-
Frontiers in Immunology 2018Systemic sclerosis (SSc) is an autoimmune T-cell disease that is characterized by pathological fibrosis of the skin and internal organs. SSc is considered a prototype... (Review)
Review
Systemic sclerosis (SSc) is an autoimmune T-cell disease that is characterized by pathological fibrosis of the skin and internal organs. SSc is considered a prototype condition for studying the links between autoimmunity and fibrosis. Costimulatory pathways such as CD28/CTLA-4, ICOS-B7RP1, CD70-CD27, CD40-CD154, or OX40-OX40L play an essential role in the modulation of T-cell and inflammatory immune responses. A growing body of evidence suggests that T-cell costimulation signals might be implicated in the pathogenesis of SSc. CD28, CTLA-4, ICOS, and OX40L are overexpressed in patients with SSc, particularly in patients with cutaneous diffuse forms. In pre-clinical models of SSc, T-cell costimulation blockade with abatacept (CTLA-4-Ig) prevented and induced the regression of inflammation-driven dermal fibrosis, improved digestive involvement, prevented lung fibrosis, and attenuated pulmonary hypertension in complementary models of SSc. Likewise, potent anti-fibrotic effects were seen with the blockade of OX40L by reducing the infiltration of inflammatory cells into lesional tissues leading to decreased fibroblast activation. Concerning clinical effects, a preliminary observational study suggested some effectiveness of abatacept on inflammatory joint involvement, whereas clinical improvement of skin fibrosis was observed in a small placebo-controlled randomized trial. Currently there is one ongoing phase II clinical trial assessing the efficacy of abatacept in SSc (ASSET trial, NCT02161406). Overall, given the lack of available effective agents and the known toxic effects of immunosuppressive agents approved for use in SSc, costimulatory pathways offer the advantage of a targeted approach to costimulatory signals and potentially a better safety profile.
Topics: Abatacept; Autoimmune Diseases; Clinical Trials, Phase II as Topic; Costimulatory and Inhibitory T-Cell Receptors; Fibrosis; Humans; Immunosuppressive Agents; Lymphocyte Activation; Scleroderma, Systemic; Skin; T-Lymphocytes; Treatment Outcome
PubMed: 30619351
DOI: 10.3389/fimmu.2018.02998 -
Reumatologia Clinica 2014To review the clinical evidence on subcutaneous (sc) abatacept and to formulate recommendations in order to clear up points related to its use in rheumatology. (Review)
Review
OBJECTIVE
To review the clinical evidence on subcutaneous (sc) abatacept and to formulate recommendations in order to clear up points related to its use in rheumatology.
METHOD
An expert panel of rheumatologists objectively summarized the evidence on the mechanism of action, practicality, effectiveness, and safety of abatacept sc and formulated recommendations after a literature review.
RESULTS
The efficacy and safety of abatacept sc was studied in 7 clinical trials, 3 double-blind, 3 open, and one mixed, with the following endpoints: comparison against abatacept iv, impact on immunogenicity, effect of replacing iv by sc, abatacept sc in monotherapy, and non-inferiority to adalimumab. No significant differences were found between sc and iv abatacept on efficacy or safety. The development of sc abatacept has allowed a complementary study to the iv, formulation, thus making the abatacept profile better defined.
CONCLUSIONS
This is a practical document to supplement the summary of product characteristics. In summary, abatacept sc is presented as an effective and safe drug and, therefore, as an alternative for use within the broad armamentarium the rheumatologist has to treat RA. It also has the advantage of being the only biological agent that can be administered iv and sc which can facilitate its use in certain patients.
Topics: Abatacept; Antirheumatic Agents; Humans; Injections, Subcutaneous; Practice Guidelines as Topic; Rheumatic Diseases
PubMed: 24387951
DOI: 10.1016/j.reuma.2013.11.006 -
Science Translational Medicine Mar 2023Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe...
Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti-CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4-Ig for their binding to clinically approved anti-CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti-CTLA-4 and anti-PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti-CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti-CTLA-4-induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4-targeting ICIs.
Topics: Humans; Abatacept; Immunotherapy; Ipilimumab; Immune Checkpoint Inhibitors; Nivolumab
PubMed: 36857433
DOI: 10.1126/scitranslmed.abm5663 -
Respiration; International Review of... 2020Interstitial lung diseases (ILDs) associated with autoimmune or systemic disease are increasingly recognized and our pathophysiological understanding rapidly expanding.... (Review)
Review
Interstitial lung diseases (ILDs) associated with autoimmune or systemic disease are increasingly recognized and our pathophysiological understanding rapidly expanding. Treatment modalities, however, are still mainly driven by established disease-modifying antirheumatic drugs (DMARDs) where, despite decades of experience of their use in the underlying diseases such as rheumatoid arthritis, mostly ret-rospective data exist informing their effect on the course of interstitial lung disease (ILD). In recent years, randomized trials investigating the effects of biological DMARDs (bDMARDs) have been completed or are currently running, generating new treatment options for often relentlessly progressive diseases. Herein, we summarize the evidence and current use of both synthetic DMARDs and bDMARDs in the context of ILDs associated with autoimmune/systemic disease.
Topics: Abatacept; Antibodies, Monoclonal; Antirheumatic Agents; Autoimmune Diseases; Humans; Immunomodulation; Immunosuppressive Agents; Lung Diseases, Interstitial; Tumor Necrosis Factor Inhibitors
PubMed: 33271551
DOI: 10.1159/000511200 -
BioDrugs : Clinical Immunotherapeutics,... Aug 2017CD4CD25FoxP3 T regulatory cells (Tregs) are immunodominant suppressors in the immune system. Tregs use various mechanisms to control immune responses. Preclinical data... (Review)
Review
CD4CD25FoxP3 T regulatory cells (Tregs) are immunodominant suppressors in the immune system. Tregs use various mechanisms to control immune responses. Preclinical data from animal models have confirmed the huge therapeutic potential of Tregs in many immune-mediated diseases. Hence, these cells are now on the road to translation to cell therapy in the clinic as the first clinical trials are accomplished. To date, clinical research has involved mainly hematopoietic stem cell transplantations, solid organ transplantations, and autoimmunity. Despite difficulties with legislation and technical issues, treatment is constantly evolving and may soon represent a valid alternative for patients with diseases that are currently incurable. This review focuses on the basic and clinical experience with Tregs with adoptive transfer of these cells, primarily from clinical trials, as well as on perspectives on clinical use and technical problems with implementing the therapy.
Topics: Abatacept; Animals; Cell Transplantation; Clinical Trials as Topic; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mice; Organ Transplantation; T-Lymphocytes, Regulatory
PubMed: 28540499
DOI: 10.1007/s40259-017-0228-3 -
Current Opinion in Rheumatology Sep 2021Biologics and novel targeted therapeutics have transformed the management of pediatric rheumatic diseases over the past two decades; however, questions about short-term... (Review)
Review
PURPOSE OF REVIEW
Biologics and novel targeted therapeutics have transformed the management of pediatric rheumatic diseases over the past two decades; however, questions about short-term and long-term safety remain. Safety data gathered from recent clinical trials, long-term extensions of prior trials, registries, and other real-world evidence are summarized here for biologics and novel therapeutics commonly prescribed for pediatric rheumatic diseases.
RECENT FINDINGS
With nearly 20 years of therapeutic experience, tumor necrosis inhibitors (TNFi) are generally well tolerated, although infections, malignancy, and development of new autoimmunity remain a concern. Risk of infections may be higher in IL-1 and IL-6 inhibitors, and lower in abatacept, compared with TNFi. Safety data for B-cell-targeted therapeutics and janus kinase inhibitors are emerging, but remain limited, especially in children.
SUMMARY
Biologic and novel targeted therapeutics offer a promising future for children with pediatric rheumatic disease. However, long-term safety data in children remain limited for several agents. With any therapeutic option, both short-term and long-term safety concerns must be weighed against individual clinical needs when choosing the optimal treatment for each child.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Registries; Tumor Necrosis Factor-alpha
PubMed: 34397604
DOI: 10.1097/BOR.0000000000000811 -
PloS One 2022The number of biological DMARDs (bDMARDs) used in elderly patients with rheumatoid arthritis (RA) has increased in recent years. We aimed to compare the drug retention...
BACKGROUND
The number of biological DMARDs (bDMARDs) used in elderly patients with rheumatoid arthritis (RA) has increased in recent years. We aimed to compare the drug retention rates and safety of abatacept (ABT) and tocilizumab (TCZ) in elderly patients with RA.
METHODS
A total 125 elderly patients with RA (>65 years) who began therapy with either ABT (n = 47) or TCZ (n = 78) between 2014 and 2021 at our institute were enrolled. We compared the drug retention rate and clinical response at 24 weeks between elderly patients with RA treated with ABT and those treated with TCZ. Adverse events (AEs) and the reasons for drug discontinuation were assessed.
RESULTS
There was no significant difference in demographic characteristics except for the use of glucocorticoid between the ABT and TCZ groups. There was no significant difference in the drug retention rate between the ABT and TCZ groups. Furthermore, there was no significant difference in the discontinuation rates due to the lack of effectiveness between these two groups. The proportions of the patients archiving low disease activity at 24 weeks did not differ significantly between the two groups. Whereas, the discontinuation rates due to AEs, including interstitial lung disease (ILD), seemed higher in the TCZ group than in the ABT group. In TCZ-treated group, the concomitant use of methotrexate (MTX) significantly increased the incidences of AEs leading to the discontinuation of TCZ. Whereas these was no significant impact of concomitant use of MTX on the incidences of AEs leading to discontinuation in ABT-treated group.
CONCLUSIONS
In elderly patients with RA treated with ABT and TCZ, drug retention rates were equivalent between the two groups. There were some differences in safety profiles between ABT and TCZ, and the rates of discontinuation due to AEs, including ILD, seem to be lower with ABT than with TCZ in elderly patients with RA.
Topics: Abatacept; Aged; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Arthritis, Rheumatoid; Glucocorticoids; Humans; Methotrexate; Treatment Outcome
PubMed: 36121851
DOI: 10.1371/journal.pone.0274775 -
Arthritis Research & Therapy Jun 2022In previous clinical trials, patients with active rheumatoid arthritis (RA) treated with upadacitinib (UPA) have improved patient-reported outcomes (PROs). This post hoc...
Patient-reported outcomes of upadacitinib versus abatacept in patients with rheumatoid arthritis and an inadequate response to biologic disease-modifying antirheumatic drugs: 12- and 24-week results of a phase 3 trial.
BACKGROUND
In previous clinical trials, patients with active rheumatoid arthritis (RA) treated with upadacitinib (UPA) have improved patient-reported outcomes (PROs). This post hoc analysis of SELECT-CHOICE, a phase 3 clinical trial, evaluated the impact of UPA vs abatacept (ABA) with background conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) on PROs in patients with RA with inadequate response or intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR).
METHODS
Patients in SELECT-CHOICE received UPA (oral 15 mg/day) or ABA (intravenous). PROs evaluated included Patient Global Assessment of Disease Activity (PtGA) by visual analog scale (VAS), patient's assessment of pain by VAS, Health Assessment Questionnaire Disability Index (HAQ-DI), morning stiffness duration and severity, 36-Item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Work Productivity and Activity Impairment (WPAI), and EQ-5D 5-Level (EQ-5D-5L) index score. Least squares mean (LSM) changes from baseline to weeks 12 and 24 were based on an analysis of covariance model. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCID) were compared using chi-square tests.
RESULTS
Data from 612 patients were analyzed (UPA, n=303; ABA, n=309). Mean age was 56 years and mean disease duration was 12 years. One-third received ≥2 prior bDMARDs and 72% received concomitant methotrexate at baseline. At week 12, UPA- vs ABA-treated patients had significantly greater improvements in PtGA, pain, HAQ-DI, morning stiffness severity, EQ-5D-5L, 2/4 WPAI domains, and 3/8 SF-36 domains and Physical Component Summary (PCS) scores (P<0.05); significant differences persisted at week 24 for HAQ-DI, morning stiffness severity, SF-36 PCS and bodily pain domain, and WPAI activity impairment domain. At week 12, significantly more UPA- vs ABA-treated patients reported improvements ≥MCID in HAQ-DI (74% vs 64%) and SF-36 PCS (79% vs 66%) and 4/8 domain scores (P<0.05).
CONCLUSIONS
At week 12, UPA vs ABA treatment elicited greater improvements in key domains of physical functioning, pain, and general health and earlier improvements in HAQ-DI. Overall, more UPA- vs ABA-treated patients achieved ≥MCID in most PROs at all timepoints; however, not all differences were statistically significant. These data, however, highlight the faster response to UPA treatment.
TRIAL REGISTRATION
NCT03086343 , March 22, 2017.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Biological Products; Double-Blind Method; Heterocyclic Compounds, 3-Ring; Humans; Methotrexate; Middle Aged; Pain; Patient Reported Outcome Measures; Quality of Life; Treatment Outcome
PubMed: 35751108
DOI: 10.1186/s13075-022-02813-x -
Journal of Medicine and Life 2016Targeting the pathogenic pathway of chronic inflammation represents an unmet challenge for controlling disease activity, preventing functional disability, and... (Review)
Review
Targeting the pathogenic pathway of chronic inflammation represents an unmet challenge for controlling disease activity, preventing functional disability, and maintaining an adequate quality of life in patients with rheumatic diseases. Abatacept, a novel molecule that inhibits co-stimulation signal, induces an inhibitory effect on the T-cells. This will further interfere with the activity of several cell lines, leading to the normalization of the immune response. In the latest years, abatacept has been extensively investigated in studies of rheumatoid arthritis for which it was recently approved as a second line biologic treatment in Romania. This review presents the clinical efficacy of abatacept in several rheumatic diseases and highlights the safety profile of this biological agent. : ACR = American College of Rheumatology, ADR = Adverse drug reaction, APC = antigen presenting cell, ApS = psoriatic arthritis, CRP = C reactive protein, CTLA-4 = Cytotoxic T-Cell Lymphocyte Antigen-4, DAS = Disease activity score, DMARDs = Disease modifying antirheumatic drugs, EMA = European Medicine Agency, EULAR = European League Against Rheumatism, FDA = Food and Drugs Administration, HBV = Hepatitis B virus, JIA = Juvenile Idiopathic Arthritis, LDA = low disease activity (LDA), MRI = magnetic resonance imaging (MRI), MTX = methotrexate, RA = rheumatoid arthritis, RCT = randomized controlled trial, SS = Sjogren's syndrome, TCR = T cell receptor.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Psoriatic; Arthritis, Rheumatoid; CTLA-4 Antigen; Humans; Lupus Nephritis; Methotrexate; Quality of Life; Rheumatic Diseases
PubMed: 27974925
DOI: No ID Found -
Scientific Reports Dec 2023Although biologics have their own characteristics, there are no clear criteria for selecting them to treat the patients with rheumatoid arthritis. To assist in selecting...
Although biologics have their own characteristics, there are no clear criteria for selecting them to treat the patients with rheumatoid arthritis. To assist in selecting biologics, we investigated the retention rates of biologics at our institution. We examined retention rates, and reasons for dropout for biologics in 393 cases and 605 prescriptions (of which 378 prescriptions were as naive) at our hospital since October 2003. Throughout the entire course of the study, etanercept (ETN) was the most frequently used biologic, followed by adalimumab (ADA) and tocilizumab (TCZ). When narrowed down to the later period from 2010, ETN was still the most used, followed by TCZ and abatacept (ABT). When the retention rates were compared in biologic naive patients, the retention rates were TCZ, ABT, ETN, certolizumab pegol (CZP), golimumab (GLM), infliximab (IFX), and ADA, in that order. The retention rates were better with the first use of each biologic. The main reasons for dropout were primary ineffectiveness, secondary ineffectiveness, and infection. ETN was the most used biologic in our hospital, with an increasing trend toward the use of non-TNF inhibitors. Retention rates were higher in non-TNF inhibitors.
Topics: Humans; Antirheumatic Agents; Biological Products; Treatment Outcome; Arthritis, Rheumatoid; Etanercept; Adalimumab; Infliximab; Abatacept
PubMed: 38040839
DOI: 10.1038/s41598-023-48537-z