Intervertebral fusion sites in patients with ankylosing spondylitis: A computed tomography study.

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.

Well-controlled disease activity with drug treatment will not improve the frailty status of RA patients to robust state: A multicenter observational study (T-FLAG).

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.

Associations of frailty with RA-ILD and poor control of disease activity in patients with rheumatoid arthritis: A multi-center retrospective observational study.

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.

Relationship between frailty and methotrexate discontinuation due to adverse events in rheumatoid arthritis patients.

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.

Periprosthetic humeral fracture revision using a massive allograft in a patient with rheumatoid arthritis: A case report.

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.

Validation of grip strength as a measure of frailty in rheumatoid arthritis.

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.

Metabolic changes in synovial cells in early inflammation: Involvement of CREB phosphorylation in the anti-inflammatory effect of 2-deoxyglucose.

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.

Enhanced Ca2+-dependent activation of phosphoinositide 3-kinase class IIα isoform-Rho axis in blood vessels of spontaneously hypertensive rats.

Rho-mediated inhibition of myosin light chain (MLC) phosphatase (MLCP), together with Ca(2+)-dependent MLC kinase activation, constitutes the major signaling mechanisms for vascular smooth muscle contraction. We recently unveiled the involvement of Ca(2+)-induced, phosphoinositide 3-kinase (PI3K) class IIα isoform (PI3K-C2α)-dependent Rho activation and resultant Rho kinase-dependent MLCP suppression in membrane depolarization- and receptor agonist-induced contraction. It is unknown whether Ca(2+)- and PI3K-C2α-dependent regulation of MLCP is altered in vascular smooth muscle of hypertensive animals and is involved in hypertension. Therefore, we studied the role of the Ca(2+)-PI3K-C2α-Rho-MLCP pathway in spontaneously hypertensive rats (SHRs). PI3K-C2α was readily detected in various vascular beds of Wistar-Kyoto rats and activated by high KCl. High KCl also stimulated vascular Rho activity and phosphorylation of the MLCP regulatory subunit MYPT1 at Thr(853) in a PI3K inhibitor wortmannin-sensitive manner. In mesenteric and other vessels of SHRs at the hypertensive but not the prehypertensive stage, the activity of PI3K-C2α but not class I PI3K p110α was elevated with concomitant rises of Rho activity and Thr(853)-phosphorylation of MYPT1, as compared with normotensive controls. Infusion of the Ca(2+) channel antagonist nicardipine reduced blood pressure with suppression of vascular activity of PI3K-C2α-Rho and phosphorylation of MYPT1 in hypertensive SHRs. Infusion of wortmannin lowered blood pressure with inhibition of PI3K-C2α-Rho activities and MYPT1 phosphorylation in hypertensive SHRs. These observations suggest that an increased activity of the Ca(2+)-PI3K-C2α-Rho signaling pathway with resultant augmented MLCP suppression contributes to hypertension in SHRs. The Ca(2+)- and PI3K-C2α-dependent Rho stimulation in vascular smooth muscle may be a novel, promising target for treating hypertension.