Public involvement is standard practice to enhance the quality, equity and impact of musculoskeletal pain research. In this review, we aimed to reflect on our own learning journey across multiple musculoskeletal projects and identify lessons learned from meaningful involvement. We then consider the changes needed at the researcher, funder and institutional levels to support involvement as a driver of relevance and impact. This is a narrative position paper drawing on experiential learning from three musculoskeletal pain studies and ongoing community engagement. We reflected on what we have learned from public contributors in our research, focusing on how involvement reshaped study priorities and tools. Lessons were synthesised to highlight recurring themes, supported by reference to reviews, guidance and empirical studies. Across all projects, several key themes emerged: (1) emphasis on purpose rather than process; (2) co-production and partnership rather than review; (3) flexibility and adaptation rather than predetermined steps; (4) relevant public contributors and partners; (5) focus on 'learning' rather than 'doing'; and (6) approaches to diversity and inclusion. Public partnerships should be a collaborative, transformative, relational and learning-based process that reshapes all aspects of research. Realising this potential might require flexible funding for early engagement, training in facilitation and reflexivity, sustained support beyond the research project to promote impact, and taking steps beyond building more infrastructure towards strengthening the systems that enable involvement to work effectively. Working together to improve muscle, joint, and bone pain research through shared learning This paper looks at how public partners (patients, service users, carers and members of the public with relevant lived experience) are involved in research on conditions affecting pain, muscles, bones, and joints. Involving the public in research is now widely expected. Not only does this approach ensures that research genuinely reflects the priorities of the public, but it also shapes the research question and methods to ensure relevance, thereby increasing the likelihood that the findings are meaningful and usable in the real-world. It ensures that research is conducted for the benefit of the public with public input. Involvement is not always meaningful. From our experience, we found that when involvement was genuine and followed the principles of good practice, it not only reshaped the research and tool design but also provided clearer pathways to end-user benefit, underpinned by continuous two-way learning. As we reflect on working with public partners as equals in co-creating our research, it has not only shaped the research to ensure it aligns with our public partners’ priorities, but it has also shaped us as researchers. As researchers, we also face challenges: we must learn to negotiate with public partners as equals and need appropriate support, such as flexible funding, to respond effectively to their knowledge and expertise.
Evidence-based practice guidelines recommend combining the long-term use of opioids for chronic noncancer pain (CNCP) with suitable nonpharmacologic treatments. Whether long-term opioid therapy (LTOT) in Germany aligns with these recommendations is unknown so far. Therefore, our objective was to determine the use of nonpharmacologic treatments among patients receiving LTOT for CNCP. The retrospective observational analysis was based on administrative claims data of the German statutory health insurance fund DAK-Gesundheit. Patients with LTOT and no cancer diagnosis were selected between January 2018 and June 2019. The utilization of nonpharmacologic treatments, including physical therapy, psychotherapy, lifestyle modification, and other inpatient and outpatient treatments, was examined over a two-year period. Subgroup analyses were conducted by age, preindex opioid prescriptions (≥ 1 year vs < 1 year), and the presence of ICD-10 diagnoses, including osteoarthritis, chronic back pain, inflammatory rheumatic diseases (excluding rheumatoid arthritis), neuropathy/polyneuropathy, radiculopathy, and chronic pain disease. Additionally, regression analyses were performed to examine the association between diagnostic groups and the utilization of treatments. A total of 113,476 patients met the inclusion criteria, of whom 25,945 (23%) did not utilize any of the defined nonpharmacologic treatments during the two-year observation period. The most frequently utilized treatment was physical therapy (62%). Psychotherapy was used by 7% of patients, outpatient special pain therapy by 16%, whereas lifestyle modification (relaxation exercises and nutrition therapy) was used by fewer than 30 patients. Patients with ≥ 1 year of opioid prescriptions prior to inclusion and elderly patients utilized most treatments less frequently. Over the 2-year period, treatment provision remained largely constant, except for a steady decline in physical therapy for patients who had initiated opioid therapy more recently. Except for chronic pain disease, certain diagnoses were only weakly associated with treatment utilization. Contrary to guideline recommendations, a notable proportion of LTOT patients may not receive pain management combining opioid therapy with nonpharmacologic treatments, particularly elderly patients and those with longer treatment duration. Future research should examine reasons for the low use of nonpharmacologic treatments. German Clinical Trials Register: DRKS00024854.
Chronic kidney disease is a common comorbidity of rheumatoid arthritis. Because there has been scarce and conflicting evidence on the use of biological and targeted synthetic therapy in patients with rheumatoid arthritis and chronic kidney disease, we aimed to examine the effectiveness and persistence of biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs) for patients with rheumatoid arthritis and chronic kidney disease. This multicentre, prospective cohort study used data from the CorEvitas Rheumatoid Arthritis registry on patients with rheumatoid arthritis who initiated each type of biological and targeted synthetic DMARD (TNF inhibitors, CTLA4 immunoglobulin, IL-6 inhibitors, B-cell depletion therapy, and JAK inhibitors) recruited from 160 rheumatology practices in the USA. Patients were required to have moderate or high disease activity according to the Clinical Disease Activity Index (CDAI; score >10). Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1·73 m2 at biological or targeted synthetic DMARD initiation. The primary outcome was the attainment of remission according to CDAI score. Propensity scores were used for overlap weighting to improve the balance of characteristics for patients with and without reduced eGFR. Cox regressions estimated the unadjusted and adjusted hazard ratio (HR) of reduced eGFR for CDAI-based remission. People with lived experience of rheumatoid arthritis were not involved in the study design or conduct. Between Oct 1, 2001, and Dec 31, 2023, 12 123 biological and targeted synthetic DMARD treatment initiations in 9601 patients with rheumatoid arthritis, with 51 931 person-years of follow-up, were identified. Of 12 123 eligible biological and targeted synthetic DMARD treatment initiations, 10 857 (89·6%) were in patients with preserved eGFR and 1266 (10·4%) were in patients with reduced eGFR. Across both groups, median age was 59·0 years (IQR 50·0-67·0), 9720 (80·2%) of 12 123 treatment initiations were in female patients and 2403 (19·8%) were in male patients, and 9908 (81·7%) were in non-Hispanic White patients. 3025 (27·9%) of 10 857 treatment initiations in patients with preserved eGFR resulted in CDAI-based remission versus 246 (19·4%) of 1266 treatment initiations in patients with reduced eGFR. Reduced eGFR was associated with a lower likelihood of attaining CDAI-based remission (unadjusted HR 0·71 [95% CI 0·62-0·82], adjusted HR 0·76 [0·66-0·88]) compared with preserved eGFR. Although biological and targeted synthetic DMARDs are generally well tolerated and effective options, patients with rheumatoid arthritis and reduced eGFR have lower likelihood of attaining remission. Tailored treatment strategies for this high-risk population should be established. National Institute of Arthritis and Musculoskeletal and Skin Diseases.
Postmenopausal women with rheumatoid arthritis (RA) experience worsening functional decline, independent of disease activity. Estrogen replacement therapy (ERT) has been proposed to mitigate musculoskeletal deterioration, but its role in RA remains unclear. This study investigated the association between ERT use and physical function in postmenopausal women with RA. This longitudinal study analyzed data from Forward, the National Databank for Rheumatic Diseases (2000-2022). Postmenopausal women with RA who initiated ERT were matched 1:1 to non-users based on menopause year or ERT initiation. The primary outcome was physical function, assessed using the Health Assessment Questionnaire (HAQ). Generalized estimating equations (GEE) were used to evaluate the association between ERT and HAQ scores, adjusting for demographics, reproductive history, RA duration, comorbidities, and medication use. Sensitivity analyses with propensity score matching were conducted. A total of 8,246 women were included, with 4,123 ERT users matched to non-users. ERT use was associated with modestly improved HAQ scores (β = -0.02, 95% CI -0.03, -0.01; p< 0.001). Later menopause correlated with better function (β = -0.008 per year after menopause, 95% CI -0.03, -0.01; p< 0.001). Women initiating ERT within five years of menopause demonstrated greater benefits. Sensitivity analyses using propensity score adjustment confirmed these findings and revealed additional improvements in patient-reported outcomes (PROs). ERT use was modestly associated with improved physical function and other PROs in postmenopausal women with RA, with the greatest benefits seen in early postmenopausal initiation. No excess crude rates of cardiovascular or cancer events were observed. Further research is needed to determine the clinical implications of ERT in RA management.
Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory disease affecting peripheral and axial joints, entheses, skin, and nails, requiring coordinated multidisciplinary management. Since the 2018 edition of ESPOGUÍA, significant advances-including the availability of IL-17A/F, IL-23, and JAK inhibitors, as well as emerging evidence regarding axial PsA-have prompted the need for an updated guideline. The 2024 ESPOGUÍA provides evidence-based recommendations for the diagnosis and management of PsA, integrating multidisciplinary collaboration, active nursing participation, lifestyle counseling, and specific considerations for axial disease. A panel comprising rheumatologists, dermatologists, gastroenterologists, ophthalmologists, nurses, methodologists, and patient representatives formulated clinical questions using the Population, Intervention, Comparator, and Outcomes (PICO) framework. Systematic literature reviews were performed, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was applied to critically assess the quality of evidence and guide the formulation of recommendations. The guideline emphasizes early intervention and the appropriate use of conventional synthetic DMARDs, biologic therapies, and JAK inhibitors across different disease domains, including the management of extra-musculoskeletal manifestations. Lifestyle measures, such as smoking cessation and weight management, are highlighted due to their demonstrated impact on disease activity and long-term outcomes. The essential role of specialized rheumatology nurses in patient education, treatment adherence, and counseling on modifiable risk factors is also underscored. ESPOGUÍA 2024 provides a comprehensive, multidisciplinary, and patient-centered framework for PsA management, including axial involvement, and identifies persistent gaps in early diagnosis, biomarker development, and long-term outcomes, thereby outlining priorities for future research. Diagnosing and Treating Psoriatic Arthritis: Highlights from the 2024 Spanish Clinical Guidelines Psoriatic arthritis (PsA) is a long-term inflammatory disease that can affect the joints, spine, skin, nails, and enthesis. Symptoms and disease severity vary widely, so many people with PsA need care from several healthcare professionals working together. Since the last Spanish clinical guideline was published in 2018, major advances have been made in PsA treatment. New targeted medicines are now available, and there is better understanding of PsA that affects the spine (axial PsA). These changes led to an update of the guideline. The 2024 ESPOGUÍA guideline provides clear, evidence-based recommendations for diagnosing and managing PsA. It emphasizes multidisciplinary care, including the important role of nurses, and highlights the value of healthy lifestyle habits such as stopping smoking and maintaining a healthy weight. The guideline also includes specific advice for people with spinal involvement. A multidisciplinary group of doctors, nurses, researchers, and patient representatives developed the guideline using internationally accepted methods. They reviewed the best available scientific evidence and assessed its quality before making recommendations. The updated recommendations focus on early diagnosis and timely treatment to reduce symptoms and prevent long-term damage. They cover the use of conventional treatments, biological therapies, and newer targeted drugs, depending on individual disease features. Conditions affecting organs beyond the joints are also addressed. Specialized rheumatology nurses are recognized as key members of the care team, supporting patient education, treatment adherence, and lifestyle counselling. Overall, ESPOGUÍA 2024 offers a comprehensive, patient-centred approach to psoriatic arthritis care and identifies priorities for future research, including earlier diagnosis and better long-term outcomes.
暂无摘要（点击查看详情）
This research focuses on exploring the modulation of pyroptosis and its underlying mechanisms via the "Tianyu" formulation (TY), a traditional Chinese medicine, in human rheumatoid arthritis fibroblast-like synovial cells (RA-HFLS) and a collagen-induced arthritis (CIA) rat model. In vitro, RA-HFLS cells were induced with tumor necrosis factor α (TNF-α). Cell viability, proliferation, migration, and invasion were assessed using CCK-8, EdU, and Transwell assays, respectively. Pyroptosis was evaluated by flow cytometry, acridine orange/ethidium bromide (AO/EB) staining, and by measuring the release of lactate dehydrogenase (LDH) and inflammatory factors (interleukin [IL]-1β, IL-18, TNF-α) in the cell culture supernatants. The expression of pyroptosis-related mRNAs and proteins was examined by RT-qPCR, immunofluorescence, and Western blotting. For in vivo analysis, a CIA rat model was established. Joint swelling was evaluated using arthritis scores and paw volume measurements, while histopathological changes in the joint tissues were examined by hematoxylin and eosin (HE) staining and Safranin O-Fast Green staining. Serum levels of autoantibodies (anti-CCP, RF), LDH, and inflammatory cytokines (IL-1β, IL-18, TNF-α) were quantified concurrently. Furthermore, the expression of pyroptosis-related molecules in joint tissues was determined using RT-qPCR, immunohistochemistry, and Western blot analysis. The major components of TY were identified by UHPLC-Q Exactive HFX. Subsequently, molecular docking simulations were performed to evaluate the binding affinities of the main bioactive compounds to the NLRP3, Caspase-1, and GSDMD proteins. In vitro experiments showed that TY significantly reduced the viability, proliferation, migration, and invasion abilities, as well as the LDH levels of TNF-α-induced RA-HFLS cells, and decreased the levels of IL-1β, IL-18, and TNF-α in the supernatant. Additionally, TY downregulated the expression of key proteins involved in pyroptosis mediated by the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome. In the CIA rat model, TY treatment alleviated arthritis symptoms, reduced paw swelling and bone erosion, improved joint pathology, decreased serum levels of IL-1β, IL-18, and TNF-α, and suppressed the expression of key proteins involved in the NLRP3 inflammasome-mediated pyroptosis pathway in synovial tissue. A total of 95 compounds belonging to 16 classes were identified from TY in both positive and negative ion scanning modes. These included 42 phenylpropanoid and polyphenolic compounds, as well as 12 organic oxides. Molecular docking showed that all five major compounds (Apigenin, Isorhamnetin, Kaempferol, Quercetin, and Salidroside) bound well to NLRP3, Caspase-1, and GSDMD, with all binding energies below -5 kcal/mol. Among them, Quercetin exhibited the highest affinity for GSDMD (-9.1 kcal/mol). By regulating the NLRP3/Caspase-1/GSDMD pathway, TY alleviates joint inflammation in CIA rats and reduces pyroptosis in RA-HFLS cells.
Current treatments for rheumatoid arthritis (RA) and psoriatic arthritis (PsA) reduce disease activity but often fail to achieve sustained remission. The Decision on Optimal Combinatorial Therapies in Immune-mediated inflammatory diseases using Systems approaches (DocTIS) program has shown that additive anti-inflammatory effects in patients with arthritis can be achieved by combining tumour necrosis factor (TNF) and interleukin (IL)-6 inhibitor therapies. The goal was to provide proof-of-principle evaluation of whether combining TNF and IL-6 inhibitors shows a signal of activity on remission outcomes in RA and PsA. This is a single-arm, multicentre, adaptive basket trial recruiting 20 patients with RA and 20 with PsA and including 24 weeks of treatment and 10 weeks of safety follow-up. Eligible participants on TNF for ≥6 weeks will proceed with the addition of IL-6 inhibitor (tocilizumab) at 162 mg every 2 weeks for 8 weeks, increasing to weekly dosing in weeks 9-24 if well tolerated. The primary outcome is remission at 24 weeks (Clinical Disease Activity Index score ≤2.8 in RA and Disease Activity in PsA score <4). Secondary outcomes include safety, tolerability and disease activity assessments. Using Simon's two-stage design (80% power, one-sided α = 0.10), the trial aims to detect an increase in remission (10% to 30%). An interim futility analysis will occur after seven participants per basket reach 24 weeks. Findings from this proof-of-principle study will inform the feasibility and design of future randomised trials evaluating combination biologic therapy in inflammatory arthritis. www.isrctn.com; ISRCTN50666516.
Rheumatoid arthritis (RA) is a prevalent autoimmune disease affecting approximately 1% of the global population, which significantly increases the risks of cardiovascular disease (CVD). RA-associated cardiovascular risks, such as pericarditis, myocarditis, heart failure, myocardial infarction, arrhythmias, atherosclerosis, and endothelial dysfunction, are major contributors to mortality in RA patients. These risks are driven by a complex interplay of chronic immune-inflammatory activation, metabolic dysregulation, genetic factors, and the adverse effects of long-term drug therapy. Despite advances in understanding the mechanisms of CVD in RA and their interplay with traditional risk factors, optimal approaches for risk management in this patient population are not yet well-defined. Cardiovascular risk assessment in RA patients requires regular monitoring of traditional risk factors and disease activity, supplemented by emerging biomarkers and imaging techniques. Disease-modifying anti-rheumatic drugs (DMARDs) are central to managing both RA and cardiovascular risks. The potential role of cell therapy in cardiovascular risk management induced by RA also is discussed. Despite progress in understanding RA-related cardiovascular risks, challenges remain in predicting patient outcomes. Future research should focus on identifying novel biomarkers for early detection, developing personalized management strategies, and evaluating the long-term effects of immunomodulatory therapies on cardiovascular risks.
The 2018 European Alliance of Associations for Rheumatology (EULAR) recommendations for physical activity (PA) in people with inflammatory arthritis (IA) and osteoarthritis (OA) required revision as new studies have been published on interventions using technology and/or the combination of educational and behavioural strategies to promote PA or reduce sedentary behaviour (SB). Moreover, the World Health Organisation released updated general PA guidelines in 2020 with an emphasis on reducing SB. This work aimed to update the 2018 EULAR recommendations for PA in IA and OA. The EULAR Standardised Operating Procedures for developing recommendations were followed. A multidisciplinary task force (TF) was established. Systematic literature searches related to 13 research questions were conducted in August 2024. Recommendations were updated, and the TF members rated their level of agreement and estimated impact and implementability (0-10 scale, with 10 highest). The revised recommendations include 4 overarching principles and 11 recommendations on PA and SB including inter alia PA promotion as standard care, measurements of PA, and intervention modalities considering dose, adaptations and the application of (technology-based) behaviour change techniques. The mean level of agreement for the recommendations ranged from 9.0 to 9.8, the mean impact between 8.3 and 9.2, and the mean feasibility of implementation between 7.2 and 8.5. In addition, quality indicators, research and educational agendas were defined. The updated EULAR recommendations for PA should guide the development, conduct and evaluation of PA interventions and promotion, including the reduction of SB, in people with IA and OA. These recommendations should be implemented with consideration of individual needs, environmental conditions, and the broader national health care context.
Janus kinase (JAK) and interleukin-6 (IL-6) inhibitors are therapeutic options for patients with rheumatoid arthritis (RA) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs); however, no randomized controlled trial has compared their efficacy and safety. Since both act through the JAK-signal transducer and activator of transcription pathway, a comparative evaluation is warranted. We conducted a prospective, randomized, open-label trial at 55 centers in Japan, randomizing patients with active RA despite csDMARD therapy in a 1:1 ratio to receive 200 mg/day filgotinib or subcutaneous tocilizumab as monotherapy; the primary endpoint was American College of Rheumatology (ACR) 50 at week 12, and secondary endpoints included clinical disease activity indices, musculoskeletal ultrasonography scores, patient-reported outcomes, and serum biomarkers through 52 weeks. Twenty-six patients were enrolled (13 per group) before study termination due to insufficient recruitment, and descriptive analyses were performed. At week 12, ACR50 was achieved in 38.5% (5/13) patients in the filgotinib group and 46.2% (6/13) in the tocilizumab group (risk difference: -7.69%; 95% confidence interval: -42.26 to 28.8). Both groups showed early and sustained improvements in disease activity from week 2. The improvement in patient global assessment scores was greater with filgotinib at week 2 but the difference diminished thereafter, and serum IL-6 level decreased with filgotinib but increased with tocilizumab. Four serious adverse events occurred with filgotinib, including infections and cardiac events. Because this study was underpowered and the analysis was descriptive, larger studies are needed to confirm these findings and define optimal use. (The study was registered in the Japan Registry of Clinical Trials (https://jrct.niph.go.jp) as jRCTs071200107 and in ClinicalTrials.gov as NCT05090410.).
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. To overcome the rapid clearance and systemic side effects of sinomenine (SIN), three critical components of peptide-drug conjugates (PDCs), including the targeting peptide, linker, and payload, were optimized, and two synovial homing peptide-sinomenine conjugates, SIN-SS-DRL and dSIN-SS-DRL, linked via reduction-sensitive disulfide bonds, were developed. Both new conjugates exhibited markedly improved plasma stability and demonstrated selective, glutathione-triggered release of SIN, with LC-MS confirming an accelerated and more complete release from the dual-disulfide conjugate. In vitro, they effectively suppressed pro-inflammatory cytokines, while in vivo studies in adjuvant-induced arthritis mice showed significant alleviation of joint inflammation and bone damage, with efficacy comparable to or exceeding methotrexate. These results highlight the potential of dual disulfide-linked PDCs as a promising targeted therapy for RA, integrating active synovial homing and passive redox-responsive release to achieve superior therapeutic outcomes with favorable safety profiles.
Periploca forrestii Schltr. (PF), traditionally used by the Miao ethnic group in China, has been reported to exert a therapeutic effect on rheumatoid arthritis (RA), potentially through regulating of the TNF-α signaling pathway. This study aimed to identify PF-derived TNF-α-targeting compounds and elucidate their anti-RA mechanisms. TNF-α-binding constituents in PF were screened using affinity ultrafiltration plus liquid chromatography-mass spectrometry (AU-LC/MS). Initial screening for TNF-α antagonistic activity was performed in L929 cells. Binding interactions were verified by biolayer interferometry (BLI), surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS). LPS-induced RAW264.7 cells were used to evaluate anti-inflammatory activity, while MH7A cells were employed to assess the effects of active compounds on inflammation and TNF-α-mediated NF-κB signaling. The underlying mechanisms were further investigated using molecular docking and competitive binding assays. The anti-RA efficacy of selected compounds was evaluated in a collagen-induced arthritis (CIA) rat model. Nine TNF-α-binding compounds were identified, among which isochlorogenic acid B, daucosterol, and vitamin E exhibited strong TNF-α binding affinity and effectively protected L929 cells from TNF-α-induced cytotoxicity. These compounds directly interacted with TNF-α as confirmed by BLI, SPR, CETSA, and DARTS, and interfered with TNF-α/TNFR1 interaction. Consequently, they suppressed NF-κB activation, decreased phosphorylation of IκBα and p65, and reduced the levels of NO and proinflammatory cytokine (such as TNF-α, IL-6, and IL-1β). Further analyses, including molecular dynamics simulations and molecular docking, demonstrated stable binding of these compounds to TNF-α, consistent with experimental findings. In CIA rats, all three compounds markedly alleviated joint swelling, histopathological damage, and inflammatory cytokine levels. Isochlorogenic acid B, daucosterol, and vitamin E are key TNF-α-targeting constituents of Periploca forrestii that exert anti-RA effects by blocking TNF-α/TNFR1 interaction and inhibiting NF-κB-mediated inflammatory responses. These findings suggest that PF may serve as a source of natural small-molecule TNF-α inhibitors for RA therapy.
Pediatric bone and joint infections (BJIs) are traditionally treated with prolonged intravenous antibiotics, although the optimal duration remains uncertain. Recent studies support shorter intravenous courses and, in some cases, oral therapy alone. However, the minimum effective intravenous duration remains undefined. To evaluate the effectiveness of abbreviated intravenous regimens in previously healthy children with acute BJIs. MEDLINE, CENTRAL and Scopus were searched up to December 31, 2024, for studies including children >3 months old with uncomplicated BJIs treated with ≤5 days of intravenous antibiotics. Studies with comorbidities, prosthetic joints or surgical-site infections were excluded. Risk of bias was assessed using RoB-2 and ROBINS-I, and certainty of evidence with GRADE. This systematic review was registered in PROSPERO (CRD42024614740). Of 6 studies (813 children) included in the qualitative synthesis, 3 were eligible for meta-analysis. The pooled odds ratio for treatment success with short-course intravenous therapy (≤5 days) or oral-only treatment compared with longer intravenous regimens was 1.65 (95% confidence interval: 0.46-5.98), showing no significant difference between groups. Statistical heterogeneity was low (I2 = 0%). Sensitivity analyses confirmed the direction and stability of findings. The certainty of evidence for treatment success was rated low due to imprecision and limited estimable studies. This systematic review and meta-analysis suggest that short-course intravenous therapy-or even exclusive oral antibiotic treatment-may be as effective as longer intravenous regimens for uncomplicated pediatric BJIs in healthy children. However, given the low certainty of evidence, these strategies should be applied cautiously and guided by clinical judgment. Further high-quality trials are needed to confirm these findings.
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation and systemic complications. Recent evidence has indicated that disrupted iron metabolism, notably elevated hepcidin expression and excessive iron accumulation in tissues, contributes to RA progression. In RA, Macrophages, which play a central role in both immune regulation and iron homeostasis, are often polarized toward the proinflammatory M1 phenotype. In this study, we investigated the therapeutic effects of Angelica sinensis polysaccharides (ASP, 100-400 mg/kg) in a collagen-induced arthritis (CIA) mouse model. ASP significantly alleviated joint swelling, histopathological damage, and iron deposition in the liver and spleen. It also downregulated hepcidin expression and restored the M1/M2 macrophage balance. Furthermore, immunofluorescence and western blotting confirmed increased ferroportin (FPN) and decreased ferritin levels in splenic macrophages. In an in vitro coculture model mimicking inflammation, ASP indirectly modulated macrophage iron handling and polarization by suppressing hepatocyte-derived hepcidin. RNA-seq analysis revealed that ASP treatment downregulated HIF-1α and NF-κB pathways, which link iron metabolism to macrophage activation, whereas the results of reactive oxygen species (ROS) assays supported its role in reducing oxidative stress associated with iron overload. Together, these findings suggest that ASP alleviates RA symptoms by restoring iron homeostasis and modulating macrophage polarization, primarily by targeting the hepcidin-FPN axis and related inflammatory pathways. ASP therefore holds promise as a low-toxicity, immunomodulatory candidate for RA therapy.
Gouty arthritis (GA) falls within the category of metabolic arthropathies. Its onset stems from abnormal uric acid metabolism, which subsequently leads to the deposition of monosodium urate (MSU) crystals and ultimately triggers a robust inflammatory response. Currently, the global prevalence rate of GA is on the rise, gradually increasing the societal disease burden it imposes. This review comprehensively examines the pathogenesis of GA. The content encompasses uric acid metabolic disorders, the innate immune activation process induced by MSU crystals, as well as various subsequently triggered programmed cell death (PCD) modalities, including pyroptosis, NETosis, apoptosis, necroptosis and ferroptosis. We then evaluate in vivo and in vitro experimental models according to the disease stage and pathogenic processes they best recapitulate. Exogenous MSU models are highly suitable for studying acute inflammatory flares; hyperuricemia models capture the metabolic basis of disease initiation; and composite models more closely reflect the chronic and multifactorial course of human gout. In vitro systems ranging from macrophage monocultures to co-culture and organoid platforms provide complementary tools for mechanistic studies and drug screening. However, current models still cannot fully reproduce the complexity of human gout, particularly with respect to metabolic initiation, tissue hierarchy, systemic context, and species-specific differences. We therefore propose a model-selection approach in which the choice of platform should be guided by the specific pathogenic process under investigation. Future model development should integrate innovative technologies to enhance the authenticity of pathological features, address the shortcomings of existing systems, and facilitate the clinical translation of GA research.
Rheumatoid arthritis (RA) is a chronic autoimmune disease with inflammation-mediated joint damage. Its pathogenesis involves synergistic impairment of multiple physiological balances, including immune cell subset dysregulation, abnormal inflammation, oxidative stress, pathological angiogenesis, bone homeostasis disorder and gut microbiota dysbiosis. Conventional therapies have high costs and adverse effects. Traditional Chinese medicine (TCM) follows a holistic balance-restoring concept and is a promising alternative, with Tripterygium wilfordii, Wutou Decoction and Toddalia asiatica extract as evidence-based representatives. This review summarizes 2020-2025 in vitro and in vivo studies on anti-RA TCM. Its core therapeutic mechanism is multi-target, network-based regulation. It rectifies various pathological imbalances simultaneously: modulating immune cell polarization, rebalancing inflammatory factors, scavenging ROS, inhibiting abnormal angiogenesis, regulating osteoblast-osteoclast crosstalk and reshaping gut microbiota. Single TCM agents act on multiple balance networks, showing complex pharmacological properties. TCM's unique advantage for RA is reestablishing the body's dynamic homeostasis by targeting interconnected pathological balances. Further research is needed to clarify TCM components' synergistic regulatory mechanisms and promote their clinical translation.
Osteoarthritis (OA), the most prevalent form of arthritis globally, is characterized by debilitating pain driven by inflammatory and degenerative processes in chondrocytes. Here, we demonstrate that arctigenin (ATG), a bioactive lignan from Arctium lappa, alleviates OA pain by suppressing chondrocyte pyroptosis through the POU Class 2 Homeobox 1 (POU2F1)/growth factor receptor Bound Protein 10 (GRB10) signaling axis. In a monosodium iodoacetate (MIA)-induced OA rat model, ATG administration reduced pain hypersensitivity, lowered pro-inflammatory cytokines, and elevated anti-inflammatory interleukin-10 (IL-10), while diminishing expression of pyroptosis effectors including cleaved caspase-1, Gasdermin-D-N (GSDMD-N), and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). In vitro studies in C28/I2 chondrocytes revealed that ATG dose-dependently attenuated inflammation and pyroptosis markers. Mechanistically, ATG upregulated POU2F1, a transcription factor that directly binds and activates the GRB10 promoter, as confirmed by enrichment and binding assays. Silencing POU2F1 or GRB10 reversed ATG's inhibitory effects on pyroptosis. In vivo validation further showed that ATG's pain-relieving effects in OA rats depend on this axis to curb chondrocyte pyroptosis. Collectively, these findings highlight ATG's potential as a novel analgesic agent for OA by targeting pyroptotic pathways, offering insights into inflammation-driven pain mechanisms.
Although there has been growing interest in better understanding risk factors for progression from psoriasis (PsO) to psoriatic arthritis (PsA), research on the role of ambient temperature in potentiating PsA risk has been limited. We sought to evaluate the association of average-annual ambient temperature exposure with prevalent PsA diagnosis among a large cohort of US adults with PsO. We studied electronic health record-data from participants with PsO, with and without an associated PsA diagnosis, who enrolled in the National Institutes of Health's All of Us Research Program between May 31, 2017, and July 1, 2022. Average-annual ambient temperature exposure data was obtained from the National Oceanic and Atmospheric Administration. Multivariable logistic regression analysis was utilized to assess the association between three-digit Zone Improvement Plan (ZIP) code-level ambient temperatures and prevalent PsA diagnosis, controlling for patient age, sex, body mass index, smoking history, race and ethnicity, income, urbanicity, and community deprivation. In this cohort of 5466 patients with PsO (mean age [SD], 61.86 years [15.45 years]; 3153 females [57.7%]) and 1080 patients with both PsO and PsA (mean age [SD], 60.76 years [13.48 years]; 665 females [61.6%]), each 1°F increase in average-annual ambient temperature was associated with 2% increased odds of prevalent PsA diagnosis (adjusted odds ratio [aOR], 1.02; 95% CI, 1.01-1.03). Our study provides data to support further investigation of long-term, warmer ambient temperature exposure as a potential risk factor for PsA among those with PsO.
Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disorder characterized by persistent synovial inflammation, pannus formation, bone erosion, and eventual joint destruction. Murraya exotica L. (ME), a botanical source of Murrayae Folium et Cacumen (MFC), has not been previously investigated for its anti-arthritic potential, which motivated this study. The chemical composition of ME was characterized using ultra-performance liquid chromatography (UPLC), and its anti-arthritic effects were evaluated in collagen-induced arthritis (CIA) rats and interleukin (IL)-1β-stimulated SW982 cells. The contents of meranzin hydrate, hainanmurpanin, murrayone, and 3',4',5,5',6,7-hexamethoxyflavone in the ME extract were quantified as 2.86% ± 0.01%, 1.88% ± 0.01%, 0.07% ± 0.00%, and 0.01% ± 0.00%, respectively. In CIA rats, ME treatment alleviated clinical symptoms, attenuated histopathological joint damage, including synovial hyperplasia, cartilage degeneration, and bone erosion, ameliorated inflammation, and reduced oxidative stress. In IL-1β-stimulated SW982 cells, ME inhibited proliferation and migration, suppressed the inflammatory response, and mitigated oxidative stress. Network pharmacology and molecular docking analyses predicted strong interactions between ME-derived compounds (e.g., murrayone) and nuclear factor-kappa B (NF-κB) p65, which were further validated by cellular thermal shift assay (CETSA) and drug affinity responsive target stability (DARTS) assay. Mechanistically, ME blocked NF-κB activation by inhibiting phosphorylation and degradation of inhibitor of NF-κB-α (IκBα) and preventing p65 nuclear translocation, while simultaneously suppressing activator protein-1 (AP-1) activation through downregulation of c-Fos and c-Jun. The involvement of the NF-κB and AP-1 pathways in ME-mediated anti-inflammatory, anti-proliferative, and anti-oxidative effects in RA was further confirmed using specific pharmacological inhibitors: pyrrolidinedithiocarbamate (PDTC) for NF-κB and SR11302 for AP-1.