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The winding path of progression

What is progression in MS?

Multiple sclerosis (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-type MS (i.e. primary or secondary progressive MS). All forms of MS progress, or change, over time.

When an individual with MS has a relapse this is sometimes referred to as progressing or ‘evolving’. This really 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. The order in which these processes happen remains unclear, and may be different for different people.

  1. Neurodegeneration, where neurons, the cells in the brain that send, receive and process information, lose structure and function, and ultimately die.
  2. 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.
  3. The breakdown of the central nervous system’s (CNS; the brain and spinal cord) tolerance and repair mechanisms. As MS progresses, the CNS’s ability to repair the damage caused by neurodegeneration and inflammation or to continue to function normally despite that damage (tolerate it) are overwhelmed.

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) that are really measures of health outcomes (the result of disease progression), not disease progression itself (the underlying biological process). These surrogate measures include disability level or relapse rate. The difficulty with surrogate measures is that they introduce uncertainty, because they are subjective. 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 biomarker, including MRI measurements and some blood tests, are underway, and is a major focus of the International Progressive MS Alliance, but we have yet to discover an effective direct measure of MS disease progression. This gap in our understanding is a stumbling block for research on disease progression.

Risk factors for disease progression

Risk factors are genes, behaviours, or aspects of the environment 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. 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 suggesting that smoking influences MS disease progression, increasing the risk of greater disability. Studies indicate that smokers had 1.5 times the risk of disease progression (meaning greater disability) compared to non-smokers.

Vitamin D

Vitamin D can be derived 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. This includes diet. Although diet is of great interest to the MS community, there is little evidence as yet of its effect on disease progression. This is largely because so little is known about disease progression generally. We simply do not know what role diet and other risk factors play in MS. Only further research can change that. 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 (DMT)

There is good evidence to suggest that disease modifying therapies for relapsing remitting MS (DMT, treatments that modify the immune system) slow disease progression, resulting in lower accumulated disability and reduced risk of relapse over the short-term (5 years or less). In some cases, DMT 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 DMT is the most effective.

While these results are exciting, it is important to note that the majority of DMT 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 with Ocrevus (ocrelizumab) for primary progressive MS, and high dose Biotin for secondary progressive MS – although this finding still needs to be confirmed. Never the less the finding that we can potentially alter the rate of disability accumulation in progressive forms of MS is of huge interest and potentially a significant improvement in our ability to deal with progressive MS.

Modifiable risk factor interventions

We can’t change our genes, but 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. For example, quitting smoking or taking vitamin D supplements.

Although two modifiable risk factors, smoking and vitamin D level, have been shown to influence disease progression there is little evidence as yet that related interventions (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 and strong study designs 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 level, 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.

Dr Suzi Claflin

Dr Suzi Claflin is a Post-doctoral Research Fellow working with Professor Bruce Taylor on the epidemiology of MS at the Menzies Institute for Medical Research in Hobart Tasmania.

Professor Bruce Taylor

Bruce Taylor is Professor of Neurological Research University of Tasmania. In 2007 he was appointed as a principal research fellow at the Menzies Institute for Medical Research in Hobart as a 50/50 conjoint position with the Royal Hobart Hospital.
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The winding path of progression