Due to the fact that symptoms and progression rates of MS vary among patients with the disease, previous implications have been made to suggest that MS may involve a combination of two or more different diseases.
Most recently, a study used computational simulations to assess whether it was possible for the wide-ranging MS phenotypes to be replicated within the same underlying mechanism involved in MS. Ekaterina Kotelnikova from the August Pi Sunyer Biomedical Research Institute at the University of Barcelona and fellow researchers hypothesized that MS is a single disease driven by the same underlying biological mechanism – attack of the protective fibers by the immune system, which are responsible for protecting nerve cells and thereby lead to loss of the axons, which are used by the nerve cells to communicate with one another. “While the evolution of MS seems to be the result of the interplay between acute inflammatory relapses, chronic inflammation in the CNS, and the degeneration of axons and myelinated cells, each process could have a distinct influence on the different patient subgroups and at different stages of the disease, consistent with the single-disease hypothesis” wrote the authors. The main question is whether the neurodegeneration process in MS is separate from the inflammation process or if it is a single advanced process that ultimately includes both biological processes, yet at a different level.
The study’s results are published in PLOS Computational Biology and support the notion that MS is a single disease, despite its varying symptoms and how quickly it progresses in some patients. “Our simulations support the concept that MS induces a chronic inflammatory process that damages the brain from the beginning, in an accumulative way, as well as with superimposed relapses. Preventing relapses is very important because they disturb patients’ quality of life and because they produce disability. For this reason, early treatment of relapsing MS is so important, but not sufficient” said Dr. Pablo Villoslada, director of the August Pi Sunyer Biomedical Research Institute at the University of Barcelona. “The presence of irreversible axon degeneration at early disease stages would appear to be mainly due to the higher rates of degeneration (transection) of myelinated axons and to a lesser extent, to a weaker capacity for remyelination. A build-up of axon degeneration is the basis of the progressive phenotype, even during early disease stages like those of RRMS. Conversely, increased resilience in both the rates of axon degeneration and in the efficiency of remyelination at early stages of the disease are the basis of the RRMS subtype. These results provide a theoretical framework to study the contribution of such pathogenic processes at the experimental level, as well as for the design of therapeutic strategies for MS. However, our model does not rule out alternative hypotheses, such as the inside-out hypothesis, the two-stage hypothesis or the influence of a deteriorated autoimmune response (e.g., epitope spreading, antigen presentation in the damaged CNS).
Therefore, we can only state that the dynamic CNS damage hypothesis of MS is consistent with the phenotype observed, while we cannot formally rule out other explanations” wrote the authors.
A mathematical model of MS
The results of the study are based on a mathematical model of MS, created by Dr. Villoslada and his team. The model was developed based on data gathered from 66 MS patients who had been monitored for 20 years. In order to verify their results from the initial group of MS patients, the researchers gathered data from another group of 120 patients who had been monitored over the course of 3 years. “We identified four clusters of patients that corresponded to the different levels of disease severity (EDSS) and disease subtypes (relapsing vs progressive disease). Thus, 86% of progressive MS cases (SPMS or PPMS) were included in Cluster 1 or 2, whereas 66% of relapsing MS (RRMS) were grouped into Cluster 3 or 4 patients. We validated this clustering using a cohort that consisted of an EDSS time-series with a three-year follow-up, producing a similar grouping into four clusters” wrote the authors.
“We found that by adjusting certain parameters, albeit within their biological range, the mathematical model reproduced the different disease courses” wrote the authors. The results supported the theory that symptoms and disease courses of MS in patients are produced by the same underlying mechanisms that cause damage to the nerve cells and despite different patterns of progression, over time; MS will worsen for all patients. “This concept has significant therapeutic implications and will drive the development of new therapies because it implies that MS will produce significant disability if suffered for enough time in all patients. Indeed, preventing relapses, although very important, will be not enough to achieve good control of the disease” said study co-author Dr. Villoslada.
Potential treatment discoveries
In addition to shaping healthcare professionals’ and researchers’ understanding of MS, the researcher team also hoped to understand and to propose how the disease can be treated. Dr. Villoslada noted that the findings could help to develop a more personalized treatment approach for MS. If the mathematical model could predict the different courses of MS, it could, in theory, predict the way an MS patient’s disease might progress. “Based on the risk analysis obtained from such an approach, patients and physicians will be able to make informed decisions” said Dr. Villoslada.
In order for these predictions to lead to more personalized care, the next step would be to collect sufficient data from patients on disease prognoses and use the mathematical model to test their accuracy. Still, Dr. Villoslada stressed that even if MS relapses could be prevented, the brain would still have to sustain damage from the disease, potentially leading to increased rates of long-term disability. For this reason, healthcare professionals should be cautious and aware when an MS patient displays no signs of relapse. “This is a call for not relaxing the surveillance about the disease in the absence of relapse because the disease will remain burning inside the brain” he said.
“In summary, our study indicates that the pathogenic processes that drive autoimmune damage in the CNS can produce all the distinct MS subtypes and explain the clinical heterogeneity in patients. However, while each phenotype requires specific parameters to be fulfilled, it appears that there is a distinct contribution of each biological process to the different disease stages (perhaps reflecting different genetic susceptibility and environmental exposure). Therefore, our model supports the notion that MS and its phenotypes can be explained as an autoimmune process, arguing in favor of the dynamic CNS damage hypothesis of MS. This hypothesis has implications for the development of new therapies and patient monitoring. Principally, it means that MS should be considered and treated from the onset as a progressive disease, with a focus on preventing CNS damage, and on avoiding reaching the thresholds associated with the progressive course of the disease and more severe disability” wrote the authors.