Clinical and ultrasound features of difficult-to-treat rheumatoid arthritis: A multicenter RA ultrasound cohort study.

OBJECTIVE: The optimal strategy for difficult-to-treat (D2T) rheumatoid arthritis (RA) has not been identified, and the ultrasound characteristics of D2T RA have not been reported. We investigated the clinical characteristics and factors contributing to the outcome in D2T RA in a multicentre RA ultrasound observational cohort. METHOD: We reviewed 307 Japanese patients diagnosed with RA who underwent treatment with biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). We compared the differences in patient characteristics between the D2T RA and non-D2T RA groups. We examined the factors contributing to a good response [defined as b/tsDMARD continuation and Clinical Disease Activity Index (CDAI) ≤ 10 at 12 months] in the D2T RA patient group. RESULTS: Forty-three patients (14%) were categorized as D2T RA and the remaining 264 (86%) as non-D2T RA at baseline. The grey-scale (GS) score, disease duration, and CDAI at the initiation of treatment were significantly higher in the D2T RA group than in the non-D2T RA group. In contrast, the power Doppler (PD) score was not significantly different between the two groups. Of the 43 D2T RA patients, 20 achieved a good response. The introduction of CTLA4-Ig (n = 5) was significantly associated with a good response in analysis based on inverse probability weighting with propensity score. GS and PD scores at baseline were not significantly associated with therapeutic response at 12 months in D2T RA patients. CONCLUSIONS: Patients with D2T RA had high clinical and ultrasound activity and poor responses to treatment with b/tsDMARDs. CTLA4-Ig was associated with a good response at 12 months in D2T RA patients.

Ultrasound efficacy of targeted-synthetic disease-modifying anti-rheumatic drug treatment in rheumatoid arthritis: a multicenter prospective cohort study in Japan.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Discrepancy between clinical and ultrasound remissions in rheumatoid arthritis: a multicentre ultrasound cohort study in Japan.

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 cohorts achieving US remission and clinical remission, and to determine the factors contributing to the discrepancy.Method: We reviewed 248 Japanese patients diagnosed with RA who underwent treatment with biological disease-modifying anti-rheumatic drugs at 13 centres. We performed US assessments of the synovia of 22 joints. We assessed the percentages of patients with clinical remission and US remission, defined as total power Doppler scores of 0 at 12 months.Results: The 87 patients who achieved US remission were divided into a group that achieved both clinical and US remission (n = 53) and a group that achieved US remission only (n = 34). Baseline factors that were significantly and independently associated with clinical remission at 12 months among patients who also achieved US remission included short disease duration, the presence of concomitant methotrexate use, and low patient global assessment score (p < 0.05, p < 0.05, and p < 0.005, respectively).Conclusions: RA patients with baseline high patient global assessment scores and long disease duration at baseline were unlikely to achieve clinical remission even after achieving US remission. Objective joint assessments using US provide additional information of potential importance for the management of RA.

Significance of anti-Ro/SSA antibodies in the response and retention of abatacept in patients with rheumatoid arthritis: a multicentre cohort study.

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 < 0.05). Conclusion: Anti-Ro/SSA antibody positivity predicts a poor response to abatacept and low retention rate.

Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan.

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.

Effect of solute atoms on dislocation motion in Mg: an electronic structure perspective.

Solution strengthening is a well-known approach to tailoring the mechanical properties of structural alloys. Ultimately, the properties of the dislocation/solute interaction are rooted in the electronic structure of the alloy. Accordingly, we compute the electronic structure associated with, and the energy barriers to dislocation cross-slip. The energy barriers so obtained can be used in the development of multiscale models for dislocation mediated plasticity. The computed electronic structure can be used to identify substitutional solutes likely to interact strongly with the dislocation. Using the example of a-type screw dislocations in Mg, we compute accurately the Peierls barrier to prismatic plane slip and argue that Y, Ca, Ti, and Zr should interact strongly with the studied dislocation, and thereby decrease the dislocation slip anisotropy in the alloy.

Multilayer coated grazing incidence condenser for large numerical aperture objective at wavelength of 4.5 nm.

A grazing incidence condenser is developed for objectives with large numerical aperture working in Carbon-window wavelength region (λ=4.4-5.0 nm) with the use of a point light source. The condenser is composed of four pieces of toroidal mirrors and a piece of the mirror was fabricated to evaluate the performance of the mirror. The radii of the toroidal mirror are determined by ray-trace calculation, and each radius of the mirror substrate and the roughness of the polished surface were evaluated to satisfy the designed parameter. A Co/C reflection multilayer is also designed to reflect soft x-ray light at 4.5 nm wavelength, and the reflection multilayer was deposited on the mirror surface. Measured reflectance of the toroidal mirror with the reflection multilayer is higher than 0.32 at 4.5 nm wavelength.

Solution softening in magnesium alloys: the effect of solid solutions on the dislocation core structure and nonbasal slip.

There is a pressing need to improve the ductility of magnesium alloys so that they can be applied as lightweight structural materials. In this study, a mechanism for enhancing the ductility of magnesium alloys has been pursued using the atomistic method. The generalized stacking fault (GSF) energies for basal and prismatic planes in magnesium were calculated by using density functional theory, and the effect of the GSF energy on the dislocation core structures was examined using a semidiscrete variational Peierls-Nabarro model. Yttrium was found to have an anomalous influence on the solution softening owing to a reduction in the GSF energy gradient.

Clock gene expression in peripheral leucocytes of patients with type 2 diabetes.

AIM/HYPOTHESIS: Recent studies have demonstrated relationships between circadian clock function and the development of metabolic diseases such as type 2 diabetes. We investigated whether the peripheral circadian clock is impaired in patients with type 2 diabetes. METHODS: Peripheral leucocytes were obtained from eight patients with diabetes and six comparatively young non-diabetic volunteers at 09:00, 15:00, 21:00 and 03:00 hours (study 1) and from 12 male patients with diabetes and 14 age-matched men at 09:00 hours (study 2). Transcript levels of clock genes (CLOCK, BMAL1 [also known as ARNTL], PER1, PER2, PER3 and CRY1) were determined by real-time quantitative PCR. RESULTS: In study 1, mRNA expression patterns of BMAL1, PER1, PER2 and PER3 exhibited 24 h rhythmicity in the leucocytes of all 14 individuals. The expression levels of these mRNAs were significantly (p < 0.05) lower in patients with diabetes than in non-diabetic individuals at one or more time points. Moreover, the amplitudes of mRNA expression rhythms of PER1 and PER3 genes tended to diminish in patients with diabetes. In study 2, leucocytes obtained from patients with diabetes expressed significantly (p < 0.05) lower transcript levels of BMAL1, PER1 and PER3 compared with leucocytes from control individuals, and transcript expression was inversely correlated with HbA(1c) levels (rho = -0.47 to -0.55, p < 0.05). CONCLUSIONS/INTERPRETATION: These results suggest that rhythmic mRNA expression of clock genes is dampened in peripheral leucocytes of patients with type 2 diabetes. The impairment of the circadian clock appears to be closely associated with the pathophysiology of type 2 diabetes in humans.

Long-term outcome of systemic cyclosporine treatment following penetrating keratoplasty.

PURPOSE: To perform a retrospective study to evaluate the long-term outcome of systemic cyclosporine treatment as an adjunct to topical corticosteroid treatment after penetrating keratoplasty (PKP). METHODS: Twenty-six high-risk patients (27 eyes) who received systemic cyclosporine following PKP for an average of 5.4 months were compared with another series of 57 patients (57 eyes) who did not receive cyclosporine after PKP. RESULTS: Endothelial rejection developed in 2 cases during cyclosporine treatment and in 6 cases after discontinuation. The rate of rejection-free graft survival was similar between the treated and the control groups. The control group showed a significantly higher rate of graft survival than the treated group. As side effects in the treatment group, transient elevation in blood urea nitrogen or creatine developed in 7 cases. Increase in glutamate oxaloacetate transaminase (GOT) or glutamate pyruvate transaminase (GPT) developed in 4 cases. Severe side effects were absent throughout the series in both groups of patients. CONCLUSION: Systemic cyclosporine treatment for several months did not reduce the incidence of rejection nor improve the rate of graft clarity in the long term in high-risk patients after PKP.

[Efficacy and safety of influenza vaccination to elderly patients with neurological diseases].

Influenza vaccination is strongly recommended for the elderly persons. Especially elderly patients with neurological diseases are at the high risk because they have more tendencies to develop pneumonia than healthy elderly persons. We vaccinated 105 elderly patients with neurological diseases (cerebrovascular disease, Parkinson disease etc.) and 134 people of a control group. Both groups were inoculated with influenza HA vaccine once. The HI titer increase in elderly patients with neurological diseases was equally good enough in the control group and no significant differences was shown in both groups. No severe side effects and adverse reactions were observed in the elderly patient group. This study shows that influenza vaccination is effective and safe for elderly patients with neurological diseases as the well as healthy elderly person and the HI titer increase after a single influenza vaccine injection is expected to be effective to protect influenza infection.

Risk factors for corneal graft failure and rejection in penetrating keratoplasty.

PURPOSE: To evaluate risk factors for graft failure and allograft rejection after penetrating keratoplasty (PK). METHODS: We retrospectively studied clinical results of PKs in terms of graft survival and rejection-free graft survival rates. PKs were done on 271 eyes between 1987 and 1997. Clinical results were analyzed by Kaplan-Meier's life table method and the log-rank test. Relative risks and adjusted survival probabilities for each value of the factor were compared with the risk for a specified reference value. RESULTS: The overall rates of graft survival and rejection-free graft survival in 10 years after PK were 79.3% and 77.9%, respectively. Higher relative risk of graft failure was associated with corneal vascularization (relative risk for within one quadrant = 1.67, two quadrants = 2.37, three or more quadrants = 3.39), regraft (relative risk for one failed previously graft = 2.08, two or more failed previously graft = 2.65), aphakia (relative risk = 2.17) or pseudophakia (relative risk = 3.02), presence of anterior synechia (relative risk = 2.91), presence of posterior synechia (relative risk = 2.56), long (more than 85 minutes) operation time (relative risk = 2.20), and older (more than 50 years) recipient age (relative risk = 2.38). Higher relative risk of rejection was associated with corneal vascularization (relative risk for within one quadrant = 2.35, two quadrants = 2.03, three or more quadrants = 2.63), long (more than 85 minutes) operation time (relative risk = 1.47), and younger (less than 60 years) donor age (relative risk = 2.10). There was no association between graft failure or allograft rejection and graft size or suture technique, respectively. CONCLUSION: The risk factors for graft failure after PK were corneal vascularization, regraft, aphakia or pseudophakia, presence of anterior synechia, presence of posterior synechia, long operation time, and older recipient age. The risk factors after PK for allograft rejection were corneal vascularization, long operation time, and younger donor age.

Risk factors for hip fracture among elderly patients with Parkinson's disease.

Incidence of hip fracture among patients with Parkinson's disease (PD) is high, especially in elderly women. To determine effects of various factors on hip fracture risk, we prospectively studied fractures in a cohort of 115 elderly patients of both genders with PD (46 men, 69 women; mean age, 71.9 years) for 1 year. At baseline, we recorded body mass index (BMI), Hoehn and Yahr stage, and postmenopausal interval, and also measured bone mineral density (BMD) and serum concentrations of ionized calcium, intact parathyroid hormone (PTH), pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP; a bone resorption marker), and 25-hydroxyvitamin (25-OHD). During the year hip fractures occurred in 18 patients (2 male and 16 female). We compared baseline variables between patients with and without hip fracture. PD patients with decreased BMI, lower BMD, and low concentrations of serum ionized calcium, and 25-OHD (mean 4.0 ng/ml) with compensatory hyperparathyroidsim had increased risk of hip fracture. Female PD patients with long postmenopausal intervals also had increased hip fracture risk. BMI, illness duration, postmenopausal intervals, Hoehn and Yahr stage, 25-OHD, PTH, calcium, and ICTP were determinants of BMD in patients with fracture. Elderly PD patients with low BMI, low BMD, and serum 25-OHD concentrations < or =5 ng/ml with secondary hyperparathyroidism have increased risk of hip fracture, as do female PD patients with long postmenopausal intervals.

Serum beta2-microglobulin reflects increased bone resorption in immobilized stroke patients.

OBJECTIVE: The so-called bone-derived growth factor, beta2-microglobulin, has a regulatory function in bone metabolism by stimulating osteoclast activity. We undertook this study because osteoclast activity is known to be enhanced in patients with immobilized stroke, suggesting that their beta2-microglobulin concentrations may be increased. DESIGN: We studied 79 patients with acute stroke hemiplegia, including 36 men and 43 postmenopausal women ranging in age between 51 and 70 yr. RESULTS: The mean Barthel Index was 43 and 42 for men and women, respectively. The serum beta2-microglobulin concentration was increased in male and female patients, compared with the findings of 44 age-matched control subjects, and the serum concentration of pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen was also increased in male and female patients, compared with the findings of the control subjects. Serum concentrations of pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen correlated negatively with Barthel Index scores in both genders, indicating increased bone resorption caused by immobilization in these patients. Linear regression analysis revealed a positive correlation between beta2-microglobulin and pyridinoline cross-linked carboxyterminal telopeptide of type 1 collagen in both genders. CONCLUSIONS: These findings suggest that beta2-microglobulin reflects osteoclastic activity in response to stroke-induced immobilization in both genders. Beta2-microglobulin is a useful indicator of bone resorption in patients with immobilized stroke.

Caspases that are activated during generation of nuclear polyglutamine aggregates are necessary for DNA fragmentation but not sufficient for cell death.

Truncated polypeptides containing expanded polyglutamine (polyQ) stretches tend to form cytoplasmic or nuclear aggregates in cultured cells, leading to cell death. Although it has been shown recently that caspase-8 coaggregates with polyQ and is activated during polyQ-mediated cell death, little is known of the location and timing of caspase-8 activation by nuclear polyQ aggregates. Also, the relationship between nuclear polyQ aggregate-mediated cell death and activation of other caspases is unclear. In P19 embryonal carcinoma (EC) cells, which can be made to differentiate into neuronal cells, polyQ72 repeats preferentially aggregate in the nucleus. Nuclear aggregates of polyQ72 induced P19 EC cell death, with a high frequency of cells exhibiting morphology characteristic of apoptosis (i.e., roundness, cell shrinkage, chromatin condensation) and DNA fragmentation. In the present study, we used antisera that specifically recognized the active forms of caspase-8, -3, and -9 but not their proforms, and showed that only caspase-8 and -3 were activated during the generation of polyQ72 aggregates in P19 EC cell nuclei. Furthermore, we showed that the caspase inhibitor z-VAD-fmk inhibited DNA fragmentation, but only partially inhibited the appearance of apoptotic morphology. Thus, caspase activation, including caspase-8 and -3, is necessary for polyQ-mediated DNA fragmentation but not sufficient for polyQ-mediated cell death in P19 EC cells.