Multiple Sclerosis: Hartung HP

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.

Comi G, Kappos L, Clanet M, Ebers G, Fassas A, Fazekas F, Filippi M, Hartung HP, Hertenstein B, Karussis D, Martino G, Tyndall A, van der Meché FG. · Multiple Sclerosis Centre, San Raffaele Scientific Institute, Milan, Italy. · J Neurol. · Pubmed #10896270 No free full text.

Abstract: Recent reports suggest the possible beneficial effects of haemopoietic stem cell transplantation (HSCT) in autoimmune diseases such as multiple sclerosis (MS). The definition of the risk/benefit ratio for such a treatment is perceived as a major issue for the neurological community worldwide. The First Consensus Conference on Bone Marrow Transplantation in Patients with Multiple Sclerosis was held in Milan, Italy on 21 February 1998. Participants from 16 European, North American, and South American countries discussed the guidelines for performing HSCT in MS. This conference was organized in order to: (a) define criteria for patient selection; (b) define transplantation procedures to maximize efficacy of the treatment and minimize its toxicity; (c) standardize patient outcome evaluation; and (d) establish an international working group to evaluate the efficacy and safety of HSCT in MS and to study the immunological changes related to HSCT in MS patients. During the meeting in Milan agreement was reached on: (a) the preparation and distribution of a consensus report on HSCT in MS and (b) the design of an open trial for an initial assessment of the safety and efficacy of HSCT in MS. The consensus reached during the meeting and the design of the clinical trial are summarized in this contribution.

Hofstetter HH, Stüve O, Hartung HP. · No affiliation provided · Arch Neurol. · Pubmed #19001158 No free full text.

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Killestein J, Hartung HP. · Department of Neurology, VU Medical Centre Amsterdam, The Netherlands. · J Neurol Neurosurg Psychiatry. · Pubmed #18487553 No free full text.

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Filippi M, Hartung HP. · No affiliation provided · Ann Neurol. · Pubmed #17894367 No free full text.

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Kieseier BC, Hemmer B, Hartung HP. · No affiliation provided · Curr Opin Neurol. · Pubmed #15891402 No free full text.

Abstract: PURPOSE OF REVIEW: This review focuses on novel aspects of the pathogenesis and advances in the therapy of multiple sclerosis (MS). RECENT FINDINGS: Recent observations suggest that early lesion development in MS may start in some forms with oligodendrocyte death and that inflammation appears as a secondary phenomenon only. The lack of sufficient remyelination in MS may be the result of a disturbed function of basic helix-loop-helix transcription factors. Clinically the identification of patients with a clinically isolated syndrome at high risk to develop clinically definite MS remains difficult; the predictive value of serum antibodies against myelin proteins remains controversial. The role of neutralizing antibodies in interferon therapy is discussed. New therapeutic approaches in MS are emerging. SUMMARY: The existing view on the pathogenesis of MS is still changing. The original assumption that cell-mediated demyelination is the key event in lesion development dictating clinical disability is critically reviewed and alternative pathways have been suggested. Oligodendrocyte death, axonal loss, the role of CD8 T lymphocytes, T regulatory cells, and B lymphocytes have come into the focus of newly evolving concepts in MS pathogenesis. A deepened understanding of the immunopathogenesis of this disease translates into innovative therapeutic approaches, such as blockade of alpha4 integrins by a humanized monoclonal antibody. In various animal models cell-replacement strategies yield promising results; however, turning these findings into an effective therapy in MS patients has a long way to go.

Neuhaus O, Archelos JJ, Hartung HP. · No affiliation provided · Mult Scler. · Pubmed #14582764 No free full text.

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Kieseier BC, Hartung HP. · No affiliation provided · Curr Opin Neurol. · Pubmed #12858058 No free full text.

Abstract: PURPOSE OF REVIEW: The present article reviews the currently ongoing scientific debate of our changing views on the pathogenesis of multiple sclerosis and the therapeutic strategies currently available for multiple sclerosis. RECENT FINDINGS: The most important observations include that (a) axonal loss accounts for permanent disability in multiple sclerosis, (b) remyelination should be possible in theory but fails for unknown reasons in the multiple sclerosis lesion, (c) inflammation can be beneficial, (d) treatment should be initiated early, and (e) immunosuppressive strategies exhibit beneficial effects in progressive forms of the disease. SUMMARY: Our current understanding of the immunopathogenesis of multiple sclerosis has changed in the past. Whereas demyelination was originally thought to be relevant for the lasting neurological deficit, it is nowadays commonly accepted that the extent of axonal loss dictates the degree of permanent clinical disability. How axonal damage can be prevented remains elusive. The interaction between the myelinating cell and the neuron gains increasing attention, however the evolving knowledge has not yet yielded new treatment concepts. Hence for the time being, it seems prudent to make optimal use of current approved therapies. Recent trials underlined the need for early initiation of treatment with immunomodulatory drugs. The superiority of one of the interferons is still a matter of debate, and a conclusive answer cannot be given at present. Finally, with mitoxantrone we have a drug at hand which can be used in progressive forms of multiple sclerosis, especially when other disease modifying drugs are not or no longer effective.

Stangel M, Hartung HP. · No affiliation provided · J Neurol Neurosurg Psychiatry. · Pubmed #11784815 links to  free full text

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Hartung HP, Grossman RI. · No affiliation provided · Neurology. · Pubmed #11376169 No free full text.

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Warnke C, Kieseier BC, Zettl U, Hartung HP. · Neurologische Klinik, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany. · Nervenarzt. · Pubmed #19296065 No free full text.

Abstract: Monoclonal antibodies are of growing interest as treatment options for immune-mediated diseases in neurology. As our knowledge of immunological principals increases, we learn to modulate specifically mechanisms of pathogenesis by the use of monoclonal antibodies. It is clearly desirable to improve efficacy in disease treatment without increasing toxicity by using drugs with more specific modes of action. Natalizumab was the first monoclonal antibody approved in the field of neurology for treatment of relapsing remitting multiple sclerosis (MS). Several other monoclonal antibodies are currently under investigation. Alemtuzumab, a monoclonal antibody targeting CD52, is a highly promising agent currently being studied in two phase III clinical trials. In this review, data from the recently published phase II clinical trial in the treatment of early relapsing remitting MS is summarized and analyzed in light of the development of alemtuzumab for MS and its potential role in treating this disease is discussed.

Hartung HP. · Heinrich-Heine-University, Department of Neurology, Moorenstreet 5, D-40225 Düsseldorf, Germany. · Expert Opin Pharmacother. · Pubmed #19236200 No free full text.

Abstract: BACKGROUND: There is at present no cure for multiple sclerosis (MS), and existing therapies are designed primarily to prevent lesion formation, decrease the rate and severity of relapses and delay the resulting disability by reducing levels of inflammation. OBJECTIVE: The aim of this review was to assess the treatment of relapsing MS with particular focus on subcutaneous (s.c.) interferon (IFN) beta-1a. METHOD: The literature on IFN beta-1a therapy of MS was reviewed based on a PubMed search (English-language publications from 1990) including its pharmacodynamics and pharmacokinetics, clinical efficacy in relapsing MS as shown in placebo-controlled studies and in comparative trials, efficacy in secondary progressive MS, safety and tolerability, and the impact of neutralizing antibodies. CONCLUSION: The literature suggests that high-dose, high-frequency s.c. IFN beta-1a offers an effective option for treating patients with relapsing MS, with proven long-term safety and tolerability, and has a favourable benefit-to-risk ratio compared with other forms of IFN beta.

Menge T, Büdingen HC, Dalakas MC, Kieseier BC, Hartung HP. · Neurologische Klinik, Heinrich-Heine-Universität, Moorenstrasse 5, 40225, Düsseldorf, Deutschland. · Nervenarzt. · Pubmed #19189075 No free full text.

Abstract: 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.

Menge T, Weber MS, Hemmer B, Kieseier BC, von Büdingen HC, Warnke C, Zamvil SS, Boster A, Khan O, Hartung HP, Stüve O. · Department of Neurology, Heinrich Heine-University, Düsseldorf, Germany. · Drugs. · Pubmed #19016573 No free full text.

Abstract: 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.

Stüve O, Bennett JL, Hemmer B, Wiendl H, Racke MK, Bar-Or A, Hu W, Zivadinov R, Weber MS, Zamvil SS, Pacheco MF, Menge T, Hartung HP, Kieseier BC, Frohman EM. · Neurology Section, VA North Texas Health Care System, Medical Service, Dallas, Texas 75216, USA. · Drugs. · Pubmed #18081373 No free full text.

Abstract: 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.

Weber MS, Stuve O, Neuhaus O, Hartung HP, Zamvil SS. · Department of Neurology and Program in Immunology, University of California, San Francisco, 513 Parnassus Avenue, S-268, San Francisco, CA 94143-0435, USA. · Int MS J. · Pubmed #18028833 links to  free full text

Abstract: Statins are among the most widely prescribed drugs to prevent cardiovascular morbidity. Over recent years, statins have also been shown to exert pleiotropic immunomodulatory effects that might be of therapeutic benefit in autoimmune disorders. Interestingly, the primary mechanism by which statins alter immune function appears to be largely independent of lipidlowering and mediated primarily through inhibition of post-translational prenylation of regulatory proteins. In experimental autoimmune encephalomyelitis, the mouse model for multiple sclerosis (MS), statins prevent and even reverse established paralysis. Furthermore, statins were recently shown to exert synergistic benefit in combination with some agents already approved for MS therapy. Based upon these encouraging results obtained in the animal model, statins are now being evaluated in clinical trials as potential therapy for MS.

Hemmer B, Hartung HP. · Department of Neurology, Heinrich Heine-University, Düsseldorf, Germany. · Ann Neurol. · Pubmed #17969020 No free full text.

Abstract: Although the cause of multiple sclerosis (MS) has remained obscure, many findings support an autoimmune pathogenesis on the background of a complex interaction between multiple genes and environmental factors. Accordingly, targeting the immune system has been a rational approach for the treatment of MS. The development of disease-modifying immunomodulatory drugs with partial efficacy, coupled with advances in understanding the pathophysiology and pathology of MS, has provided momentum to explore more specific and hopefully more effective immune-based therapeutic strategies. With increased knowledge and appreciation of the contribution of neurodegenerative processes to disease pathology, the therapeutic challenges, however, have become even more formidable. Future treatments will likely need both to target inflammation and to focus on promotion of neuroprotection and repair. In this review, we discuss the most promising therapeutic approaches for MS currently in the pipeline.

Neuhaus O, Kieseier BC, Hartung HP. · Department of Neurology, Kliniken Landkreis Sigmaringen GmbH, D-72488 Sigmaringen, Germany. · Neurotherapeutics. · Pubmed #17920546 No free full text.

Abstract: Immunosuppressive agents have been used in multiple sclerosis (MS) for decades. The approval of several immunomodulatory agents against MS beginning in the 1990s, whose putative mechanisms of action appeared "more MS-specific," curtailed the importance of immunosuppressants, which made them treatment options of second choice. However, with the recent approval of mitoxantrone for treatment of patients with active forms of relapsing-remitting or secondary progressive MS and with a number of oral immunosuppressive agents being assessed in phase II and III clinical trials, a "renaissance" of this type of agents is currently occurring. This review provides an outline of the most important clinical studies and discusses relevant side effects of the major immunosuppressants (i.e., mitoxantrone, azathioprine, cyclophosphamide, methotrexate, mycophenolate mofetil, cladribine, and sirolimus/temsirolimus). The current knowledge of the putative mechanisms of action of these compounds is discussed.

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.

Zipp F, Waiczies S, Aktas O, Neuhaus O, Hemmer B, Schraven B, Nitsch R, Hartung HP. · Cecilie-Vogt-Clinic for Molecular Neurology, Charité - Universitaetsmedizin Berlin, and Max-Delbrueck-Center for Molecular Medicine, 10117 Berlin, Germany. · Trends Pharmacol Sci. · Pubmed #17573124 No free full text.

Abstract: Over the past two decades, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (HMGCRIs), originally designed to lower cholesterol blood levels, have been found to affect GTPase signaling during normal intracellular tasks. This finding has prompted use of these drugs in pathological situations, where such signaling processes need to be manipulated. Here, we review recent progress on the outcome of modulating GTPase signaling after inhibition of protein prenylation by HMGCRIs. We also discuss current controversies over the direct implications of these cholesterol-lowering agents on cholesterol-rich membrane lipid rafts and associated signaling. By reviewing these two different cellular events and the evidence from clinical studies, an overall assessment can be made of the concept of interfering with the HMG-CoA reductase pathway in different brain pathologies. We thereby provide a rational link between the benefit of applying HMGCRIs in brain pathologies, such as multiple sclerosis, Alzheimer's disease and stroke, and the impact on signaling in specific cell types crucial to disease pathogenesis.

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.

Kieseier BC, Wiendl H, Hemmer B, Hartung HP. · Department of Neurology, Heinrich-Heine-University, Duesseldorf, Germany. · Curr Opin Neurol. · Pubmed #17495622 No free full text.

Abstract: PURPOSE OF REVIEW: This review focuses on advances in current and novel treatment approaches in multiple sclerosis. RECENT FINDINGS: New therapeutic approaches in multiple sclerosis are emerging. Orally available treatment strategies are more acceptable for patients and may improve adherence to therapy. An oral formulation of glatiramer acetate failed to demonstrate efficacy in a clinical trial, but other promising compounds are on the horizon, such as FTY720. Advances are currently being made in use of therapeutic monoclonal antibodies that specifically target key molecules involved in the immunopathogenesis of multiple sclerosis. Natalizumab directed against the adhesion molecule very late antigen-4 represents the first specific antibody to be added to our therapeutic armamentarium for multiple sclerosis. Further evidence that immunomodulation should be initiated as early as possible has been reported. SUMMARY: Treatment of multiple sclerosis has changed dramatically over the past decade. Enhanced understanding of the immunopathological processes that underlie the disease, advances in biotechnology and development of powerful magnetic resonance imaging technologies, together with improvements in clinical trial design have led to a variety of valuable therapeutic approaches, which are currently being studied in detail.

Menge T, Kieseier BC, Nessler S, Hemmer B, Hartung HP, Stüve O. · Department of Neurology, Heinrich-Heine-University of Düsseldorf, Germany. · Curr Opin Neurol. · Pubmed #17495616 No free full text.

Abstract: PURPOSE OF REVIEW: In this review, the possible etiology, clinical characteristics, diagnosis, and treatment of acute disseminated encephalomyelitis (ADEM) are discussed. ADEM is a para- or postinfectious autoimmune demyelinating disease of the central nervous system and has been considered a monophasic disease. The highest incidence of ADEM is observed during childhood. RECENT FINDINGS: Over the last decade, many cases of multiphasic ADEM have been reported. The occurrence of relapses potentially poses a diagnostic dilemma for the treating physician, as it may be difficult to distinguish multiphasic ADEM from multiple sclerosis (MS). Many retrospective patient studies have thus focused on the clinical and paraclinical features of ADEM and have attempted to define specific diagnostic criteria. Additionally, several experimental models have provided insight with respect to the pathogenic relation of an infectious event and subsequent demyelinating autoimmunity. SUMMARY: Capitalizing on experience based on a large body of well characterized patient data collected both cross-sectionally and longitudinally, pharmacotherapy has been improved and mortality and comorbidities due to ADEM have been reduced. Unfortunately, the pathogenic events that trigger the initial clinical attack, and possibly pave the way for ongoing relapsing disease, remain unknown. Clinically applicable diagnostic criteria are still lacking.

Neuhaus O, Hartung HP. · Heinrich Heine University, Department of Neurology, Düsseldorf, Germany. · Expert Rev Neurother. · Pubmed #17492904 No free full text.

Abstract: Atorvastatin and simvastatin (members of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor family) are widely prescribed as cholesterol-lowering agents. As they have been shown to exhibit potent immunomodulatory effects, they may become a future treatment option for autoimmune disease in general and multiple sclerosis (MS) in particular. Several recent reports have demonstrated that statins prevent and reverse chronic and relapsing experimental autoimmune encephalomyelitis, an animal model of MS. An open-label clinical trial assessing simvastatin in MS revealed a significant decrease in the number and volume of new MRI lesions and a favorable safety profile. The results of a large multicenter, placebo-controlled clinical trial assessing atorvastatin in patients with clinically isolated syndrome (a disease that predisposes to development MS) are expected soon. However, prospective placebo-controlled trials of atorvastatin or simvastatin in definite MS are difficult to perform due to ethical and financial objections. In this review, we discuss the backgrounds, mechanisms of action and future perspectives of atorvastatin and simvastatin as putative future treatment options in MS.

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.