Immunological effects of dimethyl fumarate treatment in blood and CSF of patients with primary progressive MS
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Abstract:
Dimethyl fumarate is an efficient therapy used widely in patients with relapsing-remitting multiple sclerosis (RRMS). However, lacking effect of treatment has recently been reported in patients with primary progressive MS (PPMS) (Højsgaard Chow et al., 2021). In order to further analyze the immunological treatment response we investigated the systemic and intrathecal immunological effects of dimethyl fumarate (DMF) treatment in 50 patients with PPMS who participated in a 48-week randomized controlled trial with dimethyl fumarate vs placebo. We found substantial systemic immunomodulatory effects of DMF treatment comparable with those observed in patients with RRMS. However, intrathecal effects were limited and restricted to CD4+ T cells presumably resulting in higher concentrations of intrathecal IL-7.Keywords:
Dimethyl fumarate
Intrathecal
Relapsing remitting
Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS) that causes significant disability. Immunosuppressive and immunomodulatory drugs have been designed for years to treat MS, as it was considered the most appropriate way to balance the effects of the patients' immune reaction. However, basic and clinical research has recently offered new data that help to better understand the nature of this complex disease, allowing changing the treatment approach. As a consequence, the first disease-modifying drug with a suggested neuroprotective and antioxidative mechanism of action has been recently approved, broadening and improving the therapeutic landscape to fight against MS. In this review, we focused our attention on promising neuroprotective or neuroregenerative drugs that are currently approved or in clinical trials. These neuroprotective therapies provide new valid alternatives that significantly could impact on disease progression and neurodegenerative changes in MS.
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Multiple sclerosis (MS) is a disease that is caused when the patient’s own immune cells attack the central nervous system, i.e. an autoimmune disease. The disease has a prevalence of 1-2.5 million people worldwide, but there is no known cure. Dimethyl fumurate (DMF), also known as Tecfidera®, is an oral therapy for the treatment of relapsing-remitting multiple sclerosis (RRMS). However, how DMF works in RRMS patients is not fully understood. The main goal of this study is to explore the effects of DMF treatment on the immune cells, as well as on their functionality. This study has provided valuable evidence on the effect of DMF on the immune system in MS and may contribute to revealing an underlying mechanism for the beneficial effects of the therapy which have been demonstrated by phase III trials. Funded by Biogen Nederland
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OBJECTIVE: Descriptively compare the impact of MS vs other chronic conditions on patient-reported health-related quality of life (HRQoL) and report the effect of oral delayed-release dimethyl fumarate (DMF) on HRQoL in a pre-specified, integrated analysis of the Phase 3 DEFINE and CONFIRM studies.
BACKGROUND: DEFINE and CONFIRM evaluated the efficacy and safety of delayed-release DMF 240mg twice (BID) and three times daily (TID) in RRMS.
DESIGN/METHODS: HRQoL was assessed at baseline and Weeks 24, 48, and 96 using the Short Form-36 version 1 [SF-36v1]). The SF-36v1 consists of 8 multi-item domains (physical functioning [PF], role-physical [RP], bodily pain [BP], general health [GH], vitality [VT], social functioning [SF], role-emotional [RE], and mental health [MH]). PF, RP, BP, and GH assess physical aspects of HRQoL (Physical Component Summary [PCS]) and VT, SF, RE, and MH assess mental aspects (Mental Component Summary [MCS]). Normative mean domain scores for hypertension, congestive heart failure, diabetes type II, recent acute myocardial infarction, and clinical depression were obtained from the SF-36v1 manual.
RESULTS: The US general population normal score for PCS and MCS is 50. Mean baseline domain score ranges across the placebo and delayed-release DMF groups were 67.1-68.9 (PF), 55.0-55.8 (RP), 68.5-68.6 (BP), 53.2-53.9 (GH), 49.2-49.8 (VT), 69.5-70.4 (SF), 63.3-64.4 (RE), and 65.0-65.1 (MH), and across the five other medical conditions were 47.5-73.4 (PF), 34.4-62.0 (RP), 58.8-72.8 (BP), 47.1-63.3 (GH), 40.1-58.3 (VT), 57.2-86.7 (SF), 38.9-76.7 (RE), and 46.3-77.9 (MH). At 2 years, compared with placebo, mean changes relative to baseline in PCS and MCS scores were statistically significantly improved in the delayed-release DMF BID (P<0.0001 and P=0.0246, respectively) and TID (P<0.0001 and P=0.0107, respectively) groups.
CONCLUSIONS: The disease burden of MS appears to be higher than the US general population and less than or comparable to other medical conditions. Delayed-release DMF demonstrates benefits on patient-reported HRQoL.
Study supported by: Biogen Idec, Inc. Disclosure: Dr. Sarda has received personal compensation for activities with Biogen Idec. Dr. Phillips has received personal compensation for activities with Biogen Idec as an employee. Dr. Phillips holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Phillips was involved as an investigator. Dr. Gaebler has received personal compensation for activities with Biogen Idec as an employee. Dr. Kurukulasuriya has received personal compensation for activities with Biogen Idec as an employee.
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Dimethyl fumarate
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Dimethyl fumarate
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