Etanercept alleviates psoriasis by reducing the Th17/Treg ratio and promoting M2 polarization of macrophages.

INTRODUCTION: This study aimed to investigate the effect of etanercept in psoriasis and its underlying mechanism. METHODS: Female mice were treated with imiquimod (IMQ) to induce psoriasis, and intraperitoneally administered etanercept (0.1-0.4 mg/ml). The RAW264.7 cells were treated with LPS and IFN-γ to polarize to M1, and were treated with IL-13 and IL-4 to polarize to M2. RESULTS: In our study, Etanercept markedly reduced the psoriasis area and severity index scores, and epidermal thickness of mice induced by IMQ. In addition, etanercept reduced the levels of TNF-α and IL-6/12/23, and enhanced the levels of IL-4/10, reduced Th17/Treg ratio and facilitated the polarization of macrophages to M2 in psoriasis model mice. Furthermore, etanercept inhibited the JAK/STAT3 pathway and increased the protein levels of SOCS1 and SOCS3. CONCLUSIONS: In conclusion, our findings indicated that etanercept could inhibit the JAK/STAT3 pathway to reduce Th17/Treg ratio and promote M2 polarization, thereby alleviating psoriasis of mice.

Cytokine modulation by etanercept ameliorates metabolic syndrome and its related complications induced in rats administered a high-fat high-fructose diet.

The aim of the present study was to investigate the effect of etanercept (ETA)-an anti-tumor necrosis factor α (TNF-α) monoclonal antibody-on metabolic disorders such as obesity, hypertension, dyslipidemia, and insulin resistance associated with the metabolic syndrome (MS). MS was induced in rats via high-fat high-fructose (HFHF) administration for 8 weeks. Rats were divided into three groups: negative control, HFHF model, and ETA-treated groups [HFHF + ETA (0.8 mg/kg/twice weekly, subcutaneously) administered in the last 4 weeks]. ETA effectively diminished the prominent features of MS via a significant reduction in the percent body weight gain along with the modulation of adipokine levels, resulting in a significant elevation of serum adiponectin consistent with TNF-α and serum leptin level normalization. Moreover, ETA enhanced dyslipidemia and the elevated blood pressure. ETA managed the prominent features of MS and its associated complications via the downregulation of the hepatic inflammatory pathway that induces nonalcoholic steatohepatitis (NASH)-from the expression of Toll-like receptor 4, nuclear factor kappa B, and TNF-α until that of transforming growth factor-in addition to significant improvements in glucose utilization, insulin sensitivity, and liver function parameter activity and histopathological examination. ETA was effective for the treatment of all prominent features of MS and its associated complications, such as type II diabetes mellitus and NASH.

Machine learning predicts response to TNF inhibitors in rheumatoid arthritis: results on the ESPOIR and ABIRISK cohorts.

OBJECTIVES: Around 30% of patients with rheumatoid arthritis (RA) do not respond to tumour necrosis factor inhibitors (TNFi). We aimed to predict patient response to TNFi using machine learning on simple clinical and biological data. METHODS: We used data from the RA ESPOIR cohort to train our models. The endpoints were the EULAR response and the change in Disease Activity Score (DAS28). We compared the performances of multiple models (linear regression, random forest, XGBoost and CatBoost) on the training set and cross-validated them using the area under the receiver operating characteristic curve (AUROC) or the mean squared error. The best model was then evaluated on a replication cohort (ABIRISK). RESULTS: We included 161 patients from ESPOIR and 118 patients from ABIRISK. The key selected features were DAS28, lymphocytes, ALT (aspartate aminotransferase), neutrophils, age, weight, and smoking status. When predicting EULAR response, CatBoost achieved the best performances of the four tested models. It reached an AUROC of 0.72 (0.68-0.73) on the train set (ESPOIR). Better results were obtained on the train set when etanercept and monoclonal antibodies were analysed separately. On the test set (ABIRISK), these models respectively achieved on AUROC of 0.70 (0.57-0.82) and 0.71 (0.55-0.86). Two decision thresholds were tested. The first prioritised a high confidence in identifying responders and yielded a confidence up to 90% for predicting response. The second prioritised a high confidence in identifying inadequate responders and yielded a confidence up to 70% for predicting non-response. The change in DAS28 was predicted with an average error of 1.1 DAS28 points. CONCLUSION: The machine learning models developed allowed predicting patient response to TNFi exclusively using data available in clinical routine.

Discovery of novel targets in a complex regional pain syndrome mouse model by transcriptomics: TNF and JAK-STAT pathways.

Complex Regional Pain Syndrome (CRPS) represents severe chronic pain, hypersensitivity, and inflammation induced by sensory-immune-vascular interactions after a small injury. Since the therapy is unsatisfactory, there is a great need to identify novel drug targets. Unbiased transcriptomic analysis of the dorsal root ganglia (DRG) was performed in a passive transfer-trauma mouse model, and the predicted pathways were confirmed by pharmacological interventions. In the unilateral L3-5 DRGs 125 genes were differentially expressed in response to plantar incision and injecting IgG of CRPS patients. These are related to inflammatory and immune responses, cytokines, chemokines and neuropeptides. Pathway analysis revealed the involvement of Tumor Necrosis Factor (TNF) and Janus kinase (JAK-STAT) signaling. The relevance of these pathways was proven by abolished CRPS IgG-induced hyperalgesia and reduced microglia and astrocyte markers in pain-associated central nervous system regions after treatment with the soluble TNF alpha receptor etanercept or JAK inhibitor tofacitinib. These results provide the first evidence for CRPS-related neuroinflammation and abnormal cytokine signaling at the level of the primary sensory neurons in a translational mouse model and suggest that etanercept and tofacitinib might have drug repositioning potentials for CRPS-related pain.

Effects of Etanercept on TNF-α Inhibition in Rats with Adenine-Induced Chronic Kidney Disease.

Introduction: Chronic kidney disease (CKD) constitutes a chronic inflammatory state associated with an increase in inflammatory mediators and profibrotic molecules such as tumor necrosis factor-α (TNF-α). Etanercept (ETA) is a TNF inhibitor widely used in treatment of autoimmune inflammatory diseases. However, the effects of TNF-α inhibition in the establishment of CKD have not been fully elucidated. We evaluate the effects of TNF inhibition by ETA in adenine- (Ad-) induced CKD in rats. Methods: Rats were divided into three groups: control, renal injury model, and model plus ETA (2 mg/kg, 3 times per week (w); sc). Renal injury was induced by Ad administration (100 mg/kg, daily for 2 or 4 w; orogastric). Serum TNF-α levels and biochemical parameters for renal function were evaluated. Histopathological changes in the kidney were assessed using H&E and Masson's trichrome staining and also immunostaining for tubular cells. Results: Ad administration produced a renal functional decline, tubular atrophy, interstitial inflammation, and fibrosis for 2 w, followed by renal anemia, several renal dysfunctions, tubular atrophy, and fibrosis at 4 w. A significant increase in serum TNF-α levels was observed from 2 w of Ad administration and remained elevated up to 4 w. Treatment with ETA partially reduced kidney damage but was very effective to blocking serum TNF-α. Conclusion: Although inhibition of TNF by ETA was very effective in reducing serum TNF-α, this strategy was partially effective in preventing Ad-induced CKD.

Immunomodulatory and immunosuppressive therapies in cardiovascular disease and type 2 diabetes mellitus: A bedside-to-bench approach.

OBJECTIVE: To assess which immunosuppressive drugs have been investigated and proven efficacious in patients with cardiovascular disease (CVD) or type 2 diabetes (T2D) without preexisting immune mediated disorders to validate in vitro and animal model findings on low grade inflammation (bedside-to-bench). METHODS: Clinical trials on immunosuppressive drugs in CVD or T2D were found in PubMed. Studies on patients with preexisting immune mediated inflammatory disease were excluded. A total of 19 clinical trials testing canakinumab, anakinra, methotrexate, colchicine, hydroxychloroquine, etanercept and sulfasalazine were found. RESULTS: Canakinumab and colchicine significantly reduced the risk of CVD, whereas methotrexate did not. Sulfasalazine showed no effect on vascular function. Anakinra and hydroxychloroquine had a positive effect on glycemic control and ß-cell function in T2D. Etanercept had no effect in patients with T2D. CONCLUSION: The observed results indicate that immunosuppressive drugs specifically targeting IL-1ß hold promise for dampening CVD and T2D. These findings validate in vitro and animal models showing involvement of the IL-1-axis in the pathogenesis of CVD and T2D. The use of immunosuppressive drugs targeting the chronic inflammation in these diseases could be a possible future treatment strategy as an add-on to the existing pharmacological treatment of CVD and T2D. However, potential treatment effects, adverse events and cost-effectiveness should be carefully considered with importance for drug development.

Treatment of male and female spontaneously hypertensive rats with TNF-α inhibitor etanercept increases markers of renal injury independent of an effect on blood pressure.

Hypertension remains the leading risk factor for cardiovascular disease. Young females tend to be protected from hypertension compared with age-matched males. Although it has become increasingly clear that the immune system plays a key role in the development of hypertension in both sexes, few studies have examined how cytokines mediate hypertension in males versus females. We previously published that there are sex differences in the levels of the cytokine tumor necrosis factor (TNF)-α in spontaneously hypertensive rats (SHR). The goal of this study was to test the hypothesis that TNF-α inhibition with etanercept will lower BP in male and female SHR. However, as male SHR have a more pro-inflammatory status than female SHR, we further hypothesize that males will have a greater decrease in BP with TNF-α inhibition than females. Young adult male and female SHR were administered increasing doses of the TNF-α inhibitor etanercept or vehicle twice weekly for 31 days and BP was continuously measured via telemetry. Following treatment, kidneys and urine were collected and analyzed for markers of inflammation and injury. Despite significantly decreasing renal TNF-α levels, renal phospho-NFκB and urinary MCP-1 excretion, etanercept did not alter BP in either male or female SHR. Interestingly, treatment with etanercept increased urinary excretion of protein, creatinine and KIM-1 in both sexes. These results indicate that TNF-α does not contribute to sex differences in BP in SHR but may be vital in the maintenance of renal health.

Restoration of Default Blood Monocyte-Derived Macrophage Polarization With Adalimumab But Not Etanercept in Rheumatoid Arthritis.

Introduction: We previously reported a specific defect of rheumatoid arthritis (RA) monocyte polarization to anti-inflammatory M2-like macrophages related to increased miR-155 expression in all RA patients except those receiving adalimumab (ADA). In this longitudinal study, we examined whether different tumor necrosis factor inhibitors were able to restore monocyte polarization to M2-like macrophages and their effect on the transcriptomic signature. Methods: M2-like polarization induced by human serum AB was studied in 7 healthy donors and 20 RA patients included in the ABIRA cohort before and 3 months after starting ADA or etanercept (ETA). The differential gene expression of M2- and M1-related transcripts was studied in macrophage-derived monocytes after differentiation. Results: At baseline, RA monocytes showed a defect of polarization to M2-like macrophages as compared with healthy donor monocytes, which was negatively correlated with disease activity. M2-like polarization from circulating monocytes was restored only with ADA and not ETA treatment. The transcriptomic signature demonstrated downregulation of M2-related transcripts and upregulation of M1-related transcripts in active RA. In patients receiving ADA, the transcriptomic signature of M2-related transcripts was restored. Conclusion: This longitudinal study demonstrates that ADA but not ETA is able to restore the M2-like polarization of monocytes that is defective in RA.

Etanercept Prevents Endothelial Dysfunction in Cafeteria Diet-Fed Rats.

Obesity is associated with endothelial dysfunction and this relationship is probably mediated in part by inflammation. Objective: The current study evaluated the effects of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, on endothelial and vascular reactivity, endothelial nitric oxide synthase (eNOS) immunoreactivity, and serum and aortic concentrations of TNF-α in a diet-induced rat model. Design and results: Male weanling Wistar rats were exposed to a standard diet and cafeteria diet (CD) for 12 weeks and etanercept was administered during CD treatment. Isolated aortas of the rats were used for isometric tension recording. Carbachol-induced relaxant responses were impaired in CD-fed rats, while etanercept treatment improved these endothelium-dependent relaxations. No significant change was observed in papaverine- and sodium nitroprusside (SNP)-induced relaxant responses. eNOS expression decreased in CD-fed rats, but no change was observed between etanercept-treated CD-fed rats and control rats. CD significantly increased both the serum and the aortic levels of TNF-α, while etanercept treatment suppressed these elevated levels. CD resulted in a significant increase in the body weight of the rats. Etanercept-treated (ETA) CD-fed rats gained less weight than both CD-fed and control rats.

The effect of TNF-α inhibitor treatment on microRNAs and endothelial function in collagen induced arthritis.

Chronic inflammation causes dysregulated expression of microRNAs. Aberrant microRNA expression is associated with endothelial dysfunction. In this study we determined whether TNF-α inhibition impacted the expression of miRNA-146a-5p and miRNA-155-5p, and whether changes in the expression of these miRNAs were related to inflammation-induced changes in endothelial function in collagen-induced arthritis (CIA). Sixty-four Sprague-Dawley rats were divided into control (n = 24), CIA (n = 24) and CIA+etanercept (n = 16) groups. CIA and CIA+etanercept groups were immunized with bovine type-II collagen, emulsified in incomplete Freund's adjuvant. Upon signs of arthritis, the CIA+etanercept group received 10mg/kg of etanercept intraperitoneally, every three days. After six weeks of treatment, mesenteric artery vascular reactivity was assessed using wire-myography. Serum concentrations of TNF-α, C-reactive protein, interleukin-6, vascular adhesion molecule-1 (VCAM-1) and pentraxin-3 (PTX-3) were measured by ELISA. Relative expression of circulating miRNA-146a-5p and miRNA-155-5p were determined using RT-qPCR. Compared to controls, circulating miRNA-155-5p, VCAM-1 and PTX-3 concentrations were increased, and vessel relaxation was impaired in the CIA (all p<0.05), but not in the CIA+etanercept (all p<0.05) groups. The CIA group had greater miRNA-146a-5p expression compared to the CIA+etanercept group (p = 0.005). Independent of blood pressure, miRNA-146a-5p expression was associated with increased PTX-3 concentrations (p = 0.03), while miRNA-155-5p expression was associated with impaired vessel relaxation (p = 0.01). In conclusion, blocking circulating TNF-α impacted systemic inflammation-induced increased expression of miRNA-146a-5p and miRNA-155-5p, which were associated with endothelial inflammation and impaired endothelial dependent vasorelaxation, respectively.

TNF antagonist sensitizes synovial fibroblasts to ferroptotic cell death in collagen-induced arthritis mouse models.

Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.

Etanercept Reduces Neuron Injury and Neuroinflammation via Inactivating c-Jun N-terminal Kinase and Nuclear Factor-κB Pathways in Alzheimer's Disease: An In Vitro and In Vivo Investigation.

Inflammation contributes to amyloid beta (Aß) aggregation and neuron loss in Alzheimer's disease (AD). Meanwhile, tumor necrosis factor-α (TNF-α) inhibitors present strong effect on suppressing inflammation. Thus, this study aimed to investigated the effect and molecular mechanism of etanercept (ETN) (a commonly used TNF-α inhibitor) on neuron injury and neuroinflammation in AD. AD cellular model was constructed by co-culture of primary embryonic neuron cells and microglial cells, followed by Aß treatment. Subsequently, ETN was used to treat AD cellular model. Besides, APPswe/PS1M146V/tauP301L transgenic (AD) mice were respectively treated with saline or ETN by intravenous injection once per 3 days for 10 times. In vitro data revealed that cell viability and neurite outgrowth were increased, but apoptosis and levels of pro-inflammatory cytokines (including TNF-α, interleukin-1ß, Interleukin-6 and C-C motif chemokine ligand 2 (CCL2)) were decreased by ETN treatment in AD cellular model. In vivo experiments found that ETN treatment improved spatial, long-term memory (reflected by Morrison water maze) and working memory (reflected by Y maze) in AD mice. Besides, ETN treatment reduced neuron injury (reflected by Hematoxylin-Eosin (HE) and terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assays) and levels of pro-inflammatory cytokines (including TNF-α, interleukin-1ß, Interleukin-6 and CCL2) in AD mice. Moreover, ETN repressed the activation of c-Jun N-terminal kinase (JNK) and nuclear factor-κB (NF-κB) pathways in AD both in vitro and in vivo. In conclusion, ETN exerts neuroprotective function via inactivating JNK and NF-κB pathways in AD, indicating the potential of ETN for improving AD management.

Etanercept Mitigates Cadmium Chloride-induced Testicular Damage in Rats "An Insight into Autophagy, Apoptosis, Oxidative Stress and Inflammation".

RATIONALE: Cadmium (Cd) is an environmental and occupational toxin that represents a serious health hazard to humans and other animals. One of the negative consequences of cadmium exposure is testicular injury. OBJECTIVE: This study aimed to investigate the therapeutic effect of etanercept against cadmium chloride-induced testicular damage and the probable underlying mechanisms of its action. METHODS: A total of sixty rats were divided into six groups: control, cadmium chloride (CdCl2) (7 mg/ kg i.p.), and CdCl2 treated with etanercept (5,10 and 15 mg/kg s.c.) and etanercept only (15 mg/kg s.c.). CdCl2 was administrated as a single dose, while etanercept was administered every 3 days for 3 weeks. RESULTS: CdCl2 reduced serum testosterone, testicular glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). However, it elevated the levels of malondialdehyde (MDA) and microtubule-associated protein light chain 3B (LC3B) in the testes. Cadmium caused pathogenic alterations as well as increased levels of inflammatory biomarkers such as tumor necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB). Besides, the gene expressions of caspase-3 and inducible nitric oxide synthase (i-NOS) and Beclin-1 protein increased with CdCl2 exposure. Interestingly, etanercept relieved the previous toxic effects induced by CdCl2 in a dose-dependent manner as evidenced by inhibition of oxidative stress, inflammatory markers, Beclin-1, LC3B, and caspase-3 accompanied by improvement in histopathological changes. CONCLUSION: Etanercept provides a potential therapeutic approach to treat testicular tissue against the damaging effects of Cd by reducing oxidative stress, inflammation, apoptosis, and autophagy.

Regulating Fibrocartilage Stem Cells via TNF-α/Nf-κB in TMJ Osteoarthritis.

In this study, we investigate harnessing fibrocartilage stem cell (FCSC) capacities by regulating tumor necrosis factor α (TNF-α) signaling for cartilage repair in temporomandibular joint osteoarthritis (TMJOA). Stem cell specifics for FCSCs were characterized in the presence of TNF-α. Etanercept as a TNF-α inhibitor and BAY 11-7082 as an Nf-κB inhibitor were used to study TNF-α regulation of FCSCs. Lineage tracing was performed in Gli1-CreERT+;Tmfl/fl mice when etanercept (1 mg/kg, every 3 d) or isometric vehicle was subcutaneously injected to trace specific changes in FCSCs. Surgically induced TMJOA Sprague-Dawley rats were generated with BAY 11-7082 (5 mg/kg, every 3 d) or vehicle subcutaneous injection to investigate the functional role of TNF-α/Nf-κB in TMJOA. Anterior disc displacement (ADD) rabbits were used to analyze the therapeutic effect of etanercept as a TMJOA intra-articular treatment with etanercept (0.02 mg in 100 µL, every 2 wk) or isometric vehicle. In vitro, TNF-α inhibited proliferation of FCSCs and increased FCSC apoptosis. TNF-α activation interfered with osteogenic and chondrogenic differentiation of FCSCs, while etanercept could partially recover FCSC specificity from TNF-α. FCSC lineage tracing in Gli1-CreERT+;Tmfl/fl mice showed that the chondrogenic capacity of Gli1+ cell lineage was markedly suppressed in osteoarthritis cartilage, the phenotype of which could be significantly rescued by etanercept. Specifically blocking the Nf-κB pathway could significantly weaken the regulatory effect of TNF-α on FCSC specificity in vitro and in TMJOA rats in vivo. Finally, intra-articular etanercept treatment efficiently rescued TMJ cartilage degeneration and growth retardation in ADD rabbits. Inhibition of TNF-α signaling reduced Nf-κB transcripts and recovered FCSC specificities. In vivo, etanercept treatment effectively rescued the osteoarthritis phenotype in TMJOA mice and ADD rabbits. These data suggest a novel therapeutic mechanism whereby TNF-α/Nf-κB inhibition promotes FCSC chondrogenic capacity for cartilage transformation in TMJOA.

Activated Peripheral Blood B Cells in Rheumatoid Arthritis and Their Relationship to Anti-Tumor Necrosis Factor Treatment and Response: A Randomized Clinical Trial of the Effects of Anti-Tumor Necrosis Factor on B Cells.

OBJECTIVE: B cells can become activated in germinal center (GC) reactions in secondary lymphoid tissue and in ectopic GCs in rheumatoid arthritis (RA) synovium that may be tumor necrosis factor (TNF) and lymphotoxin (LT) dependent. This study was undertaken to characterize the peripheral B cell compartment longitudinally during anti-TNF therapy in RA. METHODS: Participants were randomized in a 2:1 ratio to receive standard dosing regimens of etanercept (n = 43) or adalimumab (n = 20) for 24 weeks. Eligible participants met the American College of Rheumatology 1987 criteria for RA, had clinically active disease (Disease Activity Score in 28 joints >4.4), and were receiving stable doses of methotrexate. The primary mechanistic end point was the change in switched memory B cell fraction from baseline to week 12 in each treatment group. RESULTS: B cell subsets remained surprisingly stable over the course of the study regardless of treatment group, with no significant change in memory B cells. Blockade of TNF and LT with etanercept compared to blockade of TNF alone with adalimumab did not translate into significant differences in clinical response. The frequencies of multiple activated B cell populations, including CD21- double-negative memory and activated naive B cells, were higher in RA nonresponders at all time points, and CD95+ activated B cell frequencies were increased in patients receiving anti-TNF treatment in the nonresponder group. In contrast, frequencies of transitional B cells-a putative regulatory subset-were lower in the nonresponders. CONCLUSION: Overall, our results support the notion that peripheral blood B cell subsets are remarkably stable in RA and not differentially impacted by dual blockade of TNF and LT with etanercept or single blockade of TNF with adalimumab. Activated B cells do associate with a less robust response.

Effects of tumor necrosis factor-α inhibition on kidney fibrosis and inflammation in a mouse model of aristolochic acid nephropathy.

Tumor necrosis factor (TNF)-α is a potent mediator of inflammation and is involved in the pathophysiology of chronic kidney disease (CKD). However, the effects of TNF-α inhibition on the progression of kidney fibrosis have not been fully elucidated. We examined the effects of TNF-α inhibition by etanercept (ETN) on kidney inflammation and fibrosis in mice with aristolochic acid (AA) nephropathy as a model of kidney fibrosis. C57BL/6 J mice were administered AA for 4 weeks, followed by a 4-week remodeling period. The mice exhibited kidney fibrosis, functional decline, and albuminuria concomitant with increases in renal mRNA expression of inflammation- and fibrosis-related genes. The 8-week ETN treatment partially but significantly attenuated kidney fibrosis and ameliorated albuminuria without affecting kidney function. These findings were accompanied by significant suppression of interleukin (IL)-1ß, IL-6, and collagen types I and III mRNA expression. Moreover, ETN tended to reduce the AA-induced increase in interstitial TUNEL-positive cells with a significant reduction in Bax mRNA expression. Renal phosphorylated p38 MAPK was significantly upregulated by AA but was normalized by ETN. These findings indicate a substantial role for the TNF-α pathway in the pathogenesis of kidney fibrosis and suggest that TNF-α inhibition could become an adjunct therapeutic strategy for CKD with fibrosis.

Nitro-fatty acids decrease type I interferons and monocyte chemoattractant protein 1 in ex vivo models of inflammatory arthritis.

BACKGROUND: Inflammatory arthritis including rheumatoid arthritis (RA) and spondyloarthritis (SpA) is characterized by inflammation and destruction of the joints. Approximately one third of patients do not respond to first-line treatments. Nitro-fatty acids are bioactive lipids with anti-inflammatory properties and tissue-protective functions. The nitro-fatty acid 10-NO2-oleic acid (10-NO2-OA) is being tested in clinical trials for patients with fibrotic and inflammatory conditions. Here, we tested whether 10-NO2-OA could inhibit immune reactions involved in the inflammatory and joint destructive processes in inflammatory arthritis. METHODS: Synovial fluid and blood samples were obtained from 14 patients with active RA or SpA. The in vitro models consisted of synovial fluid mononuclear cells (SFMCs) cultured for 48 h, SFMCs cultured for 21 days, and fibroblast-like synovial cells (FLSs) co-cultured with peripheral blood mononuclear cells (PBMCs) for 48 h. Cells were treated with or without 10-NO2-OA or the tumor necrosis factor alpha (TNFα) inhibitor etanercept. Supernatants were analyzed for type I interferon, monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase 3 (MMP3) and tartrate resistant acid phosphatase (TRAP). RESULTS: In SFMCs cultured for 48 h, 10-NO2-OA dose-dependently decreased the secretion of bioactive type I interferons and MCP-1 but not MMP3 (P = 0.032, P = 0.0001, and P = 0.58, respectively). Both MCP-1 and MMP3 were decreased by etanercept (P = 0.0031 and P = 0.026, respectively). In SFMCs cultured for 21 days, 10-NO2-OA significantly decreased the production of MCP-1 but not TRAP (P = 0.027 and P = 0.1523, respectively). Etanercept decreased the production of TRAP but not MCP-1 (P < 0.001 and P = 0.84, respectively). In co-cultures of FLSs and PBMCs, 10-NO2-OA decreased the production of MCP-1 (P < 0.0001). This decrease in MCP-1 production was not seen with etanercept treatment (P = 0.47). CONCLUSION: 10-NO2-OA decreased the release of MCP-1 in three models of inflammatory arthritis. Of particular interest, 10-NO2-OA inhibited type I interferon, and 10-NO2-OA was more effective in reducing MCP-1 production in cultures dominated by FLSs compared with etanercept. Our results encourage clinical investigations of 10-NO2-OA in patients with inflammatory arthritis.

Efectividad, seguridad y análisis económico de Benepali en práctica clínica / Effectiveness, safety and economic analysis of Benepali in clinical practice

Objetivo: Evaluar la efectividad, la seguridad y los costes de etanercept biosimilar (BS) en pacientes con artritis reumatoide (AR), espondiloartritis (EspA) y artritis psoriásica (APs) y en comparación con su original, en condiciones de práctica clínica habitual. Pacientes y métodos: Estudio observacional retrospectivo. Se incluyeron 138 pacientes con AR, EspA o APs tratados con al menos una dosis de Benepali® (n=79) o Enbrel® (n=59). Como desenlace principal de efectividad del BS o de su original se usó el tiempo de retención del fármaco. Como desenlace secundario de efectividad se midió la proporción de pacientes que alcanzaban baja actividad o remisión a las 52semanas. La seguridad fue evaluada mediante tasas de incidencia de efectos adversos. Se hizo un análisis de minimización de costes. Resultados: No se observaron diferencias en cuanto a retención del tratamiento (mediana [intervalo de confianza del 95%, IC95%] de 12,0meses [10,2-12,0] para BS y 12,0 meses [12,0-12,0] para el original). Se obtuvieron mejorías similares después de 52semanas en actividad inflamatoria y función física, excepto en los pacientes con EspA y APs, que en general obtuvieron mejores valores de BASDAI y ASDAS con el BS. No se registraron diferencias en el número total de efectos adversos (0,43 eventos/pacientes-año con BS frente a 0,53 con original). El uso del BS, en lugar de su original, supuso un ahorro neto para el centro de 118.383,55€ (1.747,2€/pacientes-año). Conclusiones: El uso del BS parece tan eficaz y seguro como su original y mucho más coste-efectivo.(AU)

Objective: To assess the effectiveness, safety and cost of Etanercept biosimilar in patients with rheumatoid arthritis (RA), spondyloarthritis (SpA) and psoriatic arthritis (PsA) compared to the standard drug in real clinical practice. Patients and methods: Retrospective observational study. Case series of 138 patients with RA, SpA or PsA treated with at least one dose of Benepali® (n=79) or Enbrel® (n=59). Drug retention time was the primary efficacy endpoint compared to the biosimilar and the original. The proportion of patients achieving low disease activity or remission after 52weeks was used as the secondary outcome. Safety was assessed by means of the adverse effects incidence rate. A cost minimization analysis was performed. Results: No differences were observed regarding treatment retention time between drugs (median [95% confidence interval, 95%CI] at 12.0months [10.2-12.0] for the biosimilar and 12.0months [12.0-12.0] for the original). Similar improvements, in terms of inflammatory activity and physical function, were obtained after 52weeks except for patients with SpA and PsA who, in general, experienced improvements of BASDAI and ASDAS with the original compared with the biosimilar. No significant differences were observed in the total number of adverse effects (.43 events/patient-years versus the biosimilar and .53 versus the original). Using the biosimilar in place of the original drug resulted in a net savings of 118,383.55€ (1,747.20€/patient-years) for the hospital. Conclusion: The biosimilar Benepali is as effective and safe as the original and much more cost-effective.(AU)

[Effect and mechanism of TNF-α and etanercept on the invasion ability of extravillous trophoblast cell in URSA patients].

Objective: To investigate the effect and mechanism of tumor necrosis factor α (TNF-α) and its inhibitor etanercept (ETA) on the invasion ability of extravillous trophoblast in patients with unexplained recurrent spontaneous abortion (URSA). Methods: (1) Patients were collected from March to June in 2019. They were divided into the URSA group (n=15) and the normal control group (n=15), according to whether diagnosed with URSA or not. The mRNA expression levels of TNF-α in villi tissue of patients in the two groups were detected by quantitative real-time PCR (qRT-PCR). (2) The mRNA and protein expression levels of matrix metalloproteinase-2 (MMP-2), Slug and CXC chemokine rceptor 4 (CXCR4) in HTR-8/SVneo cells were detected by qRT-PCR or western blot after being stimulated by exogenous TNF-α (0.2, 2, 20 ng/ml) alone or TNF-α along with ETA, or phosphate buffered saline (PBS) as control. (3) The invasion ability of HTR-8/SVneo cells was investigated by transwell test after stimulating by TNF-α alone or TNF-α along with ETA. (4) The mRNA and protein expression levels of MMP-2, Slug and CXCR4 in HTR-8/SVneo cells, which were stimulated by TNF-α (2 ng/ml) alone after nuclear factor-κB (NF-κB) inhibitor, BAY 11-7028, preconditioning, were detected by qRT-PCR or western blot. Results: (1) The mRNA expression level of TNF-α in villi tissue of URSA group (4.10±0.49) was 4.1 times as much as the normal control group (t=10.51, P<0.05). (2) The mRNA and protein expression levels of MMP-2, Slug and CXCR4 in HTR-8/SVneo cells of TNF-α group were significantly lower than those in PBS control group (P<0.05) and those in TNF-α along with ETA group (P<0.05). (3) The invasion ability of HTR-8/SVneo cells in TNF-α group was significantly decreased than PBS group and TNF-α along with ETA group (78±14 vs 373±26 vs 227±44, P<0.05). (4) The mRNA and protein expression levels of MMP-2, Slug and CXCR4 in HTR-8/SVneo cells with BAY 11-7028 preconditioning (mRNA: 1.03±0.10, 1.03±0.06, 1.09±0.08; protein: 1.09±0.03, 1.49±0.03, 1.12±0.03) were significantly higher than without preconditioning after being stimulated by TNF-α (all P<0.05). Conclusions: The expression of TNF-α in the villi of URSA patients is much higher than normal early pregnant women. TNF-α could decrease the capacity of invasion by suppressing the expression of MMP-2, Slug and CXCR4 through NF-κB signaling pathway in extravillous trophoblast cells. While ETA could improve the invasiveness capability of extravillous trophoblast cells through inhibiting the negative effect of TNF-α.

The Clinical and MRI Effect of TNF-α Inhibitors in Spondyloarthritis Patients With Hip Involvement: A Real-World Observational Clinical Study.

Objectives: Hip involvement is an important cause of disability and poor prognosis in patients with spondyloarthritis (SpA). Tumor necrosis factor (TNF)-α inhibitor treatment has been demonstrated to be effective in SpA patients with hip arthritis; however, quantitative assessment using MRI in long-term follow-up needs further application and observation. Methods: A total of 239 patients were involved in this study. Methotrexate and sulfasalazine were given as basic treatment. In total, 165 patients received TNF-α inhibitors plus basic treatment, and 74 received basic treatment only, as controls. Clinical symptoms were assessed at baseline and at weeks 12, 24, and 52. MRI performances of hip arthritis, including bone marrow edema (BME) and synovitis, were quantitatively assessed using the Hip Inflammation MRI Scoring System (HIMRISS). Results: The clinical values of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Harris hip score, and Ankylosing Spondylitis Disease Activity Score (ASDAS)-ESR in both groups showed significant clinical remission at week 52 (p < 0.001). However, the change in disease activity levels at week 52 in the control group was significantly worse than in the TNF-α inhibitor group. At week 52, MRI showed a significant remission trend in the TNF-α inhibitor group versus baseline, and total HIMRISS scores were significantly decreased (26.49 ± 10.37 vs. 20.59 ± 9.41, p < 0.001); the control group only had slight improvement (p < 0.05). Conclusions: TNF-α inhibitors could significantly improve clinical and MRI manifestations of hip involvement in patients with SpA. Quantitative MRI assessment combined with clinical assessment can be used to accurately evaluate the treatment effect of TNF-α in SpA patients with hip involvement to help guide targeted treatment.