Multiple Sclerosis: Gold 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.

Gold R, Grond M. · No affiliation provided · Nervenarzt. · Pubmed #18806979 No free full text.

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Chan A, Gold R. · No affiliation provided · Int MS J. · Pubmed #17509245 links to  free full text

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Gold R. · No affiliation provided · J Neuroimmunol. · Pubmed #16298433 No free full text.

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Gold R, Linington C. · No affiliation provided · Brain. · Pubmed #12076994 links to  free full text

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Linker R, Gold R, Luhder F. · Department of Neurology, St. Josef Hospital Bochum, Ruhr-University Bochum, 44791 Bochum, Germany. · Crit Rev Immunol. · Pubmed #19348610 No free full text.

Abstract: In the nervous system, neurotrophic factors play a role during development, especially for the differentiation of neuronal and glial cells. Moreover, they promote cell survival of neurons, axons, and oligodendrocytes, as well as their precursors, in vitro and in lesional paradigms. In recent years, several functions of neurotrophic factors outside the nervous system have been described, with a special focus on the immune system as well as on models of autoimmune demyelination, such as experimental autoimmune encephalomyelitis (EAE). In the family of neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were investigated. NGF may influence B-cell as well as T-cell function and particularly plays a role in macrophage migration into inflamed lesions. BDNF is produced by several immune-cell subtypes in vitro and also in multiple sclerosis (MS) plaques. This observation gave rise to the concept of neuroprotective autoimmunity, implying that immune-cell infiltration in the nervous system may not only be detrimental but may also play a beneficial role, for example, through the production of neurotrophic factors. In the family of neurotrophic cytokines, ciliary neurotrophic factor (CNTF) and leukemia inhibitory factor (LIF) share some common protective roles in axons and oligodendrocytes. In EAE, endogenous CNTF targets myelin, oligodendroglial cells, and axons. In contrast, LIF exerts protective functions on oligodendrocytes in some models but is also able to interact with the immune response and may modulate T-cell, monocyte and neutrophil functions. In summary, neurotrophic factors have distinct roles in the immune system during autoimmunity and may modulate immune responses as well as the susceptibility of the target tissue.

Stüve O, Gold R, Chan A, Mix E, Zettl U, Kieseier BC. · Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd., Dallas, TX 75216, USA. · J Neurol. · Pubmed #19300961 No free full text.

Abstract: Based on the results of two phase III clinical trials, the humanized recombinant monoclonal antibody natalizumab was approved for the treatment of relapsing forms of multiple sclerosis (MS). Since its initial approval in November 2004, it has been announced that six patients who received natalizumab in the context of clinical studies acquired an infection with the human polyoma virus JC and were diagnosed with progressive multifocal leukoencephalopathy (PML). Two of these individuals had a fatal outcome. Our groups recently showed that natalizumab therapy results in a reduction of CD4(+) T cells within the cerebrospinal fluid (CSF) that is ten-fold more pronounced than the reduction in the number of CD8(+) T lymphocytes. Interestingly, it appears that the effect of natalizumab on cell numbers in the CSF persists for at least 6 months after cessation of treatment. More recently, we studied the expression of major histocompatibility complex (MHC) I and II, and the number and phenotypes of leukocytes in cerebral perivascular spaces (CPVS). We observed that natalizumab therapy was associated with a significant decrease in the cell surface expression of MHC class II molecules, and the numbers of dendritic cells in CPVS. In addition, no CD4(+) T cells were detectable in this compartment. Our observations may explain the differential and prolonged effects of natalizumab therapy on different leukocyte subsets in the central nervous system. They also suggest that natalizumab treatment may result in prolonged immunosuppression in peripheral organs, and the delayed onset of adverse events.

Schröder A, Ellrichmann G, Chehab G, Schneider M, Linker RA, Gold R. · Neurologische Klinik, St. Josef Hospital, Ruhr-Universität Bochum, 44791, Bochum, Deutschland. · Nervenarzt. · Pubmed #19183926 No free full text.

Abstract: Rituximab, a human-mouse chimeric CD20 monoclonal antibody that depletes CD20-positive B cells, has already demonstrated efficacy in hematologic and rheumatologic diseases. Treatment with rituximab results in depletion of CD20-positive cells via multiple mechanisms, including complement-mediated or antibody-dependent cytotoxicity and apoptosis. Recent histopathologic and immunologic studies reveal an influence of B cells on the development and perpetuation of many chronic inflammatory diseases of the nervous system. Promising results with rituximab were already reported in the therapy of myasthenia gravis, immunoneuropathies, neuromyelitis optica, and multiple sclerosis, in which first controlled studies have been recently published. In this review we summarize available data from these reports and also discuss possible underlying molecular mechanisms.

Linker RA, Lee DH, Stangel M, Gold R. · Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany. · Expert Rev Neurother. · Pubmed #18986239 No free full text.

Abstract: All licensed disease-modifying drugs for the treatment of relapsing-remitting multiple sclerosis (MS) only display partial efficacy and hitherto require parenteral administration. Thus, there is a high demand for innovative and at the same time orally available MS therapeutics. Fumaric acids and their esters (FAE) may represent such a new class of compounds. FAE display immunomodulatory properties and may also exert neuroprotective effects, as shown in vitro as well as in experimental models of MS. A first Phase II study with the new, modified FAE BG00012/FAG-201 (BG-12) in relapsing-remitting MS revealed significant effects on MRI parameters such as gadolinium-enhancing lesions, T1 hypointense lesions and T2 lesion load after 24 weeks of treatment. The trial also underlined the safety and good tolerability of FAE that are already in clinical use for the systemic treatment of severe psoriasis. Presently, two Phase III studies are ongoing to investigate the clinical long-term efficacy of BG-12. In summary, FAE are potential candidates that may open a new therapeutic option for relapsing-remitting MS in the near future.

Linker RA, Kieseier BC, Gold R. · Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Gudrunstrasse 56, 44791 Bochum, Germany. · Trends Pharmacol Sci. · Pubmed #18804288 No free full text.

Abstract: In recent years, large efforts have been undertaken to establish new therapeutic options for the treatment of multiple sclerosis (MS). So far, all of these strategies more or less specifically target subsets of the immune response in MS, including not only activation and expansion of T cells, their circulation and transmigration over the blood-brain barrier but also other cell types such as B cells and probably also natural killer cells. Here, we review available data on the most promising (at present) new therapeutic approaches. These involve the orally available compounds cladribine, FTY720, fumaric-acid esters, laquinimod and teriflunomide in addition to the monoclonal antibodies alemtuzumab, daclizumab, natalizumab and rituximab. After successful completion of Phase III studies, these compounds might have the potential to add to the current therapeutic armentarium especially for relapsing remitting disease courses in the near future, possibly opening the way to a more individualized treatment.

Lee DH, Linker RA, Gold R. · Department of Neurology at St Josef-Hospital, Ruhr-University Bochum, Bochum, Germany. · Int MS J. · Pubmed #18713564 links to  free full text

Abstract: The recent years have witnessed great efforts in establishing new therapeutic options for multiple sclerosis (MS). There is a clear need for more effective, safe and at the same time orally available treatment options. Here we review the potential of fumaric acid esters (FAE) as a new therapeutic option for MS. FAE have been claimed to possess immunomodulatory properties and are already in clinical use as second-line therapy for severe systemic psoriasis. They also displayed beneficial effects in experimental autoimmune encephalomyelitis (EAE), a model mimicking many aspects of MS. In addition, FAE may also act on the blood-brain barrier and exert neuroprotective properties via activation of anti-oxidative pathways. A first magnetic resonance imaging (MRI) based Phase II study in relapsing-remitting MS (RRMS) revealed a dose-dependent, significant reduction of brain lesion activity for BG-12, a dimethyl FAE compound. Currently, two multicentre, Phase III studies for testing clinical efficacy in RRMS are initiated. In view of their profile, FAE compounds may have the potential to add to our therapeutic options in RRMS in the future.

Linker RA, Gold R. · Department of Neurology, St Josef Hospital, Ruhr-University, Bochum, Germany. · Curr Opin Neurol. · Pubmed #18451723 No free full text.

Abstract: PURPOSE OF REVIEW: The most relevant indications for the use of intravenous immunoglobulins and plasma exchange in neurological disorders are described, with special emphasis on the data from clinical trials and aspects of specific importance for clinical routine. RECENT FINDINGS: Much therapeutic success in neuromuscular and neuroimmunological diseases came with the therapeutic introduction of intravenous immunoglobulin and plasma exchange. Today, intravenous immunoglobulins and plasma exchange are preferentially used to treat acute Guillain-Barré syndrome, myasthenic crisis, acute or chronic inflammatory demyelinating polyneuropathy, or stiff person syndrome. Intravenous immunoglobulins also proved valuable for refractory dermatomyositis or multifocal motor neuropathy. Owing to their generally mild side effects, intravenous immunoglobulins have now been tested in many more indications, sometimes with surprising clinical effects as in the case of postpolio syndrome. While intravenous immunoglobulin is not the treatment of first choice in many immune-mediated disorders of the central nervous system, plasma exchange has become an integral part of escalating relapse therapy in relapsing-remitting multiple sclerosis. SUMMARY: In recent years, our knowledge on neurological disease mechanisms has broadened and more specific treatment alternatives have become available. Yet, established therapeutic options such as intravenous immunoglobulins and plasma exchange are still high on the list for many neuroimmunological disorders. Controlled trials have led to a refinement of the application of both treatment modalities, whose targets can be sometimes congruent, but in other cases also very distinct.

Gold R. · University of Bochum, St. Josef-Hospital, Dept. of Neurology, Gudrunstr. 56, 44791, Bochum, Germany. · J Neurol. · Pubmed #18317677 No free full text.

Abstract: The last years have seen enormous progress in our understanding of pathophysiology of multiple sclerosis. In addition, the armamentarium of available immunomodulatory or immunosuppressive therapies has greatly increased, especially for the relapsing remitting form of the disease. Since their therapeutic efficacy is often limited in individual patients, it is conceivable that combination therapies may bring improved clinical efficacy while managing increasing side effects and toxicity. The combination of agents with additive or synergistic modes of action is of particular interest. Combination of the two classes of recognised firstline treatment, a beta-interferon and glatiramer acetate is currently under evaluation in a large Phase III trial. However, there are theoretical reasons for thinking that such a combination may not be particularly beneficial. None of the combination studies performed with beta-interferons to date have shown unequivocal evidence of benefit, including combinations with statins, natalizumab and azathioprine. On the other hand, for glatiramer acetate, the combination with mitoxantrone used as induction therapy may be of interest and preliminary data on combination with minocycline are also promising.

Gold R, Jawad A, Miller DH, Henderson DC, Fassas A, Fierz W, Hartung HP. · Department of Neurology at St. Josef-Hospital, University of Bochum, Gudrunstrasse 56, D-47901 Bochum, Germany. · J Neuroimmunol. · Pubmed #17499366 No free full text.

Abstract: Natalizumab (Tysabri) (anti-VLA4) is a novel agent for treatment of relapsing multiple sclerosis (MS) [Polman C.H., O'Connor P.W., Havrdova E. et al., 2006. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N. Engl. J. Med. 354, 899-910.]. Controlled trials have shown considerable efficacy in preventing relapses, in excess of that seen for other EMEA-approved disease modulating drugs. While well-tolerated and generally safe, three cases of progressive multifocal leukoencephalopathy (PML) occurred in the context of 3 clinical trials encompassing some 3300 patients using this drug in multiple sclerosis and Crohn's disease. Immune compromised patients, such as those receiving immunosuppressive medications, are at a higher risk of developing PML. Natalizumab was recently approved for the treatment of relapsing forms of MS. This includes patients who had an inadequate response to other therapies and some of these patients will have already received immunosuppressants. These agents have the potential to cause prolonged effects on the immune system, even after dosing has been discontinued. Determining that these patients are not immunocompromised will be an important safety issue to consider prior to the initiation of natalizumab therapy. This short report summarizes interdisciplinary practical recommendations from specialists in neuroimmunology, rheumatology, transplantation medicine and clinical immunology.

Gold R, Stangel M, Dalakas MC. · Department of Neurology at St Josef Hospital, University of Bochum, Germany. · Nat Clin Pract Neurol. · Pubmed #17205073 No free full text.

Abstract: Over the past few years, we have achieved increasing success in the treatment of a number of autoimmune-mediated disorders affecting nerves and muscles. This success is partly attributable to the use of high-dose polyclonal intravenous immunoglobulin (IVIg), which has dramatically changed our treatment options. On the basis of results from controlled, but non-FDA-approved, clinical trials, IVIg is now the treatment of choice for Guillain-Barré syndrome, chronic idiopathic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy; IVIg offers rescue therapy for patients with rapidly worsening myasthenia gravis, and is a second-line therapy for dermatomyositis, stiff-person syndrome, and pregnancy-associated or postpartum multiple sclerosis attacks. The ability of IVIg to treat such immunologically diverse disorders effectively, coupled with its excellent safety profile, has led clinicians to use the drug more liberally, even in diseases for which the data are weak and not evidence-based and in patients with coexisting conditions. Use of IVIg for such indications can increase the risk of complications while raising the cost of the drug. Practical issues regarding dosing and frequency of infusions generate dilemmas in clinical practice. In this article, we review the current indications for IVIg treatment, address practical issues related to the use and costs of the drug, and summarize its mechanisms of action.

Reichardt HM, Gold R, Lühder F. · University of Würzburg, Molecular Immunology, Institute for Virology and Immunobiology, Versbacher Strasse 7, 97078 Würzburg, Germany. · Expert Rev Neurother. · Pubmed #17144780 No free full text.

Abstract: Glucocorticoids exert a variety of immunomodulatory activities. Since changes in glucocorticoid homeostasis impact on susceptibility to autoimmune diseases, and synthetic glucocorticoids are widely used in the treatment of multiple sclerosis, a detailed understanding of their mechanism of action is desirable. Experimental autoimmune encephalomyelitis is a common animal model that mirrors many hallmarks of multiple sclerosis, a chronic inflammatory disease of the CNS with presumed autoimmune origin. Experimental autoimmune encephalomyelitis has been instrumental for many years in studying multiple sclerosis, revealing the blood-brain barrier, the microglia and T-cell apoptosis as major targets of glucocorticoids in this disease. Despite the great advances in the field, the answers to many questions concerning the mechanism of glucocorticoids; for example, the contribution of nongenomic effects or the cell-type specificity of their action, remain elusive. This review will critically discuss what we have learned so far from the analysis of animal models of the molecular mode of therapeutic and endogenous glucocorticoid action in multiple sclerosis. With this knowledge in mind, we should be able to further improve the management of multiple sclerosis using this class of drugs.

Gold R, Linington C, Lassmann H. · Institute for Multiple Sclerosis research, Department of Experimental and Clinical Neuroimmunology, University of Goettingen and Gemeinnützige Hertie Stiftung, Göttingen, Germany. · Brain. · Pubmed #16632554 links to  free full text

Abstract: In view of disease heterogeneity of multiple sclerosis and limited access to ex vivo specimens, different approaches must be undertaken to better understand disease pathogenesis and new therapeutic challenges. Here, we critically discuss models of experimental autoimmune encephalomyelitis (EAE) that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches. By using EAE models we have understood mechanisms of T-cell mediated immune damage of the CNS, and the associated effector cascade of innate immunity. Also, the importance of humoral components of the immune system for demyelination has been delineated in EAE, before it was applied therapeutically to subtypes of multiple sclerosis. Yet, similar to multiple sclerosis, EAE is also heterogeneous and influenced by the selected autoantigen, species and the genetic background. In particular, the relevance of cytotoxic CD8 T cells for human multiple sclerosis has been underestimated in most EAE models, and no EAE model exists that mimics primary progressive disease courses of multiple sclerosis. Seventy years after the first description of EAE and the publication of >7000 articles, we are aware of the obvious limitations of EAE as a model of multiple sclerosis, but feel strongly that when used appropriately it will continue to provide a crucial tool for improving our understanding and treatment of this devastating disease.

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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Linker RA, Stadelmann C, Diem R, Bähr M, Brück W, Gold R. · Institut für Multiple Sklerose Forschung, Bereich Humanmedizin, Georg-August-Universität Göttingen und Gemeinnützige Hertie-Stiftung, Göttingen. · Fortschr Neurol Psychiatr. · Pubmed #16355314 No free full text.

Abstract: In this article, recent advances in the research on pathogenesis and therapy of multiple sclerosis (MS) will be summarized. New evidence from clinical studies, imaging, histopathology and experimental models are discussed with a focus on neurodegenerative aspects and evidence from recent therapeutic studies. During the last decade, important advances in immunotherapy have been achieved, which proved especially useful for patients with relapsing remitting MS. The introduction of interferons and glatiramer acetate into MS therapy often leads to a stabilization of the disease course if administered adequately and early. The pathogenetic insights presented here may open new avenues for innovative immunomodulatory approaches and lead to an individualized MS therapy in the future. Neuroprotective treatment strategies aim at the protection of glial and neuronal cells.

Linker RA, Sendtner M, Gold R. · Department of Neurology, Clinical Research Group for Multiple Sclerosis, University of Würzburg, Josef-Schneider-Strasse 11, D-97080 Würzburg, Germany. · J Neurol Sci. · Pubmed #15949503 No free full text.

Abstract: The major pathological hallmarks of multiple sclerosis (MS) comprise inflammation, demyelination with associated gliosis and axonal damage, which most likely correlates with persisting disability. Axonal damage can occur by several mechanisms. This article focuses on myelin disintegration and direct immune attack on axons by CD8-positive T-cells as two possible scenarios for axonal injury. As protoypic models, we investigated experimental autoimmune encephalomyelitis (EAE) in ciliary neurotrophic factor gene knockout mice (CNTF-/- mice) with severe myelin pathology and EAE in beta-2 microglobulin gene knockout mice (beta2m-/- mice) lacking CD8-positive T-cells. The results from these studies indicate that the trigger attack for axonal injury even in a well-defined experimental design can be multi-faceted. No single factor seems to be absolutely necessary for the initiation of the process, but they rather act in concert and orchestrate tissue destruction, inflammation and regeneration. Some mechanisms of primary or secondary axonal damage may be shared between inflammatory and degenerative diseases of the nervous system, thereby establishing a link which might be of importance for future therapeutic strategies.

Stangel M, Gold R. · Neurologische Klinik, Medizinische Hochschule Hannover. · Nervenarzt. · Pubmed #15902390 No free full text.

Abstract: The immunomodulatory treatment of multiple sclerosis (MS) with high-dose intravenous immunoglobulins (IVIg) has been discussed with some controversy in the context of evidence-based medicine. The recent publication of eight trials investigating several aspects of MS has shed some more light on the role of IVIg treatment in MS. Here we summarize and critically discuss the new data in the context of previous studies on this treatment. In relapsing-remitting MS, IVIg remain a second-line treatment when other licensed treatments are not possible. Currently there is no role for IVIg in secondary progressive MS. Similarly, the use of IVIg during an acute relapse shows no benefit in addition to standard steroid treatment. The initiation of IVIg therapy after a clinically isolated syndrome has delayed the occurrence of definite MS, and this may become a new indication. Furthermore, previous data suggesting that IVIg can reduce the incidence of postpartal relapses have been substantiated. However, those trials unfortunately lack appropriate internal control groups. By and large, previous recommendations for the use of IVIg in MS are supported by the new data.

Ibrahim SM, Gold R. · Department of Immunology, University of Rostock, Rostock, Germany. · Curr Opin Neurol. · Pubmed #15891405 No free full text.

Abstract: PURPOSE OF REVIEW: Multiple sclerosis (MS) is the most common chronic inflammatory neurological disease. Despite major advances the aetiology of this disease it is still not completely understood. In the post-genome era, advances in global screening technologies offer an opportunity to accelerate the search of new pathological pathways and to identify new therapeutic targets. Some recent publications using novel global screening methods at the genome, transcriptome, proteome and metabolome levels are discussed. RECENT FINDINGS: The genetic association of susceptibility to MS with loci outside the MHC has been reconfirmed. Evidence of parent-of-origin and seasonal effects on disease susceptibility add further complexity to the genetics of MS. The search for MS susceptibility genes continues using the candidate-gene approach as well as large-scale single-nucleotide-polymorphism association studies and novel cross-species synteny analysis. Genome-wide expression profiling using microarrays produced numerous therapeutic targets and is progressing towards profiling of rare cells. Advances in classical proteomics methods paved the way to new initiatives aiming at determining the proteome of the nervous system in normal and diseased states. Although progress is still slow, array-based methods are making an impact on the MS field. SUMMARY: The complexity of MS is clearly reflected in the latest findings using global profiling methods. Nevertheless, these new technologies are confirming some of the basic aspects of the disease pathophysiology, i.e. its polygenicity, the central role of neuroinflammation and the emerging neurodegenerative processes. These data are primarily the results of genomic approaches, yet promising attempts are also made using proteomics and metabolomics.

Rieckmann P, Toyka KV, Bassetti C, Beer K, Beer S, Buettner U, Chofflon M, Götschi-Fuchs M, Hess K, Kappos L, Kesselring J, Goebels N, Ludin HP, Mattle H, Schluep M, Vaney C, Baumhackl U, Berger T, Deisenhammer F, Fazekas F, Freimüller M, Kollegger H, Kristoferitsch W, Lassmann H, Markut H, Strasser-Fuchs S, Vass K, Altenkirch H, Bamborschke S, Baum K, Benecke R, Brück W, Dommasch D, Elias WG, Gass A, Gehlen W, Haas J, Haferkamp G, Hanefeld F, Hartung HP, Heesen C, Heidenreich F, Heitmann R, Hemmer B, Hense T, Hohlfeld R, Janzen RW, Japp G, Jung S, Jügelt E, Koehler J, Kölmel W, König N, Lowitzsch K, Manegold U, Melms A, Mertin J, Oschmann P, Petereit HF, Pette M, Pöhlau D, Pohl D, Poser S, Sailer M, Schmidt S, Schock G, Schulz M, Schwarz S, Seidel D, Sommer N, Stangel M, Stark E, Steinbrecher A, Tumani H, Voltz R, Weber F, Weinrich W, Weissert R, Wiendl H, Wiethölter H, Wildemann U, Zettl UK, Zipp F, Zschenderlein R, Izquierdo G, Kirjazovas A, Packauskas L, Miller D, Koncan Vracko B, Millers A, Orologas A, Panellus M, Sindic CJ, Bratic M, Svraka A, Vella NR, Stelmasiak Z, Selmaj K, Bartosik-Psujik H, Mitosek-Szewczyk K, Belniak E, Mochecka A, Bayas A, Chan A, Flachenecker P, Gold R, Kallmann B, Leussink V, Mäurer M, Ruprecht K, Stoll G, Weilbach FX, Anonymous00046. · Dept. of Neurology, Josef-Schneider-Str. 11, 97080, Würzburg, Germany. · J Neurol. · Pubmed #15592728 No free full text.

Abstract: Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

Ruprecht K, Klinker E, Dintelmann T, Rieckmann P, Gold R. · Clinical Research Unit for Multiple Sclerosis and Neuroimmunology, Julius-Maximilians University, Josef-Schneider Str. 11, 97080 Würzburg, Germany. · Neurology. · Pubmed #15452303 No free full text.

Abstract: The authors reviewed a series of 10 consecutive patients treated with plasma exchange (PE) for acute, severe optic neuritis (ON) largely unresponsive to previous high-dose IV glucocorticosteroids. PE was associated with an improvement of visual acuity according to the study criteria in 7 of 10 patients. On follow-up, three of these patients continued to improve, two remained stable, and two had worsened again. PE may be beneficial as an escalating treatment in a subset of patients with severe ON. A controlled trial is warranted.

Bayas A, Gold R. · Department of Neurology, University of Würzburg, Josef-Schneider-Str. 11, 97080 Würzburg, Germany. · J Neurol. · Pubmed #14712395 No free full text.

Abstract: In 1993, interferon beta-1b (IFN beta-1b, Betaferon/Betaseron) was the first interferon approved in the USA for relapsing-remitting multiple sclerosis (RRMS). Since then, dose-dependent effects of IFN beta in MS have been extensively discussed. Such effects had already been observed in the pivotal trial and were followed by dose comparison trials with IFN beta-1a. Later, the therapeutic efficacy of IFN beta-1b could also be demonstrated in secondary progressive (SP) MS patients. We learnt from further studies that benefit from IFN beta in SPMS seems to be most pronounced in those patients still having active disease with superimposed relapses or clear progression. The most common IFN beta-related adverse events, especially in the early treatment phase, have been flu-like symptoms and injection-site reactions. The consequent management of those as well as of other, less frequent, side-effects turned out to be of tremendous importance to ensure patients' compliance. Based on the experience of 10 years, IFN beta-1b belongs to the firstline therapeutics in RR and SPMS.