RESUMEN
Introduction: Alemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS). Aim: To evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years. Methods: This prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison. Results: The study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7-42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56-10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1-3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7-52.7] pg/ml and 158.9 [IQR, 126.9-255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03-8.54] pg/ml and 91.0 [72.6-109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values. Conclusion: Alemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values.
Asunto(s)
Alemtuzumab , Proteína Ácida Fibrilar de la Glía , Esclerosis Múltiple Recurrente-Remitente , Proteínas de Neurofilamentos , Humanos , Alemtuzumab/uso terapéutico , Femenino , Masculino , Adulto , Proteínas de Neurofilamentos/sangre , Estudios Prospectivos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/inmunología , Proteína Ácida Fibrilar de la Glía/sangre , Biomarcadores/sangre , Resultado del Tratamiento , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/sangreRESUMEN
BACKGROUND: Treatment decisions for persons with relapsing-remitting multiple sclerosis (RRMS) rely on clinical and radiological disease activity, the benefit-harm profile of drug therapy, and preferences of patients and physicians. However, there is limited evidence to support evidence-based personalized decision-making on how to adapt disease-modifying therapy treatments targeting no evidence of disease activity, while achieving better patient-relevant outcomes, fewer adverse events, and improved care. Serum neurofilament light chain (sNfL) is a sensitive measure of disease activity that captures and prognosticates disease worsening in RRMS. sNfL might therefore be instrumental for a patient-tailored treatment adaptation. We aim to assess whether 6-monthly sNfL monitoring in addition to usual care improves patient-relevant outcomes compared to usual care alone. METHODS: Pragmatic multicenter, 1:1 randomized, platform trial embedded in the Swiss Multiple Sclerosis Cohort (SMSC). All patients with RRMS in the SMSC for ≥ 1 year are eligible. We plan to include 915 patients with RRMS, randomly allocated to two groups with different care strategies, one of them new (group A) and one of them usual care (group B). In group A, 6-monthly monitoring of sNfL will together with information on relapses, disability, and magnetic resonance imaging (MRI) inform personalized treatment decisions (e.g., escalation or de-escalation) supported by pre-specified algorithms. In group B, patients will receive usual care with their usual 6- or 12-monthly visits. Two primary outcomes will be used: (1) evidence of disease activity (EDA3: occurrence of relapses, disability worsening, or MRI activity) and (2) quality of life (MQoL-54) using 24-month follow-up. The new treatment strategy with sNfL will be considered superior to usual care if either more patients have no EDA3, or their health-related quality of life increases. Data collection will be embedded within the SMSC using established trial-level quality procedures. DISCUSSION: MultiSCRIPT aims to be a platform where research and care are optimally combined to generate evidence to inform personalized decision-making in usual care. This approach aims to foster better personalized treatment and care strategies, at low cost and with rapid translation to clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov NCT06095271. Registered on October 23, 2023.
Asunto(s)
Biomarcadores , Esclerosis Múltiple Recurrente-Remitente , Proteínas de Neurofilamentos , Ensayos Clínicos Pragmáticos como Asunto , Medicina de Precisión , Humanos , Proteínas de Neurofilamentos/sangre , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Biomarcadores/sangre , Medicina de Precisión/métodos , Suiza , Ensayos Clínicos Controlados Aleatorios como Asunto , Toma de Decisiones Clínicas , Estudios Multicéntricos como Asunto , Resultado del Tratamiento , Progresión de la Enfermedad , Factores de Tiempo , Valor Predictivo de las Pruebas , Evaluación de la Discapacidad , Calidad de VidaRESUMEN
BACKGROUND: Multiple sclerosis (MS) is a prevalent, disabling, inflammatory, neurodegenerative disease that typically manifests during a highly productive stage of life. Interferon beta-1a was among the first approved disease-modifying therapies for MS and remains among the first-line treatment options. Pegylation of the interferon beta-1a molecule prolongs its half-life while maintaining its efficacy and safety profile. In PEGINTEGRITY study, we aimed to compare peginterferon beta-1a with interferon beta-1a in terms of efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) patients. METHODS: This study was a randomized, active-controlled, parallel-group, multi-center Phase 3 trial conducted in Iran in participants with RRMS. Participants received 125 µg of subcutaneous peginterferon beta-1a every two weeks or 30 µg of intramuscular interferon beta-1a once a week for up to 96 weeks. The primary outcome was the non-inferiority of peginterferon beta-1a to interferon beta-1a in reducing annualized relapse rate (ARR). Other outcomes included the number of patients with 12-week confirmed disability progression, the number of new or newly-enlarging T2 hyperintense lesions, the number of gadolinium-enhancing lesions, the number of new T1 hypointense lesions, the volume of new or newly-enlarging T2 hyperintense lesions, changes in brain volume, immunogenicity, and safety assessments. RESULTS: A total of 168 patients who met the eligibility criteria were enrolled and assigned to two arms of the study, each consisting of 84 participants. Totally, 41 participants (24 patients in the peginterferon beta-1a group and 17 patients in the interferon beta-1a group) were withdrawn from the study. The withdrawn patients were included in the per-protocol analysis for the period of time they were in the study. In 96 weeks, in the per-protocol population, the ARR was 0.05 in the peginterferon beta-1a group versus 0.11 in the interferon beta-1a group, which does not reflect a statistically significant difference (p=0.09; 95 % CI, 0.18-1.14). Considering the upper limit of the one-sided 95 % CI of the rate ratio of peginterferon beta-1a compared to interferon beta-1a, as well as the non-inferiority margin, it can be concluded that the primary outcome was met. The results were also comparable for other efficacy and safety outcomes. CONCLUSION: The results demonstrate the non-inferiority of peginterferon beta-1a to interferon beta-1a with similar efficacy in 96-week ARR in RRMS patients. Both arms were also comparable in other efficacy outcomes and safety profiles with no statistically significant differences. These findings support considering peginterferon beta-1a as a safe and efficient option in patients with RRMS. This study was registered on Iranian Registry of Clinical Trials (IRCT201612306135N8) and clinicaltrials.gov (NCT05242133).
Asunto(s)
Interferón beta-1a , Esclerosis Múltiple Recurrente-Remitente , Polietilenglicoles , Humanos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Masculino , Femenino , Interferón beta-1a/administración & dosificación , Interferón beta-1a/farmacología , Interferón beta-1a/efectos adversos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/efectos adversos , Polietilenglicoles/farmacología , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacología , Persona de Mediana Edad , Interferón beta/administración & dosificación , Interferón beta/efectos adversos , Interferón beta/farmacología , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVES: Although pediatric-onset multiple sclerosis (POMS) is characterized by a more rapid accumulation of CNS inflammation than adult-onset MS (AOMS), the therapeutic algorithms applied in POMS are usually based on AOMS therapeutic outcomes. To define a high-efficacy treatment (HET)-based strategy to treat POMS, we designed an observational retrospective study aimed at evaluating the efficacy and safety of natalizumab (NTZ) in naïve POMS and AOMS. METHODS: Starting from 160 patients, we applied a 2:1 (adult:pediatric) matching on propensity scores and obtained 32 patients with NTZ-treated POMS and 64 with AOMS, estimated from a multivariable logistic regression model. All patients were clinically and radiologically followed up every 6 months for a mean period of 46.0 ± 26.9 months. RESULTS: Following re-baseline at month 6, no difference (log-rank test: p = 0.924) in new and enlarging T2 white matter lesions, postcontrast T1 lesions, and relapse rate were observed between POMS and AOMS throughout the study. Progression independent of relapse activity (PIRA) was never observed in POMS, while 9 of 64 patients with AOMS (12.5%) had PIRA events during the follow-up (40.0 ± 25.9 months; log-rank p value 0.0156). JCV seroconversion rate during NTZ infusion did not differ between POMS and AOMS (log-rank test p = 0.3231). Finally, no serious adverse event was observed in both POMS and AOMS. DISCUSSION: The favorable outcomes observed on clinical, especially in PIRA, and radiologic parameters strongly support the use of NTZ as a first-choice HET in POMS.
Asunto(s)
Edad de Inicio , Factores Inmunológicos , Natalizumab , Humanos , Natalizumab/efectos adversos , Natalizumab/administración & dosificación , Natalizumab/farmacología , Masculino , Femenino , Estudios Retrospectivos , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/farmacología , Adolescente , Niño , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Adulto Joven , Progresión de la Enfermedad , Estudios de Seguimiento , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Evaluación de Resultado en la Atención de SaludRESUMEN
BACKGROUND AND OBJECTIVES: Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome. METHODS: Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon ß, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses. RESULTS: A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%. DISCUSSION: In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.
Asunto(s)
Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente , Humanos , Femenino , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Masculino , Adulto , Crotonatos/uso terapéutico , Resultado del Tratamiento , Nitrilos/uso terapéutico , Toluidinas/uso terapéutico , Hidroxibutiratos , Dimetilfumarato/uso terapéutico , Persona de Mediana Edad , Acetato de Glatiramer/uso terapéutico , Interferón beta/uso terapéutico , Austria , Suiza , Factores Inmunológicos/uso terapéutico , Estudios de Seguimiento , Inmunosupresores/uso terapéutico , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacosRESUMEN
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.
Asunto(s)
Factores Inmunológicos , Esclerosis Múltiple Recurrente-Remitente , Natalizumab , Humanos , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Natalizumab/uso terapéuticoRESUMEN
BACKGROUND: The reason why some multiple sclerosis (MS) patients show disease activity after alemtuzumab (ALM) is still unclear, but ocrelizumab (OCR) could represent an interesting sequential therapeutic approach. OBJECTIVES: To investigate safety and efficacy of OCR in MS patients with disease activity after two ALM courses. METHODS: Observational retrospective multi-centers Italian cohort study. RESULTS: Seventy-two subjects were included. Mean follow-up (FU) was 2.4 (±1) years. Forty-five patients (62.5%) experienced at least one adverse event (AE), with infections accounting for 96.7% of cases. A reduction in total lymphocytes was observed between OCR start and 6 months FU, driven by BCD19+ lymphocytes depletion (p < 0.001). Immunoglobulin M (IgM) levels decreased between OCR start and 6 months FU (p < 0.001). At 2-year FU, relapse, magnetic resonance imaging (MRI) activity and disability worsening-free survival were 92.1%, 90.8%, and 89.2%. The evidence of inflammatory activity between the two ALM courses was associated with higher risk of relapse, MRI activity, and NEDA-3 status loss in relapsing-remitting multiple sclerosis (RRMS; p = 0.02, p = 0.05, p = 0.01, respectively). CONCLUSIONS: OCR after two ALM courses seemed to be safe and effective. Early IgM hypogammaglobulinemia occurred in a high proportion of patients. The evidence of inflammatory activity between ALM courses seemed to increase the risk of MS re-activation on OCR treatment.
Asunto(s)
Alemtuzumab , Anticuerpos Monoclonales Humanizados , Factores Inmunológicos , Humanos , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Alemtuzumab/efectos adversos , Adulto , Italia , Estudios Retrospectivos , Factores Inmunológicos/efectos adversos , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple/tratamiento farmacológico , Estudios de SeguimientoRESUMEN
BACKGROUND: Comparisons between cladribine and other potent immunotherapies for multiple sclerosis (MS) are lacking. OBJECTIVES: To compare the effectiveness of cladribine against fingolimod, natalizumab, ocrelizumab and alemtuzumab in relapsing-remitting MS. METHODS: Patients with relapsing-remitting MS treated with cladribine, fingolimod, natalizumab, ocrelizumab or alemtuzumab were identified in the global MSBase cohort and two additional UK centres. Patients were followed for ⩾6/12 and had ⩾3 in-person disability assessments. Patients were matched using propensity score. Four pairwise analyses compared annualised relapse rates (ARRs) and disability outcomes. RESULTS: The eligible cohorts consisted of 853 (fingolimod), 464 (natalizumab), 1131 (ocrelizumab), 123 (alemtuzumab) or 493 (cladribine) patients. Cladribine was associated with a lower ARR than fingolimod (0.07 vs. 0.12, p = 0.006) and a higher ARR than natalizumab (0.10 vs. 0.06, p = 0.03), ocrelizumab (0.09 vs. 0.05, p = 0.008) and alemtuzumab (0.17 vs. 0.04, p < 0.001). Compared to cladribine, the risk of disability worsening did not differ in patients treated with fingolimod (hazard ratio (HR) 1.08, 95% confidence interval (CI) 0.47-2.47) or alemtuzumab (HR 0.73, 95% CI 0.26-2.07), but was lower for patients treated with natalizumab (HR 0.35, 95% CI 0.13-0.94) and ocrelizumab (HR 0.45, 95% CI 0.26-0.78). There was no evidence for a difference in disability improvement. CONCLUSION: Cladribine is an effective therapy that can be viewed as a step up in effectiveness from fingolimod, but is less effective than the most potent intravenous MS therapies.
Asunto(s)
Alemtuzumab , Anticuerpos Monoclonales Humanizados , Cladribina , Clorhidrato de Fingolimod , Inmunosupresores , Esclerosis Múltiple Recurrente-Remitente , Natalizumab , Humanos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Femenino , Masculino , Cladribina/uso terapéutico , Cladribina/efectos adversos , Alemtuzumab/efectos adversos , Alemtuzumab/uso terapéutico , Clorhidrato de Fingolimod/uso terapéutico , Clorhidrato de Fingolimod/efectos adversos , Adulto , Natalizumab/uso terapéutico , Natalizumab/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Persona de Mediana Edad , Factores Inmunológicos/efectos adversos , Resultado del TratamientoRESUMEN
Epstein-Barr virus (EBV) infection and various chemokines, including CCL20, CXCL8 and CXCL10 are considered to participate in the pathogenesis of multiple sclerosis (MS), and several studies point to a direct regulatory effect of EBV on the expression of these chemokines. In our study we hypothesized that serum concentrations of CCL20, CXCL8 and CXCL0 are induced in patients with relapsing-remitting MS (RRMS) in comparison to healthy individuals, and that they are associated with EBV infection. Serum concentrations of CXCL8 and CXCL10 were lower in RRMS patients in relapse in comparison to healthy controls. Although potential effects of corticosteroid therapy introduced in a subgroup of RRMS patients prior to sampling were excluded by subgroup comparison, this possibility has to be considered while interpreting the results. We found an inverse association between serum concentrations of CXCL8 and anti-Epstein-Barr Virus Nuclear Antigen (EBNA) IgG and decreased expression of CXCL8 in peripheral blood mononuclear cells (PBMC) in relapse compared to remission. Lower serum concentrations of CXCL8 and CXCL10 in RRMS patients and decreased peripheral production of CXCL8 in relapse may indicate compensatory anti-inflammatory counter-regulation in MS.
Asunto(s)
Quimiocina CCL20 , Quimiocina CXCL10 , Herpesvirus Humano 4 , Interleucina-8 , Esclerosis Múltiple Recurrente-Remitente , Humanos , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/virología , Femenino , Quimiocina CXCL10/sangre , Adulto , Masculino , Herpesvirus Humano 4/inmunología , Quimiocina CCL20/sangre , Interleucina-8/sangre , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Persona de Mediana Edad , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Estudios de Casos y ControlesRESUMEN
BACKGROUND: Up to now, there is no definitive prognostic factor for patients with multiple sclerosis. OBJECTIVE: This study aimed to evaluate the neutrophil-to-lymphocyte ratio (N/L ratio) as a cheap, available, and noninvasive marker for disease activity and prognosis. MATERIAL AND METHODS: A total of 112 patients, who were diagnosed with relapsing-remitting multiple sclerosis (RRMS), and 61 healthy controls were considered. We evaluated N/L ratio, ESR, CRP in the control, and patients in the first attack of the onset of the disease, 1 month and 6 months later during remission. All patients received interferon or Glatiramer acetate as disease-modifying therapies. The correlation of parameters with Expanded Disability Scale Score (EDSS) and Functional System (FS) involvement was evaluated. RESULTS: The N/L ratio was increased significantly in patients with MS in the relapse phase (mean: 2.44 ± 0.68) compared to the healthy controls (mean: 1.84 ± 0.67) (P = 0.04). Also, we found a significant increase in CRP among the aforementioned groups (P = 0.028). A significant correlation was not found between NLR, ESR, or CRP and patient's EDSS during 6 months of follow-up. For ESR and the type of functional system, a significant difference was found between favorable and unfavorable categories, while the median (IQR) of ESR in the favorable group was 7.7 (4-12) and among unfavorable ones was 13.8 (6-17.75) (P = 0.008). CONCLUSIONS: The results showed the effect of the innate immune system and inflammation during MS attacks. We considered that neutrophils, ESR, and CRP cannot predict disease severity or prognosis at least without a combination of other biomarkers.
Asunto(s)
Biomarcadores , Proteína C-Reactiva , Linfocitos , Esclerosis Múltiple Recurrente-Remitente , Neutrófilos , Humanos , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Adulto , Femenino , Masculino , Pronóstico , Linfocitos/metabolismo , Proteína C-Reactiva/metabolismo , Biomarcadores/sangre , Índice de Severidad de la Enfermedad , Sedimentación Sanguínea , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Multiple sclerosis (MS) is a chronic, immune mediated demyelinating illness of the central nervous system. This study looks at various comorbidities associated with MS, focusing on their impact on disease progression. Understanding comorbidities in MS is important as it can impact treatment selection and overall disease management and prognosis. AIMS AND OBJECTIVES: Our aim is to show the prevalence of comorbidities along with MS. This research focuses on the comorbidities associated with MS and their impact on disease progression in the Arab Gulf region, with a special emphasis on Jeddah, Saudi Arabia. MATERIAL AND METHODS: A retrospective record review was conducted from July 2022 to July 2023. The study included 286 patients, selected based on a definitive MS diagnosis in accordance with McDonald's 2017 criteria. Data collected included demographic information, MS type, duration of diagnosis, type of disease modifying therapy (DMT) used, Expanded Disability Status Scale (EDSS) score, and type of comorbidities. RESULTS: The majority of the patients were female (70%) with an average age of 36 years. Most patients had relapsing remitting MS, and the majority were on DMTs, with fingolimod being the most common. Nearly half of the patients had comorbidities, with mood disorders, diabetes mellitus (DM), migraine, and hypertension (HTN) being prevalent. A significant positive association was found between the EDSS scores and both DM and HTN, but there was no significant link with migraine. CONCLUSION: The findings indicate that individuals with MS have an increased risk of developing comorbidities such as migraine, DM, and HTN. Emphasizing a healthy lifestyle could potentially reduce the incidence of DM and HTN and their related vascular complications. The research also notes the prevalence of mood disorders among the MS population, although it remains inconclusive whether these are separate comorbid conditions or inherent symptoms of MS.
Résumé Contexte:La sclérose en plaques (SEP) est une maladie démyélinisante chronique à médiation immunitaire du système nerveux central. Cette étude examine diverses comorbidités associées à la SEP, en se concentrant sur leur impact sur la progression de la maladie. Comprendre les comorbidités liées à la SEP est important car cela peut avoir un impact sur le choix du traitement ainsi que sur la prise en charge globale et le pronostic de la maladie.Buts et objectifs:Notre objectif est de montrer la prévalence des comorbidités ainsi que la SEP. Cette recherche se concentre sur les comorbidités associées à la SEP et leur impact sur la progression de la maladie dans la région arabe du Golfe, avec un accent particulier sur Djeddah, en Arabie Saoudite.Matériel et méthodes:Un examen rétrospectif des dossiers a été réalisé de juillet 2022 à juillet 2023. L'étude a inclus 286 patients, sélectionnés sur la base d'un diagnostic définitif de SEP conformément aux critères McDonald's 2017. Les données collectées comprenaient des informations démographiques, le type de SEP, la durée du diagnostic, le type de traitement modificateur de la maladie (DMT) utilisé, le score EDSS (Expanded Disability Status Scale) et le type de comorbidités.Résultats:La majorité des patients étaient des femmes (70 %) avec un âge moyen de 36 ans. La plupart des patients souffraient de SEP rémittente et la majorité étaient sous DMT, le fingolimod étant le plus courant. Près de la moitié des patients présentaient des comorbidités, avec des troubles de l'humeur, un diabète sucré (DM), une migraine et une hypertension (HTN) prédominants. Une association positive significative a été trouvée entre les scores EDSS et le DM et le HTN, mais il n'y avait pas de lien significatif avec la migraine.Conclusion:Les résultats indiquent que les personnes atteintes de SEP ont un risque accru de développer des comorbidités telles que la migraine, le diabète et l'HTN. Mettre l'accent sur un mode de vie sain pourrait potentiellement réduire l'incidence du diabète et du HTN et de leurs complications vasculaires associées. La recherche note également la prévalence des troubles de l'humeur au sein de la population atteinte de SEP, même si l'on ne sait toujours pas s'il s'agit de conditions comorbides distinctes ou de symptômes inhérents à la SEP.
Asunto(s)
Comorbilidad , Hipertensión , Esclerosis Múltiple , Humanos , Arabia Saudita/epidemiología , Femenino , Masculino , Adulto , Prevalencia , Esclerosis Múltiple/epidemiología , Estudios Retrospectivos , Persona de Mediana Edad , Hipertensión/epidemiología , Diabetes Mellitus/epidemiología , Progresión de la Enfermedad , Trastornos Migrañosos/epidemiología , Trastornos del Humor/epidemiología , Adulto Joven , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
BACKGROUND: Cladribine is an oral disease-modifying drug approved for the treatment of highly active relapsing multiple sclerosis (MS). The recommended number of treatment courses is two, with the courses given 1 year apart (i.e., in year 1 and year 2), followed by 2 years without treatment. Pivotal clinical trials showed that, compared with placebo, cladribine significantly reduced relapse rates, risk of disability progression and magnetic resonance imaging measures of disease activity for up to 4 years in treatment-naïve or -experienced adults with relapsing-remitting MS (RRMS). The management of patients and requirement for retreatment with cladribine beyond year 4 is unclear. METHODS: We describe the treatment history and outcomes of three people with MS retreated with cladribine, given as a third course 5 years after treatment initiation. We also include a review of evidence on retreatment with cladribine from year 3 onwards and a discussion of patient selection criteria for retreatment. RESULTS: The cases included a 53-year-old female patient with RRMS, a 43-year-old female patient with RRMS, and a 42-year-old male patient with RRMS. Six months after the third course of cladribine, all three patients were relapse-free and stable on magnetic resonance imaging, with no evidence of disease activity. At 11-12 months follow-up, all patients had clinical and radiological stability (i.e., no evidence of disease activity). CONCLUSION: Continuation of oral cladribine treatment may be considered for people with MS beyond year 5 following completion of the initial two courses. Our real-world experience is ongoing and additional data are required to obtain insight into patient phenotypes which predict response to cladribine treatment.
Asunto(s)
Cladribina , Inmunosupresores , Esclerosis Múltiple Recurrente-Remitente , Humanos , Cladribina/administración & dosificación , Femenino , Adulto , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéuticoRESUMEN
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.
Asunto(s)
Interferón beta , Esclerosis Múltiple Recurrente-Remitente , Proteómica , Transcriptoma , Humanos , Interferón beta/uso terapéutico , Interferón beta/inmunología , Femenino , Masculino , Adulto , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/sangre , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Biomarcadores/sangre , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/sangreRESUMEN
BACKGROUND: As cognitive impairment in multiple sclerosis (MS) is a frequent and disabling symptom, it is particularly important to identify treatments that have proven efficacy in this aspect of the disease. Several disease-modifying therapies for MS have been evaluated and shown to have a potential effect on cognition and its neurobiological correlates, but to date there is very little data on Teriflunomide (TRF). The aim of this study is to explore the influence of TRF on comprehensive cognitive function and its MRI correlations (global and focal brain volume) in relapsing-remitting multiple sclerosis (RRMS) after two years of therapy. METHODS: Twenty-four patients with RRMS were evaluated at baseline and after two years of treatment with BCcogSEP, a French translation of the Brief Repeatable Battery (BRB-N) including 3 additional tests. We explored the performance evolution for each test and correlation with MRI data for all patients. We also differentiated MS patients with and without cognitive impairment. RESULTS: After two years of treatment, an improvement is observed at the Selective Reminding Test for mean number of words (p = 0.044), learning (p = 0.018), and delayed recall (p = 0.002) and at GoNoGo task (p = 0.022). At MRI, the corpus callosum volume variation correlates positively with SRT total recall test (p = 0,047). Intergoup analysis shows that the evolution of group performance differs only for the SRT total recall test. The comparison of patients with or without cognitive impairment showed a clear difference in white matter substance volume (p = 0,003) and in the Percentage Brain Volume Change (p = 0,016). CONCLUSION: Results suggest that TRF treatment in RRMS has a positive effect in cognitive function, and specifically on long term verbal memory and inhibition. Neuroimaging data suggest a link between cognition and global and focal white matter volume, particularly in the corpus callosum which is involved in anatomical disconnection syndrome and therefore brain plasticity capacities.
Asunto(s)
Disfunción Cognitiva , Crotonatos , Hidroxibutiratos , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente , Nitrilos , Toluidinas , Humanos , Adulto , Toluidinas/administración & dosificación , Toluidinas/farmacología , Masculino , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Femenino , Crotonatos/farmacología , Crotonatos/administración & dosificación , Estudios Longitudinales , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/fisiopatología , Persona de Mediana Edad , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/patología , Pruebas Neuropsicológicas , Cognición/efectos de los fármacosRESUMEN
BACKGROUND: The assessment of serum neurofilament light chain (sNfL) concentration in multiple sclerosis (MS) is a useful tool for predicting clinical outcomes and assessing treatment response. However, its use in clinical practice is still limited. We aimed to assess how measurement of sNfL influences neurologists' treatment decisions in MS. METHODS: We conducted a cross-sectional, web-based study in collaboration with the Spanish Society of Neurology. Neurologists involved in MS care were presented with different simulated case scenarios of patients experiencing either their first demyelinating MS event or a relapsing-remitting MS. The primary outcome was therapeutic inertia (TI), defined as the absence of treatment initiation or intensification despite elevated sNfL levels. Nine cases were included to estimate the TI score (range 0-9, where higher values represented a higher degree of TI). RESULTS: A total of 116 participants were studied. Mean age (standard deviation-SD) was 41.9 (10.1) years, 53.4 % male. Seventy-eight (67.2 %) were neurologists fully dedicated to the care of demyelinating disorders. Mean (SD) TI score was 3.65 (1.01). Overall, 92.2 % of participants (n = 107) presented TI in at least 2/9 case scenarios. The lack of full dedication to MS care (p = 0.014), preference for taking risks (p = 0.008), and low willingness to adopt evidence-based innovations (p = 0.009) were associated with higher TI scores in the multivariate analysis after adjustment for confounders. CONCLUSION: TI was a common phenomenon among neurologists managing MS patients when faced with the decision to initiate or escalate treatment based on elevated sNfL levels. Identifying factors associated with this phenomenon may help optimize treatment decisions in MS care.
Asunto(s)
Toma de Decisiones Clínicas , Esclerosis Múltiple , Proteínas de Neurofilamentos , Neurólogos , Humanos , Femenino , Masculino , Proteínas de Neurofilamentos/sangre , Estudios Transversales , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/terapia , Esclerosis Múltiple/diagnóstico , Biomarcadores/sangre , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/terapia , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológicoRESUMEN
BACKGROUND: Several studies reported lower drug concentrations with subcutaneous natalizumab compared to intravenous natalizumab. With the emergence of extended interval dosing, gaining more insight into lower concentrations after subcutaneous administration is essential. METHODS: We compared serum trough concentrations between subcutaneous and intravenous administration within a matched cohort (n = 50). RESULTS: Subcutaneous administration (n = 25) was associated with lower concentrations compared to intravenous administration (n = 25) (log-B=-0.28, p = 0.01). In an exploratory group of 11 patients receiving extended interval dosing of subcutaneous natalizumab, the median trough concentration was even lower. CONCLUSION: Subcutaneous natalizumab can lead to lower drug concentrations, potentially limiting extended interval dosing.
Asunto(s)
Administración Intravenosa , Factores Inmunológicos , Natalizumab , Humanos , Natalizumab/administración & dosificación , Natalizumab/sangre , Femenino , Masculino , Inyecciones Subcutáneas , Adulto , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacocinética , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/sangreRESUMEN
INTRODUCTION: Melatonin is an antioxidant and anti-inflammatory agent that modulates the immune system by scavenging free radicals, reducing the upregulation of pro-inflammatory cytokines, and reducing transendothelial cell migration. Therefore, melatonin may play a role in regulating multiple sclerosis (MS) disease activity. However, little is known about how melatonin supplementation effects individuals with MS. OBJECTIVE: Determine if there was a dose-dependent elevation in urine and serum melatonin concentrations. Determine if melatonin supplementation had an impact on patient reported outcomes. METHODS: This was a randomized, dose-blinded exploratory study. Adults (age 18-65) with relapsing forms of multiple sclerosis (RMS) treated with a stable dose of oral disease modifying therapy for at least 6 months were randomized into melatonin 3 mg or 5 mg daily. Urinary and serum melatonin levels and modified fatigue impact scale (MFIS), multiple sclerosis impact scale (MSIS-29), and Pittsburgh sleep quality index (PSQI), patient determined disease steps (PDDS) and performance scales (PS) were measured at baseline, 3, 6, and 12 months. Urinary and serum melatonin analyses was performed to estimate mean concentrations and their differences between treatment arms over time by a repeated measures linear mixed model. The model included treatment, assessment time, and treatment × time interaction. RESULTS: Thirty patients, randomized 1:1, were analyzed in an intent to treat population. Twenty-three completed the study. The repeated measures linear mixed model analysis of all timepoints revealed higher melatonin concentrations in patients on 5 mg compared to 3 mg melatonin for both urinary 6-SMT (p = 0.03) and serum melatonin (p = 0.04). MFIS, MSIS-29, PSQI, and PDSS-PS scores did not significantly change from baseline to month 12. No significant differences in these measures were seen between the two doses. Five patients stopped melatonin (three on 5 mg and two on 3 mg) due to adverse events, including one patient who developed focal spongiotic dermatitis. One patient experienced three consecutive serious adverse events that were unrelated to melatonin supplementation. CONCLUSIONS: The 5 mg melatonin supplementation group had higher concentrations of urinary 6-SMT and serum melatonin compared to the 3 mg group over 12 months of treatment. There was a correlation between 6-SMT and serum melatonin concentrations. This suggests that measuring serum melatonin is a reliable alternative to measuring urinary 6-SMT. However, no differences in clinical benefit between the two dosage groups were demonstrated in the patient reported outcomes. TRIAL REGISTRATION NUMBER: NCT03498131.
Asunto(s)
Melatonina , Esclerosis Múltiple Recurrente-Remitente , Calidad de Vida , Humanos , Melatonina/administración & dosificación , Melatonina/orina , Melatonina/sangre , Melatonina/farmacología , Adulto , Femenino , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/orina , Esclerosis Múltiple Recurrente-Remitente/dietoterapia , Adulto Joven , Anciano , Administración Oral , Adolescente , Antioxidantes/administración & dosificación , Antioxidantes/farmacología , Relación Dosis-Respuesta a Droga , Suplementos DietéticosRESUMEN
BACKGROUND: Cladribine tablets for the treatment of relapsing multiple sclerosis (RMS) are administered in two pulsed treatment courses in two consecutive years, totalling a maximum of 20 treatment days. Here we present data collected shortly after the launch of cladribine tablets, focusing on the patient's perspective. The objective was to investigate patients' perceived effectiveness, tolerability, and convenience, as well as global satisfaction of and with cladribine tablets. METHODS: CLEVER was a non-interventional multicentre study conducted in Germany from 12/2017 to 7/2020. Adult patients with RMS initiating therapy with cladribine tablets were included. Observation time per patient was 24 weeks, comprising 3 visits (baseline, week 4 and 24). The primary endpoint was overall treatment satisfaction at week 24, assessed by the Treatment Satisfaction Questionnaire for Medication 14 items (TSQM 1.4). Subgroup analyses included stratification by prior treatment. RESULTS: In total, 491 patients (69.2 % female; mean (±SD) age 40.3 (±11.5) years, 85.1 % pre-treated, median EDSS 2.5) initiated therapy with cladribine tablets and were included in the analysis. At week 24, the mean (±SD) global TSQM satisfaction score was 75.6 (±19.0). For patients switching from either injectables or oral medication, the change in therapy satisfaction from baseline to week 24 was positive in all TSQM domains with clinically meaningful effect sizes in the global satisfaction and side effects domains. Most patients (85.5 %) remained relapse-free over 24 weeks. Out of 491 patients, 187 (38.1 %) experienced at least one adverse event and 8 patients (1.6 %) one serious adverse event. CONCLUSION: Treatment satisfaction with cladribine tablets was high. The switch from prior injectables or oral medication translated into increased treatment satisfaction at week 24 with clinically meaningful effects in the global satisfaction and side effects domains. Effectiveness and safety were consistent with results from clinical studies.
Asunto(s)
Cladribina , Inmunosupresores , Esclerosis Múltiple Recurrente-Remitente , Satisfacción del Paciente , Comprimidos , Humanos , Femenino , Cladribina/administración & dosificación , Masculino , Adulto , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Persona de Mediana Edad , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , AlemaniaRESUMEN
BACKGROUND: Employing a rebaselining concept may reduce noise in retinal layer thinning measured by optical coherence tomography (OCT). METHODS: From an ongoing prospective observational study, we included patients with relapsing multiple sclerosis (RMS), who had OCT scans at disease-modifying treatment (DMT) start (baseline), 6-12 months after baseline (rebaseline), and ⩾12 months after rebaseline. Mean annualized percent loss (aL) rates (%/year) were calculated both from baseline and rebaseline for peripapillary-retinal-nerve-fiber-layer (aLpRNFLbaseline/aLpRNFLrebaseline) and macular-ganglion-cell-plus-inner-plexiform-layer (aLGCIPLbaseline/aLGCIPLrebaseline) by mixed-effects linear regression models. RESULTS: We included 173 RMS patients (mean age 31.7 years (SD 8.8), 72.8% female, median disease duration 15 months (12-94) median baseline-to-last-follow-up-interval 37 months (18-71); 56.6% moderately effective DMT (M-DMT), 43.4% highly effective DMT (HE-DMT)). Both mean aLpRNFLbaseline and aLGCIPLbaseline significantly increased in association with relapse (0.51% and 0.26% per relapse, p < 0.001, respectively) and disability worsening (1.10% and 0.48%, p < 0.001, respectively) before baseline, but not with DMT class. Contrarily, neither aLpRNFLrebaseline nor aLGCIPLrebaseline was dependent on relapse or disability worsening before baseline, while HE-DMT significantly lowered aLpRNFLrebaseline (by 0.31%, p < 0.001) and aLGCIPLrebaseline (0.25%, p < 0.001) compared with M-DMT. CONCLUSIONS: Applying a rebaselining concept significantly improves differentiation of DMT effects on retinal layer thinning by avoiding carry-over confounding from previous disease activity.