Gailian Zhang

Background: Isolated tricuspid valve Libman-Sacks endocarditis (LSE) is extremely rare, and its occurrence during pregnancy with severe thrombocytopenia poses major diagnostic and therapeutic challenges. Case summary: A 21-year-old pregnant woman at 13 weeks of gestation with systemic lupus erythematosus (SLE) and secondary antiphospholipid syndrome (APS) presented with severe thrombocytopenia (platelet count 21 × 10 ⁹ /L). Echocardiography revealed two isolated tricuspid vegetations (the largest measuring 24.1 × 19.3 mm). She declined surgery and insisted on continuing the pregnancy with medical management. Treatment included pulse methylprednisolone, plasma exchange, intravenous immunoglobulin, cyclosporine, hydroxychloroquine, and anticoagulation. Anticoagulation was initiated after partial platelet recovery. The patient responded favorably, with platelet normalization, progressive vegetation regression, and successful delivery of a healthy infant. Echocardiography at nine months showed near-complete regression of the larger vegetation and complete resolution of the smaller one, with normal valve function. Conclusion: This case demonstrates that intensive immunomodulatory therapy combined with timely anticoagulation after partial platelet recovery can achieve vegetation regression and avoid cardiac surgery in pregnant patients with SLE/APS and massive isolated tricuspid LSE. To our knowledge, this is the first reported case of non-surgical management of this life-threatening condition.

Osteoarthritis (OA) is the most common joint disorder, affecting over 600 million people worldwide (1). Despite this immense burden, no disease-modifying osteoarthritis drug (DMOAD) has been approved to date that can alter the course of joint pathology (2). Consequently, the age at which patients undergo total joint replacement is decreasing, further amplifying the societal and economic burden of OA (3).Prevention and early intervention remain critical to reducing this burden-yet current treatment is initiated only after symptoms are established and relies on modalities with limited efficacy, as underscored by numerous phase II and III randomized controlled trials (RCTs) that have shown only modest or no clinical benefits (2). This therapeutic stagnation has prompted a fundamental re-evaluation of OA pathogenesis. A paradigm shift is now reframing OA from a localized "wear-and-tear" condition to a systemic disease driven by metabolic, inflammatory, and ageing-related factors (3). This new understanding opens unprecedented opportunities for therapeutic intervention, including the repurposing of existing biologics.Denosumab, a human monoclonal antibody targeting receptor activator of nuclear factor kappa-B ligand (RANKL) widely used in osteoporosis, has garnered attention for its potential efficacy in OA based on accumulating preclinical and clinical evidence. This has sparked interest in repurposing it as a DMOAD-yet critical questions remain: Which patients should receive denosumab? What is the optimal dose? How should discontinuation be managed? And can findings from hand and knee studies be extrapolated to other joints? This Opinion addresses these questions with specific evidence and proposes a research agenda to guide clinical translation.Shangguan and colleagues demonstrated that, in human chondrocytes and osteoclast precursors in vitro, denosumab blocks RANKL-induced osteoclastogenesis via nuclear factor kappa-B (NF-κB) inhibition while attenuating ROS-induced chondrocyte apoptosis, with corresponding upregulation of anabolic genes (SOX9, COL2A1) and suppression of hypertrophic markers (COL10A1, RUNX2) via TGFβ1/smad3 signaling (4).Synovial inflammation is now recognized as a key driver of OA pathogenesis, with imaging studies demonstrating its presence in both early and advanced-stage disease (5).Using single-cell RNA sequencing of murine knee joints with post-traumatic OA, Hu and colleagues identified fibroblast-like synoviocytes (FLSs) as the primary source of RANKL in the OA joint (6). Mechanistically, RANKL signals through RANK on synovial macrophages and FLSs, activating NF-κB signaling that drives transcription of pro-inflammatory mediators including tumor necrosis factor (TNF), interleukin (IL)-6, C-C motif chemokine ligand 2 (CCL2), and matrix metalloproteinases (MMPs). In FLSs, this transcriptional program also induces follistatin-like protein 1 (FSTL1), an NF-κB target gene. Secreted FSTL1 acts as a pro-inflammatory mediator that activates neighboring macrophages, establishing a forward amplification loop (6). Denosumab disrupts this pathological circuit by blocking RANK/TNF receptor-associated factor 6 (TRAF6)/NF-κB-dependent FSTL1 induction in FLSs, thereby preventing FLS-mediated paracrine activation of macrophages and targeting both the stromal and myeloid compartments (6).Macrophages are central to OA pathogenesis, with their functional state critically influencing disease progression (7). Single-cell transcriptomic studies have revealed multiple functionally distinct macrophage subpopulations in human OA synovium, spanning a continuous spectrum from pro-inflammatory and catabolic to inflammation-resolving and reparative (7). In a rodent model of OA, Ming and colleagues showed that locally delivered denosumab attenuates synovial macrophage senescence, reducing senescence-associated secretory phenotype (SASP) gene expression and p16⁺/p21⁺ macrophage abundance (8). In naturally aged mice, Liao and colleagues demonstrated that macrophage-targeted denosumab shifts the activation profile toward an inflammation-resolving state, characterized by reduced pro-inflammatory mediators and increased markers of efferocytosis and tissue repair, while improving Osteoarthritis Research Society International (OARSI) scores and bone mineral density (BMD) (9). The proposed mechanisms of denosumab in the OA joint are summarized in Figure 1.These mechanistic findings should be interpreted with caution. The molecular pathways described above have been elucidated primarily in animal models and in vitro systems, and the translational gap between preclinical OA models and human disease remains substantial. Confirmation of these mechanisms in well-phenotyped OA patient cohorts is therefore needed.The therapeutic potential of denosumab in OA was first evaluated in a single-center, randomized, double-blind, placebo-controlled phase 2a trial in erosive hand OA (10).Wittoek and colleagues enrolled 100 patients (mean age 61 years, 78% female) with at least one interphalangeal joint in the erosive or joint space loss phase and ultrasonographic evidence of active synovitis. Patients were randomized 1:1 to denosumab 60 mg subcutaneously every 3 months or placebo for 48 weeks, followed by a 48-week open-label extension. The intensified dosing-double the standard osteoporosis regimen-was informed by dose-dependent structural inhibitory effects of denosumab observed in rheumatoid arthritis (10). The primary endpoint, change in Ghent University Scoring System (GUSS) score at week 24, showed a between-group difference of 8.9 points (95% CI 1.0-16.9; p = 0.024), widening to 14.3 points (95% CI 4.6-24.0; p = 0.003) at week 48.Denosumab also reduced new erosive joints by 76% (OR 0.24, 95% CI 0.08-0.72; p = 0.009). Clinical benefits emerged in the extension phase, with significant improvements in pain and function at 96 weeks (10). Regarding safety, adverse events...

Fibroblast activation protein alpha (FAP) is a type II transmembrane protease that exhibits both dipeptidyl peptidase and endopeptidase activities. It is upregulated in activated fibroblasts, particularly in tumor stroma and in fibrotic processes associated with various benign conditions. Recent studies have revealed that FAP is also highly expressed in certain Autoimmune Diseases (AIDs) characterized by chronic inflammation and tissue remodeling. Small-molecule inhibitors targeting FAP (FAPI) positron emission tomography (PET) provides a direct imaging modality for assessing fibroblast activation in vivo . FAPI’s application in oncology has attracted considerable attention in nuclear medicine. However, evidence supporting its efficacy in AIDs remains limited. This review systematically evaluates the diagnostic and phenotyping potential of FAPI PET in AIDs, expands its applications across a broader disease spectrum, highlights technical advantages, and delineates future research directions.

Inflammatory arthritis is an inflammatory disease that involves the joints and surrounding tissues. Synovial hyperplasia often presents when joints become inflamed due to immune cell infiltration. Synovial membrane is an important as well as a highly specific component of the joint, and its lesions can lead to degeneration of the joint surface, causing pain and joint disability or affecting the patients’ quality of life in severe cases. Synovial macrophages (SMs) are one of the cellular components of the synovial membrane, which not only retain the function of macrophages to engulf foreign bodies in the joint cavity, but also interact with synovial fibroblasts (SFs), T cells, B cells, and other inflammatory cells to promote the production of a variety of pro-inflammatory cytokines and chemokines, such as TNF-α, IL-1β, IL-8, and IL-6, which are involved in the pathogenic process of inflammatory arthritis. SMs from different tissue sources have differently differentiated potentials and functional expressions. This article provides a summary on studies pertaining to SMs in inflammatory arthritis, and explores their role in its treatment, in order to highlight novel treatment modalities for the disease.

Psoriatic arthritis (PsA) is a chronic autoimmune inflammatory joint disease related to psoriasis (PsO). The risk of PsA patients with cardiovascular disease (CVD) is significantly higher than that of the general population. At present, the relevant mechanism is not clear, chronic inflammation and traditional cardiovascular risk factors are the most important factors for the increased risk of CVD in PsA patients. Early assessment of the risk of PsA patients with CVD, and active control of the disease activity of PsA patients and intervention of traditional cardiovascular risk factors can delay the progression of CVD risk. This article reviews the epidemiology and pathogenesis between PsA and CVD, and reviews the latest developments in the risk assessment and management of CVD in PsA patients.

Mesenchymal stem cells (MSCs) can be isolated from not only bone marrow, but also various adult mesenchymal tissues such as periosteum, skeletal muscle, and adipose tissue. MSCs from different tissue sources have different molecular phenotypes and differentiation potential. Synovial membrane (SM) is an important and highly specific component of synovial joints. Previous studies have suggested that the synovium is a structure with a few cell layers thick and consists mainly of fibroblast-like synoviocytes (FLS), which forms a layer that lining the synovial membrane on the joint cavity and synovial fluid through cell-cell contact. In recent years, studies have found that there are also mesenchymal stem cells in the synovium, and as an important part of the mesenchymal stem cell family, it has strong capabilities of cartilage forming and tissue repairing. This article reviews the sources, surface markers, subtypes, influencing factors, and applications in inflammatory joints of synovial membrane mesenchymal stem cells (SM-MSCs) in recent years, aiming to clarify the research status and existing problems of SM-MSCs.

Follistatin-like protein 1 (FSTL1) is a proinflammation mediator implicated in arthritis in rodent animal models. The present study is aimed at assessing FSTL1 levels in systemic autoimmune diseases and correlating them with disease activity in patients with rheumatoid arthritis (RA). Serum FSTL1 levels from 487 patients with systemic autoimmune diseases and 69 healthy individuals were measured by enzyme-linked immunosorbent assay (ELISA). FSTL1 expression in synovial fluid (SF) and synovial tissues (STs) was determined by ELISA, immunohistochemistry, real-time polymerase chain reaction (RT-PCR) and western blot analysis in RA patients and trauma controls. FSTL1 levels in fibroblast-like synoviocytes (FLSs) from RA patients were determined by real-time PCR and western blot analysis. Serum FSTL1 levels were significantly elevated in patients with RA, ulcerative colitis, systemic lupus erythematosus, Sjögren's syndrome (SS), systemic sclerosis and polymyositis/dermatomyositis. Serum FSTL1 levels in the RA and secondary SS patients were substantially higher than those in other patients. Serum FSTL1 levels were increased in early RA, rheumatoid factor (RF)- and anti-cyclic citrullinated peptide antibody (ACPA)-negative patients compared to healthy controls. Moreover, serum FSTL1 concentrations were significantly higher in long-standing RA patients than in early RA patients and in the RF- and ACPA-positive RA patients than in RF- and ACPA-negative RA patients. Elevated FSTL1 levels in the STs and SF of RA patients were also observed. FSTL1 levels in serum were markedly higher than those in SF in RA patients. The strongest FSTL1 staining was detected in the cytoplasm of synovial and capillary endothelial cells from RA synovium. Furthermore, FSTL1 was induced in FLSs by inflammatory mediators. Importantly, serum FSTL1 levels were correlated with several important biologic and clinical markers of disease activity, including erythrocyte sedimentation rate, C-reactive protein, RF, ACPA, swollen joint count, patient global visual analogue scale score and Disease Activity Score 28 in the adult RA patient population. Notably, serum FSTL1 levels were significantly diminished following successful treatment and clinical improvement. Elevated FSTL1 levels reflect not only joint diseases but also inflammation and tissue degradation in systemic autoimmune diseases. Serum FSTL1 levels may thus serve as a serological inflammatory marker of disease activity in RA patients.