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OBJECTIVE: The purpose of this study was to evaluate the extent to which treatment effect on magnetic resonance imaging (MRI)-derived measures of brain atrophy and focal lesions can mediate, at the trial level, the treatment effect on cognitive outcomes in multiple sclerosis (MS). METHODS: We collected all published randomized clinical trials in MS lasting at least 2 years and including as end points: active MRI lesions (defined as new/enlarging T2 lesions), brain atrophy (defined as a change in brain volume between month 12 and month 24), and change in cognitive performance (assessed by the Paced Auditory Serial Addition Test [PASAT]). Relative reductions were used to quantify the treatment effect on MRI markers (lesions and atrophy), whereas the standardized mean difference (Hedges g) between baseline and follow-up cognitive assessment was used to quantify the treatment effects on cognition. A linear regression, weighted for trial size, was used to assess the relationship between the treatment effects on MRI markers and cognition. RESULTS: Fourteen trials including more than 8,813 patients with MS were included in the meta-regression. Treatment effect on cognition was strongly associated with the treatment effect on brain atrophy (R2 = 0.79, p < 0.001), but was not correlated with the treatment effect on active MRI lesions (R2 = 0.16, p = 0.14). INTERPRETATION: Results reported here suggest that brain atrophy, a well-established MRI marker in MS clinical trials, can be used as a main outcome for clinical trials with drugs targeting cognitive impairment and neurodegeneration. ANN NEUROL 2023;94:925-932.
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Doenças do Sistema Nervoso Central , Disfunção Cognitiva , Esclerose Múltipla , Malformações do Sistema Nervoso , Humanos , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/tratamento farmacológico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Cognição , Disfunção Cognitiva/patologia , Doenças do Sistema Nervoso Central/complicações , Atrofia/patologia , Imageamento por Ressonância Magnética/métodos , Malformações do Sistema Nervoso/complicaçõesRESUMO
BACKGROUND: Randomized clinical trials (RCTs) in progressive multiple sclerosis (MS) often revealed non-significant treatment effects on disability progression. OBJECTIVES: To investigate whether the failure to detect a significant benefit from treatment may be motivated by a delay in treatment effect, possibly related to baseline characteristics. METHODS: We re-analyzed data from two RCTs testing interferon-beta and glatiramer-acetate versus placebo in progressive MS with no significant effect on EDSS progression. We first designed a time-dependent Cox model with no treatment effect up to time = t0, and constant hazard ratio (HR) after time = t0. We selected the best-fitting t0 from 0 (standard Cox model) to 2.5 years. Furthermore, we modeled the delay as a function of baseline EDSS and fitted the resulting Cox model to the merged dataset. RESULTS: The time-dependent Cox model revealed a significant benefit of treatment delayed by t0 = 2.5 years for the SPECTRIMS study (HR = 0.65 (0.43-0.98), p = 0.041), and delayed by t0 = 2 years for the PROMISE study (HR = 0.65, (0.42-0.99), p = 0.044). In the merged dataset, the HR for the EDSS-dependent delayed effect was 0.68 (0.56, 0.82), p < 0.001. CONCLUSION: The assumption of a delayed treatment effect improved the fit to the data of the two examined RCTs, uncovering a significant, although shifted, benefit of treatment.
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Progressão da Doença , Acetato de Glatiramer , Interferon beta , Esclerose Múltipla Crônica Progressiva , Humanos , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Acetato de Glatiramer/uso terapêutico , Interferon beta/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Distinctive differences in multiple sclerosis (MS) have been observed by race and ethnicity. We aim to (1) assess how often race and ethnicity were reported in clinical trials registered on ClinicalTrials.gov, (2) evaluate whether the population was diverse enough, and (3) compare with publications. METHODS: We included phase 3 clinical trials registered with results on ClinicalTrials.gov between 2007 and 2023. When race and/or ethnicity were reported, we searched for the corresponding publications. RESULTS: Out of the 99 included studies, 56% reported race and/or ethnicity, of which only 26% of those primarily completed before 2017. Studies reporting race or ethnicity contributed to a total of 33,891 participants, mainly enrolled in Eastern Europe. Most were White (93%), and the median percentage of White participants was 93% (interquartile range (IQR) = 86%-98%), compared to 3% for Black (IQR = 1%-12%) and 0.2% for Asian (IQR = 0%-1%). Four trials omitted race and ethnicity in publications and even when information was reported, some discrepancies in terminology were identified and categories with fewer participants were often collapsed. CONCLUSION: More efforts should be done to improve transparency, accuracy, and representativeness, in publications and at a design phase, by addressing social determinants of health that historically limit the enrollment of underrepresented population.
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Ensaios Clínicos Fase III como Assunto , Esclerose Múltipla , Humanos , Esclerose Múltipla/etnologia , Esclerose Múltipla/terapia , Etnicidade , Grupos RaciaisRESUMO
BACKGROUND: The lack of standardized disability progression evaluation in multiple sclerosis (MS) hinders reproducibility of clinical study results, due to heterogeneous and poorly reported criteria. OBJECTIVE: To demonstrate the impact of using different parameters when evaluating MS progression, and to introduce an automated tool for reproducible outcome computation. METHODS: Re-analyzing BRAVO clinical trial data (NCT00605215), we examined the fluctuations in computed treatment effect on confirmed disability progression (CDP) and progression independent of relapse activity (PIRA) when varying different parameters. These analyses were conducted using the msprog package for R, which we developed as a tool for CDP assessment from longitudinal data, given a set of criteria that can be specified by the user. RESULTS: The BRAVO study reported a hazard ratio (HR) of 0.69 (95% confidence interval (CI): 0.46-1.02) for CDP. Using the different parameter configurations, the resulting treatment effect on CDP varied considerably, with HRs ranging from 0.59 (95% CI: 0.41-0.86) to 0.72 (95% CI: 0.48-1.07). The treatment effect on PIRA varied from an HR = 0.62 (95% CI: 0.41-0.93) to an HR = 0.65 (95% CI: 0.40-1.04). CONCLUSIONS: The adoption of an open-access tool validated by the research community, with clear parameter specification and standardized output, could greatly reduce heterogeneity in CDP estimation and promote repeatability of study results.
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BACKGROUND: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes. OBJECTIVES: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection. METHODS: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders. RESULTS: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations. CONCLUSION: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes.
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Aborto Espontâneo , COVID-19 , Esclerose Múltipla , Resultado da Gravidez , Humanos , Feminino , Gravidez , COVID-19/complicações , COVID-19/epidemiologia , Adulto , Esclerose Múltipla/epidemiologia , Resultado da Gravidez/epidemiologia , Aborto Espontâneo/epidemiologia , Itália/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Complicações na Gravidez/epidemiologia , Turquia/epidemiologiaRESUMO
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 , Imunossupressores , Humanos , Cladribina/uso terapêutico , Feminino , Masculino , Adulto , Estudos Retrospectivos , Pessoa de Meia-Idade , Imunossupressores/uso terapêutico , Itália , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Resultado do Tratamento , Esclerose Múltipla/tratamento farmacológicoRESUMO
PURPOSE: To investigate, map, and synthesize evidence regarding the correlation between changes in binocular vision and fine motor skills among children. METHODS: We conducted a scoping review of existing evidence, following the guidelines and checklist outlined in "Preferred Reporting Items for Systematic Reviews and Meta-Analyses - Scoping Reviews" (PRISMAScR). RESULTS: Sixteen papers were systematically included in our scoping review. A predominant focus was placed on assessing the impact of strabismus on motor skills. Most of the studies used motor test batteries for comprehensive analysis, while the remaining employed methodologies, such as questionnaires or laboratory-based tests. CONCLUSION: Vision stands as a pivotal perceptual modality essential for the optimal development of children. Alterations in visual acuity can significantly affect fine motor skills. Pediatric ophthalmology and orthoptics frequently encounter binocular vision disorders, such as amblyopia and strabismus. Our finding showed that impaired binocular vision affects fine motor skills.
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BACKGROUND: The optimal timing and surgical approach for surgical revascularization in patients with moyamoya syndrome (MMS) associated with neurofibromatosis type I (NF1) remain so far elusive. We aimed to compare the long-term clinical, radiological, and cognitive effects of different revascularization procedures in a pediatric cohort of NF1-associated MMS. METHODS: We reviewed the clinical, radiological, and surgical data of 26 patients with NF1-associated MMS diagnosed at our institution between 2012 and 2022, at the clinical onset and last follow-up. RESULTS: Indirect bypasses were performed in 12/26 patients (57.1%), while combined direct and indirect procedures in 9/26 subjects (42.9%); 5 patients did not undergo surgery. Through logistic regression analysis, pathological Wechsler Intelligence Scale for Children (WISC) at onset was found to be associated with symptom improvement at 1-year follow up (p = 0.006). No significant differences were found in long-term neurocognitive outcome and stroke rate in patients receiving combined or indirect bypass (p > 0.05). CONCLUSIONS: Currently, whether combined or indirect bypass should be considered the treatment of choice in pediatric patients with NF1-associated MMS remains unclear, as well as the optimal time approach. In our series, no significant differences were found in long-term neurocognitive outcome and stroke rate between patients treated with either of these two approaches. Clinical evidence supports the crucial role of early diagnosis and surgical revascularization in subjects with MMS-associated NF1, even in case of mildly symptomatic vasculopathy. This allows to achieve a good long-term outcome with improved intellectual function and prevention of stroke and seizure in these patients.
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Revascularização Cerebral , Doença de Moyamoya , Neurofibromatose 1 , Humanos , Doença de Moyamoya/cirurgia , Doença de Moyamoya/complicações , Neurofibromatose 1/complicações , Neurofibromatose 1/cirurgia , Feminino , Criança , Masculino , Revascularização Cerebral/métodos , Adolescente , Pré-Escolar , Estudos Retrospectivos , Resultado do Tratamento , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controleRESUMO
BACKGROUND: Preschoolers frequently have respiratory infections (RIs), which may cause wheezing in some subjects. Type 2 polarization may favor increased susceptibility to RIs and associated wheezing. Non-pharmacological remedies are garnering increasing interest as possible add-on therapies. The present preliminary study investigated the efficacy and safety of a new multi-component nasal spray in preschoolers with frequent RIs and associated wheezing. METHODS: Some preschoolers with these characteristics randomly took this product, containing lactoferrin, dipotassium glycyrrhizinate, carboxymethyl-beta-glucan, and vitamins C and D3 (Saflovir), two sprays per nostril twice daily for 3 months. Other children were randomly treated only with standard therapy. Outcomes included the number of RIs and wheezing episodes, use of medications, and severity of clinical manifestations. RESULTS: Preschoolers treated add-on with this multicomponent product experienced fewer RIs and used fewer beta-2 agonists than untreated children (P = 0.01 and 0.029, respectively). CONCLUSIONS: This preliminary study demonstrated that a multicomponent product, administered add-on as a nasal spray, could reduce the incidence of RIs and use of symptomatic drugs for relieving wheezing in children.
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Sprays Nasais , Sons Respiratórios , Infecções Respiratórias , Humanos , Pré-Escolar , Sons Respiratórios/efeitos dos fármacos , Feminino , Masculino , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/diagnóstico , Ácido Ascórbico/administração & dosagem , Lactoferrina/administração & dosagem , Ácido Glicirrízico/administração & dosagem , Resultado do Tratamento , beta-Glucanas/administração & dosagem , Colecalciferol/administração & dosagem , LactenteRESUMO
BACKGROUND: In the general population, maternal SARS-CoV-2 infection during pregnancy is associated with worse maternal outcomes; however, only one study so far has evaluated COVID-19 clinical outcomes in pregnant and postpartum women with multiple sclerosis, showing no higher risk for poor COVID-19 outcomes in these patients. OBJECTIVE: In this multicenter study, we aimed to evaluate COVID-19 clinical outcomes in pregnant patients with multiple sclerosis. METHODS: We recruited 85 pregnant patients with multiple sclerosis who contracted COVID-19 after conception and were prospectively followed-up in Italian and Turkish Centers, in the period 2020-2022. A control group of 1354 women was extracted from the database of the Multiple Sclerosis and COVID-19 (MuSC-19). Univariate and subsequent logistic regression models were fitted to search for risk factors associated with severe COVID-19 course (at least one outcome among hospitalization, intensive care unit [ICU] admission and death). RESULTS: In the multivariable analysis, independent predictors of severe COVID-19 were age, body mass index ⩾ 30, treatment with anti-CD20 and recent use of methylprednisolone. Vaccination before infection was a protective factor. Vaccination before infection was a protective factor. Pregnancy was not a risk nor a protective factor for severe COVID-19 course. CONCLUSION: Our data show no significant increase of severe COVID-19 outcomes in patients with multiple sclerosis who contracted the infection during pregnancy.
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COVID-19 , Esclerose Múltipla , Complicações Infecciosas na Gravidez , Gravidez , Humanos , Feminino , RNA Viral , Gestantes , SARS-CoV-2 , Esclerose Múltipla/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Resultado da GravidezRESUMO
INTRODUCTION: Factor IX replacement therapy is used for treatment and prophylaxis of bleeding in haemophilia B. rIX-FP is an extended half-life albumin-fusion protein, which, in clinical studies, has demonstrated prolonged dosing intervals up to 21 days for routine prophylaxis, providing therapeutic benefit. AIMS: To describe dosing frequency and consumption (primary endpoint), efficacy and safety of rIX-FP treatment during routine clinical practice in Italy. METHODS: Patients with moderate/severe haemophilia B on prophylaxis with rIX-FP for ≥6 months, were enrolled in this observational study from October 2017 to February 2019 and followed-up for 2 years. Descriptive analysis included prospective and retrospective data (12 months prior to switching to rIX-FP). RESULTS: Data were collected from 59 male patients (median age 30.1 years) enrolled by 23 Italian centres. Of them, 50 were on prophylaxis during the entire observation period and completed the study. The infusion frequency changed from 2-3 times/week in 86.0% of patients with previous treatment, to less than once a week in 84.0% of patients treated with rIX-FP at the 2nd-year follow-up. The annual number of infusions decreased by about 70%, whereas the mean FIX activity trough level increased from 3.8% to 14.4% (mean > 10% in all the infusion regimens). Median Annualised Bleeding Rate of .0 was achieved across all prophylaxis regimens. Subjects with zero bleedings increased from 66.0% to 78.0% with rIX-FP. CONCLUSION: Treatment with rIX-FP reduced infusion frequency, while providing higher FIX trough levels with substantial benefit in terms of annualised bleeding rate and a good safety profile.
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Fator IX , Hemofilia B , Adulto , Humanos , Masculino , Albuminas , Fator IX/uso terapêutico , Hemofilia B/tratamento farmacológico , Hemorragia/prevenção & controle , Hemorragia/tratamento farmacológico , Itália , Estudos Prospectivos , Proteínas Recombinantes de Fusão/uso terapêutico , Estudos RetrospectivosRESUMO
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 , Esclerose Múltipla , Humanos , Vacinas contra COVID-19 , Formação de Anticorpos , Cloridrato de Fingolimode , Esclerose Múltipla/tratamento farmacológico , Estudos Prospectivos , Rituximab/uso terapêutico , COVID-19/prevenção & controle , SARS-CoV-2 , Anticorpos Antivirais , VacinaçãoRESUMO
Accidents are the main cause of injury in children, more than half events happen at home. Aims of this study were to assess if SARS-CoV-2 lockdown influence emergency department (ED) visits due to children domestic accident (DAs) and to identify factors associated with hospitalization. This was a multicentre, observational, and retrospective cohort study involving 16 EDs in Italy and enrolling children (3-13 years) receiving a visit in ED during March-June 2019 and March-June 2020. Risk factors for hospitalization were identified by logistic regression models. In total, 8860 ED visits due to domestic accidents in children occurred before (4380) and during (4480) lockdown, with a mean incidence of DA of 5.6% in 2019 and 17.9% in 2020 (p < 0.001) (IRR: 3.16; p < 0.001). The risk of hospitalization was influenced by the type of occurred accident, with fourfold higher for poisoning and twofold lower risk for stab-wound ones. In addition, a higher risk was reported for lockdown period vs 2019 (OR: 1.9; p < 0.001), males (OR: 1.4; p < 0.001), and it increased with age (OR: 1.1; p < 0.001). Conclusions: The main limitation of this study is the retrospective collection of data, available only for patients who presented at the hospital. This does highlight possible differences in the total number of incidents that truly occurred. In any case, the COVID-19 lockdown had a high impact on the frequency of DAs and on hospitalization. A public health campaign aimed at caregivers would be necessary to minimize possible risks at home. What is Known: ⢠In Italy, domestic accidents are the second leading cause of paediatric mortality after cancer. ⢠During the first SARS-CoV-2 lockdown in 2020, a sharp decrease in the total number of Emergency Departments visits for all causes was observed, both in children and in adults. What is New: ⢠During the first SARS-CoV-2 lockdown in 2020, domestic accidents involving children increased threefold from the previous year. ⢠Higher risk of hospitalization was showed in minors accessing during 2020 vs 2019, in males than in females and it increased with advancing age. Considering the type of injury, a significant higher risk of hospitalization for poisoning was observed.
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COVID-19 , Masculino , Adulto , Feminino , Criança , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Estudos Retrospectivos , Controle de Doenças Transmissíveis , Hospitalização , Itália/epidemiologia , Serviço Hospitalar de EmergênciaRESUMO
BACKGROUND: To demonstrate the safety and efficacy of the intracameral use of tropicamide 0.02%/phenylephrine 0.31%/lidocaine 1% in pediatric cataract surgery, a combination widely used in adult patients but still off-label in children. METHODS: Design: two-center, prospective, observational study. SETTING: San Giuseppe Hospital, Milan and Meyer Children's Hospital, Florence. STUDY POPULATION: children from 0 to 4 years of age undergoing cataract surgery with or without intraocular IOL implantation, in the absence of clinically significant systemic conditions, history of ocular surgery, concurrent ocular medication, hypersensitivity to any of the substances and post-traumatic cataracts. During the surgery, patients received the combination drug after the primary access to the anterior chamber. Efficacy was evaluated by achieving an adequate mydriasis in order to perform capsulorhexis, while safety was assessed by recording vital signs (heart rate, blood pressure, respiratory rate, temperature) pre- and post-administration of the substance. RESULTS: This study included 53 surgical procedures of 36 patients: 41 eyes were left aphakic, while 12 eyes received primary IOL implantation. The pupil size was adequate to safely perform capsulorhexis in 52 procedures of 53. The difference in pupil enlargement was significant (6.0 ± 1.14 mm, P = < 0.001). There were no notable changes in vital parameters. CONCLUSIONS: The administration of intracameral tropicamide 0.02%/phenylephrine 0.31%/lidocaine 1% in pediatric cataract surgery is effective for obtaining an adequate mydriasis without any vital parameters changes throughout the procedure.
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Catarata , Midríase , Oftalmologia , Facoemulsificação , Adulto , Humanos , Criança , Tropicamida/farmacologia , Midriáticos , Estudos Prospectivos , Fenilefrina , Pupila/fisiologia , Lidocaína/efeitos adversos , Facoemulsificação/métodosRESUMO
OBJECTIVE: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). METHODS: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. RESULTS: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. INTERPRETATION: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.
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COVID-19/fisiopatologia , Hospitalização/estatística & dados numéricos , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/complicações , COVID-19/mortalidade , Fumarato de Dimetilo/uso terapêutico , Feminino , Cloridrato de Fingolimode/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Unidades de Terapia Intensiva/estatística & dados numéricos , Interferons/uso terapêutico , Masculino , Pessoa de Meia-Idade , Mortalidade , Esclerose Múltipla/complicações , Natalizumab/uso terapêutico , SARS-CoV-2 , Índice de Gravidade de Doença , Adulto JovemRESUMO
OBJECTIVE: COVID-19 is a multisystem disease that causes endothelial dysfunction and organ damage. Aim of the study was to evaluate the microvascular status in COVID-19 survivors with past different disease severity, in comparison with age and sex-matched primary Raynaud's phenomenon (PRP) patients and control subjects (CNT), including possible effects of concomitant therapies. METHODS: Sixty-one COVID-19 survivors (mean age 58 ± 13 years, mean days from disease onset 126 ± 53 and mean days from recovery 104 ± 53), thirty-one PRP patients (mean age 59 ± 15 years, mean disease duration 11 ± 10 years) and thirty CNT (mean age 58 ± 13 years) underwent nailfold videocapillaroscopy (NVC) examination. The following capillaroscopic parameters were searched and scored (0-3): dilated capillaries, giant capillaries, isolated microhemorrhages, capillary ramifications (angiogenesis) and capillary number, including absolute capillary number per linear millimeter at the nailfold bed. RESULTS: The mean nailfold capillary number per linear millimeter was significantly lower in COVID-19 survivors when compared with PRP patients and CNT (univariate and multivariate analysis p < 0.001). On the contrary, COVID-19 survivors showed significantly less isolated microhemorrhages than PRP patients and CNT (univariate and multivariate analysis, p = 0.005 and p = 0.012, respectively). No statistically significant difference was observed between COVID-19 survivors and control groups concerning the frequency of dilated capillaries and capillary ramifications. COVID-19 selective therapies showed a promising trend on preserving capillary loss and deserving further investigations. CONCLUSIONS: SARS-CoV-2 seems to mainly induce a significant loss of capillaries in COVID-19 survivors at detailed NVC analysis in comparison to controls. The presence of a significant reduced score for isolated microhaemorrhages in COVID-19 survivors deserves further analysis.
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COVID-19 , Unhas , Adulto , Idoso , COVID-19/diagnóstico , Capilares , Humanos , Angioscopia Microscópica , Pessoa de Meia-Idade , Unhas/irrigação sanguínea , SARS-CoV-2 , SobreviventesRESUMO
BACKGROUND: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. OBJECTIVE: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. METHODS: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. RESULTS: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20, p = 0.002). CONCLUSION: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.
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COVID-19 , Esclerose Múltipla , Anticorpos Antivirais , Estudos de Coortes , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , SARS-CoV-2 , Estudos SoroepidemiológicosRESUMO
BACKGROUND: Patients with multiple sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. OBJECTIVE: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different disease-modifying therapies (DMTs). METHODS: Data on the number of vaccinated patients and the number of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT. RESULTS: 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. Compared with other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, risk ratio (RR) = 3.55, 95% CI = 2.74-4.58, p < 0.001) and fingolimod (0.58% vs 1.62%, RR = 2.65, 95% CI = 1.75-4.00, p < 0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% versus 19.4% in the pre-vaccination era (RR = 0.86, p = 0.74) and it was 3.9% in all the other DMT groups versus 11.9% in the pre-vaccination period (RR = 0.33, p = 0.02). CONCLUSIONS: The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.
Assuntos
COVID-19 , Esclerose Múltipla , Vacinas contra COVID-19 , Cloridrato de Fingolimode/uso terapêutico , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Estudos Retrospectivos , SARS-CoV-2RESUMO
BACKGROUND AND PURPOSE: We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody (anti-MAG) demyelinating polyneuropathy. METHODS: Twenty three anti-MAG-positive polyneuropathic patients were prospectively evaluated before and for 2 years after treatment with RTX 375 mg/m2 . The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (INCAT-ds), modified INCAT sensory score (mISS), Medical Research Council sum score, Patients' Global Impression of Change scale were used, IgM levels were assessed and extensive electrophysiological examinations were performed before (T0) and 1 year (T1) and 2 years (T2) after RTX treatment. RESULTS: At T1 and T2 there was a significant reduction from T0 both in mISS and in INCAT-ds, with a p value < 0.001 in the inferential Friedman's test overall analysis. Ulnar nerve Terminal Latency Index and distal motor latency significantly changed from T0 to T1 and in the overall analysis (p = 0.001 and p = 0.002), and ulnar nerve sensory nerve action potential (SNAP) amplitude was significantly increased at T2 from T1, with a p value < 0.001 in the overall analysis. Analysis of the receiver-operating characteristic curves showed that a 41.8% increase in SNAP amplitude in the ulnar nerve at T2 from T0 was a fair predictor of a mISS reduction of ≥2 points (area under the curve 0.85; p = 0.005; sensitivity: 90.9%, specificity: 83.3%). CONCLUSIONS: This study suggests that RTX is effective in patients with clinically active demyelinating anti-MAG neuropathy over 2 years of follow-up, and that some neurophysiological variables might be useful for monitoring this efficacy.
Assuntos
Paraproteinemias , Polineuropatias , Humanos , Rituximab/uso terapêutico , Seguimentos , Polineuropatias/tratamento farmacológico , Paraproteinemias/tratamento farmacológico , Imunoglobulina M , AutoanticorposRESUMO
BACKGROUND AND PURPOSE: Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS. METHODS: Data were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity. RESULTS: In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009). CONCLUSIONS: Even if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.