Effectiveness of autologous haematopoietic stem cell transplantation versus natalizumab in progressive multiple sclerosis.

BACKGROUND: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS. METHODS: Patients with primary/secondary progressive MS from seven AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab, were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise-censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARRs), using Andersen-Gill proportional hazards models and conditional negative binomial model. RESULTS: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (HR 1.49, 95% CI 0.70 to 3.14) and improvement (HR 1.50, 95% CI 0.22 to 10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±SD 0.08±0.28 vs 0.08±0.25; HR 1.05, 95% CI 0.39 to 2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required intensive care unit admission and 36 patients experienced complications after discharge. No treatment-related deaths were reported. CONCLUSION: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity.

Primary Progressive Multiple Sclerosis-A Key to Understanding and Managing Disease Progression.

Primary progressive multiple sclerosis (PPMS), the least frequent type of multiple sclerosis (MS), is characterized by a specific course and clinical symptoms, and it is associated with a poor prognosis. It requires extensive differential diagnosis and often a long-term follow-up before its correct recognition. Despite recent progress in research into and treatment for progressive MS, the diagnosis and management of this type of disease still poses a challenge. Considering the modern concept of progression "smoldering" throughout all the stages of disease, a thorough exploration of PPMS may provide a better insight into mechanisms of progression in MS, with potential clinical implications. The goal of this study was to review the current evidence from investigations of PPMS, including its background, clinical characteristics, potential biomarkers and therapeutic opportunities. Processes underlying CNS damage in PPMS are discussed, including chronic immune-mediated inflammation, neurodegeneration, and remyelination failure. A review of potential clinical, biochemical and radiological biomarkers is presented, which is useful in monitoring and predicting the progression of PPMS. Therapeutic options for PPMS are summarized, with approved therapies, ongoing clinical trials and future directions of investigations. The clinical implications of findings from PPMS research would be associated with reliable assessments of disease outcomes, improvements in individualized therapeutic approaches and, hopefully, novel therapeutic targets, relevant for the management of progression.

Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis.

BACKGROUND: Autologous mesenchymal stem cell neurotrophic factor-secreting cells (NurOwn®) have the potential to modify underlying disease mechanisms in progressive multiple sclerosis (PMS). OBJECTIVE: This open-label phase II study was conducted to evaluate safety/efficacy of three intrathecal cell treatments. METHODS: Eighteen participants with non-relapsing PMS were treated. The primary endpoint was safety. Secondary endpoints included: cerebrospinal fluid (CSF) biomarkers; timed 25-foot walk speed, nine-hole peg test (9-HPT), low-contrast letter acuity, symbol digit modalities test, and 12-item multiple sclerosis (MS) walking scale. Seventeen participants received all treatments. RESULTS: No deaths/adverse events related to worsening of MS, clinical/magnetic resonance imaging (MRI) evidence of disease activation, and clinically significant changes in safety lab results were reported. Two participants developed symptoms of low back and leg pain, consistent with a diagnosis of arachnoiditis, occurring in one of three intrathecal treatments in both participants. Nineteen percent of treated participants achieved pre-specified ⩾ 25% improvements in timed 25-foot walk speed/nine-HPT at 28 weeks compared to baseline, along with consistent efficacy signals for pre-specified response criteria across other secondary efficacy outcomes. CSF neuroprotective factors increased, and inflammatory biomarkers decreased after treatment, consistent with the proposed mechanism of action. CONCLUSION: Based on these encouraging preliminary findings, further confirmation in a randomized study is warranted.

Diagnosis and treatment of progressive multiple sclerosis: A position paper.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is an unpredictable disease characterised by a highly variable disease onset and clinical course. Three main clinical phenotypes have been described. However, distinguishing between the two progressive forms of MS can be challenging for clinicians. This article examines how the diagnostic definitions of progressive MS impact clinical research, the design of clinical trials and, ultimately, treatment decisions. METHODS: We carried out an extensive review of the literature highlighting differences in the definition of progressive forms of MS, and the importance of assessing the extent of the ongoing inflammatory component in MS when making treatment decisions. RESULTS: Inconsistent results in phase III clinical studies of treatments for progressive MS, may be attributable to differences in patient characteristics (e.g., age, clinical and radiological activity at baseline) and endpoint definitions. In both primary and secondary progressive MS, patients who are younger and have more active disease will derive the greatest benefit from the available treatments. CONCLUSIONS: We recommend making treatment decisions based on the individual patient's pattern of disease progression, as well as functional, clinical and imaging parameters, rather than on their clinical phenotype. Because the definition of progressive MS differs across clinical studies, careful selection of eligibility criteria and study endpoints is needed for future studies in patients with progressive MS.

Cycling in primary progressive multiple sclerosis (CYPRO): study protocol for a randomized controlled superiority trial evaluating the effects of high-intensity interval training in persons with primary progressive multiple sclerosis.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) is the least prevalent multiple sclerosis (MS) phenotype. For persons with PPMS (pwPPMS), pharmacological treatment options are limited. As a complementary non-pharmacological treatment, endurance training improves the health-related quality of life (HRQoL), numerous MS symptoms, and MS-related performance impediments. High-intensity interval training (HIIT) has been shown to induce superior effects compared to moderate-intensity continuous training (MCT). As current evidence is based on MS samples with mixed phenotypes, generalizability to pwPPMS remains unclear. METHODS: CYPRO is a parallel-group, single-center, and single-blind randomized controlled superiority trial evaluating the effects of HIIT compared to MCT in pwPPMS. Sixty-one pwPPMS are randomized (1:1) to perform volume-matched HIIT or MCT sessions on bicycle ergometers two to three times per week in addition to standard rehabilitative care during their three-week inpatient stay at Valens rehabilitation clinic, Switzerland. Standard rehabilitative care comprises endurance and strength training, physiotherapy, and occupational therapy. HIIT sessions include six 90-second intervals at 95% peak heart rate (HRpeak), interspersed by 90-second active breaks with unloaded pedaling, aimed to reach 60%HRpeak. MCT represents the standard treatment at Valens rehabilitation clinic and is performed as continuous cycling at 60%HRpeak for the duration of 26 minutes. The primary outcome is cardiorespiratory fitness, assessed as peak oxygen consumption (V̇O2peak) during cardiopulmonary exercise testing (CPET). Secondary outcomes include peak power output during CPET, walking capacity, cognitive performance, HRQoL, fatigue, anxiety and depressive symptoms, and blood-derived biomarkers (e.g., serum neurofilament light chain, glial fibrillary acidic protein, kynurenine pathway metabolites) related to MS pathophysiology. All outcomes are assessed at baseline and discharge after three weeks. Venous blood sampling is additionally performed immediately and two hours after the first HIIT or MCT session. DISCUSSION: CYPRO will expand current knowledge on symptom management and rehabilitation in MS to the subpopulation of pwPPMS, and will contribute to the exploration of potential disease-modifying effects of endurance training in MS. The superiority design of CYPRO will allow deriving explicit recommendations on endurance training design in pwPPMS that can be readily translated into clinical practice. TRIAL REGISTRATION: CYPRO has been prospectively registered at ClinicalTrials.gov on 8 February 2022 (NCT05229861).

Interrogating large multiple sclerosis registries and databases: what information can be gained?

PURPOSE OF REVIEW: Although substantial progress has been made in understanding the natural history of multiple sclerosis (MS) and the development of new therapies, many questions concerning disease behavior and therapeutics remain to be answered. Data generated from real-world observational studies, based on large MS registries and databases and analyzed with advanced statistical methods, are offering the scientific community answers to some of these questions that are otherwise difficult or impossible to address. This review focuses on observational studies published in the last 2 years designed to compare the effectiveness of escalation vs. induction treatment strategies, to assess the effectiveness of treatment in pediatric-onset and late-onset MS, and to identify the clinical phenotype of secondary progressive (SP)MS. RECENT FINDINGS: The main findings originating from real-world studies suggest that MS patients who will qualify for high-efficacy disease-modifying therapies (DMTs) should be offered these as early as possible to prevent irreversible accumulation of neurological disability. Especially pediatric patients derive substantial benefits from early treatment. In patients with late-onset MS, sustained exposure to DMTs may result in more favorable outcomes. Data-driven definitions are more accurate in defining transition to SPMS than diagnosis based solely on neurologists' judgment. SUMMARY: Patients, physicians, industry, and policy-makers have all benefited from real-world evidence based on registry data, in answering questions of diagnostics, choice of treatment, and timing of treatment decisions.

Anti-CD20 treatment effectively attenuates cortical pathology in a rat model of widespread cortical demyelination.

BACKGROUND: Cortical demyelination represents a prominent feature of the multiple sclerosis (MS) brain, especially in (late) progressive stages. We recently developed a new rat model that reassembles critical features of cortical pathology characteristic to progressive types of MS. In persons affected by MS, B-cell depleting anti-CD20 therapy proved successful in the relapsing remitting as well as the early progressive course of MS, with respect to reducing the relapse rate and number of newly formed lesions. However, if the development of cortical pathology can be prevented or at least slowed down is still not clear. The main goal of this study was thus to increase our understanding for the mode of action of B-cells and B-cell directed therapy on cortical lesions in our rat model. METHODS: For this purpose, we set up two separate experiments, with two different induction modes of B-cell depletion. Brain tissues were analyzed thoroughly using histology. RESULTS: We observed a marked reduction of cortical demyelination, microglial activation, astrocytic reaction, and apoptotic cell loss in anti-CD20 antibody treated groups. At the same time, we noted increased neuronal preservation compared to control groups, indicating a favorable impact of anti-CD20 therapy. CONCLUSION: These findings might pave the way for further research on the mode of action of B-cells and therefore help to improve therapeutic options for progressive MS.

Impact of autologous haematopoietic stem cell transplantation on disability and brain atrophy in secondary progressive multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (aHSCT) is a valuable option in aggressive relapsing-remitting multiple sclerosis (MS), but its efficacy in secondary progressive (SP)-MS is still controversial. OBJECTIVE: Assessing efficacy of aHSCT in SP-MS by clinical-radiological outcomes. METHODS: Open-label monocentric retrospective study enrolling consecutive SP-MS patients treated with BEAM-aHSCT in the period 1999-2016. RESULTS: In total, 26 SP-MS patients with moderate-severe disability were included. Progression-free survival (PFS) at years 5 and 10 after aHSCT were, respectively, 42% and 30%. Out of 16 patients who worsened, only 6 patients (23% overall) maintained continuous disability accrual (CDA), whereas 10 patients stabilized following one single-step Expanded Disability Status Scale (EDSS) worsening. CDA-free survival was 74% at 5-10 years. No relapses or magnetic resonance imaging (MRI) activity were reported, thus no evidence of disease activity (NEDA)-3 corresponded to PFS. Annualized rate of brain atrophy (AR-BVL) normalized after 1 year in 55% of the cases analysed (12/22). CONCLUSION: BEAM-aHSCT halted CDA and normalized AR-BVL in most of the treated patients, inducing long-term remission of inflammatory activity at a median follow-up of 99 months (range 27-222). These data suggest that CDA might still be mainly driven by inflammation in a subgroup of SP-MS and could therefore be reversed by treatments. CDA should be analysed independently from any isolated disability worsening.

Beneficial effects of autologous mesenchymal stem cell transplantation in active progressive multiple sclerosis.

In this study (trial registration: NCT02166021), we aimed to evaluate the optimal way of administration, the safety and the clinical efficacy of mesenchymal stem cell (MSC) transplantation in patients with active and progressive multiple sclerosis. Forty-eight patients (28 males and 20 females) with progressive multiple sclerosis (Expanded Disability Status Scale: 3.0-6.5, mean : 5.6 ± 0.8, mean age: 47.5 ± 12.3) and evidence of either clinical worsening or activity during the previous year, were enrolled (between 2015 and 2018). Patients were randomized into three groups and treated intrathecally (IT) or intravenously (IV) with autologous MSCs (1 × 106/kg) or sham injections. After 6 months, half of the patients from the MSC-IT and MSC-IV groups were retreated with MSCs, and the other half with sham injections. Patients initially assigned to sham treatment were divided into two subgroups and treated with either MSC-IT or MSC-IV. The study duration was 14 months. No serious treatment-related safety issues were detected. Significantly fewer patients experienced treatment failure in the MSC-IT and MSC-IV groups compared with those in the sham-treated group (6.7%, 9.7%, and 41.9%, respectively, P = 0.0003 and P = 0.0008). During the 1-year follow-up, 58.6% and 40.6% of patients treated with MSC-IT and MSC-IV, respectively, exhibited no evidence of disease activity compared with 9.7% in the sham-treated group (P < 0.0001 and P < 0.0048, respectively). MSC-IT transplantation induced additional benefits on the relapse rate, on the monthly changes of the T2 lesion load on MRI, and on the timed 25-foot walking test, 9-hole peg test, optical coherence tomography, functional MRI and cognitive tests. Treatment with MSCs was well-tolerated in progressive multiple sclerosis and induced short-term beneficial effects regarding the primary end points, especially in the patients with active disease. The intrathecal administration was more efficacious than the intravenous in several parameters of the disease. A phase III trial is warranted to confirm these findings.

The apparently milder course of multiple sclerosis: changes in the diagnostic criteria, therapy and natural history.

In the past decade, changes have occurred in the spectrum of multiple sclerosis courses. The natural history of multiple sclerosis appears milder from the first sign of demyelinating disease to the progressive course, probably as a result of an interplay between several factors including changes in the diagnostic criteria, changes in the epidemiology of multiple sclerosis, impact of early and appropriate disease-modifying treatment and improvement of the general state of health in the population. It has been suggested to regard incidental findings of demyelinating lesions in MRI in individuals without any history of clinical symptoms consistent with neurological dysfunction, so-called radiological isolated syndrome, as the initial course of multiple sclerosis. New diagnostic criteria have enabled the multiple sclerosis diagnosis in many patients at the first clinical demyelinating event, clinically isolated syndrome. The remaining patients with clinically isolated syndrome have a more benign prognosis, and for relapsing-remitting multiple sclerosis, the prognosis has become more favourable. Reduced disease activity in patients with relapsing-remitting multiple sclerosis can partly be ascribed to more efficacious new disease-modifying therapies but decrease in disease activity has also be seen in placebo-treated patients in clinical trials. This may be explained by several factors: change in the diagnostic criteria, more explicit inclusion criteria, exclusion of high-risk patients e.g. patients with co-morbidities, and more rigorous definitions of relapses and disease worsening. However, these factors also make the disease course in patients treated with disease-modifying therapies seem more favourable. In addition, change in the therapeutic target to stable disease (no evidence of disease activity = no relapses, no disease worsening and no MRI activity) could by itself change the course in relapsing-remitting multiple sclerosis. The effectiveness of disease-modifying drugs has reduced the transition from relapsing-remitting to secondary progressive multiple sclerosis. The concept of progressive multiple sclerosis has also evolved from two very distinct categories (primary progressive and secondary progressive multiple sclerosis) to a unified category of progressive multiple sclerosis, which can then be split into the categories of active or inactive. Also, an increasing tendency to treat progressive multiple sclerosis with disease-modifying therapies may have contributed to change the course in progressive multiple sclerosis. In conclusion, during the past decade the entire course of multiple sclerosis from the first sign of a demyelinating disorder through the progressive course appears to be milder due to a complex interplay of several factors.

Motor Sequence Learning across Multiple Sessions Is Not Facilitated by Targeting Consolidation with Posttraining tDCS in Patients with Progressive Multiple Sclerosis.

Compared to relapsing-remitting multiple sclerosis (MS), progressive MS is characterized by a lack of spontaneous recovery and a poor response to pharmaceutical immunomodulatory treatment. These patients may, therefore, particularly benefit from interventions that augment training-induced plasticity of the central nervous system. In this cross-sectional double-blind cross-over pilot study, effects of transcranial direct current stimulation (tDCS) on motor sequence learning were examined across four sessions on days 1, 3, 5, and 8 in 16 patients with progressive MS. Active or sham anodal tDCS of the primary motor cortex was applied immediately after each training session. Participants took part in two experiments separated by at least four weeks, which differed with respect to the type of posttraining tDCS (active or sham). While task performance across blocks of training and across sessions improved significantly in both the active and sham tDCS experiment, neither online nor offline motor learning was modulated by the type of tDCS. Accordingly, the primary endpoint (task performance on day 8) did not differ between stimulation conditions. In sum, patients with progressive MS are able to improve performance in an ecologically valid motor sequence learning task through training. However, even multisession posttraining tDCS fails to promote motor learning in progressive MS.

Epigenetic aspects of multiple sclerosis and future therapeutic options.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease accompanied by demyelination of neurons in the central nervous system that mostly affects young adults, especially women. This disease has two phases including relapsing-remitting form (RR-MS) by episodes of relapse and periods of clinical remission and secondary-progressive form (SP-MS), which causes more disability. The inheritance pattern of MS is not exactly identified and there is an agreement that it has a complex pattern with an interplay among environmental, genetic and epigenetic alternations. Epigenetic mechanisms that are identified for MS pathogenesis are DNA methylation, histone modification and some microRNAs' alternations. Several cellular processes including apoptosis, differentiation and evolution can be modified along with epigenetic changes. Some alternations are associated with epigenetic mechanisms in MS patients and these changes can become key points for MS therapy. Therefore, the aim of this review was to discuss epigenetic mechanisms that are associated with MS pathogenesis and future therapeutic approaches.

[Controversies in neurology: Diagnosis, follow up and therapy of multiple sclerosis with pathomechanismal approach]. / Ellentmondások a neurológiában: A sclerosis multiplex diagnózisának, követésének és terápiájának aktuális kérdései a patomechanizmus megközelítésével.

The clinical boundaries between the relapsing and progressive course of multiple sclerosis are often indistinct. Despite the variable patterns of evolution, there are no biological reasons for discerning different multiple sclerosis phenotypes. Indeed, both primary progressive and secondary forms of the disease share similar pathological features in respect of the extent of inflammatory infiltrates, axonal damage, and cortical demyelination. The data indicating that primary progressive multiple sclerosis is preceded by an asymptomatic relapsing remitting phase. The proposed definition of secondary progressive multiple slcerosis, the attainment of at least EDSS of 4 is required to mark the transition to the progressive phase. Therefore, the clinical progress can be uncovered in the early phase of the disease. Furthermore, a continuous progression independent of relapsing activity is commonly observed during the relapsing remitting phase. A continuous smouldering process underpins the subtle clinical deterioration, which stands out as an important unmet treatment target. Concerning cognitive dysfunction of the patients pro-inflammatory cytokines have been associated with worse cognition in active multiple sclerosis, and this inflammatory milieu could also contribute to altered mentation during relapses. Therefore, long before people with multiple sclerosis become physically disabled, they have usually acquired hidden disabilities related to cognitive impairment. Silent progression appears during the relapsing remitting phase and it associates with brain atrophy. This suggests that the same process that underlies secondary progressive multiple sclerosis likely begins far earlier than is generally recognized. This supports a unitary view of multiple sclerosis biology.

Percutaneous Venous Angioplasty in Patients with Multiple Sclerosis and Chronic Cerebrospinal Venous Insufficiency: A Randomized Wait List Control Study.

BACKGROUND: Venous percutaneous transluminal angioplasty (vPTA) in patients with multiple sclerosis (MS) and chronic cerebrospinal venous insufficiency (CCSVI) have shown contradictory results. The aim of the study is to evaluate the efficacy of the procedure in a randomized wait list control study. METHODS: 66 adults with neurologist-confirmed diagnosis of MS and sonographic diagnosis of CCSVI were allocated into vPTA-yes group (n = 31) or vPTA-not group (n = 35, control group). vPTA was performed immediately 15 days after randomization in the PTA-yes group and 6 months later in the control group. Evoked potentials (EPs), clinical-functional measures (CFMs), and upper limb kinematic measures (ULKMs) were measured at baseline (T0) and six months after in both groups, just before the venous angioplasty in the vPTA-not group (T1). RESULTS: Comparing the vPTA-yes and vPTA-not group, the CFM-derived composite functional outcome showed 11 (37%) versus 7 (20%) improved, 1 (3%) versus 3 (8%) stable, 0 versus 7 (20%) worsened, and 19 (61%) versus 18 (51%) mixed patients (χ2 = 8.71, df = 3, P = 0.03). Unadjusted and adjusted (for baseline confounding variables) odds ratio at 95% confidence interval were, respectively, 1.93 (1.3-2.8), P value 0.0007, and 1.85 (1.2-1.7), P value 0.002. EP- and ULKM-derived composite functional outcome showed no significant difference between the two groups. CONCLUSIONS: Venous angioplasty can positively impact a few CFMs especially for the quality of life but achieving disability improvement is unlikely.

[Current questions of multiple sclerosis: the secunder progressive form of the disease]. / A sclerosis multiplex néhány aktuális kérdése: a szekunder progresszív forma.

Recent data suggest that long-term worsening is common in relapsing-remitting multiple sclerosis patients and is largely independent of relapses or new lesion formation on brain MRI. The current definition of secunder progressive multiple sclerosis is worsening of disability independent of relapses over at least 6-month interval. Early focal inflammatory disease activity and spinal cord lesion are predictors of very-long term disease outcomes in relapse - onset multiple sclerosis. The potential of PET imaging to visualize hidden inflammation in MS brain in vivo is an important contribution for better understanding the progression of the disease. Therefore, PET imaging is a promising tool in detecting the conversion from relapsing remitting multiple sclerosis to secunder progressive form of multiple sclerosis. Furthermore, neuro-axonal damage is the pathological substrate of permanent disability in different neurological disorders including multiple sclerosis. The neurofilament proteins have promise in this context because their levels rise upon neuro-axonal damage not only in the cerebrospinal fluid but also in blood. Patients with increased serum levels of neurofilament at baseline, independent of other clinical and MRI variables, experience significantly more brain and spinal cord volume loss over 2 years and 5 years of follow-up. The kynurenine-pathway abnormalities may be associated with the swich from early-mild stage multiple sclerosis to debilitating progressive forms of the disease. Analysis of these metabolites in serum may have application as multiple sclerosis disease biomarkers. Free radical action has been suggested as a causal factor in the illness. Increased free radical production and consumption of the scavenger molecules were found during the active phase of the disease. Based on the clinical findings (EXPAND Study) and pathomechanism of the disease siponimod is approved by the US Food and Drug Administration for the treatment of relapsing remitting forms of multiple sclerosis, to include secunder progressive multiple sclerosis with active disease, relapsing-remitting multiple sclerosis and clinically isolated syndrome.

Prospective phase II clinical trial of autologous haematopoietic stem cell transplant for treatment refractory multiple sclerosis.

BACKGROUND: Autologous haematopoietic stem cell transplantation (AHSCT) has been explored as a therapeutic intervention in multiple sclerosis (MS) over the last two decades; however, prospective clinical trials of the most common myeloablative conditioning regimen, BEAM, are limited. Furthermore, patient selection, optimal chemotherapeutic regimen and immunological changes associated with disease response require ongoing exploration. We present the outcomes, safety and immune reconstitution (IR) of patients with active, treatment refractory MS. METHODS: This study was a single-centre, phase II clinical trial of AHSCT for patients with active relapsing remitting (RRMS) and secondary progressive MS (SPMS). Patients underwent AHSCT using BEAM (carmustine, etoposide, cytarabine, melphalan)+antithymocyte globulin chemotherapeutic regimen. OUTCOMES: The primary outcome was event-free survival (EFS); defined as no clinical or radiological relapses and no disability progression. Multiparameter flow cytometry was performed for evaluation of post-transplant IR in both MS and lymphoma patients receiving the same chemotherapy regimen. RESULTS: Thirty-five patients (20 RRMS, 15 SPMS) completed AHSCT, with a median follow-up of 36 months (range 12-66). The median Expanded Disability Status Scores (EDSS) was 6 (2-7) and patients had failed a median of 4 (2-7) disease modifying therapies. 66% failed treatment with natalizumab. EFS at 3 years was 60%, (70% RRMS). Sustained improvement in EDSS was seen in 15 (44%) of patients. There was no treatment-related mortality. A sustained rise in CD39+ T regulatory cells, immunosuppressive CD56hi natural killer cells and ablation of proinflammatory mucosal-associated invariant T cells was seen for 12 months following AHSCT in patients with MS. These changes did not occur in patients with lymphoma receiving the same chemotherapy for AHSCT. CONCLUSIONS: The EFS in our MS cohort is significantly greater than other high-efficacy immunosuppressive therapies and similar to other AHSCT studies despite a more heavily pretreated cohort. TRIAL REGISTRATION NUMBER: ACTRN12613000339752.

Over three decades study populations in progressive multiple sclerosis have become older and more disabled, but have lower on-trial progression rates: A systematic review and meta-analysis of 43 randomised placebo-controlled trials.

BACKGROUND: Progression is the major driver of disability and cost in multiple sclerosis (MS). However, the search for treatments in progressive multiple sclerosis (PMS) has not mirrored the success in relapsing MS. OBJECTIVES: To assess changes in PMS trials over time. METHODS: PubMed, MEDLINE and Embase were searched to identify randomised, double-blind, placebo-controlled trials in PMS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used, study quality was assessed and trends were examined by regression. RESULTS: Placebo groups of 43 studies published between 1988 and 2018 were included. The mean age at trial entry increased by 9.8 years per decade (95% confidence interval (CI): [2.7; 4.9]; p < 0.001). Mean baseline Expanded Disability Status Scale (EDSS) scores increased by 0.36 points (95% CI: [0.09; 0.62]; p = 0.009) and disease durations at baseline were prolonged by 1.8 years (95% CI: [0.7; 2.9]; p = 0.003) per decade. The trials became larger, specifically placebo groups increased by about 222 patients (95% CI: [36; 409]; p = 0.021) and 88 patients (95% CI: [12; 165]; p = 0.025) per decade for primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), respectively. The proportion of patients on placebo experiencing disability progression within 24 months decreased by 7.6 percentage points (95% CI: [1.2; 14.1]; p = 0.022) per year. CONCLUSION: Over three decades, PMS trial populations changed and are now older, with a longer disease duration and more disability, with lower on-trial progression rates.

High-frequency repetitive transcranial magnetic stimulation and intermittent theta-burst stimulation for spasticity management in secondary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: The spasticity phenomenon is a significant factor in the development of disability. Repetitive transcranial magnetic stimulation (rTMS) is a promising treatment method for this disorder. Our aim was to compare the effects of two protocols of rTMS - the high-frequency (HF) rTMS (20 Hz) and the intermittent theta-burst stimulation (iTBS) - on the level of spasticity and concomitant symptoms in patients with secondary progressive multiple sclerosis with an analysis of the duration of the effects up to 12 weeks after the stimulation course. METHODS: Thirty-four patients with secondary progressive multiple sclerosis and lower spastic paraparesis were randomized into three groups: (i) HF-rTMS (20 Hz); (ii) iTBS; (iii) sham stimulation. Spasticity and spasticity-associated symptoms were assessed by the Modified Ashworth Scale, the Subjective Evaluating Spasticity Scale (SESS), the numerical analog scale, the Modified Fatigue Impact Scale and the pain level scale. RESULTS: The Modified Ashworth Scale was significantly reduced after the stimulation course in the HF-rTMS and iTBS groups. The SESS was reduced post-intervention and at the two follow-ups in the iTBS group, whilst HF-rTMS produced an SESS reduction only at the 2-week follow-up, with no effects in the sham group. Conversely, reduction in pain and fatigue was found in the HF-rTMS group. CONCLUSIONS: The results show that HF-rTMS and iTBS significantly reduce spasticity measured by the Modified Ashworth Scale, in contrast to sham stimulation. Some evidence was found in favor of a longer-lasting effect of iTBS on the SESS and of a reduction in pain and fatigue after HF-rTMS.

[New therapeutic approaches in progressive multiple sclerosis]. / Neue Therapieansätze bei progredienter Multipler Sklerose.

Multiple sclerosis (MS) therapy made huge progress during the last years due to the development of new medications for the relapsing-remitting phase of the disease. The development of therapies for progressive MS was, however, less successful. New medications are the B-cell depleting antibody ocrelizumab, authorized for primary progressive MS with inflammatory activity and the sphingosine-1-receptor modulator siponimod, which is under development for secondary-progressive MS. Pathomechanisms of progressive MS comprise chronic inflammation with activation of T and B cells and microglia with release of reactive oxygen species, age-dependent accumulation of iron and neurodegeneration. In this review, we will discuss the knowledge about the pathogenesis of progression and potential therapeutic approaches in different stages of development.

Healthcare resources utilisation in primary progressive multiple sclerosis.

Epidemiological data on primary progressive multiple sclerosis (PPMS) are scarce. This study was aimed to evaluate the burden of PPMS in Italy with healthcare resources utilisation and costs for Italian National Health System (INHS). A 2-year cross-sectional analysis of real-world data collected in the ARCO database, covering > 10 million Italian inhabitants, was performed. From a cohort of patients affected by MS in 2014, those supposedly affected by PPMS were defined by the concurrent matching of absence of disease-modifying treatments and use of rehabilitation services. Any other drug prescriptions, outpatient services and hospitalisations were analysed in 2015 for each subject. The average annual cost per patient was provided both for each expenditure item and by integrating these. Of 13,253,591 inhabitants, 18,453 resulted affected by MS (prevalence 139 × 100,000). Of these, 1849 agreed with additional criteria to identify PPMS (10% of MS population). The 26.8% of these experienced at least one admission in 1 year, 97.3% used at least one outpatient service and 94.3% received at least one reimbursed drug. In the perspective of INHS, PPMS generated an average annual cost of € 3783 per person: 49% for hospitalisations, 28% for outpatient services and 23% for drugs. This study provides a reliable estimation of the PPMS burden in Italy, in terms of healthcare utilisation and direct costs. These findings could be useful to estimate the changes in health expenditure following the incoming of new drugs to treat PPMS with increase of pharmaceutical cost and potential decrease of rehabilitation and hospitalisation costs.