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The article presents the results of the discussion of the use of anti-B-cell therapy in multiple sclerosis (MS). These cells play a significant role in immunoregulation in MS, not only by producing antibodies to myelin antigens after transformation into plasma cells, but also by presenting the antigen to T cells, producing activation cytokines, and forming laminar follicles. The article provides an expert consensus statement on different drugs of this class in the MS treatment. In addition, the possibilities of determining the disease prognosis for the initially correct treatment choice are highlighted. Undoubtedly, there is a need for confirmation of the MS diagnosis, possible stratification of patients into different risk groups, and evaluation of the response to therapy. Potential additional research methods included evoked potentials and optical coherence tomography, baseline vitamin D3 level as a prognostic marker of the disease course, neurofilament levels in serum and cerebrospinal fluid to confirm neuron damage. However, it takes much time to study, determine the methodology, reference values, and develop a single standard approach to identify and implement a biomarker, which should then be implemented in routine clinical practice.

The process of neurodegeneration in multiple sclerosis (MS) remains an urgent problem of modern neurology; from the point of view of its therapy, it is especially important to identify this condition during the transition to secondary progression. This paper reflects the opinion of the Council of Leading MS Experts on the early detection of secondary progressive MS and its diagnostic tools, including the use of new online questionnaires. Special attention is paid to the concept of clinical progression verification using the indicator of the confirmed progression of disability and to the prospect for introducing siponimod (Kiendra® ) into clinical practice for the treatment of patients with secondary progressive MS.

The results of recent studies indicate that the hyperactivation of the glutamatergic system plays an important role in the pathophysiology of multiple sclerosis (MS). In addition to the well-known direct toxic effect of the excessive extracellular level of the glutamate neurotransmitter on neurons, additional mechanisms of glutamate-induced cell damage have been described in the literature, including effects on oligodendrocytes, astrocytes, endothelial cells and immune cells. The study of these toxic effects will reveal the possible link between various pathological hallmarks of MS, such as axonal damage, oligodendrocyte death, demyelination, neurodegeneration, autoimmune reactions and dysfunction of blood-brain barrier. Understanding the mechanisms underlying the glutamate toxicity will contribute to the development of new therapeutic approaches for the diagnosis and treatment of patients with MS. This review focuses on the mechanisms that lead to an increase in the concentration of neurotransmitter glutamate and excitotoxicity in the context of the pathogenesis of this disease. Also the authors present the data on existing and currently developed medicines and therapeutic approaches to regulate the activity of the glutamatergic system.Результаты исследований последних лет свидетельствуют о том, что гиперактивация глутаматергической системы играет важную роль в патофизиологии рассеянного склероза (РС). Помимо хорошо известных непосредственных токсических эффектов нейромедиатора глутамата на нейроны описаны дополнительные механизмы глутамат-индуцированного клеточного повреждения, включая воздействие на олигодендроциты, астроциты, эндотелиальные и иммунные клетки. Эти токсические эффекты могут раскрыть связь между различными патологическими звеньями РС, такими как аксональное повреждение, гибель олигодендроцитов, демиелинизация, аутоиммунные реакции, дисфункция гематоэнцефалического барьера. Понимание механизмов, лежащих в основе глутаматной токсичности при РС, может способствовать разработке новых подходов для диагностики, лечения и ведения пациентов с РС. В обзоре приводятся сведения о механизмах, приводящих к повышению концентрации нейромедиатора глутамата и эксайтотоксичности, в контексте патогенеза заболевания. Также приводятся данные о существующих и разрабатываемых в настоящее время лекарственных препаратах и терапевтических подходах, способных регулировать работу глутаматергической системы.

The study objective was to analyze the results of 20 years of clinical follow-up and genetic study of 247 patients with multiple sclerosis (MS) registered at the Republican MS Centre. Material and methods. The study comprised unrelated patients with a verified diagnosis of MS included in the register of the Republican MS Center, and age-, gender-, and ethnicity-matched controls. DNA was isolated from whole venous blood by phenol-chloroform extraction. Genotyping was performed by PCR and PCR-RFLP methods. Quantitative variables were assessed using the non-parametric Mann — Whitney test (U-test); the exact two-sided Fisher’s test was applied to compare the distribution of genotypes and alleles frequencies in the groups of patients and controls. Differences were considered statistically significant at p < 0,05. Results. The group of 247 patients enrolled in the clinical genetic study in 2000 included 123 (49,8%) Russians, 98 (39,7%) Tatars, and 26 (10,5%) Bashkirs. The ratio of women to men was 2:1 (166:81). A polysymptomatic debut with a predominance of motor disorders was more often observed in the Bashkir group compared with others. At the time of inclusion in the study, the rate of progression in the Bashkir group was statistically significantly higher than in the Russian group, and non-significantly higher than in the Tatars group. Over a 20-year follow-up period, the rate of progression slowed in all groups. With the advent of magnetic resonance imaging in the region, the time to establish a verified diagnosis of MS has significantly decreased (p = 0,001). An increase in disability was not recorded during the observation period in 46 patients, 43 of them were taking disease modifying drugs. In a clinical genetic study, ethnospecific associations between MS and the polymorphismsin TNF and IL1B genes was revealed. Conclusion. The findings of the study emphasize the need for the continued follow-up and more in-depth investigation of the regional characteristics of MS, course variants and risk factors for the development of the disease.

Multiple sclerosis is a chronic autoimmune inflammatory and neurodegenerative disease leading to demyelination of nerve cells in the brain and the spinal cord. Despite extensive research, the pathogenesis of this disease is not fully understood. A review of most recent experimental studies shows that epigenetic mechanisms regulating gene expression, such as DNA methylation, histone acetylation, and microRNAs, play the crucial role in the pathogenesis of multiple sclerosis. Analysis of the published data suggests that multiple sclerosis develops as a result of abnormal regulation of gene expression in the nervous and immune systems.

The purpose — to explore prevalence and clinical particularities of the pediatric multiple sclerosis in Bashkortostan Republic. Material and methods. The data of 21 children with multiple sclerosis were analyzed. The data were provided by the Republican Centre of the multiple sclerosis (Ufa) and outpatient records of the Kuvatov’s Republican Clinical Hospital (Ufa). All children were examined out patiently at the Neurology Department at the Republican Children’s Clinical Hospital (Ufa) and the polyclinics of the Republican Clinical Hospital (Ufa). Diagnosis «multiple sclerosis» (MS) was issued by McDonald criteria (2017). Results. MS affects female children more often. City residents are hit much more frequently. The onset occurs among senior schoolchildren in most cases. Most of the patients have remitting course of MS. Conclusion. The main epidemiological indicators of childhood onset MS in the Republic of Bashkortostan are comparable to those in neighboring regions of Russia, and the observed changes reflect the global trends. The study confirmed the findings of other authors on the main characteristics of childhood MS. Pediatric patients require a specialized approach to the diagnosis and careful monitoring of neurological symptoms in order to timely identify multiple sclerosis.

Multiple sclerosis (MS) is regarded as multifactorial, polygenic disease; its development is the result of autoimmune and neurodegenerative processes which lead to multifocal lesions of the central nervous system. The aim of the study was to analyze associations between MS and polymorphic markers rs3129934 (C6orf10), rs1109670 (DDEF2/MBOAT2 gene), rs9523762 (GPC5 gene), rs28362491 (NFKB1 gene), rs10974944 (JAK2 gene), and rs2304256 (TYK2 gene). The material for the study was DNA samples of unrelated MS patients (N = 224) aged 17 to 67 years and individuals of a control group (N = 312) aged 18 to 66 years. Both samples were formed from the ethnic group of Russians. The results of the investigation demonstrated that, for women, MS was associated with genotypes rs3129934*C/T (p = 0.001, OR = 2.23), rs3129934*T/T (p = 0.028, OR = 4.04), and rs2304256*C/C (p = 0.049, OR = 1.6); for men, with genotype rs1109670*C/A (p = 0.017, OR = 2.06). In addition, using the APSampler algorithm, we identified combinations of alleles associated with increased risk of MS separately for women and men, in which the most frequent alleles of polymorphic markers were rs3129934*T, rs1109670*C, rs10974944*G, and rs2304256*C.

Using flow cytometry and real-time RT-PCR, we studied the effect of the blockade of glutamate NMDA receptors on the quantitative distribution of IFNγ- and IL-4-producing CD4+ and CD8+ T-lymphocytes and the expression of transcription factor of genes T-bet and GATA-3 in immune cells derived from healthy individuals and multiple sclerosis patients (MS). From the results of the study, it follows that blockade of NMDA receptors leads to a decrease in the proportion of studied effector subpopulations of T-lymphocytes, as well as differential modulation of gene expression of transcription factors (TBX21, GATA3). The severity of the negative effect of receptor blockade differs in different subpopulations of CD4+ and CD8+ T cells, which leads to a shift in the cytokine balance towards “proinflammatory” type 1 T-cells, to a greater extent in patients with MS. Thus, glutamate can regulate the Th1/Th2 and Tc1/Tc2 сytokine balance by modulating the activity of NMDA receptors of T lymphocytes in MS.

The analysis of the structure and dynamics of total disability due to multiple sclerosis in the city of Ufa from 2010 to 2016 years. 256(48,5%) patients including 72% out of them of working age have the persistent disability. The majority of persons with disabilities (57%) have secondary-progressive course of the disease. The average age of persons with disabilities due to multiple sclerosis accounted of 47.3 ± 11.6 years, the average score on the EDSS of persons with disabilities was 5.3 ± 1.3 points, the average duration of the disease before the appearance of signs of persistent disability accounts of 9.8 ± 8.2 years. Economic losses due to disability from multiple sclerosis in Ufa amounted to 3 543 493 849,15 RUB.

There was performed the analysis of the primary disability of multiple sclerosis in a large industrial city of Ufa during the period of 2010-2016. There was noted the decline in levels of the disability from 0.23 in 2010 to 0,14 per 10,000 in 2016, the prevalence in the structure of disability in young and middle-aged, persons with the third disability group. During the first 5 years from the onset of the disease 36,8% of patients have signs of the permanent disability, after 10 years 62% of cases show signs of the permanent disability. The majority of the disability have secondary progressive and remission-progressive type of the disease.

To study the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis (SPMS) in the Russian population of the EXPAND study.Ninety-four patients with SPMS from Russia were included in the analysis. Sixty-three patients received siponimod and 31 patients received placebo. The primary endpoint of the study was time to 3-month confirmed disability progression (3m-CDP) events, other clinical and radiological endpoints were also evaluated.The siponimod group showed a 54% reduction in the risk of 3m-CDP compared with the placebo group (p=0.0334). Secondary endpoints also showed the advantage of the drug over placebo. In the siponimod group, mild adverse events associated with impaired liver function, as well as arterial hypertension, were more common. No patient left the study due to an adverse event.The use of siponimod in patients with SPMS in the Russian population reduced the risk of disability progression. Siponimod showed a favorable safety profile.Цель исследования. Изучить эффективность и безопасность применения сипонимода у пациентов с вторично-прогрессирующим рассеянным склерозом (ВПРС) в российской популяции в рамках исследования EXPAND. Материал и методы. В исследовании EXPAND были обследованы 94 пациента с ВПРС из России, из которых 63 получали сипонимод, 31 - плацебо. Первичной конечной точкой исследования было время до прогрессирования инвалидизации, подтвержденного в течение 3 мес (3м-ППИ), оценивались также другие клинические и радиологические параметры. Результаты. Группа получавших сипонимод продемонстрировала снижение риска 3м-ППИ на 54% по сравнению с группой, получавшей плацебо (р=0,0334). По вторичным конечным точкам также было показано преимущество препарата перед плацебо. В группе сипонимода чаще встречались нетяжелые нежелательные явления, связанные с нарушением функции печени, а также артериальная гипертензия. Ни один пациент не завершил участия в исследовании по причине нежелательного явления. Вывод. Применение сипонимода у пациентов с ВПРС в российской популяции снизило риск прогрессирования инвалидизации. Сипонимод продемонстрировал благоприятный профиль безопасности.

Modern multiple sclerosis therapy with disease-modifying drugs is characterized by the risks of dangerous infectious complications. In the last 5 years, there have been several reports of severe, sometimes lethal, listeriosis infection in patients treated with alemtuzumab. This article presents a clinical case of lethal listeriosis meningoencephalitis, which developed within 7 days after the completion of the first cycle of alemtuzumab therapy. In January 2018, a meeting of the expert Council was held, at which the clinical recommendations published in 2017 were revised and updated.Современная терапия препаратами, изменяющими течение рассеянного склероза, характеризуется рисками опасных инфекционных осложнений. В последние 5 лет появились сообщения о развитии тяжелой, иногда летальной, листериозной инфекции у пациентов, получавших терапию алемтузумабом. Представлен клинический случай летального листериозного менингоэнцефалита, возникшего через 7 сут после завершения первого цикла терапии алемтузумабом. В январе 2018 г. прошло заседание Экспертного совета, на котором были пересмотрены и обновлены клинические рекомендации, опубликованные в 2017 г.

Aim of study. To study chemotactic properties of glutamate and glutamate receptor agonists on T cells migration from healthy donors and patients with multiple sclerosis (MS) in vitro. Materials and methods. T cell migration of 15 patients with MS and 15 healthy donors was studied in vitro using transwells. Lymphocytes were activated with PMA (10 ng/mL). T cells were added to transwells with fibronectin (10 μg/mL) pretreated membrane. The lower chamber contained glutamate or AMPA or NMDA (100 μM for each) in complete RPMI medium. Migrated cells were collected and stained with antibodies to CD3-marker for subsequent analysis by cytofluorimetry. Results and conclusion. In presence of glutamate, there is a tendency to a decrease in migration activity in both groups of donors. T-cell chemotaxis of healthy donors, but not MS patients, decreased in concentration gradient of NMDA. The activation of lymphocytes with PMA leads to a decrease in the number of migrated cells by an average of 17% (p < 0.01). In MS patients there is a tendency to an increase in chemotaxis of activated cells in concentration gradient of glutamate, and a decrease with AMPA. Thus, glutamate and glutamate receptors agonists do not possess pronounced chemotactic properties, but rather enhance T-cell migration through synthesis of adhesion molecules on the surface of lymphocytes and endothelium.

Alemtuzumab (Lemtrada) is a recombinant humanized IgG1 kappa monoclonal antibody to the surface cell glycoprotein, a CD52 differentiation cluster. The drug is approved for use in more than 65 countries, including the Russian Federation. The drug is one of the most effective methods of treating patients with aggressive multiple sclerosis, but the risk management plan should be followed. The safety profile of the drug includes infusion-associated reactions, thyroid dysfunction, immune cytopenia, acute cardiovascular events, infections, and other autoimmune diseases. This publication provides updated practical recommendations for the use of the drug and ensuring the safety of patients treated with alemtuzumab.Алемтузумаб (Лемтрада) — рекомбинантное гуманизированное IgG1 каппа моноклональное антитело к поверхностному клеточному гликопротеину, кластеру дифференцировки CD52. Препарат разрешен к применению в более чем 65 странах мира, включая Российскую Федерацию. Препарат является одним из наиболее эффективных методов лечения пациентов с агрессивным течением рассеянного склероза, но при его применении необходимо тщательное соблюдение плана управления рисками. Профиль безопасности препарата включает инфузионные реакции, дисфункцию щитовидной железы, иммунные цитопении, острые сердечно-сосудистые состояния, инфекции и другие аутоиммунные заболевания. В данной публикации представлены обновленные практические рекомендации по применению препарата и обеспечению безопасности пациентов, получающих терапию алемтузумабом.

To evaluate the efficacy and safety of BCD 054 180 μg and 240 μg administered once every 2 weeks for the treatment of remitting multiple sclerosis compared to placebo and low dose interferon beta-1a (LIB) 30 μg administered once weekly. Results of a 20 week blinded interim analysis from a double blind, comparative, randomised, placebo-controlled clinical study are included.This multinational, multicentre, double blind, comparative, placebo-controlled study enrolled 399 patients with the diagnosis of remitting multiple sclerosis: 114 patients in the sampeginterferon beta 1a and LIB groups each and 57 patients in the placebo group. To ensure the objectivity of data, the study protocol includes a blinded interim analysis to demonstrate the superiority of BCD 054 over placebo based on the number of combined unique active lesions (CUA) on MRI scans after 20 weeks of treatment.An integrated analysis of the efficacy, safety, pharmacokinetics, and pharmacodynamics was performed after 20 weeks of study. Mean CUA per scan was lower in the active treatment groups compared to placebo: 0,986±2,046, 0,619±1,055, 0,665±1,165, 1,673±2,376 (groups 1, 2, 3 and placebo group, respectively). The data for CUA per scan demonstrated the superiority of both BCD 054 180 μg and 240 μg over placebo. Patients receiving active treatment had fewer new and/or enlarging lesions after 20 weeks of treatment. The proportion of patients without new T2-weighted lesions was 74,3%, 86,7%, and 78,1% in groups 1, 2, and 3 compared to 64,9% in the placebo group. Manifestations of flu-like syndrome that is expected for interferon treatment were observed with the same incidence in all the active treatment groups. Its severity, duration or the need for symptomatic treatment did not appear to depend on the type of interferon used.Цель исследования. Изучение эффективности и безопасности применения препарата BCD-054 в дозах 180 и 240 мкг (1 раз в 2 нед) для лечения ремиттирующего рассеянного склероза (РРС) в сравнении с плацебо и препаратом низкодозного интерферона β (НИБ) 30 мкг (внутримышечно, 1 раз в нед). Приводятся результаты 20-недельного заслепленного промежуточного анализа двойного слепого сравнительного рандомизированного плацебо-контролируемого клинического исследования. Материал и методы. В международном многоцентровом слепом сравнительном плацебо-контролируемом исследовании принимали участие 399 пациентов с РРС, рандомизированных в четыре группы: по 114 пациентов в группы сампэгинтерферона β-1а в дозах 180 и 240 мкг, НИБ и 57 - в группу плацебо. С целью объективизации полученных данных протоколом исследования было предусмотрено проведение промежуточного слепого анализа для доказательства превосходства BCD-054 над плацебо по показателю, отражающему совокупную оценку новых и увеличившихся очагов на МРТ после 20 нед терапии (combined unique activelesions - CUA). Результаты и заключение. Через 20 нед исследования был выполнен комплексный анализ показателей эффективности, безопасности, фармакокинетики и фармакодинамики. Средние значения показателя CUA per scan были ниже в группах пациентов, получающих терапию активными препаратами по сравнению с плацебо: 0,986±2,046, 0,619±1,055, 0,665±1,165, 1,673±2,376 (1, 2, 3-я и плацебо соответственно). Полученные данные по CUA per scan показали превосходство препарата BCD-054 как в дозе 180 мкг, так и 240 мкг над плацебо. У пациентов, принимающих терапию активными препаратами, реже определялись новые и/или увеличившиеся очаги через 20 нед терапии. Доля пациентов без новых очагов в Т2-режиме составила 74,3, 86,7, 78,1% - в группах 1-3 против 64,9% - в группе плацебо. Проявления гриппоподобного синдрома, являющегося ожидаемым при терапии препаратами интерферонов, встречались в группах активного лечения с одинаковой частотой. Степень его выраженности, а также длительность и необходимость применения симптоматической терапии не зависели от вида применяемого интерферона.

The authors present the results of an 8-year retrospective-prospective follow-up of a patient with Balo concentric sclerosis. The disease meets the diagnostic criteria of remitting-relapsing multiple sclerosis.Представлены результаты восьмилетнего ретроспективно-проспективного наблюдения клинического случая концентрического склероза Бало. Установлено соответствие заболевания диагностическим критериям ремиттирующе-рецидивирующего рассеянного склероза.

The careful differential diagnosis is very important in pediatric cases of multiple sclerosis (MS). It has special difficulties, if MS started in patients with residual neurological pathology. Two cases of development of MS in children with cerebral palsy (CP) are presented. The clinical features and diagnostic difficulties in such comorbid situations are discussed .При начале рассеянного склероза (РС) в детском возрасте очень важно правильное проведение дифференциального диагноза. Особенно это сложно при развитии РС на фоне другой органической патологии головного мозга. В статье представлены два случая развития РС у детей с детским церебральным параличом (ДЦП). Обсуждаются особенности клинических проявлений и трудности в диагностике таких случаев коморбидной патологии.

This article presents a review of international data on primary progressive multiple sclerosis (PPMS) and an analysis of factors influencing timely diagnosis of PPMS in a number of regions of the Russian Federation.В статье представлен обзор результатов международных исследований, касающихся первично-прогрессирующего рассеянного склероза с анализом ряда факторов, которые снижают выявляемость этой формы заболевания на территории ряда регионов РФ.