Learning CNS immunopathology from therapeutic interventions
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Abstract:
Modulation of immune cell trafficking across the blood-brain barrier has not only introduced a therapeutic avenue for multiple sclerosis (MS) but also represents an example of reverse translational medicine. Data from clinical trials of drugs such as natalizumab and fingolimod have revealed the involvement of different compartments in relapsing versus non-relapsing MS immune biology, contributed to our understanding of central nervous system (CNS) immune surveillance, and stimulated new fields of research. Here, we discuss the results of these trials, as well as patient biomaterial-based scientific projects, and how both have informed our understanding of CNS immunopathology.Keywords:
Natalizumab
Neuroimmunology
Objective: Estimate the cost-effectiveness of switching to natalizumab versus fingolimod for patients with highly active RRMS (HA-RRMS) and inadequate response to first-line therapies (BRACETD) from the NHS Scotland perspective using real-world data from MSBase. Background: Some patients with HA-RRMS treated with BRACETD experience disease activity and may benefit from switching to another therapy. Design/Methods: A Markov model with health states based on the Expanded Disability Status Scale (EDSS) was developed to capture disability and relapses over time. Treatment-specific annual EDSS transition matrices, annualized relapse rates (ARR) by EDSS, and comparative effectiveness results were obtained from three-way propensity score matched MSBase cohorts (companion abstract submitted at this meeting). Costs and utilities were taken from the United Kingdom (UK) MS Cost of Illness study and standard UK costing sources. Additional clinical data were obtained from publicly available sources. Lifetime clinical and economic outcomes and incremental cost per quality-adjusted life-year (QALY) gained were estimated. Sensitivity analyses estimated the impact of alternative data sources, assumptions, and parameter uncertainty. Results: MSBase HA-RRMS patients with inadequate response to BRACETD who switched to natalizumab showed a significantly reduced ARR ( P P Conclusions: Switching to natalizumab dominated switching to fingolimod in patients with HA-RRMS and inadequate response to BRACETD. Natalizumab remained dominant across alternative scenarios and was considered cost-effective with fingolimod price discounts of ≤37.6%. Study Supported by: Biogen International (Zug, Switzerland). Disclosure: Dr. Herring has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of RTI Health Solutions. Dr. Zhang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with employee of RTI Health Solutions. Dr. Pearson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of RTI Health Solutions. Dr. Tempest has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Freudensprung has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Acosta has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Hyde has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of Biogen. Dr. Spelman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis. Dr. Butzkueven has nothing to disclose.
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Relapsing remitting
Glatiramer acetate
Dimethyl fumarate
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Fingolimod is an alternative for patients with multiple sclerosis who discontinue natalizumab because of leukoencephalopathy risk. However, the interruption of natalizumab might cause disease reactivation. We aimed to describe the disease course of patients switching to fingolimod after treatment with natalizumab or β-interferon, in a real-world setting, through a retrospective analysis of data in patients with multiple sclerosis that receiving fingolimod at a single centre in Italy. Ninety patients were divided into two groups: patients switching to fingolimod from natalizumab (n = 43, Group 1), and treatment naive (n=5) plus patients switching from β-interferon (n = 42) (Group 2). In Group 1, the mean annualised relapse rate significantly increased from 0.36 at natalizumab discontinuation to 0.80 after natalizumab washout and 1.12 after the first 3 months of fingolimod, decreasing thereafter to 0.49 by the end of followup. In Group 2, the relapse rate significantly decreased from 1.16 to 0.47 at the end of follow-up. Relapses during natalizumab washout predicted increased disease activity during the first 3 months of fingolimod (p = 0.043). We conclude that fingolimod has a delayed effect in patients switching from natalizumab versus treatment-naive patients or those switching from β-interferon. Worsening of disease activity during the washout period may be predictive of treatment failure.
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Discontinuation
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Natalizumab
Relapsing remitting
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Clinicians are often faced with having to switch MS patients on natalizumab at high risk for progressive multifocal leukoencephalopathy to a different disease-modifying therapy (DMT). Previous reports have suggested that switching to fingolimod may result in a rebound of disease activity. In this study, researchers attempted to ascertain whether switching from natalizumab to fingolimod resulted in an early increase in …
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We report the case of a woman with multiple sclerosis who developed a severe neurological condition following natalizumab (NZB) withdrawal and soon after fingolimod (FTY) initiation. FTY was started 3.5 months after a two-year NZB treatment. Fifteen days later, she suffered partial repetitive seizures followed by a tonicoclonic seizure. This was associated with attention difficulties and an increased asthenia. Brain MRI follow-up disclosed large demyelinating active lesions in favour of disease reactivation. This case suggests that FTY introduction may occur less than three months after NZB withdrawal.
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Relapsing remitting
Demyelinating disease
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Discontinuation
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Clinical and/or neuroimaging evidence of disease reactivation has been described in multiple sclerosis (MS) patients after a break from natalizumab. Whether fingolimod might be a therapeutic option following natalizumab needs to be evaluated. Twenty-two relapsing remitting MS patients having JC virus antibodies (JCVAb+) in serum were shifted from natalizumab to fingolimod after a three-month washout period. Neurological evaluation with the Expanded Disability Status Scale (EDSS) was performed monthly for a mean follow-up period of nine months. In 20/22 patients, brain magnetic resonance imaging (MRI) was obtained within one month after therapy initiation. Disease reactivation was observed in 11/22 (50%) patients: clinical relapses in six patients (four patients within the first month of therapy) and MRI activity in a further five patients (three patients within the first month of therapy). Clinical and/or MRI signs suggestive of disease rebound were observed in three patients. Our data indicate that fingolimod does not exert clinical activity quickly enough to stop MS reactivation after a break from natalizumab.
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This article presents the results of the immunological profile of CD4+ T cells and Th17 cells and production of interleukin-17 (IL-17) in two groups of patients receiving treatment natalizumab and fingolimod. The results can underpin the justification for the preferred transfer of patients with relapsing-remitting multiple sclerosis after treatment by natalizumab to fingolimod.
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Objective:The aim of this study was to compare the efficacy of natalizumab and fingolimod in relapsing-remitting multiple sclerosis patients in real-world clinical setting. Methods:We enrolled 391 patients starting either natalizumab or fingolimod for relapsing-remitting multiple sclerosis, referred to four multiple sclerosis centers between March 2007 and July 2013.Cumulative proportion of patients free from any disease activity, as defined by freedom from relapse, Expanded Disability Status Scale (EDSS) progression, new or newly enlarging T2 lesions, and gadolinium enhancing lesions at magnetic resonance imaging (MRI) was assessed at 12-month follow-up.Results: Out of 391 patients, 197 were treated with natalizumab and 194 with fingolimod.The cumulative proportion of patients free from any disease activity was 72.0% in the natalizumab and 59.1% in the fingolimod group (P=0.014).This proportion was lower in fingolimod patients with prior natalizumab exposure compared to those without (51.7% vs. 61.8%;P=0.008).Moreover, the cumulative proportion of patients free from new MRI lesions was 87.5% in the natalizumab vs. 70.0% in the fingolimod group (P<0.001); the cumulative proportion of patients free from clinical relapse was 82.5% in the natalizumab vs. 81.3% in the fingolimod group (P=0.739);93.5% of patients on natalizumab were free from EDSS progression compared to 89.6% of patients on fingolimod (P=0.186). Conclusions:Results from 1-year follow-up of treatment suggest higher efficacy of natalizumab compared to fingolimod in terms of proportion of patients free from any disease activity.
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Relapsing remitting
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In post hoc analyses of an open-label, phase 3b study (FIRST), relapse rates during 4 months of fingolimod therapy were compared in patients with and without previous natalizumab exposure. Reductions in the proportion of patients experiencing relapses and annualized relapse rates (ARRs) from years 1 and 1–2 pre-study were evident between months 1 and 2 of fingolimod treatment, and were most pronounced in natalizumab-naïve patients and those who discontinued natalizumab >6 months pre-study. Patients who discontinued natalizumab 3–6 months pre-study had a peak ARR during month 1 of fingolimod treatment, followed by a decrease during months 2–4. These data indicate that fingolimod has the potential to reduce disease reactivation but that timing of treatment initiation may be critical for achieving an optimal effect.
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