RESUMEN
The interaction between ageing and multiple sclerosis is complex and carries significant implications for patient care. Managing multiple sclerosis effectively requires an understanding of how ageing and multiple sclerosis impact brain structure and function. Ageing inherently induces brain changes, including reduced plasticity, diminished grey matter volume, and ischaemic lesion accumulation. When combined with multiple sclerosis pathology, these age-related alterations may worsen clinical disability. Ageing may also influence the response of multiple sclerosis patients to therapies and/or their side-effects, highlighting the importance of adjusted treatment considerations. Magnetic resonance MRI is highly sensitive to age- and multiple sclerosis-related processes. Accordingly, MRI can provide insights into the relationship between ageing and multiple sclerosis, enabling a better understanding of their pathophysiological interplay and informing treatment selection. This review summarizes current knowledge on the immuno-pathological and MRI aspects of ageing in the central nervous system in the context of multiple sclerosis. Starting from immunosenescence, ageing-related pathological mechanisms, and specific features like enlarged Virchow-Robin spaces, this review then explores clinical aspects, including late-onset multiple sclerosis, the influence of age on diagnostic criteria, and comorbidity effects on imaging features. The role of MRI in understanding neurodegeneration, iron dynamics, and myelin changes influenced by ageing and how MRI can contribute to defining treatment effects in ageing multiple sclerosis patients, are also discussed.
RESUMEN
OBJECTIVE: To summarize the current evidence on relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA) through a quantitative synthesis of real-world studies. METHODS: Scientific databases were searched to identify suitable articles. Random-effects meta-analyses, subgroup analyses and meta-regression models were ran to provide pooled estimates of RAW and PIRA events and to identify their potential moderators (PROSPERO registration: CRD42024503895). RESULTS: Eighteen articles met the eligibility criteria, with a pooled sample size of 52,667 patients (93% relapsing-remitting, 6% clinically isolated syndrome and 1% progressive) followed for 2.4 to 12.1 years, yielding to 415,825 patient-years. Pooled event rates for RAW and PIRA were 1.6 (95 confidence interval (CI) = 1.1-2.1) and 3.1 (95% CI = 2.3-3.9) per 100 patient-years, respectively. Less RAW events were found in cohorts including patients with progressive course (ß = -0.069, p = 0.006) and under high-efficacy disease-modifying treatments (DMTs) (ß = -0.031, p = 0.007), while PIRA events were directly related to older age (ß = 0.397, p = 0.027). In addition, we found significant differences in PIRA event rates according to the criteria adopted to define confirmed disability accrual (p < 0.05). DISCUSSION: PIRA accounts for most events causing disability accumulation in the real-world setting, even at the earlier disease stages, whereas RAW represents a less frequent phenomenon, likely due to effective treatments. The detection and statistical analysis of PIRA outcomes pose challenges, raising the risk of erroneous inference. When interpreting our findings, caution is needed given the wide heterogeneity of included studies.
RESUMEN
Progression independent of relapse activity (PIRA), a recent concept to formalize disability accrual in multiple sclerosis (MS) independent of relapses, has gained popularity as a potential clinical trial outcome. We discuss its shortcomings and appraise the challenges of implementing it in clinical settings, experimental trials, and research. The current definition of PIRA assumes that acute inflammation, which can manifest as a relapse, and neurodegeneration, manifesting as progressive disability accrual, can be disentangled by introducing specific time windows between the onset of relapses and the observed increase in disability. The term PIRMA (progression independent of relapse and MRI activity) was recently introduced to indicate disability accrual in the absence of both clinical relapses and new brain and spinal cord MRI lesions. Assessing PIRMA in clinical practice is highly challenging because it necessitates frequent clinical assessments and brain and spinal cord MRI scans. PIRA is commonly assessed using Expanded Disability Status Scale, a scale heavily weighted toward motor disability, whereas a more granular assessment of disability deterioration, including cognitive decline, using composite measures or other tools, such as digital tools, would possess greater utility. Similarly, using PIRA as an outcome measure in randomized clinical trials is also challenging and requires methodological considerations. The underpinning pathobiology of disability accumulation, that is not associated with relapses, may encompass chronic active lesions (slowly expanding lesions and paramagnetic rim lesions), cortical lesions, brain and spinal cord atrophy, particularly in the gray matter, diffuse and focal microglial activation, persistent leptomeningeal enhancement, and white matter tract damage. We propose to use PIRA to understand the main determinant of disability accrual in observational, cohort studies, where regular MRI scans are not included, and introduce the term of "advanced-PIRMA" to investigate the contributions to disability accrual of the abovementioned processes, using conventional and advanced imaging. This is supported by the knowledge that MRI reflects the MS pathogenic mechanisms better than purely clinical descriptors. Any residual disability accrual, which remains unexplained after considering all these mechanisms with imaging, will highlight future research priorities to help complete our understanding of MS pathogenesis.
Asunto(s)
Progresión de la Enfermedad , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/patología , Imagen por Resonancia Magnética/métodos , Recurrencia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Evaluación de la DiscapacidadRESUMEN
Neuromyelitis optica spectrum disorders (NMOSD) include a rare group of autoimmune conditions that primarily affect the central nervous system. They are characterized by inflammation and damage to the optic nerves, brain and spinal cord, leading to severe vision impairment, locomotor disability and sphynteric disturbances. In the majority of cases, NMOSD arises due to specific serum immunoglobulin G (IgG) autoantibodies targeting aquaporin 4 (AQP4-IgG), which is the most prevalent water-channel protein of the central nervous system. Early diagnosis and treatment are crucial to manage symptoms and prevent long-term disability in NMOSD patients. NMOSD were previously associated with a poor prognosis. However, recently, a number of randomized controlled trials have demonstrated that biological therapies acting on key elements of NMOSD pathogenesis, such as B cells, interleukin-6 (IL-6) pathway, and complement, have impressive efficacy in preventing the occurrence of clinical relapses. The approval of the initial drugs marks a revolutionary advancement in the treatment of NMOSD patients, significantly transforming therapeutic options and positively impacting their prognosis. In this review, we will provide an updated overview of the key immunopathological, clinical, laboratory, and neuroimaging aspects of NMOSD. Additionally, we will critically examine the latest advancements in NMOSD treatment approaches. Lastly, we will discuss key aspects regarding optimization of treatment strategies and their monitoring.
Asunto(s)
Neuromielitis Óptica , Neuromielitis Óptica/terapia , Neuromielitis Óptica/inmunología , Neuromielitis Óptica/tratamiento farmacológico , HumanosRESUMEN
OBJECTIVE: To evaluate: (1) the distribution of gray matter (GM) atrophy in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4+NMOSD), and relapsing-remitting multiple sclerosis (RRMS); and (2) the relationship between GM volumes and white matter lesions in various brain regions within each disease. METHODS: A retrospective, multicenter analysis of magnetic resonance imaging data included patients with MOGAD/AQP4+NMOSD/RRMS in non-acute disease stage. Voxel-wise analyses and general linear models were used to evaluate the relevance of regional GM atrophy. For significant results (p < 0.05), volumes of atrophic areas are reported. RESULTS: We studied 135 MOGAD patients, 135 AQP4+NMOSD, 175 RRMS, and 144 healthy controls (HC). Compared with HC, MOGAD showed lower GM volumes in the temporal lobes, deep GM, insula, and cingulate cortex (75.79 cm3); AQP4+NMOSD in the occipital cortex (32.83 cm3); and RRMS diffusely in the GM (260.61 cm3). MOGAD showed more pronounced temporal cortex atrophy than RRMS (6.71 cm3), whereas AQP4+NMOSD displayed greater occipital cortex atrophy than RRMS (19.82 cm3). RRMS demonstrated more pronounced deep GM atrophy in comparison with MOGAD (27.90 cm3) and AQP4+NMOSD (47.04 cm3). In MOGAD, higher periventricular and cortical/juxtacortical lesions were linked to reduced temporal cortex, deep GM, and insula volumes. In RRMS, the diffuse GM atrophy was associated with lesions in all locations. AQP4+NMOSD showed no lesion/GM volume correlation. INTERPRETATION: GM atrophy is more widespread in RRMS compared with the other two conditions. MOGAD primarily affects the temporal cortex, whereas AQP4+NMOSD mainly involves the occipital cortex. In MOGAD and RRMS, lesion-related tract degeneration is associated with atrophy, but this link is absent in AQP4+NMOSD. ANN NEUROL 2024;96:276-288.
Asunto(s)
Acuaporina 4 , Atrofia , Autoanticuerpos , Sustancia Gris , Imagen por Resonancia Magnética , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica , Sustancia Blanca , Humanos , Femenino , Acuaporina 4/inmunología , Neuromielitis Óptica/patología , Neuromielitis Óptica/diagnóstico por imagen , Neuromielitis Óptica/inmunología , Masculino , Glicoproteína Mielina-Oligodendrócito/inmunología , Adulto , Atrofia/patología , Sustancia Gris/patología , Sustancia Gris/diagnóstico por imagen , Sustancia Blanca/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/inmunología , Persona de Mediana Edad , Estudios Retrospectivos , Autoanticuerpos/sangre , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adulto JovenRESUMEN
Treatment options for secondary progressive MS (SPMS) are limited, especially considering that the new drugs recently approved are licensed for actively relapsing patients. We aimed to compare the disability progression in a real-world cohort of SPMS patients treated with natalizumab (NTZ) or interferon beta-1b (IFNb-1b). This multicenter retrospective enrolled patients with a diagnosis of SPMS according to 2014 Lublin criteria, who received NTZ or IFNb-1b for at least 48 months between the 1st June 2012 and the 15th May 2018 âat 33 Italian MS centers contributing to the Italian MS Registry NTZ or IFNb-1b. Confirmed Expanded Disability Status Scale worsening (CEW) and progression independent of relapse (PIRA) were evaluated. In order to correct for non-randomization, a propensity score matching of the groups was performed. Out of 5206 MS patients identified at the time of data extraction, 421 SPMS patients treated with NTZ (224 [53.2%] females, mean age 45.3 â± â25.4 years) and 353 with IFNb-1b (133 [37.8%] females, mean age 48.5 â± â19.8 years) were enrolled. After applying the matching procedure, 102 patients were retained in the NTZ group and 98 in the IFNb-2b group. The proportion of patients who reached the 48-month 1-point CEW was significantly higher in IFNb-1b compared to NTZ group (58.2% versus 30.4%, p â= â0.01). The proportion of patients who developed PIRA at 48 months were significantly higher in IFNb-1b compared to NTZ (72.4% versus 40.2%, p â= â0.01). EDSS before treatment initiation and SPMS duration were risk factors for disability progression in terms of PIRA (HR 2.54, 25%CI 1.67-5.7; p â= â0.006 and HR 2.04, 25%CI 1.22-3.35; p â= â0.01, respectively). Patients treated with IFNb-1b were 1.64 times more to likely to develop PIRA (HR 1.64, 25%CI 1.04-4.87; p â= â0.001). Treatment with NTZ in SPMS patients showed more favorable disability outcomes compared to IFNb-1b with beneficial effects over 48 months.
RESUMEN
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a discrete nosological entity characterized by punctate and curvilinear gadolinium enhancement "peppering" the pons and a strong response to steroids. MRI images typically show pontine and cerebellar punctate-enhancing lesions, which occasionally spread up to the juxtacortical areas and down to the spinal cord. Interestingly, the more distant the lesion is from the pons, the less intense they become. Herein, we describe an extremely rare case of CLIPPERS presenting with predominant spinal cord involvement; then, we searched in the literature the available cases with a similar presentation. Our case focuses attention on a rare MRI CLIPPERS presentation. Since CLIPPERS has a dramatic response to corticosteroid treatment, it is fundamental to promptly recognize its MRI pattern to start treatment as soon as possible.
Asunto(s)
Imagen por Resonancia Magnética , Médula Espinal , Humanos , Puente/diagnóstico por imagen , Puente/patología , Médula Espinal/diagnóstico por imagen , Médula Espinal/patologíaRESUMEN
BACKGROUND: Seizures are reported to be more prevalent in individuals with multiple sclerosis (MS) compared with the general population. Existing data predominantly originate from population-based studies, which introduce variability in methodologies and are vulnerable to selection and reporting biases. METHODS: This meta-analysis aims to assess the incidence of seizures in patients participating in randomised clinical trials and to identify potential contributing factors. Data were extracted from 60 articles published from 1993 to 2022. The pooled effect size, representing the incidence rate of seizure events, was estimated using a random-effect model. Metaregression was employed to explore factors influencing the pooled effect size. RESULTS: The meta-analysis included data from 53 535 patients and 120 seizure events in a median follow-up of 2 years. The pooled incidence rate of seizures was 68.0 per 100 000 patient-years, significantly higher than the general population rate of 34.6. Generalised tonic-clonic seizures were the most common type reported, although there was a high risk of misclassification for focal seizures with secondary generalisation. Disease progression, longer disease duration, higher disability levels and lower brain volume were associated with a higher incidence of seizures. Particularly, sphingosine-1-phosphate receptor (S1PR) modulators exhibited a 2.45-fold increased risk of seizures compared with placebo or comparators, with a risk difference of 20.5 events per 100 000 patient-years. CONCLUSIONS: Patients with MS face a nearly twofold higher seizure risk compared with the general population. This risk appears to be associated not only with disease burden but also with S1PR modulators. Our findings underscore epilepsy as a significant comorbidity in MS and emphasise the necessity for further research into its triggers, preventive measures and treatment strategies.
Asunto(s)
Esclerosis Múltiple , Ensayos Clínicos Controlados Aleatorios como Asunto , Convulsiones , Humanos , Convulsiones/epidemiología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/epidemiología , Incidencia , Progresión de la EnfermedadRESUMEN
Despite its widespread use in clinical practice, the effectiveness of natalizumab extended interval dosing (EID) adopted from treatment start across different treatment intervals and individual modifiers (body mass index - BMI) is still under-investigated. Here, seven-hundred and forty-five multiple sclerosis (MS) patients, exposed to natalizumab for 3.30 â± â1.34 years, were retrospectively enrolled in an observational multicenter study. After stratifying patients in EID or standard interval dosing (SID), we assessed differences in time to relapse, MRI activity and Expanded Disability Status Scale (EDSS) progression. The primary analysis was conducted on patients exposed to EID interval from 5 weeks and 1 day to 7 weeks, while a secondary analysis included also EID periods up to 8 weeks. An additional analysis explored the impact of BMI. No differences in time to first relapse, time to radiological activity, time to EDSS progression or time to EDA (evidence of disease activity) were detected between SID and EID group (EID interval from 5 weeks to 1 day to 7 weeks). When including EID periods from 7 weeks and 1 day to 8 weeks, the EID group showed a trend towards higher risk of experience clinical relapses than the SID group. A higher EDA risk was also identified in EID patients with BMI above median. In conclusion, a higher risk of relapses seems to occur for EID above 7 weeks. Independently from the EID scheme adopted, higher BMI increases the risk of EDA in these patients.
Asunto(s)
Índice de Masa Corporal , Natalizumab , Humanos , Natalizumab/uso terapéutico , Natalizumab/administración & dosificación , Femenino , Masculino , Adulto , Estudios Retrospectivos , Italia/epidemiología , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Factores Inmunológicos/administración & dosificación , Resultado del Tratamiento , Progresión de la Enfermedad , Imagen por Resonancia Magnética/métodosRESUMEN
OBJECTIVE: Multiple sclerosis (MS) is a complex disorder in which environmental and genetic factors interact modifying disease risk and course. This multicentre, case-control study involving 18 Italian MS Centres investigated MS course by ethnicity and native-country economic status in foreign-born patients living in Italy. METHODS: We identified 457 MS patients who migrated to Italy and 893 age- and sex-matched native-born Italian patients. In our population, 1225 (93.2%) subjects were White Europeans and White Northern Americans (WENA) and 89 (6.8%) patients were from other ethnical groups (OEG); 1109 (82.1%) patients were born in a high-income (HI) Country and 241 (17.9%) in a low-middle-income (LMI) Country. Medical records and patients interviews were used to collect demographic and disease data. RESULTS: We included 1350 individuals (973 women and 377 men); mean (SD) age was 45.0 (11.7) years. At onset, 25.45% OEG patients vs 12.47% WENA (p = 0.039) had > 3 STIR spine lesions. At recruitment, the same group featured mean (SD) EDSS score of 2.85 (2.23) vs 2.64 (2.28) (p = 0.044) reached in 8.9 (9.0) vs 12.0 (9.0) years (p = 0.018) and underwent 1.10 (4.44) vs. 0.99 (0.40) annual MRI examinations (p = 0.035). At disease onset, patients from LMI countries had higher EDSS score than HI patients (2.40 (1.43) vs 1.99 (1.17); p = 0.032). DISCUSSION: Our results suggested that both ethnicity and socio-economic status of native country shape MS presentation and course and should be considered for an appropriate management of patients. To the best of our knowledge, this is the first study reporting on the impact of ethnicity in MS at an individual level and beyond an ecological population-perspective.
Asunto(s)
Esclerosis Múltiple , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios de Casos y Controles , Etnicidad , Renta , Italia/epidemiología , Italia/etnología , Esclerosis Múltiple/etnología , Población Blanca , Pueblos de América del Norte , América del Norte/etnología , Europa (Continente)/etnologíaRESUMEN
BACKGROUND AND OBJECTIVES: The optic nerve is not one of the areas of the CNS that can be used to demonstrate dissemination in space (DIS) within the 2017 McDonald criteria for the diagnosis of multiple sclerosis (MS). Objectives were (1) to assess whether optic nerve-MRI (ON-MRI), optical coherence tomography (OCT), and visual evoked potentials (VEP) detect optic nerve involvement in clinically isolated syndrome (CIS) and (2) to evaluate the contribution of the optic nerve topography to the current diagnostic criteria in a prospective, multicenter cohort. METHODS: MAGNIMS centers were invited to provide prospective data on patients with CIS who underwent a visual assessment with at least 2 of 3 investigations (ON-MRI, OCT, or VEP) within 6 months of onset. Modified DIS criteria were constructed by adding the optic nerve topography, defined by each investigation separately and any combination of them, as the fifth area of the CNS. A risk assessment analysis and the performance of the different DIS criteria were analyzed using the diagnosis of MS according to the 2017 McDonald criteria as the primary outcome and new T2 lesions and/or a second relapse as the secondary outcome. RESULTS: We included 157 patients with CIS from 5 MAGNIMS centers; 60/157 (38.2%) patients presented with optic neuritis. Optic nerve involvement on ON-MRI was found in 40.2% patients at study entry and in 72.5% of those with optic neuritis.At follow-up (mean 27.9 months, SD 14.5), 111/157 patients (70.7%) were diagnosed with MS according to the 2017 McDonald criteria. Fulfilling either 2017 DIS or any modified DIS criteria conferred a similar high risk for reaching primary and secondary outcomes. The modified DIS criteria had higher sensitivity (92.5% [with ON-MRI] vs 88.2%), but slightly lower specificity (80.0% [with GCIPL IEA ≥4 µm] vs 82.2%), with overall similar accuracy (86.6% [with ON-MRI] vs 86.5%) than 2017 DIS criteria. Consistent results were found for secondary outcomes. DISCUSSION: In patients with CIS, the presence of an optic nerve lesion defined by MRI, OCT, or VEP is frequently detected, especially when presenting with optic neuritis. Our study supports the addition of the optic nerve as a fifth topography to fulfill DIS criteria.
Asunto(s)
Enfermedades Desmielinizantes , Esclerosis Múltiple , Neuritis Óptica , Humanos , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/diagnóstico por imagen , Potenciales Evocados Visuales , Estudios Prospectivos , Nervio Óptico/diagnóstico por imagen , Neuritis Óptica/diagnóstico por imagenRESUMEN
Cortical myelin loss and repair in multiple sclerosis (MS) have been explored in neuropathological studies, but the impact of these processes on neurodegeneration and the irreversible clinical progression of the disease remains unknown. Here, we evaluated in vivo cortical demyelination and remyelination in a large cohort of people with all clinical phenotypes of MS followed up for 5â years using magnetization transfer imaging (MTI), a technique that has been shown to be sensitive to myelin content changes in the cortex. We investigated 140 people with MS (37 clinically isolated syndrome, 71 relapsing-MS, 32 progressive-MS), who were clinically assessed at baseline and after 5â years and, along with 84 healthy controls, underwent a 3â T-MRI protocol including MTI at baseline and after 1â year. Changes in cortical volume over the radiological follow-up were computed with a Jacobian integration method. Magnetization transfer ratio was employed to calculate for each patient an index of cortical demyelination at baseline and of dynamic cortical demyelination and remyelination over the follow-up period. The three indices of cortical myelin content change were heterogeneous across patients but did not significantly differ across clinical phenotypes or treatment groups. Cortical remyelination, which tended to fail in the regions closer to CSF (-11%, P < 0.001), was extensive in half of the cohort and occurred independently of age, disease duration and clinical phenotype. Higher indices of cortical dynamic demyelination (ß = 0.23, P = 0.024) and lower indices of cortical remyelination (ß = -0.18, P = 0.03) were significantly associated with greater cortical atrophy after 1â year, independently of age and MS phenotype. While the extent of cortical demyelination predicted a higher probability of clinical progression after 5â years in the entire cohort [odds ratio (OR) = 1.2; P = 0.043], the impact of cortical remyelination in reducing the risk of accumulating clinical disability after 5â years was significant only in the subgroup of patients with shorter disease duration and limited extent of demyelination in cortical regions (OR = 0.86, P = 0.015, area under the curve = 0.93). In this subgroup, a 30% increase in cortical remyelination nearly halved the risk of clinical progression at 5â years, independently of clinical relapses. Overall, our results highlight the critical role of cortical myelin dynamics in the cascade of events leading to neurodegeneration and to the subsequent accumulation of irreversible disability in MS. Our findings suggest that early-stage myelin repair compensating for cortical myelin loss has the potential to prevent neuro-axonal loss and its long-term irreversible clinical consequences in people with MS.
Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple , Humanos , Vaina de Mielina/patología , Esclerosis Múltiple/patología , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/patología , Progresión de la Enfermedad , Atrofia/patologíaRESUMEN
BACKGROUND: The assessment of treatment response is a crucial step for patients with relapsing-remitting multiple sclerosis on disease-modifying therapies (DMTs). We explored whether a scoring system developed within the MAGNIMS (MRI in Multiple Sclerosis) network to evaluate treatment response to injectable drugs can be adopted also to oral DMTs. METHODS: A multicentre dataset of 1200 patients who started three oral DMTs (fingolimod, teriflunomide and dimethyl fumarate) was collected within the MAGNIMS network. Disease activity after the first year was classified by the 'MAGNIMS' score based on the combination of relapses (0-≥2) and/or new T2 lesions (<3 or ≥3) on brain MRI. We explored the association of this score with the following 3-year outcomes: (1) confirmed disability worsening (CDW); (2) treatment failure (TFL); (3) relapse count between years 1 and 3. The additional value of contrast-enhancing lesions (CELs) and lesion location was explored. RESULTS: At 3 years, 160 patients experienced CDW: 12% of them scored '0' (reference), 18% scored '1' (HR=1.82, 95% CI 1.20 to 2.76, p=0.005) and 37% scored '2' (HR=2.74, 95% CI 1.41 to 5.36, p=0.003) at 1 year. The analysis of other outcomes provided similar findings. Considering the location of new T2 lesions (supratentorial vs infratentorial/spinal cord) and the presence of CELs improved the prediction of CDW and TFL, respectively, in patients with minimal MRI activity alone (one or two new T2 lesions). CONCLUSIONS: Early relapses and substantial MRI activity in the first year of treatment are associated with worse short-term outcomes in patients treated with some of the oral DMTs.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Inmunosupresores/efectos adversos , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Clorhidrato de Fingolimod/uso terapéutico , RecurrenciaRESUMEN
BACKGROUND: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce. OBJECTIVE: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS. METHODS: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose. RESULTS: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%. CONCLUSIONS: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS.
Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Esclerosis Múltiple , Humanos , Anticuerpos Antivirales , Enfermedad Crónica , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Esclerosis Múltiple/complicaciones , Recurrencia , Estudios Retrospectivos , Vacunación/efectos adversos , Inmunización Secundaria/efectos adversos , Vacunas de ARNm/efectos adversosRESUMEN
Importance: Although up to 20% of patients with multiple sclerosis (MS) experience onset before 18 years of age, it has been suggested that people with pediatric-onset MS (POMS) are protected against disability because of greater capacity for repair. Objective: To assess the incidence of and factors associated with progression independent of relapse activity (PIRA) and relapse-associated worsening (RAW) in POMS compared with typical adult-onset MS (AOMS) and late-onset MS (LOMS). Design, Setting, and Participants: This cohort study on prospectively acquired data from the Italian MS Register was performed from June 1, 2000, to September 30, 2021. At the time of data extraction, longitudinal data from 73â¯564 patients from 120 MS centers were available in the register. Main Outcomes and Measures: The main outcomes included age-related cumulative incidence and adjusted hazard ratios (HRs) for PIRA and RAW and associated factors. Exposures: Clinical and magnetic resonance imaging features, time receiving disease-modifying therapy (DMT), and time to first DMT. Results: After applying the inclusion and exclusion criteria, the study assessed 16 130 patients with MS (median [IQR] age at onset, 28.7 [22.8-36.2 years]; 68.3% female). Compared with AOMS and LOMS, patients with POMS had less disability, exhibited more active disease, and were exposed to DMT for a longer period. A first 48-week-confirmed PIRA occurred in 7176 patients (44.5%): 558 patients with POMS (40.4%), 6258 patients with AOMS (44.3%), and 360 patients with LOMS (56.8%) (P < .001). Factors associated with PIRA were older age at onset (AOMS vs POMS HR, 1.42; 95% CI, 1.30-1.55; LOMS vs POMS HR, 2.98; 95% CI, 2.60-3.41; P < .001), longer disease duration (HR, 1.04; 95% CI, 1.04-1.05; P < .001), and shorter DMT exposure (HR, 0.69; 95% CI, 0.64-0.74; P < .001). The incidence of PIRA was 1.3% at 20 years of age, but it rapidly increased approximately 7 times between 21 and 30 years of age (9.0%) and nearly doubled for each age decade from 40 to 70 years (21.6% at 40 years, 39.0% at 50 years, 61.0% at 60 years, and 78.7% at 70 years). The cumulative incidence of RAW events followed a similar trend from 20 to 60 years (0.5% at 20 years, 3.5% at 30 years, 7.8% at 40 years, 14.4% at 50 years, and 24.1% at 60 years); no further increase was found at 70 years (27.7%). Delayed DMT initiation was associated with higher risk of PIRA (HR, 1.16; 95% CI, 1.00-1.34; P = .04) and RAW (HR, 1.75; 95% CI, 1.28-2.39; P = .001). Conclusions and Relevance: PIRA can occur at any age, and although pediatric onset is not fully protective against progression, this study's findings suggest that patients with pediatric onset are less likely to exhibit PIRA over a decade of follow-up. However, these data also reinforce the benefit for DMT initiation in patients with POMS, as treatment was associated with reduced occurrence of both PIRA and RAW regardless of age at onset.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Adulto , Niño , Humanos , Femenino , Masculino , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/epidemiología , Estudios de Cohortes , Progresión de la Enfermedad , Enfermedad Crónica , Recurrencia , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/epidemiologíaRESUMEN
The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P-values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors.
Asunto(s)
Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Adulto , Adulto Joven , Persona de Mediana Edad , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Pronóstico , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/patología , Imagen por Resonancia Magnética/métodos , Atrofia/patología , Progresión de la EnfermedadRESUMEN
BACKGROUND: Active relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS) are currently defined as "relapsing MS" (RMS). The aim of this cross-sectional study was to assess drivers of treatment switches due to clinical relapses in a population of RMS patients collected in the Italian MS and Related Disorders Register (I-MS&RD). METHODS: RRMS and SPMS patients with at least one relapse in a time window of 2 years before of data extraction were defined as RMS. Factors associated with disease-modifying therapy (DMT) switching due to clinical activity were assessed through multivariable logistic regression models in which treatment exposure was included as the last recorded DMT and the last DMT's class [moderate-efficacy (ME), high-efficacy (HE) DMTs and anti-CD20 drugs]. RESULTS: A cohort of 4739 RMS patients (4161 RRMS, 578 SPMS) was extracted from the I-MS&RD. A total of 2694 patients switching DMTs due to relapses were identified. Switchers were significantly (p < 0.0001) younger, less disabled, more frequently affected by an RR disease course in comparison to non-switcher patients. The multivariable logistic regression models showed that Alemtuzumab (OR 0.08, 95% CI 0.02-0.37), Natalizumab (0.48, 0.30-0.76), Ocrelizumab (0.1, 0.02-0.45) and Rituximab (0.23, 0.06-0.82) exposure was a protective factor against treatment switch due to relapses. Moreover, the use of HE DMTs (0.43, 0.31-0.59), especially anti-CD20 drugs (0.14, 0.05-0.37), resulted to be a protective factor against treatment switch due to relapses in comparison with ME DMTs. CONCLUSIONS: More than 50% of RMS switched therapy due to disease activity. HE DMTs, especially anti-CD20 drugs, significantly reduce the risk of treatment switch.
Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Esclerosis Múltiple Recurrente-Remitente/inducido químicamente , Estudios Transversales , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Recurrencia , Italia/epidemiologíaRESUMEN
BACKGROUND: The question of whether multiple sclerosis requires life-long disease-modifying treatments (DMTs) remains unanswered. Some studies suggest that older patients with stable disease may safely discontinue their DMTs, yet comprehensive evidence-based data are scarce and real-world studies have provided mixed results. OBJECTIVE: The aim of this study was to assess the rate of disease reactivation and associated risk factors after discontinuation of DMTs in patients with multiple sclerosis. METHODS: We searched scientific databases (PubMed/MEDLINE, Scopus and Google Scholar) to identify real-world studies published until 31 July, 2023 that reported the number of patients who experienced relapses and/or disability accrual (outcomes of interest) following a therapy discontinuation longer than 12 months. Magnetic resonance activity and treatment re-start after DMT discontinuation were also considered as additional outcomes. We excluded studies where therapy discontinuation was explicitly related to an unintended or planned pregnancy or preceded a treatment switch. We ran random-effects meta-analyses, subgroup analyses and meta-regression models to provide pooled estimates of post-discontinuation relapse and disability events, and to identify their potential moderators (predictors). RESULTS: After an independent screening, 22 articles met the eligibility criteria, yielding a pooled sample size of 2942 patients followed for 1-7 years after discontinuation (11,689 patient-years). The pooled rates for relapse and disability events were 6.7 and 5.8 per 100 patient-years, respectively. However, available data did not allow us to disentangle isolated disability accrual from relapse-associated worsening. Studies including older patients (ß = -0.65, p = 0.006), patients with a longer exposure to DMTs (ß = -2.22, p = 0.001) and patients with a longer period of disease stability (ß = -2.74, p = 0.002) showed a lower risk of relapse events. According to meta-regression equations, the risk of relapse events after DMT discontinuation became negligible (arbitrarily set at < 1% per year) at approximately 60 years of age, and after either 10 years of DMT exposure, or 8 years of disease stability. Additional analyses showed pooled rates for magnetic resonance imaging activity and re-start events of 16.7 and 17.5 per 100 patient-years, respectively. CONCLUSIONS: Based on our quantitative synthesis of real-world data, in the absence of definitive answers from clinical trials, DMT discontinuation appears feasible with a high degree of certainty in selected patients. While our findings are robust regarding relapse events, future efforts are warranted to determine if DMT discontinuation is associated with isolated disability accrual.