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Multiple Sclerosis (Houndmills,... Sep 2021In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.
OBJECTIVE
To distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.
METHODS
Three estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.
RESULTS
Principal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.
CONCLUSION
By controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.
Topics: Azetidines; Benzyl Compounds; Disease Progression; Humans; Multiple Sclerosis, Chronic Progressive; Recurrence
PubMed: 33205682
DOI: 10.1177/1352458520971819 -
Proceedings of the National Academy of... Oct 2019Interleukin-2 (IL-2) and IL-15 play pivotal roles in T cell activation, apoptosis, and survival, and are implicated in leukemias and autoimmune diseases. Their...
Interleukin-2 (IL-2) and IL-15 play pivotal roles in T cell activation, apoptosis, and survival, and are implicated in leukemias and autoimmune diseases. Their heterotrimeric receptors share their β- and γ-chains, but have distinct α-chains. Anti-IL-2Rα (daclizumab) therapy targeting cell surface-expressed receptor subunits to inhibit T cell proliferation has only brought limited success in adult T cell leukemia/lymphoma (ATL) and in multiple sclerosis. We asked whether IL-2R subunits could already preassemble and signal efficiently in the endoplasmic reticulum (ER) and the Golgi. A combination of daclizumab and anti-IL-2 efficiently blocked IL-2-induced proliferation of IL-2-dependent wild-type (WT) ATL cells but not cells transfected with IL-2, suggesting that in IL-2-producing cells signaling may already take place before receptors reach the cell surface. In the Golgi fraction isolated from IL-2-producing ATL cells, we detected by Western blot phosphorylated Jak1, Jak3, and a phosphotyrosine signal attributed to the γ-chain, which occurred at much lower levels in the Golgi of WT ATL cells. We expressed EGFP- and mCherry-tagged receptor chains in HeLa cells to study their assembly along the secretory pathway. Confocal microscopy, Förster resonance energy transfer, and imaging fluorescence cross-correlation spectroscopy analysis revealed partial colocalization and molecular association of IL-2 (and IL-15) receptor chains in the ER/Golgi, which became more complete in the plasma membrane, further confirming our hypothesis. Our results define a paradigm of intracellular autocrine signaling and may explain resistance to antagonistic antibody therapies targeting receptors at the cell surface.
Topics: Cell Line, Tumor; Cell Proliferation; Endoplasmic Reticulum; Golgi Apparatus; HeLa Cells; Humans; Interleukin-15; Interleukin-2; Interleukin-2 Receptor alpha Subunit; Janus Kinase 1; Janus Kinase 3; Receptors, Interleukin-15; Signal Transduction
PubMed: 31570576
DOI: 10.1073/pnas.1901382116 -
Cancer Biotherapy & Radiopharmaceuticals May 2020Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a...
Y-Daclizumab (Anti-CD25), High-Dose Carmustine, Etoposide, Cytarabine, and Melphalan Chemotherapy and Autologous Hematopoietic Stem Cell Transplant Yielded Sustained Complete Remissions in 4 Patients with Recurrent Hodgkin's Lymphoma.
Despite advances in therapy of Hodgkin's lymphoma (HL), a proportion of patients will not respond or relapse. The authors had previously identified CD25, IL-2Rα, as a target for systemic radioimmunotherapy of HL since most normal cells do not express CD25, but it is expressed by a minority of Hodgkin/Reed-Sternberg (HRS) cells and most Tregs rosetting around HRS cells. This was a single institution, nonrandomized, open-label phase I/II trial of radiolabeled Y-daclizumab, an anti-CD25 monoclonal antibody, BEAM (carmustine, etoposide, cytarabine, and melphalan) conditioning treatment followed by autologous hematopoietic stem cell transplant (ASCT). Four patients with refractory and relapsed HL were treated in this trial with 3 patients receiving a single dose of 564.6-574.6 MBq Y-daclizumab and the fourth patient receiving two doses of 580.9-566.1 MBq Y-daclizumab followed by high-dose chemotherapy and ASCT. All 4 evaluable patients treated with Y-daclizumab obtained complete responses (CRs) that are ongoing 4.5-7 years following their stem cell transplant. The spectrum and severity of adverse events were mild and more importantly none of the patients, including several with multiple therapies before this treatment, developed the myelodysplastic syndrome. Targeting by daclizumab was not directed primarily at tumor cells, but rather the nonmalignant CD25-expressing T cells adjacent to the HRS cells and Y-daclizumab provided strong enough β emissions to kill CD25-negative tumor cells at a distance by a crossfire effect. Furthermore, the strong β irradiation killed normal cells in the tumor microenvironment. Y-daclizumab (anti-CD25), high-dose BEAM chemotherapy and ASCT was well tolerated and yielded sustained complete remissions in all 4 patients with recurrent HL patients who completed their treatment. Despite advances, a proportion of patients with HL will not have a CR to their initial treatment, and some with CRs will relapse. They demonstrated that the addition of Y-daclizumab into the preconditioning regimen for refractory and relapsed HL patients with high-dose BEAM chemotherapy and ASCT provided sustained CRs in the 4 patients studied. Two of these patients were highly refractory to multiple prior treatments with bulky disease at entry into this study, including 1 patient who never entered a remission and had failed 6 different therapeutic regimens. Despite the small number of patients treated in this study, the sustained clinical benefit in these patients indicates a highly effective treatment. The daclizumab was directed primarily not at HRS cells themselves but toward nonmalignant T cells rosetting around malignant cells. Y provided strong β emissions that killed antigen nonexpressing tumor cells at a distance by a crossfire effect. Furthermore, the strong β radiation killed normal cells in the tumor microenvironment that nurtured the malignant cells in the lymphomatous mass. The present study supports expanded analysis of Y-daclizumab as part of the regimen of ASCT in patients with refractory and relapsed HL.
Topics: Antineoplastic Combined Chemotherapy Protocols; Carmustine; Cytarabine; Daclizumab; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Male; Melphalan; Transplantation, Autologous
PubMed: 32275165
DOI: 10.1089/cbr.2019.3298 -
Frontiers in Immunology 2020Daclizumab beta is a humanized monoclonal antibody that binds to CD25 and selectively inhibits high-affinity IL-2 receptor signaling. As a former treatment for relapsing...
Daclizumab beta is a humanized monoclonal antibody that binds to CD25 and selectively inhibits high-affinity IL-2 receptor signaling. As a former treatment for relapsing forms of multiple sclerosis (RMS), daclizumab beta induces robust expansion of the CD56 subpopulation of NK cells that is correlated with the drug's therapeutic effects. As NK cells represent a heterogeneous population of lymphocytes with a range of phenotypes and functions, the goal of this study was to better understand how daclizumab beta altered the NK cell repertoire to provide further insight into the possible mechanism(s) of action in RMS. We used mass cytometry to evaluate expression patterns of NK cell markers and provide a comprehensive assessment of the NK cell repertoire in individuals with RMS treated with daclizumab beta or placebo over the course of 1 year. Treatment with daclizumab beta significantly altered the NK cell repertoire compared to placebo treatment. As previously reported, daclizumab beta significantly increased expression of CD56 on total NK cells. Within the CD56 NK cells, treatment was associated with multiple phenotypic changes, including increased expression of NKG2A and NKp44, and diminished expression of CD244, CD57, and NKp46. These alterations occurred broadly across the CD56 population, and were not associated with a specific subset of CD56 NK cells. While the changes were less dramatic, CD56 NK cells responded distinctly to daclizumab beta treatment, with higher expression of CD2 and NKG2A, and lower expression of FAS-L, HLA-DR, NTB-A, NKp30, and Perforin. Together, these data indicate that the expanded CD56 NK cells share features of both immature and mature NK cells. These findings show that daclizumab beta treatment is associated with unique changes in NK cells that may enhance their ability to kill autoreactive T cells or to exert immunomodulatory functions.
Topics: Adult; Aged; Aged, 80 and over; CD4-Positive T-Lymphocytes; CD56 Antigen; Cohort Studies; Daclizumab; Female; Humans; Immunosuppressive Agents; Killer Cells, Natural; Male; Mass Spectrometry; Middle Aged; Multiple Sclerosis; Receptors, Natural Killer Cell; Young Adult
PubMed: 32391016
DOI: 10.3389/fimmu.2020.00714 -
Orphanet Journal of Rare Diseases Feb 2020Despite the low prevalence of uveitis in pediatric rheumatic diseases, potential problems as well as high disease burden can complicate its management. In this review,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Despite the low prevalence of uveitis in pediatric rheumatic diseases, potential problems as well as high disease burden can complicate its management. In this review, we systematically assessed the epidemiological, etiological, and managerial aspects of uveitis in pediatric rheumatic diseases.
METHODS
This current study was conducted in accordance with the established methods and the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P). We searched the manuscript databases, including Medline, Web of Knowledge, Google Scholar, Scopus, and Cochrane for all eligible studies in line with the considered keywords. We also conducted the statistical analysis using the Stata software.
RESULTS
Considering studies focusing on uveitis in Juvenile Idiopathic Arthritis (JIA) yielded a pooled prevalence of 11.8% (95%CI: 11.2 to 12.4%) for uveitis following JIA. In this regard, the prevalence rate of uveitis related to Behçets disease and Systemic Lupus Erythematosus (SLE( was estimated to be 15.0 and 0.8%, respectively. The pooled response rate to Adalimumab and Infliximab was estimated to be 68.0% (95%CI: 65.4 to 70.6%), 64.7% (95%CI: 59.8 to 69.3%), respectively. The documents for the systematical assessment of other biological medications (e.g. Tocilizumab, Daclizumab and Rituximab) were inadequate; however, the mean response rate for these drugs was 59, 75 and 80%, respectively. Our meta-analysis showed a pooled response rate of 40.0% (95%CI, 36.0% to 44.2) to Methotrexate. Significant heterogeneity and significant diffusion bias were demonstrated by reviewing studies.
CONCLUSIONS
The pooled prevalence of uveitis in pediatric rheumatic diseases widely varied based on the underlying disease requiring more investigations in different subtypes of rheumatic diseases. The biologic medications, especially Adalimumab are the most effective treatments for uveitis in pediatric rheumatic diseases; however, a combination of the safe, available alternatives is preferred to achieve the most desirable treatment response.
Topics: Adalimumab; Antirheumatic Agents; Arthritis, Juvenile; Child; Humans; Methotrexate; Uveitis
PubMed: 32019589
DOI: 10.1186/s13023-020-1324-x -
Journal of Neurology Oct 2020SELECTED, an open-label extension study, evaluated daclizumab beta treatment for up to 6 years in participants with relapsing multiple sclerosis who completed the... (Clinical Trial)
Clinical Trial
OBJECTIVE
SELECTED, an open-label extension study, evaluated daclizumab beta treatment for up to 6 years in participants with relapsing multiple sclerosis who completed the randomized SELECT/SELECTION studies. We report final results of SELECTED.
METHODS
Eligible participants who completed 1-2 years of daclizumab beta treatment in SELECT/SELECTION received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 6 years in SELECTED. Safety assessments were evaluated for the SELECTED treatment period; efficacy data were evaluated from first dose of daclizumab beta in SELECT/SELECTION.
RESULTS
Ninety percent (410/455) of participants who completed treatment in SELECTION enrolled in SELECTED. Within SELECTED, 69% of participants received daclizumab beta for > 3 years, 39% for > 4 years, and 9% for > 5 years; 87% of participants experienced an adverse event and 26% a serious adverse event (excluding multiple sclerosis relapse). No deaths occurred. Overall, hepatic events were reported in 25% of participants; serious hepatic events in 2%. There were no confirmed cases of immune-mediated encephalitis. Based on weeks from the first daclizumab beta dose in SELECT/SELECTION, adjusted annualized relapse rate (95% confidence interval) for weeks 0-24 was 0.21 (0.16-0.29) and remained low on continued treatment. Overall incidence of 24-week confirmed disability progression was 17.4%. Mean numbers of new/newly enlarging T2 hyperintense lesions remained low; percentage change in whole brain volume decreased over time.
CONCLUSIONS
The effects of daclizumab beta on clinical and radiologic outcomes were sustained for up to ~ 8 years of treatment. No new safety concerns were identified in SELECTED.
TRIAL REGISTRATION
Clinicaltrials.gov NCT01051349; first registered on January 15, 2010.
Topics: Adult; Antibodies, Monoclonal, Humanized; Daclizumab; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Male; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 32451615
DOI: 10.1007/s00415-020-09835-y -
Pharmacoepidemiology and Drug Safety Apr 2022Multiple sclerosis (MS) is a chronic disease of the central nervous system that disproportionately affects women, with typical onset during reproductive age. Several...
PURPOSE
Multiple sclerosis (MS) is a chronic disease of the central nervous system that disproportionately affects women, with typical onset during reproductive age. Several disease-modifying therapies (DMTs) are FDA-approved to slow disease progression, but are not indicated for use during pregnancy. Our objective was to describe trends over time (2010-2019) in monthly point prevalence of DMT use among reproductive-age women, overall and by generic name.
METHODS
This study used administrative claims data from the US during 2009-2019 to identify women age 15-44 with MS and continuous insurance coverage for ≥12 months. DMTs were identified using prescription fills and procedural claims for alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta, mitoxantrone, natalizumab, ocrelizumab, and teriflunomide. Monthly prevalent use was defined as ≥1 days' supply of a DMT in the month. Age- and region-standardized monthly prevalence was estimated nonparametrically.
RESULTS
Among 42 281 reproductive-aged women over 818 179 person-months, DMT use increased from a minimum monthly prevalence of 49.3% (February, 2011) to a maximum of 58.7% (April, 2019). In 2010, prevalence of injectable DMTs was 43.1% compared to 2.5% for oral DMTs; by 2014, however, oral DMTs (26.5%) surpassed injectable DMTs (23.7%) as the most common route of administration. In the most recent data available (December, 2019), the most common DMTs were dimethyl fumarate, glatiramer acetate, and fingolimod.
CONCLUSIONS
DMT use among reproductive-aged women has rapidly evolved during the past decade. Collaborative treatment decision making between women with MS and clinicians may help optimize MS care and improve DMT uptake during reproductive years.
Topics: Adolescent; Adult; Female; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; United States; Young Adult
PubMed: 35088492
DOI: 10.1002/pds.5411 -
Frontiers in Neurology 2020Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal...
Quantifying cell subpopulations in biological fluids aids in diagnosis and understanding of the mechanisms of injury. Although much has been learned from cerebrospinal fluid (CSF) flow cytometry in neuroimmunological disorders, such as multiple sclerosis (MS), previous studies did not contain enough healthy donors (HD) to derive age- and gender-related normative data and sufficient heterogeneity of other inflammatory neurological disease (OIND) controls to identify MS specific changes. The goals of this blinded training and validation study of MS patients and embedded controls, representing 1,240 prospectively acquired paired CSF/blood samples from 588 subjects was (1) to define physiological age-/gender-related changes in CSF cells, (2) to define/validate cellular abnormalities in blood and CSF of untreated MS through disease duration (DD) and determine which are MS-specific, and (3) to compare effect(s) of low-efficacy (i.e., interferon-beta [IFN-beta] and glatiramer acetate [GA]) and high-efficacy drugs (i.e., natalizumab, daclizumab, and ocrelizumab) on MS-related cellular abnormalities using propensity score matching. Physiological gender differences are less pronounced in the CSF compared to blood, and age-related changes suggest decreased immunosurveillance of CNS by activated HLA-DR+T cells associated with natural aging. Results from patient samples support the concept of MS being immunologically single disease evolving in time. Initially, peripherally activated innate and adaptive immune cells migrate into CSF to form MS lesions. With progression, T cells (CD8+ > CD4+), NK cells, and myeloid dendritic cells are depleted from blood as they continue to accumulate, together with B cells, in the CSF and migrate to CNS tissue, forming compartmentalized inflammation. All MS drugs inhibit non-physiological accumulation of immune cells in the CSF. Although low-efficacy drugs tend to normalize it, high-efficacy drugs overshoot some aspects of CSF physiology, suggesting impairment of CNS immunosurveillance. Comparable inhibition of MS-related CSF abnormalities advocates changes within CNS parenchyma responsible for differences in drug efficacy on MS disability progression. Video summarizing all results may become useful educational tool.
PubMed: 33329307
DOI: 10.3389/fneur.2020.565957 -
Iranian Journal of Basic Medical... Mar 2021IL-2Rα plays a critical role in maintaining immune function. However, expression and secretion of CD25 in various malignant disorders and autoimmune diseases are now...
OBJECTIVES
IL-2Rα plays a critical role in maintaining immune function. However, expression and secretion of CD25 in various malignant disorders and autoimmune diseases are now well established. Thus, CD25 is considered an important target candidate for antibody-based therapy. This study aimed to find the most suitable linker peptide to construct a functional anti-CD25 single-chain fragment variable (scFv) by bioinformatics studies and its production in a bacterial expression system.
MATERIALS AND METHODS
Here, the 3D structures of the scFvs with different linkers were predicted and molecular dynamics simulation was performed to compare their structures and dynamics. Then, interactions between five models of scFv and human CD25 were calculated via molecular docking. According to MD and docking results, the anti-CD25 scFvs with (Gly4Ser)3 linker were constructed and cloned into pET-22b(+). Then, recombinant plasmids were transformed into Bl21 (DE3) for expression using IPTG and lactose as inducers. Anti-CD25 scFv was purified from the periplasm and detected by SDS-PAGE and Western blot. Afterward, functionality was evaluated using ELISA.
RESULTS
analysis showed that the model containing (Gly4Ser)3 as a linker has more stability compared with other linkers. The results of SDS-PAGE, Western blot, and ELISA confirmed the accuracy of anti-CD25 scFv production and its ability to bind to the human CD25.
CONCLUSION
Conclusively, our work provides a theoretical and experimental basis for production of an anti-CD25 scFv, which may be applied for various malignant disorders and autoimmune diseases.
PubMed: 33995947
DOI: 10.22038/ijbms.2021.51709.11728 -
American Health & Drug Benefits May 2020Multiple sclerosis (MS) is a rare, long-standing, and disabling disease that affects the central nervous system and causes several clinical manifestations. As a result,...
BACKGROUND
Multiple sclerosis (MS) is a rare, long-standing, and disabling disease that affects the central nervous system and causes several clinical manifestations. As a result, this disease is associated with a high societal economic burden.
OBJECTIVE
To analyze the trends in drug expenditure, utilization, and cost of specialty drugs for the treatment of patients with MS in the US Medicaid program.
METHODS
In this retrospective drug utilization research analysis, we obtained prescription data and reimbursement of disease-modifying therapies for MS from the Centers for Medicare & Medicaid Services Medicaid State Drug Utilization Data between January 2008 and December 2018. The specialty drugs considered in our analysis included dimethyl fumarate, fingolimod, teriflunomide, cladribine, siponimod, alemtuzumab, natalizumab, ocrelizumab, daclizumab, glatiramer acetate, peginterferon beta-1a, interferon beta-1a, and interferon beta-1b. The annual trends of the number of prescriptions, reimbursement expenditures, and costs were calculated. The average reimbursement per prescription was calculated as an estimate of the drug cost.
RESULTS
The annual MS drug utilization increased from 85,209 prescriptions in 2008 to 223,604 in 2016, and then decreased to 194,877 in 2018. The annual reimbursement surged by 633% in the 10-year study period between 2008 and 2018, from almost $172 million in 2008 to more than $1.4 billion in 2017, and then to approximately $1.26 billion in 2018. The cost per prescription increased over time for most MS brand-name drugs (eg, from $2033 in 2008 to $5114 in 2018 for natalizumab, and from $19,138 in 2016 to $23,588 in 2018 for alemtuzumab). In 2008, self-injectable drugs dominated the market. In recent years, a shift has occurred in the utilization and reimbursement of MS drugs, with oral medications becoming predominant.
CONCLUSION
The study findings indicate intermarket and interbrand competition among the MS specialty drugs. The growing utilization and spending trends for specialty MS medications are significant and sizable in the US Medicaid programs. Medicaid cost-containment strategy is warranted to control the economic burden of state budgets across the country.
PubMed: 32724502
DOI: No ID Found