RESUMO
Introduction: Progressive Multifocal Leukoencephalopathy (PML) is a rare and deadly demyelinating disease caused by JC virus (JCV) replication in the central nervous system. PML occurs exclusively in patients with severe underlying immune deficiencies, including AIDS and hematological malignancies. PML has also emerged as a significant threat to patients on potent new immunosuppressive biologics, including natalizumab in multiple sclerosis. Methods: Here, we developed an IFN-γ release assay (IGRA) that mainly detects JCV-specific effector memory T cells and effectors T cells in the blood. Results: This assay was frequently positive in patients with active PML (with a positive JCV PCR in CSF) of various underlying immunosuppression causes (84% sensitivity). Only 3% of healthy donors had a positive response (97% specificity). The frequency of positivity also increased in multiple sclerosis patients according to the time on natalizumab (up to 36% in patients treated for more than 48 months, who are considered at a higher risk of PML). Discussion: The results show this assay's frequent or increased positivity in patients with PML or an increased risk of PML, respectively. The assay may help to stratify the risk of PML.
Assuntos
Interferon gama , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Células T de Memória , Humanos , Leucoencefalopatia Multifocal Progressiva/imunologia , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Leucoencefalopatia Multifocal Progressiva/etiologia , Masculino , Vírus JC/imunologia , Feminino , Pessoa de Meia-Idade , Adulto , Células T de Memória/imunologia , Células T de Memória/metabolismo , Natalizumab/uso terapêutico , Idoso , Esclerose Múltipla/imunologia , Esclerose Múltipla/tratamento farmacológicoRESUMO
BACKGROUND: Highly active (HA) relapsing remitting multiple sclerosis (RRMS) is associated with frequent relapses and high burden of disease/disability. Natalizumab is licensed for HA RRMS, including rapidly evolving severe (RES) (≥2 relapses in previous year) and sub-optimally treated (SOT) (≥1 relapse in previous year despite treatment) populations. However, there is limited RCT evidence in the SOT subpopulation. OBJECTIVE: To review the non-RCT evidence for natalizumab in SOT HA RRMS. METHODS: Databases were searched to January 2023 for non-randomised studies of natalizumab in HA RRMS. Studies in patients with ≥1 relapse during previous treatment were eligible for inclusion. Meta-analyses were conducted to compare natalizumab with platform and higher efficacy disease-modifying therapies, with sensitivity analysis restricted to studies of low risk of bias. RESULTS: Included comparative studies (n = 16) showed natalizumab had lower relapse rates, disease activity and MRI (radiological) outcomes compared with platform and higher efficacy therapy. Case series (n = 11) showed natalizumab was associated with high rates of freedom from relapse and clinical/radiological disease activity and reductions in annualised relapse rate and disability progression. CONCLUSIONS: Literature reviewed indicates that natalizumab is more effective than other included treatments for SOT patients. Findings were consistent with studies in the broad HA RRMS population, suggesting that natalizumab may have similar efficacy for SOT and RES HA RRMS.
Assuntos
Fatores Imunológicos , Esclerose Múltipla Recidivante-Remitente , Natalizumab , Natalizumab/uso terapêutico , Humanos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Fatores Imunológicos/uso terapêuticoRESUMO
OBJECTIVE: To evaluate the effect of discontinuation or prolongation of DMT on the activity of the disease during pregnancy and in the postpartum period in patients with aggressive MS from the Moscow region. MATERIAL AND METHODS: The study included female patients with an aggressive course of MS receiving DMT at the time of pregnancy. The patients were followed-up for the period 2016 to February 2024. RESULTS: There were 17 cases of pregnancy during natalizumab (NZ) therapy; discontinuation of therapy in the first trimester of pregnancy provoked a resumption of disease activity in half of the patients. There were no exacerbations in patients whose therapy was prolonged until the 34th week of pregnancy. In 5 patients receiving fingolimod (FGL), therapy was discontinued upon the establishment of pregnancy, which caused the resumption of disease activity in three out of 5 cases. In 3 patients receiving anti-B-cell therapy, pregnancy occurred within a few months after the next infusion, there were no exacerbations during pregnancy. CONCLUSION: The cancellation of NS therapy in the early stages of pregnancy in most cases leads to the resumption of disease activity during pregnancy. Exacerbations in the postpartum period also correlated with early discontinuation of therapy and with a long period before the restart of infusions. Prolongation of infusions to 30-34 weeks of pregnancy contributed to stabilization of the condition throughout the perinatal period. Discontinuation of FGL therapy at the onset of pregnancy increased the risk of repeated relapses of the disease, up to the development of inflammatory immune restoration syndrome during pregnancy and contributed to the increase in disability in the postpartum period.
Assuntos
Cloridrato de Fingolimode , Esclerose Múltipla , Natalizumab , Complicações na Gravidez , Humanos , Feminino , Gravidez , Moscou/epidemiologia , Adulto , Complicações na Gravidez/tratamento farmacológico , Natalizumab/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Cloridrato de Fingolimode/uso terapêutico , Período Pós-Parto , Imunossupressores/uso terapêutico , Adulto JovemRESUMO
Introduction: Disease-modifying therapies (DMTs) have been shown to improve disease outcomes in multiple sclerosis (MS) patients. They may also impair the immune response to vaccines, including the SARS-CoV-2 vaccine. However, available data on both the intrinsic immune effects of DMTs and their influence on cellular response to the SARS-CoV-2 vaccine are still incomplete. Methods: Here, we evaluated the immune cell effects of 3 DMTs on the response to mRNA SARS-CoV-2 vaccination by comparing MS patients treated with one specific therapy (fingolimod, dimethyl fumarate, or natalizumab) with both healthy controls and untreated patients. We profiled 23 B-cell traits, 57 T-cell traits, and 10 cytokines, both at basal level and after stimulation with a pool of SARS-CoV-2 spike peptides, in 79 MS patients, treated with DMTs or untreated, and 32 healthy controls. Measurements were made before vaccination and at three time points after immunization. Results and Discussion: MS patients treated with fingolimod showed the strongest immune cell dysregulation characterized by a reduction in all measured lymphocyte cell classes; the patients also had increased immune cell activation at baseline, accompanied by reduced specific immune cell response to the SARS-CoV-2 vaccine. Also, anti-spike specific B cells progressively increased over the three time points after vaccination, even when antibodies measured from the same samples instead showed a decline. Our findings demonstrate that repeated booster vaccinations in MS patients are crucial to overcoming the immune cell impairment caused by DMTs and achieving an immune response to the SARS-CoV-2 vaccine comparable to that of healthy controls.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Fumarato de Dimetilo , Cloridrato de Fingolimode , Esclerose Múltipla , SARS-CoV-2 , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , Masculino , Esclerose Múltipla/imunologia , Esclerose Múltipla/tratamento farmacológico , Feminino , SARS-CoV-2/imunologia , Vacinas contra COVID-19/imunologia , Pessoa de Meia-Idade , Adulto , Cloridrato de Fingolimode/uso terapêutico , Cloridrato de Fingolimode/farmacologia , Fumarato de Dimetilo/uso terapêutico , Fumarato de Dimetilo/farmacologia , Imunossupressores/uso terapêutico , Natalizumab/uso terapêutico , Linfócitos B/imunologia , Vacinação , Linfócitos T/imunologia , Citocinas/metabolismoRESUMO
Introduction: Microglia (MG) is suggested to play an immunopathological role of in Multiple Sclerosis (MS). Since hyper-reflective foci (HRF) might mark MG activation, in vivo analysis by Optic Coherence Tomography (OCT) in MS patients under disease modifying therapies may help to clarify MS immunopathology as well as drug's mechanism of intrathecal action. Objective: To analyze HRF in patients treated with Natalizumab (NTZ), a high efficacy therapy for MS. Materials and methods: The effect of NTZ on the retina of 36 Relapsing-Remitting MS patients was investigated in a prospective, single-center study. OCT was performed immediately before the first infusion and then between infusion 3 and 4, infusion 6 and 7, infusion 11 and 13. Peripapillary and macular scans were acquired, evaluating peripapillary RNFL thickness, macular volumes (vertical scans), and HRF count (horizontal scan) in Ganglion Cell Layer (GCL), Inner Plexiform Layer (IPL) and Inner Nuclear Layer (INL). Clinical examination was performed every six months. Results: HRF count significantly increased under NTZ therapy (p<0.001) in both GCL (18.85 ± 6.93 at baseline, 28.24 ± 9.55 after 12 months) and IPL (25.73 ± 7.03 at baseline, 33.21 ± 8.50 after 12 months) but remained stable in INL (33.65 ± 7.76 at baseline, 36.06 ± 6.86 after 12 months, p=0.87), while no relevant modification of pRNFL and macular volumes were observed during the study. EDSS remained stable and no clinical relapse was observed between month 6 and 12. Conclusion: In RRMS NTZ affects HRF count in GCL and IPL, but not in INL, suggesting that NTZ does not impact on some aspects of MS immunopathology.
Assuntos
Esclerose Múltipla Recidivante-Remitente , Natalizumab , Tomografia de Coerência Óptica , Humanos , Natalizumab/uso terapêutico , Feminino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/patologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/imunologia , Adulto , Masculino , Estudos Prospectivos , Microglia/efeitos dos fármacos , Microglia/patologia , Pessoa de Meia-Idade , Fatores Imunológicos/uso terapêutico , Retina/patologia , Retina/efeitos dos fármacos , Retina/diagnóstico por imagem , Adulto JovemRESUMO
INTRODUCTION: One strategy to mitigate progressive multifocal leukoencephalopathy (PML) risk is to switch to other highly effective disease-modifying therapies (DMTs). However, the optimal switch DMT following natalizumab (NTZ) discontinuation is yet to be determined. OBJECTIVE: The objective of the study is to determine the most effective and tolerable DMTs to switch to following NTZ discontinuation due to John Cunningham virus (JCV) antibody positivity. METHODS: This is a multicenter observational cohort study that included all stable relapsing-remitting multiple sclerosis (MS) patients who were treated with NTZ for at least 6 months before switching therapy due to JCV antibody positivity. RESULTS: Of 321 patients, 255 switched from NTZ to rituximab/ocrelizumab, 52 to fingolimod, and 14 to alemtuzumab, with higher annualized relapse rate (ARR) in fingolimod switchers (0.193) compared with rituximab/ocrelizumab or alemtuzumab (0.028 and 0.032, respectively). Fingolimod switchers also had increased disability progression (p = 0.014) and a higher proportion developed magnetic resonance imaging (MRI) lesions compared with rituximab/ocrelizumab (62.9% vs. 13.0%, p < 0.001, and 66.6% vs. 24.0%, p < 0.001, respectively). Mean drug survival favored rituximab/ocrelizumab or alemtuzumab over fingolimod (p < 0.001). CONCLUSION: Our study shows superior effectiveness of rituximab/ocrelizumab and alemtuzumab compared with fingolimod in stable patients switching from NTZ due to JC virus antibody positivity.
Assuntos
Fatores Imunológicos , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Esclerose Múltipla Recidivante-Remitente , Natalizumab , Humanos , Natalizumab/uso terapêutico , Natalizumab/efeitos adversos , Feminino , Adulto , Masculino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fatores Imunológicos/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Vírus JC/imunologia , Pessoa de Meia-Idade , Substituição de Medicamentos , Rituximab/efeitos adversos , Rituximab/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Cloridrato de Fingolimode/uso terapêutico , Alemtuzumab/efeitos adversos , Alemtuzumab/uso terapêuticoRESUMO
Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.
Assuntos
Natalizumab , Estimulação Magnética Transcraniana , Humanos , Natalizumab/uso terapêutico , Natalizumab/efeitos adversos , Feminino , Masculino , Adulto , Fadiga/etiologia , Córtex Motor/fisiopatologia , Córtex Motor/efeitos dos fármacos , Pessoa de Meia-Idade , Potencial Evocado Motor/efeitos dos fármacos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/complicações , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/complicações , Fatores Imunológicos/uso terapêutico , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/administração & dosagem , Fadiga Muscular/efeitos dos fármacos , EletroencefalografiaRESUMO
OBJECTIVES: Biosimilars provide an opportunity for a more sustainable and cost-effective treatment for multiple sclerosis (MS). This study evaluated the potential financial impact of implementing a formulary change from reference to biosimilar natalizumab (NTZ) from the US commercial payer perspective. STUDY DESIGN: The budget impact of transitioning to biosimilar NTZ for the treatment of relapsing-remitting MS (RRMS) was estimated over a 3-year time horizon based on real-world dosing. Additional scenario analyses were conducted by varying the price differential of biosimilar NTZ. METHODS: The target population was estimated from a 1-million-member hypothetical commercial health plan. Model inputs were drug acquisition costs and treatment-related and patient coinsurance costs. Budget impact and cost savings per member per year were calculated by assuming a biosimilar uptake of 10% in year 1 to 20% in year 3. RESULTS: Over 3 years, 255 patients were estimated to be treated with high-efficacy disease-modifying therapies for RRMS. The inclusion of biosimilar NTZ onto a formulary would result in cumulative cost savings to payers of $452,611 over 3 years, with mean savings per treated member per year of $1179, $1769, and $2359 in years 1, 2, and 3, respectively. One-way sensitivity analyses indicated that budget impact results were most sensitive to drug acquisition costs of both reference and biosimilar NTZ. CONCLUSION: Adoption of biosimilar NTZ can yield considerable cost savings to US health plans that could result in increased treatment access for patients with RRMS.
Assuntos
Medicamentos Biossimilares , Orçamentos , Natalizumab , Humanos , Natalizumab/uso terapêutico , Natalizumab/economia , Estados Unidos , Medicamentos Biossimilares/economia , Medicamentos Biossimilares/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/economia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/economia , Análise Custo-Benefício , Redução de Custos , Custos de Medicamentos/estatística & dados numéricosRESUMO
BACKGROUND: Multiple Sclerosis (MS) a central nervous system autoimmune disorder, mainly affecting young adults and more prevalent among women, can lead to sexual dysfunction (SD) among both males and females with MS. Female sexual dysfunction can be defined as dyspareunia, a lack of sexual desire, disorders in the arousal and orgasm phases, and sexual pain disorders. The purpose of this study is to investigate the changes in sexual function among females with MS whose treatment was switched from first-line injectable medications to other agents after a six-month duration. And assess the changes in all three domains of SD. METHODS: In this longitudinal study females diagnosed with MS, aged between 18 and 50 years old, and were candidates for switching their treatment from interferon beta-1a (intra-muscular and subcutaneous), and Glatiramer Acetate (GA), to Fingolimod, Dimethyl Fumarate (DMF), or Natalizumab (NTZ) due to patients' convenience and tolerability and adverse events were included. "Multiple Sclerosis Intimacy and Sexuality Questionnaire-19" was used to evaluate the SD changes before and six months after the new treatment initiation. Statistical analysis was conducted using SPSS V.24 software. Histograms and the Shapiro-Wilk test were used to assess the normality of the variables; due to the non-normal distribution of quantitative variables (except for age), the Wilcoxon signed-rank test was used to compare the scores, before and six months after the medication change. The level of significance was considered less than 0.05. RESULTS: Out of 107 female participants (average age: 35.09 ± 5.61), The mean of overall MSISQ-19 scores, before and six months after the medication change were not significant (p-value = 0.091). However, considering the subdomains, the medication changes only affected the tertiary subdomain of MSISQ-19 (p-value = 0.017). Still, the scores of other subdomains did not change significantly (p-value = 0.761 for primary SD and 0.479 for secondary SD). Also, there wasn't any significant difference between EDSS before and after the medication change (p-value = 0.461). CONCLUSIONS: To our knowledge, this was the first study, assessing the effect of MS medication change on the improvement of SD among patients. According to the results of the presented cross-sectional study, we found that during a six-month period, the tertiary subdomain of MSISQ-19 symptoms improved significantly, while the changes in other SD domains were not significant.
Assuntos
Acetato de Glatiramer , Esclerose Múltipla , Disfunções Sexuais Fisiológicas , Humanos , Feminino , Adulto , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/complicações , Pessoa de Meia-Idade , Disfunções Sexuais Fisiológicas/etiologia , Disfunções Sexuais Fisiológicas/tratamento farmacológico , Estudos Longitudinais , Acetato de Glatiramer/administração & dosagem , Acetato de Glatiramer/uso terapêutico , Adulto Jovem , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Fumarato de Dimetilo/administração & dosagem , Fumarato de Dimetilo/uso terapêutico , Adolescente , Imunossupressores/uso terapêutico , Imunossupressores/administração & dosagem , Interferon beta-1a/administração & dosagem , Interferon beta-1a/uso terapêutico , Substituição de Medicamentos/métodos , Cloridrato de Fingolimode/uso terapêutico , Cloridrato de Fingolimode/administração & dosagem , Natalizumab/administração & dosagem , Natalizumab/uso terapêuticoRESUMO
BACKGROUND AND OBJECTIVES: Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID. METHODS: Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4-7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated. RESULTS: 255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms. DISCUSSION: Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.
Assuntos
Fatores Imunológicos , Natalizumab , Humanos , Natalizumab/administração & dosagem , Natalizumab/uso terapêutico , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Fatores Imunológicos/administração & dosagem , Esclerose Múltipla/tratamento farmacológico , Esquema de Medicação , Resultado do Tratamento , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológicoRESUMO
OBJECTIVES: This study aimed to evaluate whether switching disease-modifying therapies (DMTs) from sphingosine-1 phosphate (S1P) receptor modulators to either natalizumab (NTZ) or dimethyl fumarate (DMF) could restore the effectiveness of SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis (MS). METHODS: This study included 9 controls and 33 patients with MS: 7 patients treated with DMF, 7 patients treated with NTZ, 9 patients treated with S1P receptor modulators, and 10 patients who had switched DMTs from S1P receptor modulators to DMF or NTZ by the second vaccine dose. The patients who had switched DMTs were classified into two groups, based on whether their lymphocyte counts were above or below 1000/µL at the time of vaccination. In addition, relapses within 6 months after switching DMTs were also evaluated in these patients. Six months after the second dose of the vaccination, anti-SARS-CoV-2 spike antibodies were evaluated in all participants, and spike specific CD4+ T cells were also assessed in patients who had switched DMTs from S1P receptor modulators. RESULTS: Patients treated with S1P receptor modulators had lower levels of anti-SARS-CoV-2 spike antibodies than the controls and patients treated with DMF and NTZ. On the other hand, in patients who had switched DMTs from S1P receptor modulators, a recovery of lymphocyte counts above 1000/µL resulted in restored humoral and cellular immune responses to the vaccination. There were no neurological relapses in patients who had switched DMTs from S1P receptor modulators to NTZ. CONCLUSION: SARS-CoV-2 mRNA vaccination is expected to be effective in patients whose lymphocyte counts have recovered due to switching DMTs from S1P receptor modulators. Switching DMTs from S1P receptor modulators to NTZ before vaccination may be beneficial in achieving efficacy for SARS-CoV-2 mRNA vaccination, with a reduced risk of relapse.
Assuntos
COVID-19 , Fumarato de Dimetilo , Esclerose Múltipla , Natalizumab , SARS-CoV-2 , Humanos , Feminino , Fumarato de Dimetilo/uso terapêutico , Masculino , Adulto , Natalizumab/uso terapêutico , Pessoa de Meia-Idade , Esclerose Múltipla/imunologia , Esclerose Múltipla/tratamento farmacológico , COVID-19/prevenção & controle , COVID-19/imunologia , SARS-CoV-2/imunologia , Moduladores do Receptor de Esfingosina 1 Fosfato/uso terapêutico , Moduladores do Receptor de Esfingosina 1 Fosfato/farmacologia , Vacinas contra COVID-19/imunologia , Vacinas contra COVID-19/uso terapêutico , Imunossupressores/uso terapêutico , Vacinação/métodos , Substituição de Medicamentos , Anticorpos Antivirais/sangueRESUMO
Androgen deprivation therapy (ADT) for prostate cancer is associated with an increased risk of dementia, including Alzheimer's disease (AD). The mechanistic connection between ADT and AD-related cognitive impairment in patients with prostate cancer remains elusive. We established a clinically relevant prostate cancer-bearing AD mouse model to explore this. Both tumor-bearing and ADT induce complex changes in immune and inflammatory responses in peripheral blood and in the brain. ADT disrupts the integrity of the blood-brain barrier (BBB) and promotes immune cell infiltration into the brain, enhancing neuroinflammation and gliosis without affecting the amyloid plaque load. Moreover, treatment with natalizumab, an FDA-approved drug targeting peripheral immune cell infiltration, reduces neuroinflammation and improves cognitive function in this model. Our study uncovers an inflammatory mechanism, extending beyond amyloid pathology, that underlies ADT-exacerbated cognitive deficits, and suggests natalizumab as a potentially effective treatment in alleviating the detrimental effects of ADT on cognition.
Assuntos
Doença de Alzheimer , Antagonistas de Androgênios , Barreira Hematoencefálica , Encéfalo , Disfunção Cognitiva , Modelos Animais de Doenças , Animais , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Masculino , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/patologia , Disfunção Cognitiva/etiologia , Camundongos , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/metabolismo , Humanos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Antagonistas de Androgênios/efeitos adversos , Antagonistas de Androgênios/farmacologia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Natalizumab/efeitos adversos , Natalizumab/farmacologia , Natalizumab/uso terapêutico , Placa Amiloide/patologia , Placa Amiloide/tratamento farmacológicoRESUMO
BACKGROUND: Natalizumab is a monoclonal antibody used to treat patients with relapsing-remitting multiple sclerosis. Anemia is a recognized side effect, but it is usually mild and of a short duration when natalizumab is stopped. Here, we describe a case of a young woman with severe and especially long lasting anemia associated with treatment with natalizumab, persisting up to a year after treatment was stopped. CASE PRESENTATION: A 24 year-old Caucasian woman with relapsing-remitting multiple sclerosis developed severe transfusion dependent anemia after 27 infusions with natalizumab, which was her first and only treatment for her multiple sclerosis. Extensive hematologic diagnostics did not reveal any malignant cause or any other plausible non-malignant cause for her anemia. The bone marrow was found to be hypercellular, with a maturation arrest of the erythropoiesis and with grade 1-2 fibrosis. No specific treatment for the anemia was given. The hemoglobin level showed signs of spontaneous increase after nearly one year after natalizumab was discontinued. CONCLUSION: Severe anemia can be caused by treatment with natalizumab. This case adds information to the few other similar reported cases, demonstrating the potential duration of the anemia, as well as detailed description of hematologic findings. The mechanism is most likely due to inhibition of α4 subunit of the α4ß1-integrin, which is present on both lymphocytes and erythroid precursor cells.
Assuntos
Anemia , Esclerose Múltipla Recidivante-Remitente , Natalizumab , Humanos , Natalizumab/efeitos adversos , Natalizumab/uso terapêutico , Feminino , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Anemia/induzido quimicamente , Adulto Jovem , Fatores Imunológicos/efeitos adversos , Fatores Imunológicos/uso terapêuticoRESUMO
Background: The mechanisms of the function of interferon beta (IFN-ß) and natalizumab (NTZ) in multiple sclerosis (MS) patients have not yet been fully understood. Over the past decades, many studies have been conducted to evaluate gene expression changes especially regulatory non-coding RNAs such as microRNAs (miRNAs) following therapy in MS patients. Objective: To assess the changes in the expression of miR-20b in MS patients treated with IFN-ß or NTZ. Methods: Sixty patients with relapsing-remitting MS (RRMS) and 30 healthy controls (HCs) were enrolled. The patients were categorized as untreated (N=20), IFN-ß-treated (N=20), and NTZtreated (N=20). For the expression analysis, real-time PCR was performed on the whole blood. The bioinformatic tools were applied for signaling pathways enrichment analysis of miR-20b targetome. Results: The relative expression of miR-20b was significantly downregulated in the untreated patients compared with the HCs (-1.726-fold, p<0.001), while IFN-ß-treated and NTZ-treated patients showed no statistical difference compared with the HCs (0.733-fold, p=0.99 for IFN-ß and 1.025-fold, p=0.18 for NTZ). This indicates the restoration of miR-20b expression to normal level in the treated patients. Additionally, in silico analysis demonstrated that the Jak-STAT signaling pathway is enriched with miR-20b targets (p<0.0001). Conclusion: Our findings suggest that the positive effects of IFN-ß and NTZ in the RRMS patients could be potentially mediated by returning miR-20b expression to baseline.
Assuntos
Interferon beta , MicroRNAs , Esclerose Múltipla Recidivante-Remitente , Natalizumab , Transdução de Sinais , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Estudos de Casos e Controles , Biologia Computacional/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Interferon beta/uso terapêutico , Janus Quinases/metabolismo , MicroRNAs/genética , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/genética , Natalizumab/uso terapêutico , Fatores de Transcrição STAT/metabolismoRESUMO
BACKGROUND: in the early stages of Multiple Sclerosis (MS), initiating high-efficacy disease-modifying therapy (HE DMTs) may represent an optimal strategy for delaying neurological damage and long-term disease progression, especially in highly active MS patients (HAMS). Natalizumab (NAT) and Ocrelizumab (OCR) are recognized as HE DMTs with significant anti-inflammatory effects. This study investigates NEDA-3 achievement in treatment-naïve HAMS patients receiving NAT or OCR over three years. METHODS: we retrospectively enrolled treatment-naïve HAMS patients undergoing NAT or OCR, collecting demographic, clinical, and instrumental data before and after treatment initiation to compare with propensity score analysis disease activity, time to disability worsening, and NEDA-3 achievement. RESULTS: we recruited 281 HAMS patients with a mean age of 32.7 years (SD 10.33), treated with NAT (157) or OCR (124). After three years, the Kaplan-Meier probability of achieving NEDA-3 was 66.0 % (95 % CI: 57.3 % - 76.0 %) with OCR and 68.2 % (95 % CI: 59.9 % - 77.7 %) with NAT without significant differences between the two groups (p = 0.27) DISCUSSION AND CONCLUSION: starting HE DMT with monoclonal antibodies for HAMS could achieve NEDA-3 in a high percentage of patients without differences between NAT or OCR.
Assuntos
Anticorpos Monoclonais Humanizados , Fatores Imunológicos , Esclerose Múltipla Recidivante-Remitente , Natalizumab , Humanos , Natalizumab/uso terapêutico , Natalizumab/administração & dosagem , Feminino , Masculino , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Adulto , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/farmacologia , Estudos Retrospectivos , Adulto Jovem , Progressão da DoençaRESUMO
BACKGROUND: Natalizumab is an effective treatment for relapsing multiple sclerosis (MS). During therapy, individuals are at increased risk of developing progressive multifocal leukoencephalopathy (PML). So far, the relevant reservoir for PML-type JC polyomavirus (JCV) remains elusive. We here tested if the detection of JCV-DNA in stool of persons with MS treated with natalizumab could be a future tool for PML risk assessment. METHODS: The presence of JCV-DNA in stool, urine, and whole blood of MS patients treated with natalizumab and known serum anti-JCV antibodies index values (IV) was studied. Different DNA extraction methods, real-time (RT) and droplet digital (dd) PCR techniques were compared. JCV isolates were screened for PML-associated variants by sequencing. RESULTS: Thirty MS patients treated with natalizumab were screened. For 21 patients, blood, stool, and urine samples were available. These patients were stratified according to their serum anti-JCV antibody IV (high (>1.5, n = 12); medium (1.5-0.9, n = 2); low (<0.9, n = 1); negative (n = 6)). JCV-DNA could not be detected in the whole blood or stool samples. Four urine samples had measurable JCV-DNA, ranging from 1.71×104-1.07×108 international units (IU)/mL detected by RT-PCR, corresponding to 4.62×104-9.85×106 copies/mL measured by ddPCR. All JCV variants were wild-type and derived from patients with high antibody IV. CONCLUSION: Stool-specific DNA extraction methods provided the highest quality of DNA, while the sensitivity of ddPCR and RT- PCR was comparable. Our findings do not support assessing stool samples for PML risk stratification in persons with MS. Further studies are needed to explore where PML-associated viral variants arise.
Assuntos
Anticorpos Antivirais , DNA Viral , Fezes , Fatores Imunológicos , Vírus JC , Natalizumab , Humanos , Vírus JC/isolamento & purificação , Vírus JC/imunologia , Natalizumab/uso terapêutico , Fezes/virologia , Adulto , Masculino , Feminino , Anticorpos Antivirais/sangue , DNA Viral/sangue , DNA Viral/análise , Pessoa de Meia-Idade , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/virologia , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/virologia , Esclerose Múltipla/sangueRESUMO
BACKGROUND: The long-term effect of high efficacy disease modifying therapy (DMT) on neurodegeneration in people with multiple sclerosis (pwMS) is largely unknown. The aim of this study was to evaluate the long-term effect of natalizumab (NTZ) or fingolimod (FTY) therapy on the evolution of brain atrophy compared to moderate efficacy DMT in a real-world clinical setting. METHODS: A total of 438 pwMS with 2,439 MRI exams during treatment were analyzed: 252 pwMS treated with moderate efficacy DMT, 130 with NTZ and 56 with FTY. Evolution of brain atrophy was analyzed over an average follow-up of 6.6 years after treatment initiation. Brain segmentation was performed on clinical 3D-FLAIRs using SynthSeg and regional brain volume changes over time were compared between the treatment groups. RESULTS: Total brain, white matter and deep gray matter atrophy rates did not differ between moderate efficacy DMTs, NTZ and FTY. Annualized ventricle growth rates were lower in pwMS treated with NTZ (1.1 %/year) compared with moderate efficacy DMT (2.4 %/year, p < 0.001) and similar to FTY (2.0 %/year, p = 0.051). Cortical atrophy rates were lower in NTZ (-0.08 %/year) compared with moderate efficacy DMT (-0.16 %/year, p = 0.048). CONCLUSION: In a real-world clinical setting, pwMS treated with NTZ had slower ventricular expansion and cortical atrophy compared to those treated with moderate efficacy DMT.
Assuntos
Atrofia , Encéfalo , Cloridrato de Fingolimode , Fatores Imunológicos , Imageamento por Ressonância Magnética , Esclerose Múltipla , Natalizumab , Humanos , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Cloridrato de Fingolimode/administração & dosagem , Natalizumab/farmacologia , Natalizumab/administração & dosagem , Natalizumab/uso terapêutico , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , Esclerose Múltipla/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Fatores Imunológicos/farmacologia , Fatores Imunológicos/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/administração & dosagem , SeguimentosRESUMO
INTRODUCTION: Progressive multifocal leukoencephalopathy (PML) is a potentially life-threatening complication among Multiple Sclerosis (MS) patients under natalizumab treatment, with serum anti-JCV antibody titers being used for stratification risk. Given the critical role of interferon (IFN)/B-cell activating factor (BAFF) axis in humoral immune responses against viruses, we explored whether it is involved in the generation of serum anti-JCV antibodies among these patients. METHODS: 162 consecutive patients with relapsing-remitting MS under natalizumab treatment were included. Serum anti-JCV antibodies were measured at baseline, as well as 12 and 24 months after treatment initiation. Type I and II IFN-inducible genes and BAFF expression were quantitated in peripheral blood by qRT-PCR. Moreover, BAFF rs9514828, rs1041569, and rs9514827 gene variants were assessed by RFLP-PCR. RESULTS: While type I and II IFN inducible gene expression were not associated with anti-JCV serum titers, the latter were significantly correlated with BAFF gene expression. Of interest, the TTT haplotype of the studied BAFF variants was more frequently detected in male, but not female anti-JCV (+) MS patients compared to anti-JCV (-) counterparts at baseline, as well as at 12 months and 24 months of natalizumab treatment. Measures of clinical validity/utility for the BAFF TTT haplotype showed 88% specificity, 45%, positive predictive value, and sensitivity of 70% for the discrimination of anti-JCV (+) male MS patients after 24 months of treatment. CONCLUSIONS: Our study suggests an implication of the BAFF axis in the production of serum anti-JCV antibodies. Additionally, the BAFF TTT haplotype derived from the rs9514828, rs1041569, and rs9514827 variants may represent a novel risk factor for anti-JCV seropositivity and indirectly for PML development among male MS patients treated with natalizumab.
Assuntos
Fator Ativador de Células B , Fatores Imunológicos , Vírus JC , Leucoencefalopatia Multifocal Progressiva , Natalizumab , Humanos , Natalizumab/uso terapêutico , Fator Ativador de Células B/sangue , Fator Ativador de Células B/genética , Masculino , Leucoencefalopatia Multifocal Progressiva/sangue , Leucoencefalopatia Multifocal Progressiva/genética , Adulto , Feminino , Fatores Imunológicos/uso terapêutico , Vírus JC/imunologia , Vírus JC/genética , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/genética , Esclerose Múltipla Recidivante-Remitente/imunologia , Pessoa de Meia-Idade , Anticorpos Antivirais/sangue , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Aim: To assess time to improvement in Quality of Life in Neurological Disorders (Neuro-QoL) domains for patients treated with natalizumab versus ocrelizumab. Methods: Patients enrolled in the MS PATHS network who initiated treatment with either natalizumab or ocrelizumab rated the Neuro-QoL domains of physical function, symptoms, emotional health, cognitive function and social ability. Results: Time to clinically meaningful improvement was significantly shorter with natalizumab versus ocrelizumab for cognitive function (event time ratio [95% CI]: 0.37 [0.24-0.57]; p < 0.001), sleep disturbance (0.45 [0.28-0.72]; p = 0.001), social role participation (0.37 [0.21-0.66]; p = 0.001) and social role satisfaction (0.5 [0.31-0.8]; p = 0.004). Conclusion: Natalizumab had shorter time to clinically meaningful improvement in cognitive, sleep, and social role Neuro-QoL domains versus ocrelizumab.
Knowledge of treatment-related benefits associated with medication choices, including improvement of quality of life (QoL), are strong influential factors for patients to start and continue their therapies. Little is known about patient-reported time to onset of functional improvement upon the initiation of medications for multiple sclerosis (MS). The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network, a repository of collaborative international data on routine MS management, includes patient-reported information on the health-related QoL using the Quality of Life in Neurological Disorders (Neuro-QoL) measure. This study included data from 883 eligible patients enrolled in MS PATHS, with the aim of assessing and comparing the time to improvement in physical, mental and social health for patients treated with natalizumab versus ocrelizumab using Neuro-QoL. Natalizumab and ocrelizumab are both high-efficacy treatment options for relapsing forms of MS. The results demonstrated that, compared with ocrelizumab, natalizumab treatment led to faster effect on mental and social health, as well as quicker improvements in physical functioning in the arms and hands. Overall, it took shorter time for natalizumab-treated patients to achieve better QoL compared with ocrelizumab. These findings highlight the importance of QoL in disease management and provide a patient perspective for healthcare providers when making decisions about high-efficacy treatments for their patients with MS.
Assuntos
Anticorpos Monoclonais Humanizados , Fatores Imunológicos , Natalizumab , Qualidade de Vida , Humanos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Natalizumab/uso terapêutico , Adulto , Pessoa de Meia-Idade , Fatores Imunológicos/uso terapêutico , Resultado do Tratamento , Fatores de Tempo , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/psicologia , Doenças do Sistema Nervoso/tratamento farmacológicoRESUMO
BACKGROUND: Use of natalizumab (NTZ) is precluded in many Multiple Sclerosis (MS) patients by the risk of progressive multifocal leukoencephalopathy (PML). Regardless, some patients may commence natalizumab for short term disease control in spite of being seropositive, and others may seroconvert whilst on treatment. In these circumstances, discontinuation of NTZ should not occur until a clear exit strategy is established to prevent post-NTZ disease reactivation, which often exceeds the severity of disease activity prior to NTZ treatment. The objective of this systematic review was to summarise the available evidence for CD20-monoclonal antibodies (CD20mAb) as a suitable NTZ exit strategy, and to identify whether a superior switch protocol can be established. METHODS: In accordance with PRISMA guidelines, a total of 2393 references were extracted from a search of three online databases (PubMed, Scopus, MEDLINE). Following the application of inclusion/exclusion criteria, a total of 5 studies representing 331 patients were included. RESULTS: The overall incidence of clinical relapse during washout periods ranging from 4.4-10.7 weeks was 0 %. The incidence of clinical relapse during two-year follow-up ranged from 1.8 % to 10 % for switches to all types of CD20 monoclonal antibody. The weighted mean for clinical relapse at 12 months was 8.8 %. Three studies reported an annualised relapse rate (ARR) ranging from 0.02-0.12 with a weighted mean ARR of 0.07. The overall incidence of PML during washout was 0 % and the overall incidence of PML within 6 months follow-up was 0.6 %. CONCLUSIONS: This systematic review provides the first attempt at identifying a superior switch protocol in patients at risk of PML transitioning from NTZ to a CD20mAb. Our results indicate that CD20mAb's are a suitable transitional option for patients who discontinue NTZ, with our cohort demonstrating very low rates of carryover PML and low rates of clinical relapse. The most appropriate washout period is unclear due to confounding factors but is likely between 4 and 12 weeks.