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  • 1. Bachelet, Delphine
    et al.
    Hassler, Signe
    Mbogning, Cyprien
    Link, Jenny
    Ryner, Malin
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Auer, Michael
    Jensen, Poul Erik Hyldgaard
    Koch-Henriksen, Nils
    Warnke, Clemens
    Ingenhoven, Kathleen
    Buck, Dorothea
    Grummel, Verena
    Lawton, Andy
    Donnellan, Naoimh
    Hincelin-Mery, Agnes
    Sikkema, Dan
    Pallardy, Marc
    Kieseier, Bernd
    Hemmer, Bernard
    Hartung, Hans Peter
    Sorensen, Per Soelberg
    Deisenhammer, Florian
    Donnes, Pierre
    Davidson, Julie
    Fogdell-Hahn, Anna
    Broet, Philippe
    Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis: A Collaborative Cohort Analysis2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 11, article id e0162752Article in journal (Refereed)
    Abstract [en]

    Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in Sweden, Denmark, Austria and Germany (Dusseldorf group) and from one research study in Germany (Munich group) were gathered to build a collaborative multi-cohort dataset within the framework of the ABIRISK project. A subset of 5638 interferon-beta (IFN beta)-treated and 3440 natalizumab-treated patients having data on at least the first two years of treatment were eligible for interval-censored time-to-event analysis. In multivariate Cox regression, IFN beta-1a subcutaneous and IFN beta-1b subcutaneous treated patients were at higher risk of ADA occurrence compared to IFN beta-1a intramuscular-treated patients (pooled HR = 6.4, 95% CI 4.9-8.4 and pooled HR = 8.7, 95% CI 6.6-11.4 respectively). Patients older than 50 years at start of IFN beta therapy developed ADA more frequently than adult patients younger than 30 (pooled HR = 1.8, 95% CI 1.4-2.3). Men developed ADA more frequently than women (pooled HR = 1.3, 95% CI 1.1-1.6). Interestingly we observed that in Sweden and Germany, patients who started IFN beta in April were at higher risk of developing ADA (HR = 1.6, 95% CI 1.1-2.4 and HR = 2.4, 95% CI 1.5-3.9 respectively). This result is not confirmed in the other cohorts and warrants further investigations. Concerning natalizumab, patients older than 45 years had a higher ADA rate (pooled HR = 1.4, 95% CI 1.0-1.8) and women developed ADA more frequently than men (pooled HR = 1.4, 95% CI 1.0-2.0). We confirmed previously reported differences in immunogenicity of the different types of IFN beta. Differences in ADA occurrence by sex and age are reported here for the first time. These findings should be further investigated taking into account other exposures and biomarkers.

  • 2.
    Jensen, Poul Erik H.
    et al.
    Univ Copenhagen, Rigshosp, Danish Multiple Sclerosis Ctr, Dept Neurol, Sect 6311, Copenhagen, Denmark..
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.).
    Sorensen, Per Soelberg
    Univ Copenhagen, Rigshosp, Danish Multiple Sclerosis Ctr, Dept Neurol, Sect 6311, Copenhagen, Denmark..
    Detection and kinetics of persistent neutralizing anti-interferon-beta antibodies in patients with multiple sclerosis. Results from the ABIRISK prospective cohort study2019In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 326, p. 19-27Article in journal (Refereed)
    Abstract [en]

    Two validated assays, a bridging ELISA and a luciferase-based bioassay, were compared for detection of anti-drug antibodies (ADA) against interferon-beta (IFN-beta) in patients with multiple sclerosis. Serum samples were tested from patients enrolled in a prospective study of 18 months. In contrast to the ELISA, when IFN-beta-specific rabbit polyclonal and human monoclonal antibodies were tested, the bioassay was the more sensitive to detect IFN-beta ADA in patients' sera. For clinical samples, selection of method of ELISA should be evaluated prior to the use of a multi-tiered approach. A titer threshold value is reported that may be used as a predictor for persistently positive neutralizing ADA.

  • 3. Kavaliunas, A.
    et al.
    Manouchehrinia, A.
    Stawiarz, L.
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Agholme, J.
    Hedstrom, A. K.
    Beiki, O.
    Glaser, A.
    Hillert, J.
    Importance of early treatment initiation in the clinical course of multiple sclerosis2016In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 642-642Article in journal (Refereed)
  • 4. Kavaliunas, Andrius
    et al.
    Manouchehrinia, Ali
    Stawiarz, Leszek
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Agholme, Jonas
    Hedstrom, Anna Karin
    Beiki, Omid
    Glaser, Anna
    Hillert, Jan
    Importance of early treatment initiation in the clinical course of multiple sclerosis2017In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 23, no 9, p. 1233-1240Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to identify factors influencing the long-term clinical progression of multiple sclerosis (MS). A special objective was to investigate whether early treatment decisions influence outcome. Methods: We included 639 patients diagnosed with MS from 2001 to 2007. The median follow-up time was 99 months (8.25 years). Cox regression models were applied to identify factors correlating with the outcome variable defined as time from treatment start to irreversible score 4 of the Expanded Disability Status Scale (EDSS). Results: Patients initiated on treatment later had a greater risk of reaching EDSS 4 (hazard ratio of 1.074 (95% confidence interval (CI), 1.048-1.101)), increased by 7.4% for every year of delay in treatment start after MS onset. Patients who started treatment after 3 years from MS onset reached the outcome sooner with hazard ratio of 2.64 (95% CI, 1.71-4.08) compared with the patients who started treatment within 1 year from MS onset. Baseline EDSS and age at onset were found to be predictive factors of disability progression. Conclusion: Early treatment initiation was associated with a better clinical outcome. In addition, we confirmed the well-established prognostic factors of late age at onset and early disability.

  • 5. Link, Jenny
    et al.
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.). Karolinska Institutet, Sweden.
    Auer, Michael
    Ryner, Malin
    Hassler, Signe
    Bachelet, Delphine
    Mbogning, Cyprien
    Warnke, Clemens
    Buck, Dorothea
    Jensen, Poul Erik Hyldgaard
    Sievers, Claudia
    Ingenhoven, Kathleen
    Fissolo, Nicolas
    Lindberg, Raija
    Grummel, Verena
    Donnellan, Naoimh
    Comabella, Manuel
    Montalban, Xavier
    Kieseier, Bernd
    Sorensen, Per Soelberg
    Hartung, Hans-Peter
    Derfuss, Tobias
    Lawton, Andy
    Sikkema, Dan
    Pallardy, Marc
    Hemmer, Bernhard
    Deisenhammer, Florian
    Broet, Philippe
    Donnes, Pierre
    Davidson, Julie
    Fogdell-Hahn, Anna
    Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe: A descriptive study of test results2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 2, article id e0170395Article in journal (Refereed)
    Abstract [en]

    Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta (IFN beta) and natalizumab have been pooled and characterized through collaboration within a European consortium. The aim of this study was to report on the clinical practice of ADA testing in Europe, considering the number of ADA tests performed and type of ADA assays used, and to determine the frequency of ADA testing against the different drug preparations in different countries. A common database platform (tranSMART) for querying, analyzing and storing retrospective data of MS cohorts was set up to harmonize the data and compare results of ADA tests between different countries. Retrospective data from six countries (Sweden, Austria, Spain, Switzerland, Germany and Denmark) on 20,695 patients and on 42,555 samples were loaded into tranSMART including data points of age, gender, treatment, samples, and ADA results. The previously observed immunogenic difference among the four IFN beta preparations was confirmed in this large dataset. Decreased usage of the more immunogenic preparations IFN beta-1a subcutaneous (s.c.) and IFN beta-1b s.c. in favor of the least immunogenic preparation IFN beta-1a intramuscular (i.m.) was observed. The median time from treatment start to first ADA test correlated with time to first positive test. Shorter times were observed for IFN beta-1b-Extavia s. c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFN beta-1a i. m. (1.41 and 2.27 years), IFN beta-1b-Betaferon s. c. (2.51 and 1.96 years) and IFN beta-1a s. c. (2.11 and 2.09 years) which were available years before routine testing began. A higher rate of anti-IFN beta ADA was observed in test samples taken from older patients. Testing for ADA varies between different European countries and is highly dependent on the policy within each country. For drugs where routine monitoring of ADA is not in place, there is a risk that some patients remain on treatment for several years despite ADA positivity. For drugs where a strategy of ADA testing is introduced with the release of the drug, there is a reduced risk of having ADA positive patients and thus of less efficient treatment. This indicates that potential savings in health cost might be achieved by routine analysis of ADA.

  • 6.
    Manouchehrinia, A.
    et al.
    Karolinska Inst, Stockholm, Sweden..
    Chachólski, Wojciech
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.). Royal Inst Technol, Stockholm, Sweden..
    Hillert, J.
    Karolinska Inst, Stockholm, Sweden..
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.). Karolinska Inst, Stockholm, Sweden.;Royal Inst Technol, Stockholm, Sweden..
    Topological data analysis to identify subgroups of multiple sclerosis patients with faster disease progression2018In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 24, p. 342-343Article in journal (Other academic)
  • 7.
    Manouchehrinia, Ali
    et al.
    Karolinska Inst, Karolinska Univ Hosp Solna, Dept Clin Neurosci, Stockholm, Sweden..
    Hedstrom, Anna Karin
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden..
    Alfredsson, Lars
    Karolinska Inst, Inst Environm Med, Unit Cardiovasc Epidemiol, Stockholm, Sweden.;Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden..
    Olsson, Tomas
    Karolinska Inst, Karolinska Univ Hosp Solna, Dept Clin Neurosci, Stockholm, Sweden..
    Hillert, Jan
    Karolinska Inst, Karolinska Univ Hosp Solna, Dept Clin Neurosci, Stockholm, Sweden..
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.). Karolinska Inst.
    Association of Pre-Disease Body Mass Index With Multiple Sclerosis Prognosis2018In: Frontiers in Neurology, ISSN 1664-2295, E-ISSN 1664-2295, Vol. 9, article id 232Article in journal (Refereed)
    Abstract [en]

    Both high body mass index (BMI) and smoking tobacco are known risk factors for developing multiple sclerosis (MS). However, it is unclear whether BMI, like smoking, is a risk factor for the secondary progressive (SP) course. We, therefore, sought to determine if high/low BMI at age 20 is associated to risk of SP development, in the context of smoking status. Using data from MS patients with BMI and smoking information available, we examined relapsing onset patients with MS onset after 20 years of age. Cox regressions were conducted on smokers and non-smokers, with BMI as the main exposure. In total, 5,598 relapsing onset MS patients were included. The models demonstrated that BMI > 30 was associated to increased risk of SPMS in smokers (hazard ratio 1.50, p = 0.036). This association of obesity at age 20 with increased risk of SP was not observed in non-smokers (hazard rate 0.97, p = 0.900). Since the risk is confined to smokers, the interaction observed may give insight to disease driving mechanisms.

  • 8.
    Ramanujam, Ryan
    et al.
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Hillert, J.
    Manouchehrinia, A.
    Predicting conversion to secondary progressive multiple sclerosis using a clinical decision tree2016In: Multiple Sclerosis, ISSN 1352-4585, E-ISSN 1477-0970, Vol. 22, p. 454-454Article in journal (Refereed)
  • 9.
    Scolamiero, Martina
    et al.
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Chachólski, Wojciech
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Lundman, Anders
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Ramanujam, Ryan
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Öberg, Sebastian
    KTH, School of Engineering Sciences (SCI), Mathematics (Dept.), Mathematics (Div.).
    Multidimensional Persistence and Noise2017In: Foundations of Computational Mathematics, ISSN 1615-3375, E-ISSN 1615-3383, Vol. 17, no 6, p. 1367-1406Article in journal (Refereed)
    Abstract [en]

    In this paper, we study multidimensional persistence modules (Carlsson and Zomorodian in Discrete Comput Geom 42(1):71–93, 2009; Lesnick in Found Comput Math 15(3):613–650, 2015) via what we call tame functors and noise systems. A noise system leads to a pseudometric topology on the category of tame functors. We show how this pseudometric can be used to identify persistent features of compact multidimensional persistence modules. To count such features, we introduce the feature counting invariant and prove that assigning this invariant to compact tame functors is a 1-Lipschitz operation. For one-dimensional persistence, we explain how, by choosing an appropriate noise system, the feature counting invariant identifies the same persistent features as the classical barcode construction.

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