-
Arthritis Care & Research Jun 2024The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic...
OBJECTIVE
The objective was to develop consensus treatment plans (CTPs) for patients with refractory moderately severe juvenile dermatomyositis (JDM) treated with biologic disease-modifying antirheumatic drugs (bDMARDs).
METHODS
The Biologics Workgroup of the Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Research Committee used case-based surveys, consensus framework, and nominal group technique to produce bDMARD CTPs for patients with refractory moderately severe JDM.
RESULTS
Four bDMARD CTPs were proposed: TNF-alpha inhibitor (adalimumab or infliximab), abatacept, rituximab, and tocilizumab. Each CTP has different options for dosing and/or route. Among 76 respondents, consensus was achieved for the proposed CTPs (93% [67/72]) as well as for patient characteristics, assessments, outcome measures, and follow up. By weighted average, respondents indicated that they would most likely use rituximab followed by abatacept, TNF-alpha inhibitor, and tocilizumab.
CONCLUSION
CTPs for the use of bDMARDs in refractory moderately severe JDM were developed using consensus methodology. The implementation of the bDMARD CTPs will lay the groundwork for registry-based prospective comparative effectiveness studies.
PubMed: 38937134
DOI: 10.1002/acr.25393 -
Proceedings of the National Academy of... Jul 2024Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T...
Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether CTLA-4 or PD-1 blockade. The frequency of Tregs was significantly decreased with CTLA-4 Ig. The resulting increased CD8/Treg ratio potentially underlies the enhanced efficacy of ICT followed by CTLA-4 Ig. This paradoxical mechanism shows that a CTLA-4 Ig regimen shown to reduce irAE severity does not compromise antitumor efficacy.
Topics: Animals; Mice; Immunotherapy; CTLA-4 Antigen; Immune Checkpoint Inhibitors; CD8-Positive T-Lymphocytes; T-Lymphocytes, Regulatory; Cell Line, Tumor; Abatacept; Female; Humans; Mice, Inbred C57BL; Neoplasms; Programmed Cell Death 1 Receptor
PubMed: 38923991
DOI: 10.1073/pnas.2404661121 -
Arthritis Research & Therapy Jun 2024Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Juvenile idiopathic arthritis (JIA) comprises a heterogeneous group of conditions that can cause marked disability and diminished quality of life. Data on predictors of clinical response are insufficient to guide selection of the appropriate biologic agent for individual patients. This study aimed to investigate the propensity of S100A8/9 and S100A12 as predictive biomarkers of abatacept response in polyarticular-course juvenile idiopathic arthritis (pJIA).
METHODS
Data from a phase 3 trial (NCT01844518) of subcutaneous abatacept in patients with active pJIA (n = 219) were used in this exploratory analysis. Association between biomarker levels at baseline and improvements in JIA-American College of Rheumatology (ACR) criteria responses or baseline disease activity (measured by Juvenile Arthritis Disease Activity Score in 27 joints using C-reactive protein [JADAS27-CRP]) were assessed. Biomarker level changes from baseline to month 4 were assessed for disease outcome prediction up to 21 months.
RESULTS
At baseline, 158 patients had available biomarker samples. Lower baseline S100A8/9 levels (≤ 3295 ng/mL) were associated with greater odds of achieving JIA-ACR90 (odds ratio [OR]: 2.54 [95% confidence interval (CI): 1.25-5.18]), JIA-ACR100 (OR: 3.72 [95% CI: 1.48-9.37]), JIA-ACR inactive disease (ID; OR: 4.25 [95% CI: 2.03-8.92]), JADAS27-CRP ID (OR: 2.34 [95% CI: 1.02-5.39]) at month 4, and JIA-ACR ID (OR: 3.01 [95% CI: 1.57-5.78]) at month 16. Lower baseline S100A12 levels (≤ 176 ng/mL) were associated with greater odds of achieving JIA-ACR90 (OR: 2.52 [95% CI: 1.23-5.13]), JIA-ACR100 (OR: 3.68 [95% CI: 1.46-9.28]), JIA-ACR ID (OR: 3.66 [95% CI: 1.76-7.61]), JIA-ACR90 (OR: 2.03 [95% CI: 1.07-3.87]), JIA-ACR100 (OR: 2.14 [95% CI: 1.10-4.17]), and JIA-ACR ID (OR: 4.22 [95% CI: 2.15-8.29]) at month 16. From baseline to month 4, decreases in S100A8/9 and S100A12 generally exceeded 50% among JIA-ACR90/100/ID responders.
CONCLUSION
Lower baseline levels of S100A8/9 and S100A12 proteins predicted better response to abatacept treatment than higher levels and may serve as early predictive biomarkers in pJIA. Decreases in these biomarker levels may also predict longer-term response to abatacept in pJIA.
Topics: Humans; Abatacept; Arthritis, Juvenile; Male; Female; Child; Biomarkers; Antirheumatic Agents; Calgranulin B; Adolescent; Treatment Outcome; Child, Preschool; Calgranulin A; S100A12 Protein; S100 Proteins
PubMed: 38918871
DOI: 10.1186/s13075-024-03347-0 -
Reumatismo Jun 2024Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in...
OBJECTIVE
Data from trials demonstrated that abatacept (ABA) has a good safety and efficacy profile in treating rheumatoid arthritis. We have studied the retention rate of ABA in a real-life cohort of patients with rheumatoid arthritis.
METHODS
This is a monocentric, retrospective study including patients with rheumatoid arthritis classified by the American College of Rheumatology/European League Against Rheumatism 2010 criteria who started treatment with ABA. The Kaplan-Meier method was applied to evaluate the ABA retention rate.
RESULTS
This analysis was conducted on 161 patients [male/female 21/140, median age 65 years, interquartile range (IQR) 18.7, median disease duration 169 months, IQR 144.0]. 111 patients (68.9%) received ABA subcutaneously. ABA was associated with methotrexate in 61.9% of patients and was the first biological disease-modifying antirheumatic drug in 41%. We observed a median ABA survival of 66 months [95% confidence interval (CI) 57.3-74.7], with a retention rate of 88% at 6 months and 50.9% at 5 years. Drug survival was significantly higher in patients treated with ABA subcutaneously and in male patients (p=0.039 and p=0.018, respectively). Adjusted for main confounders, female gender was the main predictor of withdrawal (hazard ratio 5.1, 95% CI 1.2-21.3).
CONCLUSIONS
Our study shows that better survival is associated with subcutaneous administration and male gender, confirming ABA effectiveness.
Topics: Humans; Abatacept; Arthritis, Rheumatoid; Male; Female; Retrospective Studies; Aged; Antirheumatic Agents; Middle Aged; Methotrexate; Treatment Outcome; Kaplan-Meier Estimate; Drug Therapy, Combination; Cohort Studies
PubMed: 38916170
DOI: 10.4081/reumatismo.2024.1608 -
Frontiers in Neurology 2024To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and...
A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis.
OBJECTIVE
To determine whether a combination therapy with abatacept (CTLA4-Ig) and interleukin-2 (IL-2) is safe and suppresses markers of oxidative stress, inflammation, and degeneration in ALS.
METHODS
In this open-label study, four participants with ALS received subcutaneous injections of low dose IL-2 (1 × 10 IU/injection/day) for 5 consecutive days every 2 weeks and one subcutaneous injection of CTLA4-Ig (125 mg/mL/injection) every 2 weeks coinciding with the first IL-2 injection of each treatment cycle. Participants received a total of 24 treatment cycles during the first 48 weeks in this 56-week study. They were closely monitored for treatment-emergent adverse events (TEAEs) and disease progression with the ALSFRS-R. Phenotypic changes within T cell populations and serum biological markers of oxidative stress [4-hydroxynonenal (4-HNE) and oxidized-LDL (ox-LDL)], inflammation (IL-18), and structural neuronal degeneration [neurofilament light chain (Nf-L)] were assessed longitudinally.
RESULTS
CTLA4-Ig/IL-2 therapy was safe and well-tolerated in all four participants over the 56-week study. During the first 24 weeks, the average rate of change in the ALSFRS-R was +0.04 points/month. Over the 48-week treatment period, the average rate of change was -0.13 points/month with one participant improving by 0.9 points/month while the other three participants experienced an average decrease of -0.47 points/month, which is slower than the average - 1.1 points/month prior to initiation of therapy. Treg suppressive function and numbers increased during treatment. Responses in the biological markers during the first 16 weeks coincided with minimal clinical progression. Mean levels of 4-HNE decreased by 30%, ox-LDL decreased by 19%, IL-18 decreased by 23%, and Nf-L remained the same, on average, in all four participants. Oxidized-LDL levels decreased in all four participants, 4-HNE and IL-18 levels decreased in three out of four participants, and Nf-L decreased in two out of four participants.
CONCLUSION
The combination therapy of CTLA4-Ig and IL-2 in ALS is safe and well-tolerated with promising results of clinical efficacy and suppression of biomarkers of oxidative stress, neuroinflammation and neuronal degeneration. In this open-label study, the efficacy as measured by the ALSFRS-R and corresponding biomarkers suggests the therapeutic potential of this treatment and warrants further study in a phase 2 double-blind, placebo-controlled trial.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT06307301.
PubMed: 38915796
DOI: 10.3389/fneur.2024.1415106 -
Ocular Immunology and Inflammation Jun 2024To report a case of coinfection of (Tg) and (EBV) in a diabetic patient with rheumatoid arthritis and immunosuppressive biological therapy.
BACKGROUND
To report a case of coinfection of (Tg) and (EBV) in a diabetic patient with rheumatoid arthritis and immunosuppressive biological therapy.
CASE PRESENTATION
A 70-year-old female with a history of rheumatoid arthritis on therapy with corticosteroids, methotrexate, and abatacept presented bilateral granulomatous panuveitis associated with retinal necrosis and macular involvement. A diagnostic vitrectomy detected Tg and EBV. Treatment with clindamycin, trimethoprim-sulfamethoxazole, and acyclovir was established, achieving improvement.
CONCLUSIONS
Patients undergoing immunosuppressive therapy are at risk of developing opportunistic infections, often presenting with severe and atypical clinical manifestations. In such cases, multiplex polymerase chain reaction is an invaluable diagnostic tool that helps identify the specific pathogens involved. This enables healthcare professionals to make informed treatment decisions and provide targeted therapy for each identified pathogen.
PubMed: 38889439
DOI: 10.1080/09273948.2024.2367656 -
Expert Opinion on Investigational Drugs Jun 2024Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder characterized by pain and stiffness in the shoulder and pelvic girdles, constitutional symptoms, and...
INTRODUCTION
Polymyalgia rheumatica (PMR) is an inflammatory rheumatic disorder characterized by pain and stiffness in the shoulder and pelvic girdles, constitutional symptoms, and elevated acute-phase reactants. Glucocorticoids (GCs) remain the first-choice treatment for PMR, but relapses are common. Identification of steroid-sparing agents is therefore of utmost importance.
AREAS COVERED
The efficacy of conventional immunosuppressive drugs is controversial. The use of interleukin (IL)-6 receptor inhibitors proved to be effective and safe in treating PMR patients. Currently, there are 12 ongoing clinical trials exploring potential treatments such as leflunomide, low-dose IL-2, rituximab, abatacept, secukinumab, Janus kinase inhibitors, and selective inhibitors like SPI-62 and ABBV 154.
EXPERT OPINION
The high efficacy of IL-6 R receptor inhibitors as well as the numerous drug trials currently recruiting suggest that several therapeutic options will be available in the near future. Accurate diagnosis and early stratification of PMR patients according to the giant cell arteritis-PMR Spectrum Disease 'GPSD' and potential risk factors for relapsing disease or GC-related adverse events are crucial to identify patients who would benefit most from GC-sparing agents. The development of internationally accepted definitions for remission and relapse is urgently needed. Early referral strategies to specialist settings would improve disease stratification and personalized treatment.
PubMed: 38879822
DOI: 10.1080/13543784.2024.2366847 -
BMC Medical Genomics Jun 2024Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have...
Primary Sclerosing Cholangitis (PSC) is a progressive cholestatic liver disease with no licensed therapies. Previous Genome Wide Association Studies (GWAS) have identified genes that correlate significantly with PSC, and these were identified by systematic review. Here we use novel Network Proximity Analysis (NPA) methods to identify already licensed candidate drugs that may have an effect on the genetically coded aspects of PSC pathophysiology.Over 2000 agents were identified as significantly linked to genes implicated in PSC by this method. The most significant results include previously researched agents such as metronidazole, as well as biological agents such as basiliximab, abatacept and belatacept. This in silico analysis could potentially serve as a basis for developing novel clinical trials in this rare disease.
Topics: Cholangitis, Sclerosing; Humans; Genome-Wide Association Study; Models, Theoretical
PubMed: 38862968
DOI: 10.1186/s12920-024-01927-2 -
Circulation Research Jun 2024Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus... (Review)
Review
Autoimmunity significantly contributes to the pathogenesis of myocarditis, underscored by its increased frequency in autoimmune diseases such as systemic lupus erythematosus and polymyositis. Even in cases of myocarditis caused by viral infections, dysregulated immune responses contribute to pathogenesis. However, whether triggered by existing autoimmune conditions or viral infections, the precise antigens and immunologic pathways driving myocarditis remain incompletely understood. The emergence of myocarditis associated with immune checkpoint inhibitor therapy, commonly used for treating cancer, has afforded an opportunity to understand autoimmune mechanisms in myocarditis, with autoreactive T cells specific for cardiac myosin playing a pivotal role. Despite their self-antigen recognition, cardiac myosin-specific T cells can be present in healthy individuals due to bypassing the thymic selection stage. In recent studies, novel modalities in suppressing the activity of pathogenic T cells including cardiac myosin-specific T cells have proven effective in treating autoimmune myocarditis. This review offers an overview of the current understanding of heart antigens, autoantibodies, and immune cells as the autoimmune mechanisms underlying various forms of myocarditis, along with the latest updates on clinical management and prospects for future research.
Topics: Myocarditis; Humans; Autoimmune Diseases; Animals; Autoantibodies; Autoimmunity; T-Lymphocytes; Autoantigens; Cardiac Myosins
PubMed: 38843292
DOI: 10.1161/CIRCRESAHA.124.323816 -
Nature Communications Jun 2024The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction...
The efficacy of costimulation blockade with CTLA4-Ig (belatacept) in transplantation is limited due to T cell-mediated rejection, which also persists after induction with anti-thymocyte globulin (ATG). Here, we investigate why ATG fails to prevent costimulation blockade-resistant rejection and how this barrier can be overcome. ATG did not prevent graft rejection in a murine heart transplant model of CTLA4-Ig therapy and induced a pro-inflammatory cytokine environment. While ATG improved the balance between regulatory T cells (Treg) and effector T cells in the spleen, it had no such effect within cardiac allografts. Neutralizing IL-6 alleviated graft inflammation, increased intragraft Treg frequencies, and enhanced intragraft IL-10 and Th2-cytokine expression. IL-6 blockade together with ATG allowed CTLA4-Ig therapy to achieve long-term, rejection-free heart allograft survival. This beneficial effect was abolished upon Treg depletion. Combining ATG with IL-6 blockade prevents costimulation blockade-resistant rejection, thereby eliminating a major impediment to clinical use of costimulation blockers in transplantation.
Topics: Animals; Male; Mice; Abatacept; Allografts; Antilymphocyte Serum; Graft Rejection; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Interleukin-10; Interleukin-6; Lymphocyte Depletion; Mice, Inbred BALB C; Mice, Inbred C57BL; T-Lymphocytes, Regulatory
PubMed: 38830846
DOI: 10.1038/s41467-024-48574-w