Etanercept Treatment Research Articles

P11 Etanercept persistence in juvenile idiopathic arthritis up to adult care in patients in Germany: a real-world analysis

Abstract Background Although juvenile idiopathic arthritis (JIA) occurs early in life, patients can require long-term treatment into adulthood due to active disease or flares. However, most available studies show that there are gaps in care during and after the transition to adult care. Transition has been associated with higher dropout rates, and there is limited evidence on treatment persistence in JIA patients. The current analysis evaluates etanercept bio-original (ETNBo) persistence up to 5 years and reports diagnostic patterns in early adolescence and young adults in Germany. Methods Patients with JIA (ICD10: M08) between 2-30 years of age with a first recorded ETNBo prescription between 1-January-2008 and 31-December-2012 were retrospectively identified in German health insurance claims data. Patients were followed until 31-December-2015 or end-of-record, whichever came first. Index date was set at the first ETNBo prescription after a 12-month etanercept-free look-back period. Patient characteristics, concomitant treatments and prior use of other biologic Disease-modifying antirheumatic Drugs (bDMARD) were evaluated in the 12-month look-back period. The 5-year etanercept treatment persistence, defined as median (95% confidence interval [CI]) months between the index date and a discontinuation (≥90-day treatment gap after last etanercept prescription), was estimated using Kaplan-Meier analysis, overall and for bio-naïve patients. Etanercept WHO defined daily dose (DDD) was adjusted by age; for patients 2-6, 7-10, 11-14 and >15 daily doses were defined as 1.4mg, 3.6mg, 5.4mg and 7.0mg, respectively. The proportion of patients receiving an adult rheumatic diagnosis after the age of 11 was described. Results We identified 125 patients diagnosed with JIA (median age: 15 years; 30% male). At index quarter 56% of patients were in the 11-20 age group. Most patients (94%) were bio-naïve and 46%, 34%, and 17% had concomitant use of NSAIDS, other DMARDS, and corticosteroids, respectively. Overall median persistence was 13 months (95%CI: 10-16; IQR: 5-27). Persistence for the bio-naïve patients was 50% (95%CI: 41-57), 27% (95%CI: 20-34), 16% (95%CI: 10-23), 10% (95%CI: 5-17) and 9% (95%CI: 4-15) at 12, 24, 36, 48, and 60 months respectively. The majority of patients (68%) received an additional diagnosis of rheumatoid arthritis after age 11, while 15% were given other adult rheumatic diagnoses. Only 9% of JIA patients had received no additional diagnosis to JIA. Conclusion This analysis provides important understanding of care in young JIA patients. We observed a decreasing persistence of etanercept therapy as patients progressed in time through the transition period into early adulthood. Importantly, we found that the majority of JIA patients received additional adult diagnoses, which suggests the transition could impact on the clinical management of this disease. Diagnostic patterns, clinical and patient circumstances during this critical period and their impact on persistence requires further analysis. Conflicts of Interest The authors declare no conflicts of interest.

Reduction in the utilization of prednisone or methotrexate in Canadian claims data following initiation of etanercept in pediatric patients with juvenile idiopathic arthritis

BackgroundIn adult patients with arthritis, use of the tumor necrosis factor (TNF) inhibitor etanercept (ETN) is often associated with a reduction in the utilization of co-medications, particularly steroids. Comparatively little is known about the utilization of co-medications when ETN is initiated in pediatric patients with juvenile idiopathic arthritis (JIA).MethodsThis study analyzed Canadian longitudinal claims level data spanning January 2007 to April 2017. Data were collated from the IQVIA Private Drug Plan, Ontario Public Drug Plan, and the Quebec Public Drug Plan (Régie de l’assurance maladie du Québec) databases. Patients < 18 years of age were indexed when filling a prescription for ETN between January 2008 and January 2016. Those who met the inclusion and exclusion criteria were assessed for methotrexate (MTX), and prednisone (PRD) use in the 6 months prior to and 12 months following initiation of ETN.ResultsLongitudinal claims data for 330 biologic-naive pediatric patients initiating ETN therapy were included. The majority of patients were female (67%), aged 10–17 years (64%), and with a drug history consistent with JIA (96%). Most patients were from Quebec (36%) or Ontario (33%). Dosing of ETN was weight-based with a mean dosage over the first year of 31 mg per week. ETN dosing was relatively consistent over the first year. In total, 222 (67%) patients did not use MTX and 223 (68%) did not use PRD before or after starting ETN. A total of 17% (18/103) of MTX-treated and 50% (46/92) of PRD-treated patients discontinued use of those medications upon initiation of ETN treatment. In patients continuing MTX or PRD, significant reductions in the weekly dosage from 14.3 to 6.8 mg per week for MTX and from 56 to 23 mg per week for PRD were observed (P < 0.01).ConclusionsThis study of Canadian claims-level data is the first large prespecified analysis of co-medication utilization following the initiation of ETN therapy in pediatric patients. A decline in both MTX and PRD use and dosage was observed and may be associated with benefits related to safety, tolerability, and overall healthcare costs.

Costs associated with non-medical switching from originator to biosimilar etanercept in patients with rheumatoid arthritis in the UK

Aims: To estimate the cost impact of non-medical switching from originator to biosimilar etanercept in stable patients with rheumatoid arthritis (RA) in the UK.Materials and methods: A cohort-based decision tree model was developed with a 1-year time horizon. The model population included patients with stable RA (patients who responded to originator etanercept treatment with no treatment changes in the previous 6 months). Patients could undergo a non-medical switch to a biosimilar and then switch treatment again, if medically required, after 3–6 months. Data on the proportion of patients switching therapies, baseline healthcare resource use, and impact of switching on resource use were sourced from a survey of 150 rheumatologists from EU5 markets (France, Germany, Italy, Spain, UK). The average impact of switching was evaluated as mean values for change in resource utilization due to switching. Also, low- and high-impact scenarios (lower and upper values of the 95% confidence intervals for change in resource utilization due to switching) were modelled as sensitivity analyses. Cost data came from published UK sources.Results: The model assumed that 5,000 patients were treated with originator etanercept, with 1,259 (25.2%) switching to a biosimilar. Of those, 875 (69.5%) and 384 (30.5%) switched to SB4 and GP2015, respectively. After 3 months, 26.3% of patients who switched treatments did so again: 8.3% back to originator, 3.8% to the other biosimilar, and 14.2% to another biologic. Although originator etanercept was more expensive than the biosimilars, switching was more costly than continuous originator treatment across all impact scenarios. Switching treatment chains had higher overall annual per-patient costs than continuous originator treatment. Switching was associated with increased healthcare resource use.Limitations: Results from this analysis are not transferable to other (non-RA) etanercept indications.Conclusion: Non-medical switching can result in increased payer costs because of increased healthcare resource use following switching.

Abstract P1110: Tumor Necrosis Factor Alpha Blockade Improves Natural Killer Cell Activation, Hypertension, and Mitochondrial Oxidative Stress in a Preclinical Rat Model of Preeclampsia

Preeclamptic (PE) women have placental ischemia, hypertension (HTN), mitochondrial (mt) dysfunction, increased mt-reactive oxygen species (ROS), cytolytic natural killer (NK) cells, and pro-inflammatory cytokines, such as tumor necrosis factor (TNFα). The reduced uterine perfusion pressure (RUPP) preclinical rat model of PE, is a well-established model to study mechanisms of hypertension in response to placental ischemia during pregnancy. Previous studies from our lab have shown that TNFα is elevated in RUPP rats and that blockade of TNFα, via etanercept (ETAN) decreases TNFα and HTN. However, the effect of TNFα blockade on NK cell activation, mt protein/function, and mtROS is unknown. We hypothesized that ETAN would decrease blood pressure, NK cell activation, mtROS, and improve mt function in RUPP rats. Rats were divided into 4 groups: normal pregnant (NP) (n=41), RUPP (n=34), RUPP+low dose (LD) ETAN (0.4 mg/kg) (n=11), RUPP+high dose (HD) ETAN (0.8 mg/kg) (n=19). LD was used previously, while HD is clinically used to treat chronic inflammatory diseases. Gestational day 14, RUPP surgery was performed and ETAN administered subcutaneous on day 18. Day 19, conscious blood pressure (MAP), blood and tissues were collected, and mt were isolated. Flow cytometry was used for quantification of NK cells. MAP was elevated in RUPP vs. NP (119 ± 1 vs. 102± 1 mmHg, p&lt;0.05) which was reduced to 110 ± 2 in RUPP + LD ETAN (p&lt;0.05 vs. RUPP) and 116 ± 1 in RUPP + HD ETAN. Activated NK cells were increased in circulation (5.9 ± 1.8 vs. 4.0 ± 1.4 %), placenta (4.8 ± 1.3 vs. 1.9 ± 0.7 %), and kidneys (3.1 ± 0.5 vs. 0.8 ± 0.5%) of RUPP vs. NP (p&lt;0.05). Both LD (2.1 ± 0.7%, 1.7 ± 0.7%, 0.8 ± 0.5%) and HD (0.2 ± 0.1%, 0.4 ± 0.1%, 0.8 ± 0.2%) ETAN decreased activated NK cells in circulation, placenta, and kidney respectively (p&lt;0.05 vs RUPP). Placental (0.79± 0.02 vs 1±0.05 fold) and renal (0.67± 0.05 vs 1±0.06 fold) mtROS was reduced with LD ETAN vs RUPP (p&lt;0.05). ETAN treatment lowers blood pressure and reduces circulating, placental, and renal activated NK cells and mtROS in placental ischemic rats. Therefore ETAN could be a potential therapeutic for improving HTN, inflammation, and mitochondrial function during complicated pregnancies. Supported: AHA18CDA34110264, HL130456, R01HD067541, &amp; P20GM121334

TNF-\u03b1 antagonist attenuates systemic lipopolysaccharide-induced brain white matter injury in neonatal rats

BackgroundSystemic inflammation is an important risk factor for neurodevelopmental impairments in preterm infants. Premyelinating oligodendrocytes are main building blocks of white matter in preterm infants and vulnerable to oxidative stress and excitotoxic stress. Tumour necrosis factor-α (TNF-α) plays important roles in systemic inflammation and local inflammation leading to apoptosis of premyelinating oligodendrocytes and white matter injury (WMI) in brain tissue. This study was conducted to investigate whether etanercept, a TNF-α antagonist, could attenuate systemic lipopolysaccharide (LPS)-induced WMI in the immature brain.ResultsWe found that intraperitoneal LPS administration caused systemic and local inflammation in brain tissue. Subsequent etanercept treatment significantly attenuated LPS-induced inflammation in brain tissue as well as in systemic circulation. Intraperitoneal LPS also induced microgliosis and astrocytosis in the cingulum and etanercept treatment reduced LPS-induced microgliosis and astrocytosis. Additionally, systemic LPS-induced apoptosis of oligodendrocyte precursor cells was observed, which was lessened by etanercept treatment. The concentration of etanercept in the CSF was higher when it was administrated with LPS than when administrated with a vehicle.ConclusionsIt appears that etanercept reduce WMI in the neonatal rat brain via attenuation of systemic and local inflammation. This study provides preclinical data suggesting etanercept-mediated modulation of inflammation as a promising approach to reduce WMI caused by sepsis or necrotizing enterocolitis in preterm infants.

IL-1β, IL-17A, CRP and biologics history might serve as potential markers for clinical response to etanercept in rheumatoid arthritis patients.

This study aimed to explore the predictive value of 10 serum cytokines for clinical response to etanercept (ETN) in rheumatoid arthritis (RA) patients. Totally 128 active RA patients were enrolled, and their serum cytokines levels were detected by enzyme-linked immune sorbent assay at baseline. All patients received ETN treatment for 24weeks, and clinical response to ETN was assessed at week 4 (W4), week 12 (W12) and week 24 (W24). There were 40 (31.3%), 74 (57.8%) and 94 (73.4%) patients who achieved clinical response at W4, W12 and W24, respectively. Based on the clinical response status at W24, patients were divided into responders and non-responders. Baseline levels of interleukin (IL)-1β and IL-17A were higher in responders, while baseline levels of tumor necrosis factor (TNF)-α, IL-6, 1L-8, IL-21, IL-23, intercellular cell adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF) were similar in responders compared with non-responders. Responders had less of a history of biologics, and higher baseline level of C-reactive protein (CRP) compared with non-responders. Further analysis revealed that CRP and IL-1β were independent factors predicting increased clinical response. Subsequent receiver operating characteristics (ROC) curve analysis illustrated that the combination of CRP and IL-1β (AUC: 0.730, 95% CI 0.636-0.824) well distinguished responders from non-responders. In conclusion, IL-1β, IL-17A, CRP and biologics history would serve as potential markers for clinical response to ETN in RA patients.

Changes in patient-reported outcomes with etanercept treatment following apremilast failure in patients with moderate to severe psoriasis

Changes in patient-reported outcomes with etanercept treatment following apremilast failure in patients with moderate to severe psoriasis

Efficacy and retention rate of adalimumab in rheumatoid arthritis and psoriatic arthritis patients after first-line etanercept failure: the FEARLESS cohort.

Few studies have compared the efficacy of switching from etanercept to adalimumab in the real-life setting in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This study evaluated the 2-year retention rate and 12-month efficacy of adalimumab in RA and PsA patients, previously treated with etanercept. RA and PsA patients from 11 Italian Rheumatology Units received adalimumab after first-line etanercept failure. Two-year adalimumab retention rate was calculated by the Kaplan-Meier method and Cox proportional hazard models were developed to examine predictors of drug persistence. Univariate and multivariate logistic regression analyses were developed to examine potential predictors of 12-month DAS-28 remission. The study population included 117 RA (disease duration of 10.1 ± 7.7years and baseline DAS28-ESR of 4.97 ± 1.3) and 102 PsA (disease duration of 7.1 ± 5.1years and baseline DAPSA of 24.6 ± 11.8). The 2-year retention rate was 48.2% in RA and 56.5% in PsA patients. Concomitant methotrexate treatment was not associated with increased drug survival in both groups. Similarly, cause of etanercept discontinuation or treatment duration was not associated with retention rate. 12-month remission and low disease activity were achieved, respectively, in 27.3% and 23.9% of RA patients and 27.4% and 23.5% PsA of patients. In multivariate models, etanercept discontinuation due to inefficacy (OR 0.27, 95% CI 1.03-0.73; p = 0.009) and baseline DAS-28 (OR 0.45, 95% CI 0.29-0.69; p < 0.001) remained significant negative predictors of remission in RA patients. No variable was associated with remission in PsA patients. Adalimumab after etanercept failure was highly effective and safe in both RA and PsA patients.

Does a mandatory non-medical switch from originator to biosimilar etanercept lead to increase in healthcare use and costs? A Danish register-based study of patients with inflammatory arthritis

ObjectivesIn year 2016, Danish national guidelines included a mandatory switch of patients with inflammatory rheumatic diseases treated with originator etanercept (ETA) to biosimilar SB4 in routine care. We aimed to...

Correlation of microRNA expression profile with clinical response to tumor necrosis factor inhibitor in treating rheumatoid arthritis patients: A prospective cohort study.

BackgroundThis study aimed to explore the correlation of circulating microRNA (miRNA) expression profile with clinical response to tumor necrosis factor (TNF) inhibitor in treating rheumatoid arthritis (RA) patients.MethodsBaseline PBMC samples from eight responders and eight non‐responders after 24‐week TNF inhibitor (etanercept) treatment were subjected to miRNA microarray. Then, top 10 dysregulated miRNAs were selected and further validated by quantitative polymerase chain reaction (qPCR) in baseline PBMC samples from 92 RA patients treated with 24‐week TNF inhibitor (etanercept). Responders and non‐responders were divided referring to the decline in disease activity score in 28 joints.ResultsIn microarray assay, total 59 upregulated and 78 downregulated miRNAs were identified in responders compared to non‐responders, which were mainly enriched in regulating immune‐ and inflammation‐related biological processes and pathways. The top 10 dysregulated miRNAs were as follows: miR‐192‐5p, miR‐146a‐5p, miR‐19b‐3p, miR‐320c, miR‐335‐5p, miR‐149‐3p, miR‐766‐3p, let‐7a‐5p, miR‐24‐3p, and miR‐1226‐5p. In qPCR validation, miR‐146a‐5p was increased, while let‐7a‐5p was decreased in responders compared with non‐responders. Multivariate logistic analysis illuminated that miR‐146a‐5p and CRP independently correlated with higher clinical response, while let‐7a‐5p and biologics history independently associated with lower clinical response. Subsequently, receiver operating characteristic curve showed that combination of these four independent factors presented with a great predictive value for clinical response with area under curve: 0.863, 95% CI 0.781‐0.945.ConclusionmiRNA expression profile is closely implicated in the treatment efficacy of TNF inhibitor, and combined measurement of miR‐146a‐5p, let‐7a‐5p, CRP, and biologics history disclosed a great predictive value for clinical response to TNF inhibitor in RA patients.

IgG Galactosylation status combined with MYOM2-rs2294066 precisely predicts anti-TNF response in ankylosing spondylitis

BackgroundTumor necrosis factor (TNF) blockers have a high efficacy in treating Ankylosing Spondylitis (AS), yet up to 40% of AS patients show poor or even no response to this treatment. In this paper, we aim to build an approach to predict the response prior to clinical treatment.MethodsAS patients during the active progression were included and treated with TNF blocker for 3 months. Patients who do not fulfill ASASAS40 were considered as poor responders. The Immunoglobulin G galactosylation (IgG-Gal) ratio representing the quantity of IgG galactosylation was calculated and candidate single nucleotide polymorphisms (SNPs) in patients treated with etanercept was obtained. Machine-learning models and cross-validation were conducted to predict responsiveness.ResultsBoth IgG-Gal ratio at each time point and differential IgG-Gal ratios between week 0 and weeks 2, 4, 8, 12 showed significant difference between responders and poor-responders. Area under curve (AUC) of the IgG-Gal ratio prediction model was 0.8 after cross-validation, significantly higher than current clinical indexes (C-reactive protein (CRP) = 0.65, erythrocyte sedimentation rate (ESR) = 0.59). The SNP MYOM2-rs2294066 was found to be significantly associated with responsiveness of etanercept treatment. A three-stage approach consisting of baseline IgG-Gal ratio, differential IgG-Gal ratio in 2 weeks, and rs2294066 genotype demonstrated the ability to precisely predict the response of anti-TNF therapy (100% for poor-responders, 98% for responders).ConclusionsCombination of different omics can more precisely to predict the response of TNF blocker and it is potential to be applied clinically in the future.

ETA-mediated anti-TNF-α therapy ameliorates the phenotype of PCOS model induced by letrozole.

Chronic inflammation is a typical characteristic of polycystic ovary syndrome (PCOS), in which, tumor necrosis factor (TNF)-α plays an important role. We investigated whether anti-TNF-α therapy can alleviate the core phenotypes of PCOS. In pubertal female Wistar rats, release pellets of letrozole (LET) were administered continuously for 90 days to induce PCOS-like phenotypes, followed by treatment with etanercept (ETA), a TNF-α inhibitor. ETA significantly inhibited increases in body weight and androgen, TNF-α, and MCP-1 levels, excessive recruitment of lipid droplets, altered levels of pre-adipose differentiation markers, and abnormal development of follicles. In addition, TNF-α and testosterone (T) levels in the rat sera were significantly positively correlated. Further experiments were performed to investigate the relationship between TNF-α and androgen. Persistent exposure of the RAW 264.7 cell line to low doses of testosterone significantly enhanced TNF-α expression and activated the NF-κB signaling pathway, which were blocked by ETA. Furthermore, treatment with TNF-α promoted the production of testosterone in KGN granulosa cells by reducing CYP19A1 expression, whereas ETA treatment blocked this process. In conclusion, anti-TNF-α therapy with ETA may be an efficient method to alleviate PCOS, whose underlying mechanism may be associated with its ability to reduce excessive androgen levels.

Etanercept and Methotrexate as Monotherapy or in Combination for Psoriatic Arthritis: Primary Results From a Randomized, Controlled Phase III Trial

ObjectiveTo examine the efficacy of methotrexate monotherapy relative to etanercept monotherapy and the value of combining methotrexate and etanercept for the treatment of patients with psoriatic arthritis (PsA).MethodsIn this double‐blind study, 851 patients with PsA were randomized to 1 of 3 treatment arms, as follows: oral methotrexate (20 mg) plus subcutaneous placebo given weekly (n = 284), subcutaneous etanercept (50 mg) plus oral placebo given weekly (n = 284), or subcutaneous etanercept (50 mg) plus oral methotrexate (20 mg) given weekly (combination therapy; n = 283). The American College of Rheumatology 20% improvement (ACR20) response and Minimal Disease Activity (MDA) response at week 24 were the primary end point and key secondary end point, respectively. Other measures of inflammatory arthritis, radiographic progression, and nonarticular disease manifestations were also assessed.ResultsPatients with PsA had a mean ± SD age of 48.4 ± 13.1 years, and the mean ± SD duration of PsA was 3.2 ± 6.3 years (median 0.6 years). ACR20 and MDA response rates at week 24 were significantly greater in patients who received etanercept monotherapy compared with those who received methotrexate monotherapy (ACR20, 60.9% versus 50.7% of patients [P = 0.029]; MDA, 35.9% versus 22.9% of patients [P = 0.005]), and both were significantly greater in the combination therapy group compared with the methotrexate monotherapy group at week 24 (ACR20, 65.0% versus 50.7% of patients [P = 0.005]; MDA, 35.7% versus 22.9% of patients [P = 0.005]). Other secondary outcomes (ACR50 and ACR70 response rates, proportions of patients achieving a Very Low Disease Activity score, and PsA disease activity scores) showed between‐group differences that were consistent with the primary and key secondary end point results. Furthermore, patients in both etanercept treatment arms showed less radiographic progression at week 48 compared with patients who received methotrexate monotherapy. Outcomes were similar in the combination therapy and etanercept monotherapy groups, except for some skin end points. No new safety signals were seen.ConclusionEtanercept monotherapy and combination therapy with etanercept and methotrexate showed greater efficacy than methotrexate monotherapy in patients with PsA, according to the ACR and MDA response rates and extent of radiographic progression at follow‐up. Overall, combining methotrexate and etanercept did not improve the efficacy of etanercept.

Switch from reference etanercept to SDZ ETN, an etanercept biosimilar, does not impact efficacy, safety, and immunogenicity of etanercept in patients with moderate-to-severe rheumatoid arthritis: 48-week results from the phase III, randomized, double-blind EQUIRA study

BackgroundSandoz etanercept (SDZ ETN; GP2015) is an etanercept biosimilar with equivalent efficacy and comparable safety and immunogenicity to reference etanercept (ETN) in patients with moderate-to-severe chronic plaque-type psoriasis.MethodsEQUIRA was a phase III, double-blind study conducted in patients with moderate-to-severe rheumatoid arthritis and inadequate response to disease-modifying anti-rheumatic drugs. Eligible patients were randomized 1:1 to receive subcutaneous 50 mg SDZ ETN or ETN, once-weekly, for 24 weeks. At week 24, patients with at least moderate EULAR response in the SDZ ETN group continued SDZ ETN treatment, and those in the ETN group were switched to receive 50 mg SDZ ETN, for up to 48 weeks. Patients received concomitant methotrexate at a stable dose (10–25 mg/week) and folic acid (≥ 5 mg/week). Equivalence between SDZ ETN and ETN for change from baseline in disease activity score including 28 joint count C-reactive protein (DAS28-CRP) at week 24 (primary endpoint) and comparable safety and immunogenicity profile of SDZ ETN and ETN have previously been demonstrated at week 24. Herein, we present the 48-week results of the study after a single switch from ETN to its biosimilar at week 24.ResultsThe least squares mean (standard error) change in DAS28-CRP from baseline up to week 48 was comparable between “continued SDZ ETN” (− 2.90 [0.12], n = 148) and “switched to SDZ ETN” (− 2.78 [0.13], n = 131) groups. The proportion of patients achieving EULAR good/moderate responses based on DAS28-erythrocyte sedimentation rate and ACR20/50/70 response rates were comparable between the two groups. The proportion of patients with at least one treatment-emergent adverse event was 42.9% in the “continued SDZ ETN” and 38.0% in the “switched to SDZ ETN” groups. Serious adverse events occurred in 4 patients in each of the two groups. After week 24, none of the patients in the switched group developed anti-drug antibodies (ADAs), while 4 patients in the continued SDZ ETN group had single-event, very low titer, non-neutralizing ADAs detected.ConclusionsThe 48-week results from the EQUIRA study demonstrate that switch from ETN to SDZ ETN in patients with moderate-to-severe rheumatoid arthritis does not impact the efficacy, safety, or immunogenicity of etanercept.Trial registrationEudraCT number 2012-002009-23, Registered 19 April 2012—prospectively registered.

Etanercept treatment for extended oligoarticular juvenile idiopathic arthritis, enthesitis-related arthritis, or psoriatic arthritis: 6-year efficacy and safety data from an open-label trial

BackgroundTo describe the 6-year safety and efficacy of etanercept (ETN) in children with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), and psoriatic arthritis (PsA)MethodsPatients who completed the 2-year, open-label, phase III CLinical Study In Pediatric Patients of Etanercept for Treatment of ERA, PsA, and Extended Oligoarthritis (CLIPPER) were allowed to enroll in its 8-year long-term extension (CLIPPER2). Children received ETN at a once-weekly dose of 0.8 mg/kg, up to a maximum dose of 50 mg/week. Efficacy assessments included the JIA core set of outcomes, the JIA American College of Rheumatology response criteria (JIA-ACR), and the Juvenile Arthritis Disease Activity Score (JADAS). Efficacy data are reported as responder analyses using a hybrid method for missing data imputation and as observed cases. Safety assessments included treatment-emergent adverse events (TEAEs).ResultsOut of 127 patients originally enrolled in CLIPPER, 109 (86%) entered CLIPPER2. After 6 years of trial participation (2 years in CLIPPER and 4 years in CLIPPER2), 41 (32%) patients were still taking ETN, 13 (11%) entered the treatment withdrawal phase after achieving low/inactive disease (of whom 7 had to restart ETN), 36 (28%) discontinued treatment for other reasons but are still being observed, and 37 (29%) discontinued treatment permanently. According to the hybrid imputation analysis, proportions of patients achieving JIA ACR90, JIA ACR100, and JADAS inactive disease after the initial 2 years of treatment were 58%, 48%, and 32%, respectively. After the additional 4 years, those proportions in patients who remained in the trial were 46%, 35%, and 24%. Most frequently reported TEAEs [n (%), events per 100 patient-years] were headache [28 (22%), 5.3], arthralgia [24 (19%), 4.6], and pyrexia [20 (16%), 3.8]. Number and frequency of TEAEs, excluding infections and injection site reactions, decreased over the 6-year period from 193 and 173.8, respectively, during year 1 to 37 and 61.3 during year 6. A single case of malignancy (Hodgkin’s lymphoma) and no cases of active tuberculosis, demyelinating disorders, or deaths were reported.ConclusionsOpen-label etanercept treatment for up to 6 years was safe, well tolerated, and effective in patients with eoJIA, ERA, and PsA.Trial registrationClinicalTrials.gov: CLIPPER, NCT00962741, registered 20 August, 2009, CLIPPER2, NCT01421069, registered 22 August, 2011.

Effect of etanercept on post-traumatic proliferative vitreoretinopathy

To evaluate the safety and efficacy of intravitreal etanercept in the inhibiting of proliferative vitreoretinopathy (PVR) in a model of penetrating ocular injury. Penetrating ocular injury on the retina of rabbit was induced, which was subsequently treated using 0.1 mL of sterile water or 0.1 mL of 12.5 mg/mL etanercept. The development of PVR was evaluated by fundus images, the B-scan, and the histopathology. The mRNA and protein expressions of tumor necrosis factor-α (TNF-α), transforming growth factor β (TGF-β) as well as connective tissue growth factor (CTGF) were examined at various time points after the etanercept injection with the reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting, respectively. The safety of etanercept was evaluated by injection of 12.5 mg/mL etanercept into a normal rabbit eye without penetrating trauma. Clinical assessment and grading clearly demonstrated that the PVR formation was prevented in etanercept-treated animals, which was confirmed via fundus images, B-scan and histopathology. The RT-PCR and Western blotting showed increased mRNA and protein expression of TNF-α, TGF-β as well as CTGF in the retina of rabbits following penetrating ocular injury, and these factors were dramatically mitigated by ocular etanercept treatment. In addition, there was no adverse effect of etanercept intravitreal injection in normal eyes without penetrating trauma, it showed normal structure and histology. The etanercept is a potential therapy for inhibiting PVR development. To assess the clinic application of the etanercept in preventing PVR, further clinical studies are required.

Cost-Effectiveness of Secukinumab Versus Other Biologics in the Treatment of Psoriatic Arthritis: An Argentinean Perspective

ObjectivePsoriatic arthritis (PsA) is a chronic, systemic inflammatory disease. This study assessed the cost-effectiveness of secukinumab, an interleukin-17A inhibitor, versus other biologics in PsA from the Argentinean social security perspective. MethodsA semi-Markov model evaluated subcutaneous (sc) treatment with secukinumab 150 mg and 300 mg against other sc treatments such as adalimumab, certolizumab pegol, etanercept, golimumab, ustekinumab, and intravenous treatment infliximab in biologic-naïve (with or without moderate to severe psoriasis) and biologic-experienced PsA patients over a lifetime horizon. Response to treatments was determined using the PsA Response Criteria (PsARC) at 12 weeks. Model inputs were derived from randomized controlled trials, network meta-analyses, published literature, and other Argentinean sources. Model outcomes included quality-adjusted life years (QALYs) gained and incremental cost-effectiveness ratios. Sensitivity analyses and alternative scenarios with a higher cost option were also conducted. ResultsAmong biologic-naïve PsA patients without psoriasis, secukinumab 150 mg provided the highest QALYs (7.18) versus all sc biologics at the lowest cost ($3 755 678 Argentine peso), thus dominating them. Among biologic-naïve PsA patients with psoriasis and biologic-experienced PsA patients, secukinumab 300 mg provided highest QALYs (6.99 and 7.53, respectively), dominated infliximab, and was cost-effective versus other sc biologics. Deterministic sensitivity analyses indicated sensitivity of results to variation in PsARC rates, drug acquisition costs, Health Assessment Questionnaire change, and utilities. A probabilistic sensitivity analysis showed maximum net monetary benefits with both secukinumab doses. Results from an alternative scenario analysis were similar to base-case analysis. ConclusionsFor both biologic-naïve and experienced PsA patients, secukinumab is either a dominant or cost-effective treatment option compared with other biologics in Argentina.

Inhibition of tumour necrosis factor alpha in the R6/2 mouse model of Huntington\u2019s disease by etanercept treatment

Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the huntingtin (HTT) gene, which results in a mutant protein with an extended polyglutamine tract. Inflammation occurs in both the brain and the periphery of HD patients and mouse models, with increases in brain and/or plasma levels of neurotoxic TNFα and several other proinflammatory cytokines. TNFα promotes the generation of many of these cytokines, such as IL6, which raises the possibility that TNFα is central to the inflammatory milieu associated with HD. A number of mouse studies have reported that the suppression of chronic immune activation during HD has beneficial consequences. Here, we investigated whether TNFα contributes to the peripheral inflammation that occurs in the R6/2 mouse model, and whether the in vivo blockade of TNFα, via etanercept treatment, can modify disease progression. We found that etanercept treatment normalised the elevated plasma levels of some cytokines. This did not modify the progression of certain behavioural measures, but slightly ameliorated brain weight loss, possibly related to a reduction in the elevated striatal level of soluble TNFα.

Effects of etanercept, a tumor necrosis factor receptor fusion protein, on primary cell cultures prepared from intact human intervertebral disc tissue.

The aim of the present study was to investigate the effects of etanercept (ETA), a tumor necrosis factor (TNF) inhibitor, on human cell cultures prepared from intact intervertebral disc tissue. ETA is used as a treatment for cases of rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis and ankylosing spondylitis accompanied by moderate or severe joint pain. ETA was applied to primary cell cultures [annulus fibrosus and nucleus pulposus (NP) from intact intervertebral disc tissue]. Cell cultures without ETA treatment served as the control group. Morphological and quantitative molecular analyses of the two groups were performed. The number of viable cells and cell proliferation decreased in the ETA-treated cultures as compared with those in the control group. Furthermore, in the treatment group, the chondroadherin gene, an NP-specific marker, was not expressed after 24 h. By contrast, the cartilage oligo matrix protein was expressed 24, 48 and 72 h post-ETA treatment, while its expression was significantly lower than that in the control group. In addition, the expression of interleukin-1β, as well as matrix metallopeptidase-7 and −19, was markedly decreased. Overall, the cell proliferation and gene expression in the ETA-treated cells were significantly different from those in the control group (P<0.05). These results suggest that the treatment duration and dosage of TNF inhibitors, which are used to suppress active inflammation, should be considered in the clinical setting. These biological agents may delay the healing of intervertebral disc tissue damage by slowing cell proliferation and altering gene expression via anabolic and catabolic pathways.

Etanercept reduces anxiety and depression in psoriasis patients, and sustained depression correlates with reduced therapeutic response to etanercept

The purpose of this study was to explore the correlation of anxiety and depression with therapeutic response to etanercept in psoriasis patients. One hundred and thirty-three patients with moderate-to-severe plaque psoriasis undergoing etanercept treatment were consecutively enrolled in this prospective cohort study, with all patients receiving etanercept treatment for 6 months. Psoriasis Area and Severity Index (PASI) score was evaluated at baseline (M0) and at month 1 (M1), M3 and M6 after treatment, and PASI 75/90 responses were calculated. The Hospital Anxiety and Depression Scale-Anxiety (HADS-A) score and the HADS-Depression (HADS-D) score were used to evaluate patients' anxiety and depression at M0, M1, M3 and M6. Sustained anxiety/depression were defined as HADS-A/D score≥8points both at M0 and M1. Female gender and higher PASI score were associated with high risk of anxiety, while female gender, higher PASI score and longer disease duration were correlated with increased depression risk. After 6 months of etanercept treatment, 65.4% and 36.1% patients achieved PASI 75 and PASI 90 responses respectively, and both HADS-A and HADS-D scores were decreased. Most importantly, no correlation of baseline anxiety and depression with PASI 75 or PASI 90 response after 6 months of treatment was noted, while sustained depression, though not sustained anxiety, was observed to be correlated with decreased PASI 75 and PASI 90 responses. Etanercept reduces anxiety and depression in psoriasis patients, and sustained depression correlates with reduced therapeutic response to etanercept.