What are Disease-Modifying Therapies (DMTs)?

When speaking about "Disease-Modifying Therapies" (DMTs), one usually refers to the medications used to treat Multiple Sclerosis (MS) patients. DMTs do not represent a cure, since they cannot revert the damage to the central nervous system (CNS) or completely stop the progression of the disease. Still, they can affect the frequency and the severity of the typical MS relapses, thus reducing the number of new lesions, delaying the onset of significant disabilities, and extending survival. This is the short and simple version of the question asked in the title. If you are still curious and would like to know a bit more about MS, the different types of DMTs, and their working principles… Then keep reading!

Background information about Multiple Sclerosis

According to the last report of the Multiple Sclerosis International Federation (MSIF), a total of 2.8 million people were estimated to live in 2020 with MS worldwide (35.9 per 100,000 population), with women twice more likely than men to develop this condition ⁽¹⁾. Multiple Sclerosis represents, therefore, the most common non-traumatic disabling disease affecting young adults ⁽²⁾.
From a biological point of view, MS is a chronic inflammatory disorder of the CNS (brain and spinal cord), characterized by the disruption of the myelin sheath protecting the nerve fibers (demyelination), local inflammation, and ultimately neuronal damage. This degenerative process is presumably linked to an autoimmune pathogenesis, and more specifically, to a T cell-mediated inflammatory disorder. In addition, recent evidence, based on the success of some B cell-depleting therapies, indicates the role of other bone marrow-derived immune cells in the pathogenesis of the disease ⁽³⁾.
From a clinical point of view, MS can be categorized into four types ⁽⁴⁾:

• Clinically Isolated Syndrome (CIS): corresponds to the first episode of neurological symptoms lasting at least 24 hours and suggestive of MS.
• Relapsing-Remitting MS (RRMS): this is the most common first diagnosis of MS (85% of patients). It is characterized by relapsing-remitting cycles of symptoms. A relapse is defined by the appearance of new symptoms or the return of past symptoms, typically lasting from a few days to a few weeks. Relapses are caused by the immune system launching an inflammatory attack against nerve fibres. During attacks, new parts of the nervous system can become damaged, leading to new symptoms that can therefore vary, depending on which parts of the nervous system are most affected. The subsequent remission phase is characterized by repair and compensation mechanisms that can initially ease or eliminate symptoms, until the underlying neuronal damage becomes increasingly evident, and patients typically show a progressive decline.
• Secondary Progressive MS (SPMS): this stage often follows the previous one, and is the second largest category of MS. In this phase, the symptoms steadily worsen over time. There might be slight, less dramatic relapses, but the symptoms do not disappear in the remission phase.
• Primary Progressive MS (PPMS): it affects approximately 15% of MS patients. Unlike previous cases, PPMS progresses steadily from the onset, without relapsing-remitting cycles. In addition, PPMS is characterized by lower inflammatory levels, and the lesions tend to concentrate in the spinal cord more than in the brain.

Unfortunately, the etiopathogenesis of MS, probably responsible also for its different clinical manifestations, is still unclear, but certainly very complex. We know that both genetic predisposition and environmental influences are related to the risk of developing MS. Studies conducted on northern European monozygotic twins demonstrated a concordance rate of MS between 20-30% (in the general population, this rate is only 0.1-0.2%). This suggests, on the one hand, a high degree of heritability and, on the other, that non-mendelian factors also contribute to the development of the disease (i.e. epigenetic regulation, environmental factors) ⁽⁵⁾.
As for the genetic risk, it has been known for a few years that several variants of HLA antigen affect the risk of developing MS ^(5,6). In addition, in the past 15 years, large international collaborative studies allowed to associate hundreds of susceptibility variants to MS development, often located in the non-coding regions of the genome but close to genes that regulate innate or adaptive immunity, also shared by several other autoimmune diseases ⁽⁵⁾. Concerning the environmental factors whose correlation with MS development is pretty well ascertained, it is worth mentioning Epstein Barr Virus infection, low sunlight exposure and vitamin deficiency, obesity and dietary habits, and finally, smoking ⁽⁵⁾.

Examples of Disease-Modifying Therapies

Despite the scientific community's efforts, a definitive cure for Multiple Sclerosis is yet to be found. However, a number of Disease-Modifying Therapies (DMTs) are routinely used, often considerably improving the quality of MS patients' life. Because of the inflammatory autoimmune nature of MS, DMTs typically target the immune response by modulating lymphocytes number, proliferation and trafficking, or cytokine production. It is worth highlighting here that the majority of DMTs are effective only on the relapsing form of the disease, probably because the primary progressive forms of MS are less associated with inflammation, and are therefore less responsive to this kind of approach. Table 1 lists a few examples of licenced DMTs for Multiple Sclerosis, with their proposed mechanisms of action (information is summarized in ref. 7 and 8).
Since curative treatments are not available, these therapies aim mainly to decrease the risk of relapses and disability progression by reducing the appearance of new lesions in the CNS. Currently available DMTs are commonly distinguished as moderate-efficacy (e.g. interferon-beta, glatiramer acetate) and high-efficacy DMTs.
The moderate efficacy DMTs are characterized by a well-defined safety profile. In contrast, the high efficacy ones (usually newer and therefore less known) carry a higher risk of serious side effects. For this reason, a common strategy included in medical guidelines is the "escalation approach" ⁽⁹⁾: moderate-efficacy therapies are the "first line", whereas it is advised to use the high-risk treatments only in highly active disease or in case of failure of the first line.
More recently, an increasing number of studies are highlighting the importance of early intervention with high-efficacy treatments as the best window of opportunity to delay irreversible CNS damage and disability progression. The benefit/risk ratio also seems to be more positive, as information on the long-term safety risks is more and more available ⁽¹⁰⁾. The use of more effective medications from the onset of MS diagnosis could therefore be introduced in clinical guidelines in the near future, thereby increasing the options of therapies available.

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