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Nature Communications Feb 2022Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial...
Ferroptosis is a nonapoptotic cell death process that requires cellular iron and the accumulation of lipid peroxides. In progressive rheumatoid arthritis (RA), synovial fibroblasts proliferate abnormally in the presence of reactive oxygen species (ROS) and elevated lipid oxidation. Here we show, using a collagen-induced arthritis (CIA) mouse model, that imidazole ketone erastin (IKE), a ferroptosis inducer, decreases fibroblast numbers in the synovium. Data from single-cell RNA sequencing further identify two groups of fibroblasts that have distinct susceptibility to IKE-induced ferroptosis, with the ferroptosis-resistant fibroblasts associated with an increased TNF-related transcriptome. Mechanistically, TNF signaling promotes cystine uptake and biosynthesis of glutathione (GSH) to protect fibroblasts from ferroptosis. Lastly, low dose IKE together with etanercept, a TNF antagonist, induce ferroptosis in fibroblasts and attenuate arthritis progression in the CIA model. Our results thus imply that the combination of TNF inhibitors and ferroptosis inducers may serve as a potential candidate for RA therapy.
Topics: Animals; Arthritis, Experimental; Arthritis, Rheumatoid; Cells, Cultured; Disease Models, Animal; Drug Therapy, Combination; Etanercept; Ferroptosis; Fibroblasts; Glutathione; Humans; Imidazoles; Ketones; Lipid Peroxidation; Mice; Piperazines; Reactive Oxygen Species; Synovial Membrane; Tumor Necrosis Factor Inhibitors
PubMed: 35115492
DOI: 10.1038/s41467-021-27948-4 -
Arthritis & Rheumatology (Hoboken, N.J.) Jul 2019To examine the efficacy of methotrexate monotherapy relative to etanercept monotherapy and the value of combining methotrexate and etanercept for the treatment of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To 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).
METHODS
In 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.
RESULTS
Patients 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.
CONCLUSION
Etanercept 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.
Topics: Adult; Antirheumatic Agents; Arthritis, Psoriatic; Double-Blind Method; Drug Therapy, Combination; Etanercept; Female; Humans; Male; Methotrexate; Middle Aged; Tumor Necrosis Factor Inhibitors
PubMed: 30747501
DOI: 10.1002/art.40851 -
Arthritis & Rheumatology (Hoboken, N.J.) Jan 2020To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the... (Comparative Study)
Comparative Study Randomized Controlled Trial
OBJECTIVE
To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept.
METHODS
This randomized, open-label, parallel-group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open-label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group.
RESULTS
By week 4 of treatment, the serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow-up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77-1.43). Results were similar in sensitivity analyses and in the on-treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation.
CONCLUSION
The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non-CV safety of tocilizumab.
Topics: Aged; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Cardiovascular Diseases; Etanercept; Female; Humans; Male; Middle Aged; Myocardial Infarction; Proportional Hazards Models; Risk Factors; Stroke; Tumor Necrosis Factor Inhibitors
PubMed: 31469238
DOI: 10.1002/art.41095 -
Expert Opinion on Biological Therapy Jul 2020The management of a child with juvenile idiopathic arthritis (JIA) requires a combination of pharmacological, physical, and psychosocial therapies in order to induce... (Review)
Review
INTRODUCTION
The management of a child with juvenile idiopathic arthritis (JIA) requires a combination of pharmacological, physical, and psychosocial therapies in order to induce disease remission, by controlling articular and systemic inflammation. This review aims to provide a comprehensive discussion on the biological therapies currently in use in the treatment of JIA referring to existing recommendations and clinical evidence. We also discuss on the emerging biological drugs actually under consideration.
AREAS COVERED
Recent findings on immunological mechanisms involved in the pathogenesis of the disease allowed us to identify several specific targets for biologic therapies. A systematic literature review was conducted between January 1997 and January 2020 on PubMed including national and international guidelines and recommendations, trials and case-control studies.
EXPERT OPINION
There is now a plethora of therapies that are directed against variable targets, and the physician has to choose the most appropriate available medication in order to achieve early and sustained remission with as few side effects as possible. Research is advancing very fast in order to be more and more specific in suppressing inflammatory pathways without harming natural defenses. Finally, pharmacoeconomic considerations will also be very important to deal with, considering the high cost of most of these molecules.
Topics: Adalimumab; Antirheumatic Agents; Arthritis, Juvenile; Biological Products; Child; Etanercept; Humans; Interleukin 1 Receptor Antagonist Protein; Neoplasms; Recombinant Fusion Proteins
PubMed: 32116038
DOI: 10.1080/14712598.2020.1733524 -
JAMA Dermatology Sep 2021Biologics and targeted therapies, such as apremilast, are efficient treatments to manage moderate to severe psoriasis. More information about the risk of serious...
IMPORTANCE
Biologics and targeted therapies, such as apremilast, are efficient treatments to manage moderate to severe psoriasis. More information about the risk of serious infection is needed for the newest treatment options in a real-world setting.
OBJECTIVE
To assess the risk of serious infection among biologics and apremilast used to treat psoriasis, with etanercept as the comparator.
DESIGN, SETTING, AND PARTICIPANTS
This nationwide cohort study from France involved data from the National Health Data System covering approximately 99% of the French population. All adults with psoriasis, defined as receiving at least 2 prescriptions of a topical vitamin D derivative within a 2-year period, registered in the database between January 1, 2008, and May 31, 2019, were eligible. The study population included those who were new users of biologic agents or apremilast (ie, without any prescriptions of a biologic or apremilast during the previous year). Patients with HIV infection or a history of cancer, transplant, or serious infection were excluded. End of follow-up was January 31, 2020.
MAIN OUTCOME MEASURES
The primary end point was a serious infection in a time-to-event analysis using propensity score-weighted Cox proportional hazards regression models, estimating weighted hazard ratios (wHRs) and 95% CIs.
RESULTS
A total of 44 239 new users of biologic treatment were identified (mean [SD] age, 48.4 [13.8] years; 22 866 [51.7%] men; median follow-up, 12 months [interquartile range, 7-24 months]). A total of 29 618 (66.9%) were prescribed a tumor necrosis factor inhibitor first, 6658 (15.0%) an interleukin (IL) 12/23 inhibitor, 4093 (9.3%) an IL-17 inhibitor, 526 (1.2%) an IL-23 inhibitor, and 3344 (7.6%) apremilast. The total number of serious infections was 1656, and the overall crude incidence rate was 25.0 (95% CI, 23.8-26.2) per 1000 person-years. The most frequent serious infections were gastrointestinal infections (645 patients [38.9%]). After adjusting for time-dependent covariables, risk of serious infections was higher for new users of adalimumab (wHR, 1.22; 95% CI, 1.07-1.38) or infliximab (wHR, 1.79; 95% CI 1.49-2.16) vs etanercept, whereas ustekinumab was associated with a lower risk of having a serious infection (wHR, 0.79; 95% CI, 0.67-0.94). Risk of serious infections was not increased for new users of IL-17 and the IL-23 inhibitor guselkumab or apremilast vs etanercept. Risk of serious infections was increased with concomitant nonsteroidal anti-inflammatory drugs or systemic corticosteroids.
CONCLUSIONS AND RELEVANCE
In this cohort study of individuals with moderate to severe psoriasis, risk of serious infections was increased in new users of infliximab and adalimumab vs etanercept, whereas ustekinumab users had lower risk of having a serious infection but not new users of IL-17 and IL-23 inhibitors or apremilast. Other observational studies are needed to confirm results for the most recent drugs.
Topics: Adalimumab; Adult; Biological Products; Cohort Studies; Etanercept; HIV Infections; Humans; Male; Middle Aged; Psoriasis
PubMed: 34287624
DOI: 10.1001/jamadermatol.2021.2599 -
Arthritis Research & Therapy Nov 2019
Topics: Antirheumatic Agents; Etanercept; Humans; Infliximab; Lupus Erythematosus, Systemic; Tumor Necrosis Factor-alpha
PubMed: 31718696
DOI: 10.1186/s13075-019-2028-2 -
BioDrugs : Clinical Immunotherapeutics,... Dec 2017GP2015 is the second biosimilar of the reference p75 TNF receptor-Fc fusion protein etanercept. It is approved for use in all indications for which reference etanercept... (Review)
Review
GP2015 is the second biosimilar of the reference p75 TNF receptor-Fc fusion protein etanercept. It is approved for use in all indications for which reference etanercept is approved, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, plaque psoriasis and paediatric plaque psoriasis. GP2015 has similar physiochemical and pharmacodynamic properties to those of reference etanercept, and the pharmacokinetic biosimilarity of the agents has been shown in healthy volunteers. GP2015 demonstrated clinical efficacy equivalent to that of reference etanercept in patients with moderate-to-severe plaque psoriasis; the tolerability, safety and immunogenicity profiles of the two agents were also generally similar. Switching between GP2015 and reference etanercept had no impact on clinical efficacy, tolerability or immunogenicity. The role of reference etanercept in the management of inflammatory autoimmune conditions is well established and GP2015 provides an effective biosimilar alternative for patients requiring etanercept therapy.
Topics: Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; Autoimmune Diseases; Biosimilar Pharmaceuticals; Etanercept; Humans; Psoriasis; Spondylarthritis; Spondylitis, Ankylosing
PubMed: 28940172
DOI: 10.1007/s40259-017-0246-1 -
JAMA Network Open May 2023Biosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Biosimilar drugs are potentially lower-cost versions of biologics that may improve access to therapy. However, there is a lack of adequate systematic reviews demonstrating equivalence between these drugs for the treatment of rheumatoid arthritis (RA).
OBJECTIVES
To assess the efficacy, safety, and immunogenicity associated with biosimilars of adalimumab, etanercept, and infliximab compared with their reference biologics in patients with RA.
DATA SOURCES
MEDLINE via PubMed, Embase, Cochrane Central Register of Controlled Trials, and LILACS databases were searched from inception to September 2021.
STUDY SELECTION
Head-to-head randomized clinical trials (RCTs) of biosimilars of adalimumab, etanercept, and infliximab and their biologic reference drugs for RA were assessed.
DATA EXTRACTION AND SYNTHESIS
Two authors independently abstracted all data. Meta-analysis was conducted with bayesian random effects using relative risks (RRs) for binary outcomes and standardized mean differences (SMDs) for continuous outcomes, with 95% credible intervals (CrIs) and trial sequential analysis. Specific domains were assessed for the risk of bias in equivalence and noninferiority trials. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.
MAIN OUTCOMES AND MEASURES
Equivalence was tested using prespecified margins for the American College of Rheumatology criteria, with at least 20% improvement in the core set measures (ACR20) (ie, RR, 0.94 to 1.06), and for the Health Assessment Questionnaire-Disability Index (HAQ-DI) (ie, SMD, -0.22 to 0.22). Secondary outcomes included 14 items measuring safety and immunogenicity.
RESULTS
A total of 25 head-to-head trials provided data on 10 642 randomized patients with moderate to severe RA. Biosimilars met equivalence with reference biologics in terms of ACR20 response (24 RCTs with 10 259 patients; RR, 1.01; 95% CrI, 0.98 to 1.04; τ2 = 0.000) and change of HAQ-DI scores (14 RCTs with 5579 patients; SMD, -0.04; 95% CrI, -0.11 to 0.02; τ2 = 0.002) considering prespecified margins of equivalence. Trial sequential analysis found evidence for equivalence for ACR20 since 2017 and HAQ-DI since 2016. Overall, biosimilars were associated with similar safety and immunogenicity profiles compared with reference biologics.
CONCLUSION AND RELEVANCE
In this systematic review and meta-analysis, biosimilars of adalimumab, infliximab, and etanercept were associated with clinically equivalent treatment effects compared with their reference biologics for the treatment of RA.
Topics: Humans; Etanercept; Adalimumab; Infliximab; Biosimilar Pharmaceuticals; Antirheumatic Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Arthritis, Rheumatoid
PubMed: 37234004
DOI: 10.1001/jamanetworkopen.2023.15872 -
Journal of the American Academy of... Aug 2021To report the efficacy and safety of the approved ixekizumab (IXE) dose over 5 years from UNCOVER-3 (NCT01646177). (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To report the efficacy and safety of the approved ixekizumab (IXE) dose over 5 years from UNCOVER-3 (NCT01646177).
METHODS
Patients (N = 1346) were randomized 1:2:2:2 to receive subcutaneous injections of placebo, etanercept 50 mg twice weekly, or IXE 80 mg every 2 weeks or every 4 weeks after an initial dose of IXE 160 mg, respectively. At week 12, patients entered the long-term extension period with dosing of IXE every 4 weeks and could escalate to every 2 weeks after week 60. Efficacy was reported for the IXE every 2 weeks/every 4 weeks group of the intent-to-treat population. Safety was reported for patients who received at least 1 dose of IXE every 2 or every 4 weeks.
RESULTS
Using modified nonresponder imputation, 78.8%/67.1%/46.2% of patients receiving the approved dose of IXE every 2 weeks/every 4 weeks (n = 385) achieved ≥75%, ≥90%, or 100% improvement from baseline in the Psoriasis Area and Severity Index, respectively, at week 264; static Physician's Global Assessment score of 0/1 and 0 responses were 69.2% and 45.3%, respectively. Infections were the most observed treatment-emergent adverse event (72.7% of patients).
LIMITATIONS
Lack of comparison treatment group after week 12.
CONCLUSION
IXE demonstrates sustained efficacy and consistent safety through 264 weeks in patients using the approved dose.
Topics: Antibodies, Monoclonal, Humanized; Dermatologic Agents; Double-Blind Method; Drug Administration Schedule; Etanercept; Humans; Injections, Subcutaneous; Psoriasis; Time Factors; Treatment Outcome
PubMed: 33253833
DOI: 10.1016/j.jaad.2020.11.022 -
Annals of Allergy, Asthma & Immunology... Sep 2022
Topics: Etanercept; Humans; Stevens-Johnson Syndrome
PubMed: 35988972
DOI: 10.1016/j.anai.2022.06.025