[Efficacy and safety of low-dose rasburicase for refractory chronic gouty arthritis].

Objective: To explore the efficacy and safety of low-dose rasburicase for refractory chronic gouty arthritis. Methods: A cohort study. The clinical data of patients with refractory chronic gouty arthritis who were treated with rasburicase at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between January 2021 and July 2022 were retrospectively analyzed. Refractory chronic gouty arthritis was defined as serum uric acid (sUA)>360 µmol/L and urate volume>10 cm3 under dual-energy computed tomography after tolerable maximal oral urate-lowering therapy for at least 3 months. The administration of low-dose rasburicase was applied intravenously with total dosage ranging from 4.5 to 7.5 mg each dose, at 4-week intervals for a maximum of three doses. Efficacy was evaluated by the changes of sUA level, tophus and urate volume. Results: A total of 22 patients were included for analysis, with 95.4% (21/22) male, the mean age was (44±15) years, and the median duration of gout was 11 (6-15) years. The mean sUA at baseline was (667±112) µmol/L. The levels of sUA significantly decreased after each dose of rasburicase (P<0.001), and the median reduction of sUA after each dose of rasburicase was 568 (471-635), 187 (66-335) and 123 (49-207) µmol/L, respectively. At week 12, nine patients (40.9%) exhibited sUA<360 µmol/L and tophus disappeared in one patient. The urate volume significantly decreased at week 12 when compared with that before the first dose of rasburicase in all the patients [40 (16-172) cm3 vs 17 (7-134) cm3, P<0.001], with a median reduction rate of 41.6% (22.9%-58.5%). The everall safety of rasburicase was good, and no serious adverse reactions occurred. Conclusions: Low-dose rasburicase is well-tolerated and effective for decreasing the urate burden in patients with refractory chronic gouty arthritis. Further prospective randomized controlled trials are needed to validate these findings.

Muscle wasting, a neglected complication associated with physical dysfunction in elderly patients with rheumatoid arthritis: a cross-sectional observational study.

Objective: Little is known about muscle wasting in elderly patients with rheumatoid arthritis (RA). We examined muscle characteristics and their clinical significance in this group.Method: Consecutive RA patients were recruited and clinical data were collected. Muscle mass and distribution were assessed using bioelectric impedance analysis. Myopenia was defined as an appendicular skeletal muscle mass index (ASMI) ≤ 7.0 kg/m2 (men) and ≤ 5.7 kg/m2 (women).Results: Among the 643 RA patients recruited, 165 (25.7%) were elderly patients (age ≥ 60 years) with a mean age of 65.1 ± 4.5 years. Compared with young patients (age < 60 years), elderly RA patients had significantly higher Disease Activity Score based on 28-joint count-C-reactive protein (DAS28-CRP) (median 3.4 vs 3.2), Health Assessment Questionnaire Disability Index (HAQ-DI) (0.38 vs 0.13), and modified total Sharp score (mTSS) (16 vs 9), and a higher proportion of myopenia (54.5% vs 41.4%; all p < 0.01). Elderly RA patients with myopenia (n = 90, 14.0%) had significantly higher DAS28-CRP (3.6 vs 3.0), HAQ-DI (0.50 vs 0.12), and mTSS (21 vs 7) than young RA patients without myopenia (n = 280, 43.5%; all p < 0.0083). Multivariate logistic and linear regression analyses showed that myopenia, high HAQ-DI, active smoking, hypertension, diabetes, and coronary atherosclerotic heart disease were the main relevant characteristics of elderly RA patients. Age positively correlated with HAQ-DI, and ASMI negatively correlated with HAQ-DI (both p < 0.01). Further mediation analysis showed that ASMI partially mediated the association between age and HAQ-DI.Conclusion: Our data reveal that half of elderly RA patients manifest myopenia which aggravates physical dysfunction as a mediator of age. Myopenia, a neglected complication in elderly RA patients, should be recognized and further investigated.

[Predictive value of anti-mutated citrullinated vimentin antibody on one-year radiographic progression in patients with rheumatoid arthritis].

Objective: To investigate the value of baseline anti-mutated citrullinated vimentin (MCV) antibody for predicting one-year radiographic progression in patients with rheumatoid arthritis (RA). Methods: Consecutive RA patients were recruited from November 2014 to July 2018 at Department of Rheumatology, Sun Yat-sen Memorial Hospital, Clinical data were collected including disease activity score in 28 joints with four variables including C-reactive protein (CRP).Serum anti-MCV antibody at baseline was detected by enzyme-linked immunosorbent assay. X ray assessment of both hands/wrists was performed and assessed according to the Sharp/van der Heijde modified score (mTSS) at baseline and the 12th month. Univariate and multivariate logistic regression analyses were used to identify the risk factors for one-year radiographic progression. Results: Among 220 RA patients recruited, the positive rate of anti-MCV antibody at baseline was 77.7%. Compared with those with negative anti-MCV antibody, RA patients with positive anti-MCV antibody had higher disease activity score in 28 joints with four variables induding CRP [3.8 (2.4, 5.0) vs. 3.1 (2.1, 4.0), P=0.007], more physical dysfunction (21.6% vs. 8.2%, P=0.033) and higher radiographic indicators including mTSS [11 (2, 27) vs. 4 (1, 10), P=0.003], joint space narrowing [JSN, 4 (0, 14) vs. 2 (0, 6), P=0.024] and joint erosion[JE, 5 (1, 18)vs. 3 (0, 5), P=0.003]. After one-year follow-up, sixty-six RA patients (30.0%) developed radiographic progression, the percentage of whom was significantly higher in positive anti-MCV group than that in negative anti-MCV group (33.9% vs.16.3%, P=0.018). Multivariate logistic regression analysis suggested that positive anti-MCV antibody at baseline was an independent risk factor for one-year radiographic progression (OR=2.341, 95%CI 1.002-5.469). Conclusion: Positive anti-MCV antibody at baseline predicts one-year radiographic progression in RA patients. In the future, anti-MCV antibody can be used not only as a supplementary laboratory marker, but also in disease activity assessment and prognosis prediction for RA.

[Expression of peroxisome proliferator-activated receptor-gamma coactivator 1ß in synovium in patients with rheumatoid arthritis and its clinical significance].

Objective: To investigate the expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)1ß in synovium of patients with rheumatoid arthritis (RA) and its association with histological synovitis. Methods: This cross-sectional study recruited RA patients at the Department of Rheumatology, Sun Yat-Sen Memorial Hospital from May 2010 to October 2016. Clinical data were collected. Conventional radiographs of bilateral hands and wrists were performed and assessed according to Sharp/van der Heijde-modified Sharp score(mTSS). Synovial tissues from knee joints of all RA patients were obtained by biopsies, and then stained with HE and immunohistochemically for PGC-1ß, CD3, CD20, CD38, CD68, CD15 and CD34 to evaluate synovitis, synovial PGC-1ß expression and the densities of inflammatory cells and endothelial cells. The relationship between synovial PGC-1ß expression and histological synovitis, disease activity and joint destruction in RA was analyzed by Spearman's rank correlation and multivariate linear regression. Results: There were 83 RA patients recruited with 20 (24.1%) males and 63 (75.9%) females, aged (54±14) years. PGC-1ß expressed in the nuclei of lining synoviocytes, sublining inflammatory cells and vascular endothelial cells of RA synovium. The percentage of synovial PGC-1ß+cells was positively correlated with histological synovitis score (r=0.333) and the densities of sublining CD3+ T cells (r=0.259), CD20+ B cells (r=0.320), CD38+plasma cells (r=0.342) and CD68+ macrophages (r=0.309)(all P<0.05). It was also positively correlated with erythrocyte sedimentation rate, C reactive protein and total mTSS (r=0.219-0.301, all P<0.05). Multiple linear regression analysis further confirmed the positive correlation between the percentage of synovial PGC-1ß+cells and mTSS (ß=0.312, P=0.004). Conclusion: Synovial PGC-1ß is positively associated with local and systemic inflammation as well as joint destruction, which implies that PGC-1ß might involve in the pathogenesis of synovitis and joint destruction in RA.

[Characteristics and clinical significance of body composition in gout patients].

Objective: To investigate the characteristics of body composition (BC) in gout patients and its clinical significance. Methods: Consecutive gout patients were recruited between August 2017 and December 2018. Demographic information, clinical characteristics and comorbidities were collected. BC was assessed by bioelectric impedance analysis including body fat percentage (BF%), trunk and limb BF%, appendicular skeletal muscle index. Overfat was defined by BF% ≥25% for male and ≥35% for female. The association between BC and serum uric acid (sUA) was evaluated by multiple linear regression. Results: A total of 362 gout patients were recruited with median age 38 (30, 52) years, 96.1% (348/362) were male. Mean sUA was (551±133) µmol/L. The mean BF% was (25.8±6.4)% with 53.6%(194/362) patients overfat. Male gout patients with overfat showed more affected joints [4(2, 6) vs. 2(2, 5)], higher sUA [(576±126)µmol/L vs. (523±134) µmol/L], higher prevalence of dyslipidemia [70.1%(131/187) vs. 54.0%(87/161)], metabolic syndrome [60.8%(118/187) vs. 28.0%(47/161)], fatty liver [58.2%(113/187) vs. 35.1%(59/161)] and hypertension [44.4%(83/187) vs. 25.5%(41/161)] than male patients with normal fat (all P<0.05). Their BF%, trunk BF% and limb BF% were positively correlated with the numbers of affected joints, sUA, metabolic syndrome, fatty liver, and hypertension, respectively (r=0.154-0.435, all P<0.05). Multivariable linear regression suggested that BF% (ß=4.29, P=0.020) and trunk BF% (ß=9.11, P=0.007), but not limb BF%, were positively correlated with sUA. Conclusion: Overfat is very common in gout patients. The proportion of trunk fat in male patients is positively correlated with sUA. When assessing obesity in gout patients clinically, body composition analysis should be performed simultaneously.

[Potential mechanism of transcription factor peroxisome proliferator-activated receptor-gamma coactivator-1 beta on promoting osteoclastogenesis].

Objective: To investigate the role of transcription factor peroxisome proliferator-activated receptor-gamma coactivator-1 beta (PGC-1ß) on osteoclastogenesis and related regulatory mechanism in the mouse monocyte-macrophage cell line (RAW264.7). Methods: PGC-1ß expression and location in RAW264.7 cells was detected by immunofluorescence, flow cytometry and western blot analysis with nuclear protein extraction. RAW264.7 cells were transfected with lentivirus for gene silencing or over-expression of PGC-1ß and cultured with macrophage colony-stimulating factor and receptor activator for nuclear factor-κB ligand. Cell viability was detected by cell counting kit-8. Cell apoptosis and cell cycle were detected by flow cytometry. Mature osteoclasts and their bone resorption activity were determined by tartrate-resistant acid phosphatase (TRAP) expression and toluidine blue staining. Western blot analysis was performed for detecting dendritic cell-specific transmembrane protein (DC-STAMP), cathepsin K, TRAP and matrix metalloproteinase (MMP)-9 expression, as well as cytoplasmic NF-κB-inducing kinase (NIK) and nuclear RelB. Results: PGC-1ß expression was observed in the nuclei of RAW264.7 cells. Down-regulation or overexpression of PGC-1ß in RAW264.7 cells did not affect cell viability, apoptosis or cell cycle. Down-regulation of PGC-1ß decreased the count of mature osteoclasts (49±21 cells vs. 147±42 cells, P=0.004) and the pit area of bone resorption lacunae (42.11µm(2)±11.30 µm(2) vs. 204.80µm(2)±31.09 µm(2), P<0.001), as well as the expression of cathepsin K, TRAP and MMP-9, but not DC-STAMP. Overexpression of PGC-1ß promoted osteoclast differentiation and bone resorption activity, as well as the expression of cathepsin K, TRAP and MMP-9. Down-regulation of PGC-1ß suppressed the protein expression of cytoplasmic NIK and nuclear RelB in RAW264.7 cells. Conclusion: PGC-1ß can promote the differentiation of RAW264.7 into osteoclasts and improve the bone resorption ability of the cells via activation of NIK/RelB pathway, which might be a promising therapeutic target for osteoporosis.

[Clinical characteristics and renal uric acid excretion in early-onset gout patients].

Objective: To investigate clinical characteristics and renal uric acid excretion in early-onset gout patients. Methods: Consecutive inpatients with primary gout were recruited between 2013 and 2017. The patients with gout onset younger than 30 were defined as early-onset group while the others were enrolled as control group. Clinical characteristics and uric acid (UA) indicators were compared between two groups. Results: Among 202 recruited patients, the early-onset group included 36 patients (17.8%). Compared with control group, the early-onset group presented more patients with obesity [13 patients (36.1%) vs. 22 patients (13.3%), P<0.05], significantly higher serum UA level [(634±124)µmol/L vs.(527±169)µmol/L] and glomerular load of UA[(7.2±2.8)mg·min(-1)·1.73m(-2) vs. (4.4±2.2)mg·min(-1)·1.73m(-2)] and estimated glomerular filtration rate (GFR) [(83±21)ml·min(-1)·1.73m(-2) vs. (67±21)ml·min(-1)·1.73m(-2)] (all P<0.05), lower fractional excretion of UA [4.4% (3.4%,6.1%) vs. 7.2% (5.2%,9.6%),P<0.05], whereas 24h urinary UA excretion was comparable [(2 788±882)µmol/1.73m(2) vs. (2 645±1 140)µmol/1.73m(2), P=0.274]. Subgroup analysis of patients without chronic kidney disease showed significantly lower fractional excretion of UA in the early-onset group [4.5%(3.3%,6.1%) vs. 6.7% (5.1%,8.7%),P<0.05]. Logistic regression analysis showed that obesity (OR=3.25) and fractional excretion of UA less than 7% (OR=9.01, all P<0.05) were risk factors of gout early onset. Conclusion: The gout patients with early-onset younger than 30 present high serum and glomerular load of uric acid which might be due to obesity and relative under-excretion of renal uric acid.

[Andersson lesion in ankylosing spondylitis: a clinical study of 14 cases].

Objective: To investigate the clinical characteristics of ankylosing spondylitis (AS) combined Andersson lesion (AL). Methods: The clinical data of patients who were diagnosed as AS combined AL at Sun Yat-sen Memorial Hospital between January 2012 and December 2015 were reviewed retrospectively.SPSS 20.0 software was used for statistical analysis.Data of normal distribution was expressed by x±s (standard deviation) and that of abnormal distribution by median and range. Results: Fourteen patients were enrolled. Ten were male, median age (IQR, similarly hereinafter) was 46 (29-53) years, disease duration was 120 (54-150) months, 7 has symptom increased in the beginning, 6 has nerve compression symptom, 7 has kyphosis, and 4 has spinous tenderness or percussion pain in physical examination.Eleven of AL occurred in the thoracolumbar junction.Erythrocyte sedimentation rate was 24 (15-44) mm/1 h, C-reactive protein was 10 (5-18) mg/L, and Serum amyloid A was 19 (5-31) mg/L.All the 14 patients were divided into 2 groups, aggravated group (n=7) and none aggravated group (n=7) according to the symptom.It was no statistic difference between them about all the above indicators. Conclusion: Imageological diagnosis should be performed to identify Andersson lesion, while ankylosing spondylitis patients combined mechanical pain based on inflammatory back pain, or mainly with nerve compression symptom, tenderness or percussion pain, or spinous, even when inflammatory markers were normal.

Characteristics and risk factors for hyperglycemia in Chinese female patients with systemic lupus erythematosus.

The aim of the study was to investigate the characteristics and risk factors for hyperglycemia in Chinese female patients with systemic lupus erythematosus (SLE). One hundred and forty-six female SLE patients without a history of diabetes underwent a 75 g oral glucose tolerance test to evaluate glucose tolerance, insulin sensitivity and pancreatic beta cell function. According to the 1999 World Health Organization criteria, all patients were divided into three groups: normal glucose regulation, impaired glucose tolerance and diabetes mellitus. Glucocorticoid doses, insulin sensitivity and pancreatic beta cell function were compared among these groups. Risk factors for hyperglycemia were analyzed by univariate and multi-variate regression analysis. Our results showed that 46 of the 146 female SLE patients (31.5 %) were hyperglycemic, including 21 (14.4%) diabetes mellitus patients and 25 (17.1%) impaired glucose tolerance patients. These female SLE patients with hyperglycemia were characterized by insulin resistance and reduced pancreatic beta cell function, and they were relatively young. Age ≥35 years and high glucocorticoid doses were risk factors for hyperglycemia in Chinese female SLE patients. The prevalence of diabetes mellitus and impaired glucose tolerance are quite high in Chinese female SLE patients. It is suggested that plasma glucose concentration should be monitored regularly and oral glucose tolerance test should be recommended for SLE patients who have risk factors for hyperglycemia.

The synovitis of "non-inflammatory" orthopaedic arthropathies: a quantitative histological and immunohistochemical analysis.

OBJECTIVE: To quantify inflammatory changes in synovial membranes from orthopaedic "non-inflammatory" arthropathies (Orth. A). METHODS: Synovial membranes from patients with femur fracture, avascular necrosis of the femur, plica syndrome, and meniscus and/or ligament injury (n = 23); rheumatoid arthritis (n = 28); osteoarthritis (OA; n = 25); and from normal controls (n = 10) were assessed by light microscopy, a histological synovitis score, immunostaining for CD3, CD20, CD38, CD68, Ki-67 and von Willebrand factor, and with an immunohistochemical inflammation score. RESULTS: Orth. A histology varied between normal and markedly inflamed. Predominant abnormalities were mild lining hyperplasia, scattered inflammatory cells and small perivascular infiltrates. The synovitis score classified Orth. A as "mild synovitis". Inflammatory cells occurred frequently: CD68+ cells in 100% of Orth. A specimens; CD3+, 91%; CD38+, 70%; and CD20+, 39%. Orth. A had 36% greater lining thickness (p = 0.04), 40% higher vascular density (p = 0.009) and 51.3-fold higher CD38+ cell density (p = 0.02) than normal controls; and 60% fewer subintimal Ki-67+ cells (p = 0.003), 42% fewer CD68+ lining cells (p<0.01) and 40% fewer subintimal CD68+ cells (p<0.01) than OA. The immunohistochemical inflammation score was 2.2-fold higher in Orth. A than in controls (p = 0.048) and similar to OA, with three Orth. A specimens showing marked inflammation. CONCLUSIONS: Synovial membranes from "non-inflammatory" arthropathies featured neovascularisation and inflammation intermediate between normal and OA synovium. These results expand previous findings that mechanical joint injury may lead to a mild-to-moderate synovitis.

MiR-638 serves as a tumor suppressor by targeting HOXA9 in glioma.

OBJECTIVE: MiR-638 is constantly downregulated and serves as a tumor suppressor in various cancers. Its role in gliomas remains unclear. This study is designed to investigate the clinical significance and the pathogenic role of miR-638 in human gliomas. PATIENTS AND METHODS: Quantitative Real-time PCR was performed to analyze the expression of miR-638 in the tumor and adjacent tissues of 24 glioma patients. The association between the expression of miR-638 and clinical features were examined. Survival of patients was studied by Kaplan-Meier curves. The impact of miR-638 on cell growth and apoptosis was determined by CCK-8 assay, colony formation assay, cell cycle analysis and Annexin V-FITC-PI apoptosis assay. The effect of miR-638 on HOXA9 was determined by luciferase assay and Western blot. The effect of miR-638 and HOXA9 on expression of oncogenes, Cyclin D1 and C-MYC was determined by Western blot. RESULTS: MiR-638 expression was constantly downregulated in glioma tumor tissue, which is negatively correlated with the WHO grade. MiR-638 expression was associated with clinical features such as tumor size, KPS score and WHO grade. Patients with low miR-638 had a worse overall survival than those with high expression. Experimentally, miR-638 directly targeted HOXA9 to suppress its expression, leading to attenuations of cell proliferation, colony formation and cell cycle progression and enhanced basal apoptosis level. MiR-638/HOXA9 axis also suppressed the expression of Wnt/beta-catenin-regulated oncogenes, Cyclin D1 and C-MYC. CONCLUSIONS: MiR-638 is a constantly downregulated microRNA in gliomas and is associated with its prognosis. MiR-638 regulates cellular malignancy of gliomas through targeting HOXA9. Thus, miR-638/HOXA9 signaling axis may have therapeutic potential in gliomas.

[grp75 protects cells from injuries caused by glucose deprivation].

To elucidate the functions of grp75, CHL cells over-expressing grp75 are cultured in glucose-free medium in order to simulate energy metabolic stress. Their susceptibilities to injuries caused by glucose deprivation are assessed by trypan blue exclusion, LDH leakage measurement and cytometry analysis. Data shows a stronger resistance to glucose deprivation among cells over-expressing grp75 than among cells constitutively expressing grp75. The outcome suggests that grp75 can protect cells from injuries caused by glucose deprivation.

The effect of the expression of vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 on the clinical outcome in patients with gastric carcinoma.

AIMS: We aimed to investigate the relationship among VEGF-C/VEGFR-3 expression, lymphatic metastasis and patient prognosis in gastric carcinoma. MATERIAL AND METHODS: VEGF-C and VEGFR-3 expression in gastric carcinoma tissues obtained from 204 patients who underwent curative gastrectomy (105 cases presented with lymph node metastasis and 99 cases without metastasis) was examined immunohistochemically. There was no significant difference in the other clinicopathologic variables except for postoperative pathological tumor stage (pT) and TNM stage between the two groups. The results were statistically processed. RESULTS: The results showed that VEGF-C was located mainly in the cytoplasm of tumor cells and VEGFR-3 was found predominantly in the endothelium of lymphatic vessels. VEGF-C and VEGFR-3 expression was more frequent in gastric carcinoma tissues than that in normal gastric tissues, 54.90% and 35.29% respectively, which revealed that the expression of VEGF-C and VEGFR-3 was significantly stronger in patients with lymph node metastasis than in those without metastasis. Patients who had positive staining for VEGF-C showed significantly less favorable survival rates compared with patients who had negative staining for VEGF-C. The survival rates of patients who had positive staining for VEGFR-3 also were significantly lower compared with patients who had negative staining for VEGFR-3. Patients who had positive staining for both VEGF-C and VEGFR-3 exhibited the most unfavorable prognosis. Multivariate analysis demonstrated that the expression of VEGF-C and VEGFR-3 was an independent prognostic determinant. In addition, faint to moderate VEGF-C expression was detected in normal gastric epithelial cells (18/204, 8.9%). CONCLUSIONS: VEGF-C and VEGFR-3 expression could serve as a prognostic biomarker in patients with gastric carcinoma.