Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Basal Cell/drug therapy , Hedgehog Proteins/antagonists & inhibitors , Skin Neoplasms/drug therapy , Aged , Aged, 80 and over , Anilides/pharmacology , Anilides/therapeutic use , Antineoplastic Agents/pharmacology , Biphenyl Compounds/pharmacology , Biphenyl Compounds/therapeutic use , Carcinoma, Basal Cell/mortality , Carcinoma, Basal Cell/pathology , Female , Follow-Up Studies , Hedgehog Proteins/metabolism , Humans , Male , Middle Aged , Progression-Free Survival , Pyridines/pharmacology , Pyridines/therapeutic use , Retrospective Studies , Signal Transduction/drug effects , Skin Neoplasms/mortality , Skin Neoplasms/pathologyABSTRACT
BACKGROUND AND OBJECTIVE: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. METHODS: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. RESULTS: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. CONCLUSIONS: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation.
Subject(s)
Multiple Sclerosis/pathology , Adult , Cohort Studies , Disease Progression , Endonucleases , Female , Follow-Up Studies , Humans , Immunoglobulin G/analysis , Magnetic Resonance Imaging , Male , Multiple Sclerosis/cerebrospinal fluid , Nuclear Proteins/analysis , Oligoclonal Bands/genetics , Predictive Value of Tests , Prognosis , Risk Assessment , Survival Analysis , Vitamin D/bloodABSTRACT
During the last two decades, treatment options for patients with multiple sclerosis (MS) have broadened tremendously. All agents that are currently approved for clinical use have potential side effects, and a careful risk-benefit evaluation is part of a decision algorithm to identify the optimal treatment choice for an individual patient. Whereas glatiramer acetate and interferon beta preparations have been used in MS for decades and have a proven safety record, more recently approved drugs appear to be more effective, but potential risks might be more severe. The potential complications of some novel therapies might not even have been identified to their full extent. This review is aimed at the clinical neurologist in that it offers insights into potential adverse events of each of the approved MS therapeutics: interferon beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod and teriflunomide, as well as recently approved therapeutics such as dimethyl fumarate and alemtuzumab. It also provides recommendations for monitoring the different drugs during therapy in order to avoid common side effects.
Subject(s)
Immunologic Factors/therapeutic use , Multiple Sclerosis/drug therapy , Female , Humans , Immunologic Factors/adverse effects , Male , PregnancyABSTRACT
Neuromyelitis optica (NMO) predominantly affects women, some in childbearing age, and requires early therapeutic intervention to prevent disabling relapses. We report an anti-AQP4 antibody-seropositive patient who became pregnant seven months after low-dose (100 mg) rituximab application. Pregnancy showed no complications, and low-dose rituximab restarted two days after delivery resulted in neurological stability for 24 months. Remarkably, her otherwise healthy newborn presented with anti-AQP4 antibody and reduced B lymphocyte counts in umbilical cord blood, which normalized three months later. Confirming and extending previous reports, our case suggests that low-dose rituximab might be compatible with pregnancy and prevent rebound NMO disease activity postpartum.
Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Aquaporin 4/immunology , Autoantibodies/blood , B-Lymphocytes/immunology , Immunologic Factors/therapeutic use , Infant, Newborn/blood , Neuromyelitis Optica/immunology , Pregnancy Complications/immunology , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Autoantigens/immunology , Female , Fetal Blood/immunology , Humans , Immunologic Factors/administration & dosage , Infant, Newborn/immunology , Lymphocyte Depletion , Neuromyelitis Optica/blood , Neuromyelitis Optica/drug therapy , Postpartum Period , Pregnancy , Pregnancy Complications/blood , Pregnancy Complications/drug therapy , Rituximab , Secondary Prevention , Young AdultABSTRACT
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.
Subject(s)
Crotonates/administration & dosage , Crotonates/adverse effects , Evidence-Based Medicine , Multiple Sclerosis/diagnosis , Multiple Sclerosis/drug therapy , Toluidines/administration & dosage , Toluidines/adverse effects , Central Nervous System Agents/administration & dosage , Central Nervous System Agents/adverse effects , Dose-Response Relationship, Drug , Humans , Hydroxybutyrates , Nitriles , Treatment OutcomeABSTRACT
BACKGROUND: After major traumatic injury, patients often require multiple transfusions of fresh frozen plasma (FFP) to correct coagulopathy and to reduce bleeding. A spray-dried plasma (SDP) product has several logistical benefits over FFP use in trauma patients with coagulopathy. These benefits include ease of transport, stability at room temperature, and rapid reconstitution for infusion. Our past work suggests that FFP promotes endothelial stability by inhibiting endothelial permeability. STUDY DESIGN AND METHODS: The main goal of this project is to determine if solvent-detergent-treated SDP is equivalent to FFP in inhibiting vascular endothelial cell (EC) permeability and inflammation in vitro. Furthermore, this study aimed to determine if solvent-detergent treatment and spray drying of plasma alters the protective effects of FFP on EC function. The five groups tested in our studies are the following: 1) fresh frozen-thawed plasma (FFP); 2) solvent-detergent-treated FFP; 3) solvent-detergent-treated SDP; 4) lactated Ringer's solution; and 5) Hextend. RESULTS: This study demonstrates that in vitro SDP and FFP equivalently inhibit vascular EC permeability, EC adherens junction breakdown, and endothelial white blood cell binding, an effect that is independent of changes in Vascular Cell Adhesion Molecule 1, Intracellular Adhesion Molecule 1, or E-selectin expression on ECs. Solvent-detergent treatment of FFP does not alter the protective effects of FFP on endothelial cell function in vitro. CONCLUSION: These data suggest the equivalence of FFP and SDP on modulation of endothelial function and inflammation in vitro.
Subject(s)
Endothelial Cells/immunology , Plasma , Vasculitis/immunology , Vasculitis/therapy , Adherens Junctions/immunology , Cell Adhesion/immunology , Cell Membrane Permeability/immunology , E-Selectin/metabolism , Endothelial Cells/cytology , Freeze Drying , Human Umbilical Vein Endothelial Cells , Humans , In Vitro Techniques , Leukocytes/cytology , Leukocytes/immunology , Pulmonary Artery/cytology , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
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.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Immunity, Innate/drug effects , Immunity, Innate/immunology , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Alemtuzumab , Humans , Models, ImmunologicalABSTRACT
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.
Subject(s)
Autoantibodies/blood , Demyelinating Diseases/diagnosis , Encephalitis, Viral/diagnosis , Encephalomyelitis, Acute Disseminated/diagnosis , Myelin-Associated Glycoprotein/immunology , Adolescent , Biomarkers/blood , Chi-Square Distribution , Child , Child, Preschool , Demyelinating Diseases/immunology , Diagnosis, Differential , Encephalitis, Viral/immunology , Encephalomyelitis, Acute Disseminated/immunology , Enzyme-Linked Immunosorbent Assay , Epstein-Barr Virus Infections/diagnosis , Epstein-Barr Virus Infections/immunology , Female , Flow Cytometry , France , Germany , Humans , Immunity, Humoral , Male , Myelin Basic Protein , Myelin Proteins , Myelin-Oligodendrocyte Glycoprotein , Nerve Tissue Proteins/immunology , Predictive Value of Tests , Retrospective Studies , Transcription Factors/immunologySubject(s)
Autoantibodies/immunology , Interferon-beta , Multiple Sclerosis , Adult , Autoantigens/immunology , Female , Glutamate Decarboxylase/immunology , Humans , Interferon-beta/immunology , Interferon-beta/therapeutic use , Iodide Peroxidase/immunology , Middle Aged , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Peptide Fragments/immunology , Thyroglobulin/immunologyABSTRACT
Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disease of the CNS and a leading cause of lasting neurological disability in younger adults. In the last decade our knowledge of its immunopathogenesis expanded vastly. It is now widely appreciated that B cells are key players in the autoreactive immune network. They exert far more functions than merely being the precursors of antibody-producing plasma cells. B cells act as efficient antigen-presenting cells and may stimulate an autoreactive immune response through secretion of proinflammatory cytokines. It is thus only logical to test therapeutic strategies targeting B cells in MS. Rituximab is a depleting chimeric monoclonal antibody directed against CD20 and expressed on developing, naïve, and memory B cells but not stem or plasma cells. Several smaller studies have been conducted that led to a placebo controlled, double blind phase II study on efficacy which was reported recently. The results are very promising, meeting not only the primary endpoint of reduction of the surrogate MRI marker of contrast-enhancing lesions but also showing a reduction in clinical relapse rate of patients treated with rituximab. This review discusses the role of autoreactive B cells in the context of MS, analyzes the B-cell-depleting treatment studies reported, and provides information on planned and future B-cell-directed therapeutic strategies in MS.
Subject(s)
Antibodies, Monoclonal/immunology , Antigens, CD20/immunology , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Drug Delivery Systems/methods , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Antibodies, Monoclonal/therapeutic use , Drug Delivery Systems/trends , Humans , Models, Immunological , Multiple Sclerosis/drug therapyABSTRACT
3-Hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitors, "statins," are widely used oral cholesterol-lowering drugs. Statins competitively inhibit HMG-CoA reductase, the enzyme that catalyzes conversion of HMG-CoA to L-mevalonate, a key intermediate in cholesterol synthesis. Certain metabolites of L-mevalonate are also involved in posttranslational modifications of specific proteins with cell proliferation and differentiation properties. Thus, statins have important biologic effects beyond their cholesterol-reducing properties. Here we discuss recent experimental and clinical data that may support a potential role for statins in the treatment of three central nervous system (CNS) neurological diseases: Multiple sclerosis (MS), Alzheimer's disease (AD), and ischemic stroke. Despite their considerable pathogenic differences, in animal models of these disorders statins have shown beneficial effects. In both stroke and AD cohort studies suggest a beneficial treatment effect in humans; in MS, results from small open-label studies look encouraging. Multicenter, randomized, placebo-controlled clinical trials are in the planning or recruiting stage to evaluate the therapeutic effects of statins in all three disorders.
Subject(s)
Biomedical Research/trends , Brain Diseases/drug therapy , Clinical Trials as Topic/trends , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Practice Patterns, Physicians'/trends , HumansABSTRACT
Interleukin-18 (IL-18) is an important cytokine in innate immunity and in the induction phase of autoimmunity. We report the expression of IL-18 mRNA and protein after nerve crush during Wallerian degeneration (WD) of the rat nervous system. In normal optic nerves (ON) constitutive IL-18 mRNA levels as revealed by semiquantitative reverse transcriptase polymerase chain reaction were higher than in sciatic nerves (SN). After nerve crush, steady-state levels moderately increased in the distal nerve part of the SN but not the ON. By immunocytochemistry no SN or faint ON IL-18 protein expression was detectable in normal nerves. In contrast, IL-18 expression dramatically increased after SN and ON crush. On the cellular level, ED1(+) macrophages infiltrating the crush site strongly expressed IL-18 at days 2 and 4 after SN crush. By days 4 and 8, in addition, the entire distal nerve part was covered by IL-18(+) macrophages. At day 16, IL-18 immunoreactivity had disappeared despite the persistence of large numbers of ED1(+) macrophages. A similar infiltration of IL-18(+) macrophages was seen at the crush site in the ON. Moreover, microglia in the distal ON stump lacking macrophage infiltration and undergoing delayed myelin degradation up-regulated IL-18. In conclusion this study shows that IL-18 is involved in the cytokine network associated with the robust inflammatory response during WD of the SN. Despite up-regulation of the proinflammatory cytokine IL-18, major histocompatibility complex class II, and CD4 molecules similar to macrophages in the PNS, microglial activation after ON injury appears to be insufficient to mount an effective phagocytic response as a prerequisite for successful regeneration in the CNS.
Subject(s)
Axons/immunology , Interleukin-18/genetics , Interleukin-18/immunology , Nerve Regeneration/immunology , Animals , Axons/pathology , Caspase 1/genetics , Female , Gene Expression/immunology , Macrophages/immunology , Microglia/immunology , Nerve Crush , Optic Nerve Injuries/immunology , Optic Nerve Injuries/pathology , RNA, Messenger/analysis , Rats , Rats, Wistar , Sciatic Nerve/immunology , Sciatic Nerve/injuries , Sciatic Nerve/pathology , Wallerian Degeneration/immunology , Wallerian Degeneration/pathologySubject(s)
AIDS Dementia Complex/complications , AIDS Dementia Complex/drug therapy , Arterial Occlusive Diseases/chemically induced , Cerebral Cortex/pathology , HIV-1/drug effects , Middle Cerebral Artery/drug effects , Protease Inhibitors/adverse effects , Stroke/etiology , AIDS Dementia Complex/pathology , Arterial Occlusive Diseases/drug therapy , Arterial Occlusive Diseases/pathology , Arterial Occlusive Diseases/physiopathology , Cerebral Cortex/blood supply , Cerebral Cortex/drug effects , Disease Progression , Humans , Hyperlipidemias/chemically induced , Hyperlipidemias/complications , Hyperlipidemias/drug therapy , Hyperlipidemias/physiopathology , Male , Middle Aged , Middle Cerebral Artery/pathology , Middle Cerebral Artery/physiopathology , Protease Inhibitors/administration & dosage , Stroke/drug therapy , Stroke/pathology , Stroke/physiopathology , Treatment OutcomeABSTRACT
Of 78 patients with an internal carotid artery stenosis a thrombendarterectomy was performed in 46 patients whereas 32 patients were treated by conservative methods. The clinical follow-up over a period of 10 years was investigated. The percentage of patients who received drugs for anticoagulation was equal in both groups. Operated patients acquired a permanent neurologic deficit in 3% and nonoperated patients in 69%. The physical capacity improved in 92% of the operated and in 64% of patients treated conservatively. At the time of reexamination 78% of the operated and 34% of the nonoperated patients were living. The cause of death was cardiac in 42% of both groups and cerebral in 11% of the operated and in 32% of the nonoperated patients.