Multiple Sclerosis: Hohlfeld R

Anonymous00013, Wiendl H, Toyka KV, Rieckmann P, Gold R, Hartung HP, Hohlfeld R. · Department of Neurology and Clinical Research, Unit for MS and Neuroimmunology, University of Würzburg, Würzburg, Germany. · J Neurol. · Pubmed #19005625 No free full text.

Abstract: This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.

Sørensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, Polman C, Pozzilli C, Ross C, Anonymous00318. · Danish Multiple Sclerosis Research Centre, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. · Eur J Neurol. · Pubmed #16241970 No free full text.

Abstract: Therapy-induced binding and neutralizing antibodies is a major problem in interferon (IFN)-beta treatment of multiple sclerosis. The objective of this study was to provide guidelines outlining the methods and clinical use of the measurements of binding and neutralizing antibodies. Systematic search of the Medline database for available publications on binding and neutralizing antibodies was undertaken. Appropriate publications were reviewed by one or more of the task force members. Grading of evidence and recommendations was based on consensus by all task force members. Measurements of binding antibodies are recommended for IFN-beta antibody screening before performing a neutralizing antibody (NAB) assay (Level A recommendation). Measurement of NABs should be performed in specialized laboratories with a validated cytopathic effect assay or MxA production assay using serial dilution of the test sera. The NAB titre should be calculated using the Kawade formula (Level A recommendation). Tests for the presence of NABs should be performed in all patients at 12 and 24 months of therapy (Level A recommendation). In patients who remain NAB-negative during this period measurements of NABs can be discontinued (Level B recommendation). In patient with NABs, measurements should be repeated, and therapy with IFN-beta should be discontinued in patients with high titres of NABs sustained at repeated measurements with 3- to 6-month intervals (Level A recommendation).

Hohlfeld R. · No affiliation provided · Nervenarzt. · Pubmed #19159911 No free full text.

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Hohlfeld R. · No affiliation provided · Int MS J. · Pubmed #15955271 links to  free full text

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Hohlfeld R. · No affiliation provided · Int MS J. · Pubmed #14977485 links to  free full text

Abstract: In the past, neuroprotective therapies were mostly explored in neurodegenerative disorders like Parkinson's and Alzheimer's disease, and in ischaemic stroke. More recently, however, neuroprotection has been proclaimed an important goal for multiple sclerosis (MS) therapy. The basis for widening the scope of neuroprotection is evidence that neuronal and axonal injury are key features of MS lesions. In contrast with degenerative and ischaemic central nervous system injury, however, neurodegeneration in MS appears to be caused by an inflammatory, presumably autoimmune, process. The challenge for neuroprotection in MS is therefore greater than in degenerative and ischaemic disorders, because MS requires the combination of neuroprotective therapy and effective immunomodulation.

Hohlfeld R. · No affiliation provided · J Neurol. · Pubmed #12242531 No free full text.

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Meinl E, Hohlfeld R. · No affiliation provided · Clin Exp Immunol. · Pubmed #12067291 links to  free full text

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Hohlfeld R. · No affiliation provided · Med Klin (Munich). · Pubmed #11603109 No free full text.

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Hohlfeld R, Wiendl H. · No affiliation provided · Ann Neurol. · Pubmed #11261499 No free full text.

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Hohlfeld R. · No affiliation provided · Nervenarzt. · Pubmed #11256156 No free full text.

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Hohlfeld R. · No affiliation provided · Nervenarzt. · Pubmed #10354989 No free full text.

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Wiendl H, Hohlfeld R. · Department of Neurology, Julius-Maximilians-University Würzburg, Würzburg, Germany. · Neurology. · Pubmed #19289741 No free full text.

Abstract: In this essay, we draw attention to some recent downsides and surprises of multiple sclerosis (MS) therapeutics. These include experiences with recent head-to-head trials of interferon-beta and glatiramer acetate, dose escalation trials, frustrating efforts with progressive MS trials, failures of smart concepts and designer therapies, and harsh lessons from newly observed adverse reactions.

Meinl E, Krumbholz M, Derfuss T, Junker A, Hohlfeld R. · Department of Neuroimmunology, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 Martinsried, Germany. · J Neurol Sci. · Pubmed #18715571 No free full text.

Abstract: In multiple sclerosis (MS) the CNS is not only the target of the pathological immune response, but the CNS itself becomes an immunological compartment during the course of the disease. This comprises (i) inflammation beyond classical white matter lesions, (ii) intrathecal Ig production with oligoclonal bands, (iii) an environment fostering immune cell persistence, (iv) follicle-like aggregates in the meninges, (v) a disruption of the blood-brain barrier also outside of active lesions, which allows influx of autoantibodies possibly promoting demyelination or axonal injury and influx of fibrinogen driving inflammation.

Hohlfeld R, Meinl E, Dornmair K. · Department of Neuroimmunology, Max Planck Institute for Neurobiology, Am Klopferspitz, D-82152 Martinsried, Germany. · J Neurol Sci. · Pubmed #18707694 No free full text.

Abstract: In experimental autoimmune encephalomyelitis (EAE), several target antigens of encephalitogenic T- and B-cell responses have been identified. However, in human multiple sclerosis (MS) the target antigens of pathogenic T and B cells have remained conjectural. Here we discuss how recent methodological advances have offered new insights into the nature of B- and T-cell receptor repertoires expressed in MS tissues, and how novel approaches have helped to identify neurofascin as a target of anti-axonal autoantibodies in MS and EAE.

Jarius S, Paul F, Franciotta D, Waters P, Zipp F, Hohlfeld R, Vincent A, Wildemann B. · Weatherall Institute of Molecular Medicine, University of Oxford, UK. · Nat Clin Pract Neurol. · Pubmed #18334978 No free full text.

Abstract: Neuromyelitis optica (NMO) is a rare CNS inflammatory disorder that predominantly affects the optic nerves and spinal cord. Recent serological findings strongly suggest that NMO is a distinct disease rather than a subtype of multiple sclerosis. In NMO, serum antibodies, collectively known as NMO-IgG, characteristically bind to cerebral microvessels, pia mater and Virchow-Robin spaces. The main target antigen for this immunoreactivity has been identified as aquaporin-4 (AQP4). The antibodies are highly specific for NMO, and they are also found in patients with longitudinally extensive transverse myelitis without optic neuritis, which is thought to be a precursor to NMO in some cases. An antibody-mediated pathogenesis for NMO is supported by several observations, including the characteristics of the AQP4 antibodies, the distinct NMO pathology--which includes IgG and complement deposition and loss of AQP4 from spinal cord lesions--and emerging evidence of the beneficial effects of B-cell depletion and plasma exchange. Many aspects of the pathogenesis, however, remain unclear.

Weber MS, Hohlfeld R, Zamvil SS. · Department of Neurology and Program in Immunology, University of California, San Francisco, CA 94143, USA. · Neurotherapeutics. · Pubmed #17920545 No free full text.

Abstract: Glatiramer acetate (GA) (Copolymer-1, Copaxone, Teva, Israel, YEAK) is a polypeptide-based therapy approved for the treatment of relapsing-remitting multiple sclerosis. Most investigations have attributed the immunomodulatory effect of GAs to its capability to alter T-cell differentiation. Specifically, GA treatment is believed to promote development of Th2-polarized GA-reactive CD4(+) T-cells, which may dampen neighboring inflammation within the central nervous system. Recent reports indicate that the deficiency in CD4(+)CD25(+)FoxP3(+) regulatory T-cells in multiple sclerosis is restored by GA treatment. GA also exerts immunomodulatory activity on antigen presenting cells, which participate in innate immune responses. These new findings represent a plausible explanation for GA-mediated T-cell immune modulation and may provide useful insight for the development of new and more effective treatment options for multiple sclerosis.

Klatt J, Hartung HP, Hohlfeld R. · Novartis Pharma GmbH Nürnberg. · Nervenarzt. · Pubmed #17668161 No free full text.

Abstract: All currently available therapeutic options for multiple sclerosis have to be administered parenterally. Several oral substances are currently in the late clinical development stage. One of them, FTY720 (also known as fingolimod) is highlighted in this review. The biological effects of FTY720 are presented as well as animal data and first clinical data from a phase II trial in multiple sclerosis patients. The effects of FTY720 are based on an innovative approach and apparently target several key elements in the pathogenesis of multiple sclerosis. The first clinical data with FTY720 show very promising results, with a relapse reduction of over 50% compared to placebo and an acceptable safety profile. These results currently await confirmation in two international phase III studies which are recruiting patients worldwide.

Hohlfeld R. · Institute of Clinical Neuroimmunology, Campus Grosshadern, Ludwig-Maximilians University, Marchioninistr, 15, D-81366 Munich, Germany. · J Neurol Sci. · Pubmed #17459415 No free full text.

Abstract: Autoreactive T and B cells are regular components of the healthy immune system. It has been proposed that some of these cells might have a protective function. Recent studies support this notion by demonstrating that a) myelin-autoreactive T cells show neuroprotective effects in vivo, and b) activated antigen-specific human T cells and other immune cells produce bioactive brain-derived neurotrophic factor (BDNF) and other neurotrophic factors in vitro. Furthermore, neurotrophic factors are expressed in different types of inflammatory cells in brain lesions of patients with acute disseminated leukoencephalopathy or multiple sclerosis. It seems plausible that the immune cell-mediated import of neurotrophic factors into the central nervous system has functional consequences, with obvious implications for the therapy of multiple sclerosis and other neuroimmunological diseases.

Hohlfeld R, Wekerle H. · Institute for Clinical Neuroimmunology, Munich, Germany. · Nat Clin Pract Neurol. · Pubmed #16932490 No free full text.

Abstract: Multiple sclerosis (MS) is an immunopathological, presumably autoimmune, disease of the CNS. Several immunomodulatory treatments, including various preparations of interferon-beta, glatiramer acetate and mitoxantrone, have been approved for MS therapy. Because these agents are only partially effective, the search for better therapies continues. Therapeutic monoclonal antibodies (mAbs), a class of biotechnological agents, allow the precise targeting of molecules involved in pathological processes. Therapeutic mAbs have shown much promise in the treatment of many disorders, including inflammatory and putative autoimmune diseases such as MS. These agents have intrinsic limitations, however, such as induction of neutralizing 'anti-antibodies', systemic inflammatory reactions and severe adverse effects, some of which remain to be explained. Most notably, natalizumab (Tysabri), a mAb against alpha4 integrin, was very effective in suppressing MS activity, but had to be withdrawn from the market because several treated patients developed progressive multifocal leukoencephalopathy. This article reviews the state of development of various therapeutic mAbs for MS treatment.

Meinl E, Krumbholz M, Hohlfeld R. · Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Munich, Germany. · Ann Neurol. · Pubmed #16718690 No free full text.

Abstract: B cells have long played an enigmatic role in the scenario of multiple sclerosis pathogenesis. This review summarizes recent progress in our understanding of B-cell trafficking, survival, and differentiation in the central nervous system (CNS). We propose four possible routes of intrathecal immunoglobulin-producing cells. The inflammatory CNS provides a unique, B-cell-friendly environment, in which B lineage cells, notably long-lived plasma cells, can survive for many years, perhaps even for a lifetime. These new findings offer a plausible explanation for the notorious persistence and stability of cerebrospinal fluid oligoclonal bands. Furthermore, we highlight similarities and differences of intrathecal immunoglobulin production in multiple sclerosis patients and patients with other CNS inflammatory conditions. Finally, we outline the possibly double-edged effects of B cells and immunoglobulin in the CNS and discuss various therapeutic strategies for targeting the B-cell response.

Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H. · Department of Neuroimmunology, Max Planck-Institute for Neurobiology, Am Klopferspitz 18a, D-82152 Martinsried, Germany. · Neurol Sci. · Pubmed #16708174 No free full text.

Abstract: Autoreactive T cells are a regular component of the healthy immune system. It has been proposed that some of these autoreactive T cells even might have a protective function. Recent studies support this notion by demonstrating that: a) myelin-autoreactive T cells show neuroprotective effects in vivo, and b) activated antigen-specific human T cells and other immune cells produce bioactive brain-derived neurotrophic factor (BDNF) and other neurotrophic factors in vitro. Furthermore, BDNF is expressed in different types of inflammatory cells in brain lesions of patients with acute disseminated leukoencephalopathy or multiple sclerosis. It seems plausible that the immune cell-mediated import of BDNF and other neurotrophic factors into the central nervous system has functional consequences and implications for the therapy of multiple sclerosis and other neuroimmunological diseases.

Hoffmann LA, Kümpfel T, Heer I, Hohlfeld R. · Institut für Klinische Neuroimmunologie, Klinikum der Universität München-Grosshadern, München. · Nervenarzt. · Pubmed #16468069 No free full text.

Abstract: Pregnancy and family planning issues are prominent concerns in the medical care of multiple sclerosis patients, since the disease onset often coincides with a period of life that is decisive in this regard. Multiple sclerosis is a chronic disorder with an unpredictable course and is widely treated with long-term immunomodulatory agents, raising questions regarding the complications and effects of these therapies on pregnancy. This paper gives an overview of the relevant literature and provides a basis for individual counselling of this group of multiple sclerosis patients.

Gold R, Hartung HP, Hohlfeld R. · Institut für MS-Forschung, Bereich Humanmedizin der Universität Göttingen und Gemeinnützige Hertie-Stiftung, Göttingen. · Dtsch Med Wochenschr. · Pubmed #16374741 No free full text.

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Hohlfeld R, Kerschensteiner M, Stadelmann C, Lassmann H, Wekerle H. · Department of Neuroimmunology, Max-Planck-Institute for Neurobiology, Martinsried, Germany. · Ernst Schering Res Found Workshop. · Pubmed #16315607 No free full text.

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Farina C, Weber MS, Meinl E, Wekerle H, Hohlfeld R. · Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Martinsried, Germany. · Lancet Neurol. · Pubmed #16109363 No free full text.

Abstract: Glatiramer acetate is a synthetic random copolymer approved for the immunomodulatory therapy of relapsing-type multiple sclerosis (MS). Previous work has focused on the effects of this drug on T cells, especially the glatiramer-acetate-induced shift of the cytokine profile towards those characteristic of T-helper-2 (Th2) cells. Glatiramer acetate was thought to bring about this Th2 shift by acting like an altered peptide ligand but more recent work has shown that the drug notably affects the properties of antigen-presenting cells, such as monocytes and dendritic cells. These new observations might offer an explanation for the previously observed Th2 shift. In this review, we focus on these new findings. We address several controversial issues, including the possible neurotrophic effects of glatiramer acetate, the potential role of neutralising antibodies to the drug, and attempts to develop biomarkers of the treatment response. Finally, we will think about how a better understanding of glatiramer acetate might help the development of new immunomodulatory agents for MS.