Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system (CNS). Several therapies for it exist, although there is no known cure.

The most common initial course of the disease is the relapsing-remitting subtype, which is characterized by unpredictable attacks (relapses) followed by periods of relative remission with no new signs of disease activity. After some years, many of the people who have this subtype begin to experience neurologic decline without acute relapses. When this happens it is called secondary progressive multiple sclerosis. Other, less common, courses of the disease are the primary progressive (decline from the beginning without attacks) and the progressive-relapsing (steady neurologic decline and superimposed attacks). Different therapies are used for patients experiencing acute attacks, for patients who have the relapsing-remitting subtype, for patients who have the progressive subtypes, for patients without a diagnosis of MS who have a demyelinating event, and for managing the various consequences of MS.

The primary aims of therapy are returning function after an attack, preventing new attacks, and preventing disability. As with any medical treatment, medications used in the management of MS may have several adverse effects, and many possible therapies are still under investigation. At the same time different alternative treatments are pursued by many people, despite the fact that there is little supporting, comparable, replicated scientific study. Stem cell therapy is being studied.

This article focuses on therapies for standard MS; borderline forms of MS have particular treatments that are excluded.

Acute attacks

Administration of high doses of intravenous corticosteroids, such as methylprednisolone, is the routine therapy for acute relapses. This is administered over a period of three to five days, and has a well-established efficacy in promoting a faster recovery from disability after an attack. There is however insufficient evidence to indicate any significant impact on long-term disability of corticosteroid treatments. Steroids administered orally have a similar effectiveness and safety profile at treating MS symptoms as intravenous treatment. Consequences of severe attacks which do not respond to corticosteroids might be treated by plasmapheresis.

High dosage intravenous corticosteroids or plasmapheresis, designated for individuals not responding to steroids, make up the majority of acute management; Symptomatic management: Individuals with multiple sclerosis (MS) experience a range of symptoms, such as cognitive decline, discomfort, exhaustion, urinary problems, and stiffness. Both pharmaceutical and non-pharmacological approaches are used to address these symptoms. The management of MS symptoms requires a comprehensive and interdisciplinary approach from patients; illness-modifying therapies (DMTs): These medications act as moderators of illness, lowering the risk of relapses and slowing the disease's course.Ramya, T. M., Habib, S., Sangaraju, S. L., Daniela, Y., & Grandes, X. A. (2022). Multiple sclerosis: Therapeutic strategies on the horizon. Cureus, 14(5) https://doi.org/10.3389/fneur.2022.824926

Disease-modifying treatments

, several disease-modifying treatments have been approved by regulatory agencies of different countries, including the US Food and Drug Administration (FDA), the European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA) of the Japanese Ministry of Health, Labour and Welfare.

Medications approved by the FDA include: interferons beta-1a and beta-1b; monoclonal antibodies: natalizumab, alemtuzumab, ocrelizumab, ofatumumab, and ublituximab; and immunomodulators: glatiramer acetate, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, and diroximel fumarate. Siponimod was approved in March 2019. Cladribine was approved in March 2019. Ozanimod was approved in March 2020.

Daclizumab, that was once approved, was later withdrawn.

Medications In 1993, interferon beta-1b was the first drug to ever be approved for MS, being soon followed by interferon beta-1a and glatiramer acetate.

Interferon beta-1a is injected either weekly (intramuscular injection) or three times a week (subcutaneous injection) depending on commercial formulations, while interferon beta-1b is injected subcutaneously every second day. In 2014, a pegylated form of interferon beta-1a was introduced with the brand name Plegridy, which is available as a subcutaneous injection.Plegridy Prescribing Information Biogen Idec Inc. Plegridy Prescribing Information (August 2014). Retrieved on 31 October 2014 This peginterferon beta 1-a attaches polyethylene glycol to the interferon molecules allowing longer lasting biological effects in the body while decreasing the frequency of administration to once every two weeks.Peginterferon beta-1a description National Multiple Sclerosis Society (15 August 2014). Retrieved on 27 October 2014 Interferon beta balances the expression of pro- and anti-inflammatory agents in the brain, and reduces the number of inflammatory cells that cross the blood–brain barrier. Overall, therapy with interferon beta leads to a reduction of neuron inflammation. Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival.

Glatiramer acetate is a mixture of random polymers of four amino acids which is antigenically similar to the myelin basic protein, a component of the myelin sheath of nerves with which it competes for presentation to T cells . It is injected subcutaneously on a daily basis.

Mitoxantrone is an immunosuppressant also used in cancer chemotherapy which was approved for MS in the year 2000; whereas natalizumab is a monoclonal antibody that was initially approved in 2004. Both are given by intravenous infusion at monthly intervals in the case of natalizumab and every three months in the case of mitoxantrone.

In 2010, fingolimod, a sphingosine-1-phosphate receptor modulator, became the first oral drug approved by the FDA, being followed in 2012 by teriflunomide, a drug that inhibits the synthesis of pyrimidine and disrupts the interaction of T cells with antigen presenting cell. Fingolimod and teriflunomide are taken through a daily single dose. In 2013 one further oral drug, dimethyl fumarate -or BG12- (which is an improved version of fumaric acid, an already existing drug), was approved by the FDA.

Another oral drug, cladribine, was approved in Russia and Australia in 2010. Its application was rejected by the FDA and EMEA in 2011, due to safety concerns. This led the pharmaceutical to discontinue commercialization and withdraw all marketing applications.

In March 2017, ocrelizumab was approved in the United States for the treatment of primary progressive multiple sclerosis in adults. It is also used in adults for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Ocrelizumab was approved for use in the European Union in January 2018.

In 2019, siponimod and cladribine were approved in the United States for the treatment of secondary progressive multiple sclerosis. Siponimod was approved for use in the European Union in January 2020, for the treatment of adults with secondary progressive multiple sclerosis. Cladribine was approved for use in the European Union in August 2017, for the treatment of adults with relapsing forms of multiple sclerosis.

In October 2019, diroximel fumarate (Vumerity) was approved for medical use in the United States.

In March 2020, ozanimod (Zeposia) was approved in the United States for the treatment of relapsing multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

In April 2020, monomethyl fumarate (Bafiertam) was approved in the United States for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

Ponesimod (Ponvory) was approved for medical use in the United States in March 2021.

Ublituximab (Briumvi) was approved for medical use in the United States in December 2022.

Side effects

Both the interferons and glatiramer acetate are available only in injectable forms, and both can cause skin reactions at the injection site, specially with subcutaneous administration. Skin reactions vary greatly in their clinical presentation and may include bruising, erythema, pain, pruritus, irritation, swelling and in the most extreme cases cutaneous necrosis. They usually appear within the first month of treatment albeit their frequence and importance diminish after six months of use. Mild skin reactions usually do not impede treatment whereas necroses appear in around 5% of patients and lead to the discontinuation of the therapy. Also over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop.

Interferons, a subclass of cytokines, are produced in the body during illnesses such as influenza in order to help fight the infection. They are responsible of many of the symptoms of influenza infections, including fever, muscle aches, fatigue, and headaches. Many patients report influenza-like symptoms hours after taking interferon-beta that usually improve within 24 hours, being such symptoms related to the temporary increase of cytokines. This reaction tends to disappear after 3 months of treatment and its symptoms can be treated with over-the-counter nonsteroidal anti-inflammatory drugs, such as ibuprofen, that reduce fever and pain. Another common transient secondary effect with interferon-beta is a functional deterioration of already existing symptoms of the disease. Such deterioration is similar to the one produced in MS patients due to heat, fever or stress (Uhthoff's phenomenon), usually appears within 24 hours of treatment, is more common in the initial months of treatment, and may last several days. A symptom specially sensitive to worsening is spasticity. Interferon-beta can also reduce numbers of white blood cells (leukopenia), lymphocytes (lymphopenia) and neutrophils (neutropenia), as well as affect liver function. In most cases these effects are non-dangerous and reversible after cessation or reduction of treatment. Nevertheless, recommendation is that all patients should be monitored through laboratory blood analyses, including liver function tests, to ensure safe use of interferons.

Glatiramer acetate is generally well tolerated. The most common secondary effect with glatiramer acetate after skin problem is a post-injection reaction manifested by flushing, chest tightness, heart palpitations, breathlessness, and anxiety, which usually lasts less than thirty minutes and does not require additional treatment.

Mitoxantrone therapy may be associated with immunosuppressive effects and liver damage; however its most dangerous side effect is its dose-related cardiac toxicity. Careful adherence to the administration and monitoring guidelines is therefore essential; this includes obtaining an echocardiogram and a complete blood count before treatment to decide whether the therapy is suitable for the patient or the risks are too great. It is recommended that mitoxantrone be discontinued at the first signs of heart damage, infection or liver dysfunction during therapy. Heart problems (mainly systolic dysfunction) appear in over 10% of patients, while leukemia prevalence is 0.8%.