Jie Gao

Background: Growing evidence demonstrates that rheumatoid arthritis (RA), a chronic autoimmune disease characterized by joint inflammation and immune system dysfunction, can significantly accelerate the progression of atherosclerosis (AS). Studies have revealed that patients with RA and AS share numerous common features in terms of immune dysregulation and metabolic alterations, with abnormalities in lactate metabolism being particularly prominent. However, the role of lactate and its associated protein modification—lactylation—in the pathogenesis of RA‐related AS remains unclear. The primary objective of this study is to comprehensively investigate lactylation‐related genes as potential diagnostic markers for patients with concurrent RA and AS. Methods: We identified the core genes associated with lactylation by integrating and analyzing two disease‐related datasets: a RA dataset (GSE89408) and an AS dataset (GSE43292) from the GEO database. Through comprehensive analysis, we examined the functions associated with the hub genes and investigated the correlation between their expression levels and immune infiltration. Additionally, we explored the lactylation scores of different immune cells using single‐cell data. Results: We identified four lactylation‐related hub genes (SMARCC2, CCNA2, NUP50, and GATAD2B) highly associated with concurrent RA and AS, which showed high diagnostic potential (area under the curve [AUC] > 0.88). Further analysis revealed that these four hub genes were significantly correlated with the level of immune cell infiltration. To better understand the relationship between lactylation and immune cells, we analyzed single‐cell sequencing data, which demonstrated significant differences in lactylation scores across various types of immune cells. Conclusions: These findings highlight lactylation‐related genes as promising diagnostic markers and provide insights into shared pathogenic mechanisms of RA and AS.

Protein lactylation is a novel post-translational modification that has rarely been investigated in rheumatoid arthritis (RA). This study aimed to explore lactylation proteomics in RA patients and validate sorted candidate lactylation sites. Synovial tissues from ten RA and six osteoarthritis (OA) patients were subjected to lactylation proteomics via affinity enrichment and LC-MS/MS. Four candidate lactylated modification sites were validated by immunoprecipitation. Totally, 566 sites and 250 proteins with lactylated modifications in RA patients and 548 sites and 220 proteins with lactylated modifications in OA patients were identified. By comparison, 24 upregulated but 2 downregulated lactylated modification sites and 18 upregulated but 1 downregulated lactylated modification protein were discovered in RA patients versus OA patients. The dysregulated lactylated proteins were mainly enriched in biological processes such as positive regulation of plasma membrane repair by GO analysis; pathways such as neutrophil extracellular trap formation by KEGG analysis; and two metabolism-related items by COG/KOG analysis. Immunoprecipitation confirmed that FTH1-K69la (P = 0007) and PKM2-K166la (P = 0.003), but not ANXA2-K115la (P = 0.127) or ANXA5-K76la (P = 0.361), were more abundant in RA patients versus OA patients. Moreover, FTH1-K69la was positively correlated with erythrocyte sedimentation rate (ESR) in RA patients (P = 0.037). Conclusively, this study describes a general landscape of lactylation proteomics in the RA.

Background: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome has been considered as a childhood syndrome. Its etiopathogeny is unknown however, currently considered as auto‐immune inflammatory disease. Recently, a few cases of adult‐onset of PFAPA syndrome have been reported. However, there is no report about the adult‐onset of PFAPA case with a novel TNFAIP3 Mutation. Objective and Method: Followed by detailed clinical inquiry, related laboratory tests, genetic sequencing and treatment, we reported a case with the adult‐onset of PFAPA syndrome with a novel TNFAIP3 mutation. Results: We have found a novel mutation in the gene TNFAIP3 in an adult patient with periodic fever, aphthous stomatitis, pharyngitis, and adenitis—the PFAPA syndrome, under the environmental factor‐COVID‐19 vaccination. Conclusion: This case demonstrated adult‐onset of PFAPA symptoms, including periodic fever of unknown origin, which can occur in adult patients with the familial hereditary TNFAIP3 mutation and environmental factors. And the therapeutic measures provide some reference and practical significance for the treatment of PFAPA syndrome.

Objective Retroperitoneal fibrosis (RPF) is a rare condition marked by inflammation and fibrosis affecting the peritoneal and retroperitoneal soft tissues. In recent years, the identification of IgG4-related diseases has brought to light a significant association with fibrous disorders, including RPF, which were once considered independent. In this comprehensive cohort study, we performed a comparative analysis of the demographic, clinical, laboratory, histopathological, and therapeutic characteristics between patients with IgG4-related RPF and those with idiopathic retroperitoneal fibrosis (iRPF). Methods We performed a retrospective analysis of 117 patients diagnosed with RPF at the First Affiliated Hospital of Naval Medical University between July 2007 and July 2023. Results Demographic, clinical, laboratory, histopathological, and therapeutic characteristics of 70 iRPF patients and 47 IgG4-related patients were systematically compared. The IgG4-related group exhibited an older age of onset, with a predominant occurrence among adult males. Significantly elevated levels of eosinophilia and IgE were observed in the IgG4-related group. Most patients across both groups displayed elevated CRP and ESR levels. Furthermore, at the time of diagnosis, the IgG4-related group had higher serum creatinine and lower levels of complement. The most prevalent clinical manifestation in both groups was flank pain. The proportion of lymphoplasmic infiltration and storiform fibrosis in IgG4-related RPF group was significantly higher. The IgG4-related RPF group had significantly higher IgG4-positive plasma cell count, IgG4/total IgG ratio, and eosinophils count than that in iRPF group. Conclusion We conducted a comparative analysis of demographic, clinical, laboratory, histopathological, and therapeutic differences between the iRPF patients and the IgG4-related patients. Clarifying the distinctive characteristics of these two groups will contribute to a better understanding of the condition and facilitate the development of specific treatment strategies tailored to each group. Key Points • Identification of distinct clinical features and outcomes between IgG4-related and iRPF patients in a large retrospective study.

The patient presented to the clinic with painful muscle swelling in the right lower extremity, which improved with immunosuppressive therapy. Initially, the condition was diagnosed as polymyositis but recurred soon after. After imaging and biopsy, the final diagnosis was primary skeletal muscle peripheral T-cell lymphoma, not otherwise specified (PSM-PTCL, NOS). In this report, we discuss the challenges in diagnosing and treating this aggressive malignancy and review the literature on PSM-PTCL, NOS. Key Points • To date, there are few reports of PSM-PTCL, NOS, and our case is the tenth. • It is crucial to consider PSM-PTCL, NOS, when presenting with localized muscle edema and unexplained pain. • Histopathological examination is likely the most effective method for diagnosing this rare disease.

Letters to the Editor; Authors: J.-Q. Hu, Q. Cai, Y. Gao, J. Gao

Ras homolog gene family member A (RhoA) plays a major role in the Wnt/planar cell polarity (PCP) pathway, which is significantly activated in patients with rheumatoid arthritis (RA). The function of RhoA in RA synovitis and bone erosion is still elusive. Here, we not only explored the impact of RhoA on the proliferation and invasion of RA fibroblast-like synoviocytes (FLSs) but also elucidated its effect on mouse osteoclast and a mouse model of collagen-induced arthritis (CIA). Results showed that RhoA was overexpressed in RA and CIA synovial tissues. Lentivirus-mediated silencing of RhoA increased apoptosis, attenuated invasion, and dramatically upregulated osteoprotegerin/receptor activator of nuclear factor-κB ligand (OPG/RANKL) ratio in RA-FLSs. Additionally, the silencing of RhoA inhibited mouse osteoclast differentiation in vitro and alleviated synovial hyperplasia and bone erosion in the CIA mouse model. These effects in RA-FLSs and osteoclasts were all regulated by RhoA/Rho-associated protein kinase 2 (ROCK2) and might interact with Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways.

Objective: Our previous studies revealed that normal synovial exosomes promoted chondrogenesis, and microRNA (miR)-19b-3p independently related to osteoarthritis (OA) risk. Subsequently, this study intended to further explore the effect of OA fibroblast-like synoviocyte (OA-FLS) exosomal miR-19b-3p on OA ferroptosis and its potential mechanisms.Methods: Interleukin (IL)-1β-stimulated chondrocytes and medial meniscus surgery were used to construct the OA cellular model and the OA rat model, respectively. OA-FLS exosomes with/without miR-19b-3p modification were added to the IL-1β-stimulated chondrocytes and OA rat models, followed by direct miR-19b-3p mimic/inhibitor transfection with/without SLC7A11 overexpression plasmids. miR-19b-3p, ferroptosis-related markers (malondialdehyde (MDA), glutathione (GSH)/oxidized glutathione (GSSG), ferrous ion (Fe²⁺), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), and acyl-CoA synthetase long-chain family member 4 (ACSL4)), mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) levels were detected.Results: Enhanced ferroptosis reflected by dysregulated ferroptosis-related markers, a reduced MMP, and an increased ROS was observed in cartilage tissues from OA patients vs. controls, IL-1β-stimulated chondrocytes vs. normal ones, and OA rat models vs. sham, so did miR-19b-3p. OA-FLS exosomes promoted MDA, Fe²⁺, ACSL4, and ROS but reduced cell viability, GSH/GSSG, GPX4, SLC7A11, and MMP in IL-1β-stimulated chondrocytes, whose effect was enhanced by miR-19b-3p mimics and attenuated by miR-19b-3p inhibitors. miR-19b-3p negatively regulated SLC7A11 and directly bound to SLC7A11 via luciferase reporter gene assay. Furthermore, SLC7A11 overexpression weakened miR-19b-3p mimics’ effect on ferroptosis-related markers, MMP, or ROS in IL-1β-stimulated chondrocytes. OA-FLS exosomes also induced cartilage damage and ferroptosis in OA rats whose influence was tempered by miR-19b-3p inhibitors.Conclusion: OA-FLS exosomal miR-19b-3p enhances cartilage ferroptosis and damage by sponging SLC7A11 in OA, indicating a potential linkage among synovium, cartilage, and ferroptosis during the OA process.

This study aimed to examine metabolites in the plasma derived from postmenopausal women by untargeted metabolomics along with possible diagnostic markers for osteoporosis. From March 2020 through June 2020, 30 postmenopausal women with normal bone mineral density (BMD) were recruited in the N group, 30 postmenopausal women with postmenopausal osteoporosis were recruited in the postmenopausal osteoporosis (PMO) group, and 30 postmenopausal women with rheumatoid arthritis osteoporosis were recruited in the rheumatoid arthritis osteoporosis (RAOP) group. The height, weight, body mass index (BMI), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL), lumbar BMD, hip BMD, femoral neck BMD, and plasma metabolite levels were measured. Seven differential metabolites were observed between the PMO and N groups and recorded as metabolite set 1, and 38 differential metabolites were found between the RAOP and N groups and recorded as metabolite set 2. Six same metabolites were found between these two metabolite sets. The area under the curve (AUC) of the combined receiver operating characteristic (ROC) curves for the six metabolites was 0.900. In this study, six metabolites with a diagnostic value for osteoporosis were found in the plasma of postmenopausal women, and the combined diagnosis efficiency of these six metabolites was high. Key policy highlights