Publications by authors named "Johannes Lorscheider"

18 Publications

  • Page 1 of 1

When does a heap become a heap?

Mult Scler 2021 Mar;27(3):329-330

Neurologic Clinic and Policlinic, Research Centre for Neuroimmunology and Neuroscience Basel (RC2NB), University Hospital Basel and University of Basel, Basel, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458520988459DOI Listing
March 2021

Combination of teriflunomide and interferon as follow-up therapy after fingolimod-associated PML.

Neurol Neuroimmunol Neuroinflamm 2021 01 3;8(1). Epub 2020 Dec 3.

From the Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803336PMC
January 2021

Accurate classification of secondary progression in multiple sclerosis using a decision tree.

Mult Scler 2020 Dec 2:1352458520975323. Epub 2020 Dec 2.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden/The Karolinska Neuroimmunology & Multiple Sclerosis Centre, Centre for Molecular Medicine (CMM), Karolinska Institutet, Stockholm, Sweden.

Background: The absence of reliable imaging or biological markers of phenotype transition in multiple sclerosis (MS) makes assignment of current phenotype status difficult.

Objective: The authors sought to determine whether clinical information can be used to accurately assign current disease phenotypes.

Methods: Data from the clinical visits of 14,387 MS patients in Sweden were collected. Classifying algorithms based on several demographic and clinical factors were examined. Results obtained from the best classifier when predicting neurologist recorded disease classification were replicated in an independent cohort from British Columbia and were compared to a previously published algorithm and clinical judgment of three neurologists.

Results: A decision tree (the classifier) containing only most recently available expanded disability scale status score and age obtained 89.3% (95% confidence intervals (CIs): 88.8-89.8) classification accuracy, defined as concordance with the latest reported status. Validation in the independent cohort resulted in 82.0% (95% CI: 81.0-83.1) accuracy. A previously published classification algorithm with slight modifications achieved 77.8% (95% CI: 77.1-78.4) accuracy. With complete patient history of 100 patients, three neurologists obtained 84.3% accuracy compared with 85% for the classifier using the same data.

Conclusion: The classifier can be used to standardize definitions of disease phenotype across different cohorts. Clinically, this model could assist neurologists by providing additional information.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458520975323DOI Listing
December 2020

Comparative analysis of dimethyl fumarate and fingolimod in relapsing-remitting multiple sclerosis.

J Neurol 2021 Mar 24;268(3):941-949. Epub 2020 Sep 24.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Dimethyl fumarate and fingolimod are oral disease modifying treatments (DMTs) that reduce relapse activity and slow disability worsening in relapsing-remitting multiple sclerosis (RRMS).

Objective: To compare the effectiveness of dimethyl fumarate and fingolimod in a real-world setting, where both agents are licensed as a first-line DMT for the treatment of RRMS.

Methods: We identified patients with RRMS commencing dimethyl fumarate or fingolimod in the Swiss Federation for Common Tasks of Health Insurances (SVK) Registry between August 2014 and July 2019. Propensity score-matching was applied to select subpopulations with comparable baseline characteristics. Relapses and disability outcomes were compared in paired, pairwise-censored analyses.

Results: Of the 2113 included patients, 1922 were matched (dimethyl fumarate, n = 961; fingolimod, n = 961). Relapse rates did not differ between the groups (incident rate ratio 1.0, 95%CI 0.8-1.2, p = 0.86). Moreover, no difference in the hazard of 1-year confirmed disability worsening (hazard ratio [HR] 0.9; 95%CI 0.6-1.6; p = 0.80) or disability improvement (HR 0.9; 95%CI 0.6-1.2; p = 0.40) was detected. These findings were consistent both for treatment-naïve patients and patients switching from another DMT.

Conclusion: Dimethyl fumarate and fingolimod have comparable effectiveness regarding reduction of relapses and disability worsening in RRMS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-020-10226-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914245PMC
March 2021

Disability progression multiple sclerosis patients on fingolimod versus interferon-beta/glatiramer acetate.

Mult Scler 2021 Mar 28;27(3):439-448. Epub 2020 May 28.

Neurologic Clinic and Policlinic, Departments of Medicine, University Hospital Basel and University of Basel, Basel, Switzerland.

Background: Disability progression independent of relapses (PIRA) has been described as a frequent phenomenon in relapsing-remitting multiple sclerosis (RRMS).

Objective: To compare the occurrence of disability progression in relapse-free RRMS patients on interferon-beta/glatiramer acetate (IFN/GA) versus fingolimod.

Methods: This study is based on data from the Swiss association for joint tasks of health insurers. Time to relapse and 12-month confirmed disability progression were compared between treatment groups using multivariable Cox regression analysis with confounder adjustment. Inverse-probability weighting was applied to correct for the bias that patients on fingolimod have a higher chance to remain relapse-free than patients on IFN/GA.

Results: We included 1640 patients (64% IFN/GA, 36% fingolimod, median total follow-up time = 4-5 years). Disease-modifying treatment (DMT) groups were well balanced with regard to potential confounders. Disability progression was observed in 155 patients (8.8%) on IFN/GA and 51 (7.6%) on fingolimod, of which 44 and 23 were relapse-free during the initial DMT, respectively. Adjusted standard regression analysis on all patients indicated that those on fingolimod experience less frequently disability progression compared with IFN/GA (hazard ratio = 0.53 (95% confidence interval = 0.37-0.76)). After bias correction, this was also true for patients without relapses (hazard ratio=0.56 (95% confidence interval = 0.32-0.98).

Conclusion: Our analysis indicates that fingolimod is superior to IFN/GA in preventing disability progression in both relapsing , young, newly diagnosed RRMS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458520918489DOI Listing
March 2021

PML with dimethyl fumarate-No convincing case against natalizumab.

Mult Scler 2019 10 22;25(12):1687-1688. Epub 2019 Aug 22.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel and University of Basel, Basel, Switzerland.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458519872894DOI Listing
October 2019

A case of progressive multifocal leukoencephalopathy under dimethyl fumarate treatment without severe lymphopenia or immunosenescence.

Mult Scler 2019 10 18;25(12):1682-1685. Epub 2019 Jun 18.

Neurologic Clinic and Policlinic, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland.

Background: Progressive multifocal leukoencephalopathy (PML) is the main safety concern for dimethyl fumarate (DMF) treatment in persons with multiple sclerosis (pwMS). Risk stratification under DMF is currently based on age above 50 years and prolonged lymphopenia below 500 cells/μL.

Objective: To report a case of PML under DMF without severe lymphopenia or immunosenescence.

Methods: Case report.

Results: A 39-year-old female pwMS developed DMF-associated oligosymptomatic PML. The patient had not experienced any repeated lymphocyte counts below 800 cells/μL and was 15 years younger than previously described cases.

Conclusion: Despite risk stratification, vigilance for PML is advised in all pwMS under DMF. Severe CD8-lymphopenia is a common feature of all published DMF-associated cases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458519852100DOI Listing
October 2019

Hypothyroidism manifesting as multiple cranial neuropathies: a case report.

J Med Case Rep 2019 Jun 13;13(1):180. Epub 2019 Jun 13.

Department of Endocrinology, Diabetes and Metabolism, University Hospital Basel and University of Basel, Petersgraben 4, 4031, Basel, Switzerland.

Introduction: The clinical picture of hypothyroidism, including neurological symptoms, can be multiform, which may delay or hamper the correct diagnosis.

Case Presentation: We present an uncommon clinical presentation of a 38-year-old Caucasian man with mild facial palsy on the left side, uvular deviation to the left with preserved gag reflex, tongue deviation to the left, lingual dysarthria, and xerosis by severe hypothyroidism. Blood tests on admission showed elevated serum creatinine of 151 μmol/L (glomerular filtration rate 47 ml/min/1.7 CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration equation]), increased creatinine phosphokinase activity (1243 U/L), markedly elevated thyroid-stimulating hormone (292.2 mIU/L), low free thyroxine level (1.1 pmol/L), and free triiodothyronine level below the limit of detection (< 0.4 pmol/L). Results of brain magnetic resonance imaging and renal ultrasound were unremarkable. Lumbar puncture revealed a normal cell count in cerebrospinal fluid, with an increased protein level of 758 mg/L and a cerebrospinal fluid/serum albumin ratio of 10.5 × 10/L (reference range < 6.7). Further diagnostic workup did not reveal any inflammatory or infectious systemic pathologies as an underlying cause. The patient's neurological symptoms, as well as laboratory findings including renal function, creatinine phosphokinase, and initially altered blood lipid levels, normalized with levothyroxine substitution.

Conclusions: Multiple cranial neuropathy is an uncommon clinical finding in hypothyroidism, which is an important differential diagnosis in the workup of new neurological deficits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13256-019-2124-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563357PMC
June 2019

Electronic Neurostatus-EDSS increases the quality of expanded disability status scale assessments: Experience from two phase 3 clinical trials.

Mult Scler 2020 07 7;26(8):993-996. Epub 2019 May 7.

Neurology, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland.

Background: The Neurostatus-eEDSS is an electronic tool providing automated real-time feedback on inconsistencies of Neurostatus-EDSS calculations.

Objective: To analyze the performance of the Neurostatus-eEDSS in two multicenter phase 3 multiple sclerosis (MS) trials.

Methods: All assessments captured with the Neurostatus-eEDSS web service during a period of 2.5 years were analyzed.

Results: Of the total 10,789 assessments, 40.1% had inconsistencies after first entry, reduced to 22.1% due to the real-time feedback. The entire checking process resulted in a change of the expanded disability status scale (EDSS) score in 14.8% of the assessments.

Conclusion: The Neurostatus-eEDSS can increase consistency and reliability of EDSS assessments in clinical MS trials.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458519845108DOI Listing
July 2020

Association of Rituximab Treatment With Disability Progression Among Patients With Secondary Progressive Multiple Sclerosis.

JAMA Neurol 2019 03;76(3):274-281

Neurologic Clinic and Policlinic, University Hospital and University of Basel, Basel, Switzerland.

Importance: Therapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited.

Objective: To analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab.

Design, Setting, And Participants: This retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort.

Exposures: Comparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching.

Main Outcomes And Measures: The primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression.

Results: After 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, patients with SPMS who were treated with rituximab had a significantly lower EDSS score during a mean (SD) follow-up of 3.5 (2.7) years (mean difference, -0.52; 95% CI, -0.79 to -0.26; P < .001). Time to confirmed disability progression was significantly delayed in the rituximab-treated group (hazard ratio, 0.49; 95% CI, 0.26-0.93; P = .03).

Conclusions And Relevance: In this study, patients with SPMS treated with rituximab had a significantly lower EDSS score for up to 10 years of follow-up and a significantly delayed confirmed progression compared with matched controls, suggesting that B-cell depletion by rituximab may be therapeutically beneficial in these patients. A prospective randomized clinical trial with a better level of evidence is needed to confirm the efficacy of rituximab in such patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2018.4239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439730PMC
March 2019

Comparative analysis of natalizumab versus fingolimod as second-line treatment in relapsing-remitting multiple sclerosis.

Mult Scler 2018 05 24;24(6):777-785. Epub 2018 Apr 24.

Neurologic Clinic and Policlinic, Department of Neurology, University Hospital Basel, Basel, Switzerland.

Background: No randomized controlled trials have compared the efficacy of fingolimod or natalizumab as second-line treatment in patients with relapsing-remitting multiple sclerosis (RRMS).

Objective: To compare clinical outcomes after escalation to fingolimod versus natalizumab in patients with clinically active RRMS.

Methods: Using the registry of the Swiss Federation for Common Tasks of Health Insurances, we identified patients with RRMS and ≥1 relapse in the year before switching from interferon beta or glatiramer acetate to fingolimod or natalizumab. Propensity score matching was used to select patients with comparable baseline characteristics. Relapse and Expanded Disability Status Scale (EDSS) outcomes were compared in paired, pairwise-censored analyses.

Results: Of the 547 included patients, 358 were matched (fingolimod, n = 179; natalizumab, n = 179). Median follow-up time was 1.8 years (interquartile range 0.9-2.9). Patients switching to natalizumab had a lower risk of relapses (incidence rate ratio 0.5, 95% confidence interval (CI) 0.3-0.8, p = 0.001) and were more likely to experience EDSS improvement (hazard ratio (HR) 1.8, 95% CI 1.1-2.7, p = 0.01) compared to fingolimod. We found no differences in the proportion of patients free from EDSS progression (HR 0.9, 95% CI 0.5-1.5, p = 0.62).

Conclusion: Natalizumab seems to be more effective in reducing relapse rate and improving disability compared with fingolimod.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458518768433DOI Listing
May 2018

Anti-inflammatory disease-modifying treatment and short-term disability progression in SPMS.

Neurology 2017 Sep 9;89(10):1050-1059. Epub 2017 Aug 9.

Objective: To investigate the effect of disease-modifying treatment on short-term disability outcomes in secondary progressive multiple sclerosis (SPMS).

Methods: Using MSBase, an international cohort study, we previously validated a highly accurate definition of SPMS. Here, we identified patients in MSBase who were either untreated or treated with a disease-modifying drug when meeting this definition. Propensity score matching was used to select subpopulations with comparable baseline characteristics. Disability outcomes were compared in paired, pairwise-censored analyses adjusted for treatment persistence, visit density, and relapse rates.

Results: Of the 2,381 included patients, 1,378 patients were matchable (treated n = 689, untreated n = 689). Median pairwise-censored follow-up was 2.1 years (quartiles 1.2-3.8 years). No difference in the risk of 6-month sustained disability progression was observed between the groups (hazard ratio [HR] 0.9, 95% confidence interval [CI] 0.7-1.1, = 0.27). We also did not find differences in any of the secondary endpoints: risk of reaching Expanded Disability Status Scale (EDSS) score ≥7 (HR 0.6, 95% CI 0.4-1.1, = 0.10), sustained disability reduction (HR 1.0, 95% CI 0.8-1.3, = 0.79), or change in disability burden (area under the EDSS-time curve, β = -0.05, = 0.09). Secondary and sensitivity analyses confirmed the results.

Conclusions: Our pooled analysis of the currently available disease-modifying agents used after conversion to SPMS suggests that, on average, these therapies have no substantial effect on relapse-unrelated disability outcomes measured by the EDSS up to 4 years.

Classification Of Evidence: This study provides Class IV evidence that for patients with SPMS, disease-modifying treatment has no beneficial effect on short-term disability progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000004330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5589791PMC
September 2017

Defining secondary progressive multiple sclerosis.

Brain 2016 09 7;139(Pt 9):2395-405. Epub 2016 Jul 7.

1 Department of Medicine, University of Melbourne, Melbourne, Australia 2 Department of Neurology, Royal Melbourne Hospital, Melbourne, Australia.

A number of studies have been conducted with the onset of secondary progressive multiple sclerosis as an inclusion criterion or an outcome of interest. However, a standardized objective definition of secondary progressive multiple sclerosis has been lacking. The aim of this work was to evaluate the accuracy and feasibility of an objective definition for secondary progressive multiple sclerosis, to enable comparability of future research studies. Using MSBase, a large, prospectively acquired, global cohort study, we analysed the accuracy of 576 data-derived onset definitions for secondary progressive multiple sclerosis and first compared these to a consensus opinion of three neurologists. All definitions were then evaluated against 5-year disease outcomes post-assignment of secondary progressive multiple sclerosis: sustained disability, subsequent sustained progression, positive disability trajectory, and accumulation of severe disability. The five best performing definitions were further investigated for their timeliness and overall disability burden. A total of 17 356 patients were analysed. The best definition included a 3-strata progression magnitude in the absence of a relapse, confirmed after 3 months within the leading Functional System and required an Expanded Disability Status Scale step ≥4 and pyramidal score ≥2. It reached an accuracy of 87% compared to the consensus diagnosis. Seventy-eight per cent of the identified patients showed a positive disability trajectory and 70% reached significant disability after 5 years. The time until half of all patients were diagnosed was 32.6 years (95% confidence interval 32-33.6) after disease onset compared with the physicians' diagnosis at 36 (35-39) years. The identified patients experienced a greater disease burden [median annualized area under the disability-time curve 4.7 (quartiles 3.6, 6.0)] versus non-progressive patients [1.8 (1.2, 1.9)]. This objective definition of secondary progressive multiple sclerosis based on the Expanded Disability Status Scale and information about preceding relapses provides a tool for a reproducible, accurate and timely diagnosis that requires a very short confirmation period. If applied broadly, the definition has the potential to strengthen the design and improve comparability of clinical trials and observational studies in secondary progressive multiple sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/aww173DOI Listing
September 2016

Predictors of long-term disability accrual in relapse-onset multiple sclerosis.

Ann Neurol 2016 07 1;80(1):89-100. Epub 2016 Jun 1.

Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Bari, Italy.

Objective: To identify predictors of 10-year Expanded Disability Status Scale (EDSS) change after treatment initiation in patients with relapse-onset multiple sclerosis.

Methods: Using data obtained from MSBase, we defined baseline as the date of first injectable therapy initiation. Patients need only have remained on injectable therapy for 1 day and were monitored on any approved disease-modifying therapy, or no therapy thereafter. Median EDSS score changes over a 10-year period were determined. Predictors of EDSS change were then assessed using median quantile regression analysis. Sensitivity analyses were further performed.

Results: We identified 2,466 patients followed up for at least 10 years reporting post-baseline disability scores. Patients were treated an average 83% of their follow-up time. EDSS scores increased by a median 1 point (interquartile range = 0-2) at 10 years post-baseline. Annualized relapse rate was highly predictive of increases in median EDSS over 10 years (coeff = 1.14, p = 1.9 × 10(-22) ). On-therapy relapses carried greater burden than off-therapy relapses. Cumulative treatment exposure was independently associated with lower EDSS at 10 years (coeff = -0.86, p = 1.3 × 10(-9) ). Furthermore, pregnancies were also independently associated with lower EDSS scores over the 10-year observation period (coeff = -0.36, p = 0.009).

Interpretation: We provide evidence of long-term treatment benefit in a large registry cohort, and provide evidence of long-term protective effects of pregnancy against disability accrual. We demonstrate that high annualized relapse rate, particularly on-treatment relapse, is an indicator of poor prognosis. Ann Neurol 2016;80:89-100.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.24682DOI Listing
July 2016

The Swiss Multiple Sclerosis Cohort-Study (SMSC): A Prospective Swiss Wide Investigation of Key Phases in Disease Evolution and New Treatment Options.

PLoS One 2016 31;11(3):e0152347. Epub 2016 Mar 31.

Neurology, Departments of Medicine, Biomedicine and Clinical Research, University Hospital Basel, Basel, Switzerland.

The mechanisms leading to disability and the long-term efficacy and safety of disease modifying drugs (DMDs) in multiple sclerosis (MS) are unclear. We aimed at building a prospective cohort of MS patients with standardized collection of demographic, clinical, MRI data and body fluids that can be used to develop prognostic indicators and biomarkers of disease evolution and therapeutic response. The Swiss MS Cohort (SMSC) is a prospective observational study performed across seven Swiss MS centers including patients with MS, clinically isolated syndrome (CIS), radiologically isolated syndrome or neuromyelitis optica. Neurological and radiological assessments and biological samples are collected every 6-12 months. We recruited 872 patients (clinically isolated syndrome [CIS] 5.5%, relapsing-remitting MS [RRMS] 85.8%, primary progressive MS [PPMS] 3.5%, secondary progressive MS [SPMS] 5.2%) between June 2012 and July 2015. We performed 2,286 visits (median follow-up 398 days) and collected 2,274 serum, plasma and blood samples, 152 cerebrospinal fluid samples and 1,276 brain MRI scans. 158 relapses occurred and expanded disability status scale (EDSS) scores increased in PPMS, SPMS and RRMS patients experiencing relapses. Most RRMS patients were treated with fingolimod (33.4%), natalizumab (24.5%) or injectable DMDs (13.6%). The SMSC will provide relevant information regarding DMDs efficacy and safety and will serve as a comprehensive infrastructure available for nested research projects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0152347PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816556PMC
August 2016

Fingolimod and CSF neurofilament light chain levels in relapsing-remitting multiple sclerosis.

Neurology 2015 Apr 25;84(16):1639-43. Epub 2015 Mar 25.

From the Neuroimmunology Unit (J.K., G.D., G.G.), Blizard Institute, Barts and the London School of Medicine and Dentistry, London, UK; Neurology, Departments of Medicine, Clinical Research and Biomedicine (J.K., J.L., L.K.), and the Medical Image Analysis Center (MIAC) (E.-W.R.), University Hospital, Basel, Switzerland; Novartis Pharmaceuticals Corporation (T.S., Y.C., G.F.), East Hanover, NJ; Novartis Pharma AG (F.D.), Basel, Switzerland; and Novartis Healthcare Pvt Ltd (A.S.), Hyderabad, India.

Objective: We assessed CSF levels of the light chain subunit of neurofilaments (NfL) at baseline and after fingolimod therapy or placebo in patients with relapsing-remitting multiple sclerosis (RRMS). Changes in NfL levels were also correlated with relapse and MRI outcomes.

Methods: CSF samples were available, at baseline and 12 months after treatment initiation, from a subset of 36 patients with RRMS (fingolimod 0.5 mg: n = 9; fingolimod 1.25 mg: n = 15; placebo: n = 12) participating in the 2-year, phase 3 Fingolimod (FTY720) Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) study. NfL levels were determined in a blinded fashion using a commercial ELISA kit.

Results: Median NfL levels did not differ between treatment groups at baseline (0.5 mg: 644 pg/mL; 1.25 mg: 659 pg/mL; pooled 0.5/1.25 mg: 652 pg/mL, placebo: 886 pg/mL; p value [fingolimod vs placebo] = 0.619, 0.495, and 0.481, respectively). Following 12 months of treatment, median changes from baseline in NfL levels were lower than zero in the fingolimod groups (0.5 mg: -346 pg/mL, p = 0.039; 1.25 mg: -313 pg/mL, p = 0.035) and pooled 0.5/1.25 mg fingolimod group (-326 pg/mL, 83.3% with reduction, p = 0.002) but not in the placebo group (-214 pg/mL, 66.7% with reduction, p = 0.388). Reductions in NfL levels at month 12 correlated with an improvement in relapse and MRI outcomes.

Conclusions: Our results suggest a beneficial effect of fingolimod on this marker of axonal injury and support the utility of NfL as a quantitative biomarker in multiple sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000001491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409586PMC
April 2015

T-cell response against varicella-zoster virus in fingolimod-treated MS patients.

Neurology 2013 Jul 22;81(2):174-81. Epub 2013 May 22.

Clinical Neuroimmunology, Department of Biomedicine, University of Basel, Switzerland.

Objective: To study the immune response against varicella-zoster virus (VZV) in patients with multiple sclerosis before and during fingolimod therapy.

Methods: The VZV-specific immune response was studied using interferon (IFN)-γ enzyme-linked immunosorbent spot assay, proliferation assays, and upregulation of T-cell activation markers in patients before (n = 38) and after 3 months of fingolimod therapy (n = 34), in untreated (n = 33) and IFN-β-treated (n = 25) patients with multiple sclerosis, and in healthy controls (n = 22). Viral replication was analyzed by using real-time PCR in 76 peripheral blood mononuclear cell samples and 146 saliva samples.

Results: Treatment with fingolimod led to a marked reduction of CD3(+) T cells with a relative decrease of naive and central memory T cells and an increase of effector memory T cells. Expression of the activation markers CD137 and CD69 upon VZV stimulation was unaltered by fingolimod. However, the absolute number of cells proliferating upon VZV stimulation was reduced in the blood of patients treated with fingolimod. Also, VZV-specific and Epstein-Barr virus (EBV)-specific IFN-γ-producing cells were reduced after fingolimod therapy. Seven of the 35 patients treated with fingolimod showed signs of VZV or EBV reactivation in saliva compared with 3 of the 111 controls. None of the 76 tested samples showed signs of viral reactivation in the peripheral blood mononuclear cells.

Conclusion: Patients treated with fingolimod show a slightly reduced antiviral T-cell response. This reduced response is accompanied by a subclinical reactivation of VZV or EBV in the saliva of 20% of patients treated with fingolimod.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0b013e31829a3311DOI Listing
July 2013

The BAR domain protein PICK1 regulates cell recognition and morphogenesis by interacting with Neph proteins.

Mol Cell Biol 2011 Aug 20;31(16):3241-51. Epub 2011 Jun 20.

Renal Division, Department of Medicine and Center for Molecular Medicine, University of Cologne, 50937 Cologne, Germany.

Neph proteins are evolutionarily conserved membrane proteins of the immunoglobulin superfamily that control the formation of specific intercellular contacts. Cell recognition through these proteins is essential in diverse cellular contexts such as patterning of the compound eye in Drosophila melanogaster, neuronal connectivity in Caenorhabditis elegans, and the formation of the kidney filtration barrier in mammals. Here we identify the PDZ and BAR domain protein PICK1 (protein interacting with C-kinase 1) as a Neph-interacting protein. Binding required dimerization of PICK1, was dependent on PDZ domain protein interactions, and mediated stabilization of Neph1 at the plasma membrane. Moreover, protein kinase C (PKCα) activity facilitated the interaction through releasing Neph proteins from their binding to the multidomain scaffolding protein zonula occludens 1 (ZO-1), another PDZ domain protein. In Drosophila, the Neph homologue Roughest is essential for sorting of interommatidial precursor cells and patterning of the compound eye. RNA interference-mediated knockdown of PICK1 in the Drosophila eye imaginal disc caused a Roughest destabilization at the plasma membrane and a phenotype that resembled rst mutation. These data indicate that Neph proteins and PICK1 synergistically regulate cell recognition and contact formation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/MCB.05286-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3147803PMC
August 2011