Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis Rubbert-Roth, Andrea; Enejosa, Jeffrey; Pangan, Aileen L ...
New England journal of medicine/The New England journal of medicine,
10/2020, Letnik:
383, Številka:
16
Journal Article
Recenzirano
Odprti dostop
In a 24-week trial involving patients with rheumatoid arthritis that was refractory to biologic agents, the JAK1 inhibitor upadacitinib was superior to the T-cell costimulation modulator abatacept in ...reducing disease activity as assessed by a composite measure of joint changes and C-reactive protein level.
The literature on eco-innovation provides extensive contributions for the achievement of the long-term sustainability, which implies an urgent need for holistic changes around business processes. In ...this sense, several models have been proposed in order to help companies achieve greater understanding of the dynamics of eco-innovation or even structure and facilitate the integration of sustainable processes within them. These eco-innovation models may be classified into different ways, because they not always have the same approach or common language, in terms of applicability and purpose. Classification is an essential tool to facilitate the diffusion of this field of knowledge and to achieve a higher maturity level on the concept of eco-innovation. Through a systematic literature review on eco-innovation models, this study aims to present gaps and opportunities for the advancement of the field, outlining promising directions regarding potential research areas, contents and predominant characteristics for new eco-innovation models. This paper has been developed upon an analytical framework in order to explore the diversity of eco-innovations models and to present suggestions according to several classification criteria (research area, model approach, model characterization, application sectors, generalization level, among others). In general, the models that have been analysed reveal a predominance of generic and descriptive characteristics. Moreover, there is a gap of eco-innovation models related to organizational structural factors and to social aspects of sustainability. Opportunities for normative models can be highlighted, such as methods, tools and models can be adapted to systems and industrial segments. Therefore, this field of knowledge still offers broad possibilities for new research and new eco-innovation models.
•Review and classification framework of eco-innovation models.•Classification of 45 eco-innovation models in 6 major research areas.•Predominance of eco-innovation models with generic and descriptive characteristics.•Gap of eco-innovation models related to social aspects of sustainability.•Gap of eco-innovation models related to structural factors of the company.
Objective
The SELECT‐EARLY trial was undertaken to study the effect of upadacitinib, an oral, reversible Janus kinase 1–selective inhibitor, as monotherapy in patients with predominantly early ...rheumatoid arthritis who were naive for or had limited exposure to methotrexate (MTX).
Methods
Patients (n = 947) were randomized 1:1:1 to receive once‐daily doses of upadacitinib 15 mg or 30 mg or weekly MTX (7.5–20 mg/week) for 24 weeks. The primary end points were the proportion of patients who met the American College of Rheumatology 50% (ACR50) improvement criteria at week 12, and the proportion in whom a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <2.6 was achieved at week 24. Data are presented through week 24.
Results
At baseline, the median disease duration was 0.5 years (range 0–44 years). A total of 840 patients (89%) completed 24 weeks of treatment. The study met both primary end points for upadacitinib 15 mg and 30 mg versus MTX (ACR50 was achieved at week 12 in 52% and 56% of patients, respectively, versus 28% P < 0.001, and DAS28‐CRP <2.6 was achieved at week 24 in 48% and 50% of patients, respectively, versus 19% P < 0.001). Statistically significant and clinically meaningful improvements in multiple patient‐reported outcomes (PROs) were recorded for both upadacitinib doses versus MTX. Overall, 88% of patients receiving upadacitinib 15 mg and 89% of patients receiving 30 mg, respectively, had no radiographic progression (modified total Sharp score ≤0) compared to 78% of those receiving MTX (P < 0.01). Through week 24, the frequency of treatment‐emergent adverse events was similar between the MTX arm (65%) and upadacitinib 15 mg arm (64%), but was slightly higher in the upadacitinib 30 mg arm (71%). Six deaths were reported (2 in the upadacitinib 15 mg arm, 3 in the upadacitinib 30 mg arm, and 1 in the MTX arm).
Conclusion
Our findings indicate that patients receiving either dose of upadacitinib monotherapy experienced significant improvements in clinical, radiographic, and PROs compared to patients receiving MTX.
To assess the incidence of anti-drug antibodies (ADA) in patients with rheumatoid arthritis (RA) treated with the TNF inhibitors etanercept (ETN), adalimumab (ADL), or infliximab (IFX), and determine ...the potential relationship with trough drug concentration, efficacy, and patient-reported outcomes.
This multi-national, non-interventional, cross-sectional study (NCT01981473) enrolled adult patients with RA treated continuously for 6-24 months with ETN, ADL, or IFX. ADA and trough drug concentrations were measured by independent assays ≤2 days before the next scheduled dose. Efficacy measurements included Disease Activity Score 28-joint count (DAS28), low disease activity (LDA), remission, and erythrocyte sedimentation rate (ESR). Targeted medical histories of injection site/infusion reactions, serum sickness, and thromboembolic events were collected.
Baseline demographics of the 595 patients (ETN: n = 200; ADL: n = 199; IFX: n = 196) were similar across groups. The mean duration of treatment was 14.6, 13.5, and 13.1 months for ETN, ADL, and IFX, respectively. All ETN-treated patients tested negative for ADA, whereas 31.2% and 17.4% patients treated with ADL and IFX, respectively, tested positive. In ADL- or IFX-treated patients, those with ADA had significantly lower trough drug concentrations. There were negative correlations between trough drug levels and both CRP and ESR in ADL- and IFX-treated patients. DAS28-ESR LDA and remission rates were higher in patients without ADA. The rate of targeted medical events reported was low.
ADA were detected in ADL- and IFX-treated but not ETN-treated patients. Patients without ADA generally showed numerically better clinical outcomes than those with ADA.
This study was registered on www.ClinicalTrials.gov (NCT01981473).
The aim of this study was to evaluate the function of a cohort of patients with rheumatoid arthritis (RA) from the core set of the International Classification of Functioning and Health (ICF) for RA ...over 12 months. We used prospective longitudinal data to conduct a cohort study among a well-characterized group of RA patients. Ninety RA patients aged between 40 and 70 years were included in the study. Patients were evaluated at baseline and after 12 months. Age, disease duration, current smoking, erosions, disease activity, functional test, disability and physical activity were evaluated. Then, the ICF core set classification for RA was applied. 81 patients completed the assessments, the majority of patients were female (88.9%) and the mean age was 56.5 ± 7.3 years. At baseline, the median disease activity was 3.0. There was a statistically significant (p < 0.02) improvement in "Exercise tolerance functions" over 12 months and also a statistically significant (p < 0.001) decrease in "Muscle strength functions" over 12 months. The activity and participation domain showed a weak correlation with the clinical data of the DAS28-PCR (p<0.02). We conclude that relevant aspects of the ICF Core Set for RA were able to adequately express the physical and functional factors of the RA cohort. This tool provides a common language for the interdisciplinary team, which can enhance the use of timely interventions to prevent physical disability in clinical practice.
Objective To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained ...remission. Methods ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued. Results Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%). Conclusions Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement. Trial registration number NCT00810199.
Objective To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24. Methods ACT-RAY was a ...double-blind, 3-year trial. Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy). Tocilizumab 8 mg/kg was administered every 4 weeks. Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28>3.2. Results 556 patients were randomised; 85% completed 52 weeks. The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms. Overall, week 24 results were maintained or further improved at week 52 in both arms. Some endpoints favoured the add-on strategy. Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression. At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%). Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3× upper limit of normal were observed in 11% of add-on and 3% of switch patients. Conclusions Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add-on and switch strategies led to meaningful clinical and radiographic responses.
Background
Low muscle mass occurs in patients with rheumatoid arthritis without weight loss; this condition is referred as rheumatoid cachexia. The aim of the current study was to perform a ...systematic review with meta‐analysis to determine the rheumatoid cachexia prevalence.
Methods
A systematic review with meta‐analysis of observational studies published in English, between 1994 and 2016, was conducted using MEDLINE (via PubMed) and other relevant sources. Search strategies were based on pre‐defined keywords and medical subject headings. The methodological quality of included studies was assessed using the Newcastle‐Ottawa Scale. Meta‐analysis was used to estimate the prevalence, and because studies reported different methods and criteria to estimate body composition and prevalence of rheumatoid cachexia, subgroup analyses were performed. Meta‐regression adjusted for the 28‐joint disease activity score and disease duration (years) was performed (significance level at P ≤ 0.05).
Results
Of 136 full articles (one duplicate publication) screened for inclusion in the study, eight were included. The estimated overall prevalence of rheumatoid cachexia was 19% 95% confidence interval (CI) 07–33%. This prevalence was 29% (95% CI 15–46%) when body composition was measured by dual‐energy X‐ray absorptiometry. When the diagnostic criteria were fat‐free mass index below the 10th percentile and fat mass index above the 25th percentile, rheumatoid cachexia prevalence was 32% (95% CI 14–52%). The 28‐joint disease activity score and disease duration had no influence on the estimated prevalence of rheumatoid cachexia (P > 0.05). Most studies were rated as having moderate methodological quality.
Conclusions
Meta‐analysis showed a prevalence of rheumatoid cachexia of 15‐32%, according to different criteria, demonstrating that this condition is a frequent comorbidity of rheumatoid arthritis. To better understand its clinical impact, more studies using standardized definitions and prospective evaluations are urgently needed.
Abstract
Introduction
Rheumatoid arthritis (RA) is an autoimmune disease, characterized by chronic and systemic inflammation. Besides, it is known that RA patients may present several comorbidities, ...such as sarcopenia, a condition where patients present both muscle mass and muscle quality impairment. RA treatment is mostly pharmacological and consists in controlling systemic inflammation and disease activity. Despite that, the effect of pharmacological treatment on sarcopenia is not well characterized.
Objective
To summarize the effects of disease-modifying anti-rheumatic drugs (DMARDs) on skeletal muscle tissue in rheumatoid arthritis (RA) patients.
Methods
A systematic review of randomized clinical trials and observational studies was conducted using MEDLINE, Embase, Cochrane Library, and Web of Science. We selected studies with rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs (DMARDs) that analyzed muscle mass parameters such as lean mass and appendicular lean mass. Methodological quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Standardized mean difference (SMD) and 95% confidence intervals (CI) were set. A meta-analysis of observational studies was performed using the R software, and we considered significant statistics when
p
< 0.05.
Results
Nine studies were included in this systematic review. In the meta-analysis, DMARD treatment had no positive difference (
p
= 0.60) in lean mass. In the same way, in the appendicular lean mass parameter, our results showed that DMARDs did not have changes between baseline and post-treatment analysis (
p
= 0.93).
Conclusion
There is no evidence of a significant effect of DMARD therapy, either synthetic or biological, on muscle mass. However, this association should be investigated with more studies.
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