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Publications (12)29.14 Total impact

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    ABSTRACT: Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677G>T, 3435C>T and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2% of patients) was 37.7% lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P < 0.05, 14.8% of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2(-/-) animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2(-/-) mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n = 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1%)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5%) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6%), ABCB1/ABCG2-L 28/33 (84.8%), exact Cochran-Armitage test P = 0.039]. The odds ratio for response was 1.9 (95% CI 1.0-3.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to -I-, and -I to -L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m2 MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation.
    Brain 07/2009; 132(Pt 9):2517-30. · 10.23 Impact Factor
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    ABSTRACT: In patients with relapsing-remitting multiple sclerosis (MS), IVIG was shown to reduce the relapse rate and progression of disability. In patients with chronic progressive MS, a beneficial effect of IVIG was not documented in placebo controlled studies. This trial investigated the influence of IVIG in primary (PPMS) and secondary (SPMS) chronic progressive MS. Two-hundred and thirty-one patients stratified for PPMS (n=34) and SPMS (n=197) were randomly assigned to IVIG 0.4 g/kg per month or to placebo for 24 months. Primary endpoints were 1) the time to sustained progression of disease identified as worsening of the expanded disability status scale (EDSS) sustained for 3 months, and 2) the improvement of neurological functions defined by a patient's best EDSS score. Secondary endpoints were the proportion of patients with sustained progression, the relapse rate, the assessment of fine motor skills, visual evoked potentials, contrast sensitivity, depression and quality of life. Analysis of the intention-to-treat (ITT) population of combined PPMS and SPMS patients showed that the mean time to sustained progression was 74 weeks in the IVIG compared with 62 weeks in the placebo group (P=0.0406). When PPMS and SPMS patients were analysed separately, the time to sustained progression was also longer in the IVIG group, but the difference was not significant. There was no IVIG-mediated improvement in neurological functions. In the combined per protocol (PP) treated patients, IVIG treatment prolonged time to sustained progression by 13 weeks (P=0.0396). PPMS patients, but not SPMS patients showed a slight favourable IVIG effect on the best EDSS score. In the combined ITT population there were less patients with sustained progression in the IVIG than in the placebo group (P=0.028). The difference was significant in PPMS (P=0.016), but not in SPMS patients. In the combined PP population, there was a trend for a favorable IVIG effect on the rates of patients with sustained progression. In patients with PPMS, this IVIG effect reached significance (P=0.036). Other secondary endpoints did not show significant differences between treatment groups. Eighteen patients with PPMS and 102 patients with SPMS withdrew from the study for various reasons. Treatment was generally well tolerated. It was concluded that monthly IVIG infusion could delay progression of disease in patients with PPMS, and that there was a trend in favour of IVIG treatment in patients with SPMS.
    Multiple Sclerosis 12/2007; 13(9):1107-17. · 4.47 Impact Factor
  • Aktuelle Neurologie - AKTUEL NEUROL. 01/2007; 34.
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    ABSTRACT: The purpose of the study was to examine the frequency and characteristics of complementary and alternative medicine (CAM) use among patients with multiple sclerosis (MS). In order to collect sociodemographic and disease related variables as well as aspects of CAM utilisation 254 MS patients were examined with an interview. The investigation was completed by data of the neurological examination. At the time of investigation 67.3% of the MS patients reported that they were currently using one or more CAMs. Overall, most of the overall utilized therapies (90.6%) were chosen as a complement and 9.4% as an alternative therapy. Users of complementary medicine were more severely affected by the MS than non-users and had a longer duration of illness. No sociodemographic differences were found between users and non-users. When evaluating the efficacy of CAM, patients reported improvement in 67.1%, no influence in 32.3% and worsening in 0.6% of the cases. 3.7% of the CAM therapies were accompanied by minor side effects. Since MS patients are frequently using CAM despite the absence of clinically proven efficacy and appraise it positively, further research on the motivation for utilisation and on objective effects of CAM are needed.
    Journal of Neurology 11/2006; 253(10):1331-6. · 3.58 Impact Factor
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    ABSTRACT: This cost-of-illness analysis based on information from 2973 patients with multiple sclerosis (MS) in Germany is part of a Europe-wide study on the costs of MS. The objective was to analyze the costs and quality of life (QOL) related to the level of disease severity. Patients from six centres (office- and hospital-based physicians) and patients enrolled in a database were asked to participate in the survey; 38% answered a mail questionnaire. In addition to details on the disease (type of disease, relapses, level of functional disability), the questionnaire asked for information on all resource consumption, medical, non-medical, work absence, informal care, as well as QOL (measured as utility). The mean age of the cohort was 45 years, and 18% of patients were 65 years of age or older. Forty-seven percent of patients had mild disease (Expanded Disability Status Scale [EDSS] score 0-3), 36% had moderate disease (EDSS score 4-6.5) and 12% had severe disease (EDSS score > or =7). The mean EDSS score in the sample was 3.8 (median 4.0), with a mean utility of 0.62. Costs and utility are highly correlated with disease severity. Workforce participation decreases from 73% in very early disease to less than 10% in the very late stages, leading to a tenfold rise in productivity losses in the late stages of disease. Hospitalisation and ambulatory visits rise by a factor of 5-6 between early and late disease; investments and services increase from basically no cost to euro 2700; and informal care increases by a factor of 27 for patients with an EDSS score of 7 and by a factor of 50 for patients at the very severe end of the EDSS scale (8-9). Hence, total mean costs per patient are determined essentially by the distribution of the severity levels in the sample, increasing from approximately euro 18 500 at an EDSS score of 0-1 to euro 70 500 at an EDSS score of 8-9. The same is true for utility, which decreases from 0.86 to 0.10 as the disease becomes severe. However, the utility loss compared to the general population is high at all levels of the disease, leading to an estimated loss of 0.2 quality-adjusted life-years per patient. Relapses are associated with a cost of approximately euro 3 000 and a utility loss of 0.1 during the quarter in which they occur. Compared with a similar study performed in 1999, resource consumption, with the exception of drugs, is somewhat lower. This is most likely due to a difference in the severity distribution of the two samples and to changes in health-care consumption overall in the country, such as the introduction of diagnosis-related groups (DRGs, Fallpauschalen).
    The European Journal of Health Economics 09/2006; 7 Suppl 2:S34-44. · 2.10 Impact Factor
  • Aktuelle Neurologie - AKTUEL NEUROL. 01/2006; 33.
  • Aktuelle Neurologie - AKTUEL NEUROL. 01/2006; 33.
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    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.
    Journal of Neurology 12/2004; 251(11):1329-39. · 3.58 Impact Factor
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    ABSTRACT: Interleukin-6 (IL-6) plays an important role in the regulation of the inflammatory response in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Previous reports indicated that the C allele of a variable number tandem repeat (vntr) polymorphism located in the 3'flanking region of the IL-6 gene ( IL-6) is associated with reduced activity of IL-6 in vivo. Since disease-modifying genes are likely to contribute to phenotypic differences in MS patients, we tested the hypothesis that the IL-6 C allele is associated with the clinical course of MS. The IL-6 C allele was equally distributed between 217 MS patients of German Caucasian origin and 111 age-mached healthy controls. Stratification of patients according to the course of disease revealed no significant difference of IL-6 C allele distribution between patients with primary progressive and those with either relapsing-remitting or secondary progressive MS although IL-6 C allele was more frequent in patients with RR-MS. Since IL-6 C allele has been associated with a benign course in Sardinian MS patients, we further analysed an independent sample of 125 Sardinian MS patients revealing that IL-6 C allele was much more frequent than in German MS patients. Taken together, a disease-modifying effect of IL-6 C allele could not be demonstrated in MS patients of German Caucasian descent.
    Journal of Neurology 06/2003; 250(5):607-11. · 3.58 Impact Factor
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    ABSTRACT: We performed a cross-sectional, "bottom-up" observational study of resource use, costs, and quality of life in patients with multiple sclerosis (MS) in Germany. Six centers participated in the study. Patients were asked to complete a questionnaire, and a total of 737 patients returned it (response rate 66%). The questionnaire provided information on all resource consumption, medical, and nonmedical, work absence, informal care related to their MS, and quality of life (EuroQol). Simultaneously, medical charts were also abstracted for a subsample of 202 patients for comparison between answers in the questionnaires and registered data. Levels of disability were assessed using the Expanded Disability Status Scale. The mean age of the cohort was 41.9&#4514.1 years (disease onset 33.4), mean EDSS score 4.4 (range 1.0-9.5), and mean utility measured by EQ-5D 0.552&#450.331). Mean total cost per patient and year was 65,400 DM, adjusted for use of interferons, which was higher in this sample than the current average use in Germany. When this cost is extrapolated to an estimated patient population of 120,000, total costs to society are estimated at 7.85 billion DM. Direct costs represented 57.5%, informal care accounted for 12.1% and indirect costs amounted to 42.5%. Public payers pay for an estimated 24,800 DM per patient or 38% of total costs. All types of costs (direct, informal care, indirect) increased with increasing disability, while utilities decreased.
    HEPAC Health Economics in Prevention and Care 05/2001; 2(2):60-68.
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    ABSTRACT: In a survey of disease course, the efficacy and tolerability of 24-month interferon beta-1b therapy for relapsing remitting multiple sclerosis (RRMS) were evaluated in 410 patients. The investigation aimed at obtaining data from general practice and of possibly unknown, unexpected adverse reactions. In the 241 patients still on therapy, efficacy was rated after 24 months as "good" or "very good" in 75% of cases. After 24 months, 36.9% of the patients had no exacerbation (baseline 0.3%). Annual exacerbation rates dropped from 1.5 before treatment to 0.7 in the second treatment year. In the 2 years before treatment, 66.2% had worsened by at least 0.5 points on the extended disability status scale (EDSS). This proportion was reduced to 41.2% after 2 years of treatment. The safety profile corresponded to results from controlled trials. This postmarketing survey supports data from the published controlled interferon beta-1b studies and confirms the main effects of this therapy under routine conditions in general practice.
    Der Nervenarzt 05/2001; 72(4):286-92. · 0.80 Impact Factor
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    ABSTRACT: In einer Verlaufsbeobachtung bei 410 Patienten mit schubförmigem Multiple-Sklerose (MS)-Verlauf wurden Wirksamkeit und Verträglichkeit einer 24-monatigen Interferon β-1b-Therapie untersucht. Ziel der Untersuchung war es, Daten über die praktische Anwendung dieses Medikaments unter Routinebedingungen und ergänzende Informationen zum Sicherheitsprofil zu erhalten. Nach 24 Monaten Therapie beurteilten die beteiligten Ärzte bei 241 (58,8%) zu diesem Zeitpunkt noch mit Interferon β-1b behandelten Patienten den Therapieerfolg in 75% der Fälle als “gut” bzw. “sehr gut”. 36,9% der Patienten waren seit 24 Monaten schubfrei (Vorwert: 0,3%). Die jährliche Schubrate sank von 1,5 vor der Therapie auf 0,7 im 2. Behandlungsjahr. Im Zweijahreszeitraum vor der Verlaufsbeobachtung hatten sich 66,5% der Patienten auf der EDSS um ≥0,5 Punkte verschlechtert. Nach der 2-jährigen Therapie lag der Anteil bei nur 41,2%. Das Nebenwirkungsprofil entsprach dem bereits aus kontrollierten klinischen Studien bekannten. Die Resultate dieser Verlaufsbeobachtung stützen die Ergebnisse der publizierten kontrollierten klinischen Studien mit Interferon β-1b und belegen unter den Bedingungen der Routineverschreibungspraxis die Hauptwirkungen der Therapie bei der schubförmigen MS. In a survey of disease course, the efficacy and tolerability of 24-month interferon β-1b therapy for relapsing remitting multiple sclerosis (RRMS) were evaluated in 410 patients. The investigation aimed at obtaining data from general practice and of possibly unknown, unexpected adverse reactions. In the 241 patients still on therapy, efficacy was rated after 24 months as “good” or “very good” in 75% of cases. After 24 months, 36.9% of the patients had no exacerbation (baseline 0.3%). Annual exacerbation rates dropped from 1.5 before treatment to 0.7 in the second treatment year. In the 2 years before treatment, 66.2% had worsened by at least 0.5 points on the extended disability status scale (EDSS). This proportion was reduced to 41.2% after 2 years of treatment. The safety profile corresponded to results from controlled trials. This postmarketing survey supports data from the published controlled interferon β-1b studies and confirms the main effects of this therapy under routine conditions in general practice.
    Der Nervenarzt 01/2001; 72(4):286-292. · 0.80 Impact Factor