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Multiple Sclerosis Glossary of Terms Annualized relapse rate (ARR) The average number of relapses a person with multiple sclerosis (MS) has per year1. It is a key measure of relapsing MS (RMS) disease activity. Autoimmune disease A healthy immune system knows which tissues are part of the person's body and which are 'foreign' - e.g. a virus or bacterial infection - and need attacking. In some conditions, for reasons that aren't known, this protective mechanism fails to work. The body’s own immune system attacks itself (or part of itself) as if it were a foreign invader. These conditions are called autoimmune diseases2. In MS, the immune system attacks the cells of the central nervous system (CNS)3. Axon Also known as a nerve fiber, it projects from the body of a neuron and conducts the electrical impulses along the nerve4. The axon is usually insulated by a myelin sheath4, but in MS, the myelin sheath is damaged or destroyed and this affects the conduction of impulses along the axon. Brain volume loss (BVL) Also referred to as brain shrinkage, BVL refers to the loss of brain tissue (including myelin and axons) and changes in the water containing spaces in and around the brain. It is measured by Magnetic Resonance Imaging (MRI). MS patients lose brain volume around three to five times faster than people without MS, and this loss has been associated with physical (e.g. walking) and cognitive (e.g. mental tasks or memory) problems5,6. Central nervous system (CNS) Part of the nervous system consisting of the brain, the nerves leading to the eyes and the spinal cord7. It is involved in coordinating voluntary and involuntary actions and transmitting signals between different parts of the body7. It is this part of the nervous system that is damaged in MS3. Chronic A chronic disease is a long-lasting condition that can be controlled but not cured. Chronic diseases generally progress slowly. Cognition The term 'cognition' refers to the full range of mental skills and abilities, including memory, concentration, the process of thinking, decision-making and understanding. People with MS can experience difficulties with cognition. For some, cognitive problems come and go in the same way other symptoms do, but for others cognitive problems will develop soon after the onset of MS and remain8. Demyelination When the insulating coat of nerves and nerve extensions, that enables nerves to work properly, is damaged or stripped away9. Novartis Pharma AG CH-4002 Basel, Switzerland © 2015 Novartis Pharmaceuticals GLNS/GILE/0016 March 2015 Diffuse damage Diffuse damage is widespread inflammatory damage throughout the brain, in comparison to focal damage which refers to distinct areas of damage. Damage to the brain occurs early in the course of MS, as early as the first neurological episode or single attack of symptoms. Diffuse damage reflects the cumulative loss of tissue, including neurons, and is not visible on conventional MRI scans, so it often goes unnoticed. Diffuse damage can be captured by measuring brain volume loss and is associated with the loss of both physical (e.g. walking) and cognitive (e.g. memory) function over time10,11,12. Disability progression Confirmed disability progression is the rate at which a person’s disability has worsened over time. In MS clinical trials, it is usually measured using the Expanded Disability Status Scale (EDSS) over two time points. A 6 month measure is considered a more reliable assessment of long term disability accumulation13,14. Confirmed disability progression is a key measure of MS disease activity. Disease-modifying therapy (DMT) A treatment that impacts the natural course of the disease15. Expanded Disability Status Scale (EDSS) A scale used by physicians to quantify a person with MS’ level of disability. It is widely used as an endpoint in clinical trials and to assess overall disability in people with MS and monitor changes in their disability over time. Measurements are generally taken at 3 or 6 months, with 6 months considered to be a more reliable assessment of long term disability accumulation 13,14 Focal damage Distinct areas of inflammatory damage in the brain (lesions) that can clinically present as relapses. Focal damage results in the loss of brain tissue. If a patient doesn’t recover from a relapse completely, disability may accumulate for the patient9,10,11. Gd+ T1 lesion Lesions (areas of damage) that can be seen on a T1-weighted magnetic resonance imaging (MRI) scan, where a contrast agent, gadolium is injected before the scan. When injected before a scan, gadolinium makes it possible to distinguish between active MS lesions and older areas of scarring16. These types of scans are often used when diagnosing MS or measuring a patient’s response to treatment. Inflammation Inflammation is part of the body’s immune response to harm and damage17. In MS, inflammation can lead to significant nerve damage and the lesions (areas of damage) that result are visible on MRI scans18. Lesion A damaged area of tissue, usually caused by disease or trauma. In MS, the number and volume of lesions in the central nervous system, as measured by magnetic resonance imaging (MRI), has been shown to be associated with relapses and disability19. Novartis Pharma AG CH-4002 Basel, Switzerland © 2015 Novartis Pharmaceuticals GLNS/GILE/0016 March 2015 Lesion load An estimate of the cumulative volume of damaged tissue (lesions) as identified by magnetic resonance imaging (MRI). Lesion load has been shown to be associated with relapses and disability20. Lymphocytes Small white blood cells of the immune system occurring predominantly in the lymphatic system21. In some conditions, for reasons that aren't known, the immune system mistakenly turns on the body's own tissue. In MS lymphocytes attack the myelin sheath which covers the nerves within the CNS2. Magnetic resonance imaging (MRI) A type of scan that uses strong magnetic fields and radio waves to produce digital images of inside the body22. In MS, it is used to provide an estimate of the number and volume of lesions in the CNS and measure brain volume changes. Multiple sclerosis (MS) Multiple sclerosis (MS) is the term used for a disease where the immune system mistakenly attacks healthy cells in the central nervous system (CNS) – the brain, the nerves leading to the eyes and the spine3. The evolution of MS can result in a progressive loss of function, including for example both physical (e.g. walking) and cognitive (e.g. concentrating) functions. Myelin sheath The protective coating (insulation) around a nerve cell and the fiberlike extension of the nerve. The myelin sheath is essential for the proper functioning of the nervous system. In MS, the cells of the immune system damage the myelin sheath and signal conduction along the nerves is slower and less complete or interrupted3. No evidence of disease NEDA-4 is achieved when a patient has no relapses, no new MRI activity (NEDA-4) lesions, no brain shrinkage (brain volume loss) and no disability progression. These are the four key measures of relapsing MS disease activity23. Neurodegenerative disease A disease characterized by damage to nerve cells that gets worse over time24. MS, Parkinson’s Disease and Alzheimer’s Disease are all examples of neurodegenerative diseases. Neuron/nerve cell A cell present in the nervous system that processes and transmits information25. Physical function Mobility (or movement), muscle control, balance and activities such as walking and climbing stairs26. Primary-progressive multiple sclerosis (PPMS) A type of MS characterized by a person’s symptoms gradually getting worse over time, rather than appearing in sudden attacks. Approximately 10% of people diagnosed with MS have PPMS27. Real world evidence Data collected about a treatment in a practical, real-life setting rather than data taken from a clinical trial28. Provides valuable information on outcomes in clinical practice, including the benefit-risk ratio of a treatment, and is needed to complement data from clinical trials. Novartis Pharma AG CH-4002 Basel, Switzerland © 2015 Novartis Pharmaceuticals GLNS/GILE/0016 March 2015 Relapse The appearance of new symptoms of MS, or the return of old symptoms, for a period of 24 hours or more in the absence of a change in core body temperature or infection29. Relapses may have an acute disabling impact on the individual’s life. Incomplete recovery from a relapse can significantly advance the level of disability30. Relapsing multiple sclerosis (RMS) Relapsing MS is characterized by attacks (relapses) where there is a sudden appearance of previous and /or new symptoms. There are two types of RMS: Relapsing remitting MS (RRMS) and secondaryprogressive multiple sclerosis (SPMS)29,31,32. Relapsing-remitting multiple sclerosis (RRMS) A type of MS characterized by relapses with worsening neurological function, followed by periods of remission where a person partially or fully recovers. Approximately 85% of people with MS are initially diagnosed with this form of the disease29. Remission A period of time during which a person with MS’ symptoms may lessen or completely stop29. Secondaryprogressive multiple sclerosis (SPMS) A type of MS characterized by the gradual worsening of a person’s neurological function (accumulation of permanent disability) between relapses31. The majority of people with RRMS will develop SPMS over time (25% by 10 years, 50% by 20 years, and >75% by 30 years)33. The transition from RRMS to SPMS is usually gradual34. Sphingosine 1phosphate receptor A type of receptor expressed on a wide range of cells that are involved in the biological processes relevant to MS35. Symptomatic treatment A treatment that targets the symptoms of a disease, such as spasticity (muscle spasms or stiffness), depression, bladder disorder or problems walking in MS, but does not alter the course of the disease. T2 lesion Lesions identified by a T2-weighted magnetic resonance imaging (MRI) scan (a specific scan technique to visualize brain tissue). These types of scans show both new or active disease and old lesions, and are often used when diagnosing MS and measuring a patient’s response to treatment22. References: 1 Roskell NS et al. Annualized relapse rate of first-line treatments for multiple sclerosis: a meta-analysis, including indirect comparisons versus fingolimod. Curr Med Res Opin. 2012 May;28(5):767-80. http://www.mstrust.org.uk/atoz/autoimmunity.jsp. Last accessed March 2015. 3 http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001747/. Last accessed March 2015. 4 http://www.britannica.com/EBchecked/topic/46342/axon. Last accessed March 2015. 5 Calabrese M et al. Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis. Arch Neurol. 2009 Sep;66(9):1144-50. 6 Bakshi R. Regional brain atrophy is associated with physical disability in multiple sclerosis: semiquantitative magnetic resonance imaging and relationship to clinical findings. J Neuroimaging. 2001;11(2):129–36. 7 http://mcb.berkeley.edu/courses/mcb135e/central.html. Last accessed March 2015. 8 http://www.mstrust.org.uk/downloads/cognition.pdf. Last accessed March 2015. 9 http://www.msif.org/about-ms/what-is-ms/. Last accessed March 2015. 10 Filippi M et al. Association between pathological and MRI findings in multiple sclerosis. Lancet Neurol. 2012 Apr;11(4):34960. 11 Kutzelnigg A. et al. Cortical demyelination and diffuse white matter injury in multiple sclerosis. Brain. 2005 Nov;128(Pt 11):2705-12. 12 Sormani MP, Arnold DL, De Stefano N. Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. Ann Neurol. 2014 Jan;75(1):43-9. 2 Novartis Pharma AG CH-4002 Basel, Switzerland © 2015 Novartis Pharmaceuticals GLNS/GILE/0016 March 2015 13 Healy BC et al. Assessment of definitions of sustained disease progression in relapsing-remitting multiple sclerosis. Mult Scler Int. 2013; 2013:189624. Cohen, JA, et al. Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. Lancet Neurol 2012 May;11(5):467-76. 15 http://www.nationalmssociety.org/Treating-MS/Medications. Accessed March 2015. 16 http://www.mstrust.org.uk/atoz/gadolinium.jsp. Last access March 2015. 17 http://www.medicalnewstoday.com/articles/248423.php. Last accessed March 2015. 18 http://www.mswatch.ca/en/learn-about-MS/advances-in-MS/inflammation-and-neurodegeneration-in-MS.aspx. Last accessed March 2015. 19 Sormani MP, Bruzzi P. MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol. 2013Jul;12(7):669-76. 20 Popescu V, et al. Brain atrophy and lesion load predict long term disability in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013 Oct;84(10):1082-91. doi: 10.1136/jnnp-2012-304094. Epub 2013 Mar 23. 21 http://www.cancer.gov/Common/PopUps/popDefinition.aspx?id=45765&version=Patient&language=English. Last accessed March 2015. 22 http://www.nationalmssociety.org/about-multiple-sclerosis/what-we-know-about-ms/diagnosing-ms/magnetic-resonanceimaging-mri/index.aspx. Last accessed March 2015. 23 http://www.mstrust.org.uk/news/article.jsp?id=5893. Last accessed March 2015. 24 http://www.neurodegenerationresearch.eu/about/what/. Last accessed March 2015. 25 Lodish H et al. Molecular Cell Biology. 4th edition. 2000. Chapter 21, Nerve Cells. 26 http://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms. Accessed March 2015. 27 http://www.mssociety.org.uk/what-is-ms/types-of-ms/primary-progressive-ppms. Last accessed March 2015. 28 https://www.ispor.org/News/articles/Oct07/RLD.asp. Last accessed March 2015. 29 http://www.mssociety.org.uk/what-is-ms/types-of-ms/relapsing-remitting-rrms. Last accessed March 2015. 30 Lublin FD, Baier M, Cutter G. Effect of relapses on development of residual deficit in multiple sclerosis. Neurology. 2003;61(11):1528-1532. 31 http://www.nationalmssociety.org/What-is-MS/Types-of-MS/Secondary-progressive-MS. Last accessed March 2015. 32 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2015/03/WC500185161.pdf. Accessed March 2015. 33 Tremlett H, et al. The natural history of secondary-progressive multiple sclerosis Mult Scler. 2008:14:314-324. 34 Lublin FD, Reingold SC, Cohen JA et al. Defining the clinical course of multiple sclerosis. Neurology. 2014; 83(3): 278–286. 35 Chun J, Hartung HP. Mechanism of Action of Oral Fingolimod (FTY720) in Multiple Sclerosis. Clin Neuropharmacol. 2010 March-April;33(2):91-101. 14 Novartis Pharma AG CH-4002 Basel, Switzerland © 2015 Novartis Pharmaceuticals GLNS/GILE/0016 March 2015