Arthritis Research & Therapy最新文献

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.

Background: The development of personalized approaches in psoriatic arthritis (PsA) is challenging due to unclear patient phenotypes and trajectories. Machine learning (ML) could help to identify homogeneous patient groups. The objective of this analysis was to classify patients with PsA into distinct phenotypes using ML.

Methods: A post hoc analysis of PsA patients treated with risankizumab for ≤ 4 years (196 weeks) from KEEPsAKE 1 and KEEPsAKE 2. The phenotypes were based on baseline demographics and clinical characteristics using unsupervised ML (a finite mixture model). Response to risankizumab at 4 years was defined as minimal disease activity (MDA) and Disease Activity in PsA (DAPSA) low disease activity (LDA).

Results: A total of 1119 patients were classified into 5 distinct PsA phenotypes: Moderate to High Disease Activity (40.3% of patients) - characterized by lower tender joint count (TJC) and swollen joint count (SJC), dactylitis, and enthesitis; Enthesitis and Large Joints Dominant (20.8% of patients) - characterized by enthesitis and mainly active large joints; Very High Disease Activity (14.0% of patients) - characterized by high TJC/SJC, dactylitis, and enthesitis; Hand Dominant (13.8% of patients) - characterized by active joints primarily in the hands; Dactylitis and Feet Dominant (11.1% of patients) - characterized by dactylitis and active joints primarily in the feet. At 4 years, risankizumab demonstrated efficacy across all phenotypes (MDA and DAPSA LDA; range: 42.9% to 58.8% of patients and 66.0% to 82.0% of patients, respectively), with highest responses observed in the Moderate to High Disease Activity and Dactylitis and Feet Dominant phenotypes.

Conclusions: Five distinct PsA phenotypes were identified in patients starting risankizumab. Moderate to High Disease Activity, the most frequent phenotype, showed the highest response, though risankizumab demonstrated efficacy across all phenotypes. These results are a first step toward more personalized medicine for patients with PsA.

Trial registration: ClinicalTrials.gov: KEEPsAKE 1, NCT03675308; KEEPsAKE 2, NCT03671148.

Background: Birth outcomes associated with conventional synthetic and biologic disease-modifying antirheumatic drugs (csDMARDs, bDMARDs and tsDMARDs) in fathers with autoimmune rheumatic diseases (AIRDs) is not well understood.

Methods: To examine the impact of paternal exposure to csDMARDs, bDMARDs or tsDMARDs on birth outcomes of offspring, specifically with regards to small for gestational age infants, preterm labor, and congenital abnormalities. We constructed a population-based birth cohort with fathers diagnosed with AIRDs from 2004 to 2020 using data from the Maternal and Child Health Database, Taiwan Birth Certificate Registry, and Taiwan National Health Insurance Research Data. Paternal preconception exposure was fathers who had been prescribed immunosuppressants or biologic drugs between 38 and 60 weeks before their newborn's delivery date. Inverse probability of treatment-weighted (IPTW) logistic regression models were used to assess the effects of variables on associations of interest considering other covariates.

Results: The study analyzed 42,493 births to fathers with autoimmune conditions, with 14.3% of fathers exposed to immunosuppressants or biologic medications during the preconception period. The IPTW logistic regression analysis showed drug-specific risks during the preconception in preterm birth, birth defects, or very small for gestational age (VSGA). Individually, methotrexate showed no adverse effect on birth outcomes. However, certain medications, such as ciclosporin was associated with an increased risk of VSGA and preterm by 45% (95% confidence interval [CI] = 1.19 ~ 1.76) and 51% (95% CI = 1.35 ~ 1.70) respectively. Azathioprine (OR = 1.47, 95% CI = 1.31 ~ 1.65) was linked to higher birth defect risks, as were non-TNFis (OR = 1.69, 95% CI = 1.48 ~ 1.93) and tsDMARDs (OR = 5.19, 95% CI = 2.33 ~ 11.39). Fathers who received csDMARDs alone or combined with bDMARDs or tsDMARDs had an increased risk of birth defects (OR = 1.71, 95% CI = 1.47-2.00). Specific birth defects associated with bDMARDs included cardiovascular anomalies (OR: 1.61; 95% CI: 1.37-1.89), oral clefts (OR: 1.62; 95% CI: 1.15-2.29), and musculoskeletal defects (OR: 2.29; 95% CI: 1.82-2.89). Fathers exposed to csDMARDs combined with bDMARDs or tsDMARDs had increased risks of cardiovascular anomalies, oral clefts, and musculoskeletal defects.

Conclusion: While paternal use of methotrexate did not associate with adverse birth outcome, exposure to other immunosuppressants or biologic drugs may link to possible adverse birth outcomes despite small event numbers. This result highlight the importance of further clarification of drug safety in this field and medication use before planning a pregnancy, even in male patients.

Background: Bacterial (i.e., septic) arthritis requires prompt source control, including drainage of the infected synovial fluid, often through arthrocentesis (needle aspiration) or surgical intervention, in combination with antibiotics to prevent joint damage; however, when surgical intervention is required, conventional arthroscopy can lead to treatment delays and anesthesia-related complications. To overcome these delays, needle arthroscopy was recently developed to offer the possibility of 2-mm diameter arthroscopy lavage under local anesthesia. The purpose of this study was to prospectively evaluate bedside needle arthroscopy under local anesthesia to demonstrate its potential as an effective, minimally invasive alternative for timely diagnosis and joint lavage in patients with (suspected) native bacterial arthritis in a real-world clinical practice setting.

Methods: Over a 30-month period, this prospective, double center cohort study included patients with either confirmed (positive synovial fluid culture) or highly suspected (≥ 2 local signs and ≥ 1 systemic sign) native joint bacterial arthritis. The primary outcome was the need for reoperation (conventional arthroscopy or arthrotomy) within 30 days. Bivariate analysis assessed differences in patient and treatment characteristics between successful and failed needle arthroscopic debridement.

Results: Forty-two patients (44 native joints) underwent needle arthroscopy. The mean age was 67 years (SD 16), the mean BMI was 26.8 kg/m² (SD 3.9), and 69% were male. The knee (n = 34, 77%) was the most commonly involved joint. Within 30 days, 14% (6/44; 95% CI 5-27%) required a reoperation (conventional arthroscopy or arthrotomy). Two parameters were identified as risk factors for failure of a single debridement: the baseline level of ESR (112 mm/hr vs. 57 mm/hr, p = 0.027) and purulent synovial fluid (67% vs. 11%; p = 0.011). No serious procedure-related complications were observed.

Conclusions: A single bedside needle arthroscopy was effective in treating 86% of patients with confirmed or suspected native joint bacterial arthritis in a real-world practice, avoiding the need for general anesthesia or conventional surgery. This approach represents a safe and effective, minimally invasive alternative that can be rapidly implemented, enabling early joint lavage and potentially reducing the risk of secondary osteoarthritis.

Trial registration: We pre-registered this trial on the Dutch Trial Register, later called CCMO (NTR 21076, CCMO NL78387.018.21).

Background: Osteoarthritis (OA) is the leading cause of pain worldwide. However, clinical discordance between pain and cartilage damage presents challenges in determining the mechanisms of OA pain, thus creating a need for well-controlled models that probe the separable mechanisms of structural damage and knee pain. We previously identified that deletion of complement factor D (FD) results in increased pressure-pain hyperalgesia despite cartilage protection after destabilization of the medial meniscus (DMM) surgery. However, how these discordant OA phenotypes manifest is not understood. We employed a novel targeted lipidomics approach to elucidate the role of eicosanoids in FD-mediated pain. We hypothesize that the absence of Cfd (FD^-/-) will protect cartilage but cause increased pressure-pain hyperalgesia and eicosanoid dysregulation persisting throughout OA development.

Methods: Male and female FD^-/- and wild-type (WT) mice were challenged with DMM or remained naïve at 16 weeks old. Pressure-pain hyperalgesia was measured every two weeks for 8 weeks post-DMM. A second cohort was evaluated at 2 weeks post-DMM to investigate DMM injury response. Structural damage was scored using the Modified Mankin system. Eicosanoid profiles were characterized via liquid chromatography-mass spectrometry (LC-MS) on serum and synovial fluid samples. Statistical analysis was performed with unpaired t-test or two-way ANOVA with Sidak's posthoc test, p < 0.05.

Results: Unlike WT mice, FD^-/- mice exhibited no differences in Modified Mankin scores 8 weeks post-DMM in both sexes. As expected, FD^-/- and WT hyperalgesia was present at 2 weeks, persisted through 8 weeks, and was not associated with knee structural changes. Despite both sexes exhibiting similar levels of hyperalgesia, eicosanoid profiles differed. Male FD^-/- demonstrated greater pain-driving (12-HETE, 13-HODE) and lower pain-driving (15-HETE) and pain-suppressing (14-HDHA) abundances of eicosanoids compared to WT. Paradoxically, female FD^-/- exhibited bi-directional differences in pain-suppressive factors (palmitoyl ethanolamide, EPA, 14-HDHA) and lower abundances of pro-inflammatory arachidonic acid compared to WT.

Conclusion: The absence of Cfd protects cartilage but does not prevent hyperalgesia after DMM. Changes in eicosanoid profiles suggests that loss in FD drives pain acutely and creates a hyperalgesia phenotype early in response to DMM. Eicosanoid profiling is a novel tool to mechanistically determine pain drivers in osteoarthritis.