Natalizumab improves ambulation in relapsing-remitting multiple sclerosis: results from the prospective TIMER study and a retrospective analysis of AFFIRM.

BACKGROUND AND PURPOSE: Impaired ambulation is a prominent disabling symptom of multiple sclerosis and can lead to reduced quality of life. Whether natalizumab, a monoclonal antibody shown to reduce disease activity in relapsing-remitting multiple sclerosis, could impact ambulation performance was examined. METHODS: A prospective open-label study, TIMER, was conducted in natalizumab-naive patients (n = 215). The timed 25-foot walk (T25FW) and timed 100-m walk (T100MW) were assessed at baseline and at weeks 24 and 48 of natalizumab therapy, together with Expanded Disability Status Scale scores. The effects of natalizumab on T25FW performance were also examined in a retrospective analysis of natalizumab-treated patients (n = 627) and placebo control patients (n = 315) from the AFFIRM study. RESULTS: In TIMER, a significant increase from baseline in T25FW speed was seen at week 24 (P = 0.0074) and in T100MW speed at weeks 24 and 48 (both P < 0.001). A greater proportion of patients showed clinically meaningful increases (≥20%) in walking speed on the T100MW (25%) than on the T25FW (13%) at week 48 (P = 0.032). In AFFIRM, natalizumab increased the proportion of patients with ≥20% confirmed improvement in T25FW speed at year 2 by 78% versus placebo (P = 0.0133). CONCLUSIONS: Natalizumab increased walking speed in patients with relapsing-remitting multiple sclerosis. The T100MW may be more sensitive to changes in ambulation capacity than the T25FW, and both tests appear to detect clinically meaningful improvements in ambulatory function.

Neutrophil-released enzymes can influence composition of circulating immune complexes in multiple sclerosis.

During NET formation, the content of neutrophils granules is released into the intercellular milieu. Consisting of many proteases and ROS species, formed NETs were shown to degrade cytokines (Schauer, Nat Med, 2014); while the content of neutrophil's azurophilic granules proved to contain glycosidases, secreted upon activation (Thaysen-Andersen, JBC, 2015), and formation of autoantibodies to neutrophil beta-glucoronidase was connected with the level of anti-MPO antibodies (Ab) (Martensson, Autoimmunity, 1992). Taking into account these facts, we aimed to investigate the possibility of NET-related changes in glycan composition on circulating IgG molecules and IgG-IgM immune complexes in multiple sclerosis (MS). This autoimmune disorder still has no reliable detection markers or established ways of treatment, besides widely accepted interferon therapy, making it a particularly interesting clinical condition. By applying capture lectin-ELISA, we analysed binding of α2,6 sialyl-specific lectins SNA, PSqL, and core α1,6-fucose specific lectin AAL to circulating IgG and related complexes in five groups of MS patients: untreated (17 persons); undergoing therapy with interferon (IFN) ß-1 b (15 persons), corticosteroids (methylprednisolone) (12 persons) and anti-B-cell monoclonal Ab (12 persons: Ocrelizumab, 6 persons and alemtuzumab, 6 persons). A group of 23 healthy donors served as control. Significant increase in neutrophil elastase activity, observed in the group of patients under corticosteroid treatment was also accompanied by sialyl-specific PSqL and SNA lectin binding to captured IgG molecules. Subsequent analysis demonstrated that sialic acid residues were exposed on free IgG and on circulating IgG-IgM immune complexes. Increased lectin binding was not observed for anti-myelin basic protein (one of the major autoAb in MS) Ab compared to total serum Ab. IFN therapy was accompanied by low neutrophil elastase activity and low amount of circulating immune complexes. Incubation of in vitro generated NETs with human serum revealed the digestion of high-molecular weight immune complexes with subsequent exposure of hidden glycoepitops. Obtained data indicate the potential of neutrophil-derived proteases to modify (partially degrade) circulating immune complexes leading to exposure of internal glycoepitops.

[The determination of sialic acids in the lymphocytes of multiple sclerosis patients]. / Vyznachennia sialovykh kyslot u limfotsytakh khvorykh na rozsiianyi skleroz.

Overall, twenty patients with multiple sclerosis of varying degree severity, its clinical course being dissimilar among patients, were studied for lymphocyte concentration of sialic acids. It has been ascertained that multiple sclerosis provokes augmentation of lymphocyte content of sialic acids, with greater increase being noted in patients with 1 to 3 and 6 to 9 scores on the Kurtzke's scale and in women as well.

[Diagnostic significance of isoenzymes and isoforms of alkaline phosphatase in blood serum of patients with multiple sclerosis on the clinical form of the illness]. / Diagnostychne znachennia vyznachennia aktyvnosti izofermentiv ta izoform luzhnoï fosfatazy u syrovatsi krovi khvorykh na rozsiianyi skleroz zalezhno vid klinichnoï formy.

In multiple sclerosis there takes place a gradual destruction of most organs and tissues of the sick organism. With progression of the illness changes are noticeable in their functional development. A biochemical mode of assessment of functioning of organs and tissues is analysis of alkaline phosphatase, which is performed with high dilution. Activity of alkaline phosphatase was measured together with its isoenzymes and isoforms in blood serum of 101 patient with disseminated sclerosis depending on the clinical form of the illness. Measurement of blood serum alkaline phosphatase isoenzymes and isoforms can be a marker of the demyelinating process in multiple sclerosis.

[Diagnostic and prognostic ability of the peripheral mononuclear lymphocyte to produce nitric oxide in multiple sclerosis]. / Diahnostychna ta prohnostychna rol' zdatnosti monoiadernykh limfotsytiv peryferiinoï krovi produkuvaty oksyd azotu pry rozsiianomu sklerozi.

The article presents data on the chief mechanisms of human cell apoptosis, on the role of nitric oxide (NO) in modulation of the above mechanisms in cells of normal tissues and organs and in multiple sclerosis (MS) as well. Aspects are analyzed of NO action in the processes of apoptosis in MS. Corticosteroid pulse therapy is recognized as a powerful inducer of T-lymphocyte apoptosis in the condition under consideration.