Search Results (351)

Human fungal infections comprise systemic mycoses as well as various skin diseases. Rising case numbers along with inefficient therapies and the appearance of drug-resistant strains unleashed a considerable health problem over the last years. Thus, the identification and development of new antifungal drugs is mandatory, which can include the design of new antifungals, or, more time saving, the repurposing of known drugs already applied for the therapy of other human diseases. The orally applicable gold-based drug auranofin has been used for the treatment of rheumatoid arthritis since the 1980s. However, auranofin also showed marked activity against various cancers, microbes, parasites, and viruses. Facing a pressing need to find new drug candidates against mycoses, especially against those listed in the WHO fungal pathogen priority list, we have summarized the eminent antifungal activities of auranofin in this review. Given its established safety profile and broad-spectrum activity, auranofin represents a promising candidate for repurposing in antifungal therapy. The mechanism of action of auranofin was correlated with thioredoxin reductase inhibition, but other modes of action such as interference with mitochondrial protein import and NADH kinase were also described and discussed. A selection of promising antifungal gold complexes was also provided. Pertinent literature is covered until 2025. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by joint inflammation and progressive disability. While biological disease-modifying antirheumatic drugs (bDMARDs) have significantly improved disease control, predicting individual treatment response remains clinically challenging. This study presents a machine learning approach to predict 12-month disease activity, measured by DAS28-CRP, in RA patients beginning bDMARD therapy. We trained and evaluated eight regression models, including Ridge, Lasso, Support Vector Regression, and XGBoost, using baseline clinical features from 154 RA patients treated at University Hospital Erlangen. A rigorous nested cross-validation strategy was applied for internal model selection and validation. Importantly, model generalizability was assessed using an independent external dataset from the Austrian BioReg registry, which includes a more diverse, real-world RA patient population from across multiple clinical sites. The Ridge regression model achieved the best internal performance (MAE: 0.633, R²: 0.542) and showed strong external validity when applied to unseen BioReg data (MAE: 0.678, R²: 0.491). These results indicate robust cross-cohort generalization. By predicting continuous DAS28-CRP scores instead of binary remission labels, our approach supports flexible, individualized treatment planning based on local or evolving clinical thresholds. This work demonstrates the feasibility and clinical value of externally validated, data-driven tools for precision treatment planning in RA. Full article

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disorder primarily targeting joints, leading to pain, swelling, and stiffness. RA results from the body’s own immune system attacking its own tissues. Currently, there are various treatments available for RA including disease-modifying antirheumatic drugs (DMARDs) and NSAIDs. Leflunomide (LEF) is a USFDA-approved synthetic DMARD which is being widely prescribed for the management of RA; however, it faces several challenges such as prolonged drug elimination, hepatotoxicity, and others. LEF exerts its therapeutic effects by inhibiting dihydroorotate dehydrogenase (DHODH), thereby suppressing pyrimidine synthesis and modulating immune responses. Emerging nanotechnology-based therapies help in encountering the current challenges faced in LEF delivery to RA patients. This review enlists the LEF’s pharmacokinetics, mechanism of action, and clinical efficacy in RA management. A comparative analysis with methotrexate, biologics, and other targeted therapies, highlighting its role in monotherapy and combination regimens and the safety concerns, including hepatotoxicity, gastrointestinal effects, and teratogenicity, is discussed alongside recommended monitoring strategies. Additionally, emerging trends in novel formulations and drug delivery approaches are explored to enhance efficacy and minimize adverse effects. Overall, LEF remains a perfect remedy for RA patients, specifically individuals contraindicated with drugs like methotrexate. The therapeutic applicability of LEF could be enhanced by developing more customized treatments and advanced drug delivery approaches. Full article

Gaultherin [methyl salicylate 2-O-β-D-xylopyranosyl-(1→6)-β-D-glucopyranoside] is a natural salicylate found in some plant species belonging primarily to the Ericaceae and Rosaceae families. Biological studies conducted since the beginning of the 21st century have suggested the potential use of gaultherin in treating various diseases related to inflammation and oxidative stress, including rheumatoid arthritis, sciatica, neuralgia, and muscular pain. The accumulated results indicated a targeted range of biological effects, particularly anti-inflammatory, antipyretic, and anti-rheumatic properties associated with reduced adverse outcomes. The molecular mechanisms involve the influence on several signalling pathways, including NF-κB, MAPK, and potentially AMPK, as well as the inhibition of critical pro-inflammatory enzymes, such as COX-2. This inhibition is achieved without affecting the COX-1 isoform, thereby preventing side effects such as bleeding ulcers or intracranial haemorrhage. This overview summarises the current knowledge about pharmacokinetics, molecular mechanisms, pharmacology, and biocompatibility of gaultherin. Additionally, four methods for isolating gaultherin from plant material and its distribution within the plant kingdom were the focal points of review and discussion. The paper also describes significant differences between synthetic aspirin and natural gaultherin in their biological potential and side effects, resulting from their different mechanisms of action. As a prodrug of salicylic acid, gaultherin releases salicylic acid gradually through enzymatic hydrolysis in the gastrointestinal tract. This controlled release minimises direct gastric irritation and accounts for its superior gastrointestinal safety profile compared to aspirin. Unlike aspirin, which irreversibly inhibits COX-1 and can lead to serious side effects with chronic use, gaultherin selectively inhibits COX-2 while sparing COX-1. These properties position gaultherin as a compelling natural alternative for patients requiring long-term anti-inflammatory therapy with reduced risk of gastrointestinal or bleeding complications. 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/Objectives: Patients with immune-mediated inflammatory diseases (IMIDs) treated with disease-modifying antirheumatic drugs (DMARDs) are at increased risk of latent tuberculosis infection (LTBI) reactivation, influenced by DMARD type. This study aimed to determine LTBI prevalence using interferon-gamma release assays (IGRAs) and identify associated risk factors in IMID patients in a middle-high TB burden setting in Mexico. Methods: A cross-sectional study was conducted from July 2024 to April 2025 at an IMID clinic. Patients aged ≥18 years, either receiving DMARDs or prior to initiating treatment, were included. LTBI was diagnosed using the QuantiFERON-TB Gold Plus assay. Bivariate analysis was performed using the chi-square test, and multivariate analysis was conducted. Results: LTBI prevalence was 34.2% (95% CI 29.1–39.7%) according to QFT-Plus and 35.6% (95% CI 29.7–42.0%) according to TSTs (n = 230). Prior TB exposure was the strongest risk factor (aOR 4.20, 95% CI 1.74–10.12, p = 0.001), while rheumatoid arthritis was associated with a lower LTBI likelihood (aOR 0.31, 95% CI 0.16–0.59, p < 0.001). Conclusions: A high prevalence of LTBI was observed in patients with IMIDs treated with DMARDs. Prior tuberculosis exposure was strongly associated with LTBI. These findings highlight the importance of LTBI screening in this population to prevent reactivation. Full article

Objective: To evaluate the role of nurses in self-management interventions for chronic inflammatory arthritis (CIA). Key areas of interest included the following: (1) providing education on self-injection techniques for biologic disease-modifying antirheumatic drugs (bDMARDs), (2) promoting healthy lifestyles, and (3) supporting mental health. Patients’ satisfaction with the care received was also examined. Methods: A cross-sectional study involving CIA patients, rheumatologists, and nurses was conducted. Participants assessed nurses’ competence in areas such as training for bDMARD self-injection, lifestyle guidance, and emotional support. Satisfaction scores and preferences in managing side effects were also analyzed. Results: The participants expressed high confidence in the nurses’ ability to support CIA self-management. The patients rated the nurses significantly higher than doctors in training for self-injection (p = 0.002) and offering guidance on nutrition and healthy habits (p = 0.002). Although it was not a statistically significant difference, the patients also showed stronger trust in the nurses’ ability to provide psychological and emotional support. Most patients (93.0%) would contact a rheumatologist in case of side effects; 35.5% would seek a nurse. The patients attended by both a doctor and nurse reported significantly higher satisfaction compared to those seen only by a rheumatologist (p < 0.001). Both the doctors and nurses acknowledged the importance of the nurse–patient relationship for effective care (p = 0.527). Conclusions: The findings highlight the critical role of nurses in patient education—particularly in training for self-injection and promoting a healthy lifestyle and mental well-being. Their involvement is strongly associated with higher patient satisfaction and contributes significantly to the overall effectiveness of care in CIA management. 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: The management of rheumatoid arthritis (RA) has advanced significantly with the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs). Despite these therapeutic strides, RA prognosis remains profoundly affected by comorbid conditions, particularly cardiovascular and metabolic complications, which increase both morbidity and mortality. The role of bDMARDs in modulating comorbidities remains underexplored, with limited evidence on their effects across various non-RA conditions, such as respiratory, diabetic, and hematologic disorders. This systematic review aimed to evaluate the impact of bDMARDs on the progression and outcomes of comorbidities in RA patients, providing insights to guide personalized treatment approaches. Methods: This systematic review was registered in PROSPERO (CRD42022345903) and followed the PRISMA guidelines. Original research articles from PubMed and Scopus, published up to 18 July 2024, were included. Studies assessing the impact of bDMARDs on comorbidities in RA patients met the eligibility criteria. Results: A total of thirteen studies met the inclusion criteria. They were published from inception until July 2024. The studied comorbidities included pulmonary conditions (asthma, chronic obstructive pulmonary disease, and interstitial lung disease) (n = 2); diabetes (n = 3); anemia (n = 3); and malignancies (n = 3). The bDMARDs studied were tumor necrosis factor inhibitors (TNFis) (n = 9); Rituximab (n = 5); Tocilizumab (n = 5); Abatacept (n = 5); and Anakinra (n = 2). The most reported effects of bDMARDs on comorbidities were the following: (i) an exacerbation of pulmonary comorbidities for Abatacept and TNFis; (ii) patients switched to or initiated on Abatacept as their first targeted disease-modifying antirheumatic drug (tDMARD) showed directionally lower rates and costs of T2DM-related complications compared with patients switching to or initiating other tDMARDs; (iii) there was no difference between Abatacept and TNFis or Rituximab/Tocilizumab regarding diabetes treatment switching or intensification; (iv) Anakinra significantly reduced the HbA1c%; (v) decreased serum hepcidin levels and improvement in anemia were observed in patients treated with TNFis or Tocilizumab; and (vi) no decrease in overall survival time or the significant incident malignancy rate was noted in RA patients. Conclusions: Overall, bDMARDs appear safe for use in RA patients with comorbidities and may even provide specific benefits for conditions such as anemia and diabetes. These findings suggest that clinicians could consider tailoring biologic therapy based on each patient’s comorbidity profile, potentially enhancing both RA management and comorbidity outcomes. For instance, selecting biologics such as Anakinra or Tocilizumab might be advantageous for RA patients with concurrent diabetes or anemia, given their observed metabolic and hematologic benefits. This personalized approach could improve the quality of life and reduce healthcare costs by addressing RA and associated comorbidities more effectively. Full article

Methotrexate (MTX), the most common first-line treatment in rheumatoid arthritis, is often insufficient, with no model capable of predicting response. The RA classification criteria, including autoantibodies and inflammation, were applied to 257 patients with newly diagnosed inflammatory arthritis in the cohort study, estimating MTX response. A total of 172 patients received MTX as the first anti-rheumatic drug and response was recorded at 1 year follow-up. A multivariable logistic regression used variables distinct between MTX-responders and non-responders to build the predictive model of response. Overall, 53.5% of MTX treated patients responded. Non-responders were frequently autoantibody positive, and responders were older, had lower RA classification scores, frequent corticosteroid use, and high insulin levels at baseline. Inflammation parameters were comparable between the groups. In the multiple regression analysis, the RA classification score and age at the first visit were strong predictors of MTX response (AUC 0.697, p < 0.0001). Including blood levels of insulin and IFNg improved AUC to 0.782 (p < 0.0001), offering early discrimination between responders and non-responders with high accuracy. Cellular experiments showed that insulin could be used to estimate MTX response by demonstrating that insulin changed the transcription of MTX target genes in the folate metabolism after exposing CD4+ cells ex vivo, which could facilitate MTX response in immune cells. Full article

Background: The introduction of biological drugs into clinical practice for the treatment of children with systemic juvenile idiopathic arthritis (sJIA) allows disease control but increases the risk of infectious events. Infectious events cause immunosuppressive therapy interruptions, leading to disease flare and life-threatening complications, namely macrophage activation syndrome. Our study aimed to evaluate the efficacy and safety of simultaneous vaccination against pneumococcal and Haemophilus influenzae type b (Hib) in children with sJIA. Methods: This study included 100 sJIA patients receiving immunosuppressive therapy who were simultaneously vaccinated against pneumococcal and Haemophilus influenzae type b (Hib) infections. The mean age of disease onset was 5.5 years. The median age at vaccination was 10 ± 4.5 years. Clinical and laboratory parameters of sJIA activity, immunization efficacy, and safety, including anti-SP and anti-Hib IgG antibodies, as well as all vaccination-related adverse events (AEs), were recorded in every patient before, 3 weeks after, and 6 months after vaccination. Results: At the time of vaccination, 29% of patients did not meet the criteria for the inactive disease stage, as defined by C. Wallace: active joints were present in 34.5% of patients, systemic manifestations (rash and/or fever) were present in 41.3%, and 24.2% of patients had solely inflammatory laboratory activity. The protective titer of anti-SP and anti-Hib IgG antibodies was detected in the majority of patients 3 weeks after vaccination (100% and 93%, respectively). The results remained unchanged (99% and 92%, respectively) for 6 months of follow-up, compared to the baseline (91% and 37%, p = 0.000001). Anti-SP IgG and anti-Hib titers raised from 48.3 (18.2; 76.5) and 0.64 (0.3; 3.2) U/mL at the baseline to 103.5 (47.3; 185.4) and 4 (3.5; 4.2) U/mL at D22 and 105 (48.7; 171.8) and 4 (3.8; 4) U/mL (EOS), respectively. Immunosuppressive therapy regimens (combined therapy or biological disease-modifying antirheumatic drug monotherapy) did not influence the immunogenic efficacy of vaccination. The incidence of infectious complications (p = 0.0000001) and antibiotic prescriptions (p = 0.0000001) decreased by more than two times, to 29.9 and 13.8 events per 100 patient months, respectively, within 6 months after vaccination—the average duration of acute infectious events was reduced by five times after immunization (p = 0.0000001). Vaccination did not lead to disease flare: the number of patients with active joints decreased by half compared to the baseline, and the number of patients with systemic manifestations decreased by six times. All vaccine-associated adverse events were considered mild and resolved within 1–2 days. Conclusions: Simultaneous vaccination against pneumococcal and Hib infections in sJIA children is an effective and safe tool that reduces the number and duration of infectious events and does not cause disease flare-ups. Full article

Background and Clinical Significance: Methotrexate is widely used as a disease-modifying antirheumatic drug for rheumatoid arthritis (RA), yet prolonged immunosuppression may lead to rare complications, including Epstein–Barr virus (EBV)-positive lymphoproliferative disorders (LPDs). Case Presentation: We present the case of a 70-year-old woman with RA on chronic immunosuppressive therapy who developed symptoms resembling recurrent tonsillitis. CT imaging revealed bilateral necrotic palatine tonsils and extensive necrotic lymphadenopathy involving the cervical, mediastinal, and axillary regions. Bilateral tonsillectomy was performed due to concerns about malignancy or infection, and histopathology confirmed a polymorphic EBV-positive LPD with Hodgkin-like features, consistent with iatrogenic immunodeficiency-associated LPD. Methotrexate was subsequently discontinued, and the patient was managed conservatively without systemic chemotherapy. Clinical recovery was observed during follow-up. Conclusions: This case highlights the importance of considering methotrexate-associated LPDs in the differential diagnosis of atypical tonsillar infections in immunosuppressed patients, particularly when necrotic features or systemic lymphadenopathy are present. The pathogenesis may involve EBV reactivation under impaired immune surveillance due to methotrexate, leading to abnormal B-cell proliferation and clonal expansion. This case is contextualized through a comparative analysis of published reports, highlighting clinical features and treatment responses of methotrexate-associated EBV-positive LPDs in the form of a focused literature review. Full article

Osteoarthritis (OA) is a multifactorial, degenerative joint disease that significantly impairs mobility and quality of life, especially among older adults. The growing aging population and increasing obesity rates are expected to increase the incidence and prevalence of OA. In the absence of Disease-Modifying Antirheumatic Drugs (DMARDs) for OA, current treatment strategies largely focus on symptom relief rather than disease modification. These symptomatic treatments often fail to account for the substantial inter-individual variability in drug response. Pharmacogenomics (PGx), the study of how genetic variation influences drug response, offers a promising approach to personalize OA therapy. This review explores the clinical and pharmacogenomic considerations of commonly used OA medications—acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), duloxetine, and tramadol—focusing on gene–drug interactions that influence efficacy, safety, and metabolism. Evidence-based recommendations from the Clinical Pharmacogenetics Implementation Consortium guidelines are discussed, where applicable, to highlight actionable genetic variants in very important pharmacogenes such as CYP2D6, CYP2C9, and other important drug-metabolizing encoding genes such as CYP2E1 and UGT1A6. While PGx data are not currently embedded in OA clinical treatment guidelines, their integration into clinical practice may enhance therapeutic outcomes and minimize adverse drug events. This review underscores the potential of PGx as a clinical tool in OA pain management, paving the way toward truly personalized medicine. Full article