Efficacy of combination therapy with erythropoietin and methylprednisolone in clinical recovery of severe relapse in multiple sclerosis

Varzaneh, Fatemeh Najmi; Varzaneh, Farnaz Najmi; Azimi, Amir Reza; Rezaei, Nima; Sahraian, Mohammad Ali

doi:10.1007/s13760-014-0286-y

Cited by 18 publications

(13 citation statements)

References 34 publications

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“…Iron accumulation may also alter oligodendrocyte activities (reviewed in [246]). Recombinant human EPO treatment has already proven safe and effective in severely affected MS patients [247][248][249]. Testing in clinical trials of EPO variants developed to minimize the risk of thromboembolism is a promising research field.…”

Section: Therapeutic Potential Of Targeting Angiogenesismentioning

confidence: 99%

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Girolamo

Coppola

Ribatti

et al. 2014

Acta Neuropathologica Communications

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Angiogenesis, the formation of new vessels, is found in Multiple Sclerosis (MS) demyelinating lesions following Vascular Endothelial Growth Factor (VEGF) release and the production of several other angiogenic molecules. The increased energy demand of inflammatory cuffs and damaged neural cells explains the strong angiogenic response in plaques and surrounding white matter. An angiogenic response has also been documented in an experimental model of MS, experimental allergic encephalomyelitis (EAE), where blood-brain barrier disruption and vascular remodelling appeared in a pre-symptomatic disease phase. In both MS and EAE, VEGF acts as a pro-inflammatory factor in the early phase but its reduced responsivity in the late phase can disrupt neuroregenerative attempts, since VEGF naturally enhances neuron resistance to injury and regulates neural progenitor proliferation, migration, differentiation and oligodendrocyte precursor cell (OPC) survival and migration to demyelinated lesions. Angiogenesis, neurogenesis and oligodendroglia maturation are closely intertwined in the neurovascular niches of the subventricular zone, one of the preferential locations of inflammatory lesions in MS, and in all the other temporary vascular niches where the mutual fostering of angiogenesis and OPC maturation occurs. Angiogenesis, induced either by CNS inflammation or by hypoxic stimuli related to neurovascular uncoupling, appears to be ineffective in chronic MS due to a counterbalancing effect of vasoconstrictive mechanisms determined by the reduced axonal activity, astrocyte dysfunction, microglia secretion of free radical species and mitochondrial abnormalities. Thus, angiogenesis, that supplies several trophic factors, should be promoted in therapeutic neuroregeneration efforts to combat the progressive, degenerative phase of MS.

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Section: Therapeutic Potential Of Targeting Angiogenesismentioning

confidence: 99%

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Girolamo

Coppola

Ribatti

et al. 2014

Acta Neuropathologica Communications

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“…One pilot RCT involving 20 patients assessed whether the combination of IVMP and erythropoietin (EPO) acted synergistically during MS relapse (Table 9). 40 The study was based on evidence of the neuroprotective properties of EPO from in vitro and in vivo studies of brain diseases. Definitions of relapse and clinically significant improvement in EDSS were not reported.…”

Section: Resultsmentioning

confidence: 99%

<p>Efficacy, safety, and quality-of-life of treatments for acute relapses of multiple sclerosis: results from a literature review of randomized controlled trials</p>

Costello¹,

Njue²,

Lyall³

et al. 2019

DNND

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Background Intravenous methylprednisolone (IVMP), repository corticotropin injection (RCI), plasmapheresis (PMP), and intravenous immunoglobulin (IVIG) are used in the treatment of acute multiple sclerosis (MS) relapse. A systematic literature review (SLR) of randomized controlled trials (RCTs) was conducted to examine the highest quality evidence available for these therapies. Methods English-language articles were searched in MEDLINE, Embase, and Cochrane Library through May 2016 per Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards. MS conferences, SLRs, and bibliographies of included studies were also searched. Eligible studies included adults treated with ≥1 aforementioned therapy. Results Twenty-three RCTs were identified: 22 on efficacy, 11 on safety, and 3 on QOL (ie 18 IVMP, 2 RCI, 2 PMP, and 2 IVIG). IVMP and RCI improved relapse-related disability; however, IVIG and PMP showed inconsistent efficacy. QOL data were only ascertained for IVMP. Conclusions RCTs indicate IVMP and RCI are efficacious and well tolerated treatments for MS relapse. Overall, many RCTs were dated, with sample sizes of fewer than 30 patients and no definitions for relapse nor clinically significant change. Contemporary evidence generation for all relapse treatments of interest, across efficacy, safety, and QOL outcomes, is still needed.

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“…More recently, another randomized double-blind pilot study combined Epo with methylprednisolone in severe motor relapsing-remitting MS patients. Improvement in maximal distance walking was observed in the Epo group after 2 months and MRI data analysis showed a significant reduction in the number of T2WI lesions [ 41 ]. Despite these encouraging results, in the recent large-scale phase 2 trial of Epo in 52 patients with primary or secondary progressive MS, no beneficial effects of high-dose Epo treatment were detected [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms

Moransard

Bednar

Frei

et al. 2017

J Neuroinflammation

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BackgroundTreatment with erythropoietin (Epo) in experimental autoimmune encephalomyelitis (EAE), the rodent model of multiple sclerosis (MS), has consistently been shown to ameliorate disease progression and improve overall outcome. The effect has been attributed to modulation of the immune response and/or preservation of the central nervous system (CNS) tissue integrity. It remains unclear, however, if (a) Epo acts primarily in the CNS or the periphery and if (b) Epo’s beneficial effect in EAE is mainly due to maintaining CNS tissue integrity or to modulation of the immune response. If Epo acts primarily by modulating the immune system, where is this modulation required? In the periphery, the CNS or both?MethodsTo address these questions, we used two well-characterized transgenic mouse strains that constitutively overexpress recombinant human Epo (rhEpo) either systemically (tg6) or in CNS only (tg21) in a MOG-induced EAE model. We assessed clinical severity, disease progression, immunomodulation, and CNS tissue integrity, including neuronal survival.ResultsAlthough disease onset remained unaffected, EAE progression was alleviated in transgenic animals compared to controls with both lines performing equally well showing that expression of Epo in the periphery is not required; Epo expression in the CNS is sufficient. Immunomodulation was observed in both strains but surprisingly the profile of modulation differed substantially between strains. Modulation in the tg21 strain was limited to a reduction in macrophages in the CNS, with no peripheral immunomodulatory effects observed. In contrast, in the tg6 strain, macrophages were upregulated in the CNS, and, in the periphery of this strain, T cells and macrophages were downregulated. The lack of a consistent immunomodulatory profile across both transgenic species suggests that immunomodulation by Epo is unlikely to be the primary mechanism driving amelioration of EAE. Finally, CNS tissue integrity was affected in all strains. Although myelin appeared equally damaged in all strains, neuronal survival was significantly improved in the spinal cord of tg21 mice, indicating that Epo may ameliorate EAE predominantly by protecting neurons.ConclusionsOur data suggests that moderate elevated brain Epo levels provide clinically significant neuroprotection in EAE without modulation of the immune response making a significant contribution.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0976-5) contains supplementary material, which is available to authorized users.

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Efficacy of combination therapy with erythropoietin and methylprednisolone in clinical recovery of severe relapse in multiple sclerosis

Cited by 18 publications

References 34 publications

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

Angiogenesis in multiple sclerosis and experimental autoimmune encephalomyelitis

<p>Efficacy, safety, and quality-of-life of treatments for acute relapses of multiple sclerosis: results from a literature review of randomized controlled trials</p>

Erythropoietin reduces experimental autoimmune encephalomyelitis severity via neuroprotective mechanisms

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