Search Results (75)

Proteoglycans and their fragments have potential as diagnostic or theragnostic biomarkers to identify diseases characterized by dysregulated extracellular matrix remodeling, such as juvenile idiopathic arthritis (JIA). Therefore, our study aimed to evaluate the diagnostic utility of plasma proteoglycan profiles, namely, aggrecan, decorin, and biglycan, released from osteoarticular structures into the blood of children with juvenile idiopathic arthritis. These profiles are potential biomarkers of tissue destruction and/or indicators of the efficacy of therapy with the biologic agent etanercept (ETA). This study was conducted on 263 blood samples collected from 25 healthy children and 34 children at various stages of juvenile idiopathic arthritis disease: immediately after diagnosis, following treatment with disease-modifying antirheumatic drugs (DMARD) (methotrexate, sulfasalazine, and prednisone), and during 3, 6, 12, 18, and 24 months of therapy with etanercept. Quantitative levels of aggrecan, biglycan, and decorin were measured using ELISA kits. In children with JIA, plasma aggrecan levels were elevated at diagnosis, decreased after ineffective DMARD therapy, and increased again at 24 months of etanercept treatment despite clinical improvement. By contrast, biglycan levels were similar to those in healthy controls but decreased during etanercept therapy. Decorin levels were initially high in untreated and DMARD-treated patients but returned to normal after 24 months of biologic treatment. After considering these findings and the ROC analysis, we conclude that decorin appears to be a promising biomarker for diagnosing and monitoring etanercept therapy in JIA, and biglycan is a useful biochemical marker for assessing the effectiveness of ETA treatment. Full article

Background: We aimed to investigate the risk for a serious infection in rheumatoid arthritis (RA) patients after tapering the dose of biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs). Methods: This nested case–control study investigated the risk for a serious infection in RA patients who underwent mandatory b/tsDMARDs dose reduction 2.5 years after starting therapy with a single b/tsDMARD in the National Health Insurance Research Database (NHIRD). Cases were those patients who developed a serious infection afterwards. Matched controls were selected from those patients who did not develop a serious infection. We used unconditional logistic regression to analyze the odds ratios (ORs) of b/tsDMARDs dose reduction and discontinuation between cases and controls. Results: RA patients underwent an average dose reduction of 60%. Among a total of 268 cases and 1072 controls, we did not observe a lower risk for a serious infection in those patients who tapered or discontinued b/tsDMARDs. However, those patients who had discontinued b/tsDMARDs had a higher risk for a serious infection when compared with those who had not and had reduced their b/stDMARDs dose reduction below the average (i.e., ≤60%), with an adjusted OR of 1.48 (95%CI: 1.05, 2.09). Conclusions: Dose reduction in b/tsDMARDs in RA patients might not be associated with a lower risk for serious infection. Discontinuation of b/tsDMARDs, however, was likely associated with a higher risk for serious infection. Full article

Psoriatic arthritis (PsA) is a chronic, immune-mediated inflammatory arthritis associated with psoriasis, affecting joints, entheses, and the axial skeleton. While primary care providers and dermatologists frequently encounter psoriasis (PsO), early recognition of PsA remains critical to preventing irreversible joint damage. This paper is written to provide a comprehensive overview of PsA, beginning with a clinical case that highlights diagnostic and therapeutic challenges. In this review, the epidemiology of PsA will be discussed, emphasizing its prevalence and risk factors among patients with PsO. The discussion extends to the underlying pathogenesis, focusing on genetic predisposition, environmental triggers, and key cytokines, including TNF-α, IL-17, and IL-23, that have become targets for advanced therapeutics. The clinical features of PsA are explored in detail, including peripheral and axial arthritis, enthesitis, dactylitis, and extra-articular manifestations. Diagnostic approaches are discussed, with a focus on the Classification Criteria for Psoriatic Arthritis (CASPAR) and Moll & Wright criteria. Additionally, we examine screening tools designed to facilitate early detection in dermatology clinics. Diagnostic modalities, including imaging and serologic markers, are reviewed. Finally, we explore the evolving landscape of PsA treatment, spanning conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biologic agents (bDMARDs), and targeted synthetic DMARDs (tsDMARDs). Given the increasing availability of cytokine-targeted therapies, an interdisciplinary approach between dermatologists and rheumatologists is essential for optimizing outcomes in PsA patients. Patients with PsA are cared for by rheumatologists, dermatologists, and primary care providers who help manage the comorbidities associated with PsA. By bridging primary care, dermatology, and rheumatology in the care of PsA, this paper aims to enhance understanding of PsA for facilitating early identification and timely intervention for improved patient care. Full article

COVID-19 vaccination has played a pivotal role in mitigating the global health crisis and reducing morbidity and mortality associated with SARS-CoV-2 infection. While its public health benefits are unequivocal, the unprecedented scale of vaccination—reaching billions worldwide—has also enabled the detection of rare autoimmune events, including systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, and Guillain–Barré syndrome. Although such events occur in only a small subset of individuals, often influenced by genetic, environmental, or dosage-related factors, they underscore the importance of understanding immune tolerance mechanisms in vaccination. This review synthesizes clinical observations and immunological findings from the COVID-19 vaccination era, highlighting key mechanisms such as molecular mimicry, adjuvant-induced inflammation, bystander activation, epitope spreading, and polyclonal B cell activation. We also consider how novel vaccine platforms, particularly mRNA-based technologies, may influence immune regulation and self-tolerance. Importantly, we discuss the therapeutic management of vaccine-associated autoimmunity, including the use of corticosteroids, intravenous immunoglobulin (IVIG), plasma exchange, disease-modifying anti-rheumatic drugs (DMARDs), and other immunosuppressive agents, many of which have led to favorable clinical outcomes. By integrating mechanistic insights with treatment strategies, this review emphasizes that the overall benefits of COVID-19 vaccination overwhelmingly outweigh the risks, while advocating for continued surveillance, mechanistic research, and risk stratification to inform safer and more targeted vaccination strategies in future pandemics. Full article

Gout is a form of sterile inflammatory arthritis in which monosodium urate (MSU) crystals deposit and provoke a neutrophil-predominant response, primarily driven by activation of the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome. Here, we show that auranofin, a Food and Drug Administration (FDA)-approved anti-rheumatic agent, exerts anti-inflammatory effects in both in vitro and in vivo models of gout. Auranofin inhibited NLRP3 inflammasome activation in human THP-1 cells and murine macrophages, leading to reduced cleavage of caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18). In MSU crystal-induced mouse models, auranofin treatment reduced paw swelling, serum cytokine levels, and tissue inflammation. Notably, auranofin suppressed neutrophil migration and decreased expression of C-X-C motif chemokine ligand 1 (CXCL1) in inflamed foot tissue and air-pouch exudates. Mechanistically, auranofin disrupted the interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis, a key signaling pathway promoting neutrophil recruitment. Overexpression of IL-33 abolished the anti-inflammatory effects of auranofin, highlighting the central role of IL-33 in gout pathogenesis. Together, our findings suggest that auranofin alleviates MSU-induced inflammation by concurrently inhibiting NLRP3 inflammasome activation and IL-33-mediated neutrophil recruitment, supporting its potential as a dual-action therapeutic candidate for gout. Full article

Background: Rheumatoid arthritis is the most prevalent systemic inflammatory disease, mainly affecting the synovial tissue of small and large joints, also associated with significant extra-articular manifestations. Throughout the progression of the disease, cardiac structures may be affected, including the conducting system, myocardium, endocardium, coronary arteries, and valves, potentially resulting in a higher incidence of cardiac arrhythmias. Methods: We performed a narrative review of the most recent studies that highlight the epidemiology, pathophysiology, diagnosis, and management of arrhythmias occurring in patients with rheumatoid arthritis. Furthermore, we examined the impact of disease-modifying antirheumatic drugs (DMARDs)—including conventional synthetic (csDMARDs), biologic (bDMARDs), and targeted synthetic agents (tsDMARDs)—on cardiac electrophysiology. Results: Cardiac immune cells may influence arrhythmogenesis through non-canonical and inflammatory mechanisms by modifying myocardial tissue architecture or by interacting with cardiomyocytes, potentially altering their electrical function. Conclusions: This review emphasizes the essential role of a multidisciplinary approach integrating rheumatology and cardiology expertise in the screening and management of arrhythmias in patients with rheumatoid arthritis. Full article

Rheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by chronic inflammation of the synovial membrane, leading to synovial hyperplasia, infiltration of immune cells, and subsequent cartilage and bone erosion. This progressive joint pathology results in persistent pain and functional impairment. Currently, convenient oral traditional disease-modifying anti-rheumatic drugs (DMARDs) are available, and increasingly precise biologic agents and targeted synthetic DMARDs (tsDMARDs) have been developed, offering promising therapeutic options. However, systemic administration generally fails to achieve therapeutic drug concentrations in the joints owing to poor biodistribution and dose-limiting systemic toxicity. Intra-articular (IA) administration has demonstrated promising potential in addressing these challenges. Among the various strategies employed for IA administration, hydrogels have gained significant attention due to their tunable mechanical properties, biocompatibility, and controlled release capabilities. These unique properties enable hydrogel-based IA delivery systems to simultaneously modulate the inflammatory microenvironment and protect cartilage tissue. This review comprehensively summarizes the histopathological changes and associated cellular and molecular events in RA, while also highlighting the design principles of hydrogels and advanced strategies for hydrogel-based IA administration. By addressing the limitations of conventional treatments, hydrogel-based IA injection holds significant promise for improving RA treatment. Full article

Individuals with immunosuppressive conditions are at a higher risk of developing malignancies than those in the general population. Immunosuppression weakens tumor immunity, hinders the detection of pro-oncogenic cells, and activates oncogenic viruses. Malignancies arising in immunosuppressed patients tend to be aggressive, have a high incidence of virus-associated cancers, and are reversible in some cases. Notably, immunosuppressive agents influence the frequency and type of malignancies, as well as their clinicopathological features. Organ transplant recipients receive long-term immunosuppressants to prevent acute rejection. Post-transplant malignancies vary depending on the type of drug administered before the onset of these diseases. Patients with rheumatoid arthritis (RA) are treated with long-term immunosuppressive medications, such as methotrexate (MTX). MTX is widely recognized as being associated with a specific type of lymphoproliferative disorder (LPD), known as MTX-associated LPD. Our recent report indicated that the clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also vary based on the other anti-RA agents used, such as tacrolimus and tumor necrosis factor inhibitors. Therefore, the clinicopathological characteristics of post-transplant LPD and RA-LPD evolve alongside the changes in the immunosuppressants/immunomodulators administered. Understanding the various characteristics and time trends of immunosuppressive neoplasms, particularly LPDs, in relation to different immunosuppressant/immunomodulator medications is highly valuable in clinical practice. Full article

Rheumatoid arthritis (RA) is a progressive and systemic autoimmune disease, characterized by a chronic inflammatory process, affecting the lining of the synovial joints, many body organs/systems, and blood vessels. Its pathological hallmarks are hyperplasic synovium, bone erosion, and progressive joint destruction. Rheumatoid arthritis affects over 20 million people, with a worldwide prevalence of 0.5–1.0%, exhibiting gender, ethnic, and geographical differences. The progressive disability severely impairs physical motion and quality of life and is finally leading to a shortened life span. The pathogenesis of RA is a complex and still poorly understood process in which genetic and environmental factors are principally associated. Current treatment mostly relies on conventional/non-biological disease-modifying anti-rheumatic drugs (cDMARDs), analgesics, non-steroidal anti-inflammatory drugs, glucocorticoids, steroids, immunosuppresants, and biologic DMARDs, which only control inflammation and pain. Along with side effects (drug toxicity and intolerance), these anti-rheumatic drugs possess limited efficacy. Therefore, the discovery of novel multi-target therapeutics with an improved safety profile that function as inhibitors of RA-linked signaling systems are in high demand, and this is in the interest of both patients and clinicians. Plant-derived extracts, nutritional supplements, dietary medicine, and molecules with anti-inflammatory activity represent promising adjuvant agents or alternatives for RA therapeutics. This review not only aims to discuss the basic features of RA pathogenesis, risk factors, and signaling pathways but also highlights the research progress in pre-clinical RA in in vitro and in vivo models, revealing new avenues in the management of the disease in terms of comprehensive multidisciplinary strategies originating from medicinal plants and plant-derived molecules. Full article

Background and Objectives: Previous studies have shown that a major part of adverse drug reactions (ADRs) are preventable, and they contribute to increased morbidity, mortality, and costs. To our knowledge, no study investigating preventable ADRs has been carried out in Lithuania. Therefore, the aim of this study was to characterize ADRs in the intensive care unit (ICU) of a secondary care Lithuanian hospital as well as to identify drug classes and organ systems most commonly implicated in preventable and nonpreventable ADRs. Materials and Methods: This observational prospective study was conducted in an 18-bed ICU of Kaunas Hospital of the Lithuanian University of Health Sciences from 1 September 2021 to 31 August 2023. All ADRs were assessed for causality, severity, and preventability. The Anatomical Therapeutic and Chemical (ATC) system was used to classify drug classes implicated in ADRs. The organ systems affected were analyzed using the Medical Dictionary for Regulatory Activities (MedDRA). Results: A total of 154 patients with a median age of 78.8 years (range, 18–97) were enrolled into this study. There were 255 ADRs identified; preventable ADRs accounted for 87.5%. Among the preventable ADRs, the top three therapeutic subgroups were antithrombotic agents (26.5%), anti-inflammatory and antirheumatic products (22.0%), and blood substitutes and perfusion solutions (20.2%). Meanwhile, among nonpreventable ADRs, antibacterials for systemic use (62.5%) and antithrombotic agents (46.9%) were the two most common therapeutic subgroups. The gastrointestinal as well as the skin and subcutaneous tissues organ systems were more likely to be affected by nonpreventable ADRs (56.3% vs. 17.5%, p ˂ 0.05 and 12.5% vs. 0.4%, p ˂ 0.05, respectively), while the renal and urinary organ systems were more likely to be affected by preventable ADRs (38.1% vs. 6.3%, p ˂ 0.05). Conclusions: Our study showed a very high incidence of preventable ADRs (87.5%). Drugs affecting blood and blood-forming organs were most frequently implicated in these ADRs. This area deserves special attention and strategies need to be implemented to reduce the incidence of preventable ADRs and their impact on the healthcare system. Moreover, it emphasizes the need for future studies at a national level as, to our knowledge, this is the first study addressing the issues of avoidable harm at the ICU of one Lithuanian hospital. Full article

Objectives: The present study aimed to evaluate the long-term survival of patients with rheumatoid arthritis (RA) receiving biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) in a real-world setting, and to identify key prognostic factors influencing mortality within this cohort. Methods: This retrospective, observational cohort study analyzed 165 patients with confirmed RA who were on b/tsDMARD treatment for at least six months as of June 2017. Patient data, including demographics, disease duration, prior therapeutic regimens, and global functional status were extracted from medical records to collect data covering a seven-year follow-up period, extending from June 2017 to December 2024. Corticosteroid use was defined as continuous systemic intake during the RA activity analysis period. Survival outcomes were analyzed using Kaplan-Meier methods and multivariate Cox proportional hazards models to identify independent predictors of mortality. Results: Over a mean follow-up of 9.4 years, the mortality rate was 13.5 deaths per 1000 treatment-years, with an overall survival rate of 87.3%. Advanced functional disability and prolonged corticosteroid use were independently associated with higher mortality risk. In subgroup analyses, chronic kidney disease significantly increased mortality among patients on TNF inhibitors. In contrast, patients who remained on their initial anti-IL6 therapy had lower mortality, though this may reflect survivor bias. Conclusions: This study highlights the importance of long-term b/tsDMARD intervention in RA patients, with observed low mortality and high survival rates. Subgroup findings suggest the importance of comorbidity management in TNFi users and therapeutic stability in anti-IL6 users. Full article

Background/Objectives: Ankylosing spondylitis (AS) is a severe chronic inflammatory rheumatic disease involving the spine, sacroiliacs, and peripheral joints. A lack of therapeutic response leads to severe sequelae. Currently, new markers are being tested to identify patients with poor outcomes. Tenascin C (TNC) is involved in triggering some relevant mechanisms of inflammation. Today, it remains unclear whether TNC levels might be useful as a biomarker of persistent activity. The aim of this study was to evaluate in AS whether serum levels of tenascin C are associated with persistent disease activity despite treatment. Methods: We included AS patients who had been treated with conventional synthetic disease-modifying antirheumatic drugs (cs-DMARDS) or anti-TNF agents for at least three months in a cross-sectional study. Response was assessed with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); scores ≥ 4 indicate persistent disease activity, while scores < 4 indicate inactive disease. Serum TNC levels, C-reactive protein (CRP) levels, and Erythrocyte Sedimentation Rate (ESR) were determined through the ELISA technique, nephelometry, and the Westergren method, respectively. Results: We evaluated 58 patients with AS (62.1% men); of them, 33 (56.9%) had persistent active disease (BASDAI ≥ 4) despite treatment and 25 (43.1%) had inactive disease (BASDAI < 4). The median TNC level was 18.6 ng/mL. BASDAI correlated with TNC levels (rho: 0.528, p < 0.001), CRP (0.352, p = 0.007), and ESR (0.342, p = 0.009). Patients with persistently active AS had higher serum TNC levels than those with inactive AS (35.2 vs. 6 ng/mL, p < 0.001). No differences in TNC level were found in patients treated with cs-DMARDS vs. anti-TNF agents. The ROC curve for serum tenascin C in active AS patients had an area under the curve = 0.78 (CI 95%: 0.65–0.91) with optimal serum tenascin C cutoff (>13.85 ng/mL). Sensitivity for detecting active AS was higher with TNC compared to ESR and CRP. Conclusions: We suggest that an elevated TNC level may be a useful biomarker of persistent disease activity despite treatment in AS; further studies should investigate the role of TNC levels in predicting the progression of the disease. Full article

Upadacitinib has demonstrated efficacy in psoriatic arthritis in clinical trials, but its real-world performance in difficult-to-treat PsA remains underexplored. This observational, multicenter, open-label study evaluated the efficacy and safety of upadacitinib in 134 patients with psoriatic arthritis (97 women, mean age 51.8 ± 11.2 years, mean disease duration 9.94 ± 7.72 years) who showed inadequate response to advanced therapies. Most patients (74.6%) had received at least two biological/targeted synthetic disease-modifying antirheumatic drugs with different mechanisms of action. Upadacitinib was initiated at 15 mg daily, and within one month, significant improvements were observed: DAS28-ESR decreased from 4.7 to 3.77 (p < 0.001), DAPSA from 25 to 17 (p < 0.001), and CRP from 2.90 to 1.50 mg/L (p = 0.001). These reductions persisted throughout the study. Prednisone dosage decreased significantly (p = 0.049). Adverse events led to upadacitinib discontinuation in 8.2% of patients, but no serious adverse events were reported. Compared to the SELECT-PsA 2 trial, our cohort had a higher proportion of females and greater prior exposure to biologic agents but showed comparable efficacy and safety outcomes. These findings suggest that upadacitinib is a rapid, effective, and relatively safe therapeutic option for difficult-to-treat psoriatic arthritis under real-world conditions, supporting its use despite differing patient characteristics from clinical trial populations. Full article

Spondyloarthropathies (SpAs) represent a diverse group of seronegative immune-mediated inflammatory diseases characterized by a genetic predisposition and an association with human leukocyte antigen-B27. This narrative review aims to explore juvenile spondyloarthropathies (JSpAs), their classification, clinical manifestations, diagnostic challenges, and contemporary treatment strategies. According to the International League of Associations for Rheumatology criteria, JSpAs include several specific forms: enthesitis-related arthritis, psoriatic arthritis, and undifferentiated arthritis. Despite established classifications, the terms and definitions surrounding these conditions can often lead to confusion among healthcare professionals. This ambiguity underscores the need for a standardized approach to nosological classification. The clinical presentation of JSpAs can be multifaceted, encompassing both articular and extra-articular manifestations. Articular symptoms may include enthesitis and varying forms of arthritis, while extra-articular involvement can range from uveitis to gastrointestinal, cardiovascular, pulmonary, neurological, and renal complications. These diverse manifestations highlight the systemic nature of the disease and the importance of a holistic approach to diagnosis and treatment. While laboratory tests for SpAs are often non-specific, imaging modalities such as musculoskeletal ultrasound and magnetic resonance imaging play a crucial role in the early detection of inflammatory lesions. These imaging techniques can provide valuable insights into disease progression and aid in the formulation of appropriate treatment plans. Current treatment guidelines advocate for a “stepwise” approach to therapy, beginning with nonsteroidal anti-inflammatory drugs and progressing to glucocorticoids, disease-modifying antirheumatic drugs, and biological agents, particularly anti-tumor necrosis factor alpha agents. The primary objective of treatment is to achieve clinical remission or, at a minimum, to attain low disease activity. Regular monitoring of disease activity is imperative; however, the lack of validated assessment tools for the pediatric population remains a significant challenge. JSpAs pose unique challenges in terms of diagnosis and management due to their diverse manifestations and the complexities of their classification. Ongoing research and clinical efforts are essential to refine our understanding of these conditions, improve treatment outcomes, and enhance quality of life for affected children and their families. Effective management hinges on early detection, individualized treatment plans, and continuous monitoring, ensuring that patients receive the most appropriate care tailored to their specific needs. Full article

Inflammation is a multifaceted biological response of the immune system against various harmful stimuli, including pathogens (such as bacteria and viruses), cellular damage, toxins, and natural/synthetic irritants. This protective mechanism is essential for eliminating the cause of injury, removing damaged cells, and initiating the repair process. While inflammation is a fundamental component of the body’s defense and healing process, its dysregulation can lead to pathological consequences, contributing to various acute and chronic diseases, such as autoimmune disorders, cancer, metabolic syndromes, cardiovascular diseases, neurodegenerative conditions, and other systemic complications. Generally, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, disease-modifying anti-rheumatic drugs (DMARDs), antihistamines, biologics, and colchicine are used as pharmacological agents in the management of inflammatory diseases. However, these conventional treatments often have limitations, including adverse side effects, long-term toxicity, and drug resistance. In contrast, enzyme-based therapeutics have emerged as a promising alternative due to their high specificity, catalytic efficiency, and ability to modulate inflammatory pathways with reduced side effects. These enzymes function by scavenging reactive oxygen species (ROS), inhibiting cytokine transcription, degrading circulating cytokines, and blocking cytokine release by targeting exocytosis-related receptors. Additionally, their role in tissue repair and regeneration further enhances their therapeutic potential. Most natural anti-inflammatory enzymes belong to the oxidoreductase class, including catalase and superoxide dismutase, as well as hydrolases such as trypsin, chymotrypsin, nattokinase, bromelain, papain, serratiopeptidase, collagenase, hyaluronidase, and lysozyme. Engineered enzymes, such as Tobacco Etch Virus (TEV) protease and botulinum neurotoxin type A (BoNT/A), have also demonstrated significant potential in targeted anti-inflammatory therapies. Recent advancements in enzyme engineering, nanotechnology-based enzyme delivery, and biopharmaceutical formulations have further expanded their applicability in treating inflammatory diseases. This review provides a comprehensive overview of both natural and engineered enzymes, along with their formulations, used as anti-inflammatory therapeutics. It highlights improvements in stability, efficacy, and specificity, as well as minimized immunogenicity, while discussing their mechanisms of action and clinical applications and potential future developments in enzyme-based biomedical therapeutics. Full article