RESUMEN
(1) Multiple sclerosis (MS) is a chronic inflammatory disease of autoimmune origin. The Epstein−Barr virus (EBV) is associated with the onset of MS, as almost all patients have high levels of EBV-specific antibodies as a result of a previous infection. We evaluated longitudinally the effects of dimethyl fumarate (DMF), a first-line treatment of MS, on the quantity and quality of EBV-specific IgG in MS patients. (2) Serum samples from 17 MS patients receiving DMF were taken before therapy (T0) and after 1 week (T1) and 1 (T2), 3 (T3) and 6 (T4) months of treatment. Anti-EBV nuclear antigen (EBNA)-1 and capsid antigen (CA) IgG levels and anti-CA IgG avidity were measured in all samples. (3) Serum levels of anti-CA IgG were lower at T1 (p = 0.0341), T2 (p = 0.0034), T3 (p < 0.0001) and T4 (p = 0.0023) than T0. These differences were partially confirmed also in anti-EBNA-1 IgG levels (T3 vs. T0, p = 0.0034). All patients had high-avidity anti-CA IgG at T0, and no changes were observed during therapy. (4): DMF can reduce the amount but not the avidity of the anti-EBV humoral immune response in MS patients from the very early stages of treatment.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Esclerosis Múltiple , Humanos , Herpesvirus Humano 4 , Antígenos Virales , Proyectos Piloto , Dimetilfumarato/farmacología , Dimetilfumarato/uso terapéutico , Cápside , Formación de Anticuerpos , Inmunoglobulina G , Anticuerpos Antivirales , Proteínas de la CápsideRESUMEN
The gut microbiota is involved in the development of the immune system and can modulate the risk for immune-mediated disorders such as multiple sclerosis (MS). Dysbiosis has been demonstrated in MS patients and its restoration by disease-modifying treatments (DMTs) is hypothesized. We aimed to study the changes in gut microbiota composition during the first 6 months of treatment with dimethyl fumarate (DMF), an oral DMT, and to identify the microorganisms associated with DMF side effects. We collected and analyzed the gut microbiota of 19 MS patients at baseline and after 1, 3, and 6 months of DMF treatment. We then cross-sectionally compared gut microbiota composition according to the presence of gastrointestinal (GI) symptoms and flushing. Overall, the gut microbiota biodiversity showed no changes over the 6-month follow-up. At the genus level, DMF was associated with decreased Clostridium abundance after 6 months. In subjects reporting side effects, a higher abundance of Streptococcus, Haemophilus, Clostridium, Lachnospira, Blautia, Subdoligranulum, and Tenericutes and lower of Bacteroidetes, Barnesiella, Odoribacter, Akkermansia, and some Proteobacteria families were detected. Our results suggest that gut microbiota may be involved in therapeutic action and side effects of DMF, representing a potential target for improving disease course and DMT tolerability.
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Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Enfermedades Gastrointestinales , Microbioma Gastrointestinal , Esclerosis Múltiple , Humanos , Dimetilfumarato/efectos adversos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/microbiología , Enfermedades Gastrointestinales/tratamiento farmacológico , Bacteroidetes , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/tratamiento farmacológico , Inmunosupresores/uso terapéuticoRESUMEN
BACKGROUND: To assess a longitudinal follow-up of the prevalence of multiple sclerosis (MS) through 4 decades in the province of Ferrara, northern Italy, and reappraise the current rates on December 31, 2016. METHODS: We conducted a community-based intensive prevalence study, by adopting a complete enumeration approach. MS cases were identified from administrative health data and medical records from the Units of Neurology and Motor Rehabilitation, Ferrara University Hospital, from other provincial neurological structures and from archives of the National Pension Institute and National Health Insurance scheme of the study area. Case ascertainment method and case definition are analogous to those adopted in previous surveys in the same area of study. RESULTS: On December 31, 2016, 685 patients (478 women and 207 men) affected by definite or probable MS (Poser's criteria) were living in the province of Ferrara (population 386,896), yielding a crude prevalence ratio of 194.91 (95% CI 180.4-209.6) per 100,000, 260.8 (95% CI 238.10-285.82) for women and 123.1 (95% CI 106.98-141.21) for men The prevalence ratio was 26.9 per 100,000 in 1978, increased to a value of 46.1 per 100,000 in 1981, 69.4 per 100,000 in 1993, 120.9 per 100,000 in 2004. Female to male ratio was 2.31 (1.2 on December 31, 1978). The mean duration of the disease at prevalence day was 17.5 ± 11.9 years (13.9 ± 10.8 years in 1978). The mean age at prevalence day was 52.04 ± 10.8 years (13.8 ± 10.8 years in 1978). CONCLUSION: Our study has confirmed the province of Ferrara is an area at high risk for MS, in line with epidemiological data from the regions of continental and insular Italy. The sharp increase in MS prevalence over time in this population can be imputed in part to a greater exposition to risk factors in genetically susceptible subjects but also to an increased survival and improved ascertainment. So, the results suggest that both methodologic and environmental factors are essential in determining the real distribution of MS. The need to get reliable estimates of MS prevalence must be highlighted as a public health and research priority, essential to support planning and prioritization of care services and to reduce the overall burden of chronic disease.
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Esclerosis Múltiple/epidemiología , Adulto , Anciano , Estudios Transversales , Femenino , Estudios de Seguimiento , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Factores de Riesgo , Factores SexualesRESUMEN
The frequency of definitive childlessness in women with multiple sclerosis (MS) may be higher than in the general population. MS may also affect decisions on the delivery procedure and on breast-feeding issues. Aim of the study was to assess the frequency of childlessness and its possible causes, the proportion of cesarean deliveries (CD), and the frequency of breast-feeding in patients and controls who have reached the end of their reproductive period. Female MS patients (>43 years) and controls (>45 years) filled out a questionnaire. We enrolled 303 patients and 500 controls. MS was associated with a higher frequency of childlessness (22 vs 13%) and less patients were in a stable relationship (83 vs 89%). There was no difference in the reported rates of infertility and miscarriages, while elective abortions were more frequent in patients (20 vs 12%). MS did not significantly affect the frequency of CD or of breast-feeding. MS-related reasons for childlessness, reported by 16% of childless patients, included disability/fear of future disability, fear of genetically transmitting MS, fear of not starting/discontinuing treatments, and discouragement by physician. Definitive childlessness is more frequent in women with MS compared to controls. A portion of voluntary childlessness may be avoided through correct/tailored information to patients.
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Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/psicología , Conducta Reproductiva , Adulto , Anciano , Lactancia Materna/estadística & datos numéricos , Cesárea/psicología , Cesárea/estadística & datos numéricos , Femenino , Humanos , Persona de Mediana Edad , Embarazo , Conducta Reproductiva/estadística & datos numéricos , Encuestas y CuestionariosRESUMEN
BACKGROUND: The relevance of human leukocyte antigen (HLA)-G in dimeric form in multiple sclerosis (MS) is still unknown. OBJECTIVE: To investigate the contribution of cerebrospinal fluid (CSF) HLA-G dimers in MS pathogenesis. METHODS: CSF amounts of 78-kDa HLA-G dimers were measured by western blot analysis in 80 MS relapsing-remitting MS (RRMS) patients and in 81 inflammatory and 70 non-inflammatory controls. RESULTS: CSF amounts of 78 kDa HLA-G dimers were more frequent in RRMS than in inflammatory (p<0.01) and non-inflammatory controls (p<0.001) and in magnetic resonance imaging (MRI) inactive than in MRI active RRMS (p<0.00001). CONCLUSION: Our findings suggest that HLA-G dimers may be implicated in termination of inflammatory response occurring in MS.
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Encéfalo/patología , Antígenos HLA-G/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Médula Espinal/patología , Adulto , Western Blotting , Estudios de Casos y Controles , Dimerización , Femenino , Humanos , Inflamación/líquido cefalorraquídeo , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patología , Enfermedades del Sistema Nervioso/líquido cefalorraquídeoRESUMEN
BACKGROUND: The activity of matrix metalloproteinase-9 (MMP-9) depends on two isoforms, an 82 kDa active MMP-9 modulated by its specific tissue inhibitor (TIMP-1), and a 65 kDa TIMP-1 resistant active MMP-9. The relevance of these two enzymatic isoforms in multiple sclerosis (MS) is still unknown. OBJECTIVE: To investigate the contribution of the TIMP-1 modulated and resistant active MMP-9 isoforms to MS pathogenesis. METHODS: We measured the serum levels of the 82 kDa and TIMP-1 resistant active MMP-9 isoforms by activity assay systems in 86 relapsing-remitting MS (RRMS) patients, categorized according to clinical and magnetic resonance imaging (MRI) evidence of disease activity, and in 70 inflammatory (OIND) and 69 non-inflammatory (NIND) controls. RESULTS: Serum levels of TIMP-1 resistant MMP-9 were more elevated in MS patients than in OIND and NIND (p < 0.05, p < 0.02, respectively). Conversely, 82 kDa active MMP-9 was higher in NIND than in the OIND and MS patients (p < 0.01 and p < 0.00001, respectively). MRI-active patients had higher levels of TIMP-1 resistant MMP-9 and 82 kDa active MMP-9, than did those with MRI inactive MS (p < 0.01 and p < 0.05, respectively). CONCLUSION: Our findings suggested that the TIMP-1 resistant MMP-9 seem to be the predominantly active isoform contributing to MS disease activity.
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Metaloproteinasa 9 de la Matriz/sangre , Esclerosis Múltiple Recurrente-Remitente/enzimología , Esclerosis Múltiple Recurrente-Remitente/patología , Adulto , Encéfalo/patología , Femenino , Humanos , Isoenzimas/sangre , Imagen por Resonancia Magnética , Masculino , Esclerosis Múltiple Recurrente-Remitente/sangre , Inhibidor Tisular de Metaloproteinasa-1/metabolismoRESUMEN
BACKGROUND: The purpose of this study was to investigate intrathecal production and affinity distributions of Epstein-Barr virus (EBV)-specific antibodies in multiple sclerosis (MS) and controls. METHODS: Cerebrospinal fluid (CSF) and serum concentrations, quantitative intrathecal synthesis, oligoclonal bands (OCB) patterns and affinity distributions of anti-Epstein Barr virus (EBV) antibodies were evaluated in 100 relapsing-remitting MS (RRMS) patients and 200 age- and sex-matched controls with other inflammatory neurological disorders (OIND) and other noninflammatory neurological disorders (NIND). RESULTS: Levels of anti-EBNA-1 and anti-viral capsid antigen (VCA) IgG were different in both the CSF (P <0.0001 and P <0.01, respectively) and serum (P <0.001 and P <0.05, respectively) among the RRMS, OIND and NIND. An intrathecal synthesis of anti-EBNA-1 IgG and anti-VCA IgG, as indicated by the antibody index, was underrepresented in the RRMS, OIND and NIND (range 1 to 7%). EBV-specific OCB were detected in 24% of the RRMS patients and absent in the controls. High-affinity antibodies were more elevated in the RRMS and in the OIND than in the NIND for CSF anti-EBNA-1 IgG (P <0.0001) and anti-VCA IgG (P <0.0001). After treatment with increasing concentrations of sodium thiocyanate, the EBV-specific IgG OCB had low affinity in all 24 RRMS patients analyzed. CONCLUSIONS: Our findings do not support the potential role of an EBV persistent brain chronic infection in MS and suggest that an EBV-specific intrathecal oligoclonal IgG production can occur in a subset of MS patients as part of humoral polyreactivity driven by chronic brain inflammation.
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Anticuerpos Antivirales/metabolismo , Herpesvirus Humano 4/metabolismo , Inmunoglobulina G/metabolismo , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Bandas Oligoclonales/metabolismo , Adulto , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/líquido cefalorraquídeo , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Bandas Oligoclonales/sangre , Bandas Oligoclonales/líquido cefalorraquídeoRESUMEN
Acute necrotizing encephalopathy (ANE) is a rare disease not yet described in children with Covid-19. RANBP2 gene variations are implicated in recurrences in the genetic form of ANE, the so called ANE1. We report the first case of pediatric ANE1 following Sars-CoV-2 infection. She had a first episode at 2 years of age following influenza type A with full recovery, many other respiratory and non-respiratory febrile viral infections without recurrences and a severe recurrence following Sars-CoV-2 infection, suggesting a potentiation effect on cytokine cascade. Her MRI showed the typical pattern of injury resembling that of mitochondrial disorders, and supported the role of RANBP2 in mitochondrial homeostasis. This case rises attention on diagnostic challenges and offers several interesting tips for discussion about new perspectives in pathogenesis and targeted treatments.
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Encefalopatías , COVID-19 , Encefalomielitis , Leucoencefalitis Hemorrágica Aguda , Femenino , Humanos , Niño , Leucoencefalitis Hemorrágica Aguda/etiología , Leucoencefalitis Hemorrágica Aguda/genética , SARS-CoV-2 , Genotipo , Prueba de COVID-19RESUMEN
BACKGROUND: Cognitive impairment (CI) is a prevalent and debilitating manifestation of multiple sclerosis (MS); however, it is not included in the widely used concept of No Evidence of Disease Activity (NEDA-3). We expanded the NEDA-3 concept to NEDA-3 + by encompassing CI assessed through the Symbol Digit Modality Test (SDMT) and evaluated the effect of teriflunomide on NEDA3 + in patients treated in a real-world setting. The value of NEDA-3 + in predicting disability progression was also assessed. METHODS: This 96-weeks observational study enrolled patients already on treatment with teriflunomide for ≥ 24 weeks. The predictiveness of NEDA-3 and NEDA-3 + at 48 weeks on the change in motor disability at 96 weeks was compared through a two-sided McNemar test. RESULTS: The full analysis set (n = 128; 38% treatment naïve) featured relatively low level of disability (baseline EDSS = 1.97 ± 1.33). NEDA-3 and NEDA-3 + statuses were achieved by 82.8% and 64.8% of patients, respectively at 48 weeks vs. baseline, and by 57.0% and 49.2% of patients, respectively at 96 weeks vs. baseline. All patients except one were free of disability progression at Week 96, and NEDA-3 and NEDA-3 + were equally predictive. Most patients were free of relapse (87.5%), disability progression (94.5%) and new MRI activity (67.2%) comparing 96 weeks with baseline. SDMT scores were stable in patients with baseline score Ë35 and improved significantly in those with baseline score ≤ 35. Treatment persistence was high (81.0% at Week 96). CONCLUSION: Teriflunomide confirmed its real-world efficacy and was found to have a potentially beneficial effect on cognition.
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Personas con Discapacidad , Trastornos Motores , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , CogniciónRESUMEN
A number of studies have suggested that human herpesvirus 6A (HHV-6A) may play a role in multiple sclerosis (MS). Three possible hypotheses have been investigated: (1) U24 from HHV-6A (U24-6A) mimics myelin basic protein (MBP) through analogous phosphorylation and interaction with Fyn-SH3; (2) U24-6A affects endocytic recycling by binding human neural precursor cell (NPC) expressed developmentally down-regulated protein 4-like WW3* domain (hNedd4L-WW3*); and (3) MS patients who express Killer Cell Immunoglobulin Like Receptor 2DL2 (KIR2DL2) on natural killer (NK) cells are more susceptible to HHV-6 infection. In this contribution, we examined the validity of these propositions by investigating the interactions of U24 from HHV-6B (U24-6B), a variant less commonly linked to MS, with Fyn-SH3 and hNedd4L-WW3* using heteronuclear single quantum coherence (HSQC) nuclear magnetic resonance (NMR) titrations and isothermal titration calorimetry (ITC). In addition, the importance of phosphorylation and the specific role of U24 in NK cell activation in MS patients were examined. Overall, the findings allowed us to shed light into the models linking HHV-6 to MS and the involvement of U24.
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Herpesvirus Humano 6 , Esclerosis Múltiple , Infecciones por Roseolovirus , Humanos , Herpesvirus Humano 6/fisiología , Fosforilación , Resonancia Magnética Nuclear BiomolecularRESUMEN
In multiple sclerosis (MS), there is a possible relationship with viral infection, evidenced by clinical evidence of an implication of infectious events with disease onset and/or relapse. The aim of this research is to study how human herpesvirus (HHVs) infections might dysregulate the innate immune system and impact autoimmune responses in MS. We analyzed 100 MS relapsing remitting patients, in the remission phase, 100 healthy controls and 100 subjects with other inflammatory neurological diseases (OIND) (neuro-lupus) for their immune response to HHV infection. We evaluated NK cell response, levels of HHVs DNA, IgG and pro- and anti-inflammatory cytokines. The results demonstrated that the presence of KIR2DL2 expression on NK cells increased the susceptibility of MS patients to HHV infections. We showed an increased susceptibility mainly to EBV and HHV-6 infections in MS patients carrying the KIR2DL2 receptor and HLA-C1 ligand. The highest HHV-6 viral load was observed in MS patients, with an increased percentage of subjects positive for IgG against HHV-6 in KIR2DL2-positive MS and OIND subjects compared to controls. MS and OIND patients showed the highest levels of IL-8, IL-12p70, IL-10 and TNF-alpha in comparison with control subjects. Interestingly, MS and OIND patients showed similar levels of IL-8, while MS patients presented higher IL-12p70, TNF-alpha and IL-10 levels in comparison with OIND patients. We can hypothesize that HHVs' reactivation, by inducing immune activation via also molecular mimicry, may have the ability to induce autoimmunity and cause tissue damage and consequent MS lesion development.
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Background: Constipation and faecal incontinence are not so uncommon in patients with multiple sclerosis, impairing quality of life. The gut microbiota is altered in multiple sclerosis patients and likely contributes to disease pathogenesis. Trans-anal irrigation has been proven to allow treatment of neurogenic bowel dysfunction and may affect gut microbiota. Objectives: The primary outcome was trans-anal irrigation effectiveness on constipation and faecal incontinence. The secondary outcome was gut microbiota profiling compared to healthy subjects and during trans-anal irrigation adoption. Methods: We conducted a prospective cohort study on multiple sclerosis patients, screened with Patient Assessment of Constipation Quality of Life questionnaire before undergoing constipation and faecal incontinence scoring, abdomen X-ray for intestinal transit time, compilation of food and evacuation diaries and faecal sample collection for gut microbiota analysis before and after 4 weeks of trans-anal irrigation. Results and Conclusions: Eighty patients were screened of which nearly half had intestinal symptoms. The included population (n = 37) was predominantly composed of women with significantly longer disease duration, higher mean age and disability than the excluded one (p < 0.05). Twelve patients completed the trans-anal irrigation phase, which led to significant improvement of bowel dysfunction symptom-related quality of life, increase in gut microbiota diversity and reduction of the proportions of pro-inflammatory taxa (p < 0.05). Trans-anal irrigation was safe, satisfactory and could help counteract multiple sclerosis-related dysbiosis.
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Cerebrospinal fluid and serum levels and intrathecal synthesis of anti-Epstein-Barr virus (EBV) IgG were measured by enzyme-linked immunosorbent assay in 80 relapsing-remitting multiple sclerosis patients grouped according to clinical and magnetic resonance imaging (MRI) evidence of disease activity. Eighty patients with other inflammatory neurological disorders (OIND) and 80 patients with non-inflammatory neurological disorders (NIND) served as neurological controls. Cerebrospinal fluid concentrations were higher in OIND than in multiple sclerosis (p < 0.0001) and NIND (p < 0.01) for anti-viral-capsid-antigen (anti-VCA) IgG, in multiple sclerosis than in NIND (p < 0.01) and in OIND than in NIND (p < 0.05) for anti-EBV nuclear antigen-1 (EBNA-1) IgG. Serum levels were more elevated in OIND than in multiple sclerosis (p < 0.05) and in MRI inactive than in MRI active multiple sclerosis (p < 0.0001) for anti-VCA IgG, and in multiple sclerosis than in OIND and NIND (p < 0.01) for anti-EBNA-1 IgG. Serum titres of anti-VCA and anti-EBNA-1 IgG were also positively (p < 0.05) and inversely (p < 0.001) correlated, respectively, with the Expanded Disability Status Scale. An intrathecal IgG production of anti-VCA and anti-EBNA-1 IgG, as indicated by Antibody Index, was present only in a limited number of multiple sclerosis patients and controls (range from 1.3 to 6.3%). These findings do not support a direct pathogenetic role of EBV-targeted humoral immune response in multiple sclerosis.
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Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/líquido cefalorraquídeo , Antígenos Virales/inmunología , Proteínas de la Cápside/inmunología , Herpesvirus Humano 4/inmunología , Inmunidad Humoral , Esclerosis Múltiple Recurrente-Remitente/virología , Adulto , Estudios de Casos y Controles , Evaluación de la Discapacidad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Italia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/inmunología , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood-cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. METHODS: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40-60 and 9.0 over 60 years. RESULTS: 1209 subjects were included in the study. 718 females and 491 males (age: 15-88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group. CONCLUSIONS: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.
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Factores de Edad , Barrera Hematoencefálica/patología , Esclerosis Múltiple/patología , Permeabilidad , Factores Sexuales , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Barrera Hematoencefálica/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Albúmina Sérica/metabolismo , Adulto JovenRESUMEN
BACKGROUND: Both natalizumab and fingolimod are highly effective in the treatment of relapsing-remitting MS (RRMS). In the absence of head-to-head trials, some observational studies have compared their efficacy with conflicting results. OBJECTIVES: To investigate the efficacy of natalizumab and fingolimod in a cohort of RRMS patients in an observational, retrospective study. METHODS: We included all consecutive RRMS patients who started natalizumab or fingolimod in three MS centres with a follow-up to 24 months and analysed clinical and brain MRI data after propensity score (PS) matching. RESULTS: After 1:1 PS-matching, we retained 102 patients in both groups, with similar baseline features. After 24 months, although both drugs resulted highly effective, patients treated with natalizumab had a lower relapse risk (HR 0.59 CI 95% 0.35-1.00, pâ¯=â¯0.048) and higher time to first relapse. MRI-combined-unique-activity was found in 31.8% of natalizumab vs 43.2% of fingolimod treated patients (pâ¯=â¯0.28). We found a higher proportion of patients with confirmed regression of disability (19.2â¯vs 6.7%, pâ¯=â¯0.03) and 2-year no evidence of disease activity (NEDA-3, 39.0% vs 22.0%, pâ¯=â¯0.04) in the natalizumab group. CONCLUSIONS: Both drugs were highly effective in our cohort. Natalizumab proved superior in inducing regression of disability and 2-year-NEDA-3.
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Clorhidrato de Fingolimod/uso terapéutico , Factores Inmunológicos/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/uso terapéutico , Adulto , Femenino , Humanos , Italia , Masculino , Estudios RetrospectivosRESUMEN
BACKGROUND: Multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the central nervous system, typically features immune-mediated focal demyelination and secondary axonal degeneration. Cerebral hypoperfusion of the normal-appearing white matter (NAWM) has been reported in MS patients and may be mediated by elevated levels of endothelin-1 (ET-1), a most potent vasoconstrictive peptide released from reactive astrocytes in MS focal lesions. Optic neuritis (ON) is one of the most frequent manifestations of MS and also shows peripapillary vascular hypoperfusion in combination with disc swelling. AIMS: We aimed to compare serum and cerebrospinal fluid (CSF) levels of ET-1 as a potential prognostic marker of MS-ON in two groups of patients differing for severity of MS-ON clinical presentation. MATERIALS AND METHODS: A cross-sectional study to compare serum and CSF levels of ET-1 between patients with clinically aggressive MS-ON (A-MS-ON) and nonaggressive MS-ON (NA-MS-ON) according to conventional ophthalmological criteria, including optical coherence tomography. CSF and serum concentrations of ET-1 were measured using a commercially available ELISA method. RESULTS: Sixteen patients consecutively referred to the Units of Neurology for visual disturbances attributable to MS were recruited, 11 (69%) patients with A-MS-ON and 5 (31%) with NA-MS-ON. Median CSF ET-1 levels and CSF/serum ET-1 quotient were significantly higher in patients with A-MS-ON (0.30 vs. 0.56 ng/ml) as compared to NA-MS-ON (0.16 vs. 0.16). CONCLUSIONS: Severity and failure in the recovery from ON in MS patients may depend from vascular hypoperfusion of the optic nerve induced by high intrathecally produced ET-1, a potential prognostic marker of ON recovery in MS. The detection of CSF ET-1 levels may allow identifying groups of ON patients potentially benefitting from treatment with ET-1 antagonists (e.g., bosentan).
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Endotelina-1/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Nervio Óptico/metabolismo , Neuritis Óptica/líquido cefalorraquídeo , Adulto , Astrocitos/metabolismo , Astrocitos/patología , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios Transversales , Endotelina-1/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Nervio Óptico/diagnóstico por imagen , Neuritis Óptica/sangre , Neuritis Óptica/diagnóstico por imagen , Neuritis Óptica/fisiopatología , Índice de Severidad de la Enfermedad , Tomografía de Coherencia Óptica , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/metabolismoRESUMEN
OBJECTIVE: The introduction of oral disease-modifying drugs (DMDs) in addition to the available, injectable, ones for relapsing-remitting multiple sclerosis (RRMS) could be expected to improve medication persistence due to a greater acceptability of the route of administration. The aim of the study was to compare the proportion of patients discontinuing injectable DMDs (interferon beta 1a/1b, pegylated interferon, glatiramer acetate) with those discontinuing oral DMDs (dimethylfumarate and teriflunomide) during an observation period of at least 12 months. Secondary aims were to compare the time to discontinuation and the reasons for discontinuation between the two groups and to explore the demographic and clinical factors associated with DMD discontinuation. METHODS: In this prospective, multi-center, real-life observational study, patients commencing any first-line DMD between 1 January 2015 and 31 July 2016 were enrolled and followed up for at least 12 months or until the drug was discontinued. RESULTS: Of the 520 included patients, 262 (49.6%) started an injectable and 258 (50.4%) an oral DMD. There was no difference in the proportion of patients on oral (n = 62, 24%) or on injectable (n = 60, 23%) DMDs discontinuing treatment, the most frequent reason being adverse events/side-effects. Higher baseline Expanded Disability Status Scale (EDSS) scores and younger age increased the odds of treatment withdrawal. Time to treatment discontinuation was not different between the two groups and was not influenced by the initiated DMD (oral versus injectable), even after adjustment for baseline differences. CONCLUSION: The route of administration alone (i.e. oral versus injectable) was not a significant predictor of persistence with first-line DMDs in RRMS.
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Administración Oral , Antirreumáticos , Inyecciones , Cumplimiento de la Medicación/estadística & datos numéricos , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Adulto , Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Antirreumáticos/clasificación , Femenino , Humanos , Inyecciones/métodos , Inyecciones/estadística & datos numéricos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Estudios ProspectivosRESUMEN
Cerebrospinal fluid (CSF) levels of sHLA-G (sHLA-G1/HLA-G5) molecules and their soluble isoforms HLA-G5 and sHLA-G1 were measured by ELISA procedures in 68 relapsing-remitting Multiple Sclerosis (RR MS) patients, in 67 patients with other inflammatory neurological disorders (OIND) and in 70 subjects with non-inflammatory neurological disorders (NIND). CSF concentrations of sHLA-G1/HLA-G5 and HLA-G5 were higher in RR MS than in OIND and NIND, and in Magnetic Resonance Imaging (MRI) inactive as compared to MRI active RR MS. Our results indicate that the potential implication of sHLA-G proteins in the resolution of MS intrathecal inflammatory response is probably due to HLA-G5 isoform.
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Antígenos HLA/líquido cefalorraquídeo , Antígenos de Histocompatibilidad Clase I/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Adulto , Encéfalo/patología , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Antígenos HLA-G , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patologíaRESUMEN
Multiple sclerosis (MS) patients have increased brain iron deposition with higher oxidative stress (OxS). These two features can be caused by an inefficient removal of free iron from extracellular compartment. Ferroxidase activity (Feox) exerted by ceruloplasmin (FeoxCp) and by other molecules (FeoxII) appears to have a central role in this process. The aim of this study was to investigate serum and cerebrospinal fluid (CSF) total Feox, FeoxII and FeoxCp activities in MS patients and neurological controls. Serum and CSF Feox activity, FeoxII and FeoxCp activity was measured in 91 relapsing-remitting (RR) MS patients, 79 subjects with other inflammatory neurological disorders (OIND) and 65 with non-inflammatory neurological disorders (NIND), as controls. This study was approved by the Local Committee for Medical Ethics in Research. Serum total Feox activity was lower in MS group than in both NIND and OIND, with only the former control group differing significantly (p<0.001); FeoxII and FeoxCp activities were comparable among the groups. Serum Feox activities were not associated with disease activity as assessed by clinical examination or by Magnetic Resonance Imaging (MRI). Only total Feox activity was detectable in the CSF and was not different in MS compared to either OIND or NIND. In conclusion, a condition of low systemic Feox may increase the susceptibility of MS patients to iron(II) mediated-oxidative damage. This alteration is not reflected in CSF, suggesting that agents endowed with Feox activity might have different impact in iron homeostasis in the central nervous system compared to periphery.
Asunto(s)
Ceruloplasmina/metabolismo , Esclerosis Múltiple/sangre , Esclerosis Múltiple/líquido cefalorraquídeo , Oxidorreductasas/sangre , Oxidorreductasas/líquido cefalorraquídeo , Adulto , Anciano , Evaluación de la Discapacidad , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Enfermedades del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso/líquido cefalorraquídeo , Estadísticas no ParamétricasRESUMEN
We have previously demonstrated that multiple sclerosis (MS) patients with KIR2DL2 expression on Natural killer (NK) cells are more susceptible to herpes simplex virus 1 (HSV-1) infection. We explored cytokine expression by NK cells during HSV-1 infection in association with KIR2DL2 expression. MS KIR2DL2(+) NK cells failed to control HSV-1 infection and secreted high levels of Th17 cytokines, while MS KIR2DL2(-) NK cells released Th1 cytokines, mainly IFN-gamma. Our data showed, for the first time, a peculiar Th17 cytokine secretion by MS KIR2DL2(+) NK cells in the presence of HSV-1 infection, that could be implicated in MS pathogenesis.