Isolation of the hemeoxygenase-1 inducer from rice-derived peptide.

Bioactive peptides with various health benefits have been reported from rice protein hydrolysates. We previously showed that rice-derived peptides (RP) increased intracellular glutathione levels and induced the expression of γ-glutamylcysteine synthetase, which is regulated by nuclear transcription factor-erythroid 2-related factor 2 (Nrf2). Heme oxygenase-1 (HO-1) is an important Nrf2 downstream antioxidant enzyme that protects against oxidative stress. This study aimed to investigate the protective effects of RP on hydrogen peroxide (H2O2)-induced oxidative stress in human hepatoblastoma cell line HepG2 and identified HO-1 induced peptides from RP. Pretreatment of cells with RP reduced the cytotoxicity caused by H2O2 in a dose-dependent manner. Moreover, RP induced HO-1 expression in a concentration- and time-dependent manner. Next, we attempted to isolate the HO-1 inducer from RP by bioactivity-guided fractionation. Purification of the active peptides using a Sep-Pak C18 cartridge and reversed-phase HPLC, followed by sequence analysis by mass spectrometry, led to the identification of the three peptides. These peptides effectively reduced H2O2-induced oxidative stress. Among them, only P3 (peptide sequence: RSAVLLSH) increased HO-1 protein expression. Additionally, the knockdown of Nrf2 suppressed the induction of HO-1 expression by P3. Our results indicated that P3 identified from RP induced HO-1 by activating the Nrf2 signaling pathway.

Higher doses of methotrexate associated with discontinuation of oral glucocorticoids after initiation of biological DMARDs: A retrospective observational study based on data from a Japanese multicenter registry study.

OBJECTIVE: Glucocorticoids are important drugs used to treat rheumatoid arthritis. We recommend glucocorticoid discontinuation as soon as possible given the associated side-effects, but many patients continue to take oral glucocorticoids long-term. The present study aimed to explore factors associated with glucocorticoid discontinuation at 52 weeks after initiating biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: Subjects were 564 patients from a Japanese multicenter registry who were administered glucocorticoids and methotrexate (MTX) followed by initiation of the first bDMARD. We examined the status of oral glucocorticoid use at 52 weeks after initiating the first bDMARD. RESULTS: By 52 weeks after bDMARD initiation, 164 patients (29.1%) discontinued glucocorticoids. Multivariable analysis identified age, MTX dose, and glucocorticoid dose as factors independently associated with glucocorticoid discontinuation. After adjusting for baseline characteristics using propensity score matching, among patient groups administered MTX ≤ 8 mg/week and MTX > 8 mg/week, 105 pairs remained. A significantly higher rate of glucocorticoid discontinuation (41.0%) was noted for patients administered MTX > 8 mg/week. CONCLUSION: Our findings suggest that glucocorticoids may be discontinued after initiating bDMARDs. Moreover, higher MTX doses (>8 mg/week) at the time of bDMARD initiation were associated with glucocorticoid discontinuation among patients treated with bDMARDs.

Hepatoprotective Activity of Yellow Chinese Chive against Acetaminophen-Induced Acute Liver Injury via Nrf2 Signaling Pathway.

Glutathione, the most abundant intracellular antioxidant, protects cells against reactive oxygen species induced oxidative stress and regulates intracellular redox status. We previously demonstrated that yellow Chinese chive (ki-nira) increased the intracellular glutathione levels. Acetaminophen (APAP) is a commonly used analgesic. However, an overdose of APAP causes severe hepatotoxicity via depletion of the hepatic glutathione. In this study, we investigated the hepatoprotective effects of yellow Chinese chive extract (YCE) against APAP-induced hepatotoxicity in mice. YCE (25 or 100 mg/kg) was administered once daily for 7 d, and then APAP (700 mg/kg) was injected at 6 h before the mice were sacrificed. APAP treatment markedly increased the serum biological markers of liver injury such as alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase. Pretreatment with YCE significantly prevented the increases in the serum levels of these enzymes. Histopathological evaluation of the livers also revealed that YCE prevented APAP-induced centrilobular necrosis. Pretreatment with YCE dose-dependently elevated glutathione levels, but the difference was not significant. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in APAP-induced hepatotoxicity by regulating the antioxidant defense system. Therefore, we investigated the expression of Nrf2 and its target antioxidant enzyme. YCE led to an increased expression of Nrf2 and its target antioxidant enzymes, NAD(P)H quinone oxidoreductase 1 (NQO1), glutathione peroxidase (GPx), cystine uptake transporter (xCT), especially hemeoxygenase-1 (HO-1) in mice livers. These results suggest that YCE could induce HO-1 expression via activation of the Nrf2 antioxidant pathway, and protect against APAP-induced hepatotoxicity in mice.

Protective Effects of Rice Peptide Oryza Peptide-P60 against Oxidative Injury through Activation of Nrf2 Signaling Pathway In Vitro and In Vivo.

We previously showed that commercially available rice peptide Oryza Peptide-P60 (OP60) increased the intracellular glutathione levels. This study aimed to evaluate the antioxidant potential of this peptide and assess its mechanism of action. Pretreatment of HepG2 cells with OP60 reduced the cytotoxicity caused by H2O2 or acetaminophen (APAP) (47.7 ± 1.3% or 12.2 ± 1.3% of the cytotoxicity for 5 mg/mL OP60 pretreatment compared to that in H2O2- or APAP-treated groups, respectively; p < 0.01) through the restoration of glutathione homeostasis. Moreover, OP60 elevated the mRNA level of genes encoding heavy and light subunits of γ-glutamylcysteine synthetase (γ-GCS) by 2.9 ± 0.1-fold and 2.7 ± 0.2-fold (p < 0.001), respectively, at 8 h and also increased the level of mRNA encoding other antioxidant enzymes. Besides, OP60 promoted Nrf2 nuclear translocation by 2.2 ± 0.3-fold (p < 0.05) after 8 h. Conversely, knockdown of Nrf2 inhibited the increase of the intracellular glutathione levels and suppressed the induction of antioxidant enzyme expression by OP60. In animal studies, OP60 prevented APAP-induced liver injury by suppressing glutathione depletion (from 0.19 ± 0.02 mmol/mg protein to 0.90 ± 0.02 mmol/mg protein; p < 0.01, by pretreatment with 500 mg/kg OP60) and increasing heavy subunit of γ-GCS and heme oxygenase-1 expression in the liver. Our results indicated that OP60 exhibits a cytoprotective effect via the Nrf2 signaling pathway and is one of the few peptides with excellent antioxidant properties.

Association between seropositivity and discontinuation of tumor necrosis factor inhibitors due to ineffectiveness in rheumatoid arthritis.

INTRODUCTION/OBJECTIVES: Discontinuation of biologic therapy in rheumatoid arthritis is attributable to various reasons, with the most important cause being insufficient response. In this study, we investigated the association between rheumatoid factor (RF) and anti-citrullinated protein autoantibody (ACPA) status and the discontinuation of tumor necrosis factor inhibitors (TNFi) therapy due to insufficient response in bio-naïve rheumatoid arthritis (RA) patients. METHOD: This study included patients enrolled in the Tsurumai Biologic Communication Registry in Japan. The crude comparison of TNFi discontinuation due to ineffectiveness between seropositive and seronegative patients was analyzed using the cumulative incidence function of competing events and Gray test. We assessed the associations between baseline patient characteristics and discontinuation of TNFi therapy due to insufficient response using Fine-Gray proportional hazard regression. Fine-Gray proportional hazard analysis considered competing events of interest, including insufficient response, adverse event, palliation, and personal reasons. RESULTS: Of 1237 patients evaluated, 79.3% were positive for RF and 85.4% for ACPA; 72.6% were double positive and 11.1% were double negative. TNFi therapy had been discontinued because of insufficient response at 200 weeks in 19.8% RF-positive, 16.7% RF-negative, 23.0% ACPA-positive, and 13.8% ACPA-negative patients. There was a significantly higher discontinuation rate due to insufficient response in ACPA-positive patients than in ACPA-negative patients using Gray test, with a similar trend as that for RF status. RF positivity was significantly predictive of the discontinuation of TNFi therapy due to ineffectiveness using Fine-Gray proportional hazard regression analysis after adjusting for baseline characteristics, including age, sex, stage, class, disease activity at baseline, methotrexate use, and prednisolone use [hazard ratio 1.73 (95% confidence interval 1.07-2.80)]. CONCLUSIONS: Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients. Key Points • RF positivity is related to a higher discontinuation rate of TNFi therapy due to ineffectiveness. • ACPA is not predictive of a discontinuation of TNFi therapy due to ineffectiveness.

Multicenter, observational clinical study of abatacept in Japanese patients with rheumatoid arthritis.

The aim of this study was to assess abatacept in rheumatoid arthritis (RA) patient. Patients (20 men, 89 women, aged 61.9 ± 10.4 y) who responded inadequately to conventional synthetic disease-modifying anti-rheumatic drug were treated with abatacept for 24-months. Disease activity score in 28 joints (DAS28-CRP) was evaluated. Of 109 patients, 82 (75.2%) were on methotrexate (MTX; mean dosage 9.0 ± 2.7 mg/week); 48 (44.0%) were naive to biologics and 61 (56.0%) had failed biologics. The 1- and 2-year retention rates were 77% and 53%, respectively. At 24-months, the DAS28-CRP remission rates were 54.5% in the biologic-naïve patients, and 28.2% in the biologic-failure patients (p < .01), while the structural remission rates were 83.9% and 73.1%, respectively (p = .461). Abatacept was equally effective in RA patients who were and were not on concomitant MTX. Biologic-naïve was associated with better clinical outcome. Abatacept was effective in patients who showed decreasing anti-CCP antibody titers or serum MMP-3 levels during treatment. Infection was the most frequent adverse effect of abatacept therapy. In conclusion, abatacept is more effective in biologic-naïve than in biologic-failure RA patients with or without concomitant use of MTX. Abatacept is more effective in RA patients with than without decreasing serum MMP-3 or anti-CCP antibody titers during treatment.

Concomitant methotrexate has little effect on clinical outcomes of abatacept in rheumatoid arthritis: a propensity score matching analysis.

OBJECTIVE: To compare the clinical outcomes of abatacept between rheumatoid arthritis patients with and without concomitant methotrexate (MTX) treatment in daily clinical practice. METHODS: A retrospective cohort study was performed using data from a multicentre registry. A total of 176 consecutive rheumatoid arthritis patients treated with abatacept were included. The propensity score based on multiple baseline characteristic variables was calculated, and 41 of 86 patients treated without MTX (MTX(-)) and 41 of 90 patients treated with concomitant MTX (MTX(+)) were statistically extracted and analysed. Clinical outcomes were evaluated and compared between the two groups over a 52-week period. RESULTS: Baseline characteristics were statistically comparable. No significant differences were observed in the following clinical outcomes from baseline throughout the 52-week period: drug retention rate (MTX(-)/MTX(+) 79.1%/80.5%), mean change in disease activity score based on 28 joints (DAS28-CRP) from baseline (- 1.35/- 1.54), low disease activity rate (48.8%/43.9%), clinical remission rate (31.7%/36.6%), moderate European League Against Rheumatism (EULAR) response rate (68.3%/68.3%), and good EULAR response rate (36.6%/41.1%) at 52 weeks. CONCLUSION: In rheumatoid arthritis patients with similar background characteristics undergoing abatacept treatment, concomitant MTX does not seem to affect clinical outcomes. Abatacept would be a suitable treatment option in daily clinical practice in patients with contraindications to MTX. KEY POINTS: • This is the first study to directly compare the clinical efficacy and safety of abatacept between patients with and without concomitant methotrexate (MTX) treatment in 'real-world' settings using the propensity score matching method. • There were no significant differences in clinical outcomes of abatacept between patients with and without concomitant MTX treatment. • We used data from a large Japanese multicentre registry for biologics in rheumatoid arthritis, thereby decreasing selection bias based on the personal preferences of physicians.

Clinical effectiveness and long-term retention of abatacept in elderly rheumatoid arthritis patients: Results from a multicenter registry system.

Objective: To study the clinical effectiveness and long-term retention rate of abatacept (ABA) in elderly rheumatoid arthritis (RA) patients in daily clinical practice.Methods: A retrospective cohort study was performed using data from a multicenter registry. Our study population comprised 500 consecutive RA patients treated with ABA. We compared clinical effectiveness and ABA retention rates between the Young (≤62 years), Middle (62 to 72 years), and Elderly (≥72 years) groups. We also performed separate examinations to identify predictive factors for ABA discontinuation in those with versus those without concomitant methotrexate (MTX) treatment.Results: Mean age was 52.7 years in the Young group, 67.7 years in the Middle group, and 78.1 years in the Elderly group. No significant group-dependent differences were found in mean DAS28 score, categorical distribution of DAS28, and EULAR response rate across the 52 weeks. The ABA retention rates at three years as determined by the Kaplan-Meier method were similar in all three groups. Patient age was not a significant predictor of ABA discontinuation due to adverse events in patients with concomitant MTX; however, it was found to be a significant predictor for those who did not use MTX (Cox hazard model).Conclusion: ABA would be a reasonable treatment option for elderly RA patients from the viewpoints of both clinical effectiveness and long-term retention. However, physicians should watch carefully for any serious adverse reactions in elderly RA patients with intolerance to MTX.

Sake lees hydrolysate protects against acetaminophen-induced hepatotoxicity via activation of the Nrf2 antioxidant pathway.

Acetaminophen is a commonly used analgesic. However, an overdose of acetaminophen causes severe hepatotoxicity via depletion of hepatic glutathione. Here, we investigated the protective effects of sake lees hydrolysate against acetaminophen-induced hepatotoxicity in mice. Sake lees hydrolysate was administered orally to ICR mice for seven days. Six hours after acetaminophen treatment, the mice were sacrificed, and blood and liver samples were collected for analysis. Treatment with acetaminophen markedly increased the levels of serum alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase. Pretreatment with sake lees hydrolysate significantly prevented the increases in the serum levels of these enzymes and inhibited acetaminophen-mediated glutathione depletion. In addition, histopathological evaluation of the livers also revealed that sake lees hydrolysate prevented acetaminophen-induced centrilobular necrosis. The expression of γ-glutamylcysteine synthetase (γ-GCS), hemeoxygenase-1 (HO-1) and nuclear factor erythroid 2-related factor 2 (Nrf2) in the liver were decreased after acetaminophen treatment, whereas pretreatment with sake lees hydrolysate led to an increased expression of all three proteins. Furthermore, sake lees hydrolysate induced the expression of these proteins in HepG2. These results suggested that sake lees hydrolysate could induces HO-1 and γ-GCS expression via activation of the Nrf2 antioxidant pathway, and protects against acetaminophen-induced hepatotoxicity in mice.

Hepatoprotective effects of rice-derived peptides against acetaminophen-induced damage in mice.

Glutathione, the most abundant intracellular antioxidant, protects cells against reactive oxygen species induced oxidative stress and regulates intracellular redox status. We found that rice peptides increased intracellular glutathione levels in human hepatoblastoma HepG2 cells. Acetaminophen is a commonly used analgesic. However, an overdose of acetaminophen causes severe hepatotoxicity via depletion of hepatic glutathione. Here, we investigated the protective effects of rice peptides on acetaminophen-induced hepatotoxicity in mice. ICR mice were orally administered rice peptides (0, 100 or 500 mg/kg) for seven days, followed by the induction of hepatotoxicity via intraperitoneal injection of acetaminophen (700 mg/kg). Pretreatment with rice peptides significantly prevented increases in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels and protected against hepatic glutathione depletion. The expression of γ-glutamylcysteine synthetase, a key regulatory enzyme in the synthesis of glutathione, was decreased by treatment with acetaminophen, albeit rice peptides treatment recovered its expression compared to that achieved treatment with acetaminophen. In addition, histopathological evaluation of the livers also revealed that rice peptides prevented acetaminophen-induced centrilobular necrosis. These results suggest that rice peptides increased intracellular glutathione levels and could protect against acetaminophen-induced hepatotoxicity in mice.

Anti-oxidative Activity of Hydrolysate from Rice Bran Protein in HepG2 Cells.

Glutathione (GSH) is an ubiquitous thiol-containing tripeptide, which plays important roles in cellular protection from oxidative stress. In our search for a dietary source that can increase GSH levels, we discovered that a 24 h treatment of HepG2 cells with rice bran protein hydrolysate (RBPH), prepared by Umamizyme G-catalyzed hydrolysis, increased the GSH content in a dose-dependent manner. RBPH elevated the expression levels of γ-glutamylcysteine synthetase (γ-GCS), which constitutes the rate-limiting enzyme of GSH synthesis, and of another two enzymes, hemeoxygenase-1 (HO-1) and reduced nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase 1 (NQO1). This induction was preceded by the accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) inside the nucleus, which is a key transcription factor for the expression of the γ-GCS, HO-1, and NQO1. Pre-treatment of cells with RBPH produced a significant protective effect against cytotoxicity caused by H2O2 or ethanol. These results indicate that RBPH exerts a protective effect against oxidative stress by modulating GSH levels and anti-oxidative enzyme expression via the Nrf2 pathway.

Long-period ocean-bottom motions in the source areas of large subduction earthquakes.

Long-period ground motions in plain and basin areas on land can cause large-scale, severe damage to structures and buildings and have been widely investigated for disaster prevention and mitigation. However, such motions in ocean-bottom areas are poorly studied because of their relative insignificance in uninhabited areas and the lack of ocean-bottom strong-motion data. Here, we report on evidence for the development of long-period (10-20 s) motions using deep ocean-bottom data. The waveforms and spectrograms demonstrate prolonged and amplified motions that are inconsistent with attenuation patterns of ground motions on land. Simulated waveforms reproducing observed ocean-bottom data demonstrate substantial contributions of thick low-velocity sediment layers to development of these motions. This development, which could affect magnitude estimates and finite fault slip modelling because of its critical period ranges on their estimations, may be common in the source areas of subduction earthquakes where thick, low-velocity sediment layers are present.

Reduced folate carrier 1 gene expression levels are correlated with methotrexate efficacy in Japanese patients with rheumatoid arthritis.

Responsiveness to methotrexate (MTX), the "anchor drug" for treating rheumatoid arthritis (RA), varies among individual patients. In this study we investigated the effects of folate transporter gene expression levels on disease activity among 56 Japanese patients with RA who were undergoing MTX therapy. We also assessed gene expression levels for 15 healthy control subjects. The mRNA expression levels of reduced folate carrier 1 (RFC1) and proton-coupled folate transporter (PCFT) in PBMCs from these patients and controls were determined using real-time quantitative polymerase chain reaction (PCR). Compared with PCFT, there were large individual differences in RFC1 mRNA expression levels in both RA patients and healthy controls. RFC1 mRNA expression levels and RA disease activity scores were significantly negatively correlated, as disease activity scores were lower for patients with higher RFC1 mRNA expression levels. However, RFC1 mRNA levels were not correlated with MTX doses. Thus, the clinical efficacy of MTX for Japanese RA patients was associated with the expression level of a folate transporter gene. Increased RFC1 expression may increase MTX uptake by immune cells, such as lymphocytes, and as a result, RA disease activity would be reduced.

Comparison of efficacy and safety of tacrolimus and methotrexate in combination with abatacept in patients with rheumatoid arthritis; a retrospective observational study in the TBC Registry.

OBJECTIVES: Tacrolimus (TAC) and abatacept (ABT) inhibit T-cells via different mechanisms and, in combination, may be effective against rheumatoid arthritis. However, they may also disrupt normal immune functions. We compared the efficacy and safety of ABT administered to patients in combination with TAC, methotrexate (MTX), or other drugs. METHODS: This was a retrospective multicenter study conducted to compare the efficacy and safety of ABT in 211 patients: the drug was administered together with TAC (ABT+ TAC group; 22 patients), MTX (ABT+ MTX group; 102 patients), or patients treated without concomitant MTX or TAC (ABT mono group; 87 patients). The disease activity, treatment continuation rate, and reason for discontinuation of treatment were investigated. RESULTS: The retention rate at Week 24 was similar in the three groups. There were no cases of discontinuation related to the appearance of adverse events in the ABT+ TAC group. At Week 24, according to the European League Against Rheumatism response criteria, the "good" response rates were 33.3%, 13.4%, and 13.4% in the ABT+ TAC, ABT+ MTX, and ABT mono groups, respectively. Statistically significant decreases in various disease activity scores/indices were observed in all the groups as early as Week 4. CONCLUSIONS: Although the sample size was small, the results of this retrospective study suggest that the ABT+ TAC combination therapy has at least comparable safety and efficacy to those of the ABT+ MTX combination, and that it can thus be a useful option for patients who cannot take MTX.

Use of a 12-week observational period for predicting low disease activity at 52 weeks in RA patients treated with abatacept: a retrospective observational study based on data from a Japanese multicentre registry study.

OBJECTIVE: Only a few studies have assessed predictive factors for the long-term efficacy of abatacept. This study aimed to provide clinical evidence of an adequate observational period for predicting low disease activity (LDA) achievement at 52 weeks in RA patients treated with abatacept. METHODS: Participants were all patients registered in a Japanese multicentre registry who were treated with abatacept and had at least 52 weeks of follow-up (n = 254). RESULTS: Areas under the receiver operating characteristic curves for the 28-joint count with CRP (DAS28-CRP) at each time point for LDA achievement at 52 weeks were: 0.686 (cut-off score: 4.6) at baseline, 0.780 (3.8) at 4 weeks, 0.875 (3.3) at 12 weeks, and 0.900 (3.0) at 24 weeks. Although patients with a DAS28-CRP score < 3.0 at 24 weeks had the highest proportion of LDA achievement at 52 weeks (79.3%), the proportion for those with a score < 3.3 at 12 weeks was comparable (77.2%, P = 0.697). Proportions were significantly lower in patients with a score < 3.8 at 4 weeks or < 4.6 at baseline. Multivariate logistic regression demonstrated that a DAS28 score of < 3.3 at 12 weeks was an independent strong predictor for LDA at 52 weeks (adjusted odds ratio: 15.2, P < 0.001). CONCLUSION: Twelve weeks is an adequate observational period to judge the long-term clinical efficacy of abatacept, and is about as early as the period for assessing TNF blockade therapy.

Clinical efficacy of abatacept compared to adalimumab and tocilizumab in rheumatoid arthritis patients with high disease activity.

Favourable clinical results in rheumatoid arthritis (RA) patients with high disease activity (HDA) are difficult to achieve. This study evaluated the clinical efficacy of abatacept according to baseline disease activity compared to adalimumab and tocilizumab. This study included all patients registered in a Japanese multicenter registry treated with abatacept (n = 214), adalimumab (n = 175), or tocilizumab (n = 143) for 24 weeks. Clinical efficacy of abatacept in patients with HDA (DAS28-CRP > 4.1) and low and moderate disease activity was compared. Clinical efficacy of abatacept, adalimumab, and tocilizumab was compared in patients with HDA at baseline. In patients treated with abatacept, multivariate logistic regression identified HDA at baseline as an independent predictor for achieving low disease activity (LDA; DAS28-CRP < 2.7) [OR 0.26, 95 % CI 0.14-0.50] or remission (DAS28-CRP < 2.3) [OR 0.26, 95 % CI 0.12-0.56] at 24 weeks. In patients with HDA at baseline, logistic regression did not identify treatment with adalimumab or tocilizumab as independent predictors of LDA or remission compared to abatacept. Retention rates based on insufficient efficacy were significantly higher in patients treated with abatacept compared to adalimumab and lower than tocilizumab. Retention rates based on adverse events in patients treated with abatacept were significantly lower compared to tocilizumab. Clinical efficacy of abatacept was affected by baseline disease activity. There were no significant differences between the three different classes of biologics regarding clinical efficacy for treating RA patients with HDA, although definitive conclusions regarding long-term efficacy will require further research.

Clinical efficacy of abatacept in Japanese rheumatoid arthritis patients.

OBJECTIVES: The purpose of this study was to examine the treatment retention and efficacy of abatacept, the first member of a new class of biologic agents, in Japanese rheumatoid arthritis (RA) patients during clinical practice. METHODS: A retrospective multicenter study was conducted with patients who underwent abatacept therapy for 24 weeks (n = 143). RESULTS: Patients at baseline had a mean age of 63.5 years, a mean disease duration of 11.3 years, and a mean disease activity score in 28 joints (DAS28) of 4.5. Overall retention of abatacept treatment was 83.2 % at 24 weeks, when 46.2 % of patients achieved DAS28-defined low disease activity (LDA; DAS28 <3.2) and 26.6 % achieved DAS28-defined remission (DAS28 <2.6). LDA was achieved in a significantly higher proportion of patients without prior biologics therapy compared to those with prior biologics (60.9 vs. 34.2 %, p = 0.001). There was no significant difference between patients with or without concomitant methotrexate (MTX) therapy (45.2 vs. 47.5 %). CONCLUSIONS: Abatacept therapy appears to be highly effective and well tolerated during clinical treatment of RA. Abatacept was particularly effective in patients with no history of biologics use, and did not appear to be dependent on concomitant MTX therapy.

A single nucleotide polymorphism of reduced folate carrier 1 predicts methotrexate efficacy in Japanese patients with rheumatoid arthritis.

  Methotrexate (MTX) exhibits large inter-individual and inter-ethnic differences in the dose required for its anti-rheumatic effect. To maintain low disease activity, patients may require increased MTX doses or co-administration of biologic disease-modifying anti-rheumatic drugs (bDMARDs). The availability of a marker predicting the effect of MTX will make it possible to increase the MTX dose and prescribe bDMARDs to patients at an early stage. To establish individualized medication for rheumatoid arthritis (RA), we investigated genetic polymorphisms of the folate pathway in Japanese RA patients. Eighty-nine patients were treated with MTX alone (MTX group). MTX and bDMARDs were co-administered to 81 patients because of insufficient MTX efficacy (MTX + bDMARDs group); an equally stable therapeutic effect was achieved in both groups. Polymorphism analyses using bDMARD co-treatment as the objective variable revealed a significant association between age and the G80A polymorphism of the reduced folate carrier 1 gene (RFC1) as an explanatory variable. Compared to patients with the A allele, patients with the G allele may have less intracellular MTX uptake and, therefore, poor efficacy; a greater number of them were found to be bDMARD concomitant cases. The results of this study suggest that the RFC1 G80A polymorphism may be a useful marker for predicting MTX efficacy in Japanese patients with RA.

An artifact derived from a pseudogene led to the discovery of microRNA binding site polymorphism in the 3'-untranslated region of the human dihydrofolate reductase gene.

A novel single-nucleotide polymorphism (SNP) in the 3'-untranslated region of the human dihydrofolate reductase (DHFR) gene with enhanced expression was identified in 2001. In 2007, it was reported that this SNP, DHFR C829T, was located close to a microRNA binding site and contributed to the stability of mRNA. Many researchers have analyzed this SNP in several races including Asians and Caucasians. However, the mutation allele is not yet confirmed in most populations. In this study, we reinvestigated the frequency of this SNP using three methods. First, this SNP in genomic DNA was analyzed by a PCR-restriction fragment length polymorphism method. Second, this SNP in mRNA was analyzed by a single nucleotide extension method following a reverse transcription reaction. Third, the mRNA expression level was analyzed by a real-time PCR method. The findings in our study, regarding the discovery of this SNP, suggest that the SNP is an artifact caused by contamination by the genomic DNA of the pseudogene DHFRP1. This study is a reinvestigation of a newly discovered genetic polymorphism.

Anti-tumor necrosis factor therapy in rheumatoid arthritis patients with a history of deep prosthetic joint infection: a report of four cases.

Four rheumatoid arthritis patients (three women and one man) who had a history of prosthetic joint infection were treated with anti-tumor necrosis factor (TNF) agents after treatment of the infection. The anti-TNF therapy was subsequently discontinued in three patients. The reason for discontinuation was not the reactivation of infection, but disseminated tuberculosis, Pneumocystis jiroveci pneumonia, and interstitial pneumonia, respectively. These cases suggest that a history of prosthetic joint infection may be a contraindication for treatment with anti-TNF agents.