Proteoglycans and their fragments have potential as diagnostic or theragnostic biomarkers to identify diseases characterized by dysregulated extracellular matrix remodeling, such as juvenile idiopathic arthritis (JIA). Therefore, our study aimed to evaluate the diagnostic utility of plasma proteoglycan profiles, namely, aggrecan, decorin, and biglycan, released from osteoarticular structures into the blood of children with juvenile idiopathic arthritis. These profiles are potential biomarkers of tissue destruction and/or indicators of the efficacy of therapy with the biologic agent etanercept (ETA). This study was conducted on 263 blood samples collected from 25 healthy children and 34 children at various stages of juvenile idiopathic arthritis disease: immediately after diagnosis, following treatment with disease-modifying antirheumatic drugs (DMARD) (methotrexate, sulfasalazine, and prednisone), and during 3, 6, 12, 18, and 24 months of therapy with etanercept. Quantitative levels of aggrecan, biglycan, and decorin were measured using ELISA kits. In children with JIA, plasma aggrecan levels were elevated at diagnosis, decreased after ineffective DMARD therapy, and increased again at 24 months of etanercept treatment despite clinical improvement. By contrast, biglycan levels were similar to those in healthy controls but decreased during etanercept therapy. Decorin levels were initially high in untreated and DMARD-treated patients but returned to normal after 24 months of biologic treatment. After considering these findings and the ROC analysis, we conclude that decorin appears to be a promising biomarker for diagnosing and monitoring etanercept therapy in JIA, and biglycan is a useful biochemical marker for assessing the effectiveness of ETA treatment.

Treatment persistence is a surrogate marker for long-term treatment success. To assess the persistence of biological agents used for treatment of patients with rheumatoid arthritis (RA) over 5 years period and determine variables associated with persistence or discontinuation. A systematic literature review (SLR) and meta-analysis were performed. We performed a bibliographic search through Pubmed, Cochrane and Lilacs databases, and ACR, EULAR, PANLAR abstracts until January 2020. Two independent reviewers evaluated the identified publications, by title and abstract and full text, according to PICO methodology. RA patients ≥ 18 years, treated with biological agents, which measured persistence/ discontinuation for a period of time ≥ 5 years and who were in English or Spanish language. Among 809 articles, 56 articles were selected, leading to a total of 72,677 (range: 79-10,396) patients, with a mean age of 53.8 years ± 12.1, 78.2% female and an average RA disease duration of 9.7 years ± 8.4. Data from 29 publications were pooled for an exploratory meta-analysis of the persistence of b-DMARDs in the 2nd line of treatment at 5 years. Tocilizumab (TCZ) had the highest persistence 66% (CI 95% 60-72), followed by golimumab (GLM) 62% (47-75). Regarding the 3rd therapeutic line, the greater persistence corresponded to abatacept (ABA) 45% (41-50) and etanercept (ETN) 41% (30-53). Lower survival rates predictors were: greater use of steroids, higher baseline disease activity, and female gender. In this study, TCZ and GLM showed higher 5-years persistence vs other b-DMARDs in 2nd line treatment. Key Points •The persistence of biologic disease modifying anti-rheumatic drugs (b-DMARDs) is a surrogate marker of long-term treatment success as it represents an indirect measure of clinical effectiveness, the absence of significant adverse events (AE) and satisfaction with treatment. •This systematic literature review (SLR) and meta-analysis included observational studies and long-term extension of randomized controlled studies, allowing us to evaluate drug retention over a 5-year period, from different perspectives and the b-DMARDs that have been on the market for less time. •The highest 5-year persistence of b-DMARDs in patients with inadequate response to conventional synthetic (cs-) DMARDs was for tocilizumab and golimumab. While in b-DMARDs experienced patients, abatacept and etanercept presented the higher retention.

Psoriasis, a chronic inflammatory dermatological condition, exhibits heterogeneous responses to anti-TNF therapies such as etanercept (ETN), underscoring the need for predictive biomarkers. This study investigated the association of interleukin-1 beta (IL-1β) gene promoter polymorphisms (rs1143623 C/G, rs752338864 C/G, and rs1143627 C/T) with ETN efficacy in 80 Iraqi patients with moderate to severe plaque psoriasis. Patients were categorized according to treatment response: responders achieved ≥ 75% reduction in the Psoriasis Area and Severity Index (PASI), whereas non-responders demonstrated ≤ 50% reduction. Post-treatment serum IL-1β levels were significantly higher in non-responders (50.35 ± 15.81 pg/mL) compared to responders (35.38 ± 10.35 pg/mL; p = 0.001). Genotyping revealed that the rs752338864 CC genotype was exclusively present in responders (25% vs 0% in non-responders; p = 0.001) and showed a strong inverse correlation with non-responder status (ϕ = −0.342; p = 0.003), as well as a greater reduction in PASI score (p = 0.01). Logistic regression further identified serum IL-1β concentration as an independent predictor of non-response (OR = 1.11; p = 0.0115). In contrast, the other investigated SNPs (rs1143623 C/G and rs1143627 C/T) showed no significant association with treatment response. These findings suggest that the rs752338864 CC genotype may indicate a positive response, whereas increased IL-1β levels could reflect resistance to therapy. Overall, this study sheds new light on psoriasis pharmacogenetics and demonstrates the potential for incorporating genetic and biomarker assessments into individualized treatment strategies.

Objectives: To assess the association between serum concentrations of adalimumab (ADL) and etanercept (ETN) and the occurrence of a flare in rheumatoid arthritis (RA) patients who are tapering methotrexate (MTX) or their TNF inhibitor. In addition, we explored the impact of tapering MTX on immunogenicity in patients with longstanding ADL use. Methods: ADL and ETN serum concentrations and anti-drug antibodies (ADAs) quantified with a drug-tolerant assay were determined in all RA patients who participated in the TARA trial. Within the TARA trial, two tapering strategies were compared, namely gradually tapering MTX followed by tapering a TNF-inhibitor (ADL or ETN) or vice versa. Results: In the current analysis, 111 RA patients who strictly followed the tapering strategy and had >3 blood samples were included, of them 41% tapered ADL and 59% tapered ETN. Both ADL and ETN concentrations decreased during tapering and stopping, but ADL was longer detectable after cessation compared to ETN. If MTX was tapered first, more ADAs against ADL were detectable in the serum, but it did not affect the serum concentrations. Conclusions: Our data showed that the majority of flares occur when the median serum concentration of ADL and ETN falls below 1 mg/L. If MTX is tapered first, there is a notable increase in the detection of ADAs, but this does not impact the median ADL serum concentration.

Endometriosis is a chronic disorder characterized by abnormal endometrial tissue growth. This study evaluates a novel combination immunomodulatory treatment involving etanercept (ETN) and exosomes derived from human Wharton's jelly mesenchymal stem cells (hWJMSC-Exo) as a promising alternative to conventional therapies for modulating inflammation in endometriosis. Endometrial stromal cells were isolated by enzymatic digestion of eutopic (EuESCs, N = 6) and ectopic (EESCs, N = 6) tissues of endometriosis patients and non-endometriotic controls (CESCs, N = 6). hWJMSC-Exo were confirmed by flow cytometry, SEM, and DLS tests. Cells were treated with varying concentrations of ETN (0-40 μg/ml), hWJMSC-Exo (0-15 μg/ml), and their combination (E+E). IC50 values were determined using the MTT assay at 24, 48, and 72 hours. Protein levels of TNF- α, VEGF-A, and IL-10, and gene expression of MMP-2, MMP-9, MCP-1, aromatase, TSLP, and TGF-β1 were measured using ELISA and RT-PCR, respectively. The combination of ETN (10 μg/ml) and hWJMSC-Exo (10 μg/ml) at 24 and 48 hours, respectively, reduced protein expression of TNF-α, VEGF-A, and IL-10 in EESCs, EuESCs, and CESCs compared with untreated groups (P < 0.001). Additionally, E+E treatment significantly reduced mRNA expression of MMP-2, MMP-9, MCP-1, aromatase, TSLP, and TGF-β1 in all three groups compared to untreated groups. This combination therapy improves inflammation, angiogenesis, tissue remodeling, and immune regulation in endometriosis. However, clinical validation and long-term safety require further in vivo studies with larger sample sizes. E+E treatment synergistically reduced key cytokines and enzymes in endometriosis. This approach is a promising means of regulating inflammation.

ABSTRACTTherapies targeting tumor necrosis factor‐α (TNFα), including etanercept (ETN), have become a mainstay in the treatment of juvenile idiopathic arthritis (JIA). As a result, this work seeks to evaluate the relationship between pharmacologic markers of ETN activity and clinical effectiveness in a cohort of patients with JIA. This is a single‐centered, open‐label, prospective, cross‐sectional study of patients with JIA (n = 26) receiving maintenance ETN. Determination of ETN effectiveness was based on the absence of active arthritis in any joint at the time of sample collection. Patient plasma samples were collected and analyzed for ETN concentrations, anti‐ETN antibodies, anti‐TNFα activity, and TNFα concentrations. ETN was effective in 46% (n = 12) of patients assessed at the time of sampling. No differences in baseline demographics were observed between patients based on effectiveness. Median [IQR] plasma ETN concentrations were 2094 [1384, 2680] ng/mL. Anti‐ETN antibodies were undetectable in all patients. Plasma anti‐TNFα activity varied 32‐fold and was directly proportionate to plasma ETN concentrations (ρ = 0.75, p = 3.8 × 10−3). Plasma TNFα concentrations were 9‐fold higher than previous measurements in patients with JIA not receiving anti‐TNFα therapy (p = 3.6 × 10−9). ETN effectiveness was associated with 21% higher ETN concentrations (p = 0.36), 52% higher plasma anti‐TNFα activity (p = 0.14), and 84% higher plasma TNFα concentrations (p = 0.008). Among pharmacologic markers of ETN activity measured, plasma TNFα concentrations are most strongly associated with ETN effectiveness in JIA.

We aimed to estimate the global prevalence of anti-drug antibodies (ADAb), their impact on response, and associated factors in adults with rheumatoid arthritis (RA) and spondyloarthritis (SpA) treated by TNF alpha inhibitors (TNF-i). We searched PubMed, MEDLINE, Cochrane, Web of Science, and Scopus for observational, population-based studies published between Jan 2010 and Sept 2021. We included studies that reported the prevalence of ADAb (our main outcome) and examined their impact on treatment efficacy in adults treated with TNF-i (secondary outcome). To investigate heterogeneity, we used a Q-test and predictive interval. The overall global prevalence of ADAb in RA was 20.8% (95%CI,6.8-25.5) (95%PI,6.12-51.42) and in SpA 24.8% (95%CI,19.1-31.5) (95%PI,7.31-57.98). There was no significant difference in the prevalence of ADAb between infliximab (IFX) and adalimumab (ADA) in RA (p=0.21) nor in SpA (p=0.46). There was a statistically significant difference between IFX and etanercept (ETN) in RA (p<0.0001) as well as in SpA (p=0.001) and, likewise, between ADA and ETN in RA (p<0.0001) and in SpA (p=0.002). Study by subgroups of the impact of immunogenicity on response, according to the type of TNF-i, showed that the mean OR for ADA was 0.152 (CI 95%, 0.054 to 0.427) and for IFX was 0.144 (CI 95%, 0.055 to 0.378). The pairwise comparison of ADA vs IFX was not statistically significant (p=0.94). In subgroup analysis, according to the disease, the mean OR for RA was 0.149 (IC 95% 0.064 to 0.347) and for SpA was 0.303 (IC95% 0.103 to 0.890). The pairwise comparison of RA vs SpA was not statistically significant. The use of methotrexate tends to reduce the development of ADAb in RA and SpA with an OR=0.472 (CI95%,0.324-0.689) (PI95%,0.16-1.39). ADAb were equally prevalent in RA and SpA treated with TNF-i. Immunogenicity was associated with response to treatment and influenced by concomitant use of methotrexate.

This multicenter retrospective study evaluated the differential impact of concomitant methotrexate (MTX) and glucocorticoids (GCs) administration by dosage on the effectiveness and safety of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi) in a real-world cohort of patients with rheumatoid arthritis, adjusting for clinical backgrounds variables. The study included 3751 treatment courses (bDMARD- or JAKi-naïve cases, 48.9%; tumor necrosis factor inhibitors: 1668; tocilizumab [TCZ]: 865; abatacept [ABT]: 825; JAKi: 393). Hazard ratios for treatment retention were calculated using multivariate Cox proportional hazards models, adjusted for potential confounders. Improvement in the clinical disease activity index (ΔCDAI) with each formulation was analyzed using mixed-effects models for repeated measures, stratified by concomitant MTX and GCs dosages. Compared to MTX(-), a lower dose of MTX (< 10 mg/week) was associated with significant improvement in ΔCDAI with golimumab (GLM), TCZ, and JAKi and reduced discontinuation due to ineffectiveness of etanercept (ETN). A higher MTX dose (≥ 10 mg/week) demonstrated a similar trend. Compared to GCs(-), a lower dose of GCs (≤ 5 mg/day; prednisolone equivalent) was associated with a diminished ΔCDAI with GLM and an increased discontinuation due to ineffectiveness of ADA and GLM. A higher dose of GCs (> 5 mg/day) was associated with increased discontinuation due to safety with ETN, CZP, and JAKi. The effects of concomitant MTX and GCs dosages on the effectiveness and safety of biologics and JAKi vary among agents. MTX did not mitigate safety issues, and GCs did not enhance effectiveness of any agents, regardless of dosage.

Preeclampsia (PE), new onset hypertension (HTN) during pregnancy, is associated with activated CD4+ T cells, altered cerebral blood autoregulation, and impaired neurological dysfunction. Additionally, a history (Hx) of COVID-19 (CV) infection during pregnancy is associated with an increased incidence of a PE and prolonged neurological symptoms. We have previously shown that adoptive transfer of CD4+ T cells from PE patients with and without a Hx of CV causes hypertension, increased inflammation, and impaired neurological function during pregnancy. In addition, we have shown that treatment with etanercept (ETAN) decreases hypertension (HTN) in RUPP rat model of PE, however the effect of TNF-alpha blockade on neurological function during PE with or without a history (Hx) of CV infection is unknown. Therefore, we sought to examine a role for Etanercept to improve neurological and cardiovascular outcomes in postpartum (PP) recipient rats of CD4+ T cells from PE placentas with or without a CV history (Hx). A second objective was to determine if perinatal Etan improved blood pressure and neurovascular function in the offspring. One million placental CD4+ T cells from PE and normotensive (NT) patients with or without a CV Hx during pregnancy were injected i.p. into gestational day (GD) 12 nude athymic rats. ETAN was administered i.p. on day 18. HTN and neurological function was examined at 12 weeks PP in dams and 16 weeks in the offspring. Cerebral Blood Flow (CBF) was measured in dams by Doppler flowmetry and carotid catheters were placed in offspring at 16 weeks for blood pressure measurements. Neurological function was assessed by behavioral tests (Barnes maze and novel object recognition). A two-way ANOVA was used for statistical analysis. MAP remained elevated 12 weeks PP in PE CV Hx (153 mmHg±6, n=7) and PE (150±5 mmHg, n=5, p&lt;0.05) compared to NT CV Hx (121±6 mmHg, n=6) and NP (116±6 mmHg, n=6). MAP was not significantly attenuated in PP PE CV Hx+ETAN (136 mmHg±11, n=3) or PP PE+ETAN (143±9 mmHg, n=6). At 12 weeks PP, PE and CV Hx PE had impaired autoregulation and memory compared to either NP or NT CV Hx control groups, which was not improved with Etan. At 16 weeks, there were no significant changes in MAP in female or male offspring. Behavior tests in the offspring indicated a decrease in memory and learning in the Barnes maze by PE CV Hx male and female offspring compared to NT CV Hx or NP controls. Etan improved memory and cognition only in female offspring of PE CV Hx. CD4+ T cells from PE women with or without a CV Hx during pregnancy cause maternal cardiovascular and cognitive dysfunction in PP dams which was not improved with Etanercept. However, TNF alpha blockade did exhibit a sex difference to improve female offspring cognitive function. Therefore, perinatal TNF alpha. NIH grants RO1HD067541-06 (BL), P20GM121334 (BL,LMA), AHA 19CDA34670055 (LMA), and T32 Trainee Grant T32-HL105324 (ED). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

BackgroundRheumatoid arthritis (RA) is a common chronic, inflammatory autoimmune disease, and early clinical diagnosis is crucial for its treatment. CXCR4 expression was characterized in arthritic mouse models and joints of RA patients, and [18 F]AIF-NOTA-QHA-04 specificity was assessed in non-malignant cells with elevated CXCR4 expression. This study explored the application of CXCR4-targeted PET probe [18 F]AIF-NOTA-QHA-04 in monitoring disease activity and therapeutic efficacy in RA. To this aim, the metabolic characteristics of [18 F]AIF-NOTA-QHA-04 and correlation of [18 F]AIF-NOTA-QHA-04 uptake with arthritis severity were evaluated by PET imaging in arthritic mice. [18 F]AIF-NOTA-QHA-04 potential in evaluating therapeutic efficacy was further investigated in arthritic mice following methotrexate (MTX) and etanercept (ETC) treatment.ResultsCXCR4 expression was significantly increased in the inflamed joints of collagen-induced arthritis (CIA) and collagen-antibody induced arthritic (CAIA) mice, and in synovial tissues of RA patients. [18 F]AIF-NOTA-QHA-04 showed high specificity for CXCR4, with increased probe uptake in arthritic joints that was strongly correlated with arthritis severity scores. PET imaging revealed that increased uptake of [18 F]AIF-NOTA-QHA-04 in arthritic joints paralleled disease activity, with uptake decreasing upon remission. Furthermore, [18 F]AIF-NOTA-QHA-04 PET imaging provided earlier and more sensitive assessments of the efficacy of MTX and ETC compared to traditional methods.ConclusionThe CXCR4-targeted PET probe [18 F]AIF-NOTA-QHA-04 is a promising tool for RA diagnosis and monitoring, with high specificity and sensitivity. The potential of this probe as a biomarker for disease activity and therapeutic response underscores its value in personalized medication strategies for the management of RA.

Evidence on the effectiveness, long-term safety and longevity of biologic therapies in pediatric psoriasis patients is sparse. This study aims to compares the efficacy, safety and drug survival (DS) rates of etanercept (ETA), adalimumab (ADA), infliximab (INF), ustekinumab (UST), secukinumab (SEC) and ixekizumab (IXE) in pediatric and adult psoriasis patients. 293 biologic treatment cycles of 198 patients (62 pediatric and 136 adult) from three academic psoriasis referral centres were analysed. The following were the Psoriasis Area and Severity Index 90 response scores of pediatric and adult psoriasis patients, respectively: ETA, 42.3% vs. 34.6%; ADA, 53.8% vs. 59.8%; INF, 33.3% vs. 33.3%; UST, 76.5% vs. 56.8%; SEC, 60% vs. 60%; and IXE, 50% vs. 87.5%. The differences of responses between the two groups were statistically insignificant (p>0.05). ETA had the longest mean DS time in the pediatric group but it was related to a significantly shorter DS in pediatric patients than in adults (pediatrics: 30.58 [18.64-42.52] months vs. adults: 72.34 [54.70-89.99] months; p=0.025). ADA had the longest mean DS time in the adult group with 101.28 [84.88-117.68] months. All treatments had favorable safety profiles. No specific severe adverse effects necessitating treatment discontinuation were observed in pediatric patients. Although responses to ETA and UST were numerically better among children, the difference was insignificant. The DS rates in each group were comparable, and no specific safety signals, limiting the long-term use of these agents, were detected in the pediatric group.

Biosimilars Versus Originators in Children With Juvenile Idiopathic Arthritis: A Real-World Experience

Since the European Thyroid Association guidelines for the management of thyroid orbitopathy (TO) were published in 2016, a number of randomised clinical trials (RCTs) investigating the use of biologic drugs for the treatment of moderate to severe and active TO have been published. Therefore, new recommendations for its treatment were developed and published in 2021. Treatment of active TO includes 2 types of immunosuppressive agents: non-specific and specific. Specific immunosuppressive agents used to treat TO include adalimumab (ADA), infliximab (IFX), etanercept (ETA), rituximab (RTX), tocilizumab (TCZ), teprotumumab (TEP), and batoclimab (BAT). In the manuscript, we present a review of the literature on RCTs, retrospective studies, and case reports on their use in the treatment of TO. The authors emphasise the beneficial effects of TEP, indicating, however, the lack of data on its long-term efficacy and safety and the lack of head-to-head comparison with i.v. glucocorticosteroids and its huge limitation is also the high price of the drug. TCZ is a therapeutic option for glucocorticosteroid-resistant TO and should be considered for second-line treatment (due to the cost of treatment, among other reasons) or first-line treatment in patients with contraindications to i.v. glucocorticosteroids. Given its side-effect profile, especially some risk of optic nerve neuropathy (DON), RTX is considered by the authors as a second- or even third-line treatment option. The current 2021 European Group on Graves' Orbitopathy (EUGOGO) recommendations include RTX, TCZ, and TEP among the second-line drugs for the treatment of moderate to severe and active TO. BAT is under clinical trials. Given the numerous advantages of biologic drugs over glucocorticosteroids, further RCTs are indicated to confirm their possible place also as first-line treatment in TO.

The article discusses the use of bioanalogues (BAs) in the treatment of rheumatoid arthritis using the example of the comparable efficacy, tolerability and immunogenicity of the original biologic disease-modifying antirheumatic drug (bDMARD) etanercept (ETC) and its BA GP-2015. We discuss the maintenance of the improvement achieved when switching from the original ETC to BA. Recommendations of international experts and preliminary recommendations of the Association of Rheumatologists of Russia on the use of BA are given. The frequency of development and negative consequences of the nocebo effect when switching patients to BA are described. Data from randomized controlled trials and clinical practice on the safety of switching patients from original biologics to BA are presented. The economic benefits of introducing BA into the clinical practice of rheumatologists in Europe and Russian Federation are considered.

We aimed to investigate the relationship between serum antidrug antibodies (ADAbs), systemic hypersensitivity, or local injection site reactions to tumor necrosis factor (anti-TNF) drugs and to detect the role of skin tests in the diagnosis of hypersensitivity reactions (HSRs) against anti-TNFs. Sixty-nine ankylosing spondylitis (AS) and 46 rheumatoid arthritis (RA) patients taking infliximab (IFX), adalimumab (ADA), and etanercept (ETN) were enrolled. The demographical data, erythrocyte sedimentation rate (ESR), and c-reactive protein (CRP) levels of the patients were determined, and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) assessment for AS patients and DAS28 (disease activity score) for RA patients were assessed. Serum levels of anti-TNFs and ADAbs to these agents were measured with ELISA. These blood samples were taken 24 h before the next drug dose. The patients with anti-TNF-associated HSRs were evaluated with a skin-prick test (SPT) and intradermal test (IDT). Readings for the SPT and IDT were conducted after 15 min and 24, 48, and 72 h. Heel diameter of 3 mm or more greater than the negative control was considered positive for SPT, and if the size of the initial wheal had increased by at least 3 mm in diameter and was surrounded by erythema it was considered positive for IDT. Symptoms such as urticaria/angioedema and flushing were considered immediate-type HSRs. Findings developed at the injection site such as swelling and erythema were considered injection-site reactions (ISRs). An overall p < 0.05 was considered statistically significant. A statistically significant association was found between HSRs (immediate type and ISRs) and IDT reported by patients taking biological drugs (p = 0.001). In the subgroup analysis, a statistically significant association was found between ISRs and IDT in those taking ADA and ETN (respectively p = 0.012, p = 0.013). No relationship was found between skin test positivity and the presence of IgG ADAbs to anti-TNFs or disease activity scores. This study demonstrates that patients who exhibit ISRs to anti-TNFs produce notably positive results to IDT without maintaining a direct relationship to serum levels of ADAbs.

Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD), and the global incidence rate is 0.5 ~ 1%. Existing medications might reduce symptoms, however, there is no known cure for this illness. Etanercept (EN) can competitively inhibit TNF-α binding to the TNF receptor on the cell surface to treat RA. However, subcutaneous injection of free EN predisposes to systemic distribution and induces immune system hypofunction. Draining lymph nodes (LNs) play a significant role in the onset, maintenance, and progression of RA as they are the primary sites of aberrant immune response and inflammatory cytokine production. The purpose of this study was to successfully treat RA with etanercept by encapsulating it in nanoemulsions (NEs/EN) and then delivering it specifically to draining LNs. The EN-loaded NEs were prepared by high-pressure homogenization method and modified with DSPE-mPEG2000 and Ca(OH)2. A novel nano-emulsion (NE) was constructed to deliver EN (NE/EN) to RA-draining LNs. To decrease aggregation and load EN, DSPE-mPEG2000 and Ca(OH)2 were successively decorated on the surface of the lipid injectable emulsions. The hydrodynamic diameter and morphology of NEs/EN were investigated by using a laser particle size analyzer and transmission electron microscopy, respectively. The in vivo fluorescence imaging system was used to study the in vivo LN targeting ability of the formulation. In the therapeutic experiment, NEs/EN was subcutaneously administrated to inhibit the development of the mouse arthritis model. Circular dichroism spectrum and L929 cell experiment confirmed that NEs encapsulation had no impact on the biological activity of EN. In vivo investigation on collagen-induced arthritis (CIA) mouse model showed that NEs/EN have good inguinal lymph node targeting capabilities, as well as, anti-inflammatory effect against RA. Compared with the free group, the paw thickness and arthritic score in NEs/EN group were significantly alleviated. Moreover, the concentration of pro-inflammatory cytokines TNF-α and IL-1β in NEs/EN-treated mice was lower than that in free EN. NEs/EN effectively improve the effectiveness of EN in the treatment of RA. Our work provides an experimental foundation for expanding the clinical application of EN.

ObjectTo investigate the factors associated with cause-specific discontinuation of long-term anti-tumor necrosis factor (TNF) agent use in patients with ankylosing spondylitis (AS).MethodsAS patients who initiated first-line anti-TNF treatment between 2004 and 2018 and continued treatment for at least two years were enrolled in the study. Enrolled patients were observed until the last visit, discontinuation of treatment, or September 2022. Reasons for discontinuation of the first-line anti-TNF agent were categorized into the following: (1) clinical remission, (2) loss of efficacy, (3) adverse events, and (4) other reasons including loss to follow-up, cost, or reimbursement issues. A cumulative incidence function curve was used to visualize the cumulative failure rates over time for each specific reason. Univariable and multivariable cause-specific hazard models were utilized to identify factors associated with cause-specific discontinuation of the first-line anti-TNF agent.ResultsA total of 429 AS patients was included in the study, with 121 treated with adalimumab (ADA), 176 with etanercept (ETN), 89 with infliximab (INF), and 43 with golimumab (GLM). The median overall survival on the first-line anti-TNF agent was 10.6 (7.9–14.5) years. Among the patients, 103 (24.0%) discontinued treatment, with 36 (34.9%) due to inefficacy, 31 (30.1%) due to clinical remission, 15 (14.6%) due to adverse events, and 21 (20.4%) due to other reasons. Patients treated with ETN had a lower risk of discontinuation due to clinical remission compared to those receiving ADA (hazard ratio [HR] 0.45 [0.21–0.99], P = 0.048). Higher baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI; HR 1.31 [1.04–1.65], P = 0.023) and INF use were linked to a higher risk of treatment discontinuation for inefficacy compared to ADA use (HR 4.53 [1.45–14.16], P = 0.009). Older age was related to an increased risk of discontinuation due to infection-related adverse events (HR 1.07 [1.02–1.12], P = 0.005), and current smoking was a risk factor for discontinuation due to other reasons (HR 6.22 [1.82–21.28], P = 0.004).ConclusionAS patients on their first anti-TNF treatment for at least two years demonstrated a favorable long-term treatment retention rate, with a 24.0% discontinuation rate over a 10.6-year overall survival period. The predictors for discontinuation varied by causes, underscoring the complexity of treatment response and the importance of personalized approaches to treatment management.

ABSTRACT Objective The aim of this study was to assess the efficacy and safety of etanercept (ETA) use in juvenile idiopathic arthritis (JIA). Methods The 24-month data of patients with JIA on etanercept in a single center were evaluated retrospectively. Response to treatment was assessed according to 10-joint Juvenile Arthritis Disease Activity Score (JADAS10), and JIA-American College of Rheumatology (ACR) improvement criteria. Safety assessments were based on adverse event (AE) reports. Results The study included 152 patients with JIA. The mean age at diagnosis of JIA was 8.5 ± 4.4 years, and treatment with ETA started at a mean age of 11.1 ± 4.4 years. The mean duration of ETA use was 16 ± 11.1 months. The mean JADAS10 score at baseline was 18.5 ± 5.9. By the third month, it had reduced to 8.6 ± 6.6 and by the sixth month to 5.7 ± 6. By the twelfth month, the JADAS10 score was 4.9 ± 6.7, and by the twenty-fourth month, it had worsened to 7.3 ± 7.8. ACR50 response was achieved in 79.6% of patients at 3 months, 67.1% at 6 months, 79.3% at twelfth months, 70.7% at the twenty-fourth month. During ETA treatment, 10 patients required hospitalization for serious infections. Conclusion Etanercept is a safe and effective option for patients with JIA. However, variations in response between JIA subtypes highlight the need for individualized treatment strategies.

Introduction: Psoriasis is a chronic inflammatory systemic disease accompanied by systemic damage that leads to the development of multiple comorbidities including metabolic syndrome. Conventional systemic therapies for psoriasis are associated with toxicity and have a greater burden on the patients. The study aimed to assess the effectiveness of etanercept (ETN) monotherapy in comparison with methotrexate (MTX) monotherapy. Methods: In this prospective interventional comparative open-label study, 117 patients with psoriasis were randomized to 2 groups; 1 group of 42 patients; 32 (67.2%) males and 10 (23.8%) females treated with MTX, and the second group of 75 patients; 54 (72%) males and 21 (28%) females treated with ETN. Full laboratory investigations, body mass index (BMI), measurement of skin disease severity which was performed using Psoriasis Area Severity Index (PASI), and the reduction of 75% of the skin lesions (PASI 75) were calculated for all participants. Results: In the MTX group, there were no significant differences in BMI, or blood pressure after 12 weeks of the study. There is a reduction in the values of FBS, TSC, LDL, TRIG, ESR, CRP, and PASI, but this reduction was statistically not significant. Ten (23.8%) patients achieved PASI 75. In the ETN group, except for BMI, systolic and diastolic blood pressure, all other metabolic syndrome components, inflammatory markers, and PASI were decreased; the reduction was statistically significant. Sixty (80%) patients achieved PASI 75. Conclusion: Etanercept monotherapy showed greater efficacy than MTX monotherapy in the treatment of moderate to severe plaque-type psoriasis as it achieved greater reductions in PASI score and greater achievement of PASI 75 after 12 weeks. Etanercept monotherapy showed greater efficacy than MTX monotherapy in the improvement of all components of the associated metabolic syndrome except for BMI, which was increased in etanercept-treated patients.

To analyze the long-term survival of subcutaneous biosimilar tumor necrosis factor inhibitors compared to the originator molecules in patients with rheumatic diseases, as well as the factors associated with drug discontinuation. Retrospective analysis of BIOBADASER, the Spanish multicenter prospective registry of patients with rheumatic disease receiving biologic and targeted disease-modifying antirheumatic drugs. Patients who started etanercept (ETN) or adalimumab (ADA) from January 2016 to October 2023 were included. The survival probabilities of biosimilars and originators were compared using Kaplan-Meier estimating curves. To identify factors associated with differences in the retention rates, hazard ratios (HR) were estimated using Cox regression models for all and specific causes (inefficacy or adverse events [AEs]) of discontinuation. A total of 4162 patients received 4723 treatment courses (2991 courses of ADA and 1732 courses of ETN), of which 722 (15.29%) were with originator molecules and 4001 (84.71%) were with biosimilars. The originators were more frequently discontinued than biosimilars (53.32% vs 33.37%, respectively). The main reason for discontinuation was inefficacy (60.35% of the treatments). The risk of overall discontinuation was lower for biosimilars (adjusted HR 0.84, 95% CI 0.75-0.95). Female sex, obesity, and second or later treatment lines increased the risk of discontinuation, whereas disease duration and the use of concomitant methotrexate were associated with a greater survival. When assessing cause-specific reasons of discontinuation, excluding nonmedical switching, the results from the crude and adjusted analyses showed no significant differences in the retention rate between biosimilars and originators. No significant differences were found between treatments in long-term survival due to inefficacy or AEs.