Brain atrophy reflects the most destructive pathological processes, including tissue loss, neuronal damage and neurodegeneration. Neurodegeneration is a relevant hallmark of multiple sclerosis (MS), one of the most disabling neurological diseases in young adults. Measurements of percent brain volume change per year (PBVC/y) by magnetic resonance imaging (MRI) represent one of the best methods for evaluating neurodegeneration progression in MS. Many progresses have been made in drug therapy in MS, and a variety of disease-modifying drugs (DMDs) are now available. Clinical trials have shown a significant relationship between treatment effect on both brain atrophy and disability progression. However, despite of the proved efficacy of DMDs used as first-line treatment, many patients continue to experience `break- through disease¿, measured in term of either clinical or MRI activity, while being under treatment. In clinical practice, neurologists currently use different approach to manage breakthrough disease, including the switching between different classes of DMDs. During the last years, an escalation approach (switching to a more powerful drug) has demonstrated better outcomes (reduction of both clinical relapses and new MRI lesions). We aim at studying the effect of switching from a treatment to another on brain atrophy in a real-world study, in order to assess the "effectiveness" of switching treatments in routine clinical circumstances.
From a large dataset of MS patients (Italian Neuroimaging Network Initiative, INNI) containing MRI, clinical and therapeutic information, we will select those patients who switched from a first to a second drug and having MRI data available for at least three time points: at least 12 months before the switch to a second drug, at the start of the second drug and at least 12 months after the switch. The PBVC/y under different DMDs in each patient will be correlated with the clinical data obtained before and after the switching.
Brain atrophy, which reflects neurodegeneration, has shown to be a good surrogate marker of physical disability and cognitive impairment and measures of brain atrophy by using MRI has been already chosen as a primary endpoint in phase II clinical trials in MS. Stopping neurodegeneration progression in MS is one of the most important goals of current therapeutic strategies. However, there is a gap in the use of brain atrophy assessment by MRI in evaluating treatment efficacy in clinical setting. Despite numerous clinical trials, no study has explored the effect of switching from a therapy to another in terms of brain atrophy.
This information is relevant in clinical practice, where neurologists currently use different approach to manage breakthrough disease, such as switching between different classes of immunomodulators, modifying the dose and/or the frequency of administration, combination or escalation therapies. During the last years an escalation approach (switching to a more powerful drug) has demonstrated better outcomes measured as reduction of clinical relapses and inflammatory activity detected on MRI (new T2 lesions and new gadolinium enhancing lesions). The outcome on brain atrophy, which documents the progression of neurodegeneration, has not been evaluated.
As one of the four founder centers, we have the opportunity to access to a large dataset of MS patients, the Italian Neuroimaging Network Initiative (INNI), assessed using standardized procedures in 4 Italian centers. This provides a unique instrument to test hypotheses, assess sources of variability, examine new tools, provide guidelines and overcome the gap between research setting and clinical practice. A website (www.inni-ms.org) for the initiative has been created. The online INNI database is available at: https://database.inni-ms.org. It was developed in collaboration with the GARR consortium in 2015 and formally tested in November 2016. The database content is available for authorized users only, who received appropriate login and password. Several hundreds of standardized clinical, neuropsychological and MRI data of healthy individuals and MS patients assessed at the participating centers are available and allow to perform large-scale studies to determine and validate novel MRI biomarkers to be utilized as predictors and/or outcomes in MS. We have the opportunity to use this platform study to the effect of switching from a treatment (DMD1) to another (DMD2) on brain atrophy in a real-world study. The proved experience in MRI data analysis of our lab ensures the success of this project.