Neuromyelitis optica is an HLA associated disease different from Multiple Sclerosis: a systematic review with meta-analysis.

Neuromyelitis Optica and Multiple Sclerosis are idiopathic inflammatory demyelinating diseases of the central nervous system that currently are considered distinct autoimmune diseases, so differences in genetic susceptibility would be expected. This study aimed to investigate the HLA association with Neuromyelitis Optica by a systematic review with meta-analysis. The STROBE instrument guided research paper assessments. Thirteen papers published between 2009 and 2020 were eligible. 568 Neuromyelitis Optica patients, 41.4% Asians, 32.4% Latin Americans and 26.2% Europeans were analyzed. Only alleles of the DRB1 locus were genotyped in all studies. Neuromyelitis Optica patients have 2.46 more chances of having the DRB1*03 allelic group than controls. Ethnicity can influence genetic susceptibility. The main HLA association with Neuromyelitis Optica was the DRB1*03:01 allele in Western populations and with the DPB1*05:01 allele in Asia. Differences in the Multiple Sclerosis and Neuromyelitis Optica genetic susceptibility was confirmed in Afro descendants. The DRB1*03 allelic group associated with Neuromyelitis Optica has also been described in other systemic autoimmune diseases.

Lower frequency of antibodies to MOG in Brazilian patients with demyelinating diseases: An ethnicity influence?

OBJECTIVE: Antibodies against Myelin Oligodendrocyte glycoprotein (MOG-Ab) have been investigated as potential biological marker for neuromyelitis optica (NMO) and high-risk syndromes (HR) negative for AQP4-Ab in populations with different ethnic background. We tested AQP4 and MOG antibodies in a Brazilian population with high African ethnic background. METHOD: The study population was composed of adult patients from Rio de Janeiro with inflammatory demyelinating diseases (new and old cases). Blood samples were sent blindly to test the AQP4 and MOG antibodies by CBA. The frequency of positive MOG-Ab was estimated in the NMOHR and the NMO spectrum disorders (NMOSD). A systematic review with meta-analysis assessed the frequency of MOG-Ab in Caucasians and non-Caucasians. RESULTS: 200 adult patients (52% Afro-Brazilian) 115 of them with NMOHR were tested. MOG antibodies were found in 5/68 negative cases of AQP4-Ab negative (7%). The criteria for NMOSD were fulfilled by 70 patients with NMOHR and none of them was positive for MOG-Ab. A low prevalence of MOG antibodies and a predominant phenotype of bilateral Optic Neuritis were found in most non-Caucasian patients. CONCLUSION: The low frequency of MOG Ab in patients from Rio de Janeiro and in other non-Caucasian populations suggests a racial/ancestral influence.

Fatigue favors in vitro Th1 and Th17-like cell expansion and reduces corticoid sensitivity in MS patients.

Fatigue is a common "ghost" symptom in patients with multiple sclerosis (MS), an autoimmune disease mediated by T cells that target myelin antigens of the central nervous system. As fatigue has been associated with inflammatory states, its occurrence may negatively impact MS progression. The aim of this study was to evaluate the impact of fatigue on the cytokine profile of patients with relapsing-remitting (RR) MS. For our study, blood were collected from MS patients in clinical remission phase with (n=15) and without (n=15) fatigue. Cytokines were detected by ELISA in the plasma and supernatant collected from anti-CD3/anti-CD28-activated T cells or LPS-stimulated monocytes. In some wells, different doses of hydrocortisone (HC) were added at the beginning of the culture. Here, peripheral levels of IL-6 and TNF-α, as well as in vitro production of cytokines related to Th17 (IL-6, IL-17, IL-22, and GM-CSF) or Th1 (IFN-γ) phenotypes, were elevated in fatigued patients and their levels were associated with fatigue severity. The same phenomenon was observed between the production of IL-6, TNF-α, IL-1ß, and IL-23 by monocytes and fatigue. Moreover, HC was less efficient in inhibiting in vitro inflammatory cytokine production in patients with fatigue, mainly those produced by both CD8+ T cells and monocytes. Our data, although preliminary, suggests that the occurrence of fatigue, by favoring the in vitro production of Th1/Th17-related cytokines and corticoid resistance, may negatively impact the course of MS.

Combined exercise training reduces fatigue and modulates the cytokine profile of T-cells from multiple sclerosis patients in response to neuromediators.

Fatigue is a common and disabling symptom of multiple sclerosis (MS), a classical Th1- and Th17-mediated autoimmune disease. There is no effective pharmacological treatment for fatigue, but some reports point towards beneficial effects of physical activity on management of the fatigue in MS patients. As both MS and fatigue have been associated with dysregulated cytokine network production, the objective of the present study was to evaluate the impact of a physical activity program consisting of a 12-week series of combining Pilates and aerobic exercises on fatigue severity, determined by FSS, and cytokine production, quantified by ELISA, by T cells from MS patients (n=08) with low disability (EDSS≤2). The results showed decrease in FSSs in all patients at the end of physical activity intervention. Regarding the cytokines, a significant reduction of IL-22 release was observed in polyclonally-activated T cells form MS patients post-training follow-up. Interestingly, while the physical activity attenuated the ability of dopamine in up-regulating Th17-related cytokines, it enhanced the anti-inflammatory effects of serotonin, evidenced by high IL-10 production. In summary, all results suggest that programmed physical activity has beneficial effects on management of fatigue in MS patients, and it could be related, at least in part, to its ability in regulating neuroimmune parameters into T cell compartment.

Does fatigue occur in MS patients without disability?

BACKGROUND: Motor dysfunction and fatigue are the most common impairments that are associated with multiple sclerosis (MS). Walk tests and scales demonstrate the presence of fatigue in patients with MS with different levels of disability. OBJECTIVE: To evaluate objective and subjective fatigue in MS patients without disability. METHODS: Were selected MS patients with relapsing remitting clinical course, from 18 to 55 years old and EDSS 0 to 1.5; controls were paired for age, gender, body mass index, and physical activity level. Fatigue caused by pulmonary diseases, anemia, diabetes, thyroid disease, psychiatry diseases (except depression), and orthopedic and rheumatologic diseases are excluded. All participants performed the 6-minute walk test (6MWT), the MS Functional Composite (MSFC), and completed the Modified Fatigue Impact Scale (MFIS) and the Beck Depression Inventory. A multivariate model was applied to identify the variables associated with fatigue. RESULTS: 54 individuals were selected (31 patients; 23 controls). In the MSFC and 6MWT, no significant difference was observed between the groups. A MFIS total score indicated fatigue in 35% of the patients, 42% in the physical domain, 25.8% in the cognitive domain, and 29% in the psychosocial domain, which differed from the controls in all comparisons. Fatigue was associated with MS, low-physical activity, and mood disorders. CONCLUSIONS: Fatigue occurs in patients with MS in the absence of motor dysfunction and is associated with the disease itself, the sedentary lifestyle, and mood disorders. The 6MWT is not useful to demonstrate motor fatigue in subjects without neurological disability.

Is it useful to perform carbon monoxide diffusion capacity and respiratory muscle function tests in patients with multiple sclerosis without disability?

BACKGROUND AND OBJECTIVE: Impairment of respiratory function has been described in end-stage multiple sclerosis (MS), as well as in patients with mild to severe disability. No data are available regarding the respiratory function of MS patients without disability. The objective of this study was to assess the pulmonary function, respiratory muscle strength and carbon monoxide diffusion capacity of the lungs (DL(CO)) in patients with relapsing-remitting multiple sclerosis (RRMS) without disability. METHODS: Twenty-seven RRMS patients and 25 healthy control subjects were recruited. All subjects underwent clinical and neurological examination, and spirometry; lung volumes, DL(CO) and maximal respiratory pressures were measured. All subjects were rated on the Modified Fatigue Impact Scale and Fatigue Severity Scale scales. RESULTS: There were no significant differences in age, gender, height, weight or body mass index between the groups. The mean duration of illness in the MS group was 5.44 ± 3.74 years, and the mean Expanded Disability Status Scale was 0.62 ± 0.65. The mean values for total lung capacity, forced expiratory volume in 1 s (FEV(1)) and FEV(1) /FVC were normal in both groups. Fifteen RRMS patients exhibited a reduction in maximal expiratory pressure (MEP), but only one patient exhibited a reduction in maximal inspiratory pressure. The mean values for DL(CO) were lower in RRMS patients (P = 0.0004) than in the control group. DL(CO) was decreased in 15 (55.55%), out of 27 RRMS patients. The fatigue scale results were not correlated with pulmonary function test results CONCLUSIONS: DL(CO) and MEP may be impaired in RRMS patients without disability.

Principais testes utilizados na avaliação de fadiga na esclerose múltipla: revisão sistemática / Main tools for fatigue assessment in multiple sclerosis: systematic review

Estudos recentes demonstram a alta prevalência da fadiga na esclerose múltipla (EM) e seu grande impacto sobre a qualidade de vida. No entanto, ainda não há consenso sobre as diferentes dimensões da fadiga na EM. É apresentada neste trabalho uma revisão sistemática da literatura de estudos publicados entre 1988 e 2010 utilizando uma combinação das palavras-chaves: multiple sclerosis, fatigue e scales com o objetivo de descrever os instrumentos utilizados para avaliar fadiga em pacientes com EM e discutir sua aplicabilidade. Foram selecionados 12 estudos que descreveram tanto escalas subjetivas quanto instrumentos para análise objetiva. Entre as escalas subjetivas, os auto- questionários que analisam o sintoma de forma unidimensional (escala de severidade de fadiga) ou multidimensional, incluindo itens sobre seu impacto nos domínios psíquico, físico, e psicossocial (escala modificada de impacto da fadiga), foram as mais amplamente difundidas. Os instrumentos de testagem objetiva foram desenvolvidos mais recentemente e demonstraram que a fadiga motora e mental ocorre com maior freqüência em pacientes com EM do que em controles e não se correlaciona com depressão, incapacidade ou tempo de doença.

Recent studies show a high prevalence of fatigue on multiple sclerosis (MS) and its enormous impact on daily life. Thus, there is no agreement on the multiple dimensions of MS fatigue. On this work, we present a systematic review of published literature between 1988 and 2010, using keywords combination: multiple sclerosis, fatigue and scales, in order to describe the tools to analyze fatigue on MS patients and discuss its applicability. Twelve studies were selected that described subjective scales, as well as tools for objective analysis. Among subjective scales, auto-questionnaires which analyze the symptom in a one-dimensional manner (fatigue severity scale) or multi-dimensional (modified fatigue impact scale), including items about the impact on psychic, physical and psycho-social domains were the most widely used. Objective testing instruments were developed more recently and showed that motor and mental fatigue occur more frequently on patients with MS thanon controls and are not related to depression, incapacity or length of illness