Multiple sclerosis
- 1. Presented by: PT Yumna Ali 1
- 2. is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms MULTIPLE SCLEROSIS 2
- 3. Anatomy and Physiology In the normal nerve fiber, the centralcore of the fiber (axon) conducts the action potential for cellmovement. This large fiberis surrounded by a myelin sheath, made up oflipoproteins. The sheath insulates the fiber for better nerve cell transmission. 3
- 4. The myelin sheath is so thick thatalmost no ionscan flow through it. They must be transmitted through nodesof Ranvier, which occur once every 1-3 mm along the sheath. These nodes create “saltatory conduction” which allows the nerve impulse to jumpalong the fiber in succession, leading to transmission of theimpulse. This “saltatoryconduction” increases thevelocity of myelinated fiber transmissionas much as 5-50 fold. Small unmyelinated nerve fibers haveas littlevelocity as 0.25 m/sec while large mylinated fibers transmit at velocities reaching 100 m/sec which is approximately the length of a football field in one second. 4
- 5. Anatomy and Physiology In patients withmultiplesclerosis, the myelin sheath is attackedbyan immuneresponse. Specifically, CD4 T cells (helps suppress or regulate immune responses), macrophages and microglial cells initiate an attack on the sheath after passing through the BBB. The attacks leave holes in the myelin, causing the axon to be exposed, decreasing conduction of the nerve impulses in the CNS and thePNS. This leads toa slowing of conduction or complete failureof the impulse toreach itsdestination. 5
- 6. Blood–brain barrier disruption The BBB is composed of endothelial cells which line the blood vessel wallsof the central nervoussystem. Compared to normal endothelial cells, the cells lining the BBB are connected by occludin and claudin which form tight junctions in order to createa barrier to keep out larger moleculessuch as proteins. In order topass through, molecules must be taken in by transport proteins or an alteration in the BBB permeability mustoccur* 6
- 7. 7
- 8. Blood–brain barrier disruption BBB disruption is the moment in which penetration of the barrier by lymphocytes occur and has been considered one of the early problems in MS lesions. The BBB is compromised due to active recruitment of lymphocytes and monocytes and their migration across the barrier. Release of chemokines allow forthe activation of adhesion molecules on the lymphocytes and monocytes, resulting in an interaction with the endothelial cells of the BBB which then activate the expression of matrix metalloproteinases to degrade thebarrier. 8
- 9. Clinical Manifestations MS can affect any area of the brain, optic nerve, or spinal cord, causing almostany neurologic symptom. A classic MS sign: Uthoff’s phenomenon is a worsening of symptoms in theheat. Symptoms of relapse tendto: • Developovera few days • Stabilize for a fewweeks • Improveoverweeksor months • Be followed bya period of stability (a remission) 9
- 10. 1. Blurredvision 2. Unilateral loss ofvision 3. Oscillopsia 4. Diplopia Motor 1. Trunk/limbweakness 2. Spascity 3. Hyperreflexia 4. Gaitdisturbance 5. Balanceproblems Signs & Symptoms Consistent with Demyelinating Disease Visual Sensory 1. Numbness 2. Paresthesias 3. Dysesthesias 4. L’Hermitte’s sign (electrical sensations run down the spine when the patient bends her headforward) 5. “MS Hug” (tightening around thechest) 6. Trigeminal neuralgia 7. Proprioception deficits 10
- 11. 1. Tremor 2. Ataxia Genitourinary 1. Urgency/Frequency/ Retention 2. Incontinence 3. FrequentUTI 4. Constipation 5. Impotence 6. Dyspareunia Signs & Symptoms Consistent with Demyelinating Disease Cerebellar Neuropsychiatric 1. Impairment of memory, concentration, attention 2. Depression 3. Irritability 4. Anxiety 11
- 12. Diagnostics MRI (Magnetic Resonance Imaging) is used in diagnosing Multiple Sclerosis, but it should notbe used as the only diagnostictest. Other useful tests include cerebrospinal fluid via spinal tap orlumbar puncture.It commonly shows a mild lymphycytosis or a slightlyincreased protein.CSF protein electrophoresis shows the presence of discrete bands in the immunoglobulin G (IGG) region (oligoclonal bands). For a diagnosis of primary progressive MS,an abnormal CSF finding with evidenceof inflammation and immune abnormalityis necessary* 12
- 13. Classification & Prognosis MS is classified into 4types: 1-Benign Multiple Sclerosis : • Mild infrequent sensory exacerbations with fullrecovery. 2-Relapsing Remitting Multiple Sclerosis: • Episodes of exacerbations and remissions during which not all symptoms resolve completely. The patient may be left with permanent disability which may vary in severity. relapses are often more severe than in the previous group. Relapsesalso become more severewith time. 13
- 14. 3-Secondary ChronicProgressive • Condition of patients with relapsing/remitting disease begins to gradually worsen over time with resulting accumulation of neurologic signs and symptoms. In this form of the disease, relapses become more severe while remissions are less complete, shorter in duration, and eventually non-existent. The course of MS becomes steadilyprogressive. 4-Primary Progressive • There is no history of relapse in these patients. Disease begins with aslow progression of neurologic deficits. Problems appear and gradually worsen over time. 14
- 15. Approved Therapies by Efficacy Ranking Most effective 1. Ocrelizumab 2. Natalizumab 3. Alentuzumab Moderately effective 1. IFN beta 2. Glatiramer acetate immunomodulator 3. Teriflunomide pyrimidine synthesis inhibitor Highly effective 1. Fingolimod 2. Dymethyl fumarate 15
- 16. Most effective treatment OCRELIZUMAB Ocrelizumab is an experimental drug which is being tested for the treatment of relapsing remitting and primary progressive MS. • In relapsing remitting MS, ocrelizumab reduced relapse rates by approximately 50% compared to beta interferon • In primary progressive MS, ocrelizumab reduced 12 week disability progression by 24% compared to placebo 16
- 17. • Ocrelizumab is a monoclonal antibody to target a marker (anti-CD20) on the surface of B cells, a type of white blood cell (lymphocyte) which is thought to influence the abnormal immune response that attacks the myelin surrounding nerve cells. Targeted B cells are destroyed. MECHANISM OF ACTION 17
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- 19. Relapsing remitting MS • In a phase II, 24 week, clinical trial, 218 people were split into groups receiving one of two doses of ocrelizumab (600mg and 2000mg), interferon beta-1a (Avonex) or placebo. After 24 weeks, the number of active lesions as measured by MRI scans was 89% lower in the low dose group and 96% lower in the high dose group compared with the placebo group. Phase II Experimental study 19
- 20. The Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis and monitoring changes in the level of disability over time. 20
- 21. • Primary progressive MS • Oratorio - ocrelizumab compared to placebo • This phase III study recruited 732 participants with primary progressive MS and EDSS of 3 to 6.5 who took either 600mg ocrelizumab or placebo by iv infusion every 6 months for more than 2 years. Phase III experimental study 21
- 22. • Reduction of disability, compared to placebo. – 24% MS patients less likely to have an increase in their disability than those taking placebo. • After 120 weeks of treatment, increased walking speed over 25 feet • 39% slow walkers for ocrelizumab compared to 55% slow for placebo. • Brain lesion volume decreased by 3.4% with ocrelizumab and increased by 7.4% with placebo. Loss of brain volume was 0.9% for ocrelizumab and 1.09% for placebo. Results 22
- 23. • In May 2017, a first case of progressive multifocal leukoencephalopathy (PML) was reported in a person taking ocrelizumab. • Infusion-related reactions, herpes (oral herpes and shingles) • Neoplasms including several cases of breast cancer, were reported • Ocrelizumab has previously been investigated as a treatment for rheumatoid arthritis but studies were discontinued because of a high incidence of opportunistic infections in participants. ADVERSE EFFECTS 23
- 24. • Tysabri is a disease modifying drug (DMD) for very active relapsing remitting MS. • MECHANISM OF ACTION • When inflammatory cells such as T- lymphocytes pass through the BBB through interaction with receptors on the endothelial cells. Natalizumab appears to reduce the transmission of immune cells into the CNS by interfering with the α4β1-integrin receptor molecules on the surfaces of cells. The effect appears to occur on endothelial cells expressing the VCAM-1 gene. Natalizumab's mechanism of action is believed to be the prevention of immune cells from crossing blood vessel walls to reach affected organs. Most effective treatment Natalizumab (Tysabri) 24
- 25. • Evidence for the effectiveness of Tysabri has come from a large clinical trial. • AFFIRM - Tysabri compared to placebo • This two year study compared Tysabri with placebo in 942 people with relapsing remitting MS. • Tysabri reduced the number of relapses by 68% compared to placebo. • People taking Tysabri were less likely to experience worsening of their disability. After two years, 29% of the placebo group showed at least a one-point increase in the Expanded Disability Status Scale (EDSS), compared to 17% of the Tysabri group. • Tysabri has also been investigated as a treatment for secondary progressive MS where increasing disability is not the result of relapses. Tysabri clinical trial 25
- 26. • Increased risk of progressive multifocal leukoencephalopathy (PML), an uncommon brain infection that can lead to severe disability or even death. PML is caused by a mutation of the JC virus, a common infection completely unrelated to MS. It is normally kept under control by the immune system, causing no problems. If your immune system is weakened and your body less able to fight an infection, which may occur when taking Tysabri, the JC virus can become active and cause inflammation and damage to the brain. ADVERSE EFFECTS 26
- 27. • Common (affecting more than 1 person in 100) • urinary tract infections • inflammation of the nose • shivering • itchy rash (urticaria) • headache • dizziness • nausea, vomiting • joint pain • fever • Less common side effects (affecting less than 1 person in 100) • severe allergic reaction during infusion (rash, swelling of face, lips or tongue,difficulty breathing) • discomfort during the infusion including feeling sick, headache, dizziness • progressive multifocal leukoencephalopathy (PML) • serious infections • liver problems ADVERSE EFFECTS 27
- 28. • Lemtrada is a disease modifying drug for active relapsing remitting MS and for very active relapsing remitting MS. You have fewer relapses than you might have had without treatment. • Lemtrada may also slow down the build-up of disability associated with MS. • Mechanism Of Action • Anti-CD52 monoclonal antibody directed against the lymphocytes that are involved when the immune system attacks myelin. It is thought that the immune cells which grow back after treatment do not cause damage to nerves. Most effective treatment Alemtuzumab (Lemtrada) 28
- 29. • Evidence for the effectiveness Lemtrada CARE-MS I CARE-MS II TWO YEARS STUDY Lemtrada compared to Rebif 581 people who had not been treated with a DMD 667 people who had had at least one relapse while taking a DMD. Lemtrada reduced relapses by 55% compared to Rebif It reduced relapses by 49% compared to Rebif. The risk of disease progression was also reduced by 42% compared to Rebif, with 20% of the Rebif group showing an increase in disability compared to 13% of the Lemtrada group. 29
- 30. • infusion-related reactions such as headache, rashes, fever and nausea. • infections including coughs, colds, chest infections and herpes virus infections (such as cold sores or shingles) • To reduce the risk of herpes infections, an antiviral medication should be taken starting from the first day of infusion and continued for at least one month ADVERSE EFFECTS 30
- 31. • Three serious side effects have been reported from clinical trials • Overactive or underactive thyroid gland leading to thyroid disorders • Idiopathic thrombocytopenic purpura (ITP), a serious disorder which prevents blood from clotting • Kidney problems • These side effects are treatable if caught early enough. People taking Lemtrada will be informed of the early signs and symptoms of these side effects. 31
- 32. • Common side effects (affecting more than 1 person in 100) • infusion associated reactions including headaches, rashes, fever and nausea • infections - respiratory and urinary • decrease in white blood cells (lymphopenia) • changes in blood pressure, heart rate • rash • musculoskeletal pain 32
- 33. Highly Effective Therapy Fingolimod (Gilenya ) • Gilenya is a disease modifying drug for relapsing remitting MS. • In clinical trials people taking Gilenya had about 50% fewer relapses than people taking placebo. MRI scans showed that fewer, smaller or no new areas of active MS (lesions). • Gilenya may also slow down the build-up of disability associated with MS. 33
- 34. • Mechanism Of Action • Fingolimod… • is the first agent in the class of small molecules SIP-R agonists • reduces the recirculation of lymphocytes into lymphonodes by binding to their surface in the blood. Lymphocytes are then trapped in the lymph glands, preventing them from crossing BBB and reach the central nervous system. 34
- 35. • Common side effects include increased risk of infections, cough, headache, back pain, diarrhoea and increased liver enzyme levels. • Gilenya may also cause a less common side effect (affecting less 1 in 100 people) macular oedema, a swelling in the back of the eye which can affect vision. • Cases of basal cell carcinoma, a kind of skin cancer, have been reported in people taking Gilenya. Basal cell carcinoma is a slow-growing skin cancer that almost never spreads to other parts of the body or becomes life-threatening but can be disfiguring if not treated promptly. ADVERSE EFFECTS 35
- 36. • Common side effects (affecting more than 1 person in 100) • headache • back pain • diarrhoea • cough • raised liver enzyme levels • infections: herpes virus, fungal, flu • changes in heartbeat • dizziness, weakness • lowering of white blood cells • skin rash, itching • depression • eye pain, blurred vision • mild increase in blood pressure • basal cell carcinoma • Less common side effects (affecting less than 1 person in 100) • pneumonia • swelling in the back of the eye (macular oedema) • low mood • lowering of neutrophils (type of white blood cell) 36
- 37. • Tecfidera is a disease modifying drug (DMD) for relapsing remitting MS. • It reduces the number of relapses by about one half (50%), compared to taking placebo. Highly Effective Therapy Dimethylfumarate DMF (Tecfidera) 37
- 38. • DMF decreases absolute lymphocyte counts. CD8+ T-cells are the most profoundly affected, but reduction also occurs in the CD4+ population, particularly within the pro-inflammatory T-helper Th1 and Th17 subsets, • reducing the inflammation caused when the immune system attacks myelin, resulting in less damage to myelin • protecting nerve cells from the damage caused by chemicals released during the immune attack Mechanism of Action reduction in CD8+ and to lesser extent CD4+ T- cells, CD19 B cells Th1 and Th17 decrease, shifting the balance toward more anti- inflammatory Th2, T-regulatory and B-regulatory subsets In CNS DMF activators of the Nrf2-dependent pathway, which protects neurons from oxidative stress. Nrf2 increase transcription of genes encoding antioxidant enzymes Front Neurol. 2018;9:5. doi: 10.3389/fneur.2018.00005 38
- 39. • Flushing and feeling hot • Gastrointestinal upset - diarrhoea, feeling sick, stomach pains • In clinical trials changes in liver and kidney function were reported. Regular blood and urine tests are recommended to monitor for possible effects. ADVERSE EFFECTS • Common side effects (affecting more than 1 person in 100) • flushing and feeling hot • gastrointestinal upset (feeling sick, diarrhoea, abdominal pain, vomiting, indigestion) • decrease in white blood cells • rash • increased levels of liver enzymes • ketones and protein in urine 39
- 40. Compared to placebo, Tecfidera twice daily reduced the number of relapses in one year by 53%. Also reduced the risk of 3 month disability progression by 38%. 2 year study compared Tecfide ra taken either 2 or 3 times daily and placebo in more than 1,200 participants with RRMS. DEFINE - Tecfidera compared to placebo Evidence for the effectiveness of Tecfidera has come from two large clinical trials. 40
- 41. • CONFIRM - Tecfidera or Copaxone compared to placebo • This two year study with 1,232 participants was similar to DEFINE, but with an additional group who took Copaxone (glatiramer acetate) for comparison. • Tecfidera reduced the number of relapses in one year by 44% for the twice-daily dose compared to placebo. In contrast, Copaxone reduced the number of relapses by 29% compared to placebo. • The reduction in disability progression observed in the DEFINE study was not seen in the CONFIRM study. 41
- 42. Moderately Effective Therapy Beta Interferons These are treatments for relapsing MS. They have the following brand names: • Avonex, Betaferon Mechanism Of Action • Interferons (IFN) are endogenous cytokines that modulate transcription of hundred of genes involved in inflammatory responses • Interferon beta balances the expression of pro- and anti-inflammatory molecules in the brain • In vitro, interferon beta reduces production of Th17 cells which are a subset of T lymphocytes that seem to have a role in the pathophysiology of MS • IFN can reduce (and might prevent) the inflammation that damages nerves in MS. Cell migration by disturbing VLA4 and VCAM1 receptor interactions. VLA expression on T cells. Production of MMP Soluble VCAM1 levels 42
- 43. • The effectiveness of beta interferons is classed as 'moderate'. This is based on how much they reduce relapses and slow down how fast people's disability gets worse. • Relapses dropped by: 33% • This means that in trials, on average, people saw a 33% drop in the number of relapses they had. This was compared to people who took a placebo, a dummy treatment with no drug in it. • Disability getting worse was slowed down by a modest amount Beta interferons can be injected with a 'pen' that means there is no need of needle 43
- 44. • After a beta interferon injection at least one in 10 people find they feel like they have flu, with headaches, muscle aches, chills or a fever. • Your skin can become red, hard, bruised or itchy where you inject. Beta interferons might cause depression, so you might not be given one if you've had depression in the past. ADVERSE EFFECTS 44
- 45. • Copaxone is a disease modifying drug for relapsing remitting MS. • It reduces the number of relapses by about one third (30%), compared to taking placebo. • Who can take Copaxone? • Copaxone can be prescribed for adults with active relapsing remitting MS. • Conception and pregnancy • Pregnancy is not recommended during treatment but this drug has the best profile for pregnant woman with mild disease Mechanism of action • Promote the expansion of anti-inflammatory T-helper 2 and regulatory T cells, and induced the release of neurotrophic factors. Moderately effective Glatiramer acetate (Copaxone) 45
- 46. . • Common side effects (affecting more than 1 person in 100) • injection site reactions • lipoatrophy (indentations in the skin) • headache • depression, anxiety • nausea • feeling weak • chest pain • swollen lymph nodes • gastrointestinal changes • Less common side effects (affecting less than 1 person in 100) • blood cell changes • extra heartbeats • thyroid changes • dilation of blood vessels • immediate post-injection reaction (IPIR) ADVERSE EFFECTS 46
- 47. • Copaxone Clinical trial • Copolymer 1 Multiple Sclerosis Study Group - Copaxone compared to placebo • 251 people with relapsing remitting MS took either Copaxone or placebo for 2 years. • The main measure of the study was the number of relapses per year – • Copaxone reduced this by 29% compared to placebo. People taking Copaxone had improved or unchanged disability (measured as a 1 point change in EDSS) and people taking placebo had worsened disability. 47
- 48. • GALA - Copaxone three times weekly compared to placebo • 1404 people with relapsing remitting MS took either Copaxone three times weekly or placebo for one year. • Compared to placebo, Copaxone reduced relapses by 34%. MRI results showed that Copaxone significantly reduced the number of lesions compared to placebo. 48
- 49. • Aubagio is a disease modifying drug for relapsing remitting MS Mechanism of action • Antiproliferative agent that acts as a pyrimidine synthesis inhibitor. In particular, it inhibits a mitochondrial dehydrogenase, which is the key enzyme for the de novo pyrimidine synthesis • Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Moderately Effective Therapy Teriflunomide (Aubagio) 49
- 50. • teratogenic • Common side effects (affecting more than 1 person in 100) • increased levels of liver enzymes • nausea and diarrhoea • hair thinning and loss • urinary tract infection • inflammation of the nose and throat • influenza • pins and needles • infections • decrease in white blood cells (neutropenia) • mild allergic reactions • anxiety • nerve pain • decrease in red blood cells (anaemia) • increase in blood pressure • rash • musculoskeletal pain • Less common side effects (affecting less than 1 person in 100) • decrease in blood platelets (thrombocytopenia) • peripheral neuropathy ADVERSE EFFECTS 50
- 51. TEMSO - Aubagio compared to placebo TOWER - Aubagio compared to placebo TENERE - Aubagio compared to Rebif Duration two year, double- blind study 48 weeks two years No. of People 1088 people with relapsing remitting MS 1169 people with relapsing remitting MS 324 people Comparison comparing two doses of Aubagio with placebo two different doses of Aubagio or placebo two doses of Aubagio with Rebif (interferon beta 1a) Result: Drugs shows reduction no. of relapses Drug shows reduction of disability progression 31%. 29.8% 36%. 31.5%. No Change No Change Aubagio Experimental Study 51
- 52. • Managing relapses • Treating relapses • The options for managing an MS relapse are: • treatment with high-dose steroids, either as an in-patient, a ‘day-case’ or at home • rehabilitation – after steroids, or without steroids being given • no treatment NICE says that: "The course should be started as soon as possible after onset of the relapse and should be either: intravenous methylprednisolone, 1g daily, for between 3 and 5 days or high-dose oral methylprednisolone, 0.5g daily, for 5 days". 52
- 54. Social Stigma Multiple sclerosis hasa profound impacton patients’ social roles and the well-being of their families.Varying degrees of functional decline typically accompany MS. Because the onset is usually at about 30 years of age, the lossin productivity ofpeople. Stigmatized individuals are often rejected by neighbors and the community, and as a result sufferlonelinessand depression. 54
- 55. OCCUPATIONAL THERAPY (OT) IN MS Occupational therapy can help people with multiple sclerosis stay active in daily life. By improving… skills, teaching alternative ways to complete tasks, or introducing handy equipment 55
- 56. HOW CAN OT HELP? By providing recommendations in the following areas: Arm and hand therapy Handwriting aids Home modification information Driver evaluation and vehicle modification information Cooking and homemaking adaptations Eating and dinnerware adaptations Computer modifications Workplace or work equipment modifications Leisure skill development Manual or electric wheelchair use Bathtub and toilet equipment use Dressing and grooming aids 56
- 57. • Speech therapy is a type of rehablitation that focuses on improving movement of the mouth area. . Speech therapy may be part of a multiple sclerosis treatment plan if weak facial muscle lesions (damaged areas in the brain) have affected your abilty to talk or swallow SPEECH THERAPY Oral exercises Voice training Special communication devices Diet modifications Altered positions while eating 57
- 58. PHYSIOTHERAPY • A physiotherapist works with people with MS to assess physical difficulties and help improve movement and other functions of the body. Exercise is one of the key ways in which they do this. 58
- 59. Exercise training in MS For many years patients with MS had been advised not to participate in physical training but during the last decade it has been shown that worsening of the number and/or intensity of sensory symptoms which is experienced by more than 40% of MS patients after exercise is temporal and will be normalized within an hour after exercise cessation. 59
- 61. Individualized exercise in MS can promote many important therapeutic outcomes, such as improved cardiorespiratory, muscle function, decreasing depression and fatigue toward promotion of health and quality of life. 61
- 62. • Exercise is considered helpful in managing common symptoms and promoting wellness, for reducing the risk of comorbidities such as obesity, heart disease, diabetes and osteoporosis. 62
- 63. • Several studies have tested endurance training as an intervention suitable to counteract the fatigue. 63
- 64. • Endurance training with low to moderate intensity (40-60 %VO2Max) is well tolerated by MS patients too • Improvements have been found in items regarding vitality, social functioning, mood, energy, fatigue, anger, sexual function and depression. 64
- 65. It has been recommended a training frequency of two to three sessions per week starting with (50-70% VO2 Max) with a starting duration of 10-40 min with interval training using intensities of up to 90% of VO2- Max. • In general is recommended that exercise program should be planned which seeing performing before large muscles than small and multiple joint before single and lower limbs should have the priority. 65
- 66. • Very little is known about combined training in MS patients but is possible assess that is well tolerated if performed on alteranate days (two weekly days of resistance training and two days of endurance training with an interval of 24-48 hours for recovery. • Load-bearing exercise may stimulate mantainance of muscle mass sufficiently to slow the progression of sarcopenia (loss of skeletal muscle mass) in MS and weight bearing during ambulation will also likely decrease the severity of lower-extremity osteopenia (protein and mineral content of bone tissue is reduced). 66
- 67. • Slow and gentle stretching techniques are recomended and flexibility exercise should be performed by rhytmical, repetitive motion exercises with emphasis on improving motor control using proprioceptive facilitation techniques.. • Prescribing exercise on an intermittent basis helps to avoid excessive build-up of fatigue and heat stress, which worsen MS symptoms 67
- 68. BENEFITS OF EXERCISE ?? Improve overall health of people with milder MS Help people with more severe MS to stay as mobile & active as possible Help some people manage MS symptoms and decrease the risk of heart disease Improve muscle strength and fitness, helping with mobility or weakness problems Help manage weight control, especially when combined with a healthy, well- balanced diet 68
- 69. • • Kappos L, et al.Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial.Lancet 2011;378(9805):1779-1787 • Results of the OPERA and ORATORIO studies reported at the 2015 ECTRIMS conference - 16 October 2015Medscape • Further analyses of Oratorio reported at the 2016 ACTRIMS conference - 22 February 2016 • Montalban X, et al.Ocrelizumab versus placebo in primary progressive multiple sclerosis.New England Journal of Medicine 2017;376(3):209- 220.Summary • Hauser SL, et al.Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosisNew England Journal of Medicine 2017;376(3):221-234 • National Institute for Health and Care Excellence (NICE).Natalizumab for the treatment of adults with highly active relapsing–remitting multiple sclerosis.NICE technology appraisal guidance 127 • Scottish Medicines Consortium (SMC).Advice: natalizumab (Tysabri) - September 2007. • Polman CH, et al.A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.New England Journal of Medicine 2006; 354: 899-910. • Rudick RA, et al.Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.New England Journal of Medicine 2006; 354: 911-923. • Bloomgren G, et al.Risk of natalizumab-associated progressive multifocal leukoencephalopathy.New England Journal of Medicine 2012; 366:1870-1880. • National Institute for Health and Care Excellence (NICE)Dimethyl fumarate for treating relapsing-remitting multiple sclerosisNICE Technology Appraisal Guidance 320Full guideline • Scottish Medicines ConsortiumAdvice: dimethyl fumarate (Tecfidera) - 7 April 2014 • Gold R, et al.Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.New England Journal of Medicine 2012;367:1098-107 • Fox RJ, et al.Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.New England Journal of Medicine 2012;367:1087-97. • National Institute for Health and Care Excellence (NICE).Beta interferon and glatiramer acetate for the treatment of multiple sclerosisNICE technology appraisal guidance TA32 • Johnson KP, et al.Copolymer 1 reduces relapse rate and improves disability in relapsing remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. The Copolymer 1 Multiple Sclerosis Study Group.Neurology 1995;45(7):1268-76. • Khan O, et al.Three times weekly glatiramer acetate in relapsing-remitting multiple sclerosis.Annals of Neurology 2013;73(6):705-13. • National Institute for Health and Care Excellence (NICE)Teriflunomide for treating relapsing-remitting multiple sclerosisNICE Technology Appraisal Guidance 303 • Scottish Medicines Consortium (SMC)Advice: teriflunomide (Aubagio) - 10 March 2014 • O'Connor P, et al.Randomized trial of oral teriflunomide for relapsing multiple sclerosis.New England Journal Medicine 2011;365(14):1293-303. • Vermersch P, et al.Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial.Multiple Sclerosis Journal 2014;20:706-17. • Confavreux C, et al.Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Neurology 2014;13:247-256. References 69
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Editor's Notes
- #6: CD4 is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells. These cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages. Mature Th cells express the surface protein CD4 and are referred to as CD4+ T cells.
- #9: Matrix metalloproteinases (MMPs) degrade extracellular matrix, which is a crucial step involved in various stages of tumor progression, including tumor angiogenesis, tumor growth, and also local invasion and subsequent distant metastasis.
- #11: Oscillopsia is a visual disturbance in which objects in the visual field appear to oscillate. The severity of the effect may range from a mild blurring to rapid and periodic jumpingparesthesias an abnormal sensation, typically tingling or pricking (‘pins and needles’), caused chiefly by pressure on or damage to peripheral nerves. dysesthesias an abnormal unpleasant sensation felt when touched, caused by damage to peripheral nerves. Trigeminal neuralgia is sudden, severe facial pain. It's often described as a sharp shooting pain or like having an electric shock in the jaw, teeth or gums. It usually occurs in short, unpredictable attacks that can last from a few seconds to about two minutes. Proprioceptive deficits are abnormal body positions or movements due to a lack of normal perception. Loss of proprioception causes abnormal placement reactions in the limbs (legs), abnormal limb position at rest (legs crossed or paws turned under), and abnormal wearing of the toes.
- #12: Dyspareunia difficult or painful sexual intercourse.
- #14: exacerbation may refer to an increase in the severity of a disease or its signs and symptoms. Remission: Disappearance of the signs and symptoms of cancer or other disease. Relapse: The return of signs and symptoms of a disease after a remission.
- #18: Monoclonal antibody therapy is a form of immunotherapy that uses monoclonal antibodies (mAb) to bind monospecifically to certain cellsor proteins. The objective is that this treatment will stimulate the patient's immune system to attack those cells. Ocrelizumab is an immunosuppresive drug; it binds to CD20, which is selectively made by B cells, and when ocrelizumab binds to CD20 it kills B cells by causing antibody-dependent cell-mediated cytotoxicity and, to a lesser extent, complement-dependent cytotoxicity.[1 B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells
- #22: The main end point of the study was the onset of disability progression. This was measured by the number of participants with an increased EDSS which was still evident 3 months later. The study also recorded the number of participants with an increased EDSS still evident after 6 months, walking speed over 25 feet and volume of brain and MS lesions.
- #24: The case occurred in someone with relapsing remitting MS who was JC virus-positive, had stopped taking Tysabri in February after three years on the drug and had taken their first dose of ocrelizumab in April. The manufacturer of ocrelizumab is carrying out further investigations. An opportunistic infection is an infection caused by pathogens (bacteria, viruses, fungi, or protozoa) that take advantage of an opportunity not normally available, such as a host with a weakened immune system, an altered microbiota (such as a disrupted gut flora), or breached integumentary barriers. Progressive multifocal leukoencephalopathy(PML) is a rare and usually fatal viral disease characterized byprogressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal).
- #25: The integrin VLA-4 is expressed on the cell surfaces of stem cells, progenitor cells, T and B cells, monocytes, natural killer cells, eosinophils, and neutrophils. It functions to promote an inflammatory response by the immune system by assisting in the movement of leukocytes to tissue that requires inflammation.[2] It is a key player in cell adhesion
- #27: (for example azathioprine, cyclophosphamide, mitoxantrone or methotrexate)
- #29: It is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. After treatment with alemtuzumab, these CD52-bearing lymphocytes are targeted for destruction CAMPATH-1 antigen, also known as cluster of differentiation 52 (CD52), is a glycoprotein that in humans is encoded by the CD52 gene. CD52 is present on the surface of mature lymphocytes
- #30: of Lemtrada has come from two large studies.
- #35: Sphingosine 1-Phosphate Receptor
- #39: T lymphocytes play a central role in the pathogenesis of multiple sclerosis (MS) (Zhang et al., 1992). Both CD4+ and CD8+ T cells have been demonstrated in MS lesions, with CD4+ T cells predominating in acute lesions and CD8+ T cells being observed more frequently in chronic lesions (Raine, 1994). Additionally, T cells are found in all four of the described histopathologic subtypes of MS (Lucchinetti et al., 2000). Activated myelin-reactive CD4+ T cells are present in the blood and cerebrospinal fluid (CSF) of MS patients; in contrast, only nonactivated myelin-reactive T cells are present in the blood of controls (Zhang et al., 1994). The success of several T-cell-targeted therapies in MS reinforces the importance of the role of the T cell in MS pathogenesis. Here, we outline basic concepts in CD4+ T-cell immunology and summarize the current understanding of the role of CD4+ T cells in the pathogenesis of MS.
- #43: IFN-β down-regulates T-cell activation by altering the expression of proteins involved in antigen presentation, and studies indicate that it also promotes the differentiation of activated T cells away from a T-helper-type 1 Th1 response (pro-inflammatory) and towards a Th2 response (anti-inflammatory). Accordingly, IFN-β decreases the expression of IL-12 and promotes the expression of anti-inflammatory cytokines like IL-27 by macrophages.
- #46: Neurotrophic factors are molecules that enhance the growth and survival potential of neurons.
- #48: Copaxone has been studied extensively since the early 1990s. The following study first demonstrated the effectiveness of Copaxone:
- #50: A salvage pathway is a pathway in which nucleotides (purine and pyrimidine) are synthesized from intermediates in the degradative pathway for nucleotides. Salvage pathways are used to recover bases and nucleosides that are formed during degradation of RNA and DNA. De NovoSimpler compounds are used in the synthesis of nucleotides. Numerous small pathways are repeated to assemble different nucleotides.
- #52: The main measure of the study was the time to first relapse or stopping treatment for any reason. There was no difference in this measure between either dose of Aubagio or Rebif The number of relapses in one year was approximately the same for Rebif and the higher dose of Aubagio
- #54: Aspartame (APM) is an artificial non-saccharide sweetener used as a sugar substitute in some foods and beverages.