Neuroimaging analyses from a randomized, controlled study to evaluate plasma exchange with albumin replacement in mild-to-moderate Alzheimer's disease: additional results from the AMBAR study
European journal of nuclear medicine and molecular imaging. 2022
PURPOSE This study was designed to detect structural and functional brain changes in Alzheimer's disease (AD) patients treated with therapeutic plasma exchange (PE) with albumin replacement, as part of the recent AMBAR phase 2b/3 clinical trial. METHODS Mild-to-moderate AD patients were randomized into four arms: three arms receiving PE with albumin (one with low-dose albumin, and two with low/high doses of albumin alternated with IVIG), and a placebo (sham PE) arm. All arms underwent 6 weeks of weekly conventional PE followed by 12 months of monthly low-volume PE. Magnetic resonance imaging (MRI) volumetric analyses and regional and statistical parametric mapping (SPM) analysis on (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG-PET) were performed. RESULTS MRI analyses (n = 198 patients) of selected subcortical structures showed fewer volume changes from baseline to final visit in the high albumin + IVIG treatment group (p < 0.05 in 3 structures vs. 4 to 9 in other groups). The high albumin + IVIG group showed no statistically significant reduction of right hippocampus. SPM (18)FDG-PET analyses (n = 213 patients) showed a worsening of metabolic activity in the specific areas affected in AD (posterior cingulate, precuneus, and parieto-temporal regions). The high-albumin + IVIG treatment group showed the greatest metabolic stability over the course of the study, i.e., the smallest percent decline in metabolism (MaskAD), and least progression of defect compared to placebo. CONCLUSIONS PE with albumin replacement was associated with fewer deleterious changes in subcortical structures and less metabolic decline compared to the typical of the progression of AD. This effect was more marked in the group treated with high albumin + IVIG. TRIAL REGISTRATION (AMBAR trial registration: EudraCT#: 2011-001,598-25; ClinicalTrials.gov ID: NCT01561053).
Feasibility, safety, and tolerability of two modalities of plasma exchange with albumin replacement to treat elderly patients with Alzheimer's disease in the AMBAR study
Journal of clinical apheresis. 2022
BACKGROUND In the Alzheimer Management by Albumin Replacement (AMBAR) study, mild-to-moderate Alzheimer's disease (AD) patients were treated with a plasma exchange (PE) program. Feasibility and safety of PE in this specific population are poorly understood and were analyzed in detail in this study. METHODS Qualified patients were treated with 6 weeks of weekly conventional therapeutic plasma exchange (TPE) with albumin replacement followed by monthly low-volume plasma exchange (LVPE) for 12 months. The patients were divided into four groups: placebo (sham PE treatment), low-albumin (20 g), low-albumin + intravenous immunoglobulin (IVIG) (10 g), and high-albumin (40 g) + IVIG (20 g). Adverse events (AEs) were recorded and analyzed for all PE treatment groups and PE modalities. RESULTS PE procedure-related AEs were more common in the active treatment groups (16.9% out of 1283 TPE and 12.5% out of 2203 LVPE were associated with at least one AE, a similar rate than in other PE indications) than in the placebo group (0.7% out of 1223 sham PE). Percentage of procedures with at least one AEs was higher with central venous access compared to peripheral venous access in all three active treatment groups (20.1% vs 13.1%, respectively). CONCLUSION The TPE and LVPE procedures used in the AMBAR study on mild-to-moderate AD population were as safe and feasible as in other therapeutic applications of PE or routine plasmapheresis.
Neuropsychological, neuropsychiatric, and quality-of-life assessments in Alzheimer's disease patients treated with plasma exchange with albumin replacement from the randomized AMBAR study
Alzheimer's & dementia : the journal of the Alzheimer's Association. 2021
INTRODUCTION We report the effects of plasma exchange (PE) with albumin replacement on neuropsychological, neuropsychiatric, and quality-of-life (QoL) outcomes in mild-to-moderate Alzheimer's disease (AD) patients in a phase 2b/3 trial (Alzheimer's Management by Albumin Replacement [AMBAR] study). METHODS Three hundred forty-seven patients were randomized into placebo (sham-PE) and three PE-treatment arms with low/high doses of albumin, with/without intravenous immunoglobulin (IVIG). Specific test measurements were performed at baseline; month 2 (weekly conventional PE); months 6, 9, and 12 (monthly low-volume PE [LVPE]); and month 14. RESULTS The PE-treated mild-AD cohort improved their language fluency and processing speed versus placebo at month 14 (effect sizes: >100%; P-values: .03 to .001). The moderate-AD cohort significantly improved short-term verbal memory (effect sizes: 94% to >100%; P-values: .02 to .003). The progression of the neuropsychiatric symptoms of PE-treated was similar to placebo. Mild-AD patients showed improved QoL (P-values: .04 to .008). DISCUSSION PE-treated AD patients showed improvement in memory, language abilities, processing speed, and QoL-AD. No worsening of their psychoaffective status was observed.
Efficacy and safety of double-filtration plasmapheresis treatment of myasthenia gravis: A systematic review and meta-analysis
OBJECTIVES To evaluate the efficacy of double-filtration plasmapheresis (DFPP) treatment of myasthenia gravis (MG) through a systematic review and meta-analysis. METHODS PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), and Wanfang databases were searched for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) on DFPP for MG from database establishment to June 2019. Two researchers independently screened the articles, extracted the data, and cross checked the results. RevMan 5.3 was used for statistical analyses. RESULTS Seven RCTs and 2 CCTs were found comprising 329 patients. The results showed that clinical MG remission rate after DFPP treatment was significantly higher (OR = 4.33; 95% confidence interval [CI], 1.97-9.53; P < .001) and the serum levels of antititin antibody was significantly decreased (standardized mean difference [SMD] = 9.30; 95% CI, 7.51-11.08; P < .001). In addition, the quantitative MG (QMG) score, hospital stay and time to remission of MG symptoms, and acetylcholine receptor antibody (AchRAb) decreased in the DFPP treatment group; however, these outcomes had high heterogeneity among the studies. Only one study has reported on the adverse effects, including hypotension and hematoma. CONCLUSION This meta-analysis suggests that DFPP can be recommended for the short-term mitigation of MG. Because our review was limited by the quantity and quality of the included studies, the above conclusions should be verified by additional high-quality studies.
Efficacy of plasma exchange in acute attacks of neuromyelitis optica spectrum disorders: A systematic review and meta-analysis
Journal of neuroimmunology. 2020;350:577449
BACKGROUND Plasma exchange (PE) has usually to be considered as a rescue therapy when intravenous corticosteroids is insufficient in acute attacks of neuromyelitis optica spectrum disorders (NMOSD). The efficacy of PE has not been quantified. This system review and meta-analysis was aimed to evaluate the efficacy of PE therapy in acute attacks of NMOSD. METHODS Studies evaluating the efficacy of PE in patients with NMOSD were identified from PubMed and Embase. Changes of Expanded Disability Status Scale (EDSS) score between before and after PE therapy, and the rate of response to PE, were defined as the main efficacy outcomes. Meta-regression was performed to identify the sources of heterogeneity. Subgroup meta-analysis were performed based on the interval of initiation PE after attack onset and AQP4-IgG serostatus of patients. RESULTS Twenty-four studies containing 528 patients with NMOSD were included in this meta-analysis. As a rescue therapy when patients failed to respond to intravenous corticosteroids (PE rescue), PE treatment resulted in a reduction in the mean EDSS score by 1.69 (95% CI: 0.88-2.50), with a response rate of 75%(95%CI: 66%-83%). As a first-line therapy being used alone or simultaneously with intravenous corticosteroids (PE first-line), PE resulted in a reduction in the mean EDSS score by 2.34 (95% CI: 1.69-2.98), with a response rate of 71%(95%CI: 44%-93%). Overall, PE resulted in a reduction in the mean EDSS score by 1.83 (95% CI: 1.19-2.47), with a response rate of 74% (95%CI: 66%-82%). Subgroup analysis suggested that earlier PE initiation and AQP4-IgG seronegative patients seemed to be associated with a superior response to PE therapy. CONCLUSION Plasma exchange, whether used as rescue or as first-line therapy, is an effective therapeutic method in patients during acute attacks of NMOSD.
Therapeutic plasma exchange vs conventional treatment with intravenous high dose steroid for neuromyelitis optica spectrum disorders (NMOSD): a systematic review and meta-analysis
Journal of neurology. 2020
BACKGROUND Therapeutic plasma exchanges (TPE) has been recommended for neuromyelitis optica spectrum disorders (NMOSD) as a rescue therapy after nonresponding from the high-dose steroid and as an early therapy in severe attacks. We performed a systematic review to evaluate whether therapeutic plasma exchange (TPE) is better than conventional intravenous methylprednisolone (IVMP) in neuromyelitis optica spectrum disorders (NMOSD) patients. METHODS Systematic search was conducted in five databases: PubMed, Embase, Scopus, Web of Science, and CENTRAL for randomized controlled trials and observational studies of TPE compared to intravenous steroid in NMOSD patients with neurological or visual outcomes in English without publication date restriction. Quality assessment was performed using ROB2 and ROBINS-I. The meta-analysis was done using a random-effects model. Pooled risk ratio (RR) or mean difference with a 95% CIs of efficacy outcomes included the Expanded Disability Status Scale (EDSS), visual acuity, and LogMAR were measured. RESULTS Of 3439 potential studies, seven were included in the systematic review (1211 attacks; 433 patients) and three studies were included in the meta-analysis. Compared to high dose steroid alone, the add-on TPE increases a chance for the returning of EDSS to baseline at discharge (RR 3.02, 95% CI 1.34-6.81) and last follow-up (RR 1.68, 95% CI 1.01-2.79) as well as improves visual acuity at last follow-up. CONCLUSION TPE as an add-on therapy to high-dose steroid injection during an acute attack in NMOSD patients is associated with returning to baseline EDSS at discharge and last follow-up, and a trend to have a lower disability at 6-12 months.
Plasma Exchange or Immunoadsorption in Demyelinating Diseases: A Meta-Analysis
J Clin Med. 2020;9(5)
Multiple sclerosis (MS) is an inflammatory disease mainly affecting the central nervous system. In MS, abnormal immune mechanisms induce acute inflammation, demyelination, axonal loss, and the formation of central nervous system plaques. The long-term treatment involves options to modify the disease progression, whereas the treatment for the acute relapse has its focus in the administration of high-dose intravenous methylprednisolone (up to 1000 mg daily) over a period of three to five days as a first step. If symptoms of the acute relapse persist, it is defined as glucocorticosteroid-unresponsive, and immunomodulation by apheresis is recommended. However, several national and international guidelines have no uniform recommendations on using plasma exchange (PE) nor immunoadsorption (IA) in this case. A systematic review and meta-analysis was conducted, including observational studies or randomized controlled trials that investigated the effect of PE or IA on different courses of MS and neuromyelitis optica (NMO). One thousand, three hundred and eighty-three patients were included in the evaluation. Therapy response in relapsing-remitting MS and clinically isolated syndrome was 76.6% (95%CI 63.7-89.8%) in PE- and 80.6% (95%CI 69.3-91.8%) in IA-treated patients. Based on the recent literature, PE and IA may be considered as equal treatment possibilities in patients suffering from acute, glucocorticosteroid-unresponsive MS relapses.
Multiple sclerosis (MS) and neuromyelitis optica (NMO) patients (41 studies, n=1383).
Plasma exchange (PE).
Therapy response in relapsing-remitting multiple sclerosis and clinically isolated syndrome was 76.6% in PE- and 80.6% in IA-treated patients. Therapy response in NMO was 72.5% in PE-treated patients, and 100% in IA-treated patients.
A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study
Alzheimers Dement. 2020
INTRODUCTION This phase 2b/3 trial examined the effects of plasma exchange (PE) in patients with mild-to-moderate Alzheimer's disease (AD). METHODS Three hundred forty-seven patients (496 screened) were randomized (1:1:1:1) into three PE treatment arms with different doses of albumin and intravenous immunoglobulin replacement (6-week period of weekly conventional PE followed by a 12-month period of monthly low-volume PE), and placebo (sham). RESULTS PE-treated patients performed significantly better than placebo for the co-primary endpoints: change from baseline of Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL; P = .03; 52% less decline) with a trend for Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; P = .06; 66% less decline) scores at month 14. Moderate-AD patients (baseline Mini-Mental State Examination [MMSE] 18-21) scored better on ADCS-ADL (P = .002) and ADAS-Cog (P = .05), 61% less decline both. There were no changes in mild-AD patients (MMSE 22-26). PE-treated patients scored better on the Clinical Dementia Rating Sum of Boxes (CDR-sb) (P = .002; 71% less decline) and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change (ADCS-CGIC) (P < .0001; 100% less decline) scales. DISCUSSION This trial suggests that PE with albumin replacement could slow cognitive and functional decline in AD, although further studies are warranted.
Therapeutic Plasmapheresis with Albumin Replacement in Alzheimer's Disease and Chronic Progressive Multiple Sclerosis: A Review
Pharmaceuticals (Basel, Switzerland). 2020;13(2)
BACKGROUND Reducing the burden of beta-amyloid accumulation and toxic autoimmunity-related proteins, one of the recognized pathophysiological markers of chronic and common neurological disorders such as Alzheimer's disease (AD) and multiple sclerosis (MS), may be a valid alternative therapy to reduce their accumulation in the brain and thus reduce the progression of these disorders. The objective of this review was to evaluate the efficacy of plasmapheresis (PP) in AD and chronic progressive MS patients (in terms of improving clinical symptoms) and to analyze its safety and protocols. METHODS Articles related to this topic and published without time limitations in the Medline, and Cochrane databases were reviewed. RESULTS In AD patients, PP reduced amyloid beta (Abeta) levels in the brain, accompanied by a tendency towards cognitive stabilization, and improved language and verbal fluency. In regards to structural and functional brain changes, PP reduced brain volume and favored the stabilization, or absence, of the progression of perfusion. In chronic progressive form of MS patients, PP improved neurological deficits in 20-70% of patients with a chronic progressive form of MS, and restored interferon (IFN) responsiveness, which was not accompanied by any image change in brain plaques. CONCLUSIONS Therapeutic plasmapheresis with albumin replacement is a promising strategy for reducing Abeta mediated toxicity and slowing the progression of the disorder. Some patients with chronic progressive forms of MS show improvement in neurological deficits. The features of AD and MS patients who benefit most from this approach need further research.
Double-blind, randomized controlled trial of therapeutic plasma exchanges vs sham exchanges in moderate-to-severe relapses of multiple sclerosis
J Clin Apher. 2020
INTRODUCTION No randomized controlled clinical trial of therapeutic plasma exchanges (TPE) has yet been performed for moderate-to-severe relapses of multiple sclerosis (MS). OBJECTIVE To compare TPE to sham-TPE in patients with a recent steroid-resistant moderate-to-severe MS relapse. METHODS Patients presenting with an MS relapse of less than 2 months without improvement and 15 days after a course of steroids were randomized. Specific criteria were used for each relapse type to define moderate-to-severe disability. The primary endpoint was the proportion of patients with at least a moderate improvement based on objective and functional evaluation after 1 month. RESULTS Thirty-eight patients were randomized. The intention-to-treat analysis included 14 patients in the TPE group and 17 in the Sham-TPE group. The proportion of patients with at least moderate improvement at 1 month did not differ between the groups (P = .72), although 57.1% of the TPE group had full recovery compared with 17.6% of the sham group. Considering optic neuritis (ON), a significant difference in the proportion of different levels of improvement was observed in favor of the TPE group (P = .04). The combined Kurtzke's functional systems scores were significantly more improved in the TPE group than in the sham-TPE group at months 1 (P < .01), 3 (P < .05), and 6 (P < .05). No major side effects were observed. CONCLUSIONS A significant difference between TPE and Sham-TPE at the primary endpoint was only observed in patients with ON. Neurological function improved significantly more often in the TPE group than in the sham-TPE group.