[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.

[Assessment of the efficacy and safety of alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis in Russian population]. / Otsenka effektivnosti i bezopasnosti alemtuzumaba u patsientov s vysokoaktivnym techeniem rasseyannogo skleroza v rossiiskoi populyatsii.

OBJECTIVE: To evaluate the severity and frequency of infusion reactions (IR) in patients with highly active relapsing-remitting multiple sclerosis (MS) In Russian population receiving alemtuzumab therapy. MATERIAL AND METHODS: In retrospective study, we analyzed data from 50 patients with highly active relapsing-remitting multiple sclerosis (MS) from six Regional MS Centers in the Russian Federation who received two courses of alemtuzumab between 2018 and 2022. RESULTS: Among all IRs, the most frequently reported were hives-like rashes, which were registered in 27 people, mostly of mild severity (70.6%). Headaches were the second most common IR, observed in 17 patients (34%). When comparing the group of patients who underwent music therapy (MT) with those who received alemtuzumab therapy without MT, no statistically significant difference was found in the frequency and severity of IRs. CONCLUSION: All patients experienced IRs of varying degrees of severity. A decrease in the score on the EDSS disability scale was noted. MT did not affect the occurrence or severity of IRs.

[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.

[Traumatic brain injury before the multiple sclerosis onset: a relationship with the progression of neurological disorders and pathobiochemical markers of the cerebrospinal fluid]. / Cherepno-mozgovaya travma do debyuta rasseyannogo skleroza: svyaz' s progressirovaniem nevrologicheskikh rasstroistv i patobiokhimicheskimi pokazatelyami tserebrospinal'noi zhidkosti.

OBJECTIVE: To evaluate the association of traumatic brain injury (TBI) before the multiple sclerosis (MS) onset with the rate of progression of neurological disorders and cerebrospinal fluid markers of blood-brain barrier permeability, inflammation, demyelination, and gliosis. MATERIAL AND METHODS: Patients with relapsing-remitting MS in the Altai region of Russia with/without TBI before the MS onset (n=44; 19 men, 25 women in each group) participated in a prospective, controlled, randomized study. Disability rate was assessed retrospectively. Pleocytosis, levels of protein, albumin, C-reactive protein, TNF-alpha, myelin basic protein, S100 protein were measured in the cerebrospinal fluid in subgroups of patients (n=14 in each group) in MS remission and exacerbation. RESULTS: Concussion and mild brain contusion were documented in the group of patients with TBI before the MS onset in 35 (79.5%) and 9 (20.5%) patients, respectively. Traumatic brain injury was over the age of 15 in 72.5% of patients. The rate of MS progression was higher in the group with TBI compared to the group without TBI (0.76±1.28 and 0.40±0.43 EDSS points per year, respectively; p=0.014). TBI before the MS onset increases the risk of disability by more than 0.25 EDSS points per year (OR 2.74; 95 CI 1.10-6.85; p=0.029). Intergroup differences in cerebrospinal fluid parameters were not found either during MS exacerbation or remission. CONCLUSION: Concussion or mild brain contusion before the MS onset may be factors influencing the progression of neurological deficit in MS. It seems relevant to study the mechanisms of adverse effects of TBI on the MS progression.

[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.

[Therapy of moderate cognitive impairment and asthenia in patients with cerebrovascular pathology: results of a prospective observational study]. / Terapiya umerennykh kognitivnykh narushenii i astenii u patsientov s tserebrovaskulyarnoi patologiei: rezul'taty mnogotsentrovoi otkrytoi prospektivnoi nablyudatel'noi programmy.

OBJECTIVE: Obtaining additional data on the efficacy and safety of the drug Prospekta in the treatment of moderate cognitive impairment (MCI) and asthenia in patients with cerebrovascular disease (CVD). MATERIAL AND METHODS: A prospective observational study in more than 40 Russian cities enrolled 232 patients (mean age 61.5±10.0 years) with mild cognitive impairment (MCI), asthenia on ongoing basic nootropic therapy. The presence of MCI was confirmed by the Montreal Cognitive Assessment Scale (MoCA), asthenia - by 10-point Visual Analog Scale (VAS). All patients were prescribed the nootropic medication Prospekta 2 tablets 2 times a day for 8 weeks in addition to the therapy they received. Ultrasound Doppler sonography of the main arteries of the head and magnetic resonance imaging (MRI) of the brain were also assessed. At the end of treatment, the Clinical Global Impression Efficacy Index (CGI-EI) was assessed and the safety of the treatment was evaluated. RESULTS: The baseline severity of cognitive impairment according to the MoCA scale was 21.6 points, severity of asthenia according to the VAS was 6.3 points. According to Doppler flowmetry findings, hemodynamically significant stenosis was revealed in 105 (49.3%) patients, and narrowing of the main vessels without changes in hemodynamic parameters was revealed in 108 (50.7%) patients. According to MRI results, single vascular lesions in the brain matter were detected in 102 (44.0%) patients. The medications with nootropic effect were administered to 144 (62.1%) patients. A positive therapeutic response as improvement of cognitive functions was seen in 93.3% of patients after 8 weeks of taking Prospekta, including 39.4% of patients who had cognitive functions restored to the normal level. No side effects were registered during the observational study. CONCLUSIONS: The nootropic medication Prospekta is effective and safe in treatment of MCI in patients with asthenia with CVD, and improves cognitive function in patients with asthenia with CVD, both in monotherapy and in combination with other nootropic agents.

[Association of vitamin D metabolism enzyme gene polymorphisms with multiple sclerosis risk: pilot study]. / Svyaz' polimorfizmov genov fermentov metabolizma vitamina D s riskom rasseyannogo skleroza: pilotnoe issledovanie.

OBJECTIVE: To evaluate the association polymorphisms in genes coding for enzymes involved in vitamin D metabolism CYP27B1 (rs703842) and CYP24A1 (rs2248359) with the risk of multiple sclerosis (MS). MATERIAL AND METHODS: Ninety Caucasian patients with remitting MS and 87 volunteers without MS, born and living in the Altai region of Russia, participated in the study. Genotyping was performed by the TaqMan probe method. RESULTS: No association of MS with genotypes or alleles of CYP24A1 (rs2248359) is found. CYP27B1C (rs703842) is associated with the risk of MS in women. The TC genotype CYP27B1C (rs703842) is associated with an increased risk of MS (Odd Ratio 3.43; 1.48-7.93, p=0.004), while the TT genotype, on the contrary, has a protective effect on the susceptibility to MS (Odd Ratio 0.31; 0.14-0.72, p=0.005). CONCLUSION: The results indicate an increased risk of MS in female carriers of the TC genotype CYP27B1 (rs703842) and a low probability of the contribution of the CYP24A1 polymorphism (rs2248359) to the predisposition to MS in Caucasians of the Altai region.

[Association between vitamin D status and CYP27b1 and CYP24A1 gene polymorphisms in patients with multiple sclerosis in the Altai region]. / Assotsiatsiya soderzhaniya vitamina D s polimorfizmami genov CYP27B1 i CYP24A1 u bol'nykh rasseyannym sklerozom v Altaiskom krae.

Multiple sclerosis (MS) is often accompanied by a deficiency of vitamin D, the causes of which are not exactly clear how. It is suggested that this may be due to genetically determined characteristics of enzymes of vitamin D3 metabolism in patients with MS. OBJECTIVE: To evaluate the relationship between vitamin D status and polymorphisms of the genes encoding enzymes of the vitamin D metabolism CYP27B1 (rs703842) and CYP24A1 (rs2248359) in patients with MS. MATERIAL AND METHODS: Caucasians born and living in the Altai region of the Russian Federation, 90 patients with relapsing-remitting MS and 87 volunteers without MS took part in the study. The level of 25-hydroxyvitamin D (25(OH)D) in the blood serum was measured by enzyme immunoassay. Genotyping was carried out using the TaqMan probe method. RESULTS: A level of 25(OH)D of less than 30 ng/ml was more common among patients with MS compared with the control. A relationship between the MS risk and the TC genotype CYP27B1 (rs703842) was identified. In patients with MS and in the control, the GA genotype CYP24A1 (rs2248359) was associated with a 25(OH)D level of less than 30 ng/ml. CONCLUSION: The high prevalence of vitamin D deficiency in patients with MS may be associated with the genetically determined features of CYP27B1.

[Multiple sclerosis in the Altai region of Russia: a prospective epidemiological study]. / Rasseiannyi skleroz v Altaiskom krae: rezul'taty prospektivnogo épidemiologicheskogo issledovaniia.

AIM: Analysis of the dynamics of epidemiological indicators of multiple sclerosis (MS) in the Altai region of the Russian Federation for the period from 2009 to 2017. MATERIAL AND METHODS: A comparative analysis of the prevalence, incidence and main clinical characteristics of MS in the Altai region was carried out based on the data of patients with MS from 2009 (1001 patients) to 2017 (1322 patients). RESULTS AND CONCLUSION: The prevalence of MS increased from 41.2 to 56.3 per 100 000. The higher prevalence of the disease in cities compared to villages (by 1.8 times) and the ratio of women and men about 2 0 have not changed. About 2% of patients have a family history of MS. The average age of MS onset did not change significantly during the period analyzed (28.5±9.9 years in 2017). The remitting type of the disease is the most common (73%). The incidence of MS was 1.1±0.3 and 2.6±0.5 cases per 100 000 in 1998-2009 and 2010-2017, respectively. Patients with pediatric MS make up 6.5% of all patients with MS. The clinical features of MS onset before the age of 18 compared to the onset at a later age are the lower frequency of motor disorders, pelvic organ dysfunction (no cases were detected), general brain symptoms detectability (10.5%). CONCLUSION: The population of the Altai region is at high risk of MS. Monitoring and analysis of the dynamics of clinical and epidemiological characteristics of MS are rational for the planning of medical care for patients with MS.

[Pathological and protective effects of tumor necrosis factor-alpha in multiple sclerosis]. / Patologicheskie i protektivnye éffekty faktora nekroza opukholi-al'fa pri rasseiannom skleroze.

The immunomodulatory cytokine tumor necrosis factor-alpha (TNF-α) is involved in the regulation of both physiological and pathological processes in the central nervous system (CNS). The effects of TNF-α on CNS reported in clinical trials and experimental studies, evidence of involvement of this cytokine in the pathogenesis of multiple sclerosis are analyzed. Possible causes of failures of non-selective pharmacological inhibition of TNF-α effects in MS are considered in view of current concepts on mechanisms of TNF-α action.

[The efficacy and safety of siponimod in the Russian population of patients with secondary progressive multiple sclerosis]. / Éffektivnost' i bezopasnost' siponimoda u patsientov s vtorichno-progressiruiushchim rasseiannym sklerozom v rossiiskoi populiatsii.

AIM: To study the efficacy and safety of siponimod in patients with secondary progressive multiple sclerosis (SPMS) in the Russian population of the EXPAND study. MATERIAL AND METHODS: 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. RESULTS: 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. CONCLUSION: The use of siponimod in patients with SPMS in the Russian population reduced the risk of disability progression. Siponimod showed a favorable safety profile.

[The association of the FAS/APO-1 (rs2234767) gene polymorphism with the risk and rapid progression of multiple sclerosis]. / Assotsiatsiia polimorfizma gena FAS/APO-1 (rs2234767) s riskom razvitiia i bystrogo progressirovaniia rasseiannogo skleroza.

AIM: To evaluate the association of the FAS/APO-1 (rs2234767) gene polymorphism with the risk of multiple sclerosis and its progression dynamics. MATERIAL AND METHODS: A case-control study included 100 patients with recurrent multiple sclerosis (MS), Russians from the Altai Territory, and 100 healthy volunteers. Real-time polymerase chain reaction was used to genotype the 1377G>A polymorphism in the promoter of the FAS/APO-1 (rs2234767) gene. Association of this polymorphism with the risk of multiple sclerosis and its progression was evaluated. RESULTS: The G/А genotype and the А-allele were associated with the increased risk of multiple sclerosis. The G/А genotype and the А-allele were associated with the risk of high progression rate of the disease. The G/G genotype and the G-allele had a protective effect. CONCLUSION: Predisposition to MS as well as to high progression rate are associated with the FAS/APO-1*G/А gene in Russians living in the Altai Territory. Further research is required to make the conclusion.

[A study of the relation between the sCD40-sCD40L system and the course of multiple sclerosis]. / Issledovanie sviazi mezhdu sistemoi sCD40-sCD40L i techeniem rasseiannogo skleroza.

AIM: To determine the relationship between the level of soluble CD40 and CD40L (sCD40, sCD40L) and key characteristics of the course of multiple sclerosis. MATERIAL AND METHODS: A comparative cross-sectional study covered 80 patients with multiple sclerosis diagnosed according to 2005 McDonald criteria. Enzyme immunoassay method was applied to measure the concentration of sCD40 and sCD40L in venous blood serum. RESULTS: No significant changes in sCDL or sСD levels were found during acute MS periods in comparison to remission periods. The positive correlation between the frequency of exacerbations and the level of sCDL was shown. CONCLUSION: No evidence for the association between indexes of activity of the sCD40-sCD40L system in blood and both exacerbation of MS, severity and rate of neurological impairment in this disease was demonstrated.

[Relationship between biochemical parameters of cerebrospinal fluid and the course of multiple sclerosis].

We examined 60 patients with remitting multiple sclerosis (disability 3,5±1.6 EDSS scores). The relative risk of rapid progression of neurologic impairment was associated with the higher levels of matrix metalloproteinase-2, soluble platelet endothelial cell adhesion molecule-1 (sPECAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in the cerebrospinal fluid. The relative risk of exacerbation of the disease in the next three years was associated with the level of tumor necrosis factor alpha and matrix metalloproteinase-2.

[The first results of a combined all-Russian study on clinical genetics of multiple sclerosis].

Multiple sclerosis is a classic multifactorial disease in which etiology interaction of external factors and structural features of a large number of genes plays an important role. Identifying risk factors for multiple sclerosis and creating an integrated model of pathogenesis are urgent tasks of neurology. Revealing true risk factors is possible only in studies with sufficient statistical power, so with a large amount of samples. We conducted the association study of CD40 gene's polymorphisms and multiple sclerosis among residents of the Russian Federation. The results demonstrated the need to combine data from different researchers in clinical studies to increase the power of the study.

[Factors associated with the more rapid progression of multiple sclerosis].

To study the association between disease progression and some clinical features and biochemical spinal fluid parameters, we have examined 209 patients with remitting type of multiple sclerosis. The more rapid progression of multiple sclerosis was associated with male sex, a history of brain concussion, a short first remission, late disease onset, movement disorders at onset of the disease and the high level of platelet endothelial cell adhesion molecule 1 (sPECAM-1) in the spinal fluid.

[Genetic risk factors for multiple sclerosis in the population of Altay].

The "case-control" research in Russian Altai territory population has proved that DR15 and DR3 as well as the combination of female sex and alleles A of TNFα of rs1800629 locus are associated with high risk of multiple sclerosis. The relationship between disease and CD40 polymorphism (rs6074022) was not found.

[Adhesion molecule in the cerebrospinal fluid in multiple sclerosis].

Levels of adhesion molecules were measured in 24 patients with multiple sclerosis during the 3-years prospective study. The high level of adhesion molecules sPECAM in the cerebrospinal fluid was associated with the appearance of new foci according to the magnetic resonance imaging data as well as with quick disability.