Ariel Miller

Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring.

Natalizumab, a highly specific α4-integrin antagonist, is approved for treatment of patients with active relapsing-remitting multiple sclerosis (RRMS). It is generally recommended for individuals who have not responded to a currently available first-line disease-modifying therapy or who have very active disease. The expected benefits of natalizumab treatment have to be weighed against risks, especially the rare but serious adverse event of progressive multifocal leukoencephalopathy. In this Review, we revisit and update previous recommendations on natalizumab for treatment of patients with RRMS, based on additional long-term follow-up of clinical studies and post-marketing observations, including appropriate patient selection and management recommendations.

Oral CD3-specific antibody suppresses autoimmune encephalomyelitis by inducing CD4+ CD25- LAP+ T cells.

A major goal of immunotherapy for autoimmune diseases and transplantation is induction of regulatory T cells that mediate immunologic tolerance. The mucosal immune system is unique, as tolerance is preferentially induced after exposure to antigen, and induction of regulatory T cells is a primary mechanism of oral tolerance. Parenteral administration of CD3-specific monoclonal antibody is an approved therapy for transplantation in humans and is effective in autoimmune diabetes. We found that orally administered CD3-specific antibody is biologically active in the gut and suppresses autoimmune encephalomyelitis both before induction of disease and at the height of disease. Orally administered CD3-specific antibody induces CD4+CD25−LAP+ regulatory T cells that contain latency-associated peptide (LAP) on their surface and that function in vitro and in vivo through a TGF-β–dependent mechanism. These findings identify a new immunologic approach that is widely applicable for the treatment of human autoimmune conditions.

Health-related quality of life in multiple sclerosis: The impact of disability, gender and employment status.

Objectives: (1) Evaluate the impact of the patient charateristics of disability, gender and employment status on health-related quality of life (HRQOL) in multiple sclerosis (MS) and (2) Characterize the functional relationship between HRQOL and disability overall, and by gender and employment status. Methods: We assessed the HRQOL of 215 MS outpatients in our clinic using the MSQOL-54 and Fatigue Severity Scale (FSS), and that of 172 healthy controls, using the SF-36 (a subset of MSQOL-54). We compared QOL between MS subgroups defined by disability, gender and employment, and computed the linear and non-linear relationships between disability level measured by the Expanded Disability Status Scale (EDSS) and MSQOL-54 dimensions. Results: QOL of MS patients measured by SF-36 is lower than controls, varying by QOL dimension with the greatest difference emerging for physical aspects of the disease. The relationship of physical disability, measured by EDSS, and all 14 MSQOL-54 dimensions and FSS is negative; for 12 of the 14 dimensions and FSS it is also non-linear. Non-linearity is most pronounced among women, who show a weak EDSS/QOL relatioship at higher levels of physical disability, suggesting women better able to “psychologically buffer” the debilitating aspects of MS. While employed have higher QOL than unemployed, the former are more affected by physical disability. Conclusions: Multiple attributes, including disability, gender and employment status, affect QOL. QOL’s relationship with disability is complex, displaying non-linearity and interacting with patient characteristics. This has implication for QOL research methodology and provides insight into factors affecting patients’ perceptions of well-being.

Regulation of Endothelial Matrix Metalloproteinase-2 by Hypoxia/Reoxygenation

Among the consequences resulting from the exposure of endothelial cells (ECs) to ischemia/reperfusion is angiogenesis, involving degradation of vascular basement membrane and extracellular matrix. Matrix metalloproteinase (MMP)-2, a member of the MMP family, partakes in this process. MMP-2, secreted as a proenzyme, undergoes activation through interaction with membrane type (MT)1-MMP and the endogenous tissue inhibitor of MMPs (TIMP)-2. Although hypoxia and reoxygenation (H/R) are major constituents of ischemia/reperfusion processes, their direct effects on endothelial MMP-2 have been scarcely investigated. This study examined the in vitro effects of H/R on human macrovascular ECs (EAhy 926). The level of MMP-2 mRNA (Northern blot) and protein (zymography, ELISA) and the mRNA of its activator (MT1-MMP) and inhibitor (TIMP-2) were analyzed. Short (6-hour) hypoxia inhibited the mRNA expression of MMP-2, MT1-MMP, and TIMP-2, culminating in reduced latent and active MMP-2 protein. Prolonged (24-hour) hypoxia further suppressed MT1-MMP and TIMP-2 mRNA, whereas it enhanced MMP-2 mRNA and enzyme secretion (after 48-hour hypoxia). Reoxygenation did not influence the inhibited TIMP-2 but upregulated MMP-2 and MT1-MMP mRNA expression, leading to enhanced secretion of active MMP-2 protein. These results demonstrate H/R-mediated modulation of EC MMP-2 at both transcriptional and posttranscriptional levels. Prolonged hypoxia of ECs appears to enhance MMP-2 production and secretion, whereas reoxygenation further increases its level. These H/R-mediated effects on MMPs have the potential of enabling EC migration and possible angiogenesis.

Matrix metalloproteinases and their tissue inhibitors as markers of disease subtype and response to interferon-β therapy in relapsing and secondary-progressive multiple sclerosis patients

Matrix metalloproteinases (MMPs) have recently been implicated in the pathogenesis of multiple sclerosis. Their suggested role includes the disruption of the blood–brain barrier, immune cell transmigration into the central nervous system, and myelin degradation. The present study characterized the mRNA level of a wide spectrum of MMPs and tissue inhibitors of metalloproteinases (TIMPs) expressed by peripheral blood leukocytes from relapsing‐remitting (n = 16) and secondary‐progressive (n = 12) multiple sclerosis patients. The expression of the same MMPs and TIMPs was evaluated also in a prospective 12‐month follow‐up of 6 patients randomly chosen from each of the 2 groups during interferon‐β‐1a treatment. Reverse transcription‐polymerase chain reaction assessment demonstrated elevated levels of MT1‐MMP and MMP‐7 mRNA levels in both groups of patients, and no significant differences in MMP‐9 levels, compared with healthy controls. Divergent expression of MMP‐2 between relapsing‐remitting and secondary‐progressive patients compared with controls was observed. IFN‐β treatment was associated with significant suppression of MMP‐9 and MMP‐7 mRNA in relapsing‐remitting patients, though no significant changes were observed in the secondary‐progressive group. These results contribute to the understanding of the interferon‐β‐mediated immunomodulatory and therapeutic effects in multiple sclerosis patients and also support evidence for distinct immune mechanism(s) underlying relapsing‐remitting‐ versus secondary‐progressive multiple sclerosis. The study also suggests that MMPs may be considered as potential biomarkers for response to treatment as well as targets for immunotherapy in multiple sclerosis.

Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis†

To evaluate the efficacy and safety of DM/Q (capsules containing dextromethorphan [DM] and quinidine [Q]) compared with placebo, taken twice daily, for the treatment of pseudobulbar affect over a 12‐week period in multiple sclerosis patients.

Revised diagnostic criteria of multiple sclerosis

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) of presumed autoimmune etiology, characterized by localized areas of inflammation, demyelination, axonal loss and gliosis in the brain and spinal cord. Although the clinical presentation and course of the disease are highly variable, several disease types can be recognized, including relapsing-remitting-(RR), primary-progressive-(PP), secondary-progressive-(SP), progressive-relapsing-(PR) MS and clinically-isolated syndrome (CIS). There is no single clinical feature or diagnostic test that is sufficient to diagnose MS, and the diagnosis is mainly a clinical one. Over the years, several sets of criteria have been proposed for the diagnosis of MS, based on the principles of dissemination in space (DIS) and dissemination in time (DIT) of CNS lesions, and the exclusion of other diseases with similar characteristics. With each revision, new diagnostic criteria modified disease definitions and diagnostic thresholds, while aiming at maintaining sensitivity and improving specificity. According to the older Schumacher and Poser criteria, MS can be diagnosed clinically by demonstrating 2 separate attacks (fulfilling DIT criteria) involving at least 2 different areas of the CNS (fulfilling DIS criteria). The 2001 McDonald criteria and their 2005 revision incorporated defined magnetic resonance imaging (MRI) criteria for DIS and DIT that provided guidance on how to diagnose MS after CIS. The most recent 2010 McDonald criteria simplify requirements for DIS and DIT and may allow for an earlier diagnosis of MS from a single baseline brain MRI if there are both silent gadolinium-enhancing and nonenhancing lesions. Despite these important advances in the diagnosis of MS, some questions still remain regarding the application and the implications of the new criteria in the daily clinical practice and in clinical trials. Most importantly, thorough clinical evaluation and judgment along with careful differential diagnosis still remain the basics in the diagnosis of MS.

Mesenchymal stem cells as an immunomodulatory therapeutic strategy for autoimmune diseases

Mesenchymal stem cells (MSCs) are non-hematopoietic, multipotent progenitor cells which can be isolated from various human adult tissues. In recent years, MSCs have been shown to possess broad immunoregulatory capabilities, modulating both adaptive and innate immunity. This review discusses the documented immunomodulatory capabilities of the MSCs, the possible mechanisms underlying these functions and presents the potential of using this stem cell-based approach as an immunomodulatory tool for the treatment of autoimmune diseases.

Virtual reality cues for improvement of gait in patients with multiple sclerosis.

Objective: To study the effects of visual cues, provided through a portable visual-feedback virtual reality (VR) apparatus, on the walking abilities of patients with multiple sclerosis (MS). Methods: On-line (display-on) and residual short-term therapeutic effects on walking speed and stride length were measured in 16 randomly selected patients with gait disturbances predominantly due to cerebellar ataxia. Results: Patients whose baseline walking speed (BWS) was below the median showed an average on-line improvement of 13.46% in their walking speed, while patients whose BWS was above the median improved their speed by 1.47%. The average short-term residual therapeutic improvement in walking speed was 24.49% in patients with BWS below the median, and 9.09% in patients with BWS above the median. Similar results were obtained for improvements in stride length. These results of improved functions in patients are particularly noteworthy when compared with the lack of change in healthy control subjects. Conclusions: Patients with multiple sclerosis showed improvement in walking abilities using virtual reality visual-feedback cues.

Vitamin B12, demyelination, remyelination and repair in multiple sclerosis

Multiple Sclerosis (MS) and vitamin B12 deficiency share common inflammatory and neurodegenerative pathophysiological characteristics. Due to similarities in the clinical presentations and MRI findings, the differential diagnosis between vitamin B12 deficiency and MS may be difficult. Additionally, low or decreased levels of vitamin B12 have been demonstrated in MS patients. Moreover, recent studies suggest that vitamin B12, in addition to its known role as a co-factor in myelin formation, has important immunomodulatory and neurotrophic effects. These observations raise the questions of possible causal relationship between the two disorders, and suggest further studies of the need to close monitoring of vitamin B12 levels as well as the potential requirement for supplementation of vitamin B12 alone or in combination with the immunotherapies for MS patients.