Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis

Abstract

Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

“…40 A pseudoatrophy or anti-infl ammatory eff ect in white matter in the estriol group would be consistent with the reduction in relapse rates. Whether maintenance of higher estriol concentrations at 24 months in all participants in the estriol group could have resulted in more robust eff ects on relapses or enhancing lesions is unknown.…”

Evolution of Cortical and Thalamus Atrophy and Disability Progression in Early Relapsing-Remitting MS during 5 Years

“…This finding is in line with those of previous studies. 36 Previous clinical studies in MS have shown an association between whole-brain atrophy and an increases in lateral ventricle volume and have found that both measurements were associated with increased disability. 37,38 This association was confirmed in an earlier analysis of data from part of this cohort, 12 which showed that whole-brain volume was predictive of disability progression.…”

MAGNIMS consensus guidelines on the use of MRI in multiple sclerosis—establishing disease prognosis and monitoring patients

“…41 This phenomenon is called pseudo atrophy, and it seems to be directly associ ated with the resolution of ongoing white matter inflam mation induced at the time of treatment initiation. 32,[44][45][46][47] To identify pseudo atrophy during a clinical trial, brain volume should be measured every 3-6 months. 25 In addition to disease specific changes, lifestyle related factors (including alcohol consumption, smoking, dehy dration and BMI), genetics (such as the presence of an APOE*ε4 allele), and concomitant pathophysio logical conditions (such as diabetes and/or other cardio vascular risk factors) can affect brain volume.…”