Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies.

INTRODUCTION In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW. METHODS CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed. RESULTS Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores. CONCLUSION CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9

Long-term follow-up of acute partial transverse myelitis.

BACKGROUND: Acute partial transverse myelitis (APTM) may be the first clinical symptom of multiple sclerosis (MS) or may remain a monophasic event. OBJECTIVES: To evaluate the risk of conversion to MS and long-term disability, and to determine prognosis factors for disability. DESIGN: We identified patients with no previous history of neurological disease who experienced APTM between January 1998 and December 2005 and were followed up at 3 university hospitals in France. Data on the patients' demographics and clinical states during follow-up, as well as data on cerebrospinal fluid (CSF) analysis, brain and spinal cord magnetic resonance imaging (MRI), and visual evoked potentials, were analyzed. SETTING: Neurology departments of 3 university hospitals in Lille, Strasbourg, and Rouen, France, respectively. PATIENTS: A total of 85 patients with no previous history of neurological disease who experienced APTM. RESULTS: The mean (SD) follow-up period was 104.8 (29.8) months. There were 57 women (67%) and 28 men (33%), with a mean (SD) age at onset of 36.7 (11.7) years. At the end of follow-up, 53 patients (62%) were classified as having MS with a mean (SD) Expanded Disability Status Scale score of 2.6 (1.8), 1 patient (1%) was classified as having postinfectious myelitis, 1 (1%) as having neuromyelitis optica, 1 (1%) as having Sjögren syndrome, and 29 (34%) still had APTM of undetermined etiology. Oligoclonal bands in CSF were more frequent in patients with MS (92%) than in patients with APTM of undetermined etiology (38%). Brain MRI results were abnormal in 87% of patients with MS and 27% of patients with APTM of undetermined etiology; visual evoked potentials were abnormal in 43% of patients with MS and 4% of patients with APTM of undetermined etiology. Oligoclonal bands in CSF (odds ratio, 15.76 [95% CI, 2.95-84.24]) and at least 1 MRI-detected brain lesion (odds ratio, 7.74 [95% CI, 2.42-24.74]) were independent predictive factors for conversion to MS. CONCLUSION: Our study confirms that abnormal brain MRI results and the presence of oligoclonal bands in CSF are 2 independent predictive factors for conversion to MS. No clinical, biological, or MRI factor at onset was predictive of long-term disability.journal article2012 MarimportedErratum in : Arch Neurol. 2012 Jun;69(6):789. Outerryck, Olivier [corrected to Outteryck, Olivier]

The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study.

BACKGROUND:Multiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria. OBJECTIVE:The objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS. METHODS:A post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted. RESULTS:Cladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p < 0.0001. CONCLUSIONS:Regardless of the criteria used to define CIS or MS, 3.5 mg/kg cladribine tablets are effective in patients with a first clinical demyelinating attack. ClinicalTrials.gov registration: The ORACLE-MS study (NCT00725985)

The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study.

BACKGROUND:Multiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria. OBJECTIVE:The objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS. METHODS:A post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted. RESULTS:Cladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p < 0.0001. CONCLUSIONS:Regardless of the criteria used to define CIS or MS, 3.5 mg/kg cladribine tablets are effective in patients with a first clinical demyelinating attack. ClinicalTrials.gov registration: The ORACLE-MS study (NCT00725985)

Subgroup analysis of clinical and MRI outcomes in participants with a first clinical demyelinating event at risk of multiple sclerosis in the ORACLE-MS study.

BACKGROUND: In the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria (henceforth referred to as CDMS), multiple sclerosis (MS) per the 2005 McDonald criteria, and the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) lesions versus placebo in participants with a first clinical demyelinating event (FCDE). Patient demographic and disease characteristics may be predictors of disease progression. The current study analyzed the effect of cladribine tablets in subgroups of participants in the ORACLE-MS study by baseline demographics and disease characteristics. METHODS: This analysis retrospectively examined data collected from 616 participants enrolled in the ORACLE-MS study (placebo, n=206; cladribine tablets 3.5 mg/kg, n=206; cladribine tablets 5.25 mg/kg, n=204). Five subgroups were predetermined by baseline demographics, including sex, age (≥30 years), classification of FCDE, and lesion characteristics, including absence or presence of T1 Gd+ lesions and number of T2 lesions (≥9). Selected endpoints of the ORACLE-MS study were re-analyzed for these subgroups. The primary and main secondary endpoints were time to conversion to CDMS and MS (2005 McDonald criteria), respectively. Secondary magnetic resonance imaging (MRI) endpoints included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to evaluate time to conversion to CDMS and MS (2005 McDonald criteria). This analysis focused primarily on the results for the cladribine tablets 3.5 mg/kg group because this dosage is approved for relapsing forms of MS. RESULTS: In the overall intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (hazard ratio [HR]=0.326; P CONCLUSION: In this post hoc analysis of the ORACLE-MS study, cladribine tablets reduced the risk of conversion to multiple sclerosis and lesion burden in participants with an FCDE in the overall ITT population and multiple subgroups defined by baseline demographics and lesion characteristics

Inaugural tumor-like multiple sclerosis: clinical presentation and medium-term outcome in 87 patients

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