In multiple sclerosis, the immune system tragically destroys the myelin sheath of nerve fibers in the brain and spinal cord. As a result of this, various systems of the body cease to receive signals from the brain, and symptoms of the disease occur. However, the ability to think clearly remains. More recently, most patients with multiple sclerosis were quickly bedridden. However, over the past decades, doctors and researchers have made great progress. In this article, we will talk about who and why there is multiple sclerosis, how it is diagnosed, and discuss modern treatment methods.
Multiple sclerosis is a serious and unpredictable disease that can occur at any age, but more often than not, “young people” get into the most active phase of life “under attack”. And although this disease can seriously change the usual course of things, it still leaves patients the opportunity to live a full life, not stop and not humble themselves. An example of an inspiring life position in the diagnosis of multiple sclerosis is provided by Irina Yasina, a journalist, publicist, and human rights activist. In 2012, she published an autobiographical novel, Case History. In attempts to be happy, ”in which she described her illness as“ a being that changed my life, did not distort, did not rob, but slowly and steadily beat out old habits, established interests, changed tastes and attitude to home, to things, to love, to other people's weaknesses. Taking away one, always generously gave another. Even with such a serious illness as multiple sclerosis, a person can cope without losing the desire and ability to maintain an active lifestyle. In many ways, this has become possible thanks to the achievements of modern medicine. In this article we will discuss which people and under what circumstances multiple sclerosis can occur, what are the mechanisms of the development of the disease and how to treat it. We will also talk about where to look for good sources of information about the disease, and discuss patient organizations.
What is multiple sclerosis?
Multiple sclerosis (MS) was first described in 1868 by the French neurologist Jean-Martin Charcot. Now it is one of the most common chronic diseases of the central nervous system (CNS), affecting people of almost all ages in many parts of the world, but giving "preference" to young Caucasian women living in the northern latitudes. In MS, the body’s immune system attacks its own myelin — the membrane surrounding the axons of nerve cells and affecting the rate of transmission of an electrical impulse through them. Left without a protective myelin layer, the fibers of nerve cells become vulnerable and can die. The decrease in the speed of nerve impulses and the death of nerve fibers lead to the appearance of neurological symptoms. Given that different parts of the brain are responsible for different functions of the body, depending on where the axon demyelination occurred, different symptoms will appear. That is why MS is called an autoimmune (the immune system works against its own body), demyelinating (myelin is destroyed) and neurodegenerative (damaged nerve fibers) disease.
Since demyelination and neurodegeneration occur gradually, developing MS may not manifest for a long time. This latent period of the disease can last up to several years. Diagnosis of MS is quite complicated and takes time, and in addition, there are no reliable methods for predicting the disease and its treatment. All this, along with the wide distribution, makes MS one of the most socially significant diseases, and its study is one of the most important biomedical problems.
Many people, explaining their forgetfulness, refer to "sclerosis". So: in medicine, the term "sclerosis" does not mean bad memory, but the replacement of any healthy tissue (for example, muscle or nerve) with connective tissue, which performs an auxiliary function and works like a patch, that is, in essence, this is scarring. Such substitution usually occurs as a result of pathological processes, namely, after the completion of an active inflammatory reaction at the site of damage. For example, after a myocardial infarction, the restoration of dead muscle tissue of the heart does not occur, and a scar forms at the site of damage.
The foci of demyelination in MS appear to be seals that doctors first discovered in the 19th century in the brains of patients who died of MS. These foci were called "sclerosis", which in Greek means "scar." Now pathologists call them “plaques of multiple sclerosis”, and they are the most important sign of the disease. The size of the plaques varies from a few millimeters to several centimeters, and with the course of the disease, foci of demyelination can appear in all new places of the central nervous system - dissipate. That is why the disease is called "multiple sclerosis."
Risk Factors and Epidemiology
Most human diseases are considered complex, that is, developing due to the interaction of genetic, epigenetic and external factors. These diseases include MS. It occurs in people with a genetic predisposition as a result of exposure to environmental factors that trigger pathological mechanisms. A genetic predisposition is only 30% responsible for the risk of developing MS. The remaining 70% is related to the contribution of non-genetic factors. Below we find out what can affect the risk of developing MS, however, it is worth mentioning right away that it is impossible to predict the onset of the disease by these factors.
Genetics and Epigenetics
The most convincing role of heredity is shown in twin studies. If the disease is under genetic control, then MS should occur in identical twins (with a completely identical genome) more often than in opposite twins (with non-identical genomes). For identical twins, the likelihood of developing MS is 25%, and for twins it is only 5%. Family cases of MS are quite rare (on average about 5%), and the more distant relatives we consider, the lower the risk of the disease.
With the exception of family cases, MS is not inherited. With a probability of 98% in a child whose parent is ill with MS, the disease will NOT develop. However, a genetic predisposition to the disease is inherited: variants of genes (alleles) that determine a predisposition to MS can be passed from parents to children. The predisposition to MS consists of the effect of several genes, the contribution of each of which is small. In different patients, different combinations of genes may be responsible for the development of the disease. Thus, MS is a typical polygenic disease.
But in order for MS to develop, one genetic predisposition is not enough. It is necessary to influence other risk factors, which, in addition to environmental influences, include epigenetic regulation. Signals from the environment using epigenetic mechanisms (covalent modification of DNA and / or histones and the action of small regulatory RNAs) determine which genes will be active and which will not.
Genetic predisposition to multiple sclerosis: what are the chances of getting sick?
To search for susceptibility genes for MS, the genotypes of healthy people and patients are compared in the hope of noticing the difference in the frequency of any variant of the gene (allele) in the studied groups. If the difference is statistically significant, this allele is considered to be associated with the disease. So, back in the 1970s, it was revealed that the group of genes of the main histocompatibility complex (HLA genes of classes I and II) is associated with MS. These genes encode proteins that regulate the immune response, in particular by participating in the presentation of antigens to T-helpers. For most populations, one of the main risk alleles for MS is the * 1501 allele of the HLA-DRB1 gene.
To search for genes with weak contributions, research is needed on thousands of people. This circumstance led to the creation of international consortia for the study of predisposition to MS. With the improvement of technology, it became possible to search for predisposition genes throughout the genome (genome-wide association study, GWAS - genome-wide search for associations). As a result, about 100 genes associated with MS in Caucasians were found. Most of them are related to the functioning of the immune system. Only a few risk genes were common in different ethnic groups. In addition to the above HLA-DRB1, these are the genes IL7RA, IL2RA, CD40, CD6, CLEC16A, TNFRSF1A, IRF8 and some others. However, the carriage of unfavorable alleles of each of these genes increases the chances of getting sick no more than twice, which is very small. Thus, the search for susceptibility genes for MS does not greatly help predict the development of the disease, but it reveals its pathogenetic mechanisms and helps to search for new targets for the treatment of this disease. In addition, a study of the genetic predisposition to MS initiated work on the search for genetic markers for predicting the course of the disease and the effectiveness of its treatment.
It is interesting to note that approximately 30% of genes associated with the development of MS are also associated with other autoimmune diseases. For example, if you smoke, are a carrier of the Epstein-Barr virus (environmental factors) and at the same time have a certain set of alleles, then you may develop MS, however, if at least one of these conditions changes, another autoimmune disease may develop. But we do not yet understand the mechanisms of interaction of genetic and non-genetic factors responsible for the development of MS, the severity of its course and the response to treatment with immunomodulators. These questions, however, are true for almost any complex disease with a polygenic type of inheritance.
Age, gender and ethnicity
MS is a disease of young people. The peak incidence occurs in the most active period of human life - 20-40 years. However, the disease can develop even in children. As a rule, the later MS begins, the harder it is. Women get sick about three times more often than men, but men more often develop a more severe form of the disease.
An increased incidence among women is characteristic not only for MS, but also for some other autoimmune pathologies (for example, rheumatoid arthritis and systemic lupus erythematosus). It is believed that this is due to the influence of sex hormones, which, in addition to physiological and behavioral functions, also regulate the immune response. For example, in pregnant patients with MS, the condition improves significantly, but after childbirth the course of the disease worsens again, which may be associated with a drop in estrogen levels. Pregnancy is one of the strongest inducers of immunological tolerance, that is, the ability to “not notice” possible pathogens. Pregnancy hormones contribute to a sharp increase in the number of regulatory T and B lymphocytes, which weaken the development of the immune response and reduce the risk of maternal rejection of the fetus. These same cells form a temporary tolerance to their own antigens (autoantigens) in MS, weakening the manifestations of the disease.
MS is found in most ethnic groups: European, African, Asian, Latin American. The Eskimos, Hungarian Gypsies, Norwegian Sami, the indigenous people of North America, Australia and New Zealand and some others are practically not affected.
Territory of residence. In the world there are about 2.5 million patients with MS, of which, according to experts, approximately 200 thousand live in Russia. Most often, MS is found in residents of Northern Europe and Canada.
The frequency of MS increases with distance from the equator to the north. The farther the area is from the equator, the less it receives sunlight. Under the influence of ultraviolet radiation, vitamin D is synthesized in the skin, which then turns into its active form - calcitriol. This substance has hormonal activity and is involved in the formation of bone tissue, the regulation of cell division and differentiation of immune cells. Vitamin D deficiency affects the differentiation of regulatory T-lymphocytes that inhibit the immune response to autoantigens. But, although low levels of vitamin D increase the likelihood of developing MS, this does not mean at all that a constant intake of vitamin D will prevent the disease. However, in patients with MS who received this vitamin as a dietary supplement, the course of the disease was facilitated.
It has been established that the migration of people from one geographical area to another affects the risk of developing MS. Immigrants and their descendants, as a rule, “assume” the level of risk that is characteristic of a new place of residence, and if resettlement occurred in early childhood, a new risk makes itself felt immediately, and if it happened after a puberty period, the effect will manifest itself only in the next generation. It is believed that this effect is mediated by changes in hormone levels during puberty.
Infections. Infectious agents can also increase the risk of developing MS, especially some viruses: Epstein-Barr virus (herpes simplex virus (HSV) type 4), cytomegalovirus (HSV type 5), HSV type 6, and some retro- and poliomaviruses. Researchers pay special attention to the Epstein-Barr virus, which causes mononucleosis. In young children, this disease, as a rule, proceeds easily or even imperceptibly, at an older age, the clinical manifestations are nonspecific, and by the age of 40, 90% of people are already infected with this virus, but it was not necessary because of it. Once in the body, the virus remains there forever. One of the possible mechanisms of MS provocation is associated with the penetration of the virus into the central nervous system (in particular, into the brain), where it attacks the cells that produce myelin - oligodendrocytes. This can cause an immune response in which CD8 + T-lymphocytes, attacking the virus, at the same time damage oligodendrocytes and neurons with “friendly fire”. The point here may be in molecular mimicry - when the virus "fakes" under certain proteins of the body (for example, myelin). However, this theory is still considered controversial.
Intestinal microbiome. Despite the fact that the intestinal microbiome is not quite a factor in the external environment, we will consider it in this section, because a change in its composition due to external circumstances may be associated with the occurrence of autoimmunity. It is almost universally recognized that our intestinal microbiome is actively involved in the development of the immune system and maintaining its work. The bacteria that inhabit the intestines help immune cells recognize antigens and ignore autoantigens. Studies on model animals and humans have shown that sometimes, by fatal accident, antigens of the digestive tract microorganisms, which for immune cells serve as simulators for recognizing bacterial antigens, trigger the launch of autoimmune mechanisms and the progression of demyelination.
Other external risk factors are smoking and diet. Smoking increases both the risk of the disease and the rate of its progression, and a diet with a predominance of saturated / animal fats can increase the risk of MS. However, it is better to consider these results preliminary.
The pathogenesis of multiple sclerosis
What happens inside a patient with MS? This article will focus only on the remitting form of MS; in the case of progressive MS, the mechanisms are somewhat different. To better understand the molecular immunological details set forth below, we recommend that you first read the introductory article in this series: "Immunity: the fight against strangers and ... your own."
At what point does the disease begin? It turns out that despite the fact that the central nervous system is damaged primarily in MS, the start of autoimmune processes does not occur in it. The activation of autoreactive T and B lymphocytes occurs on the periphery - primarily in the lymph nodes.
Where do the autoreactive lymphocytes come from?
Auto-reactive lymphocytes have an increased autoimmune potential, that is, they are ready to "shoot at their own", destroying the cells of their own body. They are always present in the body of healthy people, but are under strict control of the immune system. The fact is that all T-lymphocytes undergo “training” in the thymus; an important part of this training is the so-called negative selection: immune cells that target autoantigens are simply destroyed. The meaning of this operation is precisely to prevent autoimmune reactions, but the imperfection of the learning mechanisms leads to the fact that some T-lymphocytes that recognize autoantigens nevertheless leave the thymus and can cause troubles.
Now let’s take a step-by-step look at the development mechanisms of MS.
Primary activation of lymphocytes
In order for autoreactive lymphocytes to reach the central nervous system, their activation outside the central nervous system must first occur. This will allow them to overcome the protective mechanisms of the brain. The signal for the primary activation of autoreactive cells is the presentation of antigen or autoantigen by antigen-presenting cells (APC). Autoreactive T- and B-lymphocytes can be activated by bacterial superantigens - substances that cause massive non-specific activation. T-lymphocytes can be activated by the mechanism of molecular mimicry, as well as by their own antigens, the immunogenicity of which is increased, for example, in chronic inflammation.
Activation of autoreactive T- and B-lymphocytes leads to the predominance of abnormal cells over populations of Treg and Th2 that maintain the immunological balance. Pathological cells create the "inflammatory background" necessary for the development of autoimmune damage, and themselves acquire the ability to perceive special signals that allow them to migrate to the central nervous system, where they can deliver their main blow.
Cancellation of privileges: how autoreactive lymphocytes penetrate the brain
Numerous experiments have shown that it is much more difficult to initiate an immune response in the central nervous system than in other body structures: the brain is called an immunologically privileged organ. The story with autoantigens of the nervous system is very interesting: during training in the thymus, T-lymphocytes simply do not meet with some of them (including myelin), which means that they do not learn to recognize (ignore) them. The body is so trying to prevent the development of an immune response in the brain. In addition, T-lymphocytes are not able to recognize autoantigens of a healthy central nervous system, since very few molecules of the main histocompatibility complex of types I and II are required for presentation in its cells. Another line of brain protection is the blood-brain barrier, which isolates the central nervous system from the bloodstream.
The vessels of the brain of healthy people are impervious to cells circulating in the blood. However, some immune cells are still able to cross the blood-brain barrier. Cerebrospinal fluid (cerebrospinal fluid) from the bloodstream separates the blood-brain barrier. T-lymphocytes within the framework of immunological surveillance "patrol" the cerebrospinal anatomical spaces of the brain and spinal cord. If everything is in order in the central nervous system, the cells go back into the bloodstream through the vascular plexus. It follows that the isolation of the central nervous system is not absolute.
The next (after the primary activation of autoreactive cells) key stage of MS development is an increase in the permeability of the blood-brain barrier. Under the influence of inflammatory cytokines produced by activated Th1 and Th17 cells, a whole series of fatal events occurs:
- various immune cells begin to produce chemokines (cytokines that regulate the migration of cells of the immune system) that “assemble” lymphocytes into the capillaries of the brain;
- endothelial cells produce more adhesion molecules on their surface, which leads to the "anchoring" of lymphocytes on the walls of blood vessels;
- developing inflammation enhances the synthesis of enzymes (matrix metalloproteinases), which disrupt tight contacts in the endothelium, as a result of which gaps appear in the blood-brain barrier that facilitate the mass migration of pathological cells from the vascular bed to the central nervous system.
Secondary Lymphocyte Activation
So, activated T- and B-lymphocytes specific for myelin components, breaking the blood-brain barrier, fall into the central nervous system, where their targets are represented in a large number. In the central nervous system, the axon myelin sheath is formed by a membrane of specialized cells - oligodendrocytes. Their processes are screwed onto the axon in a spiral like an insulating tape. From a chemical point of view, myelin is a complex of lipids (70–75%) with proteins (25–30%). And it is myelin proteins that become the main autoantigens in MS. Lymphocytes activated at the periphery continue to synthesize inflammatory cytokines, which, in turn, activate resident APCs - microglial cells and astrocytes, which present myelin autoantigens to T-helper cells in the central nervous system. This is a signal for repeated (secondary) activation.
Reactivated pathological cells continue to intensively produce inflammatory cytokines that spur the presentation of CNS autoantigens. In addition, activated macrophages synthesize a variety of neurotoxic compounds, and B-lymphocytes - antibodies to proteins and lipids of the myelin sheath that damage this membrane. At the same time, Treg and Th2 are trying to maintain immunological balance.
Neurodegeneration in the central nervous system
Neurodegeneration is the death of nerve cells, leading ultimately to a complete stop of the transmission of nerve impulses. In MS, it develops independently of autoimmune inflammation. So, neuroimaging (magnetic resonance imaging, MRI) captures the signs of neurodegeneration in the early stages of the disease.
There are several possible mechanisms leading to neurodegeneration in MS. One of them is excitotoxicity caused by glutamate, leading to the death of oligodendrocytes and neurons. Glutamate - the most important excitatory mediator of the central nervous system - is toxic in itself, and after it performs its function, it must be quickly removed. However, in MS, for various reasons, this does not happen. Moreover, activated T-lymphocytes themselves serve as a source of glutamate. It is not surprising that elevated levels are found in the brain of patients with MS.
Another mechanism is associated with the redistribution of ion channels and a change in their permeability in the axons of neurons, which leads to disruption of the ion balance, and ends with damage and death for the axon.
And finally, the cause of neurodegeneration may be a violation of the balance of remyelination factors (nerve growth factor and brain neurotrophic factor) necessary for the survival of oligodendrocytes and neurons.
The processes listed above can lead to neurodegeneration, due to which the transmission of a nerve impulse is disrupted and the symptomatology characteristic of MS develops.
So, the described series of pathological events leads to the formation on the nerve fibers of the sites of demyelination, death of oligodendrocytes and neurodegeneration. The rate of transmission of a nerve impulse from a neuron to a neuron decreases, as a result of which various body systems stop receiving signals from the brain, and symptoms of the disease occur.
Symptoms of Multiple Sclerosis and Diagnosis
How MS will manifest itself depends on the location and extent of damage to nerve fibers. Therefore, the symptoms of MS are neurological and non-specific. In other words, they are also characteristic of a number of other neurological pathologies, and therefore, do not point directly to MS. Sometimes patients retrospectively note the episode (s) of the appearance of certain symptoms several months / years before the first visit to a doctor. Some of these long-term symptoms at a young age are often attributed to fatigue, the effects of the common cold, etc. and are not taken seriously.
The main forms of multiple sclerosis
The very first neurological symptom caused by inflammation and demyelination in the central nervous system is called clinically isolated syndrome (CIS). This condition lasts at least 24 hours and includes one or more neurological symptoms characteristic of MS. The emergence of CIS increases the risk of developing MS.
Most patients (80–85%) develop a remitting form of MS, which is characterized by long-term remissions (for years, and sometimes decades), with disability increasing slowly and gradually. Later, with the transition of remitting MS to a secondary progressive form, disability increases continuously, but with remission. In 10-15% of patients, from the very beginning of the disease, their primary progressive form develops with a rapid and continuous increase in disability.
The diagnosis of multiple sclerosis must be proven. None of the symptoms, indicators of a physical examination or laboratory tests alone confirm the presence of MS in a person. In patients with CIS, the doctor can only suspect MS. The main tool for diagnosis is neuroimaging. If in the brain of a patient with CIS there are foci of demyelination (according to MRI), such a patient has a high chance of experiencing a second episode of neurological symptoms, followed by a diagnosis of "reliable multiple sclerosis." If there are no plaques in the images of a patient with CIS, then the likelihood of developing MS is low. For the diagnosis of "reliable multiple sclerosis" the doctor must simultaneously:
- find signs of demyelination in at least two different areas of the central nervous system (scattering in space);
- show that plaques appeared with a time difference;
- exclude all other possible diagnoses.
Thus, the main criterion of reliable MS is the scattering of foci of demyelination in space and time. After identifying the first lesion on the tomogram, the following images are taken at intervals of 6 months until the second lesion appears and only then the final diagnosis is made. According to retrospective estimates, almost 50% of patients have been ill for at least five years at the time of diagnosis.
The methods that clarify the diagnosis include analysis of evoked potentials and analysis of cerebrospinal fluid. In the analysis of evoked potentials, the electrical activity of the brain is measured in response to sound, light or tactile stimulation of specific sensory nerve pathways. This allows you to detect a slowdown in the conduct of a nerve impulse caused by demyelination. Since an accurate diagnosis requires proving the fact of demyelination in two different areas of the central nervous system, the analysis of evoked potentials can help to identify a new focus of demyelination, which has not yet been clinically manifested.
As for the cerebrospinal fluid, a fluid washing the brain and spinal cord, oligoclonal immunoglobulin IgG and some other proteins, the products of myelin breakdown, are often found in patients with MS. This may indicate autoimmune inflammation in the central nervous system, however, a positive result is also characteristic of a number of other central nervous system diseases. Thus, studies of evoked potentials and cerebrospinal fluid alone cannot confirm or exclude the diagnosis of MS, but are useful as links in the overall diagnostic chain.
Multiple Sclerosis Treatment
Drugs that change the course of multiple sclerosis
Multiple sclerosis requires lifelong treatment. If earlier it all came down to symptomatic therapy and attempts to suppress exacerbations of the disease, in the last 20 years, thanks to the accumulated knowledge about the mechanisms of the development of the disease, drugs have appeared that change the course of multiple sclerosis (they are called disease modifying treatments in English literature). All drugs that change the course of multiple sclerosis reduce the activity of autoimmune inflammation and slow down neurodegeneration; their action is aimed at the formation of stable and long-term remission in patients. Immediate prescription of drugs that change the course of multiple sclerosis immediately after diagnosis increases the chances of successful treatment.
Currently, more than 10 drugs that alter the course of multiple sclerosis are approved for the treatment of MS in the world. All of them with varying degrees of effectiveness and risk of side effects are used to treat the remitting form of MS, some for the treatment of the secondary progressive form. In March 2017, the U.S. Food and Drug Administration (FDA) approved the first drug for the treatment of primary progressive MS - ocrelizumab, whose effectiveness has been confirmed by clinical trials.
The safest drugs for treating MS remain interferon-β (IFN-β) and glatiramer acetate, although their effectiveness varies greatly in different patients. New drugs are more effective, but the more effective the drug, the higher the likelihood of side effects and the development of complications.
Drugs that change the course of multiple sclerosis
All drugs that change the course of multiple sclerosis can be divided into four groups (the drugs approved for the treatment of MS in the Russian Federation are marked with an asterisk):
- Immunomodulatory drugs: IFN-β * (Betaferon ™, Rebif ™, Avonex ™, Extavia ™, Infibeta ™ and others), glatiramer acetate * (Copaxone ™), teriflunomide * (Abaggio ™) and dimethyl fumarate * (Tekfidera ™). Suppress the proliferation and activation of autoreactive T-lymphocytes, as well as the migration of activated T- and B-cells through the blood-brain barrier in the central nervous system; shift the cytokine balance towards a decrease in the synthesis of inflammatory cytokines and an increase in anti-inflammatory. In addition, IFN-β and glatiramer acetate have a neuroprotective effect in the central nervous system, affecting the synthesis of neurotrophic factors that determine the growth and differentiation of neurons and oligodendrocytes.
- Drugs with a selective mechanism of action - fingolimod * (Gilenia ™). Fingolimod modulates sphingosine phosphate receptors on the surface of lymphocytes; binding to these receptors, it blocks the ability of lymphocytes to leave the lymph nodes. This leads to the redistribution of lymphocytes in the body while maintaining their total number. Delay in the lymph nodes makes it difficult to migrate autoreactive cells to the central nervous system, which leads to a decrease in inflammation and damage to the nervous tissue.
- Drugs with a selective mechanism of action are humanized monoclonal antibodies: natalizumab * (Tisabri ™), daclizumab (Zinbrita ™), alemtuzumab (Lemtrad ™) and okrelizumab.
- Natalizumab is a preparation based on humanized (containing fragments of human immunoglobulin) monoclonal antibodies to α4β1 integrin. By binding to an integrin molecule on activated immune cells, natalizumab does not allow the integrin to interact with its receptors - adhesion molecules on the surface of the cells of the vascular wall. This prevents the penetration of pathological autoreactive cells through the blood-brain barrier into the central nervous system to the site of inflammation, resulting in a reduced rate of demyelination.
- Daclizumab is a drug based on humanized monoclonal antibodies to the surface antigen CD25, which is located on activated T and B lymphocytes and is part of the IL-2 receptor. Since IL-2 is necessary for the activation of T-lymphocytes, daclizumab, “occupying” the IL-2 receptor, blocks this activation. At the same time, daclizumab activates natural killers containing the antigen CD56 on the membrane. These cells are involved in the elimination of previously activated autoreactive CD25 + T lymphocytes. Thus, daclizumab suppresses and prevents autoimmune inflammation.
- Alemtuzumab is a drug based on humanized monoclonal antibodies to the CD52 surface antigen located on the membrane of mature T and B lymphocytes, monocytes and dendritic cells, but not their predecessors. The use of alemtuzumab dramatically reduces the number of activated CD52 + cells, which leads to a decrease in MS activity, because updating the pool of T and B lymphocytes takes some time. Interestingly, there is very little CD52 on the Treg membrane, so they remain intact. This allows you to maintain the immune system in a balanced state when the restoration of the population of “pathogenic” Th1 and Th17 begins.
- Okrelizumab is a drug based on humanized monoclonal antibodies to the surface antigen CD20, located on the membrane of mature B-lymphocytes, but not stem or plasma cells. Okrelizumab, binding to its target, contributes to the destruction of B-lymphocytes, which prevents their entry into the central nervous system.
- Immunosuppressants: mitoxantrone * (Novantron ™). This antitumor drug (cytostatic) inhibits the proliferation of T and B lymphocytes and macrophages, and also prevents the presentation of antigens. Mitoxantrone is effective against secondary progressive MS, but is rarely used now because of serious hematological and cardiological side effects.
New drugs for treating multiple sclerosis
Russian researchers led by Academician of the Russian Academy of Sciences Alexander Gabibovich Gabibov from the Institute of Bioorganic Chemistry named after Academicians M.M. Shemyakina and Yu.A. Ovchinnikov is now developing a new medicine for the treatment of MS, which has already passed two phases of clinical trials. The drug was created using liposomes - artificial lipid vesicles containing specially selected myelin fragments (peptides) and targeted delivery of these fragments to antigen-presenting cells. Apparently, the presentation of peptides from liposomes activates regulatory cells that can suppress autoimmune inflammation in the central nervous system. In the second phase of clinical trials, a new experimental drug was administered to patients with remitting and secondary progressive MS who did not benefit from first-line therapy. As a result, stabilization of the patients' condition, good tolerance and safety of the drug were recorded. These promising results allow us to hope that a new treatment for MS will be approved in Russia.
Another approach under development is aimed at the active restoration of damaged myelin in the central nervous system. On the surface of oligodendrocytes there is a protein LINGO-1, which blocks the ability of these cells to differentiate and myelinate axons. Studies in model animals have shown that monoclonal antibodies block LINGO-1 and thus provide myelin repair. In the first phase of clinical trials, the efficacy, safety and good tolerance of the drug are shown. Another way to recover myelin in MS is to activate the signaling pathways that trigger its synthesis. Ensuring adequate remyelination is likely to become part of the arsenal of MS therapy in the future.
Another candidate for the role of the drug is biotin (vitamin H), high doses of which, as shown by clinical trials, reduce the rate of development of MS. The fact is that this substance is involved in the regulation of energy metabolism and lipid synthesis, necessary for the production of myelin by oligodendrocytes. However, earlier studies in animal models reported a possible teratogenic effect of biotin, so its fate as a medicine for MS has not yet been determined.
Stem Cell Treatment for Multiple Sclerosis
Autologous hematopoietic stem cell transplantation
One of the promising approaches to the treatment of MS is considered to be a "reset" of the immune system. The idea is based on the fact that the changes leading to the appearance of pathological lymphocytes that provoke MS do not occur at the level of stem cells, but much later, during their differentiation. This means that if you "restart" the process, destroying dangerous lymphocytes and allowing the immune system to restore its cells again, then serious improvements can be achieved.
Unfortunately, it is impossible to influence the pathological changes that have already occurred in the patient with MS, but there is a chance to slow down or stop the demyelination process. However, restarting the immune system is quite dangerous, as it requires the introduction of potentially deadly toxic substances that destroy all immune cells. After this, the patient undergoes transplantation of their own previously obtained hematopoietic stem cells (giving rise to blood cells). This should lead to a complete renewal of the pool of myeloid and lymphoid cells and reconfiguration of immunological tolerance.
This approach, called autologous hematopoietic stem cell transplantation, was originally developed by hematologists for the treatment of leukemia, but has long been investigated in relation to MS. So far, autologous hematopoietic stem cell transplantation is considered a kind of last resort for patients with rapidly progressing and non-responsive MS therapy. All tests involving MS patients were carried out in small groups, which does not allow us to draw final conclusions about the effectiveness of the method. Indeed, it happens that the successful results obtained in studies on a small sample of patients are not confirmed in large groups. Unfortunately, the number of cases of successful restoration of body functions in patients with MS after autologous hematopoietic stem cell transplantation is negligible compared to examples of ineffective or complicated treatment. This, however, does not prevent clinics with a dubious scientific base and doctors with low qualifications now offering patients with MS treatment with autologous hematopoietic stem cell transplantation.
Clinical studies of autologous hematopoietic stem cell transplantation are ongoing, and great progress has been made in the last decade in reducing the risks associated with this procedure. After the completion of randomized controlled clinical trials, it will be possible to finally judge which patients this method is indicated for. According to experts, an assessment of the benefits and risks of autologous hematopoietic stem cell transplantation, coupled with the availability of effective monoclonal antibody preparations that can control the disease in patients with severe MS, is likely to leave this technology that has not yet been fully developed as a backup method for treating MS.
The use of induced pluripotent stem cells to restore the structures of the central nervous system
Other promising developments for the treatment of MS are based on the use of induced pluripotent stem cells to replace dead oligodendrocytes and neurons. Induced pluripotent stem cells capable of being transformed into different types of cells can be obtained by reprogramming, for example, patient’s skin cells. These studies are just beginning. So, recently, experiments on the transplantation of stem cells obtained from the skin of patients with MS into the brain of mice, where they turned into effective producers of myelin, have been successfully completed. In another study, mouse skin stem cells were reprogrammed into neural stem cells and then transplanted into the spinal cord of animals with demyelination. As a result, the condition of the animals improved. Apparently, transplanted cells secrete substances that stimulate the processes of central nervous system repair. Manipulations with stem cells are still at the stage of detailed study and are far from being introduced into routine clinical practice.
Over the past 20 years, tremendous success has been achieved in the treatment of MS. Today, one way or another, all drugs that change the course of multiple sclerosis from the arsenal of neurologists are aimed primarily at suppressing autoimmune inflammation. In the near future, approval is expected for the use in clinical practice of the first drug for the treatment of primary progressive MS. Thanks to cellular technologies, very good results have been achieved in restoring lost functions in patients with MS. However, these cases can still be called isolated, and the risk of side effects is still very high.
Can the course of multiple sclerosis and the effectiveness of its treatment be predicted?
The issue of personalizing MS treatment is very acute. The course of the disease cannot be predicted based on the clinical manifestations of MS. This complicates the choice of tactics for conducting a particular patient and creates an additional psychological burden for the latter. There are genetic differences between different forms of MS, and several genetic markers have been found to predict how difficult MS will be, but, alas, only within individual ethnic groups. So far, most of these studies in the world have not been successful.
In addition, in different patients, the response to treatment with drugs that change the course of multiple sclerosis can vary: the effectiveness can be both high and invisible at all. The fact is that the physiological processes responsible for the metabolism of drugs are under strict genetic control. A science that studies the relationship of genetic variants with differences in these processes is called pharmacogenetics. Pharmacogenetic studies are carried out in order to select the most effective drug for him based on the genotype of a particular patient. Similar studies in relation to MS have been carried out with some success since 2001. Several genetic markers of the effectiveness of treatment with IFN-β and glatiramer acetate were found, but they differ for different ethnic groups. For example, for the “Russian” population — patients of Slavic origin who consider themselves and their closest relatives to be Russians — a complex marker has been found (a specific set of alleles of the immune response genes), whose carriers will be most likely effective for IFN-β treatment. A marker has also been found associated with the low effectiveness of glatiramer acetate - these patients are most likely indicated for the appointment of an alternative drug.
Research on the search for universal genetic markers for predicting the course and treatment of MS is being led by professors Olga Olegovna Favorova and Alexei Nikolayevich Boyko from the Russian National Research Medical University named after N.I. Pirogov. The continuation of such studies (especially taking into account the emergence of new drugs) involving thousands of patients from various ethnic groups can lead to the creation of prognostic tests. This would allow the doctor to be on the alert and determine in advance the tactics of maintaining a particular patient.
The clinical manifestations of the disease are far from the only thing the patient has to deal with. It is always also fear, loneliness, a feeling of alienation and isolation. The activities of patient organizations are necessary to provide information support, protect the rights and interests of patients, solve problems with treatment and social rehabilitation of patients and their families. The All-Russian Public Organization of Disabled Persons with Multiple Sclerosis is the largest Russian patient organization for people with MS. She calls her main goal the creation of conditions for improving the quality of life of citizens of the Russian Federation with MS. Indeed, the organization regularly publishes photo reports on social events in different cities of Russia on its website and raises important questions regarding the quality of life of MS patients: there you can find, for example, an appeal to the Minister of Health asking him to include dimethyl fumarate in the list of essential medicines.
On the information portal about multiple sclerosis, created with the support of the pharmaceutical company Teva (manufacturer of glatiramer acetate), you can leave a request for psychological support by phone and written advice from a qualified lawyer. The site has information on rehabilitation opportunities, interviews and personal stories of patients with MS, news about cultural events in Moscow.
The Moscow Society of Multiple Sclerosis recently launched a free rehabilitation program for patients with MS. Regular group yoga and physiotherapy exercises are organized according to specially developed techniques. In addition, with the support of Teva, an Accessibility Map was created for Moscow medical, social, sports, cultural and recreational facilities equipped for people with reduced mobility.
Unfortunately, there are very few materials on the websites of Russian patient organizations that would allow a patient with MS to find out relevant information about his disease: the causes of its development, diagnosis, and modern treatment methods. On foreign patient portals, such information is presented in an accessible language and is very well systematized; sections on scientific research in the field of MS are constantly updated there. Information on the current clinical trials of new drugs and the possibility of registering to participate in them are often found on the sites of patient organizations in different countries. The following are the main English-language organizations of patients with MS:
- UK: Multiple Sclerosis Society of Great Britain, Multiple sclerosis trust;
- Australia: National Multiple Sclerosis Society of Australia;
- Canada: Multiple Sclerosis Society of Canada;
- USA: National multiple sclerosis society, Multiple Sclerosis Association of America;
- New Zealand: Multiple sclerosis. Society of New Zealand.
Now, most patients with MS, subject to timely and correctly selected treatment, can live a full life. People, being almost anywhere in the world, every day remain in contact with each other, find each other support and understanding. Irina Yasina’s Facebook page is updated almost every day. One can only admire how active the author leads his life, talking about travels, impressions, sharing the perception of various events, while remaining open to his audience, and sometimes supporting her. The decision about how to use our own opportunities and participate in society, whether to be happy and free, always depends only on ourselves.