Intermittent administration of PTH for the treatment of inflammatory bone loss does not enhance entheseal pathological new bone formation.

OBJECTIVE: To investigate the effect of intermittent parathyroid hormone (iPTH) administration on pathological new bone formation during treatment of ankylosing spondylitis-related osteoporosis. METHODS: Animal models with pathological bone formation caused by hypothetical AS pathogenesis received treatment with iPTH. We determined the effects of iPTH on bone loss and the formation of pathological new bone with micro-computed tomography (micro-CT) and histological examination. In addition, the tamoxifen-inducible conditional knockout mice (CAGGCre-ERTM; PTHflox/flox, PTH-/-) was established to delete PTH and investigate the effect of endogenous PTH on pathological new bone formation. RESULTS: iPTH treatment significantly improved trabecular bone mass in the modified collagen-induced arthritis (m-CIA) model and unbalanced mechanical loading models. Meanwhile, iPTH treatment did not enhance pathological new bone formation in all types of animal models. Endogenous PTH deficiency had no effects on pathological new bone formation in unbalanced mechanical loading models. CONCLUSION: Experimental animal models of AS treated with iPTH show improvement in trabecular bone density, but not entheseal pathological bone formation，indicating it may be a potential treatment for inflammatory bone loss does in AS.

Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation in ankylosing spondylitis.

OBJECTIVE: The aim of this study was to identify the role of Piezo1-mediated mechanotransduction in entheseal pathological new bone formation and to explore the underlying molecular mechanism. METHODS: Spinal ligament tissues were collected from 14 patients with ankylosing spondylitis (AS) and 14 non-AS controls and bulk RNA sequencing was conducted. Collagen antibody-induced arthritis models were established to observe pathological new bone formation. Pharmacological inhibition and genetic ablation of Piezo1 was performed in animal models to identify the essential role of Piezo1. Entheseal osteo-chondral lineage cells were collected and in vitro cell culture system was established to study the role and underlying mechanism of Piezo1 in regulation of chondrogenesis, osteogenesis and its own expression. RESULTS: Piezo1 was aberrantly upregulated in ligaments and entheseal tissues from patients with AS and animal models. Pharmaceutical and genetic inhibition of Piezo1 attenuated while activation of Piezo1 promoted pathological new bone formation. Mechanistically, activation of CaMKII (Calcium/calmodulin dependent protein kinase II) signalling was found essential for Piezo1-mediated mechanotransduction. In addition, Piezo1 was upregulated by AS-associated inflammatory cytokines. CONCLUSION: Piezo1-mediated mechanotransduction promotes entheseal pathological new bone formation through CaMKII signalling in AS.

Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment.

Growing evidence shows that the inhibitory effect of inflammatory cytokines on new bone formation by osteogenic precursor cells is a critical cause of net bone-density reduction. Melatonin has been proven to be a potential therapeutic candidate for osteoporosis. However, whether it is capable of antagonizing the suppressing effect of inflammatory cytokines on osteogenic precursor cells is so far elusive. In this study, using the cell culture system of human bone marrow stromal cells and MC3T3-E1 preosteoblasts, we recorded the following vital observations that provided insights of melatonin-induced bone formation: 1) melatonin induced bone formation in both normal and inflammatory conditions; 2) Wnt4 was essential for melatonin-induced bone formation in inflammatory stimulation; 3) melatonin- and Wnt4-induced bone formation occurred via activation of ß-catenin and p38-JNK MAPK pathways by interaction with a distinct frizzled LDL receptor-related protein complex; 4) melatonin suppressed the inhibitory effect of NF-κB on osteogenesis in a Wnt4-dependent manner; and 5) melatonin induced Wnt4 expression through the ERK1/2-Pax2-Egr1 pathway. In summary, we showed a novel mechanism of melatonin-induced bone formation in an inflammatory environment. Melatonin-induced Wnt4 expression is essential for its osteoinductive effect and the inhibitory effect of NF-κB on bone formation. Our novel findings may provide useful information for its potential translational application.-Li, X., Li, Z., Wang, J., Li, Z., Cui, H., Dai, G., Chen, S., Zhang, M., Zheng, Z., Zhan, Z., Liu, H. Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment.

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.

Piperlongumine inhibits the proliferation, migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

OBJECTIVES: Recent studies have indicated that piperlongumine (PLM) may exert anti-inflammatory effects. In the present study, we determined the effect of PLM on the proliferation, apoptosis, migration and invasion of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) (referred to herein as RA FLS). We further explored the mechanisms by which the studied compound inhibits the functions of RA FLS. METHODS: RA FLS viability and apoptosis were tested using MTT and Annexin V/PI assays, respectively. We performed an EDU assay to examine the proliferation of RA FLS. The migration and invasion of these cells were measured using a transwell chamber method and wound closure assay. The MMP-1, MMP-3, and MMP-13 levels in the culture supernatants of RA FLS were detected using a Luminex Assay kit. The intracellular ROS levels were detected using DCFH-DA. The expression levels of signal transduction proteins were measured using western blot. RESULTS: We found that PLM induced apoptosis in RA FLS at concentrations of 15 and 20 µM. The proliferation of RA FLS was downregulated by PLM at concentrations of 1, 5 and 10 µM. Migration and invasion of RA FLS were reduced by PLM at concentrations of 1, 5 and 10 µM. PLM also inhibited cytoskeletal reorganization in migrating RA FLS and decreased TNF-α-induced intracellular ROS production. Moreover, we demonstrated the inhibitory effect of PLM on activation of the p38, JNK, NF-κB and STAT3 pathways. CONCLUSIONS: Our findings suggest that PLM can inhibit proliferation, migration and invasion of RA FLS. Moreover, these data suggests that PLM might have therapeutic potential for the treatment of RA.

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.

Piperlongumine Suppresses Dendritic Cell Maturation by Reducing Production of Reactive Oxygen Species and Has Therapeutic Potential for Rheumatoid Arthritis.

Piperlongumine (PLM) is a natural product from the plant Piper longum that inhibits platelet aggregation, atherosclerosis plaque formation, and tumor cell growth. It has potential value in immunomodulation and the management of autoimmune diseases. In this study, we investigated the role of PLM in regulating the differentiation and maturation of dendritic cells (DCs), a critical regulator of immune tolerance, and evaluated its clinical effects in a rheumatoid arthritis mouse model. We found that PLM treatment reduced LPS-induced murine bone marrow-derived DC maturation, characterized by reduced expression of CD80/86, secretion of MCP-1, IL-12p70, IL-6, TNFα, IFN-γ, and IL-23, and reduced alloproliferation of T cells; however, PLM does not affect cell differentiation. Furthermore, PLM reduced intracellular reactive oxygen species (ROS) production by DCs and inhibited the activation of p38, JNK, NF-κB, and PI3K/Akt signaling pathways. Conversely, PLM increased the expression of GSTP1 and carbonyl reductase 1, two enzymes that counteract ROS effects. ROS inhibition by exogenous N-acetyl-l-cysteine suppressed DC maturation. PLM treatment improved the severity of arthritis and reduced in vivo splenic DC maturation, collagen-specific CD4(+) T cell responses, and ROS production in mice with collagen-induced arthritis. Taken together, these results suggest that PLM inhibits DC maturation by reducing intracellular ROS production and has potential as a therapeutic agent for rheumatoid arthritis.

Early-stage hip involvement in patients with ankylosing spondylitis: A Chinese study based on magnetic resonance imaging.

OBJECTIVES: To evaluate the clinical characteristics and identify potential factors of the early-stage hip involvement in patients with ankylosing spondylitis (AS) based on the magnetic resonance imaging (MRI). METHODS: A cross-sectional retrospective study of 655 consecutive patients was performed. Patients with hip pain or limited hip function but lacking definitive evidence of hip involvement on radiography underwent hip MRI. Based on the results of the imaging tests, the patients were classified into three categories: (1) no hip involvement; (2) early-stage hip involvement according to MRI but not radiography; (3) advanced-stage hip involvement according to a Bath Ankylosing Spondylitis Radiology Index-hip score ≥2. RESULTS: One hundred and sixty-eight patients had early-stage hip involvement and 103 patients had advanced-stage hip involvement. Multivariate logistic regression analysis indicated that younger age at onset, worse BASMI score, and more active inflammation in the sacroiliac joints were associated with the occurrence of early-stage hip involvement. CONCLUSION: Negative plain radiography results cannot be used to rule out hip involvement. MRI was superior to radiography for the detection of early-stage hip involvement. Susceptible AS patients with symptoms or risk factors for hip involvement should undergo hip MRI to test for lesions in the early stage.

Increased phosphorylation of ezrin is associated with the migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis.

OBJECTIVE: Increasing evidence indicates that the cytoskeletal protein ezrin may play a critical role in cell motility. This study aims to investigate the role of ezrin in regulating the migration and invasion of fibroblast-like synoviocytes (FLSs) from patients with RA. METHODS: Synovial tissues were obtained from 12 patients with RA and 6 with OA, and then FLSs were separated from synovial tissues. The expression of ezrin and phosphorylated ezrin (p-ezrin) was examined by Western blotting or IF staining. A specific inhibitor of ezrin phosphorylation and small interference RNA-mediated ezrin knockdown were used to inhibit the phosphorylation of ezrin. Migration and invasion of FLSs in vitro were measured by the Boyden chamber assay. RESULTS: Increased expression of p-ezrin protein was found in synovial tissue and FLSs in patients with RA compared with patients with OA. Stimulation with TNF-α and IL-1ß increased ezrin phosphorylation in RA FLSs. Inhibition of p-ezrin protein by a specific inhibitor of phosphorylation of ezrin and small interfering RNA-mediated knockdown reduced in vitro migration and invasion, as well as actin stress fibre formation in RA FLS. Furthermore, rho kinase and p38 mitogen-activated protein kinase (MAPK) signal pathways were involved in the phosphorylation of ezrin and invasion of RA FLSs. CONCLUSION: Increased expression of p-ezrin may contribute to aberrant aggressive behaviours of RA FLSs, which are mediated by rho kinase and the p38 MAPK pathway. This suggests a novel strategy targeting phosphorylation of ezrin to prevent synovial invasiveness and joint destruction in RA.

Incidence and predictive factors for malignancies with dermatomyositis: a cohort from southern China.

OBJECTIVES: We aimed to explore the incidence of malignancy in dermatomyositis and assess the potential risk factors of occurrence of malignancy in DM from southern China. METHODS: A retrospective cohort study of patients admitted in the 1st affiliated university hospital between 2003 and 2012 was performed. Demographic information, clinical symptoms, laboratory findings, medications were documented. The endpoint of the study was defined as occurrence of malignancy or death. RESULTS: For this approximately 10-year retrospective study, 60 out of 246 dermatomyositis patients developed malignancies with the overall incidence of 24.4%. Nasopharyngeal carcinoma (NPC) and ovarian carcinoma were the most common malignant disease, accounting for 35% (21/60) and 15% (9/60) of malignancies, respectively. Lung and colon were followed as the third most common carcinoma (5 out of 60, 8.3%). Among these 60 patients with malignancies, 39 (65.0%, 39/60) cases occurred within 1 year after DM diagnosis. Subsequently, malignancies were detected in 13 (21.7%, 13/60) patients during the second year and 8 (13.3%, 8/60) during the third year. One patient developed cancer at the 35th month after DM as the latest. The logistic regression multivariate analysis indicated that male gender [odds ratio (OR) = 3.76, 95% confidence interval (CI ) 1.86~7.61, p<0.01], dysphagia (OR= 2.21, 95%CI 1.10~4.48, p=0.03) and elevated erythrocyte sedimentation rate (ESR) (OR= 2.37, 95% CI 1.18~4.75, p=0.02) were risk factors for the occurrence of malignancies, while interstitial lung disease (ILD) acted as a protective factor (OR=0.13, 95%CI 0.06~0.28, p<0.01). CONCLUSIONS: It was necessary to carry out routine malignancy screening for Chinese DM patients due to its high incidence. Nasopharyngeal carcinoma and ovarian cancer were the most common malignant disease. The risk of malignancy was highest in the first year after DM diagnosis and reduced thereafter. Extensive work-ups for malignancy screening should be carried out at the first year. Male gender, dysphagia and elevated ESR were risk factors for occurrence of malignancy. The presence of ILD could diminish the risk of coexisting of malignancy.

[Assessment of ovarian reserve with anti-Müllerian hormone in female patients with systemic lupus erythematosus].

OBJECTIVE: To evaluate the serum level of anti-Müllerian hormone (AMH) in female patients with systemic lupus erythematosus (SLE) and identify its correlations with age and cyclophosphamide (CYC) therapy. METHODS: A total of 77 SLE female patients and 38 control healthy women with regular menstrual cycles were recruited. AMH was measured by enzyme linked immunosorbent assay (ELISA) kit. Follicle-stimulating hormone (FSH), estradiol (E2) and antral follicle count (AFC) of bilateral ovary were detected at the third day of menstrual cycle. RESULTS: Their mean age was (29 ± 5) years (range, 20-40) and the mean duration (2.7 ± 2.4) years. The mean serum level of AMH was (1.5 ± 1.3) µg/L and AFC 10 ± 7. Linear regression revealed AFC (r = 0.9, P < 0.01) was associated with the level of AMH. The mean levels of AMH and AFC were significantly higher in patients naїve to CYC therapy than in those under exposure, but lower than that in healthy control (P < 0.01). No difference existed in FSH and E2 among 3 groups. Compared with those above 30 years old, the patients aged 30 years and younger had significantly higher level of AMH (P < 0.01). The Spearman's correlation analysis indicated that each 5 gm of CYC exposure were independently associated with a lower level of AMH (r = -0.4, P < 0.01). CONCLUSION: As a more sensitive marker of ovarian reserve, AMH is associated with age and the cumulative dose of CYC. SLE patients aged >30 years and under exposure to CYC >10 g should be closely monitored for potential adverse events.

Response to belimumab among patients with refractory lupus nephritis: a real-world observational retrospective multicenter study.

OBJECTIVES: Belimumab is a biological agent approved for the treatment of active lupus nephritis (LN), but its efficacy on refractory lupus nephritis (LN) is unknown. This study aims to evaluate the efficacy and safety of belimumab in Chinese patients with refractory LN. METHODS: This multicenter, observational, and retrospective study enrolled patients with refractory LN who failed induction therapy with steroids, cyclophosphamide, mycophenolate, and calcineurin inhibitors and received 24-week belimumab treatment before data analysis. Treatment outcomes include the overall clinical response (physician judgment, disease activity, organ damage) and renal response (complete renal response, partial renal response, no renal response). Laboratory indices and adverse events were recorded as well. RESULTS: Of the 45 patients enrolled in the study, 6 (13.3%) achieved complete renal response, 19 (42.2%) achieved partial renal response, and the overall renal response rate was 55.6%. Median rSLEDAI decreased from 12 (IQR 8-12) at baseline to 8 (IQR 4-8) (p < 0.0001), 4 (IQR 4-8) (p < 0.0001) at 12 and 24 weeks. Mean urinary protein decreased more than 50% from 3.2 g/24 h at baseline to 1.0 g/24 h at 24 weeks (p < 0.0001). The conditions of hypoalbuminemia and hypocomplementemia had also gradually improved. The levels of autoantibodies showed a significant downward trend. Additionally, 9 (20.0%) patients successfully reduced the dosage of prednisone to a safe range, and 3 of them achieved their treatment goal of prednisone cessation. The mean prednisone dosage decreased from 32.7 mg/day at baseline to 18.6 mg/day (p < 0.0001), 13.3 mg/day (p < 0.0001) at 12 and 24 weeks. There were 3 adverse events reported, including 2 cases of infection, and 1 case of allergy. No serious events occurred during the follow-up. CONCLUSIONS: Belimumab is effective and safe when used in clinical practice, which can be considered as an add-on therapy for refractory LN. Key Points • A multicenter observational study in the real clinical settings of China. • First revealed the efficacy and safety of belimumab in Chinese patients with refractory LN.

Clinical features and independent predictors in the further development of rheumatoid arthritis in undifferentiated arthritis.

This study aims to investigate the prognosis of undifferentiated arthritis (UA) and to estimate the putative predictors contributing to predict the development of UA into rheumatoid arthritis (RA); thus, it could improve appropriate medical intervention. A retrospective cohort study of 218 patients with an initial diagnosis of UA and 2-year follow-up monitoring was carried out. The baseline information including demographic variables, clinical features, and laboratory data was collected. A logistic regression model was used for the statistical analysis. After 2 years of follow-up, 20.18% of UA patients evolved into RA, but 33.03% remained undifferentiated. Meanwhile, 25.23% went into remission, and 21.56% developed into other connective tissue diseases. Univariate and multivariate analysis showed that the titer of antibodies to cyclic citrullinated peptide (anti-CCP), tender joint count and duration of morning stiffness were independent predictors for the development of RA. The area under the curve (AUC) of duration of morning stiffness (0.81) was largest, followed by tender joint count (0.74). The AUC of anti-CCP antibodies (0.68) was higher than that of rheumatoid factor of IgM type (IgM-RF) (0.60), and the combination of these two antibodies was significantly higher than each alone (P < 0.001). In conclusion, UA patients had variable clinical outcomes and prognosis. Only the titer of anti-CCP antibodies, tender joint count, and duration of morning stiffness, instead of IgM-RF, could predict the development of RA. Although the anti-CCP antibody was better than the IgM-RF in predicting RA, a combined detection of them still improved the diagnostic performance.

[Associated factors for the occurrence of lupus enteritis].

OBJECTIVE: To explore the clinical and laboratory characteristics of patients with lupus enteritis to provide rationales for clinical diagnosis and treatment. METHODS: A retrospective group control study was conducted for systemic lupus erythematosus (SLE) patients with complaints of acute abdominal pain from 2004 to 2011. They were divided into 2 groups: lupus enteritis (n = 66) and non-lupus related abdominal pain (n = 73). The associated factors included demographic, laboratory, clinical and radiographic data. RESULTS: Lupus enteritis (39.3%) was the most common cause of lupus patients with acute abdominal pain. There were no differences in autoantibody profiles, complement, erythrocyte sedimentation rate, C reactive protein and SLE disease activity index (SLEDAI) score between two groups. The level of D-dimer and European consensus lupus activity measurement (ECLAM) score were significantly higher in the group of lupus enteritis than those in non-lupus related gastrointestinal injury. Lupus enteritis had significantly higher percentage of complications with multiple serous cavity effusions and ascites. But after adjusting with logistic regression multivariate analysis, only the level of D-dimer, ECLAM and volume of ascites were associated with occurrence of lupus enteritis. CONCLUSION: Lupus enteritis is the most common cause of acute abdominal pain. D-dimer is an excellent predictor for lupus abdominal pain. As compared with SLEDAI, ECLAM may be more suitable for assessment in SLE patients with alimentary tract injury.

[Modulation of RhoA/Rho kinase on migration, invasion and proliferation of fibroblast like synoviocytes from patients with rheumatoid arthritis].

OBJECTIVE: To evaluate the modulation of RhoA/Rho kinase (ROCK), a small Rho GTPase, on migration, invasion and proliferation of fibroblast like synoviocytes (FLS) from rheumatoid arthritis (RA) patients. METHODS: RA FLS were collected from active RA patients. And 10% fetal bovine serum (FBS) and interleukin-1ß (IL-1ß) were used as stimuli in migration and proliferation experiments respectively. RhoA activity was measured by pull down assay while ROCK activity by Western blot. FLS migration and invasion in vitro were measured by the Transwell chamber method. And thiazolyl blue tetrazolium bromide (MTT) test was used to detect cell proliferation. RESULTS: There were increased activities of RhoA and ROCK in ex vivo FLS from RA versus OA patients and healthy control. The migrated cell number of FBS-induced, C3-treated and Y27632-treated groups was 85 ± 14, 51 ± 15 and 42 ± 11 respectively. The Matrigel invading cell number of 3 groups was 64 ± 13, 39 ± 12 and 26 ± 9 respectively. Statistical differences existed in cell number between FBS-induced, C3-treated or Y27632-treated group (P < 0.05) in above migration and invasion experiments. Inhibition of RhoA and ROCK activity also suppressed the cytoskeletal reorganization and proliferation of RA FLS. CONCLUSION: Increased RhoA/ROCK activity may contribute to abnormal migration, invasion and proliferation of RA FLS. Thus inhibition of ROCK activity may be a new therapeutic target for RA.

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.

Role of p21-activated kinase 1 in regulating the migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients.

OBJECTIVE: To investigate the role of p21-activated kinase 1 (PAK1) in regulating migration, invasion and MMP expression in RA fibroblast-like synoviocytes (FLS). METHODS: RA FLS migration and invasion in vitro were measured by the Boyden chamber method. Invasion of RA FLS into cartilage was detected in the severe combined immunodeficiency (SCID) mouse co-implantation model of RA in vivo. PAK1 and MT1-MMP expression were examined by western blotting. ELISA was used to measure the production and activity of MMPs. RESULTS: Phosphorylated PAK1 (p-PAK1) protein expression was increased in ex vivo synovial membrane cells from RA patients. Stimulation with IL-1ß or TNF-α up-regulated p-PAK1 expression. Inhibition of PAK1 by transfection with dominant negative PAK1 mutant (dnPAK1) reduced in vitro migration and invasion of RA FLS. In the SCID mouse model, RA FLS invasion into cartilage was attenuated by transfection with dnPAK1 in vivo. PAK1 regulated IL-1ß-induced production and activity of MMP-13 and MT1-MMP. Inhibition of MMP-13 or MT1-MMP activity also reduced RA FLS invasion. Furthermore, dnPAK1 transfection inhibited c-Jun N-terminal kinase (JNK) activation, but did not affect the activities of extracellular signal-regulated kinases and p38. Inhibition of the JNK activity by chemical inhibitor significantly reduced the migration, invasion and production of MMP-13 and MT1-MMP. CONCLUSION: PAK1 plays an important role in regulating the migration, invasion and production and activity of MMPs in RA FLS, which is mediated by the JNK pathway. This suggests a novel strategy targeting PAK1 to prevent joint destruction of RA.