Multiple Sclerosis or Multiple Sclerosis is a chronic inflammatory and autoimmune disease that affects the Central Nervous System, that is, the brain and spinal cord. It affects young adults, with a more frequent age of onset of 20 to 40 years, while it is slightly more common in women.
Its basic pathology is the destruction of myelin by autoreactive T-lymphocytes against its elements. Myelin is a fatty substance that surrounds the axon of neurons, thus providing insulation and protection from the environment. Thus, the various stimuli that are transmitted along the axon can be transmitted quickly and completely. With the destruction of myelin, this function is disrupted, resulting in the manifestation of various neurological symptoms by the patient.
After the initial destruction of myelin, the damage is partially repaired, resulting in the creation of a plaque consisting of inflammatory elements and microglia at this point. The name of the disease comes from these lesions, while due to the destruction of myelin it is included in the general category of demyelinating diseases.
The various symptoms that may occur are related to the point of attack of the central nervous system. The most common of these are diplopia, weakness of one side of the body or lower limbs, sensory disorders in the limbs or trunk, lack of balance and urination disorders. Today there are many targeted treatments for the disease, which are individualized according to the needs and condition of each patient. In order to choose the appropriate treatment, the form of the disease, as well as the pathophysiological mechanisms that caused it, are taken into account.
Based on the modern classification, there are three forms of multiple sclerosis, the relapsing-remitting, the primary progressive and the secondary progressive forms, as well as a single clinical entity, the clinically isolated episode, and a single imaging entity, the imagingly isolated episode.
In more detail, the above is presented as follows:
1. Relapsing-intermittent form (RI): The patient presents with symptoms in bursts, i.e. with flare-ups/relapses for a specific period of time, usually a few weeks, followed by remission. Imaging usually shows new plaques in various parts of the central nervous system or uptake of contrast agent in existing ones (an element of disease activity). It is also the most common form of the disease, especially in the first years of diagnosis.
2. Secondary progressive form (SP): In this form, after some years from the initial diagnosis of the disease (about 20 on average), patients begin to accumulate more and more neurological deficits, either not fully recovering after a relapse, or gradually worsening between flare-ups. Usually, patients with relapsing-remitting disease transition to this form after many years.
3. Primary progressive form (PPRP): Here, patients begin to deteriorate from the first moment of diagnosis, accumulating disability gradually and continuously without any prior relapse. This is the rarest form of the disease.
4. Clinically isolated syndrome: In this entity, the patient presents with a first demyelinating clinical episode, such as retrobulbar neuritis, without the remaining tests meeting the necessary criteria for the diagnosis of Multiple Sclerosis. Especially when there are demyelinating lesions on MRI, there is a high probability that the disease will manifest itself in the future. For this reason, there is an indication for initiating treatment in individual cases.
5. Imaging-only syndrome: With the widespread and easy access to MRI, demyelinating lesions may be found in some patients undergoing the examination, especially in brain MRI, without these being associated with the reason for which the patient was examined. Also, these patients, in addition to not presenting any neurological symptoms, have a normal neurological examination and negative other investigative tests for the disease. Then these findings are characterized as imaging-only syndrome. There is no indication for treatment in this case, but the patient should be closely monitored both clinically and imagingly for the following years, especially the first two, for the possibility of the disease occurring.
In order to diagnose multiple sclerosis, it is necessary to demonstrate, through tests and the patient's symptoms, that there is dispersion in space (central nervous system - variety of symptoms) and in time (flares and remissions, coexistence of active and inactive lesions). The last two syndromes are intended to cover the spectrum of all patients who do not meet the criteria for the diagnosis of multiple sclerosis, but are at increased risk of developing the disease in the future, and therefore require close monitoring and/or sometimes treatment. Finally, another element that has been taken into account in recent years for the selection of the appropriate treatment is the activity of the disease, that is, whether it presents clinical flares or new imaging lesions, even in progressive forms.
In recent years, many effective treatments have been developed for all forms of Multiple Sclerosis, which makes it possible to treat even the most aggressive and difficult forms of the disease. There are two general categories of treatments, disease-modifying and immunosuppressive therapies, which have as their main goal to stop the progression of the disease and prevent relapses. Disease-modifying therapies are characterized as such because by targeting specific elements of the patients' immune system, they lead to the modification of the course of the disease, keeping it as inactive as possible. These drugs are divided into mild activity (interferons, glatiramer acetate, teriflunomide), intermediate activity (cladribine, s1p receptor inhibitors, dimethyl fumarate) and high activity (natalizumab, ocrelizumab, ofatumumab, alemtuzumab). Autologous hematopoietic stem cell transplantation also belongs to the category of disease-modifying therapies.
Mildly active | Intermediate activity | High activity |
Interferons (interferon beta-1a, interferon beta-1b, pegylated interferon beta-1a) | Dimethyl fumarate | Natalizumab |
Glatiramer acetate | Cladribine | Ocrelizumab |
Teriflunomide | S1P inhibitors (fingolimod, siponimod, ozanimod) | Ofatumumab |
|
| Alemtuzumab |
Table 1. Mild, intermediate, highly effective treatments for Multiple Sclerosis.
Immunosuppressive treatments include classic immunosuppressive drugs, such as axathioprine, methotrexate, cyclophosphamide, cyclosporine, mycophenolate mofetil and mitoxandrone. They are now rarely used, in extremely isolated cases of patients, usually when another autoimmune disease coexists.
As previously mentioned, depending on the form of the disease and its activity status, there is an indication for starting or switching to a specific treatment. The table below lists the drugs that are indicated for each form of the disease.
Clinically Isolated Syndrome | Recurrent - intermittent | Secondly, I was actively progressing. | Secondary progression without clinical signs, but with imaging activity | Primarily progressive |
Interferons | Interferons, Glatiramer Acetate, Teriflunimide | Interferon beta-1a, interferon beta-1b |
|
|
Dimethyl fumarate, S1P inhibitors, cladribine | Dimethyl fumarate, Cladribine, S1P inhibitors | Cladribine, S1P inhibitors, Dimethyl fumarate | Siponimodi |
|
Natalizumab, Ofatumumab, Ocrelizumab | Natalizumab, Ofatumumab, Ocrelizumab, Alemtuzumab | Ocrelizumab, Ofatumumab, Natalizumab |
| Ocrelizumab |
|
| Mitoxantrone |
|
Table 2. Classification of treatments according to the form of Multiple Sclerosis.
Historically, the first drugs approved for the treatment of Multiple Sclerosis back in 1993 were interferons. Initially, interferon beta-1b and then interferon beta-1a were the mainstay of treatment for Multiple Sclerosis for many years. Depending on the formulation, they are administered daily, once or three times a week, or every two weeks subcutaneously. The action of interferon beta begins with its binding to cell surface receptors, leading to the inhibition of proinflammatory cytokines and the activation of T-lymphocytes. The main side effect is the flu-like syndrome and local skin reactions at the injection site.
Glatiramer acetate, the second oldest drug for Multiple Sclerosis, is administered subcutaneously and acts by reducing the production of substances that promote inflammation. Its composition mimics the myelin basic protein (Myelin Basic Protein-MBP), which is a target of T-lymphocytes. Through the mechanism of molecular mimicry, it prevents the adhesion of T-lymphocytes to MBP so that myelin is not destroyed. It is a fairly safe drug, with the only side effect being local skin reactions at the injection site.
A breakthrough in the treatment of Multiple Sclerosis has been the newer treatments, both oral and intravenous/subcutaneous, as they are significantly more effective and better regulate even the aggressive forms of the disease. Below, they are listed in more detail based on their effectiveness.
Teriflunomide is one of the first oral treatments. The substance is a metabolite of leflunomide, a broad-spectrum immunosuppressive drug, and acts by suppressing pyrimidine synthesis (a basic component of DNA) in mitochondria, possibly reducing lymphocytes in the central nervous system. This drug has teratogenic effects, so it is strictly forbidden to father a child while taking the treatment.
Dimethyl fumarate is also an oral treatment that suppresses proinflammatory cytokines and activates the Nrf2 pathway, promoting the synthesis of antioxidant enzymes. Gastrointestinal disorders are common side effects, but monitoring of lymphocytes is important as it can cause lymphopenia.
S1p receptor inhibitors prevent the exit of lymphocytes from the lymph nodes, thus suppressing the inflammatory response in Multiple Sclerosis. They are oral treatments, with the main side effect being lymphopenia and an increased risk of cryptococcal meningitis and progressive multifocal leukoencephalopathy. There are three substances in this category, fingolimod, which is the first to be released (targets the S1P1, S1P3, S1P4, S1P5 subgroups) and siponimod and ozanimod, which were released later and target the S1P1 and S1P5 subgroups.
Cladribine is administered orally and acts in a relatively targeted manner by suppressing lymphocytes. It is an analogue of purine, a substance that is a basic component of DNA and causes disruption in the DNA synthesis of lymphocytes, thus reducing their activity. It is administered in two treatment periods, the first two weeks, two consecutive months and then re-administered in one year. The main side effect is the reactivation of herpes zoster and bone marrow suppression.
Newer and more targeted, highly effective treatments in our quiver that have been approved for the fight against Multiple Sclerosis are monoclonal antibodies. The first monoclonal antibody released in 2004 is Natalizumab, which is administered once a month, subcutaneously or intravenously. It binds to the α-4 integrin on the surface of lymphocytes and in this way prevents them from migrating to various tissues and penetrating the blood-brain barrier, in order to cause inflammation. A prerequisite for the administration of Natalizumab is that patients are negative for the presence of antibodies to the JCV virus or for patients who are positive, the levels must be below 1.5, as the likelihood of progressive multifocal leukoencephalopathy, a serious disease of the white matter that causes cognitive impairment and focal neurological symptoms, increases significantly.
Ocrelizumab is an anti-CD20 monoclonal antibody that targets the specific molecule expressed on B-lymphocytes, thus reducing their number. It is administered once every six months intravenously, while before its initiation, the presence of latent hepatitis or tuberculosis must be excluded. Its most common side effects are herpes infections, upper respiratory infections and reduced response to vaccinations.
Ofatumumab, also an anti-CD20 monoclonal antibody approved in 2020, is administered subcutaneously once a month, following the starting regimen for the first 5 weeks. Similarly to ocrelizumab, priorn the beginning, it is necessary to check for hepatitis or syphilis.
Finally, Alemtuzumab is an anti-CD52 monoclonal antibody, which as it binds to the target molecule reduces the number of lymphocytes by destroying them. It is administered intravenously, initially for 5 days in the first year and after one year the supplementary dose is injected for 3 days. It has been approved as a second-line treatment for the relapsing-remitting form of Multiple Sclerosis. Due to its action on lymphocytes, there is an increased possibility of autoimmune thyroiditis, tuberculosis, HSV infection and more rarely other autoimmune diseases and hematological neoplasms. Infusion reactions are common, with the recommendation to administer intravenous corticosteroids before each infusion to prevent them.
Special mention should be made of Mitoxandrone, a chemotherapy drug that was the first to be approved for Secondary Progressive Multiple Sclerosis with activity. Due to the toxicity of the drug, with more serious side effects such as cardiotoxicity and leukemia, it is now used extremely rarely, only in patients who continue to relapse despite receiving other treatments.
In the 1990s, autologous hematopoietic stem cell transplantation began to be investigated for the treatment of the disease. The theory behind this treatment is that in this way the pathogenic copies (pathogenic clones) of the autoreactive lymphocytes are destroyed, so that with the reconstitution of the marrow they are not expressed to manifest the disease. Due to the severe suppression of the marrow that is caused, it is administered only to patients of young age, with a relapsing-remitting form of the disease with multiple relapses (more than 2 relapses in one year).
Today, it has been shown that induction therapy is more effective, especially in patients with a new diagnosis, for the effective suppression of the disease and the reduction of relapses and the accumulation of damage and disability. Based on this theory, initially the disease is treated aggressively with high-potency treatment, in order to stop the disease activity, and later, after the patient has stabilized, there is a discussion about de-escalating the treatment with the administration of another drug with the aim of preventing side effects.
Another theory for more chronic or less aggressive forms of relapsing multiple sclerosis is escalation therapy with initial administration of mild or intermediate-potency treatment and changing to more highly potent treatment only if there is evidence of clinical or imaging activity.
In conclusion, we now have in our quiver many effective drugs for the successful treatment of Multiple Sclerosis, even its most resistant forms. Each patient must be treated individually, based on their needs and preferences, by an experienced neurologist in order to receive the most appropriate, powerful, but also safe treatment. The key to this is early recognition of symptoms and diagnosis, so that the disease can be combated as early as possible for the best outcome.
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