Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm(R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Multiple sclerosis: modulation of apoptosis susceptibility by glatiramer acetate.

OBJECTIVES: We investigated whether therapy of multiple sclerosis (MS) with glatiramer acetate (GA) involves the modulation of programmed cell death (apoptosis) in disease-relevant T-helper lymphocytes. MATERIAL AND METHODS: Blood was drawn from 15 relapsing-remitting MS patients both before (baseline) as well as 6, 12, and 18 weeks after GA therapy and from 15 healthy controls. Detection of apoptosis was performed in response to in vitro stimulation with GA, myelin basic protein or medium alone. RESULTS: T-helper lymphocytes from untreated MS patients displayed an overall increased apoptosis susceptibility in vitro, compared to controls. During subsequent GA therapy, apoptosis vulnerability of these T cells in MS patients significantly declined under the initial baseline before treatment, and was finally equal in treated patients and controls. GA itself had no direct apoptosis-modulatory properties in vitro. CONCLUSION: Our findings indicate that therapy of multiple sclerosis with glatiramer acetate presumably involves the compensation of altered apoptosis in T-helper lymphocytes.

Therapeutic immunoadsorption increases the level of circulating soluble HLA molecules.

BACKGROUND AND OBJECTIVES: Immunoadsorption (IA) is an established procedure to remove Igs and immune complexes from peripheral blood. Since Igs reportedly bind to human leucocyte antigen (HLA) molecules, we were interested to know whether removal of Ig will also influence the plasma concentration of soluble HLA (sHLA). PATIENTS AND METHODS: Nine patients suffering from severe autoimmune disease and undergoing 17 single courses of IA treatment were monitored for their sHLA class I (sHLA-I) and sHLA-DR plasma levels. Plasma was separated by a hollow-fiber-type separator. Plasma samples were taken before therapy, after 15 min of recirculation (without operating the adsorber), after 1 and 2 liters of plasma adsorption, and 24 and 48 h after the end of IA. RESULTS: Before treatment the mean levels of sHLA-I and sHLA-DR were 0.37 (+/-0.06 SEM) and 0. 32+/-0.05 microg/ml, respectively. After 2 liters of plasma filtration, an increase in sHLA-DR (0.80+/-0.10 microg/ml) was observed (p<0.001), whereas sHLA-I was only slightly affected (mean: 0.45+/-0.06 microg/ml). sHLA concentrations returned to initial levels after 24 h. CONCLUSION: The significant increase in sHLA-DR may contribute to the immunomodulatory effect of IA.

Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway.

We have previously reported that the serine protease plasmin generated during contact activation of human plasma triggers biosynthesis of leukotrienes (LTs) in human peripheral monocytes (PMs), but not in polymorphonuclear neutrophils (PMNs). We now show that purified plasmin acts as a potent chemoattractant on human monocytes, but not on PMNs. Human plasmin or plasminogen activated with urokinase, but not active site-blocked plasmin or plasminogen, elicited monocyte migration across polycarbonate membranes. Similarly, stimulation of monocytes with plasmin, but not with active site-blocked plasmin or plasminogen, induced actin polymerization. As assessed by checkerboard analysis, the plasmin-mediated monocyte locomotion was a true chemotaxis. The plasmin-induced chemotactic response was inhibited by the lysine analog trans-4-(aminomethyl)cyclohexane-1-carboxylic acid (t-AMCA), which prevents binding of plasmin/ogen to the appropriate membrane binding sites. In addition, active site-blocked plasmin inhibited monocyte migration triggered by active plasmin. Further, plasmin-induced monocyte chemotaxis was inhibited by pertussis toxin (PTX) and 1-O-hexadecyl-2-O-methyl-rac-glycerol (HMG) and chelerythrine, two structurally unrelated inhibitors of protein kinase C (PKC). Plasmin, but not active site-blocked plasmin or plasminogen, triggered formation of cyclic guanosine monophosphate (cGMP) in monocytes. LY83583, an inhibitor of soluble guanylyl cyclase, inhibited both plasmin-induced cGMP formation and the chemotactic response. The latter effect could be antagonized by 8-bromo-cGMP. In addition, KT5823 and (Rp)-8-(p-chlorophenylthio)guanosine-3',5'-cyclic monophosphorothioate [(Rp)-8-pCPT-cGMPs], two structurally unrelated inhibitors of cGMP-dependent protein kinase, inhibited plasmin-mediated monocyte chemotaxis. Thus, beyond being a stimulus for lipid mediator release, plasmin is a potent and specific chemoattractant for human monocytes acting via a cGMP-dependent mechanism. Therefore, plasmin represents a proinflammatory activator for human monocytes.

[Mechanisms of action of intravenous immunoglobulins]. / Wirkmechanismen intravenöser Immunglobuline.

Intravenous immunoglobulins (IVIG) are now used to treat various diseases, including autoimmune diseases, systemic inflammatory diseases, allografts and for replacement therapy in the case of IgG deficiency. Only in some of the indications has the efficacy of this treatment been confirmed in large-scale studies. Also, in many cases the modes of action remain unclear. Principally, the following therapeutic strategies can be differentiated: Replacement treatment, blocking of the effector molecules, influencing of the cellular and humoral limbs of the immune defence system and interaction with cytokines. In certain CNS diseases, displacement of pathological immunoglobulins may be involved. It would be desirable to acquire more detailed knowledge about modes of action with the aim of using IVIG with greater specificity in the future.