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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.
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BACKGROUND AND PURPOSE: Cladribine tablets, a purine analogue antimetabolite, offer a unique treatment regimen, involving short courses at the start of the first and second year, with no further treatment needed in years 3 and 4. However, comprehensive evidence regarding patient outcomes beyond the initial 24 months of cladribine treatment is limited. METHODS: This retrospective, multicenter study enrolled 204 patients with multiple sclerosis who had completed the 2-year course of cladribine treatment. The primary outcomes were therapeutic choices and clinical disease activity assessed by annualized relapse rate after the 2-year treatment course. RESULTS: A total of 204 patients were enrolled; most patients (75.4%) did not initiate new treatments in the 12 months postcladribine. The study found a significant reduction in annualized relapse rate at the 12-month follow-up after cladribine completion compared to the year prior to starting therapy (0.07 ± 0.25 vs. 0.82 ± 0.80, p < 0.001). Furthermore, patients with relapses during cladribine treatment were more likely to start new therapies, whereas older patients were less likely. The safety profile of cladribine was favorable, with lymphopenia being the primary registered adverse event. CONCLUSIONS: This study provides insights into therapeutic choices and disease activity following cladribine treatment. It highlights cladribine's effectiveness in reducing relapse rates and disability progression, reaffirming its favorable safety profile. Real-world data, aligned with previous reports, draw attention to ocrelizumab and natalizumab as common choices after cladribine. However, larger, prospective studies for validation and a more comprehensive understanding of cladribine's long-term impact are necessary.
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Cladribina , Inmunosupresores , Humanos , Cladribina/uso terapéutico , Femenino , Masculino , Adulto , Estudios Retrospectivos , Persona de Mediana Edad , Inmunosupresores/uso terapéutico , Italia , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Resultado del Tratamiento , Esclerosis Múltiple/tratamiento farmacológicoRESUMEN
BACKGROUND AND PURPOSE: Although two doses of COVID-19 vaccine elicited a protective humoral response in most persons with multiple sclerosis (pwMS), a significant group of them treated with immunosuppressive disease-modifying therapies (DMTs) showed less efficient responses. METHODS: This prospective multicenter observational study evaluates differences in immune response after a third vaccine dose in pwMS. RESULTS: Four hundred seventy-three pwMS were analyzed. Compared to untreated patients, there was a 50-fold decrease (95% confidence interval [CI] = 14.3-100.0, p < 0.001) in serum SARS-CoV-2 antibody levels in those on rituximab, a 20-fold decrease (95% CI = 8.3-50.0, p < 0.001) in those on ocrelizumab, and a 2.3-fold decrease (95% CI = 1.2-4.6, p = 0.015) in those on fingolimod. As compared to the antibody levels after the second vaccine dose, patients on the anti-CD20 drugs rituximab and ocrelizumab showed a 2.3-fold lower gain (95% CI = 1.4-3.8, p = 0.001), whereas those on fingolimod showed a 1.7-fold higher gain (95% CI = 1.1-2.7, p = 0.012), compared to patients treated with other DMTs. CONCLUSIONS: All pwMS increased their serum SARS-CoV-2 antibody levels after the third vaccine dose. The mean antibody values of patients treated with ocrelizumab/rituximab remained well below the empirical "protective threshold" for risk of infection identified in the CovaXiMS study (>659 binding antibody units/mL), whereas for patients treated with fingolimod this value was significantly closer to the cutoff.
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COVID-19 , Esclerosis Múltiple , Humanos , Vacunas contra la COVID-19 , Formación de Anticuerpos , Clorhidrato de Fingolimod , Esclerosis Múltiple/tratamiento farmacológico , Estudios Prospectivos , Rituximab/uso terapéutico , COVID-19/prevención & control , SARS-CoV-2 , Anticuerpos Antivirales , VacunaciónRESUMEN
Patients with human immunodeficiency virus (HIV) infection have a decreased risk of developing multiple sclerosis (MS) and MS patients very rarely contract HIV infection. We report on a 35-year-old woman with relapsing-remitting MS, who acquired HIV infection 8 years after MS onset. During 7 years of follow-up without combined antiretroviral therapy (cART), CD4+ counts decreased and HIV viremia increased progressively, but slightly. These trends reverted after starting cART, with optimal viro-immunological control. While the patient had many MS relapses before acquiring HIV infection, she had then only one relapse, shortly after HIV infection, despite irregular or no MS therapy. This case contributes to the discussion about MS and HIV potential interactions and describes for the first time the effects of the MS-targeting drug natalizumab in an HIV-positive patient.
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Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/patología , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/patología , Natalizumab/uso terapéutico , Viremia/patología , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Femenino , Acetato de Glatiramer/uso terapéutico , VIH/genética , VIH/aislamiento & purificación , Infecciones por VIH/diagnóstico por imagen , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/virología , ARN Viral/genética , Carga Viral/efectos de los fármacos , Viremia/diagnóstico por imagen , Viremia/inmunología , Viremia/virologíaRESUMEN
INTRODUCTION: Natalizumab (NTZ) is one of the most effective treatment options for multiple sclerosis (MS) treatment. Our study aimed to evaluate the effectiveness of NTZ when administered according to the extended dosing strategy compared with standard 4-weekly administration in a large Italian MS population. MATERIALS AND METHODS: This retrospective multicentre study included patients with relapsing-remitting MS (RR-MS) who received NTZ administrations between the 1 June 2012 and the 15 May 2018 and were followed by the 'Italian MS Register'. All patients with MS were stratified into two groups based on NTZ administration schedule: standard interval dosing (SID) patients who received infusions on average from 28 to 32 days (median 30) and extended interval dosing (EID) including patients who have been infused with interval between 33 and 49 days (median 43). Clinical data were assessed at baseline (before starting NTZ), after 12 (T1) and 24 months (T2) of treatment. RESULTS: Out of 5231 patients with RR-MS screened, 2092 (mean age 43.2±12.0, 60.6% women) were enrolled. A total of 1254 (59.9%) received NTZ according to SID, and 838 (40.1%) according to EID. At 12 and 24 months, no differences in terms of annualised relapse rate and disability status were found between the two groups. Progression index and confirmed disability worsening were similar between the two groups. DISCUSSION: The use of NTZ with an extended interval schedule showed similar effectiveness compared with SID. Unchanged clinical efficacy of EID schedule may raise the question of a possible advantage in terms of tolerability and safety.
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Factores Inmunológicos/administración & dosificación , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/administración & dosificación , Adulto , Esquema de Medicación , Humanos , Italia , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Gait deterioration caused by prolonged walking represents one of the main consequences of multiple sclerosis (MS). This study aims at proposing quantitative indices to measure the gait deterioration effects. The experimental protocol consisted in a 6-min walking test and it involved nine patients with MS and twenty-six healthy subjects. Pathology severity was assessed through the Expanded Disability Status Scale. Seven inertial units were used to gather lower limb kinematics. Gait variability and asymmetry were assessed by coefficient of variation (CoV) and symmetry index (SI), respectively. The evolution of ROM (range of motion), CoV, and SI was computed analyzing data divided into six 60-s subgroups. Maximum difference among subgroups and the difference between the first minute and the remaining five were computed. The indices were analyzed for intra- and inter-day reliability and repeatability. Correlation with clinical scores was also evaluated. Good to excellent reliability was found for all indices. The computed standard deviations allowed us to affirm the good repeatability of the indices. The outcomes suggested walking-related fatigue leads to an always more variable kinematics in MS, in terms of changes in ROM, increase of variability and asymmetry. The hip asymmetry strongly correlated with the clinical disability.
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Fatiga/fisiopatología , Trastornos Neurológicos de la Marcha/diagnóstico , Marcha/fisiología , Esclerosis Múltiple/diagnóstico , Índice de Severidad de la Enfermedad , Caminata/fisiología , Adulto , Anciano , Fenómenos Biomecánicos/fisiología , Estudios de Casos y Controles , Evaluación de la Discapacidad , Progresión de la Enfermedad , Prueba de Esfuerzo/métodos , Femenino , Trastornos Neurológicos de la Marcha/etiología , Indicadores de Salud , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/patología , Esclerosis Múltiple/fisiopatología , Reproducibilidad de los Resultados , Proyectos de Investigación , Factores de TiempoRESUMEN
OBJECTIVE: To study the effect of natural menopause on multiple sclerosis clinical course. METHODS: This was an observational, retrospective, multicentre, cohort study. Menopause onset was defined by the final menstrual period (FMP) beyond which no menses occurred for 12 months. We included multiple sclerosis (MS) patients with FMP occurred after 2005 and a recorded follow-up of at least 2 years pre-FMP and post-FMP. We excluded patients with primary progressive course, iatrogenic menopause and with other confounders that could mask menopause onset. We compared relapse-rate and expanded disability status scale (EDSS) scores pre-FMP and post-FMP, searching for possible interactions with age, disease duration, cigarette smoking and nulliparity status. RESULTS: 148 patients were included (mean observation: 3.5 years pre-FMP and post-FMP). Most patients (92%) received disease-modifying therapies, mainly first-lines. After menopause the annualised relapse rate (ARR) significantly decreased (from 0.21±0.31 to 0.13± 0.24; p=0.005), while disability worsened (increase of mean 0.4 vs 0.2 points after menopause; p<0.001). Older age and long-lasting disease were associated with ARR reduction (p=0.013), but not with disability worsening. Cigarette smokers showed a trend to a higher disability accumulation after menopause (p=0.059). CONCLUSION: Natural menopause seems to be a turning point to a more progressive phase of MS. Relapse rate is also reduced after menopause, but this effect could be driven most by ageing and shifting to progressive phase in patients with long-lasting disease. Cigarette smoking could speed up disability progression after menopause.
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Menopausia , Esclerosis Múltiple/epidemiología , Adolescente , Adulto , Progresión de la Enfermedad , Femenino , Humanos , Italia/epidemiología , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Adulto JovenRESUMEN
Syndromes associated with multiple mtDNA deletions are due to different molecular defects that can result in a wide spectrum of predominantly adult-onset clinical presentations, ranging from progressive external ophthalmoplegia (PEO) to multisystemic disorders of variable severity. The autosomal-dominant form of PEO is genetically heterogeneous. Recently, causative mutations have been reported in several nuclear genes that encode proteins of the mtDNA replisome machinery (POLG, POLG2, and C10orf2) or that are involved in pathways for the synthesis of deoxyribonuclotides (ANT1 and RRM2B). Despite these findings, putative mutations remain unknown in half of the subjects with PEO. We report the identification, by exome sequencing, of mutations in DNA2 in adult-onset individuals with a form of mitochondrial myopathy featuring instability of muscle mtDNA. DNA2 encodes a helicase/nuclease family member that is most likely involved in mtDNA replication, as well as in the long-patch base-excision repair (LP-BER) pathway. In vitro biochemical analysis of purified mutant proteins revealed a severe impairment of nuclease, helicase, and ATPase activities. These results implicate human DNA2 and the LP-BER pathway in the pathogenesis of adult-onset disorders of mtDNA maintenance.
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ADN Helicasas/genética , ADN Mitocondrial/genética , Inestabilidad Genómica/genética , Miopatías Mitocondriales/enzimología , Miopatías Mitocondriales/genética , Mutación/genética , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Secuencia Conservada/genética , ADN Helicasas/química , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Músculos/patología , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
The comparative effectiveness of fingolimod versus interferon beta/glatiramer acetate was assessed in a multicentre, observational, prospectively acquired cohort study including 613 patients with relapsing multiple sclerosis discontinuing natalizumab in the Italian iMedWeb registry. First, after natalizumab suspension, the relapse risk during the untreated wash-out period and during the course of switch therapies was estimated through Poisson regression analyses in separated models. During the wash-out period an increased risk of relapses was found in patients with a higher number of relapses before natalizumab treatment (incidence rate ratio = 1.31, P = 0.0014) and in patients discontinuing natalizumab due to lack of efficacy (incidence rate ratio = 2.33, P = 0.0288), patient's choice (incidence rate ratio = 2.18, P = 0.0064) and adverse events (incidence rate ratio = 2.09, P = 0.0084). The strongest independent factors influencing the relapse risk after the start of switch therapies were a wash-out duration longer than 3 months (incidence rate ratio = 1.78, P < 0.0001), the number of relapses experienced during and before natalizumab treatment (incidence rate ratio = 1.61, P < 0.0001; incidence rate ratio = 1.13, P = 0.0118, respectively) and the presence of comorbidities (incidence rate ratio = 1.4, P = 0.0097). Switching to fingolimod was associated with a 64% reduction of the adjusted-risk for relapse in comparison with switching to interferon beta/glatiramer acetate (incidence rate ratio = 0.36, P < 0.0001). Secondly, patients who switched to fingolimod or to interferon beta/glatiramer acetate were propensity score-matched on a 1-to-1 basis at the switching date. In the propensity score-matched sample a Poisson model showed a significant lower incidence of relapses in patients treated with fingolimod in comparison with those treated with interferon beta/glatiramer acetate (incidence rate ratio = 0.52, P = 0.0003) during a 12-month follow-up. The cumulative probability of a first relapse after the treatment switch was significantly lower in patients receiving fingolimod than in those receiving interferon beta/glatiramer acetate (P = 0.028). The robustness of this result was also confirmed by sensitivity analyses in subgroups with different wash-out durations (less or more than 3 months). Time to 3-month confirmed disability progression was not significantly different between the two groups (Hazard ratio = 0.58; P = 0.1931). Our results indicate a superiority of fingolimod in comparison to interferon beta/glatiramer acetate in controlling disease reactivation after natalizumab discontinuation in the real life setting.
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Clorhidrato de Fingolimod/uso terapéutico , Acetato de Glatiramer/uso terapéutico , Factores Inmunológicos/uso terapéutico , Inmunosupresores/uso terapéutico , Interferón beta/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/uso terapéutico , Sistema de Registros , Adulto , Estudios de Cohortes , Sustitución de Medicamentos , Quimioterapia Combinada , Femenino , Humanos , Italia , Masculino , Persona de Mediana Edad , Distribución de Poisson , Estudios Prospectivos , Análisis de Regresión , Resultado del TratamientoRESUMEN
The pandemic changed the type of patients. The concept of "patient at the center" became concrete. The execution of simple consultancy was overcome to create effective collaboration and fruitful exchanges between specialists. The "Heart Team" model is on increasing affirmation. The TEAM-BASED approach in the cardiology field is successfully used in patients suffering from ischemic heart disease and valvulopathies for the choice of possible treatments. Degenerative type Sao is the most frequent valvulopathy among the valvulopathies in Western countries and its incidence is correlated with age. In high-risk patients, percutaneous valve replacement (transcatheter aortic valve implantation) is the most valid therapeutic option. The implantation of biological prostheses raises the problem of both degeneration and dysfunction of the prosthesis itself over time in subjects of advanced age and with comorbidities. In this scenario, valve-in-valve (VinV) is a valid therapeutic alternative in high-risk patients. A clinical case of aortic prosthetic degeneration, as an outcome of endocarditis, treated with VinV is presented. The therapeutic decision was made by an "Electronic Heart Team" which represents a further evolution of the treatment pathways and reduces the distance between the specialists in "Hub" Centers and the "Spoke" center.
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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.
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Anticuerpos Monoclonales Humanizados , Factores Inmunológicos , Esclerosis Múltiple Recurrente-Remitente , Natalizumab , Humanos , Natalizumab/uso terapéutico , Natalizumab/administración & dosificación , Femenino , Masculino , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Adulto , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/farmacología , Estudios Retrospectivos , Adulto Joven , Progresión de la EnfermedadRESUMEN
BACKGROUND: Defining immune mechanisms leading to multiple sclerosis (MS) is difficult, due to the great inter-individual difference in immune system responses. The anti-CD52 antibody alemtuzumab transiently abolishes differences in immune parameters among individuals, allowing analysis of subsequent immune cell repopulation patterns, and their possible role in MS. OBJECTIVE: To evaluate the correlation between innate and adaptive immune cell subsets and disease activity in MS in the context of treatment with alemtuzumab. METHODS: A two-center observational cohort of patients treated with alemtuzumab underwent immune profiling of T, B, and natural killer (NK) cells, biomarker, clinical and radiological follow-up. RESULTS: After treatment, the percentage of NK and B cells increased; NK, T- and B-cell populations underwent a profound rearrangement. Within the effector T-cell compartment, treatment led to a transient decrease, followed by an increase, of T-helper 1 cells, and to a transient decrease of T-helper 17 cells. Within the T-regulatory compartment, naïve T-regulatory cells increased. Within the B-cell compartment, memory B cells and mature B cells decreased, whereas transitional B cells increased. Within the NK cell compartment, CD56bright NK cells increased. Subjects without disease activity had a greater decrease in serum NfL and greater NK cell/CD3+ T cell ratio. NK cell numbers at baseline and after treatment influenced reconstitution of T and B cells, being inversely correlated with the reconstitution of proinflammatory CD3+ T cells and mature B cells, and directly correlated to the increase in transitional B cells. CONCLUSIONS: The results of this study provide novel evidence that NK cells influence reconstitution of adaptive immune cells upon alemtuzumab and that patients with a successful response to alemtuzumab have an early immune reconstitution dominated by NK cells.
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Alemtuzumab/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Células Asesinas Naturales/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Biomarcadores/sangre , Femenino , Humanos , Italia , Estudios Longitudinales , Masculino , Esclerosis Múltiple Recurrente-Remitente/inmunologíaRESUMEN
BACKGROUND: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection. METHODS: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose. FINDINGS: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave. INTERPRETATION: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response. FUNDING: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding.
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COVID-19 , Vacunas Virales , COVID-19/prevención & control , Vacunas contra la COVID-19 , Estudios de Cohortes , Humanos , Estudios Prospectivos , ARN Mensajero , SARS-CoV-2 , Vacunación , Vacunas Sintéticas , Vacunas de ARNmRESUMEN
BACKGROUND: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). However, patients and physicians may consider discontinuing NTZ therapy due to safety or efficacy issues. The aim of our study was to evaluate the NTZ discontinuation rate and reasons of discontinuation in a large Italian population of RRMS patients. MATERIALS AND METHODS: The data were extracted from the Italian MS registry in May 2018 and were collected from 51,845 patients in 69 Italian multiple sclerosis centers. MS patients with at least one NTZ infusion in the period between June 1st 2012 to May 15th 2018 were included. Discontinuation rates at each time point were calculated. Reasons for NTZ discontinuation were classified as "lack of efficacy", "progressive multifocal leukoencephalopathy (PML) risk" or "other". RESULTS: Out of 51,845, 5151 patients, 3019 (58.6%) females, with a mean age of 43.6 ± 10.1 years (median 40), were analyzed. Out of 2037 (39.5%) who discontinued NTZ, a significantly higher percentage suspended NTZ because of PML risk compared to lack of efficacy [1682 (32.7% of 5151) vs 221 (4.3%), p < 0.001]; other reasons were identified for 99 (1.9%) patients. Patients discontinuing treatment were older, had longer disease duration and worse EDSS at the time of NTZ initiation and at last follow-up on NTZ treatment. The JCV index and EDSS at baseline were predictors for stopping therapy (HR 2.94, 95% CI 1.22-4.75; p = 0.02; HR 1.36, 95% CI 1.18-5.41; p = 0.04). CONCLUSIONS: Roughly 60% of MS patients stayed on NTZ treatment during the observation period. For those patients in whom NTZ discontinuation was required, it was mainly due to PML concerns.
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Leucoencefalopatía Multifocal Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Adulto , Femenino , Humanos , Factores Inmunológicos/efectos adversos , Leucoencefalopatía Multifocal Progresiva/epidemiología , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Natalizumab/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. METHODS: We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. FINDINGS: 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128-317), p < 0·001), fingolimod (26-fold decrease (95%CI=16-42), p < 0·001) and rituximab (20-fold decrease (95%CI=10-43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46-4·27) than with the BNT162b2 vaccine (p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). INTERPRETATION: In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. FUNDING: FISM[2021/Special-Multi/001]; Italian Ministry of Health'Progetto Z844A 5 × 1000'.
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Formación de Anticuerpos/efectos de los fármacos , Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , Inmunosupresores/efectos adversos , Esclerosis Múltiple/tratamiento farmacológico , Vacuna nCoV-2019 mRNA-1273 , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Vacuna BNT162 , COVID-19/inmunología , Cladribina/efectos adversos , Cladribina/uso terapéutico , Femenino , Clorhidrato de Fingolimod/efectos adversos , Clorhidrato de Fingolimod/uso terapéutico , Humanos , Inmunosupresores/uso terapéutico , Italia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Rituximab/efectos adversos , Rituximab/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: The introduction of oral disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) changed algorithms of RRMS treatment. OBJECTIVES: To compare the effectiveness of treatment with dimethyl fumarate (DMF) and teriflunomide (TRF) in a large multicentre Italian cohort of RRMS patients. MATERIALS AND METHODS: Patients with RRMS who received treatment with DMF and TRF between January 1st, 2012 and December 31st, 2018 from twelve MS centers were identified. The events investigated were "time-to-first-relapse", "time-to-Magnetic-Resonance-Imaging (MRI)-activity" and "time-to-disability-progression". RESULTS: 1445 patients were enrolled (1039 on DMF, 406 on TRF) and followed for a median of 34 months. Patients on TRF were older (43.5 ± 8.6 vs 38.8 ± 9.2 years), with a predominance of men and higher level of disability (p < 0.001 for all). Patients on DMF had a higher number of relapses and radiological activity (p < .05) at baseline. Time-varying Cox-model for the event "time-to-first relapse" revealed that no differences were found between the two groups in the first 38 months of treatment (HRt < 38DMF = 0.73, CI = 0.52 to 1.03, p = 0.079). When the time-on-therapy exceeds 38 months patients on DMF had an approximately 0.3 times lower relapse hazard risk than those who took TRF (HRt>38DMF = 3.83, CI = 1.11 to 13.23, p = 0.033). Both DMTs controlled similarly MRI activity and disability progression. CONCLUSIONS: Patients on DMF had higher relapse-free survival time than TRF group after the first 38 months on therapy.
Asunto(s)
Crotonatos , Dimetilfumarato , Inmunosupresores , Esclerosis Múltiple Recurrente-Remitente , Toluidinas , Adulto , Crotonatos/uso terapéutico , Análisis de Datos , Dimetilfumarato/uso terapéutico , Femenino , Humanos , Hidroxibutiratos , Inmunosupresores/uso terapéutico , Italia , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Nitrilos , Toluidinas/uso terapéuticoRESUMEN
The maintenance of mitochondrial DNA (mtDNA) relies on proteins encoded by nuclear genes. Mutations in their coding sequences result in heterogenous clinical presentations featuring mtDNA instability in affected tissues. DNA2 is a multi-catalytic protein involved in the removal of single strand DNA during mtDNA replication or Long Patch Base Excision Repair pathway. We have previously described DNA2 mutations in adult patients affected with familial and sporadic forms of mitochondrial myopathy. Here we describe four novel probands presenting with limb weakness associated with novel DNA2 molecular defects. Biochemical assays were established to investigate the functional effects of these variants.
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ADN Helicasas/genética , ADN Mitocondrial/genética , Miopatías Mitocondriales/genética , Mutación , Anciano , Análisis Mutacional de ADN , Replicación del ADN , Femenino , Humanos , Masculino , Persona de Mediana EdadAsunto(s)
Herpes Simple/virología , Herpes Zóster/virología , Esclerosis Múltiple/virología , Infecciones por Roseolovirus/virología , Antivirales/uso terapéutico , Herpes Simple/complicaciones , Herpes Simple/tratamiento farmacológico , Herpes Zóster/complicaciones , Herpes Zóster/tratamiento farmacológico , Herpesvirus Humano 1 , Herpesvirus Humano 3/efectos de los fármacos , Herpesvirus Humano 3/fisiología , Herpesvirus Humano 6 , Humanos , Masculino , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/tratamiento farmacológico , Infecciones por Roseolovirus/complicaciones , Infecciones por Roseolovirus/tratamiento farmacológico , Adulto JovenRESUMEN
INTRODUCTION: Immunosuppressive agents (ISA) have been used in multiple sclerosis (MS) for decades, frequently as off label licensed therapies. Given the new MS treatment landscape, what place do ISA have in combating MS? METHODS: We conducted a retrospective multicentre study to investigate the frequency of ISA prescription in 17 Italian MS centres, and to describe the clinical factors related to ISA use. RESULTS: Out of 6,447 MS patients, 2,034 (31.6%) were treated with ISA, with Azathioprine being the most frequently used ISA overall. MS patients treated with ISA alone were more frequently affected by the progressive course (both primary and secondary) of the disease (RRR 5.82, 95% CI 4.14-8.16, p<0.0001), had higher EDSS (RRR 3.69, 95% CI 2.61-5.21, p<0.0001), higher assignment age (RRR 1.04, 95% CI 1.03-1.06, p<0.0001) than patients treated with only disease modifying drugs (DMDs). CONCLUSIONS: Progressive course, higher EDSS, higher assignment age were the strongest predictors of ISA prescription and use in our population.
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Azatioprina/uso terapéutico , Terapia de Inmunosupresión/efectos adversos , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/terapia , Adulto , Azatioprina/administración & dosificación , Azatioprina/efectos adversos , Femenino , Humanos , Terapia de Inmunosupresión/métodos , Inmunosupresores/administración & dosificación , Inmunosupresores/efectos adversos , Interferones/administración & dosificación , Interferones/efectos adversos , Interferones/uso terapéutico , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
The aims of this study were to assess the efficacy of video-assisted thoracoscopic extended thymectomy (VATET) as a treatment for myasthenia gravis (MG) and to identify prognostic factors for thymectomy success. Clinical efficacy and variables influencing outcome were assessed by life-table and Cox proportional hazards regression analysis. Complete stable remission (CSR), as defined by the MGFA Medical Task Force, was the end point for efficacy. VATET was performed in 159 MG patients and T-3b in 47 MG patients. At 6 years of follow-up, CSR, assessed by life-table analysis, was 50.6% in non-thymomatous VATET patients and 48.7% in non-thymomatous T-3b surgery. By univariate analysis, the presence of thymic hyperplasia (P=0.0002) and treatment only with anticholinesterases (P<0.0001) were positively associated with the probability of CSR. By multivariate analysis, the chance of complete remission was significantly increased by the use of anticholinesterases (odds ratio [OR] 2.45; 95% confidence interval [CI] 1.44-4.17; P=0.001) and the presence of thymic hyperplasia (OR 1.96; 95% CI 1.05-3.68; P=0.036). VATET seems to be effective in inducing CSR in MG with an efficiency similar to that of the T-3b transsternal (TS) approach; it is easy to perform in experienced hands and is associated with low morbidity and negligible esthetic sequelae.