Intestinal Permeability and Circulating CD161+CCR6+CD8+T Cells in Patients With Relapsing-Remitting Multiple Sclerosis Treated With Dimethylfumarate.

Background: The changes of the gut-brain axis have been recently recognized as important components in multiple sclerosis (MS) pathogenesis. Objectives: To evaluate the effects of DMF on intestinal barrier permeability and mucosal immune responses. Methods: We investigated intestinal permeability (IP) and circulating CD161+CCR6+CD8+T cells in 25 patients with MS, who met eligibility criteria for dimethyl-fumarate (DMF) treatment. These data, together with clinical/MRI parameters, were studied at three time-points: baseline (before therapy), after one (T1) and 9 months (T2) of treatment. Results: At baseline 16 patients (64%) showed altered IP, while 14 cases (56%) showed active MRI. During DMF therapy we found the expected decrease of disease activity at MRI compared to T0 (6/25 at T1, p = 0.035 and 3/25 at T2, p < 0.00), and a reduction in the percentage of CD161+CCR6+CD8+ T cells (16/23 at T2; p < 0.001). The effects of DMF on gut barrier alterations was variable, without a clear longitudinal pattern, while we found significant relationships between IP changes and drop of MRI activity (p = 0.04) and circulating CD161+CCr6+CD8+ T cells (p = 0.023). Conclusions: The gut barrier is frequently altered in MS, and the CD161+ CCR6+CD8+ T cell-subset shows dynamics which correlate with disease course and therapy.

Considering patient clinical history impacts performance of machine learning models in predicting course of multiple sclerosis.

Multiple Sclerosis (MS) progresses at an unpredictable rate, but predictions on the disease course in each patient would be extremely useful to tailor therapy to the individual needs. We explore different machine learning (ML) approaches to predict whether a patient will shift from the initial Relapsing-Remitting (RR) to the Secondary Progressive (SP) form of the disease, using only "real world" data available in clinical routine. The clinical records of 1624 outpatients (207 in the SP phase) attending the MS service of Sant'Andrea hospital, Rome, Italy, were used. Predictions at 180, 360 or 720 days from the last visit were obtained considering either the data of the last available visit (Visit-Oriented setting), comparing four classical ML methods (Random Forest, Support Vector Machine, K-Nearest Neighbours and AdaBoost) or the whole clinical history of each patient (History-Oriented setting), using a Recurrent Neural Network model, specifically designed for historical data. Missing values were handled by removing either all clinical records presenting at least one missing parameter (Feature-saving approach) or the 3 clinical parameters which contained missing values (Record-saving approach). The performances of the classifiers were rated using common indicators, such as Recall (or Sensitivity) and Precision (or Positive predictive value). In the visit-oriented setting, the Record-saving approach yielded Recall values from 70% to 100%, but low Precision (5% to 10%), which however increased to 50% when considering only predictions for which the model returned a probability above a given "confidence threshold". For the History-oriented setting, both indicators increased as prediction time lengthened, reaching values of 67% (Recall) and 42% (Precision) at 720 days. We show how "real world" data can be effectively used to forecast the evolution of MS, leading to high Recall values and propose innovative approaches to improve Precision towards clinically useful values.

Autoimmune Encephalitis and CSF Anti-GluR3 Antibodies in an MS Patient after Alemtuzumab Treatment.

A 45-year-old Italian woman, affected by relapsing-remitting multiple sclerosis (RR-MS) starting from 2011, started treatment with alemtuzumab in July 2016. Nine months after the second infusion, she had an immune thrombocytopenic purpura (ITP) with complete recovery after steroid treatment. Three months after the ITP, the patient presented with transient aphasia, cognitive deficits, and focal epilepsy. Serial brain magnetic resonance imaging showed a pattern compatible with encephalitis. Autoantibodies to glutamate receptor 3 peptide A and B were detected in cerebrospinal fluid and serum, in the absence of any other diagnostic cues. After three courses of intravenous immunoglobulin (0.4 mg/kg/day for 5 days, 1 month apart), followed by boosters (0.4 mg/kg/day) every 4-6 weeks, her neurological status improved and is currently comparable with that preceding the encephalitis. Autoimmune complications of the central nervous system during alemtuzumab therapy are relatively rare: only one previous case of autoimmune encephalitis following alemtuzumab treatment has been reported to date.

The Contribution of Gut Barrier Changes to Multiple Sclerosis Pathophysiology.

The gut barrier consists of several components, including the mucus layer, made of mucins and anti-bacterial molecule, the epithelial cells, connected by tight junction proteins, and a mixed population of cells involved in the interplay with microbes, such as M cells, elongations of "antigen presenting cells" dwelling the lamina propria, intraepithelial lymphocytes and Paneth cells secreting anti-bacterial peptides. Recently, the influence of intestinal permeability (IP) changes on organs far from gut has been investigated, and IP changes in multiple sclerosis (MS) have been described. A related topic is the microbiota dysfunction that underpins the development of neuroinflammation in animal models and human diseases, including MS. It becomes now of interest to better understand the mechanisms through which IP changes contribute to pathophysiology of neuroinflammation. The following aspects seem of relevance: studies on other biomarkers of IP alterations; the relationship with known risk factors for MS development, such as vitamin D deficiency; the link between blood brain barrier and gut barrier breakdown; the effects of IP increase on microbial translocation and microglial activation; the parallel patterns of IP and neuroimmune changes in MS and neuropsychiatric disorders, that afflict a sizable proportion of patients with MS. We will also discuss the therapeutic implications of IP changes, considering the impact of MS-modifying therapies on gut barrier, as well as potential approaches to enhance or protect IP homeostasis.

[Quality of life and burden of disease in peripheral arterial disease: a study among Hungarian patients]. / Magyarországi perifériás veroérbetegek életminoség és betegségteher vizsgálatának eredményei.

INTRODUCTION: Peripheral arterial disease may occur in about of 14% of patients with high blood pressure, of which 1-3% suffer from chronic critical limb ischemia. Literature data on the quality of life according to the Fontaine stages are very limited. AIM: The aim of this study was to assess the quality of life of Hungarian patients with peripheral arterial disease regarding Fontaine stages II, III and IV. METHODS: The study was based on a cross-sectional survey, which was carried out in four angiologic centres. One hundred and two respondents with peripheral arterial disease (43% woman) were evaluated. The average age of the patients was 70 years (SD-10). RESULTS: Based on the EQ-5D index, the results of the quality of life assessment with respect to Fontaine stages II, III and IV were 0.66, 0.35 and 0.18, respectively. In each stage the EQ-5D values were lower than the values of the age-matched average population. The results of the Pain Visual Analogue Scale (0-100 mm) were 38, 65 and 71 mm in Fontaine stages II, III and IV, respectively, and this showed a strong correlation with the EQ-5D (R = -0.68). In stage Fontaine IV the quality of life of the patients was significantly lower among those who had pain at rest and ALSO ulcer on the leg. CONCLUSIONS: Peripheral disease with clinical symptoms causes significant reduction in quality of life which can be measured with EQ-5D. It becomes worse as we move along the Fontaine stages. While measuring the health gain in stage Fontaine IV, the health gain from the reduction of pain in rest and partial recovery from ulcer should be taken into account.

[Effectiveness of prostanoids in patients with critical leg ischemia]. / Prosztanoidok hatásossága kritikus végtagischaemiában.

UNLABELLED: Prostanoids (alprostadil and iloprost) are used for the treatment of patients with critical limb ischemia in whom revascularization procedure is inadequate or proved to be unsuccessful. According to a Cochrane analysis (CD006544) prostanoids differ in their effects on rest-pain relief and ulcer healing. OBJECTIVES: To study the efficacy and safety of prostanoids for critical limb ischemia. METHODS: Systematic literature search and meta-analysis (mixed treatment comparison) was performed. RESULTS: Seven randomized controlled trials including 964 patients were analyzed. Compared to placebo, both alprostadil (OR: 3.2 95% CI: 1.7-5.5 and OR: 1.8 95% CI: 0.6-4.3) and iloprost (OR: 2.7 95% CI: 1.7-4.2 and OR: 2.5 95% CI: 1.0-5.4) were more efficacious with regard to rest-pain relief and ulcer healing and the difference between the two prostanoids was not significant (OR: 1.2 95% CI: 0.7-1.9 and OR: 0.74 95% CI: 0.3-1.5). Adverse events occurred significantly more often with both drugs compared to placebo, however, they were less frequent with alprostadil than with iloprost (OR 0.2 95% CI: 0.1-0.3). CONCLUSIONS: Prostanoids have favorable effect on rest-pain relief and ulcer healing in critical limb ischemia, without statistically significant difference between the two available drugs. The Cochrane study (CD006544) reported mistaken results due to defaults in the analysis.

[Risk status of patients with peripheral arterial disease (PAD)]. / Alsó végtagi obliteratív verôérbetegek rizikóstátusa.

The authors have analyzed clinical and laboratory risk factors of 168 patients with PAD and 82 control persons. Among the patients the prevalences of diabetes, coronary heart disease (CHD), and cerebrovascular disease (CVD) were 30.4%, 39.9%, and 6.5%, respectively. 7.1% of the patients had CHD and CVD. Among patients with PAD and control persons, the prevalences of hypertension and current smoking were 76.2% vs 46.3% and 49.4% vs 28%. HDL-cholesterol and ApoA1 levels were significantly lower, while the triglycerides, fibrinogen, hsCRP, homocysteine, creatinine, uric acid levels, and white blood cell count as well as plasma viscosity were significantly higher in the patient group compared with the values of control persons. Among the PAD patients the diabetics and the smokers had further unfavourable significant differencies in the laboratory findings compared with the data of non-diabetics and non-smokers. Correlations were detected between the hsCRP level and the white blood cell count, the plasma viscosity and the fibrinogen level, respectively. Examining 16 selected risk factors the average risk factor count of the patients was 7.79. 118 patients had lipid-lowering, and 142 patients had antithrombotic therapy. Our results emphasize the necessity of the secondary prevention among PAD patients.

[Arterial obliterative disease and physical activity]. / Arteriosclerosis obliterans és fizikai tréning.

Regular physical exercise represents an essential element in treating patients with second-stage peripheral arterial occlusive disease. Peripheral arterial occlusive disease is a characteristic clinical manifestation of atherothrombotic processes. Its prevalence is 2-3%, consequently, it is estimated to be 200,000-300,000 patients in Hungary. Coronary artery disease and atherothrombosis of the carotid artery system may frequently coexist with peripheral arterial obliterative disease. Treatment of peripheral arterial obliterative disease influences their prevalence and prognosis as well. The main aim of regular physical exercise is to improve the quality of life of patients by increasing the functional capacity of the lower limbs. During exercise beneficial vascular changes occur like haemodynamic changes consisting of increasing pressure-gradient of stenotic artery and opening of collateral vessels, as well as improvement of the endothelial dysfunction. It favourably influences lipid profile by decreasing LDL cholesterol and increasing HDL cholesterol. Physical exercise beneficially affects blood rheology as well. It also brings about structural changes in the skeletal muscles, increases the enzyme levels in the oxidative metabolic processes and enhances the density of capillaries in the skeletal muscle fibres. According to the data published so far, patients with peripheral arterial obliterative disease are recommended to take part in supervised treadmill walking at least 3 days per week for 30-60 minutes each session containing 5-5 minute warm-up and cool-down periods. The training should be of intermittent intensity at the pain-free threshold. The physiological benefits are optimised at 3-6 months. The home-based training programme is also remarkably useful.

[Secondary prevention and conservative therapy of obliterative arteriosclerosis]. / Az arteriosclerosis obliterans szekunder prevenciója és belgyógyászati kezelése.

The author gives an overview of the main ways of medical therapy for patients with peripheral arterial obliterative disease. The importance of possible modification of the risk factors is emphasized especially beneficial effects of supervised walking-based exercise program. It is considered proven that the antiplatelet therapy and antilipidemic treatment reduce the risk of progressive atherosclerotic processes. The author summarizes the mechanisms and clinical effects of drugs influencing haemostation and haemorheology as well as vasodynamic agents. The results of clinical trials show a marked improvement of intermittent claudication by combination of preventive and therapeutic ways in majority of patients with peripheral arterial obliterative disease.