Drug Persistence and Incidence of Active Tuberculosis of Tumor Necrosis Factor Alpha Inhibitors Versus Tocilizumab as the First-Line Biological Treatment in Patients with Rheumatoid Arthritis: A Nationwide Population-Based Retrospective Cohort Analysis.

INTRODUCTION: Drug persistence may be a surrogate marker that reflects both long-term efficacy and safety in clinical settings, and tuberculosis (TB) is considered as one of the most important opportunistic infections after the biological treatment in rheumatoid arthritis (RA). We aimed to compare drug persistence and incidence of TB between tumor necrosis factor alpha (TNFα) inhibitors and tocilizumab in patients with RA using data from the Korean Health Insurance Review and Assessment Service database. METHODS: In this analysis, 5449 patients with RA who started TNFα inhibitors, such as adalimumab, etanercept, infliximab, and golimumab or tocilizumab, as the first-line biological therapy between January 2014 and December 2017 were analyzed and followed up until December 2019. Drug persistence was defined as the duration from initiation to first discontinuation, and TB was defined as the prescription of > 2 anti-TB medications after the initiation of biologics. RESULTS: TNFα inhibitors and tocilizumab were prescribed in 4202 (adalimumab, 1413; etanercept, 1100; infliximab, 769; golimumab 920) and 1247 patients with RA, respectively. During the analysis period, 2090 (49.7%) and 477 (38.3%) patients with RA discontinued TNFα inhibitors and tocilizumab, respectively, and 42 patients with RA developed TB (TNFα inhibitors, 33; tocilizumab, 9). After adjustment for confounding factors, TNFα inhibitors were significantly associated with a higher risk of discontinuation compared with tocilizumab (hazard ratio (HR) 1.63, p < 0.001). In subgroup analysis, all types of TNFα inhibitors, except for infliximab, demonstrated a significantly lower persistence rate compared with tocilizumab. There was no significant difference in TB incidence between tocilizumab and TNFα inhibitors. In subgroup analysis, infliximab has a significantly higher risk of TB compared with tocilizumab (HR 2.84, p = 0.02). CONCLUSION: In this analysis, tocilizumab had longer persistence than TNFα inhibitors with a similar incidence of TB. Our analysis has limitations: (1) The HIRA database lacks clinical details like disease activity and joint damage extent, potentially influencing the analysis results. (2) Reasons for discontinuing biological agents were not available. (3) TB diagnoses may be inaccurate because of missing microbiological results. (4) We did not analyze the impact of treating latent TB infection on TB development post-biological treatment, despite mandatory screening in Korea.

Analysis of appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors as the first-line urate-lowering therapy in patients with gout using the Korean Health Insurance Review and Assessment Service database.

INTRODUCTION: We investigated the appropriate duration of colchicine prophylaxis to maximize the persistence of xanthine oxidase inhibitors (XOIs) as first-line urate-lowering therapy (ULT) in patients with gout. This was a nationwide population-based retrospective cohort study using the Korean Health Insurance Review and Assessment database. METHODS: Patients with gout aged ≥20 years who were newly initiated on XOIs, such as allopurinol or febuxostat, from July 2015 to June 2017 and received these medications for ≥6 months were analyzed and followed up until June 2019. Persistence of XOIs was compared according to the 6-month duration of colchicine prophylaxis. For additional subgroup analysis, we also compared the persistence of XOIs according to the 3-month duration of colchicine prophylaxis. RESULTS: This study included 43 926 patients. The frequencies of patients with gout receiving colchicine prophylaxis for ≥6 months and ≥3 months were 6.3% and 7.6%, respectively. Allopurinol (65.2%) was prescribed more frequently than febuxostat (34.8%). During the study period, 23 475 patients (53.4%) stopped using XOIs. Colchicine prophylaxis for ≥6 months did not significantly reduce the risk of XOI discontinuation in multivariable Cox regression models. Colchicine prophylaxis for ≥3 months was significantly associated with a lower risk of non-persistence to XOIs after adjusting for confounding factors (hazard ratio = 0.95, p = .041). CONCLUSION: Our data suggest that at least 3 months of colchicine prophylaxis may be more appropriate than at least 6 months in terms of maximizing the persistence of XOIs in patients with gout.

Upper gastrointestinal tract perforation assessed by contrast-enhanced ultrasonography after oral Sonazoid administration in a stomach leakage mouse model.

PURPOSE: The purpose of this study was to elucidate whether contrast-enhanced ultrasonography (CEUS) can visualize orally administered Sonazoid leaking into the peritoneal cavity in a postoperative stomach leakage mouse model. METHODS: Adult female mice (n=33, 9-10 weeks old) were used. Preoperative CEUS was performed after delivering Sonazoid via intraperitoneal injection and the per oral route. A gastric leakage model was then generated by making a surgical incision of about 0.5 cm at the stomach wall, and CEUS with per oral Sonazoid administration was performed. A region of interest was drawn on the CEUS images and the signal intensity was quantitatively measured. Statistical analysis was performed using a mixed model to compare the signal intensity sampled from the pre-contrast images with those of the post-contrast images obtained at different time points. RESULTS: CEUS after Sonazoid intraperitoneal injection in normal mice and after oral administration in mice with gastric perforation visualized the contrast medium spreading within the liver interlobar fissures continuous to the peritoneal cavity. A quantitative analysis showed that in the mice with gastric perforation, the orally delivered Sonazoid leaking into the peritoneal cavity induced a statistically significant (P<0.05) increase in signal intensity in all CEUS images obtained 10 seconds or longer after contrast delivery. However, enhancement was not observed before gastric perforation surgery (P=0.167). CONCLUSION: CEUS with oral Sonazoid administration efficiently visualized the contrast medium spreading within the peritoneal cavity in a postoperative stomach leakage mouse model.

Associations of Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio and Monocyte-to-Lymphocyte Ratio with Osteoporosis and Incident Vertebral Fracture in Postmenopausal Women with Rheumatoid Arthritis: A Single-Center Retrospective Cohort Study.

Background and Objectives: We investigated whether nutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphoycte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) are associated with the presence of osteoporosis (OP) and vertebral fractures in patients with rheumatoid arthritis (RA). Materials and Methods: This retrospective cohort study included 413 postmenopausal patients with RA and 200 healthy controls who underwent dual-energy X-ray absorptiometry (DEXA) between January 2005 and December 2017. DEXA examination data were defined as the index date, and all laboratory values were measured within one month from the index date. OP was defined as a T-score < −2.5, and incident vertebral fractures were defined as the first occurrence of non-traumatic fractures after the index date. NLR, PLR, and MLR measures were dichotomized by a median split (low vs. high). Results: The median NLR, PLR, and MLR in RA patients were significantly higher than those in controls. The frequencies of OP of the lumbar spine, hip, and either site in postmenopausal patients with RA were 24.7%, 15.5%, and 32%, respectively, and were significantly higher than those in controls. After adjusting for confounding factors, a high baseline NLR was significantly associated with OP at either site (OR = 1.61, p = 0.041). In addition, high baseline NLR (OR = 2.11, p = 0.025) and PLR (OR = 2.3, p = 0.011) were related with the presence OP at hip. During the follow-up period, 53 (12.8%) patients with RA developed vertebral fractures incidentally. In multivariable Cox regression models, a high baseline NLR (HR = 4.72, p < 0.001), PLR (HR = 1.96, p = 0.024), and MLR (HR = 2.64, p = 0.002) were independently associated with a higher risk of incidental vertebral fractures. Conclusions: Our data suggest that NLR, PLR, and MLR can be used as potential markers of systemic bone loss among individuals with RA.

Diagnostic Value of Neutrophil-to-Lymphocyte, Platelet-to-Lymphocyte, and Monocyte-to-Lymphocyte Ratios for the Assessment of Rheumatoid Arthritis in Patients with Undifferentiated Inflammatory Arthritis.

Background: To investigate the diagnostic performance of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR) in the diagnosis of rheumatoid arthritis (RA) in subjects with undifferentiated inflammatory arthritis (UIA). Methods: This retrospective cohort study investigated 201 female patients with UIA (≥1 swollen joint) and 280 age-matched, healthy female controls. "Clinical RA" was defined based on the clinical judgment of a rheumatologist and "disease-modifying anti-rheumatic drugs (DMARDs) RA" was defined as a case of initiating DMARDs treatment within 6 months after the first visit. "Classified RA" was defined as fulfilling the 2010 classification criteria for RA. Receiver operating characteristics were used to determine the optimal cut-off value. Results: UIA patients had a significantly higher NLR, PLR, and MLR than the controls. Among the 201 UIA patients, 65 (32.3%), 63 (31.3%), and 61 (30.3%) subjects were classified as clinical RA, DMARDs RA, and classified RA, respectively. At a cut-off of 0.24, MLR showed moderate accuracy for the diagnosis of DMARDs RA (sensitivity, 65.1%; specificity, 62.3%; area under the curve [AUC], 0.701; p < 0.001). However, the diagnostic accuracies of NLR and PLR were low. Conclusions: MLR may be used as a complementary diagnostic indicator for RA diagnosis in patients with UIA.

Status of Glucocorticoid-Induced Osteoporosis Preventive Care in Korea: A Retrospective Cohort Study on the Korean National Health Insurance Service Database.

Background and Objectives: It is crucial to prevent osteoporosis in patients receiving long-term glucocorticoid (GC) treatment. This study aimed to investigate the frequency and associated factors of preventive care for glucocorticoid-induced osteoporosis (GIOP) in Korea. Materials and Methods: Using the Korean National Health Insurance Service database, we identified 37,133 individuals aged ≥ 20 years who commenced long-term (≥90 days) oral GC between 2011 and 2012. High-quality GIOP preventive care was defined as either a bone mineral density (BMD) test, calcium and/or vitamin D supplementation, or prescription osteoporosis medications within 6 months of GC initiation. Multivariable logistic regression models were used to calculate odds ratios (ORs) for associated factors for high-quality GIOP preventive care. Results: The mean age was 49.8 years, and 18,476 (49.8%) patients were female. The frequency of high-quality GIOP preventive care was only 3.68% (BMD test, 1.46%; osteoporosis medications, 1.65%; calcium/vitamin D, 1.63%). Increasing age (OR = 2.53, p < 0.001; 40-49 years, OR = 3.99, p < 0.001; 50-59 years, OR = 5.17, p < 0.001; 60-69 years, OR = 8.07, p < 0.001; ≥70 years, respectively), systemic autoimmune disease (OR = 3.08, p < 0.001), rural residence (OR = 1.19, p = 0.046), concomitant hyperthyroidism (OR = 1.58, p = 0.007), and malignancy (OR = 1.59, p < 0.001) were significantly associated with a higher likelihood of receiving high-quality GIOP preventive care. Male sex (OR = 0.26, p < 0.001) and GC prescription in primary care clinics and nursing hospitals (OR = 0.66, p < 0.001) were associated with a lower rate of high-quality GIOP preventive care. Conclusions: Most Korean patients treated with GC did not receive appropriate preventive care for GIOP in real-world practice. More efforts are needed by clinicians to prevent, screen, and treat GIOP.

Intraspinal Cavity Injection of Human Mesenchymal Stem Cells and Tracking their Migration into the Rat Brain.

Mesenchymal stem cells (MSCs) have been studied for the treatment of various diseases. In neurodegenerative diseases involving defects in both the brain and the spinal cord, the route of administration is very important, because MSCs must migrate to both the brain and the spinal cord. This paper describes a method for administering MSCs into the spinal canal (intraspinal cavity injection) that can target the brain and spinal cord in a rat model. One million MSCs were injected into the spinal canals of rats at the level of lumbar vertebrae 2-3. After administration, the rats were euthanized at 0, 6, and 12 h post-injection. Optical imaging and quantitative real-time polymerase chain reaction (qPCR) were used to track the injected MSCs. The results of the present study demonstrated that MSCs administered via the spinal cavity could be detected subsequently in both the brain and spinal cord at 12 h. Intraspinal cavity injection has the advantage of not requiring general anesthesia and has few side effects. However, the drawback of the low migration rate of MSCs to the brain must be overcome.

Intrathecal Injection in A Rat Model: A Potential Route to Deliver Human Wharton's Jelly-Derived Mesenchymal Stem Cells into the Brain.

Mesenchymal stem cells (MSCs) are considered as promising therapeutic agents for neurodegenerative disorders because they can reduce underlying pathology and also repair damaged tissues. Regarding the delivery of MSCs into the brain, intravenous and intra-arterial routes may be less feasible than intraparenchymal and intracerebroventricular routes due to the blood-brain barrier. Compared to the intraparenchymal or intracerebroventricular routes, however, the intrathecal route may have advantages: this route can deliver MSCs throughout the entire neuraxis and it is less invasive since brain surgery is not required. The objective of this study was to investigate the distribution of human Wharton's jelly-derived MSCs (WJ-MSCs) injected via the intrathecal route in a rat model. WJ-MSCs (1 × 106) were intrathecally injected via the L2-3 intervertebral space in 6-week-old Sprague Dawley rats. These rats were then sacrificed at varying time points: 0, 6, and 12 h following injection. At 12 h, a significant number of MSCs were detected in the brain but not in other organs. Furthermore, with a 10-fold higher dose of WJ-MSCs, there was a substantial increase in the number of cells migrating to the brain. These results suggest that the intrathecal route can be a promising route for the performance of stem cell therapy for CNS diseases.