RESUMO
BACKGROUND: The association between tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1 and sTNFR2 with clinical characteristics of multiple sclerosis (MS) remains unclear. OBJECTIVE: To examine whether TNF-α, sTNFR1 and sTNFR2 are associated with MS diagnosis, disability, disability progression and clinical forms of MS. MATERIALS AND SUBJECTS: The study included 147 patients with relapsing-remitting MS (RRMS), 21 with progressive clinical forms (ProgMS) and 70 controls. Expanded Disability Status Scale (EDSS) evaluated disability as mild (EDSS < 3.0) or moderate/high (EDSS ≥ 3.0). Multiple Sclerosis Severity Score (MSSS) evaluated disability progression as no progression (MSSS < 5) and progression (MSSS ≥ 5). Baseline data of subjects and plasma levels of TNF-α, sTNFR1, sTNFR2 were obtained. RESULTS: The MS diagnosis explained 44.6% and 12.3% of TNF-α and sTNFR2 levels, respectively. Moderate/high disability and disability progression were best predicted by sTNFR1 and age (positively) and ProgMS were best predicted by sTNFR1 (positively) and sTNFR2 (negatively), coupled with age and sex. A composite score reflecting the sTNFR1/sTNFR2 ratio showed a positive association with ProgMS after adjusting for age and sex. CONCLUSION: Increased sTNFR1 and age were positively associated with disability and disability progression, whereas increased sTNFR1 (positively) and sTNFR2 (negatively) were associated with ProgMS, suggesting a distinct role of them in the immunopathological mechanisms of MS.
Assuntos
Esclerose Múltipla/imunologia , Receptores Tipo II do Fator de Necrose Tumoral/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: The aim of this study was to evaluate the association between rs3761548 FOXP3 (-3279 C > A) variant and multiple sclerosis (MS), disability, disability progression, as well as transforming growth factor (TGF)-ß1 and interleukin (IL)-10 plasma levels in MS patients. METHODS AND SUBJECTS: The study included 170 MS patients and 182 controls. Disability was evaluated using Expanded Disability Status Scale (EDSS) and categorized as mild (EDSS ≤ 3) and moderate/high (EDSS > 3). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS). The rs3761548 variant was determined with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Plasma levels of TGF-ß1 and IL-10 were determined using immunofluorimetric assay. RESULTS: CA and AA genotypes were associated with MS [odds ratio (OR) 2.03, 95% confidence interval (CI) 1.66-3.53, p = 0.012; OR 8.19, 95% CI 3.04-22.07, p < 0.001, respectively). With the dominant model, the CA + AA genotypes were associated with MS (OR 2.57, 95% CI 1.50-4.37, p < 0.001). In the recessive model, the AA genotype was also associated with MS (OR 5.38, 95% CI 2.12-13.64, p < 0.001). After adjustment by age, ethnicity, BMI and smoking, all these results remained significant, as well as female patients carrying the CA + AA genotypes showed higher TGF-ß1 than those carrying the CC genotype (OR 1.35, 95% CI 1.001-1.054, p = 0.043). No association was observed between the genotypes and disability, disability progression and IL-10 levels. CONCLUSION: These results suggest that the A allele of FOXP3 -3279 C > A variant may exert a role in the T regulatory cell function, which could be one of the factors involved in the susceptibility for MS in females.
Assuntos
Fatores de Transcrição Forkhead/genética , Esclerose Múltipla/sangue , Esclerose Múltipla/genética , Fator de Crescimento Transformador beta1/sangue , Adulto , Brasil , Feminino , Variação Genética , Genótipo , Humanos , Interleucina-10/sangue , Masculino , Pessoa de Meia-Idade , Caracteres SexuaisRESUMO
The aim of this study was to evaluate the immune-inflammatory, metabolic, and nitro-oxidative stress (IM&NO) biomarkers as predictors of disability in multiple sclerosis (MS) patients. A total of 122 patients with MS were included; their disability was evaluated using the Expanded Disability Status Scale (EDSS) and IM&NO biomarkers were evaluated in peripheral blood samples. Patients with EDSS ≥3 were older and showed higher homocysteine, uric acid, advanced oxidized protein products (AOPP) and low-density lipoprotein (LDL)-cholesterol and higher rate of metabolic syndrome (MetS), while high-density lipoprotein (HDL)-cholesterol was lower than in patients with EDSS <3; 84.6% of all patients were correctly classified in these EDSS subgroups. We found that 36.3% of the variance in EDSS score was explained by age, Th17/T regulatory (Treg) and LDL/HDL ratios and homocysteine (all positively related) and body mass index (BMI) (inversely related). After adjusting for MS treatment modalities, the effects of the LDL/HDL and zTh17/Treg ratios, homocysteine and age on disability remained, whilst BMI was no longer significant. Moreover, carbonyl proteins were associated with increased disability. In conclusion, the results showed that an inflammatory Th17 profile coupled with age and increased carbonyl proteins were the most important variables associated with high disability followed at a distance by homocysteine, MetS and LDL/HDL ratio. These data underscore that IM&NO pathways play a key role in increased disability in MS patient and may be possible new targets for the treatment of these patients. Moreover, a panel of these laboratory biomarkers may be used to predict the disability in MS.
Assuntos
Inflamação/metabolismo , Aprendizado de Máquina , Esclerose Múltipla/metabolismo , Estresse Nitrosativo/fisiologia , Estresse Oxidativo/fisiologia , Adulto , Fatores Etários , Biomarcadores/sangue , Índice de Massa Corporal , HDL-Colesterol/sangue , Avaliação da Deficiência , Feminino , Homocisteína/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico , Ácido Úrico/sangueRESUMO
The aims of this study were to verify whether hyperhomocysteinemia is associated with disability progression in Multiple Sclerosis (MS) patients and whether TNF pathways and cellular adhesion molecules (CAM) are involved in this process. This study included 180 MS patients, who were divided according to their levels of homocysteine (Hyperhomocysteinemia ≥11.35 µmol/L) and 204 healthy individuals (control group). MS patients showed higher levels of homocysteine (p < 0.001), tumor necrosis factor alpha (TNF-α, p < 0.001), TNF receptor 1 (TNFR1, p = 0.038), TNF receptor 2 (TNFR2, p < 0.001), and lower levels of PECAM (p = 0.001), ICAM (p < 0.001) and VCAM (p = 0.005) than controls. The multivariate binary logistic regression analysis showed that plasma levels of homocysteine, TNFR1, TNFR2 and PECAM were associated with the presence of disease. MS patients with hyperhomocysteinemia showed higher disease progression evaluated by the Multiple Sclerosis Severity Score (MSSS, p < 0.001), disability evaluated by Expanded Disability Status Score EDSS (p < 0.001), TNFR1 (p = 0.039) and ICAM (p = 0.034) than MS patients with lower levels of homocysteine. Hyperhomocysteinemia was independently associated with MSSS in MS patients, but were not associated with TNF-α, TNFR, and CAM. Homocysteine levels was higher in progressive forms than relapsing-remitting MS (p < 0.001), independently of sex and age. In conclusion, this is the first study in which homocysteinemia was associated with progression of the disease (MSSS), although this finding was not directly related to TNF-α and TNFR pathways or to CAM.
Assuntos
Homocisteína/sangue , Hiper-Homocisteinemia/complicações , Esclerose Múltipla/sangue , Adulto , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Esclerose Múltipla/diagnóstico , Molécula-1 de Adesão Celular Endotelial a Plaquetas/sangue , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVE: The aim of this study was to report the frequency of autoimmune disorders and autoantibodies in 22 patients with neuromyelitis optica (NMO), as well as whether the seropositivity for autoantibodies differs between anti-aquaporin 4 (AQP4) positive and AQP4 negative NMO patients. METHODS: Demographic, medical records, and a profile of autoantibodies were evaluated in 22 NMO patients, including AQP4, anti-thyroid-stimulating hormone receptor, antinuclear antibodies (ANA), anti-thyroperoxidase (anti-TPO), anti-thyroglobulin (anti-Tg), anti-double-stranded DNA, anti-neutrophil cytoplasmic, anti-cyclic citrullinate peptide, rheumatoid factor, anti-SSA/Ro, anti-SSB/La, anti-Smith antibodies (anti-Sm), anti-ribonucleoprotein, anti-nucleosome, and anti-Scl70. Thyroid-stimulating hormone and free thyroxin were measured. RESULTS: The frequency of women was higher than men (95.5% vs. 4.5%) and 68.2% were Afro-Brazilians. Six (27.3%) patients presented other autoimmune disorders, such as Hashimoto thyroiditis (n=2), Graves' disease (n=1), juvenile idiopathic arthritis (n=1), systemic lupus erythematosus and systemic sclerosis (n=1), and Raynaud's phenomenon (n=1). The most frequent autoantibodies were anti-AQP4 (54.5%), anti-nucleosome (31.8%), ANA (27.3%), anti-TPO (22.7%), and anti-Tg (22.7%). Difference was not observed in the frequency of autoimmune disorders when the patients were compared according to their anti-AQP4 status. CONCLUSION: The results of the present study underscored that the NMO patients present high frequency of autoantibodies against cellular antigens and the presence of autoimmune disorders. Further studies with large number of NMO patients may contribute to advances in the understanding of NMO disease mechanisms.
Assuntos
Artrite Juvenil/imunologia , Autoanticorpos/imunologia , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Neuromielite Óptica/imunologia , Escleroderma Sistêmico/imunologia , Tireoidite Autoimune/imunologia , Adulto , Aquaporina 4/imunologia , Artrite Juvenil/complicações , Artrite Juvenil/epidemiologia , Artrite Juvenil/patologia , Autoantígenos , Doenças Autoimunes/patologia , Brasil/epidemiologia , Feminino , Humanos , Iodeto Peroxidase , Proteínas de Ligação ao Ferro , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/complicações , Neuromielite Óptica/epidemiologia , Neuromielite Óptica/patologia , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/patologia , Tireoidite Autoimune/complicações , Tireoidite Autoimune/epidemiologia , Tireoidite Autoimune/patologiaRESUMO
Polymorphisms in genes coding for pro-inflammatory molecules represent important factors for the pathogenesis and outcome of stroke. The aim of this study was to evaluate the relationship between the tumor necrosis factor beta (TNF-ß) NcoI (rs909253) polymorphism with inflammatory and metabolic markers in acute ischemic stroke. Ninety-three patients and 134 controls were included. The TNF-ß polymorphism was determined using PCR-RFLP with NcoI restriction enzyme. Stroke subtypes and neurological deficit score were evaluated. White blood cell counts, erythrocyte sedimentation rate (ESR), plasma levels of IL-6 and TNF-α, serum high sensitivity C-reactive Protein (hsCRP), serum lipid profile, plasma levels of glucose and insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) were determined. Stroke patients presented higher white blood cell counts, hsCRP, ESR, glucose, insulin, and HOMA-IR, and lower HDL cholesterol than controls (p < 0.01). There was no difference in genotypic and allelic frequency of TNF-ß NcoI polymorphism among patients and controls (p > 0.05). However, stroke patients carrying the TNFB2/B2 genotype presented higher levels of TNF-α, white blood cell counts, total cholesterol, LDL cholesterol, glucose, insulin, and HOMA-IR than those with other genotypes (p < 0.05). White blood cells, IL-6, hsCRP, and ESR were positively correlated with the neurological deficit of the patients (p < 0.05). Taken together, TNF-ß NcoI polymorphism, by itself, was not associated with increased susceptibility for stroke development. However, the homozygous genotype for the allele TNFB2 was associated with higher expression of classical inflammatory and metabolic markers of development and outcome of stroke than other genotypes. The identification of variant alleles might allow both better prediction of susceptibility for stroke as well the identification of novel stroke mechanisms that could be target to new therapeutic approaches. Stroke patients carrying the TNFB2 variant allele could have a beneficial effect with the anti-inflammatory therapies in the early inflammatory phase of stroke.
Assuntos
Isquemia Encefálica/genética , Linfotoxina-alfa/genética , Polimorfismo de Fragmento de Restrição , Adulto , Idoso , Alelos , Biomarcadores , Glicemia/análise , Sedimentação Sanguínea , Isquemia Encefálica/sangue , Proteína C-Reativa/análise , Desoxirribonucleases de Sítio Específico do Tipo II , Feminino , Genótipo , Humanos , Inflamação , Resistência à Insulina , Interleucina-6/sangue , Contagem de Leucócitos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/análiseRESUMO
The aim of this study was to evaluate the association between inflammatory and metabolic markers and short-time outcome with acute ischemic stroke subtypes. A total of 121 patients was classified according to TOAST criteria, such as large artery atherosclerosis (LAAS), lacunar infarct (LAC), cardioembolic infarct (CEI), other determined etiology (ODE), and undetermined etiology (UDE). The functional impairment was evaluated within the first eight hours of stroke and the outcome after three-month follow-up using the modified Rankin Scale. Blood samples were obtained up to 24 h of stroke. Compared with 96 controls, patients with LAAS, CEI, and LAC subtypes showed higher levels of white blood cells, high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), metalloproteinase 9 (MMP-9), glucose, and iron (p < 0.05); and lower high-density lipoprotein cholesterol (HDL-C) (p < 0.0001); platelets, insulin, insulin resistance, and homocysteine were higher in LAC (p < 0.0001); ferritin was higher in LAAS (p < 0.0001); and total cholesterol (TC) was lower in LAAS and CEI (p < 0.01). When stroke subtypes were compared, insulin was higher in LAAS vs. LAC and in LAC vs. CEI (p < 0.05); and TC was lower in LAAS vs. LAC (p < 0.05). Outcome and rate of mortality after three-month were higher in LAAS vs. LAC (p < 0.001 and p = 0.0391 respectively). The results underscored the important role of the inflammatory response and metabolic changes in the pathogenesis of ischemic stroke subtypes that might be considered on the initial evaluation of stroke patients to identify those that could benefit with individualized therapeutic strategies that taken into account these markers after acute ischemic event.
Assuntos
Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Inflamação/metabolismo , Inflamação/patologia , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , Adulto , Idoso , Antropometria , Biomarcadores , Isquemia Encefálica/classificação , Brasil , Proteína C-Reativa/análise , Estudos de Casos e Controles , Infarto Cerebral/patologia , Feminino , Humanos , Interleucina-6/sangue , Masculino , Metaloproteinase 9 da Matriz/sangue , Pessoa de Meia-Idade , Fatores Socioeconômicos , Acidente Vascular Cerebral/classificação , Resultado do Tratamento , Adulto JovemRESUMO
Multiple sclerosis (MS) is a chronic, neurological, immune-mediated disease that can worsen in the postpartum period. There is no consensus on the use of immunoglobulin for prevention of disease relapses after delivery. We have shown that the controversial beneficial effect of immunoglobulin given immediately after birth could not be observed in patients with MS.
Assuntos
Imunoglobulinas Intravenosas/uso terapêutico , Mães , Esclerose Múltipla Recidivante-Remitente/prevenção & controle , Esclerose Múltipla/tratamento farmacológico , Período Pós-Parto/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imunoglobulinas Intravenosas/farmacologia , Esclerose Múltipla/complicações , Esclerose Múltipla/fisiopatologia , Gravidez , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/imunologia , Resultado da Gravidez , Transtornos Puerperais/prevenção & controle , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: To describe the clinical features and disease outcomes of coronavirus disease 2019 (COVID-19) in patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: The Neuroimmunology Brazilian Study Group has set up the report of severe acute respiratory syndrome (SARS-CoV2) cases in patients with NMOSD (pwNMOSD) using a designed web-based case report form. All neuroimmunology outpatient centers and individual neurologists were invited to register their patients across the country. Data collected between March 19 and July 25, 2020, were uploaded at the REDONE.br platform. Inclusion criteria were as follows: (1) NMOSD diagnosis according to the 2015 International Panel Criteria and (2) confirmed SARS-CoV2 infection (reverse transcription-polymerase chain reaction or serology) or clinical suspicion of COVID-19, diagnosed according to Center for Disease Control / Council of State and Territorial Epidemiologists (CDC/CSTE) case definition. Demographic and NMOSD-related clinical data, comorbidities, disease-modifying therapy (DMT), COVID-19 clinical features, and severity were described. RESULTS: Among the 2,061 pwNMOSD followed up by Brazilian neurologists involved on the registry of COVID-19 in pwNMOSD at the REDONE.br platform, 34 patients (29 women) aged 37 years (range 8-77), with disease onset at 31 years (range 4-69) and disease duration of 6 years (range 0.2-20.5), developed COVID-19 (18 confirmed and 16 probable cases). Most patients exhibited mild disease, being treated at home (77%); 4 patients required admission at intensive care units (severe cases); and 1 patient died. Five of 34 (15%) presented neurologic manifestations (relapse or pseudoexacerbation) during or after SARS-CoV2 infection. DISCUSSION: Most NMOSD patients with COVID-19 presented mild disease forms. However, pwNMOSD had much higher odds of hospitalization and intensive care unit admission comparing with the general Brazilian population. The frequency of death was not clearly different. NMOSD disability, DMT type, and comorbidities were not associated with COVID-19 outcome. SARS-CoV2 infection was demonstrated as a risk factor for NMOSD relapses. Collaborative studies using shared NMOSD data are needed to suitably define factors related to COVID-19 severity and neurologic manifestations.
Assuntos
COVID-19/fisiopatologia , Hospitalização/estatística & dados numéricos , Neuromielite Óptica/fisiopatologia , Adolescente , Adulto , Idoso , Brasil/epidemiologia , COVID-19/epidemiologia , COVID-19/terapia , Criança , Progressão da Doença , Feminino , Humanos , Imunossupressores/uso terapêutico , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/epidemiologia , Recidiva , SARS-CoV-2 , Índice de Gravidade de Doença , Adulto JovemRESUMO
The Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology (DCNI/ABN) and Brazilian Committee for Treatment and Research in Multiple Sclerosis and Neuroimmunological Diseases (BCTRIMS) provide recommendations in this document for vaccination of the population with demyelinating diseases of the central nervous system (CNS) against infections in general and against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes COVID-19. We emphasize the seriousness of the current situation in view of the spread of COVID-19 in our country. Therefore, reference guides on vaccination for clinicians, patients, and public health authorities are particularly important to prevent some infectious diseases. The DCNI/ABN and BCTRIMS recommend that patients with CNS demyelinating diseases (e.g., MS and NMOSD) be continually monitored for updates to their vaccination schedule, especially at the beginning or before a change in treatment with a disease modifying drug (DMD). It is also important to note that vaccines are safe, and physicians should encourage their use in all patients. Clearly, special care should be taken when live attenuated viruses are involved. Finally, it is important for physicians to verify which DMD the patient is receiving and when the last dose was taken, as each drug may affect the induction of immune response differently.
Assuntos
COVID-19 , Esclerose Múltipla , Neurologia , Sistema Nervoso Central , Humanos , Esclerose Múltipla/tratamento farmacológico , SARS-CoV-2 , VacinaçãoRESUMO
Until recently, neuromyelitis optica (NMO) was considered to be a sub-type of multiple sclerosis (MS), which has a strong predilection for Caucasian populations, whereas NMO is more frequent in non-Caucasian individuals. The objective of this study was to compare the HLA-DRB profile in Brazilian Mulatto patients with NMO spectrum disorders (NMOSDs) with that observed for Mulatto MS patients and healthy Mulatto controls. Twenty seven NMOSD patients (20 women), all seropositive for NMO-IgG, 29 MS patients and 28 Mulatto healthy blood donors were evaluated for HLA-DRB allele groups. HLA-DRB1*03 allele group was overrepresented in NMO patients compared with healthy controls (p = 0.0401; OR = 3.23, 95%CI: 1.07-9.82). In contrast, the HLA-DRB1*15 allele group was overrepresented in Brazilian MS patients (OR = 15.89, 95%CI: 3.51-71.85; p < 0.0001). DRB3 was overrepresented in NMO (p = 0.0064), and DRB5 overrepresented in MS patients (p = 0.0001). The low frequency of HLA-DRB1*15 alleles was associated with the presence of long and central cord lesions at magnetic resonance. In addition, DRB1*15 alleles were associated with the fulfillment of the Barkhof criteria. In conclusion, these results indicate that the DRB profile of NMO patients is different from that observed for MS patients, further corroborating the distinction between NMO and MS.
Assuntos
Antígenos HLA-DR/genética , Esclerose Múltipla/genética , Neuromielite Óptica/genética , Adulto , Idade de Início , Idoso , Alelos , Doadores de Sangue , Brasil/epidemiologia , Feminino , Frequência do Gene , Ligação Genética/genética , Teste de Histocompatibilidade , Humanos , Imunoglobulina G/imunologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Neuromielite Óptica/epidemiologiaRESUMO
The objective of this study was to evaluate the role of immune-inflammatory, metabolic, hormonal, and oxidative stress biomarkers in disability progression (DP) and clinical forms of multiple sclerosis (MS). The study evaluated 140 MS patients at admission (T0), and eight (T8) and 16 months (T16) later. The Expanded Disability Status Score (EDSS) and biomarkers were determined at T0, T8, and T16. A DP index (DPI) defined as an increase of ≥1 rank on the EDSS score indicated that 39.3% of the patients had significant DP. Quantification of the ordinal EDSS rank score was performed using optimal scaling methods. Categorical regression showed that the quantitative T16 EDSS score was predicted by T0 homocysteine (Hcy), T0 parathormone (PTH), T0 advanced oxidized protein products (AOPP) (all positively), low T0 vitamin D (<18.3 ng/mL) and T8 folic acid (<5 ng/mL) concentrations while higher T8 calcium concentrations (≥8.90 mg/dL) had protective effects. Linear Mixed Models showed that the change in EDSS from T0 to T16 was significantly associated with changes in IL-17 (positively) and IL-4 (inversely) independently from the significant effects of clinical MS forms, treatment modalities, smoking, age and systemic arterial hypertension. Hcy, PTH, IL-6, and IL-4 were positively associated with progressive versus relapsing-remitting MS while 25(OH)D was inversely associated. In conclusion, the ordinal EDSS scale is an adequate instrument to assess DP after category value estestimation. Aberrations in immune-inflammatory, metabolic and hormonal biomarkers are associated with DP and with the progressive form of MS.
Assuntos
Pessoas com Deficiência , Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Biomarcadores , Avaliação da Deficiência , Progressão da Doença , Seguimentos , Humanos , Esclerose Múltipla/diagnósticoRESUMO
An association between prolactinemia with disability, clinical forms, and sex of patients with multiple sclerosis (MS) remains unclear. The aim of this study was to evaluate the association of prolactin with clinical forms and accumulating disability over time in patients with MS. A longitudinal study was carried out with 101 patients with relapsing-remitting MS (RRMS) and 19 with progressive forms of MS (ProgMS). The disability over time, as well as prolactin and ferritin serum levels were evaluated at baseline (T0), 8-month follow-up (T8), and 16-month follow-up. The disability at T0, T8, and T16 was higher among patients with ProgMS than those with RRMS. Prolactin and ferritin levels did not differ over time between both groups. Initially, prolactin was associated with MS disability. After introducing age and sex, the effects of prolactin on disability were no longer significant. Prolactin was associated with age and sex, whereby age was positively associated with disability. In the same way, after introducing age and sex, the effects of diagnosis on prolactin levels, as well as the association between prolactin and ferritin, were no longer significant (P = 0.563 and P = 0.599, respectively). Moreover, 21.6% of the variance in the disability was predicted by age (P < 0.001), and sex (P = 0.049), while prolactin was not significant. In conclusion, the effects of prolactin on the disability and clinical forms of MS patients may be spurious results because those correlations reflect the positive associations of age with the disability and the negative association of age with prolactin.
Assuntos
Hiperprolactinemia/sangue , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Prolactina/sangue , Adulto , Fatores Etários , Idoso , Biomarcadores , Avaliação da Deficiência , Progressão da Doença , Feminino , Ferritinas/sangue , Seguimentos , Humanos , Hiperprolactinemia/etiologia , Hiperprolactinemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/complicações , Esclerose Múltipla Crônica Progressiva/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/complicações , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Estudos Prospectivos , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
An imbalance of inflammatory/anti-inflammatory and oxidant/antioxidant molecules has been implicated in the demyelination and axonal damage in multiple sclerosis (MS). The current study aimed to evaluate the plasma levels of tumor necrosis factor (TNF)-α, soluble TNF receptor (sTNFR)1, sTNFR2, adiponectin, hydroperoxides, advanced oxidation protein products (AOPP), nitric oxide metabolites, total plasma antioxidant capacity using the total radical-trapping antioxidant parameter (TRAP), sulfhydryl (SH) groups, as well as serum levels of zinc in 174 MS patients and 182 controls. The results show that MS is characterized by lowered levels of zinc, adiponectin, TRAP, and SH groups and increased levels of AOPP. MS was best predicted by a combination of lowered levels of zinc, adiponectin, TRAP, and SH groups yielding an area under the receiver operating characteristic (AUC/ROC) curve of 0.986 (±0.005). The combination of these four antioxidants with sTNFR2 showed an AUC/ROC of 0.997 and TRAP, adiponectin, and zinc are the most important biomarkers for MS diagnosis followed at a distance by sTNFR2. Support vector machine with tenfold validation performed on the four antioxidants showed a training accuracy of 92.9% and a validation accuracy of 90.6%. The results indicate that lowered levels of those four antioxidants are associated with MS and that these antioxidants are more important biomarkers of MS than TNF-α signaling and nitro-oxidative biomarkers. Adiponectin, TRAP, SH groups, zinc, and sTNFR2 play a role in the pathophysiology of MS, and a combination of these biomarkers is useful for predicting MS with high sensitivity, specificity, and accuracy. Drugs that increase the antioxidant capacity may offer novel therapeutic opportunities for MS.
Assuntos
Biomarcadores/sangue , Inflamação/sangue , Esclerose Múltipla/sangue , Redes Neurais de Computação , Máquina de Vetores de Suporte , Adiponectina/sangue , Adulto , Produtos da Oxidação Avançada de Proteínas/sangue , Antioxidantes/análise , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/tratamento farmacológico , Óxido Nítrico/sangue , Estresse Nitrosativo , Oxirredução , Estresse Oxidativo , Receptores do Fator de Necrose Tumoral/sangue , Sensibilidade e Especificidade , Compostos de Sulfidrila/sangue , Fator de Necrose Tumoral alfa/sangueAssuntos
Declaração de Nascimento , Clima , Esclerose Múltipla/epidemiologia , Feminino , Humanos , MasculinoRESUMO
The CCR5 chemokine receptor has been implicated in the pathogenesis of multiple sclerosis (MS). This research was carried out to investigate the association between the CCR5-Delta32 deletion in 124 patients with MS from Southern Brazil. Ninety-eight (79.0%) patients presented with relapsing-remitting MS (RR-MS), 17 (13.7%) secondary progressive MS (SP-MS), 8 (6.5%) primary progressive MS (PP-MS) and one (0.8%) clinically isolated syndrome (CIS). The control group consisted of 127 healthy blood donors from the same geographic region. The disease severity was assessed clinically using the Expanded Disability Status Scale (EDSS). Genomic DNA was extracted from peripheral blood cells and the genetic polymorphism was evaluated by polymerase chain reaction. Of the MS patients, 85 (68.5%) were females (p=0.0093). The CCR5-Delta32 frequency among the controls was 5.5%, and did not differ from that observed among the MS patients (4.8%) (p=0.7337). The mean (+/-SD) age at disease onset among the carriers and non-carriers of the CCR5-Delta32 allele was 31.7 (+/-11.1) and 36.6 (+/-12.0) years, respectively (p=0.1312). The duration (+/-SD) of the disease was 11.2 (+/-12.9) and 7.7 (+/- 5.6) years among the CCR5-Delta32 heterozygous, and CCR5 wild type, respectively (p=0.396). The mean (+/-SD) EDSS among the MS patients carriers and non-carriers of the CCR5-Delta32 allele was 2.4+/-1.2 and 2.67+/-2.2, respectively (p=0.9796). The MRI findings in MS patients with the CCR5-Delta32 genotype exhibited lower positive gadolinium enhancing-imaging (p=0.0013) and lower brain atrophy (p=0.1333) than MS patients with the CCR5 wild-type genotype. Despite that the differences were not significant, the results suggested that the disease onset and progression to disability may be prolonged in MS carriers of CCR5-Delta32, and CCR5-Delta32 could be considered a favorable prognostic biomarker of MS. Further studies comprising larger numbers of individuals carrying non-wild-type haplotypes are needed to determine CCR5-Delta32 involvement in the specific process of MS pathology and pathogenesis.
Assuntos
Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Polimorfismo Genético , Receptores CCR5/genética , Deleção de Sequência , Adolescente , Adulto , Idade de Início , Idoso , Sequência de Bases , Brasil , Estudos de Casos e Controles , Primers do DNA/genética , Feminino , Frequência do Gene , Marcadores Genéticos , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , PrognósticoRESUMO
The aim of the present study was to evaluate inflammatory, oxidative, and nitrosative stress (IO&NS) blood markers as possible predictors of multiple sclerosis (MS) and its clinical forms. This study included 258 MS patients (175 with relapsing-remitting MS (RRMS) and 83 with progressive MS clinical forms) and 249 healthy individuals. Peripheral blood samples were obtained to determine serum levels of albumin, ferritin, C-reactive protein (CRP), total protein, lipid hydroperoxide by tert-butyl hydroperoxide-initiated chemiluminescence (CL-LOOH), carbonyl protein content, advanced oxidation protein products (AOPP), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). MS patients showed higher ferritin (p < 0.001) and CL-LOOH (p < 0.001) and lower albumin (p = 0.001), TRAP (p < 0.001), AOPP (p = 0.013), and NOx values (p < 0.001) than controls. Difference was not observed in CRP, total protein, and carbonyl proteins between patients and controls. In the logistic regression age-adjusted, ferritin and CL-LOOH showed positive association with MS and were predictors of MS development (OR: 1.006, 95 % CI: 1.003-1.009, p < 0.001 and OR: 1.029, 95 % CI: 1.007-1.052, p = 0.009, respectively). Albumin, TRAP, AOPP, and NOx were negatively associated with MS (p = 0.019, p = 0.003, p = 0.001, and p = 0.003, respectively). Moreover, other logistic regression age-adjusted showed that MS patients with progressive clinical forms had lower albumin and higher AOPP than those with RRMS (p = 0.037). In conclusion, ferritin, albumin, and biomarkers of IO&NS, such as CL-LOOH, AOPP, TRAP, and NOx were predictors of MS diagnosis, whereas albumin and AOPP were predictors that differentiated RRMS from the progressive clinical forms of MS.
Assuntos
Albuminas/metabolismo , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Adulto , Biomarcadores/sangue , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Humanos , Inflamação/sangue , Inflamação/patologia , Modelos Logísticos , Masculino , Esclerose Múltipla Crônica Progressiva/sangue , Esclerose Múltipla Recidivante-Remitente/sangue , Nitrosação , Oxirredução , Estresse OxidativoRESUMO
The aim of this study was to evaluate the TNFß NcoI polymorphism (rs909253) and immune-inflammatory, oxidative, and nitrosative stress (IO&NS) biomarkers as predictors of disease progression in multiple sclerosis (MS). We included 212 MS patients (150 female, 62 male, mean (±standard deviation (SD)) age = 42.7 ± 13.8 years) and 249 healthy controls (177 female, 72 male, 36.8 ± 11 years). The disability was measured the Expanded Disability Status Scale (EDSS) in 2006 and 2011. We determined the TNFß NcoI polymorphism and serum levels of interleukin (IL)-6, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, IL-10, and IL-17, albumin, ferritin, and plasma levels of lipid hydroperoxides (CL-LOOH), carbonyl protein, advanced oxidation protein products (AOPPs), nitric oxide metabolites (NOx), and total radical-trapping antioxidant parameter (TRAP). The mean EDSS (±SD) in 2006 was 1.62 ± 2.01 and in 2011 3.16 ± 2.29, and disease duration was 7.34 ± 7.0 years. IL-10, TNF-α, IFN-γ, AOPP, and NOx levels were significantly higher and IL-4 lower in MS patients with a higher 2011 EDSS scores (≥3) as compared with those with EDSS < 3. The actual increases in EDSS from 2006 to 2011 were positively associated with TNF-α and IFN-γ. Increased IFN-γ values were associated with higher pyramidal symptoms and increased IL-6 with sensitive symptoms. Increased carbonyl protein and IL-10 but lowered albumin levels predicted cerebellar symptoms. The TNFB1/B2 genotype decreased risk towards progression of pyramidal symptoms. Treatments with IFN-ß and glatiramer acetate significantly reduced TNF-α but did not affect the other IO&NS biomarkers or disease progression. Taken together, IO&NS biomarkers and NcoI TNFß genotypes predict high disability in MS and are associated with different aspects of disease progression. New drugs to treat MS should also target oxidative stress pathways.
Assuntos
Pessoas com Deficiência , Marcadores Genéticos/fisiologia , Mediadores da Inflamação/sangue , Esclerose Múltipla/sangue , Esclerose Múltipla/genética , Estresse Oxidativo/fisiologia , Adulto , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Valor Preditivo dos Testes , Estudos RetrospectivosRESUMO
Inflammation is the driving force for brain injury in patients with multiple sclerosis (MS). The objective of the present study is to delineate the serum cytokine profile in patients with progressive MS in a Southern Brazilian population compared with healthy controls and patients with relapsing-remitting MS (RRMS) and its associations with disease progression and disability. We included 32 patients with progressive MS, 126 with RRMS, and 40 healthy controls. The patients were evaluated using the Expanded Disability Status Scale (EDSS) and magnetic resonance imaging (MRI) with gadolinium. Serum interleukin (IL)-1ß, IL-6, IL-12, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-10, IL-4, and IL-17 levels were assessed using an enzyme-linked immunosorbent assay. IL-1ß, IL-6, TNF-α, IFN-γ, IL-17, IL-4, and IL-10 levels were higher in progressive MS than in controls. Increased IL-1ß and IFN-γ and decreased IL-12 and IL-4 levels were found in progressive MS compared with RRMS. Patients with progressive MS with disease progression presented higher TNF-α, IFN-γ, and IL-10 levels than those without disease progression. Patients with progressive MS with disease progression showed a higher frequency of positive gadolinium-enhanced lesions in MRI; higher TNF-α, IFN-γ, and IL-17 levels; and decreased IL-12 levels compared with RRMS patients with progression. There was a significant inverse correlation between IL-10 levels and EDSS score in patients with progressive MS. The results underscore the complex cytokine network imbalance exhibited by progressive MS patients and show the important involvement of TNF-α, IFN-γ, and IL-17 in the pathophysiology and progression of the disease. Moreover, serum IL-10 levels were inversely associated with disability in patients with progressive MS.