Impact of Autologous Mesenchymal Stem Cell Infusion on Neuromyelitis Optica Spectrum Disorder: A Pilot, 2-Year Observational Study.
ABSTRACT: AIMS:We evaluate safety and efficacy of autologous bone marrow-derived mesenchymal stem cells (MSCs) as a potential treatment for neuromyelitis optica spectrum disorder (NMOSD). METHODS:Fifteen patients with NMOSD were recruited. All patients received a single intravenous infusion of 1.0 × 10(8) autologous MSC within 3-4 generations derived from bone marrow. The primary endpoints of the study were efficacy as reflected by reduction in annualized relapse rates (ARRs) and inflammatory lesions observed by MRI. RESULTS:At 12 months after MSC infusion, the mean ARR was reduced (1.1 vs. 0.3, P = 0.002), and the T2 or gadolinium-enhancing T1 lesions decreased in the optic nerve and spinal cord. Disability in these patients was reduced (EDSS, 4.3 vs. 4.9, P = 0.021; visual acuity, 0.4 vs. 0.5, P = 0.007). The patients had an increase in retinal nerve fiber layer thickness, optic nerve diameters and upper cervical cord area. We did not identify any serious MSC-related adverse events. At 24 months of MSC infusion, of 15 patients, 13 patients (87%) remained relapse-free, the mean ARR decreased to 0.1; the disability of 6 patients (40%) was improved, and the mean EDSS decreased to 4.0. CONCLUSIONS:This pilot trial demonstrates that MSC infusion is safe, reduces the relapse frequency, and mitigates neurological disability with neural structures in the optic nerve and spinal cord recover in patients with NMOSD. The beneficial effect of MSC infusion on NMOSD was maintained, at least to some degree, throughout a 2-year observational period.
Project description:Since its initial reports in the 19th century, neuromyelitis optica (NMO) had been thought to involve only the optic nerves and spinal cord. However, the discovery of highly specific anti-aquaporin-4 antibody diagnostic biomarker for NMO enabled recognition of more diverse clinical spectrum of manifestations. Brain MRI abnormalities in patients seropositive for anti-aquaporin-4 antibody are common and some may be relatively unique by virtue of localization and configuration. Some seropositive patients present with brain involvement during their first attack and/or continue to relapse in the same location without optic nerve and spinal cord involvement. Thus, characteristics of brain abnormalities in such patients have become of increased interest. In this regard, MRI has an increasingly important role in the differential diagnosis of NMO and its spectrum disorder (NMOSD), particularly from multiple sclerosis. Differentiating these conditions is of prime importance because early initiation of effective immunosuppressive therapy is the key to preventing attack-related disability in NMOSD, whereas some disease-modifying drugs for multiple sclerosis may exacerbate the disease. Therefore, identifying the MRI features suggestive of NMOSD has diagnostic and prognostic implications. We herein review the brain, optic nerve, and spinal cord MRI findings of NMOSD.
Project description:Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease that mainly involves the optic nerves and spinal cord, causing blindness and paralysis. Although some immunosuppressants such as rituximab and azathioprine have proven to be effective in relapse prevention, the high costs or intolerable adverse events preclude their wide application. Thus, we have conducted a retrospective study in 25 NMOSD patients who were treated with tacrolimus, an immunosuppressant with high efficacy and good tolerance in other autoimmune diseases, to assess its efficacy and safety in NMOSD treatment during the last five years (2011-2016). The results revealed that tacrolimus could reduce the relapse rate by 86.2% and improve the Expanded Disability Status Scale (EDSS) scores (4.5 vs 2.3; P?<?0.001) significantly. Relapses in tacrolimus treatment were associated with serum titers of aquaporin 4 antibody (AQP4-IgG) (P?=?0.028). Further Cox proportional analysis demonstrated that patients with high titers of AQP4-IgG (?1:64) had a significantly higher risk of relapse than those with low titers after tacrolimus therapy (HR:5.665; CI95: 1.012-31.705; P?=?0.048). Tacrolimus tended to be superior to azathioprine (29 patients) in terms of efficacy and safety during the same period. Our study suggests that tacrolimus may be another promising immunosuppressant for NMOSD.
Project description:OBJECTIVE:To test the safety of ublituximab, a B cell depleting agent, as add-on therapy in the acute treatment of relapses of neuromyelitis optica spectrum disorder. METHODS:We conducted an open-label phase 1b safety and proof-of-concept trial in 5 subjects with aquaporin-4 (AQP4)-immunoglobulin G (IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD) who presented with acute transverse myelitis and/or optic neuritis. In addition to treating with 1?g of daily intravenous methylprednisolone, we infused a single dose of 450?mg of ublituximab within 5 days of relapse onset. The primary outcome measure was safety, and the secondary efficacy measures included change in Expanded Disability Status Scale (EDSS), durability of remission and B cell counts. RESULTS:Five NMOSD subjects were enrolled, 4 of whom presented with acute transverse myelitis and 1 with acute optic neuritis. Ublituximab proved to be safe in all 5 NMOSD subjects, with no serious adverse events recorded. There were no opportunistic infections in any of the subjects; however, 1 subject experienced a transient leukopenia. EDSS scores dropped from a median of 6.5 on admission to 4.0 on 90-day follow up. Two subjects did not achieve total B cell depletion and relapsed within 3 months. CONCLUSIONS:Ublituximab is a safe add-on therapy for NMOSD patients presenting with acute transverse myelitis and optic neuritis. Preliminary evidence suggests a promising benefit on durability of remission when B cell depletion is achieved. A placebo-controlled trial is necessary to confirm these findings. CLASSIFICATION OF EVIDENCE:This study provides Class IV evidence that for patients with NMOSD with acute transverse myelitis or optic neuritis, ublituximab is safe and may improve neurological outcome.
Project description:Patients with autoimmune disorders often have low levels of 25-hydroxyvitamin D [25(OH)D3], which correlates with disability or disease activity. Vitamin D may play a role in neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD), as an important factor involved in immunological pathways. We investigated the relationship between vitamin D levels and disease related disability and clinical activity in patients with NMOSD. Blood samples from 51 patients with NMOSD who were positive for anti-aquaporin4-antibody (AQP4-ab) and 204 healthy controls were collected for 25(OH)D3 measurement. Clinical parameters, including expanded disability status scale (EDSS) score, annualized relapse rate (ARR) and time of blood sampling relative to attack, were determined in patients with NMOSD. We found that 25(OH)D3 levels were significantly lower in patients with NMOSD compared to healthy controls. There was no difference between 25(OH)D3 levels in blood samples taken at relapse or remission, and no association between 25(OH)D3 levels and ARR, but there was an inverse correlation between 25(OH)D3 levels and EDSS scores in patients with NMOSD. It remains to be determined whether low vitamin D levels predispose to NMO and/or modify disease severity, or are secondary to neurological disability. In either case the results could also be of relevance to other neurological diseases such as multiple sclerosis as well as NMO.
Project description:Mycophenolate mofetil (MMF) is an immunosuppressive agent (IS) which is widely prescribed in neuromyelitis optica spectrum disorder (NMOSD) patients. We aim to assess the efficacy and safety of MMF in controlling relapse and disease severity. Eligible studies obtained from the EMBASE and Ovid MEDLINE databases were studies of NMOSD patients treated with MMF, which reported treatment outcomes as Annualized Relapse Rate (ARR) or Expanded Disability Status Scale (EDSS) before and after treatment. Fifteen studies included 1047 patients, of whom 915 (87.4%) were aquaporin-4 immunoglobulin seropositive. The total number of patients that received MMF was 799. A meta-analysis on ARR was conducted in 200 patients from 4 studies and on EDSS in 158 patients from 3 studies. The result showed a significant improvement with a mean reduction of 1.13 [95% confidence interval (CI) 0.60–1.65] in ARR, and a mean reduction of 0.85 (95% CI 0.36–1.34) in EDSS after MMF therapy. Adverse events occurred in 106 (17.8%) of 594 patients during MMF therapy. This systematic review and meta-analysis showed that using MMF as a preventive therapy in NMOSD patients can significantly reduce relapse rates and improve disease severity with acceptable tolerability.
Project description:To minimize complement-mediated damage in acute relapses of neuromyelitis optica (NMO) by adding treatment with a complement inhibitor, purified C1-esterase inhibitor, to the current standard of care (high-dose glucocorticoids).We conducted an open-label phase 1b safety and proof-of-concept trial in 10 patients with NMO-immunoglobulin G seropositive NMO or NMO spectrum disease (NMOSD) who presented with acute transverse myelitis and/or optic neuritis. In addition to treating with 1 g of daily IV methylprednisolone, we infused 2,000 units of C1-esterase inhibitor daily for 3 days, beginning on day 1 of hospitalization. The primary outcome measure was safety, and the secondary efficacy measure was change in Expanded Disability Status Scale (EDSS) scores.Ten patients with NMO/NMOSD were enrolled, 7 of whom presented with acute transverse myelitis and 3 with acute optic neuritis. C1-esterase inhibitor proved to be safe in all 10 patients, with no serious adverse events recorded. There were no thromboembolic events or related lab abnormalities in any of the subjects. EDSS scores dropped from a median of 4.5 on admission to 4.0 on discharge and then down to 2.5 on 30-day follow-up. All but 1 patient returned to preattack EDSS or better and only 2 patients required escalation to plasmapheresis.C1-esterase inhibitor is a safe add-on therapy for patients with NMO/NMOSD presenting with acute transverse myelitis and optic neuritis. Preliminary evidence suggests a promising benefit with C1-esterase inhibitor in reducing neurologic damage and improving outcomes. A placebo-controlled trial is necessary to confirm these findings.This study provides Class IV evidence that for patients with NMO with acute transverse myelitis or optic neuritis, C1-esterase inhibitor is safe and improves disability.
Project description:Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon antibody-mediated disease of the central nervous system. Long segments of spinal cord inflammation (myelitis), severe optic neuritis, and/or bouts of intractable vomiting and hiccoughs (area postrema syndrome) are classic presentations of the disease and may alert the clinician to the diagnosis. Untreated, approximately 50% of NMOSD patients will be wheelchair users and blind, and a third will have died within 5 years of their first attack. Unlike multiple sclerosis, a progressive clinical course is very unusual and the accrual of disability is related to relapses. Approximately 75% of patients have antibodies against aquaporin-4, a water channel expressed on astrocytes. Relapses are treated aggressively to prevent residual disability with high-dose steroids and often plasma exchange. Relapse prevention is crucial and achieved with long-term immunosuppression. In this article we review the pathogenesis, clinical features, diagnosis and management of NMOSD.
Project description:Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS.
Project description:Background: Blood-brain barrier (BBB) pathology exists in neuromyelitis optica spectrum disorders (NMOSD). However, the clinical use of BBB permeability, such as predicting disease severity of NMOSD, has rarely been studied in a large cohort of patients. Objectives: The current study explored the association between BBB permeability and clinical parameters in order to assess if BBB permeability could be a biomarker to predict disease severity and clinical characteristics of NMOSD. Methods: Among 69 enrolled NMOSD patients, 47 with albumin index over 5 × 10-3 were assigned to the increased BBB permeability group, and the remaining 22 were to the normal BBB permeability group. Disease severity was assessed using the Expanded Disability Status Scale (EDSS). Results: Patients in the increased BBB permeability group had significantly higher EDSS scores, anti-aquporin-4 immunoglobulin G titers, more dense cerebrospinal fluid protein concentrations, white blood cell counts, myelin basic protein levels and more dense complement 3 concentrations than found in the comparative normal BBB permeability group. The albumin index was positively correlated to the length of lesions in spinal cord. Conclusions: BBB permeability was associated with clinical features, laboratory results and radiological data of NMOSD patients, and may be a potential biomarker to predict disease severity and clinical characteristics of NMOSD.
Project description:Background: Neuromyelitis optica spectrum disorder (NMOSD), an autoimmune inflammatory disorder of the central nervous system, often leads to vision loss or paralysis. This meta-analysis focused on the assessment of the monoclonal antibody therapy in NMOSD and compared different targets of monoclonal antibodies with each other in terms of efficacy and safety outcomes. Method: We searched through the databases of MEDLINE, EMBASE, Central Register of Controlled Trials (CENTRAL), and clinicaltrials.gov for randomized controlled trials (RCTs) evaluating monoclonal antibody therapy in NMOSD up to April 2020. Results: We identified seven randomized controlled trials (RCTs), including 775 patients (monoclonal antibody group, n = 485 and placebo group, n = 290). Monoclonal antibody therapy decreased relapse risk (RR 0.33, 95% CI 0.21–0.52, P < 0.00001), annualized relapse rate (ARR) (mean ?0.28, 95% CI ?0.35?0.20, P < 0.00001), expanded disability status scale score (EDSS) (mean ?0.19, 95% CI ?0.32?0.07, P = 0.002) and serious adverse events (RR 0.78, 95% CI 0.61–1.00, P = 0.05). However, we did not observe any significant difference in terms of adverse events or mortality. Further, the subgroup analysis demonstrated that the anti-complement protein C5 monoclonal antibody (eculizumab) might have a lower relapse risk (RR 0.07, 95% CI 0.02–0.23, P < 0.0001) in the AQP4 seropositive patients, and anti-interleukin-6 receptor monoclonal antibodies (satralizumab and tocilizumab) showed decreased EDSS score (mean ?0.17, 95% CI ?0.31?0.02, P = 0.02) more effectively than other monoclonal antibodies. Conclusions: Monoclonal antibodies were effective and safe in NMOSD. Different targets of monoclonal antibodies might have their own advantages.