Autologous hematopoietic stem cell transplantation (AHSCT) may be effective in aggressive forms of multiple sclerosis (MS) that fail to respond to standard therapies.
To evaluate the long-term ...outcomes in patients who underwent AHSCT for the treatment of MS in a large multicenter cohort.
Data were obtained in a multicenter, observational, retrospective cohort study. Eligibility criteria were receipt of AHSCT for the treatment of MS between January 1995 and December 2006 and the availability of a prespecified minimum data set comprising the disease subtype at baseline; the Expanded Disability Status Scale (EDSS) score at baseline; information on the administered conditioning regimen and graft manipulation; and at least 1 follow-up visit or report after transplant. The last patient visit was on July 1, 2012. To avoid bias, all eligible patients were included in the analysis regardless of their duration of follow-up. Data analysis was conducted from September 1, 2014 to April 27, 2015.
Demographic, disease-related, and treatment-related exposures were considered variables of interest, including age, disease subtype, baseline EDSS score, number of previous disease-modifying treatments, and intensity of the conditioning regimen.
The primary outcomes were MS progression-free survival and overall survival. The probabilities of progression-free survival and overall survival were calculated using Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analysis models.
Valid data were obtained from 25 centers in 13 countries for 281 evaluable patients, with median follow-up of 6.6 years (range, 0.2-16 years). Seventy-eight percent (218 of 281) of patients had progressive forms of MS. The median EDSS score before mobilization of peripheral blood stem cells was 6.5 (range, 1.5-9). Eight deaths (2.8%; 95% CI, 1.0%-4.9%) were reported within 100 days of transplant and were considered transplant-related mortality. The 5-year probability of progression-free survival as assessed by the EDSS score was 46% (95% CI, 42%-54%), and overall survival was 93% (95% CI, 89%-96%) at 5 years. Factors associated with neurological progression after transplant were older age (hazard ratio HR, 1.03; 95% CI, 1.00-1.05), progressive vs relapsing form of MS (HR, 2.33; 95% CI, 1.27-4.28), and more than 2 previous disease-modifying therapies (HR, 1.65; 95% CI, 1.10-2.47). Higher baseline EDSS score was associated with worse overall survival (HR, 2.03; 95% CI, 1.40-2.95).
In this observational study of patients with MS treated with AHSCT, almost half of them remained free from neurological progression for 5 years after transplant. Younger age, relapsing form of MS, fewer prior immunotherapies, and lower baseline EDSS score were factors associated with better outcomes. The results support the rationale for further randomized clinical trials of AHSCT for the treatment of MS.
Human mesenchymal stem cells (hMSCs) suppress T-cell and dendritic-cell function and represent a promising strategy for cell therapy of autoimmune diseases. Nevertheless, no information is currently ...available on the effects of hMSCs on B cells, which may have a large impact on the clinical use of these cells. hMSCs isolated from the bone marrow and B cells purified from the peripheral blood of healthy donors were cocultured with different B-cell tropic stimuli. B-cell proliferation was inhibited by hMSCs through an arrest in the G0/G1 phase of the cell cycle and not through the induction of apoptosis. A major mechanism of B-cell suppression was hMSC production of soluble factors, as indicated by transwell experiments. hMSCs inhibited B-cell differentiation because IgM, IgG, and IgA production was significantly impaired. CXCR4, CXCR5, and CCR7 B-cell expression, as well as chemotaxis to CXCL12, the CXCR4 ligand, and CXCL13, the CXCR5 ligand, were significantly down-regulated by hMSCs, suggesting that these cells affect chemotactic properties of B cells. B-cell costimulatory molecule expression and cytokine production were unaffected by hMSCs. These results further support the potential therapeutic use of hMSCs in immune-mediated disorders, including those in which B cells play a major role.
To describe the occurrence of abnormal hyperintensity in the dentate nucleus on T1-weighted magnetic resonance (MR) images in patients with multiple sclerosis (MS) as a neuroradiologic sign of gray ...matter involvement. Presence of the finding was evaluated for association with disability, clinical MS subtype, total lesion volume on T1- and T2-weighted MR images (lesion load), and brain atrophy.
Written informed consent was waived by the Ethics Committee because of the retrospective nature of this single-center Institutional Review Board-approved study. MR examinations of 185 patients with MS were reviewed, and 119 patients were included for analysis. Two neuroimagers, who were blinded to clinical data, assessed the presence of a hyperintense dentate nucleus on T1-weighted MR images. The presence of this radiologic alteration was then evaluated in relation to MS subtype, clinical disability, T1 and T2 lesion load, and whole-brain atrophy measurements. Fisher exact, chi(2), and Mann-Whitney U tests were used to evaluate differences in clinical and imaging features between patients with and those without a T1 hyperintense dentate nucleus.
Twenty-three (19.3%) of the 119 patients had a hyperintense dentate nucleus on unenhanced T1-weighted MR images. This finding was related to the secondary progressive subtype of the disease, a higher score on the Expanded Disability Status Scale, a higher brain lesion load, and tissue loss. None of the patients with primary progressive MS had a hypterintense dentate nucleus.
Hyperintensity of the dentate nucleus may be present on unenhanced T1-weighted MR images of patients with MS and is associated with the secondary progressive disease subtype and with increased clinical disability, lesion load, and brain atrophy.
To address the disability impact on fine hand motor functions in patients with Multiple Sclerosis (MS) by quantitatively measuring finger opposition movements, with the aim of providing a new "score" ...integrating current methods for disability assessment.
40 MS patients (Expanded Disability Status Scale (EDSS): 0-7) and 80 healthy controls (HC) performed a repetitive finger-to-thumb opposition sequence with their dominant hand at spontaneous and maximal velocity, and uni- and bi-manually metronome-paced. A sensor-engineered glove was used to measure finger motor performance. Twenty-seven HC were tested twice, one month apart, to assess test-retest reliability.
The motor parameters showed a good reproducibility in HC and demonstrated significantly worse performance in MS patients with respect to HC. A multivariate model revealed that rate of movement in the spontaneous velocity condition and inter-hand interval (IHI), indicating bimanual coordination, contributed independently to differentiate the two groups. A finger motor impairment score based on these two parameters was able to discriminate HC from MS patients with very low EDSS scores (p<0.001): a significant difference was already evident for patients with EDSS = 0. Further, in the MS group, some motor performance parameters correlated with the clinical scores. In particular, significant correlations were found between IHI and EDSS (r = 0.56; p<0.0001), MS Functional Composite (r = -0.40; p = 0.01), Paced Auditory Serial Addition (r = -0.38; p = 0.02). No motor performance parameter correlated with Timed 25-Foot Walk.
A simple, quantitative, objective method measuring finger motor performance could be used to define a score discriminating healthy controls and MS patients, even with very low disability. This sensitivity might be of crucial importance for monitoring the disease course and the treatment effects in early MS patients, when changes in the EDSS are small or absent.
Abstract Patients with Multiple Sclerosis (PwMS) with severe sensorimotor and cognitive deficits show reduced ability in motor sequence learning. Conversely, in PwMS with minimal disability (EDSS≤2), ...showing only subtle neurological impairments and no particular deficits in everyday life activities, motor sequence learning has been poorly addressed. Here, we investigated whether PwMS with minimal disability already show a specific impairment in motor sequence learning and which component of this process can be first affected in MS. We implemented a serial reaction time task based on thumb-to-finger opposition movements in response to visual stimuli. Each session included 14 blocks of 120 stimuli presented randomly or in ten repetitions of a 12-item sequence. Random (R) and sequence (S) blocks were temporally alternated (R1, R2, S1/S5, R3, S6/S10, R4). Random blocks were designed to evaluate the motor component; sequence blocks, beside the motor component, allowed to discriminate the procedural performance. Twenty-two PwMS and 22 control healthy subjects were asked to perform the task under implicit or explicit instructions (11 subjects for each experimental condition). PwMS with minimal disability improved motor performance in random blocks reducing response time with practice with a trend similar to control subjects, suggesting that short-term learning of simple motor tasks is nearly preserved at this disease stage. Conversely, they found difficulties in sequence-specific learning in implicit and explicit condition, with more pronounced impairment in the implicit condition. These findings could suggest an involvement of different circuits in implicit and explicit sequence learning that could deteriorate at different disease stages.
Over the last months, due to coronavirus disease (COVID-19) pandemic, containment measures have led to important social restriction. Healthcare systems have faced a complete rearrangement of ...resources and spaces, with the creation of wards devoted to COVID-19 patients. In this context, patients affected by chronic neurological diseases, such as amyotrophic lateral sclerosis (ALS), are at risk to be lost at follow-up, leading to a higher risk of morbidity and mortality. Telemedicine may allow meet the needs of these patients. In this commentary, we briefly discuss the digital tools to remotely monitor and manage ALS patients. Focusing on detecting disease progression and preventing life-threatening conditions, we propose a toolset able to improve ALS management during this unprecedented situation.
Multiple sclerosis (MS) is a complex neurological disease where, in genetically predisposed individuals, the unbalanced interplay between pathogenic and regulatory T cells will result in the ...progression of the autoimmune assault to neural antigens. Fingolimod (FTY720), an oral sphingosine 1-phosphate modulator recently approved for the treatment of MS, inhibits the egress of T cells from lymph nodes acting specifically on naïve and memory T cells and sparing effector T cells. Here we characterized IL-17 and IFNγ producing effector CD4 and CD8 positive T cells as well as CD4 positive CD25
high
CD127
low
regulatory T cells in MS patients before and 1 month after treatment was started. We observed that fingolimod did not significantly affect the percentage of CCR6 and CD161 positive T cells in both CD4 and CD8 compartments. In contrast, it significantly reduced the levels of both CD4+ CCR6+ CD161+ and CD8+ CCR6+ CD161+ producing IFNγ alone or in combination with IL-17. The percentage of IL-17 secreting cells in both subsets was affected by the treatment to a lesser extent. Finally, we observed that CD4+ CD25
high
CD127
low
regulatory T cells were decreased in MS patients compared to healthy controls and fingolimod significantly increased their frequencies. All together these findings demonstrate that fingolimod functionally modulates the ability of potentially pathogenic effector cells to produce relevant pro-inflammatory cytokines and increases the number of circulating regulatory T cells possibly contributing in restoring a balance between these populations.
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