[DNA Methylation Profile of CD14+ Monocytes Changes in Primary Progressive Multiple Sclerosis].

Multiple sclerosis (MS) is a chronic autoimmune inflammatory and neurodegenerative disease of the central nervous system, which is characterized by significant clinical heterogeneity. Primary progressive MS (PPMS) develops in 10-15% of patients. Unlike the most common relapsing-remitting form of MS, PPMS involves steady progress of neurodegeneration and, as a consequence, a persistent gradual increase in neurological symptoms. The peculiarities of epigenetic regulation of gene expression may be one of the reasons for the differences in the pathogenesis of the two MS forms. DNA methylation is one of the key epigenetic mechanisms, which remains almost unexplored in different cell populations of PPMS patients. The goal of this work was to identify differential methylation profiles of the CpG sites in the CD14+ monocyte DNA, which characterize PPMS. A genome-wide analysis of DNA methylation in PPMS patients and healthy individuals has identified 169 differentially methylated positions (DMPs), 90.5% of which were hypermethylated in PPMS patients. More than half of all DMPs are located in/near known genes and within CpG islands and their neighboring regions, which indicates their high functional significance. We have found six differentially methylated regions (DMRs) in the OR2L13, CAT, LCLAT1, HOXA5, RNF39, and CRTAC1 genes involved in inflammation and neurodegeneration, which indicates active epigenetic regulation of their expression.

[Genome-Wide Analysis of DNA Methylation in Cd4+ T Lymphocytes of Patients with Primary Progressive Multiple Sclerosis Indicates Involvement of This Epigenetic Process in the Disease Immunopathogenesis].

The pathogenesis of multiple sclerosis (MS), a chronic disease of the CNS, includes autoimmune and neurodegenerative components. In most cases, patients develop relapsing-remitting MS (RRMS), while 10-15% of patients develop primary progressive MS (PPMS), which differs from RRMS in the mechanisms of the pathological process, some demographic, and some clinical characteristics. These differences may be explained by the epigenetic regulation of gene expression in PPMS including DNA methylation as one of the key epigenetic processes. The features of DNA methylation in various cell populations in PPMS patients remain understudied. The goal of this study is to identify differentially methylated CpG sites (DMSs) of the genome of CD4+ T lymphocytes, which characterize PPMS. The study included eight treatment-naive PPMS patients and eight healthy controls. Genome-wide analysis of DNA methylation of CD4+ T lymphocytes was performed using high-density DNA microarrays. We have identified 108 DMSs, which distinguish PPMS patients from healthy controls. In PPMS patients 81% of the DMSs are hypermethylated. More than a half of the identified DMSs are located in known genes in CpG islands and adjacent regions, which indicates a high functional significance of these DMSs in PPMS development. Analysis of the overrepresentation of DMS-containing genes in the main biological processes demonstrates their involvement in the regulation of cell adhesion to the extracellular matrix and the development of the immune response, i.e., antigen processing and presentation, and development of the immune system. Genome-wide analysis of DNA methylation in CD4+ T lymphocytes of PPMS patients indicates the involvement of this epigenetic process in the immunopathogenesis of the disease. These results may help better understand the pathogenesis of this severe form of MS.

Evaluation of the structure of the human microbiome in multiple sclerosis by the concentrations of microbial markers in the blood.

The relationship between multiple sclerosis and the state of the human microbiome was studied, namely, the change in the representation of microbiota phylotypes, the proportion of coccal flora, the proportion of anaerobic, gram-negative, proteolytically active microflora, as well as the concentration of markers of bacterial plasmalogen and endotoxin in the blood. Microbiome studies were carried out by gas chromatography - mass spectrometry of microbial markers in the blood. A statistically significant increase in blood concentrations of the total level of microbial markers of bacterial plasmalogen and endotoxin was determined in multiple sclerosis, which may be associated with an increase in the permeability of the intestinal wall. In multiple sclerosis, the proportion of coccal, gram-negative, anaerobic microflora with a proteolytic type of metabolic activity increases. The correlations of the representation of microbiota phylotypes change due to the switching of the direct relationship Proteobacteria-Bacteroides to Proteobacteria-Firmicutes. In multiple sclerosis, Actinobacteria and Proteobacteria increase and Firmicutes decrease. Conclusion. The multiple sclerosis disease may be associated with pathological changes in the structure of the microbiome and the growth of endotoxemia, which may be one of the factors in the pathogenesis of the disease. New laboratory markers for diagnosing and predicting the course of MS have been proposed.

[Risk of Multiple Sclerosis: Analysis of Interactions Between Variants of Nuclear and Mitochondrial Genomes].

There is increasing evidence that the interaction of the mitochondrial and nuclear genomes substantially affects the risk of neurodegenerative diseases. The role of mitonuclear interactions in the development of multiple sclerosis, a severe chronic neurodegenerative disease of a polygenic nature, is poorly understood. In this work, we analyzed the association of multiple sclerosis with two-component mitonuclear combinations that include each of seven polymorphic variants of the nuclear genome localized in the region of the UCP2, and KIF1B genes and in the PVT1 locus (MYC, PVT1, and MIR1208 genes) and each often polymorphisms of the mitochondrial genome, as well as individual genetic variants that make up these combinations. Association of the individual components of these combinations with multiple sclerosis was also evaluated. 507 patients with multiple sclerosis and 321 healthy individuals were enrolled in the study, all participants were ethnic Russians. Two mitonuclear combinations associated with multiple sclerosis were identified: the UCP2 (rs660339)*A + MT-ATP6 (rs193303045)*G combination was characterized by p-value = 0.015 and OR= 1.39 [95% CI 1.05-1.87], and the PVT1 (rs2114358)*G + MT-ND1 (rs1599988)*С combination - by p-value = 0.012 and OR = 1.77 [95% CI 1.10-2.84]. Only one of the individual components of these combinations, allele rs660339*A of the nuclear gene UCP2 encoding uncoupling protein 2 of the mitochondrial anion carrier family, was independently associated with multiple sclerosis (p = 0.028; OR = 1.36 [95% CI 1.01-1.84]). This study expands the current understanding of the role of mitonuclear interactions and variance of nuclear genes, whose products function in mitochondria, and in risk of MS.

[Variability of the Mitochondrial Genome and Development of the Primary Progressing form of Multiple Sclerosis].

Recently, it has been shown that dysfunction of mitochondria is an important component of the molecular mechanisms of the development of many neurodegenerative diseases. These include multiple sclerosis, a chronic autoimmune and neurodegenerative disease of the central nervous system, which is characterized by clinical heterogeneity. The role of genetic variability of mitochondrial DNA in the development of various clinical forms of multiple sclerosis is poorly understood. The aim of present study was to analyze the association often mitochondrial DNA single nucleotide polymorphisms and the nine most common European mitochondrial haplogroups (H, J, K, U, T, I, V, W and X) with a severe and relatively rare multiple sclerosis disease form-primary progressive multiple sclerosis. 110 patients with primary progressive multiple sclerosis and 406 healthy controls were enrolled in the study, all ethnic Russians. For the first time association of the m.12308*G (rs2853498) variant (P = 0.024) and haplogroup U (P = 0.0004, passes the adjustment for multiple comparisons: Pcorr = 0.0076) with primary progressive multiple sclerosis was shown. Comparison of these data with the results of our previous study [1], that was focused on the role of mitochondrial genome variability in susceptibility to the most common form of multiple sclerosis, relapsing-remitting multiple sclerosis, leads to the conclusion that two different mitochondrial haplogroups, U and J, are involved in the development of two different clinical forms of multiple sclerosis. The results may contribute to the identification of new targets for the treatment of primary progressive multiple sclerosis, for which there is no effective pathogenetic treatment at the moment.

[Genetic Markers for Personalized Therapy of Polygenic Diseases: Pharmacogenetics of Multiple Sclerosis].

Pharmacogenetics (PG) investigates the inherited variants of the human genome that underlie individual differences in drug metabolic transformation, delivery, and mechanism of action. Not only the contributions of individual genes, but also their cumulative effect should be considered in the case of polygenic diseases, which include the majority of human diseases. Multiple sclerosis (MS) is a severe autoimmune neurodegenerative disorder of the central nervous system (CNS) and is polygenic in nature. Understanding the role that the immune system plays in the pathogenesis of MS helped to design drugs for its pathogenetic therapy. These drugs are known as the disease-modifying treatments (DMTs). Among these are interferon ß (IFN-ß) and glatiramer acetate (GA), whose treatment efficacy and long-term safety have been proven in many clinical trials. However their efficacy on MS course varies from highly effective to lack of response. Prognostic genetic biomarkers of treatment efficacy can help to identify the MS patient groups where a particular drug is preferential or even strictly indicated to use. The review summarizes the findings from pharmacogenetic studies evaluating the efficacy of IFN-ß and GA in MS patients, including the author's original data.

[Variability of the MIR196A2 Gene as a Risk Factor in Primary-Progressive Multiple Sclerosis Development].

Multiple sclerosis is a chronic disease of the central nervous system, combining in its pathogenesis both autoimmune and neurodegenerative components, and is characterized by a highly heterogeneous clinical phenotype. Genetic susceptibility to the development of the most common relapsing-remitting course of the disease is extensively studied, while the genetic architecture of the aggressive primary progressive course of multiple sclerosis remains poorly understood. We analyzed the association of polymorphic variants in miRNA genes MIR146A, MIR196A2, and MIR499A with the risk of primary progressive multiple sclerosis one by one and in biallelic combinations with variants of immune-related genes; the analysis was performed in comparison with healthy individuals and with relapsing-remitting multiple sclerosis patients. The allele MIR196A2*C was useful in discriminating between two main courses of multiple sclerosis, one by one and in combination with alleles of the IFNAR2, IL7RA, IL6, PVT1, CD86, CCL5, and PSMB9 genes. The data presented in the current work may be used for the construction of a biomarker panel, to differentiate primary progressive and relapsing-remitting courses of multiple sclerosis on the initial stages of the disease.

Loading Rate of Exogenous and Autoantigenic Determinants on Major Histocompatibility Complex Class II Mediates Resistance to Multiple Sclerosis.

Genetic analysis of thousands of patients with multiple sclerosis (MS) and healthy Russian donors showed that the carriage of groups of HLA-DRB1*15 and HLA-DRB1*03 alleles is associated with the risk of MS, whereas the carriage of groups of HLA-DRB1*01 and HLA-DRB1*11 alleles is protective. Recombinant HLA-DRB1*01:01 with a high affinity can recognize the fragments of myelin basic protein (MBP), one of the autoantigens in MS. However, the comparison of the kinetic parameters of the load of MBP and viral HA peptides on HLA-DRB1*01:01, which is catalyzed by HLA-DM, showed a significantly lower rate of exchange of CLIP for MBP peptides. We assume that the observed protective properties of the group of HLA-DRB1*01 alleles may be directly associated with the ability of HLA-DRB1*01:01 to kinetically distinguish peptides of exogenous and endogenous nature.

A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches.

Multiple sclerosis (MS) is a common complex neurodegenerative disease of the central nervous system. It develops with autoimmune inflammation and demyelination. Genome-wide association studies (GWASs) serve as a powerful tool for investigating the genetic architecture of MS and are generally used to identify the genetic factors of disease susceptibility, clinical phenotypes, and treatment response. This review considers the main achievements and challenges of using GWAS to identify the genes involved in MS. It also describes hypothesis-driven studies with extensive genome coverage of the selected regions, complementary to GWASs. To date, over 100 MS risk loci have been identified by the combination of both approaches; 40 of them were found in at least two GWASs and meet genome-wide significance threshold (p ≤ 5 × 10(-8)) in at least one GWAS, whereas the threshold for the rest of GWASs was set in our review at p < 1 × 10(-5). Yet, MS risk loci identified to date explain only a part of the total heritability, and the reasons of "missing heritability" are discussed. The functions of MS-associated genes are described briefly; the majority of them encode immune-response proteins involved in the main stages of MS pathogenesis.

Revised McDonald criteria for multiple sclerosis diagnostics in central Russia: sensitivity and specificity.

BACKGROUND: The 2010 revised McDonald criteria were developed with data gathered from Caucasian European and North American populations, and their applicability has been questioned for the Russian population. OBJECTIVE: The objective of this report is to compare the specificity, accuracy, sensitivity and predictive value of MRI criteria incorporated to the new (2010) and old (2005) McDonald criteria for early multiple sclerosis (MS) diagnostics in the Nyzhnyi Novgorod (Russia) population. METHODS: A total of 103 patients with symptoms suggestive of MS were recruited from 2008 to 2011 retrospectively. Patients were followed up until MS was confirmed or other proved diagnoses were determined. Their baseline and follow-up brain and spinal cord MRIs were retrospectively evaluated. Sixty-two patients (60%) converted to MS during the follow-up period (mean in 11±4.2 months). RESULTS: In 41 cases (38%) diagnoses another than MS were established. The sensitivity, specificity, accuracy, PPV and NPV of the revised MRI criteria were 74%, 93%, 82%, 94%, 70%, respectively. CONCLUSIONS: Despite the limitations of our study, we conclude that the ability of the revised MRI criteria for early MS diagnostics in the Russian population is approximately similar to that determined by the international panel in Europe.

[Modern pathogenetic treatment of rare demyelinating diseases]. / Sovremennoe patogeneticheskoe lechenie redkikh demieliniziruyushchikh zabolevanii.

Rare demyelinating diseases are a group of diseases whose pathogenesis is based on the process of demyelination. This group of diseases includes acute multiple encephalomyelitis (ADEM), opticoneuromyelitis spectrum diseases (NMOSD) and anti-myelin-oligodendrocyte glycoprotein-associated diseases (MOG-antibodies-associated diseases - MOGAD). Recently, new biological drugs for pathogenetic therapy have been developed, which have shown their effectiveness and good tolerability in comparison with therapy with first- and second-line drugs. Aim of the study - analysis of modern possibilities of pathogenetic treatment of patients with ADEM, seronegative and seropositive patients with NMOSD. The analysis was carried out on the basis of English-language publications in PubMed published over the past five years. This review summarizes current ideas about the possibilities of pathogenetic treatment of rare diseases. The advantages of using ravulizumab over other representatives of a new biological therapy associated with the use of monoclonal antibodies are shown. The analyzed data allow us to conclude that there is a significant development of pathogenetic treatment options for ZSONM. However, the effectiveness of new therapeutic biological drugs is still limited due to the lack of a large amount of clinical data to confirm, which creates the need to continue analyzing the experience of their use.

[The central vein sign in the differential diagnosis of multiple sclerosis]. / Simptom tsentral'noi veny v differentsial'noi diagnostike rasseyannogo skleroza.

OBJECTIVE: To carry out a clinical and radiological assessment of the central vein sign (CVS) as a diagnostic marker for multiple sclerosis (MS) and other demyelinating and non-demyelinating diseases with focal brain damage, using clinical and laboratory examination data, as well as MRI. MATERIAL AND METHODS: The results of clinical and neuroradiological examination of 107 patients diagnosed with MS or with other diseases accompanied by focal brain damage according to MRI data were analyzed. RESULTS: CVS is a sensitive but low-specific diagnostic marker of MS. According to our data, the sensitivity and specificity of 40 and 50% of the threshold of perivenular lesions in the diagnosis of MS are the same and amount to 100% and 39.4%, respectively. Neither the type of MS course, nor the severity of the course, nor the intake of DMT (disease modifying treatment), affect the proportion of foci with CVS. The spread of the proportion of foci with CVS in patients with MS was 60-100%. The proportion of foci with CVS is below 40 and 50% of the threshold in patients with demyelinating and non-demyelinating diseases (NMOSD, migraine, systemic lupus erythematosus, Susak disease, CLIPPERS), which allows for differential diagnosis with MS. The proportion of foci with CVS comparable to MS in patients with acute disseminated encephalomyelitis, small vessel disease, as well as in patients with radiologically isolated syndrome does not allow using this symptom in the differential diagnosis of these conditions. CONCLUSION: The use of CVS as a diagnostic marker of MS is possible only in combination with the already existing diagnostic criteria of MS.

[Optimal patient profile for ofatumumab treatment: analysis of Russian data from the Phase 3 study]. / Optimal'nyi profil' patsienta dlya lecheniya ofatumumabom: analiz rossiiskikh dannykh iz issledovaniya 3-i fazy.

The article provides an analysis of the features of the action of ofatumumab in subgroups of patients with multiple sclerosis (MS) who participated in phase 3 ASCLEPIOS I and II studies both in the general subgroup of 1882 patients and among 352 patients from the Russian Federation who participated in these studies. The results of the influence of age, gender, body weight of patients, as well as the basic level of disability on the EDSS scale, the presence of active foci on MRI and previously received therapy with drugs that alter the course of MS (PITRS) are presented. In a total group of 1.882 patients, a more positive effect of ofatumumab compared with teriflunomide was noted on the average annual incidence of exacerbations in men, younger people and with a mild baseline disability level - with a baseline EDSS level less than or equal to 3. In a subgroup of 352 patients from Russia, the same trends were noted, but dependencies were also revealed from the number of previously taken PITRS: a more significant difference was noted in patients with the lowest number of PITRS in the anamnesis. This feature was also confirmed by analyzing the secondary endpoints of the study: the number of active foci on MRI and the confirmed progression of disability according to the EDSS scale. Analysis in clinical subgroups makes it possible to clarify the profile of patients in whom the greatest clinical effect can be expected when using this new drug for the treatment of MS.

[Questionnaires for arm function assessment in patients with multiple sclerosis]. / Oprosniki dlya otsenki funktsii ruki u patsientov s rasseyannym sklerozom.

Arm dysfunction is one of the disabling manifestations of multiple sclerosis (MS), especially in later stages of the disease. Assessment of the functioning of the upper limbs is necessary to objectify the course of MS, determine the effectiveness of therapy, and individualize rehabilitation measures. The tools that assess the upper extremity dysfunction include tests and questionnaires. Questionnaires (patient-reported outcome measures) represent the special importance, since the opinions and preferences of patients themselves help to implement a patient-centered approach to treatment. The article presents a brief description of three multidimensional MS-specific and four unidimensional MS-nonspecific questionnaires that used in assessment of upper limb function in MS patients. The disease-specific unidimensional Arm Function in Multiple Sclerosis Questionnaire (AMSQ), specifically designed to assess the arm use in patients with MS, is discussed in more detail. The use of AMSQ in the Russian population is possible only after the procedure of cultural adaptation and validation of the Russian version.

[Mistakes in the diagnosis of neuromyelitis optic spectrum diseases lead to wrong therapy and deterioration of patients' condition]. / Oshibki v diagnostike zabolevanii spektra optikoneiromielita privodyat k nepravil'noi terapii i ukhudsheniyu sostoyaniya patsientov.

Neuromyelitis optic spectrum diseases (NMOSD) are a group of rare neuroimmunological diseases involving mainly the optic nerves and spinal cord, to a lesser extent the brain, and causing severe exacerbations that lead to persistent disability of patients. For many years, opticoneuromyelitis was considered a prognostically unfavorable variant of the course of multiple sclerosis (MS), however, in 2004, specific autoantibodies to aquaporin-4 were found in such patients, which made it possible to isolate NMOSD into a separate group of demyelinating diseases other than MS. Due to similar clinical signs and the predominantly remitting course of diseases, it is often difficult to make a correct diagnosis and, accordingly, prescribe effective therapy, which often leads to incorrectly selected therapy with incorrect diagnosis. In some cases, this leads to a worsening of the course of NMOSD. We present a case of late diagnosis of NMOSD that confirms the development of exacerbation in the patient 2 months after the first course of therapy with alemtuzumab prescribed as a highly effective therapy for highly active remitting MS. Timely diagnosis of NMOSD makes it possible to exclude such cases.

[A role of cerebrovascular diseases in the progression of multiple sclerosis]. / Rol' tserebrovaskulyarnykh zabolevanii v progressirovanii rasseyannogo skleroza.

OBJECTIVE: To identify the association between cerebrovascular diseases (CVD) and multiple sclerosis (MS) among patients over 50 years old in two independent populations of Moscow and Tyumen. MATERIAL AND METHODS: The study included 94 patients with MS in combination with CVD (main group) and 90 age-and sex-matched patients with MS without a vascular history (comparison group). An analysis of parameters such as disease duration, EDSS at different time points, disease progression index, duration of first remission in each population separately and in both populations together was carried out. RESULTS: The presence of CVD in patients with MS was associated with the presence of other diseases that are associated with an increased risk of developing cerebrovascular pathology. In the main group, there was a statistically significant decrease in the duration of the first remission and an increase in the disease progression index. In addition, other diseases and syndromes were identified in the main group that, in combination with CVD in patients with MS, could lead to a worsening of the course of MS. These included arterial hypertension, diabetes mellitus, obesity, dyslipidemia, chronic venous insufficiency, and regular use of proton pump inhibitors. CONCLUSION: Comorbid vascular pathology can affect the severity of MS from the very beginning of the disease. It can lead to a shorter duration of the first remission and a higher disease progression index, increasing the degree of disability. The combination of autoimmune-inflammatory, demyelinating, and vascular processes can worsen the prognosis for MS.

[The effectiveness of tele-rehabilitation for patients with multiple sclerosis during the COVID-19 pandemic in 2020-2021 was evaluated in this study]. / Effektivnost' telereabilitatsii patsientov s rasseyannym sklerozom v usloviyakh pandemii koronavirusnoi infektsii v 2020­2021 gg.

OBJECTIVE: To evaluate the effectiveness of telerehabilitation (TELEREBT) of patients with multiple sclerosis (MS) in the context of the coronavirus pandemic 2020-2021. MATERIAL AND METHODS: The study included 37 patients with MS who underwent a course of teleRBT. The course included 10 classes of 60 minutes for 10 days with a two-day break. Various questionnaires and scales were used to assess the effectiveness, as well as an assessment of the neurological status. RESULTS: 19 patients refused to participate in the program. The level of disability on the EDSS scale decreased from 4.86±1.19 at the initial level to 4.73±1.12 after the course of teleRBT, while no statistically significant changes were found. CONCLUSION: TeleRPT in patients can be an effective way to correct existing disorders. Further research is required to establish the effectiveness of teleRBT.

[The diagnostic effectiveness of criteria for neuromyelitis optica spectrum disorders in the Russian clinical practice]. / Diagnosticheskaya effektivnost' kriteriev zabolevanii spektra optikoneiromielita v rossiiskoi klinicheskoi praktike.

OBJECTIVE: To compare the diagnostic criteria of 2006 (DC 2006) and 2015 (DC 2015) in the Russian population of patients with suspected neuromyelitis optica spectrum disorders (NMOSD), with the calculation of their sensitivity, specificity, accuracy and predictive value. MATERIAL AND METHODS: We reviewed medical records of suspected NMOSD patients who were therefore examined for the presence of serum autoantibodies targeting the aquaporin-4 water channel protein (AQP4-IgG) in 6 specialized Russian (Nizhny Novgorod and Moscow) medical centers. One hundred patients (78 female), aged 17 to 74 years (mean 38.1±13.3 years), were included. The follow-up period ranged from 4 to 108 months (mean 59.7±31.6 months). RESULTS: During the follow-up the diagnosis of NMOSD was confirmed in 32 people, and 68 patients had diagnoses different from NMOSD. At the disease onset, 68.8% of patients were seropositive for AQP4-IgG. The mean time for confirming NMOSD diagnosis was 15.2±14.2 months. At the disease onset, 36% of patients fulfilled the DC 2015, the diagnosis was subsequently confirmed in 77.8% out of them. 26% of the patients fulfilled the DC 2006, the diagnosis was subsequently confirmed in 84.6% out of them. The sensitivity of DC 2006/DC 2015 was 69%/88%, specificity 94%/88%, accuracy 86%/88%, negative predictive value 85%/94%, positive predictive value 86%/78%. CONCLUSION: The specificity, sensitivity and accuracy of modern diagnostic criteria for NMOSD In Russian patients is comparable to those obtained in foreign studies. DC 2015 helps to diagnose NMOSD earlier than DC 2006, but they have a lower specificity.

[Long-term efficacy and safety of divozilimab during 2-year treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-4/MIRANTIBUS]. / Effektivnost' i bezopasnost' dvukhletnei terapii divozilimabom u patsientov s rasseyannym sklerozom v ramkakh randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo klinicheskogo issledovaniya BCD-132-4/MIRANTIBUS.

OBJECTIVE: To evaluate the efficacy and safety of the anti-CD20 monoclonal antibody divozilimab (DIV) used as an intravenous infusion at a dose of 500 mg every 24 weeks during 100 weeks for the treatment of patients with multiple sclerosis (MS), including relapsing-remitting multiple sclerosis (RRMS) and secondary progressive MS (SPMS) with relapses. MATERIAL AND METHODS: The multicenter, randomized, double-blind and double-masked phase III clinical trial (CT) BCD-132-4/MIRANTIBUS (NCT05385744) included 338 adult patients with MS distributed in a 1:1 ratio into two groups: DIV 500 mg and teriflunomide (TRF) 14 mg. After screening, subjects were included in the main CT period, which consisted of two cycles of therapy over 48 weeks, then entered an additional period from weeks 49 to 100, which included three cycles of therapy. The efficacy was assessed based on the results of brain MRI and registration of data on relapses. RESULTS: 308 subjects completed 5 therapy cycles according to the study protocol. An analysis of the effectiveness of DIV therapy over 2 years showed a persistent suppression of MRI and clinical activity of the disease in comparison with TRF, which was confirmed by all the studied MRI indicators (including CUA; total number of gadolinium-enhancing (GdE) lesions on T1-weighted scans ; number of new or enlarged lesions on T2-weighted scans; lesions volume change on T2-weighted scans; change in the volume of hypointense lesions on T1-weighted scans). The use of DIV was associated with a statistically significant decrease in ARR compared to TRF (p=0.0001). The ARR in the DIV group was 0.057, in the TRF group - 0.164 with 95% confidential interval for the frequency ratio [0.202; 0.593]. The incidence of GdE lesions on T1-weighted scans in the DIV group was significantly lower than in the TRF group. The average number of such lesions was 0.0±0.08 and 1.0±4.46 in the DIV and TRF groups, respectively (p<0.0001). Progression of EDSS was detected in 18 (10.7%) and 36 (21.3%) patients in the DIV and TRF groups, respectively (p=0.0075). The proportion of patients with relapses was 11.2% (n=19) in the DIV group and 23.1% (n=39) in the TRF group (p=0.0039). In the subpopulation of patients with SPMS, no cases of increase in EDSS were detected, and not a single case of exacerbation was recorded over 2 years of using DIV. Also, DIV has shown a favorable safety profile. Among the adverse reactions (AR), infusion reactions and laboratory abnormalities, such as a decrease in the number of leukocytes, neutrophils, and lymphocytes, were most often recorded. Identified AR were expected, had mild to moderate severity, and resolved without any negative consequences. CONCLUSION: The results of the BCD-132-4/MIRANTIBUS CT indicate a high sustained efficacy and safety of long-term use of DIV in comparison with TRF during 2 years of therapy.

[Knee range of motion as a marker of the effectiveness of medical intervention in multiple sclerosis]. / Diapazon dvizheniya v kolennom sustave kak marker effektivnosti meditsinskogo vmeshatel'stva pri rasseyannom skleroze.

OBJECTIVE: To measure the knee range of motion (ROM) in the sagittal plane by video analysis in patients with multiple sclerosis (MS) after a course of medical rehabilitation and determine the minimal clinically important differences (MCID). MATERIAL AND METHODS: We examined 45 patients (37 women, 8 men) with relapsing-remitting (n=38) and secondary-progressive MS before and after a course of medical rehabilitation. Gait parameters were recorded on video analysis system Physiomed Smart («Physiomed¼, Germany, the Davis protocol). RESULTS: The course of complex medical rehabilitation contributes to an increase knee ROM in MS patients in a wide range of disability (EDSS <6.5 points). MCID is estimated as 7.14° in mild (EDSS ≤4.0) and as 7.67° in moderate (EDSS=4.5-5.5) gait impairment. CONCLUSION: The results will assist clinicians and researchers in interpreting the significance of observed kinematic changes in the knee joint in MS patients after medical intervention.