Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder characterized by progressive joint destruction and erosive pathology. Synovitis is considered the hallmark pathological manifestation of RA, often affecting multiple joints throughout the body. Hence, developing strategies for accurate delivery of therapeutics to inflamed joints is crucial to improving drug delivery efficiency. Herein, we rationally constructed a nanosystem that consists of gold nanoparticles serving as both drug carriers and radiosensitizers, fibroblast activation protein inhibitor (FAPI) as a targeting ligand for pathological neovascularization, and β-cyclodextrin (β-CD) as a host matrix for encapsulating BET inhibitor I-BET151. The targeted delivery enabled selective accumulation of I-BET151 at inflamed joints to mitigate immune activation by inhibiting the abnormal proliferation and migration of synovial fibroblasts in collagen-induced arthritis mice. Single-cell profiling dissected this nanosystem effectively suppressing synovial inflammation by eliminating activated B cells and reversing the hypoxia-inducible factor 1-alpha (Hif 1α)-driven profibrotic and migratory program of fibroblast-like synoviocytes. Combined with low-dose radiotherapy, comprehensive transcriptome standardization and cellular remodeling in RA were achieved. Therefore, our strategy holds considerable promise for advancing the management of rheumatoid arthritis and offers a potent therapeutic modality for refractory RA.

Whipple's disease (WD) is a rare chronic infection caused by Tropheryma whipplei, often presenting initially with musculoskeletal (MSK) manifestations that precede gastrointestinal (GI) or systemic symptoms by years. Its protean features and response to immunosuppression make it a diagnostic challenge in rheumatology. We conducted a national, multicenter, retrospective study of WD cases initially assessed for suspected rheumatic disease in Portuguese Rheumatology departments. Diagnosis was confirmed by duodenal histopathology and/or polymerase chain reaction (PCR) detection of T. whipplei. Demographic, clinical, laboratory, and therapeutic data were analyzed descriptively. Seven patients were identified (71.4% male; mean age 59.9 ± 8.2 years). The median diagnostic delay from MSK symptom onset was 4 years. MSK presentations included migratory arthritis/arthralgia (n=4), polymyalgia rheumatica-like symptoms (n=1), asymmetric sacroiliitis (n=1), and rheumatoid arthritis mimics (n=2). GI symptoms occurred in 57.1% and systemic manifestations in 85.7%, all with weight loss. One patient had central nervous system involvement. All showed anemia and elevated inflammatory markers. The median interval between MSK and extra-articular symptoms was 2.6 years. Five patients received immunosuppressive therapy; notably, earlier systemic/GI involvement occurred in those without such exposure, while the only patient treated with biologics did not develop extra-articular symptoms. WD may mimic diverse rheumatic diseases, causing diagnostic delay. A high index of suspicion is warranted in patients with refractory rheumatic symptoms, anemia, and weight loss. The observed variability in systemic progression highlights a potentially complex relationship between immunosuppression and host immune response to T. whipplei, warranting further investigation.

Acute lymphoblastic leukaemia (ALL) can mimic diverse musculoskeletal conditions, often resulting in diagnostic delays. Genetic predisposition to various cancer syndromes further complicates the clinical picture, influencing disease presentation and treatment response. We report an adolescent boy who presented with a 2-month history of episodic fever, persistent low back pain and non-migratory joint pain, with a history of growth failure, developmental delay and seizures since childhood. There was a history of malignancy in multiple family members. The clinical examination revealed no features suggestive of systemic involvement. The joint examination revealed swelling around the knee joints. Initial work-up for chronic infections and autoimmune diseases was negative. Magnetic resonance imaging spine findings of multiple T2 hyperintense lesions warranted a bone marrow examination, which confirmed the diagnosis of Ph+ B- ALL. Molecular analysis revealed a pathogenic heterozygous missense variant in the TP53 gene, leading to the diagnosis of Li-Fraumeni syndrome. This case highlights the importance of recognizing musculoskeletal symptoms as a potential presentation of ALL. Early consideration of leukaemia in the differential diagnosis can prevent delays in treatment, ultimately improving outcomes.

Extrapulmonary tuberculosis is uncommon, and musculoskeletal involvement presenting as migratory arthritis is particularly rare in immunocompetent individuals, often leading to misdiagnosis and delayed treatment. We report the case of a 66-year-old man with diabetes mellitus who presented with recurrent migratory inflammatory arthritis affecting multiple joints over 1 year, without initial pulmonary symptoms. He was initially diagnosed with rheumatoid arthritis based on positive rheumatoid factor and elevated inflammatory markers and was treated with disease-modifying antirheumatic drugs without clinical improvement. At presentation, he reported severe shoulder pain, morning stiffness, weight loss, and night sweats. Imaging revealed right upper lobe consolidation and a metabolically active cavitary lung lesion on PET-CT. Bronchoalveolar lavage culture confirmed Mycobacterium tuberculosis. Antituberculous therapy was initiated, resulting in marked clinical improvement and resolution of arthritis within weeks. This case highlights tuberculosis as an important, underrecognized cause of migratory arthritis and emphasizes the need to consider infectious etiologies in treatment-resistant inflammatory joint disease, particularly in endemic regions.

Neural crest cells contribute to craniofacial formation by differentiating into skeletogenic mesenchyme and neuro-glial lineages. Using Smart-seq2 single-cell transcriptomics, we show that mesenchymal fate commitment correlates specifically with the expression of rRNA-modifying and ribosome assembly factors, rather than structural ribosomal proteins. Notably, EMG1 and NHP2 introduce key post-transcriptional modifications into 18S rRNA, including m[1]acp[3]ψ at U1248, which requires TSR3 for final maturation. Disrupting NHP2 or TSR3 in vitro and in vivo perturbs cranial neural crest differentiation; post-migratory temporal knockout of Polr1a or Polr1c also causes craniofacial malformations. These findings align with cell type-specific m[1]acp[3]ψ levels during neural crest differentiation. Given the neural crest contribution to neuroblastoma, we analyze patient data to find that elevated ribosomal control and rRNA-modifying proteins predict poorer outcomes. Complementary experiments in neuroblastoma cell lines reveal functional roles for TSR3 and WDR74 in mesenchymal-like tumor states. Together, our results link rRNA modifications and ribosome assembly to fate decisions, suggesting ribosomal heterogeneity shapes both normal development and tumor progression.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by cartilage and bone erosion. The development process of RA could be divided into early, full blown, and late stages. The pathogenesis of those stages is still far from fully understood, which poses a tremendous challenge for developing nano-preparations for efficiently treating RA across all phases. Activated neutrophils continuously infiltrate inflamed joints and exacerbate joint cartilage and bone damage by releasing neutrophil extracellular traps (NETs). Therefore, constructing a drug delivery system based on inhibiting NETs is beneficial for blocking a series of inflammatory response cascades and joint injuries, achieving effective treatment of RA at various stages. To achieve targeted treatment of inflamed joints, we utilized the phagocytic function and migratory chemotaxis of activated neutrophils to design a drug delivery system (BTST NPs) that could hitchhike activated neutrophils to arrive at the inflamed joints. BTST was synthesized by conjugating bovine serum albumin (BSA) and sivelestat (ST) via ROS-sensitive thioketal bonds. Activated neutrophils could engulf BTST NPs through specific binding between Fcγ receptors and BSA, and transport BTST NPs to inflamed joints. In vitro studies showed that BTST NPs could release ST in response to ROS to block NETs release. In vivo biodistribution and pharmacological experiments illustrated that BTST NPs could be efficiently transported by activated neutrophils to inflamed joints and exhibit favorable therapeutic effects across different RA stages. The construction of BTST NPs provides a new strategy for functional integration in treating RA at various stages.

Asprosin, a recently identified adipokine involved in metabolic and inflammatory processes. The case-control study was conducted to explore how asprosin is involved in the pathogenesis of rheumatoid arthritis (RA). 205 RA patients and 205 healthy controls were included, and MH7A cells were used for in vitro studies. Plasma asprosin was elevated in RA patients [11.4 (8.2, 15.6) ng/mL] compared to healthy controls [9.3 (7.5, 10.5) ng/mL] (Z = 5.978, P < 0.001) and exhibited moderate diagnostic accuracy (AUC = 0.67). Asprosin significantly enhanced the proliferation of synovial fibroblasts and upregulated the proinflammatory cytokines, while promoting their migratory and invasive capacities. TNF-α led to a marked downregulation of PPAR-γ, which was associated with increased asprosin levels, treatment with rosiglitazone effectively attenuated asprosin overproduction. Elevated circulating asprosin levels serve as an independent risk factor for RA and demonstrate promising diagnostic potential. PPAR-γ-mediated overexpression of asprosin contributes to synovial fibroblast dysfunction, suggesting a pathogenic role in RA development.

Chronic joint pain in rheumatoid arthritis (RA) represents a persistent therapeutic challenge, and although luteolin (LUT) exhibits established anti-inflammatory properties, its precise mechanism for alleviating RA-associated chronic pain remains undefined. Through systematic investigation in collagen-induced arthritis (CIA) mice, we demonstrated that LUT administration effectively attenuated chronic pain by modulating spinal cluster of differentiation 4 positive T (CD4+ T) cell dynamics and suppressing microglial activation. Integrated multi-omics profiling (cleavage under targets and tagmentation (CUT&Tag), RNA sequencing (RNA-seq), and metabolomics) coupled with functional validation revealed nuclear factor of activated T cells 2 (NFATC2) as the central transcriptional regulator governing T helper 17 (Th17) cell differentiation and spinal infiltration through protein kinase C epsilon (PRKCE)-signal transducer and activator of transcription 3 (STAT3) signaling transduction. Significantly, our mechanistic studies uncovered a previously unrecognized epigenetic cascade: LUT-mediated suppression of lactate dehydrogenase A (LDHA) activity disrupts glycolysis-fueled histone 3 lysine 9 lactylation (H3K9la), thereby epigenetically silencing NFATC2 transcription. Translational studies using RA patient-derived CD4+ T cells confirmed LUT's capacity to normalize pathological hyperactivity of the LDHA/H3K9la/NFATC2 axis, concomitantly regulating CD4+ T dynamics. Biophysical validation through molecular docking, surface plasmon resonance (SPR), and molecular dynamics (MD) simulations established LUT's direct binding to LDHA with high affinity. Collectively, these findings delineate a novel therapeutic paradigm wherein LUT alleviates RA-associated chronic pain by orchestrating Th17 differentiation and migratory capacity through coordinated blockade of the LDHA-H3K9la-NFATC2 signaling network, highlighting its potential as a disease-modifying agent for chronic pain management in RA.

Streptobacillus moniliformis is considered normal flora of the upper respiratory tract of rodents and is the predominant cause of rat bite fever in North America. Although patients with rat bite fever oftentimes present with migratory polyarthralgia, cultures of affected joints do not grow bacteria in the vast majority of cases. We present a case of a 32-year-old woman who initially presented with a painful, swollen right index finger proximal interphalangeal (PIP) joint following a bite from her pet rat. After initial treatment with empiric antibiotics did not clear the infection, PIP joint irrigation and debridement revealed culture-positive septic arthritis. This case illustrates the patient's unusual presentation of S. moniliformis infection through septic arthritis of the PIP joint.