The winding path of MS progression

MS progression refers to the development of the disease after onset (when symptoms first appear). Although the names are similar, MS progression is not limited to progressive forms of MS (i.e. primary or secondary progressive MS). All forms of MS progress, or change, over time.

When someone with MS has a relapse, this is sometimes referred to as progressing or ‘evolving’, which describes the frequency and severity of relapses. However, true MS disease progression is the gradual accumulation of disability in between, or in the absence of, relapses.

Progression is the result of three inter-related biological processes.

Neurodegeneration, where neurons, the cells in the brain that send, receive and process information, lose structure and function, and ultimately die.

Inflammation, where the immune system mistakenly registers something in the body – usually harmless – as foreign, and triggers targeted inflammatory cell infiltration to the area and swelling. This response is what classifies MS as an autoimmune disease, where the immune system misfires and attacks healthy tissue.

As MS progresses, the ability of the central nervous system (CNS – the brain and spinal cord) to repair the damage caused by neurodegeneration and inflammation, or to continue to function normally despite that damage,are overwhelmed.

The order in which these processes happen remains unclear and they may be different for different people. Acting together, these three processes lead to the increased disability that characterises MS disease progression.

Measuring disease progression

Currently, when we measure disease progression, we use stand-in measures known as surrogates. Essentially, these are measures of health outcomes – the results of disease progression – rather than measures of the underlying biological process of disease progression itself. These surrogate measures include disability level or relapse rate.

One limitation of using surrogate measures is that they are subjective and therefore introduce uncertainty. In contrast, a direct measure of disease progression would be a single, objective biological measure (a biomarker) that directly reflects the process of progression.

Studies searching for a better biomarkers, including MRI measurements and some blood tests, are underway and this is a major focus of the work of the International Progressive MS Alliance. However, we have yet to discover an effective direct measure of MS disease progression. This gap in our understanding is a stumbling block for research.

Risk factors for disease progression

Risk factors are genes, behaviours or environmental factors that may influence disease progression. Risk factors typically have a detrimental effect, meaning that they increase the chance of greater levels of disability. However, some can have a protective effect, meaning that they decrease the chances of greater levels of disability. Although a great deal is known about the risk factors influencing disease onset (reviewed in this recent article from MS Research Australia), far less is understood about the risk factors influencing disease progression. Nevertheless, we are slowly beginning to build a clearer picture of the reasons why the disease may progress faster in some people than in others.

Smoking

Smoking causes inflammation in the body and can alter immune cell function. There is good evidence to suggest that smoking influences MS disease progression, increasing the risk of greater disability. Studies have indicated that smokers have 1.5 times the risk of disease progression (meaning greater disability) compared to non-smokers.

Vitamin D

Vitamin D can come from your diet or from exposure of the skin to sunlight. Lower vitamin D levels in the blood increases the risk of greater disability, suggesting that vitamin D might be protective against disease progression. It remains unclear exactly how vitamin D causes this response in the body and we need future research to confirm that increasing vitamin D levels through sun exposure, diet or supplements can delay progression.

Other risk factors

No other risk factors have been conclusively shown to influence disease progression. Although diet, for example, is of great interest to the MS community, there is little evidence as yet of its effect on disease progression and scientists simply do not know what role diet and other risk factors play in MS. Fortunately, there are many ongoing research projects working on these questions.

Treatments for MS progression

Treatments for disease progression aim to slow the rate of disability progression (the speed that disability level increases). There are two major types of treatments: disease modifying therapies and modifiable risk factor interventions.

Disease modifying therapies (DMTs)

There is good evidence to suggest that disease modifying therapies (DMTs) for relapsing remitting MS, which are treatments that modify the immune system, do slow disease progression. They can result in lower accumulated disability and reduced risk of relapse over the short-term (5 years or less). In some cases, DMTs have been shown to reduce disability progression by more than 40%. Scientists are currently working to unravel the long-term (greater than 10 years) effects of these treatments, and to determine which DMTs are the most effective.

While these results are exciting, it is important to note that the majority of DMTs have only been demonstrated to be effective treatments for relapsing-remitting MS. However, more recently, progressive forms of MS have been shown to be responsive, to a certain extent, to some DMTs – most notably, Ocrevus (ocrelizumab) for primary progressive MS and high dose Biotin for secondary progressive MS (although this finding still needs to be confirmed). Nevertheless, establishing that we may be able to alter the rate of disability accumulation in progressive forms of MS is of great interest and could significantly improve our ability to deal with progressive MS.

Modifiable risk factor interventions

Although we can’t change our genes, some risk factors for disease progression are modifiable. Modifiable risk factors are behaviours that can be changed or environmental factors that can be avoided. These include smoking, exercise and diet. Modifiable risk factor interventions are treatments that alter the modifiable risk factor in order to improve health outcomes, such as quitting smoking, or taking vitamin D supplements.

Although two modifiable risk factors – smoking and vitamin D levels – have been shown to influence disease progression, there is little evidence as yet that the related interventions of quitting smoking and increasing vitamin D intake slow disease progression. This apparent contradiction is likely due to the very small amount of scientific evidence that is currently available. More studies with larger numbers of people need to be conducted in this area before we can really understand the potential effects of modifiable risk factor interventions on MS disease progression.

In summary

A great deal is still unknown about MS disease progression. For now, living as healthy a lifestyle as possible remains the best overall approach for people living with MS, along with appropriate prescription medications, such as DMTs. A healthy lifestyle includes physical activity and exercise, maintaining a healthy weight and cholesterol level, no smoking, adequate sun exposure and vitamin D levels, and a well-balanced diet.
Scientists continue to address these questions in their work, and future research projects will deepen our understanding of the causes and consequences of disease progression in MS.

With thanks to MS Research Australia – the lead provider of research summaries on our website.