Safety and Clinical Outcomes of Rituximab Treatment in Patients with Multiple Sclerosis and Neuromyelitis Optica: Experience from a National Online Registry (GRAID).

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disease. Over the last decades therapeutic options have broadened tremendously. Nevertheless, various therapeutic agents, e.g., rituximab, are currently used in the treatment of MS off label. Disease or health registries are useful methods to collect information about off-label treatments. The German registry for autoimmune disease (GRAID) is a multicenter, retrospective, non-interventional database of patients with various autoimmune diseases. AIM/METHODS: The aim of this observational analysis is to present safety data of rituximab in the treatment of MS and neuromyelitis optica (NMO) in a real life clinical setting based on the available registry data. RESULTS: Data were collected nationwide in patients who received rituximab. 56 patients were treated with rituximab for MS or NMO. Average observation period was 9.6 months (SD 7.6, ranging from 6 to 29.7 months). Interval between treatments cycles differed tremendously (ranging from 0 to 21 months, median 10 months). Number of infusions ranged from 1 up to more than 8. The analysis provides experience on almost 50 patient years. Infusion related reactions were most common and reported in four patients; infections were seen in three patients (two of them were hospitalized for urinary tract infection and urosepsis). All patients recovered from infection. Full treatment response was attested in a quarter of the patients; two thirds benefited partially from treatment. DISCUSSION: Safety data of almost 50 patient years of treatment with rituximab show that rituximab is tolerated well in MS/NMO patients. Infections and infusion reactions are the most common adverse events. Our data may help the individual physician to balance efficacy of rituximab against the risk. • Data on rituximab in MS and NMO are provided for almost 50 patientyears • Rituximab was tolerated well • No unexpected side effects were seen • Almost 80% of the patients benefited at least partially from treatment.

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.

[Pegylated interferon beta 1a. A new therapy option for treatment of relapsing-remitting multiple sclerosis]. / Pegyliertes Interferon-beta 1a. Eine neue Therapieoption zur Behandlung der schubförmigen multiplen Sklerose.

Pegylation of pharmacological substances was developed in the 1970s as a way of improving their efficacy and elimination and hence reducing the dosage frequency. A prominent example is pegylation of IFNα, which revolutionized the treatment of virus hepatitis in the late 1990s. Efforts have now succeeded in producing a pegylated interferon beta (PEG-IFN-ß1a) to treat multiple sclerosis (MS) and the efficacy and safety have been investigated in a phase III trial called the ADVANCE study. The 1-year results of this randomized, double blind, multicenter, placebo-controlled study in more than 1500 MS patients show that administration of subcutaneous PEG-IFN-ß1a significantly reduces the annual relapse rate and disability progression. The safety and tolerability profile of PEG-IFN-ß1a was found to be similar to that of conventional IFN-ß drugs. The most common adverse events were flu-like symptoms and redness at the injection site. The results of this study underscore that PEG-IFN-ß1a is an interesting new therapeutic option in the treatment of relapsing-remitting MS that combines highly effective interferon with the established tolerability and safety profile of IFN-ß at a reduced dosage frequency.

Bacteria and their cell wall components uniformly co-activate interleukin-17-producing thymocytes.

Interleukin (IL)-17-producing T cells play a critical role in the immune response against microbial pathogens. Traditionally, experimental studies have focused upon understanding the activity of IL-17-producing T cells which differentiate from naive T cells in the peripheral immune system. However, we have demonstrated previously that IL-17-producing T cells are also present in the thymus of naive wild-type mice and can be co-activated there by microbial stimuli. Other studies have supported the concept that IL-17-producing thymocytes have a specific role in the immediate defence against microbial pathogens, which is independent from the development of an adaptive immune response. Given an important role of the thymus in systemic bacterial infection and sepsis, in this study we investigate the effect of a broad spectrum of bacteria and cell wall components on thymocyte cytokine production. Surprisingly, we find that all types of bacteria investigated (including non-pathogenic species) uniformly activate IL-17-producing thymocytes upon α-CD3 stimulation. In contrast, there is a heterogeneous effect on IL-6 and interferon (IFN)-γ-production with Gram-negative bacteria inducing far higher frequencies of IL-6- and IFN-γ-producing thymocytes than Gram-positive bacteria. We conclude that IL-17-producing thymocytes constitute a 'first line of recognition', but not a 'first line of defence' against bacteria in general. Their activity might lead to immune activation, but not necessarily to a pathological inflammatory disease condition. The difference between these two states might be determined by other immunological effector molecules, such as IL-6 and IFN-γ.

[Multiple erythema migrans and facial nerve paralysis: clinical manifestations of early disseminated Lyme borreliosis]. / Multilokuläre Erythemata migrantia und Fazialisparese : Klinische Manifestationsformen der disseminierten Frühinfektion der Lyme-Borreliose.

Lyme borreliosis is a common vector-borne disease in Europe. The infection follows different stages with a broad variability of clinical symptoms and manifestations in different organs. A 49-year-old man presented with flu-like symptoms, facial nerve paralysis and multiple erythematous macular on his trunk and extremities. We diagnosed Lyme disease (stage II) with facial nerve paralysis and multiple erythema migrans. Intravenous ceftriaxone led to complete healing of hissymptoms within 2 weeks.

Monomethylfumarate reduces in vitro migration of mononuclear cells.

Migration of immunocompetent cells into the central nervous system represents a key event in the immunopathogenesis of multiple sclerosis (MS). Fumaric acid esters have recently been approved for patients with MS. Their mode of action is not fully understood so far. We analyzed the effect of monomethylfumarate (MMF), the immediate metabolite of dimethylfumarate, on migration of lymphocytes and macrophages. Peripheral blood mononuclear cells (PBMCs) were isolated from patients with MS and healthy donors. PBMCs were treated with MMF in vitro and their migratory capacity was studied in a Boyden chamber assay. In addition, expression of matrix metalloproteinases (MMPs), chemokine receptors, adhesion molecules, and molecules of the oxidative stress cascade was assessed. MMF decreased the migratory capacity of T lymphocytes, but not of macrophages. Lymphocytes as well as macrophages responded to MMF by the upregulation of oxidative stress molecules; however, no effect was seen on the expression of MMPs, chemokine receptors, and adhesion molecules. There was no difference in comparison with cells from healthy controls. MMF reduces the migratory activity of lymphocytes most likely by changing their activational state. This points to a potential novel mode of action differentiating this drug from other available immunotherapies.

[Teriflunomide for treatment of multiple sclerosis]. / Teriflunomid zur Behandlung der Multiplen Sklerose.

Interferon beta and glatiramer acetate are still considered to be the first-line therapeutics for treatment of relapsing forms of multiple sclerosis (MS). The use of new compounds, such as natalizumab or fingolimod, is restricted to severe forms of relapsing MS or cases refractory to first-line treatment owing to substance-specific risk-benefit considerations. Teriflunomide is a new compound which has recently been approved as a first-line treatment of relapsing forms of MS in the USA and Australia. It is characterized by a once daily oral administration and a comparably well-established long-term safety profile. The main therapeutic effect is considered to be mediated via the inhibition of the de novo synthesis of pyrimidine in proliferating immune cells. The pro-drug of teriflunomide, leflunomide, has a label for treating rheumatoid arthritis (RA) for many years. Two recently published phase III clinical trials (TEMSO, TOWER) tested teriflunomide in patients with relapsing forms of MS and efficacy was demonstrated, with positive effects on relapse rates and disease progression using 14 mg/day. Overall, the safety profile in these studies was favorable as expected from experiences with leflunomide in RA. In patients treated with teriflunomide regular monitoring of blood cell counts and liver enzymes is required. Teriflunomide must not be used during pregnancy. In this article the recent phase II and phase III clinical trial data are reviewed and the potential of teriflunomide for the treatment of relapsing forms of MS is discussed.

T cell activation status determines the cytokine pattern induced by zymosan and bacterial DNA both in thymocytes and splenocytes.

Proinflammatory cytokines are essential mediators of the immunopathology associated with microbial sepsis. The fungal cell wall component zymosan and bacterial DNA are well-studied experimental tools for investigating these processes, simulating the presence of fungal or bacterial infection. Cells of the immune periphery, but also immune cells in the thymus, are affected essentially by the presence of microbes or their immune stimuli in sepsis. For this reason, we investigated the cytokine pattern present in the spleen (containing mature immune cells) and the thymus (containing immature immune cells) upon exposure to zymosan and Escherichia coli DNA. To study the role of T cell activation status, we investigated ex-vivo cultures with and without αCD3 stimulation for changes in their cytokine secretion pattern as measured by cytokine enzyme-linked immunospot (ELISPOT) and flow cytometry analysis. We found that both substances strongly co-stimulate αCD3-induced interferon (IFN)-γ and interleukin (IL)-6 secretion in the thymus and in the spleen, but stimulate IL-17 production only moderately. Moreover, zymosan increases PLP peptide (PLPp)-specific IFN-γ and IL-6 production in experimental autoimmune encephalomyelitis (EAE) induced in Swiss Jim Lambert (SJL)/J mice, confirming that T cell activation status is crucial for the cytokines secreted by an immune cell population encountering a microbial pathogen or immunostimulating parts of it.

Peripheral blood levels of matrix metalloproteinase-9 predict lesion volume in acute stroke.

Matrix metalloproteinases (MMPs) have been implicated to play an important role in the destruction of the extracellular matrix in diseases of the central nervous system. This study investigated whether the expression of one of these proteases, MMP-9 in blood, is related to the size of human brain infarcts assessed with magnetic resonance imaging. Consecutively, twenty-one acute stroke patients were included prospectively into our study. In blood samples drawn within 24 h after onset, MMP-9 RNA-expression and proteolytic-activity were analyzed by quantitative polymerase chain reaction and gelatin zymography, respectively. The ischemic lesion volumes in time to peak perfusion maps and diffusion weighted imaging were measured morphometrically. RNA-expression levels of MMP-9 in peripheral blood mononuclear cells (PBMCs) correlated with the brain infarct lesion (TTP-delay 4 s, r = -0.61, p = 0.007; TTP-delay 6 s: r = -0.58, p = 0.012; DWI r = -0.47; p = 0.047). Our preliminary results demonstrate that MMP-9 RNA is upregulated in PBMCs in proportion to ischemia. These findings suggest that MMP-9 might contribute to the manifestation of ischemic brain damage. Since MMP-9 is upregulated in acute ischemia inhibition of MMP-9 may represent a complementary treatment target in acute stroke therapy.

Fatal PML associated with efalizumab therapy: insights into integrin αLß2 in JC virus control.

OBJECTIVES: Progressive multifocal leukoencephalopathy (PML) has become much more common with monoclonal antibody treatment for multiple sclerosis and other immune-mediated disorders. METHODS: We report 2 patients with severe psoriasis and fatal PML treated for ≥3 years with efalizumab, a neutralizing antibody to αLß2-leukointegrin (LFA-1). In one patient, we conducted serial studies of peripheral blood and CSF including analyses of leukocyte phenotypes, migration ex vivo, and CDR3 spectratypes with controls coming from HIV-infected patients with PML. Extensive pathologic and histologic analysis was done on autopsy CNS tissue of both patients. RESULTS: Both patients developed progressive cognitive and motor deficits, and JC virus was identified in CSF. Despite treatment including plasma exchange (PE) and signs of immune reconstitution, both died of PML 2 and 6 months after disease onset. Neuropathologic examination confirmed PML. Efalizumab treatment was associated with reduced transendothelial migration by peripheral T cells in vitro. As expression levels of LFA-1 on peripheral T cells gradually rose after PE, in vitro migration increased. Peripheral and CSF T-cell spectratyping showed CD8+ T-cell clonal expansion but blunted activation, which was restored after PE. CONCLUSIONS: From these data we propose that inhibition of peripheral and intrathecal T-cell activation and suppression of CNS effector-phase migration both characterize efalizumab-associated PML. LFA-1 may be a crucial factor in homeostatic JC virus control.

[Cannabinoids for symptomatic therapy of multiple sclerosis]. / Cannabinoide zur symptomatischen Therapie der Multiplen Sklerose.

Spasticity represents a common troublesome symptom in patients with multiple sclerosis (MS). Treatment of spasticity remains difficult, which has prompted some patients to self-medicate with and perceive benefits from cannabis. Advances in the understanding of cannabinoid biology support these anecdotal observations. Various clinical reports as well as randomized, double-blind, placebo-controlled studies have now demonstrated clinical efficacy of cannabinoids for the treatment of spasticity in MS patients. Sativex is a 1:1 mix of delta-9-tetrahydocannabinol and cannabidiol extracted from cloned Cannabis sativa chemovars, which recently received a label for treating MS-related spasticity in Germany. The present article reviews the current understanding of cannabinoid biology and the value of cannabinoids as a symptomatic treatment option in MS.

[Alemtuzumab: a further option for treatment of multiple sclerosis]. / Alemtuzumab: eine weitere Chance zur Therapie der Multiplen Sklerose.

Alemtuzumab is a humanized monoclonal therapeutic antibody that targets the CD52 antigen which s expressed on most cells of the lymphoid lineage, exclusive of precursors. Alemtuzumab rapidly depletes CD52(+) cells from the peripheral blood. This depletion is long-lasting, and cells repopulate in a specific pattern with B cells and regulatory T cells peaking first. Alemtuzumab was examined for clinical utility in two open-labelled intervention trials in multiple sclerosis (MS). Because of very promising results its clinical efficacy was further explored in a clinical phase-II trial using s.c. interferon beta-1a as the active comparator. Severe or opportunistic infections were surprisingly rare given the long-term lymphopenia. However, up to 30% of patients developed some antibody-mediated autoimmunity. The thyroid gland was the most frequently affected organ. Immune-mediated thrombocytopenic purpura and Goodpasture's syndrome were additionally observed. This review summarizes the pre-clinical and clinical development of alemtuzumab and discusses potential modes of action as well as the pathogenetic link to the treatment emergent autoimmune phenomena.

[Progressive multifocal leukoencephalopathy under natalizumab. Initial possibilities for risk stratification?]. / Progressive multifokale Leukenzephalopathie unter Natalizumab. Erste Möglichkeiten einer Risikostratifizierung?

Natalizumab (Tysabri®) is the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS) but while treatment is highly efficient, it carries the risk of progressive multifocal leukoencephalopathy (PML). Based on reports of confirmed cases of PML, the risk of PML might increase beyond 24 months of treatment. Thus, attempts to stratify patients treated with natalizumab into those carrying higher or lower risk for developing PML are currently being undertaken. Among these strategies JC virus serology might potentially be the first tool available. As a large variety of methods have been published resulting in controversial results for JC virus seroprevalence, standardized testing will be mandatory when applying this method in clinical practice. In addition, risk management strategies for the seropositive majority of patients need to be redefined and optimized further.

The Global Adherence Project (GAP): a multicenter observational study on adherence to disease-modifying therapies in patients with relapsing-remitting multiple sclerosis.

BACKGROUND: most disease-modifying therapies (DMTs) for multiple sclerosis (MS) are self-injectable medications that must be taken on an ongoing basis to reduce disease activity. Thus, adherence to therapy becomes an important challenge that must be addressed to maximize benefits of therapy. This study evaluated rates of adherence to prescribed treatment and explored factors affecting adherence amongst patients with relapsing-remitting MS. METHODS: this was an observational, multicenter, multinational, phase 4 study. Patients and physicians received paper questionnaires regarding adherence to DMTs approved at the time of the study, including intramuscular interferon beta-1a (IFNß-1a), subcutaneous IFNß-1a, IFNß-1b, and glatiramer acetate. Quality of life and cognition data also were collected. Multivariate analysis was conducted to identify factors associated with adherence to long-term DMTs. RESULTS: two thousand six hundred and forty-eight patients were studied, revealing an average treatment duration of 31 months. Seventy-five percent of patients (n = 1923) were adherent to therapy. The most common reasons for non-adherence were forgetting to administer the injection (50.2%) and other injection-related reasons (32.0%). Adherent patients reported better quality of life (P < 0.05) and fewer neuropsychological issues (P < 0.001) than non-adherent patients. Adherent patients had significantly shorter duration of disease (P < 0.001) and shorter duration of therapy (P = 0.005) than non-adherent patients. Women were more likely than men to adhere to treatment. CONCLUSION: identifying factors that affect adherence to prescribed treatments is the first step in improving adherence of patients with MS to therapy, thereby helping maximize the benefits of long-term DMTs.

Highly reactive anti-myelin oligodendrocyte glycoprotein antibodies differentiate demyelinating diseases from viral encephalitis in children.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) may be implicated in the immunopathogenesis of multiple sclerosis (MS) inducing demyelination in the animal model of MS. In adults reported anti-MOG antibody frequencies have been variable across a number of studies and can also be detected in controls. OBJECTIVE: To measure antibodies against MOG in paediatric patients with demyelinating disorders of the central nervous system and in controls. METHODS: Serum antibodies against MOG and myelin basic protein were measured by ELISA, flow cytometry (FACS) and in the liquid phase in 11 children with acute disseminated encephalomyelitis (ADEM), 22 children with MS, seven children with acute viral encephalitis and 13 healthy controls. The serostatus of Epstein-Barr virus (EBV) infections were assessed. RESULTS: Anti-MOG antibodies, measured either by ELISA or FACS were exclusively detected in children with demyelination. In ADEM these antibodies were highly reactive. Anti-MBP reactivity was detectable equally in all groups. The presence of either autoantibodies did not associate with EBV serostatus, age, gender or disease course. CONCLUSIONS: This study independently corroborates recently published results of seroprevalence and specificity of the assay. Due to their low sensitivity anti-MOG antibodies will not serve as disease-specific biomarkers, but could help to support the diagnosis of ADEM in difficult cases.