Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial

Coles, Alasdair; Twyman, Cary; Arnold, Douglas L.; Cohen, Jeffrey A.; Confavreux, Christian; Fox, Edward J.; Hartung, Hans Peter; Havrdová, Eva; Selmaj, Krzysztof; Weiner, Howard L.; Miller, Tamara; Fisher, Elizabeth; Sandbrink, Rupert; Lake, Stephen; Margolin, David; Oyuela, Pedro; Panzara, Michael A.; Compston, D. A. S.

doi:10.1016/s0140-6736(12)61768-1

Cited by 1,075 publications

(1,303 citation statements)

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“…Studies on MS disease activity, such as clinical drug trials, indicate that the number of new MRI lesions is approximately 4–12 times larger than the number of new clinical relapses during the same time period 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. Such “clinically silent” MRI lesions stress the importance of monitoring patients with MRI even in the absence of clinical signs of disease activity.…”

Section: Resultsmentioning

confidence: 99%

“…While we acknowledge this and would like to emphasize that the MRI frequency and timing should be adapted to the clinical situation, it is our opinion that general recommendations of MRI frequency are still valuable in the clinical care of patients. The recommendations regarding MRI frequency presented here are based on clinical experience and extrapolation of study data on the level of disease activity seen in treated and untreated patients with MS in phase III studies 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20…”

Section: Resultsmentioning

confidence: 99%

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Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

et al. 2016

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Multiple sclerosis (MS) is associated with inflammatory lesions in the brain and spinal cord. The detection of such inflammatory lesions using magnetic resonance imaging (MRI) is important in the consideration of the diagnosis and differential diagnoses of MS, as well as in the monitoring of disease activity and predicting treatment efficacy. Although there is strong evidence supporting the use of MRI for both the diagnosis and monitoring of disease activity, there is a lack of evidence regarding which MRI protocols to use, the frequency of examinations, and in what clinical situations to consider MRI examination. A national workshop to discuss these issues was held in Stockholm, Sweden, in August 2015, which resulted in a Swedish consensus statement regarding the use of MRI in the care of individuals with MS. The aim of this consensus statement is to provide practical advice for the use of MRI in this setting. The recommendations are based on a review of relevant literature and the clinical experience of workshop attendees. It is our hope that these recommendations will benefit individuals with MS and guide healthcare professionals responsible for their care.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

et al. 2016

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“…Indeed, subclinical reactivation as determined by detection of VZV in saliva is a common consequence of fingolimod treatment (Ricklin et al., 2013). Prevention and management of VZV infections, predominantly herpes zoster, in adults with MS receiving newer DMTs, is a topic of clinical relevance: symptomatic reactivation of latent VZV has been reported in patients who received Monoclonal Antibodies (natalizumab, alemtuzumab) (Coles et al., 2012; Fine, Sorbello, Kortepeter, & Scarazzini, 2013), and prophylactic aciclovir can reduce the proportion of patients who had herpes zoster (HZ) (Coles et al., 2012). Current data do not support the general use of antiviral prophylaxis in patients receiving FTY given the low incidence of HZ infection (Arvin et al., 2015).…”

Section: Discussionmentioning

confidence: 99%

Gender differences in safety issues during Fingolimod therapy: Evidence from a real‐life Relapsing Multiple Sclerosis cohort

et al. 2017

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ObjectiveBenefits and risks of new therapies in Multiple Sclerosis (MS) must be balanced carefully and tailored to patients. We aimed to describe our experience with Fingolimod (FTY), correlating demographics, clinical and hematological features of the Relapsing MS (RMS) cohort with the occurring Adverse Events (AEs).Material and MethodsPretreatment screening tests, cardiological observation, and safety follow‐up data were analyzed in 225 RMS patients. Changes in continuous data were analyzed post hoc with Wilcoxon ranks test; categorical variables were examined using McNemar test. Two‐way repeated‐measures analysis of variance (ANOVA) was used to analyze differences between baseline characteristic of the cohorts and Liver Function Tests (LFT) alterations. Binary logistic regression models were used to identify which of the baseline factors influenced LFT alterations and the occurrence of infections.ResultsDuring 2 years of follow‐up 24 patients (10%) interrupted FTY. Discontinuation most often was due to AEs (n = 14) or breakthrough disease (n = 5). The most frequently AEs were infections (10.6%). After the first year patients showing an infectious episode were mostly female (p = .04). The infections did not correlate with the decrease in white blood cells or to lymphocyte count. AST and ALT alterations were observed mostly in males (p = .002 and p = .01, respectively), and increase in GGT was reported in subjects older at FTY beginning (p < .05).ConclusionsFor a patient‐centered safety monitoring of FTY, we may apply gender‐specific warnings, for the detection of transaminases abnormalities and infectious episodes.

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“…Some studies have reported no significant, or conflicting, effects of DMTs on brain atrophy (Bermel & Bakshi, 2006; Calabrese et al., 2012; Lublin et al., 2016; Tiberio et al., 2005). Others have reported statistically significant slowing of brain atrophy, but only after 24 months or more (Cohen et al., 2012; Coles et al., 2012; Kappos et al., 2010; Mattioli, Stampatori, Bellomi, Scarpazza, & Capra, 2015; Miller et al., 2007; Rinaldi et al., 2012). Brain atrophy is considered predictive of progression in cognitive and/or motor disability (Bermel & Bakshi, 2006; Deloire et al., 2011; Morgen et al., 2006), emphasizing a need for early intervention to prevent brain atrophy and forestall the advance of disability.…”

Section: Introductionmentioning

confidence: 99%

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

et al. 2018

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IntroductionProgressive gray matter (GM) atrophy is a hallmark of multiple sclerosis (MS). Cognitive impairment has been observed in 40%–70% of MS patients and has been linked to GM atrophy. In a phase 2 trial of estriol treatment in women with relapsing–remitting MS (RRMS), higher estriol levels correlated with greater improvement on the paced auditory serial addition test (PASAT) and imaging revealed sparing of localized GM in estriol‐treated compared to placebo‐treated patients. To better understand the significance of this GM sparing, the current study explored the relationships between the GM sparing and traditional MRI measures and clinical outcomes.MethodsSixty‐two estriol‐ and forty‐nine placebo‐treated RRMS patients underwent clinical evaluations and brain MRI. Voxel‐based morphometry (VBM) was used to evaluate voxelwise GM sparing from high‐resolution T1‐weighted scans.ResultsA region of treatment‐induced sparing (TIS) was defined as the areas where GM was spared in estriol‐ as compared to placebo‐treated groups, localized primarily within the frontal and parietal cortices. We observed that TIS volume was directly correlated with improvement on the PASAT. Next, a longitudinal cognitive disability‐specific atlas (DSA) was defined by correlating voxelwise GM volumes with PASAT scores, that is, areas where less GM correlated with less improvement in PASAT scores. Finally, overlap between the TIS and the longitudinal cognitive DSA revealed a specific region of cortical GM that was preserved in estriol‐treated subjects that was associated with better performance on the PASAT.ConclusionsDiscovery of this region of overlap was biology driven, not based on an a priori structure of interest. It included the medial frontal cortex, an area previously implicated in problem solving and attention. These findings indicate that localized GM sparing during estriol treatment was associated with improvement in cognitive testing, suggesting a clinically relevant, disability‐specific biomarker for clinical trials of candidate neuroprotective treatments in MS.

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Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial

Cited by 1,075 publications

References 31 publications

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

Guidelines for the use of magnetic resonance imaging in diagnosing and monitoring the treatment of multiple sclerosis: recommendations of the Swedish Multiple Sclerosis Association and the Swedish Neuroradiological Society

Gender differences in safety issues during Fingolimod therapy: Evidence from a real‐life Relapsing Multiple Sclerosis cohort

Estriol‐mediated neuroprotection in multiple sclerosis localized by voxel‐based morphometry

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