Etanercept Treatment Research Articles

A cytokine signal inhibitor for rheumatoid arthritis enhances cancer metastasis via depletion of NK cells in an experimental lung metastasis mouse model of colon cancer.

Current therapy for rheumatoid arthritis (RA) relies on global suppression of the immune response or specific blockade of inflammatory cytokines. However, it is unclear how immunosuppressants affect patients with cancer. Therefore, in the present study, the effect of three biological agents, tofacitinib, anti-mouse IL-6 receptor antibody (MR16-1) and etanercept, which are used for the treatment of RA diseases, on a tumor-bearing mouse model was investigated. The effect of the three agents was examined using a mouse lung-metastasis model with the murine colon 26 cancer cell line. Lymphocyte subsets and natural killer (NK) cells in peripheral blood and spleen were analyzed using fluorescence-activated cell sorting, and the number of lung surface nodules was examined. In the continuous tofacitinib administration (15 mg/kg/day) group, the number of lung surface nodules was significantly increased compared with that of the vehicle-treated group (vehicle, 1.20±0.58; tofacitinib, 35.6±10.81; P<0.01). NK cell number in the blood and spleen of tofacitinib-treated mice was decreased 10-fold, and the percentage of cluster of differentiation (CD)11+CD27- NK cells was significantly reduced. MR16-1 [8 mg/mouse; once a week; intraperitoneal (i.p.)] or etanercept (1 mg/mouse; 3 times a week; i.p.) treatment did not affect the number of NK cells or lung metastasis. In the present study, immunosuppressants that target cytokines, including tofacitinib, were demonstrated to inhibit the proliferation and differentiation of NK cells, and exhibit the potential to promote cancer metastasis using a mouse model of lung metastasis.

Predictors of the response to etanercept in patients with juvenile idiopathic arthritis without systemic manifestations within 12 months: results of an open-label, prospective study conducted at the National Scientific and Practical Center of Children's Health, Russia

BackgroundThe aim of this study was to investigate the efficacy of etanercept treatment and to identify predictors of response to therapy within 12 months in patients with juvenile idiopathic arthritis (JIA) without systemic manifestations.MethodsA total of 197 juvenile patients were enrolled in this study. Response to therapy was assessed using the ACRPedi 30/50/70/90 criteria, the Wallace criteria, and the Juvenile Arthritis Disease Activity Score 71 (JADAS-71). Univariate and multivariate logistic regression analyses were performed to identify potential baseline factors associated with treatment response in different JIA categories.ResultsOne year after treatment initiation, 179 (90.9%) patients achieved ACRPedi30; 177 (89.8%) patients achieved ACRPedi50; 168 (85.3%) patients achieved ACRPedi70; and 135 (68.5%) patients achieved ACRPedi90 response. A total of 132 (67.0%) and 92 (46.7%) patients achieved inactive disease according to the Wallace criteria and the JADAS-71 cut-off point, respectively. Excellent response (achieving ACRPedi90 and clinically inactive disease according both to the Wallace criteria and the JADAS71 cut-off point) was associated with persistent oligoarticular JIA category, shorter disease duration before the start of etanercept, a lower number of DMARDs used before the introduction of etanercept, a lower number of joints with limited motion, and lower C-reactive protein at baseline. Poor response (failure to achieve ACR 70 or active disease according to both the Wallace criteria and JADAS71 even when ACR 70 was achieved) was associated with the polyarticular or enthesitis-related JIA categories, higher disease duration before the start of etanercept, and older age at disease onset.ConclusionAlmost half (45.7%) of the patients who initiated etanercept treatment achieved an excellent response (inactive disease and ACRPedi90) after 1 year. What may be novel is our finding that the response to etanercept therapy was strongly associated with the JIA category. The response to etanercept therapy was also associated with the disease duration before the start of etanercept treatment.

Intermittent therapy for long-term etanercept treatment survival in patients with severe and moderate psoriasis

Intermittent therapy for long-term etanercept treatment survival in patients with severe and moderate psoriasis

Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment in the LIBERATE study

Safety and efficacy of apremilast through 104 weeks in patients with moderate to severe psoriasis who continued on apremilast or switched from etanercept treatment in the LIBERATE study

Treatment response to etanercept in methotrexate refractory juvenile idiopathic arthritis: an analysis of predictors and long-term outcomes.

The aim of the study is to evaluate the long-term outcomes, predictors, and the role of inflammatory cytokines in methotrexate (MTx) refractory juvenile idiopathic arthritis (JIA) patients. This is a retrospective cohort study. MTx refractory JIA patients who received etanercept as their first biological agent in National Taiwan University Hospital (NTUH) were enrolled. Patients were classified into remission group, non-remission group, relapsing group, and non-relapsing group according to the criteria of disease remission and disease flares defined by Wallace et al. We compared the differences in the baseline data, therapeutic responses, time to etanercept tapering, and inflammatory cytokine (IL-12p70, TNF-α, IL-10, IL-6, and IL-1β) levels between these groups. Among the 58 patients, 30 (52%) reached remission. Seventeen of the 30 patients had episodes of disease flares. We found that more patients in the remission group achieved ACR pediatric 70 response at the fourth month after etanercept treatment (p<0.002). When comparing the relapsing group and non-relapsing group, we found that patients were more likely to have disease flares if it took longer to achieve remission (p=0.0008). Besides, etanercept was tapered earlier in the non-relapsing group (p=0.0006). There was no significant difference in levels of inflammatory cytokine between groups. No parameter before treatment could be used as a single predictor of long-term outcomes. However, ACR pediatric 70 response at the fourth month after etanercept treatment might predict disease remission. Besides, patients who achieved remission more rapidly were less likely to have disease flares.

Inflammation Is an Important Covariate for the Crosstalk of Sleep and the HPA Axis in Rheumatoid Arthritis

Rheumatoid arthritis (RA) patients have sleep problems, and inflammation influences sleep. We demonstrated that sleep quality improves during intensified treatment with methotrexate (MTX) or etanercept (ETA). Since the hypothalamic-pituitary-adrenal (HPA) axis is involved in sleep regulation, this study investigated the interrelation between sleep parameters, inflammation as objectified by C-reactive protein (CRP), and serum cortisol and adrenocorticotropic hormone (ACTH) levels. Thirty-one eligible patients (disease activity score, DAS28_CRP ≥3.2) participated in a 16-week, open, prospective study of HPA axis outcomes. MTX was initiated in 15 patients (female-to-male ratio 9/6) and ETA in 16 patients (14/2). Clinical, laboratory (after polysomnography [PSG] between 8 and 9 a.m.), sleep (PSG), and HPA axis outcome parameters (after PSG between 8 and 9 a.m.) were recorded at baseline and week 16. Clinical characteristics of patients markedly improved throughout the study (e.g., DAS28_CRP: p < 0.001; CRP: p < 0.001). Sleep efficiency and wake time after sleep onset markedly improved in the ETA group. Serum cortisol and ACTH did not change during observation. At baseline, serum cortisol levels were negatively correlated to sleep efficiency; this may depend on inflammation, because controlling for CRP eliminated this negative correlation. After ETA treatment, serum cortisol had a high positive correlation with total sleep time, sleep efficiency, and a negative correlation with wake time before and after sleep onset, which was not eliminated by controlling for CRP. In RA patients, the data indicate that inflammation is an important covariate for the crosstalk of sleep and the HPA axis.

Tumour necrosis factor-α/etanercept complexes in serum predict long-term efficacy of etanercept treatment in seronegative rheumatoid arthritis

Objective: To study whether serum levels of tumour necrosis factor-α (TNF-α), free or bound to etanercept, in biological-naïve adults with rheumatoid arthritis (RA) could predict the long-term efficacy of etanercept, measured as drug survival.Method: We identified 145 biological-naïve patients with RA starting treatment with etanercept at the Department of Rheumatology, Skåne University Hospital (1999–2008), of whom 16 had seronegative and 129 seropositive RA. TNF-α in serum was quantified using enzyme-linked immunosorbent assay in samples from the onset of treatment and at 6 week follow-up. Drug survival time was used to evaluate the long-term efficacy of etanercept.Results: Levels of TNF-α were significantly increased at follow-up compared to at the start. At the 6 week follow-up, circulating TNF-α mainly comprised TNF-α in complex with etanercept. Longer drug survival time correlated with increased TNF-α at 6 week follow-up in the patients with seronegative RA, but not in the seropositive patients.Conclusion: We demonstrated that levels of circulating TNF-α increased in almost all individuals after initiation of treatment with etanercept and that this increase mainly comprised TNF-α in complex with etanercept. More importantly, this increase may predict drug survival in adults with seronegative, but not seropositive, RA and suggests that measuring TNF-α/etanercept complexes in serum may be relevant in patients with seronegative RA.

Efficacy and safety of adalimumab every other week versus methotrexate once weekly in children and adolescents with severe chronic plaque psoriasis: a randomised, double-blind, phase 3 trial

Adalimumab is indicated for the treatment of moderate to severe psoriasis in adults. We assessed the efficacy and safety of adalimumab in children and adolescents with severe plaque psoriasis. This randomised, double-blind, multiperiod, phase 3 trial was done at 38 clinics in 13 countries. Patients (aged ≥4 to <18 years) with severe plaque psoriasis who had not responded to topical therapy were randomly assigned with an interactive voice or web-response system (1:1:1) to receive adalimumab 0·8 mg/kg or 0·4 mg/kg subcutaneously at week 0, then every other week starting at week 1, or oral methotrexate once weekly (0·1-0·4 mg/kg) for 16 weeks. Randomisation was stratified by history of etanercept treatment, with a block size of three. Responders were withdrawn from treatment (for up to 36 weeks) and re-treated with adalimumab (for 16 weeks) if disease became uncontrolled. Ranked primary efficacy endpoints were the proportion of patients who achieved at least 75% improvement from baseline in Psoriasis Area and Severity Index (PASI75) score and clear or minimal physician global assessment (PGA) score at week 16, comparing adalimumab 0·8 mg/kg with methotrexate. Efficacy analysis was by intention to treat, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01251614, and has been completed. Between Dec 14, 2010, and Feb 5, 2015, 114 patients were randomly assigned to adalimumab 0·8 mg/kg (n=38), adalimumab 0·4 mg/kg (n=39) or methotrexate (n=37). At week 16, PASI75 was achieved in 22 (58%) of 38 patients in the adalimumab 0·8 mg/kg group compared with 12 (32%) of 37 patients in the methotrexate group (p=0·027). 23 (61%) of 38 patients in the adalimumab 0·8 mg/kg group and 15 (41%) of 37 in the methotrexate group achieved clear or minimal PGA (p=0·083). In the adalimumab 0·4 mg/kg group, 17 (44%) of 39 patients achieved PASI75 and 16 (41%) achieved clear or minimal PGA. The most frequent adverse events were infections (17 [45%] of 38 in the adalimumab 0·8 mg/kg group during initial treatment; 22 [56%] of 39 in the adalimumab 0·4 mg/kg group; 21 [57%] of 37 in the methotrexate group). Three serious adverse events were reported, all in patients in the adalimumab 0·4 mg/kg group, and were not judged to be related to study drug. Treatment with adalimumab 0·8 mg/kg in children and adolescents with severe plaque psoriasis provided significant improvements in PASI75 and a non-significant increase in the proportion of patients who achieved clear or minimal PGA compared with methotrexate. No new safety risks were identified. AbbVie.

Improvement of DAS-28 ESR score in Egyptian children and adolescents with juvenile idiopathic arthritis treated with etanercept

Aim of studyTo assess the efficacy and safety of using anti-tumor necrosis factor-α (TNF-α), Etanercept (ETN) in treatment of children and adolescents with Juvenile Idiopathic arthritis (JIA). Patients and methodsThis retrospective cohort study included 18 children and adolescents who were diagnosed as JIA and treated with anti-tumor necrosis factor-α (TNF-α), ETN for at least 6months due to failure of synthetic disease-modifying antirheumatic drugs (sDMARDS) as methotrexate (MTX). Before starting ETN treatment, all patients were receiving MTX in addition to non-steroidal anti-inflammatory drugs (NSAIDs). Other medications used were Prednisolone, Leflunamide and Hydroxychloroquine. As per recommendations of the European League Against Rheumatism (EULAR), failure of these DMARDs is an indication to start biological DMARDs. Anti TNF-α, mainly ETN is one of the most commonly used biological DMARDs in treating JIA. Clinical scoring using DAS28-ESR score was done for all patients at time of enrollment, 3months and 6months after starting ETN. The effect of different clinical and laboratory variables on the outcome of ETN treatment was assessed. ResultsThere was statistically significant improvement in DAS28-ESR after 3months of treatment (p=0.001) and after 6months (p=0.049). There was no statistically significant difference in DAS-28 score between males and females, patients younger than 10years and patients older than 10years, neither at onset nor at 6months’ follow up. Similarly, the duration of illness before starting ETN did not affect DAS28 score at 6months of treatment. ConclusionETN treatment of JIA children and adolescents demonstrated safety and efficacy in clinical improvement of DAS28-ESR score at 3 and 6months of treatment. However, further studies on a bigger number of patients, longer duration and using different biological agents are needed.

Correlations of CYP2C9*3/CYP2D6*10/CYP3A5*3 gene polymorphisms with efficacy of etanercept treatment for patients with ankylosing spondylitis: A case-control study.

Background:The tumor necrosis factor alpha (TNF-α) inhibitor etanercept has been proven to be effective in the treatment of ankylosing spondylitis (AS), while genetic polymorphism may affect drug metabolism or drug receptor, resulting in interindividual variability in drug disposition and efficacy. The purpose of this study is to investigate the correlations between CYP2C9∗3/CYP2D6∗10/CYP3A5∗3 gene polymorphisms and the efficacy of etanercept treatment for patients with AS.Methods:From March 2012 to June 2015, 312 AS patients (174 males and 138 females, mean age: 35.2 ± 5.83 years) from 18 to 56 years old were enrolled in this study. Polymerase chain reaction-restriction fragment length polymorphism was applied to detect the allele and genotype frequencies of CYP2C9∗3, CYP2D6∗10, and CYP3A5∗3 gene polymorphisms. The joint swelling score, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level of AS patients were compared before and after 24-week etanercept treatment. Assessment in Ankylosing Spondylitis (ASAS) and bath ankylosing spondylitis disease activity index (BASDAI) scores were recorded to assess the efficacy of etanercept treatment.Results:The AS patients with wild-type ∗1/∗1 and heterozygous ∗1/∗3 genotypes of CYP2C9∗3 polymorphism accounted for 93.59% and 6.41%, respectively, without ∗3/∗3 genotype. The AS patients with wild-type CC, heterozygous CT, and mutation homozygous TT genotypes of CYP2D6∗10 polymorphism accounted for 19.23%, 39.10%, and 41.67%, respectively. The AS patients with wild-type ∗1/∗1, heterozygous ∗1/∗3, and mutation homozygous ∗3/∗3 genotypes of CYP3A5∗3 polymorphism accounted for 7.69%, 36.22%, and 56.09%, respectively. After 24-week treatment, AS patients with wild-type ∗1/∗1 genotype of CYP2C9∗3, CC genotype of CYP2D6∗10, and ∗3/∗3 genotype of CYP3A5∗3 polymorphisms had lower joint swelling score, ESR, and CRP level. The joint swelling score, ESR, and CRP levels were significantly lower in the patients with CC genotype of CYP2D6∗10 polymorphism than in CT and TT genotype patients, and they were lower in patients with ∗3/∗3 genotype of CYP3A5∗3 polymorphism compared to those with ∗1/∗1 and ∗1/∗3 genotypes. Average visual analog scale scores of 4 ASAS20 indexes were decreased after treatment. The patients with CC genotype of CYP2D6∗10 polymorphism and ∗3/∗3 genotype of CYP3A5∗3 polymorphism exhibited higher scores of >ASAS20, >BASDAI50%, and effective rate.Conclusion:Our results indicate that CC genotype of CYP2D6∗10 polymorphism and ∗3∗3 genotype of CYP3A5∗3 polymorphism are correlated with the efficacy of etanercept treatment for AS patients.

The TNF-\u03b1 antagonist etanercept reverses age-related decreases in colonic SERT expression and faecal output in mice

Treatment for chronic constipation in older people is challenging and the condition has a major impact on quality of life. A lack of understanding about the causes of this condition has hampered the development of effective treatments. 5-HT is an important pro-kinetic agent in the colon. We examined whether alterations in colonic 5-HT signalling underlie age–related changes in faecal output in mice and whether these changes were due to an increase in TNF-α. Components of the 5-HT signalling system (5-HT, 5-HIAA, SERT) and TNF-α expression were examined in the distal colon of 3, 12, 18 and 24-month old mice and faecal output and water content monitored under control conditions and following the administration of etanercept (TNF-α inhibitor; 1 mg Kg−1). Faecal output and water content were reduced in aged animals. Age increased mucosal 5-HT availability and TNF-α expression and decreased mucosal SERT expression and 5-HIAA. Etanercept treatment of old mice reversed these changes, suggesting that age-related changes in TNFα expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. These data point to “anti-TNFα” drugs as potential treatments for age-related chronic constipation.

Tumor necrosis factor alpha inhibitors have no effect on a human T-lymphotropic virus type-I (HTLV-I)-infected cell line from patients with HTLV-I-associated myelopathy

BackgroundWhile tumor necrosis factor alpha (TNF-α) inhibitors (TNFi) and other biologics are very effective against autoimmune diseases, they can also cause infectious diseases. Therefore, it is important to clarify whether the TNFi sometimes used to treat patients with rheumatoid arthritis (RA) complicated with human T-lymphotropic virus type-I (HTLV-I) infection have the unintended side effect of promoting HTLV-I proliferation.MethodsWe used the HTLV-I-infected cell line HCT-5, derived from spinal fluid cells of a patient with HTLV-I associated myelopathy, to evaluate the production of cytokines and chemokines, TNF-α receptor (TNFR), the expression of HTLV-I associated genes, the HTLV-I proviral load (PVL), the expression of HTLV-I structural protein, and apoptosis. We used Jurkat cells as a control.ResultsSupernatants of HCT-5 showed time-dependent elevations of IL-6, RANTES and ICAM-1. HCT-5 supernatants treated with infliximab, adalimumab, etanercept (ETN), golimumab and certolizumab pegol showed no significant differences in the levels of these molecules compared to the control. Neither TNFR1 nor TNFR2 expression was altered by any TNFi treatment, relative to phosphate-buffered saline (PBS) treatment, with the exception that TNFR2 was significantly decreased and internalized in HCT-5 cells by ETN treatment. The HTLV-I associated genes Tax and HBZ and the PVL levels were not significantly changed. Immunofluorescence staining of HCT-5 for an HTLV-I-associated protein, GAG, was also not significantly different between any of the TNFi treatments and the PBS treatment. DNA ladders as an index of apoptosis were not detected. Apoptotic cells were not increased by the addition of any TNFi.ConclusionsIn vitro, TNFi did not affect the cytokine profiles, expression of associated genes and proteins, proviral load or apoptosis of HCT-5 cells. The results suggested that TNFi treatment of RA patients complicated with HTLV-I might have no effect on HTLV-I infection.

Reduced risk of all-cancer and solid cancer in Taiwanese patients with rheumatoid arthritis treated with etanercept, a TNF-α inhibitor.

Biologics has been widely used in the treatment of rheumatoid arthritis. We aimed to determine whether etanercept, a TNF-α inhibitor (TNFi) that is used to treat patients with rheumatoid arthritis (RA), affects cancer risk.This retrospective matched cohort study used data in the Registry of Catastrophic Illness Database in Taiwan from January 1, 1996 to December 31, 2010. RA, all-cancer, and solid cancer were defined using International Classification of Disease codes (ICD-9-CM 714.X, 140-208, and 140-199, respectively). Cox proportional hazard modeling was used to estimate the hazard ratio (HR) of cancer in all TNFi-treated RA patients, with a focus on the risk in the etanercept-treated patients, after adjusting for comorbidities and concomitant medication.In this Taiwanese dataset, there were 1111 TNFi-treated RA patients and 16,812 RA patients who were naive to all biologics identified. Among the 1002 pairs of etanercept-treated and biologic-naive patients who were matched 1-to-1 for age, gender, RA duration, methotrexate-use, and index date of TNFi prescription, the mean age was 48.9 ± 15.0 years. The highest proportion of patients was in the age subgroup of 30 to 60 years (63.8%). Most patients (77.2%) were women. The mean RA duration before etanercept treatment was 2.0 ± 1.5 years. During a mean 2.1 years of observation, etanercept was associated with significant risk reduction for all-cancer (HR 0.59, 0.36-0.98) and solid cancer (HR 0.46, 0.27-0.79) relative to the matched biologic-naive patients.The current study explored the safety profile of TNFi and identified a potential benefit of etanercept on the incidence of all-cancer and solid cancer in RA patients.

Single nucleotide polymorphisms of ABCB1 gene and response to etanercept treatment in patients with ankylosing spondylitis in a Chinese Han population.

Background:Etanercept was highly recommended for patients with ankylosing spondylitis (AS), as its efficacy has been confirmed in AS, while genetic polymorphisms, by affecting drug metabolism or drug receptor, lead to interindividual variability in drug disposition and efficacy. Therefore, this study aims to investigate whether ABCB1 gene polymorphisms can predict therapeutic response to etanercept in patients with AS.Methods:A total of 185 patients with AS in our hospital were recruited into our study from December 2012 to May 2015. The frequency distributions of genotype and allele of rs2032582, rs1128503, and rs1045642 were detected by polymerase chain reaction (PCR) and electrophoresis verification enzyme products method. AS patients received etanercept treatment for 12 weeks, followed by this would be evaluated by the bath AS disease activity index (BASDAI) score improvement and the assessment of spondyloArthritis international society 20/50/70 (ASAS20/50/70) score improvements to explore the relationship between genotype of ABCB1 gene polymorphisms and therapeutic response to etanercept in patients with AS.Results:After 12 weeks, the BASDAI score mean improvement value of rs2032582 A/A genotype was 2.87 ± 0.52. The ratios of patients with rs2032582 A/A genotype reaching the BASDAI50 and ASAS20 evaluation criteria were 64.29% and 92.86%, respectively. The results indicated that efficacy of etanercept was promoted in rs2032582 A/A genotype. The BASDAI score mean improvement value of rs1128503 C/C genotype was 2.79 ± 0.54 after 12 weeks. The ratios of patients with rs1128503 C/C genotype reaching the BASDAI50 and ASAS20 evaluation criteria were 66.67% and 93.94%, respectively. The results indicated that efficacy of etanercept was promoted in rs1128503 C/C genotype. However, no significant associations were observed between rs1045642 and therapeutic response to etanercept in AS patients.Conclusion:ABCB1 gene rs2032582 and rs1128503 polymorphisms may be associated with the efficacy of etanercept in AS patients. ABCB1 gene polymorphisms can act as biological indicators of etanercept efficacy.

The association of NLRP3 and TNFRSF1A polymorphisms with risk of ankylosing spondylitis and treatment efficacy of etanercept

To discover how NLRP3 and TNFRSF1A polymorphisms affect the efficacy of traditional medicine and etanercept for ankylosing spondylitis (AS) patients. Single nucleotide polymorphism (SNP) and haplotype analyses were conducted based on determined NLRP3 and TNFRSF1A among AS patients. We subsequently analyzed the relationship between relevant clinical indexes and polymorphisms of NLRP3 and TNFRSF1A. The 4 SNP loci on NLRP3 and 3 SNP loci on TNFRSF1A showed significant linkage disequilibrium, respectively. The T allele of NLRP3 rs4612666 and the T allele of TFRSF1A rs4149570 are both associated with AS (P<.05). The T-A-C-T haplotype of NLRP3 as well as the G-C-C, T-C-C, T-C-T, and T-T-T haplotypes of TFRSF1A are associated with AS (P<.05). The morning stiffness time, BASDAI scoring, and ESR of patients receiving etanercept were significantly higher than those receiving traditional medicine. T allele of NLRP3 rs4612666 had a significantly greater negative impact on the ASAS20 improvement than C allele. Whereas the A allele of NLRP3 rs3806268 had a significantly greater positive impact on the ASAS20 improvement than G allele. There is no significant association between SNP and efficacy of traditional medicine in the treatment of AS. NLRP3 and TFRSF1A (rs4149570) are associated with AS susceptibility. There is a significant association between NLRP3 polymorphisms and treatment of etanercept.

Effects of Tumor Necrosis Factor Inhibitor on Stress-Shielded Tendons.

Mechanical stress plays an important role in preserving the integrity of bone and ligament. Stress shielding reduces mechanical load on bone or tendons, resulting in tissue degradation. Previous studies showed that deterioration of the tendon structure during stress shielding is associated with elevated expression of tumor necrosis factor (TNF)-α. This study examined the therapeutic potential of the TNF inhibitor etanercept in preventing morphologic deterioration of the Achilles tendon after stress shielding. Rats (N=48) were exposed to stress shielding of the left Achilles tendon and treated with etanercept or phosphate-buffered saline for 2 or 4 weeks. The right Achilles tendons were used as controls. After 2 or 4 weeks, stress-shielded tendons appeared less smooth than control tendons, and the stress-shielded tendons formed adhesions with surrounding tissues. Transmission electron microscopy also showed disarray of the collagen fibrils and a significant increase in the number of small-diameter collagen fibrils. These changes were associated with increased expression of TNF-α, matrix metalloproteinase (MMP)-13, MMP-3, collagen I, and collagen III. Treatment with 2 weeks of etanercept injection reduced morphologic changes in collagen organization and structure induced by stress shielding. Etanercept treatment also attenuated upregulation of MMP-13, MMP-3, and collagen III levels. However, no significant difference was observed between the etanercept group and the phosphate-buffered saline group after 4 weeks of treatment. The current findings show that TNF-α inhibition can protect against the early stages of tendon tissue remodeling induced by stress shielding, but additional interventions may be necessary to prevent tendon degeneration with long-term stress shielding. [Orthopedics. 2017; 40(1):49-55.].

VP53 Cost-Utility Analysis: Adalimumab Verus Etanercept in Rheumatoid Arthritis – Brazil

INTRODUCTION:Rheumatoid arthritis (RA) is an inflammatory, autoimmune disease of unknown etiology that usually results in joint lesions and physical incapacitation. RA treatment includes disease-modifying antirheumatic drugs (DMARD), synthetic (sDMARD) and/or biologics (bDMARD). In this study we carried out a cost-utility analysis comparing Adalimumab (ADA) versus Etanercept (ETA), with or without synthetic DMARDs (± sDMARD).METHODS:Effectiveness measures used were the Clinical Disease Activity Index (CDAI) and Quality-Adjusted Life Years (QALY) obtained from an open prospective cohort study with Brazilian RA patients. Costs were obtained from a historical cohort composed of every patient who was prescribed medicines to treat RA in the State of Minas Gerais, Brazil. A public sector perspective was adopted. The Markov model included six-month cycles, time horizon of 5 years and 5 percent discount rates. Sensitivity analyses were performed by varying costs and outcome values.RESULTS:There was no significant difference in effectiveness between the two bDMARDs. Treatment with ETA (± sDMARD) was more expensive after 5 years of follow-up: incremental cost of USD28,210.87. Overall, treatment with ADA (± sDMARD) was more cost-effective: incremental cost-effectiveness ratio for ETA (± sDMARD) was USD79,148.34/ QALY. Sensitivity analysis showed that this was sensitive to changes in the cost of ETA (± sDMARD).CONCLUSIONS:Currently two Anti-tumour Necrosis Factor Alpha (anti-TNF alpha) medicines – ADA and ETA are available within the Brazilian public health system in addition to infliximab. Treatment with ADA (±sDMARD) was more cost-effective with an incremental cost effectiveness ratio for ETA (±sDMARD) at USD79,148.34 per QALY. Sensitivity analysis showed that outcomes are sensitive to changes in the cost of ETA (± sDMARD) treatment. Overall, both therapeutic alternatives are valuable from the public sector perspective especially when the Clinical Protocol and Therapeutic Guidelines are properly applied in patients no longer responding to treatment. Alternatives are needed as some patients will respond differently to different anti-TNF alpha medicines.

CD3+ CD56+ natural killer T cell activity in children with different forms of juvenile idiopathic arthritis and the influence of etanercept treatment on polyarticular subgroup

Juvenile idiopathic arthritis (JIA) has three major onset types with widely varying clinical features. We assessed the natural killer T (NKT) cell function in patients with different JIA subtypes, and found systemic patients exhibited lower NKT cell counts, perforin and granzyme B expression, while the pauciarticular and polyarticular patients displayed higher perforin and granzyme B expression as compared with the controls. The synovial fluid had more NKT cells with higher levels of perforin, granzyme B, and tumour necrosis factor (TNF)-α than peripheral cells. The polyarticular patients that responded to etanercept had lower NKT cell counts, intracellular perforin, granzyme B and the mean fluorescence intensity of TNF-α than the patients that did not respond. Treatment with etanercept reduced the granzyme B and perforin, interferon (IFN)-γ and TNF-α expression in NKT cells in the responsive group. Therefore, a higher NKT cell function may indicate a decreased response to etanercept in polyarticular patients.

ASSESSING ANTI-TNF TROUGH LEVELS AND ITS APPLICABILITY IN DAILY PRACTICE IN SPONDYLOARTHRITIS PATIENTS

Objective. The purpose of the present study was to assess the relevance of therapeutic drug monitoring in spondyloarthritis patients, by determining drug serum levels and anti-drug antibodies and estimating cut-off values for three TNF inhibitors. Methods. Over one year, we enrolled 100 patients with SpA, under consequent treatment with adalimumab (ADL), etanercept (ETA) or infliximab (IFX). Demographic, clinical (BASDAI, ASDAS) and laboratory (ESR, CRP) data was collected together with drug serum level and anti-drug antibodies using the ELISA technique. The statistical analysis was performed using the SPSS software, version 20.0 with the aid of Student t-test, Spearman and Pearson tests. Results. Out of the study cohort, 35% were on ADL, 33% on IFX, and 32% under ETA treatment. Undetectable drug levels correlated to the presence of anti-drug antibodies and to disease activity scores. There were no identified anti-ETA antibodies. For this study lot trough levels are estimated between 2 and 4 μg/mL for an ASDAS-CRP under 2.1. Conclusion. Serum drug level measurement and anti-drug antibody detection can be used as a completion to a clinician’s tools in assessing disease activity, leading to an optimal and personalized manner of patient management.

Glomerular filtration rate in patients with psoriasis treated with etanercept

ObjectiveTo estimate the prevalence of chronic kidney disease (CKD) and evaluate renal function in patients with moderate-to-severe chronic plaque psoriasis treated with etanercept (an anti-tumour necrosis factor-α drug).MethodsThis retrospective cohort study included patients with moderate-to-severe chronic plaque psoriasis. Kidney function was evaluated using estimated glomerular filtration rate (EGFR).ResultsThe prevalence of CKD at baseline was 3.9% (two of 51 patients). EGFR was unaffected by etanercept therapy (83.6 ± 23.9 at baseline vs 82.2 ± 21.6 ml/min per 1.73 m2 after 6 months).ConclusionEGFR was unaffected by 6 months’ etanercept treatment. Physicians should be aware of the risk of CKD when providing comprehensive care to patients with moderate-to-severe psoriasis.