New Oral Agents for Multiple Sclerosis: A Healthcare Professional's Guide
Medically reviewed by Leigh Ann Anderson, PharmD. Last updated on June 17, 2022.
Intro: The Pathology of Multiple Sclerosis (MS)
You may not know that multiple sclerosis (MS), an autoimmune disease, is the leading cause of disability in young adults. There is no cure for multiple sclerosis (MS) and nerve damage can't be reversed, so early treatment is crucial.
Experts believe that MS begins as an inflammatory immune-mediated disorder leading the body's immune system to attack the protective myelin sheaths around nerves in the brain, spinal cord, and optic nerve. When the myelin is damaged and forms scar tissue -- also called sclerosis -- this disrupts the flow of nerve impulses, causing the symptoms of MS.
As noted, the nerve damage that occurs with MS is not reversible or curable. However, early treatment and lifestyle changes can positively affect a patient's quality of life. Most people with MS will live a normal life-span.
MS: Symptoms and Clinical Diagnosis
For diagnosis, the patient's history and physical exam are initially evaluated. Typical presenting symptoms include:
- limb sensations such as numbness and paresthesia
- motor weakness
- vision loss, eye pain, diplopia (double vision) or ocular movements
- gait and balance disruption
- Lhermitte sign
- sexual and bladder dysfunction.
The diagnosis of MS requires clinical findings of CNS lesions; in addition a magnetic resonance image (MRI) is often used.
The MRI, while not required, is the diagnostic test of choice to support the clinical findings. Gadolinium contrast enhancement of the MRI helps to gauge disease activity and inflammation.
Risk Factors for MS
Today, roughly 1 million people in the U.S. are living with MS (known as the prevalance), according to the National Multiple Sclerosis Society.
Younger people -- in the age range of 15 to 50 -- are most frequently diagnosed with MS. There is a wide range of risk factors:
- being a woman
- living further from the equator geographically
- vitamin D deficiency (possibly due to low sunlight exposure).
Women are three times more likely than men to develop this disorder. However, more studies are needed to confirm the risk of MS among different ethnic populations, although whites appear more at risk.
MS is more common in countries with temperate climates; for example, Canada, the northern U.S., New Zealand, southeastern Australia and Europe.
Progression of Multiple Sclerosis
Historically there have been 4 main types of MS:
- Relapsing-remitting MS (RRMS)
- Secondary-progressive MS (SPMS)
- Primary-progressive MS (PPMS)
- Progressive-relapsing MS (PRMS)
RRMS: About 80 to 85 percent of MS patients are initially diagnosed with RRMS. In RRMS, relapses of new or worsening symptoms can last from a few days to a few months and patients may remain in remission (recovery period with few or no symptoms) for months or even years.
SPMS: SPMS usually develops over time following RRMS; relapses can occur, but not remissions. Without treatment, approximately half of individuals with RRMS convert to SPMS within 10 years.
PPMS: In PPMS, there is no recovery period - symptoms slowly worsen with no distinct relapses or remissions.
PRMS: In PRMS, MS progresses with intermittent relapses, but no remissions.
As published in The Lancet Neurology, researchers have discovered a newly identified subtype of MS -- called myelocortical MS (MCMS) -- which features the loss of neurons but no damage to the brain's white matter. The new subtype shows that neuron loss and demyelination can occur independently in MS. Clinicians noted the need to develop more sensitive strategies for properly diagnosing and understanding the pathology of MCMS.
Treatment Options for MS
Treatment of MS revolves primarily around three goals:
- treatment of the acute attack
- prevention of future relapses
- treatment of symptoms such as bladder dysfunction or depression
Patients and clinicians should make treatment decisions considering: disease severity, drug safety and effectiveness, patient preference, convenience (oral, self-injectable, infusion), child-bearing status, and cost concerns of specialty medications.
After having these discussions, clinicians may initially recommend treatment of RRMS with a disease-modifying agent such as:
- injectable interferon beta-1a (Avonex), or other interferon beta-1a or 1b
- glatiramer (Copaxone, Glatopa)
- natalizumab (Tysabri)
- oral dimethyl fumarate (Tecfidera), diroximel fumarate (Vumerity), or monomethyl fumarate (Bafiertam)
- oral teriflunomide (Aubagio)
- intravenous ocrelizumab (Ocrevus)
- subcutaneous ofatumumab (Kesimpta)
- oral fingolimod (Gilenya, Tascendo ODT)
Disease modifying drugs work by:
- slowing the neurologic disease process in MS, reducing the frequency of attacks, and decreasing the severity of the attack.
- suppressing the immune system and helping to reduce the accumulation of CNS lesions and destruction of the myelin sheaths.
In patients with a definitive diagnosis of MS, most neurologists recommend treatment as soon as possible. Disease modifying drugs can slow down the rate of MS progression, and may best be started at or near the initial diagnosis. However, many of the disease-modifying therapies used to treat MS carry significant health risks.
For patients with RRMS whose symptoms are refractory to initial therapy, switching to another disease-modifying agent is recommended.
The Oral Agents for MS
Oral agents provide novel disease-modifying treatment options for patients with relapsing-remitting MS and secondary progressive MS.
Although interferon beta or Copaxone are often selected as the first drug of choice, injections may be inconvenient for patients.
- Gilenya (fingolimod) was the first FDA-approved oral treatment for MS in 2010. The FDA also cleared Gilenya in 2018 as the first approved drug to treat MS in pediatric patients 10 years and older.
- In Dec. 2021, Tascenso ODT, a 0.25 mg orally disintegrating formulation of fingolimod was FDA-approved. It is also used in pediatric patients 10 years of age and older and weighing less than or equal to 40 kg. The approval of Tascenso ODT is based on clinical studies for Gilenya.
Since Gilenya, other oral therapies have become available, too:
- Aubagio (teriflunomide) in 2012
- Zeposia (ozanimod) in 2020
- Ponvory (ponesimod) in 2021
A brief review of clinical data for these newer agents are outlined on the following slides.
Clinical Trial Data: Tecfidera
Tecfidera (dimethyl fumarate or BG-12) has been shown in clinical trials to have positive benefits in MS. The exact mechanism of action is unknown, but may be due to activation of the nuclear factor-like 2 (Nrf2) pathway leading to a reduction in oxidative stress. This action is thought to protect nerve cells from damage and inflammation.
In the pivotal CONFIRM and DEFINE clinical trials, oral dimethyl fumarate significantly lowered relapse rates, the number of new brain lesions on MRI, and in one study, helped to delay physical disability progression.
Over a 2-year study, 27% of those taking dimethyl fumarate experienced relapse (46% placebo). In addition, 38% fewer people had disability progression compared to placebo, and from 72-90% of MRI brain lesions slowed down in development.
Tecfidera: Dosing and Side Efects
Tecfidera comes in a delayed-release capsule dose form in 120-mg and 240-mg strengths. The initial adult dose is 120 mg two times a day for 7 days, followed by 240 mg two times daily thereafter. Patients may want to take the dose with food to reduce flushing. Alternatively, administration of a non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to Tecfidera dosing may reduce the incidence or severity of flushing. The capsule should not be opened, sprinkled on food, crushed or chewed.
Tecfidera is relatively tolerable from a side effect standpoint; common but possibly transient side effects include flushing (redness, itching and rash), diarrhea and nausea.
A CBC is performed at baseline, after 6 months, and every 6 to 12 months thereafter to monitor for lymphocytopenia. Monitor liver enzymes at the start of treatment and as clinically indicated; stop treatment if liver injury.
In April 2020, Bafiertam (monomethyl fumarate) was approved by the FDA as a bioequivalent alternative to Tecfidera (dimethyl fumarate).
In October 2019 the FDA approved Vumerity (diroximel fumarate) capsules from Biogen / Alkermes to treat relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease. Vumerity is an inactive prodrug that is converted into its active form, monomethyl fumarate (MMF), and may cause less stomach irritation than Tecfidera.
Tecfidera: Important Warnings
Serious allergic reactions can occur at first dose or any time during treatment. Stop Tecfidera permanently if serious allergic reactions such as anaphylaxis and angioedema occur. Also, consider stopping Tecfidera if lymphocyte counts are less than 0.5 x 109/L for longer than six months. If a serious infection develops, the provider may withhold treatment until resolved.
Progressive multifocal leukoencephalopathy (PML) is a rare brain infection caused by the John Cunningham (JC) virus. Drugs that weaken the immune system, such as many drugs used to treat patients with MS, can elevate the risk of PML. PML usually leads to death or severe disability.
A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who received Tecfidera for 4 years while enrolled in a clinical trial. Typical symptoms associated with PML can progress over days to weeks and include:
- loss of coordination or clumsiness
- loss of language ability, speaking or understanding speech (aphasia/dysphasia)
- memory loss (dementia), confusion
- vision problems, blurred vision
- weakness of the legs and arms that progresses; may be unilateral
Patients should be monitored for signs/symptoms of hypersensitivity, infections, and/or progressive multifocal leukoencephalopathy (PML) with Tecfidera. At the first sign or symptom suggestive of PML, withhold the MS drug and evaluate the patient. In addition to Tecfidera, PML could also be a risk with other MS drugs, for example: natalizumab (Tysabri), fingolimod (Gilenya), ocrelizumab (Ocrevus), and rituximab (Rituxan).
Clinical Trial Data: Aubagio
Aubagio's (terifluamide) proposed mechanism in MS is via inhibition of pyrimidine synthesis leading to decreased inflammation, reduced white blood cells in the CNS, and nerve protection in MS.
In the TEMSO trial, Aubagio significantly reduced:
- Annualized relapse rates at both doses of 7 or 14 mg once a day (0.54 for placebo vs. 0.37 for teriflunomide).
- Disability progression at the higher 14 mg dose (27.3% with placebo and 20.2% with teriflunomide).
- MRI evidence of disease activity, as compared with placebo.
In the study there was a high drop-out rate for all active and placebo groups, ranging from 25% to 29% of participants.
Aubagio: Dosing and Side Effects
The oral dose of Aubagio is 7 or 14 mg once a day with or without food. Aubagio may cause severe liver injury, and contains a boxed warning contraindicating use in patients with severe hepatic impairment.
LFTs and bilirubin should be measured within 6 months of treatment initiation and ALTs should be monitored monthly for the first 6 months after treatment begins. If liver injury is suspected, patients should undergo accelerated drug removal outlined in the package insert. Patients should also receive all needed vaccinations prior to treatment.
The most common adverse effects include:
- elevated alanine aminotransferase (ALT) levels
Aubagio: Other Important Warnings
- Aubagio labeling also has a boxed warning for teratogenicity, and it is contraindicated for use in pregnant women and females of reproductive potential not using effective contraception.
- Aubagio is found in a man's semen and can remain in the blood serum for up to 2 years. Therefore, men or women using Aubagio who plan to conceive a child must first contact their physician to undergo accelerated drug elimination using cholestyramine or activated charcoal powder, which is outlined in the package insert.
- Aubagio labeling also contains a boxed warning for hepatotoxicity and is contraindicated in severe liver disease.
- Measure transaminase and bilirubin levels within 6 months before starting Aubagio and monitor ALT levels at least monthly for six months. If drug induced liver injury is suspected, discontinue Aubagio and start the accelerated elimination procedure.
- Aubagio should also be avoided by patients taking leflunomide (Arava), a similar drug used in rheumatoid arthritis, due to possible additive liver toxicity.
- Drug interactions should be monitored.
Clinical Trial Data: Gilenya
The immunosuppressant Gilenya (fingolimod) modulates the sphingosine-1-phosphate receptor and reduces lymphocyte migration into the CNS. This proposed mechanism reduces inflammation and damage to nerve cells.
Gilenya has been shown to cut relapses by 52% when compared to interferon beta-1a (Avonex) in a one-year study. In addition, at one year, 13% more patients on Gilenya were relapse-free when compared to interferon beta-1a. Gilenya has also been shown to slow disease progression and the number of brain lesions on an MRI.
Data from a two-year study showed a significant 54% reduction in relapse rate compared with placebo and a 30% reduction in risk of disability progression among Gilenya patients at three-month follow-up visit, compared to placebo.
The approval of Tascenso ODT (fingolimod) 0.25 mg, an orally disintegrating dosage form, was based on clinical studies for Gilenya.
In March 2020, the FDA approved Zeposia (ozanimod) capsules for the treatment of elapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Like Gilenya, Zeposia is classified as a sphingosine-1-phosphate (S1P) receptor modulator, but at initiation requires no genetic test and no label-based first-dose observation.
Gilenya: Dosing and Side Effects
In patients 10 years of age and older weighing more than 40 kg, Gilenya is dosed as a 0.5 mg capsule once a day; higher doses do not offer additional benefit but can worsen side effects. It can be used as a first-line agent.
In children 10 years of age and older who weigh less than or equal to 40 kg, the recommended dosage of Gilenya is 0.25 mg orally once daily. Likewise, the orally disintegrating form of fingolimid, Tascenso ODT, is dosed at 0.25 mg orally once a day for children 10 years of age and older weighing 40 kg or less.
Patients with hepatic impairment should be monitored closely. Common side effects with fingolimod may include:
- elevated liver enzymes
- back pain
- abdominal pain
- pain in extremity
Other serious side effects have included macular edema, heart rhythm abnormalities, syncope, skin and breast cancers, breathing problems, progressive multifocal leukoencephalopathy (PML), liver injury, Posterior Reversible Encephalopathy Syndrome (PRES), fetal risk, and other serious infections.
First dose response bradycardia:
- Gilenya and Tascenso ODT prescribing information states that patients should be monitored with a heart ECG before and 6 hours after the first dose of Gilenya, in addition to hourly measurements of blood pressure and heart rate.
- Additional monitoring may be needed and is outlined in the product label.
- If a patient stops treatment for more than 14 days after their first month of treatment, they will need to repeat this observation.
These products should not be used in patients who in the last 6 months experienced myocardial infarction (heart attack), certain levels of AV block, baseline QTc interval ≥ 500 msec, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization or Class III/IV heart failure.
Gilenya: Important Warnings
- After the first dose, fingolimod (Gilenya / Tascenso ODT) has caused symptomatic bradycardia, therefore first dose monitoring is required.
- Do not start fingolimod in patients with active infections. Obtain baseline CBC and monitor for infections during and for 2 months after discontinuation.
- Obtain baseline liver function tests before treatment. Stop drug if severe liver injury occurs.
- Withhold treatment if suspected progressive multifocal leukoencephalopathy (PML).
- Monitor for macular edema with a fundus exam before and 3 to 4 months after starting treatment.
- Stop treatment if suspected posterior reversible encephalopathy syndrome (PRES).
- Women of childbearing potential should use effective contraception during and for 2 months after stopping treatment.
- Monitor blood pressure during treatment.
- Monitor for respiratory effects if indicated
- Monitor for severe disability or relapse during or following discontinuation, obtain imaging and treat as needed.
Place in MS Therapy: Disease Modifying Agents
The choice of initial treatment in MS depends upon patient choices and their level of disease activity: convenience, safety, effectiveness and cost or coverage all come into play.
- Interferon beta and glatiramer (Copaxone), although self-injected, are often selected first-line based on longer-term history and a greater level of drug safety.
- Oral dimethyl fumarate (Tecfidera) or teriflunomide (Aubagio) offer convenience. There may be a preference to Tecfidera due to a better safety profile over Aubagio or fingolimod (Gilenya).
- Mayzent (siponimod) and Mavenclad (cladribine) were approved in 2019 and are the first agents approved for active secondary progressive multiple sclerosis (SPMS), in adults. They are also used in relapsing disease.
- Natalizumab (Tysabri) infusion may be an appropriate choice for patients with more severe disease.
- If a patient has a poor response or cannot tolerate one therapy, it's reasonable to try another.
Tysabri and Lemtrada: IV Agents For Refractory MS Patients
Tysabri is given every 4 weeks by IV infusion and is linked with a rare, often fatal brain disease known as progressive multifocal leukoencephalopathy (PML), as with many other MS drugs. This agent has a boxed warning describing this serious side effect.
- autoimmune conditions
- infusion reactions
- the risk of cancer - including thyroid cancer, melanoma, and lymphoproliferative disorders. Perform baseline and yearly skin exams.
Ocrevus is First Drug Approved for PPMS
The much anticipated multiple sclerosis (MS) treatment Ocrevus (ocrelizumab) was FDA-approved in March of 2017. Ocrevus is a humanized monoclonal antibody designed to selectively target CD20-positive B cells.
Ocrevus was unique; it's the first treatment approved for primary progressive multiple sclerosis (PPMS), plus it’s also indicated for relapsing multiple sclerosis (RMS).
In both forms of MS, Phase III studies demonstrated that Ocrevus slowed disability progression and reduce signs of disease activity in the brain (by looking for MRI lesions). In the RMS group, relapses per year were reduced by nearly 50%. Mild to moderate side effects include infusion reactions and upper respiratory tract infections. Ocrevus may also be linked with progressive multifocal leukoencephalopathy (PML).
- Initial dosing: 300 mg IV infusion, followed two weeks later by a second 300 mg IV infusion. Duration of each infusion: 2.5 hours or longer
- Subsequent dosing: single 600 mg IV infusion every 6 months. Duration of infusion: 3.5 hours or longer
- Observe the patient for at least one hour after the completion of the infusion.
- A shorter 2-hour dosing time was approved in Dec. 2020 for subsequent dosing (600 mg IV infusion), if there has been no prior serious infusion reaction with any previous Ocrevus infusion.
Latest Options for Secondary Progressive MS (SPMS)
Secondary Progressive MS (SPMS) is a level of MS that occurs after relapsing remitting MS, the first stage. With SPMS, disability steadily gets worse. Several new oral options for SPMS have been approved since 2019.
Mayzent - In March 2019, the FDA approved Mayzent (siponimod) tablets, a sphingosine-1-phosphate (S1P) receptor modulator from Novartis. Mayzent is approved for clinically isolated syndrome (CIS), relapsing remitting disease, and active secondary progressive MS (SPMS). Adverse effects in studies included headache, high blood pressure and elevated liver function tests.
Mavenclad - Mavenclad (cladribine), from EMD Serono is a purine antimetabolite and was cleared in March 2019 for both both relapsing-remitting disease and active secondary progressive disease. Mavenclad, an oral tablet, is not recommended for MS patients with clinically isolated syndrome or as a first-line agent. In studies, common adverse events were upper respiratory tract infections, headache and lymphopenia. In addition, Mavenclad should not be used in patients with an active cancer.
Zeposia - In March 2020, an oral once-daily S1P receptor modulator, Zeposia (ozanimod) from Bristol-Myers Squibb was approved. Zeposia binds with high affinity to S1P receptors 1 and 5. Zeposia capsules are used to treat relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. Side effects (in at least 4% of patients) can include upper respiratory infection, liver enzyme elevation, low blood pressure when standing, urinary tract infection, back pain, and high blood pressure. In May 2021, Zeposia was also approved to treat ulcerative colitis.
Ponvory - In March 2021, the FDA approved Janssen’s once-daily oral Ponvory (ponesimod), also for treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing remitting disease, and active secondary progressive disease, in adults. Ponvory is a S1P1 modulator that binds with high affinity to S1P receptor 1. Common side effects (in at least 10% of patients) may include upper respiratory tract infection, liver enzyme elevation, and high blood pressure.
Zinbryta: Withdrawn from Worldwide Use in 2018
In March 2018 Biogen and AbbVie announced the voluntary worldwide withdrawal of Zinbryta for relapsing multiple sclerosis. The companies stated that "characterizing the complex and evolving benefit-risk profile of Zinbryta will not be possible going forward given the limited number of patients being treated." Safety issues, such as encephalitis, meningoencephalitis, and liver toxicity have been factors involved in it's withdrawal.
It had been on the market for only two years. In May 2016, the FDA originally approved Zinbryta (daclizumab) for the treatment of adults with relapsing forms of multiple sclerosis (MS).
Zinbryta is a monoclonal antibody and a long-acting injection that is self-administered by the patient monthly. Clinically, it was used after an MS patient had tried at least 2 other treatments without success, and was accompanied by a strict REMS safety program.
Treatment of Acute MS Symptoms
When MS symptoms flare up, added treatments can further ease the burden. For example:
- Injectable corticosteroids (prednisone, methylprednisolone) may be used to reduce inflammation
- Plasma exchange (plasmapheresis) has been used to treat severe symptoms in patients who do not respond to corticosteroids
- Ampyra (dalfampridine) is an oral MS medication that inhibits potassium channels to increase action potentials in demyelinated axons. Ampyra has been shown to improve weakness and walking in those with MS.
Other symptoms of MS - from anxiety to bladder control to tremors - may be treated with various agents specific for those syndromes.
Does Medical Marijuana Ease MS Symptoms?
According to the American Academy of Neurology (AAN), they do not support the use of, nor any assertion of therapeutic benefits of, cannabis products as medicines for neurologic disorders in the absence of sufficient scientific peer-reviewed research to determine their safety and specific efficacy.
Spasticity is a painful symptom for MS patients, mimicking a charley horse muscle spasm. Some studies have shown effectiveness for spasticity, but further research is needed. Evidence for an effect, or lack of effect, is outlined in this systematic review as published by AAN.
- There is strong evidence that oral cannabis extract (OCE) pills made from pure cannabidiol (CBD) can help lessen patients’ reported spasticity symptoms short-term. Oral cannabis extract (OCE) is a pill made of either pure CBD or a combination of CBD and THC.
- There is strong evidence that OCE can help lessen central pain (feelings of painful burning, pins and needles, and numbness).
- Other study results for a moderate, weak or unknown effect on MS spasticity, bladder problems, and tremor are outlined in the document.
- There is not enough evidence to show if smoked cannabis is safe or helpful for pain related to spasticity
Recommendations for Lifestyle Changes
Healthcare providers should encourage a healthy living style for patients with MS. In fact, certain behaviors can trigger MS symptoms, and patients should learn to manage or avoid these triggers.
- Avoid extreme heat or cold; cool down regularly when exercising.
- Don't smoke and avoid second-hand smoke.
- Encourage patients to enjoy life and reduce stress.
Other actions can boost a patient's quality of life and make for a more engaged patient.
- Educate patients about their various medications.
- Encourage regular exercise.
- Find emotional support.
- Eat a healthy, balanced diet.
- Attend their rehabilitation therapy regularly.
Patient Resources for MS
If patients are interested in joining a clinical trial, health care providers can refer patients to Clinicaltrials.gov., a comprehensive listing of federally and privately supported clinical trials.
The Multiple Sclerosis Association of America maintains a website with easy-to-read patient resources. The National Institute of Health (NIH) also has information on research studies and other MS facts.
Patients may also consider joining the Drugs.com Multiple Sclerosis Support Group to ask questions, voice concerns and share experiences with other MS patients. A regular update of MS health news is also provided.
Finished: New Oral Agents for Multiple Sclerosis: A Healthcare Professional's Guide
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- Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis. Neurology Apr 2018, 90 (17) 777-788; DOI: 10.1212/WNL.0000000000005347.
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- Progressive Multifocal Leukoencephalopathy (PML). Multiple Sclerosis Society of Canada. Accessed April 16, 2020 at https://mssociety.ca/managing-ms/treatments/medications/disease-modifying-therapies-dmts/progressive-multifocal-leukoencephalopathy-pml
- Multiple Sclerosis Association of America (MSAA). MS Overview. Sept. 2015. https://mymsaa.org/ms-information/overview/process-symptoms/
- National Multiple Sclerosis Society. Medical Marijuana (Cannabis). Accessed April 16, 2020 at https://www.nationalmssociety.org/Treating-MS/Complementary-Alternative-Medicines/Marijuana#section-1
- Koppel, BS, Brust J, Fife T, et al. Systematic review: Efficacy and safety of medical marijuana in selected neurologic disorders. Neurology 2014;82:1556-63. DOI: https://doi.org/10.1212/WNL.0000000000000363
- American Academy of Neurology (AAN). Medical Marijuana in Certain Neurological Disorders. Summary of Systematic Review for patients and their families. Accessed June 17, 2022.
- Olek M, Mowry E (authors). Up To Date. Initial disease-modifying therapy for relapsing-remitting multiple sclerosis in adults. Updated: Feb 01, 2022. https://www.uptodate.com/contents/treatment-of-relapsing-remitting-multiple-sclerosis-in-adults
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