Immune-mediated necrotizing myopathy: A comprehensive review of the pathogenesis, clinical features, and treatments.

Immune-mediated necrotizing myopathy (IMNM) is a rare and newly recognized autoimmune disease within the spectrum of idiopathic inflammatory myopathies. It is characterized by myositis-specific autoantibodies, elevated serum creatine kinase levels, inflammatory infiltrate, and weakness. IMNM can be classified into three subtypes based on the presence or absence of specific autoantibodies: anti-signal recognition particle myositis, anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase myositis, and seronegative IMNM. In recent years, IMNM has gained increasing attention and emerged as a research hotspot. Recent studies have suggested that the pathogenesis of IMNM is linked to aberrant activation of immune system, including immune responses mediated by antibodies, complement, and immune cells, particularly macrophages, as well as abnormal release of inflammatory factors. Non-immune mechanisms such as autophagy and endoplasmic reticulum stress also participate in this process. Additionally, genetic variations associated with IMNM have been identified, providing new insights into the genetic mechanisms of the disease. Progress has also been made in IMNM treatment research, including the use of immunosuppressants and the development of biologics. Despite the challenges in understanding the etiology and treatment of IMNM, the latest research findings offer important guidance and insights for delving deeper into the disease's pathogenic mechanisms and identifying new therapeutic strategies.

Macrophage-derived mir-100-5p orchestrates synovial proliferation and inflammation in rheumatoid arthritis through mTOR signaling.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation, causing substantial disability and reducing life quality. While macrophages are widely appreciated as a master regulator in the inflammatory response of RA, the precise mechanisms underlying the regulation of proliferation and inflammation in RA-derived fibroblast-like synoviocytes (RA-FLS) remain elusive. Here, we provide extensive evidence to demonstrate that macrophage contributes to RA microenvironment remodeling by extracellular vesicles (sEVs) and downstream miR-100-5p/ mammalian target of rapamycin (mTOR) axis. RESULTS: We showed that bone marrow derived macrophage (BMDM) derived-sEVs (BMDM-sEVs) from collagen-induced arthritis (CIA) mice (cBMDM-sEVs) exhibited a notable increase in abundance compared with BMDM-sEVs from normal mice (nBMDM-sEVs). cBMDM-sEVs induced significant RA-FLS proliferation and potent inflammatory responses. Mechanistically, decreased levels of miR-100-5p were detected in cBMDM-sEVs compared with nBMDM-sEVs. miR-100-5p overexpression ameliorated RA-FLS proliferation and inflammation by targeting the mTOR pathway. Partial attenuation of the inflammatory effects induced by cBMDM-sEVs on RA-FLS was achieved through the introduction of an overexpression of miR-100-5p. CONCLUSIONS: Our work reveals the critical role of macrophages in exacerbating RA by facilitating the transfer of miR-100-5p-deficient sEVs to RA-FLS, and sheds light on novel disease mechanisms and provides potential therapeutic targets for RA interventions.

Efferocytosis: Current status and future prospects in the treatment of autoimmune diseases.

Billions of apoptotic cells are swiftly removed from the human body daily. This clearance process is regulated by efferocytosis, an active anti-inflammatory process during which phagocytes engulf and remove apoptotic cells. However, impaired clearance of apoptotic cells is associated with the development of various autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. In this review, we conducted a comprehensive search of relevant studies published from January 1, 2000, to the present, focusing on efferocytosis, autoimmune disease pathogenesis, regulatory mechanisms governing efferocytosis, and potential treatments targeting this process. Our review highlights the key molecules involved in different stages of efferocytosis-namely, the "find me," "eat me," and "engulf and digest" phases-while elucidating their relevance to autoimmune disease pathology. Furthermore, we explore the therapeutic potential of modulating efferocytosis to restore immune homeostasis and mitigate autoimmune responses. By providing theoretical underpinnings for the targeting of efferocytosis in the treatment of autoimmune diseases, this review contributes to the advancement of therapeutic strategies in this field.

BTF3L4 Overexpression Mediates APAP-induced Liver Injury in Mouse and Cellular Models.

Background and Aims: Acetaminophen (APAP)-induced liver injury (AILI) has an increasing incidence worldwide. However, the mechanisms contributing to such liver injury are largely unknown and no targeted therapy is currently available. The study aimed to investigate the effect of BTF3L4 overexpression on apoptosis and inflammation regulation in vitro and in vivo. Methods: We performed a proteomic analysis of the AILI model and found basic transcription factor 3 like 4 (BTF3L4) was the only outlier transcription factor overexpressed in the AILI model in mice. BTF3L4 overexpression increased the degree of liver injury in the AILI model. Results: BTF3L4 exerts its pathogenic effect by inducing an inflammatory response and damaging mitochondrial function. Increased BTF3L4 expression increases the degree of apoptosis, reactive oxygen species generation, and oxidative stress, which induces cell death and liver injury. The damage of mitochondrial function by BTF3L4 triggers a cascade of events, including reactive oxygen species accumulation and oxidative stress. According to the available AILI data, BTF3L4 expression is positively associated with inflammation and may be a potential biomarker of AILI. Conclusions: Our results suggest that BTF3L4 is a pathogenic factor in AILI and may be a potential diagnostic maker for AILI.

Pathogenic role and clinical significance of neutrophils and neutrophil extracellular traps in idiopathic inflammatory myopathies.

Idiopathic inflammatory myopathies (IIM) are a heterogeneous group of chronic autoimmune diseases characterized by muscle damage and extramuscular symptoms, including specific skin rash, arthritis, interstitial lung disease, and cardiac involvement. While the etiology and pathogenesis of IIM are not yet fully understood, emerging evidence suggests that neutrophils and neutrophil extracellular traps (NETs) have a role in the pathogenesis. Recent research has identified increased levels of circulating and tissue neutrophils as well as NETs in patients with IIM; these contribute to the activation of the type I and type II interferons pathway. During active IIM disease, myositis-specific antibodies are associated with the formation and incomplete degradation of NETs, leading to damage in the lungs, muscles, and blood vessels of patients. This review focuses on the pathogenic role and clinical significance of neutrophils and NETs in IIM, and it includes a discussion of potential targeted treatment strategies.

Interleukin-18 Gene Polymorphisms and Rheumatoid Arthritis Susceptibility: An Umbrella Review of Meta-Analyses.

This study systematically analyzes the association between interleukin-18 (IL-18) gene polymorphisms and rheumatoid arthritis (RA) susceptibility. The electronic databases Ovid MEDLINE, Ovid Excerpta Medica Database, and Cochrane Library were searched to identify meta-analyses that included case-control studies reporting IL-18 gene polymorphisms and RA susceptibility. Data were reanalyzed using Review Manager Software 5.1, and Mantel-Haenszel random effects were applied for the five genetic models: allelic, recessive, dominant, homozygote, and heterozygote. The effect size of odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated. A total of seven meta-analyses with poor quality were included. The IL-18 polymorphisms -607 A/C, -137 C/G, -920 T/C, and -105 C/A have been reported. With weak evidence, IL-18 -607 A/C polymorphisms were associated with a reduced risk of RA susceptibility using the allele model (OR = 0.76, 95% CI: 0.61 - 0.93, p=0.01), dominant model (OR = 0.67, 95% CI: 0.50 - 0.90, p=0.008), homozygote model (OR = 0.57, 95% CI: 0.35 - 0.91, p=0.02), and heterozygote model (OR = 0.71, 95% CI: 0.54 - 0.93, p=0.01) in the overall population. IL-18 gene polymorphisms and RA susceptibility are affected by ethnicity: With weak evidence, IL-18 -137 C/G polymorphisms were related to reduce RA susceptibility in the Asian population (allele model: OR = 0.59, 95% CI: 0.40 - 0.88, p=0.01; dominant model: OR = 0.57, 95% CI: 0.37 - 0.89, p=0.01; heterozygote model: OR = 0.60, 95% CI: 0.38 - 0.94, p=0.03). IL-18 -607 A/C gene polymorphisms are a protective factor for RA susceptibility in the overall population, and IL-18 -137 C/G gene polymorphisms are a protective factor for RA susceptibility in the Asian population. Further studies are needed to confirm these results owing to the limitations of the included studies.

Augmenting regulatory T cells: new therapeutic strategy for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune condition marked by inflammation of the joints, degradation of the articular cartilage, and bone resorption. Recent studies found the absolute and relative decreases in circulating regulatory T cells (Tregs) in RA patients. Tregs are a unique type of cells exhibiting immunosuppressive functions, known for expressing the Foxp3 gene. They are instrumental in maintaining immunological tolerance and preventing autoimmunity. Increasing the absolute number and/or enhancing the function of Tregs are effective strategies for treating RA. This article reviews the studies on the mechanisms and targeted therapies related to Tregs in RA, with a view to provide better ideas for the treatment of RA.

ASM is a therapeutic target in dermatomyositis by regulating the differentiation of naive CD4 + T cells into Th17 and Treg subsets.

BACKGROUND: This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM. METHODS: Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro. RESULTS: A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80-4.94) ng/mL and 1.64 (1.47-1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins. CONCLUSION: ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target.

Hypouricemia as a novel predictor of mortality in anti-MDA5 positive dermatomyositis patients with ILD: A retrospective cohort study.

OBJECTIVE: Anti-melanoma differentiation-associated gene 5 antibody positive dermatomyositis (MDA5+ DM) is a unique subtype of idiopathic inflammatory myopathy (IIM) that is associated with rapidly progressive interstitial lung disease (RPILD) and high mortality. This retrospective study aimed to identify predictors of mortality and discover novel easily detectable indicators. METHODS: We retrospectively reviewed 183 MDA5+ DM-ILD patients who were from West China Hospital of Sichuan University myositis cohort, the largest single-center cohort of southwest China, from January 2016 to October 2021. Clinical characteristics were reviewed, and risk factors for mortality were determined by univariate and multivariable Cox regression analyses. RESULTS: Of the 183 MDA5+ DM-ILD patients, 59 were presented with RP-ILD, and 53 died during the follow-up period. Compared with the survived patients, deceased patients had higher rates of dyspnea, higher concentrations of CRP, and LDH, but lower rates of heliotrope sign, lower quantity of lymphocyte and lower levels of serum uric acid (SUA). Notably, patients with hypouricemia (SUA <154 µmol/L) had higher concentrations of CRP and LDH, higher neutrophil counts, lower lymphocyte counts and higher mortality rate when compared with the non-hypouricemia group. Multivariate Cox regression analyses confirmed that hypouricemia, smoking, RPILD, high HRCT score, elevated LDH, and lymphopenia were independent risk factors for mortality in MDA5+ DM-ILD patients. Moreover, patients with hypouricemia had significantly lower survival rates than non-hypouricemia patients. CONCLUSION: Our study identified hypouricemia as a non-redundant promising prognostic factor for the mortality of MDA5+ DM-ILD patients, which may hopefully provide insight into the prevention and pathogenesis study.

Repurposed drug agomelatine is therapeutic against collagen-induced arthritis via iNOS targeting.

BACKGROUND: The most promising biologics tumor necrosis factor α (TNFα) inhibitors are effective in treating rheumatoid arthritis (RA) in only 50-70 % of the cases; thus, new drugs targeting TNFα-mediated inflammation are required. METHODS: Firstly, the drugs that could inhibit FLS proliferation and TNFα induced inflammatory cytokine production were screened. Secondly, treatment effects of the identified drugs were screened in collagen-induced arthritis (CIA) mouse model. Thirdly, the inhibitory effect of the identified drug, agomelatine (AOM), on TNFα induced inflammatory cytokine production and NF-κB activity were confirmed. Fourthly, bioinformatics was applied to predict the binding target of AOM and the binding was confirmed, and the already known inhibitor of target was used to test the treatment effect for CIA mouse model. Finally, the effect of AOM on signaling pathway was tested and on TNFα induced inflammatory cytokine production was observed after inhibiting the target. RESULTS: AOM effectively inhibited TNFα-induced NF-κB activation, NF-κB p65 translocation, and inflammatory cytokines production in vitro and was therapeutic against CIA. The mechanistic study indicated inducible nitric oxide synthase (iNOS) as the binding target of AOM. 1400 W, a known inhibitor of iNOS, could effectively treat CIA by decreasing iNOS activity and the levels of inflammatory cytokines. The inhibitory effect of AOM on TNFα-induced inflammation was further elucidated by 1400 W, or NF-κB p65 inhibitor JSH-23, indicating that AOM is therapeutic against CIA via iNOS/ERK/p65 signaling pathway after binding with iNOS. CONCLUSIONS: AOM is therapeutic against CIA via inhibition of the iNOS/ERK/p65 signaling pathway after binding with iNOS.

Predictive modeling of co-infection in lupus nephritis using multiple machine learning algorithms.

This study aimed to analyze peripheral blood lymphocyte subsets in lupus nephritis (LN) patients and use machine learning (ML) methods to establish an effective algorithm for predicting co-infection in LN. This study included 111 non-infected LN patients, 72 infected LN patients, and 206 healthy controls (HCs). Patient information, infection characteristics, medication, and laboratory indexes were recorded. Eight ML methods were compared to establish a model through a training group and verify the results in a test group. We trained the ML models, including Logistic Regression, Decision Tree, K-Nearest Neighbors, Support Vector Machine, Multi-Layer Perceptron, Random Forest, Ada boost, Extreme Gradient Boosting (XGB), and further evaluated potential predictors of infection. Infected LN patients had significantly decreased levels of T, B, helper T, suppressor T, and natural killer cells compared to non-infected LN patients and HCs. The number of regulatory T cells (Tregs) in LN patients was significantly lower than in HCs, with infected patients having the lowest Tregs count. Among the ML algorithms, XGB demonstrated the highest accuracy and precision for predicting LN infections. The innate and adaptive immune systems are disrupted in LN patients, and monitoring lymphocyte subsets can help prevent and treat infections. The XGB algorithm was recommended for predicting co-infection in LN.

Effects of medications on incidence and risk of knee and hip joint replacement in patients with osteoarthritis: a systematic review and meta-analysis

Abstract Background: This systematic review and meta-analysis aimed to investigate the incidence and risk of knee and hip replacement in patients with osteoarthritis (OA) treated with different medications. Methods: OVID MEDLINE, OVID EMBASE, Cochrane and Web of Science electronic databases were searched from inception to May 4th, 2022. Clinical trials, including randomized controlled trials, cohort studies and case-control studies, were selected. The meta-analysis effect size was estimated using either incidence with 95% confidence intervals (CIs) or odds ratio (OR)/relative risk (RR) with 95% CIs. The risk of bias and heterogeneity among studies were assessed and analyzed. Results: Forty studies were included, involving 6,041,254 participants. The incidence of joint replacement in patients with OA varied according to the study design and treatments. The incidence of knee arthroplasty varied from 0 to 70.88%, while the incidence of hip arthroplasty varied from 11.71 to 96.43%. Compared to non-users, bisphosphonate users had a reduced risk of knee replacement (RR = 0.71, 95% CI: 0.66-0.77; adjusted hazard ratio [aHR] = 0.76, 95% CI: 0.70-0.83). Compared to intra-articular corticosteroid users, hyaluronic acid (HA) users had a higher risk of knee arthroplasty (RR = 1.76, 95% CI: 1.38-2.25). No publication bias was observed. Conclusion: Bisphosphonate treatment is associated with a reduced risk of knee replacement. More studies are needed to validate our results due to the limited number of eligible studies and high heterogeneity among studies.