Long-Term Effects of Alemtuzumab on CD4+ Lymphocytes in Multiple Sclerosis Patients: A 72-Month Follow-Up.

Introduction: Alemtuzumab is highly effective in the treatment of patients with relapsing multiple sclerosis (PwRMS) and selectively targets the CD52 antigen, with a consequent profound lymphopenia, particularly of CD4+ T lymphocytes. However, the immunological basis of its long-term efficacy has not been clearly elucidated.

Methods: We followed up 29 alemtuzumab-treated RMS patients over a period of 72 months and studied the immunological reconstitution of their CD4+ T cell subsets by means of phenotypic and functional analysis and through mRNA-related molecule expression, comparing them to healthy subject (HS) values (rate 2:1).

Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses.

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab.

Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months.

Objective: To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS).

Methods: Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24.

Alemtuzumab-related thyroid dysfunction in a phase 2 trial of patients with relapsing-remitting multiple sclerosis.

Context: Alemtuzumab, an anti-CD52 monoclonal antibody, increased the risk of thyroid dysfunction in CAMMS223, a phase 2 trial in relapsing-remitting multiple sclerosis.

Objective: The objective of the study was a detailed description of thyroid dysfunction in CAMMS223.

Design: Relapsing-remitting multiple sclerosis patients (n=334) were randomized 1:1:1 to 44 μg sc interferon-β-1a (SC IFNB-1a, Rebif) or annual courses of 12 or 24 mg iv alemtuzumab.

"Compensated hyperosmolarity" of cerebrospinal fluid and the development of hydrocephalus.

Acute osmolar loading of cerebrospinal fluid within one lateral ventricle of dogs was examined as a cause of water extraction from the bloodstream and an increase in intracranial pressure. We have shown that a certain amount of (3)H₂O from the bloodstream enters osmotically loaded cerebrospinal fluid significantly faster, hence causing a significant increase in intracranial pressure. The noted phenomenon in which intracranial pressure still significantly increases, but in which the hyperosmolarity of the cerebrospinal fluid is no longer present, was named "compensated hyperosmolarity".

Recommendations for diagnosis and management of multiple sclerosis.

Multiple sclerosis (MS) is a chronic demyelinating neurologic disorder that mainly affects young individuals (aged 20 to 50 years). Approximately 85% of patients experience an initial course with relapses and remissions (relapsing-remitting multiple sclerosis). Guidelines for the management of MS should be focused on three main areas: (a) the diagnosis of MS; (b) treatment of relapses; and (c) long-term preventive treatment including clinical follow up, dose adjustment, drug switch, control of therapeutic efficacy, and disease progression.

Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial.

Objective: To report the long-term safety and efficacy results from CAMMS223 comparing alemtuzumab with interferon β-1a in early, active relapsing-remitting multiple sclerosis (RRMS). What are the long-term effects of alemtuzumab treatment, received 36 to 48 months previously, on relapse and disability in early, active RRMS? This study provides evidence of the effectiveness of alemtuzumab in reducing the relapse rate and accumulation of disability compared with interferon β-1a (IFNβ-1a) through extended follow-up (up to 60 months from baseline).

Methods: Of 334 patients originally randomized, 198 participated in the extension phase (151 [68%] alemtuzumab and 47 [42%] IFNβ-1a).

Arylsulfatase a gene polymorphisms in relapsing remitting multiple sclerosis: genotype-phenotype correlation and estimation of disease progression.

Arylsulfatase A (ASA) is a lysosomal enzyme involved in catabolism of cerebroside-sulfate, major lipid constituent of oligodendrocyte membranes. Various polymorphisms in ASA gene have been described, leading to different levels of enzyme deficiency. Progressive demyelination occurs in metachromatic leukodystrophy (MLD), while the condition of ASA-pseudodeficiency (ASA-PD) is suggested to contribute to complex pathogenesis of multiple sclerosis (MS).

Alemtuzumab versus interferon β-1a in early relapsing-remitting multiple sclerosis: post-hoc and subset analyses of clinical efficacy outcomes.

Background: Alemtuzumab is a humanised monoclonal antibody that depletes lymphocytes, causing long-term immunomodulation. In a 3-year, rater-blinded phase 2 study (the CAMMS223 study) in patients with relapsing-remitting multiple sclerosis (RRMS), alemtuzumab reduced relapse rate and the risk of sustained accumulation of disability compared with subcutaneous interferon beta-1a, and the mean expanded disability status scale (EDSS) score of the alemtuzumab cohort improved compared with baseline. Adverse events included infusion-associated reactions, predominantly mild to moderate infections, thyroid disorders, and immune thrombocytopenia.

Dynamics of distribution of 3H-inulin between the cerebrospinal fluid compartments.

Since the distribution of substances between various cerebrospinal fluid (CSF) compartments is poorly understood, we studied (3)H-inulin distribution, over time, after its injection into cisterna magna (CM) or lateral ventricle (LV) or cisterna corporis callosi (CCC) in dogs. After the injection into CM (3)H-inulin was well distributed to cisterna basalis (CB), lumbar (LSS) and cortical (CSS) subarachnoid spaces and less distributed to LV. When injected in LV (3)H-inulin was well distributed to all CSF compartments.

Monoamine oxidases A and B gene polymorphisms in migraine patients.

Abnormal cortical activity and brainstem functioning are considered the possible etiopathogenetic factors of migraine. Monoamine oxidase A and B (MAO-A and -B) regulate the levels of monoamine neurotransmitters, so changes in their activity could participate in migraine pathogenesis. We have investigated the possible association of MAO-A and -B alleles and haplotypes with two common types of migraine, i.

Platelet serotonin measures in migraine.

Objective And Background: Serotonergic mechanisms play an important role in the pathogenesis of headache. To search for potential indicators of altered serotonin homeostasis in migraine, we have investigated three parameters of the platelet serotonin (5HT) system, platelet serotonin level (PSL), platelet serotonin uptake (PSU), and monoamine oxidase (MAO-B) activity, in a group of 55 patients with migraine and in 81 healthy controls.

Methods: After platelet separation, PSL was determined fluorimetrically; PSU was measured by incubating aliquots of platelet-rich plasma with six concentrations of 14C-5-HT for 60 seconds at 37 degrees C, followed by vacuum filtration; platelet MAO-B activity (toward kynuramine as a substrate) was determined fluorimetrically.

Cerebrospinal fluid and serum protein levels of tumour necrosis factor-alpha (TNF-alpha) interleukin-6 (IL-6) and soluble interleukin-6 receptor (sIL-6R gp80) in multiple sclerosis patients.

The aim of this study was to evaluate soluble proteins of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-6 receptor subunit gp80 (sIL-6R gp80), as markers of multiple sclerosis (MS). Paired cerebrospinal fluid (CSF) and serum samples of 20 MS patients and 15 controls suffering from non-inflammatory neurological diseases have been assayed retrospectively using monoclonal antibodies-based ELISAs. While TNF-alpha could not be detected in CSF, it was measurable in 20% of total sera.

Homeostatic role of the active transport in elimination of [3H]benzylpenicillin out of the cerebrospinal fluid system.

Cerebral acidic metabolites and penicillin are organic anions which can be carried by active transport into capillaries of the central nervous system (CNS). However, it is generally believed that these metabolites are mainly delivered from CNS to cerebrospinal fluid (CSF) and eliminated by CSF circulation over cortex and its absorption into dural venous sinuses. To test this hypothesis we studied fate of penicillin ([3H]benzylpenicillin) in the CSF under control conditions and when its active transport was blocked by probenecid.

Effect of active transport on distribution and concentration gradients of [3H]benzylpenicillin in the cerebrospinal fluid.

After application of [3H]benzylpenicillin ([3H]BP) in lateral brain ventricle in dogs, the distribution of [3H]BP to contralateral ventricle and cisterna magna was much higher when its active transport from cerebrospinal fluid (CSF) was blocked by probenecid than under control conditions. Analysis of [3H]BP concentrations in both lateral ventricles and cisterna magna over time indicates that active transport restricts distribution of substances along CSF spaces and contributes to the maintenance of their concentration gradients between CSF compartments. This suggests that biochemical changes in a part of the brain and the adjacent CSF compartment may not be reflected into remote compartments of CSF such as lumbar CSF if substances in question are removed from CSF by active transport.