis: a cross-sectional and longitudinal study

The occurrence of vertebral fracture was examined cross-sectionally and longitudinally over a 4-year interval in 117 menopausal and postmenopausal Japanese women with rheumatoid arthritis (RA), whose ages ranged from 50 to 64 years. Patients treated with bisphosphonate were excluded. Vertebral fracture was diagnosed by lateral thoracic and lumbar spine radiography at the start and end of a 4-year period. Bone mineral density (BMD) at L2–L4 according to dual-energy X-ray absorptiometry (DXA), the administration of corticosteroids or methotrexate, and urinary excretion of N-telopeptide of type I collagen (NTx) were also recorded. In the cross-sectional study, the prevalence of vertebral fracture in the initial radiographs of RA patients was 21%, while it was 5% in healthy age-matched controls. Among RA patients treated with corticosteroids, 33% had vertebral fracture, which was a significantly higher prevalence than that in RA patients without steroid administration. In the longitudinal study, vertebral fracture prevalence was also increased in patients more than 60 years old. RA patients having steroid treatment and a BMD/YAM (young adult mean) ratio below 70% had higher risk of vertebral fracture than patients with a BMD/YAM ratio of 70%–80%, which in turn exceeded the risk with a BMD of 80% or more. No adverse effect of low-dose methotrexate on vertebral fracture was found. Urinary NTx was high in RA patients, as reported previously, and did not differ between patients with or without new fracture after 4 years. In conclusion, Japanese RA patients more than 60 years old who were treated with corticosteroid or had a BMD below 80% had high risk of vertebral fracture.

Histomorphometric assessment of bone changes in rats with type II collagen-induced arthritis

Numerous studies have demonstrated bone loss in rats following immobilization by tenotomy or nerve sectioning and following ovariectomy. However, few experiments have focused on bone change in rats with arthritis. We investigated bone loss in the proximal tibia and lumbar vertebra in rats with type II collagen-induced arthritis, an experimental model of rheumatoid arthritis, using histomorphometry. Bone loss in the early phase after immunization reflected a significant increase in numbers of osteoclasts and temporarily decreased bone formation. In the proximal tibia, near an arthritic joint, osteoclast numbers associated with bone trabeculae were increased four times over control numbers 4 weeks after immunization. In the lumbar vertebra, where arthritis was not shown, recruitment of osteoclasts occurred later than in the proximal tibia. With time, in both the proximal tibia and lumbar vertebra bone resorption normalized, but bone formation rate and double-label surface by tetracycline, a parameter reflecting bone formation, were increased above control values. We conclude that differences between the proximal tibia and lumbar vertebra probably reflected resumption of function as well as distance from areas of inflammation. These findings indicate that collagen-induced arthritis in rats is a useful model not only of autoimmunity, but also of juxta-articular and generalized osteoporosis in rheumatoid arthritis.

Mineral density and histomorphometric assessment of bone changes in the proximal tibia early after induction of type II collagen-induced arthritis in growing and mature rats

Abstract Bone changes in both actively growing (6-week-old) and mature (6-month-old) rats with collagen-induced arthritis (CIA) were investigated in order to clarify the mechanisms of osteoporosis near inflamed joints in patients with early rheumatoid arthritis (RA) and juvenile RA. In female Sprague-Dawley rats, the proximal tibiae from the CIA and control groups early after immunization, when any influence of immobilization due to joint pain and swelling is minimal, were studied using dual X-ray absorptiometry and histomorphometry after double-labeling with tetracycline. Arthritis developed within 10–14 days after immunization in both growing and mature rats. Physical activity, growth, and body weight continued to resemble that of the control group for at least 10 days. The bone mineral density in the proximal tibia did not differ significantly between the CIA and control groups. In growing rats, a highly significant increase in bone resorption, and decreases in bone formation and trabecular bone volume became evident histomorphometrically before visible signs of arthritis had developed. In mature rats, bone formation was markedly decreased without an increase in bone resorption. The differences in the reaction between growing and mature rats reflected a difference in the number of remodeling sites (units) and an uncoupling between osteoblasts and osteoclasts. We conclude that osteoporosis near inflamed joints results from an imbalance between bone resorption and formation caused by immune reactions in the CIA rats. Moreover, a decrease in bone formation may, in part, precede the clinical onset of arthritis.

A Similar Expression Pattern of Adhesion Molecules between Intermediate TCR Cells in the Liver and Intraepithelial Lymphocytes in the Intestine

Two major populations of extrathymically differentiated T cells exist in the liver and intestine. Such T cells in the liver have TCR of intermediate intensity (i.e., intermediate TCR cells) and constitutively express IL‐2 receptor β‐chain (IL‐2Rβ), whereas those in the intestine, especially intraepithelial lymphocytes, have TCR of bright intensity, consisting of a mixture of IL‐2Rβ+ and IL‐2Rβ–. All mature thymocytes and thymus‐derived T cells seen in the peripheral immune organs are TCR‐bright+IL‐2Rβ– under resting conditions. When the expression pattern of adhesion molecules, including CD44, L‐selectin, LFA‐1 and ICAM‐1, was compared among these T‐cell populations, they displayed quite unique patterns of expression. All extrathymic T cells in the liver, intestine, and even other organs were CD44+L‐selectin– LFA‐1++ICAM‐1+, whereas thymocytes and thymus‐derived T cells were CD44– L‐selectin+LFA‐1+ICAM‐1–. This inverted expression of adhesion molecules between extrathymic T cells and thymus‐derived T cells might be associated with their unique tissue‐localization.

Structural mechanisms of bone loss in iliac biopsies : comparison between rheumatoid arthritis and postmenopausal osteoporosis

Abstract To assess the mechanisms that cause generalized osteoporosis in rheumatoid arthritis (RA), 40 postmenopausal women with RA (46–74 years) and 40 age-matched controls with osteopenia underwent iliac bone biopsies. A structural analysis of histomorphometry and two-dimensional strut analysis were performed As compared to those with primary osteoporosis, there were a few unique characteristics in those with RA. Trabecular thickness and wall thickness declined with age, and this decline was especially accelerated by glucocorticoids. Decreased connectivity of the trabecular (Nd.Nd) was more prominent than the disappearance of the nodes. The connectivity of cortical bone to the nodes (Ct.Nd) and cortical thickness significantly decreased with age. With glucocorticoid therapy, the disappearance of the nodes was accelerated. In the case of vertebral compression fractures, the parameters of Nd.Nd and Ct.Nd significantly decreased. Although a bone biopsy is needed to analyze strut, this method is useful to evaluate the quality or intensity of the bone.

URINARY THROMBOMODULIN IN PATIENTS WITH RHEUMATOID ARTHRITIS : RELATIONSHIP TO DISEASE SUBSET

Abstract: In 110 patients with rheumatoid arthritis (RA), the mean (± SD) urinary thrombomodulin (TM) concentration was 74.4 ± 19.5 ng/mg creatinine (Cre), which was significantly higher than the mean in age-matched healthy controls (49.9 ± 10.8 ng/mg Cre; p<0.0001). The mean urinary TM concentration in the RA subset with least erosive disease (LES) was 65.2 ± 12.4 ng/mg Cre (n= 41), with more erosive disease (MES) was 77.4 ± 20.4 ng/mg Cre (n= 58) and with mutilating disease (MUD) was 92.6 ± 20.2 ng/mg Cre (n= 11). TM in the MUD group was the highest of the three subsets (ANOVA, p<0.0001). By contrast, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in the MES and MUD groups were not significantly different. Urinary TM levels may allow differentiation of RA subsets, unlike markers of inflammation such as ESR and CRP.

Long-term methotrexate (MTX) combination therapy versus MTX alone for active rheumatoid arthritis

In 37 patients with active rheumatoid arthritis (RA) responding insufficiently to a diseasemodifying anti-rheumatic drug (DMARD), we compared the safety and efficacy of methotrexate (MTX) used alone (MTX-only group) with MTX used in combination (combined-treatment group). Patients were assigned randomly to 5 years of treatment with MTX alone (initial dose, 7.5 mg/week) or with MTX (initial dose, 5 mg/week) plus their previous DMARD continued at half dosage. After 3 years of therapy, the combined-treatment group showed significantly better sustained response of the Lansbury index, erythrocyte sedimentation rate and C-reactive protein than the MTX-only group. Ten patients withdrew because of adverse drug effects, with a somewhat higher frequency in the combined-treatment group (six of 19, 32%) than in the MTX-only group (four of 18,22%) difference not significant). One patient in each group withdrew because of insufficient response to therapy. We found that combining the original drug with MTX in previously intractable RA cases resulted in at least additive efficacy.

Osteoconductive action of alendronate after implantation of beta tricalcium phosphate in rat adjuvant-induced arthritis

The aim of the study was to determine the effect of alendronate on resorption of β-tricalcium phosphate (β-TCP) and bone formation in rats with adjuvant-induced arthritis (AIA). After preparation of a model of AIA in rats (day 0), alendronate or vehicle was injected intraperitoneally once daily five times in a week. Cylindrical β-TCP was implanted into the rat femoral condyle on day 7. Rats were killed on days 12, 15, and 21, and specimens and serum samples were collected. Specimens were analyzed by tartrate-resistant acid phosphate (TRAP) staining, immunohistochemistry of the ED1 protein, and in situ hybridization with digoxigenin-labeled α1 chain of type I procollagen (COL1A1). Mineralized bone sections were analyzed by Villanueva bone stain. The serum osteocalcin level was measured using an enzyme-linked immunosorbent assay kit. Alendronate decreased the number of TRAP-positive cells attached to β-TCP, the numbers of ED1-positive multinucleated giant cells, and resorption of β-TCP. In AIA rats treated with alendronate, COL1A1 mRNA-positive cells adhered to β-TCP were round or cuboid whereas the cells in untreated AIA rats were fibroblast-like cells. Alendronate increased calcification of newly formed bone whereas it did not restore the bone formation suppressed with inflammation. These results suggest that alendronate has the potential to conduct mature bone after implantation of β-TCP in AIA. Alendronate may help to reduce insufficiency of newly formed bone after implantation of β-TCP in diseases characterized by increased bone resorption such as rheumatoid arthritis.

Revision metacarpophalangeal joint replacement 30 years after primary swanson flexible silicone implant arthroplasty in a rheumatoid patient: a case report.

We report a case of a patient with rheumatoid arthritis undergoing revision surgery 30 years after primary metacarpophalangeal joint arthroplasty using a Swanson implant. Removal and replacement of the implant were successfully performed, and the patient was satisfied with the revision surgery.

Osteoblastic bone metastasis with unusual synthesis of trabeculae in the bone marrow space: a case report with a node-strut analysis.

was no record of bone disease before the operation and no history of bone disease in her extended family. She reached menopause at age 48. She had no pain or limitation of the activity of daily life. No local recurrence in the stomach was seen with an endoscopic examination. The laboratory data on her first visit to our clinic were as follow. The plasma ALP was extremely high (1711 IU/l; normal, 60–250), and most of it was the bone isozyme. The serum calcium level was 8.2mg/dl (normal, 8.0–11.0) and the IP was 4.2mg/dl (normal, 2.5–4.5). Osteocalcin, one of the osteoblastic markers, was high (30ng/ml; normal, 2.5–13). Estradiol was low (,10 pg/ml; normal menopausal women, ,10 pg/ ml). The serum level of 1.25-(OH)-vitamin D was low (15.1 pg/ml; normal, 20–60). Parathyroid hormone (HSPTH) was in the upper limit of the normal range (490 pg/ml; normal, 160–520). Plain X-rays of the lumbar spine and pelvis showed no osteoporosis or compression fractures. Dual-energy X-ray absorptiometry (DTX-200; Toyo Medic, Tokyo, Japan) showed that the bone mineral density of her distal radius was 0.383g/cm2, which was 90% that of ageand sex-matched controls. 99mTc-bone scintigraphy showed a high uptake throughout her entire skeleton including the ilium. The changes were diffuse, indicating systemic bone metastasis in this patient. After double tetracycline labeling (labeling schedule: 02-07-02-06), an iliac bone biopsy to measure her bone histomorphometry was performed in January 1996. This specimen was fixed in 70% alcohol and embedded in methylmethacrylate without decalcification after Villanueva bone staining [3] and cut into 5-μm-thick sections. Bone histomorphometric measurements were then made using a semiautomatic image analyzer system (System Supply, Nagano, Japan). The iliac bone specimen showed a cancer nest with signet cells in the bone marrow space, indicating that the tumor cells were derived from her gastric cancer. Furthermore, there