OBJECTIVE:The aim of this study was to establish a fast, practical and automated assay to measure the expression of interferon-stimulated genes (ISGs) in whole peripheral blood and evaluate the utility of these markers in distinguishing active SLE. METHODS:A total of 102 SLE patients (38 active, 64 inactive) were enrolled. The mRNA levels of five ISGs (IFI27, OAS1, IFI44L, LY6E, IFIT1) in whole blood were quantified using an automated multiplex RT-qPCR platform. Multivariable linear regression was performed to evaluate the influence of medications and specific autoantibodies on ISG expression. Diagnostic performance was evaluated via receiver operating characteristic curves. Backward stepwise logistic regression was employed to identify optimal predictors and subsequently construct a diagnostic probability matrix for disease activity. RESULTS:ISGs expression were significantly elevated in active SLE patients (2.9-17.3 fold) and positively correlated with disease activity indictors. Multivariable analysis confirmed that ISGs expression reflected disease activity independent of treatments and autoantibody status. Subsequently, IFI27 and OAS1 were identified as the optimal combination, forming the ISG2 Score. Multivariable analysis confirmed that the ISG2 Score and complement-3 (C3) were independent predictors of active SLE. An ISG2-C3 matrix was developed and revealed a dramatic stepwise escalation in disease probability. Notably, we observed that elevated IFI27 in clinically inactive patients was associated with persistent leukopoenia. CONCLUSION:This automated whole-blood assay offers a rapid and reliable method for ISGs detection. IFI27 and OAS1 combined with C3, serve as sensitive biomarkers for monitoring of active SLE in routine care.

OBJECTIVES:This study aimed to evaluate the efficacy and safety of mufemilast, a novel small-molecule selective phosphodiesterase 4 (PDE4) inhibitor, in patients with Behçet's syndrome (BS). METHODS:Patients diagnosed with BS according to the International Diagnostic (Classification) Criteria for Behçet's Disease 2013 and with active oral ulcers were eligible. Patients were randomly assigned to mufemilast (45 mg or 60 mg) or placebo, administered orally twice daily for 12 weeks. The primary endpoint was the area under the curve (AUC) for the number of oral ulcers from baseline to week 12. Safety was measured in all patients who received at least 1 dose of the study drug (ClinicalTrials: NCT04609397). RESULTS:Ninety patients were randomly assigned to the mufemilast 45 mg, 60 mg, or placebo groups (29, 31, and 30, respectively). The least-squares mean difference in AUC0-12 for oral ulcers between the 45 mg and 60 mg groups and the placebo was -104.8 (95% CI, -156.3 to -53.2; P < .001) and -142.5 (95% CI, -192.4 to -92.7; P < .001), respectively. The visual analogue pain scores and time to ulcer-free remission were significantly improved with mufemilast (P < .001). PDE4-related side effects were transient and resolved spontaneously, and discontinuation rates were low (7% for 45 mg, 7% for 60 mg, and 3% for placebo). No serious adverse events were reported related to the drug. CONCLUSIONS:Among patients with oral ulcers associated with BS, mufemilast significantly reduced the number of oral ulcers, improved pain scores, and induced significantly more ulcer-free remissions compared with placebo, with an acceptable safety profile.

Objective To develop and validate a noninvasive predictive model for labial focus score (FS) ≥ 1 in patients suspected of having Sjögren disease (SjD) by integrating salivary gland ultrasound (SGUS) findings with clinical variables. Methods A novel semiquantitative SGUS scoring system was applied to 449 prospectively recruited patients. Multivariable logistic regression analysis was conducted to identify independent predictors of FS ≥ 1, which were subsequently incorporated into a risk stratification matrices model. The model underwent both internal (n = 139) and external validation (n = 57). Results The derivation cohort included 449 patients (mean age 44.0 years, 94.7% female), with 284 (63.3%) showing labial FS ≥ 1. Patients with FS ≥ 1 were older and had higher total SGUS scores and hyperglobulinemia. Multivariable logistic regression identified the SGUS score (odds ratio [OR] 1.44), age (OR 1.51), and hyperglobulinemia (OR 1.91) as independent outcome predictors. This led to an age-stratified prediction model categorizing patients into high-, moderate-, and low-risk groups across 3 age brackets. This model showed strong predictive value for labial FS ≥ 1 in both high-risk and low-risk populations (area under the curve [AUC] 0.91, 95% CI 0.87-0.96, P < 0.001), with specificity of 81%, sensitivity of 95%, positive predictive value of 92%, and negative predictive value of 87%. The model performed well in both internal validation (AUC 0.90) and external validation (AUC 0.83). Conclusion Our SGUS-based predictive model provides an exploratory, hypothesis-generating tool for guiding labial minor salivary gland biopsy decisions in SjD by integrating imaging with clinical variables, enabling personalized risk stratification. It effectively identifies high-risk patients needing biopsy and low-risk patients who can avoid unnecessary procedures, offering a significant diagnostic advance.

Objective To characterize the epidemiological characteristics of malignancy in Chinese patients with rheumatoid arthritis (RA) versus American patients and investigate their associated factors. Methods Data were collected from a real-world Chinese RA population and American patients with RA from the National Health and Nutritional Examination Survey. The prevalence and subtypes of malignancy and their potential associated factors were investigated in both populations. Results A total of 2,073 Chinese and 2,928 American patients with RA were included. There was a lower prevalence of malignancy in Chinese than in their American counterparts before (5.7% vs. 17.1%) and after matching (6.2% vs. 12.6%, both P < 0.001). Gender discrepancies in malignancy prevalence were observed, with a male predilection for RA with malignancy in China (8.2% vs. 5.5%), while it was the opposite in American patients (10.1% vs. 13.5%, both P < 0.05). The top type of malignancy among male patients with RA was lung cancer in Chinese (2.29%), but non-melanoma skin cancer (3.43%) in American; while among female patients was breast cancer both in Chinese (1.72%) and American (3.43%). Multivariate logistic regression analyses showed that older age (odds ratio (OR) = 1.050) and positive anti-cyclic citrullinated peptide antibody (OR = 2.752) were independently associated with malignancy in Chinese patients with RA, while female (OR = 1.395), older age (OR = 1.033), active smoking (OR = 1.580) and cardiovascular diseases (OR = 1.523) in American patients. Conclusion The prevalence, subtypes and risk factors of malignancy were substantially different in Chinese patients with RA and their American counterparts, which implied the importance of individualized malignancy screening strategies for patients with RA.

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 cm 3 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) cm 3 vs 17 (7-134) cm 3, 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.

目的 探讨系统性红斑狼疮(systemic lupus erythematosus,SLE)患者的血尿酸联合胆固醇检测对蛋白尿的预测价值.方法 纳入2020年3月至2020年7月门诊及住院的SLE患者309例为SLE组,以242名年龄、性别匹配的健康人群为对照组.检测SLE患者血尿酸、血脂水平及其他临床指标(性别、年龄、体重、系统性红斑狼疮疾病活动指数(SLEDAI)评分、肾脏指标(肌酐、尿常规、24 h尿蛋白定量)、C反应蛋白(CRP)、红细胞沉降率、SLE血清学活动指标(补体C3、补体C4和抗dsDNA)及当前糖皮质激素用量].根据24 h尿蛋白定量结果将309例SLE患者(SLE组)分为两亚组:蛋白尿亚组63例[24 h尿蛋白>0.5 g)和非蛋白尿亚组246例(24 h尿蛋白≤0.5 g).以logistic回归分析SLE患者蛋白尿的危险因素,以受试者操作特征(receiver operator characteristic,ROC)曲线评价血尿酸、胆固醇对蛋白尿的预测价值.结果 SLE组的高尿酸血症(≥360μmol/L)比例显著高于对照组(P=0.001);SLE组血三酰甘油水平显著高于对照组(P<0.001),高密度脂蛋白显著低于对照组(P<0.001);蛋白尿亚组的血尿酸、胆固醇、三酰甘油显著高于非蛋白尿亚组(均P<0.001),其中尿酸、胆固醇水平升高是SLE患者出现蛋白尿的危险因素(OR分别为1.004、1.486,均P<0.001).ROC曲线提示尿酸、胆固醇的曲线下面积分别为0.739、0.754(P<0.001),阈值分别为335.50μmol/L、4.73 mmol/L.尿酸、胆固醇同时超过阈值预测蛋白尿的特异度最高(91.46％,P<0.001).结论 SLE患者的血尿酸及胆固醇升高与蛋白尿密切相关,尿酸与胆固醇水平可能对蛋白尿有一定预测价值.

目的 提高临床医生对应用糖皮质激素患者感染粪类圆线虫继发细菌性脑膜炎的认识.方法 报道1例于2018年12月5日在广州市番禺区中心医院内分泌科住院,因长期应用糖皮质激素患者感染粪类圆线虫继发细菌性脑膜炎患者的临床资料,并在Pubmed数据库以"Strongyloidiasis"或"Strongyloides"和"bacterial meningitis"或"meningitis"检索,对1980年1月至2022年3月相关英文文献进行复习.结果 患者男,59岁,因"恶心、呕吐1d"入院.既往因类风湿关节炎长期使用糖皮质激素.入院检查提示低钠、低氯,皮质醇节律低下,予激素替代治疗过程中出现发热、意识不清,脑膜刺激征阳性,脑脊液培养阳性,抗感染等治疗效果欠佳.后大便检查找到粪类圆线虫卵,明确诊断为粪类圆线虫感染继发细菌性脑膜炎,抗感染同时加用抗寄生虫治疗,好转出院.检索文献,共10例应用糖皮质激素患者合并粪类圆线虫感染继发细菌性脑膜炎病例,通过找到虫卵或虫体确诊,8例脑脊液培养阳性,以肠科杆菌为主,5例合并机会致病菌感染,其中8例死亡.结论 应用糖皮质激素患者感染粪类圆线虫易继发细菌性脑膜炎,脑脊液培养以肠科杆菌为主,易合并机会致病菌感染,死亡率高,需要抗感染同时抗寄生虫治疗,并适当延长抗寄生虫治疗时间.

OBJECTIVE:To explore the clinical and genetic characteristics of a Chinese pedigree affected by glycogen storage disease (GSD) type Ia with gout as the first manifestation.METHODS:Clinical and biochemical data of the pedigree were collected. Available members of the pedigree were subjected to gene sequencing, and the result was analyzed by bioinformatics software. The pedigree was followed up for five years.RESULTS:The proband was a young female manifesting recurrent gout flare, hypoglycemia, and hypertriglyceridemia. One of her younger brothers also presented with dysplasia and hepatic adenoma. Gene sequencing revealed that the proband and her younger brother both harbored c.1022T>A (p.I1e341Asn) and c.230+5G>A compound heterozygous variants of the G6PC gene , which were inherited from their father and mother, respectively. Among these, the c.230+5G>A is an intron region variant which was unreported previously, and bioinformatics analysis showed that it may impact mRNA splicing of the gene. The proband was treated with raw corn starch, allopurinol, and fenofibrate. Gout was well controlled, and she had given birth to a baby girl without GSD.CONCLUSION:GSD Ia should be considered among young gout patients with hypoglycemia and hepatomegaly, for which gene sequencing is warranted. GSD Ia has a good prognosis after comprehensive treatment with diet and medicine.

ObjectivesThe purpose of this study was to investigate the baseline independent risk factors for predicting 6-month mortality of patients with anti-melanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis (DM) and develop a matrix prediction model formed by these risk factors.MethodsThe hospitalized patients with DM who completed at least 6-month follow-up were recruited as a derivation cohort. The primary exposure was defined as positive anti-MDA5 at the baseline. The primary outcome was all-cause 6-month mortality after enrollment. A matrix prediction model was developed in the derivation cohort, and another published cohort was used for external validation.ResultsIn derivation cohort, 82 patients with DM were enrolled (mean age of onset 50 ± 11 years and 63% women), with 40 (49%) showing positive anti-MDA5. Gottron sign/papules (OR: 5.135, 95%CI: 1.489–17.708), arthritis (OR: 5.184, 95%CI: 1.455–18.467), interstitial lung disease (OR: 7.034, 95%CI: 1.157–42.785), and higher level of C4 (OR: 1.010, 95%CI: 1.002–1.017) were the independent associators with positive anti-MDA5 in patients with DM. Patients with anti-MDA5-positive DM had significant higher 6-month all-cause mortality than those with anti-MDA5-negative (30 vs. 0%). Among the patients with anti-MDA5-positive DM, compared to the survivors, non-survivors had significantly advanced age of onset (59 ± 6 years vs. 46 ± 9 years), higher rates of fever (75 vs. 18%), positive carcinoma embryonic antigen (CEA, 75 vs. 14%), higher level of ferritin (median 2,858 ug/L vs. 619 ug/L, all p < 0.05). A stepwise multivariate Cox regression showed that ferritin ≥1,250 μg/L (HR: 10.4, 95%CI: 1.8–59.9), fever (HR: 11.2, 95%CI: 2.5–49.9), and positive CEA (HR: 5.2, 95%CI: 1.0–25.7) were the independent risk factors of 6-month mortality. A matrix prediction model was built to stratify patients with anti-MDA5-positive DM into different subgroups with various probabilities of 6-month mortality risk. In an external validation cohort, the observed 6-month all-cause mortality was 78% in high-risk group, 43% in moderate-risk group, and 25% in low-risk group, which shows good accuracy of the model.ConclusionBaseline characteristics such as fever, ferritin ≥1,250 μg/L, and positive CEA are the independent risk factors for 6-month all-cause mortality in patients with anti-MDA5-positive DM. A novel matrix prediction model composed of these three clinical indicators is first proposed to provide a chance for the exploration of individual treatment strategies in anti-MDA5-positive DM subgroups with various probabilities of mortality risk.

本文报道1例从全身型幼年特发性关节炎发展到成人斯蒂尔病,在糖皮质激素、传统改善病情抗风湿药及生物制剂和小分子靶向药治疗下仍出现双腕、髋及膝关节滑膜炎及骨质破坏,右侧股骨头缺血坏死,并且反复左膝关节肿胀伴活动受限,最后诊断腘窝多发滑膜囊肿.经托珠单抗联合甲氨蝶呤、来氟米特及甲泼尼龙积极控制基础疾病、关节腔抽液及倍他米松注射等治疗后病情控制,左膝肿胀缓解.

BackgroundRecombinant uricase such as pegloticase are indicated for chronic gouty arthritis who have failed to achieve serum urate level <300μmol/L even though receiving conventional urate-lowering drugs. Rasburicase which is currently approved at a dosage of 0.2 mg/(kg.d) for 5 days for the prevention of tumor lysis syndrome in pediatric patients with hematological tumors, is the only available uricase in China at present.ObjectivesTo evaluate the efficacy and safety of low-dose rasburicase in refractory chronic gouty arthritis.MethodsWe retrospectively collected data of 17 patients with refractory chronic gouty arthritis who were treated with rasburicase from January 2021 to September 2021 at Sun Yat-sen Memorial Hospital, Sun Yat-sen University. The refractory chronic gouty arthritis was defined as serum urate level was still more than 300μmol/L and dual-energy CT showed the volume of urate more than 10 cm3, even though the allopurinol, febuxostat, and/or benzbromarone of the maximum tolerable amount were received for more than 3 months. Rasburicase was added every four weeks (week 0, week 4, and week 8) with a dosage of 1.5 mg/d for three consecutive days, on the basis of daily oral urate-lowering drugs of the maximum tolerable amount. The serum urate level was monitored. The primary outcome was the change in urate volume at week 12 compared to week 0 by dual-energy CT.Results① Seventeen patients were recruited with 16 males (94%) and mean age 47±15 years old. The median gout course was 11 (6.5, 15) years with gout flares number 20 (11, 36) times in the previous year. At week 0 before the rasburicase add-on treatment, the mean serum urate was 652±94μmol/L and the median urate volume was 44 (21, 215) cm3 (Table 1). ② Urate level after the rasburicase add-on treatment was significantly decreased than that before the treatment either at week 0, week 4, or week 8 (Figure 1A, all p< 0.001). The median reduction of serum urate were 565 (446, 621) at week 4, 214 (57, 373) at week 8, and 118 (21, 185) at week 12 (all p<0.017). Five cases (29%) showed serum urate lower than 300μmol/L at week 12. ③ The urate volume decreased at week 12 compared to week 0 in all patients (Figure 1B~D). The median volume of urate reduction was 24 (12, 60) cm3 (p<0.001) and the median percentage of urate reduction 42% (25%, 66%). Urate reduction volume was positively correlated with baseline urate volume (r=0.890, p<0.001), while the percentage of urate reduction volume negatively correlated with baseline urate volume (r=-0.689, p=0.002). ④ Rasburicase was generally well tolerated. No gout attack occurred on the basis of intravenous methylprednisone 20mg before each rasburicase add-on treatment and oral colchicine 0.5mg/d to 1mg/d. No hypersensitive reaction occurred during the treatment. Phlebitis occurred in a patient (6%), while dizziness and nausea occurred in two patients (13%). One patient (6%) who was suffering chronic kidney disease of stage 3 developed acute kidney injury after rasburicase injection at week 0 and week 8, but the serum creatinine spontaneously returned to the baseline level during follow-up.Figure 1.The serum urate and urate volume before and after rasburicase add-on treatment. A: Paired comparison of serum urate level before and after each time of rasburicase administration; B. Reduction value and percentage of urate volume at week 12 for each patient. C&D: Dual-energy CT (DECT) showed a dramatical reduction in urate volume from week 0 (C, urate volume: 72.15 cm3) to week 12 (D, urate volume: 7.66 cm3). ***: p< 0.001; #: Received rasburicase at week 0 only; ####: Received rasburicase 7.5mg at week 0.ConclusionThis pilot study shows rasburicase is well tolerated in patients with refractory chronic gouty arthritis and may be a reasonable option to effectively lower the urate burden of these patients, although this is an off-label use. Further prospective randomized controlled studies to verify the efficacy and safety are needed.FundingThis study was funded by Yat-sen Clinical Research Project.Disclosure of InterestsNone declared

Background: Systemic lupus erythematosus (SLE) commonly occurs in premenopausal women and is associated with elevated estrogen levels. Patients with SLE may have abnormal serum triglyceride (TG) levels, and lipid reportedly promotes kidney damage in patients with nephrosis. Since estrogen regulates lipid levels, we investigated the serum lipid levels of premenopausal women with SLE and their relationship with proteinuria. Methods: This cross-sectional study included 123 premenopausal women with SLE (SLE group), who were classified into 24-h urine protein exceeding 0.5 g (24 h-UPRO > 0.5 g, n = 22) and 24 h-UPRO ≤ 0.5 g ( n = 101) subgroups, and 100 similarly aged healthy women (control group). Clinical characteristics and biomarker levels were compared between these groups. The associated factors of proteinuria over 0.5 g/day were evaluated using multivariate logistic regression. A receiver operating characteristic (ROC) curve was plotted to assess the cholesterol (CH) cut-off associated with increased development of proteinuria over 0.5 g/day. Results: The SLE group had significantly higher serum TG levels than that of control group. 24 h-UPRO were significantly correlated with serum creatinine, CH, TG, and uric acid levels. Serum CH level was the greatest associated factor for proteinuria over 0.5 g/day. The area under the ROC curve was 0.843, with a CH cut-off of 4.58 mmol/L. Patients with serum CH above 4.58 mmol/L had a higher proportion of type IV LN, but with no statistical difference. Conclusions: In premenopausal SLE patients, serum TG levels were higher than in healthy women, and serum CH levels were the primary associated factor for proteinuria over 0.5 g/day. Proteinura over 0.5 g/day may occur in women with SLE with serum CH levels >4.58 mmol/L. CH levels may be useful for predicting proteinuria.

Background Recently, the autoantibody recognizing melanoma differentiation-associated gene 5 (anti-MDA5) is of the greatest concern as a specific autoantibody of dermatomyositis (DM), since it delineates a unique clinical phenotype of DM with a high risk of life-threatening lung complications. Considering routine clinical characteristics at baseline are still desired candidates for screening potential mortality predictors, in order to as early as possible stratify the mortality risk in anti-MDA5 positive DM patients before making therapeutic strategies. Objectives To investigate the baseline independent risk factors for predicting 6-month mortality of anti-MDA5-positive DM patients and develop a matrix prediction model formed by these risk factors. Methods This was a real-world prospective observational study. The hospitalized patients with DM were included if they fulfilled the criteria including: aged over 18 years old; diagnosed as having DM according to the criteria proposed by Bohan and Peter or the modified Sontheimer definitions; and positive anti-MDA5 which was determined by both line immunoassay testing and enzyme-linked immunosorbent testing. The primary outcome was all-cause 6-month mortality after enrolment. A matrix prediction model was built with the mortality risk probability. Results There were 82 DM patients enrolled (mean age of onset 50±11 years and 63% female), with 40 (49%) showing positive anti-MDA5. Gottron sign/papules (OR: 5.135, 95%CI: 1.489~17.708), arthritis (OR: 5.184, 95%CI: 1.455~18.467), interstitial lung disease (ILD, OR: 7.034, 95%CI: 1.157~42.785), and higher level of C4 (OR: 1.010, 95%CI: 1.002~1.017) were independent associators with positive anti-MDA5 in DM patients. Anti-MDA5-positive DM patients had significant higher 6-month all-cause mortality than those with anti-MDA5-negative (30% vs. 0%). Among anti-MDA5-positive DM patients, compared to the survivors, non-survivors had significantly advanced age of onset (59±6 years vs. 46±9 years), higher rates of fever (75% vs. 18%), positive carcinoma embryonic antigen (CEA, 75% vs. 14%), higher level of ferritin (median 2858 ug/L vs. 619 ug/L, all p<0.05). Multivariate COX regression showed ferritin≥1250 μg/L (HR: 10.4, 95%CI: 1.8~59.9), fever (HR: 11.2, 95%CI: 2.5~49.9), and positive CEA (HR: 5.2, 95%CI: 1.0~25.7) were independent risk factors of 6-month mortality. According to the matrix prediction model, anti-MDA5-positive DM patients could be stratified into three subgroups based on various probabilities of predicted mortality: (i) High-risk: eight patients with two of the above three features (including fever, serum ferritin≥1250 μg/L, and positive CEA) had high predicted mortality probability with 64%~85% (three red grids in Figure 1A), and the actual mortality was 75% (n=6) with 60%, 100%, and 100% respectively in three red grids (Figure 1B). Five patients with all of three features had extremely high predicted mortality probability with 97% (95%CI: 70%~100%, the dark red grid of Figure 1A), and the actual mortality was 100% in Figure 1B; (ii) Moderate-risk: nine patients with one of the above three features had moderate predicted mortality probability with 11%~29% (three yellow grids in Figure 1A), and the actual mortality was 11% (n=1) with 0%, 0%, and 17% respectively in three yellow grids (Figure 1B); (iii) Low-risk: eighteen patients with none of the above three features had low predicted mortality probability with 2% (95%CI: 0.2%~20%, the green grid in Figure 1A), and the actual mortality was 0% in the green grid (Figure 1B). Conclusion Baseline characteristics of fever, positive CEA, and ferritin≥1250 μg/L are risk factors for 6-month all-cause mortality in anti-MDA5-positive DM patients. A novel matrix prediction model composed of these three clinical indicators is firstly proposed to provide a chance for exploration of individual treatment strategies in anti-MDA5-positive DM subgroups with various probabilities of mortality risk. Disclosure of Interests None declared

Background: Although antinuclear antibodies (ANAs), anti-SSA and anti-Ro52, are present in immunoglobulin preparations, it is unknown whether intravenous immunoglobulin (IVIG) therapy influences the testing of serum autoantibodies in patients with connective tissue diseases (CTDs). The present study aimed to investigate the dynamic change over time of serum ANA-related autoantibodies in patients with CTDs receiving IVIG therapy. Methods: Serum ANA-related autoantibodies were monitored in two patients with CTD before IVIG therapy and at different times after therapy. These autoantibodies were tested in different batches of immunoglobulin preparations from seven pharmaceutical companies. Results: One patient developed a new ANA pattern (cytoplasmic dense fine speckled pattern, AC-19) just after IVIG therapy. Both patients developed de novo positivity for AMA-M2 and anti-SSA, but returned negative 1 month after IVIG therapy. The residual liquid in patients' immunoglobulin preparations showed positive ANAs with a high titer of AC-19 (1:640), a low titer of the nuclear fine speckled pattern (AC-4, 1:80), positive AMA-M2, and positive anti-SSA. ANA-related autoantibodies were tested in 16 batches of immunoglobulin preparations and all had positive ANAs with two patterns: AC-19 (1:640 or 1:320) and AC-4 (1:80). AMA-M2 and anti-SSA were positive in 100% of the batches. Conclusion: Our study highlights high-titer AMA-M2 autoantibodies in immunoglobulin preparations and suggests their transient transfer into a patient's circulation via IVIG therapy. To avoid incorrect clinical decisions based on postinfusion antibody titers, our data recommend retesting 1-2 months after high-dose IVIG immunomodulatory treatment.

Background:Cholesterol crystal embolism (CCE) syndrome is a multisystemic disorder caused by small arteries cholesterol crystal emboli subsequent to small pieces of atheromatous plaques from the aorta or other major arteries break off. CCE is often overlooked because it mimics symptoms of systemic vasculitis due to its clinical characteristics such as ulceration and gangrene of toes, livedo reticularis, renal insufficiency. Acute inflammatory reactants such as ESR, CRP may elevate in CCE patients since the cholesterol crystals trigger a foreign-body inflammatory reaction around the arterioles.Objectives:This study aimed to explore the clinical characteristics of CCE patients, to make rheumatologists learn more about this disease.Methods:Peer-reviewed articles in the electronic databases Medline, PubMed, Science Citation Index, China Biomedical Literature Database (CBM), China Journal Full Text Database (CNKI), and WANFANG Data were searched using the terms “cholesterol crystal embolism syndrome”, “cholesterol embolism”, “atherosclerotic embolism”, “atherosclerotic nephropathy”, or “CCE”. Only articles or case reports containing detailed medical records of CCE patients were included. We also included CCE patients in our department.Results:A 66-year-old male CCE patient presented with multiple ulceration and gangrene of toes and heels (Figure 1), subacute renal insufficiency, and elevated CRP and ESR. This patient had been considered as “suspected systemic vasculitis” and was referred to our rheumatology department. Another 39 Chinese CCE patients from the above databases were qualified for analysis. Among these 40 patients, 87.5% (35/40) were male and the mean age was 68±6 years. The most common involved was kidney and 90% (36/40) of patients presenting with renal insufficiency including the progressive increase of serum creatinine, hematuria, proteinuria, or sudden (or sharp) aggravation of hypertension. Next common involved was skin that occurred in 87.5% (35/40) of patients, especially in the toes and heels. For skin manifestations, blue toe syndrome occurred in 82.5% (33/40) of patients, ulceration or gangrene in 25% (10/40), and livedo reticularis in 15% (6/40). Additionally, 12.5% (5/40) showed ocular involvement such as visual impairment and visual field defect. In 2 patients, embolized cholesterol crystal in retinal arteries that is called Hollenhorst plaques was detected by fundoscopy. There were 62.5% (25/40) of patients having elevated CRP or ESR. The positive rate for skin or subcutaneous biopsies was 58% (11/19) and for kidney biopsies was 100% (6/6). The precipitating factors preceding the occurrence of classical symptoms such as blue toe syndrome, livedo reticularis and/or subacute renal insufficiency is important for CCE diagnosis especially for patients who had contraindications or were intolerant to biopsy. The precipitating factors include endovascular intervention (80%), vascular surgery (5%), and anticoagulant or thrombolytic therapy (2.5%). Only 12.5% (5/40) of patients were spontaneous and didn’t have any predisposing factors. General interventions of CCE included statins (82.5%), antiplatelets (32.5%), and dialysis (32.5%). Twelve patients (30%) received glucocorticoids and 75% (9/12) of them renal function improved and ulceration healed (Figure 1). Among 36 patients who presented with renal insufficiency, the renal function returned to normal after treatment in 2 patients (5.6%), but 27 patients (75%) still showed abnormal renal function even though somewhat improved, and 7 patients (19.4%) needed renal replacement therapy or dialysis for maintenance.Conclusion:This study reported CCE patients had high prevalence of renal insufficiency, blue toe syndrome, and ulceration or gangrene of toes, as well as elevated CRP or ESR, thus rheumatologists should be alert to this disease as one of the differential diagnosis of systemic vasculitis, especially for elderly patients with evidence of atherosclerosis who undergo a recent cardiovascular procedure.Disclosure of Interests:None declared

Objective: To investigate the expression of peroxisome proliferator-activated receptor-gamma coactivator (PGC)1β 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-1β, CD3, CD20, CD38, CD68, CD15 and CD34 to evaluate synovitis, synovial PGC-1β expression and the densities of inflammatory cells and endothelial cells. The relationship between synovial PGC-1β 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-1β expressed in the nuclei of lining synoviocytes, sublining inflammatory cells and vascular endothelial cells of RA synovium. The percentage of synovial PGC-1β+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-1β+cells and mTSS (β=0.312, P=0.004). Conclusion: Synovial PGC-1β is positively associated with local and systemic inflammation as well as joint destruction, which implies that PGC-1β might involve in the pathogenesis of synovitis and joint destruction in RA.

Passive transfer of ANA and anti-SSA has been reported in patients with common variable immunodeficiency disorder who received intravenous immunoglobulin (IVIG). IVIG is also recommended to treat some special or life-threatening rheumatic diseases.This study was aimed to explore whether any extractable nuclear antibodies (ENAs) were transferred to these rheumatic patients who received IVIG therapy.IVIG products of three batches were tested for ANA by using indirect immunofluorescent assay, and for ENAs by using line immunoassay (LIA) and chemiluminescence immunoassay (CLIA). These IVIG products were administrated to rheumatic patients at a dose of 20g/d×3 days (day1 to day3). Serum samples of these patients before IVIG (day0) and after IVIG (day4, day8, day10, day12, and more than one month) were tested by using LIA and CLIA. Anti-SSA was also detected using ELISA.In these IVIG products, ANA was positive at a titer of 1:640 (cytoplasmic speckled) and 1:80 (speckled). Among 14 types of ENAs that could be tested using LIA, anti-SSA, anti-Ro52, anti-mitochondrial M2, and anti-centromere B antibodies were clearly detectable in IVIG products (Table 1). Likewise, another assay CLIA also detected the same positive autoantibodies in these products. LIA showed the highest concentration in anti-mitochondrial M2, while CLIA showed the highest concentration in anti-mitochondrial M2 and anti-Ro52. One 31-year-old male patient who was diagnosed as SLE (Figure 1) and one 72-year-old male patients who was diagnosed as necrotizing myositis received these IVIG products. Anti-SSA, anti-Ro52, anti-mitochondrial M2, but not anti-centromere B, were positive in the day4 serum samples, although all of these antibodies were negative at baseline (day0). The concentration of these antibodies decreased gradually as days passed and became undetectable around one month after IVIG.Table 1.The concentration of autoantibodies in intravenous immunoglobulin productsanti-SSAanti-Ro-52anti-mitochondrial M2anti-centromere BCut-offLIA(grey value)20±328±369±1019±4≥11CLIA (U/ml)333±107444±86434±66390±89>20ELISA (U/ml)90±13NANANA>20LIA, line immunoassay; CLIA, chemiluminescence immunoassay; ELISA, enzyme linked immunosorbent assayThis study preliminarily reported transient positivity of anti-SSA, anti-Ro52, and anti-mitochondrial M2 in rheumatic patients maybe because the passive transfer of these antibodies from IVIG products to the patients, although the potential influence of this transfer on the rheumatic diseases remained unknown.Figure 1.The concentration of autoantibodies in a 31-year-old male SLE patient receiving intravenous immunoglobulin at a dose of 20g/d×3 days (day1 to day3). Serum samples of these patients before IVIG (day0) and after IVIG (day4, day8, day10, day12, and day51) were tested by using line immunoassay (LIA) and chemiluminescence immunoassay (CLIA). Anti-SSA was also detected using ELISA. The horizontal red lines were the corresponding cut-off values of each assay.None declared

本文报道一例罕见的确诊弥漫皮肤型系统性硬化症和高血压3年的女性患者，近2个月出现血尿、蛋白尿及血肌酐进行性升高，经肾活检病理确诊为合并显微镜下多血管炎引起的急进性肾小球肾炎，予糖皮质激素冲击及免疫抑制剂治疗后病情好转，未出现硬皮病肾危象。

OBJECTIVETo clarify the function of microRNA-15a in the spinal cord injury (SCI) and its potential mechanism.PATIENTS AND METHODSThe plasma levels of microRNA-15a and signal transducer and activator of transcription 3 (STAT3) in SCI patients were determined by quantitative Real Time-Polymerase Chain Reaction (qRT-PCR). The correlation between the expressions of microRNA-15a and STAT3 was analyzed. The in vitro SCI model was established in H2O2-induced C8-D1A and C8B4 cells, and in vivo SCI model was established in mice by hitting T10. The mRNA and protein expressions of tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) were detected in the SCI model. The apoptosis was examined by flow cytometry or TUNEL staining, respectively. The motor function of mouse hindlimb was evaluated using the Basso Beattie Bresnahan (BBB) standard scale. The target gene of microRNA-15a was predicted by bioinformatics and further verified by dual-luciferase reporter gene assay. The expression changes of target genes in C8-D1A and C8B4 cells with microRNA-15a overexpression or knockdown were examined by qRT-PCR and Western blot. Finally, rescue experiments were performed to evaluate the regulatory effects of microRNA-15a and STAT3 on cell apoptosis.RESULTSMicroRNA-15a was lowly expressed in plasma of SCI patients, while STAT3 was highly expressed with a negative correlation to microRNA-15a. Identically, microRNA-15a was lowly expressed in H2O2-induced C8-D1A and C8B4 cells, and STAT3 was highly expressed. MicroRNA-15a overexpression downregulated mRNA and protein levels of TNF-α and IL-6 in C8-D1A and C8B4 cells. BBB score was markedly low in SCI mice relative to controls. SCI mice injected with microRNA-15a mimics had higher BBB score than those injected with negative control. Besides, SCI mice with microRNA-15a overexpression had downregulated expressions of STAT3, TNF-α, and IL-6 in the impaired spinal cord tissues, as well as lower apoptotic rate. Through bioinformatics, we found binding sites between STAT3 and microRNA-15a. Their binding conditions were further verified by dual-luciferase reporter gene assay. Moreover, STAT3 expression was negatively regulated by microRNA-15a. Finally, rescue experiments showed that STAT3 overexpression could reverse the regulatory effects of microRNA-15a on expressions of TNF-α and IL-6, as well as apoptosis.CONCLUSIONSMicroRNA-15a expression decreases in the SCI model, which participates in the process of SCI by regulating inflammatory response and cell apoptosis via targeting STAT3.

目的 探讨小剂量甲氨蝶呤治疗类风湿关节炎(RA)出现骨髓抑制患者的临床特点及危险因素.方法 收集995例治疗方案包含小剂量甲氨蝶呤的RA住院患者临床资料,选择甲氨蝶呤致骨髓抑制的17例患者为骨髓抑制组,按1:4的比例配比同一时期入院、使用甲氨蝶呤而无骨髓抑制、同性别、同年龄、同病程的68例RA患者为对照组,观察甲氨蝶呤致骨髓抑制RA患者的临床表现、出现甲氨蝶呤致骨髓抑制的可能原因及治疗转归.分析老年(年龄≥60岁)RA患者使用甲氨蝶呤的骨髓抑制发生风险,对比骨髓抑制组与对照组RA患者的临床特征差异,探讨甲氨蝶呤致骨髓抑制的危险因素.结果 使用甲氨蝶呤的995例RA患者中,17例(1.7％)因甲氨蝶呤致骨髓抑制入院,其原因可能为误服、超敏反应、剂量累积及加量,患者临床表现主要为皮肤黏膜溃疡、发热和感染.17例均有白细胞减少、中性粒细胞减少、血红蛋白下降、血小板减少.16例经治疗患者康复出院,1例经治疗血细胞恢复,但因合并急性脑干梗死而死亡.老年RA患者使用甲氨蝶呤的骨髓抑制发生风险高于非老年RA患者(OR=18.7,P<0.001).与对照组相比,骨髓抑制组RA患者血清白蛋白及肾小球滤过率较低(P均<0.001).多因素Logistic回归分析示,校正年龄和肾小球滤过率后,低蛋白血症仍是小剂量甲氨蝶呤引起骨髓抑制的危险因素(OR=4.7,P=0.016);校正年龄和白蛋白后,中-重度肾功能不全是小剂量甲氨蝶呤致骨髓抑制的危险因素(OR=3.6,P=0.036).结论 RA患者在使用小剂量甲氨蝶呤过程中如出现口腔溃疡并发热,须警惕骨髓抑制的可能,应尽早行血常规检查.老年、低蛋白血症、肾功能不全是小剂量甲氨蝶呤致骨髓抑制的危险因素.