Til Menge

Natalizumab and progressive multifocal leukoencephalopathy: What are the causal factors and can it be avoided?

Natalizumab (Tysabri) was the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS). After its initial approval, 3 patients undergoing natalizumab therapy in combination with other immunoregulatory and immunosuppressive agents were diagnosed with progressive multifocal leukoencephalopathy (PML). The agent was later reapproved and its use restricted to monotherapy in patients with relapsing forms of MS. Since reapproval in 2006, additional cases of PML were reported in patients with MS receiving natalizumab monotherapy. Thus, there is currently no convincing evidence that natalizumab-associated PML is restricted to combination therapy with other disease-modifying or immunosuppressive agents. In addition, recent data indicate that risk of PML might increase beyond 24 months of treatment.

Frontline: Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination

Preliminary observations of humoral immunity against the myelin oligodendrocyte glycoprotein (MOG) in experimental allergic encephalomyelitis (EAE) and human multiple sclerosis (MS) suggest that a subset of anti‐MOG autoantibodies directed against conformational epitopes is of pathogenic predominance. Here, we provide proof that in marmoset EAE, autoantibodies reactive against conformational epitopes of MOG are not only responsible for aggravating demyelination, but also an essential factor for disease dissemination in space within the central nervous system, a hallmark for typicalforms of human MS. In terms of effector mechanisms, IgG deposition and complement activation occur exclusively in association with presence of these conformational antibodies, while microglial/macrophage activation appears to be a common immunopathological finding regardless of the fine determinant specificity of anti‐MOG antibodies. These findings highlight for the first time the complex heterogeneity of function and pathogenicity in the polyclonal anti‐MOG antibody repertoire of outbred species. Because the linear and conformational antibody determinants of MOG are shared between marmosets and humans, these results are directly relevant to understanding effector mechanisms of organ damage in MS.

Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis.

The choice of appropriate control group(s) is critical in cerebrospinal fluid (CSF) biomarker research in multiple sclerosis (MS). There is a lack of definitions and nomenclature of different control groups and a rationalized application of different control groups. We here propose consensus definitions and nomenclature for the following groups: healthy controls (HCs), spinal anesthesia subjects (SASs), inflammatory neurological disease controls (INDCs), peripheral inflammatory neurological disease controls (PINDCs), non-inflammatory neurological controls (NINDCs), symptomatic controls (SCs). Furthermore, we discuss the application of these control groups in specific study designs, such as for diagnostic biomarker studies, prognostic biomarker studies and therapeutic response studies. Application of these uniform definitions will lead to better comparability of biomarker studies and optimal use of available resources. This will lead to improved quality of CSF biomarker research in MS and related disorders.

Disease-modifying agents for multiple sclerosis: Recent advances and future prospects

Multiple sclerosis (MS) is a chronic autoimmune disease of the CNS. Currently, six medications are approved for immunmodulatory and immunosuppressive treatment of the relapsing disease course and secondary-progressive MS. In the first part of this review, the pathogenesis of MS and its current treatment options are discussed.During the last decade, our understanding of autoimmunity and the pathogenesis of MS has advanced substantially. This has led to the development of a number of compounds, several of which are currently undergoing clinical testing in phase II and III studies. While current treatment options are only available for parenteral administration, several oral compounds are now in clinical trials, including the immunosuppressive agents cladribine and laquinimod. A novel mode of action has been described for fingolimod, another orally available agent, which inhibits egress of activated lymphocytes from draining lymph nodes. Dimethylfumarate exhibits immunomodulatory as well as immunosuppressive activity when given orally. All of these compounds have successfully shown efficacy, at least in regards to the surrogate marker contrast-enhancing lesions on magnetic resonance imaging.Another class of agents that is highlighted in this review are biological agents, namely monoclonal antibodies (mAb) and recombinant fusion proteins. The humanized mAb daclizumab inhibits T-lymphocyte activation via blockade of the interleukin-2 receptor. Alemtuzumab and rituximab deplete leukocytes and B cells, respectively; the fusion protein atacicept inhibits specific B-cell growth factors resulting in reductions in B-cells and plasma cells. These compounds are currently being tested in phase II and III studies in patients with relapsing MS.The concept of neuro-protection and -regeneration has not advanced to a level where specific compounds have entered clinical testing. However, several agents approved for conditions other than MS are highlighted. Finally, with the advent of these highly potent novel therapies, rare, but potentially serious adverse effects have been noted, namely infections and malignancies. These are critically reviewed and put into perspective.

Quantification and Functional Characterization of Antibodies to Native Aquaporin 4 in Neuromyelitis Optica

BACKGROUND Antibodies targeting membrane proteins play an important role in various autoimmune diseases of the nervous system. So far, assays allowing proper analysis of such autoantibodies are largely missing. A serum autoantibody to aquaporin 4 (AQP4) is associated with neuromyelitis optica (NMO). Although several assays are able to detect this autoantibody, they do not allow determination of the biological activity of anti-AQP4 antibodies. OBJECTIVE To develop a bioassay for quantification and characterization of human anti-AQP4 antibodies. DESIGN, SETTING, AND PARTICIPANTS We developed a novel bioassay for quantification and characterization of human anti-AQP4 antibodies based on high-level expression of native AQP4 (nAQP4) protein on the surface of human astroglioma cells. The test was validated in 2 independent cohorts of patients with NMO spectrum disease. RESULTS We detected anti-nAQP4-IgG with a sensitivity of 57.9% and specificity of 100% in patients with NMO spectrum diseases, suggesting that our bioassay is at least as sensitive and specific as the gold-standard NMO-IgG assay. The anti-AQP4 antibodies belonged predominantly to the IgG1 isotype and bound with high affinity to the extracellular domain of nAQP4. Our data suggest that the autoantibody exerts pathological properties because nAQP4-IgG-positive sera induced cell death of nAQP4-expressing cells by antibody-dependent cellular natural killer cell cytotoxic effect and complement activation. Furthermore, nAQP4-IgG titers strongly correlated with in vitro cytotoxic effect. CONCLUSIONS In NMO, this assay may help to unravel the biological function of anti-nAQP4-IgG. Our findings demonstrate the potential of bioassays to characterize biologically relevant antibodies in human autoimmune diseases.

Induction of the proinflammatory cytokine interleukin-18 by axonal injury

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 presistence 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 histocompatiblity 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. J. Neurosci. Res. 65:332–339, 2001.

Long-term B-lymphocyte depletion with rituximab in patients with relapsing-remitting multiple sclerosis.

OBJECTIVE To describe 2 patients with relapsing-remitting multiple sclerosis (RRMS) receiving long-term treatment with the monoclonal antibody rituximab. The clinical and paraclinical efficacy of rituximab was demonstrated recently in a phase 2 clinical trial in patients with RRMS. DESIGN Case series. SETTING Tertiary care university medical center. PATIENTS Two young patients with highly active RRMS in whom standard therapy had failed before receiving rituximab for up to 48 months. MAIN OUTCOME MEASURES Relapse rate, clinical disability, and results of magnetic resonance imaging. RESULTS Both patients tolerated rituximab treatment well and have been clinically stable throughout the study period. CONCLUSION Long-term therapy with rituximab appears safe and effective in some patients with RRMS. Our observation should be confirmed in controlled long-term trials.

Requirement for safety monitoring for approved multiple sclerosis therapies: an overview

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.

Pharmacological Treatment of Early Multiple Sclerosis

Currently, six medications are approved by the US FDA for the treatment of relapsing forms of multiple sclerosis (MS). In contrast, no pharmacological agent has proved to be effective in patients with secondary-progressive MS without relapses, or in patients with primary-progressive MS. One of the principal issues concerning an optimal pharmacotherapy for relapsing forms of MS is the optimal time of treatment initiation. There is now an almost universal consensus among MS experts that many patients will benefit from early therapy. However, several formidable challenges exist in identifying individuals who will benefit versus those who will do well without intervention. How do we define early MS and what clinical and paraclinical markers may be useful in defining the timing and nature of therapy? Do patients with a benign form of MS require therapy or are they exposed unnecessarily to adverse effects of our currently available medications? How do we identify disease progression and treatment failures? This review discusses these issues and outlines the evidence for application of ‘early’ treatment in patients with relapsing forms of MS.

Identification of new serum autoantibodies in neuromyelitis optica using protein microarrays

Neuromyelitis optica (NMO) or Devic’s disease is a severe demyelinating disease of the CNS affecting primarily optic nerves and spinal cord, secondary to a B-cell- and Ab-mediated autoimmune condition.1 This concept was recently bolstered by the demonstration of disease-specific NMO-Abs,2 and the apparent beneficial effect of B-cell depletion.3 Here, we used a protein microarray approach to profile the Ag reactivity of serum IgG from NMO patients. Sera from five patients fulfilling NMO criteria (Cases 2 through 6 described elsewhere3) and five healthy controls were tested. Because patients experienced relapses and progressive clinical impairment despite therapy, they received rituximab as an off-label, innovative treatment.3 A 20-year-old woman with NMO associated with a high relapse rate (19 relapses within the last 6 years) was blind, wheelchair bound, and had a mid-thoracic sensory level and urinary and stool incontinence. Following treatment with rituximab, she experienced improved strength and sensation in her legs. She had an attack of myelitis approximately 1 month after her first course of rituximab from which she recovered spontaneously without additional treatment. At 1 year follow up, her vision remained impaired but she recovered full strength in her legs, normal …