Frailty and osteoarthritis (OA) frequently coexist in older adults, yet the extent to which they share molecular programs across tissues remains unclear. We integrated bulk transcriptomics, peripheral immune and OA meniscal single-cell atlases, inferred cell-cell communication, and an in vitro myeloid-chondrocyte conditioned-medium model. Frailty-associated vastus lateralis and OA synovium shared a 16-gene program enriched for inflammatory and migratory processes, which was refined by protein-protein interaction analysis into a 15-gene hub module (Hub-15). Donor-aware pseudobulk analysis showed coordinated Hub-15 upregulation in CD8 T, natural killer, B, and monocyte/macrophage-like cells, with the highest scores in monocyte/macrophage populations. In the meniscal atlas, donor-level analysis of 7 normal and 6 OA donors identified a 20.5 percentage point lower proportion of inflammatory/stress cells and a 17.3 percentage point higher proportion of fibrochondrocyte-like cells in OA (both false discovery rate = 0.010), whereas state-specific Hub-15 differences were not significant after correction. Exploratory communication analysis nominated directionally consistent candidate myeloid-to-structural signaling axes, although none remained significant after multiple-testing correction. Conditioned medium from cytokine-primed THP-1 cells elicited inflammatory and matrix-catabolic responses in C28/I2 cells. These findings identify a cross-tissue, leukocyte-shared, and myeloid-enriched inflammatory program that converges across independent frailty and OA cohorts, providing a hypothesis-generating framework for future mechanistic testing.

Ankylosing spondylitis (AS) is an inflammatory disease marked by aberrant new bone formation and spinal ankylosis. Transforming growth factor-β1 (TGFβ1) is implicated in osteogenesis, yet its downstream effectors in AS remain unclear. Osteonectin, a glycoprotein secreted by osteoblasts, plays a critical role in bone formation with TGFβ1, but has not been studied in AS. This study aimed to investigate the TGFβ1-osteonectin mediated regulation of osteogenic activity in AS. Serum levels of TGFβ1, osteonectin, and osteocalcin were measured in AS patients and healthy controls. Measured these serum levels were compared with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Enthesis cells isolated from AS spinal tissues were stimulated with recombinant TGFβ1 in vitro. Proliferation, matrix production, migration, and clonogenicity were evaluated. Immunohistochemical staining of spinal tissues was performed to assess osteonectin expression. AS patients showed significantly elevated serum levels of TGFβ1 and osteonectin compared to healthy controls. Osteonectin expression, but not osteocalcin, was significantly correlated with serum level of TGFβ1. TGFβ1 stimulation enhanced proliferation, collagen deposition, migratory capacity, and colony formation in enthesis cells derived from AS patients. Immunohistochemistry revealed increase of osteonectin expression in periosteal regions of AS tissues. These findings suggest that osteonectin is a TGFβ1-responsive effector involved in early osteoprogenitor activation and may contribute to pathological bone formation in AS. Osteonectin represents a potential biomarker and therapeutic target for early structural progression in AS.

Currently, utilized disease-modifying antirheumatic drugs (DMARDs) do not provide a complete cure for rheumatoid arthritis (RA) and are associated with side effects related to prolonged use. In contrast, natural products have demonstrated promising efficacy and low toxicity in treating various diseases. This study employed network pharmacology and virtual screening to identify natural products with potential therapeutic effects for RA, followed by molecular dynamics simulations and experimental validation. Through network pharmacology, we identified interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) as RA-related targets, and subsequently prioritized neoprzewaquinone A (NEO) via virtual screening and molecular dynamics simulations for further validation. Subsequent experiments indicated that NEO could inhibit the binding of IL-1β, IL-6, and TNF-α to their respective receptors, reduce proliferation, and downregulate the migratory and invasive capacities of RA fibroblast-like synoviocytes (RA-FLS). Furthermore, NEO alleviated RA-related symptoms and diminished tissue damage in collagen-induced arthritis (CIA) mice. RNA sequencing suggested that the alleviative effect of NEO on RA may be attributed to the inhibition of the activation of the MAPK signaling pathway. Additionally, NEO appeared to reduce the phosphorylation levels of MEK and ERK. Importantly, safety evaluations did not reveal a clear increase in liver or kidney toxicity associated with NEO, within the scope of this study. Collectively, these findings suggested that NEO shows promise as a potential natural therapeutic option for RA and offers a new direction and theoretical foundation for future pharmacotherapy research in this area.

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently described adult-onset autoinflammatory disorder caused by somatic mutations in the UBA1 gene, characterized by systemic inflammation and hematologic abnormalities. Due to its broad and overlapping clinical manifestations, VEXAS is frequently misdiagnosed as other rheumatologic or hematologic conditions, leading to delays in diagnosis. We present the case of a 67-year-old man initially diagnosed with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who developed progressive multisystem inflammatory disease, including migratory inflammatory arthritis, chondritis, scleritis, constitutional symptoms, and persistent macrocytic anemia. Despite treatment with corticosteroids and rituximab, his symptoms persisted. Bone marrow biopsy demonstrated cytoplasmic vacuolization in myeloid and erythroid precursors, and subsequent next-generation sequencing identified a somatic UBA1 mutation, confirming the diagnosis of VEXAS syndrome. His clinical course was further notable for the development of neutrophilic dermatosis consistent with Sweet's syndrome. This case highlights the diagnostic complexity of VEXAS syndrome and underscores the importance of recognizing characteristic clinical patterns, including macrocytic anemia, chondritis, and dermatologic manifestations, particularly in older male patients with refractory inflammatory disease. Early consideration of VEXAS and timely molecular testing may reduce diagnostic delay and facilitate more targeted management of this emerging hematoinflammatory disorder.

Myeloid lineage-derived cells are key orchestrators of immune function and contribute to several chronic inflammatory disorders, such as rheumatoid arthritis (RA). The landscape of how these detrimental pro-inflammatory roles evolve over the course of the disease and the impact of therapies on them is being unraveled by recent immune-cell profiling studies. An alternative phenotyping using CD4 and CD45R0 expression to assess monocyte (Mo) and DC subsets allowed us to re-evaluate CD26 expression, an antigen with key migratory functions via its dipeptidyl peptidase (DPP4) activity on chemokines, in myeloid cells. Myeloid DCs barely express CD26 (while plasmacytoid pDCs do), and the intermediate Mo (intMo) subset is enriched in CD26. In a cohort of RA patients under treatment, together with the known expansion of Mo and the impairment of DC subsets and intMo, the CD26 expression was reduced, except for the intMo subset, enriched in CD26. The CD26 expression levels correlated with disease activity (DAS28 and its components), with therapy-specific patterns. Treatment with classical or biologic DMARDs, anti-IL6R, CTLA4-Ig, anti-TNF and anti-CD20, differentially modulated Mo subsets, the latter two reducing classical monocytes (cMo) while anti-TNF modestly increasing pDCs frequencies. Only anti-IL6R therapy increased total intMo % while decreasing the CD26+ intMo % (anti-CD20 also decreased the latter; on the contrary, CTLA4-Ig and anti-TNF increased it). Therapies variably restored CD26 density, except for anti-IL6R and anti-CD20. In conclusion, given that DPP4 inhibitors have shown contradictory effects in RA, their specific impact on these CD26+ APC functions warrants further investigation. Furthermore, the strong both positive and negative correlations found between soluble sCD26 levels and CD26+ frequencies (most strongly with pDCs) might support a sCD26 secretion independent of membrane-bound CD26, and CD26+ cell frequency associations with levels of anti-CD26 autoantibodies might suggest Ag-Ab complexes involvement on CD26 expression only in certain contexts.

Spatial organisation of immune cells reflects a balance between tissue anchoring and migratory compatibility, yet how this balance is structured within inflammatory skin disease remains poorly understood. Spatial transcriptomic analyses defined transit-retention immune organisation across lesional and non-lesional skin in atopic dermatitis (AD) and psoriasis (PsO). A unified transit-retention axis captured contextual immune organisation within leukocyte-rich tissue microenvironments. Non-lesional skin in both diseases exhibited retention-dominant organisation. In contrast, psoriatic lesions showed disruption of retention dominance, accompanied by coordinated alignment of antigen presentation, T cell activation, Th17, and B cell programmes with transit-compatible organisation, a pattern not observed in AD. An independent spatial transcriptomic dataset of psoriatic skin enabled assessment of compartmental specificity and clinical relevance. These analyses identified the epidermis as the primary site of transit-skewed reorganisation, with epidermal transit alignment scaling with disease severity. Extension of the same transcriptional framework to circulating adaptive immune cells using CITE-seq revealed lineage-specific transit-associated features in psoriatic disease. Circulating CD4 T cells and B cells showed stronger transcriptional and protein-level alignment with transit-associated states in PsO and psoriatic arthritis. Together, these analyses reveal transit-skewed adaptive immune organisation as a unifying feature of psoriatic disease.

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.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial hyperplasia, oxidative stress, and dysregulated immune responses that culminate in progressive joint destruction. Fibroblast-like synoviocytes (FLS) acquire an aggressive, invasive phenotype, while peripheral blood mononuclear cells (PBMCs) perpetuate inflammatory responses. 6-Bromoindirubin-3′-oxime (6BIO) has been shown to modulate signalling pathways associated with inflammation, oxidative stress, and immune cell activation, processes that are critically dysregulated in RA. This study evaluates the mechanistic effects of 6BIO on pathogenic FLS behaviour and PBMC-mediated immune regulation in RA. METHODS AND RESULTS: Primary cultures of FLS were established from synovial tissues of patients with RA and controls. In addition, peripheral blood samples were collected from 14 RA patients and 10 healthy blood donors. RA-FLS and PBMCs were treated with 6BIO followed by assessment of fibroblasts migration, ROS levels, Nrf2 localization, antioxidant protein expression, MMP2/9 activity, antioxidant gene expression, T-cell subsets and cytokine levels. 6BIO significantly inhibited RA-FLS migration, reduced MMP2 and MMP-9 levels, suppressed ROS, promoted Nrf2 nuclear translocation, and upregulated antioxidant genes including HO-1 and NQO1. In PBMCs, 6BIO significantly increased CD4+ CD25+ FoxP3+ regulatory T cells, lowered IL-1/TNF-α, and elevated IL-4/IL-13 cytokines. CONCLUSIONS: Our findings demonstrate that 6BIO modulates key pathogenic processes in RA by exerting anti-migratory, antioxidant, and immunomodulatory effects, thereby supporting its therapeutic potential for rheumatoid arthritis.