AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

• MeSH
• analýza nákladové efektivity MeSH
• analýza nákladů a výnosů MeSH
• fingolimod hydrochlorid terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• lidé MeSH
• natalizumab terapeutické užití   MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• státní lékařství MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Spojené království MeSH

Okrelizumab je první monoklonální protilátka zamířená proti povrchovému znaku CD20 vyskytujícím se na subpopulaci B lymfocytů, která byla schválena pro léčbu roztroušené sklerózy. Doposud byla tato léčba dostupná pouze jako intravenózní forma s relativně dlouhou dobou podávání, byť vysokou účinností. Od července tohoto roku byla schválena její subkutánní forma, a to na základě studie OCARINA II, ve které participovalo i naše centrum. V tomto krátkém sdělení shrnujeme základní dosažené výsledky ze studie i naše vlastní zkušenosti s touto léčbou, jejíž subkutánní forma má potenciál odlehčit našim pacientům s dávkováním jednou za půl roku. Nová forma přichází i ve spojitosti se zajímavou technologií rekombinantní hyaluronidázy, která umožňuje podávání velkých objemů subkutánně, což byl donedávna limitující faktor subkutánních terapií obecně.

Ocrelizumab is the first monoclonal antibody targeting the CD20 surface marker found on a subpopulation of B lymphocytes, which has been approved for the treatment of multiple sclerosis. Until now, this treatment was only available as an intravenous form with a relatively long administration time, albeit with high efficacy. As of July this year, its subcutaneous form has been approved based on the OCARINA II study, in which our center also participated. In this brief report, we summarize the basic achieved results from the study as well as our own experiences with this treatment, whose subcutaneous form has the potential to ease the burden on our patients with dosing once every six months. The new form also comes with an interesting recombinant hyaluronidase technology that allows the administration of large volumes subcutaneously, which has been a limiting factor for subcutaneous therapies in general until recently.

• Klíčová slova
• okrelizumab,
• MeSH
• antigeny CD20 účinky léků   MeSH
• humanizované monoklonální protilátky * terapeutické užití   MeSH
• injekce subkutánní * metody   MeSH
• intravenózní podání metody   MeSH
• klinická studie jako téma metody   MeSH
• lidé MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• Check Tag
• lidé MeSH

Ocrelizumab is a second generation recombinant humanized IgG1 monoclonal antibody used for the treatment of multiple sclerosis that selectively target B cells expressing the CD20 antigen. This study aimed to develop and validate a UPLC-MS/MS method for quantification of ocrelizumab in human serum, which can be used in clinical applications for therapeutic drug monitoring. The analysis of ocrelizumab was performed using a bottom-up approach on a liquid chromatography coupled to tandem mass spectrometry detection. The method involved immunoglobulin precipitation with cold methanol followed by peptide digestion with trypsin. The resulting specific peptides were separated on an Acquity UPLC BEH C18 column at 55 °C using gradient elution. The method was validated according to European Medicines Agency (EMEA) guidelines and demonstrated intra- and inter-assay precision with coefficients of variation ranging from 1.6 % to 6.1 % and accuracies between 90.2 % and 107.2 %. Stability testing, including autosampler, long-term and freeze-thaw stability, showed no more than 15 % variation. The method was successfully applied to 169 patient samples, revealing ocrelizumab concentrations ranging from 0.5 to 21.8 mg/L in patients on 6-month dosing regimen and 20.5-65.0 mg/L in 16 patients receiving an initial two-week dose of 300 mg. The newly developed UPLC-MS/MS method met all criteria for accuracy, precision and stability, confirming its suitability for clinical use in monitoring ocrelizumab levels in multiple sclerosis patients.

• MeSH
• chromatografie kapalinová metody   MeSH
• humanizované monoklonální protilátky * terapeutické užití   krev   MeSH
• lidé MeSH
• monitorování léčiv metody   MeSH
• roztroušená skleróza * farmakoterapie   krev   MeSH
• tandemová hmotnostní spektrometrie * metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND OBJECTIVES: Women with multiple sclerosis (MS) are at risk of disease reactivation in the early postpartum period. Ocrelizumab (OCR) is an anti-CD20 therapy highly effective at reducing MS disease activity. Data remain limited regarding use of disease-modifying therapies (DMTs), including OCR, and disease activity during peripregnancy periods. METHODS: We performed a retrospective cohort study using data from the MSBase Registry including pregnancies conceived after December 31, 2010, from women aged 18 years and older, with relapsing-remitting MS or clinically isolated syndrome. Women were classified by preconception exposure to DMTs, including OCR, rituximab (RTX), natalizumab (NAT), stratified into active (NAT-A; continued ≥28 weeks of gestation, restarted ≤1 month postpartum) or conservative (NAT-C; continued ≤4 weeks of gestation, restarted >1 month postpartum) strategies, dimethyl fumarate (DMF) or low-efficacy DMTs (interferon-beta, glatiramer acetate). Annualized relapse rates (ARRs) were calculated for 12-month prepregnancy, pregnancy, and 6-month postpartum periods. RESULTS: A total of 2,009 live births from 1,744 women were analyzed, including 73 live births from 69 women treated with preconception OCR. For OCR, no within-pregnancy relapse was observed and 3 women (4.1%) experienced 1 relapse in the postpartum period (ARR 0.09 [95% CI 0.02-0.27]). For NAT-A, 3 (3.7%) of 82 women relapsed during pregnancy (0.05 [0.01-0.15]) and 4 (4.9%) relapsed during postpartum (0.10 [0.03-0.26]). However, for NAT-C, 13 (15.9%) of 82 women relapsed within pregnancy (0.32 [0.20-0.51]) and 25 (30.5%) relapsed during postpartum (0.74 [0.50-1.06]). In the low-efficacy DMT group, 101 (7.6%) of 1,329 women experienced within-pregnancy relapse (0.12 [0.10-0.14]), followed by an increase in postpartum relapse activity with 234 women (17.6%) relapsing (0.43 [0.38-0.48]). This was similarly seen in the DMF group with 13 (7.9%) of 164 women experiencing within-pregnancy relapse (0.12 [0.06-0.20]) and 25 (15.2%) of 164 relapsing postpartum (0.39 [0.26-0.57]). Our RTX cohort had 0 of 24 women experiencing within-pregnancy relapse and 3 (12.5%) of 24 experiencing postpartum relapse. DISCUSSION: Women treated with OCR or NAT-A were observed to have low relapse rates during pregnancy and postpartum. NAT-C was associated with increased risk of relapses. There was no within-pregnancy relapse in our RTX cohort, although we caution overinterpretation due to our sample size. An effective DMT strategy with a favorable safety profile for the mother and infant should be discussed and implemented well in advance of planning a family. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for women with relapsing-remitting MS or clinically isolated syndrome who become pregnant, ocrelizumab, rituximab, and natalizumab (continued ≥28 weeks of gestation and restarted ≤1 month postpartum) were associated with reduced risk of relapses, compared with other therapeutic strategies.

• MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * farmakologie   aplikace a dávkování   MeSH
• imunologické faktory * farmakologie   aplikace a dávkování   MeSH
• komplikace těhotenství * farmakoterapie   MeSH
• lidé MeSH
• mladý dospělý MeSH
• poporodní období * MeSH
• registrace MeSH
• relabující-remitující roztroušená skleróza farmakoterapie   MeSH
• retrospektivní studie MeSH
• roztroušená skleróza farmakoterapie   MeSH
• těhotenství MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

This review addresses current changes in the approach to treating patients with multiple sclerosis (MS). The widely practiced approach of utilizing agents with lower treatment efficacy (LETA) at onset with subsequent escalation has been challenged by new data suggesting that MS patients derive greater benefit when therapy is initiated with high-efficacy treatment agents (HETA). Several recent studies compared treatment efficacy and safety of early administration of HETA versus LETA. The results of randomized, double blind, phase III studies with LETA as a control arm and population-based larger and longer studies using propensity scoring, marginal structural modeling and weighted cumulative exposure analysis support the benefit of early treatment with HETA. Patients initiating their treatment with HETA, regardless of prognostic factors and MRI burden at baseline, showed significantly lower annualized relapse rate (ARR) and reduced disability progression in follow-up periods of up to 10-15 years. Moreover, the safety profile of recently approved HETA ameliorates concerns about off-target effects associated with a number of earlier high-efficacy drugs. Patient perception has also changed with an increasing preference for medication profiles that both improve symptoms and prevent disease progression. Accumulating data from randomized studies and the results of large population-based studies demonstrating short-term and longer-term patient benefits support the view that HETA should be more widely used. The adoption of early treatment with HETA capitalizes on a window of opportunity for anti-inflammatory drugs to maximally impact disease pathology and heralds a sea change in clinical practice toward pro-active management and away from a philosophy routed in generating clinical benefit as a consequence of treatment failure.

• MeSH
• léčivé přípravky MeSH
• lidé MeSH
• randomizované kontrolované studie jako téma MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   MeSH
• roztroušená skleróza * diagnostické zobrazování   farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

AIMS: The aim of this study was to evaluate the association of serum neurofilament heavy chain (sNfH) and chitinase 3-like 1 (sCHI3L1) with treatment response and disease activity in multiple sclerosis (MS). METHODS: This single-center, prospective, observational cohort study was conducted at the MS Centre, University Hospital Ostrava, Czech Republic, from May 2020 to August 2023. sNfH and sCHI3L1 were determined using ELISA. A mixed-effects linear model with a log-transformed outcome variable was applied. RESULTS: We analyzed 459 samples from 57 people with MS. Patients were sampled an average of 8.05 times during 21.9 months of follow-up. Those experiencing a relapse at sampling had a sNfH concentration 50 % higher than those in remission (exp(β) 1.5, 95 % CI 1.15-1.96). A longer duration of treatment was associated with lower sNfH (exp(β) 0.95, 95 % CI 0.94-0.96). Patients switched from low- to high-efficacy disease-modifying therapies (DMTs) had higher sNfH than patients treated with low-efficacy DMTs only (exp(β) 1.95, 95 % CI 1.35-2.81). Higher sCHI3L1 was associated with older age (exp(β) 1.01, 95 % CI 1.00-1.02) and longer DMT use (exp(β) 1.01, 95 % CI 1.00-1.02). sCHI3L1 values were not associated with relapse at the time of sampling, renal function, sex, or type of DMT. CONCLUSION: In contrast to sCHI3L1, sNfH may be a potential biomarker for monitoring treatment response and confirming clinical relapse in MS. Further research is needed to determine the long-term dynamics of sNfH and develop related treatment strategies.

• MeSH
• biologické markery * krev   MeSH
• dospělí MeSH
• hodnocení výsledků zdravotní péče MeSH
• imunologické faktory aplikace a dávkování   farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• následné studie MeSH
• neurofilamentové proteiny * krev   MeSH
• prospektivní studie MeSH
• protein CHI3L1 * krev   MeSH
• roztroušená skleróza krev   farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

Roztroušená skleróza je nejčastějším získaným chronickým zánětlivým demyelinizačním onemocněním CNS. Do diferenciální diagnostiky roztroušené sklerózy patří akutní diseminovaná encefalomyelitida, jež je monofázickým autoimunitním demyelinizačním onemocněním. Klinicky se akutní diseminovaná encefalomyelitida projevuje encefalopatií a multifokálním postižením. V rozlišení těchto dvou jednotek nám kromě klinického nálezu může pomoci magnetická rezonance a likvorologické vyšetření. Formou kazuistiky popisujeme vzácnou tumoriformní variantu roztroušené sklerózy, která se v úvodu projevila epileptickým záchvatem a encefalopatií.

Multiple sclerosis is the most common acquired chronic inflammatory demyelinating disease of the central nervous system. The diffferential diagnosis of multiple sclerosis includes acute disseminated encephalomyelitis, which is a monophasic autoimmune demyelinating disease. Clinically, acute disseminated encephalomyelitis is manifested by encephalopathy and multifocal involvement. In addition to clinical findings, magnetic resonance imaging and cerebrospinal fluid examination can hepl us to differentiate these two entities. This case report describes a rare variant of tumefactive multiple sclerosis, which was initially presented with epileptic seizure and encephalopathy.

• Klíčová slova
• ofatumumab,
• MeSH
• akutní diseminovaná encefalomyelitida diagnóza   terapie   MeSH
• demyelinizační autoimunitní nemoci CNS MeSH
• dospělí MeSH
• humanizované monoklonální protilátky aplikace a dávkování   terapeutické užití   MeSH
• imunosupresiva aplikace a dávkování   terapeutické užití   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• roztroušená skleróza * diagnóza   farmakoterapie   MeSH
• záchvaty etiologie   farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• kazuistiky MeSH

Anti-drug antibodies (ADA) reduce the efficacy of immunotherapies in multiple sclerosis (MS) and are associated with increased disease progression risk. Blood biomarkers predicting immunogenicity to biopharmaceuticals represent an unmet clinical need. Patients with relapsing remitting (RR)MS were recruited before (baseline), three, and 12 (M12) months after commencing interferon-beta treatment. Neutralising ADA-status was determined at M12, and patients were stratified at baseline according to their M12 ADA-status (ADA-positive/ADA-negative). Patients stratified as ADA-positive were characterised by an early dampened response to interferon-beta (prior to serum ADA detection) and distinct proinflammatory transcriptomic/proteomic peripheral blood signatures enriched for 'immune response activation' including phosphoinositide 3-kinase-γ and NFκB-signalling pathways both at baseline and throughout the treatment course, compared to ADA-negative patients. These immunogenicity-associated proinflammatory signatures significantly overlapped with signatures of MS disease severity. Thus, whole blood molecular profiling is a promising tool for prediction of ADA-development in RRMS and could provide insight into mechanisms of immunogenicity.

• MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• interferon beta * terapeutické užití   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• proteomika * MeSH
• relabující-remitující roztroušená skleróza * farmakoterapie   imunologie   krev   MeSH
• roztroušená skleróza farmakoterapie   imunologie   krev   MeSH
• stupeň závažnosti nemoci MeSH
• transkriptom * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Almost all currently licensed disease-modifying therapies (DMTs) for MS treatment require prolonged if not lifelong administration. Yet, as people age, the immune system has increasingly reduced responsiveness, known as immunosenescence. Many MS DMTs reduce the responsiveness of the immune system, increasing the risks for infections and possibly cancers. As people with MS (pwMS) age, it is recognized that inflammatory MS activity declines. Several studies have addressed de-escalation of DMTs for relapsing MS under special circumstances. Here, we review evidence for de-escalating DMTs as a strategy that is particularly relevant to pwMS of older age. Treatment de-escalation can involve various strategies, such as extended or reduced dosing, switching from high-efficacy DMTs having higher risks to moderately effective DMTs with lesser risks, or treatment discontinuation. Studies have suggested that for natalizumab extended dosing maintained clinical efficacy while reducing the risk of PML. Extended interval dosing of ocrelizumab mitigated the decline of Ig levels. Retrospective and observational discontinuation studies demonstrate that age is an essential modifier of drug efficacy. Discontinuation of MS treatment in older patients has been associated with a stable disease course, while younger patients who discontinued treatment were more likely to experience new clinical activity. A recently completed 2-year randomized-controlled discontinuation study in 260 stable pwMS > 55 years found stable clinical multiple sclerosis with only a small increased risk of new MRI activity upon discontinuation. DMT de-escalation or discontinuation in MS patients older than 55 years may be non-inferior to continued treatment with immunosuppressive agents having higher health risks. However, despite several small studies, a definite conclusion about treatment de-escalation in older pwMS will require larger and longer studies. Ideally, comparison of de-escalation versus continuation versus discontinuation of DMTs should be done by prospective randomized-controlled trials enrolling sufficient numbers of subjects to allow comparisons for MS patients of both sexes within age groups, such as 55-59, 60-65, 66-69, etc. Optimally, such studies should be 3 years or longer and should incorporate testing for specific markers of immunosenescence (such as T-cell receptor excision circles) to account for differential aging of individuals.

• MeSH
• imunologické faktory aplikace a dávkování   MeSH
• lidé MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• imunoterapie MeSH
• lidé MeSH
• methylprednisolon farmakologie   terapeutické užití   MeSH
• monoklonální protilátky farmakologie   terapeutické užití   MeSH
• roztroušená skleróza * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH