A patient with axial spondylarthritis who experienced pancytopenia while receiving anti-TNF therapy.

Aplastic anemia is a rare and heterogeneous disease that causes pancytopenia and aplasia of the bone marrow. It is characterized by a failure of hematopoiesis. It is believed that approximately 65% of cases of acquired aplastic anemia are idiopathic. In a subset of cases, a drug or infection is the cause of bone marrow failure. This case report presents a 38-year-old patient with axial spondylarthritis who developed pancytopenia and was diagnosed with aplastic anemia during anti-TNF-α treatment.

The Use of TNF-α Inhibitors in Active Ankylosing Spondylitis Treatment.

Ankylosing spondylitis (AS) is a challenging disease, characterized by chronic inflammation and structural damage primarily affecting the axial skeleton, while extra-articular manifestations may also appear. This results in the deterioration of patients' quality of life. Over the past few decades, tumor necrosis factor-α (TNF-α) inhibitors have revolutionized the management of AS, offering substantial relief from symptoms and improving patient outcomes. The aim of this review is to assess the efficacy of TNF-α inhibitors in patients with active AS. A search was performed in the PubMed database using the following keywords: ("TNF alpha inhibitors" OR "anti TNF-a" OR "TNF-a inhibitors" OR "anti TNF-alpha" OR "Etanercept " OR "Golimumab" OR "Infliximab" OR "Certolizumab pegol" OR "Adalimumab") AND "ankylosing spondylitis". The search was completed in February 2024, and 35 studies were included in this review following PRISMA guidelines. The findings reveal evidence supporting the efficacy of TNF-α inhibitors in reducing inflammation, preventing structural damage, and enhancing overall well-being in AS patients. Overall, TNF-α inhibitors have emerged as a cornerstone in the therapeutic algorithm against AS with a very satisfactory safety profile.

Etanercept ameliorates chronic mild stress-induced depressive-like behavior in rats: Crosstalk between MAPK and STAT3 pathways and norepinephrine and serotonin transporters.

Depression is a serious medical illness characterized by persistent feelings of sadness, hopelessness, and lack of interest in daily activities. It can interfere with daily functioning and quality of life. Despite decades of research, the pathophysiology of depression remains incompletely understood. The correlation between depression and inflammation has recently attracted considerable attention. This study investigated the potential antidepressant effect of etanercept, a tumor necrosis factor-alpha (TNF-α) inhibitor, utilizing a chronic mild stress (CMS) model in rats. Male Wistar rats were divided into two groups; one following a non-stressed protocol and the other a stressed protocol for 5 weeks. From the beginning of the third week, rats were treated either with saline daily or with etanercept twice a week (0.3 mg/kg, i.p.) or with fluoxetine daily (10 mg/kg, i.p) as a reference. Etanercept exhibited comparable effects to those of fluoxetine in counteracting CMS-induced behavioral manifestation in the forced swimming and splash tests. Etanercept also restored serotonin and norepinephrine levels to control values in the prefrontal cortex (PFC). Moreover, the current study verified the antioxidant and anti-inflammatory effects of etanercept. Interestingly, etanercept halted the expression of both norepinephrine and serotonin transporters in stressed rats. This could be attributed to abrogation of the p38 mitogen-activated protein kinase (p38 MAPK) and signal transducer and activator of transcription 3 (STAT-3) pathways in the PFC. The findings of the present study contribute to the understanding of the potential of etanercept as an antidepressant and provide insights into the neurobiological mechanisms underlying its therapeutic effects.

Efficacy of switching from originator etanercept to biosimilar YLB113 in real-world patients with rheumatoid arthritis: A retrospective 12 months follow-up study.

Purpose: To investigate the disease activity in real-world patients with rheumatoid arthritis (RA) who switched from originator etanercept (ETN) to biosimilar YLB113. Methods: Forty one RA patients who switched from ETN to YLB113 were divided into 2 groups based on the Disease Activity Score based on the 28-joint count (DAS28) 12 months after switching (R group: DAS28 < 2.6, N group: DAS28 ≥ 2.6), and the baseline characteristics were statistically examined. A receiver operating characteristics (ROC) analysis was performed to estimate the cut-off value of DAS28 at baseline to achieve remission 12 months after switching. Results: There was no significant difference in the DAS28 at baseline and 12 months after switching (p = .83). Sixteen out of the 20 patients in remission at baseline achieved remission after switching. A univariate analysis revealed the rheumatoid factor (p = .04) and DAS28 (p < .001) at baseline were significantly lower in the R group than in the N group. Furthermore, logistic regression analysis revealed DAS28 was an independent factor (p = .004) for achieving remission 12 months after switching. An ROC curve analysis showed the optimal cut-off value for DAS28 at baseline to achieve remission at 12 months after switching was 2.5. Conclusions: RA patients who achieved remission using originator ETN, were able to maintain remission even if they switched to YLB113.

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

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Dynamics of serum levels of TNF-α in a longitudinal follow-up study in 98 patients with juvenile idiopathic arthritis treated with anti-TNF-α biological drugs.

OBJECTIVE: To determine the dynamics of serum levels of TNF-α in patients with juvenile idiopathic arthritis (JIA) treated with anti-TNF-α biological drugs and investigate their association with the disease activity. METHODS: We conducted a single-centre, observational cohort study in 98 patients with JIA (30 boys, 68 girls, mean age 11.3 years) treated with anti-TNF-α biological drugs. Clinical examinations and laboratory assessments of serum levels of TNF-α were performed before starting therapy with biological drug and at 6-month intervals afterwards up to 2.5 years. RESULTS: The analysis of serum levels of TNF-α in relation to the disease activity states showed the highest mean serum levels of TNF-α in patients on etanercept who had low disease activity states and in patients on adalimumab who had inactive disease. The correlation analysis in patients with JIA treated with etanercept or adalimumab showed a weak negative correlation between the serum levels of TNF-α and JADAS10 scores (p = 0.007), (r = - 0.177). CONCLUSION: The assessment of serum levels of TNF-α in children with JIA during treatment with etanercept or adalimumab is not a reliable biomarker of disease activity or immunological remission. Longitudinal measurement of TNF-α has no added clinical value in patients with JIA treated with anti-TNF-α biological drugs. Key Points • There is limited evidence regarding the effect of anti-TNF therapy on serum concentrations of TNF-α in patients with juvenile idiopathic arthritis • Our study showed an increase in the serum level of TNF-α after the initiation of therapy with either etanercept or adalimumab, which was more significant in patients with inactive or low disease activity • Serum TNF-α is most likely not biologically active during therapy with TNF-α inhibitors and therefore not a reliable biomarker of disease activity or immunological remission in patients with juvenile idiopathic arthritis.

Increasing the etanercept dose in a treat-to-target approach in juvenile idiopathic arthritis: does it help to reach the target? A post-hoc analysis of the BeSt for Kids randomised clinical trial.

BACKGROUND: Etanercept has been studied in doses up to 0.8 mg/kg/week (max 50 mg/week) in juvenile idiopathic arthritis (JIA) patients. In clinical practice higher doses are used off-label, but evidence regarding the relation with outcomes is lacking. We describe the clinical course of JIA-patients receiving high-dose etanercept (1.6 mg/kg/week; max 50 mg/week) in the BeSt for Kids trial. METHODS: 92 patients with oligoarticular JIA, RF-negative polyarticular JIA or juvenile psoriatic arthritis were randomised across three treat-to-target arms: (1) sequential DMARD-monotherapy (sulfasalazine or methotrexate (MTX)), (2) combination-therapy MTX + 6 weeks prednisolone and (3) combination therapy MTX + etanercept. In any treatment-arm, patients could eventually escalate to high-dose etanercept alongside MTX 10mg/m2/week. RESULTS: 32 patients received high-dose etanercept (69% female, median age 6 years (IQR 4-10), median 10 months (7-16) from baseline). Median follow-up was 24.6 months. Most clinical parameters improved within 3 months after dose-increase: median JADAS10 from 7.2 to 2.8 (p = 0.008), VAS-physician from 12 to 4 (p = 0.022), VAS-patient/parent from 38.5 to 13 (p = 0.003), number of active joints from 2 to 0.5 (p = 0.12) and VAS-pain from 35.5 to 15 (p = 0.030). Functional impairments (CHAQ-score) improved more gradually and ESR remained stable. A comparable pattern was observed in 11 patients (73% girls, median age 8 (IQR 6-9)) who did not receive high-dose etanercept despite eligibility (comparison group). In both groups, 56% reached inactive disease at 6 months. No severe adverse events (SAEs) occurred after etanercept dose-increase. In the comparison group, 2 SAEs consisting of hospital admission occurred. Rates of non-severe AEs per subsequent patient year follow-up were 2.27 in the high-dose and 1.43 in the comparison group. CONCLUSIONS: Escalation to high-dose etanercept in JIA-patients who were treated to target was generally followed by meaningful clinical improvement. However, similar improvements were observed in a smaller comparison group who did not escalate to high-dose etanercept. No SAEs were seen after escalation to high-dose etanercept. The division into the high-dose and comparison groups was not randomised, which is a potential source of bias. We advocate larger, randomised studies of high versus regular dose etanercept to provide high level evidence on efficacy and safety. TRIAL REGISTRATION: Dutch Trial Register; NTR1574; 3 December 2008; https://onderzoekmetmensen.nl/en/trial/26585 .

Efficacy and safety of tumor necrosis factor inhibitors for systemic juvenile idiopathic arthritis: a systematic review.

OBJECTIVES: This systematic review assessed the efficacy and safety of tumor necrosis factor (TNF) inhibitors in patients with systemic juvenile idiopathic arthritis (JIA). METHODS: Studies were searched using PubMed, Embase, Cochrane, Ichushi-Web, and clinical trial registries (from 2000 to 2021). The risk of bias was assessed using the Cochrane Risk of Bias version 2 for randomized controlled trials (RCTs) and the manual for development clinical practice guidelines by Minds, a project promoting evidence-based medicine in Japan, for observational studies. RESULTS: One RCT and 22 observational studies were included. In the RCT on infliximab, the American College of Rheumatology pediatric (ACR Pedi) 30/50/70 responses at 14 weeks were 63.8%/50.0%/22.4%, with relative risks of 1.30 (95% confidence interval [CI]: 0.94-1.79)/1.48 (95% CI: 0.95-2.29)/1.89 (95% CI: 0.81-4.40), respectively. In the observational studies, ACR Pedi 30/50/70 responses for etanercept at 12 months were 76.7%/64.7%/46.4%, respectively. Infliximab treatment caused anaphylaxis in 17% and an infusion reaction in 23% of patients. The incidence of macrophage activation syndrome, serious infection and malignancy caused by TNF inhibitors was 0%-4%. CONCLUSIONS: Thus, although TNF inhibitors were relatively safe, they were unlikely to be preferentially administered in patients with systemic JIA because of their inadequate efficacy. Further studies, particularly well-designed RCTs, are necessary to confirm the efficacy and safety of TNF inhibitors for systemic JIA.

The Role of Etanercept in Controlling Clinical and Radiological Progression in Rheumatoid Arthritis: A Systematic Review.

Etanercept (ETN) is a disease-modifying anti-rheumatic drug (DMARD) used in the treatment of rheumatoid arthritis (RA) that works as a tumor necrosis factor inhibitor (TNF inhibitor) by blocking the effects of naturally occurring TNF. This review will evaluate the effect of ETN as a monotherapy or combination therapy with methotrexate (MTX) in the treatment of RA. This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 guidelines. A systematic search was done on PubMed and Google Scholar from 1999 to 2023. Predefined eligibility criteria were set for selected studies, which include: free full-text articles published; randomized control trials (RCTs); systematic reviews and meta-analyses; and observational studies in a patient with RA treated with ETN as initial therapy or as an add-on to conventional disease-modified therapy. Hence, the data had been extracted, and a quality assessment of each study was done by two individual authors. When comparing patients who received 15-25 mg of MTX with those who also received 25 mg of ETN in combination, 71% achieved American College of Rheumatology 20 (ACR20) by 24 weeks, compared to 27% in the MTX and placebo groups (p<0.001), and 39% achieved American College of Rheumatology 50 (ACR50), compared to 3% in the placebo + MTX group (p<0.001). Low disease activity (DAS 28) was more common in patients who had both MTX and ETN (64.5% with DAS <2.4 and 56.3% with DAS 28 <3.2) compared to patients who received only one medication (44.4% with DAS <2.4 and 33.2% with DAS 28 <3.2 for ETN and 38.6% with DAS <2.4 and 28.5% with DAS 28 <3.2 for MTX, with P<0.01). ETN demonstrated smaller changes from baseline in the modified Sharp score (TSS) and erosion scores (ES) at 12 months and two years, as well as a decreased change in the ES score at one year (with a trend of P value = 0.06 for the TSS score), in comparison to those receiving DMARD. Reactions at the injection site (42% vs. 7%, P<0.001) were the only events that occurred significantly more frequently in the ETN plus-MTX group. Combining ETN and MTX appears to help control RA symptoms by decreasing the American College of Rheumatology (ACR) response and DAS score, as well as halting the disease's progression on X-rays. The most common adverse effects were reactions to ETN administered alone at the injection site, likely because of patient awareness of the treatment received. There was also concern about tuberculosis and malignancy, but no recent data is available. Therefore, a larger clinical trial with longer follow-up is required to ascertain long-term safety and benefits.

The risk of tuberculosis infection in Saudi patients receiving adalimumab, etanercept, and tocilizumab therapy.

BACKGROUND: The risk of infection including tuberculosis (TB) infection or reactivation during biological therapy with the current various clinical application is a major concern. This risk may be higher in countries endemic to TB. Our aim of this study is to determine the risk of TB infection in patients receiving 3 biological treatments, Adalimumab, Etanercept and Tocilizumab. METHODS: A retrospective cohort study extending over 2 years follow-up for all patients receiving Adalimumab, Etanercept and Tocilizumab for various clinical indications in a tertiary care center in Saudi Arabia. RESULT: Over the period of 2015-2019, A total of 410 patients received Adalimumab, 271 received Etanercept and 58 patients received Tocilizumab. Rheumatoid arthritis was the most common indication for therapy in all groups and for Adalimumab the most common indication was inflammatory bowel disease, for Etanercept was psoriatic arthritis and for Tocilizumab was juvenile idiopathic arthritis. After a mean follow up period of 36 ± 8.9 months for patients receiving Adalimumab, 21.5 ± 8.4 months for patients receiving Etanercept and 21 ± 2.5 months for patients receiving Tocilizumab there were no reported cases of TB infection in all groups. Only one patient was diagnosed with latent TB 7 months later after starting Adalimumab and tow patients after starting Etanercept. The overall Interferon Gamma Release Assays (IGRA) positivity rate was 9.7%. There was significant association between IGRA positivity rate and patient age. The cutoff age in which IGRA positivity has significantly increased was 53.20 years. CONCLUSION: In our study, patients receiving Etanercept, Adalimumab and Tocilizumab had no increased risk of TB infection. Only 0.3% of patients treated with Adalimumab and 0.9% of patients treated with Etanercept converted to a positive IGRA during therapy.

Use of biologics in Chinese pregnant patients with deficiency of interleukin-36 receptor antagonist (DITRA): A case series.

OBJECTIVE: Impetigo herpetiformis (IH) is a rare form of pustular psoriasis which may result in maternal and fetal morbidity and even mortality. Deficiency of interleukin-36 receptor antagonist (DITRA) is the most frequently identified genetic defect of IH. Currently there are no biologics approved for IH despite the revolutionary role of biologics in the treatment of plaque and pustular psoriasis. Anecdotal reports of biologics use in DITRA patients with IH are also limited. CASE REPORTS: We present herein a case series of 6 Chinese IH patients harboring IL36RN gene c.115+6T>C mutation during 8 pregnancies, treated with various biologics, including adalimumab, etanercept and secukinumab. CONCLUSION: Most pregnancy courses were uneventful, except for one woman who had recurrent episodes of decreased fetal heart rate variability after adalimumab injections, which subsided after switching to etanercept. The treatment effectiveness and safety demonstrated in our cases suggested the role of biologics for the treatment of IH in patients with DITRA.

Etanercept-synthesizing adipose-derived stem cell secretome: A promising therapeutic option for inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, with tumor necrosis factor (TNF)-α playing a key role in its pathogenesis. Etanercept, a decoy receptor for TNF, is used to treat inflammatory conditions. The secretome derived from adipose-derived stem cells (ASCs) has anti-inflammatory effects, making it a promising therapeutic option for IBD. AIM: To investigate the anti-inflammatory effects of the secretome obtained from ASCs synthesizing etanercept on colon cells and in a dextran sulfate sodium (DSS)-induced IBD mouse model. METHODS: ASCs were transfected with etanercept-encoding mini-circle plasmids to create etanercept-producing cells. The secretory material from these cells was then tested for anti-inflammatory effects both in vitro and in a DSS-induced IBD mouse model. RESULTS: This study revealed promising results indicating that the group treated with the secretome derived from etanercept-synthesizing ASCs [Etanercept-Secretome (Et-Sec) group] had significantly lower expression levels of inflammatory mediators, such as interleukin-6, Monocyte Chemoattractant Protein-1, and TNF-α, when compared to the control secretome (Ct-Sec). Moreover, the Et-Sec group exhibited a marked therapeutic effect in terms of preserving the architecture of intestinal tissue compared to the Ct-Sec. CONCLUSION: These results suggest that the secretome derived from ASCs that synthesize etanercept has potential as a therapeutic agent for the treatment of IBD, potentially enhancing treatment efficacy by merging the anti-inflammatory qualities of the ASC secretome with etanercept's targeted approach to better address the multifaceted pathophysiology of IBD.

Perispinal Etanercept to improve STroke Outcomes (PESTO): Protocol for a multicenter, international, randomized placebo-controlled trial.

RATIONALE: A large proportion of stroke survivors will have long-lasting, debilitating neurological impairments, yet few efficacious medical treatment options are available. Etanercept inhibits binding of tumor necrosis factor to its receptor and is used in the treatment of inflammatory conditions. Perispinal subcutaneous injection followed by a supine, head down position may bypass the blood brain barrier. In observational studies and one small randomized controlled trial the majority of patients showed improvement in multiple post stroke impairments. AIM: Perispinal Etanercept to improve STroke Outcomes (PESTO) investigates whether perispinal subcutaneous injection of etanercept improves quality of life and is safe in patients with chronic, disabling, effects of stroke. METHODS AND DESIGN: PESTO is a multicenter, international, randomized placebo-controlled trial. Adult participants with a history of stroke between 1 and 15 years before enrollment and a current modified Rankin scale between 2 and 5 who are otherwise eligible for etanercept are randomized 1:1 to single dose injection of etanercept or placebo. STUDY OUTCOMES: The primary efficacy outcome is quality of life as measured using the Short Form 36 Health Inventory at day 28 after first injection. Safety outcomes include serious adverse events. SAMPLE SIZE TARGET: A total of 168 participants assuming an improvement of the SF-36 in 11% of participants in the control arm and in 30% of participants in the intervention arm, 80% power and 5% alpha. DISCUSSION: PESTO aims to provide level 1 evidence on the safety and efficacy of perispinal etanercept in patients with long-term disabling effects of stroke.

Development of anti-MDA5 autoantibody-positive dermatomyositis following the use of etanercept biosimilar in rheumatoid arthritis.

The induction of autoimmune diseases during tumour necrosis factor-alpha inhibitor (TNFi) usage has been described. Herein, we report a rare case of a 49-year-old woman with antimelanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive dermatomyositis (DM), which developed 5 weeks after the introduction of an etanercept biosimilar to rheumatoid arthritis (RA). Four of the five known cases, including ours, of anti-MDA5Ab-positive DM complicated with RA revealed anti-MDA5Ab-positive DM following TNFi usage. When patients with RA are diagnosed with interstitial lung disease during TNFi usage, anti-MDA5 Ab-positive DM could be a differential diagnosis.

(Re-)introduction of TNF antagonists and JAK inhibitors in patients with previous tuberculosis: a systematic review.

BACKGROUND: Tuberculosis (TB) is a common complication associated with treatment with tumour necrosis factor (TNF) antagonists and Janus kinase (JAK) inhibitors. However, there is uncertainty about the risk of TB relapse in patients with TB and comorbidities requiring treatment with these agents. OBJECTIVES: To assess the risk of TB relapse in patients (re-)started on TNF antagonists or JAK inhibitors. METHODS: Systematic review. DATA SOURCES: PubMed and Cochrane Library databases until 11 December 2023. STUDY ELIGIBILITY CRITERIA: Randomized control trials, prospective and retrospective cohort studies, case reports and case series. PARTICIPANTS: Patients with current or previous TB who were (re-)started on TNF antagonists or JAK inhibitors. INTERVENTIONS: (Re-)introduction of TNF antagonists and JAK inhibitors. ASSESSMENT OF RISK OF BIAS: All studies meeting entry criteria were included regardless of quality. METHODS OF DATA SYNTHESIS: Categorical data are presented as frequencies and percentages. For non-normally distributed aggregated data, we calculated the pooled weighted median with 95% CI. For individual patient data, the median and interquartile range (IQR) were calculated. RESULTS: Of 5018 articles screened for eligibility, 67 publications reporting on 368 TB patients who (re-)initiated treatment with TNF antagonists for underlying diseases were included. The median age was 42.5 years (95% CI: 40.4-42.5) and the proportion of female patients was 36.6% (n = 74) of patients whose sex was reported. A total of 14 patients (3.8%, 95% CI: 2.1-6.3%) developed TB relapse after a median of 8.5 months (interquartile range, 6.8-14.8 months) following (re-)initiation of anti-TNF treatment. Furthermore, among 251 articles screened for eligibility, 11 reports on TB patients who were (re-)started on JAK inhibitors for underlying diseases were identified. The median age was 62 years (interquartile range, 48.5-68.5 years) and 45.5% (n = 5) were female. Only one patient (9.1%; 95% CI: 0.2-41.3%) had TB reactivation 10 months after starting treatment with ruxolitinib. In addition, 94 patients who were treated with TNF antagonists and two patients temporarily treated with JAK inhibitors for the prevention or treatment of paradoxical reactions were analysed. None of the publications reported microbiological failure or worsening of TB-related symptoms. CONCLUSIONS: (Re-)initiation of TNF antagonists and JAK inhibitors may be relatively safe in patients with current or previous TB and the need for further treatment of underlying diseases.

Inhibition of both NOX and TNF-α exerts substantial renoprotective effects in renal ischemia reperfusion injury rat model.

BACKGROUND AND AIMS: Acute kidney injury (AKI) due to renal ischemia-reperfusion injury (RIRI) is associated with high morbidity and mortality, with no renoprotective drug available. Previous research focused on single drug targets, yet this approach has not reached translational success. Given the complexity of this condition, we aimed to identify a disease module and apply a multitarget network pharmacology approach. METHODS: Identification of a disease module with potential drug targets was performed utilizing Disease Module Detection algorithm using NADPH oxidases (NOXs) as seeds. We then assessed the protective effect of a multitarget network pharmacology targeting the identified module in a rat model of RIRI. Rats were divided into five groups; sham, RIRI, and RIRI treated with setanaxib (NOX inhibitor, 10 mg/kg), etanercept (TNF-α inhibitor, 10 mg/kg), and setanaxib and etanercept (5 mg/kg each). Kidney functions, histopathological changes and oxidative stress markers (MDA and reduced GSH) were assessed. Immunohistochemistry of inflammatory (TNF-α, NF-κB) apoptotic (cCasp-3, Bax/Bcl 2), fibrotic (α-SMA) and proteolysis (MMP-9) markers was performed. RESULTS: Our in-silico analysis yielded a disease module with TNF receptor 1 (TNFR1A) as the closest target to both NOX1 and NOX2. Targeting this module by a low-dose combination of setanaxib, and etanercept, resulted in a synergistic effect and ameliorated ischemic AKI in rats. This was evidenced by improved kidney function and reduced expression of inflammatory, apoptotic, proteolytic and fibrotic markers. CONCLUSIONS: Our findings show that applying a multitarget network pharmacology approach allows synergistic renoprotective effect in ischemic AKI and might pave the way towards translational success.

Comparison of safety and effectiveness between etanercept biosimilar LBEC0101 and reference in patients with rheumatoid arthritis in real-world data using the KURAMA cohort.

OBJECTIVES: Biosimilars are anticipated to be widely used in the treatment of rheumatoid arthritis (RA), owing to their cost efficiency; LBEC0101 was the first etanercept (ETN) biosimilar approved in Japan. However, there are limited real-world data comparing its safety and effectiveness with those of a reference product. METHODS: This study used data from the Kyoto University Rheumatoid Arthritis Management Alliance cohort, including patients with RA who received ETN therapy-ETN reference product (ETN-RP) or LBEC0101-between 2015 and 2021. Serum ETN levels were measured using liquid chromatography-tandem mass spectrometry. RESULTS: The 1-year continuation rates of ETN-RP and LBEC0101 were 58.7% and 74.4%, respectively. Effectiveness of treatment was evaluated in 18 patients; both products significantly reduced the 28-joint RA disease activity score and erythrocyte sedimentation rate (DAS28-ESR). Moreover, to determine equivalence, we analysed 11 patients who switched from ETN-RP to LBEC0101; the DAS28-ESR and serum ETN levels before and after switching were not significantly different. CONCLUSIONS: This real-world cohort study confirmed that the biosimilar of ETN, LBEC0101, was comparable to the reference product in terms of continuation rate, effectiveness at initiation of introduction, and effect persistence before and after switching in clinical practice.

Pulmonary Embolism in a Patient with Rheumatoid Arthritis on Etanercept Therapy.

Pulmonary embolism (PE) represents mechanical obstruction of one or more branches of pulmonary vasculature due to thromboembolism from a deep vein thrombosis. Hormonal contraceptives, hormonal replacement therapy, antipsychotics and fibrates are medications that are associated with increased risk of venous thromboembolism(VTE). Etanercept is a TNF alpha and beta receptor blocker. Rarely this medication has been identified as a risk factor for VTE. There is a possible correlation between rheumatoid arthritis(RA) and risk of VTE in patients with RA. Use of medication that can increase risk of VTE in a patient with systemic inflammatory condition that in itself may be a risk factor for VTE requires shared decision and risk versus benefit discussion with the patient. We present a case of unprovoked PE in a patient on Etanercept treatment for RA. Though in this case, a causal relationship between the drug use and the event could not be proved, the patient preferred to discontinue the medication. In newer classes of medications, when the mechanism of side effects is unclear, we strongly recommend extensive discussion with patients about available scientific literature and encourage shared decision making with the patient.

Safety and efficacy of biologic immunosuppressive treatment in juvenile idiopathic arthritis associated with inborn errors of immunity.

Objectives: This study aims to describe clinical features, therapeutic outcomes, and safety profiles in patients affected by juvenile idiopathic arthritis (JIA) and inborn errors of immunity (IEI) treated with biological Disease-modifying antirheumatic drugs (DMARDs). Methods: We enrolled three patients who were followed in the Pediatric Rheumatology Unit at Meyer Children's Hospital in Florence; these patients were affected by JIA, according to ILAR criteria, and IEI, according to the IUIS Phenotypical Classification for Human Inborn Errors of Immunity. Among them, two patients had 22q11.2 deletion syndrome (22q11.2DS) and one patient had X-linked agammaglobulinemia (XLA). Results: Case 1: A 6-year and 2-month-old boy was affected by 22q11.2DS, associated with oligoarticular JIA, at the age of 2 years. He was treated with non-steroidal anti-inflammatory drugs (NSAIDs) and methotrexate, along with oral glucocorticoids but with no benefits. Treatment with etanercept allowed him to achieve remission after 10 months. Case 2: A 6-year and 2-month-old girl was affected by 22q11.2DS, associated with oligoarticular JIA, at the age of 3 years and 11 months. She was treated with NSAIDs, joint injections, and methotrexate but without clinical response. Treatment with Adalimumab allowed her to achieve remission after 6 months. Case 3: A 12-year and 2-month-old boy was affected by XLA, associated with polyarticular JIA, at the age of 9 years and 11 months. He was treated with NSAIDs, methotrexate, joint injections, and oral glucocorticoids with no benefits. He failed to respond to anti-TNF-alpha, tocilizumab, and abatacept. Currently, he is undergoing therapy with sirolimus plus abatacept, which allowed him to achieve remission after 4 months. Conclusions: Results suggest that the use of immunosuppressive biological therapies can control disease activity in these patients. No adverse drug-related reactions were observed during the follow-up.