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Calcium/calmodulin-dependent protein kinase IV (CaMK4) serves as a pivotal mediator in the regulation of gene expression, influencing the activity of transcription factors within a variety of immune cells, including T cells. Altered CaMK4 signaling is implicated in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and psoriasis, which are characterized by dysregulated immune responses and clinical complexity. These conditions share common disturbances in immune cell functionality, cytokine production, and autoantibody generation, all of which are associated with disrupted calcium-calmodulin signaling. This review underscores the consequences of dysregulated CaMK4 signaling across these diseases, with an emphasis on its impact on Th17 differentiation and T cell metabolism-processes central to maintaining immune homeostasis. A comprehensive understanding of roles of CaMK4 in gene regulation across various autoimmune disorders holds promise for the development of targeted therapies, particularly for diseases driven by Th17 cell dysregulation.
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Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Humanos , Calmodulina/metabolismo , Calmodulina/uso terapêutico , Cálcio/metabolismo , Cálcio/uso terapêutico , Diferenciação Celular , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/metabolismo , Doenças Autoimunes/genética , Doenças Autoimunes/metabolismo , Células Th17RESUMO
OBJECTIVES: Monocyte-derived dendritic cells (DCs) are key players in the induction of inflammation, autoreactive T cell activation and loss of tolerance in rheumatoid arthritis (RA), but the precise mechanisms underlying their activation remain elusive. Here, we hypothesized that extracellular microRNAs released in RA synovial fluids may represent a novel, physiological stimulus triggering unwanted immune response via TLR8-expressing DC stimulation. METHODS: Human monocyte-derived DCs were stimulated with a mixture of GU-rich miRNAs upregulated in RA tissues and released in synovial fluids (Ex-miRNAs). Activation of DCs was assessed in terms of NF-κB activation by Western blot, cytokine production by ELISA, T cell proliferation and polarization by allogeneic mixed lymphocyte reaction. DC differentiation into osteoclasts was evaluated in terms of tartrate-resistant acid phosphatase production and formation of resorption pits in dentine slices. Induction of joint inflammation in vivo was evaluated using a murine model of DC-induced arthritis. TLR7/8 involvement was assessed by specific inhibitors. RESULTS: Ex-miRNAs activate DCs to secrete TNFα, induce joint inflammation, start an early autoimmune response and potentiate the differentiation of DCs into aggressive osteoclasts. CONCLUSIONS: This work represents a proof of concept that the pool of extracellular miRNAs overexpressed in RA joints can act as a physiological activator of inflammation via the stimulation of TLR8 expressed by human DCs, which in turn exert arthritogenic functions. In this scenario, pharmacological inhibition of TLR8 might offer a new therapeutic option to reduce inflammation and osteoclast-mediated bone destruction in RA.
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Artrite Reumatoide , Diferenciação Celular , Células Dendríticas , MicroRNAs , Osteoclastos , Receptor 7 Toll-Like , Receptor 8 Toll-Like , Humanos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , MicroRNAs/genética , Receptor 8 Toll-Like/metabolismo , Osteoclastos/metabolismo , Osteoclastos/imunologia , Animais , Receptor 7 Toll-Like/metabolismo , Camundongos , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Células Cultivadas , Feminino , MasculinoRESUMO
BACKGROUND: Rheumatoid arthritis (RA) is a chronic inflammatory disease induced by TNF-α, which increases fibroblast-like synoviocytes inflammation, resulting in cartilage destruction. The current work sought to comprehend the pathophysiological importance of TNF-α stimulation on differential protein expression and their regulation by apigenin using in-vitro and in-vivo models of RA. METHODS: The human RA synovial fibroblast cells were stimulated with or without TNF-α (10 ng/ml) and treated with 40 µM apigenin. In-silico, in-vitro and in-vivo studies were performed to confirm the pathophysiological significance of apigenin on pro-inflammatory cytokines and on differential expression of TTR and RAGE proteins. RESULTS: TNF-α induced inflammatory response in synoviocytes revealed higher levels of IL-6, IL-1ß, and TNF-α cytokines and upregulated differential expression of TTR and RAGE. In-silico results demonstrated that apigenin has a binding affinity towards TNF-α, indicating its potential effect in the inflammatory process. Both in-vitro and in-vivo results obtained by Western Blot analysis suggested that apigenin reduced the level of p65 (p = 0.005), TTR (p = 0.002), and RAGE (p = 0.020). CONCLUSION: The findings of this study suggested that TNF-α promotes the differential expression of pro-inflammatory cytokines, TTR, and RAGE via NF-kB pathways activation. Anti-inflammatory effect of apigenin impedes TNF-α mediated dysregulation or expression associated with RA pathogenesis.
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Apigenina , Artrite Reumatoide , Receptor para Produtos Finais de Glicação Avançada , Fator de Necrose Tumoral alfa , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Apigenina/farmacologia , Humanos , Fator de Necrose Tumoral alfa/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Sinoviócitos/metabolismo , Sinoviócitos/efeitos dos fármacos , Membrana Sinovial/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Citocinas/metabolismo , Animais , Inflamação/metabolismo , Inflamação/tratamento farmacológicoRESUMO
PURPOSE: This aimed to identify the factors associated with severe/critical coronavirus disease 2019 (COVID-19) infection in rheumatoid arthritis (RA) patients. METHODS: Two-hundred RA patients diagnosed according to the American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) classification criteria with proven COVID-19 infection were recruited and categorized according to the world health organization (WHO) COVID-19 severity grading into 2 groups: patients with mild/moderate COVID-19 (n = 164) and patients with severe/critical COVID-19 (n = 36). Comparison between both groups was done to identify the risk factors associated with severe/critical infection. Incidence of RA disease activity flare defined as increase in clinical disease activity index (CDAI) more than 10 points following infection was calculated. RESULTS: Multivariate analysis identified history of previous serious infection, age > 60 years, and diabetes as factors positively associated, whereas COVID-19 vaccination was negatively associated with severe/critical infection. Following COVID-19 infection, the number of patients with severe/critical COVID-19 who had high RA disease activity and the incidence of flares was significantly higher in comparison to patients with mild/moderate COVID-19 (P < 0.001 and 0.003; respectively). CONCLUSION: Age > 60 years, diabetes, and history of previous serious infections are risk factors for severe/critical COVID-19, while vaccination has a protective role in RA patients. Infection particularly when severe is associated with risk of disease flare.
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Artrite Reumatoide , COVID-19 , SARS-CoV-2 , Índice de Gravidade de Doença , Humanos , Artrite Reumatoide/complicações , Artrite Reumatoide/epidemiologia , COVID-19/epidemiologia , Pessoa de Meia-Idade , Masculino , Feminino , Fatores de Risco , Idoso , Adulto , Fatores Etários , IncidênciaRESUMO
Janus Kinase 3 (JAK3) is important for the signaling transduction of cytokines in immune cells and is identified as potential target for treatment of rheumatoid arthritis (RA). Recently, we designed and synthesized two JAK3 inhibitors J1b and J1f, which featured with high selectivity but mild bioactivity. Therefore, in present study the structure was optimized to increase the potency. As shown in the results, most of the compounds synthesized showed stronger inhibitory activities against JAK3 in contrast to the lead compounds, among which 9a was the most promising candidate because it had the most potent effect in ameliorating carrageenan-induced inflammation of mice and exhibited low acute in vivo toxicity (MTD > 2 g/kg). Further analysis revealed that 9a was highly selective to JAK3 (IC50 = 0.29 nM) with only minimal effect on other JAK members (>3300-fold) and those kinases bearing a thiol in a position analogous to that of Cys909 in JAK3 (>150-fold). Meanwhile, the selectivity of JAK3 was also confirmed by PBMC stimulation assay, in which 9a irreversibly bound to JAK3 and robustly inhibited the signaling transduction with mild suppression on other JAKs. Moreover, it was showed that 9a could remarkably inhibited the proliferation of lymphocytes in response to concanavalin A and significantly mitigate disease severity in collagen induced arthritis. Therefore, present data indicate that compound 9a is a selective JAK3 inhibitor and could be a promising candidate for clinical treatment of RA.
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Artrite Reumatoide , Janus Quinase 3 , Inibidores de Proteínas Quinases , Pirimidinas , Janus Quinase 3/antagonistas & inibidores , Janus Quinase 3/metabolismo , Artrite Reumatoide/tratamento farmacológico , Animais , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinas/síntese química , Humanos , Relação Estrutura-Atividade , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/síntese química , Estrutura Molecular , Relação Dose-Resposta a Droga , Pirróis/química , Pirróis/farmacologia , Pirróis/síntese química , Carragenina , Masculino , Artrite Experimental/tratamento farmacológico , Artrite Experimental/induzido quimicamente , Antirreumáticos/farmacologia , Antirreumáticos/química , Antirreumáticos/síntese química , Simulação de Acoplamento MolecularRESUMO
BACKGROUND: Endometriosis is an underdiagnosed disorder that affects an estimated 6-10% of women of reproductive age. Endometriosis has been reported in epidemiological studies to be associated with autoimmune diseases. However, the relationship remains controversial. METHODS: A meta-analysis of observational studies was undertaken to evaluate the risk of autoimmune diseases in patients with endometriosis. The relevant studies were retrieved via the databases Medline, Embase and Web of Science until July 20, 2023. Mendelian randomization (MR) was subsequently utilized to scrutinize the causal influence of genetic predisposition toward endometriosis on three autoimmune diseases. RESULTS: The meta-analysis findings revealed a relationship between endometriosis and the onset of SLE (cohort studies: RR = 1.77, 95% confidence interval (CI): 1.47-2.13, I2 = 0%; Case-control and cross-sectional studies: OR = 5.23, 95% CI: 0.74-36.98, I2 = 98%), RA (cohort studies: RR = 2.18, 95% CI: 1.85-2.55, I2 = 92%; Case-control and cross-sectional studies: OR = 1.40, 95% CI: 1.19-1.64, I2 = 0%) and SS (cohort studies: RR = 1.49, 95% CI: 1.34-1.66, I2 = 0%). Similarly, in our MR study, the results of the inverse-variance-weighted (IVW) model suggested that genetic predisposition to endometriosis was causally associated with an increased risk for SLE (OR = 1.915, 95% CI: 1.204-3.045, p = 0.006) and RA (OR = 1.005, 95% CI: 1.001-1.009, p = 0.014). CONCLUSIONS: Both our meta-analysis and MR study indicate that endometriosis increases the risk of autoimmune diseases. These findings not only broaden our understanding of the genetic mechanisms underlying the comorbidity of endometriosis and autoimmune diseases, but also offer a new strategy for autoimmune disease prevention.
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Artrite Reumatoide , Doenças Autoimunes , Endometriose , Lúpus Eritematoso Sistêmico , Humanos , Feminino , Artrite Reumatoide/complicações , Artrite Reumatoide/genética , Endometriose/epidemiologia , Endometriose/genética , Endometriose/complicações , Estudos Transversais , Análise da Randomização Mendeliana , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/genética , Estudo de Associação Genômica AmplaRESUMO
ANCA-associated vasculitis (AAV) can affect multiple organs with severe life-threatening manifestations. Disease monitoring is difficult due to a lack of defined biomarkers. We aimed to assess the diagnostic role of serum interleukin-6 and vascular ultrasonography in AAV and subclinical atherosclerosis. The study included 20 AAV patients and two control groups of 34 patients with rheumatoid arthritis (RA) and 35 healthy controls. The levels of Il-6, carotid intima-media thickness test (CIMT), atherosclerotic plaque, and degree of stenosis were investigated. A GRACE-risk score was calculated for AAV and RA patients. The AAV patients had elevated levels of IL-6 (115 ± 23.96) compared to the RA patients (91.25 ± 42.63) and the healthy controls (15.65 ± 3.30), p < 0.001. IL-6 showed a diagnostic accuracy of 73% in distinguishing AAV from RA patients (AUC = 0.730; 95% CI 0.591 to 0834). In the AAV group, CIMT was 1.09, above the upper reference value of 0.90, p < 0.001. The AAV patients had a higher median GRACE risk score, and 60% of them had a high risk of cardiovascular events as compared to 35% of the RA patients. Sonography of extracranial vessels and serum levels of IL-6 can be used in daily clinical practice to diagnose and monitor patients with AAV.
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Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Artrite Reumatoide , Aterosclerose , Biomarcadores , Espessura Intima-Media Carotídea , Interleucina-6 , Humanos , Interleucina-6/sangue , Feminino , Masculino , Pessoa de Meia-Idade , Artrite Reumatoide/sangue , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico por imagem , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Biomarcadores/sangue , Prognóstico , Adulto , Aterosclerose/sangue , Aterosclerose/diagnóstico por imagem , Aterosclerose/etiologia , Aterosclerose/diagnóstico , Idoso , Estudos de Casos e Controles , Artérias Carótidas/diagnóstico por imagem , Valor Preditivo dos Testes , Ultrassonografia das Artérias CarótidasRESUMO
Angiogenesis is critical for rheumatoid arthritis (RA) progression. The effects of tofacitinib, a JAK-STAT inhibitor used for RA treatment, on angiogenesis in RA are unclear. We, therefore, evaluated the levels of angiogenic factors in two systems of a human co-culture of fibroblast (HT1080) and monocytic (U937) cell lines treated with tofacitinib and in serum samples from RA patients before and after six months of tofacitinib treatment. Tofacitinib reduced CD147 levels, matrix metalloproteinase-9 (MMP-9) activity, and angiogenic potential but increased endostatin levels and secreted proteasome 20S activity. In vitro, tofacitinib did not change CD147 mRNA but increased miR-146a-5p expression and reduced STAT3 phosphorylation. We recently showed that CD147 regulates the ability of MMP-9 and secreted proteasome 20S to cleave collagen XVIIIA into endostatin. We show here that tofacitinib-enhanced endostatin levels are mediated by CD147, as CD147-siRNA or an anti-CD147 antibody blocked proteasome 20S activity. The correlation between CD147 and different disease severity scores supported this role. Lastly, tofacitinib reduced endostatin' s degradation by inhibiting cathepsin S activity and recombinant cathepsin S reversed this in both systems. Thus, tofacitinib inhibits angiogenesis by reducing pro-angiogenic factors and enhancing the anti-angiogenic factor endostatin in a dual effect mediated partly through CD147 and partly through cathepsin S.
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Artrite Reumatoide , Basigina , Catepsinas , Endostatinas , Piperidinas , Pirimidinas , Humanos , Basigina/metabolismo , Basigina/genética , Piperidinas/farmacologia , Endostatinas/metabolismo , Endostatinas/farmacologia , Pirimidinas/farmacologia , Catepsinas/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Metaloproteinase 9 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Fator de Transcrição STAT3/metabolismo , Neovascularização Patológica/metabolismo , Neovascularização Patológica/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Feminino , Pessoa de Meia-Idade , Masculino , Pirróis/farmacologia , Linhagem CelularRESUMO
PURPOSE: The present study aims to evaluate the optic nerve, macula, and choroidal changes in both rheumatoid arthritis (RA) and primary Sjögren's syndrome (SjS) patients, and to compare these findings with age-matched healthy volunteers. METHODS: This study included 46 RA patients, 33 primary SjS patients, and 37 age-matched healthy volunteers. All of the patients underwent a thorough ophthalmological examination, during which measurements of the retinal nerve fiber layer (RNFL), ganglion cell layer(GCL), and subfoveal choroidal thickness (CT) were taken using OCT (optical coherence tomography). The measurements taken from the right eye of each patient were used to compare among the groups. RESULTS: RNFL thickness in superior quadrant was found to be statistically significantly thinner in the eyes with RA when compared to the control group (p = 0.022). In the nasal quadrant, the RNFL thickness was significantly thinner in patients with primary SjS compared to healthy individuals (p = 0.036). Also, the temporal quadrant RNFL was significantly thinner in RA patients than in the primary SjS patients (p = 0.033). GCL thickness was observed to be thinner in all quadrants of both RA and primary SjS groups compared to the control group. However, the difference was not found to be statistically significant. Subfoveal CT was observed to be thicker in RA and SjS groups compared to the control group, but this difference was also not statistically significant. CONCLUSION: Systemic autoimmune diseases like RA and primary SjS can lead to a decrease in RNLF and GCL thickness, which can impair visual acuity even in the absence of ocular symptoms. Therefore, monitoring changes in the optic nerve, retina, and choroid layer are crucial in these patients.
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Artrite Reumatoide , Síndrome de Sjogren , Humanos , Voluntários Saudáveis , Retina , Nervo Óptico , CorioideRESUMO
Rheumatoid arthritis(RA) is a condition in which the joints are in a weakly acidic environment. In RA, RA fibroblastlike synoviocytes( RAFLS) in the joints become abnormally activated and secrete a large amount of matrix metalloproteinases(MMPs), and the receptor protein CD44 on the cell membrane is specifically upregulated. Xuetongsu(XTS), an active ingredient in the Tujia ethnomedicine Xuetong, is known to inhibit the proliferation of RAFLS. However, its development and utilization have been limited due to poor targeting ability. A biomimetic XTS-Prussian blue nanoparticles(PB NPs) drug delivery system called THMPX NPs which can target CD44 was constructed in this study. The surface of THMPX NPs was modified with hyaluronic acid(HA) and a long chain of triglycerol monostearate(TGMS) and 3-aminobenzeneboronic acid(PBA)(PBA-TGMS). The overexpressed MMPs and H+ in inflammatory RAFLS can synergistically cleave the PBA-TGMS on the surface of the nanoparticles, exposing HA to interact with CD44. This allows THMPX NPs to accumulate highly in RAFLS, and upon near-infrared light irradiation, generate heat and release XTS, thereby inhibiting the proliferation and migration of RAFLS. Characterization revealed that THMPX NPs were uniform cubes with a diameter of(190. 3±4. 7) nm and an average potential of(-15. 3± 2. 3) m V. Upon near-infrared light irradiation for 5 min, the temperature of THMPX NPs reached 41. 5 â, indicating MMPs and H+-triggered drug release. Safety assessments showed that THMPX NPs had a hemolysis rate of less than 4% and exhibited no cytotoxicity against normal RAW264. 7 and human fibroblast-like synoviocytes(HFLS). In vitro uptake experiments demonstrated the significant targeting ability of THMPX NPs to RAFLS. Free radical scavenging experiments revealed excellent free radical clearance capacity of THMPX NPs, capable of removing reactive oxygen species in RAFLS. Cell counting kit-8 and scratch assays demonstrated that THMPX NPs significantly suppressed the viability and migratory ability of RAFLS. This study provides insights into the development of innovative nanoscale targeted drugs from traditional ethnic medicines for RA treatment.
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Movimento Celular , Proliferação de Células , Metaloproteinases da Matriz , Nanopartículas , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Nanopartículas/química , Humanos , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Metaloproteinases da Matriz/metabolismo , Metaloproteinases da Matriz/genética , Ferrocianetos/química , Concentração de Íons de Hidrogênio , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/efeitos da radiação , Sinoviócitos/metabolismo , Lasers , Receptores de Hialuronatos/metabolismo , Receptores de Hialuronatos/genética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismoRESUMO
BACKGROUND: The objective of this investigation is to analyze the levels and clinical relevance of serum PYCARD (Pyrin and CARD domain-containing protein, commonly known as ASC-apoptosis-associated speck-like protein containing a caspase activation and recruitment domain), interleukin-38 (IL-38), and interleukin-6 (IL-6) in individuals afflicted with rheumatoid arthritis (RA). METHODS: Our study comprised 88 individuals diagnosed with RA who sought medical attention at the Affiliated Hospital of Chengde Medical University during the period spanning November 2021 to June 2023, constituting the test group. Additionally, a control group of 88 individuals who underwent health assessments at the same hospital during the aforementioned timeframe was included for comparative purposes. The study involved the assessment of IL-38, IL-6, PYCARD, anti-cyclic citrullinated peptide antibody (anti-CCP), and erythrocyte sedimentation rate (ESR) levels in both groups. The research aimed to explore the correlations and diagnostic efficacy of these markers, employing pertinent statistical analyses for comprehensive evaluation. RESULTS: The test group had higher expression levels of PYCARD, IL-6, and IL-38 than the control group (P < 0.05). Based on the correlation analysis, there was a strong relationship between PYCARD and IL-38 (P < 0.01). The receiver operating characteristic (ROC) curve analysis revealed area under the curve (AUC) values of 0.97, 0.96, and 0.96 when using combinations of PYCARD and anti-CCP, IL-38 and anti-CCP, and IL-6 and anti-CCP for predicting RA, respectively. Importantly, all three of these pairs demonstrated superior AUC values compared to PYCARD, IL-38, IL-6, ESR, or anti-CCP used as standalone diagnostic indicators. CONCLUSION: PYCARD, IL-6, and IL-38 exhibit promising potential as novel diagnostic markers and may constitute valuable tools for supporting the diagnosis of RA.
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Anticorpos Antiproteína Citrulinada , Artrite Reumatoide , Humanos , Interleucina-6 , Artrite Reumatoide/diagnóstico , Autoanticorpos , Curva ROC , Peptídeos Cíclicos , Biomarcadores , Proteínas Adaptadoras de Sinalização CARD/genética , InterleucinasRESUMO
Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by inflammation in the synovial lining of the joints. Key inflammatory cytokines such as interleukin-6 (IL-6), TNF-α, and others play a critical role in the activation of local synovial leukocytes and the induction of chronic inflammation. Tocilizumab (TCZ), a humanized anti-IL-6 receptor monoclonal antibody, has demonstrated significant clinical efficacy in treating RA patients. However, similar to other inflammatory cytokine blockers, such as TNF-alpha inhibitors, Interleukin-1 inhibitors, or CD20 inhibitors, some patients do not respond to treatment. To address this challenge, our study employed a high-precision proteomics approach to identify protein biomarkers capable of predicting clinical responses to Tocilizumab in RA patients. Through the use of data-independent acquisition (DIA) mass spectrometry, we analyzed serum samples from both TCZ responders and non-responders to discover potential biomarker candidates. These candidates were subsequently validated using individual serum samples from two independent cohorts: a training set (N = 70) and a test set (N = 18), allowing for the development of a robust multi-biomarker panel. The constructed multi-biomarker panel demonstrated an average discriminative power of 86 % between response and non-response groups, with a high area under the curve (AUC) value of 0.84. Additionally, the panel exhibited 100 % sensitivity and 60 % specificity. Collectively, our multi-biomarker panel holds promise as a diagnostic tool to predict non-responders to TCZ treatment in RA patients.
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The most prevalent inflammatory arthritis and a leading contributor to disability is rheumatoid arthritis (RA). Although it may not have arrived in Europe until the 17th century, it was present in early Native American communities several thousand years ago. Exosomes released by mesenchymal stem cells (MSCs) are highly immunomodulatory due to the origin of the cell. As a cell-free therapy, MSCs-exosomes are less toxic and elicit a weakened immune response than cell-based therapies. Exosomal noncoding RNAs (ncRNAs) are closely associated with a number of biological and functional facets of human health, especially microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Various exo-miRNAs and lncRNAs such as HAND2-AS1, miR-150-5p, miRNA-124a, and miR-320a lodged with MSC could be appropriate therapeutic ways for RA treatment. These MSC-derived exosomes affect RA disorders via different molecular pathways such as NFK-ß, MAPK, and Wnt. The purpose of this review is to review the research that has been conducted since 2020 so far in the field of RA disease treatment with MSC-loaded exo-miRNAs and exo-lncRNAs.
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Background: Rheumatoid arthritis (RA), a systemic autoimmune disease with approximately 1% prevalent population worldwide, which the etiology is still unclear. RA cannot be completely cured at present, which seriously affects the quality of life of patients. This study is to compare the peripheral blood α-L-fucosidase (AFU) between RA and healthy persons. Methods: A cross-sectional study was performed using total of 96 patients with RA served as case group and another 94 age-matched healthy volunteers served as a control group. AFU assay is detected by continuous monitoring method using Toshiba TBA-120FR (Tokyo, Japan) fully automatic biochemical analyzer in Japan, and the reagent is purchased from Zhejiang Quark Biological Company (Zhejiang, China). Statistical analysis was performed using SPSS 24.0 (SPSS, Inc., Chicago, IL, USA). Results: AFU activity in peripheral blood of RA patients were lower than healthy controls. The higher AFU activity, the shorter the course of disease (r=-0.2790, P=0.0065). The activity of lactate dehydrogenase in patients with RA is higher than that of healthy control, but the activity of acetylcholinesterase is lower than that of normal people. Finally, AFU activity was negatively correlated with the activity of lactate dehydrogenase (r=-0.2381, P=0.0208) and positively correlated with the activity of acetylcholinesterase (r=0.2985, P=0.0035). Conclusions: Changes of peripheral blood AFU activity might be associated with progression of disease in RA patients. The changes of AFU activity may lead to disturbances in glucose and lipid metabolism.
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Background: Despite evidence linking viruses and oral microbiome to rheumatoid arthritis (RA), limited whole genome sequencing research has been conducted on the oral virome (a viral component of the microbiome) of untreated RA patients. This pilot research seeks to address this knowledge gap by comparing the oral virome of untreated rheumatoid arthritis patients (RAs) and healthy individuals (HCs). Method: Whole genome DNA sequence of saliva samples from 45 participants including 21 RAs and 24 age and gender matched HCs was obtained from the BioProject: PRJEB6997. Metaphlan3 pipeline and LEfSe analysis were used for the viral signature detection. Wilcoxon pairwise test and ROC analysis were used to validate and predict signatures. Results: RA exhibits higher alpha diversity compared to HCs. Callitrichine gammaherpesvirus 3, Human gammaherpesvirus 4 (EBV), Murid betaherpesvirus 8, and Suid alphaherpesvirus 1 were enriched in RAs, while Aotine betaherpesvirus 1 from the Cytomegalovirus genus was enriched in HCs. In addition, Saccharomyces cerevisiae killer virus M1 (ScV-M1) was found to be enriched in RAs, whereas bacteriophage Hk97virus (Siphoviridae) and Cd119virus (Myoviridae) were enriched in HCs. Conclusion: This study identifies significant DNA oral viral signatures at species level as potential biomarkers for the early detection and diagnosis of rheumatoid arthritis.
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BACKGROUND: Vaccines are a crucial component of the global efforts to control the spread of COVID-19. Very little is known about COVID-19 vaccine responses in patients living with autoimmune rheumatic conditions in Africa. We examined the clinical reaction to COVID-19 vaccinations in Ghanaians diagnosed with autoimmune rheumatic disease. METHODS: This was a hospital-based interventional cohort study of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients recruited via regular face-to-face clinic visits. The systemic lupus erythematosus disease activity index Selena modification (SELENA-SLEDAI) and the disease activity score 28-joint count-erythrocyte sedimentation rate (DAS28-ESR) were used to measure changes in disease activity levels. RESULTS: Thirty-eight (38) patients of which 21 (55.3%) were diagnosed with SLE and 17 (44.7%) with RA contributed data for analyses. Most (89.5%) of the patients were females, with a mean age of 37.4 years. The SLE patients experienced a notable increase in severe flares during weeks three and six, as well as the third and sixth months, followed by subsequent decreases in the twelfth month, while remission levels increased throughout the same period. Among RA patients, high disease activity decreased during weeks three and six, as well as the third, sixth, and twelfth months, with remission levels increasing during the same time. A low dose (≥ 50 < 75 mg) dose of azathioprine was at some point associated with having a severe flare among SLE patients. After both vaccine doses, SLE patients were the majority having experienced both local and systemic reactions, all resolving within 24 h. Approximately 73.7% of the patients were COVID-19 negative at baseline. During post-vaccination visits, this increased to 100% by week six, with no positives thereafter. CONCLUSION: This study explores COVID-19 vaccine responses in Ghanaian autoimmune rheumatic disease patients, revealing disease activity levels in RA patients improved after vaccination compared to SLE patients. Our findings identify a potential link between low-dose azathioprine and severe flares in SLE patients, particularly evident in the third-week post-vaccination. Further research is warranted to clarify these findings and guide tailored treatment approaches in this medically significant population during pandemics and vaccination efforts.
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Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease, and one of the main complications of RA is osteoporosis, which can cause osteoporotic vertebral compression fractures (OVCFs) that lead to low back pain and spinal deformation. For RA patients with OVCFs, the symptoms of osteoporosis are more severe, if surgical treatment is to be carried out, it is important to focus on the treatment of osteoporosis caused by RA. Case Description: We report a case of a 68-year-old woman with RA and successional osteoporotic vertebral body fractures treated by percutaneous vertebroplasty (PVP) and percutaneous kyphoplasty (PKP). The patient experienced spontaneous multiple OVCFs on three occasions: in the course of 5 months, she underwent one PKP and two PVP operations with five cement-augmented vertebrae from the first to fifth lumbar vertebrae. The mean interval between each operation was 75 days (range, 2-3 months). The case report makes us look into the treatment of each stage and think about the reasons, we reviewed the literatures on advancements in the treatment of OVCFs caused by RA, so that we can choose a better method for similar patients in the future. Conclusions: For OVCFs secondary to RA without neurological damage, if we carry out surgical treatment, the systematic treatments, including RA treatment, pain management, brace treatment, and anti-osteoporosis measures are important. among them, anti-osteoporosis treatment has the highest priority because of the reversible nature of osteoporosis caused by RA.
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BACKGROUND: Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory diseases in which innate and adaptive responses of the immune system are induced. RA and PsA have complex signaling pathways. Despite the differences in their clinical presentation, there is a great demand for fast and accurate diagnosis of diseases to implement treatment and plan an individual therapeutic strategy quickly. In this report, we present the results of differential diagnosis of patients with RA and PsA and healthy subjects (C, control group), allowing for reliable differentiation of groups of rheumatoid patients based on biochemical parameters, attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectra, and combined data sets. MATERIALS AND METHODS: Biochemical analyses, ELISA (enzyme-linked immunosorbent assays), and multiplex assays were conducted for blood sera from patients with RA (n = 32), patients with PsA (n = 28), and the control group (n = 18). ATR-FTIR spectra were collected for lyophilized sera. RESULTS: The combination of six biochemical parameters (WBC, ESR, RF, CRP, HCC-4/CCL16, and HMGB1/HMGB) allowed the development of the partial least squares discriminant analysis (PLS-DA) model with an overall accuracy (OA) of 80% for test samples. The best separation between RA, PsA, and the control group was obtained utilizing spectral data. Using the interval PLS algorithm (iPLS) specific spectral ranges were selected and a classifier characterized by OA value for test set equal to 88% was obtained. This parameter, for the hybrid PLS-DA model constructed using selected biochemical parameters and a significantly reduced number of spectral variables, reached the level of 84%. CONCLUSIONS: PLS-DA models developed on the basis of spectral data enable effective differentiation of patients with RA, patients with PsA, and healthy subjects. They appeared to be insensitive to existing inflammation processes which opens interesting perspectives for new diagnostic tests and algorithms for identification of patients with RA and PsA.