Takefumi Furuya

IL-23 induces human osteoclastogenesis via IL-17 in vitro , and anti-IL-23 antibody attenuates collagen-induced arthritis in rats

This study demonstrates that IL-23 stimulates the differentiation of human osteoclasts from peripheral blood mononuclear cells (PBMC). Furthermore, in vivo blockade of endogenous IL-23 activity by treatment with anti-IL-23 antibody attenuates collagen-induced arthritis in rats by preventing both inflammation and bone destruction. IL-23 induced human osteoclastogenesis in cultures of PBMC in the absence of osteoblasts or exogenous soluble-receptor activator of NF-kappaB ligand (RANKL). This IL-23-induced osteoclastogenesis was inhibited by osteoprotegerin, anti-IL-17 antibody, and etanercept, suggesting that RANKL, IL-17, and TNF-alpha are involved. In addition, we found the ratio of production levels of IL-17 to those of IFN-gamma from activated human T cells was elevated at 1 to 10 ng/ml IL-23. The inductive effect of IL-17 and the inhibitory effect of IFN-gamma on osteoclastogenesis indicate that the balance of these two cytokines is particularly important. We also demonstrated that IL-23 administered at a later stage significantly reduced paw volume in rats with collagen-induced arthritis, in a dose-dependent manner. Furthermore, anti-IL-23 antibody reduced synovial tissue inflammation and bone destruction in these rats. These findings suggest that IL-23 is important in human osteoclastogenesis and that neutralizing IL-23 after onset of collagen-induced arthritis has therapeutic potential. Thus, controlling IL-23 production and function could be a strategy for preventing inflammation and bone destruction in patients with rheumatoid arthritis.

IFN-γ-producing human T cells directly induce osteoclastogenesis from human monocytes via the expression of RANKL

The current study explored our hypothesis that IFN‐γ‐producing human T cells inhibit human osteoclast formation. Activated T cells derived from human PBMC were divided into IFN‐γ‐producing T cells (IFN‐γ+ T cells) and IFN‐γ‐non‐producing T cells (IFN‐γ– T cells). IFN‐γ+ T cells were cultured with human monocytes in the presence of macrophage‐CSF alone. The concentration of soluble receptor activator of NF‐κB ligand (RANKL) and IFN‐γ, and the amount of membrane type RANKL expressed on T cells, were measured by ELISA. In the patients with early rheumatoid arthritis (RA) treated with non‐steroidal anti‐inflammatory drugs alone, CD4+ T cells expressing both IFN‐γ and RANKL were detected by flow cytometry. Surprisingly, IFN‐γ+ T cells, but not IFN‐γ– T cells, induced osteoclastogenesis from monocytes, which was completely inhibited by adding osteoprotegerin and increased by adding anti‐IFN‐γ antibodies. The levels of both soluble and membrane type RANKL were elevated in IFN‐γ+ T cells. The ratio of CD4+ T cells expressing both IFN‐γ and RANKL in total CD4+ T cells from PBMC was elevated in RA patients. Contrary to our hypothesis, IFN‐γ+ human T cells induced osteoclastogenesis through the expression of RANKL, suggesting that Th1 cells play a direct role in bone resorption in Th1 dominant diseases such as RA.

Brief Report: Association of HLA–DRB1*0101/*0405 with susceptibility to anti–melanoma differentiation–associated gene 5 antibody–positive dermatomyositis in the Japanese population

OBJECTIVE The complication of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) is associated with anti-aminoacyl-transfer RNA synthetase (anti-aaRS) antibody or anti-melanoma differentiation-associated gene 5 (anti-MDA-5) antibody positivity. Anti-MDA-5 antibody is associated with clinically amyopathic DM and fatal outcome due to rapidly progressive ILD in Asian populations. The association between genetic factors and anti-MDA-5 antibody-positive DM is unclear. This study was undertaken to investigate the HLA-DRB1 genotype in patients with anti-MDA-5 antibody-positive DM. METHODS We examined genetic differences among 17 patients with anti-MDA-5 antibody-positive DM, 33 patients with anti-aaRS antibody-positive PM/DM, 33 patients with PM/DM without anti-aaRS antibody or ILD, and 265 healthy controls. RESULTS The frequencies of HLA-DRB1*0101 and DRB1*0405 were 29% and 71%, respectively, in patients with anti-MDA-5 antibody-positive DM, which were higher than the frequencies in healthy controls (10% and 25%, respectively). Among the 17 patients with anti-MDA-5 antibody-positive DM, 16 (94%) harbored either the DRB1*0101 or DRB1*0405 allele. The combined frequency of the DRB1*0101 allele and the DRB1*0405 allele was significantly higher in patients with anti-MDA-5 antibody-positive DM than in patients with PM/DM without anti-aaRS antibody or ILD, with an odds ratio (OR) of 42.7 (95% confidence interval [95% CI] 4.9-370.2) (P = 1.1 × 10(-5)), or in patients with anti-aaRS antibody-positive PM/DM (OR 13.3 [95% CI 1.6-112.6], P = 4.5 × 10(-3)). CONCLUSION Our findings indicate that HLA-DRB1*0101/*0405 is associated with susceptibility to anti-MDA-5 antibody-positive DM in the Japanese population.

Risk factors associated with incident fractures in Japanese men with rheumatoid arthritis: a prospective observational cohort study

There are limited data in the literature concerning risk factors for incident fractures in men with rheumatoid arthritis (RA). We evaluated the association between potential risk factors and incident clinical fractures in male Japanese patients with RA. A total of 1050 male patients with RA were enrolled in a prospective, observational cohort study from 2000 to 2005. Participants were followed from 6 to 66 months (median follow-up, 48.7 months) and classified into three groups according to their incident fracture status from baseline: no new fracture, any new nonvertebral fracture, and new clinical vertebral fracture. The associations of potential risk factors were analyzed by Cox proportional hazards models. During follow-up, 30 patients (2.9%) developed a new nonvertebral fracture or a vertebral fracture. The baseline age, history of total knee replacement (TKR), and serum C-reactive protein (CRP) levels were associated with any nonvertebral fracture [baseline age: hazard ratio (HR), 1.08, 95% confidence interval (CI), 1.03–1.14; history of TKR: HR 6.02, 95% CI 1.19–30.42; and CRP: HR 0.60, 95% CI 0.38–0.95]. The baseline Japanese health assessment questionnaire (HAQ) score and daily dose of prednisolone were also associated with the incidence of clinical vertebral fractures (HR 7.74, 95% CI 2.10–28.48, and HR 1.28, 95% CI 1.14–1.45, respectively). Older age, history of TKR, and low serum CRP levels appear to be associated with any incident nonvertebral fracture in Japanese men with RA. High HAQ disability score and baseline doses of daily prednisolone may correlate with incident clinical vertebral fracture in Japanese men with RA.

Positive association between STAT4 polymorphisms and polymyositis/dermatomyositis in a Japanese population

Objectives To investigate associations between signal transducer and activator of transcription 4 (STAT4), one of the most commonly acknowledged genes for the risk of multiple autoimmune diseases, with susceptibility to adult-onset polymyositis/dermatomyositis among Japanese individuals. Methods A single nucleotide polymorphism of STAT4, rs7574865, was genotyped using TaqMan assay in 1143 Japanese individuals. The first set comprised 138 polymyositis/dermatomyositis patients and 289 controls and the second set comprised 322 patients and 394 controls. 460 patients (273 polymyositis and 187 dermatomyositis patients) and 683 controls were genotyped. Results rs7574865T conferred a risk of polymyositis/dermatomyositis with an OR of 1.37 (95% CI 1.16 to 1.64; p=4x10−4; pcorr=0.0012). Both polymyositis and dermatomyositis exhibited high associations with the rs7574865T allele (polymyositis: OR=1.36, 95% CI 1.11 to 1.67; p=0.0039; pcorr=0.012; dermatomyositis: OR=1.40, 95% CI 1.10 to 1.78; p=0.0054; pcorr=0.016). The association between this STAT4 polymorphism and interstitial lung disease (ILD) was also investigated in the first set of polymyositis/dermatomyositis patients (n=138); those with ILD (n=79) bore rs7574865T more frequently compared with controls (OR 1.59, 95% CI 1.10 to 2.28; p=0.013; pcorr=0.039). Conclusion This is the first study to show a positive association between a STAT4 polymorphism and polymyositis/dermatomyositis, suggesting that polymyositis/dermatomyositis shares a gene commonly associated with the risk of other autoimmune diseases.

Therapeutic effects of hyaluronate injections in patients with chronic painful shoulder: A meta-analysis of randomized controlled trials

To elucidate the therapeutic efficacy and safety of injection of hyaluronate (HA) for chronic painful shoulder.

Risk factors for established vertebral fractures in Japanese patients with rheumatoid arthritis: Results from a large prospective observational cohort study.

Abstract Objective. The aim of this study was to evaluate the associations between potential risk factors and the occurrence of established vertebral fractures in Japanese patients with rheumatoid arthritis (RA). Methods. A total of 10,469 patients with RA were enrolled in a prospective, observational study from 2000 to 2011. Self-reported vertebral fractures were verified using patients medical records and radiographs. Cox proportional hazards models were used to analyze independent contributions of various risk factors for established vertebral fracture occurrence. Results. During a mean follow-up of 5.8 years, established vertebral fractures in 170 patients were verified with medical records and radiographs. Multivariate Cox regression analyses estimated that the hazards ratios of sustaining vertebral fractures increased by 1.84 for female gender, 1.72 for every 10 years of increased age, 1.26 for Disease Activity Score in 28 joints (DAS28), 1.44 for Japanese Health Assessment Questionnaire-Disability Index (J-HAQ-DI), 2.21 for history of any previous fractures, and 1.09 for daily prednisolone dose (mg/day). Conclusion. We confirmed the associations between vertebral fractures and advanced age, J-HAQ-DI, and high daily prednisolone dose; and found significant correlations between vertebral fractures and female gender, DAS28, and history of any previous fracture in Japanese RA patients.

Association between a C8orf13–BLK Polymorphism and Polymyositis/Dermatomyositis in the Japanese Population: An Additive Effect with STAT4 on Disease Susceptibility

Background Accumulating evidence has shown that several non-HLA genes are involved in the susceptibility to polymyositis/dermatomyositis. This study aimed to investigate the involvement of C8orf13–BLK, one of the strongest candidate genes for autoimmune diseases, in susceptibility to polymyositis/dermatomyositis in the Japanese population. A possible gene–gene interaction between C8orf13–BLK and STAT4, which we recently showed to be associated with Japanese polymyositis/dermatomyositis, was also analyzed. Methods A single-nucleotide polymorphism in C8orf13–BLK (dbSNP ID: rs13277113) was investigated in the Japanese population using a TaqMan assay in 283 polymyositis patients, 194 dermatomyositis patients, and 656 control subjects. Results The C8orf13–BLK rs13277113A allele was associated with overall polymyositis/dermatomyositis (P<0.001, odds ratio [OR] 1.44, 95% confidence interval [CI] 1.19–1.73), as well as polymyositis (P = 0.011, OR 1.32, 95% CI 1.06–1.64) and dermatomyositis (P<0.001, OR 1.64, 95% CI 1.26–2.12). No association was observed between the C8orf13–BLK rs13277113A allele and either interstitial lung disease or anti-Jo-1 antibody positivity. The C8orf13–BLK rs13277113 A and STAT4 rs7574865 T alleles had an additive effect on polymyositis/dermatomyositis susceptibility. The strongest association was observed in dermatomyositis, with an OR of 3.07 (95% CI; 1.57–6.02) for the carriers of four risk alleles at the two SNP sites, namely, rs1327713 and rs7574865. Conclusions This study established C8orf13–BLK as a new genetic susceptibility factor for polymyositis/dermatomyositis. Both C8orf13–BLK and STAT4 exert additive effects on disease susceptibility. These observations suggested that C8orf13–BLK, in combination with STAT4, plays a pivotal role in creating genetic susceptibility to polymyositis/dermatomyositis in Japanese individuals.

An Osteoprotegerin Gene Polymorphism Is Associated with an Increased Risk of Hip Fracture in Japanese Patients with Rheumatoid Arthritis: Results from the IORRA Observational Cohort Study

Introduction Patients with rheumatoid arthritis (RA) have a higher prevalence of osteoporosis and hip fracture than healthy individuals. Multiple genetic loci for osteoporotic fracture were identified in recent genome-wide association studies. The purpose of this study was to identify genetic variants associated with the occurrence of hip fracture in Japanese patients with RA. Methods DNA samples from 2,282 Japanese patients with RA were obtained from the DNA collection of the Institute of Rheumatology Rheumatoid Arthritis cohort (IORRA) study. Six single nucleotide polymorphisms (SNPs) that have been reported to be associated with fractures in recent studies were selected and genotyped. Forty hip fractures were identified with a maximum follow-up of 10 years. The genetic risk for hip fracture was examined using a multivariate Cox proportional hazards regression model. Results The risk analyses revealed that patients who are homozygous for the major allele of SNP rs6993813, in the OPG locus, have a higher risk for hip fracture (hazard ratio [95% CI]  = 2.53 [1.29–4.95], P  = 0.0067). No association was found for the other SNPs. Conclusions Our results indicate that an OPG allele is associated with increased risk for hip fracture in Japanese patients with RA.

Factors associated with decreasing serum 25(OH)D among Japanese patients with rheumatoid arthritis: Results from the IORRA cohort study

Abstract Objective: The aim of this study was to investigate factors that predict a decrease in serum 25(OH)D among Japanese patients with rheumatoid arthritis (RA). Methods: In 2011 and 2013, serum 25(OH)D was evaluated in the same 2534 Japanese patients with RA (2179 women and 355 men) who participated in the Institute of Rheumatology Rheumatoid Arthritis (IORRA) cohort study. A vitamin D deficiency was defined as serum 25(OH)D levels <20 ng/mL. Predictive factors resulting in decreased serum 25(OH)D over a 2-year period were evaluated using multivariate logistic regression. Results: The prevalence of vitamin D deficiency was 73.3% in 2011 and 68.2% in 2013. Serum 25(OH)D levels decreased by >5 ng/mL from 2011 to 2013 in 224 (8.8%) patients. A serum 25(OH)D decrease of >5 ng/mL was significantly associated with female gender, younger age, and disuse of bisphosphonates among all patients, and younger age, higher Japanese health assessment questionnaire disability index (JHAQ-DI), increased tender joint counts, and disuse of bisphosphonates and/or active vitamin D3 among women with RA. Conclusion: Female gender, younger age, JHAQ-DI, tender joint counts, and disuse of bisphosphonates and/or active vitamin D3 appear to be associated with a decrease in serum 25(OH)D in Japanese patients with RA.