Search Results (2,991)

Background/Objectives: This study aimed to evaluate the pharmacokinetics (PK), effectiveness, and safety of the direct interleukin-6 (IL-6) inhibitor olokizumab (OKZ) in adolescent patients with active polyarticular juvenile idiopathic arthritis (pJIA) who had an inadequate response or intolerance to methotrexate (MTX). Methods: We analyzed results from an open-label, single-arm trial of OKZ therapy at a dose of 64 mg every 4 weeks for 24 weeks. We evaluated pharmacokinetic (PK) parameters, clinical effectiveness, serum C-reactive protein (CRP) dynamics, and adverse events (AEs). Results: Sixteen patients were included in the study, of whom 13 (81.2%) received OKZ through Week 24. The PK profile was consistent with observations in adults with rheumatoid arthritis (RA). By Week 16, 12 (80%) patients achieved an ACRpedi30 response, 11 (73.3%) achieved an ACRpedi50 response, and 2 (13.3%) reached inactive disease status. This response was sustained through Week 24, and no disease flares were observed. A trend toward a better response was noted among patients with baseline CRP > 10 mg/L, higher baseline IL-6, and those naïve to biologic DMARDs. Twelve patients (75.0%) experienced twenty-three mild or moderate AEs. Infections were the most frequent AEs (in 6 patients, 37.5%). No serious AEs or deaths occurred. Conclusions: OKZ treatment reduced pJIA disease activity and was well tolerated. The safety profile was consistent with that of other IL-6 inhibitors, and the PK profile matched that seen in adult RA patients. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of cartilage, as well as by extra-articular manifestations. Rheumatoid nephropathy is a common complication of RA and its principal target is the renal corpuscle. Vitamin D and its analogs exert immunomodulatory actions throughout the body due to the widespread of their receptors. Our study aimed to compare the effects of cholecalciferol (vitamin D3) and alfacalcidol on renal corpuscle changes in pristane-induced RA model following a 28-day treatment, using geometric morphometrics. Forty female Wistar rats (190–210 g; 12–13 weeks old) were randomly assigned to four groups: the control (Cont) group (n = 10) received saline i.c., the PIA group (n = 10) was administered pristane i.c., PIA-ALF group (n = 10) was administered pristane i.c. and alfacalcidol orally, and the PIA-CH group (n = 10) was injected i.c. with pristane and received cholecalciferol orally. Pristane administration was used for RA induction. At the end of the experiment, the left kidneys were removed and processed by standard histological procedures for geometric morphometric analysis. Geometric morphometric analysis demonstrated that, compared with the control group, the architecture of the renal corpuscles was altered in the PIA (p < 0.0001) and PIA-CH (p = 0.0065) groups. In contrast, no statistically significant differences were observed in the PIA-ALF group (p = 0.3011). Geometric morphometric analysis demonstrated that alfacalcidol, but not cholecalciferol, exertedaprotective effect on the renal corpuscle architecture in pristane-induced rheumatoid arthritis in rats. Full article

Background: Janus kinase inhibitors (JAKi) are approved for the treatment of rheumatoid arthritis (RA), aiming to achieve clinical remission. Composite scores such as Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) are influenced by subjective factors, and JAKi may impact these dimensions beyond inflammation. Ultrasound provides a sensitive and objective assessment of synovial activity. Objective: To evaluate clinical and ultrasound-defined remission in RA patients treated with JAKi under routine care. Methods: This cross-sectional study included all consecutive patients treated with baricitinib, filgotinib, tofacitinib, or upadacitinib between 1 November 2022 and 30 April 2023. Clinical remission was defined as DAS28-CRP and ultrasound remission as absence of power Doppler (PD) signal across a standardized 32-joint evaluation. Results: We include 78 patients with established RA; 87.2% were female, with mean age of 59.5 ± 10.8 years and disease duration of 10.6 ± 8.0 years. Most were seropositive for RF and/or ACPA (74.4%), and comorbidities were highly prevalent (93.6%). Clinical remission was observed in 42.3% and ultrasound remission in 56.4%, with no statistically significant differences between JAKi groups. Among 50 patients meeting remission by either definition, 30 (60%) fulfilled both criteria, 11 (22%) had ultrasound remission only, and 9 (18%) met clinical remission without sonographic confirmation. Discordant cases were often associated with osteoarthritis, fibromyalgia, mood disorders, and elevated inflammatory markers. Conclusions: JAKi were effective in achieving remission in many RA patients. Ultrasound revealed residual synovitis despite clinial remission and, conversely, silent remission in cases not meeting DAS28-CRP criterion, reinforcing its value for accurate monitoring and personalized therapeutic decisions. No meaningful clinical or ultrasonographic differences were observed between the various JAK inhibitors, indicating comparable perfomance across agents in routine practice. Full article

Background/Objective: In recent years, artificial intelligence (AI) has gained increasing prominence in the fields of diagnostic decision-making in medicine. The aim of this study was to compare multidisciplinary team (MDT: rheumatology, pulmonology, thoracic radiology) decisions with single-session plans generated by ChatGPT-4o. Methods: In this cross-sectional concordance study, adults (≥18 years) with confirmed systemic autoimmune rheumatic disease (SARD) and having MDT decisions within the last 6 months were included. The study documented diagnostic, treatment, and monitoring decisions in cases of SARDs by recording answers to six essential questions: (1) What is the most likely clinical diagnosis? (2) What is the most likely radiological diagnosis? (3) Is there a need for anti-inflammatory treatment? (4) Is there a need for antifibrotic treatment? (5) Is drug-free follow-up appropriate? and (6) Are additional investigations required? Consequently, all evaluations were performed with ChatGPT-4o in a single-session format using a standardized single-prompt template, with the system blinded to MDT decisions. All data analyses in this study were conducted using the R programming language (version 4.3.2). An agreement between AI-generated and MDT decisions was assessed using Cohen’s Kappa (κ) statistic where κ (kappa) values represent the level of agreement: <0.20 = slight, 0.21–0.40 = fair, 0.41–0.60 = moderate, 0.61–0.80 = substantial, >0.80 = almost perfect agreement. These analyses were performed using the irr and psych packages in R. Statistical significance of the models was evaluated through p-values, while overall model fit was assessed using the Likelihood Ratio Test. Results: A total of 47 patients were involved in this study, with a predominance of female patients (61.70%, n = 29). The mean age was 61.74 ± 10.40 years. The most frequently observed diagnosis was rheumatoid arthritis (RA), accounting for 31.91% of cases (n = 15). This was followed by cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, interstitial pneumonia with autoimmune features (IPAF), and sarcoidosis. The analyses indicate a statistically significant level of agreement across all decision types. For clinical diagnosis decisions, agreement was moderate (κ = 0.52), suggesting that the AI system can reach partially consistent conclusions in diagnostic processes. The need for an immunosuppressive treatment and follow-up without medication decisions demonstrated a higher level of concordance, reaching the moderate-to-high range (κ = 0.64 and κ = 0.67, respectively). For antifibrotic treatment decisions, agreement was moderate (κ = 0.49), while radiological diagnosis decisions also fell within the moderate range (κ = 0.55). The lowest agreement—though still moderate—was observed in further investigation required decisions (κ = 0.45). Conclusions: In patients with SARDs with pulmonary involvement, particularly in complex cases, concordance was observed between MDT decisions and AI-generated recommendations regarding prioritization of clinical and radiologic diagnoses, treatment selection, suitability for drug-free follow-up, and the need for further diagnostic investigations. Full article

Three-dimensional (3D) bioprinting is a rapidly evolving technology that uses complementary biomaterials to emulate native extracellular matrices, enabling the generation of finely patterned, multicellular tissue architectures. Autoimmune diseases (AD), which are characterized by chronic, often organ-specific, immune response, are ideally suited to these in vitro models. This review summarizes the current state of 3D bioprinting for modelling AD, focusing on rheumatoid arthritis (RA), type 1 diabetes (T1D) and inflammatory bowel disease (IBD), as well as applications to systemic lupus erythematosus (SLE), neuroinflammatory conditions such as multiple sclerosis (MS) and other AD. Bioprinting modalities, advances in immune competent bioinks, strategies for vascularization and approaches to the hybridization of printed tissues with organoids and organ-on-chip systems are reviewed. From a clinical perspective, this review focuses on applications with translational potential, including immune-competent models derived from patients for biomarker discovery, drug screening and treatment response prediction. The key challenges, notably the reconstitution of full immune complexity, stable and perfusable vasculature, and maintenance of long-term viability and function are highlighted. Finally, future directions are defined to enhance the clinical utility and impact of 3D bioprinting across preclinical development and precision medicine. Full article

Background: Seronegative rheumatoid arthritis (SNRA), defined by the absence of rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA), represents 20–30% of rheumatoid arthritis cases. Once considered a milder phenotype, SNRA is now recognised as a heterogeneous entity in which a substantial subset of patients develops structural progression comparable to seropositive RA. The binary RF/ACPA-based definition is increasingly viewed as insufficient, as the broader anti-modified protein antibody (AMPA) family—including antibodies against carbamylated, acetylated and malondialdehyde–acetaldehyde–modified proteins—indicates that many “seronegative” patients may harbour unconventional humoral autoimmunity undetected by standard assays. Objectives: To synthesise contemporary insights into the epidemiology, immunopathology, diagnostic challenges and therapeutic management of SNRA, with emphasis on erosive versus non-erosive phenotypes and the implications of the AMPA paradigm. Methods: A comprehensive literature search of PubMed, Cochrane Library and Google Scholar identified randomised trials, observational cohorts and systematic reviews, with focus on studies published within the past decade. Results: SNRA displays partially distinct immune features, including lower formation of tertiary lymphoid structures and variable activation of innate inflammatory circuits. However, the traditional adaptive–versus–innate dichotomy is overly reductionist. Growing evidence suggests that unconventional humoral responses directed against non-classical post-translational modifications may be present in a proportion of RF/ACPA-negative patients. Additional qualitative dimensions—such as IgA isotypes and fine-specificity profiles—represent further heterogeneity with potential prognostic significance. Although ACPA remains the strongest predictor of erosive progression, up to one-third of seronegative patients develop erosions within five years. The 2010 ACR/EULAR criteria may delay diagnosis in SNRA. Cytokine inhibitors and JAK inhibitors show largely serostatus-independent efficacy, whereas B-cell and T-cell–targeted therapies demonstrate attenuated responses in SNRA. Conclusions: SNRA is clinically and immunologically diverse. Integrating the AMPA framework is essential for refining classification and prognostication. Distinguishing erosive from non-erosive forms may guide treatment, while future work should prioritise biomarkers predicting progression and therapeutic response. Full article

Cytokines are a diverse group of signaling proteins that regulate immune responses by mediating cell communication. Among them, interleukins (ILs) play essential roles in immune regulation, influencing diverse cell processes through tightly controlled signaling networks. Dysregulation of interleukin signaling could lead to chronic inflammation, contributing to the development of autoimmune and inflammatory diseases as well as cancer. IL-26, a cytokine of the IL-10 family, has emerged as a unique modulator of immune function. Although structurally related to IL-10 and sharing one of its receptor subunits, IL-26 exerts distinct biological effects, particularly in promoting inflammatory responses and interacting with extracellular DNA to activate immune pathways. Increasing evidence implicates IL-26 in the development of several chronic conditions, such as psoriasis, rheumatoid arthritis, inflammatory bowel disease, asthma, and various types of cancer. This review summarizes current knowledge on IL-26’s biology, including its structural and receptor characteristics, immunomodulatory functions, and roles in inflammation and disease. Understanding IL-26’s dual functions in normal and inflammatory states may provide insights into novel therapeutic strategies targeting IL-26-mediated pathways in pathological conditions. Full article

Background: Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease with a complex etiology, creating a significant unmet clinical need for safer and more effective therapeutics. Coix seed oil (CSO), a traditional Chinese medicine with a long history of use against RA, represents a promising candidate; however, its precise mechanisms of action remain largely unexplored. Objectives: This study aimed to elucidate the mechanistic basis for the anti-arthritic effects of CSO, with a specific focus on its role in modulating the gut-joint axis. Methods: A collagen-induced arthritis (CIA) rat model was employed. The therapeutic efficacy of CSO was evaluated through detailed assessments of arthritic symptoms, joint histopathology, and Micro-CT analysis. To unravel the mechanism, an integrative multi-omics approach was applied, combining untargeted fecal metabolomics with targeted serum metabolomics, which pinpointed butyric acid as a key differential metabolite. This was integrated with 16S rRNA sequencing to profile gut microbiota remodeling. The causal role of butyrate was further verified by exogenous sodium butyrate supplementation in CIA mice. Finally, network pharmacology predictions of potential effector proteins were experimentally validated in vivo using immunofluorescence and qPCR. Results: CSO treatment significantly alleviated joint swelling and bone damage in CIA rats after the treatment of 7 days, especially on day 35. CSO primarily restored gut dysbiosis in the CIA model by upregulating butyrate levels, increasing four butyrate-producing probiotics at the genus level, and reducing two pathogenic bacteria. Further exogenous butyrate supplementation validated its ability to improve RA phenotypes. Network pharmacology analysis speculated that there were 142 common targets between CSO and RA, among which NLRP3 was its potential effector protein. In vivo studies verified the suppression of NLRP3 inflammasome activation and reduced expression of subsequent inflammatory mediators by CSO. Conclusions: Coix Seed Oil alleviates RA by orchestrating a dual-mechanism action, it remodels the gut microbiota to enhance the production of the microbiotic metabolite butyrate, while also inhibiting the NLRP3 inflammasome pathway. These findings collectively elucidate that CSO mediates its anti-arthritic effects through a novel “gut-butyrate-joint” axis, underscoring its potential as a promising dietary supplement or therapeutic agent derived from medicine-food homology for the management of RA. Full article

Background: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation and progressive bone destruction. However, its complex pathogenesis remains poorly understood, and effective therapeutic targets are still lacking. Objective: This study aimed to identify key genes associated with RA and elucidate their biological significance by integrating bioinformatic analysis with experimental validation. Methods: Whole-transcriptome data from the anterior cingulate cortex (ACC) of Complete Freund’s Adjuvant (CFA)-induced inflammatory pain and control mice (GSE147216 dataset, GEO database) were collected from NCBI (National Center for Biotechnology Information). Differentially expressed genes (DEGs) were first identified. Subsequent analyses included Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, construction of a protein–protein interaction (PPI) network, and identification of hub genes using a Random Forest machine learning algorithm. Quantitative PCR (qPCR) was performed to validate gene expression levels. Results: A total of 76 DEGs were identified, including 64 upregulated and 12 downregulated genes. Among them, Fn1 (fibronectin 1), Bgn (biglycan), and Lum (lumican) were identified as hub genes. Functional enrichment analysis revealed inflammatory responses, extracellular matrix (ECM) remodeling, and the TGF-β signaling pathway. qPCR validation confirmed significant upregulation of Fn1, Bgn, and Lum mRNA in the CFA group. Conclusions: This study highlights the potential roles of Fn1, Bgn, and Lum in the central sensitization associated with inflammatory pain, offering insights relevant to RA. Full article

Background/Objectives: Serum calprotectin is a promising biomarker of inflammation in rheumatoid arthritis (RA), yet real-world longitudinal comparisons across different targeted therapies remain limited. We aimed to evaluate the dynamics and remission-predictive ability of serum calprotectin and C-reactive protein (CRP) in RA patients treated with adalimumab, upadacitinib, or tocilizumab. Methods: In this retrospective cohort study, patients with RA initiating one of the above therapies were included. Serum calprotectin and CRP were measured at baseline, month 3, and month 6. Disease activity was assessed by DAS28 and Clinical Disease Activity Index (CDAI). Linear mixed-effects models adjusted for cumulative prednisone dose were used to assess biomarker trends over time. ROC curve analyses based on CDAI remission (≤2.8) evaluated the discriminative performance of calprotectin and CRP, stratified by treatment subgroups. Results: Sixty patients were enrolled (20 receiving tocilizumab, 20 adalimumab and 20 upadacitinib). Significant reductions in serum calprotectin, CRP, and DAS28 were observed over time (p < 0.001 for all), independent of treatment group. In the overall cohort including baseline, CRP outperformed calprotectin (AUC 0.739 vs. 0.636; p = 0.044). Among patients treated with adalimumab or upadacitinib, calprotectin significantly outperformed CRP (AUC 0.929 vs. 0.857; p = 0.049). In the tocilizumab group, both biomarkers showed similar AUCs (p = 0.888). Conclusions: Serum calprotectin declined significantly after treatment initiation and outperformed CRP in identifying remission under TNFα and JAK inhibition. It also retained a good performance under IL-6 blockade. These findings support its role as a treatment-sensitive biomarker suggesting a complementary role alongside CRP in RA monitoring, particularly in settings where CRP reliability is pharmacologically suppressed. Full article

Chronic kidney disease (CKD) is a frequent and clinically significant comorbidity in patients with rheumatoid arthritis (RA), with a reported prevalence ranging from 20% to 50% depending on the cohort and definition applied. The high burden of CKD in RA reflects the complex interplay between traditional risk factors (aging, hypertension, diabetes, and dyslipidemia) and RA-specific factors such as persistent systemic inflammation, immune complex deposition, and long-term exposure to nephrotoxic agents, including older DMARDs (gold, D-penicillamine) and calcineurin inhibitors. Histopathologically, RA-associated kidney involvement encompasses a broad spectrum of conditions, including mesangial proliferative glomerulonephritis, membranous nephropathy, AA amyloidosis, and drug-induced interstitial nephritis. Recent advances in RA therapy, particularly the widespread use of biologic DMARDs, have markedly reduced the incidence of AA amyloidosis and may exert indirect renoprotective effects through stringent inflammation control. However, targeted synthetic DMARDs such as Janus kinase (JAK) inhibitors require careful dose adjustment in CKD and heightened infection vigilance. CKD in RA is a strong predictor of cardiovascular events, serious infections, and all-cause mortality. Importantly, recent data indicate that even low-grade albuminuria below the traditional microalbuminuria threshold is associated with excess mortality in RA. Early detection through routine monitoring of eGFR and urinary albumin-to-creatinine ratio (uACR), combined with individualized pharmacologic adjustment and close collaboration with nephrologists, is essential for optimizing long-term outcomes. This review provides an updated synthesis of the epidemiology, pathophysiological mechanisms, therapeutic strategies, and prognostic implications of CKD in RA, with a particular focus on both Japanese and international evidence. Full article

Progressive pulmonary fibrosis (PPF) is an emerging subset of fibrotic interstitial lung diseases (ILD), defined by progressive fibrosis despite standard treatment in patients with other than idiopathic pulmonary fibrosis. The international guidelines recommended the use of nintedanib for PPF, while evidence supporting pirfenidone remains insufficient. In this study, we aimed to evaluate the efficacy and safety of pirfenidone in treating PPF. In this retrospective single-center study, we analyzed clinical data from patients with PPF who were treated with pirfenidone. Lung function data from six months before and after pirfenidone treatment were collected to assess changes over time. Missing values were imputed using a general linear mixed model (GLMM) for longitudinal data analysis. Of 33 subjects, the median age was 65.0 years, and 51.5% were female. Rheumatoid arthritis-related ILD was the most common subtype (45.5%). The median daily dose of pirfenidone was 600 mg, with a median treatment duration of 7.3 months. GLMM analysis showed a significant forced vital capacity (FVC) improvement, from −114 mL in the 6 months before treatment to +47.3 mL in the 6 months after treatment (p = 0.001). All adverse events related to pirfenidone were mild. In conclusion, the use of pirfenidone in PPF can potentially reduce the rate of FVC decline in real clinical practice. Full article

Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint damage. Although serum biomarkers such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) are widely used, blood-based testing is invasive. Saliva has emerged as a noninvasive diagnostic medium with clinical potential. This study aimed to evaluate the potential utility of salivary calprotectin and anti-CCP antibodies for discriminating patients with RA from healthy controls. Methods: Saliva samples were collected from 58 RA patients and 50 healthy controls. Salivary calprotectin and anti-CCP antibody levels were quantified using enzyme-linked immunosorbent assay. The diagnostic performance was evaluated using receiver operating characteristic curve analysis and logistic regression models that incorporated both biomarkers and clinical variables. Results: Patients with RA exhibited significantly higher salivary calprotectin and anti-CCP levels than controls (both p < 0.001). Calprotectin showed high sensitivity (79.31%), whereas anti-CCP displayed high specificity (84.00%). Salivary calprotectin was associated with disease duration and joint damage, while anti-CCP correlated with the erythrocyte sedimentation rate, RF, and serum anti-CCP. A multivariate model combining salivary biomarkers with clinical factors indicated an excellent diagnostic discrimination. Conclusions: Salivary calprotectin and anti-CCP antibodies show potential as complementary noninvasive biomarkers for distinguishing patients with established RA from healthy controls. However, as saliva samples were not collected at the time of initial diagnosis, these findings primarily support disease discrimination rather than early detection. Further prospective studies involving newly diagnosed and at-risk populations are required to clarify their role in early diagnosis, monitoring, and clinical implementation. Full article

The relationship between the oral microbiome and autoimmune diseases (ADs) has attracted considerable research interest. This study employed two-sample Mendelian randomization (MR) to investigate causal relationships between oral microbiota and six ADs, including rheumatoid arthritis (RA), type 1 diabetes (T1D), inflammatory bowel disease (IBD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS). Using genome-wide association study data from oral microbiome features and ADs, we applied inverse-variance weighted estimation complemented by sensitivity analyses and reverse MR to assess robustness and reverse causation. Analysis of 309 tongue dorsum and 285 salivary microbial features identified four tongue dorsum and five salivary taxa with genome-wide significant causal effects. Specific microbial taxa from both oral niches demonstrated protective or risk-enhancing effects for RA, T1D, IBD, and MS, while no causal associations were found for SLE or SS. These findings establish the causal role of specific oral microbiota in autoimmune pathogenesis and highlight priority candidates for further investigation as potential microbial biomarkers. Full article

Connective tissue disease-associated interstitial lung disease (CTD-ILD) comprises a heterogeneous group of immune-mediated pulmonary disorders with significant morbidity and mortality. The pathogenesis involves complex interactions of autoimmunity, chronic inflammation, and fibrosis. B cells play a central role in these processes through antigen presentation, autoantibody production, cytokine secretion, and the formation of ectopic lymphoid tissue within the lung parenchyma. Rituximab (RTX)—a chimeric anti-CD20 monoclonal antibody—depletes B cells and has emerged as a promising therapeutic agent for CTD-ILD. This review comprehensively presents the immunopathogenic mechanisms underlying CTD-ILD, elaborating on the multifaceted mode of action of RTX and summarizing the evolving clinical evidence. Full article