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DOI： 10.1093/mr/roae040

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Oxford University Press (OUP)  

ABSTRACT

Objective

To compare the effectiveness of methotrexate (MTX) as initial therapy in patients with late-onset and younger-onset rheumatoid arthritis (LORA and YORA).

Methods

Of 114 patients with YORA and 96 patients with LORA, defined as RA occurring at ≥65 years of age, enrolled in a multicentre RA inception cohort study, 71 and 66 patients who had been followed up to 6 months after starting MTX treatment were included in this study.

Results

Proportions of patients on MTX treatment at 6 months were 96% and 92% in the YORA and LORA groups, respectively. Despite lower doses of MTX in the LORA group compared with the YORA group, no significant difference was observed in clinical disease activity index scores between the two groups throughout the follow-up period. The proportion of patients in clinical disease activity index remission at 6 months was 35% in both groups. Logistic regression analysis revealed that knee joint involvement and high Health Assessment Questionnaire-Disability Index were significant negative predictors of achieving clinical disease activity index remission at 6 months in the LORA group.

Conclusion

Observations up to 6 months revealed that the effectiveness of MTX administered based on rheumatologist discretion in patients with LORA is comparable to that in patients with YORA in clinical settings.

DOI： 10.1093/mr/roae027

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OBJECTIVES: To investigate factors predicting frailty for one year in pre-frail patients with rheumatoid arthritis (RA). METHOD: A total of 298 RA patients who were pre-frail in 2020 were evaluated in this structured, retrospective observational study. Of the 298 patients, 42 who were frail and 256 who were not in 2021 were assigned to the frailty and non-frailty groups, respectively. After comparing characteristics of both groups using univariate analysis, predictive factors of frailty were assessed by logistic regression analysis. The proportion of frail patients in 2021 by DAS28-ESR level in 2020 was examined by the Cochran-Armitage trend test and chi-squared test. After dividing pre-frail patients into those with DAS28-ESR ≥3.2 and DAS28-ESR <3.2 in 2020, one-year change in DAS28-ESR in the frailty and non-frailty groups for both subgroups were compared by the paired t-test. RESULTS: The frailty group was older (mean: 71.0 vs. 65.4 years) and had a higher DAS28-ESR (mean: 3.22 vs. 2.70) than the non-frailty group. DAS28-ESR was identified as a predictive factor for frailty (OR: 1.49). Among patients with DAS28-ESR ≥3.2 in 2020, DAS28-ESR improved in the non-frailty group in 2021 (mean: 3.97 in 2020 vs. 3.13 in 2021) but did not in the frailty group (3.97 in 2020 vs. 3.81 in 2021). Among those with DAS28-ESR <3.2 in 2020, DAS28-ESR was unchanged in the non-frailty group in 2021 (2.15 in 2020 vs. 2.23 in 2021) but increased in the frailty group (2.53 in 2020 vs. 3.23 in 2021). CONCLUSIONS: Disease activity at baseline is an independent predictor of frailty one year later in pre-frail patients with RA.

DOI： 10.1016/j.jos.2022.10.025

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DOI： 10.1111/1756-185X.15034

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: This study aimed to investigate factors associated with frailty in rheumatoid arthritis (RA) patients. METHODS: A total of 656 RA patients were evaluated using data from an observational study in 2022. Among these patients, 152 with frailty were assigned to the frailty group, and 504 without frailty were assigned to the non-frailty group. Patient characteristics were compared between the two groups by univariate analysis, and factors associated with frailty were assessed by logistic regression analysis. Patient characteristics were also compared between patients with RA-associated interstitial lung disease (RA-ILD) (n = 102) and those without RA-ILD (n = 554). RESULTS: The frailty group was older (mean: 73.6 vs. 66.8 years) and had a higher DAS28-ESR (3.67 vs. 2.66), a higher HAQ-DI (1.13 vs. 0.32), and a higher rate of RA-ILD (25.0 vs. 12.7 %) than the non-frailty group. Age (OR: 1.03, 95 % CI: 1.01-1.05), HAQ-DI (3.22, 2.28-4.56), DAS28-ESR (1.44, 1.19-1.75), and RA-ILD (2.21, 1.24-3.94) were associated with frailty. RA patients with RA-ILD were older (73.3 vs. 67.5 years) and had a higher DAS28-ESR (3.30 vs. 2.80), a higher HAQ-DI (1.19 vs. 0.32), a higher proportion of frail patients (37.3 vs. 20.6 %), lower MTX use (26.5 vs. 62.9 %), and higher steroid use (44.1 vs. 26.8 %) than those without RA-ILD. CONCLUSIONS: Maintaining reasonable control of disease activity is necessary for RA patients, including those with RA-ILD, to recover from frailty.

DOI： 10.1016/j.jos.2023.11.012

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OBJECTIVES: To investigate a plateau in treatment enhancement for improving the frailty status of rheumatoid arthritis (RA) patients. METHODS: A total of 345 RA patients who were not robust in 2021 were assigned to the improved ("robust 2022," n = 51) and non-improved ("pre-frailty/frailty 2022," n = 294) groups. Factors associated with "robust 2022" were examined by logistic regression analysis. Patients were assigned to the stable (Follow-up mean DAS28-ESR in 2020 and 2021 < 3.2, n = 225) and unstable (≥3.2, n = 120) groups, which were further divided into the non-improved (stable: n = 180, unstable: n = 114) and improved (stable: n = 45, unstable: n = 6) groups. Factors influencing Japanese Cardiovascular Health Study (J-CHS) score were examined by multiple regression analysis. Changes over 2 years were compared between the non-improved and improved groups of the stable group. RESULTS: The associated factor of "robust 2022" was the follow-up meanDAS28-ESR in 2020 and 2021 < 3.2 (i.e., stable state) (OR: 4.01). Follow-up mean DAS28-ESR in 2020 and 2021 was associated with J-CHS score (T = 2.536, p = .013) only in the unstable group. In the stable group, HAQ-DI was lower (2020: 0.32 vs. 0.16; 2021: 0.32 vs. 0.17; 2022: 0.32 vs. 0.21), and the proportion of J-CHS: Q4 (weakness) was lower (2020: 48.4 vs. 17.8%; 2021: 55.0 vs. 29.2%; 2022: 50.4 vs. 0%), in the improved group than in the non-improved group, whereas both groups maintained clinical and functional remission over 2 years. CONCLUSIONS: Drug treatment to maintain well-controlled disease activity alone is insufficient for improving patients' frailty status after achieving treat-to-target goals, suggesting the need for multifaceted approaches.

DOI： 10.1111/1756-185X.14946

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PubMed

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Staphylococcus aureus (S. aureus) nasal carriage is a well-known risk factor for surgical site infection (SSI) after total joint arthroplasty. This study aimed to compare the prevalence of S. aureus nasal carriage between patients with osteoarthritis (OA), a degenerative joint disease, and those with rheumatoid arthritis (RA), a chronic autoimmune inflammatory disease, who underwent total joint arthroplasty, and to investigate the influence of RA disease activity on nasal carriage rate. METHODS: This retrospective study targeted 508 OA and 107 RA patients who underwent S. aureus nasal screening prior to primary total knee and/or hip arthroplasty. RA patients were divided into two groups based on disease activity: the remission/low disease activity (REM/LDA) group and the moderate/high disease activity (MDA/HDA) group. Factors associated with S. aureus nasal carriage were assessed with multivariate logistic regression models. RESULTS: Of all 615 patients, 155 (25%) carried S. aureus in their nares. Compared to OA patients, RA patients had a significantly higher rate of S. aureus nasal carriage (24% vs. 33%, p = 0.049). Compared to the REM/LDA group (n = 39), the MDA/HDA group (n = 58) had a significantly higher rate of S. aureus nasal carriage (21% vs. 41%, p = 0.032). Multivariate analysis revealed that the MDA/HDA group, but not the REM/LDA group, had a significantly higher odds of S. aureus nasal carriage compared to the OA group (odds ratio: 2.76, 95% confidence interval: 1.07-7.12). CONCLUSION: Preoperative nasal screening for S. aureus is beneficial, especially in RA patients with moderate/high disease activity.

DOI： 10.1016/j.jos.2022.09.014

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DOI： 10.1111/1756-185X.14947

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PubMed

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INTRODUCTION: Methotrexate (MTX) is an anchor drug in the treatment of rheumatoid arthritis (RA). Frailty is the intermediate condition between being healthy and disabled, and can lead to negative health outcomes. Adverse events (AEs) due to RA drugs are expected to be higher in frail patients. The present study aimed to investigate the relationship between frailty and MTX discontinuation due to AEs in RA patients. METHODS: Of 538 RA patients who visited us between June and August 2020 as part of the retrospective T-FLAG study, 323 used MTX. After 2 years of follow-up, we investigated AEs leading to MTX discontinuation. Frailty was defined as a Kihon Checklist (KCL) score ≥ 8. Cox proportional hazards regression analysis was performed to identify factors associated with MTX discontinuation due to AEs. RESULTS: Of the 323 RA patients (251 women, 77.7%) who used MTX, 24 (7.4%) discontinued MTX due to AEs during the 2-year follow-up period. Mean ages in the MTX continuation/discontinuation groups were 64.5 ± 13.9/68.5 ± 11.7 years (p = 0.169), Clinical Disease Activity Index was 5.6 ± 7.3/6.2 ± 6.0 (p = 0.695); KCL was 5.9 ± 4.1/9.0 ± 4.9 points (p < 0.001); and the proportion of frailty was 31.8%/58.3% (p = 0.012). MTX discontinuation due to AEs was significantly associated with frailty (hazard ratio 2.34, 95% confidence interval 1.02-5.37) even after adjusting for age and diabetes mellitus. AEs included liver dysfunction (25.0%), pneumonia (20.8%), and renal dysfunction (12.5%). CONCLUSIONS: Because frailty is a significant factor contributing to MTX discontinuation due to AEs, the latter should be carefully monitored in frail RA patients who use MTX. Key Points • Of the 323 rheumatoid arthritis (RA) patients (251 women, 77.7%) who used methotrexate (MTX), 24 (7.4%) discontinued MTX due to adverse events (AEs) during the 2-year follow-up period. • MTX discontinuation due to AEs was significantly associated with frailty (hazard ratio 2.34, 95% confidence interval 1.02-5.37) even after adjusting for age and diabetes mellitus, and neither the MTX dose, folic acid supplementation, nor GC co-therapy were factors in MTX discontinuation. • Frailty is a predominant factor in MTX discontinuation among established, long-term pretreated RA patients, and the occurrence of AEs due to MTX should be carefully monitored when frail RA patients use MTX.

DOI： 10.1007/s10067-023-06639-z

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OBJECTIVES: To examine intervertebral fusion sites along the whole spine of patients with ankylosing spondylitis using computed tomography. METHODS: This retrospective study examined intervertebral fusion of five sites (anterior/posterior vertebrae, left/right zygapophyseal joints, and spinous process) on 23 vertebrae in the cervical, thoracic, and lumbar regions of the spine in 40 patients diagnosed with ankylosing spondylitis at our institute between January 2004 and December 2022. RESULTS: Mean age [± standard deviation (SD)] was 40.5 (± 17) years, and mean disease duration (± SD) was 11.4 (± 10.5) years at computed tomography evaluation; 55.9% were human leukocyte antigen B-27-positive. Fifteen (37.5%) patients showed intervertebral fusion in the thoracic and/or cervical regions, but not in the lumbar region. Fusion of posterior vertebrae was observed most frequently in the thoracic region, compared to the cervical and lumbar regions. In particular, more than half of the patients showed fusion of posterior vertebrae Th4-Th5 to Th7-Th8. CONCLUSIONS: In 37.5% of patients, intervertebral fusion was evident in the thoracic and/or cervical regions but not in the lumbar region. The most common site and region of intervertebral fusion were the posterior vertebrae of the middle thoracic region.

DOI： 10.1093/mr/road065

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OBJECTIVES: To examine the age at onset and initial symptoms as clinical features of ankylosing spondylitis in Japanese patients. METHODS: This retrospective study included 60 Japanese patients diagnosed with ankylosing spondylitis at our institute between January 2004 and June 2021. Initial symptoms were considered pain in axial joints and/or extra-axial joints. If a patient had initial symptoms at multiple sites, each site was counted. We assessed trends for the number of patients and sites of initial symptoms according to age at onset. RESULTS: Mean age (± standard deviation) at onset was 28.9 (± 14.3) years. Approximately one-third of patients experienced onset before age 20. The back was the most common site of initial symptoms (36.7%), followed by the hip (26.7%), knee (15%), buttocks (15%), neck (10%), finger (6.7%), shoulder (3.3%), and others (including overlapping sites). Thirty-two (53.3%) and 25 (41.7%) patients had initial symptoms only in axial joints and only in extra-axial joints, respectively. The proportion of patients with initial symptoms only in extra-axial joints significantly decreased with increasing age (p = .024). CONCLUSIONS: Sites of initial symptoms were frequently the back, hip, knee, and buttocks, and 41.7% had initial symptoms only in extra-axial joints. Younger onset patients frequently had extra-axial involvement.

DOI： 10.1093/mr/roac081

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Total elbow arthroplasty (TEA) is a surgical option for patients with rheumatoid arthritis (RA). Periprosthetic fractures during and after TEA are one of the most common causes of reoperation. Fractures around the stem of a loose prosthesis with associated bone loss are the most technically challenging to treat. Previous reports have demonstrated that the use of massive allografts is a reasonable alternative in salvage situations. Here, we report the case of a 78-year-old woman with RA who underwent revision TEA using massive allografts with modifications to the methods described in previous reports. She suffered a right periprosthetic humeral fracture 5 years after primary TEA, with a fracture in the proximal humeral diaphysis and a long spiral fracture in the diaphysis. The fracture around the stem of a loose prosthesis was associated with bone loss. We performed revision TEA using an allograft of the proximal femoral diaphysis. In contrast to previous reports, we preserved part of the humeral diaphysis, which was thin due to osteolysis, without removal. The advantage of this approach was that it preserved attachments, such as the deltoid and brachioradialis muscles. The patient had good elbow function and minimal pain without adverse events at 1 year postoperatively. Our findings suggest that preserving part of a thinned humeral diaphysis is a reasonable option in revision TEA with a massive composite allograft.

DOI： 10.1093/mrcr/rxad001

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DOI： 10.1136/annrheumdis-2023-eular.2586

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DOI： 10.1136/annrheumdis-2023-eular.2604

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DOI： 10.1136/annrheumdis-2023-eular.2449

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DOI： 10.1136/annrheumdis-2023-eular.503

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DOI： 10.1136/annrheumdis-2023-eular.2884

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OBJECTIVE: Various guidelines recommend that patients with early rheumatoid arthritis (RA) try to achieve clinical remission within 6 months, and early therapeutic intervention is important to this end. This study aimed to investigate short-term treatment outcomes of patients with early-diagnosed RA in clinical practice and to examine predictive factors for achieving remission. METHODS: Of the 210 patients enrolled in the multicenter RA inception cohort, 172 patients who were followed up to 6 months after treatment initiation (baseline) were included. Logistic regression analysis was used to examine the impact of baseline characteristics on achievement of Boolean remission at 6 months. RESULTS: Participants (mean age, 62 years) initiated treatment after a mean of 19 days from RA diagnosis. At baseline and 3 and 6 months after treatment initiation, proportions of patients using methotrexate (MTX) were 87.8%, 89.0%, and 88.3%, respectively, and rates of Boolean remission were 1.8%, 27.8%, and 34.5%, respectively. Multivariate analysis revealed that physician global assessment (PhGA) (Odds ratio (OR): 0.84, 95% confidence interval (CI): 0.71-0.99) and glucocorticoid use (OR: 0.26, 95% CI: 0.10-0.65) at baseline were independent factors that predicted Boolean remission at 6 months. CONCLUSION: After a diagnosis of RA, satisfactory therapeutic effects were achieved at 6 months after the initiation of treatment centered on MTX according to the treat to target strategy. PhGA and glucocorticoid use at treatment initiation are useful for predicting the achievement of treatment goals.

DOI： 10.1016/j.jos.2023.03.020

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OBJECTIVES: The study aimed to investigate the effectiveness and tolerance of biological disease-modifying antirheumatic drugs (bDMARDs) therapy administered concomitantly with tacrolimus (TAC) treatment in patients with rheumatoid arthritis. METHODS: 2792 patients who underwent therapy with five bDMARDs (etanercept: ETN, adalimumab, golimumab, tocilizumab, and abatacept: ABT) were enrolled. Among the study subjects, 1582 were concomitant methotrexate (MTX group), 147 were concomitant TAC (TAC group), and 1063 were non-concomitant MTX and TAC (non-MTX/TAC group). The primary outcome was the incident rate of discontinuation of bDMARDs by adverse events (AEs) or loss of efficacy. RESULTS: Concerning the analysis for each reasons of discontinuation, including AEs and loss of efficacy, the hazards ratio (HR) was significantly lower in the TAC group than in non-MTX/TAC groups (AEs: HR = 0.39, 95% confidence interval, 0.23-0.68, loss of efficacy: HR = 0.49, 95% confidence interval, 0.30-0.78). The loss of efficacy with the use of ETN and ABT was lower in the TAC group than in non-MTX/TAC groups. Concomitant TAC did not induce elevated risk for discontinuation of AEs in all bDMARD analyses. CONCLUSIONS: Concomitant TAC with ABT or ETN showed higher retention rates than bDMARDs therapy without TAC or MTX. AEs did not increase over long-term observation.

DOI： 10.1093/mr/roac025

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OBJECTIVES: To investigate factors associated with frailty in rheumatoid arthritis (RA) patients with decreased renal function. METHODS: RA patients who visited outpatient clinics from June to August 2021 were included (N = 625). Patients with estimated glomerular filtration rate <60 ml/min/1.73 m2 were defined as having decreased renal function (N = 221) and divided into the non-frailty (N = 153) and frailty (N = 58) groups. Patient characteristics were compared between the two groups by univariate analysis. Significant factors in univariate analysis were assessed by logistic regression analysis to determine their association with frailty in patients with decreased renal function. RESULTS: Patients in the frailty group were older (74.0 vs.79.0 years) and had a longer duration of disease (11.1 vs. 17.8 years), higher Disease Activity Score erythrocyte sedimentation rate (DAS28-ESR; 2.99 vs. 3.80), higher Health Assessment Questionnaire Disability Index (0.42 vs. 1.43), and a lower rate of methotrexate (MTX) use (46.4% vs. 25.9) compared to those in the non-frailty group. Factors associated with frailty in patients with decreased renal function were age (odds ratio: 1.07), duration of disease (1.06), DAS28-ESR (1.85), and MTX use (0.42). CONCLUSIONS: Among factors associated with frailty in RA patients with decreased renal function, improving DAS28-ESR is likely to be the most feasible approach to promote recovery from frailty (200/200 words).

DOI： 10.1093/mr/roac018

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Rheumatoid arthritis (RA) patients often exhibit finger/wrist joint symptoms and reduced grip strength. This study aimed to validate grip strength as a measure of frailty in RA patients. Subjects were 424 female RA patients (mean age ± standard deviation, 66.8 ± 14.5 years). Frailty was defined as a score of ≥ 8 points on the Kihon Checklist (KCL). Finger/wrist joint symptoms were defined based on tender or swollen joints. Associations between frailty and grip strength were determined using receiver operating characteristic (ROC) curve analysis and multivariable logistic regression analysis. There were 179 subjects with frailty (42.2%). Multivariable logistic regression analysis revealed that frailty was significantly associated with grip strength independently of finger/wrist joint symptoms. In ROC curves, cut-off scores of grip strength for frailty in subjects without and with finger/wrist joint symptoms were 17 kg (sensitivity, 62.1%; specificity, 69.0%) and 14 kg (sensitivity, 63.2%; specificity, 73.0%), respectively. The results of the present study suggest that grip strength in female RA patients is associated with frailty, with a cut-off score of 17 kg (equivalent to Cardiovascular Health Study criteria, < 18 kg) when RA patients have no finger/wrist joint symptoms. However, when RA patients have finger/wrist joint symptoms, it may be considered to reduce the cut-off score of grip strength.

DOI： 10.1038/s41598-022-21533-5

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This study aimed to longitudinally evaluate the development of locomotive syndrome (LS) in rheumatoid arthritis (RA) patients during the COVID-19 pandemic using the 25-question Geriatric Locomotive Function Scale (GLFS-25). Subjects were 286 RA patients (female, 70.6%; mean age, 64.2 years) who had GLFS-25 and Clinical Disease Activity Index (CDAI) data available for a 1-year period during the COVID-19 pandemic and who did not have LS at baseline. Associations between subject characteristics and development of LS were determined using logistic regression analysis. Among the 286 patients, 38 (13.3%, LS group) developed LS at 1 year after baseline. In the LS group, scores of the GLFS-25 categories "GLFS-5" and "Social activities" were significantly increased at 1 year relative to baseline. GLFS-5 is a quick 5-item version of the GLFS-25, including questions regarding the difficulty of going up and down stairs, walking briskly, distance able to walk without rest, difficulty carrying objects weighing 2 kg, and ability to carry out load-bearing tasks and housework. A significant correlation was also observed between changes in "Social activities" and that of "GLFS-5." Multivariable logistic regression analysis revealed that the development of LS was significantly associated with BMI (OR: 1.11 [95% confidence interval (CI): 1.00-1.22]) and CDAI (OR: 1.08 [95%CI: 1.00-1.16]) at baseline. Adequate exercise and tight control of RA disease activity are important for preventing the development of LS in view of restrictions on going out imposed during the COVID-19 pandemic. GLFS-5 is useful for evaluating the physical function of RA patients.

DOI： 10.18999/nagjms.84.4.799

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DOI： 10.1111/ggi.14475

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PubMed

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AIM: Patient Global Assessment (PtGA; range 0-10 cm) is an important indicator of clinical outcomes, including physical function, in self-assessment of patients with rheumatoid arthritis (RA). Frailty is a concept that encompasses not only physical, but also mental, psychological and social vulnerability. This study aimed to investigate the influence of frailty on PtGA in patients with RA. METHODS: Among 581 patients with RA who completed a questionnaire survey on frailty between June and August 2020, 559 who completed the Kihon Checklist (KCL; a 25-item questionnaire with seven domains) were included. The proportion of patients with PtGA ≤1 was compared between the frailty (KCL score ≥8), pre-frailty (KCL score 4-7) and robust (KCL score 0-3) groups. Factors associated with PtGA ≤1 were examined using multivariate logistic regression models. RESULTS: Of the 559 patients, 221 (39.5%) had frailty. The proportion of patients with PtGA ≤1 was significantly lower in the frailty group (33.9%) than in the robust (65.4%, P < 0.001) and pre-frailty (55.7%, P < 0.001) groups. Multivariate analysis revealed that frailty (vs robust, OR 0.37, 95% CI 0.22-0.69), as well as disease duration and tender joint count, were factors independently associated with PtGA ≤1. When each domain of the KCL was examined, activities of daily living, physical strength, isolation and depressive mood were factors associated with PtGA ≤1. CONCLUSION: Frailty affects PtGA in patients with RA. As frailty impacts the physical, mental and social vulnerability aspects of PtGA, a multifaceted approach, including inflammation suppression, is required to improve PtGA in patients with RA. Geriatr Gerontol Int 2022; 22: 399-404.

DOI： 10.1111/ggi.14375

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This study aimed to investigate changes in and factors associated with perioperative serum C-reactive protein (CRP) levels in rheumatoid arthritis (RA) patients undergoing total knee arthroplasty (TKA) in the biologic era. A total of 173 patients (228 knees) with RA underwent elective primary TKA at our institute between January 1, 2006 and December 31, 2018. Of these, 214 cases among 161 patients were examined in this retrospective study after excluding 3cases among 3 patients who developed postoperative complications and 11 cases among 9 patients who were treated with tocilizumab. Factors associated with changes in CRP levels between baseline (preoperative) and day 7 after TKA [ΔCRP (0-7days)] were assessed by multiple regression analysis. Median (interquartile range) CRP levels were 0.69 (0.21, 1.82) mg/dl preoperatively, 5.66 (4.21, 7.61) mg/dl on postoperative day 1, 12.75 (9.79, 16.74) mg/dl on postoperative days 3-4, 3.26 (2.21, 4.85) mg/dl on postoperative day 7, and 0.87 (0.45, 1.81) mg/dl on postoperative day 14. Multivariate regression analysis revealed that body mass index ≥25 [partial regression coefficient (B)=1.03, P=0.012] and use of glucocorticoids (B=-0.86, P=0.017) were independently associated with ΔCRP (0-7days), whereas use of methotrexate and targeted drug modifying antirheumatic drugs and preoperative CRP levels (an objective biomarker of RA activity) were not. In conclusion, serum CRP levels increased rapidly after TKA and peaked on postoperative days 3-4, followed by a return to preoperative levels by postoperative day 14 in patients with RA. Obesity and the use of glucocorticoids were independently associated with changes in CRP levels.

DOI： 10.18999/nagjms.84.2.286

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OBJECTIVES: This study aimed to evaluate the association between locomotive syndrome (LS) and frailty in rheumatoid arthritis (RA) patients. METHODS: Subjects were 538 RA patients (female, 72.9%; mean age ± standard deviation, 66.8 ± 13.4 years). LS and frailty were defined as ≥16 points on the 25-question Geriatric Locomotive Function Scale (Stage ≥2) and ≥8 points on the Kihon Checklist (KCL), respectively. RESULTS: There were 214 subjects with Stage ≥2 LS (39.8%) and 213 subjects with frailty (39.6%). Among subjects with Stage 0, 1, 2, and 3 LS, 11.0%, 21.9%, 48.3%, and 84.6% had frailty, respectively. The KCL points for cognitive and psychosocial factors had no significant differences across LS stages. Multivariable logistic regression analysis revealed that the Health Assessment Questionnaire was independently associated with frailty and LS stage, and the Clinical Disease Activity Index was associated with LS stage but not frailty. CONCLUSIONS: As LS worsens in RA patients, the likelihood of developing physical frailty increases. RA patients with a low LS stage can still develop frailty, and suppressing disease activity may not be sufficient to prevent frailty. These findings highlight the need to screen for frailty in RA patients and consider appropriate interventions based on each patient's condition, focusing on nonphysical factors.

DOI： 10.1093/mr/roab024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Kurume University School of Medicine  

To improve component-placement accuracy in total knee arthroplasty, we developed two devices: an original extramedullary patient-specific guide for the femur and an original extramedullary universal guide for the tibia (EM-TIBIA). We also developed a new function in ZedView, a three-dimensional surgical assistive software, that provides the parameters necessary to install the EM-TIBIA. Compared with conventional manual methods based on X-ray two-dimensional images or ZedView, these newly developed devices function as an extramedullary intraoperative support guide in conjunction with ZedView, simplifying surgical procedures. We conducted a study to evaluate the efficacy and safety of the surgery using the new guides and software function. Nineteen patients underwent surgery. On the femoral side, the mean absolute difference of the installation alignment was within 3° for all parameters. On the other hand, on the tibial side, the mean absolute difference from the preoperative plan for the rotation was 5.26±5.30°. The proportion of patients whose difference fell within ±3° was 52.6% (95% confi dence interval: 28.9 to 75.6%), and did not meet the pre-specified criteria for efficacy (P=0.261). No serious adverse events were reported, and no excessive bleeding, thrombosis, infections, or intraoperative or postoperative fractures were noted. The two new guides can easily reproduce the preoperative plan as 3D intraoperative support jigs, but errors can occur on the tibia side due to soft tissue that is not recognized by CT, creating problems in installation accuracy.

DOI： 10.2739/kurumemedj.MS671002

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

The involvement of metabolic reprogramming has been suggested to contribute to the pathophysiology of rheumatoid arthritis (RA). Glycolysis is enhanced in synovial cell metabolism in RA patients. Inhibitors of glycolysis are known to have anti-inflammatory effects. But, changes in the metabolism of normal synovial membranes or synovial cells during the early stages of inflammation remains unknown. Moreover, there are still many aspects of inflammatory signaling pathways altered by glycolysis inhibitors, that remain unclear. In this study we found that, in normal, non-pathological bovine synovial cells, most of ATP synthesis was generated by mitochondrial respiration. However, during the early of stages inflammation, initiated by lipopolysaccharide (LPS) exposure, synovial cells shifted to glycolysis for ATP production. The glycolysis inhibitor 2-deoxyglucose (2DG) reversed LPS induced increases in glycolysis for ATP production and suppressed the expression of inflammatory cytokines and proteolytic enzymes. 2DG suppressed the phosphorylation of the transcription factor cAMP response element binding protein (CREB) enhanced by LPS. Treatment with a CREB inhibitor reversed the expression of LPS-stimulated inflammatory cytokines and proteolytic enzymes. This study showed that changes in metabolism occur during the early stages of inflammation of synovial cells and can be reversed by 2DG and signaling pathways associated with CREB phosphorylation.

DOI： 10.1016/j.abb.2021.108962

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PubMed

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OBJECTIVE: This study aimed to compare the effects of baricitinib, a Janus kinase inhibitor, and tocilizumab, a monoclonal anti-interleukin-6 receptor antibody, on disease activity in patients with rheumatoid arthritis (RA), and to investigate the influence of inflammation on improvement in patient global assessment (PGA) of disease activity. METHODS: This study was performed based on data from a multicenter registry, and included 284 and 113 patients treated with tocilizumab and baricitinib, respectively, who were observed for longer than 24 weeks. Propensity score matching was performed to address potential treatment-selection bias. To assess the influence of inflammation on PGA, patients were divided into two groups based on whether or not they achieved improvement in C-reactive protein (CRP, an objective marker of inflammation) at 24 weeks. RESULTS: A total of 48 matched pairs of patients were identified. Compared to treatment with tocilizumab, baricitinib showed a similar improvement in tender and swollen joint count and serum CRP levels, and a significantly greater improvement in PGA at 24 weeks. As a result, the baricitinib group had a significantly higher proportion of patients who achieved Boolean remission at 24 weeks. In subgroups of patients who did not achieve 50% or 70% CRP improvement, significant decreases from baseline to 24 weeks were observed in PGA in patients treated with baricitinib, but not in those treated with tocilizumab. CONCLUSION: Compared to tocilizumab, baricitinib significantly improved PGA despite similar effects on inflammation in patients with RA. Moreover, the influence of inflammation on PGA improvement differed between baricitinib and tocilizumab. Key-points • Baricitinib and tocilizumab had similar effects on inflammation in RA patients. • Baricitinib improved patient global assessment (PGA) more than tocilizumab. • Baricitinib had a higher Boolean remission rate than tocilizumab at 24 weeks. • Influence of inflammation on PGA improvement differed between the two drugs.

DOI： 10.1007/s10067-021-05815-3

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Transient receptor potential vanilloid 4 (TRPV4) plays an important role in chondrocytes via Ca2+ signaling. However, its role in the progression of osteoarthritis is unclear. This study aimed to evaluate the effects of TRPV4 activation on articular cartilage and chondrocytes stimulated with interleukin (IL)-1β. Bovine and human articular chondrocytes were stimulated with various agents, including IL-1β, GSK1016790A (GSK101; a TRPV4 agonist), Compound C (an AMP-activated protein kinase (AMPK) inhibitor), and STO-609 (a calmodulin-dependent protein kinase kinase (CaMKK) inhibitor), and were processed for Western blot analysis and real-time PCR. The dimethylmethylene blue (DMMB) assay and Safranin O staining were also performed. GSK101 reversed the IL-1β-induced increase in expression of matrix metalloproteinase (MMP)-13 and decrease in expression of aggrecan. GSK101 also decreased proteoglycan release in the DMMB assay and retained Safranin O staining of articular cartilage tissue. Furthermore, GSK101 increased AMPK phosphorylation and decreased IL-1β-induced nuclear factor kappa B (NF-κB) phosphorylation. Compound C and STO-609 reversed the suppressive effects of GSK101 on NF-κB activation and MMP-13 expression. In conclusion, TRPV4 activation had chondroprotective effects on articular cartilage stimulated with IL-1β by activating CaMKK/AMPK and suppressing the NF-κB pathway. TRPV4 activators may offer a promising therapeutic option for preventing the progression of osteoarthritis.

DOI： 10.1038/s41598-021-94938-3

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Metabolic dysfunction in chondrocytes drives the pro-catabolic phenotype associated with osteoarthritic cartilage. In this study, substitution of galactose for glucose in culture media was used to promote a renewed dependence on mitochondrial respiration and oxidative phosphorylation. Galactose replacement alone blocked enhanced usage of the glycolysis pathway by IL1β-activated chondrocytes as detected by real-time changes in the rates of proton acidification of the medium and changes in oxygen consumption. The change in mitochondrial activity due to galactose was visualized as a rescue of mitochondrial membrane potential but not an alteration in the number of mitochondria. Galactose-replacement reversed other markers of dysfunctional mitochondrial metabolism, including blocking the production of reactive oxygen species, nitric oxide, and the synthesis of inducible nitric oxide synthase. Of more clinical relevance, galactose-substitution blocked downstream functional features associated with osteoarthritis, including enhanced levels of MMP13 mRNA, MMP13 protein, and the degradative loss of proteoglycan from intact cartilage explants. Blocking baseline and IL1β-enhanced MMP13 by galactose-replacement in human osteoarthritic chondrocyte cultures inversely paralleled increases in markers associated with mitochondrial recovery, phospho-AMPK, and PGC1α. Comparisons were made between galactose replacement and the glycolysis inhibitor 2-deoxyglucose. Targeting intermediary metabolism may provide a novel approach to osteoarthritis care.

DOI： 10.1038/s41598-021-94611-9

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

DOI： 10.1080/14397595.2021.1879428

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DOI： 10.1136/annrheumdis-2021-eular.3387

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OBJECTIVE: This study aimed to longitudinally evaluate the association between rheumatoid arthritis (RA) and locomotive syndrome (LS) in RA patients using the 25-question Geriatric Locomotive Function Scale (GLFS-25). METHODS: Subjects were 58 RA patients (female, 48 (82.8%); mean age, 60.9 ± 10.9 years) who had GLFS-25 scores available for five consecutive years and who did not have LS at baseline (i.e. GLFS-25 < 16 points). Associations between DAS28-CRP and the development of LS were determined using linear regression analysis and receiver operating characteristic (ROC) curve analysis. RESULTS: Subjects were divided into the LS group (n = 15, GLFS-25 ≥ 16 points) and non-LS group (n = 43, GLFS-25 < 16 points) based on GLFS-25 scores at the 5th year of the study period. In the LS group, DAS28-CRP worsened every year. The linear regression model adjusted for age and sex revealed that ΔGLFS-25 increased by 3.80 (95% confidence interval: 1.81-5.79) each time ΔDAS28-CRP increased by 1 (p<.001). Among patients in remission (DAS28-CRP < 2.3), 13.5% had LS. ROC curve analysis yielded a five-year mean DAS28-CRP of 1.99 (sensitivity, 86.7%; specificity, 62.8%) as the cut-off point for the development of LS. CONCLUSION: Tight control of RA disease activity for deeper remission may be needed to prevent the development of LS.

DOI： 10.1080/14397595.2020.1744828

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This study aimed to evaluate the short-term effectiveness and safety profiles of baricitinib and explore factors associated with improved short-term effectiveness in patients with rheumatoid arthritis (RA) in clinical settings. A total of 113 consecutive RA patients who had been treated with baricitinib were registered in a Japanese multicenter registry and followed for at least 24 weeks. Mean age was 66.1 years, mean RA disease duration was 14.0 years, 71.1% had a history of use of biologics or JAK inhibitors (targeted DMARDs), and 48.3% and 40.0% were receiving concomitant methotrexate and oral prednisone, respectively. Mean DAS28-CRP significantly decreased from 3.55 at baseline to 2.32 at 24 weeks. At 24 weeks, 68.2% and 64.1% of patients achieved low disease activity (LDA) and moderate or good response, respectively. Multivariate logistic regression analysis revealed that no previous targeted DMARD use and lower DAS28-CRP score at baseline were independently associated with achievement of LDA at 24 weeks. While the effectiveness of baricitinib was similar regardless of whether patients had a history of only one or multiple targeted DMARDs use, patients with previous use of non-TNF inhibitors or JAK inhibitors showed lower rates of improvement in DAS28-CRP. The overall retention rate for baricitinib was 86.5% at 24 weeks, as estimated by Kaplan-Meier analysis. The discontinuation rate due to adverse events was 6.5% at 24 weeks. Baricitinib significantly improved RA disease activity in clinical practice. Baricitinib was significantly more effective when used as a first-line targeted DMARDs.

DOI： 10.1038/s41598-020-78925-8

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This study aimed to evaluate the effectiveness of abatacept (ABA) by anti-cyclic citrullinated peptide (ACPA) status on disease activity as well as radiographic progression in patients with rheumatoid arthritis (RA) in clinical settings. A retrospective cohort study was conducted using data from a multicenter registry. Data from a total of 553 consecutive RA patients treated with intravenous ABA were included. We primarily compared the status of disease activity (SDAI) and radiographic progression (van der Heijde modified total Sharp score: mTSS) between the ACPA-negative (N = 107) and ACPA-positive (N = 446) groups. 'ACPA positive' was defined as ≥ 13.5 U/mL of anti-CCP antibody. Baseline characteristics between groups were similar. The proportion of patients who achieved low disease activity (LDA; SDAI ≤ 11) at 52 weeks was significantly higher in the ACPA-positive group. Multivariate logistic regression analysis identified ACPA positivity as an independent predictor for achievement of LDA at 52 weeks. Drug retention rate at 52 weeks estimated by the Kaplan-Meier curve was significantly higher in the ACPA-positive group. Achievement rate of structural remission (ΔmTSS ≤ 0.5) at 52 weeks was similar between groups. ABA treatment demonstrated a significantly higher clinical response and higher drug retention rate in ACPA-positive patients. Progression of joint destruction was similar between the ACPA-negative and ACPA-positive groups. Close attention should be paid to joint destruction even in patients showing a favorable response to ABA, especially when the ACPA status is positive.

DOI： 10.1038/s41598-020-76842-4

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OBJECTIVE: Periarticular osteophyte formation is observed during the repair of damaged joints in rheumatoid arthritis (RA); however, little is known about its clinical and functional roles. This study aimed to determine the influence of periarticular osteophyte formation on the incidence of total knee arthroplasty (TKA) (a surrogate for long-term outcomes of joint destruction) in patients with RA. METHODS: This retrospective longitudinal study included a total of 130 symptomatic (tender and/or swollen) knee joints in 80 patients starting biologics. Cumulative incidences of TKA were compared according to the presence or absence of osteophyte on plain anteroposterior radiograph (osteophyte (±)) and the extent of advanced joint damage as defined by Larsen's grading system (0-II vs. III-V). RESULTS: Kaplan-Meier estimates showed a significantly lower cumulative incidence of TKA for the osteophyte (+) group (n = 33) compared with the osteophyte (-) group (n = 31) in the Larsen grades III-V group (38 vs. 74% at 10 years, P = 0.010), whereas no significant difference was observed between the osteophyte (+) (n = 11) and osteophyte (-) (n = 55) groups in the Larsen grades 0-II group (9 vs. 10% at 10 years). Multivariate Cox proportional hazards analysis revealed that older age (hazard ratio (HR), 1.04 per 1 year; 95% confidence interval (CI), 1.01-1.08) and osteophyte formation (HR, 0.39; 95% CI, 0.19-0.79) independently predicted TKA in the Larsen grades III-V group, whereas none of the assessed variables predicted TKA in the Larsen grades 0-II group. CONCLUSION: Osteophyte formation reduces the incidence of TKA in patients with RA who have advanced joint damage. Key Points • Older age and Larsen grade were independent predictors of total knee arthroplasty (TKA) in rheumatoid arthritis (RA) patients. • Periarticular osteophyte formation reduced the incidence of TKA in RA patients with Larsen grades III-V.

DOI： 10.1007/s10067-020-05140-1

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Clinical and Experimental Rheumatology  

Objective To explore predictive factors including MMP-3 for achievement of low disease activity (LDA) at 52 weeks in bio-switch rheumatoid arthritis (RA) patients treated with abatacept, for whom obtaining a good clinical response can be difficult. Methods Participants were 423 consecutive patients with RA treated with abatacept who were observed for longer than 52 weeks and registered in the TBCR, a Japanese multicentre registry system. Multivariate logistic regression analysis was used to study factors that predict the achievement of LDA at 52 weeks in bio-naïve (n=234) and bio-switch (n=189) groups. Results ROC analysis revealed that MMP-3 improvement rates at 12 weeks in bio-switch patients had the highest AUC with a cut-off value of 20.0% for predicting LDA achievement at 52 weeks. Multivariate logistic regression analysis revealed that, in addition to DAS28-CRP at baseline, achieving 20% improvement in MMP-3 levels at 12 weeks was an independent predictive factor (adjusted OR: 4.277, p=0.003) in the bio-switch group, whereas DAS28 was the only predictor in the bio-naïve group. Patients who achieved 20% improvement in MMP-3 levels at 12 weeks had significantly higher achievement rates of LDA at 52 weeks compared to those who did not achieve 20% improvement in the bio-switch group (60.0 vs. 33.3%, p=0.001). Conclusions Our findings suggest that improvement in MMP-3 levels is key to predicting the clinical efficacy of abatacept. Closer attention paid not only to major clinical indices, but also changes in MMP-3 levels, could improve our ability to optimise clinical results when treating bio-switch patients.

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PubMed

Language：Japanese   Publisher：(一社)日本リウマチ学会  

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: To examine time trends in the characteristics of patients with rheumatoid arthritis (RA) undergoing primary total joint replacement (TJR).Methods: Biologics were approved in Japan for use in patients with RA in July 2003. A total of 403 large joints in 282 patients who underwent TJR at our institute between 1 January 2004 and 31 December 2017 were retrospectively examined.Results: A significant decreasing trend was observed in the number of TJRs performed from 2004 to 2017 (p = 0.013). No significant trend was observed in time from RA onset to TJR (p = 0.294). Age at RA onset (p = 0.034) showed a significant increasing trend, and serum C-reactive protein (CRP) levels showed a significant decreasing trend (p < 0.001). Negative CRP (defined as ≤0.3 mg/dl; partial regression coefficient (B) = 2.44, p = 0.016) was independently associated with time from RA onset to TJR as well as age at RA onset and juxta-articular osteophyte formation.Conclusion: The number of TJRs decreased since the approval of biologics in Japan, and changes were observed in the characteristics of patients with RA undergoing TJR. Negative CRP was an independent factor associated with longer time from RA onset to TJR.

DOI： 10.1080/14397595.2019.1649111

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Language：English   Publisher：Frontiers in Neuroscience  

In this study, we investigated the effect of the dynamic changes in brain activation during neurofeedback training in the classification of the different brain states associated with the target tasks. We hypothesized that ongoing activation patterns could change during neurofeedback session due to learning effects and, in the process, could affect the performance of brain state classifiers trained using data obtained prior to the session. Using a motor imagery paradigm, we then examined the application of an incremental training approach where classifiers were continuously updated in order to account for these activation changes. Our results confirmed our hypothesis that neurofeedback training could be associated with dynamic changes in brain activation characterized by an initially more widespread brain activation followed by a more focused and localized activation pattern. By continuously updating the trained classifiers after each feedback run, significant improvement in accurately classifying the different brain states associated with the target motor imagery tasks was achieved. These findings suggest the importance of taking into account brain activation changes during neurofeedback in order to provide more reliable and accurate feedback information to the participants, which is critical for an effective neurofeedback application.

DOI： 10.3389/fnins.2020.00623

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.1136/annrheumdis-2020-eular.3541

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DOI： 10.1136/annrheumdis-2020-eular.5881

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DOI： 10.1136/annrheumdis-2020-eular.2857

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DOI： 10.1136/annrheumdis-2020-eular.2715

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DOI： 10.1136/annrheumdis-2020-eular.1209

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DOI： 10.1136/annrheumdis-2020-eular.5350

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DOI： 10.1136/annrheumdis-2020-eular.2697

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Hyaluronan is a critical component of articular cartilage and partially helps retain aggrecan within the extracellular matrix of this tissue. During osteoarthritis, hyaluronan and aggrecan loss are an early sign of tissue damage. However, our recent attempts to mimic hyaluronan loss with the hyaluronan inhibitor 4-methylumbelliferone (4MU) did not exacerbate arthritis-like features of in vitro models of arthritis, but surprisingly, caused the reverse (i.e. provided potent chondroprotection). Moreover, the protective effects of 4MU did not depend on its role as a hyaluronan inhibitor. To understand the molecular mechanism in 4MU-mediated chondroprotection, we considered recent studies suggesting that shifts in intracellular UDP-hexose pools promote changes in metabolism. To determine whether such metabolic shifts are associated with the mechanism of 4MU-mediated pro-catabolic inhibition, using molecular and metabolomics approaches, we examined whether bovine and human chondrocytes exhibit changes in the contribution of glycolysis and mitochondrial respiration to ATP production rates as well as in other factors that respond to or might drive these changes. Overexpression of either HA synthase-2 or 4MU effectively reduced dependence on glycolysis in chondrocytes, especially enhancing glycolysis use by interleukin-1β (IL1β)-activated chondrocytes. The reduction in glycolysis secondarily enhanced mitochondrial respiration in chondrocytes, which, in turn, rescued phospho-AMP-activated protein kinase (AMPK) levels in the activated chondrocytes. Other glycolysis inhibitors, unrelated to hyaluronan biosynthesis, namely 2-deoxyglucose and dichloroacetate, caused metabolic changes in chondrocytes equivalent to those elicited by 4MU and similarly protected both chondrocytes and cartilage explants. These results suggest that fluxes in UDP-hexoses alter metabolic energy pathways in cartilage.

DOI： 10.1074/jbc.RA119.009556

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CD44 fragmentation is enhanced in chondrocytes of osteoarthritis (OA) patients. We hypothesized that mechanical stress-induced enhancement of CD44-intracellular domain (CD44-ICD) production plays an important role in the de-differentiation of chondrocytes and OA. This study aimed to assess the relationship between CD44-ICD and chondrocyte gene expression. Monolayer cultured primary bovine articular chondrocytes (BACs) were subjected to cyclic tensile strain (CTS) loading. ADAM10 inhibitor (GI254023X) and γ-secretase inhibitor (DAPT) were used to inhibit CD44 cleavage. In overexpression experiments, BACs were electroporated with a plasmid encoding CD44-ICD. CTS loading increased the expression of ADAM10 and subsequent CD44 cleavage, while decreasing the expression of SOX9, aggrecan, and type 2 collagen (COL2). Overexpression of CD44-ICD also resulted in decreased expression of these chondrocyte genes. Both GI254023X and DAPT reduced the production of CD44-ICD upon CTS loading, and significantly rescued the reduction of SOX9 expression by CTS loading. Chemical inhibition of CD44-ICD production also rescued aggrecan and COL2 expression following CTS loading. Our findings suggest that CD44-ICD is closely associated with the de-differentiation of chondrocytes. Excessive mechanical stress loading promoted the de-differentiation of BACs by enhancing CD44 cleavage and CD44-ICD production. Suppression of CD44 cleavage has potential as a novel treatment strategy for OA.

DOI： 10.1038/s41598-019-50166-4

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Osteoarthritis (OA) is a progressive degenerative disease of the joints caused in part by a change in the phenotype of resident chondrocytes within affected joints. This altered phenotype, often termed proinflammatory or procatabolic, features enhanced production of endoproteinases and matrix metallo-proteinases (MMPs) as well as secretion of endogenous inflammatory mediators. Degradation and reduced retention of the proteoglycan aggrecan is an early event in OA. Enhanced turnover of hyaluronan (HA) is closely associated with changes in aggrecan. Here, to determine whether experimentally increased HA production promotes aggrecan retention and generates a positive feedback response, we overexpressed HA synthase-2 (HAS2) in chondrocytes via an inducible adenovirus construct (HA synthase-2 viral overexpression; HAS2-OE). HAS2-OE incrementally increased high-molecular-mass HA >100-fold within the cell-associated and growth medium pools. More importantly, our results indicated that the HAS2-OE expression system inhibits MMP3, MMP13, and other markers of the procatabolic phenotype (such as TNF-stimulated gene 6 protein (TSG6)) and also enhances aggrecan retention. These markers were inhibited in OA-associated chondrocytes and in chondrocytes activated by interleukin-1β (IL1β), but also chondrocytes activated by lipopolysaccharide (LPS), tumor necrosis factor α (TNFα), or HA oligosaccharides. However, the enhanced extracellular HA resulting from HAS2-OE did not reduce the procatabolic phenotype of neighboring nontransduced chondrocytes as we had expected. Rather, HA-mediated inhibition of the phenotype occurred only in transduced cells. In addition, high HA biosynthesis rates, especially in transduced procatabolic chondrocytes, resulted in marked changes in chondrocyte dependence on glycolysis versus oxidative phosphorylation for their metabolic energy needs.

DOI： 10.1074/jbc.RA119.008567

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The story of hyaluronan in articular cartilage, pericellular hyaluronan in particular, essentially is also the story of aggrecan. Without properly tethered aggrecan, the load bearing function of cartilage is compromised. The anchorage of aggrecan to the cell surface only occurs due to the binding of aggrecan to hyaluronan-with hyaluronan tethered either to a hyaluronan synthase or by multivalent binding to CD44. In this review, details of hyaluronan synthesis are discussed including how HAS2 production of hyaluronan is necessary for normal chondrocyte development and matrix assembly, how an abundance or deficit of pericellular hyaluronan alters chondrocyte metabolism, and whether hyaluronan size matters or changes with aging or disease. The biomechanical role and matrix assembly function of hyaluronan in addition to the functions of hyaluronidases are discussed. The turnover of hyaluronan is considered including mechanisms by which its turnover, at least in part, is mediated by endocytosis by chondrocytes and regulated by aggrecan degradation. Differences between turnover and clearance of newly synthesized hyaluronan and aggrecan versus the half-life of hyaluronan remaining within the inter-territorial matrix of cartilage are discussed. The release of neutral pH-acting hyaluronidase activity remains one unanswered question concerning the loss of cartilage hyaluronan in osteoarthritis. Signaling events driven by changes in hyaluronan-chondrocyte interactions may involve a chaperone function of CD44 with other receptors/cofactors as well as the changes in hyaluronan production functioning as a metabolic rheostat.

DOI： 10.1016/j.matbio.2018.02.005

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In this study we examined whether the action of simvastatin affects re-differentiation of passaged chondrocytes and if so, whether this was mediated via changes in cholesterol or cholesterol intermediates. Bovine articular chondrocytes, of varying passage number, human knee chondrocytes and rat chondrosarcoma chondrocytes were treated with simvastatin and examined for changes in mRNA and protein expression of markers of the chondrocyte phenotype as well as changes in cell shape, proliferation and proteoglycan production. In all three models, while still in monolayer culture, simvastatin treatment alone promoted changes in phenotype and morphology indicative of re-differentiation most prominent being an increase in SOX9 mRNA and protein expression. In passaged bovine chondrocytes, simvastatin stimulated the expression of SOX9, ACAN, BMP2 and inhibited the expression of COL1 and α-smooth muscle actin. Co-treatment of chondrocytes with simvastatin plus exogenous cholesterol-conditions that had previously reversed the inhibition on CD44 shedding, did not alter the effects of simvastatin on re-differentiation. However, the co-treatment of chondrocytes with simvastatin together with other pathway intermediates, mevalonate, geranylgeranylpyrophosphate and to a lesser extent, farnesylpyrophosphate, blocked the pro-differentiation effects of simvastatin. Treatment with simvastatin stimulated expression of SOX9 and COL2a and enhanced SOX9 protein in human OA chondrocytes. The co-treatment of OA chondrocytes with mevalonate or geranylgeranylpyrophosphate, but not cholesterol, blocked the simvastatin effects. These results lead us to conclude that the blocking of critical protein prenylation events is required for the positive effects of simvastatin on the re-differentiation of chondrocytes.

DOI： 10.1016/j.abb.2019.01.038

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DOI： 10.18926/AMO/56186

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Language：English   Publisher：Frontiers in Human Neuroscience  

Motor imagery (MI), a covert cognitive process where an action is mentally simulated but not actually performed, could be used as an effective neurorehabilitation tool for motor function improvement or recovery. Recent approaches employing brain- computer/brain-machine interfaces to provide online feedback of the MI during rehabilitation training have promising rehabilitation outcomes. In this study, we examined whether participants could volitionally recall MI-related brain activation patterns when guided using neurofeedback (NF) during training. The participants’ performance was compared to that without NF. We hypothesized that participants would be able to consistently generate the relevant activation pattern associated with the MI task during training with NF compared to that without NF. To assess activation consistency, we used the performance of classifiers trained to discriminate MI-related brain activation patterns. Our results showed significantly higher predictive values of MI-related activation patterns during training with NF. Additionally, this improvement in the classification performance tends to be associated with the activation of middle temporal gyrus/inferior occipital gyrus, a region associated with visual motion processing, suggesting the importance of performance monitoring during MI task training. Taken together, these findings suggest that the efficacy of MI training, in terms of generating consistent brain activation patterns relevant to the task, can be enhanced by using NF as a mechanism to enable participants to volitionally recall task-related brain activation patterns.

DOI： 10.3389/fnhum.2018.00158

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Language：Japanese   Publisher：Acta Medica Okayama  

There is no assistive device for extramedullary surgery coordinated with 3D surgical assistive software for the total knee arthroplasty (TKA). We developed a novel extramedullary universal guide coordinated with 3D surgical assistive software and a novel extramedullary patient-specific assistive guide for the placement of femoral components by referring to an area not affected by cartilage or bone spurs, and filed a patent application. In this study, we visualize and reconstruct the total alignment of the lower extremity in TKA using these surgical devices, and validate their precision. A report releasing study results will be submitted in an appropriate journal.

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OBJECTIVE: Whether the Boolean-based American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for rheumatoid arthritis (RA) including patient-reported outcome measures (PROMs) for remission are strict for use in daily clinical practice is controversial. This study aimed to clarify the differences in the remission status defined by the criteria, including and excluding PROMs, and to identify the baseline predictors of long-term prognosis using 7-year follow-up data. METHOD: A total of 103 RA outpatients completed the baseline and 7-year follow-up questionnaire surveys. Pain visual analogue scale (VAS) of ≤ 1/10 was used as a PROM criterion for remission. RESULTS: Only 10 patients achieved full-remission, whereas 18 met the partial-remission criteria excluding PROM at baseline. Although 70.0% of those who achieved full remission at baseline had full or partial remission status, 77.8% of those with partial remission were categorized as having no remission at 7 years. Significant baseline differences in the remission status at 7 years were observed with regard to disease duration, pain VAS, and physical function (Short Form 36 [SF-36]). Stepwise logistic regression analysis adjusted for age and sex identified disease duration and general health perception (SF-36) as independent predictors of full-remission. CONCLUSION: Remission criteria including PROMs are stringent but important to achieve sustained remission. Early intensive treatment and efforts to improve patients' health perceptions may result in better prognosis for RA.

DOI： 10.1111/1756-185X.12789

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Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(一社)日本リウマチ学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：中部リウマチ学会  

47歳男。22年前に左母指MP関節の腫脹・疼痛が出現し、その後1年間で両膝関節や左肩関節、左足関節など多関節に痛みを自覚するようになった。近医でseronegative RAと診断され、csDMARDs投与を開始されたが、関節痛は持続した。腰背部や肩甲骨間の痛みも出現し、20年前にRAの治療強化目的で当院に紹介され、MTX投与を開始したが、症状は改善しなかった。18年前にEtanerceptを導入し、症状は一時的に改善したが再燃した。13年前の検査でDAS28-CRPが4.86と高疾患活動性の状態であったため、治療薬をEtanerceptからTocilizumabに変更し、DAS28-CRPは2.61に改善したが、歩行時の股関節痛が続くため、今回THA目的で入院となった。手術は無事終了し、股関節痛は改善したが、手術の麻酔導入時に開口障害と頸椎の可動域制限を認めていたため、その原因検索を術後に行い、両顎関節と頸椎の強直を認めた。仙腸関節にも強直を認め、HLA-B27が陽性であったことから強直性脊椎炎と診断した。

Language：Japanese   Publisher：(一社)中部日本整形外科災害外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Language：Japanese   Publisher：(公社)日本整形外科学会  

Event date： 2021.4

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：WEB   Country：Japan  

Event date： 2021.3

Event date： 2020.8 - 2020.9

Language：English   Presentation type：Oral presentation (general)  

Country：Japan  

Event date： 2020.6

Language：English  

Event date： 2020.8 - 2020.9

Language：Japanese   Presentation type：Poster presentation  

Event date： 2020.6

Language：English   Presentation type：Poster presentation