Using Disease Modifying Agents

Multiple Sclerosis (MS) treatment has two main aspects: managing the underlying disease to slow the progression of the disease and treating the acute attacks and symptoms. Immunomodulatory therapy is used to treat the underlying immune disorder, while various therapies aim to relieve acute flares. Immunosuppressive therapies have positive clinical effects, but they only slow the course of the disease and their use is dangerous to the patient’s overall health beyond a year or two.

There are different types of MS, which is important to acknowledge as currently available treatments are very specific to those various types:

  • Secondary progressive MS (SPMS) initially presents as relapsing-remitting but is later characterized by a steady deterioration in function and fewer acute flares. This type of MS affects 80% of patients with relapsing-remitting MS and is responsible for the most significant neurologic disabilities. Most disease-modifying agents for MS have been approved for use only in relapsing forms of MS or SPMS1.
  • Primary progressive MS (PPMS) presents with a steady decline in function from the onset of the disease and no acute attacks; it affects 10% of patients.
  • Progressive relapsing MS (PRMS) has a steady progressive course with occasional acute flares. Treating the progressive forms of MS is more difficult than treating the relapsing forms. 
  • Clinically isolated syndrome (CIS) is characterized by a single episode, sometimes two, of neurologic symptoms. Treating CIS is not standard, but new studies suggest that teriflunomide  (Aubagio) may delay its conversion to MS2.

Disease-Modifying Agents

Disease-modifying agents slow the progression of the disease, reduce accumulation of lesions in the brain and spinal cord as measured by MRI, and also reduce acute attacks. Choosing the appropriate regimen should take into account: lifestyle, disease stage, tolerance, anticipated adverse effects, and cost.

Interferons: The exact mechanism of action is unknown, but they inhibit the pro-inflammatory cascade including IFN-γ, which is believed to be the major cytokine involved in the autoimmune pathophysiology of MS. They should be used with caution in patients with uncontrolled depression, for whom glatiramer acetate (Copaxone) may be considered.

Interferon beta-1b (Betaseron, Extavia): It was the first medication approved by the FDA for MS treatment in 1993. It has shown efficacy specifically for patients with relapsing-remitting forms of MS who have had a first clinical episode and also have MRI features. In studies, Betaseron reduced the frequency and severity of the acute inflammatory component of MS, reduced progression of the disease, delaying time to wheelchair-bound by one year3, and slowed the accumulation of MRI lesions compared to placebo4. Benefits of Betaseron have not been shown in patients without relapses. Adverse effects include flu-like symptoms, elevated liver enzymes, and injection-site reactions. Co-administer with analgesics or antipyretics for flu-like symptoms. Dose is 0.0625mg self-administered SQ every other day.

Interferon beta-1a (Avonex, Rebif): This decreases the annual exacerbations rate, decreases disease progression, and reduces lesions’ volume and number on MRI compared to placebo5. Rebif is a subcutaneous interferon beta-1a associated with fewer flu-like symptoms. Other adverse effects include hepatic and hematologic complications, which are are usually asymptomatic and did not warrant discontinuation of treatment during clinical trials. Recommended dosage for IM Avonex is 30mcg per week, and can be titrated up from 7.5mcg per week to avoid flu-like symptoms. Rebif is available in a monthly pack of 22υg and 44υg doses as well as in a titration pack.

Rebidose: This subcutaneous single-use auto injector of interferon beta-1a (Rebif) was approved by the FDA in January 2013 for patients with relapsing forms of MS6. It should be prescribed to patients who are still competent enough to use it on their own despite their neurologic deficits. Rebidose was manufactured by Serono and Pfizer and is available in a monthly pack of 22υg and 44υg doses as well as in a titration pack.

Fingolimod (Gilenya): This is the first oral therapy approved to reduce the frequency of acute exacerbations and to delay physical disability for patients with MS7. The exact mechanism of action is unknown, but it modulates a subset of G-protein receptors, mediating the effects of lysophospholipids. This leads to lymphocyte sequestration in the lymph nodes and reduces their migration in the nervous system. Fingolimod is associated with bradycardia and prolonged QT syndrome. A baseline EKG should be obtained prior to starting treatment, and it should be administered in a setting allowing management of symptomatic bradycardia should it occur. Recommended dosage is 0.5mg per day.

Teriflunomide (Aubagio): This an oral pyrimidine synthesis inhibitor that decreases activation of T- and B- cell activation and their response to autoantigens. It has been shown to delay onset of disease, improve neurologic function, and significantly reduce the annual relapse rates for MS patients8. Black box warnings include hepatotoxicity and teratogenicity. Severe hepatic injury requires accelerated elimination with activated charcoal or cholestyramine. Teriflunomide is associated with a long list of adverse effects, notably peripheral neuropathy, renal failure, electrolyte imbalance, and interstitial lung disease. Recommended dosage is 7 or 14mg tablets per day.

Dimethyl fumarate (Tecfidera) oral: This is an oral Nrf2 pathway activator, an antioxidant response pathway acting as cellular defense against oxidative stress. Dimethyl fumarate reduces the annual relapse rate, slows disability progression, and reduces MRI lesions. Recommended dosage is 120mg by mouth twice a day for seven days and then a maintenance dose of 240mg by mouth twice a day.

Glatiramer acetate (Copaxone) : This is a polypeptide involved in immune process modification in the pathogenesis of MS. It has been shown to decrease the acute exacerbation rate by 29% in patients with SPMS and is approved to reduce their frequency. However, it did not show convincing changes in MRI lesions and thus is not currently approved by the FDA to slow disease progression. Recommended dosage is 20mg per day SQ1.

Natalizumab (Tysabri): This monoclonal antibody binds to α-4 integrin and inhibits  binding to its receptors. This monotherapy delays physical disability and decreases frequency of acute attacks. Natalizumab is associated with progressive multifocal leukoencephalopathy and is only available via a restricted prescribing program called TOUCH. Standard dose for the IV infusion is 300mg over one hour every four weeks9.

Methotrexate: This is an immunomodulator used for rheumatoid arthritis that has been shown to delay impairment of upper extremity function in MS. Recommended dosage is 20mg SQ weekly10.

Treatments for Aggressive MS

Cyclophosphamide (Cytoxan): Has been found to be the most effective treatment for aggressive MS in patients younger than 40. High-dose cyclophosphamide has been used for induction therapy to decrease relapses, disease progression, and MRI lesions in aggressive MS11. Adverse effects include leukemia, lymphoma, and hemorrhagic cystitis. It is a teratogenic drug that is also associated with a risk of developing bladder cancer. Induction dose is 200mg/Kg IV infusion over four days followed by glatiramer acetate as maintenance therapy. The outpatient option is a pulse therapy that consists of administering 1gm IV methylprednisolone followed by 800mg/m² IV cyclophosphamide. The following doses should be titrated to the patient’s white blood cell count, and the maximum dose is 1,600mg/m².

Mitoxantrone (Novantrone): Mitoxantrone is a chemotherapeutic agent approved for reducing neurologic disability and/or the frequency of clinical relapses in patients with SPMS but is also approved for PRMS, or worsening RRMS. Mitoxantrone should be considered for patients with aggressive MS who have failed other treatments. Its use is limited by the risk of cardiotoxicity, which is not linked to cardiovascular risk factors, as well as the risk of developing therapy-related Acute Myeloid Leukemia (AML) for cancer patients. Mitoxantrone does not affect MRI lesions. Adverse cardiac effects include systolic dysfunction and heart failure; therefore patients should have their left ventricular ejection fraction evaluated prior to initiating therapy. Recommended dosage is 12mg/m² IV every three months12; the maximum cumulative dose is 140mg/m².

Future Treatments

New and promising studies include autologous hematopoietic stem cell transplantation for MS patients and total lymphoid irradiation.

  • Alemtuzumab: This is a monoclonal antibody approved for B-cell chronic lymphocytic leukemia. It has received fast-track status for FDA approval for MS. Early studies have found it to be more effective than interferon.
  • Daclizumab and ocrelizumab: These are monoclonal antibodies currently being studied that also have shown promise for patients with MS.
  • Cladribine and laquinimod: New oral agents under investigation.