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This study investigated the effectiveness of treatment with Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) assessed by ultrasonography (US) activity, and the influence of patient characteristics and previous treatments.This prospective study assessed 60 treatment initiations among 53 Japanese patients diagnosed with RA who underwent treatment with JAK inhibitors during June 2013 to February 2020. Of the 53 patients, seven patients were enrolled in duplicate because they were treated with two different JAK inhibitors at different periods. For each case, the improvement rate on the power Doppler (PD) score was assessed at 6 month follow-up. Median improvement rate of PD score was used to classify cases as either US responders or non-responders, and patient characteristics were compared between the two groups.All indicators of clinical disease activity and US activity showed a significant improvement at 3 months compared with baseline. Although the JAK inhibitor-cycler group and the interleukin-6 (IL-6) inhibitor inadequate response (IR) group tended to show a later improvement for US activity, all indicators of clinical disease activity and US activity showed a significant improvement at 6 months compared with baseline for both groups. Multivariate analysis showed that concomitant methotrexate use and an IR to the previous biologic or targeted-synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) treatment were independently and significantly associated with US responders.Use of a JAK inhibitor in combination with methotrexate and an absence of IR to any previous b/tsDMARDs demonstrated superior effectiveness for patients with RA.

Objectives: Using multicentre ultrasound (US) cohort data among patients with rheumatoid arthritis (RA), we aimed to identify baseline factors that permit differentiation between two patient cohort...

Objective: To determine whether the positivity of baseline anti-Ro/Sjögren’s syndrome antigen A (SSA) antibodies influences the response to abatacept, we compared therapeutic responses between anti-Ro/SSA antibody-negative and -positive patients with rheumatoid arthritis (RA) using a multicentre RA ultrasonography prospective cohort. Method: We reviewed Japanese patients with RA who started abatacept as the first biological disease-modifying anti-rheumatic drug between June 2013 and April 2018. We assessed 28-joint Disease Activity Score–erythrocyte sedimentation rate (DAS28-ESR) change between baseline and 6 or 12 months after treatment in RA patients treated with abatacept, and European League Against Rheumatism (EULAR) response at 6 and 12 months. The Global OMERACT-EULAR Synovitis Score (GLOESS) was calculated at baseline and at 6 and 12 months. Results: Overall, 51 patients were enrolled and divided into anti-Ro/SSA antibody-negative and -positive groups of 35 and 16, respectively. Median age at baseline was significantly higher in the anti-Ro/SSA antibody-negative group (p = 0.04). The retention rate and percentage of EULAR good responders at 12 months were significantly higher in the anti-Ro/SSA antibody-negative group (both p = 0.02). Anti-Ro/SSA antibody-negative patients exhibited larger decreases in both DAS28-ESR and DAS28-C-reactive protein at 12 months than anti-Ro/SSA antibody-positive patients (p = 0.02 and 0.04, respectively). GLOESS decreased significantly at 6 months in anti-Ro/SSA antibody-negative patients (p = 0.03). Multivariate analyses showed that anti-Ro/SSA antibody positivity was an independent factor associated with change in the DAS28-ESR at 6 months (p Conclusion: Anti-Ro/SSA antibody positivity predicts a poor response to abatacept and low retention rate.

For the 2017-18 influenza season, A/Saitama/103/2014 (CEXP-002) (Saitama strain) was antigenically more similar to prior circulating strains than A/Hong Kong/4801/2014 (X-263) (Hong Kong strain) in a ferret model and was selected as the A(H3N2) vaccine virus strain in Japan. However, the Saitama strain grew poorly, and the Japanese government switched to the Hong Kong strain, raising public concerns of poor effectiveness. To enhance understanding of the correlation between antigenicity in experimental models and immunogenicity, as a surrogate measure of vaccine effectiveness, in the human population, we compared the immunogenicity of specially-prepared single dose monovalent influenza A(H3N2) vaccines containing the Saitama or the Hong Kong strain.A randomized controlled trial of 100 healthy adults aged 20-64 years (n = 50/group) was conducted. Virus neutralization assay was performed on sera from days 0 (pre-vaccination) and 21 (post-vaccination). Geometric mean titer (GMT), mean fold rise (MFR), seroconversion proportion (SCP), and seroprotection proportion (SPP) were calculated for vaccine strains and a representative circulating A(H3N2) virus strain (A/Osaka/188/2017).For the Hong Kong strain, post-vaccination GMT was significantly higher in the Hong Kong vaccine recipients (1:546 vs 1:260, p 0.01), but MFR, SCP, and SPP were similar for both vaccine groups. For the Saitama strain, post-vaccination GMT (1:116 vs 1:61, p = 0.01) and SPP (86% vs 68%, p = 0.03) were significantly higher in the Hong Kong vaccine recipients, but MFR and SCP were similar for both vaccine groups. Against A/Osaka/188/2017, post-vaccination GMT and MFR were similar in both vaccine groups, but SCP (32% vs 4%, p 0.01) and SPP (28% vs. 6%, p 0.01) were significantly higher in the Hong Kong vaccine recipients.The Hong Kong vaccine induced better or equivalent immunogenicity in comparison to the Saitama vaccine. Our trial showed that antigenic similarity in experimental models does not necessarily correlate with immunogenicity in the human population.UMIN000029293.

To compare therapeutic efficacy of tumour necrosis factor inhibitor (TNFi) cyclers and non-TNFi switchers in patients with rheumatoid arthritis (RA) having inadequate response to previous TNFis (TNF-IR patients) using composite measures including imaging assessment with power Doppler ultrasonography (PDUS). Patients with RA who had inadequate response to one or more previous TNFi agents with moderate or higher disease activity were enrolled. The outcomes of 56 TNF-IR patients were analysed. Patients were divided into 19 TNFi cyclers and 37 non-TNFi switchers (16 abatacept [ABT] and 21 tocilizumab [TCZ] switchers). Retention ratio at 6 months was significantly higher in non-TNFi switchers than in TNFi cyclers (p

Background To further improve rheumatoid arthritis (RA) treatment, it is necessary to understand each RA patient’s satisfaction and to identify the factors affecting their satisfaction. Despite the rise in medical costs for RA, little is known about the factors that influence patient satisfaction with the cost of treatment in RA patients. Methods This is a multicenter observational study of Japanese RA patients from the FRANK Registry with data analyzed from March 2017 to August 2020. We collected data on demographic characteristics, clinical data, quality of life which was evaluated using the EuroQol 5-dimensional questionnaire (EQ5D), and patient satisfaction. The four categories of patient satisfaction were evaluated individually (i.e., cost, treatment efficacy, activities of daily living [ADL], and global treatment satisfaction). We analyzed the factors that affected each patient’s satisfaction, such as age, sex, EQ5D, disease duration, disease activity, and treatment. Results This study included 2235 RA outpatients (406 males, 1829 females). In RA patients, “very satisfied” and “satisfied” were given for nearly half of each satisfaction aspect (cost 49%; efficacy 72%; ADL 58%; global treatment 66%) at the time of the initial registration. To investigate the factors influencing each satisfaction, multivariate analysis has revealed that the use of b/tsDMARDs increased satisfaction of treatment effect (odds ratio [OR] 0.66) and ADL (OR 0.78) but decreased cost satisfaction (OR 2.21). Age (50–64 years; OR 0.91; 65–74 years, 0.55: ≥ 75 years, 0.35), female (OR 0.81), and history of musculoskeletal surgery (OR 0.60) all increased cost satisfaction. Patients with lower disease activity and higher EQ5D scores had higher levels of satisfaction in all areas. Conclusions In this study, patient satisfaction in terms of cost, treatment effect, ADL, and overall treatment was generally higher, but some patients were dissatisfied. The cost of satisfaction increased with age and a history of musculoskeletal surgery, while it decreased with a lower EQ5D score and the use of b/tsDMARDs.

Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting.Me...

The essential trace element zinc maintains liver functions. Liver diseases can alter overall zinc concentrations, and hypozincemia is associated with various hepatic pathologies. Modulating systemic zinc through dietary supplementation is potentially useful for liver diseases. We evaluated the usefulness of zinc (NPC-02; acetate formulation) supplementation. We conducted two NPC-02 studies on zinc-deficient patients (serum zinc

Background To analyse the subsequent clinical course of patients with rheumatoid arthritis (RA) who either continued or discontinued biologic agents after hospitalization for infections. Methods We retrospectively reviewed the clinical records of 230 RA patients with 307 hospitalizations for infections under biologic therapy between September 2008 and May 2014 in 15 institutions for up to 18 months after discharge. The risks of RA flares and subsequent hospitalizations for infections from 61 days to 18 months after discharge were evaluated. Results Survival analyses indicated that patients who continued biologic therapy had a significantly lower risk of RA flares (31.4% vs. 60.6%, P P = 0.37). Multivariate analysis showed that discontinuation of biologic therapy, diabetes, and a history of hospitalization for infection under biologic therapy were associated with RA flares. Oral steroid therapy equivalent to prednisolone 5 mg/day or more and chronic renal dysfunction were independent risk factors for subsequent hospitalizations for infections. Conclusions Discontinuation of biologic therapy after hospitalization for infections may result in RA flares. Continuation of biologic therapy is preferable, particularly in patients without immunodeficiency.

Coronavirus disease 2019 (COVID-19) has become a serious public health problem worldwide. In general, healthcare workers are considered to be at higher risk of COVID-19 infection. However, the prevalence of COVID-19 among healthcare workers in Japan is not well characterized. In this study, we aimed to examine the seroprevalence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies among 2160 healthcare workers in hospitals and clinics that are not designated to treat COVID-19 patients in Japan. The prevalence of SARS-CoV-2 immunoglobulin G was 1.2% in August and October 2020 (during and after the second wave of the pandemic in Japan), which is relatively higher than that in the general population in Japan (0.03–0.91%). Because of the higher risk of COVID-19 infection, healthcare workers should be the top priority for further social support and vaccination against SARS-CoV-2.

BackgroundFine specificity of anti-citrullinated protein antibodies (ACPAs), in which cross-reactivity exists, varies among patients with rheumatoid arthritis (RA), but it is unclear whether the mechanism of ACPA production is same or different among individuals. Since avidity of serum antibody reflects the direction of immune response, we compared the levels of avidity and cross-reactivity between various ACPAs in a cohort of RA patient.MethodsSera from 180 RA patients positive for anti-cyclic citrullinated peptide (CCP) 2 antibody were screened for positivity of antibodies against CCP1, and citrullnated fibrinogen (cFib), enolase (cEno), and vimentin (cVim) peptides. Avidity of the four ACPAs, and some autoantibodies and antibodies against foreign antigens was determined by an elution assay using sodium thiocyanate solution. Cross-reactivity between different ACPAs was estimated by measuring the inhibition of binding by competitor peptides. ResultsThe prevalence of anti-CCP1, anti-cFib, anti-cEno, and anti-cVim antibodies in the anti-CCP2-positive RA cohort were 37.7%, 38.3%, 15.6%, and 23.9%, respectively. The avidity of ACPAs, except for anti-cVim antibody, was significantly lower than that of antibodies against foreign antigens, while there was a large variety in the avidity of other autoantibodies. At individual levels, the avidity of anti-cVim was significantly higher than that of other ACPAs, and there was a significant correlation in the avidity of anti-CCP and anti-cFib antibodies. Substantial extent of cross-reactivity was seen between different ACPAs, which also showed a fixed hierarchy.ConclusionThe fixed hierarchy in the avidity and cross-reactivity between different ACPAs suggests that the mechanism underlying ACPA production is common to all RA patients. Presence of a dominant antigen that induces whole ACPA response is speculated.

Objective To explore the variables associated with initial favorable power Doppler (PD) ultrasound (US) response induced by biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in patients with rheumatoid arthritis (RA). Methods We have been prospectively investigating the course of active RA patients using US after the introduction of b/tsDMARDs in the Kyushu region of Japan since June 2013. One hundred fifty patients have completed the first 6 months of observation at present and have been evaluated. US was assessed in 22 joints of bilateral hands using gray-scale (GS) and PD images on a scale from 0 to 3. The sum of these scores was used as the indicator of US disease activity. We defined PD remission by total PD score=0 at 6 months and investigated the associated variables by multivariate logistic regression analysis. Results The total PD and GS scores and the clinical composite measures significantly improved at 6 months, whereas these reductions were less in bDMARDs switchers as compared with bDMARDs-naive patients. Multivariate logistic regression analysis showed that short disease duration (odds ratio 0.99, 95% confidence interval (CI) 0.99-1.00, p=0.031), the absence of any previous use of bDMARDs (odds ratio 0.27, 95% CI 0.10-0.68, p=0.0047) and low total PD scores (odds ratio 0.85, 95% CI 0.76-0.94, p=0.0003) at baseline were independent predictors of PD remission at 6 months. Conclusion The present prospective US cohort has for the first time shown the variables that are associated with initial PD response to b/tsDMARDs. This article is protected by copyright. All rights reserved.

Abatacept may exert its clinical effect on rheumatoid arthritis (RA) by suppressing anti-cyclic citrullinated peptide (CCP) antibody production. This study was undertaken to test this hypothesis by examining the changes of disease activity of RA and anti-CCP antibody levels over time after starting abatacept. Sixty Japanese RA patients who started abatacept were included in this multicenter, prospective observational study. Simple Disease Activity Index (SDAI) and anti-CCP antibody levels were evaluated at 12, 24, and 52 weeks. The mean SDAI score significantly decreased within 12 weeks after starting abatacept and was maintained thereafter. On the contrary, the mean anti-CCP antibody levels did not change until 52 weeks. At the individual level, there were substantial changes of anti-CCP antibody levels, but these were not correlated with the changes of disease activity at any time points. Thus, abatacept reduces the disease activity of RA independently of modulating anti-CCP antibody production.

Sex differences in the prevalence of autoimmune diseases such as rheumatoid arthritis (RA) are well known, but little is known about those differences in relation to therapeutic response. Reduced folate carrier-1 (RFC-1), folypolyformyl glutamate synthase (FPGS), and γ-glutamyl hydrolase (GGH) are important transporters and enzymes that convert methotrexate (MTX) in the body. This study investigated the sex differences in mRNA expression of RFC-1, FPGS, and GGH in 190 unrelated healthy Japanese people. The genotypes and mRNA expression were determined using the real-time PCR method. Significant differences between men and women were observed in RFC-1, FPGS, and GGH mRNA expression. The mRNA expression of FPGS and GGH was greater in women than that in men, but the expression of RFC-1 was less in the former than the latter. In stratified analysis by genotype, significant differences in sex-specific mRNA expression were observed in G/G of FPGS, C/C of GGH 452, and C/C of GGH -401. All showed greater mRNA expression in women than in men. In the 5 single-nucleotide polymorphisms RFC-1 80G>A, RFC-1 -43T>C, FPGS 1994G>A, GGH 452C>T, and GGH -401C>T examined, the FPGS 1994 G/G (1.46-fold), GGH 452 C/C (2.16-fold), and GGH -401 C/C (2.68-fold) genotypes showed significantly higher mRNA expression in women than in men. Healthy Japanese adults in this study showed sex-specific differences in mRNA expression that differed among RFC-1, FPGS, and GGH. Therefore, the relationship between genetic polymorphisms and mRNA expression including sex differences might contribute to the variation in the efficacy/toxicity of MTX in patients with RA.

We aimed to evaluate the utility of a simplified ultrasonography (US) scoring system, which is desired in daily clinical practice, among patients with rheumatoid arthritis (RA) receiving biological/targeted synthetic disease-modifying antirheumatic drugs (DMARDs).A total of 289 Japanese patients with RA who were started on tumor necrosis factor inhibitors, abatacept, tocilizumab, or Janus kinase inhibitors between June 2013 and April 2019 at one of the 15 participating rheumatology centers were reviewed. We performed US assessment of articular synovia over 22 joints among bilateral wrist and finger joints, and the 22-joint (22j)-GS and 22-joint (22j)-PD scores were evaluated as an indicator of US activity using the sum of the GS and PD scores, respectively.The top 6 most affected joints included the bilateral wrist and second/third metacarpophalangeal joints. Therefore, 6-joint (6j)-GS and -PD scores were defined as the sum of the GS and PD scores from the 6 synovial sites over the aforementioned 6 joints, respectively. Although the 22j- or 6j-US scores were significantly correlated with DAS28-ESR or -CRP scores, the correlations were weak. Conversely, 6j-US scores were significantly and strongly correlated with 22j-US scores not only at baseline but also after therapy initiation.Using a multicenter cohort data, our results indicated that a simplified US scoring system could be adequately tolerated during any disease course among patients with RA receiving biological/targeted synthetic DMARDs., Medicine, 100(1), e23254; 2021

Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment. Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation. Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months. Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.

Objectives: This 12-week, randomized, double-blind, placebo-controlled, multicenter phase 1/2 study (NCT01449071) assessed the safety, pharmacokinetics, and pharmacodynamics of epratuzumab in Japanese patients with moderate-to-severe systemic lupus erythematosus despite standard of care.Methods: Twenty patients were randomized 1:1:1:1:1 to placebo or one of four epratuzumab dose regimens (100 mg every other week [Q2W], 400 mg Q2W, 600 mg every week [QW], or 1200 mg Q2W) administered during an initial 4-week dosing period. Adverse events (AEs), pharmacokinetics and pharmacodynamics were assessed.Results: Nineteen of 20 patients completed the study. All placebo patients and 13 of 16 epratuzumab patients reported ≥1 AE, 2 of 16 epratuzumab patients reported a serious AE. Cmax and AUCτ increased proportionally with dose after first and last infusion, t1/2 was similar across groups (∼13 days). Epratuzumab treatment was associated with decreased CD22 mean fluorescence intensity in total B cells (CD19+CD22+) and unswitched memory B cells (CD19+IgD+CD27+). Small-to-moderate decreases were observed in total B cell (CD20+) count.Conclusions: Epratuzumab was well-tolerated, with no new safety signals identified. The pharmacokinetics appeared linear after first and last infusions. Treatment with epratuzumab was associated with CD22 downregulation and with small-to-moderate decreases in total B cell count.

This study aimed to evaluate the remission in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ), based on prospectively registered data in clinical practice.We studied 114 consecutive RA patients treated with TCZ for an average of 3.5 years. Remission was evaluated by using the EULAR criteria and the new ACR/EULAR Boolean-based criteria.Among 114 patients (average age 52.2 years; average disease duration 10.6 years), 76 (67 %) had previously received anti-TNF biologics. Mean baseline DAS28-ESR of 5.4 and improved to 2.4 at 36 months. Overall, DAS28-ESR2.6 was attained by 66.7 %, while ACR/EULAR remission was attained by 35.1 %. ACR/EULAR remission rate was significantly higher in the patients who were biologics-naïve and had good response at the first month. Among 23 patients who completed the treatment for 3 years and had ACR/EULAR remission at 1 year, 15 (65 %) remained in the remission and 16 (70 %) had a DAS28-ESR2.6 at the final follow-up. The retention rate at 36 months was 68.2 %.In patients with RA, TCZ is highly effective for both biologics-naïve patients and patients previously exposed to biologics, achieving a high remission rate and drug continuation rate (68.2 %) in clinical practice.

To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study (Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy.Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks.A total of 164 eligible patients, including 161 who experienced loss of efficacy within 52 weeks of the DREAM study, resumed treatment: 157 with TCZ and 7 with DMARDs and/or infliximab. Of TCZ-treated patients, 88.5 % (139 patients) achieved DAS282.6 within 12 weeks, whereas among patients treated with DMARDs and/or infliximab only 14.3 % (1 patient) achieved DAS282.6. Adverse events were observed in 70 TCZ-treated patients (44.0 %), but no serious infusion reactions were observed.Retreatment with TCZ was well-tolerated and effective in patients who had responded to the preceding TCZ monotherapy but had experienced loss of efficacy after cessation of TCZ.

To evaluate humoral immune response to influenza vaccine and polysaccharide pneumococcal vaccine in patients with rheumatoid arthritis (RA) or Castleman's disease (CD) during tocilizumab therapy.Thirty-eight patients (28 RA and 10 CD) receiving tocilizumab and 39 RA patients receiving TNF inhibitors and/or synthetic DMARDs subcutaneously received a single dose of a split-virion inactivated influenza vaccine containing A(New Caledonia (NC):H1N1), A(Hiroshima (HIR):H3N2) and B(Malaysia (MAL)) strains. Twenty-one RA patients using tocilizumab also received 23-valent polysaccharide pneumococcal vaccine. Antibody titers were measured every 4 weeks for a total of 12 weeks after vaccination.In the tocilizumab group, seroprotective titers (40-fold or more) were obtained in 36/38(95%) for A(NC), 35/38(92%) for A(HIR) and 32/38(84%) for B(MAL). In the patients with baseline antibody titer40-fold, 11/11(100%), 7/8(88%) and 18/20(90%) patients showed four-fold or more increase in the titer from baseline to A(NC), A(HIR) and B(MAL), respectively. Patients using TNF inhibitors and/or DMARDs showed similar responses. Pneumococcal antibody titers increased at least two-fold in more than 9 of 12 serotypes, which continued for longer than 12 weeks in all the patients.Interleukin-6 (IL-6) blocking therapy with tocilizumab did not affect the humoral immune response to both influenza and pneumococcal vaccines.

Background Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by systemic inflammatory status, joint destruction, disability, and pain. Methotrexate (MTX) has been confirmed to reduce disease activity and delay or stabilize the development of bone erosions. However, major drawbacks are that patients show great interindividual variability in response to MTX and the unpredictable occurrence of side effects. A strategy for personalized MTX treatment to predict its efficacy and toxicity has not yet been determined. To establish personalized MTX therapy in Japanese patients with rheumatoid arthritis, we performed a preliminary study for predicting better methotrexate efficacy including single-nucleotide polymorphisms (SNPs) for MTX-related transporters/enzymes. Methods Disease control status (good or poor) was judged by the number of Disease Activity Scores (DAS28) of A, RFC1 –43 T > C, FPGS 1994G > A, GGH 401C > T, MTHFR 1298A > C, and TYMS 3'-UTR (−6/+6) was performed using the real-time PCR system. Results Seven of 21 patients were judged as good responders in terms of disease control, and the remainder as poor responders. For 0–3 months after starting MTX administration, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 96.0 mg and 25.4 and 118.0 mg and 23.4, respectively. For 0–6 months, the median cumulative dose and improved DAS28 AUC in the good and poor response groups were 192.0 mg and 51.0 and 214.0 mg and 47.6, respectively. Statistically significant differences between the 2 groups in the 0–6-month period were observed in DAS28 AUC improvement and index R. A slight tendency for a correlation between G/G genotypes and A allele genotypes in RFC1 80 genotypes was observed, although it did not reach statistical significance. Conclusion This study suggested that aggressive RA treatment with MTX from the early period of administration is necessary to obtain a good response after 6 months, although no SNPs predicting a better treatment response to MTX were identified.

There is increasing awareness of nonerosive reflux disease (NERD) as a disease requiring treatment in Japan. This randomized, double-blind, placebo-controlled, parallel-group study was conducted to investigate the efficacy and safety of omeprazole 10 mg and 20 mg once daily in Japanese patients with NERD.Patients with heartburn for at least 2 days a week during the month before entry into the study and no endoscopic signs of a mucosal break (grade M or N according to Hoshihara's modification of the Los Angeles classification) were randomly assigned to one of three groups (omeprazole 10 mg or 20 mg, or placebo) once daily for 4 weeks.Overall, 355 patients were enrolled, of whom 284 were randomly assigned to one of the three groups (omeprazole 10 mg, n = 96; omeprazole 20 mg, n = 93; placebo, n = 95). The rate of complete resolution of heartburn in week 4 was significantly higher in patients treated with omeprazole 10 mg [32.3%, 95% confidence interval (CI), 22.9%-41.6%] or 20 mg (25.8%, 95% CI, 16.9%-34.7%) than in the placebo group (12.0%, 95% CI, 5.3%-18.6%). No significant difference between the two omeprazole groups was observed. The rate of complete resolution of heartburn by omeprazole was similar between patients with grade M and those with grade N esophagus. Omeprazole also increased the rate of sufficient relief from heartburn. Omeprazole was well tolerated.Omeprazole 10 mg or 20 mg once daily is effective and well tolerated in patients with NERD regardless of their endoscopic classification.

Background DMB-3111 is a biosimilar trastuzumab drug being jointly developed by Meiji Seika Pharma (Japan) and Dong-A Socio Holdings (Korea). We investigated the bioequivalence of DMB-3111 relative to trastuzumab. Objectives The aim of this study was to investigate the bioequivalence between DMB-3111 and trastuzumab and the pharmacokinetic, safety, and immunogenicity of both drugs in healthy Japanese adult males. Methods Seventy healthy Japanese adult males were randomized 1:1 to receive either DMB-3111 or trastuzumab as a single intravenous infusion (6 mg/kg) over 90 min. Bioequivalence was assessed in terms of the pharmacokinetic parameters of both drugs. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Immunogenicity was tested using anti-drug antibody (ADA) assays. Results The 90 % confidence intervals of the treatment differences (DMB-3111 versus trastuzumab) in the mean log-transformed maximum concentration, the area under the concentration–time curves (from 0 min to the last measured value or from 0 min to infinity), mean residence time, and the terminal half-life were within the accepted range for bioequivalence [log(0.80) to log(1.25)]. The frequencies of AEs and adverse drug reactions were similar with both drugs. No ADA reactivity to DMB-3111 or trastuzumab was observed in any subject. Conclusions DMB-3111, a trastuzumab biosimilar, was bioequivalent to trastuzumab in terms of its pharmacokinetics and showed similar safety after a single intravenous infusion at 6 mg/kg over 90 min in healthy Japanese adult males. DMB-3111 is likely to show similar efficacy and safety profiles to trastuzumab in cancer patients (ClinicalTrials.gov #NCT02100917).

Heat-killed Lactobacillus plantarum strain L-137 (HK-LP) is a potent inducer of IL-12 in vitro as well as in vivo in mice. HK-LP has been shown to suppress IgE production against food allergens, as well as tumor growth in mice, through IL-12 production, which induces the T helper (Th) 1 type immune response. To determine whether the intake of HK-LP influences immune function and the quality of life (QOL), a randomized, double-blind, placebo-controlled, parallel study was conducted in healthy subjects. Sixty subjects (30 men and 30 women, mean age 56.3 y) were randomly assigned to receive a capsule containing 10 mg of HK-LP daily or a matching capsule for 12 wk. Biomarkers for innate immunity such as the natural killer activity of peripheral blood mononuclear cells, neutrophil phagocytosis, and cell surface expression of CD64 on monocytes were measured every 4 wk. Biomarkers for acquired immunity such as concanavalin A (Con A)-induced proliferation, percentages of INF-gamma and IL-4-producing cluster of differentiation (CD)4(+) T cells (Th1:Th2 ratio), and the serum IgG4:IgG ratio were measured every 4 wk or at wk 0 and wk 12. Health-related QOL was assessed using a self-rating questionnaire with 26 items. Among the measured biomarkers, the percent change in Con A-induced proliferation and the Th1:Th2 ratio in the HK-LP group was greater than those in the control group (P = 0.036 and P = 0.002, respectively). The degree of improvement in QOL was higher in the HK-LP group than in the control group at wk 8 (P = 0.049) and tended to be higher at wk 12 (P = 0.092). These results suggest that a daily intake of HK-LP augments acquired immunity, especially Th1-related immune functions in healthy subjects, thereby improving the health-related QOL.

In Japan, the routine immunization program with oral polio vaccine (OPV) has been suspended since September 2012, when a program with 4 doses of inactivated monovalent polio vaccine (IPV) or quadrivalent vaccine against diphtheria, pertussis, and tetanus with IPV (DTaP-IPV) was introduced. The aim of this study was to examine the interchangeability among these 3 types of polio vaccines.We conducted a prospective cohort study at 5 pediatric clinics in Japan. A total of 153 infants were assigned to 1 of the 4 groups by considering the vaccination history of OPV and trivalent vaccine against DTaP. Eleven infants with a history of OPV received 3 doses of DTaP-IPV; 49 infants with a history of OPV and DTaP received 3 doses of IPV; 50 polio vaccine-naive infants received 2 doses of IPV followed by 2 doses of DTaP-IPV; and 43 polio vaccine-naive infants received 2 doses of DTaP-IPV followed by IPV. The immunogenicity after polio vaccination was evaluated among these 4 groups.After 2 doses of polio vaccination, more than 80% of the infants exhibited a neutralization antibody titer ≥1:8 for all Sabin strains and wild strains in all groups. After the third dose, the seroprotection proportion (i.e., a neutralization antibody titer ≥1:8) reached about 100%. After the fourth dose, a neutralization antibody titer exceeded the required protective levels (i.e., a neutralization antibody titer ≥1:8) considerably in all groups.Four doses of polio vaccines induced a sufficient level of immunity in Japanese infants, irrespective of vaccine combinations or order.

We report a case of dermatomyositis (DM) associated with invasive thymoma in a 22-year-old woman who was admitted to our hospital complaining of dyspnea which required ventilation support. The reddened elevated scaly eruptions were prominent over the extensor surfaces. Chest X-ray and computed tomography showed mediastinal masses, which were diagnosed as mixed type thymoma. Muscle and skin biopsy specimens were compatible with DM. She was treated with methylprednisolone pulse therapy followed by extended removal of the anterior mediastinal tumor and subsequent radiotherapy. She has had a good clinical course without recurrence of thymoma or DM for more than 3 years. The role of thymoma in the development of DM is discussed.

A multicenter, open-label, dose-escalation phase 1/2 study was undertaken to evaluate the optimal subcutaneous tocilizumab dose that would result in exposure comparable to the intravenous tocilizumab 8-mg/kg approved dose in patients with rheumatoid arthritis. A pharmacokinetic and biomarker approach was used to estimate the clinical optimal dose regimen of subcutaneous tocilizumab. Safety and efficacy of subcutaneous tocilizumab were assessed as secondary end points. Patients received subcutaneous tocilizumab at 81 mg every 2 weeks (q2w) (n = 8), 162 mg q2w (n = 12), or 162 mg weekly (qw) (n = 12) for 24 weeks. 88% of 162-mg q2w patients and 100% of 162-mg qw patients maintained mean serum trough tocilizumab concentrations of ≥1 µg/mL, and had exposure comparable with the approved intravenous tocilizumab dose of 8 mg/kg; this resulted in normalized C-reactive protein levels and improvement in ACR20/50/70 responses. The most common adverse events were abnormal laboratory results, which were mild in severity. Anti-tocilizumab antibodies were detected in a few patients in the 81-mg q2w and 162-mg qw groups. In conclusion, coupled with efficacy and tolerability results, the appropriate dose of subcutaneous tocilizumab was determined to be 162 mg q2w for Japanese patients.

OBJECTIVES: This study aimed to evaluate the remission in rheumatoid arthritis (RA) patients treated with tocilizumab (TCZ), based on prospectively registered data in clinical practice. METHODS: We studied 114 consecutive RA patients treated with TCZ for an average of 3.5 years. Remission was evaluated by using the EULAR criteria and the new ACR/EULAR Boolean-based criteria. RESULTS: Among 114 patients (average age 52.2 years; average disease duration 10.6 years), 76 (67 %) had previously received anti-TNF biologics. Mean baseline DAS28-ESR of 5.4 and improved to 2.4 at 36 months. Overall, DAS28-ESR2.6 was attained by 66.7 %, while ACR/EULAR remission was attained by 35.1 %. ACR/EULAR remission rate was significantly higher in the patients who were biologics-naïve and had good response at the first month. Among 23 patients who completed the treatment for 3 years and had ACR/EULAR remission at 1 year, 15 (65 %) remained in the remission and 16 (70 %) had a DAS28-ESR2.6 at the final follow-up. The retention rate at 36 months was 68.2 %. CONCLUSIONS: In patients with RA, TCZ is highly effective for both biologics-naïve patients and patients previously exposed to biologics, achieving a high remission rate and drug continuation rate (68.2 %) in clinical practice.

The fourth component of complement (C4) in urine was measured in 19 patients with systemic lupus erythematosus (SLE). Urinary C4 was detectable in all SLE patients using an enzyme linked immunosorbent assay. In 11 of 13 patients whose urinary C4 was serially measured, a decrease of urinary C4 was found in parallel with a decrease of disease activity of SLE. In the remaining 2 patients, the amount of C4 increased preceding a flare-up of the disease. The measurement of urinary C4 may be useful in evaluating the disease activity of SLE in individual patients and sometimes in predicting the flare-up of the disease. The specific hemolytic activity of excreted C4 and Western blotting analysis showed that urinary C4 consisted mainly of degraded fragments of C4. In two cases, camostat, a serine protease inhibitor, rapidly decreased the urinary C4 excretion, suggesting that the complement activation occurred in the glomerulus in lupus nephritis.

Okadaic acid is a potent tumor promoter and an inhibitor of serine/threonine-specific protein phosphatases. We studied the effect of okadaic acid in human T cell activation and phosphorylation of internal substrates. Okadaic acid at up to 4 nM enhanced phorbol myristate acetate (PMA)-induced proliferation and CD25 (IL-2 receptor, p55) expression, although it showed no activation by itself. Okadaic acid induced hyperphosphorylation of a 60 kDa protein in T cells as well as non-T cells, as reported in fibroblasts and keratinocytes. Preincubation with 4 nM okadaic acid enhanced PMA induced phosphorylation of the 80 kDa protein, an internal substrate of protein kinase C in T cells. These results suggest that okadaic acid inhibited dephosphorylation of protein kinase C specific substrates, and as a result, enhanced T cell activation mediated by protein kinase C pathway.

SummaryTissue factor (TF) is an integral membrane glycoprotein that serves as a cofactor for blood coagulation factor VIIa. The induction of TF on the surface of endothelial cells is initiated by various stimuli including lipopolysaccharide, interleukin-1β, and tumor necrosis factor α. We have demonstrated that recombinant human C5a induces TF activity in a dose-dependent fashion in human umbilical vein endothelial cells (HUVEC). Peak activity (4.9-fold increase) was obtained 3-6 h after treatment with 10 μM C5a. TF mRNA as assessed by RT-PCR method was also significantly increased (3.75-fold) after 3 h incubation with C5a, suggesting that C5a induces TF activity on HUVEC, at least in part, by enhancing the level of TF mRNA. The increase in TF activity by C5a was inhibited by methylprednisolone. The induction of TF on endothelial cells by C5a may represent one of many potential interrelationships between the inflammatory and coagulation schemes.

We studied the role of T cells in the regulation of C3 or C4 production by monocytes. While cocultured T cells reduced C3 production, they enhanced C4 production by monocytes in a number-dependent manner. Interleukin-2 enhanced these effects of T cells on C3 and C4 production, indicating that activated T cells had greater effects on complement production by monocytes. CD4 + T cells had greater effects than those of CD8 1 T cells on the C3 or C4 production by monocytes, indicating that CD4 + T cells were mainly involved in the regulation of C3 and C4 production by monocytes. T-cell-conditioned medium (T-CM) also decreased C3 and enhanced C4 production, but the effect of T-CM on C3 and C4 production was less remarkable than that of T cells. T cells separated by transwell inserts from monocytes had similar effects as those of T-CM on complement production. Anti-IFN-γ antibody completely blocked the suppressing effect on C3 production and partially blocked the stimulating effect of T cells on C4 production. These results indicate that T cells regulate C3 or C4 production by monocytes via IFN-γ as a humoral factor. Moreover, the stimulating effect of T cells on C4 production was partially blocked when monocytes and T cells were incubated with anti-CD2, anti-LFA-I, and anti-HLA-DR antibodies, and anti-CD2 partially blocked the suppressing effect of T cells on C3 production by monocytes. These results indicate that T cells modulate the C3 and C4 production by monocytes not only via a humoral factor but also via a direct interaction with monocytes.