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Reactions of aziridines and carbon dioxide (CO2) proceed under supercritical conditions to give random copolymers containing urethane and amine moieties. The formation of branched structures at high temperature was clearly revealed by ¹H NMR spectra of the products from 2,2-dimethylaziridine. The copolymers obtained from 2-methylaziridine display quick responses to changes in temperature in their aqueous solutions. An increase in the CO2 pressure causes a significant decrease in the LCST of the polymers, possibly due to an increase in their urethane contents. Substitution of the amine moieties with a loss of protons to form the branched polymer results in lowering of the hydrophilicity of the copolymer and drops in the LCST. The use of supercritical CO2 provides a synthetic advantage in the effective chemical fixation of CO2 and a novel method for synthesis of functional materials. [ABSTRACT FROM AUTHOR]

Our previous survey in 2008 revealed that only 22% of Japanese rheumatologists used musculoskeletal ultrasonography (MSUS) for patient management, because of insufficient educational opportunities. To clarify the current state of MSUS usage and to identify further challenges, we conducted a second survey between October 2010 through January 2011 by sending questionnaires to 200 randomly selected Japanese rheumatologists, consisting of 100 participants in a meeting in 2009 on imaging in rheumatic diseases and 100 board-certified rheumatologists. Among the respondents, a majority (85 and 67%, respectively) used magnetic resonance imaging (MRI). MSUS users had increased from 32 to 60% of meeting participants and from 11 to 27% of other rheumatologists. The majority of MSUS users had begun using MSUS within the previous 3 years. Whereas most respondents in the previous survey had been self-taught, in the current survey many had attended training courses or had received informal training from skilled users. Despite an increase in skills and equipment ownership, obstacles to implementing MSUS remained, most prominently a lack of time. In conclusion, training courses and informal training have contributed to the popularization of MSUS in Japan. To further increase MSUS usage, additional training opportunities and education about the advantages of MSUS will be needed. [ABSTRACT FROM AUTHOR]

Objective: The human leukocyte antigen (HLA) is the strongest genetic risk factor for idiopathic inflammatory myopathy (IIM), and different HLA alleles have been reported to be associated with IIM susceptibility among different ethnic groups. In this study, we have investigated HLA alleles associated with IIM in Japanese patients. Methods: Genotyping of HLA-DRB1 and DPB1 were performed in 252 Japanese IIM patients (166 dermatomyositis [DM] and 86 polymyositis [PM] patients) and the association was analyzed with comparison to controls (n = 1026 for DRB1 and n = 413 for DPB1). Results: DRB1*08:03 was associated with IIM (p = 1.60 x 10-5, pc = .0005, odds ratio [OR] 2.11, 95% confidence interval [CI] 1.52-2.92) and DM (p = .0004, pc = .0128, OR 2.06, 95%CI 1.40--3.02). DPB1*05:01 was also associated with IIM (p = .0001, pc = .0021, OR 1.96, 95%CI 1.38--2.77) and DM (p = .0005, pc = .0075, OR 2.05, 95%CI 1.37--3.08). DRB1*09:01 (p = .0012, pc = .0368, OR 0.35, 95% CI 0.18--0.69) and DPB1*04:01(p = .0004, pc = .0057, OR 0.05, 95% CI 0.00--0.85) were protectively associated with PM. Two locus analyses suggested that DRB1*09:01 and DPB1*04:01 were independently associated with PM. Conclusion: Protective associations of HLA were detected in Japanese PM patients. [ABSTRACT FROM AUTHOR]

The High Resolution Chopper Spectrometer (HRC) is installed at the Japan Proton Accelerator Research Complex (J-PARC) and is utilized for a wide range of dynamical studies of materials over a wide energy-momentum space with high resolution. Neutron Brillouin scattering (NBS), i.e., inelastic neutron scattering close to the forward direction, can be performed with the HRC, because this instrument utilizes low angle detectors and high-energy neutrons which facilitates a high resolution. Since the solid angle of the detection area for NBS experiments is limited to very low scattering angles, improvements of the HRC are required to increase the neutron flux with reducing the background. Given the success of the HRC for NBS studies, the neutron intensities for NBS experiments have been improved by changing the detector layout, reducing deformation of the slit package during rotation of the Fermi chopper, and fabricating a longer collimator. At present, we have made further improvements. At around the incident neutron energy E i = 100 meV, the neutron flux was significantly increased for an energy resolution of Δ E ∕ E i = 2%, and the best energy resolution achieved was nearly 1% resolution with an acceptable neutron flux. [ABSTRACT FROM AUTHOR]

Objectives Depression is frequently observed in patients with systemic lupus erythematosus (SLE). Neuropsychiatric SLE (NPSLE) patients often exhibit cerebral hypometabolism, but the association between cerebral metabolism and depression remains unclear. To elucidate the features of cerebral metabolism in SLE patients with depression, we performed brain 18F-fluoro- d -glucose positron emission tomography (FDG-PET) on SLE patients with and without major depressive disorder. Methods We performed brain FDG-PET on 20 SLE subjects (5 male, 15 female). The subjects were divided into two groups: subjects with major depressive disorder (DSLE) and subjects without major depressive disorder (non-DSLE). Cerebral glucose metabolism was analyzed using the three-dimensional stereotactic surface projection (3D-SSP) program. Regional metabolism was evaluated by stereotactic extraction estimation (SEE), in which the whole brain was divided into segments. Results Every SLE subject exhibited cerebral hypometabolism, in contrast to the normal healthy subjects. Regional analysis revealed a significantly lower ER in the left medial frontal gyrus ( p = 0.0055) and the right medial frontal gyrus ( p = 0.0022) in the DSLE group than in the non-DSLE group. Conclusion Hypometabolism in the medial frontal gyrus may be related to major depressive disorder in SLE. Larger studies are needed to clarify this relationship. [ABSTRACT FROM AUTHOR]

Objective: Several studies on associations between human leukocyte antigen (HLA) allele frequencies and susceptibility to systemic sclerosis (SSc) have been reported. Anti-centromere antibodies (ACA) and anti-topoisomerase I antibodies (ATA) are found in SSc patients. Here, we sought to identify HLA alleles associated with SSc in Japanese, and explored their associations with SSc phenotypes including the presence of autoantibodies. Methods: Associations of HLA-DRB1, DQB1, and DPB1 were analyzed in 463 Japanese SSc patients and 413 controls. Results: We found that DRB1*13:02 (P = 0.0011, Pc = 0.0319, odds ratio [OR] 0.46, 95% confidence interval [CI] 0.29–0.73), DRB1*14:06 (P = 6.60X10-5, Pc = 0.0020, OR 0.05, 95%CI 0.01–0.41), DQB1*03:01 (P = 0.0009, Pc = 0.0150, OR 0.56, 95%CI 0.40–0.79), and DPB1*02:01 (P = 5.16X10-6, Pc = 8.77X10-5, OR 0.52, 95%CI 0.39–0.69) were protectively associated with SSc. In addition, these four alleles seemed to be independently associated with the protection against the susceptibility of SSc. On the other hand, we could not find predisposing alleles for overall SSc. With respect to SSc subsets, a tendency for these four alleles to be protectively associated was observed. However, there was a significant association between DRB1*01:01, DRB1*10:01, DQB1*05:01, and DPB1*04:02 and the susceptibility to SSc with ACA. On the other hand, the presence of DRB1*15:02, DQB1*06:01, DPB1*03:01, and DPB1*09:01 was associated with SSc with ATA. Conclusion: Thus, the present study has identified protective associations of the four HLA class II alleles with overall Japanese SSc and predisposing associations of HLA class II alleles with Japanese SSc subsets. [ABSTRACT FROM AUTHOR]

To investigate changes in the risk for serious infections (SIs) over time in Japanese rheumatoid arthritis (RA) patients treated with tumor necrosis factor inhibitors (TNFIs). This prospective cohort study included Japanese RA patients who began treatment with a TNFI from 2005 to 2007 (2005 group, n = 716, 634.2 patient years [PY]) and from 2008 to 2011 (2008 group, n = 352, 270.1 PY) at the time or after their enrollment in the registry of Japanese RA patients on biologics for long-term safety (REAL) database. Patients were observed for 12 months or until discontinuation of their initial TNFI in the REAL database. Drug discontinuation reasons and retention rates were analyzed. Incidence rates of serious adverse events (SAEs) were calculated with 95 % confidence intervals (CIs). The Cox proportional hazard model was applied to estimate the risk for SIs. The retention rate in the 2008 group was significantly lower than the 2005 group ( p < 0.001). Discontinuation rates due to lack of efficacy or good control for the 2008 group were significantly higher than the 2005 group ( p < 0.001). The crude incidence rate ratios comparing the 2008 group with the 2005 group for SAEs were 0.93 (95 % CI 0.65-1.34) and for SIs were 0.50 (0.24-1.03). The 2008 group had significantly lower risk for SIs than the 2005 group after adjusting for covariates (hazard ratio: 0.43 [0.20-0.93]). These results indicate significant decrease of the risk for SIs with TNFI treatment over time; this may be explained by evidence-based risk management of RA patients given TNFIs. [ABSTRACT FROM AUTHOR]

Objectives: Although 'clinical remission' has been a realistic goal of treatment in rheumatoid arthritis (RA), there is evidence that subclinical synovitis is associated with ongoing structural damage even after clinical remission is achieved. In the study reported here, we assessed whether ultrasonography (US) can predict progressive joint destruction during clinical remission of RA. Methods: Thirty-one patients with RA in clinical remission based on the disease activity score in 28 joints were recruited for this study. Bilateral wrists and all of the metacarpophalangeal and proximal interphalangeal (PIP) joints were examined by power Doppler (PD) ultrasonography (US), and the PD signals were scored semiquantitatively in each joint. The total PD score was calculated as the sum of individual scores for each joint. Results: Among 22 RA patients who maintained clinical remission during the 2-year follow-up period, seven showed radiographic progression. Radiographic progression was strongly associated with total PD score at entry, with all patients showing radiographic progression having a total PD score of ≥2 at entry and none of the patients with a total PD score of ≤1 showing any radiographic progression. There was no significant association of therapeutic agents with progressing or non-progressing cases. Conclusions: PD-US detects synovitis causing joint destruction even when the patient is in clinical remission. Thus, remission visible on US is essential to reach 'true remission' of RA. [ABSTRACT FROM AUTHOR]

Abstract: Patients with anti-thyroid antibodies (ATAs) present various kinds of psychiatric conditions. When these psychiatric patients with ATAs (PPATs) show responsiveness to immunotherapy, they are frequently diagnosed with a diffuse progressive type of Hashimoto''s encephalopathy (HE). Anti-glutamate receptor ɛ2 subunit (GluRɛ2) antibodies have previously been reported in HE patients. However, it is unclear whether there is any relationship between PPATs, including HE patients, and anti-GluRɛ2 antibodies. We investigated anti-GluRɛ2 antibodies in the serum and cerebrospinal fluid (CSF) of 15 PPATs, and we compared the results with those of 11 patients with neuropsychiatric systemic lupus erythematosus (NPSLE), an anti-glutamate receptor antibody-related disease. We then compared the neuropsychiatric symptoms between the PPATs with and without anti-GluRɛ2 antibodies. The prevalence of anti-GluRɛ2 antibodies was significantly higher in the CSF than in the serum of PPATs (41.7% versus 6.7%; p =0.040). The prevalence of anti-GluRɛ2 antibodies was slightly higher in the CSF of PPATs than NPSLE patients. PPAT-GluR(+)s showed a significantly higher prevalence of emotional instability (100% versus 33.3%; p =0.03) and also showed a significantly lower prevalence of delusions (0% versus 100%; p =0.001) and hallucinations (17% versus 83%; p =0.038) than PPAT-GluR(−)s. Our results suggest that anti-GluRɛ2 antibodies may be associated with the neuropsychiatric manifestation of PPATs. [Copyright &y& Elsevier]

To evaluate the responsiveness of power Doppler ultrasonography (PDUS) in comparison with conventional measures of disease activity and structural damage in rheumatoid arthritis (RA) patients receiving tocilizumab (TCZ). Seven RA patients with active arthritis were enrolled in the study and prospectively monitored for 12 months. They were treated with TCZ (8 mg/kg) every 4 weeks as monotherapy or in combination with disease-modifying antirheumatic drugs (DMARDs). Clinical, laboratory, and ultrasound examinations were conducted at baseline, 1, 3, 6, 9, and 12 months. Power Doppler (PD) signals were graded from 0 to 3 in 24 joints, and total PD score was calculated as the sum of scores of individual joints. One-year radiographic progression of the hands was estimated by using Genant-modified Sharp scoring. The averages of the clinical parameters rapidly improved, and all patients achieved good response within 6 months based on standard 28-joint Disease Activity Score (DAS28). Although the average total PD score declined in parallel with clinical improvement, radiography of the hands showed progression of destruction in the joints where PD signals remained, even among clinical responders. ΔSharp score correlated with the time-integrated value (TIV) of total PD scores (Δtotal Sharp score: r = 0.77, P = 0.04; Δerosion: r = 0.78, P = 0.04; Δjoint-space narrowing (JSN): r = 0.75, P = 0.05), but not with TIVs of clinical parameters including DAS28. PDUS can independently evaluate disease activity in RA patients receiving TCZ and is superior to DAS28, especially in predicting joint destruction. [ABSTRACT FROM AUTHOR]

The type and frequency of neurological manifestations of Behçet’s disease (BD) vary with ethnicity. We analyzed the neurological manifestations of BD in Japanese patients. All patients undergoing treatment at one of the two Yokohama City University hospitals from July 1991 to December 2007 and who fulfilled the Japanese criteria for BD revised in 1987 were studied retrospectively by chart review. Patients had been neurologically assessed by neurologists. We recorded neurological signs and symptoms, magnetic resonance imaging or computed tomography findings, and results of cerebrospinal fluid examinations from the records of each patient. We studied 412 patients with BD, of whom 54 (13%) had neurological involvement (neuro-Behçet’s disease: NB). NB patients included a significantly higher proportion of males (61%) than non-NB patients (42%, P = 0.009). The majority of patients ( n = 38, 70%) had acute parenchymal NB, 15 (28%) had chronic progressive parenchymal NB, and 1 (2%) had the non-parenchymal type. Headache and fever were more frequently reported by patients with acute parenchymal NB. Personality changes, sphincter disturbances, involuntary movements, and ataxia occurred predominantly in patients with chronic progressive parenchymal NB. Lesions were distributed throughout the CNS, but mainly in the brainstem, white matter, and basal ganglia. Analysis of end-point clinical outcomes revealed a poor prognosis for patients with chronic progressive NB. In Japan, most NB patients have the parenchymal type, and male gender is a predisposing factor. Because of the unfavorable prognosis associated with chronic progressive NB, development of effective therapies are urgently needed. [ABSTRACT FROM AUTHOR]

A 55-year-old man, diagnosed with systemic sclerosis (SSc) for 20 years, was admitted to our hospital for exertional dyspnea and pleural effusion. Computed tomography scan and cytological findings of the pleural fluid suggested malignant mesothelioma. In the postmortem examination, the tumor was pathologically diagnosed as pseudomesotheliomatous adenocarcinoma (PMA) of the lung, classified into pleomorphic carcinoma with adenocarcinoma component according to the new World Health Organization guidelines. This is the first case report of SSc with PMA. [ABSTRACT FROM AUTHOR]

Introduction: Janus kinase (JAK) inhibitors are an important therapeutic option in the treatment of rheumatoid arthritis, but increase the risk of developing herpes zoster. Although a dry recombinant zoster vaccine (RZV) that can be used under immunosuppressive conditions has recently been developed, its optimal use and appropriate timing in patients scheduled to start JAK inhibitors is still unclear. The present study is designed to clarify the appropriate timing of JAK inhibitor initiation to measure varicella zoster virus (VZV)-specific IgG titers and VZV-specific T cell response in patients with rheumatoid arthritis who start tofacitinib at the first RZV vaccination or at the second one., Methods and Analysis: STOP HZ (Effectiveness and S afe T y O f P rophylactic Recombinant H erpes Z oster Virus Vaccination for Rheumatoid Arthritis Patients with Tofacitinib Treatment) study is a multicentre, open-label, randomised, comparative study in patients with rheumatoid arthritis who are scheduled to start tofacitinib. This study enrols 60 study subjects in 12 sites. Enrolled subjects receive RZV two times on day 1 and week 8 and initiate tofacitinib 5 mg two times a day at the time of their first RZV (day 1, group A) or second RZV (week 8, group B) based on randomisation. The random assignment is performed centrally in a 1:1 ratio. Patients in Group B continue the same treatment until the start of tofacitinib treatment. Primary endpoint is VZV-specific IgG antibody titers at week 12 compared with those at baseline in each group. Secondary endpoints include comparison of VZV-specific IgG antibody between the groups, changes in disease activity of rheumatoid arthritis, VZV-specific T cell response and adverse events., Ethics and Dissemination: The study has been approved by the Certified Review Board of Keio (No. 2022008), and conforms to the Declaration of Helsinki and good clinical practice guidelines. Written informed consent is obtained from participants prior to enrolment. The results of this study are planned to be submitted for publishment in relevant peer-review journals., Trial Registration Number: jRCTs031230329., Competing Interests: Competing interests: STa has received honoraria from Abbvie, Astellas, Eisai, Eli Lilly and Pfizer. KO has received honoraria and research support from Eisai, Gilead and AstraZeneca. KM has received honoraria and research support from AbbVie, Eli Lilly and Company, Eisai and Ono Pharmaceutical Co. Ltd. AI received research grant and speaker fees from AbbVie, Asahikasei, AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, Ono, Pfizer, Tanabe and Taisho pharmaceutical. TMatsui has received honoraria and research support from Pfizer, Chugai Pharmaceutical Co. Ltd and AsahiKASEI Co. Ltd. STo has received honoraria and research support from Pfizer Japan, Abbvie Japan Co. Ltd, Chugai pharmaceutical Co. Ltd, AsahiKASEI Co. Ltd, Mitsubishi-Tanabe Pharm Co, Eisai Co. Ltd. Janssen pharmaceutical K.K. SS has received honoraria, research support from Eisai Pharma and received honoraria from Abbvie, GlaxoSmithKline, Eli lilly, Pfizer, Astellas Pharma. TMatsub has received research support and/or speaker honoraria from Astellas Pharma, Bristol-Myers Squibb., AbbVie GK, Eli Lilly Japan K.K., Pfizer Japan, Gilead Sciences K.K. and AYUMI Pharmaceutical Corporation. KY has received honoraria, consultant fees and research support from Pfizer, Abbvie, GlaxoSmithkline, Eli lilly, Astellas Pharma, Gilead G.K., Eisai Pharma. KA has received honoraria from Pfizer Japan and GlaxoSmithKline. YK has received research grants and speaking fees from AbbVie, Astellas, Eisai, Eli Lilly, Pfizer and Gilead Sciences. JS, TMi and YM have no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA)., Methods: In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models., Results: Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens., Conclusion: Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: The hallmarks of the chronic inflammatory disease polymyalgia rheumatica (PMR) include pain, and morning stiffness in areas of the neck, shoulder and pelvic girdle. The human leucocyte antigen ( HLA ) gene was reported to be an important risk factor for PMR, but it has not been analysed precisely, especially in populations other than Europeans., Methods: Genotyping of DRB1 and DQB1 was performed in Japanese PMR patients (n=270) and controls (n=413). Associations between allele carrier and genotype frequencies were determined for PMR., Results: DRB1*04:05 was associated with a predisposition to PMR (p=0.0006, Pc =0.0193, OR 1.85, 95% CI 1.31 to 2.62). DRB1*09:01 was associated with protection against PMR (p=1.46×10 -5 , Pc =0.0004, OR 0.40, 95% CI 0.26 to 0.61). A shared epitope (SE) associated with PMR (p=3.07×10 -6 , OR 2.11, 95% CI 1.54 to 2.88). DQB1*03:03 (p=0.0010, P c=0.0140, OR 0.52, 95% CI 0.35 to 0.77) was associated with protection against PMR and DQB1*04:01 (p=0.0009, P c=0.0140, OR 1.82, 95% CI 1.28 to 2.58) was associated with predisposition to PMR. A gene dosage effect was observed for DRB1*09:01 and DQB1*03:03 , but not for DRB1*04:05, SE or DQB1*04:01 . Haplotype and logistic regression analyses suggested a protective effect for DRB1*09:01 ., Conclusion: This study is the first to demonstrate predisposing associations of DRB1*04:05, SE, and DQB1*04:01 , and protective associations of DRB1*09:01 and DQB1*03:03 with PMR in Japanese patients. Our data indicate HLA has predisposing and protective effects on the pathogenesis of PMR., Competing Interests: Competing interests: ST was supported by research grants from Astellas Pharma,Teijin Pharma, Mitsubishi Tanabe Pharma, Abbott Japan, Merck Sharp and Dohme, Takeda Pharmaceutical Company, Eisai, Chugai Pharmaceutical and Pfizer Japan. ST received honoraria from Chugai Pharmaceutical, Pfizer Japan, Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical, Asahi Kasei Pharma Corporation, Astellas Pharma and AbbVie GK. HF received honoraria from Pfizer Japan, Takeda Pharmaceutical Company, Dainippon Sumitomo Pharma, Luminex Japan Corporatio, Ayumi Pharmaceutical Corporation, Daiichi Sankyo and Ajinomoto. HF was supported by grants from Daiwa Securities Health Foundation, Takeda Science Foundation, Takeda Science Foundation, Bristol-Myers-Squibb Co., the Nakatomi Foundation, Japan Research Foundation for Clinical Pharmacology and Mitsui Sumitomo Insurance Welfare Foundation., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Interstitial lung disease (ILD) is the principal cause of death in polymyositis/dermatomyositis (PM/DM). Here we investigated prognostic factors for death and serious infection in PM/DM-ILD using the multicenter database., Methods: We retrospectively reviewed baseline demographic, clinical and laboratory findings, treatment regimens and outcomes in patients with PM/DM-ILD. The distribution of ILD lesions was evaluated in four divided lung zones of high-resolution computed tomography images., Results: Of 116 patients with PM/DM-ILD, 14 died within 6 months from the diagnosis. As independent risk factors for early death, extended ILD lesions in upper lung fields (odds ratio (OR) 8.01, p = 0.016) and hypocapnia (OR 6.85, p = 0.038) were identified. Serious infection was found in 38 patients, including 11 patients who died of respiratory or multiple infections. The independent risk factors were high serum KL-6 (OR 3.68, p = 0.027), high initial dose of prednisolone (PSL) (OR 4.18, p = 0.013), and combination immunosuppressive therapies (OR 5.51, p < 0.001)., Conclusion: The present study shows the progression of ILD at baseline is the most critical for survival and that infection, especially respiratory infection, is an additive prognostic factor under the potent immunosuppressive treatment.

Background: It has been suggested that the phenotypes of Behçet's disease (BD) in Japan are changing. To ask whether the evolution of BD holds true in recent-onset cases in Japan, we performed a retrospective study., Methods: We reviewed the records of 578 patients with BD who met the 1987 revised diagnostic criteria of the Behçet's disease research committee of Japan. The patients were divided into three groups based on the date of disease onset. We compared the demography, clinical features, and treatments among them with or without adjustment for the observation period. Patients having oral ulcers, genital ulcers, regional skin involvement, and uveitis are categorized as having complete-type BD, and the associated factors were determined by univariate and multivariate logistic regression analyses., Results: Male patients had a higher propensity for uveitis and central nervous system (CNS) involvement, whereas female patients had higher rates of genital ulcers and arthritis. We found a significant trend in reduction of complete-type, genital ulcer, HLA-B51 carriers, and increment of gastrointestinal BD over time. Multiple regression analysis identified HLA-B51 positivity, earlier date of disease onset, and younger age of onset as independently associated with complete-type BD. Although treatments had been also chronologically changed, the causative relationship between therapeutic agents and phenotypical changes was not determined from the study., Conclusion: The present study revealed that phenotypical evolution was characterized by decreased incidence of the complete type and increment of gastrointestinal involvement in Japanese patients with BD during the last 30 years.

We present a case-control study that was conducted to examine the factors associated with intermittent home care on elderly inpatients in home care wards. The results showed that the proportion of intermittent home care was approximately 20%, and the risks for intermittent home care were strongly associated with a lack of intention for continued home care for the elderly, lack of experience of home care, refusal of the family caregiver, and protracted length of stay.

Objective: To compare reasons for discontinuation and drug retention rates per reason among anticytokine therapies, infliximab, etanercept and tocilizumab, and the risk of discontinuation of biological agents due to adverse events (AE) in patients with rheumatoid arthritis (RA)., Method: This prospective cohort study included Japanese RA patients who started infliximab (n=412, 636.0 patient-years (PY)), etanercept (n=442, 765.3 PY), or tocilizumab (n=168, 206.5 PY) as the first biological therapy after their enrolment in the Registry of Japanese Rheumatoid Arthritis Patients for Long-term Safety (REAL) database. Drug retention rates were calculated using the Kaplan-Meier method. To compare risks of drug discontinuation due to AE for patients treated with these biological agents, the Cox proportional hazard model was applied., Results: The authors found significant differences among the three therapeutic groups in demography, clinical status, comorbidities and usage of concomitant drugs. Development of AE was the most frequent reason for discontinuation of biological agents in the etanercept and tocilizumab groups, and the second most frequent reason in the infliximab group. Discontinuation due to good control was observed most frequently in the infliximab group. Compared with etanercept, the use of infliximab (HR 1.69; 95% CI 1.14 to 2.51) and tocilizumab (HR 1.98; 95% CI 1.04 to 3.76) was significantly associated with a higher risk of discontinuation of biological agents due to AE., Conclusions: Reasons for discontinuation are significantly different among biological agents. The use of infliximab and tocilizumab was significantly associated with treatment discontinuation due to AE compared with etanercept.

Objectives: We simultaneously assessed ultrasonography (US) and magnetic resonance imaging (MRI) in comparison with histopathological changes in the knee joints of long-lasting arthritis patients., Methods: We studied 15 patients with rheumatoid arthritis and 5 patients with osteoarthritis, who underwent total knee arthroplasty. On the day before surgery, the joints were examined by US and contrast-enhanced MRI. In US, synovitis was graded with 0-3 grey scale (GSUS) and power Doppler (PDUS). In MRI, synovitis was graded according to OMERACT-RAMRIS (grade 0-3). Synovial tissue samples were obtained during arthroplasty and evaluated on the basis of inflammatory cell infiltrates (grade 0-3), synovial lining layer thickness (grade 0-3) and vascularity (grade 0-3)., Results: Positive findings of PDUS and contrast-enhanced MRI were 45% and 85% of 20 operated joints, respectively. GSUS, PDUS and MRI synovitis were well correlated with overall histopathological grades of synovitis (Spearman correlation coefficients 0.48, 0.84 and 0.48, p<0.05, p<0.01 and p<0.05, respectively). Moreover, positive PDUS findings were closely associated with all pathological comportments of synovitis including inflammatory cell infiltrates, synovial lining layer thickness and vascularity., Conclusions: The present study revealed that positive PDUS findings more faithfully illustrated active synovitis than MRI, whereas contrast-enhanced MRI was more sensitive in detecting synovitis in patients with long-lasting arthritis. It is important to understand distinct features of the both modalities for clinical assessment of chronic joint diseases.

We examined the efficacy and safety of autologous transplantation of bone-marrow-derived cells in patients with intractable ulcers caused by systemic sclerosis. Eight patients with ulcers resistant to treatment were enrolled. Bone marrow cells were gathered from the bilateral iliac crests with multiple repositioning bone marrow needles, and bone-marrow-derived mononuclear cells were isolated and injected into skeletal muscles of the ischemic limb. Visual analog scale (VAS), Sclerosis Health Assessment Questionnaire (SHAQ), modified Rodnan total skin score (mTSS), and the size and depth of the ulcer were examined. Thermography, capillaroscopy, intra-arterial digital subtraction angiography (IA-DSA), and laser Doppler flowmetry were also examined before and after transplantation. In all patients, reduction of ulcer size and improvement of VAS were observed after treatment. Elevation of surface temperature, increase of blood flow volume, and new capillaries of the nail bed were also found after our treatment. There were no major adverse effects of this treatment. Autologous transplantation of bone-marrow-derived cells was shown to be a novel and useful approach to intractable ulcers in systemic sclerosis.

Infection with Mycobacterium tuberculosis (M. tuberculosis) is a critical complication in anti-TNF therapies. In 141 BCG vaccinated healthy individuals and 71 rheumatoid arthritis (RA) patients as screening before anti-TNF therapies, M. tuberculosis specific immune responses were evaluated by tuberculin skin test (TST) and enzyme-linked immunospot assay (ELISPOT), which detected antigen specific IFN-gamma secreting cells in peripheral blood mononuclear cells simulated with either purified protein derivative (PPD), early secretory antigen target 6 (ESAT-6) or culture filtrate protein 10 (CFP-10). Induration over 5 mm in TST was found in 87.9% of controls and 21.4% of RA patients. Erythema size in TST was significantly suppressed in RA patients, especially those receiving prednisolone (PSL), whereas the PPD specific IFN-gamma secretion was less attenuated. Significant responses to either ESAT-6 or CFP-10 in ELISPOT were detected in 14.1% of RA patients including those having positive TST, while the ELISPOT assay was negative in all healthy individuals and 73.3% of RA patients having positive TST. Of ELISPOT positive RA patients, mean dosage of PSL was 4.58 mg and 1.25 mg in TST negative and positive patients, respectively. Thus, ELISPOT is useful for screening of tuberculosis in RA patients, even in those receiving corticosteroids.

Multiple extra-articular synovial cysts (MESC) are rarely complicated with various rheumatic diseases. We here first report a rheumatoid arthritis (RA) patient with MESC, which were extensively analyzed by a series of imaging techniques including fluorine-18-2-fluoro-D: -glucose positron emission tomography ((18)F-FDG-PET), magnetic resonance imaging (MRI), and ultrasonography. FDG uptakes in joint lesions with MESC were much higher than those reported in typical lesions of RA, suggesting that marked joint inflammation is implicated in the development of MESC.

No one knows the timing when influenza pandemic will occur, but that catastrophe will undoubtedly happen. Current vaccines elicit antibodies to membranes of viruses effective against highly specific strains, however they are not effective against multiple strains. New strategies are urgently needed for the protection against multiple strains. It is necessary to develop immunologically superior vaccines. DNA vaccination is an established immunization method in animal models. DNA vaccines are gaining importance due to the induction of a strong cellular immunity. Moreover, the protection against multiple strains of influenza A virus has already been achieved. But their immunogenicity is not so strong that to improve the efficacy of this method is very important. This article highlights some of the recent developments in investigational DNA vaccines. Various tactics for enhancement of their immunity are considered. DNA vaccines together with DNA encoding various cytokines showed better immunological responses in several animal models. Alteration in the vector, inclusion of CpG-ODN motifs, addition of transcriptional factor and appropriate vaccine delivery mechanisms are expected to further improve the efficacy of these vaccines.

We studied the use of a DNA vaccine expressing the matrix (M) gene of the influenza virus A/PR/8/34. Mice were immunized by painting the DNA vaccine three times on the skin after removal of its keratinocytic layers. Immunization by this method produced M-specific antibodies and cytotoxic T lymphocyte (CTL) response, and acquired resistance against influenza virus challenge. This protection was abrogated by the in vivo injection of anti-CD8 or anti-CD4 monoclonal antibody. We further found that simultaneous topical application (t.a.) of GM-CSF expression plasmid (pGM-CSF) or liposomes plus mannan produced stronger immune response competence and enhanced the protective effect against influenza virus challenge. The present study revealed that administering DNA vaccine by topical application can elicit both humoral and cell-mediated immunity (CMI).

DNA vaccination is characterized by its preferential induction of the cytotoxic T cell lymphocyte (CTL) response and is expected to be a useful means of protection against viral infection. We examined the protective effect of an expression plasmid (pME18S-M) containing M1 and M2 genes of influenza A/PR/8/34. We detected the CTL activity by introducing these plasmids into BALB/c mice by either the intramuscular or the intranasal route. The influenza-specific antibody response was also induced, although its neutralizing effect against influenza virus was not observed. From 70 to 80% protection was observed in the mice immunized with the pME18S-M plasmid followed by lethal infection with influenza viruses of the A/WSN/33 and A/PR/8/34 strains, whereas all mice without the plasmid vaccination failed to survive. This protective activity was significantly weakened when the CD8(+) cells of these immunized mice were eliminated by several injections of anti-CD8 antibody. The protective activity was also weakened when anti-CD4 antibody was injected in the early phase of DNA vaccination. These data suggest that the pME18S-M plasmid is useful as a DNA vaccine for overcoming highly mutational influenza viruses.

Systemic lupus erythematosus (SLE) is characterized by immune abnormalities explained by the overproduction of Th(2)cytokines such as autoantibody production and polyclonal B cell activation. We examined the effect of administering a DNA plasmid encoding IL-12 on the lupus-like disease of MRL/MP-lpr/lpr (MRL/lpr) mice. Treatments were delivered intramuscularly every 4 weeks, starting at 4 weeks of age. This intervention significantly inhibited the accumulation of CD4(-)CD8(-)T cells, and reduced lymphadenopathy and splenomegaly. A significant decrease in serum IgG anti-DNA autoantibody titers was observed, and plasmid IL-12 therapy was also associated with a reduction in the proteinuria and glomerulonephritis characteristic of this disease. Serum IFN-gamma level was increased by inoculating IL-12 encoding plasmid, suggesting that the cytokine balance was skewed towards Th(1). The clinical implications of this suppression of autoimmune disease are also discussed., (Copyright 2000 Academic Press.)

Objective: To examine the relationship between the clinical severity of seropositive isolated Raynaud's phenomenon (RP) and its serological background by analyzing digital blood flow data obtained by laser Doppler flowmetry (LDF)., Methods: We analyzed digital blood flow by LDF in 13 healthy volunteers, 55 patients with seropositive isolated RP, and 13 patients with anti-Scl-70 antibody positive systemic sclerosis (SCL). The serological profiles of patients with RP were as follows: 30 patients had the anti-centromere antibody (C) and 19 the anti-RNP antibody (RNP). We designated the RP in each patient group as C-RP, RNP-RP, and SCL-RP. We used an "arm-raising test" by which blood pressure could be passively depressed, and the cold provocation test, which induced vasoconstriction through the sympathetic reflex. We defined 2 variables, the recovery velocity after cold exposure (RV-CE) and the increase in the amplitude of the digital pulse wave during the arm-raising test (IA-AR), that are the most reliable and sensitive variables indicating the severity of RP., Results: Both RV-CE and IA-AR correlated significantly with the clinical severity of RP. In IA-AR and RV-CE, there was a significant difference between C-RP and RNP-RP (IA-AR 107.1 +/- 25.63 vs 37.4 +/- 17.25%; RV-CE 0.0667 +/- 0.010 vs 0.035 +/- 0.0096 V/s), showing that C-RP tended to be less severe than RNP-RP., Conclusion: We defined 2 variables that correlated with the clinical severity of RP; using them we found that anti-centromere antibody positive RP is less severe than RNP-RP

Objective: To determine whether intravenous cyclophosphamide pulse therapy (IVCY) is effective for treating patients with diffuse proliferative lupus nephritis (DPLN) who were 1) refractory to methylprednisolone pulse therapy (MP) or 2) could not be treated with MP because of severe diabetes or steroid induced psychosis., Methods: Seven patients with biopsy proven DPLN were studied after informed consent. Five of them received IVCY after a failure to achieve renal remission with at least 2 cycles of MP therapy. Of the other 2 patients, one had severe diabetes and the other a history of steroid induced psychosis. Bolus therapy with cyclophosphamide (0.5 g/m2 body surface area) was given once a month for 6 consecutive months and then once every 3 months for a total treatment period of 1 year. All patients were given oral prednisone, 0.5 mg/kg per day. The prednisone dose was tapered to the minimal dose required for controlling the disease. After 1 year, the renal status of the patients were evaluated., Results: At 1 year, 4 of the 7 patients achieved substantial improvement. Although the other 3 patients did not satisfy the definition of substantial improvement, none of them had progressive disease. Adverse events were mild and did not require any treatment, with 2 cases of leukocytopenia without fever or major infection. No cases of hemorrhagic cystitis or amenorrhea were observed., Conclusions: IVCY was 1) effective in the treatment of DPLN which was refractory to MP and 2) relatively safe with minimal side effects.

CD40 ligand is a costimulatory molecule which acts a potent immunomodulator. We found the mice inoculated with human CD40 ligand expression plasmid (pMEhCD40L) combined with human immunodeficiency virus type-1 (HIV-1) DNA vaccine exhibited both humoral and cellular antigen-specific immunological enhancement. The expression of hCD40L induced predominantly antigen-specific immunoglobulin G (IgG) antibody response while it failed to induce mucosal IgA response. Delayed-type hypersensitivity (DTH) and cytotoxic T lymphocyte (CTL) activity were induced in a dose-dependent manner. Examination of the relative levels of the two IgG subclasses showed that co-injection of pMEhCD40L enhanced IgG2a response without suppressing IgG1 response. Similarly, the expression of pMEhCD40L enhanced not only T helper 1 (Th1)- but also Th2-type cytokine production. In conclusion, co-inoculation of pMEhCD40L with DNA vaccine was shown to be a useful way to enhance CTL responses without suppressing the humoral immune response in acquired immune deficiency syndrome (AIDS) patients.

The patient, a 51-year-old male with a two year history of AIDS, was admitted to our hospital because of hemiparalysis and vomiting. The MRI study showed multiple lesions with ring-enhancement in the right basal brain area. Empirical therapy for toxoplasma encephalitis was started. After 64 days, the subsequent brain MRI showed deterioration. A 201Tl-SPECT study was performed and the findings were consistent with those of malignant lymphoma (ML). The patient was treated with 40 Gy of whole brain radiation, MRI showed partial response to this therapy, and clinical improvement was achieved. The definitive diagnosis of primary CNS lymphoma can be made only by brain biopsy, and many cases have been diagnosed at autopsy. The clinical and radiological findings of primary CNS lymphoma resemble toxoplasma encephalitis. An empirical therapy for toxoplasma encephalitis is recommended to avoid brain biopsy in these cases. The use of 201Tl-SPECT for the differential diagnosis of these diseases have been reported. Considering the poor prognosis of primary CNS lymphoma in AIDS, the application of 201Tl-SPECT before empirical therapy for toxoplasma must be important for appropriate treatment.