Yoshitaka Toda

The homozygote of HLA-DRB1*0901, not its heterozygote, is associated with rheumatoid arthritis in Japanese

To assess the association between HLA-DRB1*0901 and Japanese rheumatoid arthritis (RA) patients, we analyzed the frequency of HLA-DRB1*0901 in 852 Japanese RA patients. We found that the homozygote of DRB1*0901 was associated with Japanese RA patients, while the heterozygote of DRB1*0901 was not. These findings suggest that DRB1*0901 is a weakly susceptible allele of RA, which in our investigation was not associated with RA by a single allele, but can be by a homozygote. DRB1*0901 does not have the shared epitope, and it is suggested that there may be some mechanism ofthe association between HLA-DRB1 and RA other than the shared epitope, which was not strong.

Absolute Reduction in Lower Limb Lean Body Mass in Japanese Women With Knee Osteoarthritis

Background:Knee osteoarthritis (OA) is a significant contributor to disability, and obesity is one of the most modifiable risk factors. The association between knee OA and obesity has been reported to relate to quadriceps strength. To begin to examine this hypothesis, independent measures of quadriceps lean mass are needed. Objective:The objective of this study was to characterize the absolute lower limb lean body mass in women with knee OA. Methods:Japanese women, aged 45 and over, who presented to a community orthopedics clinic, were categorized as 1) those with no knee pain, presenting with fracture, sprain, or back pain (n = 604); and 2) those presenting with knee pain meeting clinical and radiographic criteria for knee OA (n = 341). Segmental lower limb lean body mass (L-LBM) was measured with multifrequency bioelectrical impedance analysis and subjects were stratified by body mass index (BMI) by Western Pacific Region World Health Organization weight categories. Results:Control and knee OA groups were comparable with respect to age and BMI. Despite an increase in L-LBM with increasing BMI, there was a statistically significant reduction in L-LBM in knee OA subjects in comparison with control subjects in matched normal weight, overweight, and obese strata (11.1, 12.4, and 13.1 kg in the nonknee OA compared with 10.5, 10.6, and 11.6 kg in the knee OA group). Conclusions:A reduction in absolute L-LBM is observed in older Japanese women with knee OA in comparison with control subjects. Longitudinal studies are warranted in which L-LBM can be prospectively evaluated in a cohort followed for incident knee OA to better characterize the temporal relationship with L-LBM decline. Clinicians should consider this reduction in L-LBM in women with knee OA to recommend therapy aimed at reducing risk for atrophy and disability.

Dynamic effect of an elastically strapped lateral wedged insole on the subtalar joint in convenient foot print analysis using facsimile paper

Abstract We previously reported that insoles with subtalar strapping lead to valgus realignment of the femorotibial angle during the static phase in patients with osteoarthritis of the knee (knee OA) with varus deformity. In a follow-up study, we assessed the effect of an insole with subtalar strapping during the dynamic phase of the gait. Twenty-eight female patients with unilateral medial compartment knee OA and thirty-eight age- and sex-matched control subjects were enrolled. Gait analysis was performed for each subject while barefoot, with the insole with subtalar strapping, and with the insole with talonavicular strapping. In the knee OA group, the average foot angle while barefoot (12.4 ± 2.3°) was significantly higher than that in the control group (10.6 ± 3.4°) (P = 0.018). In the knee OA group, the angle while barefoot was significantly reduced after wearing the insole with subtalar strapping (9.4 ± 2.3°) (P < 0.0001), but not with use of the insole with talonavicular strapping (11.1 ± 2.8°) (P = 0.12). There was no significant difference in the foot angle among the three conditions in the control group (P > 0.05). This result suggests that the insole with subtalar strapping contributes to an adaptive mechanism which reduces the adductive moment at the knee through decreasing both the femorotibial angle and the external rotation of the foot position during walking.

Participation of substance P distribution in the cytokine production of rheumatoid synovium

Abstract Based on findings which suggested the involvement of the neuropeptide substance P in the pathogenesis of rheumatoid arthritis (RA), we investigated the mechanism of synovial pannus formation in RA, and examined the interaction between the cytokine production of synovial tissues and the concentration of substance P in the cartilage–pannus junction (CPJ). The CPJ and other peripheral synovial tissues were separately obtained from each part of the synovium from the knee joints of seven RA patients. The concentrations of substance P and the cytokines interleukin (IL)-1β and IL-6 in the CPJ and peripheral synovial tissues were determined by enzyme-linked immunosorbent assays. In addition, synovial cells were isolated from the CPJ and peripheral synovial tissues and treated with substance P or neurokinin-1 receptor antagonist to analyze the changes in cytokine production. The substance P levels were 211.2 and 50.5 pg/mg protein in the CPJ and the peripheral synovium, respectively. The IL-1β and IL-6 levels in the CPJ were 24.6 and 12.8 pg/mg protein, respectively. In the peripheral synovium, these levels were 4.3 and 2.5 pg/mg protein, respectively. In the CPJ, the IL-1β and IL-6 levels in tissue containing a high concentration of substance P (>200 pg/mg protein) were 39.4 and 21.6 pg/mg protein, respectively, and those in tissue containing a low concentration of substance P (≤200 pg/mg protein) were 11.6 and 5.1 pg/mg protein, respectively. Synovial cells from the CPJ produced higher levels of IL-1β and IL-6 than those from peripheral tissues. In addition, treatment of the cells with an NK-1 antagonist significantly reduced the production of these cytokines by the synovial cells. The theory that substance P plays a role in the pathogenesis of RA via the upregulation of cytokine production should be considered in further studies on the immunomodulatory properties of substance P in arthritis.

Substance P-induced priming effects on synovial cells

We detected and analyzed an intracellular mechanism of a substance P-induced priming effect on cytokine production using human synovial cells. The synovial tissues were isolated from the knee joints of osteoarthritis patients. After the administration of a low dose of substance P (1 nM) without significant effect alone, the synovial cells were stimulated with substance P (30 μM), phorbol 12-myristate 13-acetate (PMA) (100 nM), and calcium ionophore (A23187), (1 μM). The total interleukin (IL)-1β and IL-6 levels in the supernatant was measured by an enzymelinked immunosorbent assay (ELISA) kit, and the changes in the intracellular calcium concentration ([Ca2+]i) and protein kinase C (PKC) activation were measured by the fura 2-AM fluorescence method and a radioimmunoassay, respectively. The substance P-induced cytokine production was accompanied by an elevation of [Ca2+]i and PKC activation. The amounts of cytokines produced from the substance P (1 nM)-primed synovial cells stimulated with 30 μM substance P were approximately 4 times as much as that observed in non-primed cells. In addition, the priming treatment with 1 nM substance P enhanced not only the subsequent substance P-induced cytokine production, but also the PMA-induced response. However, substance P (1 nM) priming treatment did not affect the A23187-induced response. Furthermore, in substance P-primed cells, substance P (30 μM) induced a significant activation of PKC without changing the [Ca2+]i elevation response. These results suggest that the substance P-priming effect on synovial cells contributed to changes in intracellular mechanisms such as PKC activation.

Relationship Between HLA-DRB1-DQB1 Haplotypes and the Effect of Chicken Cartilage Soup Containing Type II Collagen on Rheumatoid Arthritis

The HLA-DQB1 and HLA-DRB1 genotypes were determined by a PCR-SSO technique in 65 Japanese outpatients with rheumatoid arthritis (RA). Group A consisted of patients having one or two HLA-DRB1*0405-HLA-DQB 1*0401 haplotypes. Group B consisted of patients without the haplotype. Eighteen and 14 patients were given chicken cartilage soup containing type II collagen (32mg/160ml) daily for over 3 weeks in group A and B, respectively (CII group). Nineteen and 14 patients were not treated with the soup in groups A and B, respectively (non-CII group).