Disease activity guided stepwise tapering or discontinuation of rhTNFR:Fc, an etanercept biosimilar, in patients with ankylosing spondylitis: a prospective, randomized, open-label, multicentric study.
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SUBMITTER: Zhang T
PROVIDER: S-EPMC7268122 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Disease activity guided stepwise tapering or discontinuation of rhTNFR:Fc, an etanercept biosimilar, in patients with ankylosing spondylitis: a prospective, randomized, open-label, multicentric study.
Zhang Ting T Zhu Jianing J He Dongyi D Chen Xiaowei X Wang Hongzhi H Zhang Ying Y Xue Qin Q Liu Weili W Xiang Guangbo G Li Yasong Y Yu Zhongming Z Wu Huaxiang H
Therapeutic advances in musculoskeletal disease 20200602
<h4>Background</h4>The aim of this study was to evaluate disease-activity-guided stepwise tapering or discontinuation of rhTNFR:Fc, an etanercept biosimilar, in patients with ankylosing spondylitis (AS) in a prospective, randomized, open-label, multicentric study.<h4>Methods</h4>Active AS patients with AS disease activity score (ASDAS) ⩾2.1 recruited from 10 hospitals were treated with rhTNFR:Fc 50 mg weekly for 12 weeks, and further randomized into different tapering or discontinuation groups a ...[more]
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Project description:IntroductionThe aim of this work is to examine the efficacy and safety of prefilled liquid etanercept-biosimilar Yisaipu versus lyophilized Yisaipu in active ankylosing spondylitis (AS) patients.MethodsThis double-blind, phase III trial with non-inferiority design randomized adult patients with active AS in a 3:1:1 ratio to receive twice-weekly 25-mg prefilled liquid Yisaipu for a total of 48 injections (group I, n = 330), once-weekly 50-mg prefilled liquid Yisaipu for 24 injections (group II, n = 110), or twice-weekly 25-mg lyophilized Yisaipu for 48 injections (group III, n = 110). Both physicians and patients who received 25-mg twice-weekly lyophilized or liquid Yisaipu were blinded to treatment assignment while patients who received 50-mg once-weekly liquid Yisaipu received treatment in an open-label design. In addition, 90 patients in the PK/PD study were randomized in a 1:1:1 ratio to each group. The primary outcome was the proportion of patients who achieved ASAS20 at week 24.ResultsA total of 640 subjects were enrolled. The proportion of patients who attained ASAS20 at week 24 was 85.56% in group I, 85.71% in group II, and 83.45% in group III (group I vs. III, P = 0.545; group II vs. III, P = 0.605). The difference between group I and III was 2.10% (95% CI - 5.06%, 9.27%) and 2.26% (95% CI - 6.21%, 10.73%) between group II and III, meeting the non-inferiority threshold (Δ = - 15%) (P < 0.001). Except for a statistical difference between group I (75.83%) and group III at week 8 (64.75%, P = 0.011), there was no statistical difference in the ASAS20 attainment rate among the three groups at other time points. The incidence of serious adverse events was comparable among the three groups (group I, 2.50%, II, 2.86% and III, 1.43%; P > 0.05). No deaths were reported.ConclusionsOnce-weekly 50-mg or twice-weekly 25-mg prefilled liquid Yisaipu is safe and non-inferior to twice-weekly 25-mg lyophilized Yisaipu.Trial registrationCTR20130124 and NCT04345458.
| S-EPMC7991065 | biostudies-literature
Project description:ObjectiveTo investigate the efficacy and safety of clinical, magnetic resonance imaging (MRI) changes in active ankylosing spondylitis (AS) patients with etanercept and celecoxib alone/combined treatment.MethodsA randomized controlled trial was conducted in three medical centers in China. Adult AS patients with BASDAI ≥4 or ASDAS ≥2.1, CRP >6 mg/L, or ESR 28 mm/1st hour were randomly assigned (1:1:1 ratio) to celecoxib 200 mg bid or etanercept 50 mg qw or combined therapy for 52 weeks. The primary outcomes were SPARCC change of the sacroiliac joint (SIJ) and spine and the proportion of patients achieving ASAS20 response at 52 weeks.ResultsBetween September 2014 and January 2016, we randomly assigned 150 patients (mean age, 32.4 years; mean disease duration, 109 months), and 133 (88.6%) completed the study. SPARCC inflammation scores of the SIJ and spine decreased in the three groups, and significant differences were found between the combined group and the celecoxib group [between-group difference: -6.33, 95% CI (-10.56, -2.10) for SIJ; -9.53, 95% CI (-13.73, -5.33) for spine] and between the etanercept group and the celecoxib group [between-group difference: -5.02, 95% CI (-9.29, -0.76) for SIJ; -5.80, 95% CI (-10.04, -1.57) for spine]. The ASAS20 response rates were 44%, 58%, and 84% in the celecoxib, etanercept, and combined groups, respectively, and a significant difference was only found between the combined and the celecoxib groups.ConclusionEtanercept with or without celecoxib decreases inflammation detected by MRI at 1 year compared to celecoxib alone in active AS patients. The combination of etanercept and celecoxib was superior to celecoxib alone for the primary clinical response.Clinical trial registrationClinicalTrials.gov, identifier NCT01934933.
| S-EPMC9458864 | biostudies-literature
Project description:Background: Anti-tumor necrosis factor biological agents had been proved to have a dramatic effect in ankylosing spondylitis (AS). We aimed to determine the efficacy and safety of crossover effects of adalimumab vs. etanercept in AS patients. Methods: A randomized, open-label crossover study was done in patients with active AS. Patients were randomized into two sequence groups, etanercept first (treatment arm) vs. adalimumab first (control arm) 8 weeks and then switched over for another 8 weeks. The primary endpoints were the difference of the Bath AS activity index and AS disease activity score (ASDAS)crp at week 16. Secondary endpoints were ASDASesr, ASAS20, and ASAS40 response rates and the proportion of patients achieving ASDAS inactive disease and low disease activity at weeks 8 and 16. Patient global assessment and preference was grading on a numerical scale. Results: A total of 21 patients were screened, and 19 of them were randomly allocated into the treatment arm (n = 9) and control arm (n = 9). At baseline, age, sex, Bath AS activity index, and ASDAS of both arms were comparable (p > 0.05). Both arms showed dramatic improvement, whereas no significance was observed between the changes of ASDAScrp (0.90 ± 1.39 vs. 1.24 ± 1.40 at week 8, p = 0.612; 1.02 ± 1.22 vs. 1.26 ± 1.44 at week 16, p = 0.707, respectively). ASAS20 and ASAS40 response rates were also comparable at week 8 (33 vs. 44%, p = 1.000; 22 vs. 22%, p = 1.000) and week 16 (22 vs. 22%, p = 1.000; 22 vs. 22%, p = 1.000), respectively. Both arms were well-tolerated without a serious adverse event. Adalimumab was relatively more favorable by patients in both arms, with a total mean grading score of 0.4 (-5-5, p = 0.218). Conclusion: Etanercept and adalimumab can both dramatically improve disease activity in 16 weeks. Crossover administration of etanercept and adalimumab revealed comparable efficacy and safety. Trial Registration: The protocol was approved by the Institutional Review Board with the register CS08019 from Chung Shan Medical University Hospital (CSMUH), Taichung, Taiwan and registered at ClinicalTrials.gov Protocol Registration and Results System: NCT02489760.
| S-EPMC7662505 | biostudies-literature
Project description:ObjectiveTo investigate the impact of dose reduction of tumor necrosis factor inhibitor (TNFi) on radiographic progression in ankylosing spondylitis (AS).MethodsOne hundred and sixty-five patients treated with etanercept or adalimumab were selected from a consecutive single-center observational cohort based on the availability of radiographs at baseline and after two- and/or four-years of follow up. Radiographs were assessed by two blinded readers using the modified Stokes AS Spinal Score (mSASSS). Radiographic progression in patients treated with standard-dose TNFi (standard-dose group, n = 49) was compared with patients whose dosage was tapered during the treatment (tapering group, n = 116) using linear mixed models.ResultsBaseline characteristics between two groups were comparable except for higher BASDAI (7.1 vs. 6.3, p = 0.003) in the standard-dose group. At two years after the treatment, mean dose quotient (S.D.) of the tapering group was 0.59 (0.17). During follow up, rate of radiographic progression in overall patients was 0.90 mSASSS units/year. Radiographic progression over time between the two groups was similar at the entire group level. However, in the subgroup of patients with baseline syndesmophytes, progression occurred significantly faster in the tapering group after the adjustment for baseline status (1.23 vs. 1.72 mSASSS units/year, p = 0.023). Results were consistent when radiographic progression was assessed by the number of newly developed syndesmophytes (0.52 vs. 0.73/year, p = 0.047). Sensitivity analysis after multiple imputation of missing radiographs also showed similar results.ConclusionA dose tapering strategy of TNFi is associated with more rapid radiographic progression in AS patients who have syndesmophytes at baseline.
| S-EPMC5199008 | biostudies-literature
Project description:BackgroundWork disability remains a significant problem in ankylosing spondylitis (AS) and rheumatoid arthritis (RA), despite biological therapy. This study aimed to test the hypothesis that the prevalent symptom of fatigue longitudinally predicts work disability among RA and AS patients commencing etanercept.MethodsTwo observational studies, comprising RA and AS etanercept commencers, respectively, were analysed. Both provided data on work disability over 1 year and a comprehensive set of putative predictors, including fatigue. A series of repeated measures models were conducted, including baseline variables, visit (6/12 months), and the interaction between visit and each of the explanatory variables.ResultsA total of 1003 AS and 1747 RA patients were assessed. For AS, fatigue was significantly associated with presenteeism (linear mixed model coefficient 3.75, 95% confidence interval (CI) 2.14 to 5.36) and activity impairment (2.62, 1.26 to 3.98), but not with work productivity loss (1.81, -0.40 to 4.02) or absenteeism (generalised linear mixed model odds ratio (OR) 1.18, 95% CI 0.92 to 1.51). In RA, fatigue was associated with presenteeism (coefficient 3.44, 95% CI 2.17 to 4.70), activity impairment (1.52, 0.79 to 2.26), work productivity loss (4.16, 2.47 to 5.85), and absenteeism (OR 1.23, 95% CI 1.02 to 1.49). The lack of significant interactions between fatigue and visit supported a consistent effect of baseline fatigue over time.ConclusionsAmong patients beginning etanercept therapy, fatigue has a significant and independent effect on absenteeism, presenteeism, productivity loss, and activity impairment for RA patients and a significant but dimension-selective effect on work disability among AS patients.Trial registrationClinicalTrials.gov, NCT00544557 . Registered on 16 October 2007. ClinicalTrials.gov, NCT00488475 . Registered on 20 June 2006.
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Project description:BACKGROUND:To discover how NLRP3 and TNFRSF1A polymorphisms affect the efficacy of traditional medicine and etanercept for ankylosing spondylitis (AS) patients. METHODS: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. RESULTS: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. CONCLUSION:NLRP3 and TFRSF1A (rs4149570) are associated with AS susceptibility. There is a significant association between NLRP3 polymorphisms and treatment of etanercept.
| S-EPMC6817003 | biostudies-literature
Project description:Data from clinical studies on the long-term efficacy and safety of anti-tumor necrosis factor (TNF)-? therapy in patients with ankylosing spondylitis (AS) are scarce. This is the first report on continuous treatment with the TNF? fusion protein etanercept over seven years (y).Overall, 26 patients with active AS were initially treated with etanercept 2 × 25 mg s.c./week with no concomitant disease modifying anti-rheumatic drugs (DMARDs) or steroids. The clinical response was assessed by standardized parameters. The primary outcome was the proportion of patients in the Spondyloarthritis International Society (ASAS) partial remission at seven years. AS disease activity scores (ASDAS) for status and improvement were compared to conventional outcome measures.Overall, 21/26 patients (81%) completed two years of treatment and 16/26 patients (62%) completed seven years. In the completer analysis, 31% patients were in ASAS partial remission at seven years, while 44% patients showed an ASDAS inactive disease status. Mean Bath AS activity index (BASDAI) scores, which were elevated at baseline (6.3 ± 0.9), showed constant improvement and remained low: 3.1 ± 2.5 at two years and 2.5 ± 2.2 at seven years, while ASDAS also improved (3.9 ± 0.7 at baseline, 1.8 ± 0.9 at two years, 1.6 ± 0.8 at seven years), all P <0.001. From the 10 dropouts, only 5 patients discontinued treatment due to adverse events. Patients who completed the study had lower baseline Bath AS function index (BASFI) scores vs. patients who discontinued. No other clinical parameter at baseline could predict any long-term outcome.This study confirms the clinical efficacy and safety of etanercept in patients with active AS over seven years of continuous treatment. After seven years, more than half of the initially treated patients remained on anti-TNF therapy, and one-third were in partial remission.ClinicalTrials.gov: NCT01289743
| S-EPMC4060369 | biostudies-literature
Project description:The recent approval of reference etanercept (re-ETN) biosimilars SB4, GP2015, and HD203 produced relevant changes in the management of rheumatoid arthritis (RA), psoriatic arthritis, and ankylosing spondylitis due to the considerably lower cost of these products and the consequent savings.To review the pharmacodynamics, pharmacokinetics, efficacy, and safety of ETN biosimilars when employed as first-line therapy or after transition from re-ETN. Patients' acceptability was also addressed.The available literature was reviewed through a search of PubMed database, and abstract books of the American College for Rheumatology and European League Against Rheumatism annual meetings. SB4, GP2015, and HD203 were licensed by the US, European and South Korea regulatory agencies after the bioequivalence to re-ETN was demonstrated through pharmacodynamic and pharmacokinetic studies, and randomized, head to head, controlled trials. Based on the evidence of efficacy and safety of SB4 and HD203 in RA, and of GP2015 in psoriasis, by the extrapolation principle, the three biosimilars were approved for all indications licensed for re-ETN, and the regulatory agencies introduced the interchangeability from the originator to the biosimilar. Extrapolation of indications, and particularly interchangeability raised relevant concerns among the rheumatologists due to the low level of evidence supporting the switching strategy (or transition). Rheumatologists' concerns are oriented toward the relevant number of biosimilar discontinuations after the transition ranging from 7%-17% over a short-term follow-up period. As resulted from two studies, at least 20%-30% of the patients claimed more exhaustive information on the switching procedure.Based on the available evidence, re-ETN biosimilars may be a good option as first-line therapy, while further data are needed to definitively establish the efficacy, safety, and the economic reflexes of transitioning from re-ETN.
| S-EPMC6121755 | biostudies-other
Project description:AIM: To investigate the population pharmacokinetics of recombinant human tumor necrosis factor receptor-Fc fusion protein (rhTNFR-Fc) administered via subcutaneous (SC) injection in healthy Chinese volunteers and in Chinese patients with ankylosing spondylitis (AS). METHODS: Thirty-two healthy volunteers were randomly assigned to receive a single SC injection of 12.5, 25, 37.5, or 50 mg of rhTNFR-Fc. Twenty male patients with moderate AS were randomly assigned to receive seven consecutive SC injections of rhTNFR-Fc at either 25 mg twice a week (BIW) or 50 mg once a week (QW). Population pharmacokinetic (PK) analysis was applied to obtain PK parameters of rhTNFR-Fc by the NONMEM method. RESULTS: The data were best described by a one-compartment model with lag time. We found that gender had a significant effect on the apparent clearance (CL/F), with the male CL/F ratio being only 0.665 times the female ratio; the absorption coefficient (F) of multiple dosages of rhTNFR-Fc was only 0.674 times that of a single dosage. The outcome parameters were CL/F (female: 0.168 L/h, male: 0.110 L/h), the apparent volume of distribution (Vd/F: 15.5 L), the absorption rate constant (Ka) (single dosage: 0.0605 h⁻¹, multiple dosage: 0.0408 h⁻¹), and the lag time (T(lag): 1.03 h). The inter-individual variability in the CL/F, Vd/F, Ka, and T(lag) were 33.3%, 42.7%, 55.6%, and 81.8%, respectively. CONCLUSION: Chinese females have a higher CL/F than Chinese males, and multiple dosings can significantly decrease the absorption of rhTNFR-Fc (SC). The population PK parameters of rhTNFR-Fc in healthy Chinese volunteers and patients with AS were similar to those reported for subjects in published American studies.
| S-EPMC4003328 | biostudies-other
Project description:BACKGROUND:C-reactive protein (CRP) level is one of the most widely used parameters to assess ankylosing spondylitis (AS), since CRP is associated with poor radiographic progression of AS patients. Recent studies have investigated the association between CRP gene variants and AS risk, but with conflicting findings. MATERIAL AND METHODS:We enrolled 232 AS cases and 314 controls in this case-control study. Next, we assessed the association of CRP gene rs3091244 polymorphism with the efficacy of etanercept for AS. Genotyping was done using a custom-by-design 48-Plex SNP scanTM Kit. RESULTS:CRP gene rs3091244 polymorphism was associated with an increased risk of AS in this Chinese population. Clinical indicators of AS patients including morning stiffness time, Bath AS function index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Visual Analogue Scale (VAS), erythrocyte sedimentation rate (ESR), and CRP were significantly decreased after 12 weeks of etanercept treatment. Furthermore, AA genotype carriers showed higher values of VAS, BASDAI, BASFI, and CRP before etanercept treatment. AA genotype or A allele of rs3091244 polymorphism was associated with Ankylosing Spondylitis Assessment Study group response criteria 20 scores (ASAS20) and Assessment in SpondyloArthritis international Society 40 response (ASAS40) improvement. In addition, AA genotype carriers showed significantly higher CRP levels compared with genotype GG carriers (16.3 vs 8.8 mg/L). CONCLUSION:CRP gene rs3091244 polymorphism is associated with an increased risk of AS. Additionally, rs3091244 polymorphism could serve as a biomarker for good response to etanercept treatment in AS.
| S-EPMC7439327 | biostudies-literature