TNF-α Inhibitors Research Articles

Drug Persistence and Incidence of Active Tuberculosis of Tumor Necrosis Factor Alpha Inhibitors Versus Tocilizumab as the First-Line Biological Treatment in Patients with Rheumatoid Arthritis: A Nationwide Population-Based Retrospective Cohort Analysis.

Drug persistence may be a surrogate marker that reflects both long-term efficacy and safety in clinical settings, and tuberculosis (TB) is considered as one of the most important opportunistic infections after the biological treatment in rheumatoid arthritis (RA). We aimed to compare drug persistence and incidence of TB between tumor necrosis factor alpha (TNFα) inhibitors and tocilizumab in patients with RA using data from the Korean Health Insurance Review and Assessment Service database. In this analysis, 5449 patients with RA who started TNFα inhibitors, such as adalimumab, etanercept, infliximab, and golimumab or tocilizumab, as the first-line biological therapy between January 2014 and December 2017 were analyzed and followed up until December 2019. Drug persistence was defined as the duration from initiation to first discontinuation, and TB was defined as the prescription of > 2 anti-TB medications after the initiation of biologics. TNFα inhibitors and tocilizumab were prescribed in 4202 (adalimumab, 1413; etanercept, 1100; infliximab, 769; golimumab 920) and 1247 patients with RA, respectively. During the analysis period, 2090 (49.7%) and 477 (38.3%) patients with RA discontinued TNFα inhibitors and tocilizumab, respectively, and 42 patients with RA developed TB (TNFα inhibitors, 33; tocilizumab, 9). After adjustment for confounding factors, TNFα inhibitors were significantly associated with a higher risk of discontinuation compared with tocilizumab (hazard ratio (HR) 1.63, p < 0.001). In subgroup analysis, all types of TNFα inhibitors, except for infliximab, demonstrated a significantly lower persistence rate compared with tocilizumab. There was no significant difference in TB incidence between tocilizumab and TNFα inhibitors. In subgroup analysis, infliximab has a significantly higher risk of TB compared with tocilizumab (HR2.84, p = 0.02). In this analysis, tocilizumab had longer persistence than TNFα inhibitors with a similar incidence of TB. Our analysis has limitations: (1) The HIRA database lacks clinical details like disease activity and joint damage extent, potentially influencing the analysis results. (2) Reasons for discontinuing biological agents were not available. (3) TB diagnoses may be inaccurate because of missing microbiological results. (4) We did not analyze the impact of treating latent TB infection on TB development post-biological treatment, despite mandatory screening in Korea.

A Case of Refractory Cutaneous Sarcoidosis Successfully Treated with Infliximab

Sarcoidosis is an inflammatory granulomatous disease affecting multiple organs with cutaneous sarcoidosis occurring in 25% of patients. There are several treatment options available, but alternative therapies should be considered in patients with refractory disease to standard intervention. Though they are not been FDA-approved for sarcoidosis, TNF-a inhibitors have demonstrated significant therapeutic intervention targeting proinflammatory cytokines involves in pathogenesis of sarcoidosis. Herein, we present a case of refractory cutaneous sarcoidosis successfully treated with infliximab therapy with significant hair regrowth on the scalp.

Progressive multifocal leukoencephalopathy reports in rheumatoid arthritis concerning different treatment patterns-an exploratory assessment using the food and drug administration adverse event reporting system

Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare but potentially life-threatening brain infection caused by the John Cunningham virus. PML is a known adverse effect associated with molecular-targeted drugs and immunosuppressive agents. Recent concerns have emerged regarding the link between methotrexate (MTX) and PML. However, limited information exists on the influence of concomitant drug use in rheumatoid arthritis (RA) treatment, where various medications are often used together.Methods: To explore treatment patterns and patient background that affect PML reporting in RA, we analyzed data on RA cases from the Food and Drug Administration Adverse Event Reporting System (FAERS; JAPIC AERS) database between 1997 and 2019.Results and Discussion: Our analysis revealed significantly elevated crude and adjusted reporting odds ratios (aROR) for MTX, rituximab (RIT), azathioprine, and cyclophosphamide. When considering treatment patterns, the concomitant use of MTX and RIT showed a higher aROR than using MTX or RIT alone. Additional TNF-α inhibitors or glucocorticoids did not increase PML reports. Moreover, male sex and older age were associated with increased PML reports. While limitations are inherent in studies using spontaneous reporting data, our exploratory assessment suggests an association between PML and the combination of MTX and RIT and a higher risk in men and older patients. These findings help enhance our understanding of PML risk factors in the context of RA treatment.

Certolizumab pegol effectiveness, survival and safety in patients with psoriasis: A multicenter retrospective analysis in daily clinical practice by the Spanish Psoriasis Group.

Certolizumab is an Fc-free PEGylated tumor necrosis factor-alpha (TNFα) inhibitor recently approved for the treatment of moderate-to-severe plaque psoriasis, although there is limited real-world evidence on the effectiveness and safety in patients with plaque psoriasis treated with certolizumab. The objective of this article is to determine the effectiveness, drug survival, and safety, including pregnancy, childbirth, and lactation, of certolizumab in moderate-to-severe plaque psoriasis under real-world conditions. This is a retrospective, multicenter, observational study performed in 15 hospitals in Spain. It evaluates the effectiveness and safety of certolizumab in plaque psoriasis in the clinical practice setting. A total of 67 patients (73% female) were evaluated with a mean baseline Psoriasis Area Severity Index (PASI) of 8.9. At Week 12, the mean PASI was 2.3 (n = 67), 1.3 (n = 57) at Week 24 and 1.3 at Week 52 (n = 34). Absolute PASI < 3 was achieved in 69, 86, and 92% of patients at Weeks 12, 24, and 52, respectively, as observed. For its part, using the under-response imputation analysis, PASI < 3 at Weeks 12, 24, and 52 were achieved by 69, 73, and 49% of the patients, respectively. A total of 35 patients (52%) had concomitant psoriatic arthritis, and, in 24 of them, Disease Activity in Psoriatic Arthritis Score (DAPSA) was recorded at baseline, with a mean value of 17.9 which decreased to 8.2 at Week 12 (n = 22) and to 3.6 at Week 24 (n = 18). Certolizumab treatment was discontinued in 14 out of 67 patients (21%), due to lack/loss of cutaneous or articular effectiveness (n = 11) or patient decision (n = 2) or adverse event in only one patient who developed active tuberculosis. A lower baseline PASI [hazard ratio (HR): 1.12 (1.02-1.23); P = 0.023] and a more significant reduction in PASI at Week 12 [HR: 1.16 (1.07-1.27); P < 0.001] and Week 52 [HR: 1.47 (1.11-1.96); P = 0.007] was shown to be significantly related with better survival for the entire follow-up period. Fourteen patients were treated during pregnancy and/or lactation without reporting adverse events in either the patient or the newborn. Certolizumab consistently showed high effectiveness and drug survival rates in this real-life cohort. The safety demonstrated in clinical trials during pregnancy and lactation seems to be confirmed in clinical practice.

Switching patterns of biological drugs in patients with psoriasis and psoriatic arthritis: insight from the VALORE database network

ABSTRACT Background Switch patterns among different biologics and from originators to biosimilars (and vice versa) can be complex in patients with psoriasis (PsO) and psoriatic arthritis (PsA). Objective The aim of this study was to describe switching patterns of biological drugs in PsO/PsA patients and to explore predictors of multiple switches and switch-back. Research design and methods A large-scale retrospective cohort study was conducted using the Italian VALORE database. Bio-naïve users treated for PsO/PsA during 2010–2022 were included. Time to switch/swap and predictors of multiple switches and switch-back were analyzed. Results Thirty-thousand seven hundred bio-naïve users were included. At 3 and 5 years of follow-up, patients with at least one switch/swap were 37.1% and 47.8%, respectively. The median time to first switch/swap was significantly shorter (p< 0.001) for TNF-α inhibitors (2,068 days) than anti-IL (2,780 days). At 1 year of follow-up patients starting with IL-23 switched/swapped biological therapy less frequently than those with anti-IL-12/23 and anti-IL-17 (4.9% vs. 8.7% and 9.4%, respectively). Patients starting with anti-IL-12/23 reported a significantly lower risk of multiple switches and switch-back (0.74, 95% CI, 0.67–0.83; 0.58, 95% CI, 0.44–0.77, respectively) than those with TNF-α inhibitors. Conclusions Patients with PsO/PsA starting with TNF-α inhibitors switch/swap more rapidly and frequently than those with anti-IL, which are also associated with a reduced risk of multiple switches during follow-up.

An Amino Acids and Dipeptide Injection Inhibits the TNF-α/HMGB1 Inflammatory Signaling Pathway to Reduce Pyroptosis and M1 Microglial Polarization in POCD Mice: the Gut to the Brain.

Peripheral surgery-induced neural inflammation is a key pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the mechanism underlying neuroinflammation and associated neural injury remains elusive. Surgery itself can lead to gut damage, and the occurrence of POCD is accompanied by high levels of TNF-α in the serum and blood‒brain barrier (BBB) damage. Reductions in stress, inflammation and protein loss have been emphasized as strategies for enhanced recovery after surgery (ERAS). We designed an amino acids and dipeptide (AAD) formula for injection that could provide intestinal protection during surgery. Through the intraoperative infusion of AAD based on the ERAS concept, we aimed to explore the effect of AAD injection on POCD and its underlying mechanism from the gut to the brain. Here, we observed that AAD injection ameliorated neural injury in POCD, in addition to restoring the function of the intestinal barrier and BBB. We also found that TNF-α levels decreased in the ileum, blood and hippocampus. Intestinal barrier protectors and TNF-α inhibitors also alleviated neural damage. AAD injection treatment decreased HMGB1 production, pyroptosis, and M1 microglial polarization and increased M2 polarization. In vitro, AAD injection protected the impaired gut barrier and decreased TNF-α production, alleviating damage to the BBB by stimulating cytokine transport in the body. HMGB1 and Caspase-1 inhibitors decreased pyroptosis and M1 microglial polarization and increased M2 polarization to protect TNF-α-stimulated microglia in vitro. Collectively, these findings suggest that the gut barrier-TNF-α-BBB-HMGB1-Caspase-1 inflammasome-pyroptosis-M1 microglia pathway is a novel mechanism of POCD related to the gut-brain axis and that intraoperative AAD infusion is a potential treatment for POCD.

Paradoxical and bimodal immune-mediated dermatological side effects of TNF-α inhibitors: A comprehensive review.

Due to the increasing prevalence of immune-mediated diseases such as psoriasis, lichen planus, rheumatoid arthritis and inflammatory bowel disease, dermatologists have turned to new biologic drugs known as DMARDs (disease-modifying anti-rheumatic drugs) in recent years. In this study, we evaluate the immune-mediated dermatological side effects of DMARDS by reviewing and analyzing previous peer-reviewed research on the effects of TNF-α inhibitors in the treatment of skin diseases, as well as adverse effects of these drugs and some of the main causes of these effects. DMARDs are very effective in improving control of the above diseases. TNF-α inhibitors are an important group of DMARDs that are widely used. The paradoxical adverse events (PAEs) associated with the use of TNF-α inhibitors are divided into three categories: true paradoxical, borderline paradoxical, and non-paradoxical. True PAEs include conditions for which TNF-α inhibitors are approved for treatment. Borderline PAEs are considered to occur with this class of drugs for which there is no definite approval but for which there is sufficient evidence. Although these events are rare, early recognition of the accused drug and appropriate decision-making may prevent progression of complications and irreversible side effects.

Inflammatory Bowel Disease and Associated Placental Histopathology [ID 2683599

INTRODUCTION: Inflammatory bowel disease (IBD) has been associated with adverse obstetric outcomes, but its effect on placental histopathology is not well studied. We sought to determine the placental histopathology findings associated with maternal IBD. METHODS: This is an IRB-approved retrospective cohort study of patients with IBD who delivered singleton live births at a single institution from October 2019 to April 2023 and had placental pathology available. Participants were identified using an ultrasound query for “Crohn’s” or “ulcerative colitis” (UC). Cases with fetal aneuploidy or major anomalies were excluded. Controls were matched 2:1 for maternal age, gestational age at delivery, and medical comorbidities. Demographics, pregnancy outcomes, and pathology findings were obtained from the electronic medical record. Mann–Whitney and Fisher's exact tests were used with significance set at P&lt;.05. RESULTS: Placental pathology was compared between 18 IBD participants (11 Crohn's, seven UC) and 36 controls. Of 18 IBD participants, three were treated with sulfasalazine, seven with TNF-α inhibitors, and eight used no medication. Baseline demographics and cesarean delivery rates were similar between groups. Five participants per group had histologic evidence of acute chorioamnionitis and/or funisitis (27.8% versus 13.9%; P=.27). Three IBD participants demonstrated maternal vascular malperfusion (MVM) versus 15 controls (16.7% versus 41.7%; P=.07). There were no differences in placental weight, meconium, or fetal vascular malperfusion. CONCLUSION: Inflammatory bowel disease was not associated with adverse placental histopathology. Decreased incidence of MVM may result from IBD medications reducing systemic inflammation. Larger studies are warranted to further evaluate the effect of IBD on placental pathology.

Bifidobacterium bifidum inhibits the TNF-α induced increase in intestinal epithelial tight junction permeability via a TLR-2/TLR-6 and PPAR-γ dependent inhibition of NF-κB p50/p65

Background: Bifidobacterium bifidum (BB) is one of the most widely used probiotic bacterial species and BB has been shown to have a protective effect against intestinal inflammation by an enhancement of the intestinal epithelial tight junction (TJ) barrier. Previous studies from our laboratory showed that a specific BB strain, referred to as BB1, caused a marked enhancement of intestinal epithelial TJ barrier, while strain BB4 had no effect. TNF-α contributes to the development of intestinal inflammation in inflammatory conditions of the gut, in part by increasing intestinal permeability and antigenic penetration. TNF-α induced increase in intestinal epithelial TJ permeability is mediated by an NF-κB p50/p65 activation of myosin light chain kinase (MLCK) gene and MLCK-induced opening of the intestinal TJ barrier. Peroxisome proliferator-activated receptor gamma (PPAR-γ) is an important nuclear receptor known to have anti-inflammatory activity by interfering with NF-κB activation. However, the protective effect of BB1 against TNF-α induced increase in intestinal TJ permeability remain unclear. Aims: The major purpose of this study was to delineate the protective effect of BB1 against the TNF-α induced increase in intestinal TJ permeability and to elucidate the intracellular mechanism involved. Methods: Filter-grown Caco-2 monolayers ( in vitro) and recycling intestinal perfusion of live mice ( in vivo) were the model systems used to assess intestinal TJ permeability. Results: 1) TNF-α caused an increase Caco-2 TJ permeability, as assed by Caco-2 trans-epithelial resistance (TER) and trans-epithelial flux of paracellular marker, FITC-Dextran 10kD. 2) Addition of BB1 (1x108 CFU/ml) to the apical membrane compartment inhibited the TNF-α increase in Caco-2 epithelial TJ permeability, while strain BB4 had no effect. 3) BB1 but not BB4, caused an increase in Caco-2 TLR-2 expression on the apical membrane surface, and siRNA induced knockdown of TLR-2 prevent the BB1 inhibition of TNF-α induced increase in Caco-2 TJ permeability. 4) TNF-α caused a rapid phosphorylation and degradation of Caco-2 IKK-α, as well as and phosphorylation and nuclear translocation of NF-κB p50/p65, indicating NF-κB activation. BB1, but not BB4, inhibited the NF-κB activation. 5) TNF-α activation of NF-κB was associated with an increase in MLCK gene (increase in MLCK promoter activity and mRNA transcription) and kinase activity. BB1, but not BB4, inhibited the TNF-α induced increase in MLCK gene and kinase activity. 6) BB1 but not BB4, caused a rapid PPAR-γ activation (PPAR-γ phosphorylation and nuclear translocation), and siRNA induced knockdown of PPAR-γ inhibited the TNF-α induced activation of NF-κB and increase in Caco-2 TJ permeability. 7) Intraperitoneal injection of TNF-α (5 mg) also caused time-dependent increase in mouse small intestinal permeability (IP) to FITC-Dextran 10kD. TNF-α caused a degradation of IkB-α in intestinal tissue and nuclear translocation of NF-kB in mouse enterocyte. 8) BB1, but not BB4, selectively activated PPAR-γ in mouse enterocytes and inhibited the TNF-α-induced activation of NF-κB, resulting in a decrease in mouse IP. 9) BB1 inhibition of TNF-α activation of mouse enterocyte NF-κB and increase in IP was prevented in mice with intestinal epithelial cell-specific knockout of PPAR-γ Villin-cre and TLR-2 Villin-cre mice. Conclusion: BB1 protects against the TNF-α induced increase in intestinal TJ permeability in a strain-specific manner. BB1 protects against the TNF-α induced increase in intestinal TJ permeability via a novel intracellular mechanism involving BB1/TLR-2 pathway activation of PPAR-γ, and PPAR-γ mediated inhibition of NF-κB p50/p65 and MLCK gene in enterocyte. This research project was supported by the National Institute of Diabetes and Digestive and Kidney Diseases R01-DK-121073-01. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

TNF-α can promote membrane invasion by activating the MAPK/MMP9 signaling pathway through autocrine in bone-invasive pituitary adenoma.

A bone-invasive pituitary adenoma exhibits aggressive behavior, leading to a worse prognosis. We have found that TNF-α promotes bone invasion by facilitating the differentiation of osteoclasts, however, before bone-invasive pituitary adenoma invades bone tissue, it needs to penetrate the dura mater, and this mechanism is not yet clear. We performed transcriptome microarrays on specimens of bone-invasive pituitary adenomas (BIPAs) and noninvasive pituitary adenomas (NIPAs) and conducted differential expressed gene analysis and enrichment analysis. We altered the expression of TNF-α through plasmids, then validated the effects of TNF-α on GH3 cells and verified the efficacy of the TNF-α inhibitor SPD304. Finally, the effects of TNF-α were validated in invivo experiments. Pathway act work showed that the MAPK pathway was significantly implicated in the pathway network. The expression of TNF-α, MMP9, and p-p38 is higher in BIPAs than in NIPAs. Overexpression of TNF-α elevated the expression of MAPK pathway proteins and MMP9 in GH3 cells, as well as promoted proliferation, migration, and invasion of GH3 cells. Flow cytometry indicated that TNF-α overexpression increased the G2 phase ratio in GH3 cells and inhibited apoptosis. The expression of MMP9 was reduced after blocking the P38 MAPK pathway; overexpression of MMP9 promoted invasion of GH3 cells. Invivo experiments confirm that the TNF-α overexpression group has larger tumor volumes. SPD304 was able to suppress the effects caused by TNF-α overexpression. Bone-invasive pituitary adenoma secretes higher levels of TNF-α, which then acts on itself in an autocrine manner, activating the MAPK pathway and promoting the expression of MMP9, thereby accelerating the membrane invasion process. SPD304 significantly inhibits the effect of TNF-α and may be applied in the clinical treatment of bone-invasive pituitary adenoma.

Study on Cloning and Expression of TNF-α Variants in E. coli: Production, Purification, and Interaction with Anti-TNF-α Inhibitors.

TNF-α is a proinflammatory cytokine and plays a role in cell proliferation, differentiation, survival, and death pathways. When administered at high doses, it may cause damage to the tumor vasculature, thereby increasing the permeability of the blood vessels. Therefore, monitoring the dose and the response of the TNF-α molecule is essential for patients' health. This study aimed to clone, express, and purify the active form of the TNF-α protein, which can interact with various anti-TNF-α inhibitors with high efficiency. Recombinant DNA technology was used to clone three different versions of codon-optimized human TNF-α sequences to E. coli. Colony PCR protocol was used for verification and produced proteins were analyzed through SDS-PAGE and western blot. Size exclusion chromatography was used to purify sTNF-α. ELISA techniques were used to analyze and compare binding efficiency of sTNF-α against three different standards. Under native condition (25°C), interaction between sTNF-α and anti-TNF-α antibody was 3,970, compared to positive control. The interaction was 0,587, whereas it was 0,535 for TNF- α and anti-TNF-α antibodies under denaturing conditions (37°C). F7 of sTNF-α (920 μg/mL) had the same/higher binding efficiency to adalimumab, etanercept, and infliximab, compared to commercial TNF-α. This study was the first to analyze binding efficiency of homemade sTNF-α protein against three major TNF-α inhibitors (adalimumab, etanercept, and infliximab) in a single study. The high binding efficiency of sTNF-α with adalimumab, etanercept, and infliximab, evidenced in this study supports the feasibility of its use in therapeutic applications, contributing to more sustainable, cost-effective, and independent healthcare system.

MicroRNA-5196 as an Accurate Biomarker of Disease Activity and Response to Treatment in Rheumatoid Arthritis

Objective: Methods: One hundred patients divided into two groups’ 50 responders and 50 non responders with 50 healthy individuals were studied. The serum expression ofmiRNA-5196 was detected by using real-time polymerase chain reaction. Results: miRNA-5196 expression was significantly higher in rheumatoid arthritis patients versus control group P &lt;0.05. Sub-group of patients into responders and non-responders showed that miRNA-5196 expression higher in non-responders than responders.miRNA-5196 expression related with response to TNF-α inhibitor and disease activity in patients with rheumatoid arthritis. Conclusion: miRNA-5196 may consider as a valid target for monitoring progression of RA disease and response to TNF-α inhibitor therapy.

Cochlear implantation in patients with autoimmune hearing loss

Autoimmune inner ear disease (AIED) manifests with recurrent fluctuating sensorineural hearing loss and vestibular symptoms. Treatment includes steroids and avariety of immunosuppressants. Despite adequate treatment, sensorineural hearing loss can be progressive to the point of deafness. In these patients, acochlear implant (CI) is indicated. We present the case of a25-year-old male who underwent cochlear implantation in the left ear. After implantation we noticed brisk variations in impedances which were related to application of the previously prescribed tumor necrosis alpha (TNFα) inhibitor adalimumab. Can immunomodulatory therapy in AIED patients after CI fitting affect the quality of hearing rehabilitation? We documented impedances and speech intelligibility (Freiburg monosyllable test) of our patient for 1year in dependence on adalimumab therapy. Directly after implantation, impedances were within the normal range. During the further course, impedances started to rise, and recurrent adjustments of the implant were needed. Adalimumab therapy was reinitiated, which resulted in asubsequent reduction of impedances. Cochlear implantation can be necessary in some AIED patients and poses asufficient method for hearing rehabilitation. Depending on the activity of the underlying disease, arise in impedances may occur. Immunomodulatory treatment may therefore be necessary to maintain adequate hearing results with the CI.

Dose-Ranging Effects of the Intracerebral Administration of Atsttrin in Experimental Model of Parkinson’s Disease Induced by 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Mice

Parkinson’s disease is one of the most common neurodegenerative disorders characterized by a multitude of motor and non-motor clinical symptoms resulting from the progressive and long-lasting abnormal loss of nigrostriatal dopaminergic neurons. Currently, the available treatments for patients with Parkinson’s disease are limited and exert only symptomatic effects, without adequate signs of delaying or stopping the progression of the disease. Atsttrin constitutes the bioengineered protein which ultrastructure is based on the polypeptide chain frame of the progranulin (PGRN), which exerts anti-inflammatory effects through the inhibition of TNFα. The conducted preclinical studies suggest that the therapeutic implementation of Atsttrin may be potentially effective in the treatment of neurodegenerative diseases that are associated with the occurrence of neuroinflammatory processes. The aim of the proposed study was to investigate the effect of direct bilateral intracerebral administration of Atsttrin using stereotactic methods in the preclinical C57BL/6 mouse model of Parkinson’s disease inducted by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication. The analysis of the dose dependency effects of the increasing doses of Atsttrin has covered a number of parameters and markers regarding neurodegenerative processes and inflammatory responses including IL-1α, TNFα, IL-6, TH, and TG2 mRNA expressions. Accordingly, the evaluation of the changes in the neurochemical profile included DA, DOPAC, 3-MT, HVA, NA, MHPG, 5-HT, and 5-HIAA concentration levels. The intracerebral administration of Atsttrin into the striatum effectively attenuated the neuroinflammatory reaction in evaluated neuroanatomical structures. Furthermore, the partial restoration of monoamine content and its metabolic turnover were observed. In this case, taking into account the previously described pharmacokinetic profile and extrapolated bioavailability as well as the stability characteristics of Atsttrin, an attempt was made to describe as precisely as possible the quantitative and qualitative effects of increasing doses of the compound within the brain tissue microenvironment in the presented preclinical model of the disease. Collectively, this findings demonstrated that the intracerebral administration of Atsttrin may represent a potential novel therapeutic method for the treatment of Parkinson’s disease.

Evaluating the docetaxel effect in an animal model of polyarthritis.

To evaluate the anti-inflammatory effects of DTX in RA and the effect of methotrexate on PAD4 to investigate its potential as an RA biomarker. Forty male Wistar rats were divided into five groups of eight rats. Healthy rats formed the control group. The Second Group to Fifth group were induced with Complete Freund's adjuvant. The third group received DTX at a dosage of 1mg/kg on alternate days, as determined by a preliminary experiment. The fourth group was given 1mg/kg/week of methotrexate intraperitoneally. The fifth group was treated with a half dose of DTX and methotrexate simultaneously. Significant Arthritis index and knee joint circumference decrease in the DTX group. No significant difference in body weight, platelet-lymphocyte ratio, and white blood cell count between the groups. Neutrophile lymphocyte ratio showed weak correlation with ACPA, while PAD4 showed good correlation with RA markers. Level of ACPA, PAD4, TNF-α, IL-1β, and VEGF significantly decreased in the DTX group than induction group (p < 0.05). DTX reduces the progression and joint destruction in rats induced by Complete Freund's Adjuvant which may due to inhibition of PAD4, TNF-α, IL-1β, VEGF, and ACPA. Also, methotrexate exhibited anti PAD4 effect.

Evaluation of inflammatory biomarkers and the ratio of hemoglobin-red cell distribution width in patients with rheumatoid arthritis treated with tumor necrosis factor-alpha inhibitors.

The aim of this study was to examine pre-treatment and post-treatment hemogram-derived inflammatory biomarkers in patients with rheumatoid arthritis (RA) who received anti-tumor necrosis factor (TNF)-α treatment. The data of 1182 patients with RA were screened. Among them, 207 patients who met the eligibility criteria were included in the retrospective study. Demographic parameters, disease activity, and blood cell-derived indexes were evaluated. The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), lymphocyte-monocyte ratio (LMR), and hemoglobin-red cell distribution width (Hb/RDW) rates were evaluated before treatment and at the third month of treatment in patients with RA who received anti-TNF-α treatment. According to the EULAR response criteria, 12.6% of the 207 patients responded to anti-TNF-α treatment as none, 21.3% as good, and 66.2% as moderate, respectively. Post-treatment NLR and PLR values were significantly lower than pre-treatment values (p < 0.001), whereas post-treatment LMR and Hb/RDW values were significantly higher than pre-treatment values (respectively, p = 0.001 and p = 0.012). The difference between pre-treatment and post-treatment values of LMR and Hb/RDW was significantly higher when compared to the moderate + good response groups than the none-response group (p = 0.002 and p = 0.014, respectively). However, in the receiver operating characteristic curve analysis, these parameters were not found to be significant in predicting treatment response. Significant changes were detected in hemogram-derived inflammatory markers of the groups responding to anti-TNF-α treatment. They can be used as a guide during treatment follow-up. Yet, they do not predict treatment response. Key Points • RA may manifest with periods of remission and activation, and regular follow-up is essential. • There is a demand for readily available, reproducible, and cost-effective parameters to assess treatment response. • Hemogram-derived inflammatory markers differ in relation to anti-TNF-α treatment response in RA. • None of those markers demonstrate an acceptable predictive performance in distinguishing patients based on their response to TNF-α inhibitors.

A TNF-α inhibitor abolishes sepsis-induced cognitive impairment in mice by modulating acetylcholine and nitric oxide homeostasis, BDNF release, and neuroinflammation

Neurodegenerative disorders have a pathophysiology that heavily involves neuroinflammation. In this study, we used lipopolysaccharide (LPS) to create a model of cognitive impairment by inducing systemic and neuroinflammation in experimental animals. LPS was injected intraperitoneally at a dose of 0.5 mg/kg during the last seven days of the study. Adalimumab (ADA), a TNF-α inhibitor, was injected at a dose of 10 mg/kg a total of 3 times throughout the study. On the last two days of the experiment, 50 mg/kg of curcumin was administered orally as a positive control group. Open field (OF) and elevated plus maze tests (EPM) were used to measure anxiety-like behaviors. The tail suspension test (TST) was used to measure depression-like behaviors, while the novel object recognition test (NOR) was used to measure learning and memory activities. Blood and hippocampal TNF α and nitric oxide (NO) levels, hippocampal BDNF, CREB, and ACh levels, and AChE activity were measured by ELISA. LPS increased anxiety and depression-like behaviors while decreasing the activity of the learning-memory system. LPS exerted this effect by causing systemic and neuroinflammation, cholinergic dysfunction, and impaired BDNF release. ADA controlled LPS-induced behavioral changes and improved biochemical markers. ADA prevented cognitive impairment induced by LPS by inhibiting inflammation and regulating the release of BDNF and the cholinergic pathway.

Suppression of inflammation in ulcerative colitis rats by avocado and pomegranate

BackgroundPomegranate seed oil (PSO) and avocado seed oil (ASO) are natural polyphenols with established anti-inflammatory activity. PurposeThis study aimed to investigate the molecular mechanisms underlying the therapeutic efficacy of PSO and ASO in experimental ulcerative colitis (UC) with reference to sulfasalazine (SLZ). MethodsEighty male albino rats were divided equally into 8 groups; Normal, PSO, ASO, SLZ, UC-control, (UC+PSO), (UC+ASO) and (UC+SLZ) groups. Colitis was induced by intra-rectal injection of acetic acid. PSO (0.5ml/ 200g), ASO (1ml/ 250g) and SLZ (100mg/kg) were administered orally once/day for 14 days, 24h after colitis induction. Colitis was evaluated by measuring disease activity index (DAI), colon weight/length ratio and histologic inflammatory score. Vascular endothelial growth factor receptor-2 (VEGFR-2), colonic macrophage migration inhibitory factor (MIF), and malondialdehyde (MDA) were determined. Colonic gene expression of TNF-α, VEGF and heme oxygenase-1 (HO-1) were also estimated. ResultsPSO and ASO treatments to UC rats significantly reduced DAI, weight/length ratio, VEGFR-2, and colon histologic inflammatory score versus UC-controls. ASO significantly suppressed MIF levels and TNF-α expression greater than PSO. However, PSO was more significant than ASO in reducing MDA levels and up-regulating HO-1 expression. Both oils significantly down-regulated VEGF expression. The obtained biochemical and histological changes induced by UC were nearly corrected by SLZ. ConclusionThe proved beneficial effect of PSO and ASO as anti-inflammatory, anti-angiogenic, and antioxidant in UC rats could be mediated by suppression of TNF-α, VEGF, and MIF and up-regulation of HO-1.

Paradoxical psoriasis induced by IL-17 antagonists.

Background The paradoxical occurrence of psoriasis triggered by Interleukin-17 (IL-17) inhibitors is notable due to its prominent symptoms and the therapeutic dilemma it presents for follow-up care. Objective To describe cases in our clinic, perform an in-depth literature review, and suggest the most probable mechanisms of action. Method We conducted a literature review on published cases of IL-17 inhibitor-induced psoriasis. Results We found 22 articles reporting 30 cases of IL-17 inhibitor-induced paradoxical psoriasis, primarily observed in patients with a previous psoriasis history. Almost 60% of cases showed a change in lesion morphology, with the plaque or pustular type being prevalent. About 73.3% of patients had to discontinue the implicated drug, leading to partial or complete symptom resolution. The mechanism behind this response seemed to involve IL-17 inhibitors downregulating Tumour Necrosis Factor alpha (TNF-α), subsequently upregulating plasmacytoid dendritic cells and triggering unopposed IFN-alpha (IFN-α) production. Limitation Data are confined to case reports and case series. Conclusion More assertive measures are recommended for treating paradoxical psoriasis induced by IL-17 inhibitors than those caused by TNF-α inhibitors. Reintroducing an IL-17 inhibitor is not advised, as patients did not show improvement.

Manufacturing, quality control, and GLP-grade preclinical study of nebulized allogenic adipose mesenchymal stromal cells-derived extracellular vesicles

BackgroundHuman adipose stromal cells-derived extracellular vesicles (haMSC-EVs) have been shown to alleviate inflammation in acute lung injury (ALI) animal models. However, there are few systemic studies on clinical-grade haMSC-EVs. Our study aimed to investigate the manufacturing, quality control (QC) and preclinical safety of clinical-grade haMSC-EVs.MethodshaMSC-EVs were isolated from the conditioned medium of human adipose MSCs incubated in 2D containers. Purification was performed by PEG precipitation and differential centrifugation. Characterizations were conducted by nanoparticle tracking analysis, transmission electron microscopy (TEM), Western blotting, nanoflow cytometry analysis, and the TNF-α inhibition ratio of macrophage [after stimulated by lipopolysaccharide (LPS)]. RNA-seq and proteomic analysis with liquid chromatography tandem mass spectrometry (LC–MS/MS) were used to inspect the lot-to-lot consistency of the EV products. Repeated toxicity was evaluated in rats after administration using trace liquid endotracheal nebulizers for 28 days, and respiratory toxicity was evaluated 24 h after the first administration. In vivo therapeutic effects were assessed in an LPS-induced ALI/ acute respiratory distress syndrome (ARDS) rat model.ResultsThe quality criteria have been standardized. In a stability study, haMSC-EVs were found to remain stable after 6 months of storage at − 80°C, 3 months at − 20 °C, and 6 h at room temperature. The microRNA profile and proteome of haMSC-EVs demonstrated suitable lot-to-lot consistency, further suggesting the stability of the production processes. Intratracheally administered 1.5 × 108 particles/rat/day for four weeks elicited no significant toxicity in rats. In LPS-induced ALI/ARDS model rats, intratracheally administered haMSC-EVs alleviated lung injury, possibly by reducing the serum level of inflammatory factors.ConclusionhaMSC-EVs, as an off-shelf drug, have suitable stability and lot-to-lot consistency. Intratracheally administered haMSC-EVs demonstrated excellent safety at the tested dosages in systematic preclinical toxicity studies. Intratracheally administered haMSC-EVs improved the lung function and exerted anti-inflammatory effects on LPS-induced ALI/ARDS model rats.