Publications by authors named "Per S Sorensen"

20 Publications

  • Page 1 of 1

Cardiovascular Safety of Degarelix versus Leuprolide in Patients with Prostate Cancer: The Primary Results of the PRONOUNCE Randomized Trial.

Circulation 2021 Aug 30. Epub 2021 Aug 30.

Department of Medicine, Division of Cardiology, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.

The relative cardiovascular safety of gonadotropin-releasing hormone (GnRH) antagonists compared with GnRH agonists in men with prostate cancer and known atherosclerotic cardiovascular disease (ASCVD) remains controversial. In this international, multicenter, prospective, randomized, open-label trial, men with prostate cancer and concomitant ASCVD were randomized 1:1 to receive the GnRH antagonist degarelix or the GnRH agonist leuprolide for 12 months. The primary outcome was the time to first adjudicated major adverse cardiovascular event (MACE) (composite of death, myocardial infarction, or stroke) through 12 months. Due to slower than projected enrollment and fewer than projected primary outcome events, enrollment was stopped before the 900 planned participants were accrued. From 3 May 2016 to 16 April 2020, a total of 545 patients from 113 sites across 12 countries were randomized. Baseline characteristics were balanced between study groups. The median age was 73 years, 49.8% had localized prostate cancer; 26.3% had locally advanced disease and 20.4% had metastatic disease. MACE occurred in 15 (5.5%) patients assigned to degarelix and 11 (4.1%) assigned to leuprolide (hazard ratio [HR] 1.28, 95% confidence interval [CI] 0.59-2.79; p=0.53). PRONOUNCE is the first, international, randomized clinical trial to prospectively compare the cardiovascular safety of a GnRH antagonist and a GnRH agonist in patients with prostate cancer. The study was terminated prematurely due to smaller than planned number of participants and events and no difference in MACE at 1 year between patients assigned to degarelix or leuprolide was observed. The relative cardiovascular safety of GnRH antagonists and agonists remains unresolved. URL: https://clinicaltrials.gov Unique Identifier: NCT02663908.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.056810DOI Listing
August 2021

Editorial: Challenges in the diagnosis and treatment of multiple sclerosis.

Authors:
Per S Sørensen

Curr Opin Neurol 2021 06;34(3):275-276

Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Rigshospitalet.

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http://dx.doi.org/10.1097/WCO.0000000000000940DOI Listing
June 2021

Highly effective disease-modifying treatment as initial MS therapy.

Curr Opin Neurol 2021 06;34(3):286-294

The Blizard Institute, Centre for Neuroscience, Surgery & Trauma, Barts and The London School of Medicine and Dentistry, Queen Mary University of London.

Purpose Of Review: Using highly effective (HE) compounds right from the beginning of disease-modifying immunotherapy (DMT) in people with multiple sclerosis (pwMS) has gained popularity among clinicians and pwMS alike. We discuss the most recent evidence supporting this approach, and whether any of the associated risks should stop us adopting it as a default strategy.

Recent Findings: With the addition of injectable ofatumumab, and the two oral sphingosine one phosphate modulators siponimod and ozanimod, ten HE DMTs are now available for pwMS, though variation in licensing status and cost may limit their use in some healthcare environments. Real World evidence based on large MS registry data suggests the superiority of early HE DMT over a slow treatment escalation approach; delaying HE DMT leads to more rapid and often irreversible disability accrual. Mechanistically, B-cell depletion, particularly memory B-cell suppression, is a common denominator closely associated with DMT efficacy.

Summary: The concept that HE DMTs are necessarily associated with a high risk of adverse effects, is no longer supported by the evidence. The rather predictable and manageable risk profile of most HE DMTs should lower the threshold for clinicians to discuss such treatment with pwMS as a first line approach.
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http://dx.doi.org/10.1097/WCO.0000000000000937DOI Listing
June 2021

Efficacy and safety of degarelix in patients with prostate cancer: Results from a phase III study in China.

Asian J Urol 2020 Jul 23;7(3):301-308. Epub 2019 Sep 23.

Department of Urology, Peking University People's Hospital, Beijing, China.

Objective: To establish non-inferiority of gonadotropin-releasing hormone degarelix compared with goserelin in suppressing and maintaining castrate testosterone levels from Day 28 to Day 364 in Chinese patients with prostate cancer.

Methods: This is an open-label, multi-centre study in which men aged ≥18 years were randomised in a 1:1 ratio to once-a-month subcutaneous injection of either degarelix (240/80 mg) or goserelin (3.6 mg) for 12 months. The primary endpoint was difference in 1-year cumulative probability of suppressing testosterone to ≤0.5 ng/mL. Non-inferiority was to be established if the lower 95% confidence interval (CI) limit for difference in cumulative probability between the treatment arms was greater than -10%. Secondary endpoints included cumulative probability of prostate-specific-antigen-progression-free-survival (PSA-PFS). Safety was also assessed.

Results: Baseline demographics and disease characteristics were similar between degarelix (=142) and goserelin (=141) treatment arms. The difference in cumulative probability of maintaining castrate levels from Day 28-364 was 3.6% (95% CI:-1.5%, 8.7%), demonstrating non-inferiority of degarelix. The cumulative probability of PSA-PFS at Day 364 was higher for degarelix (82.3%, 95% CI: 74.7%, 87.7%) versus goserelin (71.7%, 95% CI: 63.2%, 78.5%, =0.038). Adverse events (AEs) were similar between treatment arms, except for more injection site reactions with degarelix versus goserelin. Four (2.8%) and nine (6.4%) patients discontinued due to AEs in degarelix and goserelin groups, respectively.

Conclusion: Degarelix was non-inferior to goserelin in achieving and maintaining testosterone suppression at castrate levels during 1-year treatment. PSA-PFS was significantly higher with degarelix, suggesting improved disease control. Both treatments were well tolerated.
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http://dx.doi.org/10.1016/j.ajur.2019.09.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385516PMC
July 2020

Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study.

Neurology 2018 05 25;90(20):e1805-e1814. Epub 2018 Apr 25.

From the Department of Neurology (A.B.-O.), Perelman School of Medicine, University of Pennsylvania, Philadelphia; Neuroimmunology Unit (A.B.-O.), Montreal Neurological Institute and Hospital, McGill University and McGill University Health Center, Quebec, Canada; Neurosciences Clinical Statistics (R.A.G.), Clinical Pharmacology (R.A.G., D.J.A.), and Modeling and Simulation (D.J.A.), GlaxoSmithKline, Uxbridge, Middlesex, UK; Neurosciences Therapy Area Unit (J.M.T., S.A.V., E.W.L., F.J.D., M.C.L., S.T.K.), SAVM (F.J.D., M.C.L.), Global Clinical Safety and Pharmacovigilance (E.W.L.), and Neurosciences Clinical Statistics (SecTK), GlaxoSmithKline, Research Triangle Park, NC; Department of Neurology (A.E.M.), Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Icahn School of Medicine at Mount Sinai, New York, NY; and Danish Multiple Sclerosis Center (P.S.S.), Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. Dr. Derosier is now at Clinical Development, Isis Pharmaceutical, Carlsbad, CA.

Objective: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS).

Methods: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B-lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion.

Results: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo ( < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a ≥90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses ≥30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing.

Conclusion: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses ≥30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells.

Classification Of Evidence: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation.
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http://dx.doi.org/10.1212/WNL.0000000000005516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957306PMC
May 2018

Smoking affects the interferon beta treatment response in multiple sclerosis.

Neurology 2018 02 17;90(7):e593-e600. Epub 2018 Jan 17.

From the Danish Multiple Sclerosis Center (E.R.P., A.B.O., M.M., P.S.S., F.S., H.B.S.), Department of Neurology, and Danish Multiple Sclerosis Treatment Register (N.K.-H., M.M.), Rigshospitalet, University of Copenhagen; and Department of Clinical Epidemiology (N.K.-H), Clinical Institute, University of Aarhus, Denmark.

Objective: To investigate whether smoking in patients with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta (IFN-β) is associated with the relapse rate and whether there is an interaction between smoking and human leukocyte antigen (HLA)-DRB1*15:01, HLA-A*02:01, and the N-acetyltransferase-1 () variant rs7388368A.

Methods: DNA from 834 IFN-β-treated patients with RRMS from the Danish Multiple Sclerosis Biobank was extracted for genotyping. Information about relapses from 2 years before the start of treatment to either the end of treatment or the last follow-up visit was obtained from the Danish Multiple Sclerosis Treatment Register. Smoking information came from a comprehensive questionnaire.

Results: We found that the relapse rate in patients with RRMS during IFN-β treatment was higher in smokers compared to nonsmokers, with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 1.021-1.416, = 0.027) and with an IRR increase of 27% per pack of cigarettes per day (IRR 1.27, 95% CI 1.056-1.537, = 0.012). We found no association or interaction with HLA and the NAT1 variant.

Conclusion: In this observational cohort study, we found that smoking is associated with increased relapse activity in patients with RRMS treated with IFN-β, but we found no association or interaction with HLA or the NAT1 variant.
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http://dx.doi.org/10.1212/WNL.0000000000004949DOI Listing
February 2018

Multiple sclerosis risk loci and disease severity in 7,125 individuals from 10 studies.

Neurol Genet 2016 Aug 4;2(4):e87. Epub 2016 Aug 4.

Author affiliations are listed at the end of the article.

Objective: We investigated the association between 52 risk variants identified through genome-wide association studies and disease severity in multiple sclerosis (MS).

Methods: Ten unique MS case data sets were analyzed. The Multiple Sclerosis Severity Score (MSSS) was calculated using the Expanded Disability Status Scale at study entry and disease duration. MSSS was considered as a continuous variable and as 2 dichotomous variables (median and extreme ends; MSSS of ≤5 vs >5 and MSSS of <2.5 vs ≥7.5, respectively). Single nucleotide polymorphisms (SNPs) were examined individually and as both combined weighted genetic risk score (wGRS) and unweighted genetic risk score (GRS) for association with disease severity. Random-effects meta-analyses were conducted and adjusted for cohort, sex, age at onset, and HLA-DRB1*15:01.

Results: A total of 7,125 MS cases were analyzed. The wGRS and GRS were not strongly associated with disease severity after accounting for cohort, sex, age at onset, and HLA-DRB1*15:01. After restricting analyses to cases with disease duration ≥10 years, associations were null (p value ≥0.05). No SNP was associated with disease severity after adjusting for multiple testing.

Conclusions: The largest meta-analysis of established MS genetic risk variants and disease severity, to date, was performed. Results suggest that the investigated MS genetic risk variants are not associated with MSSS, even after controlling for potential confounders. Further research in large cohorts is needed to identify genetic determinants of disease severity using sensitive clinical and MRI measures, which are critical to understanding disease mechanisms and guiding development of effective treatments.
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http://dx.doi.org/10.1212/NXG.0000000000000087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974846PMC
August 2016

Endogenous interferon-β-inducible gene expression and interferon-β-treatment are associated with reduced T cell responses to myelin basic protein in multiple sclerosis.

PLoS One 2015 4;10(3):e0118830. Epub 2015 Mar 4.

Danish Multiple Sclerosis Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

Autoreactive CD4+ T-cells are considered to play a major role in the pathogenesis of multiple sclerosis. In experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis, exogenous and endogenous type I interferons restrict disease severity. Recombinant interferon-β is used for treatment of multiple sclerosis, and some untreated multiple sclerosis patients have increased expression levels of type I interferon-inducible genes in immune cells. The role of endogenous type I interferons in multiple sclerosis is controversial: some studies found an association of high expression levels of interferon-β-inducible genes with an increased expression of interleukin-10 and a milder disease course in untreated multiple sclerosis patients, whereas other studies reported an association with a poor response to treatment with interferon-β. In the present study, we found that untreated multiple sclerosis patients with an increased expression of interferon-β-inducible genes in peripheral blood mononuclear cells and interferon-β-treated multiple sclerosis patients had decreased CD4+ T-cell reactivity to the autoantigen myelin basic protein ex vivo. Interferon-β-treated multiple sclerosis patients had increased IL10 and IL27 gene expression levels in monocytes in vivo. In vitro, neutralization of interleukin-10 and monocyte depletion increased CD4+ T-cell reactivity to myelin basic protein while interleukin-10, in the presence or absence of monocytes, inhibited CD4+ T-cell reactivity to myelin basic protein. Our findings suggest that spontaneous expression of interferon-β-inducible genes in peripheral blood mononuclear cells from untreated multiple sclerosis patients and treatment with interferon-β are associated with reduced myelin basic protein-induced T-cell responses. Reduced myelin basic protein-induced CD4+ T-cell autoreactivity in interferon-β-treated multiple sclerosis patients may be mediated by monocyte-derived interleukin-10.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118830PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349448PMC
December 2015

A systematic review of the incidence and prevalence of autoimmune disease in multiple sclerosis.

Mult Scler 2015 Mar 22;21(3):282-93. Epub 2014 Dec 22.

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

Background: As new therapies emerge which increase the risk of autoimmune disease it is increasingly important to understand the incidence of autoimmune disease in multiple sclerosis (MS).

Objective: The purpose of this review is to estimate the incidence and prevalence of comorbid autoimmune disease in MS.

Methods: The PUBMED, EMBASE, SCOPUS and Web of Knowledge databases, conference proceedings, and reference lists of retrieved articles were searched, and abstracts were independently screened by two reviewers. The data were abstracted by one reviewer using a standardized data collection form, and the findings were verified by a second reviewer. We assessed quality of the included studies using a standardized approach and conducted meta-analyses of population-based studies.

Results: Sixty-one articles met the inclusion criteria. We observed substantial heterogeneity with respect to the populations studied, methods of ascertaining comorbidity, and reporting of findings. Based solely on population-based studies, the most prevalent autoimmune comorbidities were psoriasis (7.74%) and thyroid disease (6.44%). Our findings also suggest an increased risk of inflammatory bowel disease, likely uveitis and possibly pemphigoid.

Conclusion: Fewer than half of the studies identified were of high quality. Population-based studies that report age, sex and ethnicity-specific estimates of incidence and prevalence are needed in jurisdictions worldwide.
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http://dx.doi.org/10.1177/1352458514564490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429166PMC
March 2015

Secondary progressive and relapsing remitting multiple sclerosis leads to motor-related decreased anatomical connectivity.

PLoS One 2014 18;9(4):e95540. Epub 2014 Apr 18.

Danish Research Centre for Magnetic Resonance, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark.

Multiple sclerosis (MS) damages central white matter pathways which has considerable impact on disease-related disability. To identify disease-related alterations in anatomical connectivity, 34 patients (19 with relapsing remitting MS (RR-MS), 15 with secondary progressive MS (SP-MS) and 20 healthy subjects underwent diffusion magnetic resonance imaging (dMRI) of the brain. Based on the dMRI, anatomical connectivity mapping (ACM) yielded a voxel-based metric reflecting the connectivity shared between each individual voxel and all other brain voxels. To avoid biases caused by inter-individual brain-shape differences, they were estimated in a spatially normalized space. Voxel-based statistical analyses using ACM were compared with analyses based on the localized microstructural indices of fractional anisotropy (FA). In both RR-MS and SP-MS patients, considerable portions of the motor-related white matter revealed decreases in ACM and FA when compared with healthy subjects. Patients with SP-MS exhibited reduced ACM values relative to RR-MS in the motor-related tracts, whereas there were no consistent decreases in FA between SP-MS and RR-MS patients. Regional ACM statistics exhibited moderate correlation with clinical disability as reflected by the expanded disability status scale (EDSS). The correlation between these statistics and EDSS was either similar to or stronger than the correlation between FA statistics and the EDSS. Together, the results reveal an improved relationship between ACM, the clinical phenotype, and impairment. This highlights the potential of the ACM connectivity indices to be used as a marker which can identify disease related-alterations due to MS which may not be seen using localized microstructural indices.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095540PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991654PMC
May 2015

Natalizumab in progressive MS: results of an open-label, phase 2A, proof-of-concept trial.

Neurology 2014 Apr 28;82(17):1499-507. Epub 2014 Mar 28.

From the Danish Multiple Sclerosis Center (J.R.C., R.R., L.B., P.S.S., F.S.), Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen; Danish Research Center for Magnetic Resonance (M.L., E.G., T.B.D., H.R.S.), Copenhagen University Hospital Hvidovre, Denmark.

Objective: Natalizumab inhibits the migration of systemic immune cells to the CNS and may be beneficial in progressive multiple sclerosis (MS). The objective of the study was to examine the effects of natalizumab in progressive MS.

Methods: In an open-label phase 2A study, 24 patients with progressive MS were included to receive natalizumab treatment for 60 weeks. Response to natalizumab was assessed in CSF and MRI studies. The primary endpoint was change in CSF osteopontin, a biomarker of intrathecal inflammation, from baseline to week 60.

Results: Seventeen patients completed the study. No new safety issues were encountered. CSF osteopontin decreased by 65 ng/mL (95% confidence interval 34-96 ng/mL; p = 0.0004) from baseline to week 60 in conjunction with decreases in other CSF biomarkers of inflammation, axonal damage, and demyelination. Magnetization transfer ratio increased in both cortical gray and normal-appearing white matter and correlated with decreases in CSF neurofilament light chain.

Conclusions: Natalizumab treatment of progressive MS reduces intrathecal inflammation and tissue damage, supporting a beneficial effect of natalizumab treatment in progressive MS and suggesting that systemic inflammation contributes to the pathogenesis. Moreover, the study establishes the feasibility of using CSF biomarkers in proof-of-concept trials, allowing a low number of participants and short study duration.

Classification Of Evidence: This study provides Class IV evidence that in patients with progressive MS, natalizumab reduces biomarkers of intrathecal inflammation.
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http://dx.doi.org/10.1212/WNL.0000000000000361DOI Listing
April 2014

Safety and efficacy of ofatumumab in relapsing-remitting multiple sclerosis: a phase 2 study.

Neurology 2014 Feb 22;82(7):573-81. Epub 2014 Jan 22.

From the Danish Multiple Sclerosis Center (P.S.S.), Rigshospitalet, Copenhagen; Genmab (S.L.), Copenhagen, Denmark; GlaxoSmithKline (R.G.), Uxbridge, Middlesex, UK; GlaxoSmithKline (F.D.), Research Triangle Park; GlaxoSmithKline (S.S.), Raleigh, NC; Charles University (E.H.), Prague, Czech Republic; School of Medicine University of Belgrade (J.D.), Serbia; and San Raffaele Scientific Institute and Vita-Salute San Raffaele University (M.F.), Milan, Italy.

Objectives: We present the first study to explore safety and efficacy of the human CD20 monoclonal antibody ofatumumab in relapsing-remitting multiple sclerosis (RRMS).

Methods: In this randomized, double-blind, placebo-controlled study, patients received 2 ofatumumab infusions (100 mg, 300 mg, or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment. Safety and efficacy were assessed.

Results: Thirty-eight patients were randomized (ofatumumab/placebo, n = 26; placebo/ofatumumab, n = 12) and analyzed; 36 completed the study. Two patients in the 300-mg group withdrew from the study because of adverse events. No unexpected safety signals emerged. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. None of the patients developed human anti-human antibodies. Ofatumumab was associated with profound selective reduction of B cells as measured by CD19(+) expression. New brain MRI lesion activity was suppressed (>99%) in the first 24 weeks after ofatumumab administration (all doses), with statistically significant reductions (p < 0.001) favoring ofatumumab found in new T1 gadolinium-enhancing lesions, total enhancing T1 lesions, and new and/or enlarging T2 lesions.

Conclusions: Ofatumumab (up to 700 mg) given 2 weeks apart was not associated with any unexpected safety concerns and was well tolerated in patients with RRMS. MRI data suggest a clinically meaningful effect of ofatumumab for all doses studied. Results warrant further exploration of ofatumumab in RRMS.

Classification Of Evidence: This study provides Class II evidence that in patients with RRMS, ofatumumab compared with placebo does not increase the number of serious adverse events and decreases the number of new MRI lesions.
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http://dx.doi.org/10.1212/WNL.0000000000000125DOI Listing
February 2014

Prolonged-release fampridine improves walking in a proportion of patients with multiple sclerosis.

Expert Rev Neurother 2013 Dec;13(12):1309-17

Danish Multiple Sclerosis Center - Neurological Department, Copenhagen University Hospital, Rigshospitalet, Blegdamsvej 9 Copenhagen 2100, Denmark.

Fampridine is indicated to improve walking in adult multiple sclerosis (MS) patients. Indications vary between countries and the prescribing neurologist should be aware of the labeling and indication in his own country. The prolonged-release formulation of 4-aminopyridine has reduced the risk of seizure to a level near the intrinsic MS risk, and the risk can be further minimized if it emphasized that patients should not exceed the recommended dose of 10 mg twice a day, should not catch up on missed doses and should not divide, crush or chew tablets. It is imperative to check the renal function before and during treatment and make sure the patient does not get concomitant medications affecting the renal elimination. The use of fampridine is considered safe, and the side effects are often mild and acceptable. Approximately one-third of MS patients treated with fampridine will experience an improvement of their walking speed above 20% on the timed 25-foot walk test (T25FW), which is considered to be clinically relevant.
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http://dx.doi.org/10.1586/14737175.2013.859523DOI Listing
December 2013

Prediction of antibody persistency from antibody titres to natalizumab.

Mult Scler 2012 Oct 27;18(10):1493-9. Epub 2012 Mar 27.

Danish Multiple Sclerosis Centre, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.

Background: In a subgroup of patients with multiple sclerosis natalizumab therapy causes generation of anti-natalizumab antibodies that may be transient or persistent. It is recommended to discontinue natalizumab therapy in persistently antibody-positive patients.

Objective: To use titres of anti-natalizumab antibodies to predict persistency of antibodies.

Patients And Methods: In 525 consecutive natalizumab treated patients tested for anti-natalizumab antibodies 43 (8.2%) were antibody-positive. Thirty of the antibody-positive patients, who were tested both at three and at six months after treatment start, had antibody titres in blood measured using an extended ELISA method.

Results: Samples from persistently positive patients ( N =18) had higher titre values than samples from transiently positive patients ( N =12). A cut-off value for high titre values was generated, above which patients may discontinue natalizumab therapy after three months. The method had a sensitivity of 0.83, a specificity of 1.00 and a diagnostic accuracy of 0.90.

Conclusion: An extended ELISA method for measuring anti-natalizumab antibody titres in multiple sclerosis patients on natalizumab therapy may be used for evaluation of antibody persistence. A test at three months may identify patients with high titres, who should discontinue natalizumab therapy, and patients with transient low-titre antibodies, who may continue natalizumab therapy despite development of antibodies.
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http://dx.doi.org/10.1177/1352458512441688DOI Listing
October 2012

Cerebral metabolism, magnetic resonance spectroscopy and cognitive dysfunction in early multiple sclerosis: an exploratory study.

Neurol Res 2012 Jan;34(1):52-8

Department of Neurology, Copenhagen University Hospital, Copenhagen, Denmark.

Objectives: Positron emission tomography (PET) studies have shown that cortical cerebral metabolic rate of glucose (CMRglc) is reduced in multiple sclerosis (MS). Quantitative magnetic resonance spectroscopy (MRS) measures of N-acetyl-aspartate (NAA) normalized to creatine (NAA/Cr) assess neuronal deterioration, and several studies have shown reductions in MS. Furthermore, both PET and MRS reductions correlate with cognitive dysfunction in MS. Our aim was to determine if changes in cortical CMRglc in early MS correlate with NAA/Cr measurements of neuronal deterioration, as well as cognitive dysfunction and neurological disability.

Methods: We studied 20 recently diagnosed, clinically definite, relapsing-remitting MS patients. Global and cortical CMRglc was estimated using PET with 18-F-deoxyglucose and NAA/Cr ratio was measured using multislice echo-planar spectroscopic imaging. All subjects were neuro-psychologically tested and a cognitive dysfunction factor (CDF) was calculated.

Results: Cortical CMRglc correlated with cortical NAA/Cr (r = 0.45; P < 0.05), but there were no correlation between CMRglc and other NAA/Cr measurements, conventional magnetic resonance imaging measurements, or CDF. Stepwise regression analysis showed association between cortical NAA/Cr and CMRglc of the left ventrolateral prefrontal cortex (P < 0.001), left putamen (P = 0.010), and left hippocampus (P = 0.011). Furthermore, CDF was related to CMRglc in the left cerebellum (P = 0.001) and the left caudate nucleus (P = 0.013). The results of the statistical analysis should be regarded as exploratory, since we did not correct for multiple comparisons.

Conclusion: Our findings suggest that reductions in cortical CMRglc are associated with reductions in cortical NAA/Cr in early MS. These changes affect cortical and subcortical neural circuits of importance to cognitive function.
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http://dx.doi.org/10.1179/1743132811Y.0000000059DOI Listing
January 2012

Demyelination versus remyelination in progressive multiple sclerosis.

Brain 2010 Oct 20;133(10):2983-98. Epub 2010 Sep 20.

Laboratory of Neuropathology, Copenhagen University Hospital Rigshospitalet, Blegdamsvej 9, Copenhagen, Denmark.

The causes of incomplete remyelination in progressive multiple sclerosis are unknown, as are the pathological correlates of the different clinical characteristics of patients with primary and secondary progressive disease. We analysed brains and spinal cords from 51 patients with progressive multiple sclerosis by planimetry. Thirteen patients with primary progressive disease were compared with 34 with secondary progressive disease. In patients with secondary progressive multiple sclerosis, we found larger brain plaques, more demyelination in total and higher brain loads of active demyelination compared with patients with primary progressive disease. In addition, the brain density of plaques with high-grade inflammation and active demyelination was highest in secondary progressive multiple sclerosis and remained ~18% higher than in primary progressive multiple sclerosis after adjustments for other plaque types and plaque number (P<0.05). Conversely, the proportion of remyelinated shadow plaques (P<0.05) and the overall remyelination capacity (P<0.01) per brain were higher in primary, compared with secondary, progressive multiple sclerosis. By contrast, there were no group differences in the brain load or frequency of low-grade inflammatory plaques with slowly expanding demyelination. Spinal cord lesion loads and remyelination capacity were also comparable in the two patient groups. Remyelinated areas were more vulnerable than the normal-appearing white matter to new demyelination, including active demyelination in secondary progressive multiple sclerosis. 'Recurrent' slowly expanding demyelination, affecting remyelinated areas, and the load of slowly expanding demyelination correlated with incomplete remyelination in both groups. In turn, incomplete remyelination in the spinal cord correlated with higher disease-related disability (determined retrospectively; r = -0.53; P<0.05 for remyelination capacity versus disease severity). By contrast, such a correlation was not observed in the brain. We propose that regulatory and reparative properties could protect the white matter of the brain in patients with primary progressive multiple sclerosis. These patients may, thereby, be spared symptoms until the spinal cord is affected. By contrast, recurrent active demyelination of repaired myelin could explain why similar symptoms often develop in consecutive relapses in relapsing-remitting/secondary progressive multiple sclerosis. Our data also indicate that slowly expanding demyelination may irreparably destroy normal and repaired myelin, supporting the concept of slowly expanding demyelination as an important pathological correlate of clinical progression.
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http://dx.doi.org/10.1093/brain/awq250DOI Listing
October 2010

The SH2D2A gene and susceptibility to multiple sclerosis.

J Neuroimmunol 2008 Jul 12;197(2):152-8. Epub 2008 Jun 12.

Department of Neurology, University of Oslo, Oslo, Norway; Institute of Immunology, Rikshospitalet University Hospital, Oslo, Norway.

We previously reported an association between the SH2D2A gene encoding TSAd and multiple sclerosis (MS). Here a total of 2128 Nordic MS patients and 2004 controls were genotyped for the SH2D2A promoter GA repeat polymorphism and rs926103 encoding a serine to asparagine substitution at amino acid position 52 in TSAd. The GA(16)-rs926103()A haplotype was associated with MS in Norwegians (OR 1.4, P=0.04). A similar trend was observed among Danes. In the independent Norwegian, Danish and Swedish sample sets the GA(16) allele showed a combined OR of 1.13, P=0.05. Thus, the present study shows that the SH2D2A gene may contribute to susceptibility to MS.
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http://dx.doi.org/10.1016/j.jneuroim.2008.04.037DOI Listing
July 2008

Widespread demyelination in the cerebellar cortex in multiple sclerosis.

Brain Pathol 2007 Jan;17(1):38-44

Center for Brain Research, Medical University of Vienna, Austria.

Neocortical demyelination in the forebrain has recently been identified as an important pathological feature of multiple sclerosis (MS). Here we describe that the cerebellar cortex is a major predilection site for demyelination, in particular in patients with primary and secondary progressive MS. In these patients, on average, 38.7% of cerebellar cortical area is affected, reaching in extreme examples up to 92%. Cerebellar cortical demyelination occurs mainly in a band-like manner, affecting multiple folia. The lesions are characterized by primary demyelination with relative axonal and neuronal preservation, although some axonal spheroids and a moderate reduction of Purkinje cells are present. Although cortical demyelination sometimes occurs together with demyelination in the adjacent white matter (leukocortical lesions), in most instances, the cortex was affected independently from white matter lesions. We found no correlation between demyelination in the cortex and the white matter, and in some cases, extensive cortical demyelination was present in the near absence of white matter lesions. Our data identify cortical demyelination as a potential substrate of cerebellar dysfunction in MS.
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http://dx.doi.org/10.1111/j.1750-3639.2006.00041.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095596PMC
January 2007

Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial.

Lancet 2004 Sep 25-Oct 1;364(9440):1149-56

European Charcot Foundation, Nijmegen, Netherlands.

Background: Several double-blind placebo-controlled trials of relapsing-remitting multiple sclerosis have shown beneficial effects of intravenous immunoglobulin (IVIG) on relapse rate and disability. The European Study on Intravenous Immunoglobulin in Multiple Sclerosis set out to test IVIG in the secondary progressive phase of the disease.

Methods: 318 patients with clinically definite secondary progressive multiple sclerosis (mean age 44 years [SD 7]) were randomly assigned IVIG 1 g/kg per month (n=159) or an equivalent volume of placebo (albumin 0.1%; n=159) for 27 months. After baseline investigation, clinical assessments were made every 3 months and MRI was repeated after 12 months and 24 months. The primary outcome was confirmed worsening of disability as defined by the time to first confirmed progression on the expanded disability status scale (EDSS). Analyses were by intention to treat.

Findings: 19 patients in the IVIG group and 39 in the placebo group terminated study treatment prematurely but were included in the analyses. IVIG treatment had no beneficial effect on time to confirmed EDSS progression (hazard ratio 1.11 [95% CI 0.80-1.53] for IVIG versus placebo). The annual relapse rate was 0.46 in both groups. No significant differences between the treatment groups were found in any of the other clinical outcome measures or in the change of T2-lesion load over time. The treatment was generally well tolerated, although deep venous thrombosis, pulmonary embolism, or both occurred in seven patients with risk factors for thromboembolism (IVIG six, placebo one).

Interpretation: Treatment with IVIG in this study did not show any clinical benefit and therefore cannot be recommended for patients with secondary progressive multiple sclerosis.
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http://dx.doi.org/10.1016/S0140-6736(04)17101-8DOI Listing
October 2004

Concordance for disease course and age of onset in Scandinavian multiple sclerosis coaffected sib pairs.

Mult Scler 2004 Feb;10(1):5-8

Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.

Background: Investigation of coaffected sib pairs is one method to determine the genetic influence on the clinical presentation of many complex diseases, such as multiple sclerosis (MS). Investigation of the clinical concordance in coaffected sib pairs may be a prerequisite to identify genes that modify the clinical outcome. The aim of this study was to investigate a possible genetic influence on selected demographic and clinical variables among familial Scandinavian MS cases.

Material And Methods: We identified 136 Caucasian Scandinavian families with MS coaffected sib pairs from Denmark, Norway and Sweden. Cohen's kappa coefficient and the intraclass correlation coefficient were used to assess concordances in sib pairs. Furthermore, clinical features and HLA-DR2 carrier status were compared among the probands of sib pairs.

Results: We found significant concordance of the disease course (kappa = 0.28, P < 0.001) and adjusted age of onset (r = 0.23, P = 0.028). Among probands of sib pairs, HLA-DR2 carrier patients had a younger age of onset (P = 0.024).

Conclusion: Analyses of Scandinavian coaffected sib pairs suggest that disease course and age of onset are partly under genetic control. Furthermore, HLA-DR2 in probands of sib pairs suggests importance for age of onset.
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http://dx.doi.org/10.1191/1352458504ms975oaDOI Listing
February 2004
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