Multiple Sclerosis: Giovannoni G

Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G, Keir G, Ohman S, Racke MK, Sharief M, Sindic CJ, Sellebjerg F, Tourtellotte WW. · Department of Medicine (Neurology), University of Ottawa, Multiple Sclerosis Research Clinic, The Ottawa Hospital, Ottawa, Ontario, Canada. · Arch Neurol. · Pubmed #15956157 links to  free full text

Abstract: New criteria for the diagnosis of multiple sclerosis (MS) were published as the result of an internationally formed committee. To increase the specificity of diagnosis and to minimize the number of false diagnoses, the committee recommended the use of both clinical and paraclinical criteria, the latter involving information obtained from magnetic resonance imaging, evoked potentials, and cerebrospinal fluid (CSF) analysis. Although rigorous magnetic resonance imaging requirements were provided, the "new criteria paper" fell short in terms of guidelines as to how the CSF analysis should be performed and simply equated the IgG index with isoelectric focusing, without any justification. The spectrum of parameters analyzed and methods for CSF analysis differ worldwide and often yield variable results in terms of sensitivity, specificity, accuracy, and reliability, with no decided "optimal" CSF test for the diagnosis of MS. To address this question specifically, an international panel of experts in MS and CSF diagnostic techniques was convened and the result was this article, representing a consensus of all the participants. These recommendations for establishing a standard for the evaluation of CSF in patients suspected of having MS should greatly complement the new criteria in ensuring that a correct diagnosis of MS is being made.

Giovannoni G. · No affiliation provided · Neurology. · Pubmed #18519868 No free full text.

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Hintzen RQ, Giovannoni G. · No affiliation provided · Neurology. · Pubmed #18362264 No free full text.

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Amor S, Giovannoni G. · No affiliation provided · Mult Scler. · Pubmed #17967836 No free full text.

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Giovannoni G. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #16709582 No free full text.

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Giovannoni G. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #16361582 links to  free full text

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Giovannoni G, Goodman A. · No affiliation provided · Neurology. · Pubmed #16009876 No free full text.

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Giovannoni G. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #15314107 links to  free full text

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Giovannoni G, Bever CT. · No affiliation provided · Neurology. · Pubmed #12525709 No free full text.

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Giovannoni G, Munschauer FE, Deisenhammer F. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #12397132 links to  free full text

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Giovannoni G, Thorpe J. · No affiliation provided · Neurology. · Pubmed #11673570 No free full text.

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Salvetti M, Giovannoni G, Aloisi F. · Department of Neurology and Center for Experimental Neurological Therapy, S. Andrea Hospital, University of Rome La Sapienza, Rome, Italy. · Curr Opin Neurol. · Pubmed #19359987 No free full text.

Abstract: PURPOSE OF REVIEW: Recent studies have revived interest in the long-scrutinized association between Epstein-Barr virus (EBV) and multiple sclerosis (MS). We review this evidence and discuss it in relation to MS pathological and clinical features and patients' response to immunosuppressive therapies. RECENT FINDINGS: Serological evidence of previous exposure to EBV in children with MS supports a role for EBV infection early in MS pathogenesis, as already indicated by prospective studies in adults. Higher antibody titers and T-cell responses to EBV in patients compared to healthy EBV carriers indicate possible continuous viral reactivation, whereas there is some evidence that EBV could break immune tolerance to myelin antigens through molecular mimicry. Detection of EBV-infected B-cells in patients' brain raises the possibility that intrathecal B-cell abnormalities and T-cell-mediated immunopathology in MS are the consequence of a persistently dysregulated EBV infection. Accordingly, targeting T-cells and/or B-cells with monoclonal antibody therapies ameliorates MS. Whether EBV has a causative or pathogenic role in MS can now be addressed in relation to genetic, hormonal and other environmental influences that may affect EBV-host interactions. SUMMARY: By shedding light on the involvement of EBV in MS, these findings will pave the way to disease prevention and increase the therapeutic index of future treatments.

Cohen BA, Oger J, Gagnon A, Giovannoni G. · Davee Department of Neurology, Feinberg School of Medicine, Northwestern University, 710 North Lake Shore Drive, Abbott Hall 1121, Chicago IL 60611, USA. · J Neurol Sci. · Pubmed #18822434 No free full text.

Abstract: Administered proteins are inherently immunogenic, which may influence their efficacy or safety when used therapeutically. A review of the published literature was performed to compare and evaluate the development and consequences of antibodies against therapeutic protein agents for the treatment of multiple sclerosis (MS). Interferon beta (IFNbeta), glatiramer acetate (GA), and natalizumab are all protein-based therapeutic agents approved to treat MS and are associated with the development of antibodies. Both binding antibodies and neutralizing antibodies (NAbs) develop to varying degrees in patients treated with any of the formulations of IFNbeta. Comparison between studies is complicated by differences in methods, assays, criteria for determining NAb positivity, treatment duration, and fluctuation of NAb status. Despite these confounding factors, current data indicate that high-titer persistent NAbs may be relevant in terms of their effect on IFNbeta bioavailability and bioefficacy. GA-reactive antibodies developed in a high proportion of GA-treated patients, but the clinical relevance of these antibodies remains to be established. Immunogenicity against natalizumab was associated with reduced efficacy and increased incidence of infusion reactions. Other emerging monoclonal antibody therapeutics have also been associated with the development of antibodies. Experience with generic biosimilars of other protein therapeutics suggests that the immunogenicity of generic biosimilar agents cannot be assumed and must be established for each formulation.

Giovannoni G, Kinkel P, Vartanian T. · Neuroimmunology Unit, Neuroscience Centre, Institute of Cell and Molecular Science, Queen Mary's School of Medicine and Dentistry, Whitechapel, London. · Rev Neurol Dis. · Pubmed #18195670 No free full text.

Abstract: Multiple sclerosis (MS) is the most common cause of nontraumatic severe neurological disability in young adults. If left untreated, most individuals with MS will accumulate significant physical and/or cognitive disability as the consequence of demyelination and axonal injury. Treatment has focused on disease-modifying therapies (DMTs) and questions remain about timing and indications for their use. Natalizumab is a humanized monoclonal antibody directed against alpha4-integrin that prevents migration of leukocytes into the brain parenchyma. The clinical and radiological efficacy of natalizumab has been shown in several randomized trials; however, adverse events associated with natalizumab have limited its use as a first-line agent. In this review we compare current recommendations for the use of first-line DMTs, adverse events associated with MS therapies, and differences between the practices in North American and the European Union.

Jaber A, Driebergen R, Giovannoni G, Schellekens H, Simsarian J, Antonelli M. · Merck Serono International SA, Geneva, Switzerland (an affiliate of Merck KGaA, Darmstadt, Germany). · Drugs R D. · Pubmed #17963425 No free full text.

Abstract: The rapid evolution of the biopharmaceutical industry and the development of innovative technologies have provided an opportunity to improve recombinant interferon (IFN)-beta formulations. A number of strategies have been developed to improve the stability, tolerability and immunogenicity of IFNbeta formulations that are used in the long-term treatment of patients with multiple sclerosis (MS). This review focuses on the production of recombinant IFNs and discusses the development of one such biopharmaceutical, Rebif New Formulation (RNF).RNF was developed with the aim of further improving the tolerability and immunogenicity of Rebif, an approved IFNbeta-1a formulation administered subcutaneously three times per week (sc tiw).To this end, numerous candidate drug vehicles and formulations were developed. However, unlike other formulations of IFNbeta, the new candidate formulations in this case were free from all serum-derived components. Specifically, each RNF candidate was free from human serum albumin and produced without fetal bovine serum. The physicochemical stability, injection-site tolerability, pharmacokinetic profile and immunogenic potential of each candidate formulation were systematically tested. This involved initial screening of a large pool of formulations for promising candidates. Two candidate formulations were selected and subjected to further, extensive evaluation.Ex vivo T-cell assays were used to compare the immunogenicity of RNF candidates with that of the current (at the time of writing) approved formulation and an IFNbeta standard. A single RNF candidate induced less T-cell activation, in terms of proliferation and proinflammatory cytokine secretion, than the other two formulations. The results provided ex vivo evidence of the improved immunogenic potential of RNF. A murine model was used to compare the relative immunogenicity of RNF in vivo with two approved formulations of IFNbeta-1a. Mice treated with RNF developed neutralising antibodies more slowly and produced lower titres than mice treated with equivalent doses of the current IFNbeta-1a sc tiw formulation or another approved IFNbeta-1a formulation administered intramuscularly once per week (Avonex). RNF also demonstrated better local tolerability than the current IFNbeta-1a sc tiw formulation after single subcutaneous doses in healthy volunteers.One RNF candidate was superior to the others in all preclinical and phase I studies, and was chosen as the final RNF. This formulation is currently undergoing assessment in a 96-week, phase IIIb clinical trial in patients with MS. This single-arm, open-label, multicentre study will compare the immunogenicity and tolerability of RNF with historical data on the current formulation; results of a 48-week, interim analysis indicate that RNF has improved local tolerability and immunogenicity compared with the current formulation. It is anticipated that the benefits of RNF will translate into an improved long-term benefit-to-risk profile. Further assessment of RNF and other MS drugs is ongoing with the aim of enhancing the therapeutic options available for patients with MS.

Farrell RA, Giovannoni G. · Department of Neuroimmunology, Institute of Neurology, London, UK. · Mult Scler. · Pubmed #17548434 No free full text.

Abstract: Interferon Beta is well established as a first line agent to treat relapsing remitting Multiple Sclerosis. It frequently induces the formation of neutralising anti-Interferon Beta Antibodies (Nabs) which may abrogate the clinical efficacy of the drug. Numerous studies have shown a loss of bioactivity of the drug in the presence of Nabs. The focus has shifted to reliable quantification of Nabs and their appropriate incorporation into clinical practice. Here we review the development and persistence of Nabs, the effect on Interferon beta bioactivity, clinical and para-clinical autocome measures in trials, Nab assays and discuss management strategies to optimise the use of Interferon beta in relapsing remitting MS.

Giovannoni G, Ebers G. · Institute of Cell and Molecular Science, Queen Mary University London, London, UK. · Curr Opin Neurol. · Pubmed #17495618 No free full text.

Abstract: PURPOSE OF REVIEW: We review current thinking on the aetiology of multiple sclerosis, how genetic susceptibility interacts with environmental risk factors at the population level, multiple sclerosis-associated risk factors and contemporary causation theory. RECENT FINDINGS: Two large genomic studies have confirmed the unambiguous associations with the DRB1 and DQB alleles of the human leucocyte antigen class II region. No other region with genome-wide significance has been identified. Family-based genetic epidemiological approaches have found no evidence of nongenetic transmissibility. This indicates that the action of the environment in influencing multiple sclerosis risk is operative at a macroenvironmental or population level, and not within families or the microenvironment. Environmental factors receiving renewed attention include vitamin D status, Epstein-Barr virus infection and smoking. Bradford Hill's criteria for causation have been modified and should be adopted as a framework for demonstrating causation in relationship to multiple sclerosis. SUMMARY: Multiple sclerosis is a complex disease because of interaction between genes and the environment. Any theory of causation for a specific agent will have to be congruent with the biology of the disease.

Hartung HP, Polman C, Bertolotto A, Deisenhammer F, Giovannoni G, Havrdova E, Hemmer B, Hillert J, Kappos L, Kieseier B, Killestein J, Malcus C, Comabella M, Pachner A, Schellekens H, Sellebjerg F, Selmaj K, Sorensen PS. · Dept. of Neurology, Heinrich-Heine-University, Moorenstrasse 5, 40225, Düsseldorf, Germany. · J Neurol. · Pubmed #17457510 No free full text.

Abstract: Interferon beta (IFNbeta) therapy for multiple sclerosis (MS) is associated with a potential for the development of neutralising antibodies (NAbs) that negatively affect therapy. Several factors influence the development of NAbs, such as lack of complete sequence homology with the endogenous IFNbeta sequence, frequency of administration, level of dose and formulation of IFNbeta. Taken together, the evidence that NAb status reduces clinical efficacy in MS patients is strong. Standardised assays for NAbs are lacking, and titres vary over time. NAb testing is a critical component of care for MS patients because it provides information on one of the most important factors determining clinical responsiveness to IFNbeta therapy. This expert panel report attempts to move the field towards resolution of the remaining issues and considers several aspects of NAbs, including their clinical relevance, factors influencing immunogenicity, assays to quantify NAbs and the definition of clinically relevant titres.

Giovannoni G. · Department of Neuroinflammation, Institute of Neurology, University College London, Queen Square, London, UK. · Dis Markers. · Pubmed #17124340 No free full text.

Abstract: Cerebrospinal fluid (CSF) is the body fluid closest to the pathology of multiple sclerosis (MS). For many candidate biomarkers CSF is the only fluid that can be investigated. Several factors need to be standardized when sampling CSF for biomarker research: time/volume of CSF collection, sample processing/storage, and the temporal relationship of sampling to clinical or MRI markers of disease activity. Assays used for biomarker detection must be validated so as to optimize the power of the studies. A formal method for establishing whether or not a particular biomarker can be used as a surrogate end-point needs to be adopted. This process is similar to that used in clinical trials, where the reporting of studies has to be done in a standardized way with sufficient detail to permit a critical review of the study and to enable others to reproduce the study design. A commitment must be made to report negative studies so as to prevent publication bias. Pre-defined consensus criteria need to be developed for MS-related prognostic biomarkers. Currently no candidate biomarker is suitable as a surrogate end-point. Bulk biomarkers of the neurodegenerative process such as glial fibrillary acidic protein (GFAP) and neurofilaments (NF) have advantages over intermittent inflammatory markers.

Giovannoni G, Cutter GR, Lunemann J, Martin R, Münz C, Sriram S, Steiner I, Hammerschlag MR, Gaydos CA. · Department of Neuroinflammation, Institute of Neurology, University College London, UK. · Lancet Neurol. · Pubmed #16987736 No free full text.

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Giovannoni G, Chapman MD, Thompson EJ. · Department of Neuroimmunology, Institute of Neurology, Queen Square, London WC1N 3BG, UK. · J Neuroimmunol. · Pubmed #16934336 No free full text.

Abstract: Affinity maturation has previously been shown with assays for total IgG for specific antigens using the technique of competition by chaotropic ions. We have extended this technique to individual clones and followed the maturation of clones during the course of herpes encephalitis. This has important implications for our understanding of the pathogenesis of multiple sclerosis.

Farrell R, Heaney D, Giovannoni G. · Department of Neuroinflammation, Institute of Neurology, Queen Square, London, WC1N 3BG, UK. · Expert Opin Emerg Drugs. · Pubmed #16262563 No free full text.

Abstract: Multiple sclerosis (MS) is the most common neurological cause of disability in young people. The disease-modifying treatments, IFN-beta and glatiramer acetate, have been widely available over the last decade and have shown a beneficial effect on relapse rate and magnetic resonance imaging parameters of disease activity; however, their effect on disease progression and disability is modest. Therefore, the search for alternative treatment strategies continues. As understanding of the heterogeneous pathophysiology of MS has increased, emphasis has shifted to more selective therapy that targets components of the inflammatory cascade and the promotion of remyelination and neuroprotection. These agents target the blood-brain barrier, systemic immune dysfunction, local inflammation and neurodegeneration. Combination therapies are being investigated for patients who fail first-line treatments. Many new drugs are being developed and tested that address these issues with the aim of finding a more effective and convenient therapy. These include humanized monoclonal antibodies such as daclizumab (IL-2 antagonist), oral immunomodulators such as sirolimus and statins and neuroprotective agents such as NMDA antagonists and Na+-channel blockers. Many of the treatments discussed in this review are still at early stages of development, but provide exciting potential treatment options; others have proved disappointing in larger extended-phase studies.

Lim ET, Giovannoni G. · University College London, Department of Neuroinflammation, Institute of Neurology, Queen Square, London, WC1N 3BG, UK. · Expert Rev Neurother. · Pubmed #15938671 No free full text.

Abstract: Multiple sclerosis is an organ-specific autoimmune disease, characterized pathologically by cell-mediated inflammation, demyelination and variable degrees of axonal loss. Although inflammation is considered central to the pathogenesis of multiple sclerosis, to date, the only licensed and hence widely used multiple sclerosis immunotherapies are interferon-beta, glatiramer acetate and mitoxantrone. This review discusses the immunopathogenesis of multiple sclerosis, focusing on a number of emerging immunotherapies. A number of new approaches likely to manipulate the immunopathogenesis of multiple sclerosis and which may ultimately allow for the development of more effective immunotherapy are also highlighted.

Giovannoni G. · Department of Neuroinflammation, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. · J Neurol. · Pubmed #15549353 No free full text.

Abstract: A proportion of people with multiple sclerosis (MS) treated with interferon (IFN) a develop neutralising anti-IFN beta antibodies (NABs). The immunogenicity of the available commercial compounds relates to the genetic structure of the IFN beta molecule, its mode of production, glycosylation status, aggregate formation, commercial formulation, potency, dose, frequency and, possibly, route of administration. At present, it is not possible to predict who will develop NABs usually appear within the first 2 years of starting therapy. In patients treated with IFN beta in whom NABs persist for a significant period of time, their presence is associated with a reduction in both the biological effects and clinical efficacy. Approximately one third of NAB-positive patients with a titre > 20 NU/mL will revert to NAB-negative status with long-term follow-up. The persistence of NABs appears to be linked to the type of IFN beta treatment as well as the titre of antibodies. The overall efficacy of IFN beta and, hence, of any biological disease-modifying treatment (DMT) would be substantially improved if the development of NABs could be prevented or reversed. Although the overall efficacy of IFN beta in MS is relatively modest, the efficacy in individuals who remain NAB-negative is considerably better than in those who become persistently NAB-positive. One could argue that when comparing the 'true' clinical efficacy of different IFN beta products, the comparisons should be limited to the cohorts that remain NAB-negative. As a corollary, the therapeutic efficacy of IFN beta could be maximised if patients who tolerate higher-dose preparations could be prevented from developing persistent NABs. Strategies employed to prevent or reverse the development of NABs with other biological compounds (e. g. insulin, factor VIII, IFN beta, recombinant human erythropoietin) include improvements in the manufacturing process, immunosuppression, induction of tolerance and deimmunisation, and these should be considered in relation to biological DMT therapy as part of future clinical studies.

Giovannoni G. · Department of Neuroinflammation, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, London, UK. · CNS Drugs. · Pubmed #15270594 No free full text.

Abstract: The majority of patients with relapse-onset multiple sclerosis (MS) will go on to develop secondary-progressive MS (SPMS) disease, with approximately 50% developing SPMS after 10 years. It remains unknown whether the relapsing and progressive phases of MS differ qualitatively. The pathogenesis of SPMS is poorly understood. The specific role that inflammation plays in disease progression is not well defined. Immunosuppressive therapies, which are capable of reducing or stopping clinical relapses and suppressing MRI activity, generally do not stop disease progression. Recent natural history studies suggest that disease progression occurs regardless of the presence of superimposed relapses. However, poor recovery from clinical relapses does account for the acquisition of disability. Therefore, stopping relapses with appropriate therapy delays the acquisition of disability but does not necessarily delay or prevent the development of SPMS. At present, the only disease-modifying therapies licensed for use in SPMS are interferon-beta-1b in Europe and the US, and mitoxantrone in the US. These agents can only be recommended for patients who continue to have relapses. Symptomatic therapies remain the cornerstone of treatment for patients with SPMS. Delivering high-quality, effective symptomatic therapies requires a multidisciplinary approach. The aim of symptomatic therapies should not only be to reduce neurological impairments but also to decrease disability and handicap and to improve the emotional well-being and health-related quality of life of patients with SPMS.