Arthritis Research & Therapy最新文献

Background: Idiopathic inflammatory myopathy (IIM) is a chronic autoimmune disorder characterized by muscle inflammation and weakness. If a muscle is already damaged, muscle strength often fails to restore with current treatments. Although, NADPH oxidase 4 (NOX4) is the main source of reactive oxygen species (ROS) and has been suggested to contribute to the pathogenesis of various disease by inducing ROS production and mitochondrial dysfunction, its role in IIM has not been fully explained.

Methods: Primary myoblasts from IIM patients and non-myopathic controls, as well as human skeletal muscle cells (SkMCs), were cultured under inflammatory conditions induced by interleukin (IL)-15, IL-6, and interferon-gamma (IFN-γ). NOX4 inhibitors, GKT137831 and GLX351322, were administered prior to cytokine stimulation. The effects of NOX4 inhibition were assessed in vitro and in vivo using a C protein-induced myositis (CIM) mouse model.

Results: IIM-derived myoblasts showed impaired myotube formation and elevated NOX4 expression compared to controls. Cytokine stimulation for SkMCs recapitulated key features of inflammatory myopathy, increased NOX4 and myoblast determination protein 1 (MyoD) expression. Treatment with NOX4 inhibitors reduced NOX4 and MyoD levels, restored myotube differentiation, and normalized the elevated oxygen consumption rate (OCR) associated with mitochondrial dysfunction. In the CIM model, NOX4 inhibition significantly reduced muscle inflammation (p < 0.05), preserved muscle mass (p < 0.001), increased cross-sectional area (CSA, p < 0.0001), and improved grip strength (p < 0.01).

Conclusions: We showed that NOX4 is associated with muscle damage in IIM and suggest that its inhibition may have novel therapeutic effect for mitigating muscle damage and disease progression in IIM.

Objectives: Research indicates that low doses of interleukin-2 (IL-2) can effectively mitigate Rheumatoid arthritis (RA) symptoms by promoting Treg cells, while high doses may enhance immune responses and exacerbate the disease. Consequently, this study employed mutated IL-2 to minimize its impact on CD8⁺ T and NK cell activation while preserving its influence on Treg cells.

Methods: We used a previously published mutation sites to construct the murine IL-2 mutants by overlap PCR. Then we assessed its impact on the proliferation and functionality of Treg cells by flow cytometry and PCR. The synergistic effects of mutated IL-2 and MSC on collagen-induced arthritis (CIA) in mice were evaluated through the infusion of lentiviral-transduced umbilical cord-derived mesenchymal stromal cell (UC-MSC) for CIA treatment and through pathological section staining to assess inflammatory joint injury, cartilage destruction, and osteoclast infiltration.

Results: Mutant IL-2 demonstrated targeted enhancement of both the proportion and proliferative activity of Treg cells with a diminished capacity to stimulate the proliferation of CD8⁺ T cells and NK cells relative to wild-type IL-2. Moreover, MSC-mutant IL-2 significantly augmented the proportion of Treg cells compared to either MSC or mutant IL-2 in isolation. Treatment with MSC-mutant IL-2 infusion in CIA mice ameliorated arthritis symptoms and reduced inflammatory infiltration and cartilage damage in their joints.

Conclusion: Mutant IL-2 enhances Treg function and proliferation while exerting reduced effects on CD8⁺ T and NK cell activation. MSC expressing mutant IL-2 demonstrates therapeutic benefits in CIA by increasing the proportion of Treg cells and reducing the proportion of CD8⁺ T cells.

Background: Evidence on the association between sleep disorders and rheumatoid arthritis (RA) remains limited. This study aimed to investigate this relationship in U.S. adults using data from the National Health and Nutrition Examination Survey (NHANES).

Methods: This cross-sectional study included adults aged ≥ 18 years from the 2005-2018 NHANES cycles. A total of 28,040 participants were included. Weighted multivariate logistic regression models were employed to assess the association between sleep disorders and RA. Three models were constructed: an unadjusted model, a minimally adjusted model controlling for demographic variables, and a fully adjusted model incorporating additional lifestyle and clinical covariates. Subgroup analyses were performed to assess the consistency of associations across different population strata, and sensitivity analyses were conducted to confirm the robustness of the results.

Results: Of the 28,040 participants, 4168 (14.32%) were identified as having sleep disorders, and 1589 (4.28%) reported having RA. In the fully adjusted model, sleep disorders were significantly associated with increased odds of RA (OR = 1.76, 95% CI: 1.46-2.13, P < 0.001). Subgroup analyses showed that this positive association persisted across all examined strata, with no significant interactions (P for interaction > 0.05).

Conclusions: In conclusion, our findings indicate a statistically significant association between sleep disorders and the prevalence of RA in U.S. adults. However, given the limitations of the cross-sectional design, causal inferences cannot be made. Future longitudinal and mechanistic studies are warranted to clarify the temporal direction and biological pathways underlying this association.

Objectives: Peripheral helper T (Tph) cells, a recently identified Th cell subset, have been implicated in various autoimmune diseases. However, their role in granulomatosis with polyangiitis (GPA) remains unclear. This study aimed to investigate the potential clinical significance of circulating Tph cells (cTph) in GPA.

Methods: Peripheral blood mononuclear cells were collected from 74 remission GPA-patients, 26 active GPA-patients and 22 age- and sex-matched healthy controls. Flow cytometry was used to quantify cTph cells and their subset distribution. Single-cell multi-omics profiling was performed in an independent cohort (5 remission GPA-patients, 5 active GPA-patients and 5 healthy controls). Plasma IL-21 levels were measured by enzyme-linked immunosorbent assay, and associations between cTph cells and clinical parameters were evaluated.

Results: active GPA-patients showed an increased frequency and absolute number of cTph compared to remission GPA-patients, and both GPA groups exhibited cTph2-skewed distribution compared to healthy controls. Remission GPA-patients with generalized disease exhibited higher cTph frequencies than those with localized disease. cTph cells from active GPA-patients displayed an activated phenotype and a transcriptional profile marked by pro-inflammatory and survival-associated genes. Plasma IL-21 levels did not differ significantly between the three groups. Notably, absolute counts of memory cTph and cTph2 cells correlated positively with clinical markers of disease activity, and were significantly elevated in GPA patients with higher cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) titers.

Conclusions: cTph cells are expanded and exhibit an activated, pro-inflammatory profile with a cTph2-skewed distribution in active GPA-patients. Their association with disease activity may support a potential role in disease pathogenesis and highlight their potential as therapeutic targets, warranting further investigation.

CAR-T cells (CAR-Ts) are genetically engineered T lymphocytes to express a receptor construct bearing an extracellular recognition domain that guides the killing specificity, a transmembrane domain, and an intracellular domain that elicits effector signaling. Upon encountering the target cell, CAR-Ts accomplish their cytolytic effector function directly via engagement of pro-apoptotic pathways and exocytosis of perforin and granzymes, or indirectly via secretion of cytokines that activate NK cells. Autologous CAR-Ts, bearing an extracellular recognition domain specific for the B-cell surface markers CD19 or BCMA, were initially approved for the treatment of late-stage hematologic malignancies. The last five years, mounting evidence from small studies in humans, employing autologous CAR-Ts targeting CD19 to selectively eliminate CD19 + cell subsets from the pool of the B-cell lineage, have revealed acceptable safety profile and encouraging efficacy in treatment-resistant systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myositis. Herein, we focus on a series of groundbreaking reports published within 2025 that enlighten the arising transformational potential and the emerging challenges of the CAR-based therapies regarding the management of life-threatening endotypes of autoimmune diseases.

Background: Osteoarthritis (OA) is a chronic degenerative joint disease driven by multifactorial causes, including aging, mechanical stress, and inflammation. Mechanical loading through exercise can either exacerbate or alleviate OA symptoms depending on intensity. Substance P (SP), a neuropeptide involved in inflammation and mechanotransduction, has been implicated in cartilage and bone remodeling. This study aimed to investigate how SP deficiency plus exercise intensity interact to influence disease progression in a surgical murine OA model.

Methods: OA was induced in male wild-type (WT) and SP knockout (Tac1-/-) mice via destabilization of the medial meniscus (DMM). Mice were then exposed to moderate or intense treadmill exercise for up to eight weeks. Cartilage degeneration was assessed histologically using OARSI scoring. Cartilage stiffness was evaluated via atomic force microscopy (AFM), and subchondral and metaphyseal bone morphology was analyzed by high-resolution nanoCT. Serum cytokine levels were measured with multiplex ELISA.

Results: DMM surgery induced OA-like cartilage damage in most groups, and moderate exercise failed to prevent degeneration. However, SP-deficient mice subjected to intense exercise showed preserved cartilage matrix stiffness and morphology comparable to Sham controls. In contrast, SP deficiency as well as intense exercise promoted meniscal ossification and subchondral bone sclerosis, with increased bone volume fraction and trabecular thickness. These changes were consistent with prior findings in SP-deficient mice without exercise. Serum analysis revealed elevated levels of proinflammatory cytokines (e.g., CXCL10, VEGF-A, CCL2, CCL4) in SP-deficient mice after Sham surgery, although these did not correspond to the cartilage degradation timeline.

Conclusions: SP plays a dual role in OA pathogenesis: its absence may protect cartilage from mechanical stress-induced stiffening but also promotes ectopic meniscal ossification and subchondral bone alterations. Additionally, SP appears to modulate systemic inflammatory responses independently of joint degeneration. These findings position SP as a key regulator of neuroimmune and mechanobiological processes in OA and highlight its potential as a therapeutic target for load-induced joint pathology.

Objectives: Mixed connective tissue disease (MCTD) is characterized by positivity for anti-U1-RNP antibodies and a combination of symptoms of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and inflammatory myositis (IIM). The aim of this study was to elucidate the similarities and differences in gene expression profiles of peripheral blood immune cells between MCTD and its related diseases, as well as their association with clinical parameters.

Methods: Transcriptome analysis was performed in peripheral blood immune cells from 19 MCTD patients, 58 SLE patients, 63 SSc patients, 64 IIM patients, and 79 healthy controls (HC), comprising a total of 283 individuals across 27 immune cell subsets. Differential gene expression and enrichment analyses were conducted to compare MCTD with related diseases and HC. The association between dysregulated pathways in MCTD and clinical parameters was assessed. Gene modular and machine learning analyses were employed to identify related gene signatures in other immune cells.

Results: MCTD exhibited a higher number of differentially expressed genes (DEGs) in Th1 cells compared to other related diseases and HC. Although the DEGs between MCTD and SLE were limited, Th1 cells in MCTD shared common DEGs with each disease, and enrichment analysis revealed upregulation of cell cycle pathways in MCTD Th1 cells. This gene signature showed upregulation in high disease activity and in anti-U1-RNP antibody positive patients in related diseases, and it was associated with severity of Raynaud's phenomenon. Furthermore, the Th1 cell cycle signature correlated with interferon signature in other immune cells.

Conclusions: Transcriptome analysis of peripheral blood immune cells revealed that MCTD Th1 cells share many transcriptional features with those in SLE, yet display distinctive cell cycle signature. Particularly, upregulation of cell cycle pathways was associated with characteristic clinical features of MCTD, such as positivity for anti-U1-RNP antibodies and Raynaud's phenomenon. This Th1 cell cycle signature holds promise for shedding light on the underlying pathophysiology of MCTD.

Objective: To evaluate maternal-fetal outcomes and therapeutic efficacy in Takayasu arteritis (TA)-complicated pregnancies through integrated retrospective analysis and meta-analytic synthesis.

Methods: A dual-design study was conducted: (1) retrospective analysis of 20 pregnancies (17 patients) at West China Second Hospital (2012-2024), stratifying TA phases (acute/prolonged/stable); (2) systematic review with random-effects meta-analysis of 16 studies (568 pregnancies globally). Clinical data encompassed maternal-fetal profiles, TA-specific variables, laboratory metrics (hematologic/coagulation parameters), and therapies (glucocorticoids /immunosuppressants /antihypertensives). Outcomes were compared against normative standards using t-tests, Wilcoxon, chi-square, and meta-regression.

Results: Among 20 pregnancies (median maternal age 28.5 years), 50% had at least one obstetric complication, with arterial stenosis (80%) and hypertension (40%) predominant. Meta-analysis revealed 42.6% adverse outcomes: gestational hypertension (26.1%), fetal growth restriction (17.7%), and preterm delivery (13.6%). Hematological analysis (n = 20) showed elevated WBC, PCT, TT, fibrinogen, urinary protein, and ALT (all P < 0.05), alongside reduced PT, albumin, and bilirubin (P < 0.05). Regarding the analysis results of inflammatory indicators, CRP (prepartum) (95%CI = 0.969-1.034, OR = 1.001), CRP (postpartum) (95%CI = 0.920-1.217, OR = 1.058), and ESR (95%CI = 0.952-1.101, OR = 1.024) showed no statistically significant association with pregnancy outcomes. Neither pre-pregnancy nor gestational glucocorticoids (prednisone vs methylprednisolone) or immunosuppressants significantly reduced complications (all RR 95% CI crossed 1; P > 0.05). Antihypertensive therapy showed no correlation with preeclampsia (P > 0.05).

Conclusion: TA significantly elevates maternal-fetal risks, driving hypertension, growth restriction, and preterm birth via vasculopathic-inflammatory pathways. Postpartum hypercoagulability (↑fibrinogen, ↓prothrombin time) necessitates multidisciplinary coagulation monitoring and mandatory thromboprophylaxis.

Background: The C-X-C motif chemokine 12 (CXCL12) and its receptor CXCR4 are pivotal in tissue regeneration and inflammation, yet their role in osteoarthritis (OA) remains ambiguous. However, it is assumed that the CXCL12/CXCR4 axis likely contributes to OA progression through subchondral bone-cartilage crosstalk. This study compares the efficacy of the CXCR4 inhibitors AMD31000 and novel endogenous peptide inhibitors in human cartilage and isolated chondrocytes (hAC).

Methods: Human cartilage and hAC were obtained from OA patients undergoing arthroplasty. Expression of both CXCL12 receptors CXCR4 and ACKR3, were assessed by immunohistology and qRT-PRC. The effects of CXCR4 inhibitors, including AMD3100, EPI-X4, and its derivative EPI-X4 JM#21, were evaluated regarding cell viability, migration, chondrogenic and osteogenic differentiation, and proliferation of chondrocytes in presence of 200 ng/mL CXCL12.

Results: The current data demonstrate that CXCR4 is significantly upregulated in OA cartilage and senescent chondrocytes, while ACKR3 expression remains largely unchanged. CXCR4 inhibition had no detrimental effects on chondrocyte viability, proliferation, or chondrogenic differentiation potential but effectively reduced CXCL12-induced cell migration. EPI-X4 JM#21 emerged as a potent CXCR4 antagonist and ACKR3 agonist, outperforming AMD3100 in suppressing chondrocyte migration. Although CXCR4 was significantly upregulated during osteogenic differentiation of hAC, the inhibition of the receptor had no effect on calcium deposition.

Conclusions: These findings suggest that EPI-X4 JM#21 may represent potential alternative to AMD3100 for targeting the CXCL12/CXCR4 pathway in OA, warranting further in vivo validation.