[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.

[Efficacy and safety of antiCD20 monoclonal antibody divozilimab during 48-week treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-4/MIRANTIBUS]. / Effektivnost' i bezopasnost' 48 nedel'nogo primeneniya monoklonal'nogo antitela protiv CD20 divozilimaba u patsientov s rasseyannym sklerozom: rezul'taty 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 for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS) in comparison with the teriflunomide (TRF). The study of the efficacy and safety of the use of the drug DIV was carried out for 48 weeks of therapy. MATERIAL AND METHODS: The multicenter, randomized, double-blind and double-masked phase III clinical trial (CT) BCD-132-4/MIRANTIBUS included 338 adult patients with RRMS distributed in a 1:1 ratio into two groups: DIV 500 mg and TRF 14 mg. After screening, subjects were included in the main CT period, which consisted of two cycles of therapy over 48 weeks. The primary end point was «Mean annualized relapse rate 48 weeks after the last patient is randomized in the study¼. RESULTS: 321 subjects completed 48 weeks of therapy according to the study protocol. The analysis of the of efficacy data for the primary endpoint successively proved the hypothesis of superiority of the test drug DIV at a dose of 500 mg over the reference drug TRF. A rapid suppression of acute disease activity according to the brain MRI and clinical manifestations of the disease was shown after the first infusion of DIV in patients with RRMS. Thus, after 48 weeks of therapy in patients treated with DIV, there were no T1 gadolinium-enhancing lesions, while in the TRF group such lesions were observed in 20.7% (35/169) of subjects. Evaluation of the CUA per scan showed that the mean values for the estimated period were statistically significantly lower in the DIV drug group compared to the TRF group: the ratio of the adjusted per scan rates (DIV/TRF) was 0.125 [95% CI: 0.089; 0.177]. Over the 48 weeks of therapy, the proportion of subjects with relapses was 9.5% (n=16/169) in the DIV group and 19.5% (33/169) in the TRF group (p=0.0086). DIV has shown a favorable safety profile. Among the adverse reactions (AR), infusion reactions and deviations of laboratory data, 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 clinical study indicate the high efficacy and safety of DIV in comparison with TRF.

[Efficacy and safety of divozilimab during 24-week treatment of multiple sclerosis patients in randomized double-blind placebo-controlled clinical trial BCD-132-2]. / Effektivnost' i bezopasnost' 24 nedel' primeneniya divozilimaba sredi patsientov s rasseyannym sklerozom v ramkakh randomizirovannogo dvoinogo slepogo platsebo-kontroliruemogo klinicheskogo issledovaniya BCD-132-2.

OBJECTIVE: To find the optimal therapeutic dose of the anti-B cell mAb divozilimab (DIV) based on the efficacy and safety data of intravenous administration at a dose of 125 mg or 500 mg in patients with relapsing remitting multiple sclerosis (RRMS) compared to placebo (PBO) and teriflunomide (TRF). To study the efficacy and safety of DIV within 24 weeks of treatment. MATERIAL AND METHODS: A multicenter, randomized, double-blind and double-masked, placebo-controlled phase 2 clinical trial (CT) BCD-132-2 involved 271 adult patients with RRMS from 25 centres In Russia. Patients were randomly assigned (2:2:2:1) into 4 groups: TRF, DIV 125 mg, DIV 500 mg and PBO. After screening patients entered to the main period, which consisted of one cycle of therapy for 24 weeks. The primary endpoint was the total number of gadolinium-enhancing T1 lesions (Gd+) observed on brain MRI scans after 24 weeks (per scan - involves estimating the mean value of the score from all the MRI assessments performed for each participant in the study). RESULTS: 263 patients completed 24 weeks of treatment. Most of the patients in the DIV groups had no lesions on T1-weighted MRI after 24 weeks of treatment (94.44% on 125 mg and 93.06% on 500 mg). In the TRF and PBO groups the values were significantly lower: 68.06% and 56.36% respectively (both p<0.05). The proportions of relapse-free patients in the DIV groups were 93.06% and 97.22% (125 mg and 500 mg, respectively). As expected, DIV reduced the CD19+ B-cells. However, the repopulation rate of CD19+ B-cells in the 125 mg group was more pronounced (mainly due to the recovering pool of CD27-naive B-cells) compared to the 500 mg group. DIV showed a favorable safety profile at both doses. CONCLUSION: Thus, the assessment of 24 weeks treatment demonstrated that DIV is a highly effective, safe and convenient option for the treatment of RRMS patients, both naive and previously treated with disease modifying therapy. A dose of 500 mg is recommended for further efficacy and safety evaluation during phase 3 CT.

[Local experience of IL-6 pathway inhibition with satralizumab for patients with neuromyelitis optica spectrum disorder]. / Lokal'nyi opyt primeneniya preparata satralizumab, podavlyayushchego put' IL-6, dlya terapii zabolevanii spektra optikoneiromielita.

Satralizumab is a monoclonal anti-IL6-anibody for patients with neuromyelitis optica or neuromyelitis optica spectrum disorder (NMOSD) seropositive for anti-AQP4-antibody. Satralizumab has been approved in 2021 in the Russian Federation for usage in adults and adolescents from 12 years and older in combination with basic therapy or in monotherapy. The efficacy and safety of satralizumab in comparison with placebo have been demonstrated in two international randomized clinical trials SakuraStar and SakuraSky, phase III. We present clinical experience with satralizumab gained in frames of the Compassionate Use Program that have been initiated in Russia for NMOSD patients. Here, we summarized the results of treatment with satralizumab of 16 patients (14 men and 2 women), aged 13-69 years. Duration of therapy was 9 to 41 week. The first experience of using satralizumab in the Russian Federation in the small group of patients does not yet allow us to draw conclusions about the efficacy due to the short follow-up period. It can be concluded that the safety profile of satralizumab is consistent with the results obtained in international clinical trials. The experience gained in the ongoing program allows us to conclude that satralizumab is a valuable and convenient therapeutical option for seropositive for anti-AQP4-antibodies patients with NMOSD.

[The first russian experience of use of siponimod in real clinical practice]. / Pervyi rossiiskii opyt primeneniya siponimoda v real'noi klinicheskoi praktike.

Despite significant success in the treatment of multiple sclerosis achieved in the recent years, the issues of therapy for progressive forms of the disease are far from being resolved. The first medication with proven efficiency at SPMS is the oral selective sphingosine 1 phosphate (S1P) receptor modulator siponimod. Before the registration of siponimod in Russia, Novartis company organized a «Managed access program to enable siponimod in patients with secondary progressive multiple sclerosis without satisfactory alternative therapy¼. For the period from September 2020 to May 2021, 10 patients with SPMS with exacerbations were included in the programme by RAS. The results of the treatment of the patients under the programme were similar to the results of previously controlled studies. The medication was well tolerated and the expected side effects (mainly lymphopenia and Elevated transaminases) were not more severe than moderate and were stopped by temporary cancel of the current treatment or concomitant therapy. During 1 year of therapy, the stabilization of condition of all patients and positive dynamics was noticed, including a decrease in the EDSS score in 44% of patients. Despite the limited number of patients and time of observation, the safety and efficacy of siponimod in patients with SPMS are quite high. The use of the medication in routine clinical practice does not require extraordinary methods of observation and control, but nevertheless includes genetic examination before the prescription of therapy, regular monitoring of clinical blood and biochemical parameters.

[Results of a phase 1 clinical study of anti-CD20 monoclonal antibody (BCD-132): pharmacokinetics, pharmacodynamics and safety]. / Rezul'taty I fazy klinicheskogo issledovaniia monoklonal'nogo antitela protiv CD20 (BCD-132): farmakokinetika, farmakodinamika i bezopasnost'.

AIM: To study the pharmacokinetics, pharmacodynamics, and immunogenicity of two intravenous dosing regimens of the new anti-B-cells drug BCD-132 (JSC BIOCAD, Russia) at ascending doses in patients with remitting multiple sclerosis. MATERIAL AND METHODS: Twenty-four patients with multiple sclerosis were sequentially randomized in the multicenter open-label uncontrolled multicohort phase I study (3+3 design) and assigned to 4 cohorts (8 groups). Patients in each cohort received an intravenous infusion of BCD-132 at a predefined dose ranging from 100 to 1000 mg based on the planned algorithm of dose escalation if no dose-limiting toxicities occurred. RESULTS: The assessment of the number of cells positive for the main B-cell antigens over time demonstrated a direct effect of BCD-132 on B lymphocytes when used at a wide range of doses (100 to 1000 mg) in patients with remitting multiple sclerosis. No significant variation of the number of T-cells was observed, which clearly proves strict specificity of BCD-132 exclusively to B lymphocytes. CONCLUSION: BCD-132 has an expected pharmacodynamic effect of long-term depletion of CD19+ and CD20+ B lymphocytes and an acceptable safety profile when used to treat patients with remitting multiple sclerosis at all tested doses.

[A case-report of Balo concentric sclerosis transformed into definite multiple sclerosis]. / Klinicheskii sluchai kontsentricheskogo skleroza Balo, transformirovavshegosia v dostovernyi rasseiannyi skleroz.

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.

[Capabilities of positron emission tomography to study mecha-nisms of multiple sclerosis: own data and literature]. / Vozmozhnosti pozitronno-emissionnoi tomografii dlya izucheniya mekhanizmov razvitiya rasseyannogo skleroza (literaturnye i sobstvennye dannye).

The article presents the literature data and results of our own researchon the use of positron emission tomography (PET) with different radiotracersin multiple sclerosis (MS). Informationon the operating principles of PET and PET studies with different radiotracers are considered. The results of PET studiesin different typesof MS, including determinationof the localization of neuronal damagein the corticalgray matter, assessmentof microglial activation, study of the relationship between glucose metabolismin the brain and the severity of cognitive impairmentin MS, can providenew information about the pathogenesis ofMS.

[Neuroprotection therapy of multiple sclerosis with high doses of ethylmethylhydroxypyridine succinate]. / Vozmozhnosti neiroprotektsii pri rasseyannom skleroze: opyt primeneniya vysokikh doz preparata etilmetilgidroksipiridina suktsinat.

AIM: To study the therapeutic action of ethylmethylhydroxypyridine succinate (mexidol) on the neurodegeneration in multiple sclerosis (MS). MATERIAL AND METHODS: Fifty-two MS patients and 24 healthy controls were examined using DTI MRI with tractography. RESULTS AND CONCLUSION: Ethylmethylhydroxypyridine succinate can prevent the progression of neurodegenerative processes in MS. However, further clinical trials are needed to confirm the results obtained in this study.

[Regional metabolic changes of supraventricular tissue in patients with relapsing-remitting and secondary-progressive multiple sclerosis]. / Regionarnye osobennosti metabolizma strukturno neizmenennogo veshchestva supraventrikuliarnykh prostranstv golovnogo mozga pri remittiruiushchem i vtorichno-progressiruiushchem tipakh techeniia rasseiannogo skleroza.

AIM: To evaluate and compare the intensity of changes in a regional meta-analysis in relapsing-remitting and secondary-progressive multiple sclerosis (RRS and SPMS). MATERIAL AND METHODS: The results of longitudinal studies of multiple sclerosis (MS) using positron emission tomography, magnetic resonance spectroscopy and diffusion tensor imaging are presented. RESULTS: In MS, metabolic changes precede the structural ones. The markers of neuronal and axonal dysfunction (a decrease in NAA/Cr ratios in the white and grey matters, without the structural changes) are recorded in the early stages. The metabolic changes in the grey matter were recorded mostly in the middle frontal gyrus and posterior cingulate cortex. With the increase of duration and severity of MS, the metabolic changes spread to the other regions of supraventricular areas. The distribution of degeneration zones is related to MS course. CONCLUSION: There is substantial evidence on the irreversible damage of neurons in the medial prefrontal cortex in SPMS that confirms the vulnerability of the frontal cingulate gyrus in MS.

[Cortical atrophy in multiple sclerosis]. / Atrofiia kory golovnogo mozga pri rasseiannom skleroze.

Objective. To identify clear patterns of the cerebral cortex atrophy in multiple sclerosis that may provide valuable information for the development of additional paraclinical methods of stages and variants of MS objectification and verification and used for assessing treatment efficacy. Material and methods. The results of morphometric data analysis of 117 patients with different variants of MS and 25 healthy volunteers are presented. The original algorithm for postprocessing MRI images was used. Age, disease duration, type of disease, FS and EDSS scores, morphometric results were the source parameters for the statistical analysis. Results. The correlation analysis showed that the total cortex volume was in inverse correlation with EDSS score, pyramidal and cerebellar dysfunction, but not with disease duration. An analysis of regional changes in 43 bilateral regions of interest (ROI) demonstrated similar results in 7 ROIs in the left (dominant) hemisphere and in 4 ROIs in the right hemisphere. ANOVA revealed atrophic changes in 20 ROIs bilaterally. Deficit of certain functional systems was accompanied by the atrophy of various functional cortex regions. ANOVA of the regional cortical atrophy in groups with varying disease severity showed the presence of significant changes in patients with moderate to severe disability. Duration and type of MS were not predictive for development of atrophy, with the exception of the precuneus bilaterally, the right paracentral lobule and right posterior cingulate gyrus. Conclusion. Regional cortical atrophy is detected in the earliest stages of the disease and increases as the disease progresses. Inconsistency of data across studies can be explained by the lack of generally accepted morphometric standards and pathogenetic heterogeneity of MS. Regional cortical atrophy may be considered as a sensitive neuroradiological biomarker for MS.

[PET-patterns of cognitive impairment in patients with multiple sclerosis].

Neuropsychological and PET-FDG examination and assessment with the EDSS scale in patients with different types (relapsing-remitting or progressive) of multiple sclerosis (MS) were performed in order to determine the relationship between cognitive impairment and changes in the regional cerebral metabolic rate of glucose (rCMRglu) in the brain gray matter. A study included 61 patients with relapsing-remitting (n=38) and progressive (n=23) types of MS. A statistical analysis revealed significant correlations between cognitive impairment and rCMRglu dependent on the type of MS. The changes in the functional activity of the brain gray matter during the progression of the disease and increasing disability were identified.

[Intrathecal immunoglobulin production in the diagnosis and differential diagnosis of multiple sclerosis].

The evaluation of diagnostic significance of different immunological tests for intrathecal immunoglobulin production is summarized on the historical basis of investigation of patients with inflammatory, demyelinating and other neurological disorders. The assessment of cerebrospinal fluid lost its previous significance in the 2010 revision of diagnostic criteria for multiple sclerosis. Nowadays, it is used only for the diagnosis of primary progressive multiple sclerosis. Nevertheless, the requirements of the analysis of the cerebrospinal fluid are increasing due to subtle, subclinical and atypical cases of multiple sclerosis as well as undetermined demyelinating disorders. Intrathecal humoral immune response may be pathogenic in multiple sclerosis as suggest immunological data and effectiveness of anti-B cells treatment. Based on these tests, it is useful, to differentiate subgroups of patients and to evaluate different effects of treatment in perspective.

[Current possibilities of the comprehensive diagnostic assessment in the differential diagnosis of inflammation and tumors of the spine cord].

The article discusses the differential diagnosis of transverse myelitis. An algorithm for the assessment of patients was given. The authors present two clinical examples demonstrating the role of the integrated neuroradiological approach in the differential diagnosis of difficult cases.

[The role of brain glucose metabolism in the development of cognitive dysfunctions in patients with remitting and secondary-progressive multiple sclerosis].

To study mechanisms of development of cognitive dysfunctions in multiple sclerosis (MS), brain glucose metabolism has been investigated using PET method. We have studied 61 patients with different types of MS course. Correlations between cognitive dysfunctions and regional glucose metabolic rate were revealed. The authors suggest that metabolic dysfunctions of the grey matter play the important role in the pathogenesis of cognitive disturbances in MS.

[Symptomatic epilepsy in inflammatory demyelinating diseases].

Based on the own observations, we have summarized the features of symptomatic epilepsy in multiple sclerosis and conducted a clinical analysis of the most diagnostically difficult cases of inflammatory and demyelinating diseases in which epilepsy was the major clinical syndrome. The cases of post-infectious acute disseminated encephalomyelitis, idiopathic cerebral angiitis, Rasmussen's encephalitis are reviewed. Peculiarities of MRI structural brain lesions in these patients are discussed. The use of additional laboratory studies, including a study of cerebrospinal fluid, is considered.

[Factor analysis of brain structure reorganization in patient with multiple sclerosis (based on pet data)].

The goal of present study was to investigate the functional reorganization of brain structures in patients with multiple sclerosis (MS). The patterns of distribution of relative estimations of local cerebral metabolic rate of glucose (ICMRglu) in regions of interest (ROIs), corresponding to anatomo-functional brain areas are obtained in groups of healthy volunteers (n=31 subjects) and patients with relapsing-remitting and progressive types of MS (n=59 and 39 accordingly). The analysis of factor structure of the obtained patterns allowed to make a conclusion about the existence of a common features with the factor structure of the distribution of another functional parameter--a regional cerebral blood flow (rCBF). This indicates that both factor solutions mainly reflect the functional organization of a brain. The differences revealed in factor structures of ICMRglu distribution in groups of patients with various types of MS and healthy volunteers allowed to assume that even at early stages of the disease despite the close anatomic and functional connectivity that normally exists between basal ganglia, MS patients have a functional dissociation of these structures. The bipolarity of revealed factors probably reflects the different directionality of the processes: relative decrease of functional activity in the areas which are directly responsible for performance of broken functions, caused by the deafferentation of the specified areas and its compensatory relative increase in functionally connected zones.

[Brain atrophy and neurological impairment in patients with multiple sclerosis].

An aim of the study was to investigate a relationship between global and local brain atrophy with neurological impairment (motor dysfunction) in multiple sclerosis (MS) patients with different levels of disease severity. Fifty five patients with definite MS (Mc Donald's criteria), aged 18-60 years, disease duration 1-30 years, and 25 healthy age-matched controls have been studied. Neurological assessment (Kurtzke and EDSS scales) was performed in the all patients. The patients were divided into 3 groups: EDSS<3.5 mild disability, EDSS 3.5-6.0 moderate disability, EDSS>6.0 severe disability. In MS patients, the global brain atrophy was accompanied by the local atrophy of subcortical structures (thalamus, basal ganglia) and cerebellum. The processes of cerebral grey matter total and local atrophy were not similar. The progression of MS, neurological impairment is accompanied by the cerebellum and lentiform nuclei atrophy. There was the decrease of brain parenchyma volume, nucleus caudate and cerebellar local atrophy in patients with moderate disability. The severe disability was correlated with the thalamic atrophy and marked basal ganglia and cerebellar atrophy. Thus, we can suppose that the thalamic atrophy is important for the development of severe motor dysfunctions in MS patients.

[Neuromyelitis optica: problems of heterogeneity and systematization].

Prospective-retrospective data on 10 cases of neuromyelitis optica (NO) have been analyzed. Demographic and clinical features of patients with primary NO as well as NO comorbid with other organospecific disorders are discussed. Magnetic-resonance imaging data of the brain and spinal cord are summarized and discussed in the context of its heterogeneity. Positron emission tomography with the functional imaging of the brain performed in 3 patients revealed changes in glucose metabolism in the brain regions corresponding to deficits in motor and sensory functional systems. The issues of additional laboratory analyses, including those of cerebrospinal fluid, are reviewed.