Showing papers by "Atsuo Taniguchi published in 2012"

Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population

Abstract: Rheumatoid arthritis is a common autoimmune disease characterized by chronic inflammation. We report a meta-analysis of genome-wide association studies (GWAS) in a Japanese population including 4,074 individuals with rheumatoid arthritis (cases) and 16,891 controls, followed by a replication in 5,277 rheumatoid arthritis cases and 21,684 controls. Our study identified nine loci newly associated with rheumatoid arthritis at a threshold of P < 5.0 × 10(-8), including B3GNT2, ANXA3, CSF2, CD83, NFKBIE, ARID5B, PDE2A-ARAP1, PLD4 and PTPN2. ANXA3 was also associated with susceptibility to systemic lupus erythematosus (P = 0.0040), and B3GNT2 and ARID5B were associated with Graves' disease (P = 3.5 × 10(-4) and 2.9 × 10(-4), respectively). We conducted a multi-ancestry comparative analysis with a previous meta-analysis in individuals of European descent (5,539 rheumatoid arthritis cases and 20,169 controls). This provided evidence of shared genetic risks of rheumatoid arthritis between the populations.

Functional variants in NFKBIE and RTKN2 involved in activation of the NF-κB pathway are associated with rheumatoid arthritis in Japanese.

Abstract: Rheumatoid arthritis is an autoimmune disease with a complex etiology, leading to inflammation of synovial tissue and joint destruction. Through a genome-wide association study (GWAS) and two replication studies in the Japanese population (7,907 cases and 35,362 controls), we identified two gene loci associated with rheumatoid arthritis susceptibility (NFKBIE at 6p21.1, rs2233434, odds ratio (OR) = 1.20, P = 1.3 × 10(-15); RTKN2 at 10q21.2, rs3125734, OR = 1.20, P = 4.6 × 10(-9)). In addition to two functional non-synonymous SNPs in NFKBIE, we identified candidate causal SNPs with regulatory potential in NFKBIE and RTKN2 gene regions by integrating in silico analysis using public genome databases and subsequent in vitro analysis. Both of these genes are known to regulate the NF-κB pathway, and the risk alleles of the genes were implicated in the enhancement of NF-κB activity in our analyses. These results suggest that the NF-κB pathway plays a role in pathogenesis and would be a rational target for treatment of rheumatoid arthritis.

Anti-cyclic citrullinated peptide antibody predicts functional disability in patients with rheumatoid arthritis in a large prospective observational cohort in Japan

Abstract: To clarify the clinical significance of anti-cyclic citrullinated peptide antibody (anti-CCP) in the long-term outcome of RA, we established a large observational cohort of RA patients (IORRA) in our institute beginning in 2000. Essentially all RA patients who consulted our institute were registered, and clinical parameters, including disease activity and drug use, were assessed biannually based on patient reports, physician examinations, and laboratory data. In the third phase (October 2001) of the IORRA survey, anti-CCP levels were measured in 1,226 RA patients. In a cross-sectional analysis, clinical variables were compared in anti-CCP-positive versus -negative patients and in RF-positive versus -negative patients. In a longitudinal analysis, subsequent progression of disability was analyzed in anti-CCP-positive versus -negative and in RF-positive versus -negative patients. A verified Japanese version of the Health Assessment Questionnaire (J-HAQ) was used to measure functional disability. In the cross-sectional analysis, anti-CCP-positive patients (84.2%) had a significantly longer disease duration and higher disease activity score and more frequently used corticosteroids and methotrexate compared to anti-CCP-negative patients statistically. Similar phenomena were noted between RF-positive and -negative patients. In contrast, the longitudinal analysis revealed that J-HAQ slopes—a measure of progression of functional disability—were strongly associated with anti-CCP positivity but not with RF positivity. In a linear regression model, J-HAQ scores significantly worsened in anti-CCP-positive patients compared to anti-CCP-negative patients at the third year (annual progression 0.0317, P = 0.001) and the fifth year (annual progression 0.0199, P = 0.0012); however, J-HAQ progression was not influenced by RF status. Anti-CCP is a better predictive and discriminative marker for progression of disability in the long-term outcome of RA patients compared to RF.

Quantitative effect of HLA-DRB1 alleles to ACPA levels in Japanese rheumatoid arthritis: no strong genetic impact of shared epitope to ACPA levels after stratification of HLA-DRB1*09:01

Abstract: Anti-citrullinated peptide antibody (ACPA) is a highly specific serological marker for rheumatoid arthritis (RA).1,–,3 Different HLA-DRB1 alleles have been shown to be associated with the susceptibility to ACPA-positive RA.4 5 Former studies demonstrated that HLA-DRB alleles carrying a shared epitope (SE),6 consisting of a conserved amino acid motif at positions 70–74 of the HLA-DRβ chain, were strongly associated with ACPA-positive RA and with higher ACPA levels in European and Japanese populations.7,–,9 On the other hand, HLA-DRB1*09:01 was recently found to be negatively associated with ACPA levels in the Japanese.9 These observations imply that combinations of HLA-DRB1 alleles differentially influence ACPA levels in ACPA-positive RA. To address this question, we conducted a genetic association study employing 2457 ACPA-positive Japanese RA patients. ACPA was quantified by MESACUP CCP ELISA kit (MBL Co Ltd, Nagoya, Japan) with a cut-off level of 4.5 U/ml. The patients were then divided into three groups …

Performance of hands and feet radiographs in differentiation of psoriatic arthritis from rheumatoid arthritis

Abstract: Aim The purpose of this study was to determine useful radiographic findings for differentiating psoriatic arthritis (PsA) from rheumatoid factor (RF)-positive or -negative rheumatoid arthritis (RA) in Japanese patients. Methods We accrued 85 patients with PsA. Controls included 135 patients with RA (85 RF-positive, 50 RF-negative) matched for gender and disease duration with PsA patients. Radiographs of hands and feet were obtained, and distal interphalangeal (DIP) erosive disease, joint osteolysis, tuft osteolysis, juxta-articular bony proliferation (JBP), periosteal new bone formation and bony ankylosis, which were identified using the definitions developed by an earlier study, were compared between the PsA and RA groups. Results For radiographic features of hands, the frequencies of JBP, periosteal new bone, and diffuse soft tissue swelling of the fingers were significantly higher in PsA patients than in RF-positive RA patients. However, only the frequency of JBP significantly differed between PsA and RF-negative RA patients. In feet, the frequencies of DIP erosive disease, tuft osteolysis, JBP, and diffuse soft tissue swelling of the toes were significantly higher in PsA patients than in RF-positive RA patients. However, only the frequency of JBP significantly differed between PsA and RF-negative RA patients. Conclusion JBP was the most important radiographic feature for discriminating PsA from both RF-positive and -negative RA, confirming the study by the CASPAR group that showed that JBP is the only radiologic feature that can discriminate PsA from other inflammatory arthritides. This study showed the utility of plain radiographs for diagnosis of PsA.

Comparison of characteristics and therapeutic efficacy in rheumatoid arthritis patients treated by rheumatologists and those treated by orthopedic surgeons under a team medicine approach at the same institute

Abstract: The treatment of rheumatoid arthritis (RA) has improved dramatically with the advent of the latest generation of disease-modifying antirheumatic drugs. Despite these advances, in some patients inflammation is not diminished sufficiently to prevent irreversible musculoskeletal damage, thereby necessitating surgical intervention to reduce pain and improve function. For RA treatment, Japanese orthopedic surgeons also prescribe medication. In this study, we examined whether this Japanese system is effective for RA treatment. We analyzed the clinical condition of RA patients treated by rheumatologists and those treated by orthopedists in a linked registry study using information from a large observational cohort of RA patients followed every half year from 2000 to 2010 (the IORRA cohort). Two groups of patients were compared: patients treated by rheumatologists (rheumatologic group) and patients treated by orthopedists (orthopedic group). The results revealed that patients in the orthopedic group were older, more likely to be female, and had a longer disease duration than patients in the rheumatologic group. The proportion of patients with a history of joint surgery was also much higher in the orthopedic group than in the rheumatologic group. The average scores on the Japanese version of the Health Assessment Questionnaire, and the remission ratio determined using a Boolean-based definition gradually increased from 2000 until 2010, and these findings were consistently better in the rheumatologic group than in the orthopedic group. These data suggest that patients treated primarily by orthopedists are more likely to have long-standing RA compared to patients treated by rheumatologists. Therefore, it is critical for rheumatologists and orthopedists to complement each other medically in the treatment of RA patients.

The Influence of Individual Joint Impairment on Functional Disability in Rheumatoid Arthritis Using a Large Observational Database of Japanese Patients

Abstract: Objective. To clarify the influence of individual joint impairment on functional capacity through a retrospective study with a 3-year interval, using a large cohort of Japanese patients with rheumatoid arthritis (RA). Methods. Subjects included 3457 patients with RA who participated in a large observational cohort study in both April 2004 and April 2007; 43 joints were assessed and classified into 10 joint areas. Impairment of each joint area was scored based on the presence of swelling or tenderness: score 0 (no swelling or tenderness in either joint), score 1 (swelling or tenderness in a unilateral joint), and score 2 (swelling or tenderness in bilateral joints). Score change was defined as the difference between scores from 2004 and 2007. The Japanese validated version of the Health Assessment Questionnaire is the J-HAQ; ΔJ-HAQ score was determined by subtracting J-HAQ score in 2007 from that in 2004. The relationship between score change and ΔJ-HAQ score, and the effect of joint impairment on ΔJ-HAQ score were assessed. Results. Major joint areas that contributed to ΔJ-HAQ score included the wrist (31%), shoulder (21%), knee (13%), and ankle (10%). The shoulder, wrist, knee, and ankle in the worsening group were associated with a J-HAQ score increase of 0.13 to 0.18 compared to the improvement group. Conclusion. Our study demonstrated that impairment of the shoulder, wrist, knee, and ankle significantly affects functional capacity in patients with RA. Care of these joints is suggested to be especially important for better functional outcomes.

Effects of long-term corticosteroid usage on functional disability in patients with early rheumatoid arthritis, regardless of controlled disease activity

Abstract: We investigated the effect of long-term corticosteroid usage in suppressing the progression of functional disability in patients with early rheumatoid arthritis (RA). We studied 3,982 RA patients, who had continuous enrollment for at least 3 years, among 9,132 RA patients enrolled in an observational cohort study, IORRA, in Tokyo, Japan, from 2000 to 2007. The DAS28 and Japanese version of Health Assessment Questionnaire (J-HAQ) scores were collected at 6-month intervals (each phase). Among these patients, those with DAS28 values under 3.2 in all phases and RA disease duration under 2 years at study entry were selected as "early RA patients with well-controlled disease". These patients were further classified into 3 groups based on average months of steroid usage per year: Non-users, Medium-users, and Frequent-users. Multiple linear regression analysis was used to study the relationship between steroid usage and the final J-HAQ scores. Among the 3,982 patients, 109 had DAS28 values under 3.2 in all the phases and were selected as study cohort. The average Final J-HAQ in Non-user (N = 64), in Medium-user (N = 25), in Frequent-user group (N = 20) was 0.04, 0.06, and 0.33, respectively. Multiple linear regression analysis after adjusting for all potential covariates confirmed that frequent steroid usage was the most significant factor associated with higher final J-HAQ scores (P < 0.05). Frequent steroid usage was associated with significantly higher final J-HAQ scores in early RA patients, even though their disease was managed efficiently by maintaining the DAS28 values under 3.2 over a long-term period.

A Japanese Family Suffering from Familial Juvenile Hyperuricemic Nephropathy due to a Rare Mutation of the Uromodulin Gene.

Abstract: We report the case of a Japanese family suffering from familial juvenile hyperuricemic nephropathy (FJHN) due to a rare missense mutation of the uromodulin (UMOD) gene. An 18-year-old male presented with gout, hyperuricemia, and stage 3 chronic kidney disease. Mostly, FJHN is caused by a mutation altering the cystine residue of UMOD/Tamm-Horsfall protein. However, in the present case, a T688C mutation was identified in exon 4, resulting in amino acid substitution with arginine replacing tryptophan at position 230 (Trp230Arg). This mutation was also found in his brother and father with the same phenotype, indicating autosomal dominant inheritance. The affected amino acid was conserved in 200 healthy Japanese controls. Therefore, mutation T688C most likely causes rare structural and/or functional abnormalities in UMOD/Tamm-Horsfall protein.

The increasing disease duration of patients at the time of orthopaedic surgery for rheumatoid arthritis

Abstract: In recent years, disease-modifying antirheumatic drugs (DMARDs), including biological agents, have been used to inhibit or halt the underlying immune process and prevent long-term damage in rheumatoid arthritis (RA). The introduction of biological DMARDs has increased treatment options for RA, and clinical remission is now considered to be the primary goal of RA treatment. Despite the availability of such aggressive therapies, ongoing progressive destruction of joints occurs in a subgroup of RA patients, who eventually require joint surgery [1]. Orthopaedic procedures can substantially improve the overall function and quality of life in such patients. However, some reports have suggested that improvements in medical treatment might partially explain the reduction in the incidence of orthopaedic joint surgery, resulting in a worldwide trend towards better long-term outcomes [2–5]. In this study, we investigated the disease duration at the time of orthopaedic surgery among RA patients who participated in a large observational cohort study established by our institute (IORRA) [4]. Outpatients who fulWlled the American College of Rheumatology criteria for RA and/or 2010 rheumatoid arthritis classiWcation criteria were registered in this cohort study [6, 7]. An average of 4,990 outpatients with RA were seen each month from 2003 to 2009. Patient information was collected biannually (April/May and October/November) when the patients visited the outpatient unit of the Institute of Rheumatology, Tokyo Women’s Medical University [8]. Figure 1a shows the average RA disease activity from 2003 to 2009. As previously reported, disease activity decreased during this period [9]. Figure 1b shows the disease duration trend at the time of surgery. Surprisingly, the disease duration of patients who underwent total knee arthroplasty (TKA) gradually increased during this period. In addition, the disease duration of patients who underwent any type of surgery, including TKA, total hip arthroplasty, wrist and Wnger joint surgeries, and foot surgeries, was also increased. The reason for the observed increase in disease duration at the time of RA-associated surgery may be related to the decreased number of synovectomies and suppression of disease activity that has resulted from the use of methotrexate (MTX) and biological agents [9]. MTX was approved for the treatment for RA by the Japanese Ministry of Health, Labor and Welfare in 1999, while inXiximab was approved in 2003, etanercept was approved in 2005, adalimumab and tocilizumab were approved in 2008, and abatacept was approved in 2009. In addition, the use and dosage of MTX and the number of use of biological agents have been increasing every year [9]. Conversely, disease activity score (CDAI: clinical disease activity index, SDAI: simpliWed disease activity index) has been decreasing. Therefore, the recent implementation of medical therapy in RA patients may have suppressed and delayed the progression of destruction in arthritic joints, thereby resulting in postponement of surgery. We believe that these clinical results also provide evidence that these recently introduced medical therapies result in better long-term outcomes for RA patients. However, further studies, including analyses of RA databases that collect long-term data on a variety of surgical interventions, are required to conWrm this hypothesis. S. Momohara (&) · K. Ikari · K. Kawakami · T. Iwamoto · E. Inoue · K. Yano · Y. Sakuma · R. Hiroshima · A. Tokita · A. Taniguchi · H. Yamanaka Institute of Rheumatology, Tokyo Women’s Medical University, 10-22 Kawada, Shinjuku, Tokyo 162-0054, Japan e-mail: smomohara@ior.twmu.ac.jp