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
Roztroušená skleróza (RS) je chronické a nevyléčitelné autoimunitní onemocnění centrálního nervového systému (CNS). Cílem chorobu modifikující léčby (DMT - disease modifying therapy) je zpomalit progresi onemocnění, zabránit relapsům a zvýšit celkovou kvalitu života pacienta. Adherence označuje míru spolupráce pacienta při léčbě a je nezbytná pro účinnou léčbu. Non-adherence je spojená s rizikem progrese disability a se zvýšenými náklady na zdravotní péči. Cílem tohoto článku je představení tří kazuistik pacientů s vysoce účinnou terapií (HET - high efficacy therapy). První pacientka je léčena HET od počátku choroby a má výbornou adherenci. Druhá kazuistika referuje o pacientce s non‐adherencí na interferonu beta s následnou těžkou atakou po vysazení léčby. Pacientka je nyní stabilizovaná na ocrelizumabu. Třetí pacientka měla nežádoucí účinky na perorální léčbě dimethyl fumarátem a byla také převedena na ocrelizumab.
Multiple sclerosis (MS) is a chronic and incurable autoimmune disease of the central nervous system (CNS). The goals of disease-modifying therapy (DMT) are to slow down disease progression, prevent relapses, and increase the overall quality of life of the patient. Adherence refers to the degree to which a patient complies with prescribed treatment and as such is required for the treatment to be effective. Non-adherence is associated with a risk of disability progression and increased healthcare costs. The aim of the article is to present three case reports of female patients on high-efficacy therapy (HET). Patient 1 has been treated with HET since disease onset and has excellent adherence. The second case report presents a patient with non-adherence to interferon beta with a subsequent severe attack following treatment discontinuation. The patient is now stabilized with ocrelizumab. Patient 3 had experienced adverse effects while on oral treatment with dimethyl fumarate and was also switched to ocrelizumab.
- Klíčová slova
- ocrelizumab,
- MeSH
- adherence k farmakoterapii statistika a číselné údaje MeSH
- dimethyl fumarát škodlivé účinky terapeutické užití MeSH
- dospělí MeSH
- humanizované monoklonální protilátky * ekonomika terapeutické užití MeSH
- imunologické faktory ekonomika terapeutické užití MeSH
- interferon beta škodlivé účinky terapeutické užití MeSH
- intravenózní podání MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mladý dospělý MeSH
- roztroušená skleróza * diagnostické zobrazování farmakoterapie patologie MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- mladý dospělý MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon β-1a (IFN) using observational data. METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression. RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51). CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.
- MeSH
- dospělí MeSH
- fingolimod hydrochlorid * terapeutické užití MeSH
- imunosupresiva terapeutické užití MeSH
- interferon beta 1a * terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- randomizované kontrolované studie jako téma * MeSH
- registrace * MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group ( - 30.5%; hazard ratio 0.695 [95% CI, 0.547-0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b.
- MeSH
- demyelinizační nemoci farmakoterapie MeSH
- dospělí MeSH
- dvojitá slepá metoda MeSH
- interferon beta 1b * terapeutické užití farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- následné studie MeSH
- progrese nemoci MeSH
- roztroušená skleróza * farmakoterapie MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease that secondarily leads to axonal loss and associated brain atrophy. Disease-modifying drugs (DMDs) have previously been studied for their ability to affect specific immunity. This study investigates the effect of interferon beta-1a (INF) and glatiramer acetate (GA) administration on changes in innate immunity cell populations. METHODS: Sixty Caucasian female patients with relapsing-remitting MS undergo blood sample testing for 15 blood parameters at baseline, 1 month, 3 months, and 6 months after treatment by GA or IFN (started as their first-line DMD). RESULTS: A statistically significant difference in the change after 6 months was found in the parameter monocytes (relative count) in the group of patients treated with IFN. The median increase was 27.8%. Changes in many of the other 15 parameters studied were 10-20%. CONCLUSION: Innate immunity has long been neglected in MS immunopathology. The findings suggest that IFN treatment may modulate the immune response in MS by affecting monocyte function and may provide insight into the mechanisms of action of IFN in MS.
- MeSH
- glatiramer acetát terapeutické užití MeSH
- interferon beta 1a terapeutické užití MeSH
- interferon beta terapeutické užití MeSH
- lidé MeSH
- peptidy terapeutické užití MeSH
- přirozená imunita MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie patologie MeSH
- roztroušená skleróza * farmakoterapie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Simultaneous comparisons of multiple disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS) over an extended follow-up are lacking. Here we emulate a randomised trial simultaneously comparing the effectiveness of six commonly used therapies over 5 years. METHODS: Data from 74 centres in 35 countries were sourced from MSBase. For each patient, the first eligible intervention was analysed, censoring at change/discontinuation of treatment. The compared interventions included natalizumab, fingolimod, dimethyl fumarate, teriflunomide, interferon beta, glatiramer acetate and no treatment. Marginal structural Cox models (MSMs) were used to estimate the average treatment effects (ATEs) and the average treatment effects among the treated (ATT), rebalancing the compared groups at 6-monthly intervals on age, sex, birth-year, pregnancy status, treatment, relapses, disease duration, disability and disease course. The outcomes analysed were incidence of relapses, 12-month confirmed disability worsening and improvement. RESULTS: 23 236 eligible patients were diagnosed with RRMS or clinically isolated syndrome. Compared with glatiramer acetate (reference), several therapies showed a superior ATE in reducing relapses: natalizumab (HR=0.44, 95% CI=0.40 to 0.50), fingolimod (HR=0.60, 95% CI=0.54 to 0.66) and dimethyl fumarate (HR=0.78, 95% CI=0.66 to 0.92). Further, natalizumab (HR=0.43, 95% CI=0.32 to 0.56) showed a superior ATE in reducing disability worsening and in disability improvement (HR=1.32, 95% CI=1.08 to 1.60). The pairwise ATT comparisons also showed superior effects of natalizumab followed by fingolimod on relapses and disability. CONCLUSIONS: The effectiveness of natalizumab and fingolimod in active RRMS is superior to dimethyl fumarate, teriflunomide, glatiramer acetate and interferon beta. This study demonstrates the utility of MSM in emulating trials to compare clinical effectiveness among multiple interventions simultaneously.
- MeSH
- dimethyl fumarát terapeutické užití MeSH
- fingolimod hydrochlorid terapeutické užití MeSH
- glatiramer acetát terapeutické užití MeSH
- imunosupresiva terapeutické užití MeSH
- interferon beta terapeutické užití MeSH
- lidé MeSH
- natalizumab terapeutické užití MeSH
- recidiva MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie MeSH
- roztroušená skleróza * farmakoterapie MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- MeSH
- abnormality vyvolané léky epidemiologie prevence a kontrola MeSH
- imunologické faktory metabolismus terapeutické užití MeSH
- interferon beta metabolismus terapeutické užití MeSH
- kojenec MeSH
- kojení MeSH
- komplikace těhotenství etiologie farmakoterapie MeSH
- lidé MeSH
- mateřské mléko MeSH
- monoklonální protilátky metabolismus terapeutické užití MeSH
- nežádoucí účinky léčiv MeSH
- progrese nemoci MeSH
- roztroušená skleróza * farmakoterapie MeSH
- těhotenství MeSH
- trimestry těhotenství účinky léků MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
Roztroušená skleróza (RS) je chronické autoimunitní a neurodegenerativní onemocnění postihující mozek a míchu. Onemocnění začíná nejčastěji mezi 20.-30. rokem věku a vyskytuje se třikrát častěji u žen. Léčbu je nutné zahájit co nejdříve po stanovení diagnózy. U pacientek ve fertilním věku je vhodné zvolit lék, jehož podávání je bezpečné i po početí.
Multiple sclerosis (MS) is a chronic autoimmune and neurodegenerative disease affecting the brain and spinal cord. Most often the disease begins between the ages of 20-30 and occurs three times as often in women. Treatment is initiated early, preferably after the first symptom of the disease. In patients of childbearing age, it is advisable to choose a drug that is safe after conception. The period of pregnancy has a favourable effect on the course of the disease, with a decrease in activity in most cases. In stable patients, therapy is discontinued. If patients have unplanned pregnancy and the disease is not stable, therapy with certain drugs can be continued. This communication gives an overview of the drugs that can be given not only during pregnancy but also during lactation. The procedures used in the care of women after childbirth and during lactation are mentioned. Stabilized patients are assured of safe therapy during this time and can continue breastfeeding for 4-6 months. Other drugs from both the first and escalation lines do not yet have a proven safety profile during pregnancy or lactation and are therefore not mentioned in the article.
- MeSH
- glatiramer acetát škodlivé účinky terapeutické užití MeSH
- interferon beta škodlivé účinky terapeutické užití MeSH
- kojení MeSH
- komplikace těhotenství * MeSH
- lidé MeSH
- roztroušená skleróza * farmakoterapie MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- přehledy MeSH
Autophagy is a lysosomal degradative pathway responsible for recycling cytosolic proteins and organelles and also functions as an innate defense mechanism that host cells use against viral infection. While many viruses have evolved mechanisms to antagonize the antiviral effects of the autophagy pathway, others subvert autophagy to facilitate replication. For flaviviruses, both the positive and negative role of autophagy in virus replication has been reported. The interplay between autophagy and tick-borne encephalitis virus (TBEV) in innate immune cells is largely unknown. Here we report the relationship between an autophagy and TBEV replication in mouse macrophage cell line PMJ2-R using Hypr strain of TBEV. First, we examined the effect of Hypr infection on the autophagy pathway. We detected a mild and a temporary increase of autophagy marker LC3-II in Hypr-infected cells. The role of autophagy in TBEV replication was evaluated in autophagy related gene 5 (Atg5) knockdown cells (shAtg5). Our results showed that during an early stage of Hypr infection the viral titers were increased, while later on, at 72 hpi, the titers have declined in shAtg5 cells compared to control. Moreover, the higher number of virus-positive cells was observed in shAtg5 cells in early stage of infection and correlated with enhanced virus entry. Finally, we found an increased production of IFN-β in Hypr-infected shAtg5 cells in comparison to control at 48 and 72 hpi implicating that autophagy restricts the amount of IFN produced by TBEV-infected macrophages. To conclude, in mouse macrophages TBEV replication is controlled by autophagy in time dependent manner, having temporally an antiviral and then a pro-viral role during infection. Our study points out to a delicate and complex involvement of autophagy machinery at level of virus entry and IFN-β production when controlling TBEV infection.
- MeSH
- antivirové látky metabolismus MeSH
- autofagie MeSH
- interferon beta genetika metabolismus MeSH
- klíšťová encefalitida * genetika MeSH
- makrofágy metabolismus MeSH
- myši MeSH
- replikace viru MeSH
- viry klíšťové encefalitidy * genetika MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
