RCSI Drugs in Multiple Sclerosis PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Drugs in Multiple Sclerosis Class Year 2 Semester 1 Course CNS Code CNS Title Drugs in Multiple Sclerosis Lecturer Dr. Colin Greengrass (RCSI-BH) Date 3.12.2023  DRUGS IN MULTIPLE SCLERO...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn Drugs in Multiple Sclerosis Class Year 2 Semester 1 Course CNS Code CNS Title Drugs in Multiple Sclerosis Lecturer Dr. Colin Greengrass (RCSI-BH) Date 3.12.2023  DRUGS IN MULTIPLE SCLEROSIS Describe the role of the immune system in Multiple Sclerosis and define associated drug targets Describe the mechanism of action and adverse effects of disease modifying agents in MS BY DR. COLIN GREENGRASS  MULTIPLE SCLEROSIS AS WITH OTHER AUTOIMMUNE DISEASES, MULTIPLE SCLEROSIS IS A CHRONIC (LONG-TERM) DISEASE IT IS PROGRESSIVE Introduction to Multiple Sclerosis Multiple Sclerosis (MS) is a chronic, immune-mediated disorder Where the body's immune system attacks the central nervous system (CNS). Gender Disparity: Females More Affected (2:1 Ratio) Affects Young Adults. It predominantly affects young adults, Onset typically between 20-40 years. Prevalence: Higher in Northern Latitudes  Pathophysiology of MS MS is characterized by an abnormal immune response, where the body's immune system mistakenly targets its own CNS In MS, immune cells; T cells and B cells attack the myelin sheath, leading to demyelination. This demyelination disrupts nerve signal transmission, causing various neurological symptoms. Multiple sclerosis (MS) Disease progression ranges from benign and relatively stable to devastating with rapid deterioration and early death. MYELIN SHEATH THE IMPORTANCE OF MYELINATION You don’t need to know the speeds, just fast vs slow Self-antigens  Genetic and Blood-Brain Immune System Environmental Barrier Misidentification Triggers Disruption 1.Genetic susceptibility. 1.Autoreactive T cells and B 1.Inflammation increases BBB 2.Environmental factors (e.g., cells mistake myelin as permeability. viral infections, smoking, foreign. 2.Entry of T lymphocytes vitamin D deficiency). (CD4+, CD8+) and B lymphocytes into CNS.  Activation of Impaired CNS Immune Demyelination Nerve Cells Conduction 1.Microglia and astrocytes 1.Myelin and 1.Slowed/blocked electrical activated by infiltrating oligodendrocytes attacked signals in nerve fibers. immune cells. by immune cells and 2.Symptoms like motor autoantibodies. weakness, sensory issues, 2.Formation of sclerosis (scar vision problems. tissue).  Limited Chronic Axonal Remyelinat- Neurodege- Damage ion neration Exposed nerve fibres Incomplete myelin Progressive phase of undergo repair by CNS. MS characterized degeneration. by ongoing neurodegeneration. Initial Immune System Activation Abnormal immune response, possibly triggered by genetics and environmental factors Involvement of genetic factors (HLA-DRB1 gene). Environmental triggers: Viral infections (Epstein-Barr virus), smoking, vitamin D deficiency. Genetic and Environmental Triggers Initial Immune System Activation Immune System Misidentification Immune system misidentifies CNS myelin as foreign; particularly involving autoreactive CD4+ T cells (Th1 and Th17 cells) and B cells Activation of B cells, possibly into memory B cells and plasmablasts. Immune System Misidentification  Disruption of Blood-Brain Barrier (BBB) Permeability Normally, the BBB protects the CNS from pathogens and immune cells. In MS, inflammation compromises the BBB, enabling T and B lymphocytes to infiltrate the CNS and leads to increased BBB permeability. Pro-inflammatory cytokines (e.g., IFN-γ from Th1 cells, IL-17 from Th17 cells) increase BBB permeability. Blood-Brain Barrier Disruption Disruption of Blood-Brain Barrier (BBB) Permeability In MS, the compromised BBB, enables Migration of CD4+ T cells (Th1, Th17), CD8+ T cells, and B cells into the CNS. Key inflammatory signals include: These signals trigger a cascade of events within the endothelial cells of the blood-brain barrier (BBB) and other vascular beds. Blood-Brain Barrier Disruption  Blood-Brain Upregulation of Adhesion Molecules Barrier Disruption Inflammatory signals can lead to an increased expression of adhesion molecules on the surface of endothelial cells, facilitating the attachment and passage of immune cells. 1.Cytokines: such as tumour necrosis factor-alpha (TNF-α), interleukins (e.g., IL-1, IL-6), and interferons (e.g., IFN-γ). 2.Chemokines: such as CCL2 (MCP-1) and CXCL8 (IL-8). 3.In MS, the upregulation of VCAM-1 and ICAM-1 on the BBB endothelium is a key factor in enabling immune cells, especially T lymphocytes and B lymphocytes, to adhere to the endothelial surface. Upregulation of Adhesion Molecules Blood-Brain Barrier The adhesion molecule are proteins expressed on the surface of Disruption endothelial cells that facilitate the binding and transmigration of immune cells from the bloodstream into the tissue. Adhesion Molecule Examples Role Mediate initial tethering and rolling of Selectins E-selectin, P-selectin leukocytes on the endothelial surface. VLA-4 on immune cells binds to VCAM-1 Integrins VLA-4 on endothelial cells. Binds to integrins like LFA-1 on Intercellular Adhesion ICAM-1 leukocytes, facilitating firmer adhesion Molecule-1 and transmigration.  Activation of CNS-Resident Immune Cells Infiltrating immune cells activate microglia (CNS-resident macrophages) and astrocytes. T cells and B cells entering the CNS can activate microglia either directly through cell-to-cell contact or indirectly through cytokines. Activation of CNS Immune Cells  Activation of CNS-Resident Immune Cells These activated resident cells contribute to inflammation, further attracting peripheral immune cells. CNS resident microglia become activated and secrete chemokines (CCL2, CXCL10) attracting more peripheral immune cells. Astrocytes release cytokines (TNF-α, IL-6) contributing to inflammation. Activation of CNS Immune Cells Demyelination Immune cells release cytokines and toxic compounds, damaging myelin and oligodendrocytes. T cells (CD4+ and CD8+) and B cells release inflammatory cytokines, leading to myelin destruction. Myelin-specific CD4+ T cells (Th1/Th17) and CD8+ T cells attack myelin. B cells differentiate into plasma cells, producing autoantibodies against myelin. Release of pro-inflammatory cytokines (TNF-α, IL-1β) and chemokines. S1P Signalling Peripheral Lymph Node S1P Role in Immune Cell Dynamics S1P Signaling: Bioactive lipid mediator, crucial for lymphocyte migration. Receptors: Lymphocytes express S1P receptors (S1PR1-S1PR5), controlling egress from lymphoid organs. Lymphocyte Trafficking Retention in Lymph Nodes: Low S1P concentration in lymph nodes keeps lymphocytes (T and B cells) contained. Egress to Bloodstream: Higher S1P levels in blood promote lymphocyte exit to bloodstream.  Peripheral Lymph Node S1P in MS Pathogenesis Dysregulated Lymphocyte Movement: Autoreactive lymphocytes migrate to CNS, driving inflammation and demyelination. Therapeutic Target: S1P receptor modulation to prevent damaging lymphocyte CNS infiltration. S1P Modulators as Therapeutics Mechanism of Action (MOA): Drugs like Fingolimod bind to S1PR1, blocking lymphocyte egress, reducing CNS inflammation.  B cells differentiate into plasma cells, producing autoantibodies against Demyelination myelin. The formation of autoantibody-myelin complexes can recruit other immune cells, like macrophages, to the site of inflammation. Macrophages phagocytose the myelin-autoantibody complexes, contributing to demyelination and neuronal damage. Axonal Damage Exposure of Axons: Demyelination leaves nerve fibres vulnerable to injury. Demyelination exposes axons to inflammatory cytokines and reactive oxygen/nitrogen species. CD8+ T cells may directly attack neurons and axons. Long-Term Consequences: Chronic inflammation and demyelination lead to axonal degeneration  Impaired Nerve Conduction Impact on Nerve Signals Damaged myelin disrupts the fast transmission of electrical signals in nerve fibres. Symptomatic Outcomes: Leads to MS symptoms like motor weakness, sensory issues, vision problems, cognitive impairment. Limited Remyelination The CNS has a limited capacity for myelin repair (remyelination), However, in MS, incomplete remyelination is slower than the rate of damage due to limited oligodendrocyte precursor cell differentiation. Furthermore, failure of repair mechanisms are exacerbated by ongoing inflammation. Limited Remyelinat- ion The Role of T-Cells and B-Cells in Multiple Sclerosis Cell Type/Signaling Function in Immune Molecule System Role/Change in MS Interrelationships In MS, they mistakenly Activated by antigen- attack myelin; CD4+ cells Coordinate immune presenting cells; interact T Cells (CD4+, (Th1, Th17) promote responses; directly attack with B cells and influence CD8+) inflammation, while CD8+ infected or abnormal cells microglia/astrocyte cells directly damage activation myelin and neurons Contribute to myelin destruction via Produce antibodies; Interact with T cells; can autoantibody production B Cells present antigens; secrete become plasma cells that and cytokine release; cytokines produce autoantibodies antigen presentation activates T cells The Role of Glial Cells in Multiple Sclerosis Cell Type/Signaling Function in Immune Molecule System Role/Change in MS Interrelationships Become activated in MS, Activated by T cells, B Resident macrophages of contributing to cells, and damaged Microglia the CNS; respond to inflammation and myelin; release cytokines infection and injury neurodegeneration and chemokines Release pro-inflammatory Support neuronal Influenced by cytokines cytokines in MS, function; regulate from T cells and microglia; Astrocytes contributing to neurotransmitters and contribute to the BBB inflammation and BBB blood-brain barrier integrity disruption The Role of Cytokines and Chemokines in Multiple Sclerosis Cell Type/Signaling Function in Immune Molecule System Role/Change in MS Interrelationships Produced by T cells, B Elevated in MS, driving cells, microglia, and Cytokines (e.g., TNF-α, Mediate and regulate inflammation, BBB astrocytes; exacerbate IL-6, IFN-γ) immune responses breakdown, and tissue inflammation and damage immune cell infiltration Produced by activated Facilitate the recruitment Chemokines (e.g., Attract immune cells to microglia, astrocytes, of more immune cells CCL2, CXCL10) sites of inflammation and infiltrating immune into the CNS in MS cells; enhance immune cell migration across BBB The Role of AutoAbs and CAMs in Multiple Sclerosis Cell Type/Signaling Molecule Function in Immune System Role/Change in MS Interrelationships In MS, target myelin, Produced by plasma cells Myelin-specific Normally target foreign contributing to its (differentiated B cells); Autoantibodies antigens destruction facilitate myelin degradation Expression induced by Upregulated on BBB Adhesion inflammatory cytokines; Facilitate cell-cell adhesion endothelium in MS, aiding Molecules (VCAM- facilitate T and B cell in the immune system immune cell infiltration into 1, ICAM-1) adhesion and transmigration CNS into CNS CLINICAL MANIFESTATIONS OF MULTIPLE SCLEROSIS  Relapsing-Remitting Multiple Sclerosis (RRMS) Relapsing-Remitting Multiple Sclerosis (RRMS) is the most common form of Multiple Sclerosis (MS), affecting about 85% of patients at diagnosis. RRMS is characterized by clearly defined attacks of new or increasing neurological symptoms, known as relapses or exacerbations. These are followed by periods of partial or complete recovery, termed remissions.  Relapsing-Remitting Multiple Sclerosis (RRMS) Symptoms: During relapses, symptoms can vary widely and may include visual disturbances, muscle weakness, sensory loss, coordination and balance issues, and cognitive impairment. The specific symptoms depend on the areas of the CNS affected. Disease Course: RRMS is noted for its unpredictability, with relapses occurring sporadically. The frequency and severity of relapses can vary greatly among individuals. In between relapses, patients may experience a complete or partial return to their baseline, with no apparent progression of the disease. Transition from RRMS to Secondary Progressive Multiple Sclerosis Some individuals with RRMS may eventually transition to a secondary progressive course (SPMS), where there is a gradual worsening of symptoms and disability independent of relapses. Secondary Progressive Multiple Sclerosis (SPMS) Secondary Progressive Multiple Sclerosis (SPMS) is a phase of Multiple Sclerosis (MS) that typically follows Relapsing-Remitting MS (RRMS). SPMS develops in individuals who initially have RRMS. It is marked by a shift from the relapsing-remitting pattern to a phase where neurological function progressively worsens over time. Secondary Progressive Multiple Sclerosis (SPMS) Decrease in Relapses: While early stages of SPMS may include occasional relapses, these tend to diminish as the disease progresses. The primary feature becomes the steady progression of disability and neurological decline. SPMS is characterized more by neurodegenerative processes than by the inflammatory attacks seen in RRMS. There is a gradual loss of nerve cells and brain atrophy, contributing to the accumulation of disability. Primary Progressive Multiple Sclerosis (PPMS) Primary Progressive Multiple Sclerosis (PPMS) is one of the forms of Multiple Sclerosis (MS), marked by a continuous worsening of neurological function from the onset of symptoms, without distinct relapses or remissions that are typical in Relapsing-Remitting MS (RRMS). While inflammation is a component, PPMS is more characterized by neurodegenerative processes, leading to progressive nerve damage and brain atrophy.  CAN INHIBIT THE EXPRESSION OF Drug Targets in MS PROINFLAMMATORY CYTOKINES Therapeutic strategies in MS target the immune system to reduce inflammation and slow disease progression. CAN ALTER RESPONSE CAN REDUCE OF LYMPHOCYTE TO SURFACE ANTIGEN MIGRATION INTO THE CENTRAL NERVOUS SYSTEM Immune Modulating Therapies Immune modulators work by modifying specific aspects of the immune response without broadly suppressing it. These drugs can help restore the normal balance of the immune system, targeting specific pathways or types of immune cells involved in the disease process. Immune modulating drugs are paticularly effective in autoimmune diseases like Multiple Sclerosis (MS) Immune Modulating Therapies works by modulating the immune response, aiming to Interferon-beta reduce the frequency of MS flare-ups. Glatiramer believed to alter T cell responses, promoting a shift towards a more protective immune profile. acetate works by modulating the immune response, specifically Teriflunomide targeting the proliferation of rapidly dividing immune cells such as activated T and B lymphocytes Interferon-Beta Mechanism of Action Interferon-beta is a cytokine in the interferon family that modulates the immune response. It is thought to reduce the migration of inflammatory cells across the blood- brain barrier It also alters the expression of surface antigens and has immunomodulatory effects on T cells, B cells, and macrophages – precise mechanism unknown. Interferon-Beta Adverse Effects Common adverse effects include flu-like symptoms (such as fever, chills, fatigue, and muscle aches), injection site reactions, and potential liver damage. Less common but more severe effects include depression and leukopenia (a reduction in white blood cells). Glatiramer Acetate Mechanism of Action Glatiramer acetate is a synthetic polymer that resembles myelin basic protein, a component of the myelin sheath. It acts as a decoy, diverting the immune response away from myelin. It stimulates regulatory T cells and shifts the balance of cytokines towards a more anti-inflammatory profile – mechanism unknown Glatiramer Acetate Adverse Effects Side effects include injection site reactions, chest pain, palpitations, anxiety, and shortness of breath. It is generally well-tolerated, with no known severe long-term adverse effects. Teriflunomide Mechanism of Action: Teriflunomide inhibits dihydroorotate dehydrogenase, an enzyme essential for pyrimidine synthesis, thus reducing the proliferation of rapidly dividing cells, including activated T and B lymphocytes, that can participate in the autoimmune attack on the central nervous system in MS. This results in a reduction of the inflammatory response and helps in controlling the disease activity. Teriflunomide Adverse Effects: Side effects include hair thinning, diarrhoea, nausea, and liver function abnormalities. Teriflunomide is teratogenic and should not be used during pregnancy. Immunosuppressants in MS Immunosuppressors act by broadly reducing the activity of the immune system. They decrease the body's immune response, which can be beneficial in conditions where the immune system is overactive or attacks the body, such as in autoimmune diseases. They often target rapidly dividing cells, which include many components of the immune system. Traditional immunosuppressants exert a more global effect, indiscriminately dampening various aspects of the immune system, including both innate and adaptive immunity. Immunosuppressants in MS Mitoxantrone is an immunosuppressant used in MS to reduce immune activity and decrease the frequency of relapses. Fingolimod, by modulating sphingosine 1-phosphate receptors, prevents lymphocytes from exiting lymph nodes, reducing their presence in the CNS Mitoxantrone – Mechanism DNA Interaction and Topoisomerase II Inhibition: Intercalates into DNA, disrupting replication and transcription. Inhibits Topoisomerase II, leading to DNA strand breaks and cell death. Immunomodulatory Effects: Reduces proliferation of B cells, T cells, and macrophages. Decreases pro-inflammatory cytokine secretion and may increase anti- inflammatory cytokines.  Fingolimod Mechanism of Action: Therapeutic modulation of S1P receptors, particularly S1PR1, is effective in managing MS by reducing the migration of autoreactive lymphocytes into the CNS. S1P receptor modulators like Fingolimod represent a targeted approach to reduce inflammatory processes in MS It traps lymphocytes in lymph nodes, preventing them from reaching the CNS and causing damage.  Siponimod (Mayzent), Ozanimod (Zeposia) Peripheral Lymph Node Primary Action: Similar to fingolimod, these drugs are S1P receptor modulators. Effect on Immune Cells and BBB: By sequestering lymphocytes in lymph nodes, they reduce the number of these cells in the CNS, Potentially decreasing inflammation and the associated BBB disruption. Monoclonal Antibodies Natalizumab works by inhibiting leukocytes from crossing the BBB, reducing inflammation in the CNS Ocrelizumab targets CD20 on B cells, reducing B cell mediated damage in the CNS.  Natalizumab Mechanism of Action Natalizumab (Tysabri) is a monoclonal antibody that targets the α4-integrin molecule on the surface of immune cells. By blocking this molecule, it prevents immune cells from adhering to and crossing the blood-brain barrier into the CNS. Natalizumab Adverse Effects: Risks include allergic reactions, increased risk of infections (due to immune suppression), and a rare but serious brain infection called progressive multifocal leukoencephalopathy (PML). Regular monitoring for signs of PML is necessary Ocrelizumab Mechanism of Action Ocrelizumab is a monoclonal antibody targeting CD20, found on the surface of B cells. It depletes these cells, which are believed to play a key role in the pathogenesis of MS. Ocrelizumab Adverse Effects: Common side effects include infusion reactions, upper respiratory tract infections, and skin infections. Long-term use can lead to a reduction in immunoglobulin levels, potentially increasing the risk of infections. Antioxidants Dimethyl Fumarate Mechanism of Action: Dimethyl fumarate is believed to activate the Nrf2 pathway, which helps protect against oxidative stress-induced neuronal damage. It also has anti-inflammatory properties. Adverse Effects: Common side effects include flushing, gastrointestinal symptoms (such as diarrhea, nausea, abdominal pain), and lymphopenia (decreased white blood cell count). Regular monitoring of lymphocyte counts is recommended. Treatment for Relapsing-Remitting MS (RRMS) RRMS is characterized by clear relapses (flare-ups of symptoms) followed by periods of remission. The majority of disease-modifying therapies (DMTs) are approved for RRMS due to its more inflammatory nature compared to progressive forms of MS. Targets for therapy focus on reducing the frequency and severity of relapses. Treatment for Relapsing- Remitting MS (RRMS) These include: Interferon-beta (e.g., Avonex, Rebif, Betaseron): Reduce the frequency and severity of relapses. Glatiramer Acetate (Copaxone): Modulates the immune response to be less reactive to myelin. Natalizumab (Tysabri): Highly effective in reducing relapse rate and slowing disease progression, but with a risk of PML. Fingolimod (Gilenya): A sphingosine 1-phosphate receptor modulator that prevents lymphocytes from contributing to CNS inflammation. Treatment for Relapsing- Remitting MS (RRMS) Dimethyl Fumarate (Tecfidera): Has anti-inflammatory effects and protects against oxidative stress-induced neuronal damage. Teriflunomide (Aubagio): Reduces the proliferation of activated lymphocytes. S1P Receptor Modulators (e.g., Similar mechanism to Fingolimod but with Siponimod, Ozanimod): potentially fewer side effects. Monoclonal Antibodies (e.g., Target specific components of the immune Ocrelizumab, Ofatumumab, Ublituximab): system; Ocrelizumab is also approved for PPMS. Drugs for Primary Progressive MS (PPMS) Fewer treatment options compared to RRMS; Ocrelizumab is currently the only approved Disease modifying therapy for PPMS. Management focuses on symptom control, physical therapy, and supportive care to maintain mobility and function. Research ongoing for more effective treatments and understanding the unique progression of PPMS. Drugs for Primary Progressive MS (PPMS) There are fewer treatment options for PPMS, as many DMTs for RRMS are not effective in slowing its progression. The primary drug approved for PPMS is: Ocrelizumab (Ocrevus): The first and currently only drug approved specifically for PPMS. It targets CD20-positive B cells, which are believed to play a key role in the pathology of PPMS.  Key: Therapeutic strategies for each stage of Multiple : Approved or commonly used. Sclerosis (MS) – Relapsing-Remitting MS (RRMS), : Not typically used or not approved. Secondary Progressive MS (SPMS), and Primary *: May be used in cases with active disease (evidenced by Progressive MS (PPMS) relapses or MRI activity). Therapeutic Strategy (Drugs) RRMS SPMS PPMS Interferon-beta products (e.g., Avonex, Rebif) * (active disease) Glatiramer Acetate (Copaxone) * (active disease) Natalizumab (Tysabri) * (active disease) For SPMS patients with active disease (evidenced by relapses or MRI activity)  Key: Therapeutic strategies for each stage of Multiple : Approved or commonly used. Sclerosis (MS) – Relapsing-Remitting MS (RRMS), : Not typically used or not approved. Secondary Progressive MS (SPMS), and Primary *: May be used in cases with active disease (evidenced by Progressive MS (PPMS) relapses or MRI activity). Therapeutic Strategy (Drugs) RRMS SPMS PPMS Fingolimod (Gilenya) Dimethyl Fumarate (Tecfidera) Teriflunomide (Aubagio)  Key: Therapeutic strategies for each stage of Multiple : Approved or commonly used. Sclerosis (MS) – Relapsing-Remitting MS (RRMS), : Not typically used or not approved. Secondary Progressive MS (SPMS), and Primary *: May be used in cases with active disease (evidenced by Progressive MS (PPMS) relapses or MRI activity). Therapeutic Strategy (Drugs) RRMS SPMS PPMS Siponimod (Mayzent) Ocrelizumab (Ocrevus) * (active disease) Cladribine (Mavenclad) * (active disease) Mitoxantrone Drug Mechanism of Action at Cellular Level Therapeutic Effect Enhances production of anti-inflammatory agents and Interferon beta Reduces inflammation and relapse rate in MS. reduces pro-inflammatory cytokines. Glatiramer Mimics myelin basic protein to act as an antigen, altering the Diverts immune response from attacking myelin. acetate immune response and promoting Treg cell proliferation. Binds to α4-integrin on lymphocytes, inhibiting their Inhibits lymphocyte migration into CNS, reducing MS Natalizumab migration across the blood-brain barrier. activity. Acts as a sphingosine-1-phosphate receptor modulator, Prevents lymphocyte migration to CNS, reducing MS Fingolimod sequestering lymphocytes in lymph nodes. progression. Reduces B cell-mediated inflammation and demyelination in Ocrelizumab Targets CD20 on B cells leading to their depletion. CNS. Dimethyl Activates the Nrf2 pathway leading to a reduction in Lowers immune cell activation and CNS damage. fumarate oxidative stress and inflammation. Interacts with DNA to disrupt replication and repair, and Reduces immune-mediated CNS damage and slows MS Mitoxantrone inhibits macrophage activity. progression. Binds CD52 on lymphocytes and monocytes, causing cell Leads to long-term suppression of the autoimmune Alemtuzumab lysis and depletion. response. Mimics adenosine deaminase leading to DNA damage and Decreases lymphocyte counts, mitigating autoimmune Cladribine selective lymphocyte apoptosis. attack in CNS. Modulates sphingosine-1-phosphate receptors, preventing Reduces CNS inflammation and slows secondary progressive Siponimod lymphocyte egress from lymph nodes. MS. Treatment Option General Effect on Disease Progression Notes Modest reduction in relapse rate and disease Interferon beta Often used as first-line therapy; effect on long-term disability varies progression Glatiramer Similar to interferon beta in reducing relapse Often used as first-line therapy; well-tolerated acetate rate Significant reduction in relapse rate and disease Natalizumab Used for more active forms of MS; risk of PML in some patients activity Reduces relapse rate; may slow disability Fingolimod First oral MS therapy; heart rate monitoring required upon first dose progression Effective in reducing relapse rate and Ocrelizumab Used in both relapsing and primary progressive MS progression Dimethyl Reduces relapse rate and delays disability Good efficacy and safety profile fumarate progression Mitoxantrone Reduces disease activity and progression Limited by cumulative lifetime dose due to cardiac toxicity risk Significant reduction in relapse rate; may slow High efficacy but with serious side effects; intensive monitoring Alemtuzumab progression needed Cladribine Reduces relapse rate; may slow progression Oral therapy; used in highly active MS Reduces risk of disability progression in Siponimod Newer oral therapy; specific for secondary progressive MS secondary progressive MS  Severity of Adverse Drug First-Line Therapy Effects Efficacy Specialized for MS Forms Interferon beta Yes Mild to Moderate Moderate Relapsing-remitting MS Glatiramer acetate Yes Mild Moderate Relapsing-remitting MS Moderate to Severe (Risk Natalizumab No (Second-line) High Highly active relapsing-remitting MS of PML) Fingolimod No (Second-line) Moderate (Cardiac risks) High Relapsing-remitting MS Moderate (Infusion Relapsing-remitting and primary Ocrelizumab No (Second-line) High reactions, infections) progressive MS Dimethyl fumarate Yes Mild to Moderate High Relapsing-remitting MS Severe (Cardiotoxicity, Secondary progressive MS, progressive- Mitoxantrone No Moderate leukemia risk) relapsing MS Severe (Autoimmune Alemtuzumab No (Second-line) High Highly active relapsing-remitting MS disorders, infections) Moderate (Similar to Siponimod No Moderate Secondary progressive MS Fingolimod) TREATMENT For active relapsing-remitting MS without significant risk factors for high-efficacy treatments: Start with a safer, SELECTION well-tolerated first-line agent like interferon-beta, glatiramer acetate, or dimethyl fumarate. For highly active or aggressive MS or in cases where rapid control of the disease is needed: Consider a high- efficacy treatment early on, such as natalizumab or ocrelizumab, after evaluating the risks Drugs Used to Manage Symptoms 1. Muscle Spasticity Baclofen: A muscle relaxant that helps relieve muscle spasticity. Tizanidine: An α2-adrenergic agonist used to manage spasticity. Diazepam: A benzodiazepine that can be used for severe spasticity. Drugs Used to Manage Symptoms Pain Gabapentin and Pregabalin: Used for neuropathic pain. Tricyclic Antidepressants (e.g., Amitriptyline): Can be effective for certain types of MS-related pain. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): For musculoskeletal pain. Drugs Used to Manage Symptoms Fatigue Amantadine: An antiviral drug that can help reduce fatigue. Modafinil: Used off-label for MS-related fatigue (commonly used in narcolepsy). A cure for Multiple Sclerosis? Autologous Hematopoietic Stem Cell Transplant (aHSCT) The trials of autologous hematopoietic stem cell transplantation (AHSCT) in Multiple Sclerosis (MS) have shown promising results. Autologous Hematopoietic Stem Cell Transplantation Autologous hematopoietic stem cell transplant (aHSCT), is still considered experimental and is typically reserved for patients with aggressive forms of MS who have not responded to other treatments. It carries significant risks due to the use of chemotherapy and the potential for infection while the immune system is weakened. JAMA Neurology. "Efficacy of Autologous Hematopoietic Stem Cell Transplantation in Patients With Multiple Sclerosis." Available at: https://jamanetwork.com/journals/jamaneurology/fullarticle/260 4135.  Studies have demonstrated that AHSCT can suppress MS disease activity for a number of years in a significant proportion of patients, a rate that is higher than those achieved with other therapies for this condition. The National Multiple Sclerosis Society (USA) has recognized AHSCT as a potential treatment option for people with relapsing forms of MS who have not responded to high-efficacy disease-modifying therapies. JAMA Neurology. "Efficacy of Autologous Hematopoietic Stem Cell Transplantation in Patients With Multiple Sclerosis." Available at: https://jamanetwork.com/journals/jamaneurology/fullarticle/260 4135. Autologous Hematopoietic Stem Cell Transplantation However, AHSCT is a complex procedure with considerable risks, and it is not suitable for all patients with MS. It should only be considered after careful evaluation of the potential benefits and risks JAMA Neurology. "Efficacy of Autologous Hematopoietic Stem Cell Transplantation in Patients With Multiple Sclerosis." Available at: https://jamanetwork.com/journals/jamaneurology/fullarticle/2604135.