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Arthritis Research & Therapy Apr 2024We aimed to reveal the effect of abatacept (ABT) on atherosclerosis in rheumatoid arthritis (RA) patients, 3-year efficacy for arthritis, and safety in a population of... (Observational Study)
Observational Study
Long-term effects of abatacept on atherosclerosis and arthritis in older vs. younger patients with rheumatoid arthritis: 3-year results of a prospective, multicenter, observational study.
BACKGROUND
We aimed to reveal the effect of abatacept (ABT) on atherosclerosis in rheumatoid arthritis (RA) patients, 3-year efficacy for arthritis, and safety in a population of older vs. younger patients.
METHODS
In this open-label, prospective, observational study, patients were stratified into four groups: younger (20-64 years old) and older (≥ 65 years) patients taking ABT (AY and AO) and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) (CY and CO). Primary endpoints were change from baseline in mean intima-media thickness (IMT) of the common carotid artery, IMT max (bulbus, bifurcation, and internal and common carotid artery), and plaque score at Week 156. Disease activity, retention rate, and adverse effects were also evaluated.
RESULTS
The ABT group (AY + AO) tended to have smaller increases in mean IMT, max IMT, and plaque score than the csDMARD group (CY + CO) at Week 156, although the differences between groups were not statistically significant. Multivariate analysis showed significantly lower increases in plaque score with ABT than with csDMARDs, only when considering disease activity at 156 weeks (p = 0.0303). Proportions of patients with good or good/moderate European League Against Rheumatism response were higher in the ABT group, without significant difference between older and younger patients. No significant differences were observed in ABT retention rates between older and younger patients. Serious adverse effects, especially infection, tended to be more frequent with ABT than with csDMARDs, although no significant differences were found.
CONCLUSIONS
ABT may decelerate atherosclerosis progression and may be useful for patients with high risk of cardiovascular disease, such as older patients.
TRIAL REGISTRATION NUMBER
UMIN000014913.
Topics: Humans; Aged; Young Adult; Adult; Middle Aged; Abatacept; Carotid Intima-Media Thickness; Prospective Studies; Arthritis, Rheumatoid; Antirheumatic Agents; Atherosclerosis; Treatment Outcome
PubMed: 38627782
DOI: 10.1186/s13075-024-03323-8 -
Seminars in Arthritis and Rheumatism Aug 2020Localized scleroderma (LS) is a rare chronic immune-mediated skin condition of unknown etiology characterized by an inflammatory response in the skin and subcutaneous... (Review)
Review
BACKGROUND
Localized scleroderma (LS) is a rare chronic immune-mediated skin condition of unknown etiology characterized by an inflammatory response in the skin and subcutaneous tissues resulting in collagen deposition and subsequent fibrosis. There is no cure for LS. No therapies have been licensed specifically for the treatment of LS and the clinical management of the disease remains largely empirical. Abatacept, a recombinant fusion protein interfering with the T-cell costimulatory pathway, has been reported to be effective in adult cases of LS. We report the successful use of abatacept in a juvenile localized scleroderma (jLS) cohort and conduct a systematic literature review to evaluate the evidence supporting the use of abatacept in the treatment of LS.
METHODS
We compiled retrospectively the clinical data on 8 cases of jLS that were treated with abatacept in our academic center. A systematic review protocol was developed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA-P) guidelines and has been registered with the international prospective register of systematic reviews (PROSPERO). Standardized searches of MEDLINE/PubMed and EMBASE were undertaken to identify studies reporting the use of abatacept in the treatment of LS. Heterogeneity in study design, interventions and reported outcomes necessitated a qualitative data synthesis.
RESULTS
The use of abatacept was effective and safe in our cohort of jLS patients. Our standardized searches identified 30 articles, of which 3 deemed eligible for full data extraction. All 3 studies were small (total of 18 patients; mean 6 subjects per study), single center, open-label, uncontrolled and non-randomized. The Risk of Bias Assessment Tool for Non-randomized Studies (RoBANS) identified high risk-of bias for confounding variables and blinding of assessors in each of the 3 studies evaluated and in our pediatric case series.
CONCLUSIONS
The evidence-base to support the use of abatacept in the treatment of LS is currently limited and clinical practice guidelines should take a measured approach to such recommended therapy. Nonetheless, as the empirical evidence on the clinical effectiveness of abatacept in the treatment of LS accumulates, a double-blind placebo-controlled randomized clinical trial is necessary to formally evaluate the observations documented by case-based reports.
Topics: Abatacept; Adolescent; Child; Child, Preschool; Disease Progression; Female; Humans; Male; Scleroderma, Localized; Treatment Outcome
PubMed: 32504991
DOI: 10.1016/j.semarthrit.2020.03.020 -
Pediatric Nephrology (Berlin, Germany) Jan 2023Primary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes....
Benefit of B7-1 staining and abatacept for treatment-resistant post-transplant focal segmental glomerulosclerosis in a predominantly pediatric cohort: time for a reappraisal.
BACKGROUND
Primary FSGS manifests with nephrotic syndrome and may recur following KT. Failure to respond to conventional therapy after recurrence results in poor outcomes. Evaluation of podocyte B7-1 expression and treatment with abatacept (a B7-1 antagonist) has shown promise but remains controversial.
METHODS
From 2012 to 2020, twelve patients developed post-KT FSGS with nephrotic range proteinuria, failed conventional therapy, and were treated with abatacept. Nine/twelve (< 21 years old) experienced recurrent FSGS; three adults developed de novo FSGS, occurring from immediately, up to 8 years after KT. KT biopsies were stained for B7-1.
RESULTS
Nine KTRs (75%) responded to abatacept. Seven of nine KTRs were B7-1 positive and responded with improvement/resolution of proteinuria. Two patients with rFSGS without biopsies resolved proteinuria after abatacept. Pre-treatment UPCR was 27.0 ± 20.4 (median 13, range 8-56); follow-up UPCR was 0.8 ± 1.3 (median 0.2, range 0.07-3.9, p < 0.004). Two patients who were B7-1 negative on multiple KT biopsies did not respond to abatacept and lost graft function. One patient developed proteinuria while receiving belatacept, stained B7-1 positive, but did not respond to abatacept.
CONCLUSIONS
Podocyte B7-1 staining in biopsies of KTRs with post-transplant FSGS identifies a subset of patients who may benefit from abatacept. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Adult; Child; Humans; Young Adult; Glomerulosclerosis, Focal Segmental; Abatacept; Proteinuria; Podocytes; Staining and Labeling; Recurrence
PubMed: 35507150
DOI: 10.1007/s00467-022-05549-7 -
Advances in Therapy Feb 2016The purpose of the present study was to determine whether the abatacept autoinjector can be used by the intended population without patterns of preventable use errors,...
INTRODUCTION
The purpose of the present study was to determine whether the abatacept autoinjector can be used by the intended population without patterns of preventable use errors, and is acceptable when assessed against key user needs.
METHODS
Two independently conducted simulated-use studies, with no active drug administered, quantified use errors and evaluated the abatacept autoinjector and competitor devices on key attributes (comfort, control, ease of use, confidence of dose) and overall acceptability. Autoinjector preference was also assessed. Participants were patients with rheumatoid arthritis, caregivers, and healthcare professionals (HCPs). Participants were informed that a new rheumatoid arthritis autoinjector was being tested but were blinded to the intended drug and sponsor identity.
RESULTS
In the formative (pre-validation) study (n = 54), two high-priority use errors occurred, both of which resulted from protocol non-compliance rather than mental confusion or physical limitations. In the summative (validation) study (n = 99), one high-priority use error occurred; this was deemed a simulated-use study artifact as participant behavior was guided by actual experience associated with the feel of drug delivery into the skin rather than by protocol, so no mitigation steps were considered necessary. Across user groups, average scores were consistently high for the pre-defined key attributes. Overall acceptability scores (7-point scale) were significantly higher for the abatacept versus competitor autoinjectors-formative study: patients 6.7 vs 5.2 (P = 0.0001), caregivers 7.0 vs 4.6 (P = 0.0093), HCPs 6.8 vs 5.1 (P = 0.0020); summative study: patients 6.5 vs 5.9 (P = 0.0404), caregivers 6.8 vs 5.8 (P = 0.0047), HCPs 6.8 vs 5.1 (P = 0.0002). The abatacept autoinjector was preferred to competitor devices: patients 85.7% vs 14.3% (P = 0.00002), caregivers 84.2% vs 15.8% (P = 0.00443), HCPs 95.0% vs 5.0% (P = 0.00004). Positive experiences with the abatacept autoinjector were attributed to the rubberized grip, device size, visualization of dose progression, button ergonomics, and ease of use.
CONCLUSION
The abatacept autoinjector demonstrated usability without patterns of preventable use errors, and with high acceptability ratings across all key attributes assessed. Preference over competitor autoinjectors was due to device ergonomics, visualization of dose progression, confidence of dose delivery, and overall ease of use.
FUNDING
Bristol-Myers Squibb.
Topics: Abatacept; Adolescent; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Disease Progression; Drug Delivery Systems; Female; Humans; Male; Middle Aged; Needles; Patient Preference; Treatment Outcome; Young Adult
PubMed: 26833303
DOI: 10.1007/s12325-016-0286-9 -
BMC Musculoskeletal Disorders Jun 2021To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis... (Observational Study)
Observational Study
Association between serum bone biomarker levels and therapeutic response to abatacept in patients with rheumatoid arthritis (RA): a multicenter, prospective, and observational RA ultrasound cohort study in Japan.
BACKGROUND
To evaluate the effect of treatment on serum bone biomarkers and explore whether serum bone biomarkers are associated with therapeutic response in rheumatoid arthritis (RA) patients treated with abatacept.
METHODS
We enrolled 59 RA patients treated with abatacept from a multicenter, exploratory, short-term, prospective and observational ultrasound cohort study of patients who received biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) therapy. We evaluated the patients' clinical disease activity and musculoskeletal ultrasound (MSUS) scores. The serum concentrations of five bone biomarkers were evaluated (dickkopf-1 [Dkk-1], sclerostin [SOST], osteocalcin [OC], osteopontin [OPN], and osteoprotegerin [OPG]) by multiplex bead assays at baseline, 3, and 6 months: the change over 6 months was defined as the Δ value. 'Power Doppler (PD) responder' was defined as a patient whose Δtotal PD score over 6 months was greater than the median change.
RESULTS
Abatacept significantly improved the clinical disease activity and MSUS score over 6 months. Serum OPG was significantly elevated at 6 months after the abatacept introduction (p = 0.016). The ΔSOST and ΔOPG were significantly greater in the PD responders versus the non-PD responders (p = 0.0041 and 0.0073, respectively). The serum Dkk-1 at baseline was significantly lower in the PD responders (n = 30) vs. the non-PD responders (n = 29) (p = 0.026). A multivariate logistic regression analysis showed that the serum Dkk-1 at baseline (odds ratio 0.50, 95% confidence interval [CI] 0.23-0.91, p = 0.043) was an independent predictor of PD responder status.
CONCLUSION
Serum levels of bone biomarkers may be useful for predicting RA patients' therapeutic responses to abatacept.
TRIAL REGISTRATION
Name of the registry: Assessment of therapeutic responsiveness by imaging of the joints in patients with rheumatoid arthritis; A observational cohort study Trial registration number: UMIN000012524 Date of registration: 12/9/2013 URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000014657.
Topics: Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; Cohort Studies; Humans; Japan; Prospective Studies; Treatment Outcome
PubMed: 34074293
DOI: 10.1186/s12891-021-04392-5 -
Seminars in Respiratory and Critical... Jun 2024Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for... (Review)
Review
Interstitial lung disease (ILD) is a common pulmonary complication of rheumatoid arthritis (RA), causing significant morbidity and mortality. Optimal treatment for RA-ILD is not yet well defined. Reliable prognostic indicators are largely byproducts of prior ILD progression, including low or decreasing forced vital capacity and extensive or worsening fibrosis on imaging. In the absence of validated tools to predict treatment response, decisions about whether to initiate or augment treatment are instead based on clinical judgment. In general, treatment should be initiated in patients who are symptomatic, progressing, or at high risk of poor outcomes. Retrospective data suggest that mycophenolate mofetil, azathioprine, and rituximab are likely effective therapies for RA-ILD. Abatacept is also emerging as a potential first-line treatment option for patients with RA-ILD. Further, recent data demonstrate that immunosuppression may be beneficial even in patients with a usual interstitial pneumonia (UIP) pattern on imaging, suggesting that immunosuppression should be considered irrespective of imaging pattern. Recent randomized controlled trials have shown that antifibrotic medications, such as nintedanib and likely pirfenidone, slow forced vital capacity decline in RA-ILD. Consideration can be given to antifibrotic initiation in patients progressing despite immunosuppression, particularly in patients with a UIP pattern. Future research directions include developing tools to predict which patients will remain stable from patients who will progress, discriminating patients who will respond to treatment from nonresponders, and developing algorithms for starting immunosuppression, antifibrotics, or both as first-line therapies.
Topics: Humans; Lung Diseases, Interstitial; Arthritis, Rheumatoid; Immunosuppressive Agents; Disease Progression; Antirheumatic Agents; Abatacept; Prognosis; Mycophenolic Acid; Rituximab; Vital Capacity; Pyridones; Randomized Controlled Trials as Topic; Azathioprine; Indoles
PubMed: 38484788
DOI: 10.1055/s-0044-1782218 -
Seminars in Arthritis and Rheumatism Feb 2024To evaluate the risk of malignancy (overall, breast, lung, and lymphoma) in patients with rheumatoid arthritis treated with abatacept, conventional synthetic (cs)... (Observational Study)
Observational Study
Malignancy outcomes in patients with rheumatoid arthritis treated with abatacept and other disease-modifying antirheumatic drugs: Results from a 10-year international post-marketing study.
OBJECTIVE
To evaluate the risk of malignancy (overall, breast, lung, and lymphoma) in patients with rheumatoid arthritis treated with abatacept, conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), and other biologic/targeted synthetic (b/ts)DMARDs in clinical practice.
METHODS
Four international observational data sources were included: ARTIS (Sweden), RABBIT (Germany), FORWARD (USA), and BC (Canada). Crude incidence rates (IRs) per 1000 patient-years of exposure with 95% confidence intervals (CIs) for a malignancy event were calculated; rate ratios (RRs) were estimated and adjusted for demographics, comorbidities, and other potential confounders. RRs were then pooled in a random-effects model.
RESULTS
Across data sources, mean follow-up for patients treated with abatacept (n = 5182), csDMARDs (n = 73,755), and other b/tsDMARDs (n = 37,195) was 3.0-3.7, 2.9-6.2, and 3.1-4.7 years, respectively. IRs per 1000 patient-years for overall malignancy ranged from 7.6-11.4 (abatacept), 8.6-13.2 (csDMARDs), and 5.0-11.8 (other b/tsDMARDs). IRs ranged from: 0-4.4, 0-3.3, and 0-2.5 (breast cancer); 0.1-2.8, 0-3.7, and 0.2-2.9 (lung cancer); and 0-1.1, 0-0.9, and 0-0.6 (lymphoma), respectively, for the three treatment groups. The numbers of individual cancers (breast, lung, and lymphoma) in some registries were low; RRs were not available. There were a few cases of lymphoma in some of the registries; ARTIS observed an RR of 2.8 (95% CI 1.1-6.8) with abatacept versus csDMARDs. The pooled RRs (95% CIs) for overall malignancy with abatacept were 1.1 (0.8-1.5) versus csDMARDs and 1.0 (0.8-1.3) versus b/tsDMARDs.
CONCLUSIONS
This international, post-marketing observational safety study did not find any statistically significant increase in the risk of overall malignancies in pooled data in patients treated with abatacept compared with csDMARDs or with other b/tsDMARDs. Assessment of larger populations is needed to further evaluate the risks for individual cancers, especially lymphoma.
Topics: Humans; Abatacept; Antirheumatic Agents; Arthritis, Rheumatoid; Lung Neoplasms; Lymphoma; Marketing; Biological Products
PubMed: 37500379
DOI: 10.1016/j.semarthrit.2023.152240 -
Arthritis Research & Therapy Feb 2018The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and...
BACKGROUND
The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Considering that autoantibodies trigger inflammatory cytokine production by monocytes and that abatacept binds to monocytes, influencing their functional state, we hypothesized that abatacept may effectively inhibit the production of several different cytokines by ACPA- or RF-challenged monocytes.
METHODS
Peripheral blood CD68 monocytes stimulated with macrophage colony-stimulating factor for 24 h were exposed to random immunoglobulin G alone (negative control), purified ACPA, purified RF, or lipopolysaccharide (positive control) in cell culture plates coated with citrullinated vimentin (to allow ACPA immune complex formation). Stimulations were done in the presence or absence of abatacept or tumor necrosis factor (TNF) antibody (adalimumab) with or without indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan. Supernatants were analyzed for key proinflammatory cytokines TNF-α, interleukin (IL)-1β, IL-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) after 24 h.
RESULTS
Exposure to ACPA or RF significantly induced the production of TNF-α (20-fold and 27-fold, respectively), IL-1β (each 4-fold), IL-6 (12-fold and 11-fold, respectively), IL-8 (43-fold and 30-fold, respectively), and CCL2 (each 4-fold) in human monocytes. Abatacept inhibited this autoantibody-mediated upregulation of cytokines, reducing TNF-α by > 75%, IL-1β by > 65%, IL-6 and IL-8 by > 80%, and CCL2 by > 60%. In contrast, a TNF inhibitor did not influence autoantibody-induced proinflammatory cytokine production. IDO inhibition reversed the effect of abatacept and again permitted the induction of cytokine production by ACPA and RF.
CONCLUSIONS
These data show that abatacept interferes with autoantibody-mediated cytokine production by monocytes through induction of IDO. This inhibitory effect on the production of several effector cytokines in RA may explain the fast anti-inflammatory effect of abatacept as well as its preferential efficacy in patients with high-titer ACPA and RF.
Topics: Abatacept; Adalimumab; Anti-Citrullinated Protein Antibodies; Antirheumatic Agents; Cells, Cultured; Cytokines; Humans; Indoleamine-Pyrrole 2,3,-Dioxygenase; Macrophages; Monocytes; Rheumatoid Factor; Tryptophan
PubMed: 29415763
DOI: 10.1186/s13075-018-1527-x -
Transplantation Sep 2023Posttransplant fertility returns quickly, and female recipients of child-bearing age may conceive while on immunosuppression. However, pregnancy after transplantation...
BACKGROUND
Posttransplant fertility returns quickly, and female recipients of child-bearing age may conceive while on immunosuppression. However, pregnancy after transplantation confers risks to the recipient, transplant, and fetus, including gestational hypertension, preeclampsia, gestational diabetes, transplant dysfunction, preterm labor, and low birthweight infants. Additionally, mycophenolic acid (MPA) products are teratogenic. Literature evidence regarding belatacept, a selective T-cell costimulation blocker, during pregnancy and while breastfeeding is extremely limited. When female transplant recipients on a belatacept-based regimen are desirous of pregnancy or at the time of conception, transplant providers manage the immunosuppression regimen in 1 of 2 ways: (1) switch both belatacept and MPA to a calcineurin inhibitor-based regimen with or without azathioprine, which is the more common practice but requires several modifications, having potential negative outcomes; or (2) only switch MPA to azathioprine while continuing belatacept.
METHODS
This case series includes 16 pregnancies in 12 recipients with exposure to belatacept throughout pregnancy and while breastfeeding. Patient information was obtained from several sources, including Transplant Pregnancy Registry International, providers at Emory University, and Columbia University, as well as literature review.
RESULTS
Pregnancy outcomes included 13 live births and 3 miscarriages. No birth defects or fetal deaths were reported in any of the live births. Seven infants were breastfed while their mothers continued belatacept. Outcomes appear comparable to those documented with the administration of calcineurin inhibitors.
CONCLUSIONS
This case series provides data supporting the continued administration of belatacept during pregnancy. Additional research will assist in developing better guidelines to counsel female transplant recipients on belatacept desiring to pursue pregnancy.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Abatacept; Transplant Recipients; Azathioprine; Kidney Transplantation; Graft Rejection; Immunosuppressive Agents; Calcineurin Inhibitors; Pregnancy Outcome; Mycophenolic Acid
PubMed: 37287109
DOI: 10.1097/TP.0000000000004634 -
Modern Rheumatology Jul 2016To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA).
OBJECTIVE
To perform a postmarketing surveillance study evaluating the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis (RA).
METHODS
Safety and effectiveness data were collected for all RA patients (at 772 sites) treated with intravenous abatacept between September 2010 and June 2011. Patients were treated by the approved dosing regimen according to the package insert. Treatment effectiveness was evaluated at baseline and at weeks 4, 12, and 24 using Disease Activity Score 28 (DAS28) according to erythrocyte sedimentation rate or serum C-reactive protein concentrations.
RESULTS
Overall, 3882 and 3016 abatacept-naïve RA patients were included in safety and effectiveness analyses, respectively. Adverse drug reactions (ADRs) were reported for 15.66% of patients and serious ADRs were detected for 2.52% of patients. The incidence of serious infections was 1.03% and these were mainly attributed to different types of bacterial pneumonia. Disease activity improved significantly over 6 months. Separate multivariate analysis identified predictors of severe ADR, and severe infections and factors predictive of clinically meaningful DAS28 improvement after 6 months of treatment with abatacept.
CONCLUSIONS
Abatacept was efficacious and well tolerated in a clinical setting. No new safety concerns were detected.
Topics: Abatacept; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Blood Sedimentation; C-Reactive Protein; Female; Humans; Japan; Male; Middle Aged; Product Surveillance, Postmarketing; Treatment Outcome
PubMed: 26635183
DOI: 10.3109/14397595.2015.1123211