Rheumatoid meningitis presented as recurrent stroke-like symptoms: A case report and literature review.

Pulmonary involvement in the form of interstitial lung disease (ILD) is an important organ manifestation of many autoimmune diseases (AID). The management of ILD in different types of AID is described. This review is based on pertinent publications retrieved by a search in PubMed, with particular emphasis on meta-analyses and randomized controlled trials, supplemented by guidelines, expert consensus statements, and the authors' clinical experience. The prevalence of ILD among patients with inflammatory rheumatic systemic diseases ranges from 7% to 50% (7-15% in rheumatoid arthritis, 44-50% in systemic sclerosis, and 33-50% in idiopathic inflammatory myopathies). ILD is much less common in organ-specific types of AID (e.g., multiple sclerosis). ILD takes a progressive, fibrosing course in 16-40% of cases. If the patient's history or clinical manifestations suggest the possibility of ILD, pulmonary function tests and thin-slice computed tomography of the lung (high-resolution computed tomography, HRCT) should be performed. Patients with types of AID associated with a high prevalence of ILD should undergo regular pulmonary function testing in addition to directed history-taking and lung auscultation. Pulmonary HRCT should be performed on initial diagnosis of an AID. Invasive measures are needed only to resolve differential diagnostic uncertainty. The pharmacotherapy of ILD is initially oriented toward the immune-modulating or immunosuppressive treatment of the underlying disease. Antifibrotic treatment is given in addition in cases of progressive pulmonary fibrosis. The management of ILD should ideally be decided on by an interdisciplinary ILD board. The prognosis of ILD depends on that of the underlying disease; ILD is associated with elevated mortality. ILDs are critical manifestations of a variety of systemic autoimmune and inflammatory rheumatic diseases. Early recognition and targeted pharmacotherapy optimize the clinical outcome.

CD36-mediated fatty acid metabolic reprogramming activates synovial fibroblasts and promotes rheumatoid arthritis progression.

Rheumatoid arthritis (RA) is an auto-immune disease characterized by inflammatory episodes and joint degradation. Activated macrophages produce large amounts of reactive oxygen species (ROS) and pro-inflammatory cytokines, which damage chondrocytes and destroy the cartilage matrix. Therefore, a promising therapeutic strategy for the treatment of RA is to inhibit the secretion of pro-inflammatory cytokines and ROS to promote macrophage polarization and facilitate cartilage repair. In this paper, an active targeting nanomedicine based on metal-phenolic networks (MPNs) is constructed to re-polarize activated macrophages for RA therapy. Sr2+ and Cu2+ are first coordinated with tannic acid (TA) to prepare TSC, and TNF-α siRNA is loaded into TSC via simple ultrasonic treatment to obtain TSSC. Finally, TSSC is coated with M1 macrophage membrane (termed as TSSC@M1) to enhance its inflammatory targeting ability. TSSC@M1 can actively target macrophages by releasing TA, Cu2+, and TNF-α siRNA to synergistically scavenge ROS and inhibit the expression of TNF-α to induce macrophage polarization, while Sr2+ can further protect cartilage. In the collagen-induced arthritis (CIA) mouse model, TSSC@M1 can accumulate at inflamed joints and alleviate RA symptoms by modulating macrophage phenotype and repairing cartilage. Overall, TSSC@M1 NPs offer a promising and safe approach to treat RA.

To investigate the relationship between wrist deterioration and each of disease activity and physical function in patients with rheumatoid arthritis (RA). We analyzed 434 wrists in patients with RA who initiated treatment within the first year of disease onset. The annual mean Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR), the annual mean Health Assessment Questionnaire Disability Index (HAQ-DI), and the biennial decrease in the carpo: metacarpal ratio (c/MC) on plain radiographs were assessed. At year 10, wrists were classified into three groups according to Larsen grade (LG): LG 0, LG I-II, and LG ≥ III. In LG ≥ III, the annual mean DAS28-ESR at year 1 was particularly high, and both the annual mean HAQ-DI and the decrease in c/MC remained the highest throughout the study. The decrease in c/MC for 10 years had a weak positive correlation with the annual mean DAS28-ESR for 10 years (r=0.301, p<0.001). The mean DAS28-ESR cut-off value indicating progression to LG ≥ III at year 10 was 3.59 during the first two years. Control of disease activity in the early stage is crucial to prevent wrist joint deterioration and preserve physical function in patients with RA.

Rheumatoid arthritis is a chronic systemic inflammatory disease that predominantly affects synovial joints, resulting in progressive joint damage, disability, and systemic effects. There are still unanswered questions regarding the origin and pathophysiological complexities of the disease despite advances in treatment. A systematic review of the complex molecular pathways involved in RA pathophysiology is presented. Among the molecular processes involved in RA pathophysiology are oxidative stress, activation of fibroblast-like synoviocytes, aberrant innate and adaptive immunity, and dysregulated cytokine signalling. Important inflammatory signalling pathways related to the inflammation and destruction of joints including NF-κB, JAK/STAT, and RANK will be detailed. We will discuss the molecular components of the disease and the genetic and epigenetic predispositions such as HLA-DRB1 alleles, non-HLA loci, and regulation of miRNA and DNA methylation. We will highlight environmental and lifestyle related risk factors including smoking, infections, gut dysbiosis, and hormones contributing to disease manifestation and maintenance. We will describe the autoantibodies, rheumatoid factor and anti-citrullinated protein antibodies, as diagnostic and prognostic RA biomarkers. This review will summarize studies from in vivo animal models and translational studies to illustrate contemporary treatment strategies and drug development based on lessons from molecular knowledge of RA studies. Furthermore, progressive paradigms such as personalized medicine and multi-omics methodologies are discussed as potential future strategies to advance prediction, monitoring, and management of RA. This review seeks to provide an updated, broader view of the molecular biology and risk factors for RA, ultimately supporting better clinical outcomes and precision therapy.

Methotrexate (MTX) is one of the most commonly used therapeutic agents for rheumatologic inflammatory diseases and is generally considered a safe medication. Its negative effects on bone mineral density and the occurrence of fractures were first described as side effects of high-dose MTX in pediatric cancer patients. MTX-associated osteopathy in adults receiving moderate or low doses of MTX (up to 25mg/week) for rheumatic musculoskeletal disorders remains a controversial topic. The pathogenesis and clinical significance of MTX-associated osteopathy are still incompletely understood. Clinically, it presents as atraumatic stress fractures of the distal or proximal tibia and the calcaneus, most often in elderly women with longstanding rheumatic musculoskeletal diseases, particularly rheumatoid arthritis (RA) and reduced bone mineral density. Its characteristic hallmark remains the imaging finding of band- or meander-shaped fractures along the growth plate, which are commonly multiple. The diagnosis is challenging and requires the exclusion of other causes of lower limb pain. Moreover, overlapping risk factors for insufficiency fractures are common and should be carefully investigated. The diagnosis must be made with caution, as the clinical consequences are discontinuation of MTX. In this paper, we describe four female patients with RA who presented with stress, meander-shaped fractures of the calcaneus and tibia (two with multiple fractures), showing rapid clinical improvement after MTX discontinuation, which can be attributed to MTX-associated osteopathy. Additionally, we performed a systematic review of this condition, focusing on its most common clinical and radiological features, as well as the effects of MTX on bone mineral density and fracture risk.

Shi Zheng (Dampness syndrome) is a prevalent condition in traditional Chinese medicine (TCM) syndrome caused by the humid environment (external dampness) or metabolic imbalance (internal dampness) and characterized by sense of heaviness in the body and numbness in the limbs. Most Shi Zheng patients suffer from metabolic disorders and inflammation, and they were diagnosed as the diseases such as rheumatoid arthritis, gouty arthritis, nonalcoholic fatty liver disease or type 2 diabetes mellitus by modern medicine, and they are prone to complications or recurrent episodes despite long-term medication. Chinese medicine formulas (CMFs) and their effective compounds have shown promising results in treating these diseases, with high cure rates and a low incidence of adverse events. However, modern science has yet to establish a clear understanding of the underlying mechanisms between Shi Zheng, related diseases, and CMFs, probably because of the extremely abstract concept of TCM syndrome. Therefore, this review aims to provide an overview of the characteristics of Shi Zheng and the effects of CMFs and active compounds in TCMs on typical diseases associated with Shi Zheng to clarify the concrete connection between TCM symptoms and modern diseases, thereby to bridge the gap between TCM syndrome concepts and modern medicine.

Rheumatoid arthritis (RA) is a chronic, progressive autoimmune disease characterized by persistent joint inflammation, cartilage degradation, and systemic complications. Phytochemicals such as curcumin, resveratrol, phenolic acids, flavonoids, lignans, and organosulfur compounds have demonstrated significant disease-modifying potential through modulation of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and key signaling pathways (NF-κB, MAPK, PI3K/AKT/mTOR). Curcumin, for example, regulates immune homeostasis by restoring the Th17/Treg balance and inhibiting NF-κB and mTOR signaling, while resveratrol suppresses angiogenesis via VEGF inhibition and induces apoptosis in fibroblast-like synoviocytes. Despite their pharmacological promise, poor aqueous solubility, rapid metabolism, and low systemic bioavailability limit clinical translation. Advances in nanoformulation technologies-including polymeric nanoparticles, liposomes, micelles, solid lipid nanoparticles, and stimuli-responsive carriers-have markedly improved phytochemical stability, pharmacokinetics, targeted delivery, and therapeutic efficacy. Analytical characterization methods such as dynamic light scattering, zeta potential analysis, FTIR, HPLC, and TEM facilitate precise formulation optimization and evaluation of biological interactions. Preclinical studies reveal that nano-curcumin can achieve efficacy comparable to methotrexate, while resveratrol-loaded gold nanoparticles enhance anti-inflammatory effects and joint-specific accumulation. This review integrates mechanistic insights, formulation strategies, and analytical approaches, highlighting the opportunities and regulatory considerations for translating nano-phytochemicals into clinically viable RA therapies.

To identify systemic conditions associated with dry eye disease (DED) symptoms, signs, and their discordance in a clinically diagnosed DED cohort. In this prospective cross-sectional study, participants with DED were assessed for systemic conditions through self-reported history, health records, and specialist referrals. Dry eye disease symptom and sign scores were transformed to a 0 to 1 scale using linear transformation. A discord score (symptom score-sign score) was calculated. Associations between systemic conditions and DED parameters were analyzed using linear regression. The study included 371 DED participants (mean age: 52.9±14.0 years; 226 women). No significant correlation was observed between signs and symptoms (Spearman rho = -0.08; P=0.08). Increasing age (β = -0.005; P<0.001) and longer DED duration (β = -0.003; P<0.001) were associated with higher signs than symptoms. Atopy, chronic gastrointestinal disorders, psychological disorders, and hormonal replacement therapy use were associated with more severe DED symptoms than signs (all P≤0.03). Female sex, graft-versus-host disease, Sjögren disease, and rheumatoid arthritis were associated with more severe DED signs and a symptom-sign discordance (all P≤0.04). Systemic conditions significantly affect how DED presents and may cause symptom-sign mismatch, highlighting the need for thorough systemic history and evaluation in DED.

Chronic pain is the major complaint of most Rheumatoid arthritis (RA) patients, which still lacks fully understanding and effective management. This study aims to establish a connection of RA pain with osteoclast activity and validate the effect of AP39 as a potential therapeutic agent. Synovial tissue from RA patients were employed with histological and immunofluorescent assay to determine the inflammatory and innervation status. CCK8 assay and TRAP staining were conducted to verify the effect of AP39 on osteoclast differentiation. The expression of axon guidance factors was then determined by qPCR and WB assay. Hematoxylin and Eosin (HE) staining and immunofluorescence presented a hyper-inflammation status and increased nerve distribution on RA synovial membrane. And the CCK8 assay and TRAP staining indicated 20 µM of AP39 inhibited LPS-stimulated osteoclast differentiation without cytotoxicity. qPCR assay and Western blot analyses validated AP39 suppressed genes and proteins expression of axon guidance factors on osteoclast after LPS stimulation. Our study validates a hyper-inflammation and hyper-innervation status in the synovial membrane of RA patients, which may be related to the exaggerated inflammatory osteoclast activity. Additionally, we proved that AP39 may serve as a therapeutic agent for suppressing the cellular differentiation and axon guidance factors expression of osteoclast under inflammatory circumstance, thereby indicating AP39 a potential option for RA management.

Background. Rheumatoid arthritis (RA) is a severe chronic disease affecting the joints and associated with autoimmune imbalance and inflammation in the synovium. Despite the introduction of biologic drugs, a significant proportion of patients remain refractory to standard therapy. In this regard, the development of monoclonal antibodies (mA) with fundamentally new targets is of particular interest, as well as utilizing the potential of nanotheranostics to improve the efficacy and selectivity of therapy. Objectives. To critically review promising targets for future mA-based therapies: IFN-γ, GM-CSF, IL-7RA, BSSL, PD-1. To evaluate nanotheranostic approach as a method to improve RA treatment. Results. Novel mAs against inflammatory effectors including emapalumab, otilimumab, OSE-127, SOL-116, and perezolimumab can reduce RA progression and increase the chances of favorable outcome. However, the nonspecificity of mA toward autoreactive cells may lead to serious side effects, and this fact requires consideration of more advanced approaches such as nanotheranostics. Current trends in RA therapy point to the increasing use of nanomaterials, particularly liposomes delivered with monoclonal antibodies. Liposome-encapsulated drugs, such as miRNAs, which are able to inhibit specific genes responsible for the development and persistence of RA, may enhance the efficacy of such a combination. Targeted localization and internalization of liposome contents can be activated by physical factors including IR radiation, ultrasound, or realized by targeting cellular receptors that are overexpressed on autoreactive cells and that are capable of internalization into cellular compartments. Conclusion. The integration of monoclonal antibodies with nanomaterials as drug carriers represents a promising direction in RA therapy, providing higher selectivity, safety and potential for a personalized approach. Further development of these strategies has the potential to significantly improve the prognosis and quality of life of patients resistant to conventional therapies.

Evidence on the association between sleep disorders and rheumatoid arthritis (RA) remains limited. This study aimed to investigate this relationship in U.S. adults using data from the National Health and Nutrition Examination Survey (NHANES). This cross-sectional study included adults aged ≥ 18 years from the 2005-2018 NHANES cycles. A total of 28,040 participants were included. Weighted multivariate logistic regression models were employed to assess the association between sleep disorders and RA. Three models were constructed: an unadjusted model, a minimally adjusted model controlling for demographic variables, and a fully adjusted model incorporating additional lifestyle and clinical covariates. Subgroup analyses were performed to assess the consistency of associations across different population strata, and sensitivity analyses were conducted to confirm the robustness of the results. Of the 28,040 participants, 4168 (14.32%) were identified as having sleep disorders, and 1589 (4.28%) reported having RA. In the fully adjusted model, sleep disorders were significantly associated with increased odds of RA (OR = 1.76, 95% CI: 1.46-2.13, P < 0.001). Subgroup analyses showed that this positive association persisted across all examined strata, with no significant interactions (P for interaction > 0.05). In conclusion, our findings indicate a statistically significant association between sleep disorders and the prevalence of RA in U.S. adults. However, given the limitations of the cross-sectional design, causal inferences cannot be made. Future longitudinal and mechanistic studies are warranted to clarify the temporal direction and biological pathways underlying this association.

Rheumatoid arthritis (RA) is an autoimmune disease that primarily affects hyaline cartilage, except in the case of the temporomandibular joint (TMJ), which is covered by fibrocartilage. This study compared the progression of RA in these two types of cartilage by examining the TMJ and knee joints of rats in both the acute and chronic phases of the disease. Forty-eight male Wistar rats were divided into groups: Control (animals without RA in the TMJ or knee), RA-24h, and RA-7d (animals with RA in the TMJ or knee, euthanized 24 h or 7 days after the last intra-articular injection, respectively). The rats were sensitized with subcutaneous injections containing complete/incomplete Freund's adjuvant and methylated bovine serum albumin (mBSA), followed by three intra-articular mBSA injections (one per week) into either the TMJ or knee. Euthanasia was performed 24 h (acute phase) or 7 days (chronic phase) after the third injection. The following parameters were assessed: nociceptive thresholds, cellular influx in synovial fluid, histopathology, immunohistochemistry for metalloproteinase-9 (MMP-9), and birefringence of collagen fibers in articular cartilage. A significant reduction in the nociceptive threshold was observed in arthritic animals in both joints compared to the control groups. Additionally, a significant increase in cellular influx in the synovial membrane was noted in both joints after the third mBSA injection, as well as in the knee after 7 days. Histopathological analysis revealed reduced metachromasia, increased MMP-9 immunoexpression, and higher levels of type III collagen in the articular cartilage compared to the respective controls (p < 0.05). The nociceptive response was similar in both joints during the acute and chronic phases of RA. However, evidence of articular repair was observed in the TMJ, accompanied by a sustained reduction in the nociceptive threshold, suggesting central sensitization without ongoing peripheral damage.

The cause of rheumatic diseases is poorly understood; many appear to have a dominant inheritance with low, incomplete penetrance. A recent theory poses that all DNA is continuously damaged at a constant rate, causing a constant rate of mutations. Here, the hypothesis is tested that a constant, low rate of somatic mutations explains the low, incomplete penetrance of autoimmune rheumatic diseases and the increased penetrance of monogenic inflammatory rheumatic disease driven by multiple DNA loci prone to somatic mutation. Monogenic rheumatic diseases are proposed to require two mutations according to the two-hit hypothesis by Knudson: a germline mutation on one allele, and a somatic mutation initiating rheumatic disease on the wild-type allele. Two approaches are taken. The first one investigates whether the epidemiology of autoimmune rheumatic diseases adheres to two expected characteristics: a linear prevalence of disease and a tapering distribution of multiple disease events in individuals at risk. The second approach analyses at-risk DNA for evidence of hypermutable loci: somatic hypermutation (SHM) hotspots. Autoimmune and monogenic inflammatory rheumatic diseases provide an opportunity to determine whether more than one similar SHM hotspot leads to earlier onset of disease and a higher degree of disease penetrance. Results show that examples of rheumatic diseases, such as rheumatoid arthritis, systemic sclerosis, lupus and Sjogren's syndrome, show a linear prevalence and an exponential distribution of one or more additional autoimmune diseases. SHM hotspots in HLA and non-HLA genes in at-risk people are associated with the risk of rheumatic diseases, and the difference in the number of SHM hotspots, one in autoimmune and PLB1 arthritis and several in COPA syndrome, associated with autoimmune and monogenic non-HLA rheumatic diseases, explains the time of onset of disease and the degree of incomplete penetrance. This clarifies why autoimmune rheumatic diseases are inherited as true autosomal dominant traits with incomplete penetrance and non-HLA monogenic rheumatic diseases as pseudo-dominant traits with incomplete penetrance in accordance with the two-hit hypothesis. Therefore, epidemiology and genetics are compatible with a constant rate of DNA damage and associated somatic mutations as the cause of autoimmune and monogenic rheumatic diseases among at-risk people.

To develop a multimodal ultrasound radiomics model integrating power Doppler (PD) and superb microvascular imaging (SMI) data, combined with clinical baseline characteristics, and to evaluate its predictive performance for active inflammation in rheumatoid arthritis (RA). A total of 2,503 PD and 2,503 SMI ultrasound images of metacarpophalangeal and proximal interphalangeal joints were collected from RA patients with active inflammation and non-active controls between December 2022 and March 2024. Single-modality (PD/SMI), multimodal (SMI_PD), and clinical-integrated models were developed. Diagnostic performance was evaluated using receiver operating characteristic (ROC) analysis. The area under the curve (AUC) values for PD, SMI, multimodal SMI_PD, and clinical-integrated models were 0.76, 0.75, 0.82, and 0.83, respectively. The multimodal radiomics model demonstrated superior diagnostic performance for RA active inflammation. SMI shows potential as a tool for subclinical inflammation monitoring, while the integration of multimodal ultrasound radiomics with clinical data further enhances clinical utility.

This study aimed to evaluate the risk of hepatitis B virus reactivation (HBVr) in patients with HBV-related rheumatoid arthritis (RA) undergoing TNF inhibitor (TNFi) therapy. A systematic search of Embase, PubMed/MEDLINE, Scopus, Web of Science, ClinicalTrials.gov and the Cochrane Library was conducted, and pooled HBVr rates were calculated using random-effects models with subgroup analyses based on region, HBV serostatus, glucocorticoid use, antiviral prophylaxis, and TNFi type. Data from 15 studies, including 916 patients, were analyzed, revealing a pooled HBVr rate of 2% (95% CI: 0.01-0.03) with low heterogeneity (I² = 0.79%, p = 0.133). Regional variation was observed, with no HBVr cases in European studies (0.01; 95% CI: -0.01-0.03) and a 2% rate in Asian studies (95% CI: 0.01-0.04). HBsAg-positive patients demonstrated significantly higher HBVr rates (16%; 95% CI: 0.04-0.28) compared with HBsAg-negative patients (4%; 95% CI: -0.01-0.09), corresponding to an odds ratio (OR) of 12.60 (95% CI: 3.73-42.53). Patients receiving antiviral prophylaxis had a 6% HBVr rate compared to 3% in those without prophylaxis, though the difference was not statistically significant (OR: 1.30; p = 0.726). Similarly, glucocorticoid use did not significantly influence HBVr risk (6% vs. 5%; OR: 0.73; p = 0.563). HBVr rates also varied by TNFi type, with 4% for adalimumab, 3% for etanercept, and 2% for infliximab. Overall, TNFi therapy in HBV-related RA is associated with a low but clinically relevant risk of HBVr, with higher rates in HBsAg-positive patients and modest variation by region and drug type, while antiviral prophylaxis and glucocorticoid use appear to have no significant effect on risk.

Synovial-joint abnormalities in children can be caused by different conditions, including autoimmune arthritis, infection, and neoplasm. An ultrasound-guided biopsy targeting the synovial membrane can aid in determining the etiology when the cause is unclear. To determine the diagnostic performance, findings, and outcomes of ultrasound-guided joint biopsy in children. This is a retrospective study on patients who underwent ultrasound-guided joint biopsy from May 2000 to December 2024. Patient demographics, clinical information, imaging, procedure details, pathology findings, adverse events, and clinical outcomes were collected and reviewed. Thirty-one patients (25 females) with a mean age of 10.2years underwent 34 biopsies. Presenting symptoms were pain (33/34), mobility issues (33/34), and swelling (20/34). Effusion (19/28), joint capsule thickening (24/28), and contrast enhancement (20/28) were the most common MRI findings, while joint capsule thickening (29/29) and effusion (19/29) were the most frequent ultrasound findings. The most common joints biopsied were the hip (16/34), knee (9/34), and ankle (4/34). Core needle biopsy was performed in all cases. The mean number of passes was 4.5 (SD 1.8), obtaining a mean of 4.1 cores (SD 1.9). Biopsy was diagnostic in 20/34 (59% [CI 41-76%]) joints, and only one patient required surgical biopsy. Synovitis was the most common diagnosis (14/34), followed by pigmented villonodular synovitis (2/34). No major adverse events were observed. Ultrasound-guided joint biopsy in children has moderate diagnostic performance; however, it can be clinically impactful, even when non-diagnostic, helping in joint disease management, potentially preventing surgery, with low adverse event incidence.

Patients with rheumatoid arthritis (RA) can develop interstitial lung disease (ILD) with increased morbidity and mortality. The diagnostic values of serum carcinoembryonic antigen (CEA), cancer antigen (CA) 125, and human epididymis protein 4 (HE4) in these patients was unclear. A cross-sectional study enrolled patients with RA and healthy control individuals from January 2020 to August 2024. Demographics, disease duration, high-resolution computed tomography scan images, and laboratory test results were collected and analyzed. The cohort comprised 87 patients with RA (40 with and 47 without ILD) and 82 healthy individuals. Serum CEA, CA125, and HE4 levels were clinically significantly higher in patients with RA than in healthy control individuals; they were also elevated in patients with RA and ILD compared with patients with RA but not ILD. Increased levels of CEA, CA125, and HE4 were associated with more severe impairments in pulmonary function. Each biomarker demonstrated satisfactory performance, with the combination of all 3 yielding the highest efficacy (sensitivity = 95.00%, specificity = 95.74%, area under the curve = 0.993) for evaluating ILD. Serum CEA, CA125, and HE4 levels were clinically significantly elevated in patients with RA, particularly in those patients with ILD, and higher levels correlated with poorer pulmonary function. Their combination could facilitate accurate assessment of RA-associated ILD.

Helix-Guarded Molecular Clips Confer Robust Scavenging of Intra-Articular Cell-Free DNA for the Treatment of Rheumatoid Arthritis.