Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis

Coles, Alasdair; Wing, Mark; Molyneux, Paul; Paolillo, Andrea; Davie, Charlie M.; Hale, Geoff; Miller, David H.; Waldmann, H; Compston, Alastair

doi:10.1002/1531-8249(199909)46:3<296::aid-ana4>3.0.co;2-#

Cited by 475 publications

(291 citation statements)

References 41 publications

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“…Therapeutic trials have evaluated the effect of three immunomodulatory agents in secondary progressive MS: ␤-interferon, 44 Campath-1H, 77 and cladribine. 78,79 In spite of all three therapies suppressing inflammatory MRI lesions, there was no evidence for a significant slowing in the rate of ongoing cerebral atrophy.…”

Section: Atrophy Measuresmentioning

confidence: 99%

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

Miller¹

2004

Neurotherapeutics

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Summary:Multiple sclerosis (MS) is a chronic disease of the CNS that most commonly affects young adults. It is usually characterized in the early years by acute relapses followed by partial or complete remission; in later years progressive and irreversible disability develops. Because of the protracted and unpredictable clinical course, biological surrogate markers are much needed to make clinical trials of potential disease-modifying treatments more efficient. Magnetic resonance (MR) outcome measures are now widely used to monitor treatment outcome in MS trials. Areas of multifocal inflammation are detected with a high sensitivity as new areas of gadolinium enhancement and T2 abnormality, and these may be considered as surrogate markers for clinical relapses. However, progressive disability is not clearly related to inflammatory lesions but rather to a progressive and diffuse process with increasing neuroaxonal loss. MR surrogate measures for neuroaxonal loss include atrophy (tissue loss in brain and spinal cord), N-acetyl aspartate, and T1 hypointense lesions. Diffuse abnormality in normal appearing brain tissue may also be monitored using magnetization transfer ratio and other quantitative MR measures. For treatment trials of new agents aimed at preventing disability, measures of neuroaxonal damage should be acquired, especially atrophy, which occurs at all stages of MS and which can be quantified in a sensitive and reproducible manner. Because the MR surrogates for neuroaxonal loss are not yet validated as predicting future disability, definitive trials should continue to monitor an appropriate disability endpoint.

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Section: Atrophy Measuresmentioning

confidence: 99%

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

Miller¹

2004

Neurotherapeutics

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“…Thus, although immunomodulatory therapies are proving to be increasingly effective in controlling the initial relapsing-remitting phase of MS, the secondary progressive phase, in which there is continual atrophy of demyelinated axons, remains largely untreatable. Indeed, axon degeneration occurs despite immunomodulatory therapies, suggesting that axon integrity and protection may occur through mechanisms independent of inflammation [10,11]. Several lines of evidence suggest that the basis of axon atrophy in chronically demyelinated lesions is due, in part, to the absence of myelin-associated trophic signals that are critical for maintaining axon integrity.…”

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confidence: 99%

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

et al. 2011

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Regeneration of myelin sheaths (remyelination) after central nervous system demyelination is important to restore saltatory conduction and to prevent axonal loss. In multiple sclerosis, the insufficiency of remyelination leads to the irreversible degeneration of axons and correlated clinical decline. Therefore, a regenerative strategy to encourage remyelination may protect axons and improve symptoms in multiple sclerosis. We highlight recent studies on factors that influence endogenous remyelination and potential promising pharmacological targets that may be considered for enhancing central nervous system remyelination.

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“…This experience led us to conclude that disability accumulation early in MS is driven by inflammation and that anti-inflammatory treatments are effective if given early in the course of the disease [20]. From this analysis, our suggestion emerged that there is a "window of therapeutic opportunity" for immunotherapies in MS [21].…”

Section: Open-label Trialsmentioning

confidence: 99%

Alemtuzumab Therapy for Multiple Sclerosis

Coles

2013

Neurotherapeutics

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Alemtuzumab is a humanized monoclonal antibody that is administered daily for 5 days, and then no further therapy is required for 12 months. It causes rapid and prolonged lymphocyte depletion; the consequent homeostatic reconstitution leads to a radically reformed lymphocyte pool with a relative increase in regulatory T cells and expansion of autoreactive T cells. Although previously licensed for the treatment of B-cell chronic lymphocytic leukemia, it is now been considered for licensing in the treatment of multiple sclerosis (MS). From a disappointing experience with alemtuzumab in progressive MS, Alastair Compston and I argued that immunotherapies should be given early in the course of the disease. In a unique program of drug development in MS, alemtuzumab has been compared in 1 phase 2 trial and 2 phase 3 trials with the active comparator interferon beta-1a. In all trials, alemtuzumab was more effective in suppressing relapses than interferon beta-1a. In one phase 2 and one phase 3 trial, alemtuzumab also reduced the risk of accumulating disability compared with interferon beta-1a. Indeed, alemtuzumab treatment led to an improvement in disability and a reduction in cerebral atrophy. The safety issues are infusion-associated reactions largely controlled by methylprednisolone, antihistamines, and antipyretics; mild-to-moderate infections (with 3 opportunistic infections from the open-label experience: 1 case each of spirochaetal gingivitis, pyogenic granuloma, and Listeria meningitis); and autoimmunity. Usually autoimmunity is directed against the thyroid gland, but causes (1 %) immune thrombocytopenia, and in a few cases antiglomerular basement membrane syndrome. Alemtuzumab is an effective therapy for early relapsing-remitting MS, offering disability improvement at least to 5 years after treatment. Its use requires careful monitoring so that potentially serious side effects can be treated early and effectively.

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Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis

Cited by 475 publications

References 41 publications

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

Biomarkers and surrogate outcomes in neurodegenerative disease: Lessons from multiple sclerosis

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

Alemtuzumab Therapy for Multiple Sclerosis

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