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Expert Review of Clinical Pharmacology 2024Pemphigus, an uncommon autoimmune blistering disorder affecting the skin and mucous membranes, currently with mortality primarily attributed to adverse reactions... (Review)
Review
INTRODUCTION
Pemphigus, an uncommon autoimmune blistering disorder affecting the skin and mucous membranes, currently with mortality primarily attributed to adverse reactions resulting from treatment protocols. Additionally, the existing treatments exhibit a notable recurrence rate. The high incidence of relapse and the considerable adverse effects associated with treatment underscore the imperative to explore safer and more effective therapeutic approaches. Numerous potential therapeutic targets have demonstrated promising outcomes in trials or preliminary research stages. These encompass anti-CD-20 agents, anti-CD-25 agents, TNF-α inhibition, FAS Ligand Inhibition, FcRn inhibition, BAFF inhibition, Bruton's tyrosine kinase (BTK) inhibition, CAAR T Cells, JAK inhibition, mTOR inhibition, abatacept, IL-4 inhibition, IL-17 inhibition, IL-6 inhibition, polyclonal Regulatory T Cells, and autologous hematopoietic stem cell transplantation.
AREAS COVERED
The most significant studies regarding the impact and efficacy of the mentioned treatments on pemphigus were meticulously curated through a comprehensive search conducted on the PubMed database. Moreover, the investigations of interest cited in these studies were also integrated.
EXPERT OPINION
The efficacy and safety profiles of the other treatments under discussion do not exhibit the same level of robustness as anti-CD20 therapy, which is anticipated to endure as a critical element in pemphigus treatment well into the foreseeable future.
Topics: Pemphigus; Humans; Animals; Recurrence; Molecular Targeted Therapy
PubMed: 38712540
DOI: 10.1080/17512433.2024.2350943 -
Transplant International : Official... 2024
Topics: Humans; Abatacept; Pancreas Transplantation; Immunosuppressive Agents; Male; Female; Adult; Middle Aged; Graft Rejection; Cohort Studies; Graft Survival; Retrospective Studies
PubMed: 38689693
DOI: 10.3389/ti.2024.12778 -
Transplant International : Official... 2024
Topics: Adult; Female; Humans; Male; Middle Aged; Abatacept; Graft Rejection; Immunosuppressive Agents; Kidney Transplantation; Pancreas Transplantation
PubMed: 38665473
DOI: 10.3389/ti.2024.12628 -
JAMA Network Open Apr 2024The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The pharmacokinetics of abatacept and the association between abatacept exposure and outcomes in patients with severe COVID-19 are unknown.
OBJECTIVE
To characterize abatacept pharmacokinetics, relate drug exposure with clinical outcomes, and evaluate the need for dosage adjustments.
DESIGN, SETTING, AND PARTICIPANTS
This study is a secondary analysis of data from the ACTIV-1 (Accelerating COVID-19 Therapeutic Interventions and Vaccines) Immune Modulator (IM) randomized clinical trial conducted between October 16, 2020, and December 31, 2021. The trial included hospitalized adults who received abatacept in addition to standard of care for treatment of COVID-19 pneumonia. Data analysis was performed between September 2022 and February 2024.
EXPOSURE
Single intravenous infusion of abatacept (10 mg/kg with a maximum dose of 1000 mg).
MAIN OUTCOMES AND MEASURES
Mortality at day 28 was the primary outcome of interest, and time to recovery at day 28 was the secondary outcome. Drug exposure was assessed using the projected area under the serum concentration time curve over 28 days (AUC0-28). Logistic regression modeling was used to analyze the association between drug exposure and 28-day mortality, adjusted for age, sex, and disease severity. The association between time to recovery and abatacept exposure was examined using Fine-Gray modeling with death as a competing risk, and was adjusted for age, sex, and disease severity.
RESULTS
Of the 509 patients who received abatacept, 395 patients with 848 serum samples were included in the population pharmacokinetic analysis. Their median age was 55 (range, 19-89) years and most (250 [63.3%]) were men. Abatacept clearance increased with body weight and more severe disease activity at baseline. Drug exposure was higher in patients who survived vs those who died, with a median AUC0-28 of 21 428 (range, 8462-43 378) mg × h/L vs 18 262 (range, 9628-27 507) mg × h/L (P < .001). Controlling for age, sex, and disease severity, an increase of 5000 units in AUC0-28 was associated with lower odds of mortality at day 28 (OR, 0.52 [95% CI, 0.35-0.79]; P = .002). For an AUC0-28 of 19 400 mg × h/L or less, there was a higher probability of recovery at day 28 (hazard ratio, 2.63 [95% CI, 1.70-4.08] for every 5000-unit increase; P < .001). Controlling for age, sex, and disease severity, every 5000-unit increase in AUC0-28 was also associated with lower odds of a composite safety event at 28 days (OR, 0.46 [95% CI, 0.33-0.63]; P < .001). Using the dosing regimen studied in the ACTIV-1 IM trial, 121 of the 395 patients (30.6%) would not achieve an abatacept exposure of at least 19 400 mg × h/L, particularly at the extremes of body weight. Using a modified, higher-dose regimen, only 12 patients (3.0%) would not achieve the hypothesized target abatacept exposure.
CONCLUSIONS AND RELEVANCE
In this study, patients who were hospitalized with severe COVID-19 and achieved higher projected abatacept exposure had reduced mortality and a higher probability of recovery with fewer safety events. However, abatacept clearance was high in this population, and the current abatacept dosing (10 mg/kg intravenously with a maximum of 1000 mg) may not achieve optimal exposure in all patients.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04593940.
Topics: Humans; Abatacept; Male; Female; Middle Aged; Aged; COVID-19; SARS-CoV-2; COVID-19 Drug Treatment; Hospitalization; Adult; Area Under Curve; Aged, 80 and over
PubMed: 38662372
DOI: 10.1001/jamanetworkopen.2024.7615 -
Frontiers in Immunology 2024Exhausted CD8 T cells (T) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGITKLRG1 T with...
Exhausted CD8 T cells (T) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGITKLRG1 T with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGITKLRG1 T is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGITKLRG1 CD8 T population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive , together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells. In HC and RA subjects, lower levels of EOMES transcriptional modules and frequency of TIGITKLRG1 T were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and cytomegalovirus (CMV) seropositivity. Moreover, the frequency of TIGITKLRG1 T was significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig). The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of T may be more effective in DR4 subjects and T may be indirectly influenced by cellular interactions that are blocked by abatacept.
Topics: Humans; Abatacept; Receptors, Immunologic; Arthritis, Rheumatoid; Alleles; Male; Female; CD8-Positive T-Lymphocytes; Adult; Lectins, C-Type; HLA Antigens; Middle Aged; Antirheumatic Agents; Genetic Predisposition to Disease; T-Cell Exhaustion
PubMed: 38650930
DOI: 10.3389/fimmu.2024.1383110 -
Cell Transplantation 2024Calcineurin inhibitors (CNIs) are critical in preventing rejection posttransplantation but pose an increased risk of post-transplant diabetes (PTD). Recent studies show...
Calcineurin inhibitors (CNIs) are critical in preventing rejection posttransplantation but pose an increased risk of post-transplant diabetes (PTD). Recent studies show that late conversion from CNIs to belatacept, a costimulation blocker, improves HbA1c in kidney transplant recipients with PTD or diabetes. This study investigates whether the observed effects on PTD stem solely from CNI withdrawal or if belatacept influences PTD independently. The study assessed the impact of tacrolimus and belatacept on insulin secretion in MIN6 cells (a beta cell line) and rat islets. Tacrolimus and belatacept were administered to the cells and islets, followed by assessments of cell viability and insulin secretion. Tacrolimus impaired insulin secretion without affecting cell viability, while belatacept showed no detrimental effects on either parameter. These findings support clinical observations of improved HbA1c upon switching from tacrolimus to belatacept. Belatacept holds promise in islet or pancreas transplantation, particularly in patients with unstable diabetes. Successful cases of islet transplantation treated with belatacept without severe hypoglycemia highlight its potential in managing PTD. Further research is needed to fully understand the metabolic changes accompanying the transition from CNIs to belatacept. Preserving insulin secretion emerges as a promising avenue for investigation in this context.
Topics: Tacrolimus; Abatacept; Animals; Rats; Insulin; Immunosuppressive Agents; Humans; Male; Insulin Secretion; Mice; Islets of Langerhans Transplantation; Cell Line; Cell Survival; Diabetes Mellitus; Islets of Langerhans
PubMed: 38646716
DOI: 10.1177/09636897241246577 -
Clinical and Experimental Immunology Jun 2024B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as... (Review)
Review
B and T cells collaborate to drive autoimmune disease (AID). Historically, B- and T-cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B-cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab, or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells, and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T-cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T-cell therapy and T-cell engagers (TCE) that recruit T cells to induce B-cell cytotoxicity have delivered promising results for anti-CD19 CAR T-cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab, or epcoritamab. Limited evidence suggests that anti-CD19 CAR T-cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T-cell collaboration toward overcoming rituximab-resistant AID.
Topics: Humans; Autoimmune Diseases; B-Lymphocytes; T-Lymphocytes; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Rituximab; Cell Communication; Animals
PubMed: 38642912
DOI: 10.1093/cei/uxae031 -
Current Opinion in Rheumatology Jul 2024This review summarizes latest developments in treatment of juvenile spondyloarthritis (JSpA), specifically enthesitis-related arthritis (ERA) and juvenile psoriatic... (Review)
Review
PURPOSE OF REVIEW
This review summarizes latest developments in treatment of juvenile spondyloarthritis (JSpA), specifically enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA).
RECENT FINDINGS
There has been addition of biologic disease modifying antirheumatic drugs (bDMARDs) beyond tumor necrosis factor inhibitors (TNFi) for JSpA such as IL-17 blockers, IL-23 blockers, and janus activating kinase inhibitors with favorable safety profile. Conducting robust clinical trials for this subpopulation of JIA remains a challenge; extrapolation studies are being used to obtain approval from regulatory agencies.
SUMMARY
Newer drug therapies have expanded the scope of treatment for patients with JSpA. bDMARDs such as adalimumab, etanercept, infliximab, and secukinumab have demonstrated clinically significant treatment efficacy in ERA and JPsA. Based on extrapolation studies, intravenous golimumab, etanercept, abatacept, and ustekinumab have gained Food and Drug Administration (FDA) approval for JPsA. Long-term follow-up studies continue to demonstrate acceptable safety profiles. There is need for more real-world data on drug efficacy from Registry studies and research on effective de-escalation strategies.
Topics: Humans; Antirheumatic Agents; Arthritis, Juvenile; Spondylarthritis; Arthritis, Psoriatic; Biological Products; Treatment Outcome; Child
PubMed: 38639758
DOI: 10.1097/BOR.0000000000001016 -
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 -
Transplantation and Cellular Therapy Apr 2024Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the...
Although unrelated-donor (URD) hematopoietic cell transplantation (HCT) is associated with many toxicities, a detailed analysis of adverse events, as defined by the Common Terminology Criteria for Adverse Events (CTCAE), has not previously been curated. This represents a major unmet need, especially as it relates to assessing the safety of novel agents. We analyzed a detailed AE database from the "ABA2" randomized, double-blind, placebo-controlled clinical trial of abatacept for acute graft-versus-host disease (aGVHD) prevention, for which the FDA mandated a detailed AE assessment through Day +180, and weekly neutrophil and platelet counts through Day +100. These were analyzed for their relationship to key transplant outcomes, with a major focus on the impact of aGVHD on the development/severity of AEs. A total of 2102 AEs and 1816 neutrophil/platelet counts were analyzed from 142 8/8-HLA-matched URD HCT recipients on ABA2 (placebo cohort, n = 69, abatacept cohort, n = 73). This analysis resulted in 2 major observations. (1) Among graft source, conditioning intensity, age, and Grade 2 to 4 aGVHD, only aGVHD impacted Grade 3 to 5 AE acquisition after the first month post-transplant. (2) The development of Grade 3 to 4 aGVHD was associated with thrombocytopenia. We have created a detailed resource for the transplant community by which to contextualize clinical toxicities after transplant. It has identified aGVHD as a major driver of post-HCT Grade 3 to 5 AEs, and underscored a link between aGVHD and thrombocytopenia. This establishes a critical safety framework upon which the impact of novel post-transplant aGVHD therapeutics should be evaluated. This trial was registered at www.clinicaltrials.gov (#NCT01743131).
PubMed: 38583802
DOI: 10.1016/j.jtct.2024.03.030