Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis

Metz, Luanne M.; Li, David K.B.; Traboulsee, Anthony; Duquette, Pierre; Eliasziw, Misha; Cerchiaro, Graziela; Greenfield, Jamie; Riddehough, Andrew; Yeung, Michael; Kremenchutzky, Marcelo; Vorobeychik, Galina; Freedman, Mark S.; Bhan, Virender; Blevins, Gregg; Marriott, James; Grand’Maison, François; Lee, Liesly; Thibault, Manon; Hill, Michael D.; Yong, V. Wee; Team, Minocycline in Ms Study

doi:10.1056/nejmoa1608889

Cited by 161 publications

(130 citation statements)

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“…In addition, to minimize the recall bias, we recruited only incidence cases. Although the validity of self-reported data on antibiotic use was not fully acknowledged, we also gathered further information, that is, the name and indication of consumed antibiotics to decrease the likelihood of major measurement errors Although the new Minocycline data have supported the benefit of antibiotics in delaying the clinically definite MS development, 35 the possibility of reverse causation is an issue threatening the validity of estimated ORs for antibiotic consumption. The index date in this study were the time of MS diagnosis rather than the time of the first symptoms.…”

Section: Discussionmentioning

confidence: 99%

Infectious exposure, antibiotic use, and multiple sclerosis: A population-based incident case-control study

et al. 2018

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Section: Discussionmentioning

confidence: 99%

Infectious exposure, antibiotic use, and multiple sclerosis: A population-based incident case-control study

et al. 2018

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“…There is, however, one example of translation of the knowledge on the role of MMPs in MS. Minocycline, a tetracycline antibiotic that exerts broad-spectrum inhibition of MMPs, demonstrated in two phase 2 studies in MS efficacy in reducing gadolinium-enhancing lesions [215,216], which encouraged the study group to execute a phase 3 clinical trial [217] with 142 patients with a first MS attack. Clinical and MRI findings suggested that minocycline in comparison to placebo reduced the risk for patients after a first attack to reach the criteria for formal MS diagnosis within 6 months by 28% (p = 0.006).…”

Section: Mmp Inhibitors As Treatment Options For Msmentioning

confidence: 99%

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Muri

Leppert

Grandgirard

et al. 2019

Cell. Mol. Life Sci.

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Metalloproteinases-such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs)-are involved in various diseases of the nervous system but also contribute to nervous system development, synaptic plasticity and neuroregeneration upon injury. MMPs and ADAMs proteolytically cleave many substrates including extracellular matrix components but also signaling molecules and receptors. During neuroinfectious disease with associated neuroinflammation, MMPs and ADAMs regulate blood-brain barrier breakdown, bacterial invasion, neutrophil infiltration and cytokine signaling. Specific and broad-spectrum inhibitors for MMPs and ADAMs have experimentally been shown to decrease neuroinflammation and brain damage in diseases with excessive neuroinflammation as a common denominator, such as pneumococcal meningitis and multiple sclerosis, thereby improving the disease outcome. Timing of metalloproteinase inhibition appears to be critical to effectively target the cascade of pathophysiological processes leading to brain damage without inhibiting the neuroregenerative effects of metalloproteinases. As the critical role of metalloproteinases in neuronal repair mechanisms and regeneration was only lately recognized, the original idea of chronic MMP inhibition needs to be conceptually revised. Recently accumulated research urges for a second chance of metalloproteinase inhibitors, which-when correctly applied and dosed-harbor the potential to improve the outcome of different neuroinflammatory diseases.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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“…Alternative models are currently available, which involve different animal strains and species and different immune mechanisms, which will have to be analyzed in detail in future studies, despite of being more complex and difficult to handle.Active demyelination and neurodegeneration in multiple sclerosis and in autoimmune encephalomyelitis is invariably associated with the presence of activated macrophages and/or microglia (Brück et al, ; Ferguson et al, ) and blockade of macrophage function has been suggested as a therapeutic strategy for inflammatory brain diseases. So far, however, selective blockade of macrophage and microglia activation has not been established in multiple sclerosis treatment with the exception of a single phase II clinical trial, which showed a moderate beneficial effect of minocycline (Metz et al, ). To develop such a therapeutic strategy for MS patients, efficacy and safety have to be demonstrated in a broad spectrum of experimental models.…”

Section: Conclusion and Open Questionsmentioning

confidence: 99%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an‐anti‐inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.

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Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis

Abstract: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).

Cited by 161 publications

References 20 publications

Infectious exposure, antibiotic use, and multiple sclerosis: A population-based incident case-control study

Infectious exposure, antibiotic use, and multiple sclerosis: A population-based incident case-control study

MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

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