Role of small ubiquitin-like modifier proteins-1 (SUMO-1) in regulating migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is featured by erosive cartilage and bone destruction. The enhancing aggressive property of fibroblast-like synoviocytes (FLSs) plays a critical role in this process. Small ubiquitin-like modifier (SUMO) proteins, including SUMO-1, SUMO-2, SUMO-3 and SUMO-4, participate in regulating many cellular events such as survival, migration and signal transduction in some cell lines. However, their roles in the pathogenesis of RA are not well established. Therefore, we evaluated the role of SUMO proteins in RA FLSs migration and invasion. We found that expression of both SUMO-1 and SUMO-2 was elevated in FLSs and synovial tissues (STs) from patients with RA. SUMO-1 suppression by small interference RNA (siRNA) reduced migration and invasion as well as MMP-1 and MMP-3 expression in RA FLSs. We also demonstrated that SUMO-1 regulated lamellipodium formation during cell migration. To explore further into molecular mechanisms, we evaluated the effect of SUMO-1 knockdown on the activation of Rac1/PAK1, a critical signaling pathway that controls cell motility. Our results indicated that SUMO-1-mediated SUMOylation controlled Rac1 activation and modulated downstream PAK1 activity. Inhibition of Rac1 or PAK1 also decreased migration and invasion of RA FLSs. Our findings suggest that SUMO-1 suppression could be protective against joint destruction in RA by inhibiting aggressive behavior of RA FLSs.

Role of foetal umbilical artery Doppler on prediction of adverse pregnancy outcomes in patients with systemic lupus erythematosus.

OBJECTIVES: To investigate the foetal outcomes and examine the predictive value of the third-trimester umbilical artery Doppler in systemic lupus erythematosus (SLE) pregnancies. METHODS: Data of 180 pregnancies in 175 SLE patients from Jan 2007 to Jan 2017 were analysed retrospectively. Pulsatility index (PI), resistance index (RI), and systolic/diastolic ratio (S/D) of the umbilical artery flow velocity data were monitored by Doppler ultrasound. RESULTS: One or more composite adverse pregnancy outcomes (APOs) occurred in 46.7% of patients with SLE. A total of 62 (34.4%) pregnancies were pre-term birth, and 34 (18.9%) newborns were small for gestational age (SGA). Twenty-two of pregnancies (12.2%) resulted in foetal distress. In multivariate analysis, predictors of composite APOs included positive anti-Ro (OR 5.5, 95% CI 1.7-18.2, p=0.005) and low complement (OR 3.9, 95% CI 1.1-13.6, p=0.04). Doppler PI, RI, and S/D were significantly higher in the pre-term birth, SGA, and composite APO groups than in the patients without APOs. RI with cut-off values of 0.57 and 0.70 indicated the highest risk of pre-term birth and composite APOs, with sensitivities of 50.0% and 21.4%, as well as specificities of 59.6% and 97.7%, respectively. PI emerged as the best predictor of SGA. The optimal cutoff value for PI was 0.77, at which sensitivity (90.9%) and specificity (49.2%) had the best combination. CONCLUSIONS: Pregnancies in lupus still had an increased risk of APOs in terms of pre-term birth. Third-trimester umbilical artery Doppler was useful in predicting pre-term birth, SGA, and composite APOs in lupus pregnancies.

Protein Inhibitor of Activated STAT3 Regulates Migration, Invasion, and Activation of Fibroblast-like Synoviocytes in Rheumatoid Arthritis.

The aggressive phenotype displayed by fibroblast-like synoviocytes (FLSs) is a critical factor of cartilage destruction in rheumatoid arthritis (RA). Increased FLSs migration and subsequent degradation of the extracellular matrix are essential to the pathology of RA. Protein inhibitor of activated STAT (PIAS), whose family members include PIAS1, PIAS2 (PIASx), PIAS3, and PIAS4 (PIASy), play important roles in regulating various cellular events, such as cell survival, migration, and signal transduction in many cell types. However, whether PIAS proteins have a role in the pathogenesis of RA is unclear. In this study, we evaluated the role of PIAS proteins in FLSs migration, invasion, and matrix metalloproteinases (MMPs) expression in RA. We observed increased expression of PIAS3, but not PIAS1, PIAS2, or PIAS4, in FLSs and synovial tissues from patients with RA. We found that PIAS3 knockdown by short hairpin RNA reduced migration, invasion, and MMP-3, MMP-9, and MMP-13 expression in FLSs. In addition, we demonstrated that PIAS3 regulated lamellipodium formation during cell migration. To gain insight into molecular mechanisms, we evaluated the effect of PIAS3 knockdown on Rac1/PAK1 and JNK activation. Our results indicated that PIAS3-mediated SUMOylation of Rac1 controlled its activation and modulated the Rac1 downstream activity of PAK1 and JNK. Furthermore, inhibition of Rac1, PAK1, or JNK decreased migration and invasion of RA FLSs. Thus, our observations suggest that PIAS3 suppression may be protective against joint destruction in RA by regulating synoviocyte migration, invasion, and activation.

Factors Associated with Erosive Arthritis in Rheumatoid Arthritis and Other Connective Tissue Diseases: A Retrospective Study From a Southern Chinese Population.

OBJECTIVE: To investigate the clinical predictors of erosive arthritis (EA) in patients with rheumatoid arthritis (RA) and other connective tissue diseases. METHODS: Four hundred and one consecutive patients with newly diagnosed RA between January 2010 and January 2013 were enrolled in the study. During the study period, 729 consecutive patients with non-RA connective tissue diseases were also included, and a cross-sectional study was performed. Medical records were reviewed. Only those patients with data for 2 years were considered in the analysis (338). RESULTS: Erosive arthritis was noted in 60.4% (204 /338) of patients with RA and occurred early in RA. The multivariate logistic regression analysis indicated that rheumatoid nodules, anemia, and positive anticyclic citrullinated peptide antibody (ACPA) were strongly associated factors for the occurrence of EA in RA patients. Erosive arthritis was also noted in 1.5% of patients with SLE, 5.8% of patients with primary Sjögren syndrome, and 9.1% (3/33) of patients with systemic sclerosis. When compared with patients without EA, high level and prominently higher positive rate of ACPA was found in these patients with EA. On receiver operating characteristic curve analysis, ACPA exhibited a maximum sensitivity with a cutoff value of 1.6 U/mL and 0.6 U/mL for RA and SLE patients, respectively. CONCLUSION: Erosive arthritis had a high prevalence in Chinese RA patients and occurred early. Anemia, rheumatoid nodules, and ACPA were associated with EA in RA. Erosive arthritis also could be detected in SLE, primary Sjögren syndrome, and systemic sclerosis. Anticyclic citrullinated peptide antibodies were also associated with EA in these diseases. Intensive monitoring for erosions was recommended for RA patients with a cutoff of ACPA greater than 1.6 U/mL and greater than 0.6 U/mL for SLE patients.

Clinical Characteristics and Associated Factors for Infection and in-Hospital Mortality in Inpatients with Polymyositis/Dermatomyositis in China: A Retrospective Study.

Purpose: To investigate the clinical features of infection, and associated factor for in-hospital mortality in a southern Chinese cohort with polymyositis/dermatomyositis (PM/DM). Patients and Methods: Clinical data were retrospectively reviewed from 2015 to 2022 from a tertiary hospital in southern China. Associated factors for infection and in-hospital mortality were analyzed by multivariate logistic regression analysis. Results: A total of 554 patients with PM/DM were included, and 35.6% (197/554) of them developed 404 episodes of infection. Half of the patients developed infection within 4 months after disease onset. Bacterial infection was predominant (249/404, 61.6%). Lung was the most involved (242/404, 59.9%). Gram-negative bacteria the leading pathogens (64/84, 76.2%). Patients with anti-MDA5 positive were prone to develop severe infections (35.1% vs 16.4%, P<0.001) and had higher mortality (11.7% vs 3.4%, P=0.01). The in-hospital mortality was 6.5% (36/554). Infection was the leading cause of death (20/36, 55.6%). Older age (adjusted odds ratio (OR): 1.05, 95% confidential interval (CI): 1.02-1.09, P=0.004), ILD (adjusted OR: 2.76, 95% CI: 1.11-6.84, P=0.03), number of episodes of infection (adjusted OR: 1.91, 95% CI: 1.53-2.38, P<0.001), and elevated serum creatinine (Scr) (adjusted OR: 6.83, 95% CI: 1.77-26.40, P=0.01) were associated with in-hospital mortality. Conclusion: Infection is an early complication in PM/DM with a high proportion of lung involvement and predominance of gram-negative bacteria. It is a major contributor to in-hospital mortality. Older age, ILD, and number of episodes of infection are associated with poor prognosis.

Pregnancy outcomes in patients receiving assisted reproductive therapy with systemic lupus erythematosus: a multi-center retrospective study.

OBJECTIVES: To evaluate the safety, efficacy, and maternal and fetal outcomes of assisted reproductive therapy (ART) in systemic lupus erythematosus (SLE). METHODS: Patients from three tertiary hospitals from Guangzhou, China followed-up from 2013 to 2022 were included retrospectively. Patients with planned or unplanned natural pregnancy were chosen as controls. ART procedure and pregnancy outcomes were recorded and compared. RESULTS: A total of 322 ART cycles in 142 women were analyzed. Sixty-six intrauterine pregnancies out of 72 clinical pregnancies yielded 65 live infants, including 5 pairs of twins. The clinical pregnancy rate was 46.5% (66/142). The mean age at the first clinical pregnancy was 34.0 ± 3.8 years. The median (interquartile range, IQR) disease course was 42.5 (25, 84.8) months. Twenty-seven (40.9%) of them had a history of adverse pregnancy. Primary infertility occurred in 20 (30.3%) patients. Obstruction of fallopian tubes (17/66, 25.8%) and premature ovarian failure (9/66, 13.6%) were the leading causes for infertility. Ovulation induction therapy (OIT) were conducted in 60 (83.3%) pregnancies, and no ovarian hyperstimulation syndrome (OHSS) or thrombosis was observed. The leading maternal adverse pregnancy outcomes (APOs) included premature delivery (21/66, 31.8%), gestational diabetes mellitus (GDM) (15/66, 22.7%), and disease flares (10/66, 15.2%). Spontaneous premature delivery (9/21, 42.9%) and preterm premature rupture of membranes (PPROM) (6/21, 28.6%) were the leading causes for premature delivery. Preeclampsia (19.0% vs 0%, P = 0.012) increased in premature delivery. Infants delivered prematurely were likely to be low-birth-weight (LBW)/very-low-birth-weight (VLBW) (81.0% vs 7.7%, P < 0.001). Disease flares were mild (4/10, 40.0%) or moderate (5/10, 50.0%), and developed during the second (3/10, 30.0%) or third (6/10, 60.0%) trimester with favorable outcomes. Fetal loss in ART (6/66, 9.1%) was primarily attributed to early spontaneous abortion (n = 5). The average delivery time was 36.8 ± 2.1 weeks of gestation. The average birth weight was 2653.5 ± 578.6 g. LBW infants accounted for 30.8% (20/65). No neonatal death or neonatal lupus occurred. The incidence of adverse pregnancy outcomes did not increase in patients with ART compared with planned pregnancy and reduced significantly compared with an unplanned pregnancy. CONCLUSION: The safety and efficacy of ART is assured in lupus patients with stable disease. Maternal and fetal APOs are comparable with planned pregnancy, with a relatively high incidence of premature delivery, GDM, and LBW infants.

Pregnancy Outcomes in Patients with Primary Sjögren's Syndrome Undergoing Assisted Reproductive Therapy: A Multi-center Retrospective Study.

INTRODUCTION: The aim of this work was to investigate the pregnancy outcomes in infertile patients with primary Sjögren's syndrome (pSS) undergoing assisted reproductive therapy (ART). METHODS: A multi-center retrospective study was performed in pregnant women with pSS and ART from five tertiary hospitals from Guangdong Province from 2013 to 2022. Natural planned pregnancy in pSS and healthy people undergoing ART were selected as controls. Pregnancy outcomes were collected from medical records and compared among groups. RESULTS: Twenty-four pregnancies in pSS with ART, 70 natural planned pregnancies in pSS, and 96 pregnancies in healthy people with ART were analyzed. More than half of the pSS mothers undergoing ART have a past history of adverse pregnancy and spontaneous abortion was the most common (10/24, 41.7%). Primary infertility (25.0%) and recurrent spontaneous abortion (16.7%) were the leading causes of infertility in pSS. The major maternal adverse pregnancy outcome (APO) in pSS patients with ART was premature delivery (11/24, 45.8%), likely attributed to twin gestation (4/11, 36.4%) and fetal distress (3/11, 27.3%). Twenty-seven live infants were born from 22 successful deliveries. The live birth rate was 93.1% (27/29). The average delivery time was 36.1 ± 3.3 weeks of gestation. The average birthweight was 2434.4 ± 722.1 g, compared with 2844.9 g in natural planned pregnancy in pSS, and 3072.1 g from healthy mothers with ART (P < 0.001). Seven (25.9%) low-birthweight (LBW) infants were born, and the incidence was comparable to the other two groups (22.2% in natural pregnancy, 13.0% in healthy people, P = 0.09). No infants developed congenital heart block (CHB). CONCLUSIONS: ART is an effective method for infertility in patients with pSS. Premature delivery is the leading maternal APOs. The incidence of fetal APOs does not increase, while birthweight is lower in offspring from pSS mothers with ART.

The suppression of Brd4 inhibits peripheral plasma cell differentiation and exhibits therapeutic potential for systemic lupus erythematosus.

The mechanisms that control B cell terminal differentiation remain undefined. Here, we investigate the role of bromodomain-containing protein 4 (Brd4) in regulating B cell differentiation and its therapeutic potential for B cell-mediated autoimmune diseases including systemic lupus erythematosus (SLE). We showed that Brd4 inhibitor PFI-1 suppressed plasmablast-mediated plasma cell differentiation in healthy human CD19+ B cells. PFI-1 reduced IgG and IgM secretion in costimulation-induced human B cells. We also observed a reduced percentage of plasma cells in mice with B cell-specific deletion of the Brd4 gene (Brd4flox/floxCD19-cre+). Mechanistically, using the luciferase reporter assay and the chromatin immunoprecipitation, we explored that Brd4 regulates the expression of B lymphocyte-induced maturation protein 1 (BLIMP1), an important transcript factor that is involved in modulation of plasma cell differentiation. Interestingly, PFI-1 decreased the percentages of plasmablasts and plasma cells from patients with SLE. PFI-1 administration reduced the percentages of plasma cells, hypergammaglobulinemia, and attenuated nephritis in MRL/lpr lupus mice. Pristane-injected Brd4flox/floxCD19-cre+ mice exhibited improved nephritis and reduced percentages of plasma cells. These findings suggest an essential factor of Brd4 in regulating plasma cell differentiation. Brd4 inhibition may be a potential strategy for the treatment of B cell-associated autoimmune disorders.

Increased long noncoding RNA LINK-A contributes to rheumatoid synovial inflammation and aggression.

Fibroblast-like synoviocytes (FLSs) play a key role in controlling synovial inflammation and joint destruction in rheumatoid arthritis (RA). The contribution of long noncoding RNAs (lncRNAs) to RA is largely unknown. Here, we show that the lncRNA LINK-A, located mainly in cytoplasm, has higher-than-normal expression in synovial tissues and FLSs from patients with RA. Synovial LINK-A expression was positively correlated with the severity of synovitis in patients with RA. LINK-A knockdown decreased migration, invasion, and expression and secretion of matrix metalloproteinases and proinflammatory cytokines in RA FLSs. Mechanistically, LINK-A controlled RA FLS inflammation and invasion through regulation of tyrosine protein kinase 6-mediated and leucine-rich repeat kinase 2-mediated HIF-1α. On the other hand, we also demonstrate that LINK-A could bind with microRNA 1262 as a sponge to control RA FLS aggression but not inflammation. Our findings suggest that increased level of LINK-A may contribute to FLS-mediated rheumatoid synovial inflammation and aggression. LINK-A might be a potential therapeutic target for RA.

Involvement of long non-coding RNAs in the pathogenesis of rheumatoid arthritis.

Long non-coding RNA (lncRNA) plays a contributory role in rheumatoid arthritis (RA). In this review, we summarized the current findings of lncRNAs in RA, including cellular function and the potential mechanisms. Serum lncRNA levels are associated with serum proinflammatory cytokines and disease activity. LncRNAs regulate proliferation, migration, invasion and apoptosis of RA fibroblast-like synoviocytes (FLSs), modulate the differentiation of T lymphocytes and macrophages, and affect bone formation-destruction balance of chondrocytes. Besides, lncRNAs are involved in inflammation and cell motivation signaling pathways. In-depth research on lncRNAs may help elucidate the pathogenesis of RA and provides clues for novel treatment targets.

Caveolin­1 modulates hypertensive vascular remodeling via regulation of the Notch pathway.

Hypertension is one of the critical risk factors of cerebrovascular disease. Caveolin­1 (Cav­1) has been suggested to be involved in the development of hypertension; however, the underlying mechanism remains largely unknown. Therefore, the present study aimed to investigate the mechanism underlying Cav­1 in hypertension. In the present study, the hypertension model was induced by infusion of angiotensin II (Ang­II) in rats. Cell Counting Kit­8 assay was used to detect the viability of human umbilical vein endothelial cells (HUVECs). Flow cytometry was used to determine the apoptosis of HUVECs. Transmission electron microscopy was utilized to address the thickness of the vessel walls. Reverse transcription­quantitative PCR, western blotting and immunofluorescence staining were used to assess the mechanism of cav­1/Notch1 involved in hypertensive vascular remodeling. In the present study, an Ang­II­induced hypertension model was successfully established in rats. With this model, it was found that the expression levels of cav­1 and Notch1 were significantly increased in brain tissues in the hypertension group compared with the sham­operated group. In cultured HUVECs, knockdown of cav­1 regulated Ang­II­induced HUVEC viability and apoptosis, and modulated hypertensive vascular remodeling, which was mediated by the Notch pathway. The data of the present study demonstrated that the cav­1/Notch signaling plays an important role in the regulation of Ang­II­induced hypertension and vascular remodeling.

Epidemiology and Mortality-Associated Factors of Invasive Fungal Disease in Elderly Patients: A 20-Year Retrospective Study from Southern China.

INTRODUCTION: Invasive fungal disease (IFD) is a life-threatening infection. The epidemiology and clinical features of IFD in the elderly population are less discussed. The aim of this study was to explore the epidemiology and mortality-associated factors for IFD in the elderly inpatients. METHODS: A retrospective study enrolling 512 elderly inpatients from The First Affiliated Hospital of Sun Yat-sen University during the last two decades was performed. RESULTS: The annual prevalence of IFD was 0.1-0.5%. Candidiasis was the most common (236/521, 45.3%). An increasing trend was observed in aspergillosis from 11.1% in year 1998 to 28.8% in year 2018. The common infective sites of candidiasis were abdominal cavity (83/236, 35.2%) and bloodstream (55/236, 23.3%). Invasive aspergillosis mainly developed in the sinus (74/149, 49.7%) and lung (65/149, 43.6%). Patients with diabetes mellitus (DM) (59/126, 46.8%), solid organ malignancy (84/114, 73.7%), chronic kidney disease (CKD) (40/62, 64.5%) or receiving operation (109/147, 74.1%) were prone to develop candidiasis, while aspergillosis was usually complicated in patients with chronic obstructive pulmonary disease (COPD) (25/51, 49.0%). The all-cause mortality rate was 25.9% (135/521), and patients aged ≥80 years were the riskiest (20/51, 39.2%). Lymphopenia (59.5% vs 17.3%, P<0.001) was significant in deceased patients with mold infection. Higher proportion of non-survivors with invasive candidiasis received central venous catheterization (CVC) (68.4% vs 40.6%, P<0.001) or indwelling urinary catheter (68.4% vs 46.3%, P=0.001). CONCLUSION: IFD is a life-threatening complication especially in the oldest-old. Surveillance on lymphopenia, prompt treatment and reduce invasive procedures could benefit the prognosis.

Infective patterns of cryptococcosis in patients with connective tissue disease: a retrospective study.

OBJECTIVES: To explore the clinical features and associated factors of cryptococcosis in patients with connective tissue disease (CTD) from Southern China. METHODS: Demographic and clinical data were collected between 2007 and 2018. Associated factors were analyzed by logistic regression analysis. RESULTS: A total of 6809 inpatients with CTD were included. Cryptococcosis was diagnosed in 30 patients (prevalence, 0.4%). Cryptococcosis was predominant in patients with ANCA-associated vasculitis (AAV) (prevalence, 6/530, 1.1%). Lung was commonly involved (18/30, 60.0%), followed by meninges (6/30, 20.0%), blood stream (5/30, 16.7%), and disseminated cryptococcosis (involved blood stream and meninges) (1/30, 3.3%). Infiltrates (10/18, 55.6%) and small nodules (8/18, 44.4%) were the main radiographic manifestation of pulmonary cryptococcosis (PC). The positive rate of serum cryptococcal antigen (CrAg) in patients with PC was 88.2%. Cryptococcus spp. were found in 75% (3/4) patients who underwent lung biopsy. Most of the patients with cryptococcal meningitis (CM) had elevated cerebrospinal fluid (CSF) opening pressure (6/7, 85.7%) and decreased CSF glucose level (5/7, 71.4%). Positive blood culture confirmed the diagnosis of cryptococcal sepsis (CS). Three patients died (10.0%), including one with CM and two with PC. Multivariate logistic regression analysis showed that accumulated dose of glucocorticoid (GC) [odds ratio (OR) = 1.42, 95% confidence interval (CI) 1.04-1.93, P = 0.03] was associated with cryptococcosis in patients with CTD. CONCLUSIONS: Cryptococcosis develops in various organs. Typical radiological manifestation accompanied with positive serum CrAg provides helpful clues for the diagnosis. Lumbar puncture is a critical diagnostic method to distinguish CM. The accumulated dose of GC is associated with cryptococcosis in patients with CTD. Key Points • Pulmonary cryptococcosis is suspected if pulmonary nodules adjacent to the pleura are present, with serum CrAg positive. • Cryptococcal meningitis has insidious onset and the diagnosis mainly depends on lumber puncture. • Cryptococcal sepsis is not rare and needs timely blood culture in suspected patients.

Opportunistic invasive fungal disease in patients with type 2 diabetes mellitus from Southern China: Clinical features and associated factors.

AIMS/INTRODUCTION: A retrospective study was carried out to investigate the clinical characteristics and associated factors for invasive fungal disease in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: Demographic and clinical data were recorded. Associated factors were analyzed by logistic regression analysis. RESULTS: Invasive fungal disease was diagnosed in 120 patients with type 2 diabetes mellitus (prevalence, 0.4%). Yeast infection (56/120, 46.7%), including candidiasis (31/56, 55.4%) and cryptococcosis (25/56, 44.6%), was the most common. The urinary tract was mainly involved in candidiasis (12/31, 38.7%). More than half of the cryptococcosis (16/25, 64.0%) presented as pneumonia. Mold infection accounted for 40.8% of the cases, and predominantly involved the lung (34/49, 69.4%). A total of 15 (12.5%) patients had mixed fungal infection. Candida albicans (24/111, 21.6%), Cryptococcus neoformans (19/111, 17.1%) and Aspergillus fumigatus (14/111, 12.6%) were the leading agents. Co-infection occurred in 58 (48.3%) patients, mainly presenting as pneumonia caused by Gram-negative bacteria. The inpatient mortality rate of invasive fungal disease was 23.3% (28/120). Glycated hemoglobin levels were higher in non-survivors than survivors (8.8 ± 2.5 vs 7.7 ± 2.1%, P = 0.02). Anemia (adjusted odds ratio, 3.50, 95% confidence interval 1.95-6.27, P < 0.001), hypoalbuminemia (adjusted odds ratio, 5.42, 95% confidence interval 3.14-9.36, P < 0.001) and elevated serum creatinine (adjusted odds ratio, 2.08, 95% confidence interval 1.07-4.04, P = 0.03) were associated with invasive fungal disease in type 2 diabetes mellitus patients. CONCLUSIONS: Invasive fungal disease is a life-threatening complication in type 2 diabetes mellitus patients. C. a albicans, C. neoformans, and A. fumigatus are the leading agents. Prolonged hyperglycemia results in unfavorable outcomes. Correction of anemia and hypoalbuminemia might improve prognosis.

Infectious profile in inpatients with ANCA-associated vasculitis: a single-center retrospective study from Southern China.

OBJECTIVES: Infection is a common complication in ANCA-associated vasculitis (AAV). The study goal was to investigate the infectious profile in patients with AAV from Southern China. METHODS: A retrospective study was performed on the inpatients from the First Affiliated Hospital of Sun Yat-sen University from 2012 to 2017. Demographic and clinical characteristics were recorded. RESULTS: A total of 132 AAV inpatients with 174 episodes of infection (prevalence, 63.8%) were included. Lung was the most commonly involved. Ninety-six (72.7%) patients developed infection during the first 6 months after AAV diagnosis. Bacteria (75.9%) were the prominent microbes. Gram-negative bacteria were predominant (71.4%). The most frequently isolated bacteria were P. aeruginosa (16.7%) and A. baumannii (16.7%). Mixed infection accounted for 14.9% of the episodes, while fungal infection accounted for 6.3%. Mortality rate was 12.9% (17/132). Six deceased patients (46.2%) were infected with multiple pathogens. In multivariate analysis, smoking (odds ratio (OR) 2.38, 95% confidence interval (CI) 1.13-5.03, P = 0.02), kidney involvement (OR 2.56, 95% CI 1.11-5.88, P = 0.03), lymphopenia (OR 2.33, 95% CI 1.20-4.55, P = 0.01), and dialysis (OR 3.06, 95% CI 1.14-8.20, P = 0.03) were associated with infection in patients with AAV. CONCLUSIONS: Bacteria, especially Gram-negative bacteria, were the major pathogens in Chinese AAV patients. Mixed infection was a great threat to death. Infection tended to develop within the 6 months after AAV diagnosis. Smoking, kidney involvement, dialysis, and lymphopenia increased the risk of infection in patients with AAV.Key Points• Infection tended to develop within the 6 months after AAV diagnosis.• Gram-negative bacteria were the leading pathogens.• Smoking, kidney involvement, dialysis, and lymphopenia increased the risk of infection in patients with AAV.

Clinical Features and Co-Infections in Invasive Pulmonary Aspergillosis in Elderly Patients.

INTRODUCTION: Invasive pulmonary aspergillosis (IPA) is a potentially lethal opportunistic infection. Old age is one of the important risk factors of IPA. However, data regarding the clinical characteristics and prognostic factors of elderly patients with IPA are limited, with data regarding co-infection of other bacteria or fungi even scarcer. METHODS: We performed a retrospective study of elderly patients (aged≥60) with IPA diagnosed in the First Affiliated Hospital of Sun Yat-sen University from January 2000 to December 2019. Data collection included demographic characteristics, premorbid conditions, underlying diseases, clinical manifestations, therapeutic procedures, and pathogenic detection. Associated factors were analyzed by logistic regression analysis. RESULTS: A total of 97 elderly patients (75 males, 22 females) with IPA were included. The all-cause mortality rate was 36.1% (35/97). Body mass index (BMI) (adjusted odds ratio (OR) 1.27, 95% confidence interval (CI) 1.08-1.50, P=0.01), solid organ malignancy (adjusted OR 5.37, 95% CI 1.35-21.33, P=0.02), and co-infections (adjusted OR 5.73, 95% CI 1.40-23.51, P=0.02) were associated with mortality in the elderly patients with IPA. Nearly, 76.3% (74/97) of the patients developed co-infections. Most of the infections (55/74, 74.3%) involved the lung. A total of 77 strains of bacteria were isolated, and Gram-negative bacteria (63/77, 81.3%) were predominant. Patients with co-infections are older (72.3±7.6 vs 67.4±7.4, P=0.04), prone to admit to the intensive care unit (ICU) (59.5% vs 26.1%, P=0.01), and present lymphopenia (60.8% vs 26.1%, P=0.004). In multivariate analysis, ICU admission (adjusted OR 4.57, 95% CI 1.53-13.67, P=0.01), and lymphopenia (adjusted OR 4.82, 95% CI 1.62-14.38, P=0.01) were significantly associated with co-infection in the elderly patients with IPA. CONCLUSION: IPA is a fatal disease in the elderly population. Co-infection is closely associated with mortality. Lymphopenia could be an indicator for co-infection in the elderly patients with IPA.

Increased SUMO-activating enzyme SAE1/UBA2 promotes glycolysis and pathogenic behavior of rheumatoid fibroblast-like synoviocytes.

Fibroblast-like synoviocytes (FLSs) are critical to joint inflammation and destruction in rheumatoid arthritis (RA). Increased glycolysis in RA FLSs contributes to persistent joint damage. SUMOylation, a posttranslational modification of proteins, plays an important role in initiation and development of many diseases. However, the role of small ubiquitin-like modifier-activating (SUMO-activating) enzyme 1 (SAE1)/ubiquitin like modifier activating enzyme 2 (UBA2) in regulating the pathogenic FLS behaviors is unknown. Here, we found an increased expression of SAE1 and UBA2 in FLSs and synovial tissues from patients with RA. SAE1 or UBA2 knockdown by siRNA and treatment with GA, an inhibitor of SAE1/UBA2-mediated SUMOylation, resulted in reduced glycolysis, aggressive phenotype, and inflammation. SAE1/UBA2-mediated SUMOylation of pyruvate kinase M2 (PKM2) promoted its phosphorylation and nuclear translocation and decreased PK activity. Moreover, inhibition of PKM2 phosphorylation increased PK activity and suppressed glycolysis, aggressive phenotype, and inflammation. We further demonstrated that STAT5A mediated SUMOylated PKM2-induced glycolysis and biological behaviors. Interestingly, GA treatment attenuated the severity of arthritis in mice with collagen-induced arthritis and human TNF-α transgenic mice. These findings suggest that an increase in synovial SAE1/UBA2 may contribute to synovial glycolysis and joint inflammation in RA and that targeting SAE1/UBA2 may have therapeutic potential in patients with RA.

Hypertensive disorders of pregnancy associated with adverse pregnant outcomes in patients with systemic lupus erythematosus: a multicenter retrospective study.

BACKGROUND: Hypertension disorders in pregnancy (HDP) were common complications in women with systemic lupus erythematosus (SLE). However, the impact of HDP and the measures to prevent HDP-related fetal adverse pregnancy outcomes (APOs) remained to be explored. METHODS: A multicenter retrospective study of 342 pregnant women with SLE was performed. Variables related to SLE and APOs were recorded. Fetal development was evaluated by umbilical artery Doppler ultrasonography. RESULTS: HDP was diagnosed in 45 (13.2%) patients, including pre-eclampsia in 42 and gestational hypertension in 3. Patients with HDP had higher incidence of preterm birth (71.1% vs 20.9%, P < 0.001), intrauterine growth retardation (IUGR) (37.8% vs 11.8%, P < 0.001), low-birth-weight infants (62.2% vs 17.2%, P < 0.001), and very-low-birth-weight infants (37.8% vs 2.7%, P < 0.001), compared with lupus patients without HDP. A total of 35 (77.8%) HDP patients had disease activation during pregnancy. All the events occurred during the second and third trimesters, mainly presenting as moderate-to-high activity (65.7%). Active disease [odds ratios (OR) = 3.9, 95% confidential interval (CI) 1.5-9.7, P = 0.004] and positive anticardiolipin (aCL) antibody (OR = 7.6, 95% CI 2.7-18.6, P < 0.001) were independent risk factors for HDP in lupus patients. Doppler RI and S/D ratio predicted APOs in patients with HDP. The optimal cut-off values for RI and S/D ratio were 0.7 (sensitivity 48.1%, specificity 53.3%) and 3.4 (sensitivity 66.7%, specificity 100%), respectively. CONCLUSIONS: HDP was a common pregnant complication and caused various fetal and maternal adverse outcomes in patients with SLE. Umbilical artery Doppler ultrasonography was effective in predicting fetal APOs in lupus patients with HDP.Key Points• HDP induced preterm birth, IUGR, low-birth-weight infants, and very-low-birth-weight infants in patients with SLE.• HDP led to lupus activation during the second and third trimesters.• Disease activation and aCL positivity were predictors for HDP.• RI and S/D ratio from umbilical artery Doppler predicted APOs in patients with HDP.

Active tuberculosis in patients with systemic lupus erythematosus from Southern China: a retrospective study.

To investigate the characteristics and associated factors for Mycobacterium tuberculosis (TB) infection in patients with systemic lupus erythematosus (SLE) from Southern China. A retrospective study of 1108 patients admitted to the First Affiliated Hospital of Sun Yat-Sen University from January 2007 to December 2017 was performed. Demographic and clinical characteristics, laboratory data, and radiographic manifestations were recorded. A total of 59 (5.3%) lupus patients with active TB were included. Pulmonary TB occurred in 41 (69.5%) patients. Single lobe involvement was showed in 14 (34.1%) patients. Multi-lobar involvement, including miliary TB (36.6%), was presented in 27 (65.8%) patients. Lower lobe involvement accounted for 31 (75.6%) of the cases. Extrapulmonary TB occurred in 18 (30.5%) patients. Nearly one-third (35.6%) of the patients developed disseminated TB. T-SPOT.TB assay was performed in 23 patients and positive in 18 patients (78.3%). Nineteen patients (32.2%) had co-infection with TB and other pathogens, most of which were bacterial-associated (52.6%). Lymphopenia was predominant in TB-infected patients, especially in those with disseminated TB. Multivariate logistic regression analysis found that lymphopenia [odds ratio (OR) = 2.19, 95% confidence interval (CI) 1.03-4.63, P = 0.04] and the accumulated doses of glucocorticoid (GC) (OR = 2.32, 95% CI 1.69-3.20, P < 0.001) were associated with TB. TB infection is a common comorbidity in patients with SLE. Manifestations of pulmonary computed tomography (CT) scan are relatively atypical. Co-infection with TB and other pathogens is not rare. Lymphopenia and the accumulated doses of GC are associated with TB infection in lupus patients.