Autoimmune Inflammatory Disease Research Articles

Efficacy of N-Acetylcysteine as an Adjuvant Therapy for Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Aims/Background Rheumatoid arthritis (RA) is an inflammatory autoimmune disease and N-acetylcysteine (NAC) is considered a potential therapeutic agent for RA due to strong antioxidant and anti-inflammatory properties. Therefore, this systematic review and meta-analysis aimed to evaluate the efficacy of NAC as an adjuvant therapy for RA. Methods A systematic search was conducted across five databases from inception to 1 August 2024, including CINAHL, Cochrane Library, EMBASE, PubMed, and Web of Science. The Cochrane risk-of-bias tool for randomized trials was used to assess the quality of the included studies. Sensitivity analysis was performed when significant heterogeneity was identified. Results Four studies involving 204 patients were included in our meta-analysis. The results indicated that NAC alleviated disease activity in RA patients (Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR): mean difference (MD) = 0.54). Additionally, NAC reduced inflammatory markers (erythrocyte sedimentation rate (ESR): MD = 3.00). However, the beneficial effects of NAC on oxidative stress in RA patients were not observed. Conclusion This meta-analysis demonstrated the efficacy of NAC in reducing inflammatory markers, improving joint tenderness, and swelling in patients with RA.

Efficacy and safety of Piclidenoson in the treatment of plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials.

Psoriasis, an autoimmune inflammatory disease characterized by hyperproliferation of keratinocytes, affects 0.2-4.8% of the global population. The disease manifests primarily as plaque psoriasis, causing chronic physical and psychological burdens. Although numerous treatments exist, there is ongoing exploration for novel therapies due to concerns about the toxicity, efficacy, and costs of current options. An A3 adenosine receptor (A3AR) agonist called Piclidenoson has been shown to reduce inflammation and could be used to treat moderate to severe psoriasis. This meta-analysis evaluates the safety and efficacy of Piclidenoson in psoriasis treatment. This meta-analysis was conducted accordance with the PRISMA guidelines and has been registered on PROSPERO (CRD42024566459). A comprehensive search on Cochrane CENTRAL, PubMed/MEDLINE, and Google Scholar was conducted up to July 2024. Included studies were randomized controlled trials (RCTs) involving Piclidenoson. Efficacy outcomes included PASI 75 and PGA 0 or 1, while safety outcomes included adverse events. Pooled outcomes were presented as odds ratio (OR) with 95% confidence intervals (CI). Statistical analysis employed the Mantel-Haenszel random-effects model, and heterogeneity was assessed using the I2 and X2index. Three RCTs with 574 patients (313 Piclidenoson, 261 placebo) met the inclusion criteria. The pooled analysis showed no significant difference in achieving PASI 75 between Piclidenoson and placebo (OR: 1.62, 95% CI 0.70-3.75, P = 0.26, I2 = 12%). However, Piclidenoson significantly improved PGA scores (OR: 2.74, 95% CI 1.22-6.16, P = 0.01, I²=0%). Safety assessment revealed no significant differences in adverse events, including nervous system, gastrointestinal, musculoskeletal, renal, and infections, compared to placebo. Piclidenoson demonstrates a significant improvement in PGA scores and a favorable safety profile, suggesting it could be a valuable addition to plaque-like psoriasis treatment. Further research with larger, longer-term RCTs is needed to confirm its efficacy and optimize clinical use.

Immunomodulatory effects of HYCO-3, a dual action CO-releaser/Nrf2 activator.

HYCOs are hybrid molecules consisting of activators of the transcription factor Nrf2 conjugated to carbon monoxide (CO)-releasing moieties. These "dual action" compounds have been designed to mimic the activity of heme oxygenase-1 (HO-1), a stress inducible cytoprotective enzyme that degrades heme to CO which expression is regulated by Nrf2. HYCOs have recently shown efficacy in ameliorating experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, the mechanism(s) of action of HYCOs still remain to be fully investigated. Here, we assessed the effects of HYCO-3, a prototype of these hybrids, on myeloid-derived cells, microglial cells and T lymphocytes obtained from EAE-immunized mice. HYCO-3 exerted immunomodulatory effects on all the examined cell populations by inhibiting the generation of pro-inflammatory cytokines and nitric oxide, and downregulating antigen-presenting capacity of these cells. The observed effects support the view that HYCOs are promising candidates to be developed for the treatment of autoimmune and chronic inflammatory disorders.

Impact of Gut Microbiota on the Development of Diseases

Aim: The aim of this article is to review the latest scientific research on the influence of intestinal microbiota on the development of diseases. In this article we will discuss the importance of the intestinal microbiota, the differences in the composition of the microbiota between healthy and sick people and the relationship between the intestinal microbiota and metabolic, inflammatory, cardiovascular and neurodegenerative diseases. Abbreviated description of the state of knowledge: The gut microbiota plays a key role in human health by influencing the development and progression of various diseases. Numerous studies have shown that an imbalance in gut microbiota, called dysbiosis, may be linked to a number of conditions. Intestinal microflora interacts with the immune system, modulates inflammation and influences metabolic pathways, which emphasizes its importance in the development of diseases. Conclusions: Intestinal microflora is crucial to health, regulating immune, metabolic and neurological functions. Dysbiosis, i.e. disturbance of the balance of intestinal microflora, is associated with diseases such as type 2 diabetes, obesity, inflammatory bowel diseases, allergies, autoimmune diseases and neuropsychiatric disorders. Healthy microflora, influenced by diet, pH and nutrients, are essential for metabolism, immune system regulation and neuronal communication. Recently, scientists have become interested in the possibility of using this knowledge in treatment. Appropriate dietary management, probiotic supplementation and fecal microflora transplantation show promising potential. Future research should focus on elucidating the specific mechanisms by which the gut microbiota influences disease processes and developing targeted therapies to exploit the therapeutic potential of the microbiota.

Development of a Panel of Biomarkers for Differential Diagnosis of Multiple Sclerosis.

Demyelinating diseases are a group of heterogeneous pathologies that affect the nervous system and reduce the quality of life. One of such diseases is multiple sclerosis (MS), an inflammatory autoimmune neurodegenerative disease of the central nervous system (CNS). At the initial stages, MS can mimic some infectious, neoplastic, genetic, metabolic, vascular, and other pathologies. Accurate differential diagnosis of this disease is important to improve the quality of life of patients and reduce possible irreversible damage to the central nervous system. In this work, we confirmed the possibility of using our previously proposed candidate panel of MS biomarkers to distinguish MS from neuromyelitis optica spectrum disorder (NMOSD) and amyotrophic lateral sclerosis (ALS). We have shown that our proposed panel (SPTAN1601-644 + PRX451-494 + PTK6301-344 + LMP1285-330) allows us to distinguish MS from ALS (AUC = 0.796) and NMOSD (AUC = 0.779).

Gut dysbiosis mediates the association between antibiotic exposure and chronic disease

Antibiotics are safe, effective drugs and continue to save millions of lives and prevent long-term illness worldwide. A large body of epidemiological, interventional and experimental evidence shows that exposure to antibiotics has long-term negative effects on human health. We reviewed the literature data on the links between antibiotic exposure, gut dysbiosis, and chronic disease (notably with regard to the “developmental origins of health and disease” (“DOHaD”) approach). Molecular biology studies show that the systemic administration of antibiotic to infants has a rapid onset but also often a long-lasting impact on the microbial composition of the gut. Along with other environmental factors (e.g., an unhealthy “Western” diet and sedentary behavior), antibiotics induce gut dysbiosis, which can be defined as the disruption of a previously stable, functionally complete microbiota. Gut dysbiosis many harmful long-term effects on health. Associations between early-life exposure to antibiotics have been reported for chronic diseases, including inflammatory bowel disease, celiac disease, some cancers, metabolic diseases (obesity and type 2 diabetes), allergic diseases, autoimmune disorders, atherosclerosis, arthritis, and neurodevelopmental, neurodegenerative and other neurological diseases. In mechanistic terms, gut dysbiosis influences chronic disease through direct effects on mucosal immune and inflammatory pathways, plus a wide array of direct or indirect effects of short-chain fatty acids, the enteric nervous system, peristaltic motility, the production of hormones and neurotransmitters, and the loss of intestinal barrier integrity (notably with leakage of the pro-inflammatory endotoxin lipopolysaccharide into the circulation). To mitigate dysbiosis, the administration of probiotics in patients with chronic disease is often (but not always) associated with positive effects on clinical markers (e.g., disease scores) and biomarkers of inflammation and immune activation. Meta-analyses are complicated by differences in probiotic composition, dose level, and treatment duration, and large, randomized, controlled clinical trials are lacking in many disease areas. In view of the critical importance of deciding whether or not to prescribe antibiotics (especially to children), we suggest that the DOHaD concept can be logically extended to “gastrointestinal origins of health and disease” (“GOHaD”) or even “microbiotic origins of health and disease” (“MOHaD”).

Collagen triple helix repeat-containing 1 protein: an emerging biomarker and its influence on the clinical and sonographic disease severity in Egyptian medicated female rheumatoid arthritis patients

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of synovial joints, with a multifactorial etiology. Collagen triple helix repeat-containing 1 protein (CTHRC1) is a biomarker produced by fibroblast-like synoviocytes, which was shown to be highly expressed in RA patients. The study aimed to measure serum CTHRC1 level in female RA patients currently on medical treatment and its influence on the clinical and sonographic severity of the disease.ResultsThe patients’ mean age was 43.39 ± 8.55 years and median RA disease duration of 5.5 (0.33–20) years. RA patients showed significantly higher serum CTHRC1 level [89.71 ng/ml (53.95–353.45)] in comparison to controls [87.38 ng/ml (44.47–110.3)] (U = 430, P = 0.014). Furthermore, higher serum CTHRC1 levels were recorded in seropositive versus seronegative patients (U = 76, P = 0.022) and in RA patients with severe disease activity compared to those with lower disease activity (H = 9.79, P = 0.007). Furthermore, serum CTHRC1 levels were lower in RA patients receiving biological therapy compared to those receiving conventional therapy; however, this difference did not reach statistical significance.Significant positive correlations were found between CTHRC1 and disease activity, acute-phase reactants, serological markers, functional assessment, fatigue, and erosions detected by ultrasound, while a significant negative correlation was recorded between CTHRC1 and duration of biologic intake (rs = − 0.45, P = 0.036). Furthermore, on multivariate linear regression analysis, serum CTHRC1 was the only significant predictor for higher disease activity (P = 0.028, B = 0.009, 95% CI 0.001 to 0.017).ConclusionRA patients showed higher CTHRC1 serum levels compared to healthy controls, especially those with seropositivity and highly active disease. Furthermore, it was positively associated with poor patient functional outcome, fatigability, and erosive findings by ultrasound, thus suggesting that serum CTHRC1 can be a good predictor for high RA disease activity and possibly severity. Moreover, biological therapy could influence serum CTHRC1 levels in these patients.

Multiscale, mechanistic model of Rheumatoid Arthritis to enable decision making in late stage drug development

Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease that affects about 0.1% to 2% of the population worldwide. Despite the development of several novel therapies, there is only limited benefit for many patients. Thus, there is room for new approaches to improve response to therapy, including designing better trials e.g., by identifying subpopulations that can benefit from specific classes of therapy and enabling reverse translation by analyzing completed clinical trials. We have developed an open-source, mechanistic multi-scale model of RA, which captures the interactions of key immune cells and mediators in an inflamed joint. The model consists of a treatment-naive Virtual Population (Vpop) that responds appropriately (i.e. as reported in clinical trials) to standard-of-care treatment options—Methotrexate (MTX) and Adalimumab (ADA, anti-TNF-α) and an MTX inadequate responder sub-population that responds appropriately to Tocilizumab (TCZ, anti-IL-6R) therapy. The clinical read-outs of interest are the American College of Rheumatology score (ACR score) and Disease Activity Score (DAS28-CRP), which is modeled to be dependent on the physiological variables in the model. Further, we have validated the Vpop by predicting the therapy response of TCZ on ADA Non-responders. This paper aims to share our approach, equations, and code to enable community evaluation and greater adoption of mechanistic models in drug development for autoimmune diseases.

ROLE OF INNATE IMMUNE RECEPTORS IN THE PSORIASIS DEVELOPMENT

Psoriasis is an immune-mediated autoimmune inflammatory skin disease with a prevalence of 2 to 3% worldwide. In the psoriasis development and pathogenesis an important role is played by disorders in the immune system. Disruption of the innate and adaptive immune response mechanisms with the involvement of keratinocytes leads to the initiation and maintenance of inflammation. Immune reactions are activated in the skin, in which various cells participate (macrophages, dendritic cells, mast cells, innate immune lymphoid cells, melanocytes, keratinocytes, Langerhans cells and γδT cells; T and B cells; epithelial endothelial and stromal cells of the skin), each of which expresses pattern recognition receptors that respond to pathogens and cell damage itself. Many of these receptors, in particular Toll-like receptors and NOD-like receptors play an important role in the pathogenesis of psoriasis. The associated innate receptors signaling cascades that activate in the skin cells may become potential targets for the treatment of this disease. To date, there are several approved drugs for biological therapy of psoriasis. The study of the role of the innate immune cells receptors in inflammatory skin pathologies requires further exploration and new developments.

Neuropsychiatric Symptoms in Corticosteroid Induced Systemic Lupus Erythematosus (Sle) Patients: a Case Report

Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with an unknown etiology and various clinical manifestations, course, and prognosis. Classes of medication used in the management of SLE include non-biological immunosuppressives, corticosteroids, biologic therapy, and immunoglobulins. The effect of using corticosteroids in the management of SLE still evokes debate regarding the emergence of mental health disorders. Case: A 24-year-old female patient was admitted to the hospital with an initial diagnosis of acute confusional stage, anemia, chronic disease, and systemic lupus erythematosus (SLE). Anticonvulsants, corticosteroids, and packed red blood transfusions had been given to the patient. The course of the disease during the hospitalization the next days, the patient experienced slurred speech, giggling, place and time disorientation, and visual hallucinations. The patient was consulted to a psychiatrist, got atypical antipsychotics and benzodiazepines, and then experienced improvement. Discussion: Patients with moderate SLE, in this case characterized by lupus nephritis, were given corticosteroids. Administration of corticosteroids to SLE patients will increase the risk of developing neuropsychiatric symptoms such as acute confusional state, anxiety, mood disorders, cognitive disorders, and seizures. This can occur due to increased permeability of the blood-brain barrier mediated by pro-inflammatory cytokines, resulting in the formation of autoantibodies against neural antigens, in which phospholipid proteins appear intracranially. Conclusion: Corticosteroid administration in SLE will cause neuropsychiatric symptoms such as slurred speech, giggling to herself, delirium, and visual hallucinations. Further design studies are needed to address the neuropsychiatric effects of corticosteroids in SLE.

Recent Progress in Microenvironment-Responsive Nanodrug Delivery Systems for the Targeted Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that often causes joint pain, swelling, and functional impairments. Drug therapy is the main strategy used to alleviate the symptoms of RA; however, drug therapy may have several adverse effects, such as nausea, vomiting, abdominal pain, diarrhea, gastric ulcers, intestinal bleeding, hypertension, hyperglycemia, infection, fatigue, and indigestion. Moreover, long-term excessive use of drugs may cause liver and kidney dysfunction, as well as thrombocytopenia. Nanodrug delivery systems (NDDSs) can deliver therapeutics to diseased sites with the controlled release of the payload in an abnormal microenvironment, which helps to reduce the side effects of the therapeutics. Abnormalities in the microenvironment, such as a decreased pH, increased expression of matrix metalloproteinases (MMPs), and increased concentrations of reactive oxygen species (ROS), are associated with the progression of RA but also provide an opportunity to achieve microenvironment-responsive therapeutic release at the RA site. Microenvironment-responsive NDDSs may overcome the abovementioned disadvantages of RA therapy. Herein, we comprehensively review recent progress in the development of microenvironment-responsive NDDSs for RA treatment, including pH-, ROS-, MMP-, and multiresponsive NDDSs. Furthermore, the pathological microenvironment is highlighted in detail.

Connecting the dots: NETosis and the periodontitis-rheumatoid arthritis nexus.

Periodontitis (PD) is characterized by the host's inflammatory responses to microbial dental biofilm dysbiosis, potentially resulting in tooth loss if left untreated. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease leading to synovial inflammation and destruction of joint cartilage and bone. The suggested association between PD and RA is based on the potential of chronic inflammation present in periodontitis, which could induce alterations in proteins through post-translational modifications, leading to the formation of citrullinated and carbamylated protein antigens. Antibodies directed against these antigens can serve as biomarkers for the underlying immunological processes in RA. Recent studies have also focused on bacterial proteolytic enzymes released from PD-associated bacteria, such as Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans, which are also sources of these antibodies. Chronic inflammation in PD causes increased levels of inflammatory cytokines (interferon-α, interleukins-6 and 8, tumor necrosis factor-α) and neutrophil extracellular traps (NETs). The oral microbiota in PD is also associated with the release of NETs (a process known as NETosis). Elevated NET levels are a source of citrullinated and carbamylated proteins which highlights their role in an individual's risk of developing RA (pre-RA individuals) and the progression of chronic RA. This narrative review describes periodontitis and the dysbiotic subgingival microbiota and its role in NETosis as risk factors for inducing early RA and the prospects of identifying pre-RA individuals and seronegative RA patients with these risk factors.

Immune-Mediated Inflammatory Diseases, Dyslipidemia, and Cardiovascular Risk: A Complex Interplay.

Individuals with autoimmune inflammatory diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, are at increased risk for cardiovascular disease. While these diseases share common features of systemic inflammation, the impact of individual autoimmune inflammatory conditions on circulating lipids and lipoproteins varies by specific disease, disease activity, and the immune-suppressing medications used to treat these conditions. A common feature observed in many autoimmune inflammatory diseases is the development of a proatherogenic dyslipidemic state, characterized by dysfunctional HDLs (high-density lipoproteins) and increased oxidation of LDLs (low-density lipoproteins). Various disease-modifying antirheumatic drugs also have complex and variable effects on lipids, and it is critical to take this into consideration when evaluating lipid-related risk in individuals with immune-mediated inflammatory conditions. This review aims to critically evaluate the current understanding of the relationship between immune-mediated inflammatory diseases and dyslipidemia, the underlying mechanisms contributing to atherogenesis, and the impact of various pharmacotherapies on lipid profiles and cardiovascular risk. We also discuss the role of lipid-lowering therapies, particularly statins, in managing residual risk in this high-risk population and explore the potential of emerging therapies with complementary anti-inflammatory and lipid-lowering effects.

HLA-DRB1*01 predicts treatment outcome in juvenile idiopathic arthritis: A retrospective-prospective cohort study.

Juvenile idiopathic arthritis (JIA) is the most common chronic inflammatory autoimmune disease in childhood, significantly contributing to both short- and long-term disability. While certain human leukocyte antigen (HLA) class II alleles are known to be associated with specific subgroups of JIA, emerging evidence suggests a strong correlation between these alleles and treatment response. This study involved 143 JIA patients diagnosed according to International League of Associations for Rheumatology criteria. Each patient underwent HLA class II typing, including HLA-B27, as well as tests for rheumatoid factor (RF) and antinuclear antibodies (ANA). Comprehensive rheumatological assessments were conducted at diagnosis, with follow-ups at three and six months post-onset. After six months of methotrexate (MTX) treatment, patients were categorized as responders or non-responders. Responders achieved clinically inactive disease based on the American College of Rheumatology Provisional Criteria for Defining Clinical Inactive Disease and Clinical Remission. Non-responders, who did not reach clinically inactive disease after six months of treatment, required the addition of another non-biological disease-modifying antirheumatic drug (DMARD) or a biological DMARD. Our analysis revealed that the HLA-DRB1*01 allele is a significant prognostic marker for therapeutic response, predicting therapeutic resistance (P=0.01). The most prevalent HLA-DRB1 alleles in the treatment-resistant group were HLA-DRB1*08:11 (11.3%), HLA-DRB1*01:01 (8.5%), HLA-DRB1*01:13, HLA-DRB1*04:11 (7%), HLA-DRB1*08:13, and HLA-DRB1*08:15 (4.2%). These findings highlight the critical role of HLA class II alleles in pediatric rheumatology, particularly in relation to treatment response and disease prognosis. In the era of personalized medicine, understanding the genetic contributions to treatment response and outcomes in JIA patients is essential. A key limitation of this study was the lack of comparison of treatment responses across different JIA subtypes. Future studies should prioritize evaluating MTX efficacy within specific JIA subgroups to enable a more tailored understanding of its effectiveness.

N-acetyltransferase 10 is implicated in the pathogenesis of cycling T cell-mediated autoimmune and inflammatory disorders in mice

T cell expansion has a crucial function in both autoimmune and chronic inflammatory diseases, with cycling T cells contributing to the pathogenesis of autoimmune diseases by causing uncontrolled immune responses and tissue damage. Yet the regulatory mechanisms governing T cell expansion remain incompletely understood. Here we show that the enzyme N-acetyltransferase 10 (NAT10) regulates T cell activation and proliferation upon antigen stimulation. T cell-specific NAT10 deficiency in mice reduces the number of mature T cells in peripheral lymphoid organs. Mechanistically, NAT10 acetylates RACK1 at K185, preventing subsequent RACK1 K48-linked ubiquitination and degradation. The increased RACK1 stability alters ribosome formation and cellular metabolism, leading to enhanced supply of energy and biosynthetic precursors and, eventually, T cell proliferation. Our findings thus highlight the essential function of NAT10 in T cell self-renewal and metabolism and elucidate NAT10 mode of action for the potential development of novel therapies for immune-related disorders.

Information and communication technology-based patient education for autoimmune inflammatory rheumatic diseases: A scoping review

ObjectiveThis review aimed to map the existing the information and communication technology (ICT)-based patient education for autoimmune inflammatory rheumatic diseases and identify key effectiveness factors and guidelines for professionals. MethodsA scoping review systematically reviewed PubMed, Cochrane library, EMBASE and Web of Science. We designed search strategies to identify ICT-based patient education for autoimmune inflammatory rheumatic diseases focused on rheumatoid arthritis, ankylosing spondylitis, and systemic lupus erythematosus, published between January 2011 and October 2023. Data extraction was independently screened by two reviewers according to the eligibility criteria. ResultsOf 13,861 records, 18 met the eligibility criteria. Most studies were randomized controlled trials, primarily conducted in the USA, focusing on rheumatoid arthritis. ICT-based interventions included web-based platforms, aiming to improve self-management, medication adherence, with most interventions showing significant improvements. Digital tools such as websites, chatbots were common. Five groups representing the ICT functions were identified: digital self-management tools, multimedia learning materials, personalized educational sessions, behavior change and empathy games, and interactive online communities and peer support. Most studies lacked theoretical frameworks, or guidelines for developing patient education. ConclusionICT-based patient education has significant potential for enhancing self-management and behavior changes in patients with autoimmune inflammatory rheumatic diseases.

Exercise for improving bone health in patients with AIRDs: Understanding underlying biology and physiology.

Exercise has numerous health benefits in patients with autoimmune inflammatory rheumatic diseases (AIRDs). Regular physical activity can help maintain/improve bone health. The aim of the present article was to review current knowledge on the effects of exercise on bone health in patients with AIRDs, particularly in those experiencing a high corticosteroid burden. The article also aimed to discuss potential mechanisms underlying the benefits of physical activity/exercise on bone tissue. Potential explanations regarding the role of exercise on bone health in AIRDs include anti-inflammatory effects, mechanical loading, improvement in muscle strength, hormonal changes, improvement in balance, and effects on telomere erosion, deoxyribonucleic acid methylation, and gene expression. Current evidence regarding the outcomes of exercise on bone health in patients with AIRDs is predominantly derived from studies focused on rheumatoid arthritis. Expanding research to include other rheumatic conditions would enhance the overall understanding of this topic.

Association of inflammation with left ventricular mass index in patients with rheumatoid arthritis

Abstract Background Rheumatoid arthritis (RA) is an inflammatory autoimmune disease associated with cardiovascular organ damage. Purpose We explored the association of inflammatory markers with left ventricular (LV) mass index during 22 months of follow-up in patients with RA. Methods Eighty-three outpatients with RA (age 55±12 years, 71 % women) with indication for biological (b) or targeted synthetic (ts) disease modifying antirheumatic drug (DMARD) therapy were examined with echocardiography at baseline and after 22 months. LV mass was indexed for height in the allometric power of 2.7. Serum concentrations of the inflammatory markers, C-reactive protein (CRP), serum amyloid A (SAA) and calprotectin were measured by MALDI-TOF mass spectrometry. Results At baseline, 37% had hypertension, 6% diabetes, 21% obesity and 100% were using b/ts DMARDs. The inflammatory markers decreased during follow-up (all p<0.001), while the LV mass index did not change (33.1±8.1 g/m^2.7 vs. 33.5±7.3 g/m^2.7, p=0.57). The prevalence of hypertension, diabetes and obesity were unchanged at follow-up (p>0.05), but the percentage of patients using b/ts DMARDs had decreased to 83% (p<0.001). In multivariable analyses, higher CRP and SAA at baseline were associated with higher LV mass index at both baseline and follow-up independent of presence of obesity, hypertension, age, sex or treatment with b/ts DMARDs at follow-up (Table 1). Inflammatory markers at follow-up were not associated with LV mass index (Table 1), but use of b/ts DMARDs at follow-up were associated with lower LV mass index after adjusting for inflammatory markers, age, sex, presence of obesity and hypertension (Table 1). Conclusion Higher levels of inflammatory markers at baseline were associated with greater LV mass index in RA patients. The use of immunosuppressive treatment throughout the study period was associated with lower LV mass index at follow-up, pointing to a role of chronic inflammation in LV hypertrophy.

TNF inhibitors target a mevalonate metabolite/TRPM2/calcium signaling axis in neutrophils to dampen vasculitis in Behçet’s disease

TNF inhibitors have been used to treat autoimmune and autoinflammatory diseases. Here we report an unexpected mechanism underlying the therapeutic effects of TNF inhibitors in Behçet’s disease (BD), an autoimmune inflammatory disorder. Using serum metabolomics and peripheral immunocyte transcriptomics, we find that polymorphonuclear neutrophil (PMN) from patients with BD (BD-PMN) has dysregulated mevalonate pathway and subsequently increased farnesyl pyrophosphate (FPP) levels. Mechanistically, FPP induces TRPM2-calcium signaling for neutrophil extracellular trap (NET) and proinflammatory cytokine productions, leading to vascular endothelial inflammation and damage. TNF, but not IL-1β, IL-6, IL-18, or IFN-γ, upregulates TRPM2 expression on BD-PMN, while TNF inhibitors have opposite effects. Results from mice with PMN-specific FPP synthetase or TRPM2 deficiency show reduced experimental vasculitis. Meanwhile, analyses of public datasets correlate increased TRPM2 expressions with the clinical benefits of TNF inhibitors. Our results thus implicate FPP-TRPM2-TNF/NETs feedback loops for inflammation aggravation, and novel insights for TNF inhibitor therapies on BD.

Advances in the study of artemisinin and its derivatives for the treatment of rheumatic skeletal disorders, autoimmune inflammatory diseases, and autoimmune disorders: a comprehensive review.

Artemisinin and its derivatives are widely recognized as first-line treatments for malaria worldwide. Recent studies have demonstrated that artemisinin-based antimalarial drugs, such as artesunate, dihydroartemisinin, and artemether, not only possess excellent antimalarial properties but also exhibit antitumor, antifungal, and immunomodulatory effects. Researchers globally have synthesized artemisinin derivatives like SM735, SM905, and SM934, which offer advantages such as low toxicity, high bioavailability, and potential immunosuppressive properties. These compounds induce immunosuppression by inhibiting the activation of pathogenic T cells, suppressing B cell activation and antibody production, and enhancing the differentiation of regulatory T cells. This review summarized the mechanisms by which artemisinin and its analogs modulate excessive inflammation and immune responses in rheumatic and skeletal diseases, autoimmune inflammatory diseases, and autoimmune disorders, through pathways including TNF, Toll-like receptors, IL-6, RANKL, MAPK, PI3K/AKT/mTOR, JAK/STAT, and NRF2/GPX4. Notably, in the context of the NF-κB pathway, artemisinin not only inhibits NF-κB expression by disrupting upstream cascades and/or directly binding to NF-κB but also downregulates multiple downstream genes controlled by NF-κB, including inflammatory chemokines and their receptors. These downstream targets regulate various immune cell functions, apoptosis, proliferation, signal transduction, and antioxidant responses, ultimately intervening in systemic autoimmune diseases and autoimmune responses in organs such as the kidneys, nervous system, skin, liver, and biliary system by modulating immune dysregulation and inflammatory responses. Ongoing multicenter randomized clinical trials are investigating the effects of these compounds on rheumatic, inflammatory, and autoimmune diseases, with the aim of translating promising preclinical data into clinical applications.