[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.

[Relapsing-remitting multiple sclerosis: clinical and immunological aspects of the pathology on the example of molecules Sema4D and CD72]. / Remittiruyushchii rasseyannyi skleroz: kliniko-immunologicheskie aspekty patologii na primere molekul Sema4D i CD72.

OBJECTIVE: To study the expression of Sema4D (CD100), receptor CD72 and a role of Sema4D-CD72-dependent signal in the control of the functions of immunocompetent cells in relapsing-remitting multiple sclerosis (RRMS). MATERIAL AND METHODS: We studied 76 patients, including 52 with RRMS (41 in remission and 11 in exacerbation), 35 women (67.3%) and 17 men (32.7%) aged 18-55 years, who did not receive disease-modifying drugs, and 24 healthy donors. A controlled clinical and immunological examination of patients with RRMS was carried out proving the involvement of the Sema4D molecule and its CD72 receptor in pathological reactions in this autoimmune disease. RESULTS AND CONCLUSION: The use of SemaD as a target in the treatment of RRMS is scientifically substantiated. In case of a positive decision on the use of anti-Sema4D drugs, it will be necessary to take into account the effects of semaphorin not only in the central nervous system, but also in the immune system of patients with RRMS.

[Factors regulating the activity of b-lymphocytes, as potential biomarkers of multiple sclerosis]. / Faktory, reguliruiushchie aktivnost' V-limfotsitov, kak potentsial'nye biomarkery rasseiannogo skleroza.

AIM: To assess the possibility of using serum levels of chemokine CXCL13, B-cell activating factor (BAFF), interleukin 1 and 17 (IL-10, IL-17) as markers of the development/progression of multiple sclerosis (MS). MATERIAL AND METHODS: Sixty-seven patients with MS in remission and 14 healthy volunteers were examined. The levels of BAFF, CXCL13 and the main products of Th17 and Treg - interleukin 17 (IL-17) and IL-10 in the serum were determined, their relationship with clinical characteristics of MS during remission was assessed. RESULTS AND CONCLUSION: The content of IL-17 and BAFF in the serum of patients with MS did not differ significantly from the control group, and the levels of IL-10 and CXCL13 were lower than the corresponding indicators of healthy donors. In patients with MS, no correlation was found between IL-17, IL-10, BAFF and clinical characteristics of MS. The level of CXCL13 correlated with quality of life, fatigue, clinical and functional status of patients. According to the results of this study, BAFF and CXCL13 cannot be proposed as diagnostic biomarkers of MS.

[The association of psychological gender characteristics with quality of life and clinical aspects in patients with multiple sclerosis]. / Sviaz' gendernykh osobennostei patsientov s rasseiannym sklerozom s kachestvom zhizni i klinicheskimi osobennostiami zabolevaniia.

AIM: To study the association between psychological gender characteristics and illness duration, severity of disability, asthenia, depression, anxiety and quality of life in multiple sclerosis (MS). MATERIAL AND METHODS: One hundred patients (62 females and 38 males) with multiple sclerosis were studied. The following methods were used: The Mini-Mental State Examination, The Bem Sex Role Inventory adapted in Russia, The Expanded Disability Status Scale, The Multidimensional Fatigue Inventory-20, The Beck Depression Inventory, The Spilberger State-Trait Anxiety Inventory, The Short Form-36 (The Life Quality Questionnaire). RESULTS AND CONCLUSION: The majority of patients had an androgynous type of psychological gender, some of patients were feminine. It was shown that there was an association between the number of feminine and masculine traits and MS duration, worsening of disability characteristics and life quality, increase in asthenia, depression and anxiety.

[Relapsing-remitting multiple sclerosis: clinical and immunological aspects of the pathology on the example Sema4D and CD72]. / Remittiruiushchii rasseiannyi skleroz: kliniko-immunologicheskie aspekty patologii na primere molekul Sema4D i CD72.

AIM: To explore the expression of Sema4D, CD72 receptor and a role of Sema4D-CD72 signal in the control of immunocompetent cell function in remitting-relapsing multiple sclerosis (RRMS). MATERIAL AND METHODS: Fifty-two patients with RRMS diagnosis according to 2010 revised McDonald's criteria were studied. The control group included 24 healthy people. A flow cytometry method was used to measure the expression of semaphorin Sema4D by T-lymphocytes of peripheral blood, expression of CD72 receptor by B-lymphocytes, percentage of cells containing pro- and anti-inflammatory cytokines. The level of soluble Sema4D (sSema4D) was evaluated by ELISA. RESULTS: The level of Sema4D expression on T-lymphocytes (Mean Fluorescence Intensity - MFI) prevailed in cell subpopulations in patients with RRMS compared with the control group. Characteristics of membrane and sSema4D correlate with clinical presentations of the autoimmune disease. An increase in sSema4D level during cell cultivation was identified in RRMS patients. The results show the involvement of Sema4D in the hyperactivation of B-cell-mediated immunity through CD72 receptor and induction of proinflammatory cytokine synthesis. CONCLUSION: RRMS is associated with elevated expression of Sema4D in the immune system. Membrane and sSema4D involved in the pathological process in RRMS. The authors suggest several mechanisms of the involvement of semaphorin and its receptor in the pathogenesis of RRMS: the direct damage of nervous tissues by sSema4D penetrated through the blood brain barrier disrupted in RRMS or by membrane Sema4D due to the infiltration of the central nervous system by T-lymphocytes and hyperactivation of B-cell-mediated immunity.

[The effect of psychological gender on adherence to immunomodulatory therapy in patients with multiple sclerosis]. / Vliianie gendera bol'nykh rasseiannym sklerozom na priverzhennost' immunomoduliruiushchei terapii.

AIM: To study the association between psychological gender and adherence to immunomodulatory therapy in patients with multiple sclerosis. MATERIAL AND METHODS: Thirty-four patients (25 women and 9 men) with the diagnosis of multiple sclerosis were examined. The following methods were used: MMSE, The Bem Sex Role Inventory adapted in Russia, Beck Depression Inventory, State-Trait Anxiety Inventory. During three months patients reported the first and the last immunomodulator injections dates from every new pack. Then the patients' self-reports systematization and analysis were performed, drug-taking compliance and timing compliance were calculated. RESULTS AND CONCLUSION: Twenty-eight patients had an androgynous type of psychological gender and six persons were feminine. The association was determined between high compliance and such psychological gender peculiarities as a significantly large number of feminine traits than masculine ones and the low number of masculine characteristics in men.

[Interferon-induced depression and peripheral blood serotonin in patients with multiple sclerosis]. / Interferon-indutsirovannaia depressiia i soderzhanie serotonina v perifericheskoi krovi u bol'nykh rasseiannym sklerozom.

AIM: To study the dynamics of anxiety-depressive disorders and peripheral blood serotonin in patients with multiple sclerosis (MS) during interferon-ß (IFN-ß) therapy. MATERIAL AND METHODS: The level of anxiety and depression in 227 MS patients was measured by psychometric testing at baseline and during treatment. The concentration of serotonin in serum of patients was determined by enzyme immunoassay. RESULTS: The presence of emotional disorders in patients with MS was confirmed. Their relationship with personality characteristics of the patient, the course of the disease and social status was shown. The level of humoral serotonin was lower in patients with MS. The relationship between the serotonergic system deficiency in patients with MS and anxiety disorders was shown. Interferon-induced depression was not associated with serotonin metabolism. It is a multifactor condition influenced by the patient's initial emotional level, personality characteristics, psychological reaction to therapy and the unfavorable dynamics of the disease. CONCLUSION: IFN-ß does not appear to induce depression in MS patients.

[The case-report of progressive multifocal leukoencephalopathy in a patient with multiple sclerosis treated with natalizumab]. / Sluchai razvitiia progressiruiushchei mul'tifokal'noi leikoéntsefalopatii u patsienta s rasseiannym sklerozom na fone priema natalizumaba.

The article describes the first case of progressive multifocal leukoencephalopathy in a patient with multiple sclerosis, developed during treatment with natalizumab. The causes, possibly, influencing the outcome of the disease, are analyzed.

[Primary progressive multiple sclerosis: current issues of timely diagnosis]. / Pervichno-progressiruiushchii rasseiannyi skleroz: sovremennoe sostoianie problemy svoevremennoi postanovki diagnoza.

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.

[A chronic fatigue syndrome and blood platelet serotonin levels in patients with multiple sclerosis]. / Sindrom khronicheskoi ustalosti u bol'nykh rasseiannym sklerozom i soderzhanie serotonina v trombotsitakh perifericheskoi krovi.

Sixty patients with multiple sclerosis and 12 healthy controls were examined. The fatigue was measured by the Fatigue Severity Scale (FSS). Concentration of platelet serotonin was analyzed with immunoassay techniques («Serotonin ELISA"). The results of the study have shown the primary role of fatigue in multiple sclerosis, with the prevalence of this syndrome reached 57.6%. The patients with multiple sclerosis had low concentration of platelet serotonin that was correlated with clinical features of the disease.

[Brain-derived and ciliary neurotrophic factors in patients with multiple sclerosis]. / Mozgovoi i tsiliarnyi neirotroficheskie faktory u bol'nykh rasseiannym sklerozom.

Objective. To study serum concentrations of BDNF and CNTF in patients with multiple sclerosis (MS) and compare them to clinical characteristics of MS. Material and methods. We examined 43 patients with confirmed diagnosis of MS according to McDonald's criteria with remitting type of disease course. Patients were in a stable condition and did not receive hormone treatment during the last 30 days. Serum concentrations of BDNF and CNTF were measured using ELISA. Results. Mean serum BDNF concentration was 7.9 (5.21; 14.7) ng/ml that was significantly lower (p=0.0001) compared to control values and was correlated with depression severity (r= -0.31, p=0.04) and physical asthenia (r= -0.32, p=0.04). CNTF concentration was 69.9 (31.2; 123.3) pg/ml (CNTF was not found in healthy people) and was correlated with the results of cognitive function assessment (the PASAT test) (r= -0.30, p=0.046). Conclusion. The difference in BDNF and CNTF serum concentrations between MS patients and healthy people and correlations with some clinical characteristics of MS provide evidence for the involvement of these factors in MS pathogenesis.

[The CD100 semaphorin expression on peripheral blood T-lymphocytes in patients with relapsing-remitting multiple sclerosis].

The expression of CD100 semaphorin by the intact peripheral blood T lymphocytes in multiple sclerosis (MS) has been studied. The level of middle florescence intensity (MFI) and the number of B-lymphocytes bearing CD72 were evaluated. There were significant differences in the level of CD100 in patients compared to healthy volunteers. These data suggest the use of semaphorin as a possible therapeutic target in pathological inflammation in MS.