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1.  Pharmacokinetics, efficacy and safety profiles of etanercept monotherapy in Japanese patients with rheumatoid arthritis: review of seven clinical trials 
Modern Rheumatology  2014;25(2):173-186.
Conventional synthetic disease-modifying anti-rheumatic drugs, including methotrexate, may not be tolerated by all patients with rheumatoid arthritis (RA), and limited international data for etanercept (ETN) monotherapy are available. The aim of this review was to summarize the clinical program for ETN monotherapy in Japanese patients with RA, which has included a pharmacokinetic study, clinical trials for registration, long-term studies, and once-weekly dosing studies. Pharmacokinetic results showed that serum concentrations of ETN were linear with dose levels and were similar to other international studies. Across interventional studies, 652 Japanese patients with active RA were treated with ETN. In the registration studies, ETN treatment led to consistent improvement in American College of Rheumatology 20/50/70 scores, European League Against Rheumatism Good Response, Disease Activity Score 28 erythrocyte sedimentation rate remission, and Health Assessment Questionnaire disability index. In the long-term studies, efficacy was maintained for up to 180 weeks. Similar results were seen in the once-weekly studies. Across the studies, more than 870 patient-years of exposure to ETN were recorded. Discontinuations owing to lack of efficacy or adverse events were modest and no new safety signals were recorded. These studies demonstrated that ETN monotherapy is efficacious and well-tolerated in Japanese patients with RA.
PMCID: PMC4445012  PMID: 24842477
Clinical trial; Etanercept; Monotherapy; Review; Rheumatoid arthritis
2.  Anti-citrullinated peptide/protein antibody (ACPA)-negative RA shares a large proportion of susceptibility loci with ACPA-positive RA: a meta-analysis of genome-wide association study in a Japanese population 
Although susceptibility genes for anti-citrullinated peptide/protein antibodies (ACPA)-positive rheumatoid arthritis (RA) have been successfully discovered by genome-wide association studies (GWAS), little is known about the genetic background of ACPA-negative RA. We intended to elucidate genetic background of ACPA-negative RA.
We performed a meta-analysis of GWAS comprising 670 ACPA-negative RA and 16,891 controls for 1,948,138 markers, followed by a replication study of the top 35 single nucleotide polymorphisms (SNPs) using 916 cases and 3,764 controls. Inverse-variance method was applied to assess overall effects. To assess overlap of susceptibility loci between ACPA-positive and -negative RA, odds ratios (ORs) of the 21 susceptibility markers to RA in Japanese were compared between the two subsets. In addition, SNPs were stratified by the p-values in GWAS meta-analysis for either ACPA-positive RA or ACPA-negative RA to address the question whether weakly-associated genes were also shared. The correlations between ACPA-positive RA and the subpopulations of ACPA-negative RA (rheumatoid factor (RF)-positive and RF-negative subsets) were also addressed.
Rs6904716 in LEMD2 of the human leukocyte antigen (HLA) locus showed a borderline association with ACPA-negative RA (overall p = 5.7 × 10−8), followed by rs6986423 in CSMD1 (p = 2.4 × 10−6) and rs17727339 in FCRL3 (p = 1.4 × 10−5). ACPA-negative RA showed significant correlations of ORs with ACPA-positive RA for the 21 susceptibility SNPs and non-HLA SNPs with p-values far from significance. These significant correlations with ACPA-positive RA were true for ACPA-negative RF-positive and ACPA-negative RF-negative RA. On the contrary, positive correlations were not observed between the ACPA-negative two subpopulations.
Many of the susceptibility loci were shared between ACPA-positive and -negative RA.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0623-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4431175  PMID: 25927497
3.  Peripheral blood CD4+CD25+CD127low regulatory T cells are significantly increased by tocilizumab treatment in patients with rheumatoid arthritis: increase in regulatory T cells correlates with clinical response 
Tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, is clinically effective against rheumatoid arthritis (RA), and several reports have indicated how TCZ influences a number of mechanisms underlying RA pathogenesis. However, it is still unclear whether TCZ affects inflammatory cells in peripheral blood and whether any such changes are associated with clinical response. We evaluated associations between proportions of subsets of peripheral immune cells and clinical response in patients with RA treated with TCZ.
Thirty-nine consecutive patients with RA who started to receive TCZ as their first biologic between March 2010 and April 2012 were enrolled. The proportions of several subsets of peripheral cells with their levels of expression of differentiation markers, activation markers and costimulatory molecules were measured sequentially from baseline to week 52 by flow cytometry analysis.
Clinical Disease Activity Index (CDAI) remission was achieved in 53.8% of patients at week 52 of TCZ therapy. The proportions of CD4+CD25+CD127low regulatory T cells (Treg) and HLA-DR+ activated Treg cells significantly increased with TCZ therapy (P < 0.001 and P < 0.001, respectively), whereas proportions of CD3+CD4+CXCR3−CCR6+CD161+ T helper 17 cells did not change over the 52 weeks. The proportions of CD20+CD27+ memory B cells, HLA-DR+CD14+ and CD69+CD14+ activated monocytes, and CD16+CD14+ monocytes significantly decreased (P < 0.001, P < 0.001, P < 0.001 and P < 0.001, respectively). Among them, only the change in Treg cells was inversely correlated with the change in CDAI score (ρ = −0.40, P = 0.011). The most dynamic increase in Treg cells was observed in the CDAI remission group (P < 0.001).
This study demonstrates that TCZ affected proportions of circulating immune cells in patients with RA. The proportion of Treg cells among CD4+ cells correlated well with clinical response.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0526-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4332922  PMID: 25604867
4.  Biologic-free remission of established rheumatoid arthritis after discontinuation of abatacept: a prospective, multicentre, observational study in Japan 
Rheumatology (Oxford, England)  2014;54(4):683-691.
Objective. The aim of this study was to determine whether biologic-free remission of RA is possible with discontinuation of abatacept.
Methods. Japanese RA patients in 28-joint DAS with CRP (DAS28-CRP) remission (<2.3) after >2 years of abatacept treatment in a phase II study and its long-term extension entered this 52 week, multicentre, non-blinded, prospective, observational study. At enrolment, the patients were offered the option to continue abatacept or not. The primary endpoint was the proportion of patients who remained biologic-free at 52 weeks after discontinuation. Clinical, functional and structural outcomes were compared between those who continued and those who discontinued abatacept.
Results. Of 51 patients enrolled, 34 discontinued and 17 continued abatacept treatment. After 52 weeks, 22 of the 34 patients (64.7%) remained biologic-free. Compared with the continuation group, the discontinuation group had a similar remission rate (41.2% vs 64.7%, P = 0.144) although they had a significantly higher mean DAS28-CRP score at week 52 (2.9 vs 2.0, P = 0.012). The two groups were also similar with regard to mean HAQ Disability Index (HAQ-DI) score (0.6 for both, P = 0.920), mean change in total Sharp score (ΔTSS; 0.80 vs 0.32, P = 0.374) and proportion of patients in radiographic remission (ΔTSS ≤ 0.5) at the endpoint (64.3% vs 70.6%, P = 0.752). Those attaining DAS28-CRP < 2.3 or < 2.7 without abatacept at the endpoint had significantly lower HAQ-DI score and/or CRP at enrolment. Non-serious adverse events occurred in three patients who continued or resumed abatacept.
Conclusion. Biologic-free remission of RA is possible in some patients after attaining clinical remission with abatacept. Lower baseline HAQ-DI or CRP may predict maintenance of remission or low disease activity after discontinuation of abatacept.
Trial registration: UMIN Clinical Trials Registry, (UMIN000004137).
PMCID: PMC4372674  PMID: 25257039
rheumatoid arthritis; abatacept; biologic-free remission; observational study
5.  Mice Lacking Inositol 1,4,5-Trisphosphate Receptors Exhibit Dry Eye 
PLoS ONE  2014;9(6):e99205.
Tear secretion is important as it supplies water to the ocular surface and keeps eyes moist. Both the parasympathetic and sympathetic pathways contribute to tear secretion. Although intracellular Ca2+ elevation in the acinar cells of lacrimal glands is a crucial event for tear secretion in both the pathways, the Ca2+ channel, which is responsible for the Ca2+ elevation in the sympathetic pathway, has not been sufficiently analyzed. In this study, we examined tear secretion in mice lacking the inositol 1,4,5-trisphosphate receptor (IP3R) types 2 and 3 (Itpr2−/−;Itpr3−/−double-knockout mice). We found that tear secretion in both the parasympathetic and sympathetic pathways was abolished in Itpr2−/−;Itpr3−/− mice. Intracellular Ca2+ elevation in lacrimal acinar cells after acetylcholine and epinephrine stimulation was abolished in Itpr2−/−;Itpr3−/− mice. Consequently, Itpr2−/−;Itpr3−/− mice exhibited keratoconjunctival alteration and corneal epithelial barrier disruption. Inflammatory cell infiltration into the lacrimal glands and elevation of serum autoantibodies, a representative marker for Sjögren’s syndrome (SS) in humans, were also detected in older Itpr2−/−;Itpr3−/− mice. These results suggested that IP3Rs are essential for tear secretion in both parasympathetic and sympathetic pathways and that Itpr2−/−;Itpr3−/− mice could be a new dry eye mouse model with symptoms that mimic those of SS.
PMCID: PMC4047094  PMID: 24901844
6.  Recovery of clinical but not radiographic outcomes by the delayed addition of adalimumab to methotrexate-treated Japanese patients with early rheumatoid arthritis: 52-week results of the HOPEFUL-1 trial 
Rheumatology (Oxford, England)  2014;53(5):904-913.
Objective. The aim of this study was to compare efficacy outcomes of initial treatment with adalimumab + MTX vs adalimumab addition following 26 weeks of MTX monotherapy in Japanese early RA patients naive to MTX with high disease activity.
Methods. Patients completing the 26-week, randomized, placebo-controlled trial of adalimumab + MTX were eligible to receive 26 weeks of open-label adalimumab + MTX. Patients were assessed for mean change from baseline in the 28-joint DAS with ESR (DAS28-ESR) and modified total Sharp score (mTSS), and for the proportions of patients achieving clinical, functional or radiographic remission.
Results. Of 333 patients assessed, 278 (137 from the initial adalimumab + MTX and 141 from the initial placebo + MTX groups) completed the 52-week study. Significant differences in clinical and functional parameters observed during the 26-week blinded period were not apparent following the addition of open-label adalimumab to MTX. Open-label adalimumab + MTX slowed radiographic progression through week 52 in both groups, but patients who received adalimumab + MTX throughout the study exhibited less radiographic progression than those who received placebo + MTX during the first 26 weeks (mean ΔmTSS at week 52 = 2.56 vs 3.30, P < 0.001).
Conclusion. Delayed addition of adalimumab in Japanese MTX-naive early RA patients did not impact clinical and functional outcomes at week 52 compared with the earlier addition of adalimumab. However, the accrual of significant structural damage during blinded placebo + MTX therapy contributed to the persistence of differences between the treatment strategies, suggesting that Japanese patients at risk for aggressive disease should benefit from the early inclusion of adalimumab + MTX combination therapy.
Trial registration. (, NCT00870467.
PMCID: PMC3988871  PMID: 24441150
adalimumab; rheumatoid arthritis; Japanese patients; MTX naive; safety
7.  The Multicenter Study of a New Assay for Simultaneous Detection of Multiple Anti-Aminoacyl-tRNA Synthetases in Myositis and Interstitial Pneumonia 
PLoS ONE  2014;9(1):e85062.
Autoantibodies to aminoacyl-tRNA synthetases (ARSs) are useful in the diagnosis of idiopathic inflammatory myopathy (IIM) with interstitial pneumonia (IP). We developed an enzyme-linked immunosorbent assay (ELISA) system using a mixture of recombinant ARS antigens and tested its utility in a multicenter study. Methods: We prepared six recombinant ARSs: GST-Jo-1, His-PL-12, His-EJ and GST-KS expressed in Escherichia coli, and His-PL-7 and His-OJ expressed in Hi-5 cells. After confirming their antigenic activity, with the exception of His-OJ, we developed our ELISA system in which the five recombinant ARSs (without His-OJ) were mixed. Efficiency was confirmed using the sera from 526 Japanese patients with connective tissue disease (CTD) (IIM n = 250, systemic lupus erythematosus n = 91, systemic sclerosis n = 70, rheumatoid arthritis n = 75, Sjögren’s syndrome n = 27 and other diseases n = 13), 168 with idiopathic interstitial pneumonia (IIP) and 30 healthy controls collected from eight institutes. IIPs were classified into two groups; idiopathic pulmonary fibrosis (IPF) (n = 38) and non-IPF (n = 130). Results were compared with those of RNA immunoprecipitation. Results: Sensitivity and specificity of the ELISA were 97.1% and 99.8%, respectively when compared with the RNA immunoprecipitation assay. Anti-ARS antibodies were detected in 30.8% of IIM, 2.5% of non-myositis CTD, and 10.7% of IIP (5.3% of IPF and 12.3% of non-IPF). Anti-ARS-positive non-IPF patients were younger and more frequently treated with glucocorticoids and/or immunosuppressants than anti-ARS-negative patients. Conclusion: A newly established ELISA detected anti-ARS antibodies as efficiently as RNA immunoprecipitation. This system will enable easier and wider use in the detection of anti-ARS antibodies in patients with IIM and IIP.
PMCID: PMC3891809  PMID: 24454792
8.  Safety and efficacy of long-term esomeprazole 20 mg in Japanese patients with a history of peptic ulcer receiving daily non-steroidal anti-inflammatory drugs 
BMC Gastroenterology  2013;13:54.
Non-steroidal anti-inflammatory drugs (NSAIDs) are an effective and common treatment for chronic pain disorders, but long-term use is associated with risk of potentially life-threatening gastrointestinal adverse events (AEs). The proton pump inhibitor esomeprazole has been found to be effective for gastroprotection in NSAID users, but few long-term studies have been conducted in Japan.
This was an open-label, multicentre, single-arm, prospective 1-year study of treatment with esomeprazole (20 mg once daily) in Japanese patients (aged ≥20 years) with endoscopic evidence of previous peptic ulcer and receiving daily oral NSAID therapy (at a stable dose) for a chronic condition. Eligibility was not dictated by type of oral NSAID. The primary objective was to determine long-term safety and tolerability of esomeprazole. Efficacy for prevention of peptic ulcers was also determined (Kaplan-Meier method). All statistical analyses were descriptive.
A total of 130 patients (73.1% women, mean age 62.1 years, 43.8% Helicobacter pylori-positive) received treatment with esomeprazole in addition to long-term NSAID therapy (most commonly for rheumatoid arthritis [n=42] and osteoarthritis [n=34]). Loxoprofen, meloxicam and diclofenac were the most commonly used NSAIDs; cyclo-oxygenase (COX)-2 selective agents were used by 16.2% of patients (n=21). Long-term compliance with esomeprazole (capsule counts) was >75% for the majority of patients. Although 16.9% of patients (n=22) experienced AEs judged to be possibly related to treatment with esomeprazole, they were mostly mild and transient. The most commonly reported possibly treatment-related AEs were abnormal hepatic function, headache, increased γ-glutamyltransferase levels and muscle spasms (2 patients each). Overall, 95.9% (95% confidence interval: 92.3, 99.4) of patients remained ulcer free at 1 year.
Long-term treatment with esomeprazole (20 mg once daily) is well tolerated and efficacious for preventing ulcer recurrence in Japanese NSAID users with a history of peptic ulcer.
Trial registration identifier NCT00595517.
PMCID: PMC3623652  PMID: 23530709
Esomeprazole; Non-steroidal anti-inflammatory drugs; Peptic ulcer; Safety
9.  Distribution of Subsidized Insecticide-treated Bed Nets through a Community Health Committee in Boboye Health District, Niger 
Tropical Medicine and Health  2012;40(4):125-131.
In Niger, insecticide-treated bed nets (ITNs) have been distributed to the target group of households with young children and/or pregnant women at healthcare facilities in the course of antenatal/immunization clinics. With the aim of universal coverage, ITNs were additionally distributed to households through strengthened community health committees in 2009. This study assessed the impact of the community-based net distribution strategy involving community health committees in the ITN coverage in Boboye Health District, Niger. A cross-sectional survey was carried out on 1,034 households drawn from the intervention area (the co-existence of the community-based system together with the facility-based system) and the control area (the facility-based system alone). In the intervention area, 55.8% of households owned ITNs delivered through the community-based system, and 29.6% of households exclusively owned ITNs obtained through the community-based system. The community-based system not only reached households within the target group (54.6% ownership) but also those without (59.1% ownership). Overall, household ITN ownership was significantly higher in the intervention area than in the control area (82.5% vs. 60.7%). In combination, the community-based system and the facility-based system achieved a high ITN coverage. The community-based system contributed to reducing leakage in the facility-based system.
PMCID: PMC3597783  PMID: 23532450
insecticide-treated bed net; community-based net distribution; community participation; malaria; Niger
10.  Crystallization and preliminary X-ray structural analysis of nucleoside triphosphate hydrolases from Neospora caninum and Toxoplasma gondii  
Recombinant nucleoside triphosphate hydrolases from N. caninum and T. gondii have been purified and crystallized for X-ray structure analysis.
The nucleoside triphosphate hydrolases that are produced by Neospora caninum (NcNTPase) and Toxoplasma gondii (TgNTPase-I) have a different physio­logical function from the ubiquitous ecto-ATPases. The recombinant enzymes were crystallized at 293 K using polyethylene glycol 3350 as a precipitant and X-­ray diffraction data sets were collected for NcNTPase (to 2.8 Å resolution) and TgNTPase-I (to 3.1 Å resolution) at 100 K using synchrotron radiation. The crystals of NcNTPase and TgNTPase-I belonged to the orthorhombic space group I222 (unit-cell parameters a = 93.6, b = 140.8, c = 301.1 Å) and the monoclinic space group P21 (unit-cell parameters a = 87.1, b = 123.5, c = 120.2 Å, β = 96.6°), respectively, with two NcNTPase (V M = 3.7 Å3 Da−1) and four TgNTPase-I (V M = 2.7 Å3 Da−1) molecules per asymmetric unit. SAD phasing trials using a data set (λ = 0.97904 Å) collected from a crystal of seleno­methionylated NcNTPase gave an initial electron-density map of sufficient quality to build a molecular model of NcNTPase.
PMCID: PMC3001644  PMID: 21045291
nucleoside triphosphate hydrolases; Neospora caninum; Toxoplasma gondii
11.  What is the future of CCR5 antagonists in rheumatoid arthritis? 
Fleishaker and colleagues reported on a double-blind placebo controlled clinical trial of a C-C chemokine-receptor type 5 (CCR5) antagonist, maraviroc, in rheumatoid arthritis (RA) patients with inadequate response to methotrexate, showing that it was ineffective. Two additional CCR5 antagonists, SCH351125 and AZD5672, also failed to demonstrate clinical efficacy. In addition, CCR5-blocking antibodies could not inhibit synovial fluid-induced monocyte chemotaxis. Thus, CCR5 appears not to be a desirable target in RA treatment. Given the multiple functions of CCR5, redundancies in the chemokine system, and patient selection in the trial, we overview the recent understanding for chemokine receptor blockade in the treatment of RA
PMCID: PMC3446428  PMID: 22494450
12.  IgG4-Related Disease without Overexpression of IgG4: Pathogenesis Implications 
Case Reports in Rheumatology  2012;2012:754935.
IgG4-related disease is a new disease group that affects multiple organs. It is characterized by high serum IgG4 and abundant infiltration of IgG4-bearing plasma cells in the affected organ. Here, we describe an intriguing case that suggested that IgG4-related disease might present without IgG4 overexpression or infiltration, at least during a relapse. A 47-year-old man had been diagnosed with systemic lupus erythematosus 15 years. He was admitted due to a pituitary mass, systemic lymphadenopathy, and multiple nodules in the lungs and kidneys. The serum IgG4 level was normal and histopathological examination of the pituitary mass showed abundant lymphocyte and plasma cell infiltration with very few IgG4-positive cells. When we examined specimens preserved from 15 years ago, we found high serum IgG4 levels and IgG4-bearing plasma cell infiltration. This resulted in a diagnosis of IgG4-related disease, and we considered the current episode to be a relapse without IgG4 overexpression. This case indicated that, to clarify the pathogenesis of IgG4-related disease, current cases should repeat specimen evaluations over the course of IgG4-related disease to define diagnostic markers.
PMCID: PMC3420564  PMID: 22937457
13.  Golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis: results of the GO-FORTH study 
Annals of the Rheumatic Diseases  2011;71(6):817-824.
To assess the efficacy and safety of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA).
269 Japanese patients with active RA despite treatment with MTX were randomised (1:1:1) to placebo + MTX (Group 1), golimumab 50 mg + MTX (Group 2) or golimumab 100 mg + MTX (Group 3). Subcutaneous golimumab/placebo was injected every 4 weeks; stable doses of oral MTX (6–8 mg/week) were continued. Patients were allowed to enter early escape (Group 1 added golimumab 50 mg, Group 2 increased golimumab to 100 mg, Group 3 continued golimumab 100 mg) based on swollen/tender joint counts at week 14. The primary study endpoint was achievement of at least 20% improvement in the American College of Rheumatology (ACR20) response criteria at week 14. To control for multiplicity of testing, treatment group comparisons were first made between combined Groups 2 and 3 versus Group 1, followed by comparisons of Group 2 and Group 3 versus Group 1.
The proportion of patients with an ACR20 response at week 14 was significantly higher in combined Groups 2 and 3 (73.4%, 127/173) and in each of Group 2 (72.1%, 62/86) and Group 3 (74.7%, 65/87) compared with Group 1 (27.3%, 24/88; p<0.0001 for all comparisons). Golimumab + MTX also elicited a significantly better response than placebo + MTX in other efficacy parameters, including disease activity score (DAS28) response/remission and radiographic assessments. During the 16-week fixed treatment regimen study period, 72.7%, 75.6% and 78.2% of patients had adverse events and 1.1%, 1.2% and 2.3% had serious adverse events in Groups 1, 2 and 3, respectively.
In Japanese patients with active RA despite MTX therapy, golimumab + MTX was significantly more effective than MTX monotherapy in reducing RA signs/symptoms and limiting radiographic progression with no unexpected safety concerns.
PMCID: PMC3372319  PMID: 22121129
14.  Clinical Significance of Cartilage Biomarkers for Monitoring Structural Joint Damage in Rheumatoid Arthritis Patients Treated with Anti-TNF Therapy 
PLoS ONE  2012;7(5):e37447.
With the current use of biologics in rheumatoid arthritis (RA), there is a need to monitor ongoing structural joint damage due to the dissociation of articular cartilage damage from disease activity of RA. This study longitudinally analyzed levels of serum cartilage biomarkers during 54 weeks of infliximab therapy, to evaluate the feasibility of biomarkers for monitoring structural joint damage.
Subjects comprised 33 patients with early RA and 33 patients with established RA. All patients received 3 mg/kg of infliximab and methotrexate for 54 weeks. Levels of the following serum cartilage markers were measured at baseline and at weeks 14, 22, and 54: hyaluronan (HA); cartilage oligometric matrix protein (COMP); type II collagen (CII)-related neoepitope (C2C); type II procollagen carboxy-propeptide (CPII); and keratin sulfate (KS). Time courses for each biomarker were assessed, and relationships between these biomarkers and clinical or radiographic parameters generally used for RA were investigated.
Levels of CRP, MMP-3, DAS28-CRP, and annual progression of TSS were improved to similar degrees in both groups at week 54. HA and C2C/CPII were significantly decreased compared to baseline in the early RA group (p<0.001), whereas HA and COMP, but not C2C/CPII, were decreased in the established RA group. Strikingly, serum C2C/CPII levels were universally improved in early RA, regardless of EULAR response grade. Both ΔHA and ΔC2C/CPII from baseline to week 54 correlated significantly with not only ΔCRP, but also ΔDAS28 in early RA. Interestingly, when partial correlation coefficients were calculated by standardizing CRP levels, the significant correlation of ΔHA to ΔDAS28 disappeared, whereas correlations of ΔC2C/CPII to ΔDAS28, ΔJNS, and ΔHAQ remained significant. These results suggest a role of ΔC2C/CPII as a marker of ongoing structural joint damage with the least association with CRP, and that irreversible cartilage damage in established RA limits restoration of the C2C/CPII level, even with tight control of joint inflammation.
The temporal course of C2C/CPII level during anti-TNF therapy indicates that CII turnover shifts toward CII synthesis in early RA, but not in established RA, potentially due to irreversible cartilage damage. ΔC2C/CPII appears to offer a useful marker reflecting ongoing structural joint damage, dissociated from inflammatory indices such as CRP and MMP-3.
PMCID: PMC3357428  PMID: 22629396
15.  Lansoprazole for secondary prevention of gastric or duodenal ulcers associated with long-term non-steroidal anti-inflammatory drug (NSAID) therapy: results of a prospective, multicenter, double-blind, randomized, double-dummy, active-controlled trial 
Journal of Gastroenterology  2012;47(5):540-552.
Low-dose lansoprazole has not been intensively evaluated for its efficacy in the prevention of recurrent gastric or duodenal ulcers in patients receiving long-term non-steroidal anti-inflammatory drug (NSAID) therapy for pain relief in such diseases as rheumatoid arthritis, osteoarthritis, and low back pain.
This multi-center, prospective, double-blind, randomized, active-controlled study involving 99 sites in Japan was designed to compare the efficacy of lansoprazole (15 mg daily) with gefarnate (50 mg twice daily). Patients with a history of gastric or duodenal ulcers who required long-term NSAID therapy were randomized to receive lansoprazole 15 mg daily (n = 185) or gefarnate 50 mg twice daily (n = 181) and followed up for 12 months or longer prospectively.
The cumulative incidence of gastric or duodenal ulcer at days 91, 181, and 361 from the start of the study was calculated by the Kaplan–Meier method as 3.3, 5.9, and 12.7%, respectively, in the lansoprazole group versus 18.7, 28.5, and 36.9%, respectively, in the gefarnate group. The risk for ulcer development was significantly (log-rank test, P < 0.0001) lower in the lansoprazole group than in the gefarnate group, with the hazard ratio being 0.2510 (95% CI 0.1400–0.4499). A long-term follow-up study showed an acceptable safety profile for low-dose lansoprazole therapy, with diarrhea as the most frequent adverse event.
Lansoprazole was superior to gefarnate in reducing the risk of gastric or duodenal ulcer recurrence in patients with a definite history of gastric or duodenal ulcers who required long-term NSAID therapy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00535-012-0541-z) contains supplementary material, which is available to authorized users.
PMCID: PMC3360874  PMID: 22388884
Non-steroidal anti-inflammatory drugs; Rheumatoid arthritis; Osteoarthritis; Gastric or duodenal ulcers; Prevention; Lansoprazole; Active-controlled trial
19.  Regulatory mechanisms for the production of BAFF and IL-6 are impaired in monocytes of patients of primary Sjögren's syndrome 
Arthritis Research & Therapy  2011;13(5):R170.
In this study, we investigated possible aberrations of monocytes from patients with primary Sjögren's syndrome (pSS). We focused on B-cell-activating factor of the TNF family (BAFF) and IL-6 because they are both produced by monocytes and are known to be involved in the pathogenesis of pSS.
Peripheral monocytes were prepared from both pSS patients and normal individuals. The cells were stimulated in vitro with IFN-γ, and the amounts of IL-6 and soluble BAFF (sBAFF) produced by the cells were quantitated. The effect of sBAFF itself on the production of IL-6 was also studied. To investigate the response of pSS monocytes to these stimuli, the expression levels of the genes encoding BAFF receptors and IL-6-regulating transcription factors were quantitated.
Peripheral pSS monocytes produced significantly higher amounts of sBAFF and IL-6 than normal monocytes did, even in the absence of stimulation. The production of these cytokines was significantly increased upon stimulation with IFN-γ. The elevated production of IL-6 was significantly suppressed by an anti-BAFF antibody. In addition, stimulation of pSS monocytes with sBAFF induced a significant increase in IL-6 production. Moreover, the expression levels of a BAFF receptor and transcription factors regulating IL-6 were significantly elevated in pSS monocytes compared to normal monocytes.
The results of the present study suggest that the mechanisms underlying the production of sBAFF and IL-6 are impaired in pSS monocytes. Our research implies that this impairment is due to abnormally overexpressed IL-6-regulating transcription factors and a BAFF receptor. These abnormalities may cause the development of pSS.
PMCID: PMC3308105  PMID: 22018243
20.  Effectiveness and safety of adalimumab in Japanese patients with rheumatoid arthritis: retrospective analyses of data collected during the first year of adalimumab treatment in routine clinical practice (HARMONY study) 
Modern Rheumatology  2011;22(3):327-338.
We retrospectively investigated the ability of adalimumab (ADA) to reduce disease activity, improve physical function, and retard the progression of structural damage in 167 patients with rheumatoid arthritis. Clinical and functional outcomes were compared between patients with or without prior biologic treatment and those with or without concomitant methotrexate (MTX) treatment. At week 52, 38.3% achieved clinical remission: 42.4 and 28.6% of patients achieved remission in those without and with previous biologics, respectively, while 42.7 and 12.5% of patients achieved remission in those with and without concomitant MTX, respectively. ADA treatment significantly reduced the rate of radiographic progression from 27.1 ± 46.0 (median 13.6; 25th–75th percentiles 8.3 to 28.9) at baseline to 0.8 ± 5.0 (median 0.0; 25th–75th percentiles −0.9 to 2.0) at week 52 (P < 0.0001). Radiographic progression was absent in 59.8% of patients. Sixty adverse events (34.21/100 patient-years) were reported, 16 of which were serious (9.12/100 patient-years). ADA therapy is highly effective for reducing disease activity, improving physical function, and limiting radiographic progression. It is generally safe and well tolerated by Japanese RA patients in routine clinical practice.
PMCID: PMC3375429  PMID: 21898074
Adalimumab; Japanese; Retrospective study; Radiographic outcome; Rheumatoid arthritis
21.  Clinical, radiographic and functional effectiveness of tocilizumab for rheumatoid arthritis patients—REACTION 52-week study 
Rheumatology (Oxford, England)  2011;50(10):1908-1915.
Objectives. To evaluate the effectiveness and safety of tocilizumab in RA patients in clinical practice.
Methods. We observed 232 consecutive RA patients who began tocilizumab in three rheumatology centres in Japan for 52 weeks. Clinical, radiographic and functional status and safety were evaluated.
Results. Mean age of the 232 patients was 59.1 years, mean duration of disease was 12.4 years and average DAS using the 28-joint count (DAS-28) was 5.6. Although 62.8% of the patients had been treated previously with anti-TNF biologics, clinical remission at Week 52 was achieved in 43.7%, radiographic non-progression in 62.8% and functional remission in 26.4%. Retention rate at Week 52 was 71.1%, and the same for those with or without previous anti-TNF treatment. Adverse drug reactions leading to tocilizumab discontinuation were observed in 15.5% of patients, the most frequent adverse drug reaction being pneumonia in eight cases. On multivariate logistic regression analysis, DAS-28, HAQ-disability index (HAQ-DI), concomitant MTX and concomitant glucocorticoids (GCs) were predictive variables for clinical remission at Week 52 of tocilizumab treatment. In particular, HAQ-DI was found to be a predictive variable for remission of all three types—clinical, radiographic and functional—at Week 52 of tocilizumab treatment.
Conclusions. In daily clinical practice, tocilizumab exhibited excellent effectiveness in established RA patients, some of whom had failed to respond to previous anti-TNF treatment. Although further detailed safety findings are required, this study provides valuable real-world findings on the management of RA with tocilizumab.
PMCID: PMC3176715  PMID: 21752873
Rheumatoid arthritis; Tocilizumab; Remission; Joint destruction; Health assessment questionnaire
22.  Baseline tumour necrosis factor alpha levels predict the necessity for dose escalation of infliximab therapy in patients with rheumatoid arthritis 
Annals of the Rheumatic Diseases  2011;70(7):1208-1215.
To investigate the possible role of baseline plasma tumour necrosis factor alpha levels (baseline-TNF) on the clinical response to infliximab in patients with rheumatoid arthritis (RA).
Patients with RA refractory to methotrexate received 3, 6, or 10 mg/kg of infliximab every 8 weeks, in a randomised, double-blind manner: the RISING study. Clinical response (disease activity score in 28 joints based on C-reactive protein or American College of Rheumatology core set) at week 54 and serum infliximab levels were compared in three patient groups with low, intermediate, or high baseline-TNF (TNF-low, TNF-int, or TNF-high).
In TNF-low patients, the clinical response to different doses of infliximab was comparable, whereas TNF-int patients exhibited a dose-dependent trend. In contrast, TNF-high patients (approximately 13% of the total patients) had a clinical response to 10 mg/kg significantly better than the response to 3 and 6 mg/kg of infliximab. In TNF-high patients, the median trough serum levels of infliximab were below the detection limit (<0.1 μg/ml) at 3 and 6 mg/kg but were greater than 2 μg/ml at 10 mg/kg, whereas the levels were approximately 1 μg/ml for each dosage group in TNF-low patients.
In patients with RA, baseline-TNF is significantly associated with the clinical response to infliximab in patients with a high baseline-TNF. A higher dose of infliximab may be necessary in these patients, whereas lower doses of infliximab are sufficient for those with a low baseline-TNF. Baseline-TNF may be a useful measure for personalising the treatment of RA using infliximab.
PMCID: PMC3103666  PMID: 21478189
23.  Safety and effectiveness of switching from infliximab to etanercept in patients with rheumatoid arthritis: results from a large Japanese postmarketing surveillance study 
Rheumatology International  2011;32(6):1617-1624.
Finding an effective treatment strategy for rheumatoid arthritis (RA) patients who have not benefited from previous tumor necrosis factor–α antagonist treatment is important for minimizing RA disease activity and improving patient outcomes. The aim of this study was to compare the safety and effectiveness of etanercept in patients with and without infliximab (IFX) treatment experience. Patients (n = 7,099) from a large postmarketing observational study of etanercept use in Japan were divided into 2 cohorts based on previous IFX use (pre-IFX and non-IFX). Baseline characteristics were assessed in each cohort. Adverse events (AEs) and European League Against Rheumatism (EULAR) responses were monitored every 4 weeks for 24 weeks. At baseline, pre-IFX patients were younger and had fewer comorbidities and a shorter RA duration than non-IFX patients. During the study, pre-IFX patients received concomitant methotrexate more often than non-IFX patients. The incidence of AEs and serious AEs were significantly lower in pre-IFX patients, as was the percentage of patients who discontinued treatment. Both cohorts had significant improvement (P < 0.001) in EULAR responses at the end of the treatment period. This study demonstrated that etanercept was effective and well tolerated in active RA patients with and without prior IFX treatment.
PMCID: PMC3364424  PMID: 21331576
Etanercept; Infliximab; Postmarketing surveillance study; Rheumatoid arthritis; TNF-α antagonists
24.  Safety and effectiveness responses to etanercept for rheumatoid arthritis in Japan: a sub-analysis of a post-marketing surveillance study focusing on the duration of rheumatoid arthritis 
Rheumatology International  2011;32(6):1511-1519.
The aim is to investigate the relationship of duration of rheumatoid arthritis (RA) with safety and effectiveness of etanercept (ETN) in Japan. Post-marketing surveillance data for 7,099 patients treated with ETN were analyzed. Baseline characteristics, treatment effectiveness, incidence of adverse events (AEs), and serious AEs (SAEs) in relation to duration of RA were studied. At baseline, patients with RA for longer duration were older, weighed less, had more comorbidities, allergies, and corticosteroid use, but smoked less and had less morning stiffness. By 2–5 years with RA, more than half of the patients had advanced to Steinbrocker radiographic stage III or IV. Methotrexate (MTX) was the most commonly used pre-treatment disease-modifying antirheumatic drug; however, concomitant MTX use and its dose were lower among patients with longer duration of RA. Remission rates (26.6%) were greatest among patients having RA for <2 years. Less AEs and SAEs were observed among patients with shorter duration of RA. These results suggest that RA treatment in Japan in the era pre-biologics may not have been adequate to control disease activity and prevent joint destruction. Patients with shorter duration of RA may have better physical status which allows the opportunity to treat more intensively putting a higher percentage of patients in remission and possibly decreasing exposure to SAEs.
PMCID: PMC3364409  PMID: 21327436
Antirheumatic agents/adverse effects; Antirheumatic agents/therapeutic use; Arthritis, rheumatoid/drug therapy; Product surveillance, Postmarketing/statistics & numerical data; Receptors, tumor necrosis factor/therapeutic use; Japan
25.  Postmarketing surveillance of safety and effectiveness of etanercept in Japanese patients with rheumatoid arthritis 
Modern Rheumatology  2011;21(4):343-351.
Our aim was to evaluate real-world safety and effectiveness in a 6-month postmarketing surveillance study covering all Japanese patients with rheumatoid arthritis (RA) who received etanercept during a 2-year period. Data for 13,894 patients (1334 sites) enrolled between March 2005 and April 2007 were collected. Adverse events (AEs) and serious adverse events (SAEs) were reported in 4336 (31.2%) and 857 (6.2%) patients, respectively. The most frequent AEs were injection site reactions (n = 610, 4.4%) and rash (n = 339, 2.4%), whereas pneumonia (n = 116, 0.8%) and interstitial lung disease (n = 77, 0.6%) were the most frequent SAEs. Significant improvement in the proportion of patients with a good European League Against Rheumatism (EULAR) response was observed from week 4 (17.6%) to week 24 (31.6%) (p < 0.001); 84.3% of patients had good or moderate EULAR responses at week 24. The percentage of patients achieving remission increased significantly from week 4 (9.3%) to week 24 (18.9%) (p < 0.001). Patients with early moderate RA were less likely to experience SAEs and were more likely to achieve remission compared with patients with more severe disease. The safety and effectiveness of etanercept was demonstrated in Japanese patients in one of the largest observational trials conducted thus far in RA patients treated with biologics.
PMCID: PMC3152707  PMID: 21264488
DAS28; Etanercept; Postmarketing surveillance study; Rheumatoid arthritis

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