ArticleLiterature Review

Aggressive multiple sclerosis: Proposed definition and treatment algorithm

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Abstract

Multiple sclerosis (MS) is a CNS disorder characterized by inflammation, demyelination and neurodegeneration, and is the most common cause of acquired nontraumatic neurological disability in young adults. The course of the disease varies between individuals: some patients accumulate minimal disability over their lives, whereas others experience a rapidly disabling disease course. This latter subset of patients, whose MS is marked by the rampant progression of disability over a short time period, is often referred to as having 'aggressive' MS. Treatment of patients with aggressive MS is challenging, and optimal strategies have yet to be defined. It is important to identify patients who are at risk of aggressive MS as early as possible and implement an effective treatment strategy. Early intervention might protect patients from irreversible damage and disability, and prevent the development of a secondary progressive course, which thus far lacks effective therapy.

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... Whether it is called "aggressive", "highly active", or "malignant" [9][10][11], most definitions (spanning decades) usually agree that it should be a rapid deterioration to a certain EDSS (usually to a score of 6.0 over 5 to 10 years), with some authors considering other conditions such as the number or features of relapses (aggressiveness, sequelae, EDSS impact, certain functional systems involved, etc.) or failure of DMTs. Others considered that a time of 3 years from RRMS onset to SPMS phase would also qualify as aggressive. ...
... GdE lesions have also been found to be associated with the risk of future relapses and directly correlated with the relapse rate [55]. When two or more GDE lesions are present on the baseline MRI scan, they predict the risk of aggressive MS with a sensitivity of 0.73 and a specificity of 0.79 [11,13,81]. ...
... They can be detected in vivo using software analysis capable of proving expansion within existing T2-lesions on longitudinal MRI scans. Whether these two types of lesions are truly pathologically different or just different stages of chronically active lesions remains to be seen [11,38]. Other imaging modalities have also been tried for detecting these lesions, such as positron emission tomography (PET) using radiotracers specific to microglia/macrophages and sodium (23 Na) MRI, but their clinical use is so far very restricted [117]. ...
Article
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Background and Objectives: In this critical review, we explore the potential use of MRI measurements as prognostic biomarkers in multiple sclerosis (MS) patients, for both conventional measurements and more novel techniques such as magnetization transfer, diffusion tensor, and proton spectroscopy MRI. Materials and Methods: All authors individually and comprehensively reviewed each of the aspects listed below in PubMed, Medline, and Google Scholar. Results: There are numerous MRI metrics that have been proven by clinical studies to hold important prognostic value for MS patients, most of which can be readily obtained from standard 1.5T MRI scans. Conclusions: While some of these parameters have passed the test of time and seem to be associated with a reliable predictive power, some are still better interpreted with caution. We hope this will serve as a reminder of how vast a resource we have on our hands in this versatile tool—it is up to us to make use of it.
... These patients do not respond adequately to first-line disease-modifying therapies (DMTs) and should therefore be treated early with one of the higher efficacy DMTs, although a high proportion of them do not respond optimally to these agents. [11][12][13][14][15][16] Autologous haematopoietic stem cell transplantation (AHSCT) has gained considerable interest in recent years as an efficacious therapy for a selected group of patients with MS who have clinically and radiologically active disease, despite the use of standard DMTs. 17 Treatment-related mortality has reduced significantly in the last two decades through better patient selection, optimisation of transplant technique and increased centre experience. ...
... A total of 20 patients with 'aggressive' MS who received AHSCT as a first-line DMT were identified from five centres ( Table 1). There was an equal proportion of male and female with a median age of 28 years at diagnosis and a median interval of 5 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) months between diagnosis and treatment. The median last EDSS score before transplant was 5 (1.5-9.5). ...
... There are no universally accepted diagnostic criteria which would allow an early prospective identification of patients with 'aggressive' MS. Rush et al. 16 have recently suggested that 'aggressive' MS could be defined as relapsing-remitting MS with one or more of the following features: (1) EDSS score of 4 within 5 years of disease onset, (2) two or more relapses with incomplete recovery in the past 12 months, (3) three or more MRI studies showing new or enlarging T2 lesions or gadolinium-enhancing lesions despite treatment and (4) unresponsive to one or more DMTs for up to 1 year. When these criteria were applied to our cohort retrospectively, 18 patients satisfied the 11,13,26,27 If the diagnosis of this phenotype is only made retrospectively, valuable time would be lost during which unsuccessful and sometimes futile therapeutic attempts would be made using standard DMTs, while disability will progress significantly and become irreversible, potentially compromising the feasibility, safety and efficacy of AHSCT at a later stage. ...
Article
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Background: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established. Objectives: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS. Methods: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated. Results: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans. Conclusion: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.
... There is, however, no universally accepted definition of aggressive multiple sclerosis and a number of different criteria have been used. For example, in terms of the rate of disability accrual, Rush et al. (2015) suggest that reaching an Expanded Disability Status Scale (EDSS) of 4 within 5 years of symptom onset is a core feature of the phenotype. Some researchers used more severe criteria, requiring an EDSS of 56 within 5 years (Menon et al., 2017), while others have required a gain of two or more EDSS points over a 2-year period (Scott et al., 2013). ...
... The determinants and clinical predictors of aggressive multiple sclerosis are not well understood; however, a number of risk factors of more rapid disability accrual have been identified (for a recent review see Rush et al., 2015). Patient characteristics, such as being older at symptom onset or of male sex, have been recognized (Kantarci et al., 1998;Held et al., 2005;Tremlett et al., 2006;Ribbons et al., 2015). ...
... In a number of areas, our results may seem to diverge from previously reported findings. For example, we did not find evidence for an independent, unequivocal effect of sex (Kantarci et al., 1998;Tremlett et al., 2006), incomplete recovery from relapse (Trojano et al., 1995;Scott and Schramke, 2010), severity of relapse (Rush et al., 2015), the number of relapses early in the disease course (Weinshenker et al., 1989;Confavreux et al., 2003;Ebers, 2005), and relapses presenting with cerebellar (Weinshenker et al., 1989;Phadke, 1990;Amato et al., 1999) or bowel/bladder (Citterio et al., 1989;Runmarker and Andersen, 1993;Amato et al., 1999;Langer-Gould et al., 2006) signs on the risk of developing aggressive disease. Because of issues of multi-collinearity, we were unable to investigate the independent effect of cognitive impairment, which has previously been suggested to be a poor prognostic sign (Zarei et al., 2003). ...
Article
Patients with the 'aggressive' form of multiple sclerosis accrue disability at an accelerated rate, typically reaching Expanded Disability Status Score (EDSS) ≥ 6 within 10 years of symptom onset. Several clinicodemographic factors have been associated with aggressive multiple sclerosis, but less research has focused on clinical markers that are present in the first year of disease. The development of early predictive models of aggressive multiple sclerosis is essential to optimize treatment in this multiple sclerosis subtype. We evaluated whether patients who will develop aggressive multiple sclerosis can be identified based on early clinical markers. We then replicated this analysis in an independent cohort. Patient data were obtained from the MSBase observational study. Inclusion criteria were (i) first recorded disability score (EDSS) within 12 months of symptom onset; (ii) at least two recorded EDSS scores; and (iii) at least 10 years of observation time, based on time of last recorded EDSS score. Patients were classified as having 'aggressive multiple sclerosis' if all of the following criteria were met: (i) EDSS ≥ 6 reached within 10 years of symptom onset; (ii) EDSS ≥ 6 confirmed and sustained over ≥6 months; and (iii) EDSS ≥ 6 sustained until the end of follow-up. Clinical predictors included patient variables (sex, age at onset, baseline EDSS, disease duration at first visit) and recorded relapses in the first 12 months since disease onset (count, pyramidal signs, bowel-bladder symptoms, cerebellar signs, incomplete relapse recovery, steroid administration, hospitalization). Predictors were evaluated using Bayesian model averaging. Independent validation was performed using data from the Swedish Multiple Sclerosis Registry. Of the 2403 patients identified, 145 were classified as having aggressive multiple sclerosis (6%). Bayesian model averaging identified three statistical predictors: age > 35 at symptom onset, EDSS ≥ 3 in the first year, and the presence of pyramidal signs in the first year. This model significantly predicted aggressive multiple sclerosis [area under the curve (AUC) = 0.80, 95% confidence intervals (CIs): 0.75, 0.84, positive predictive value = 0.15, negative predictive value = 0.98]. The presence of all three signs was strongly predictive, with 32% of such patients meeting aggressive disease criteria. The absence of all three signs was associated with a 1.4% risk. Of the 556 eligible patients in the Swedish Multiple Sclerosis Registry cohort, 34 (6%) met criteria for aggressive multiple sclerosis. The combination of all three signs was also predictive in this cohort (AUC = 0.75, 95% CIs: 0.66, 0.84, positive predictive value = 0.15, negative predictive value = 0.97). Taken together, these findings suggest that older age at symptom onset, greater disability during the first year, and pyramidal signs in the first year are early indicators of aggressive multiple sclerosis.
... Currently in clinical practice, escalation is intended to be suitable for most patients [1], while induction is mainly restricted to patients with aggressive RRMS [12]. However, the escalation approach has recently been criticized since considered not adequate or not sufficient in conferring the greatest possible long-lasting therapeutic effect [13]. ...
... Although this proportion was lower after induction than after escalation (34.7% versus 53.4%), one can argue that not all patients may benefit from early immunosuppression to reset immune system over the longterm period. Albeit encouraging, findings on early immunosuppression have raised relevant safety concerns; thus, their use has been restricted only to patients with aggressive MS [12]. In our study, induction was associated with an approximately fourfold increased risk of SAEs, especially malignant neoplasms, as compared to escalation. ...
... This implies that the hypothesis regarding the superiority of induction versus escalation must be restricted only to older patients with higher EDSS scores (see also Table 1). Regarding hidden bias, we cannot exclude that induction was adopted in some patients due to unmeasured prognostic factors (not encompassed among the baseline variables), including (but not limited to) symptom onset, cognitive deficit, MRI characteristics including lesion burden, pd: treatment permanently discontinued due to SAE black holes, discernable brain atrophy, and infratentorial and/ or spinal cord involvement [12]. ...
Article
In this independent, multicenter, post-marketing study, we directly compare induction immunosuppression versus escalation strategies on the risk of reaching the disability milestone of Expanded Disability Status Scale (EDSS) ≥ 6.0 over 10 years in previously untreated patients with relapsing-remitting multiple sclerosis. We collected data of patients who started interferon beta (escalation) versus mitoxantrone or cyclophosphamide (induction) as initial treatment. Main eligibility criteria included an EDSS score ≤ 4.0 at treatment start and either ≥ 2 relapses or 1 disabling relapse with evidence of ≥ 1 gadolinium-enhancing lesion at magnetic resonance imaging scan in the pre-treatment year. Since patients were not randomized to treatment group, we performed a propensity score (PS)–based matching procedure to select individuals with homogeneous baseline characteristics. Comparisons were then conducted using Cox models stratified by matched pairs. Overall, 75 and 738 patients started with induction and escalation, respectively. Patients in the induction group were older and more disabled than those in the escalation group (p < 0.05). The PS-matching procedure retained 75 patients per group. In the re-sampled population, a lower proportion of patients reached the outcome after induction (21/75, 28.0%) than escalation (29/75, 38.7%) (hazard ratio = 0.48; p = 0.024). Considering the whole sample, serious adverse events occurred more frequently after induction (8/75, 10.7%) than escalation (18/738, 2.4%) (odds ratio = 3.36, p = 0.015). These findings suggest that, in patients with poor prognostic factors, induction was more effective than escalation in reducing the risk of reaching the disability milestone, albeit with a worse safety profile. Future studies are warranted to explore if newer induction agents may provide a more advantageous long-lasting risk:benefit profile.
... Although there is not an established definition of aggressive MS, the early identification of this population would be nowadays of utmost importance for establishing an accurate and personalized treatment strategy (6). ...
... In terms of CIS topography, there was a lower proportion of optic neuritis and a higher proportion of spinal cord CIS in patients with aggressive MS although these differences were not statistically significant. On the other hand, there were evident differences in the baseline MRI variables: The median (IQR) number of baseline T2 lesion was 71 (28-95) compared to 7 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and for CEL it was 3 (1-24) compared to 0 (0-1) (p<0.0001, for both tests) ( Figure 4). ...
... In patients with aggressive MS, a higher proportion of OB was found in comparison to patients with a milder MS phenotype (90.0% vs. 65.4%). Comparing patients with an aggressive phenotype to those with a more standard evolution, the former mainly differed in their baseline brain MRIs: the median number of baseline T2 lesion was 71 (28-95) compared to 7 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) and the median for CEL was 3 (1-24) compared to and 0 (0-1). The cutoffs that better classify patients with aggressive MS were 20 for T2 lesions and 2 for CEL. ...
Article
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Objective To explore the long-term outcomes of patients with clinically isolated syndromes from the Barcelona cohort. Methods We selected patients with a follow-up longer than 10 years to (1) estimate the risks of multiple sclerosis (MS) and disability accumulation according to the baseline number of T2 lesions and to compare treated versus untreated patients and early versus delayed treatment, and (2) to study baseline features of patients with aggressive MS (Expanded Disability Status Scale (EDSS) ⩾6.0 at 10 years). Results In all, 401 patients were included (mean follow-up of 14.4 (standard deviation of 2.9) years). A higher number of T2 lesions was associated with an earlier MS diagnosis and an earlier risk of irreversible disability. Early treatment was associated with a decreased risk of EDSS of 3.0: adjusted hazard ratio = 0.4, 95% confidence interval = (0.2, 0.7). Patients with aggressive MS differed in their baseline brain magnetic resonance images: The median (interquartile range) number of T2 lesions and contrast-enhancing lesions (CEL) was 71 (28–95) versus 7 (1–19) and 3 (1–24) versus 0 (0–1), respectively. The cut-offs that better classified patients with aggressive MS were 20 for T2 lesions and 2 for CEL. Conclusion Although MS natural history is changing, a high lesion load at onset is helpful to identify patients at risk of presenting an aggressive MS.
... Assessment of disease activity is crucial for the management of relapsing-remitting multiple sclerosis (RRMS) in order to monitor the effectiveness of treatment and make any necessary adjustments. An absence of relapses, disease progression, and active MRI lesions [no evidence of disease activity-3 (NEDA- 3)] has been proposed by some investigators as a stringent treatment goal in clinical practice [1]. When disease activity remains high, second-line disease-modifying treatments (DMTs) should be considered [2]. ...
... When disease activity remains high, second-line disease-modifying treatments (DMTs) should be considered [2]. In particular, second-line DMTs should be offered to patients with rapidly evolving severe MS and those whose disease is not controlled by first-line DMTs [3]. ...
Article
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Introduction: In Poland, access to second-line disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis is limited by reimbursement criteria that require evidence of more aggressive disease compared to the approved indications. Material and methods: In a retrospective study carried out in DMT clinics across Poland, we asked neurologists to provide patient data on relapses and neuroimaging disease activity. Included were only patients with active disease, defined as one or more relapse and at least one new lesion between starting DMT and the last visit. For patients who had not received DMT, active disease was defined as at least one gadolinium-positive lesion or two or more new T2 lesions and two or more relapses within 12 months. We analysed the proportions of patients eligible for second-line DMTs based on the current reimbursement criteria and based on the broader criteria, which were in line with the approved indications. Results: In total, 48 neurologists provided data for 641 patients (women 64%; mean age 38 years). Of the 641 patients, 610 (95%) received DMTs: 532 first-line and 78 second-line. Of the 532 patients on first-line DMTs, 40 (7.5%) were eligible for second-line treatment based on the current reimbursement criteria, and an additional 126 (23.6%) would be eligible for second-line treatment based on the broader criteria. Of the 31 patients who did not receive any DMTs, one patient was eligible for second-line treatment, and another two patients would be eligible for second-line treatment based on the broader criteria. Moreover, 13 previously treated patients would be eligible for second-line DMTs based on the broader criteria. When extrapolated to the whole of Poland, our study shows that an additional 1,581 patients would be eligible for second-line DMTs if the current reimbursement criteria were to be replaced by broader criteria complying with the approved indications. Conclusions: An urgent change is required in the reimbursement criteria in order to expand access to second-line DMTs for patients with relapsing-remitting MS in Poland.
... These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability within a short time frame. 6,7 Although it was not possible to come to consensus about a definition of aggressive MS at the end of the workshop, we considered radiological, clinical and biological features that might be used to obtain such a consensus. Two recent papers proposed reaching an Expanded Disability Status Scale (EDSS) ⩾ 6.0 within 10 years of disease onset as aggressive MS (please refer to the companion paper 7 for a more detailed discussion). ...
... While it is tempting to extrapolate results from past successful clinical trials to all patients with MS when considering treatment options, data are not necessarily applicable to individuals with a more aggressive disease because of differences in underlying disease processes, 10 demographic considerations that may have an impact on treatment outcomes, 6 differences in comorbidities 11 and other factors compared with the general relapsing MS trial population. ...
... 2,3 There is growing awareness of the long-term benefit of early initiation of DMTs. 4-6 particularly higher-efficacy DMTs in patients with a high likelihood of relapse and accelerated disability accrual consistent with aggressive MS. [7][8][9][10][11][12] The ability to predict a patient's future relapse risk is crucial to guide the clinical decision on initiating higherefficacy DMTs, given the trade-off of potential DMT-associated adverse events and costs. Well-established clinical predictors of future aggressive MS disease activity include older age at first neurological symptom onset, male sex, non-European descent, and importantly, frequency, and severity of prior relapse. ...
... Well-established clinical predictors of future aggressive MS disease activity include older age at first neurological symptom onset, male sex, non-European descent, and importantly, frequency, and severity of prior relapse. 7,10 Additional neuroimaging and laboratory predictors of relapse include gadolinium enhancement on magnetic resonance imaging (MRI) 13 and low serum 25-OH vitamin D. 14 These factors each have modest power for predicting future relapse. While predictive models of neurological disability accrual are available, 15,16 to our knowledge, there has been no clinically deployable predictive model of future relapse that incorporates multiple predictors. ...
Article
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Objective No relapse risk prediction tool is currently available to guide treatment selection for multiple sclerosis (MS). Leveraging electronic health record (EHR) data readily available at the point of care, we developed a clinical tool for predicting MS relapse risk. Methods Using data from a clinic‐based research registry and linked EHR system between 2006 and 2016, we developed models predicting relapse events from the registry in a training set (n = 1435) and tested the model performance in an independent validation set of MS patients (n = 186). This iterative process identified prior 1‐year relapse history as a key predictor of future relapse but ascertaining relapse history through the labor‐intensive chart review is impractical. We pursued two‐stage algorithm development: (1) L1‐regularized logistic regression (LASSO) to phenotype past 1‐year relapse status from contemporaneous EHR data, (2) LASSO to predict future 1‐year relapse risk using imputed prior 1‐year relapse status and other algorithm‐selected features. Results The final model, comprising age, disease duration, and imputed prior 1‐year relapse history, achieved a predictive AUC and F score of 0.707 and 0.307, respectively. The performance was significantly better than the baseline model (age, sex, race/ethnicity, and disease duration) and noninferior to a model containing actual prior 1‐year relapse history. The predicted risk probability declined with disease duration and age. Conclusion Our novel machine‐learning algorithm predicts 1‐year MS relapse with accuracy comparable to other clinical prediction tools and has applicability at the point of care. This EHR‐based two‐stage approach of outcome prediction may have application to neurological disease beyond MS.
... These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability within a short time frame. 6,7 Although it was not possible to come to consensus about a definition of aggressive MS at the end of the workshop, we considered radiological, clinical and biological features that might be used to obtain such a consensus. Two recent papers proposed reaching an Expanded Disability Status Scale (EDSS) ⩾ 6.0 within 10 years of disease onset as aggressive MS (please refer to the companion paper 7 for a more detailed discussion). ...
... While it is tempting to extrapolate results from past successful clinical trials to all patients with MS when considering treatment options, data are not necessarily applicable to individuals with a more aggressive disease because of differences in underlying disease processes, 10 demographic considerations that may have an impact on treatment outcomes, 6 differences in comorbidities 11 and other factors compared with the general relapsing MS trial population. ...
Article
Full-text available
The natural history of multiple sclerosis (MS) is highly heterogeneous. A subgroup of patients has what might be termed aggressive MS. These patients may have frequent, severe relapses with incomplete recovery and are at risk of developing greater and permanent disability at the earlier stages of the disease. Their therapeutic window of opportunity may be narrow, and while it is generally considered that they will benefit from starting early with a highly efficacious treatment, a unified definition of aggressive MS does not exist and data on its treatment are largely lacking. Based on discussions at an international focused workshop sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), we review our current knowledge about treatment of individuals with aggressive MS. We analyse the available evidence, identify gaps in knowledge and suggest future research needed to fill those gaps. A companion paper details the difficulties in developing a consensus about what defines aggressive MS.
... well as higher levels of serum neurofilament light chain (NfL). 7,8 Patients with a very active form of disease, both clinically, with frequent disabling relapses, and radiologically, with MRI evidence of high lesion load, who are poor responders to first-line DMT, are said to have "highly active" MS and are at risk of developing aggressive MS. Early intervention with more highly effective DMTs may prevent accrual of disability from further attacks; however, these patients with highly active MS may benefit the most from AHSCT. ...
... Identifying patients who may have a more aggressive disease course as early as possible will afford an earlier treatment decision which should include the possibility of AHSCT. 7 The great efficacy and improved safety of AHSCT have led the American Society for Blood and Marrow Transplantation to recommend it as a standard treatment option for patients with treatment-refractory relapsing MS with high risk of future disability. 12 An important consideration in patients who failed DMT with a risk of rebound, such as natalizumab or fingolimod, is sequencing to AHSCT, especially since both drugs also carry a risk of PML. ...
Article
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The most effective treatment at halting inflammation in patients with highly active multiple sclerosis (MS) is immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT). Better patient selection and supportive management, as well as advances in conditioning regimens have resulted in improved safety with AHSCT. However, which comorbidities or prior therapies increase the risks associated with AHSCT still need to be determined. In addition, there is still debate as to which AHSCT conditioning regimen offers the best balance of long-term efficacy and safety. New studies comparing AHSCT with highly effective disease-modifying therapies will help to inform on the ideal placement of AHSCT in the treatment algorithm. Currently, many centers are experienced and use AHSCT to treat select patients with MS, contributing to ongoing registries and clinical trials which will help answer these questions.
... Recent approval of cladribine tablets was based on efficacy shown in three Phase 3 clinical trials (CLARITY (NCT00213135), CLARITY Extension (NCT00641537), and ORACLE MS (NCT00725985)), in addition to over a decade of accumulated safety data from all MS patients exposed to cladribine in either parenteral or oral form (Premiere Registry, Premier, Inc., Charlotte, NC, USA), which clearly failed to demonstrate any substantial malignancy risk [9]. Post hoc analysis of CLARITY and CLARITY Extension showed up to 90% of patients were free of new lesions as demonstrated by MRI, and up to 81% of MS patients remained relapse-free four years after treatment with cladribine tablets, regardless of cumulative dose [10][11]. ...
... Four of the study cohort patients presented with aggressive MS, which is defined as MS with multiple relapses in one year with an incomplete resolution, or those with an EDSS score of 4 within five years of the disease onset [10].These patients were given cladribine first as induction therapy before being prescribed any further DMT. We evaluated all patients in terms of the following standard outcomes: relapse rate, EDSS progression, and radiological evidence derived from brain MRIs for increased disease activity. ...
Article
Background Multiple sclerosis (MS) is an autoimmune and demyelinating inflammatory disease that affects the central nervous system (CNS). The etiology of the disease remains unknown. Multiple theories highlight genetic, environmental, and infectious factors that may a role. MS is considered as the main cause of disability in young people. Cladribine, known chemically as (2-Chloro-2'-deoxyadenosine), is a purine analog chemotherapy used for hairy cell leukemia and other B-cell lymphomas. The goal of this study was to evaluate the safety and efficacy of cladribine in patients with rapidly evolving or early secondary progressive MS. Methods This observational, single-center, retrospective chart review at the MS Clinic in the Ottawa General Hospital, Ottawa, Canada. A total of 24 patients (median Expanded Disability Status Scale (EDSS) of 4.5) received cladribine (0.07 mg/kg/day) for four consecutive days every six months for ≥ 2 cycles with further cycles depending on lymphocyte recovery or disease activity to a maximum of eight cycles from 2005 until 2016 were included. Four patients who were already diagnosed with rapidly evolving or early secondary progressive multiple sclerosis (SPMS) were induced with cladribine. We evaluated relapse, EDSS, and magnetic resonance imaging (MRI) results. Results Out of 24 patients (ages ranging from 30 - 60), 80% were female. Median follow-up time was seven years. The mean relapse rate in the two years before patients were given cladribine was 1.25. Twenty patients had previously received multiple disease-modifying therapies (DMTs) (≥ 2) prior to receiving cladribine. Following cladribine, eight patients suffered 10 relapses (33.3% of the cohort). Annualized relapse rates (ARRs) were reduced from 1.25 to 0.42, which was statistically significant (p-value = 0.002). There was no mean difference in EDSS (p-value = 0.06): 16% deteriorated, 62% did not change, and 12.5% improved. New MRI activity (new T2 or Gad+ lesions) was noted in only seven of 24 patients. Conclusion Parenteral cladribine reduced the relapse rate from 1.25 to 0.42, which was statistically significant (p-value = 0.002). MRI activity in patients with rapidly evolving or early secondary progressive multiple sclerosis had a reasonable safety profile.
... Lacking a universally accepted definition, aggressive/malignant/fulminant MS is characterized by a rapid disease progression often resistant to disease-modifying treatments (DMTs) resulting in significant disability or death within several months from the onset of symptoms. In 1996, the US National MS Society (NMSS) Advisory Committee on Clinical Trials in Multiple Sclerosis, defined malignant MS as "a disease with a rapidly progressive course, leading to significant disability in multiple neurologic systems or death in a relatively short time after disease onset" [5]. ...
Article
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Multiple sclerosis (MS) is a debilitating, demyelinating disease of the central nervous system, with manifestations ranging from numbness and blindness to paralysis. Typical MS is a slowly progressive demyelinating disease, causing significant morbidity spanning over many years. In contrast, “Marburg’s disease” is a rare variant of MS which demonstrates a malignant monophasic disease progression leading to death within weeks to months. We present a rapidly fatal demyelinating disease with the clinicopathological findings on par with the handful of reported cases of “Marburg’s disease” in the literature. A previously healthy 30-year-old mother of two children was extensively investigated for focal neurological signs succumbing to death 5 weeks after the onset. Antemortem investigations for tuberculosis, autoimmune diseases, and viral studies were negative. Magnetic resonance imaging of the brain showed hyperintense lesions with contrast enhancement compatible with MS. Histopathologic examination confirmed numerous inflammatory and demyelination foci scattered throughout the brain and brain stem predominantly involving the white matter. There were extensive perivascular inflammatory cell cuffs containing lymphocytes admixed with histiocytes. Also, a few foci of vasculitis with fibrinoid necrosis, mediated by lymphocytes and neutrophils were noted associated with parenchymal haemorrhages. Considered a rare variant of MS, the case of Marburg’s disease presented here shows an infrequent association with active vasculitis and haemorrhage, described only a few times in the literature. This wide spectrum of rapidly fatal demyelinating diseases consisting of rare variants with overlapping clinicopathological features makes diagnosis challenging. Therefore, it is important to correlate clinical-radiological and histopathological findings to arrive at an accurate final diagnosis.
... Current evidence [9][10][11][12][13][14][15]61] and treatment guidelines [4,5] suggest that early use of HE-DMTs may represent the appropriate therapeutic approach in the presence, already from the earliest phases of MS, of negative prognostic factors being associated with long-term disease progression (Table 3) [11,[62][63][64]. ...
Article
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Multiple sclerosis (MS) is a chronic and progressive neurological disease that is characterized by neuroinflammation, demyelination and neurodegeneration occurring from the earliest phases of the disease and that may be underestimated. MS patients accumulate disability through relapse-associated worsening or progression independent of relapse activity. Early intervention with high-efficacy disease-modifying therapies (HE-DMTs) may represent the best window of opportunity to delay irreversible central nervous system damage and MS-related disability progression by hindering underlying heterogeneous pathophysiological processes contributing to disability progression. In line with this, growing evidence suggests that early use of HE-DMTs is associated with a significant greater reduction not only of inflammatory activity (clinical relapses and new lesion formation at magnetic resonance imaging) but also of disease progression, in terms of accumulation of irreversible clinical disability and neurodegeneration compared to delayed HE-DMT use or escalation strategy. These beneficial effects seem to be associated with acceptable long-term safety risks, thus configuring this treatment approach as that with the most positive benefit/risk profile. Accordingly, it should be mandatory to treat people with MS early with HE-DMTs in case of prognostic factors suggestive of aggressive disease, and it may be advisable to offer an HE-DMT to MS patients early after diagnosis, taking into account drug safety profile, disease severity, clinical and/or radiological activity, and patient-related factors, including possible comorbidities, family planning, and patients’ preference in agreement with the EAN/ECTRIMS and AAN guidelines. Barriers for an early use of HE-DMTs include concerns for long-term safety, challenges in the management of treatment initiation and monitoring, negative MS patients’ preferences, restricted access to HE-DMTs according to guidelines and regulatory rules, and sustainability. However, these barriers do not apply to each HE-DMT and none of these appear insuperable.
... MS is a considerable socioeconomic burden because it reflects the most common cause of nontraumatic neurological disability among young adults (Rush et al., 2015). It affects more than 2.3 million people worldwide (Thompson et al., 2018). ...
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Objectives: This study aimed to investigate the pharmacokinetic characteristics of siponimod in healthy volunteers and patients with MS based on aggregated data from published clinical trials, and to explore the factors influencing siponimod exposure. Methods: A total of 476 siponimod plasma concentrations aggregated from 28 dosage groups (corresponding to 294 healthy volunteers and 207 patients with MS) were collected from published clinical trials. Population pharmacokinetic (PPK) analysis was performed using a nonlinear, mixed-effect modeling approach. The pharmacokinetic properties of siponimod in healthy volunteers and patients with MS were compared, and the influence of covariates on siponimod exposure was evaluated using both PPK analysis and noncompartmental analysis (NCA). Results: A one-compartment model with first-order absorption and elimination adequately described siponimod pharmacokinetics. The typical population parameter estimates of clearance (CL/F), apparent volume of distribution (V/F), and absorption rate constant (ka) were 3.17 L/h, 112.70 L, and 0.38 h ⁻¹ , respectively. An 11.85% lower siponimod clearance was estimated for patients with MS relative to healthy volunteers. Subgroup analyses using NCA assessments revealed that siponimod presented an accumulation index of approximately 2 after multiple administration. Compared with nonobese participants, obese participants had a relatively lower dose-corrected area under the concentration-time curve (AUC 0-∞ /D) (0.31 vs. 0.42 h/L) and V/F (120.95 vs. 133.75 L), and a relatively higher CL/F (3.25 vs. 3.21 L/h). Participants with CYP2C9*2/*3, *1/*3, and *3/*3 genotypes experienced an increased (1.3- and 3.4-fold, respectively) AUC 0-∞ /D and a decreased (0.7- and 0.3-fold, respectively) CL/F compared with those in participants with the CYP2C9*1/*1, *1*2, and *2*2 genotypes. Fluconazole combination led to a decrease in CL/F (approximately 0.5 times) and an increase in AUC 0-∞ /D (approximately 1.3 times). Conclusion: Siponimod pharmacokinetic properties in healthy volunteers and patients with MS were explored using complementary model-based meta-analysis (MBMA) and NCA approaches. A slightly lower siponimod clearance was observed in patients with MS than in healthy volunteers. The dosage regimen, body mass index, CYP2C9 genetic polymorphism and fluconazole combination may had influences on siponimod pharmacokinetics. Such model paves the road to more population-based analyses in different patient populations with MS to quantify the effect of any influencing factors on siponimod pharmacokinetics.
... 12 A recent review on treatment algorithms for aggressive MS similarly added 'unresponsiveness to first and/or second line treatment', as a defining feature to be considered along with clinical and MRI parameters. 10 In spite of these reports with various suggestions for the definition of severe or aggressive MS, there is no consensus about which, if any, of these definitions is most appropriate or most useful in clinical practice or in a research setting. All are hampered by the need for either a retrospective assessment of the disease course or a prolonged prospective evaluation until fulfilling the proposed criteria and thus hinder the ability to make rapid and efficient treatment decisions. ...
... It has the advantage that a score of > 3 can be achieved only with baseline clinical and demographic variables. Thus, in these patients with poor prognosis before the start of the DMD, the initiation of induction or intensive treatment could be considered to minimize the risk of long-term disability [22]. ...
Article
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Background and objectivesDifferent treatment response scoring systems in treated MS patients exist. The objective was to assess the long-term predictive value of these systems in RRMS patients treated with self-injectable DMTs. MethodsRRMS-treated patients underwent brain MRI before the onset of therapy and 12 months thereafter, and neurological assessments every 6 months. Clinical and demographic characteristics were collected at baseline. After the first year of treatment, several scoring systems [Rio score (RS), modified Rio score (MRS), MAGNIMS score (MS), and ROAD score (RoS)] were calculated. Cox-Regression and survival analyses were performed to identify scores predicting long-term disability. ResultsWe included 319 RRMS patients. Survival analyses showed that patients with RS > 1 and RoS > 3 had a significant risk of reaching an EDSS of 4.0 and 6.0 The score with the best sensitivity (61%) was the RoS, while the MRS showed the best specificity (88%). The RS showed the best positive predictive value (42%) and the best accuracy (81%). Conclusions The combined measures integrated into different scores have an acceptable prognostic value for identifying patients with long-term disability.Thus, these data reinforce the concept of early treatment optimization to minimize the risk of long-term disability.
... As exploratory analyses, re-baseline of MRI activity was performed 100 and 180 days after ocrelizumab start. Recent highly active MS was defined, based on the criteria proposed by Rush et al. [17], as the presence of MRI activity and at least one relapse in the year before ocrelizumab start in patients with accelerated accrual of disability (EDSS ≥ 4.0). In line with post hoc analyses of OPERA and ORATORIO studies [9], we separately explored efficacy outcomes in patients with baseline EDSS score ≥ 4 at ocrelizumab start. ...
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Data regarding effectiveness and safety of ocrelizumab in the post-marking setting are lacking. The aim of our study was to provide effectiveness and safety data of ocrelizumab treatment in patients with relapsing–remitting (RR-) and progressive multiple sclerosis (PMS) and to evaluate clinical and immunological predictors of early treatment response. In this single-center prospective observational study, we investigated effectiveness outcomes (time-to-confirmed disability worsening, time-to-first relapse, time-to-first evidence of MRI activity and time-to-first evidence of disease activity), clinical and immunological predictors of early treatment response, and incidence of adverse events (AEs). One hundred and fifty-three subjects were included (93 RRMS; 84 females). Median follow-up was 1.9 (1.3–2.7). At 2-year follow-up (FU), disability worsening-free survival were 90.5%, 64.7%, and 68.8% for RRMS, primary-progressive MS (PPMS), and secondary-progressive MS (SPMS) patients, respectively. At 2-year FU, 67.1%, 72.7%, and 81.3% of patients with RRMS, PPMS, and SPMS were free of MRI activity, with NEDA-3 percentages of 62.1%, 54.6%, and 55.1%, respectively. Lower baseline EDSS was independently associated with a reduced risk of disability worsening (HR(95%CI) = 1.45(1.05–2.00), p = 0.024) and previous treatment exposure was independently associated with increased probability of radiological activity (HR = 2.53(1.05–6.10), p = 0.039). At 6-month FU, CD8 + cell decrease was less pronounced in patients with inflammatory activity ( p = 0.022). Six patients (3.9%) discontinued ocrelizumab due to severe AEs. Our findings suggest that ocrelizumab is an effective treatment in real-world patients with RRMS and PMS, with a manageable safety profile. Better outcomes were observed in treatment-naïve patients and in patients with a low baseline disability level. Depletion of CD8 + cells could underlie early therapeutic effects of ocrelizumab.
... However, the optimal treatment strategy with DMTs in RRMS remains elusive [2,[7][8][9]. Current treatment approaches may miss a window of opportunity for achieving the highest effectiveness of DMTs [9][10][11][12]. ...
Article
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Background The optimal treatment strategy with disease-modifying therapies (DMTs) in relapsing–remitting multiple sclerosis (RRMS) remains uncertain. Objective To compare outcomes of initial treatment with infusion therapies and starting therapy with medium efficacy therapy in a propensity-matched cohort of Finnish RRMS patients. Methods A total of 154 RRMS patients initiating natalizumab, alemtuzumab, ocrelizumab or rituximab as first DMT (high efficacy DMT, heDMT group) and 1771 patients initially treated with injectable therapies, teriflunomide or dimethylfumarate and escalated based on disease activity (moderate efficacy DMT, meDMT group) were identified from the Finnish MS registry. Nearest neighbor propensity matching (1:1, caliper 0.1) was performed for age, sex, baseline Expanded Disability Status Scale (EDSS), annual relapse rate (ARR) one year prior DMT and time since MS symptom onset. Primary outcome was time to 6-month confirmed EDSS progression and the secondary outcome time to first relapse. Results In the propensity-matched group comparisons, the probability of 6-month confirmed disability progression (CDP) at 5 years after DMT start was 28.4% (95% CI 15.7–39.3) in the heDMT group ( n = 66) and 47.0% (95% CI 33.1–58.1) in meDMT group ( n = 66), p = 0.013. Probability of relapse at 5 years was 34.6% (95% CI 24.1–43.6) for heDMT ( n = 105) and 47.2% (95% CI 36.6–56.1) for meDMT ( n = 105), p = 0.019. Conclusions Initiating MS-therapy with heDMT significantly reduced the risk of 5-year disability progression and relapse compared to using meDMT as first DMT choice in propensity-matched groups of Finnish MS-patients.
... Delay in treating with ocrelizumab was personalized for each patient, considering MS severity and the risk of developing severe COVID-19 related complications. With regard to MS severity, we identified "aggressive MS" patients [5], as patients showing MRI activity and at least one relapse in the year before ocrelizumab start associated with accelerated accrual of disability (EDSS≥ 4.0). Of the remaining patients, those who did not present clinical activity after ocrelizumab start were defined "clinically stable". ...
Article
During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103,1 [SD 40,6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation. Two patients contracted SARS-CoV2 with complete recovery. Definitive data about Sars-Cov2 vaccine efficacy in patients treated with ocrelizumab are still lacking. Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.
... Disease control is particularly relevant for aggressive MS, 4 characterized by accelerated accrual of irreversible disability. Intense immunosuppression followed by autologous hematopoietic stem cell transplantation (aHSCT) has been explored extensively as a treatment strategy for aggressive MS. [5][6][7][8][9][10][11][12] The rationale of aHSCT in MS is to eliminate selfreacting cell clones and to induce self-tolerance through a profound renewal of the immune system. ...
Article
Objective To determine whether autologous hematopoietic stem cell transplantation (aHSCT) is able to induce durable disease remission in people with multiple sclerosis (MS), we analyzed the long-term outcomes after transplant in a large cohort of MS patients. Methods To be included, a minimum data set (consisting of age, MS phenotype, EDSS at baseline, information on transplant technology and at least 1 follow-up visit after transplant) was required. Results 210 patients were included [relapsing-remitting (RR)MS=122(58%)]. Median baseline EDSS was 6(1-9), mean follow-up was 6.2(±5.0) years. Among RRMS patients, disability worsening-free survival (95%CI) was 85.5%(76.9-94.1%) at 5 years and 71.3%(57.8-84.8%) at 10 years. In patients with progressive MS, disability worsening-free survival was 71.0%(59.4-82.6%) and 57.2%(41.8-72.7%) at 5 and 10 years, respectively. In RRMS patients, EDSS significantly reduced after aHSCT [p=0.001; mean EDSS change per year -0.09 (95%CI=-0.15 to -0.04%)]. In RRMS patients, the use of the BEAM+ATG conditioning protocol was independently associated with a reduced risk of NEDA-3 failure [HR=0.27(0.14-0.50), p<0.001]. Three patients died within 100-days from aHSCT (1.4%); no deaths occurred in patients transplanted after 2007. Conclusions: aHSCT prevents disability worsening in the majority of patients and induces durable improvement in disability in patients with RRMS. The BEAM+ATG conditioning protocol is associated with a more pronounced suppression of clinical relapses and MRI inflammatory activity. Classification of Evidence This study provides Class IV evidence that for people with MS, aHSCT induces durable disease remission in most patients.
... Monitoring biomarkers play a relevant role in MS, allowing neurologists to serially assess the status of the disease [13] . Particularly, disease activity biomarkers may crucially affect therapeutic decisions by detecting high disease activity and rapid disability worsening in early phases of MS [9,14] . Correlating with clinical and radiological activity, they may aid in identifying aggressive forms of MS and also provide an indirect assessment of low therapeutic response in patients under DMDs [1] . ...
... [28][29][30] Further, systemic inflammatory activity is a more predominant mechanism of the disease earlier in the disease course when compared with the more complex pathogenesis in late-stage MS, which is also evidenced by the superior efficacy of DMT in the earlier stages of MS. 16 Recent evidence points to a window of opportunity for achieving the highest effectiveness of DMT, which is open during the period of highest inflammatory activity, usually initiated by the first demyelinating attack. 31 Accordingly, it may be that more effective therapy early in the disease course improves long-term outcomes, which was the finding of this study. However, the balance of risk vs benefit of starting initial heDMT likely differs according to the individual patient, and a one size fits all approach is probably not optimal. ...
Article
Objective To determine the effectiveness of high-efficacy disease-modifying therapies (heDMT) versus medium-efficacy disease-modifying therapies (meDMT) as the first treatment choice in treatment-naïve patients with multiple sclerosis (MS) on disability worsening and relapses. We assessed this using a nationwide population-based MS registry. Methods We identified all patients starting a heDMT as first-time treatment from the Danish Multiple Sclerosis Registry and compared treatment outcomes with a propensity-score matched sample of patients starting meDMT. Results We included 388 patients in the study: 194 starting initial therapy with heDMT matched to 194 patients starting meDMT. At 4 years of follow-up, the probabilities of a 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening were 16.7% (95% confidence interval (CI): 10.4%-23.0%) and 30.1% (95% CI: 23.1%-37.1%) for heDMT- and meDMT-initiators, respectively (Hazard ratio (HR): 0.53, 95% CI 0.33-0.83, p=0.006). Patients initiating heDMT also had a lower probability of a first relapse (HR 0.50, 95% CI 0.37-0.67). Results were similar after pairwise censoring and in subgroups with high-baseline activity, diagnosis after year 2006 or information on baseline T2 lesion load. Conclusion We found a lower probability of 6-month confirmed EDSS score worsening and lower probability of a first relapse in patients starting a heDMT as first therapy, compared to a matched sample starting meDMT. Classification of Evidence This study provides Class III evidence that for patients with MS, starting heDMT lowers the risk of EDSS worsening and relapses compared to starting meDMT.
... 12 A recent review on treatment algorithms for aggressive MS similarly added 'unresponsiveness to first and/or second line treatment', as a defining feature to be considered along with clinical and MRI parameters. 10 In spite of these reports with various suggestions for the definition of severe or aggressive MS, there is no consensus about which, if any, of these definitions is most appropriate or most useful in clinical practice or in a research setting. All are hampered by the need for either a retrospective assessment of the disease course or a prolonged prospective evaluation until fulfilling the proposed criteria and thus hinder the ability to make rapid and efficient treatment decisions. ...
Article
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While the major phenotypes of multiple sclerosis (MS) and relapsing–remitting, primary and secondary progressive MS have been well characterized, a subgroup of patients with an active, aggressive disease course and rapid disability accumulation remains difficult to define and there is no consensus about their management and treatment. The current lack of an accepted definition and treatment guidelines for aggressive MS triggered a 2018 focused workshop of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) on aggressive MS. The aim of the workshop was to discuss approaches on how to describe and define the disease phenotype and its treatments. Unfortunately, it was not possible to come to consensus on a definition because of unavailable data correlating severe disease with imaging and molecular biomarkers. However, the workshop highlighted the need for future research needed to define this disease subtype while also focusing on its treatment and management. Here, we review previous attempts to define aggressive MS and present characteristics that might, with additional research, eventually help characterize it. A companion paper summarizes data regarding treatment and management.
... To help a medical practitioner лее в течение первых 5 лет болезни, выраженная активность по данным МРТ головного и спинного мозга [2][3][4][5][6]. Однако единого понимания критериев высокоактивного, или агрессивного, РС в настоящее время нет. ...
Article
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Alemtuzumab (Lemtrada) is a recombinant humanized IgG1 kappa monoclonal antibody to the surface cell glycoprotein, a CD52 differentiation cluster. The drug is approved for use in more than 65 countries, including the Russian Federation. The drug is one of the most effective methods of treating patients with aggressive multiple sclerosis, but the risk management plan should be followed. The safety profile of the drug includes infusion-associated reactions, thyroid dysfunction, immune cytopenia, acute cardiovascular events, infections, and other autoimmune diseases. This publication provides updated practical recommendations for the use of the drug and ensuring the safety of patients treated with alemtuzumab.
... AHSCT may also be considered in patients with early aggressive disease with a poor prognosis or worsening disability despite treatment with a higher-efficacy DMT. 175 ...
Article
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The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.
... Çëîêà÷åñòâåííûì ñ÷èòàëîñü òå÷åíèå ïðè íàëè÷èè îäíîãî è áîëåå êðèòåðèåâ, îïðåäåëåííûõ â ðàáîòå C.A. Rush è ñîàâò. [7].  ãðóïïó ñî çëîêà÷åñòâåííûì òå÷åíèåì âîøåë 21 áîëüíîé, ñ äîáðîêà-÷åñòâåííûì -31. ...
Article
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Objective: to study the probable laboratory predictors of aggressive multiple sclerosis. Materials and methods . Antibodies to myelin oligodendrocyte glycoprotein (MOG), antibodies to thyroperoxidase and markers of endothelial dysfunction in blood serum were determined in patients with multiple sclerosis (MS). These indicators were analyzed for different courses of the demyelinating process, for different severity of neurological disorders, and for various sizes of focal lesions on magnetic resonance images. Results . In patients with aggressive multiple sclerosis, higher titers of antibodies to both myelin oligodendrocyte glycoprotein and thyroperoxidase were detected. A relationship between von Willebrand factor (vWf) and matrix metalloproteinase-9 (MMP-9) and the stage of multiple sclerosis was identified. A higher level of matrix metalloproteinase-9 was detected in MS patients with active foci of the disease on magnetic resonance images. Conclusion . Thus, antibodies to myelin oligodendrocyte glycoprotein, antibodies to thyroperoxidase, the levels of von Willebrand factor, matrix metalloproteinase-9 and adhesion molecule sPECAM-1 can be used as laboratory predictors of the malignant course of multiple sclerosis.
... Negative prognostic factors at MS onset. EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; MS, Multiple Sclerosis susceptibility to opportunistic infections or neoplasms, could be considered immunosuppressant[33][34][35]. ...
Article
Introduction Therapeutic armamentarium in Multiple Sclerosis (MS) has radically changed in the last few decades due to the development of disease modifying treatments (DMTs) with highly selective mechanisms of action. Areas covered In this review, the authors will focus on the current role of immunosuppressive DMTs in the management of the relapsing remitting form of MS (RRMS), moving from the rationale of its use and looking at the possibility to design an idealistic scenario of a personalized approach for each single patient. Expert opinion Questions remain open about whether initial high-efficacy immunosuppressive DMTs improve long-term outcomes, whether prolonged exposure to these agents increases adverse events and what the strongest early surrogate markers are for predicting long-term treatment responses to high-efficacy drugs. In this way, the immunosuppressive DMTs, are used to hit the immune system early and hard with the idealistic goal of striking the autoimmune activities before the neurological damage becomes irreversible.
... On one extreme, there are patients who are seemingly asymptomatic, with incidentally detected demyelinating lesions detected on MRI ("radiologically isolated syndrome") 7 or autopsy, 8 or with "benign," non-disabling course, 9 while, on the other end, there are patients with rapidly disabling disease, variably described as "malignant," "fulminant," and "catastrophic." 10,11 Benign and malignant forms of MS are rare, but of considerable research interest as they may shed light on protective and aggravating factors that influence disease course. In order to study such outliers, one first needs to be able to identify them. ...
Article
Severity score represents disease duration–adjusted mean rank of disability in multiple sclerosis (MS) patients from the reference population. This measure allows one to compare the relative rates of disease progression among patients, patient subgroups, and across epochs, which opens up new question of what accounts for the observed differences in severity, and can be used to assess correlation between disease severity and clinical, radiologic, immunologic, genetic, and environmental variables of interest. Severity score can also prove useful for developing prognostic tools in MS. This article discusses the diverse applications of severity score concept in MS research, and (re)introduces Herbert’s proposal of severity-based MS classification in the context of variability of MS severity.
... In their review of the British Colombia MS database, 14.3% of patients fulfilled either one of the 2 definitions, 86% of whom were relapsing remitting. Rush et al. defined aggressive MS in treatment naïve patients as 2 or more relapses with incomplete recovery in the past year (Rush et al., 2015). The EMA definition of rapidly evolving severe disease was ≥ 2 disabling relapses in 1 year with ≥1 Gd+ lesion or significant increase in T2 lesion load. ...
Article
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With evolving diagnostic criteria and the advent of new oral and parenteral therapies for MS, most current diagnostic and treatment algorithms need revision and updating. The diagnosis of MS relies on incorporating clinical and paraclinical findings to prove dissemination in space and in time, and exclude alternative diseases that can explain the findings at hand. The differential diagnostic workup should be guided by clinical and laboratory red flags to avoid unnecessary tests. Appropriate selection of multiple sclerosis (MS) therapies is critical to maximize patient benefit. The current guidelines review the scientific evidence supporting treatment of acute relapses, radiologically isolated syndrome, clinically isolated syndrome, relapsing remitting MS, and progressive MS. The purpose of these guidelines is to provide practical recommendations and algorithms for the diagnosis and treatment of MS based on current scientific evidence and clinical experience.
... Early identification of the specific immune-phenotype of each multiple sclerosis (MS) patient would be particularly important at a stage in which the most appropriate disease modifying agents could be early provided, in order to improve outcomes before the onset of irreversible tissue damage [1]. Up to now, only a detailed clinical and imaging follow-up analysis has helped to either obtain early disease diagnosis or to monitor the response to treatments. ...
Article
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Background: Clinical and imaging follow-up coupled with cerebrospinal fluid (CSF) and possibly serum profiling could provide information on disease activity and disability evolution in multiple sclerosis patients. Case presentation: We describe the case of a relapsing-remitting MS patient whose history was characterized by failure of several therapeutic approaches and sustained disease activity. By using a highly sensitive immunoassay methodology, we examined protein expression of 70 inflammatory/cytotoxic molecules in two consecutive paired CSF and serum samples, obtained respectively in 2006 and 2013. At disease diagnosis, elevated CSF protein levels of an inflammatory pattern, including CXCL13, CXCL12, IFNγ, TNF, sTNFR1, IL8, sCD163, APRIL, BAFF, pentraxin III and MMP2 were found compared with a group of controls. At the second lumbar puncture, sustained disease activity was accompanied by considerable (more than 2 fold changes) increase expression of most of these inflammatory molecules while no significant changes in serum inflammatory markers were detected in the two consecutive serum samples. Conclusions: Elevated CSF protein expression of pro-inflammatory mediators, possibly specifically associated to GM demyelination, could remain stable or increase over time in patients with active multiple sclerosis. We underline the role of fluid analysis in understanding the pathophysiology of the disease and providing information on possible markers of disease activity and evolution.
... 27 The proportion of patients with the aggressive form of the disease is estimated to be between 4% and 14%. 25 Proposed criteria for its definition include patients with RRMS who develop an EDSS greater than 4.0 (disability causing limitation of their daily activities) within 5 years or continued clinical or radiographic relapses despite a year of therapy. 28,29 There are new biomarkers being studied to assist in the prediction of patients with aggressive MS including neurofilament light chain (NfL), a measure of axonal destruction, with higher baseline levels associated with higher 10-year brain atrophy and disability. 30 Other poor prognostic factors less clearly defined but understood to increase risk of transition to SPMS despite therapy are advanced age, male gender, non-Caucasian ethnic background, smoking, and multifocal relapses. ...
Article
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Multiple sclerosis is the leading non-traumatic cause of disability in young adults, affecting up to 100,000 Canadians. This chronic inflammatory and neurodegenerative disease of the central nervous system leads to irreversible neurologic disability if inadequately controlled. Though many current medications are available that reduce inflammatory damage, most patients continue to show some evidence of disease activity and accrue disability. In this review, we discuss the role of immune ablation followed by autologous hematopoietic stem cell transplantation (AHSCT), a therapeutic option for select patients with a more aggressive disease course. By "resetting" the immune system with a variety of ablative conditioning regimens, followed by immune reconstitution, this therapy has shown a durable response in halting evidence of inflammatory activity in most patients, without the need for continued disease-modifying therapies (DMT). Since the introduction of this therapy, there have been advances in patient selection and supportive care, such that morbidity has significantly declined and treatment-related mortality is minimized. Recent phase-II trials have shown excellent results in efficacy and safety of AHSCT; however, challenges exist which require ongoing study. The future challenges include comparing the variety of AHSCT conditioning regimens with each other as well as with existing highly effective DMT; identifying patients with an aggressive disease course through novel biomarkers who may benefit the most from AHSCT; and surveillance of long-term outcomes of different treatment protocols. In select patients, replacing the immune system with AHSCT holds promise of fundamentally altering the trajectory of their aggressive disease course.
Article
Background: multiple sclerosis (MS) has an extremely heterogeneous disease course. Relapsing course leading to rapid accrual of physical and cognitive disability, often despite treatment, is referred to as “aggressive” disease. Case presentation: definition and treatment of aggressive multiple sclerosis (MS) are poorly standardized. No clear reports of ocrelizumab in tumefactive, breakthrough disease are available in current literature. Case report: a 34-year-old Caucasian woman was admitted to hospital with dizziness, nausea, vomiting, and mild gait ataxia. Brain magnetic resonance imaging (MRI) revealed multiple demyelinating lesions, many of which were infratentorial, showing tumefactive aspect and gadolinium enhancement. Cerebrospinal fluid analysis revealed presence of oligoclonal bands, and a diagnosis of MS was made. She was treated with 2 cycles of intravenous methylprednisolone 1000 mg and seven sessions of plasma exchanges. Despite this intensive treatment, her clinical condition worsened, reaching a score of 8.0 on the Expanded Disability Status Scale (EDSS), and MRI revealed many new/enlarged/enhancing lesions. Finally, she underwent ocrelizumab treatment (2 × 300 mg iv two weeks apart) and started to recover. During a 12-month follow-up she pursued ocrelizumab treatment (600 mg every 24 weeks). Her clinical condition continued to improve (EDSS 1.5), and two consecutive MRI showed no new lesions and reduction in size of the pre-existing ones. Conclusions: our patient, with a tumefactive MS onset, showed a very brilliant response to ocrelizumab treatment. Ocrelizumab should be considered in cases of tumefactive MS.
Article
Objective: The objective of this study was to identify predictors in common between different clinical and magnetic resonance imaging (MRI) outcomes in multiple sclerosis (MS) by comparing predictive models. Methods: We analyzed 704 patients from our center seen at MS onset, measuring 37 baseline demographic, clinical, treatment, and MRI predictors, and 10-year outcomes. Our primary aim was identifying predictors in common among clinical outcomes: aggressive MS, benign MS, and secondary-progressive (SP)MS. We also investigated MRI outcomes: T2 lesion volume (T2LV) and brain parenchymal fraction (BPF). The performance of the full 37-predictor model was compared with a least absolute shrinkage and selection operator (LASSO)-selected model of predictors in common between each outcome by the area under the receiver operating characteristic curves (AUCs). Results: The full 37-predictor model was highly predictive of clinical outcomes: in-sample AUC was 0.91 for aggressive MS, 0.81 for benign MS, and 0.81 for SPMS. After variable selection, 10 LASSO-selected predictors were in common between each clinical outcome: age, Expanded Disability Status Scale, pyramidal, cerebellar, sensory and bowel/bladder signs, timed 25-foot walk ≥6 seconds, poor attack recovery, no sensory attacks, and time-to-treatment. This reduced model had comparable cross-validation AUC as the full 37-predictor model: 0.84 versus 0.81 for aggressive MS, 0.75 versus 0.73 for benign MS, and 0.76 versus 0.75 for SPMS, respectively. In contrast, 10-year MRI outcomes were more strongly influenced by initial T2LV and BPF than clinical outcomes. Interpretation: Early prognostication of MS is possible using LASSO modeling to identify a limited set of accessible clinical features. These predictive models can be clinically usable in treatment decision making once implemented into web-based calculators. ANN NEUROL 2022.
Article
Resumen Introducción No existe una definición universalmente aceptada de esclerosis múltiple altamente activa (EMAA), y no existen guías de práctica clínica ni consensos que la definan con claridad, por lo que la ausencia de esta definición dificulta la toma de decisiones terapéuticas. Objetivo Definir con la mejor precisión posible la EMAA, y armar una propuesta de diagnóstico y manejo de estos pacientes. Comentarios Un grupo de neurólogos argentinos con experiencia en el manejo de pacientes con esclerosis múltiple fue convocado para debatir e intentar dar respuesta a las preguntas más frecuentes sobre EMAA. Conclusiones La presencia de recaídas, en primer lugar, de nuevas lesiones con realce, en segundo, y la aparición de nuevas lesiones T2 en el transcurso de un año, en tercero, son suficientes para definir la EMAA. No se logró identificar con precisión el número de nuevas lesiones en T2 o con captación de contraste que se requieren para cumplir la definición. La mejor opción recomendada de tratamiento para estos pacientes, ya sean naive o bajo otro tratamiento, son las terapias de alta eficacia.
Article
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Idiopathic inflammatory demyelinating diseases (IIDDs) of the central nervous system (CNS) are rare but serious neurological complications of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). However, the risk factors and a method to predict the prognosis of posttransplantation CNS IIDDs are not available. This retrospective study first reviewed data from 4532 patients who received haplo-HSCT during 2008-2019 in our center, and 184 patients (4.1%) with IIDDs after haplo-HSCT were identified. Grades II to IV acute graft-versus-host disease (aGVHD) (p < 0.001) and chronic GVHD (cGVHD) (p = 0.009) were identified as risk factors for developing IIDDs after haplo-HSCT. We then divided the 184 IIDD patients into a derivation cohort and validation cohort due to transplantation time to develop and validate a model for predicting the prognosis of IIDDs. In the multivariate analysis of the derivation cohort, four candidate predictors were entered into the final prognostic model: cytomegalovirus (CMV) infection, Epstein-Barr virus (EBV) infection, IgG synthesis (IgG-syn) and spinal cord lesions. The prognostic model had an area under the receiver operating characteristic curve of 0.864 (95% CI: 0.803–0.925) in the internal validation cohort and 0.871 (95% CI: 0.806–0.931) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. Decision curve analysis indicated that IIDD patients could benefit from the clinical application of the prognostic model. The identification of IIDD patients after allo-HSCT who have a poor prognosis might allow timely treatment and improve patient survival and outcomes. This article is protected by copyright. All rights reserved.
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Introduction Demyelinating lesions occasionally present as mass-like lesions on imaging, raising concern for malignancy. The disease course of such tumefactive demyelinating lesions (TDLs) is still being defined. Methods We retrospectively analyzed 21 patients with new-onset neurologic symptoms and mass-like lesions on brain magnetic resonance imaging (MRI), which resulted in biopsy-proven diagnoses of demyelination. 18 patients had a median follow-up of 52 months. The clinical, radiologic and histologic features were associated with disease course. Results An aggressive disease course (ADC) was noted in 33% of the patients and was associated with an initial largest lesion size ≥35 mm (p = 0.0007), mass effect (p = 0.01) and perilesional edema (p = 0.01) on MRI. Age 30 years and older, at presentation (p = 0.05), as well as the absence of a prior tonsillectomy (p = 0.0128) were also associated with an ADC. Conclusions We identified several factors, including initial larger lesion size, mass effect and perilesional edema on MRI, presentation after 30 years of age and the absence of a prior tonsillectomy, that predict an ADC in patients presenting with TDLs. These predicators can help guide patient follow-up and stratification for intervention.
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Multiple sclerosis is a major socio-economical burden as it represents the most common cause of non-traumatic neurological disability in young adults [1]. It affects also children with a lower prevalence and incidence but remains a major concern as disability may occur later during their adulthood. Therefore, there is an absolute need for earlier diagnosis and treatment. In this review, we would focus on how these objectives can be achieved.
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Relapsing multiple sclerosis (RMS) presents a highly variable clinical evolution among patients, and its management should be personalized. Although there is no cure at present, effective disease-modifying therapies (DMTs) are available. Selection of the most appropriate DMT for each patient is influenced by several clinical, radiological and demographic aspects as well as personal preferences that, at times, are not covered in the regulatory criteria. This may be a source of difficulty, especially in certain situations where so-called ‘high-efficacy DMTs’ (usually considered second-line) could be of greater benefit to the patient. In this narrative review, we discuss evidence and experience, and propose a pragmatic guidance on decision-making with respect to the indication and management of high-efficacy DMT in adult patients with RMS based on expert opinion.
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Cladribine is a modified deoxyadenosine that evades the action of the enzyme adenosine deaminase, which results in an immunosuppressive effect through lymphopenia, leading to an immune cells reconstitution that helps in the treatment of autoimmune diseases such as relapsing–remitting multiple sclerosis (RRMS). Since we currently have a wide range of medications to treat RRMS, it is of great interest to identify the role that cladribine plays among all options. The main objective of this narrative review is to provide useful information, with the aid of a clinical case study, which helps physicians in making decisions to treat patients with RRMS, and provide them with the best options for efficacy and safety. Due to its selective immunosuppressive effects, cladribine is indicated for the treatment of moderate to severe activity RRMS, either in escalation therapy or as induction therapy. In this article we will also analyze the characteristics of this drug to establish the scientific bases that guide the therapeutic decision making, taking into account the balance of risks and benefits for the patient.
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Background Both baseline prognostic factors and short‐term predictors of treatment response can influence the long‐term risk of disability accumulation in patients with relapsing‐remitting multiple sclerosis (RRMS). Objective To develop and validate scoring system combining baseline prognostic factors and one‐year variables of treatment response into a single numeric score predicting the long‐term risk of disability. Methods We analyzed two independent datasets of patients with RRMS who started Interferon Beta or Glatiramer Acetate, had an Expanded Disability Status Scale (EDSS) score <4.0 at treatment start and were followed for at least 10 years. The first dataset (“training set”) included patients attending three MS Centers in Italy and served as framework to create the so‐called RoAD score (Risk of Ambulatory Disability). The second (“validation set”) included a cohort of patients followed in Barcelona, Spain, to explore the performance of RoAD score in predicting the risk of reaching an EDSS score≥6.0. Results The RoAD score, derived from the training set (n = 1,225), was based on demographic (age) and clinical baseline prognostic factors (disease duration, EDSS) and one‐year predictors of treatment response (number of relapses, presence of gadolinium‐enhancement and new T2 lesions). The best cut‐off score for discriminating patients at higher risk of reaching the disability milestone was ≥4. When applied to the validation set (n = 296), patients with a RoAD score ≥4 had an approximately 4‐fold increased risk for reaching the disability milestone (p<0.001). Discussion We propose the RoAD score as an useful tool to predict individual prognosis of patients with RRMS to optimize treatment strategy.
Chapter
Multiple sclerosis (MS) is a heterogeneous immune-mediated disease that involves demyelination with inflammation in the central nervous system (CNS), as well as a neurodegenerative component. The natural history of the disease has changed favorably over time with the advent of efficacious disease modifying therapies (DMTs) that prevent or limit inflammatory disease activity. In this chapter, we discuss the various phenotypes of MS and their individual characteristics. Next, we discuss important imaging and clinical prognostic factors in MS that may help predict the natural history of an individual patient’s disease. We then review the impact of the advent of the DMT era on the natural history of MS. Comorbidities and health behaviors as they influence MS and its natural history are then discussed.
Article
Introduction: Autologous hematopoietic stem cell transplantation (AHSCT) has become increasingly popular in recent years as an effective treatment of immune mediated neurological diseases. Treatment related mortality has significantly reduced primarily through better patient selection, optimization of transplant technique and increased center experience. Area covered: Multiple sclerosis is the main indication, but people with neuromyelitis optica spectrum disorder, stiff person spectrum disorder, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis and other immune-mediated neurological disorders also have been treated. The review herein discusses the use of AHSCT in these neurological disorders, the importance of patient selection and transplant technique optimization and future directions. Expert opinion: Phase II and III clinical trials have confirmed the safety and efficacy of AHSCT in multiple sclerosis and recent phase II clinical trials have also suggested its safety and efficacy in chronic inflammatory demyelinating polyneuropathy and neuromyelitis optica spectrum disorder, with the evidence in other neurological disorders limited to individual case reports, small case series and registry data. Therefore, further randomized controlled clinical trials are required to assess its safety and efficacy in other neurological conditions. However, in rare neurological conditions, pragmatic treatment trials or registry-based studies may be more realistic options for gathering efficacy and safety data.
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Background Alemtuzumab efficacy versus subcutaneous interferon-β-1a (SC IFNB-1a) was demonstrated over 2 years in patients with relapsing-remitting multiple sclerosis, with continued efficacy over 7 additional years. Alemtuzumab is included as a recommended treatment for patients with highly active disease (HAD) by the American Academy of Neurology Practice Guidelines, and the label indication in Europe was recently restricted to the treatment of HAD patients. There is currently no consensus definition for HAD, and alemtuzumab efficacy across various HAD definitions has not been explored previously.Objectives In this post hoc analysis, we assess the efficacy and safety of alemtuzumab in Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) trial patients who met criteria for at least one of four separate definitions of HAD (one primary and three alternatives). Over 2 years, alemtuzumab-treated HAD patients were compared with SC IFNB-1a-treated HAD patients, with additional 7-year follow-up in patients from the alemtuzumab arm.Methods Patients in the CARE-MS studies received either alemtuzumab (baseline: 5 days; 12 months later: 3 days) or SC IFNB-1a (3 times weekly). Alemtuzumab-treated patients who enrolled in the extensions could receive additional courses ≥ 12 months apart. Four definitions of HAD were applied to assess alemtuzumab efficacy: the pre-specified primary definition (two or more relapses in the year prior to baseline and at least one gadolinium [Gd]-enhancing lesion at baseline) and three alternative definitions that focused on relapse, magnetic resonance imaging (MRI), or prior treatment response criteria. Efficacy outcomes were annualized relapse rate, change in Expanded Disability Status Scale score, 6-month confirmed disability worsening, 6-month confirmed disability improvement, MRI disease activity, and brain volume change. Adverse events were summarized for HAD patients meeting the primary definition.ResultsIn the pooled CARE-MS population, 208 alemtuzumab-treated patients met the primary HAD definition. Annualized relapse rate was 0.27 in years 0–2 and 0.16 in years 3–9. Over 9 years, 62% of patients were free of 6-month confirmed disability worsening, 50% had 6-month confirmed disability improvement, and median cumulative change in brain volume was − 2.15%. During year 9, 62% had no evidence of disease activity, and 69% were free of MRI disease activity. Similar efficacy outcomes were observed using an alternative relapse-driven HAD definition. For patients meeting alternative HAD definitions focused on either higher MRI lesion counts or disease activity while on prior therapy, reduced efficacy for some endpoints was seen. Safety was consistent with the overall CARE-MS population through year 9.Conclusions Over 9 years, alemtuzumab efficacy was maintained in CARE-MS HAD patients based on four HAD definitions. These results support intervention with alemtuzumab in patients with early indicators of HAD, including frequent relapse without high MRI activity. No safety signals were observed over 9 years that were unique to the HAD populations.ClinicalTrials.gov IdentifiersNCT00530348; NCT00548405; NCT00930553; NCT02255656.
Article
Background The best therapeutic approach for aggressive relapsing‐remitting multiple sclerosis (RRMS) remains unknown. Objective To compare efficacy and safety of autologous haematopoietic stem cell transplantation (aHSCT) and alemtuzumab in aggressive RRMS. Methods Time‐to‐first relapse, time‐to‐confirmed disability worsening, time‐to‐first evidence of MRI activity and time‐to‐first evidence of disease activity were compared between the two treatment groups. Secondary outcomes included the 12,24 and 36 months annualized‐relapse‐rate (ARR) and the 6‐months confirmed EDSS changes at month 12 and 24. Results Fifty‐seven patients treated with aHSCT (n=25) or alemtuzumab (n=32) were included. At baseline, aHSCT patients had higher EDSS (median score of 6 versus 3; p<0.001), higher ARR (mean ARR of 3.2 versus 1.7; p=0.001) and a higher number of baseline T1‐gadolinium enhancing lesions at MRI (mean number of 15.5 versus 1.6; p<0.001). NEDA‐3 status was more frequently achieved in aHSCT‐treated patients than in alemtuzumab‐treated patients (75% versus 56% of patients at the end of the observation period; HR[95%CI]=0.27 [0.08‐0.84]; p=0.023). aHSCT significantly reduced the risk of relapse (relapse‐free survival of 84% versus 69%; HR[95%CI]=0.13 [0.02‐0.63]; p=0.012) and MRI activity (MRI activity‐free survival of 85% versus 59%; HR[95%CI]=0.13 [0.03‐0.59] ; p=0.009). The ARR at 36 months was significantly lower in the aHSCT group (0.05 vs 0.35 p=0.02). A significant effect of aHSCT in promoting EDSS improvement compared with alemtuzumab was noted (p=0.035). Conclusions Alemtuzumab and aHSCT are effective treatment choices for aggressive MS. aHSCT seems to be superior to alemtuzumab in inducing complete disease control and in promoting short‐term disability improvement.
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Multiple sclerosis (MS) ranks first for prevalence among diseases affecting the CNS white matter with 2.5 million cases estimated globally. InRussia, the number of cases is about 200 thousand. MS in most cases has a wavy course (periods of exacerbations and remissions), over time the progression of disease worses the quality of life of patients. The “gold standard” at the beginning of MS is first-line drugs disease-modifying therapies (DMT). If they are ineffective, it is necessary to strengthen the effect on the immune processes and the patient is prescribed second-line drugs (escalation of therapy). There is a method of induction therapy, when high activity of MS is recommended to start with drugs that have a strong immunosuppressive effect with a possible subsequent transition to soft supportive treatment. In patients with frequent exacerbations and signs of radiological activity of the disease, according to magnetic resonance imaging (MRI) of the brain and spinal cord, monoclonal antibody preparations are effectively used. Except of escalation and induction, it is also used the method of immune system reconstruction, which leads to a decrease in autoagression in MS. This article discusses a clinical case of using a drug of monoclonal antibodies that selectively bind to CD 52 on the surface of lymphocytes. The issues of efficacy and safety of alemtuzumab therapy in patients with MS are considered.
Article
Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system (CNS), affecting patients of all ages, causing neurologic disability if inadequately treated. Some patients have a relatively benign disease course without significant disability after decades, while a more aggressive course ensues in others and disability progression occurs after only several years. Certain risk factors confer a higher chance of a patient having aggressive MS. Currently over 15 disease-modifying treatments (DMTs) are approved for MS with different efficacy and safety profiles. Deciding which DMT to use in a specific patient requires a careful analysis of a patient’s disease course for high-risk factors for early progression, consideration of the efficacy and safety profile for potential therapy, as well as understanding of a patient’s lifestyle and expectations. The integration of these factors is the art of precision medicine, a necessary practice in the treatment of patients with MS.
Article
The clinical course of multiple sclerosis (MS) is characterized by great variability. 'Aggressive' MS, a concept used in the last 10 years, is associated with atypical course of the disease, which is manifested by more frequent exacerbations, the rapid increase in disability and pronounced signs of radiological activity according to MRI. The review presents data on the effectiveness of three monoclonal antibody drugs - natalizumab, alemtuzumab and ocrelizumab. In addition, updated data on the safety of monoclonal antibodies are presented to help the physician make a balanced choice of a drug and therapy strategy.
Chapter
Disease-modifying treatment of multiple sclerosis (MS) has been rapidly evolving over the last two decades with a shift toward a more targeted and aggressive intervention early in the disease course. Long-term remission from disease activity can now be achieved using several different therapeutic options. Unfortunately, the risk of serious adverse events such as progressive multifocal leukoencephalopathy (PML) has also increased, and careful monitoring of treated patients is essential. Treatment options for progressive forms of MS are very limited.
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Purpose of review This review presents a critical appraisal of the use of autologous hematopoietic cell transplant (AHCT) for the treatment of multiple sclerosis. We present the reader with a brief review on the AHCT procedure, its immunomodulatory mechanism of action in MS, the most recent evidence in support of its use in patients with relapsing-remitting multiple sclerosis (RRMS), as well as its cost considerations. Recent findings The first meta-analysis of clinical trials of AHCT for patients with MS demonstrated durable 5-year progression-free survival rates and low treatment-related mortality. Recently, the first randomized controlled phase III clinical trial demonstrated AHCT to be superior to best available therapy for a subset of patients with RRMS. This led to the American society for transplant and cellular therapies (ASTCT) to recommend AHCT “for patients with relapsing forms of MS who have prognostic factors that indicate a high risk of future disability.” Summary AHCT should be considered for patients with RRMS with evidence of clinical activity who have failed 2 lines of therapy or at least one highly active disease-modifying therapy.
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No current therapy for relapsing-remitting multiple sclerosis (MS) results in significant reversal of disability. To determine the association of nonmyeloablative hematopoietic stem cell transplantation with neurological disability and other clinical outcomes in patients with MS. Case series of patients with relapsing-remitting MS (n = 123) or secondary-progressive MS (n = 28) (mean age, 36 years; range, 18-60 years; 85 women) treated at a single US institution between 2003 and 2014 and followed up for 5 years. Final follow-up was completed in June 2014. Treatment with cyclophosphamide and alemtuzumab (22 patients) or cyclophosphamide and thymoglobulin (129 patients) followed by infusion of unmanipulated peripheral blood stem cells. Primary end point was reversal or progression of disability measured by change in the Expanded Disability Status Scale (EDSS) score of 1.0 or greater (score range, 0-10). Secondary outcomes included changes in the Neurologic Rating Scale (NRS) score of 10 or greater (score range, 0-100), Multiple Sclerosis Functional Composite (MSFC) score, quality-of-life Short Form 36 questionnaire scores, and T2 lesion volume on brain magnetic resonance imaging scan. Outcome analysis was available for 145 patients with a median follow-up of 2 years and a mean of 2.5 years. Scores from the EDSS improved significantly from a pretransplant median of 4.0 to 3.0 (interquartile range [IQR], 1.5 to 4.0; n = 82) at 2 years and to 2.5 (IQR, 1.9 to 4.5; n = 36) at 4 years (P < .001 at each assessment). There was significant improvement in disability (decrease in EDSS score of ≥1.0) in 41 patients (50%; 95% CI, 39% to 61%) at 2 years and in 23 patients (64%; 95% CI, 46% to 79%) at 4 years. Four-year relapse-free survival was 80% and progression-free survival was 87%. The NRS scores improved significantly from a pretransplant median of 74 to 88.0 (IQR, 77.3 to 93.0; n = 78) at 2 years and to 87.5 (IQR, 75.0 to 93.8; n = 34) at 4 years (P < .001 at each assessment). The median MSFC scores were 0.38 (IQR, -0.01 to 0.64) at 2 years (P < .001) and 0.45 (0.04 to 0.60) at 4 years (P = .02). Total quality-of-life scores improved from a mean of 46 (95% CI, 43 to 49) pretransplant to 64 (95% CI, 61 to 68) at a median follow-up of 2 years posttransplant (n = 132) (P < .001). There was a decrease in T2 lesion volume from a pretransplant median of 8.57 cm3 (IQR, 2.78 to 22.08 cm3) to 5.74 cm3 (IQR, 1.88 to 14.45 cm3) (P < .001) at the last posttransplant assessment (mean follow-up, 27 months; n = 128). Among patients with relapsing-remitting MS, nonmyeloablative hematopoietic stem cell transplantation was associated with improvement in neurological disability and other clinical outcomes. These preliminary findings from this uncontrolled study require confirmation in randomized trials.
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Accurate clinical course descriptions (phenotypes) of multiple sclerosis (MS) are important for communication, prognostication, design and recruitment of clinical trials, and treatment decision-making. Standardized descriptions published in 1996 based on a survey of international MS experts provided purely clinical phenotypes based on data and consensus at that time, but imaging and biological correlates were lacking. Increased understanding of MS and its pathology, coupled with general concern that the original descriptors may not adequately reflect more recently identified clinical aspects of the disease, prompted a re-examination of MS disease phenotypes by the International Advisory Committee on Clinical Trials of MS. While imaging and biological markers that might provide objective criteria for separating clinical phenotypes are lacking, we propose refined descriptors that include consideration of disease activity (based on clinical relapse rate and imaging findings) and disease progression. Strategies for future research to better define phenotypes are also outlined. Open access full paper at //www.neurology.org/content/83/3/278.abstract
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Registry to Evaluate Novantrone Effects in Worsening Multiple Sclerosis (RENEW) was a 5-year, phase IV study in which the safety of Mitoxantrone was monitored in a patient cohort from the United States (US). The objective of the study was to evaluate the long-term safety profile of Mitoxantrone in patients with secondary progressive multiple sclerosis (SPMS), progressive relapsing multiple sclerosis (PRMS), and worsening relapsing-remitting multiple sclerosis (RRMS). Overall, 509 patients (395 SPMS, 81 worsening RRMS, 33 PRMS) were enrolled and treated at 46 multiple sclerosis (MS) treatment centers located in the US. Patients received Mitoxantrone in accordance with the package insert every 3 months. During the treatment phase, patients received laboratory workups and cardiac monitoring every 3 months and then annually for a total of 5 years. Five hundred and nine subjects were enrolled in this trial and received at least one infusion of Mitoxantrone. Overall, 172 (33.8%) completed the 5-year trial (i.e., participated for 5 years +/- 3 months [treatment + follow-up]); 337 (66.2%) did not complete the 5-year trial. Annual follow-up data were available for 250 of 509 enrolled patients. Left ventricular ejection fraction reduction under 50% was reported in 27 (5.3%) patients during the treatment phase (n = 509) and 14 (5.6%) patients during the annual follow-up phase (n = 250). Signs and symptoms of congestive heart failure were observed in 10 (2.0%) patients (six during treatment phase and four during the annual follow-up phase). Post-hoc analyses of the risk for cardiotoxicity outcomes revealed that cumulative dose exposure is the primary risk factor associated with the risk of cardiac toxicity with Mitoxantrone. Therapy-related leukemia was reported in three (0.6%) patients who received total cumulative Mitoxantrone doses of 73.5 mg/m2, 107.3 mg/m2, and 97.1 mg/m2 respectively. During the treatment phase, persistent amenorrhea developed in 22% (28/128) of women with regular menses and 51% (25/49) of women with irregular menses at baseline. During the annual follow-up phase, persistent amenorrhea developed in 5% (4/73) of women with regular menses at baseline. RENEW results are consistent with the known safety profile of Mitoxantrone, and provide additional long-term safety data for Mitoxantrone in MS patients.
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Objective: To explore the occurrence and characteristics of aggressive multiple sclerosis (AMS) in adult-onset multiple sclerosis (MS) patients. Methods: Prospectively collected data (1980-2009) from British Columbia, Canada, were retrospectively analysed. AMS was defined in three different ways (AMS1, 2 and 3): 'AMS1'--confirmed Expanded Disability Status Scale (EDSS) ≥ 6 within 5 years of MS onset; 'AMS2'--confirmed EDSS ≥ 6 by age 40; and 'AMS3'--secondary progressive MS within 3 years of a relapsing-onset course. Three respective 'non-aggressive' MS comparison cohorts were selected. Patients' characteristics were compared between aggressive and non-aggressive cohorts using multivariable logistic regression, with findings expressed as adjusted OR (AOR) and 95% CI. Results: Application of the three definitions to the source population of 5891 patients resulted in 235/4285 (5.5%) patients fulfilling criteria for AMS1 (59.6% were female; 74.5% had relapsing-onset MS), 388/2762 (14.0%) for AMS2 (65.2% were female; 92.8% had relapsing-onset MS) and 195/4918 (4.0%) patients for AMS3 (61.0% were female). Compared to the respective control cohorts, those with AMS were more likely to be male (AOR=1.5, 95% CI 1.1 to 2.0 (AMS1); 1.6, 95% CI 1.3 to 2.1 (AMS2); 1.8, 95% CI 1.3 to 2.4 (AMS3)), older at MS symptom onset (AOR=1.1; 95% CI 1.1 to 1.1 (AMS1 and AMS3)) and have primary progressive MS (AOR=2.3, 95% CI 1.6 to 3.3 (AMS1); 2.7, 95% CI 1.7 to 4.4 (AMS2)). Conclusions: AMS was identified in 4-14% of patients, depending on the definition used. Although there was a relative preponderance of men and primary progressive MS presenting with AMS, the majority of patients were still women and those with relapsing-onset MS.
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The concept of induction treatment followed by long-term maintenance treatment in multiple sclerosis (MS) has attracted considerable attention. The combination of mitoxantrone as the induction therapy followed by an immunomodulatory drug (e.g., interferon beta or glatiramer acetate) as the maintenance therapy is of particular interest. This approach is suitable for patients with particularly aggressive disease, characterised by frequent relapses with incomplete recovery and the accumulation of focal lesions visible on magnetic resonance imaging. A long-term study has shown that a short (6 month) course of mitoxantrone followed by maintenance therapy with an immunomodulatory drug brings about a rapid reduction in disease activity and subsequent sustained disease control for at least 5 years. Furthermore, randomised studies have demonstrated that induction with mitoxantrone followed by maintenance treatment affords better disease control than monotherapy with an interferon beta. Natalizumab is also effective in patients with very active MS, but has a propensity to result in rebound inflammatory disease activity on withdrawal. More recently, a mere 5-day course of 12-mg intravenous perfusions of alemtuzumab was found to bring long-term clinical benefits in early relapsing MS patients at risk of developing severe systemic autoimmune disease within the space of a few years.
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To determine if there are variables linked to responsiveness to pulse cyclophosphamide/methylprednisolone therapy in progressive Multiple Sclerosis (MS). MS is a presumed autoimmune disease of the CNS in which immunosuppressive and immunomodulatory treatments are being used. We have treated patients with the progressive form of MS using a regimen consisting of pulse cyclophosphamide/methylprednisolone that is given as an outpatient at 4 - 8 week intervals similar to lupus nephritis protocols. We investigated a series of 95 consecutive progressive MS patients treated in an open label fashion in an effort to identify factors linked to response to treatment. Clinical outcome measures included status at 12 months and time to failure determined by EDSS change and global physician impression. For each endpoint, associations were examined between outcome and patient characteristics including gender, age at onset of disease and treatment, EDSS 1 year previously and at start of treatment, duration of MS, previous treatment, age at onset and duration of progression, and primary vs secondary progressive MS. Of the variables studied, age, gender, age at onset, and age at treatment did not correlate with response to therapy. The most significant variable that correlated with response was length of time the patient was in the progressive phase (P=0.048, 12 month change in EDSS; P=0.017, risk for time to failure). Patients that improved on therapy at 12 months had progressive disease for an average of 2.1 years prior to treatment, whereas those stable or worse had progressive disease for 5.0 and 4.1 years respectively. There was a trend (P=0.08) favoring positive clinical responses in secondary progressive as opposed to primary progressive patients. Our data suggest that progressive MS may become refractory to immunosuppressive therapy with time and early intervention when patients enter the progressive stage should be considered. Furthermore, in trials of immunosuppressive agents for progressive MS, duration of progression should be considered as a randomization and analysis variable.
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Haematopoietic stem cell transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with poor-prognosis autoimmune disease who do not respond to conventional treatments. Worldwide, more than 600 patients with multiple sclerosis (MS) have been treated with HSCT, most of them having been recruited in small, single-centre, phase 1-2 uncontrolled trials. Clinical and magnetic resonance imaging outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted during the relapsing-remitting phase than in those in the secondary progressive stage. An interdisciplinary group of neurologists and haematologists has been formed, following two international meetings supported by the European and American Blood and Marrow Transplantation Societies, for the purpose of discussing a controlled clinical trial, to be designed within the new scenarios of evolving MS treatments. Objectives of the trial, patient selection, transplant technology and outcome assessment were extensively discussed. The outcome of this process is summarized in the present paper, with the goal of establishing the background and advancing the development of a prospective, randomized, controlled multicentre trial to assess the clinical efficacy of HSCT for the treatment of highly active MS.
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Background. Multiple sclerosis (MS) patients of African ancestry have a more aggressive disease course than white patients and could be resistant to interferon-beta (INFB). Methods. We studied the impact of INFB in treatment-naive Afro-Caribbean (AC) with clinically definite MS using our European Database for Multiple Sclerosis (EDMUS) (2003-2010). Main outcome measures were annual relapse rate after 2 years of treatment, proportion of exacerbation-free subjects 48 weeks after initiating INFB, and time to first relapse. Results. 76 AC-MS (59F/17M) were identified. Annual relapse rate of 1.29 decreased to 0.83 (-35.6%) after 2 years of treatment. The proportion of relapse-free patients at 48 weeks was 46.2%. Median time to first relapse was 52 weeks. Conclusion. INFB is not strong enough to control AC-MS patients in many cases which is problematic in a population of worse MS prognosis.
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A definitive diagnosis of multiple sclerosis cannot be made at presentation on patients with a clinically isolated syndrome of the optic nerve, spinal cord or brainstem suggestive of demyelination, as dissemination in time is not established. To determine the long-term risk of abnormalities on brain MRI for the development of multiple sclerosis and disability we performed a 10-year follow-up on 81 such patients who had T2-weighted brain MRI at presentation. Initial brain MRI was abnormal in 54 (67%). Follow up of those patients with an abnormal MRI revealed progression to clinically definite multiple sclerosis in 45 out of 54 (83%), of whom 11 (20%) had relapsing/remitting disease (EDSS > 3), 13 (24%) secondary progressive and 21 (39%) benign (relapsing/remitting with EDSS < or = 3) disease. For those with a normal MRI progression to clinically definite multiple sclerosis occurred in only three out of 27 (11%), all benign. There was a significant relationship between the number of lesions at presentation and both EDSS (r = 0.45, P < 0.001) and the type of disease at follow-up (P < 0.0001). Brain MRI at presentation with a clinically isolated syndrome is predictive of the long-term risk of subsequent development of multiple sclerosis, the type of disease and extent of disability.
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To examine the predictive value of central atrophy in early multiple sclerosis (MS) patients, for medium term clinical outcome. In 54 patients with recently diagnosed MS, clinical and MRI parameters were obtained at baseline, and after 2 and 5.5 years of follow-up. In addition to conventional MRI parameters and the annualised percentage brain volume change (aPBVC), the annualised percentage ventricular volume change (aPVVC) was quantified. Main outcome measure was disease progression, defined by an increase in Expanded Disability Status Scale of ≥1 after 5.5 years. Disease progression occurred in 29 patients. aPVVC within the first two years was significantly higher in these progressing patients (median 4.76%; IQR 3.05-9.17) compared with stable patients (median 3.23%; IQR -0.1-6.02) (p=0.02). A logistic regression model selected aPVVC within the first 2 years as the only MRI marker predicting progression after 5.5 years (OR 1.17, 95% CI 1.02 to 1.35). When entering all MRI and clinical markers, again aPVVC within the first 2 years was the only MRI marker selected. While aPVVC was correlated between the two consecutive time intervals (ρ=0.41, p<0.01), aPBVC was not. Furthermore, baseline T2 lesion load and gadolinium enhancing lesion load were correlated with aPVVC in the second time interval (2-5.5 years) but not with aPBVC. The rate of ventricular enlargement seems to be even more strongly predictive of disease progression after medium term follow-up than whole brain atrophy rate, and also outperforms lesion measures. Central atrophy rate could therefore be an important prognostic marker, especially in the early stages of MS.
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Natalizumab is associated with the potentially life-threatening side-effect progressive multifocal leukoencephalopathy (PML). Little is known about patients' and physicians' risk estimates and attitudes towards natalizumab treatment. Consecutive natalizumab-treated patients (n = 69) and neurologists (n = 66) in two centres and cooperating private practices received an evidence-based three-page information leaflet about natalizumab-associated PML and an evaluation sheet. After reading the information, patients were significantly more likely than physicians to intend continuation of natalizumab treatment and willing to accept higher risks of PML: 49% of physicians would stop treatment at a PML risk of 2:10,000 or lower, while only 17% of patients would do so (p < 0.001). This difference could not be explained by risk calculation abilities or lack of understanding. Both groups overestimated natalizumab treatment effects. Patients had a significantly worse perception of multiple sclerosis as a malignant disease. We conclude that patients were willing to accept a higher risk of PML than neurologists. Coherent with their perception of risks and benefits, patients were also more willing to continue treatment. Open information about treatment-related risks is appreciated and might support shared decision making.
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A multivariate hierarchical analysis was used to assess the significance of several demographic and clinical factors in multiple sclerosis patients. We used the time to reach level 6 on the disability status scale (DSS) of Kurtzke as endpoint. Several factors at presentation were significantly associated with an adverse outcome including older age at onset, male sex, cerebellar involvement or insidious onset of a motor deficit as first symptom. Factors ascertained later which were associated significantly with a worse outcome, even after controlling for those previously mentioned, included persisting deficits in brainstem, cerebellar or cerebral systems, a higher frequency of attacks in the first 2 yrs after onset of disease, a short first interattack interval and higher DSS at 2 yrs and 5 yrs from onset. An analysis similar to multiple regression was used to generate predictive models which permit the calculation of the median time to DSS 6 for patients with a given set of covariates. The goodness of fit of these models to the data and their predictive accuracy are discussed.
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Standardization of terminology used to describe the pattern and course of MS is essential for mutual understanding between clinicians and investigators. It is particularly important in design of, and recruitment for, clinical trials statistically powered for expected outcomes for given patient populations with narrowly defined entry criteria. For agents that prove safe and effective for MS, knowledge of the patient populations in definitive clinical trials assists clinicians in determining who may ultimately benefit from use of the medication. An international survey of clinicians involved with MS revealed areas of consensus about some terms classically used to describe types of the disease and other areas for which there was lack of consensus. In this report, we provide a summary of the survey results and propose standardized definitions for the most common clinical courses of patients with MS.
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Objective: To examine the natural history, survival, and prognostic factors in a sample of Turkish MS patients. Method: This multicenter study included 1,259 definite MS patients diagnosed according to the criteria of Poser et al. Actuarial analysis of selected disability levels of 3, 6, 8, and 10 achieved with the Expanded Disability Status Scale (EDSS); a multivariate Cox regression analysis for prognostic factors related to time to reach EDSS ≥ 6; and Pearson's correlation coefficient for individual factors were performed. Results: The survival (±SE) at 15 years from onset was 94.6 ± 2.9%, and at 25 years was 89.0 ± 5.8%. The disability reached by 15 years was EDSS ≥ 3 in 66.4%, EDSS ≥ 6 in 41.2%, EDSS ≥ 8 in 10.5%, and EDSS = 10 in 5.4%. The most significant unfavorable prognostic factors were progressive course (relative risk [RR], 3.73; CI, 2.71 to 5.13) and sphincter symptoms at onset (RR, 1.86; CI, 1.23 to 2.82), followed by male sex, motor symptoms at onset, and a high attack frequency within the first 5 years. Primary progressive disease was correlated positively with male sex ( r = 0.0895, p = 0.001), older age ( r = 0.1807, p = 0.000), and motor ( r = 0.1433, p = 0.000) or sphincter symptoms ( r = 0.1001, p = 0.000) at onset, unlike relapsing-remitting and secondary progressive disease. Conclusions: Although a slightly better prognosis is observed in the Turkish MS population, early prognostic factors are similar to most of the previous Western series. Primary progressive disease, mostly seen in older men with motor and sphincter involvement at onset, has a worse prognosis and may represent a distinct behavioral variant of MS.