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The major goal of disease-modifying therapies for MS and myasthenia gravis, and for related neuroinflammatory disorders, is to reduce the severity and frequency of relapses, thus changing the trajectory of the disease process. However, comparing the efficacy of the various drug therapies available is challenging because the clinical trials that led to the drugs’ approval often do not match the clinical scenarios in which the drugs are used today. A major limitation of many available therapies for neuroinflammatory conditions is that they must be given parenterally, by either intravenous or intramuscular injection. More recently approved drugs, which are effective by oral administration, have begun to mitigate this challenge.
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There are multiple ways that current drug therapies can be categorized. One approach is to group drugs by their presumed mechanism of action. Over the past decade several monoclonal antibodies originally approved for treatment of myeloid malignancies or small-molecule drugs originally used to prevent organ transplant rejection have been brought to bear in the treatment of MS. Another grouping strategy is by molecular class in which treatments affect a particular aspect of the immune response. The agents described below are grouped as those that: (1) impair antigen presentation, (2) alter lymphocyte function, (3) alter cellular proliferation, and (4) alter the functioning of the neuromuscular junction 12–6. As the newer therapies enter wider clinical use, undoubtedly our understanding of the complex interactions between components of the immune system and functioning of the nervous system will grow.
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Drugs With Specific Immune-Directed Mechanisms
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Glatiramer acetate is a first-line disease-modifying drug to treat MS. It is a random polymer of glutamate, lysine, alanine, and tyrosine, with a structure similar to myelin basic protein. Glatiramer acetate, which must be given intravenously, was shown to significantly lower the number of lesions and exacerbations compared with patients who received placebo. The mechanism of action of glatiramer acetate is not completely understood. The results of in vitro and in vivo systems suggest that glatiramer acetate has multiple effects on the host’s innate and adaptive immune system. By binding to MHC class II molecules, glatiramer acetate can prevent the presentation of other antigens and stop subsequent T-cell activation. Glatiramer acetate also appears to have other effects on T cells, B cells, and monocytes: it promotes the production of anti-inflammatory cytokines, as well as increases the number of certain regulatory T cells while decreasing the number of proinflammatory T cells (ie, Th17 lineage cells). Furthermore, it has been demonstrated that glatiramer acetate treatment promotes remyelination and axonal repair in MS lesions by inducing secretion of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3 and -4. Response to glatiramer acetate varies, with approximately 50% of patients not responding to therapy.
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Interferons (IFNs) are a family of pleiotropic cytokines produced by immune cells in response to viral infections. IFNs exhibit antiviral, immunomodulatory, and antitumor properties by regulating the expression of hundreds of genes involved in crucial biological processes such as cell cycle progression, cell proliferation, and apoptosis. While the exact mode of action of IFN-β in MS is complex, and not yet fully understood, the effects in the periphery include inhibition of antigen presentation, and at the blood–brain barrier there is downregulation of adhesion molecules and decreased production of matrix metalloproteinases. This limits the entry of T cells into the CNS. Furthermore, IFN-β is linked with alterations in the generation of specific T-cell subtypes, causing a shift from T helper 1 to T helper 2 cells, creating an anti-inflammatory milieu. More recently, IFN-β has been shown to downregulate the T helper 17 cell subset, also an anti-inflammatory action. Several IFN-β products are available (all given by intramuscular injection) for treating relapsing-remitting MS, and clinical trials have shown that they reduce the rate of relapse, slow the appearance of new and enhancing lesions on MRI, and delay progression of disability.
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Fingolimod is a once-daily oral medication that was approved by the US Food and Drug Administration (FDA) in 2010 for the treatment of relapsing forms of MS. It is derived from myriocin, a metabolite of the fungus Isaria sinclairii. Fingolimod is believed to work by sequestering autoreactive T and B cells within lymph nodes, preventing their release into the bloodstream and subsequent migration into the CNS. Fingolimod, a structural analogue of sphingosine, is a negative modulator of the sphingosine-1-phosphate receptor, by inducing receptor internalization and degradation. The sphingosine-1-phosphate receptor is a member of the lysophospholipid receptor family, a group of G protein–coupled receptors important for lipid signaling. Lymphocytes migrate along a sphingosine-1-phosphate gradient to egress from lymph nodes. Blockade of the sphingosine receptor blocks this migration and the egress of the cells from lymph nodes.
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Rituximab is a monoclonal antibody, given intravenously, that targets the B-cell surface molecule CD20. This chimeric mouse/human IgG antibody binds CD20 and lyses B cells, primarily via complement-dependent mechanisms. Rituximab has been shown in phase 2 trials to reduce MRI contrast-enhancing lesions and to reduce frequency of relapses in MS. Despite encouraging clinical trials, the drug is not yet approved by the FDA in part because of ongoing development of fully humanized monoclonal anti-B-cell antibodies that are in development and are expected to have fewer side effects.
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Natalizumab is a humanized monoclonal antibody, given intravenously, which acts as an α4 integrin antagonist. α4β1 integrin, a protein on the surface of lymphocytes, interacts with vascular cell adhesion molecule 1 (VCAM1), which is expressed on the surface of vascular endothelial cells in the brain and spinal cord, mediating the adhesion and migration of lymphocytes as they cross the blood–brain barrier. Natalizumab thus blocks the binding of lymphocytes to endothelial receptors. It was approved by the FDA in 2004 for the treatment of relapsing forms of MS based on trials that showed reduced clinical relapses and decreased lesions by MRI. Natalizumab acts rapidly, and its benefits appear to persist. After its approval, however, the incidence of progressive multifocal encephalopathy (PML), caused by reactivation of latent JC virus infection, resulted in the drug’s voluntary removal from the market in 2005. Although natalizumab has since been reintroduced to the market given its strong efficacy and safety in most patients, a major focus of research has centered around monitoring JC virus reemergence and identifying patient attributes that put them at risk for this serious side effect.
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Alemtuzumab is a humanized monoclonal antibody against CD52, an antigen found on the surface of most B and T cells and monocytes. The antibody, administered intravenously, causes rapid complement-mediated lysis of almost all circulating lymphocytes by targeting this antigen. The impact is long-lasting, with time to recovery to the lower limit of normal circulating lymphocytes averaging 35 months. Alemtuzumab was first approved for treatment of B-cell chronic lymphocytic leukemia in 2001. Since that time it has been studied in a variety of autoimmune conditions. Numerous studies supporting the efficacy of alemtuzumab in MS have been published over the past few years, and studies comparing its efficacy with that of IFN are ongoing. However, there have been multiple reports of serious side effects as might be expected when depleting major components of the immune system.
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Daclizumab is a humanized monoclonal antibody, requiring intravenous administration, being evaluated for MS. Daclizumab targets the α subunit (CD25) of the interleukin-2 receptor found on regulatory and antigen-activated T cells. By targeting CD25, daclizumab interferes with expansion of activated T cells. It was introduced originally for prevention of rejection after organ transplantation.
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General Immunosuppressive Agents
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Teriflunomide is a once-daily oral medication that was approved by the FDA in 2012 for the treatment of relapsing forms of MS. It is the active metabolite of leflunomide, a previously released medication used to treat rheumatoid arthritis. Teriflunomide reversibly inhibits dihydroorotate dehydrogenase, a mitochondrial enzyme involved in pyrimidine synthesis required for DNA replication. The drug limits stimulated T- and B-cell activation, proliferation, and function in response to autoantigens. Slowly dividing or resting cells, which rely on the salvage pathway for pyrimidine synthesis, are relatively unaffected by teriflunomide.
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Azathioprine is a prodrug that generates mercaptopurine, which inhibits the amidophosphoribosyltransferase enzyme that is required for the synthesis of purines required for DNA synthesis. It most strongly affects proliferating cells, such as T and B cells, and thus exerts broad immunosuppressive effects. Azathioprine is effective in the treatment of several autoimmune disorders. Its full clinical effects occur after several months of administration, and, once improvement begins, it is maintained for as long as the drug is given, but symptoms often recur within a few months after the drug is discontinued. Azathioprine is often used in conjunction with corticosteroids (see below). Approximately one third of patients have mild dose-dependent side effects that may require dose reductions. The main side effect of azathioprine is bone marrow suppression, usually manifested as leukopenia, but anemia, thrombocytopenia, and bleeding may also occur.
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Dimethyl fumarate was first described in 1959 for the use in psoriasis. It was found subsequently to be effective for the treatment of several other immune-mediated dermatologic conditions. Dimethyl fumarate was approved in 2013 as a twice-daily oral medication for use in relapsing forms of MS. It is thought to activate the nuclear factor–like 2 (NFR2) antioxidant response pathway, the primary cellular defense against the cytotoxic effects of oxidative stress. Fumaric acid esters may decrease leukocyte passage through the blood–brain barrier and exert neuroprotective properties via the activation of antioxidative pathways. It may also suppress proinflammatory cytokine production or signaling pathways.
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Mitoxantrone is a synthetic antineoplastic anthracenedione approved in 1987 as a treatment for acute myeloid leukemia and in 1996 for hormone-refractory prostate cancer. Mitoxantrone, a topoisomerase II inhibitor, prevents the unwinding of DNA and thereby inhibits cell proliferation. Although it must be given intravenously, it is a small molecule able to cross the blood–brain barrier, where it inhibits dividing cells in the CNS and suppresses T-cell, B-cell, and monocyte proliferation and function. Its use is limited by cardiac toxicity.
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Methotrexate was developed in 1950 initially as a treatment for lymphoblastic leukemia. It is an antimetabolite and acts by inhibiting the metabolism of folic acid by binding to the active catalytic site of dihydrofolate reductase. Methotrexate interrupts the synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine, thereby interfering with DNA, RNA, and protein synthesis. Methotrexate has been studied as single drug and combination treatment for both MS and myasthenia gravis. Side effects are usually observed in the bone marrow and to a lesser extent in the skin and gastrointestinal mucosa.
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Mycophenolate is a semisynthetic molecule derived from the mold Penicillium glaucum. It is an immunosuppressive agent that acts by inhibiting purine synthesis and thereby antagonizes T- and B-cell responses. It is used as an adjunct in the treatment of MS for patients with breakthrough relapses while on injectable therapies.
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Cyclosporine, isolated from the fungus Tolypocladium inflatum, inhibits predominantly T-cell-dependent immune responses. It binds to the cytosolic protein, cyclophilin. The complex of cyclosporine and cyclophilin inhibits calcineurin (also known as protein phosphatase 3; Chapter 4), which is required for normal T-cell function. Cyclosporine is a general immunosuppressive agent. Most patients with myasthenia gravis improve several months after starting cyclosporine, and improvement is maintained as long as therapeutic doses are given. There is evidence that cyclosporine is also useful in the treatment of MS. In addition, cyclosporine has been investigated as a possible neuroprotective agent in conditions such as traumatic brain injury, and has been shown in animal experiments to reduce brain damage associated with injury. Renal toxicity and hypertension are important adverse reactions to cyclosporine.
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Corticosteroids were the first class of hormonal agents recognized to have immunosuppressive properties. These steroids are thought to interfere with the cell cycle of activated lymphocytes. In myasthenia gravis, marked improvement or complete relief of symptoms occurs in the vast majority of patients treated with prednisone, a synthetic corticosteroid, and some improvement occurs in most of the rest. The best responses occur in patients with recent onset of symptoms, but patients with chronic disease may also respond. The major disadvantages of chronic corticosteroid therapy are the side effects of weight gain, osteoporosis, diabetes, hair loss, and skin fragility (Chapter 10).
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Drugs Acting at the Neuromuscular Junction
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Pyridostigmine’s use in myasthenia gravis began in the 1930s. It acts as an acetylcholinesterase inhibitor, blocking the catabolism of ACh at the neuromuscular junction and thereby enhancing cholinergic transmission. Acetylcholinesterase inhibitors can result in dramatic improvement in some patients and certain muscle groups and little to none in others. Use of pyridostigmine alone rarely results in return to normal strength. Neostigmine is another acetylcholinesterase inhibitor often used in the treatment of myasthenia gravis. The doses of acetylcholinesterase inhibitors vary from day to day and even during the same day in response to infection, antibiotic use, menstruation, or emotional stress. Use of acetylcholinesterase inhibitors is associated with numerous prominent adverse effects based on the enhancement of cholinergic function in the autonomic nervous system and CNS (Chapter 9).