Multiple Sclerosis: Deisenhammer F

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).

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

This publication has no abstract.

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.

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.

Deisenhammer F, Schellekens H, Bertolotto A. · Department of Neurology, University of Innsbruck, Innsbruck, Austria. · J Neurol. · Pubmed #15264110 No free full text.

Abstract: Treatment of multiple sclerosis (MS) with interferon beta (IFNbeta) can be associated with the development of binding antibodies (BAbs) and neutralizing antibodies (NAbs). NAbs are a subset of BAbs that prevent IFNbeta from effectively binding to or activating its receptor, thereby blocking its biologic effects and inhibiting its therapeutic effects. Several factors can affect the incidence and titers of NAbs that develop to IFNbeta, including the type of IFNbeta preparation used for treatment. One of the major limitations to evaluating the relative importance of these factors is the variation in assays used to detect IFNbeta antibodies. Two major types of assays are used to detect antibodies to IFNbetas: [1] binding assays, which measure the ability of antibodies in patients' sera to bind to IFNbeta; and [2] neutralization assays (or bioassays), which measure the ability of patients' sera to neutralize the biologic effects of IFNbeta. Assays used to detect NAbs differ in their sensitivity and specificity, and there can be high variability between laboratories in how these assays are performed (e. g., types of cells, quantity of IFNbeta). This article reviews assays currently used for detecting NAbs to IFNbeta and discusses the development of an international standard NAb assay. The myxovirus resistance protein A (MxA) assay is recommended as the standard assay for the quantification of NAbs providing availability of reagents.

Bertolotto A, Deisenhammer F, Gallo P, Sölberg Sørensen P. · Centro Riferimento Regionale Sclerosi Multipla and Laboratori di Neurobiologia Clinica, Ospedale Universitario San Luigi, Orbassano, Italy. · J Neurol. · Pubmed #15264108 No free full text.

Abstract: Protein-based therapies are useful in a variety of diseases; however, their potential for immunogenicity is a disadvantage. Neutralizing antibodies (NAbs) that develop to interferon beta (IFNbeta) products (IFNbeta-1b, IFNbeta-1a-Avonex((R)), or IFNbeta-1a-Rebif((R))), which are first-line therapies for the treatment of multiple sclerosis, are reported to reduce the clinical efficacy of these agents. In individual clinical studies of each commercially available IFNbeta product, 28% to 47% of patients develop NAbs to IFNbeta-1b, 12% to 28 % to IFNbeta-1a-Rebif, and 2% to 6% to IFNbeta-1a-Avonex. Problems exist in comparing the incidence of NAbs among IFNbeta products across studies because of differences in study methodology, including assay methods, treatment duration, and the definition of NAb positive. Results from studies that have directly compared these products are consistent with results from the respective clinical trials of IFNbetas. Both the clinical trials and the independent studies have shown that NAbs develop more frequently with IFNbeta-1b treatment than with IFNbeta-1a treatment and that, among IFNbeta-1a products, NAbs develop more frequently with IFNbeta-1a-Rebif treatment than with IFNbeta-1a-Avonex treatment. Factors that may affect the immunogenicity of IFNbetas, including the dosing regimens and the biochemical properties of the products, are discussed.

Pachner AR, Bertolotto A, Deisenhammer F. · Department of Neurology and Neurosciences, UMDNJ-New Jersey Medical School, Newark, NJ, USA. · Neurology. · Pubmed #14610107 No free full text.

Abstract: Myxovirus A (MxA) is a protein that is specifically induced by treatment with type I cytokines and has proven to be a reliable biomarker of interferon-beta (IFNbeta) bioactivity. IFNbeta-induced MxA can be measured as either protein or mRNA in the blood of IFNbeta-treated patients with MS. In patients with MS who are treated with IFNbeta, loss of the MxA response is caused by high levels of anti-IFNbeta antibodies and is a sensitive marker of lost bioactivity.

Millonig A, Dressel A, Bahner D, Bitsch A, Bogumil T, Elitok E, Kitze B, Tumani H, Weber F, Gneiss C, Deisenhammer F. · Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Eur J Neurol. · Pubmed #18549400 No free full text.

Abstract: BACKGROUND AND PURPOSE: Interferon beta (IFNbeta) preparations have some effect on the progressive phase of multiple sclerosis (MS). This limited effect might be partially because of a certain number of IFNbeta non-responders. Myxovirus resistance protein A (MxA)--a marker of IFNbeta bioactivity--was correlated with the clinical response during an uncontrolled trial, investigating the safety of IFNbeta-1b in primary progressive (PPMS) patients. METHODS: Twenty PPMS were treated with IFNbeta-1b (s.c.) for 1 year. Blood samples were taken before and 1, 2, 3, 6, 9, 12, and 15 months after treatment initiation and MxA protein levels were measured. Patients were clinically evaluated by EDSS and the more sensitive Incapacity Status Scale (ISS) and stratified in a stable and a progressing group. RESULTS: Using ISS criteria, 11 patients remained stable and nine patients progressed during treatment. The mean area under the curve of log MxA levels during treatment were significantly higher in stable than in progressing patients (10.87 vs. 5.99; P = 0.002). CONCLUSION: A good biological response to IFNbeta might be associated with a better clinical effect of this drug and could be helpful in future clinical studies for early identification of treatment responders.

Gneiss C, Tripp P, Ehling R, Khalil M, Lutterotti A, Egg R, Mayringer I, Künz B, Berger T, Reindl M, Deisenhammer F. · Department of Neurology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. · J Neuroimmunol. · Pubmed #16556466 No free full text.

Abstract: In this study, we investigated the affinity, determined by a relative affinity assay, using increasing concentrations of sodium-isothiocyanate to disrupt the antigen antibody binding of neutralizing and non-neutralizing antibodies against interferon-beta (IFNbeta)-1a and -1b in 73 serum samples of MS patients treated with IFNbeta-1a or -1b. Relative affinity values were significantly higher in NAB-positive compared to NAB-negative samples and in samples of IFNbeta-1a-treated patients compared to IFNbeta-1b. A significant positive correlation between relative affinity values and therapy duration indicates affinity maturation as another qualitative factor in IFNbeta neutralization.

Khalil M, Reindl M, Lutterotti A, Kuenz B, Ehling R, Gneiss C, Lackner P, Deisenhammer F, Berger T. · Clinical Department of Neurology, Innsbruck Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria. · J Neuroimmunol. · Pubmed #16516980 No free full text.

Abstract: Only few reports are available on the epitope specificity of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in multiple sclerosis (MS). In the present study we provide a precise characterization of the epitope specificity of serum antibodies directed against the extracellular domain of MOG, including IgG, IgM and IgA immunoglobulin isotypes in 28 relapsing remitting MS patients and report that linear epitopes amino-acid (aa) 37-48 and aa42-53 are immunodominant. Recently experienced relapses intensified the anti-MOG peptide antibody response. Immunomodulatory treatment with interferon-beta or glatiramer-acetate had no major impact on the anti-MOG peptide immunoreactivity after 1 year of therapy.

Bitsch A, Dressel A, Meier K, Bogumil T, Deisenhammer F, Tumani H, Kitze B, Poser S, Weber F. · Neurologische Klinik, Ruppiner Kliniken GmbH, Fehrbelliner Strabe 38, 16816, Neuruppin, Germany. · J Neurol. · Pubmed #15645350 No free full text.

Abstract: We conducted an open-labeled clinical trial of interferon beta-1b (IFNB) treatment in 20 patients with primary progressive multiple sclerosis (PPMS) and longitudinally monitored autoantibodies against double-stranded DNA (dsDNA), thyroid peroxidase (TPO),myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin and S-100B. Before treatment, one patient had elevated TPO antibodies, four patients had elevated antibodies against S-100B, two patients against MOG or synapsin and one patient against MBP. In two patients we observed a continuous increase of dsDNA or TPO antibodies above the normal range. This rise paralleled IFNB treatment. In addition, 11 of 20 patients developed neutralizing antibodies against IFNB. There was no increase of autoantibodies directed against central nervous system antigens. Like patients with relapsing remitting or secondary progressive multiple sclerosis, PPMS patients may be at risk of an autoimmune response during IFNB treatment.

Schocke MF, Berger T, Felber SR, Wolf C, Deisenhammer F, Kremser C, Seppi K, Aichner FT. · Department of Radiology, the University of Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria. · Neuroimage. · Pubmed #14568494 No free full text.

Abstract: To evaluate biochemical changes in contrast-enhancing multiple sclerosis (MS) lesions, we examined 14 patients with relapsing-remitting MS at acute clinical exacerbation with the help of contrast-enhanced magnetic resonance imaging (MRI) and 1H magnetic resonance spectroscopic imaging (1H MRSI). Using a 1.5-tesla MR system (Magnetom Vision, Siemens, Germany), we followed 29 contrast-enhancing and 24 nonenhancing MS lesions as well as normal-appearing white matter (NAWM) before and during high-dose methylprednisolone (HDMP) therapy. Metabolite ratios of N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and lactate (Lac) were calculated. A transient decrease in contrast enhancement under HDMP therapy was observed. Both groups of MS lesions showed significantly decreased NAA to Cr ratios compared to NAWM with no changes in time. Baseline 1H MRSI revealed significantly increased Cho to Cr ratios in the contrast-enhancing MS lesions (1.13 +/- 0.25) compared to the nonenhancing MS lesions (0.85 +/- 0.26, P < 0.001) and NAWM (0.97 +/- 0.22, P = 0.015). Both the contrast-enhancing and the nonenhancing MS lesions exhibited a significant increase in Cho to Cr ratios from the second to the third 1H MRSI. We identified resonances of lactate in both groups of MS lesions and NAWM without any significant group differences or changes over time. 1H MRSI provides additional information that help to estimate macrophages' activity, cell membrane activation, and neuronal impairment within MS lesions. We believe that combined contrast-enhanced MRI and 1H MRSI may help to further investigate inflammatory processes within active MS lesions and should be employed more frequently to the research on therapy effects in MS.

Strasser-Fuchs S, Fazekas F, Deisenhammer F, Nahler G, Mamoli B. · Department of Neurology, Karl-Franzens University, Graz, Austria. · Mult Scler. · Pubmed #11188778 No free full text.

Abstract: From observational studies and positive experience in other autoimmune disorders it has been speculated that intravenous immunoglobulin (IVIG) may be effective for the interval treatment of MS. The Austrian Immunoglobulin in Multiple Sclerosis (AIMS) study was the first to test this assumption in a randomized, double-blind, placebo controlled trial of 148 patients with relapsing remitting MS. IVIG given monthly at a dosage of 0. 15-0.2 g/kg bodyweight over 2 years was associated with a significantly more favourable course of disability as measured by the EDSS (- 0.23 vs 0.12; P=0.008) and caused a significant reduction of the frequency of relapses (0.52 vs 1.26; P=0.011). Beneficial effects on these outcome measures were already seen within 6 months of treatment and did not appear to depend on the severity of baseline disability. IVIG treatment also had a positive effect on daily and social living according to patient' self rating on the Incapacity Status and Environmental Status Scales and was associated with a lower, though not significantly different number of hospital admissions and days spent in hospital. These data support IVIG as an alternative treatment option for relapsing-remitting MS and encourage further studies to clarify the optimal usage of this substance for this indication.

Deisenhammer F, Mayringer I, Harvey J, Dilitz E, Gasse T, Stadlbauer D, Reindl M, Berger T. · Department of Neurology, University of Innsbruck, Austria. · Neurology. · Pubmed #10851362 No free full text.

Abstract: BACKGROUND: Three different recombinant interferon beta (IFNbeta) preparations are currently available for the treatment of MS, two IFNbeta-1a products (Rebif and Avonex) and one IFNbeta-1b product (Betaferon). These products differ with respect to the recommended dose, the dosage regimen, and the injection route. This study compared the relative biologic activity of these three products in vitro and in vivo. METHODS: Blood samples were collected from 237 patients with MS (170 on IFNbeta therapy and 67 control subjects receiving no therapy). Samples with neutralizing antibodies were excluded. Levels of the antiviral protein MxA and soluble vascular cell adhesion molecule-1 (sVCAM) in the four groups were measured by ELISA. In the in vitro investigation, untreated blood was incubated for 24 hours with increasing concentrations of the three IFNs from a dose of 1 IU/mL to 1000 IU/mL, after which levels of MxA were measured. RESULTS: A difference between the groups was observed in vitro, with a significant change from baseline in MxA levels being observed at 10 IU for Betaferon compared with 100 IU for Rebif and Avonex. However, this might be due to the different methods used for the determination of IU by the manufacturers. At the single-dose level there were no significant differences between IFNbeta preparations. In vivo, there were significantly different levels of MxA in the four groups. In the Betaferon group, the median value for MxA was 2.29 ng/105 peripheral blood leukocytes (PBL), compared with 1.00 ng/105 PBL for Rebif, 0.57 ng/105 PBL for Avonex, and 0.14 ng/105 PBL for the control group. Some significant differences between the groups were also apparent with respect to levels of sVCAM, which were higher with Betaferon than with Rebif. CONCLUSION: IFNbeta-1b induces higher levels of the above markers of IFNbeta bioactivity than either of the two IFNbeta-1a preparations. Moreover, there is a less striking difference between the two IFNbeta-1a preparations in favor of subcutaneous IFNbeta-1a.

Reindl M, Linington C, Brehm U, Egg R, Dilitz E, Deisenhammer F, Poewe W, Berger T. · Department of Neurology, University of Innsbruck, Innsbruck, Austria and Department of Neuroimmunology, Max Planck Institute for Neurobiology, Martinsried, Germany. · Brain. · Pubmed #10545390 links to  free full text

Abstract: In experimental animal models of multiple sclerosis demyelinating antibody responses are directed against the myelin oligodendrocyte glycoprotein (MOG). We have investigated whether a similar antibody response is also present in multiple sclerosis patients. Using the recombinant human extracellular immunoglobulin domain of MOG (MOG-Ig) we have screened the sera and CSFs of 130 multiple sclerosis patients, 32 patients with other inflammatory neurological diseases (OIND), 30 patients with other non-inflammatory neurological diseases (ONND) and 10 patients with rheumatoid arthritis. We report that 38% of multiple sclerosis patients are seropositive for IgG antibodies to MOG-Ig compared with 28% seropositive for anti-myelin basic protein (MBP). In contrast, OIND are characterized by similar frequencies of serum IgG antibody responses to MOG-Ig (53%) and MBP (47%), whereas serum IgG responses to MOG-Ig are rare in ONND (3%) and rheumatoid arthritis (10%). Anti-MBP IgG antibodies, however, are a frequent finding in ONND (23%) and rheumatoid arthritis (60%). Our results provide clear evidence that anti-MOG-Ig antibodies are common in CNS inflammation. However, in OIND these antibody responses are transient, whereas they persist in multiple sclerosis. We demonstrate that the serum anti-MOG-Ig response is already established in early multiple sclerosis (multiple sclerosis-R0; 36%). In later multiple sclerosis stages frequencies and titres are comparable with early multiple sclerosis. In contrast, the frequency of anti-MBP antibodies is low in multiple sclerosis-R0 (12%) and increases during disease progression in relapsing-remitting (32%) and chronic progressive multiple sclerosis (40%), thus suggesting that anti-MBP responses accumulate over time. Finally we provide evidence for intrathecal synthesis of IgG antibodies to MOG-Ig in multiple sclerosis.

Deisenhammer F. · Department of Neurology, Innsbruck Medical University, Anichstrasse 35, Innsbruck 6020, Austria. · CNS Drugs. · Pubmed #19453200 No free full text.

Abstract: Biopharmaceuticals can induce antibodies, which interact with and neutralize the therapeutic effect of such drugs and are therefore termed neutralizing antibodies (NAbs). In the treatment of multiple sclerosis, NAbs against interferon (IFN)-beta and natalizumab have been recognized. The prevalence of NAbs against different IFNbeta preparations varies widely, mainly depending on the product but also on other factors such as amino acid sequence variations, glycosylation, formulation, route and frequency of application, dose, duration of treatment and patient characteristics (human leukocyte antigen [HLA] status). IFNbeta-1a given intramuscularly induces significantly less NAbs than any other IFNbeta formulation. The longitudinal development of NAbs also differs between IFNbeta preparations, with higher reversion rates in IFNbeta-1b-treated compared with IFNbeta-1a-treated patients. The negative effect of NAbs on various outcome measures is very consistent across many studies, specifically when observation periods are longer than 2 years. NAbs against natalizumab occur less frequently (6%) and, like NAbs against IFNbeta, they are associated with a loss of clinical and radiological efficacy of the drug.

Tumani H, Hartung HP, Hemmer B, Teunissen C, Deisenhammer F, Giovannoni G, Zettl UK, Anonymous00125. · Department of Neurology, University of Ulm, Oberer Eselsberg 45, Ulm D-89081, Germany. · Neurobiol Dis. · Pubmed #19426803 No free full text.

Abstract: In patients with multiple sclerosis (MS) intensive efforts are directed at identifying biomarkers in bodily fluids related to underlying disease mechanisms, disease activity and progression, and therapeutic response. Besides MR imaging parameters cerebrospinal fluid (CSF) biomarkers provide important and specific information since changes in the CSF composition may reflect disease mechanisms inherent to MS. The different cellular and protein-analytical methods of the CSF and the recommended standard of the diagnostic CSF profile in MS are described. A brief update on possible CSF biomarkers that might reflect key pathological processes of MS such as inflammation, demyelination, neuroaxonal loss, gliosis and regeneration is provided.

Comabella M, Río J, Espejo C, Ruiz de Villa M, Al-Zayat H, Nos C, Deisenhammer F, Baranzini SE, Nonell L, López C, Julià E, Oksenberg JR, Montalban X. · Unitat de Neuroimmunologia Clínica, CEM-Cat, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain. · Clin Immunol. · Pubmed #18945642 No free full text.

Abstract: Matrix metalloproteinases (MMPs) and tissue inhibitors (TIMPs) play a key role in the pathogenesis of multiple sclerosis (MS) and have been proposed as biomarkers of response to therapy. We investigated serum levels of several MMPs and TIMPs in 43 relapsing-remitting MS (RRMS) patients undergoing interferon-beta (IFN-b) treatment and classified as responders and non-responders based on clinical criteria. Levels of MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 were determined by ELISA before treatment and after 3, 6, 12, and 24 months of therapy. Neutralizing antibodies were determined by the myxovirus A induction bioassay. Treatment with IFN-b induced changes in levels of MMP-9 and TIMP-1. In contrast to non-responders, IFN-b resulted in an early and sustained increase in TIMP-1 levels in MS patients who showed clinical response to IFN-b. The early and sustained increase in TIMP-1 levels could be a marker of the response to IFN-b during the first 2 years of treatment.

Wanschitz J, Ehling R, Löscher WN, Künz B, Deisenhammer F, Kuhle J, Budka H, Reindl M, Berger T. · Clinical Department of Neurology, Innsbruck Medical University, Anichstrasse 35, 6020 Innsbruck, Austria. · J Neurol. · Pubmed #18712293 No free full text.

Abstract: OBJECTIVE: alphaB-crystallin (alphaBC), a small stress protein with cytoprotective and anti-apoptotic functions, is a potent antigen in autoimmune demyelinating diseases. To address the role of alphaBC in Guillain-Barré syndrome (GBS) we analyzed humoral responses against alphaBC in relation to clinical, electrophysiological and CSF features in GBS. METHODS: Anti-alphaBC-IgG antibodies were measured in serum and cerebrospinal fluid (CSF) of patients with GBS (n = 41), infectious inflammatory neurological diseases (n = 21), multiple sclerosis (n = 42), and other, non-inflammatory neurological disorders (n = 40) by ELISA using human recombinant alphaBC. Expression of alphaBC was immunohistochemically analyzed in postmortem peripheral nerve tissue of GBS and controls without neuropathy. RESULTS: Serum alphaBC-IgG antibody levels did not differ between disease groups, whereas alphaBC-IgG antibodies in CSF were increased in GBS and infectious inflammatory neurological diseases. Calculation of an antigen specific alphaBC-IgG index (alphaBC-Ig-G(CSF) x total IgG(CSF))/(alphaBC-IgG(Serum) x total IgG(Serum)) revealed significantly elevated values in patients with GBS compared to other disease groups (p < 0.001). alphaBC-IgG indices exceeding a cut off value > 0.8 had an 85 % specificity and a 76 % sensitivity for GBS. alphaBC was overexpressed in dorsal root ganglia and spinal roots of autopsy cases with GBS. CONCLUSIONS: We demonstrate increased alphaBC-IgG indices in a high proportion of our GBS patients, which reflect enhanced antigen-specific intrathecal antibody responses against abnormally expressed alphaBC in inflamed peripheral nerve tissue. Elevated alphaBC-IgG indices might therefore serve as markers of PNS inflammation and supplement currently used laboratory tests in the diagnosis of GBS.

Hoffmann S, Cepok S, Grummel V, Lehmann-Horn K, Hackermüller J, Hackermueller J, Stadler PF, Hartung HP, Berthele A, Deisenhammer F, Wassmuth R, Wasmuth R, Hemmer B. · Department of Bioinformatics, Interdisciplinary Center for Bioinformatics, University Leipzig, Leipzig, Germany. · Am J Hum Genet. · Pubmed #18656179 links to  free full text

Abstract: The formation of antibodies to interferon-beta (IFN-beta), a protein-based disease-modifying agent for multiple sclerosis (MS), is a problem in clinical practice. These antibodies may neutralize the biological effects of the protein drug, potentially decreasing its therapeutic effects. By high-resolution HLA class I and II typing we identified two HLA class II alleles associated with the development of antibodies to IFN-beta. In two independent continuous and binary-trait association studies, HLA-DRB1*0401 and HLA-DRB1*0408 (odds ratio: 5.15)--but not other HLA alleles--were strongly associated with the development of binding and neutralizing antibodies to IFN-beta. The associated HLA-DRB1*04 alleles differ from nonassociated HLA-DRB1*04 alleles by a glycine-to-valine substitution in position 86 of the epitope-binding alpha-helix of the HLA class II molecule. The peptide-binding motif of HLA-DRB1*0401 and *0408 might promote binding and presentation of an immunogenic peptide, which may eventually break T cell tolerance and facilitate antibody development to IFN-beta. In summary, we identified genetic factors determining the immunogenicity of IFN-beta, a protein-based disease-modifying agent for the treatment of MS.

Di Pauli F, Reindl M, Ehling R, Schautzer F, Gneiss C, Lutterotti A, O'Reilly E, Munger K, Deisenhammer F, Ascherio A, Berger T. · Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Mult Scler. · Pubmed #18632775 No free full text.

Abstract: BACKGROUND: Cigarette smoking increases the risk for development of multiple sclerosis and modifies the clinical course of the disease. In this study, we determined whether smoking is a risk factor for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome. METHODS: We included 129 patients with a clinically isolated syndrome, disseminated white-matter lesions on brain magnetic resonance imaging, and positive oligoclonal bands in the cerebrospinal fluid. The patients' smoking status was obtained at the time of the clinically isolated syndrome. RESULTS: During a follow-up time of 36 months, 75% of smokers but only 51% of non-smokers developed clinically definite multiple sclerosis, and smokers had a significantly shorter time interval to their first relapse. The hazard ratio for progression to clinically definite multiple sclerosis was 1.8 (95% confidence interval, 1.2-2.8) for smokers compared with non-smokers (P = 0.008). CONCLUSIONS: Smoking is associated with an increased risk for early conversion to clinically definite multiple sclerosis after a clinically isolated syndrome, and our results suggest that smoking is an independent but modifiable risk factor for disease progression of multiple sclerosis. Therefore, it should be considered in the counseling of patients with a clinically isolated syndrome.

Kuenz B, Lutterotti A, Ehling R, Gneiss C, Haemmerle M, Rainer C, Deisenhammer F, Schocke M, Berger T, Reindl M. · Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · PLoS One. · Pubmed #18596942 links to  free full text

Abstract: BACKGROUND: There is accumulating evidence from immunological, pathological and therapeutic studies that B cells are key components in the pathophysiology of multiple sclerosis (MS). METHODOLOGY/PRINCIPAL FINDINGS: In this prospective study we have for the first time investigated the differences in the inflammatory response between relapsing and progressive MS by comparing cerebrospinal fluid (CSF) cell profiles from patients at the onset of the disease (clinically isolated syndrome, CIS), relapsing-remitting (RR) and chronic progressive (CP) MS by flow cytometry. As controls we have used patients with other neurological diseases. We have found a statistically significant accumulation of CSF mature B cells (CD19+CD138-) and plasma blasts (CD19+CD138+) in CIS and RRMS. Both B cell populations were, however, not significantly increased in CPMS. Further, this accumulation of B cells correlated with acute brain inflammation measured by magnetic resonance imaging and with inflammatory CSF parameters such as the number of CSF leukocytes, intrathecal immunoglobulin M and G synthesis and intrathecal production of matrix metalloproteinase (MMP)-9 and the B cell chemokine CxCL-13. CONCLUSIONS: Our data support an important role of CSF B cells in acute brain inflammation in CIS and RRMS.

Gneiss C, Brugger M, Millonig A, Fogdell-Hahn A, Rudzki D, Hillert J, Berger T, Reindl M, Deisenhammer F. · Clinical Department of Neurology, Innsbruck Medical University, Innsbruck, Austria. · Mult Scler. · Pubmed #18535018 No free full text.

Abstract: BACKGROUND: Binding antibodies (BAB) against interferon-beta (IFNbeta) are often determined as screening assays before performing an expensive and elaborate neutralizing antibody (NAB) test. METHODS: In this study, we compared four BAB tests, a western blot (WB), a direct binding enzyme-linked immunosorbent assay (ELISA) (dELISA), a capture ELISA (cELISA), and a commercial enzyme immuno-assay (EIA) in 325 multiple sclerosis patients with and without neutralizing antibodies to evaluate the sensitivity and specificity to detect NAB by receiver operating characteristics analysis. RESULTS: The area under the curve (AUC) values were 0.907 for the dELISA, 0.925 for the cELISA, and 0.776 for the EIA (P < 0.0001 for all). At a sensitivity of 95%, the specificity was approximately 30% in the dELISA, 55% in the cELISA, and 13% in the EIA. The WB as a qualitative BAB detection method had a given sensitivity of 97% and a specificity of 55%. There was a strong and significant correlation between high NAB titers (>500 neutralizing units [NU]) and titers obtained by all quantitative BAB assays. However, low to medium NAB titers (20-500 NU) did not significantly correlate with BAB titers. CONCLUSION: We conclude that the cELISA seems to be most suitable for NAB screening, but BAB titers cannot reliably predict NAB titers.

Sominanda A, Rot U, Suoniemi M, Deisenhammer F, Hillert J, Fogdell-Hahn A. · Department of Clinical Neuroscience, Division of Neurology R54, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden. · Mult Scler. · Pubmed #17439886 No free full text.

Abstract: Development of neutralizing antibodies (NAbs) reduces the clinical efficacy of interferon beta (IFNbeta) treatment in multiple sclerosis (MS) patients. The aim of this study was to evaluate NAb seroprevalence (frequency of patients with NAbs) and immunogenicity (titer levels) of IFNbeta preparations in a clinical setting. We analysed 1115 consecutive MS patients, treated with one of the three available IFNbeta preparations, for an average of 40 months (1-120 months), for the presence of NAbs with the MxA protein induction assay. Overall, 32% of patients were positive for NAbs with neutralizing titers above 10. The frequency of NAbs, ie, the seroprevalence, was 13% in Avonex-treated patients, 43% for Betaferon, 39% for Rebif22 and 30% for Rebif44. In addition, the potential to induce high titer levels, ie, the immunogenicity, was observed to differ between preparations. Avonex, showing the lowest seroprevalence, also showed low immunogenicity and typically induced low titers. Betaferon, showing the highest seroprevalence when inducing NAbs, induced lower titers compared to Rebif22 and Rebif44. Treatment duration over five years only marginally correlated with decreased seroprevalence and titer levels.In conclusion, NAbs to IFNbeta are common in a clinical setting and the IFNbeta preparations differ not only in NAb seroprevalence, but also in immunogenicity.