Survey of diagnostic and treatment practices for multiple sclerosis in Russian Federation in comparison to European data.

INTRODUCTION: The data of the survey of European (EU) neurologists on the methods of diagnosis and treatment of multiple sclerosis in Europe were compared with the data of the similar survey of neurologists of the Russian Federation (RF). METHOD: Seventy-five neurologists specialized in MS from RF completed questionnaires on radiologically isolated syndrome (RIS), clinically isolated syndrome (CIS), relapsing-remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS) multiple sclerosis. RESULTS: In the case of RIS, only 46% of neurologists from the RF recommended CSF analysis for oligoclonal IgG and only 54.3% performed magnetic resonance imaging (MRI) of the spinal cord, which is significantly lower than in the EU (78% and 80%, respectively). In the case of CIS, significantly more neurologists from the Russian Federation would have tested for antibodies to disorders of the optical spectrum of neuromyelitis (57% in the EU and 94% in the RF). In case of typical RRMS, more neurologists from the RF preferred to start with the second line of disease-modifying therapy (DMT), a lower percentage would choose dimethyl fumarate as the first line DMT (9% in the RF and 25% in the EU). In case of escalating therapy, the majority of EU respondents (68%) indicated that one relapse would be sufficient (only 28% in RF), while in RF, 58% indicated that two relapses would be sufficient (22% in EU). Fewer neurologists from RF would use fingolimod, natalizumab or mitoxantrone for SPMS. 91% of neurologists in RF would like to prescribe ocrelizumab for PPMS. CONCLUSION: MS specialists from RF are less active in monitoring RIS than MS specialists from EU. CIS is not indication to use any DMT in RF. MS specialists in RF are more conservative in changing DMT as escalation in cases with breakthrough RRMS. The products without indication to be used in SPMS are rarely prescribed in RF in comparison to EU. Most cases of PPMS in RF would be treated with ocrelizumab.

Real-world study of efficacy, risk management and reasons for discontinuation of natalizumab for treatment of multiple sclerosis in Russia.

BACKGROUND: NTZ is approved in Russia for the treatment of highly active relapsing remitting multiple sclerosis and is reimbursed via federal budget program. However, no data about NTZ treatment in Russia and the effect of federal reimbursement have been performed so far. OBJECTIVE: To characterize the population of patients receiving natalizumab and assess the efficacy and risk-management plan (RMP) implementation of NTZ therapy in routine clinical practice in Russia. METHODS: We analyzed data for 334 patients, who received at least one infusion of NTZ. Relapse rate, MRI activity, NEDA-3 status after 2 years were assessed. Anti-JC virus antibodies status and RMP implementation were evaluated. Drop-out rate and reasons for therapy discontinuation were analyzed. RESULTS: Patients switched to natalizumab in Russia are mainly female (63%), with median EDSS score of 3.5 and high disease activity: 93% had at least 1 relapse and 58% had both T1Gd+ and new T2 lesion a year before therapy initiation. Introduction of federal reimbursement allowed patients with less relapses to start therapy with natalizumab. The only predictor of 6-month progression was EDSS score at the baseline of therapy (HR = 2.1375, 95%CI 1.0026-4.5570, p = 0.0492). 82% patients reached NEDA-3 at 24 month of therapy. 25% of patients discontinued NTZ for reasons: tolerability (14.5%), JCV antibody status (61%), and patient's decision (17%). RMP was implemented in only 36% patients. CONCLUSION: Natalizumab appeared to have high efficacy in Russian clinical practice. Federal reimbursement allowed less active patients to start natalizumab. More efforts should be done to improve RMP implementation.

Pharmacogenetics of glatiramer acetate therapy for multiple sclerosis: the impact of genome-wide association studies identified disease risk loci.

AIM: Association analysis of genome-wide association studies (GWAS) identified multiple sclerosis (MS) risk genetic variants with glatiramer acetate (GA) treatment efficacy. PATIENTS & METHODS: SNPs in 17 GWAS-identified immune response loci were analyzed in 296 Russian MS patients as possible markers of optimal GA treatment response for at least 2 years. RESULTS: Alleles/genotypes of EOMES, CLEC16A, IL22RA2, PVT1 and HLA-DRB1 were associated by themselves with event-free phenotype during GA treatment for at least 2 years (p f  = 0.032 - 0.00092). The biallelic combinations including EOMES, CLEC16A, IL22RA2, PVT1, TYK2, CD6, IL7RA and IRF8 genes were associated with response to GA with increased significance level (p f  = 0.0060 - 1.1 × 10-5). The epistasic interactions or additive effects were observed between the components of the identified biallelic combinations. CONCLUSION: We pinpointed the involvement of several GWAS-identified MS risk loci in GA therapy efficacy. These findings may be aggregated to predict the optimal GA response in MS patients.

Allelic combinations of immune-response genes as possible composite markers of IFN-ß efficacy in multiple sclerosis patients.

BACKGROUND: IFN-ß is widely used as the first-line disease-modifying treatment for multiple sclerosis. However, 30-50% of multiple sclerosis patients do not respond to this therapy. Identification of genetic variants and their combinations that predict responsiveness to IFN-ß could be useful for treatment prognosis. MATERIALS & METHODS: The combinations of alleles of nine polymorphic loci in immune-response genes were analyzed in 253 Russian multiple sclerosis patients as possible determinants of clinically optimal IFN-ß treatment response using APSampler software. RESULTS: Carriage of TGFB1*-509C and CCR5*d was associated with favorable IFN-ß response by itself. CCR5*d, IFNAR1*16725G, IFNG*874T and IFNB1*153T/T were the components of the combinations, associated with clinically optimal response to IFN-ß. Carriage of composite markers (CCR5*d + IFNAR1*G + IFNB1*T/T) or (CCR5*d + IFNAR1*G + IFNG*T) is beneficial for IFN-ß treatment efficacy. DISCUSSION: The data obtained provides evidence of the cumulative effect of immune-response genes on IFN-ß treatment efficacy. This joint contribution may reflect the additive effect of independent allelic variants and epistatic interactions between some of them.

Allelic combinations of immune-response genes associated with glatiramer acetate treatment response in Russian multiple sclerosis patients.

BACKGROUND: Glatiramer acetate (GA) is widely used as a first-line disease-modifying treatment for multiple sclerosis (MS). However, a significant proportion of MS patient appears to experience modest benefit from GA-treatment. Genetic variants affecting the clinical response to GA are believed to be relevant as biomarkers of GA-treatment efficiency. PATIENTS & METHODS: Nine polymorphisms in candidate genes were analyzed as possible determinants of GA response in 285 Russian MS patients. Special attention was given to identification of response-associated allelic combinations by means of the APSampler algorithm. RESULTS: No significant associations were found for individual polymorphisms. Alleles DRB1*15, TGFB1*T, CCR5*d and IFNAR1*G were the components of the combinations, of which carriage was significantly higher in nonresponders than in responders. Carriers of the most significant combinations: DRB1*15 + TGFB1*T + CCR5*d + IFNAR1*G and DRB1*15 + TGFB1*T + CCR5*d (permutation p-values: 0.0056 and 0.013, respectively) had a 14 to 15-times increased risk of ineffective response to GA therapy. DISCUSSION: The results suggest that the influence of immune-response genes on GA-induced response has a polygenic nature. The data are interpreted as evidence of additive and epistatic influences of the genes on GA efficiency for MS treatment.