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When does the transition from RRMS to SPMS or PPMS occur and is it inevitable?

Relapsing Remitting Multiple Sclerosis (RRMS)

Progressive Disease (Secondary Progression (SPMS)

Primary Progression (PPMS)

The majority of disease modifying therapies (DMTs) are very effective in shutting down relapses. In fact, once the DMT is started, effectiveness is judged by “Activity.” This is defined as either onset of new T 2 or enhancing lesions on interval MRI scans or increased disabling symptoms. As long as one is experiencing a true relapse (a new symptom or intensified manifestation of an old symptom which has severely worsened lasting greater than 24 hours), at some point treatment with an effective DMT, usually results in a cessation of relapses. Upon administration of an effective DMT, the patient maybe completely asymptomatic or left with slight residual symptoms. There appears to be a stage when the transition from RRMS to SPMS/PPMS subtly takes place over time. This usually involves subtle and progressive increased difficulty with ambulation, unsteadiness, or cognitive issues amongst others. The questions arise as to what causes it and is it inevitable?

Many scientists and healthcare researchers propose evidence for one possible mechanism of transition from relapsing remitting disease to progression and degeneration involves the immune system. This system is made up of two main parts: The innate (general) immune system and the adaptive (specialized) immune system. The innate system is the body’s first line of defense against germs entering the body. It responds in the same way to all germs and foreign substances. It consists of cells that are neutrophils, antigen presenting, phagocytes, natural killer cells, dendritic cells, cytokines, complement, and microglia. The adaptive system consists of T and B cells, as well as antibodies. The difference is that the adaptive cells have memory of previous contact with noxious agents.

In SPMS/PPMS, certain aspects of immunity have been identified and potentially linked to development of progression. In the meninges there are collections of nodules of inflammatory cells that are believed to be active. Cells present in the edges of existing plaques multiply and the plaque expands. The innate immune system is active with proliferation of microglia as identified in specialized neuroimaging studies. These observations are intriguing and support ongoing immunological activity associated with degeneration.

The issue of inevitability, centers around aging. It is argued that when we reach a certain age and regardless of what is done, this transition from RRMS to Progression occurs. This theory is tied to the concept of “brain plasticity” and “brain reserve.” Brain Plasticity is the ability of the nervous system to change its structure and functioning throughout a person’s life as a reaction to the environment. Brain Reserve increases the tolerance of the brain to physiological or pathological changes. This reserve is initially acquired genetically, but there are environmental factors such as education and participation levels in social and physical activities that potentially can increase reserve. There are interindividual differences in brain reserve that provide a greater or lesser tolerance in terms of protection produced by the effects of ageing or disease.

Multiple Sclerosis (MS) produces a constant involvement of demyelination but at various rates of occurrence. Aging plus demyelination are ongoing and definitely at some point produces a major negative impact on brain reserve. It is argued that aging maybe the key factor in development of progression through this mechanism. The use of “DMTs” appears to decrease this process but doesn’t eliminate it.

Stephen C Krieger MD put forth an explanatory model of one theory for the mechanism of progression in MS. A recent Scientific American article authored by Brett Stetke, June 2015, summarized the Krieger approach: He stated:

….Imagine a pool with mountains rising up from the bottom. The mountains represent scars in the central nervous system; the water surface is the threshold at which symptoms appear. Lesions below the water line do not cause symptoms whereas those jutting out of the water do.

The water surface can also be seen as the body's neurologic reserve capacity. Our brains are astoundingly resilient: If one part of the brain is injured, neighboring neurons can step in and take over. But according to Krieger, as we age and as MS progresses, not only does the scarring worsen (that is, the mountains grow higher), the brain also loses its ability to compensate for injured tissue—meaning water starts draining out of the pool and more lesions appear and resulting symptoms become apparent.

Krieger calls his view of MS the topographical model (referring to the mountains jutting out of the water). He believes his concept unites the MS categories and demonstrates the relationship between relapsing and progressive disease. Relapsing-remitting patients have mountains that temporarily rise above the waterline but then sink again. In those with the other two forms of MS—the more consistently progressive forms—the mountains e

merge above the surface but never recede and the symptoms never go away.

Thus, with aging, the level of the pool drops. Stress and illness can also affect the level. The lower the level the more symptomatic and potentially progressive the patient. Early research into strategies of intervention emphasized treatment and prevention of relapsing-remitting disease. It turned out that efficacy could be easily demonstrated through imaging with MRI. This surrogate marker for relapses could be easily counted, measured, and quantified. Measuring of disability was challenging but possible. However, often the time frame chosen for disability was too short. These three outcome measures (MRI, relapses and disability) could potentially establish objective efficacy and safety of various DMTs in a relatively short period of time. Progressive disease turns out to be a totally different ball game. Potentially, outcomes measures are far more subjective and challenging to demonstrate. The biomarkers are limited. The process occurs over prolonged time (multiple years to decades rather than months to years). It is reassuring to note that the research emphasis of the MS Society and the NIH has shifted from relapsing disease to progressive disease. Varying mechanism of actions for progression are being identified and potential targets assessed.

One of these new strategies being developed presently and in clinical trials consists of the discovery of the Bruton’s Kinase Inhibitors (BTKs). BTKs were initially discovered to be active against certain hematological malignancies. BTK is an enzyme that increases B cell antigen receptors downstream. This results in an increase of substances that transmit the signals that allow immune cells to respond to foreign antigens by targeting the cells and presenting them for destruction. This consists of highly selective B cells. This strategy differs considerably from the ongoing complete depletion of all B cells through the anti-CD20 mechanism (Ocrevist, Rituxan, Kesimpta). BTK inhibitors are being advanced by several different pharma companies. These products are in various stages of development to establish their safety and clinical efficacy. Initial studies have been encouraging but we must wait for the final data that will address their safety and effectiveness.

Written By: Jay Rosenberg, MD


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