Multiple%20sclerosis Treatment

Disease-Modifying Therapy

• Goals: To reduce the rate of disease/disability progression, decrease the number of relapses, and help reduce development of new lesions
• Risks versus benefits need to be reviewed with patient before starting therapy
• Patients with relapsing-remitting multiple sclerosis that had 2 or more clinical relapses for the past 2 years can be considered as having active disease
• Have been shown in multiple class I and class II clinical trials to significantly delay second clinical relapse or new brain magnetic resonance imaging-detected lesions in those with a first demyelinating event and considered at high risk for multiple sclerosis
• Some live vaccines may be contraindicated in patients with multiple sclerosis that is being treated with disease-modifying therapies
  • Assess the vaccination status of patients with multiple sclerosis prior to prescribing immunosuppressive or immunomodulating agents and vaccinate as needed, at least 4-6 weeks before starting therapy per prescribing information

Dimethyl fumarate

• A metabolite of fumaric acid that has an anti-inflammatory and anti-oxidant property that reduces oxidative cell stress
• May be considered in patients with active relapsing-remitting multiple sclerosis whose disease is not highly active or rapidly evolving severe relapsing-remitting multiple sclerosis
• Placebo-controlled studies showed it is effective in reducing the number of new or enlarging T2 lesions in patients with relapsing-remitting multiple sclerosis at 2 years
• Efficacy in reducing risk of disability worsening over 2 years in patients with relapsing-remitting multiple sclerosis has been shown in 2 placebo-controlled clinical trials
• Other fumarate drugs with same bioequivalence, safety, and efficacy: Diroximel fumarate and Monomethyl fumarate
  • Also approved treatment options for secondary progressive multiple sclerosis

Fingolimod

• Recommended as a treatment option for adult patients with highly active relapsing-remitting multiple sclerosis with unchanged or increased relapse rate or ongoing severe relapses when compared to the prior year despite Interferon beta therapy 
• May be used as an alternative in patients with active relapsing-remitting multiple sclerosis who are intolerant of interferons and Glatiramer acetate
• Has been shown to reduce the relapse rate in patients with relapsing-remitting multiple sclerosis based on 2 large controlled trials
• Studies showed that it is more effective compared with placebo in decreasing the risk of new or enlarging T2 lesions at 2 years in patients with relapsing-remitting multiple sclerosis
• Efficacy in decreasing risk of disability progression over 2 years in patients with relapsing-remitting multiple sclerosis was seen in 2 placebo-controlled clinical trials

Glatiramer acetate 

• Alternative to Interferon in patients with active relapsing-remitting multiple sclerosis
• Has been shown to reduce the clinical relapse rate (either clinically or by magnetic resonance imaging) in patients with relapsing-remitting multiple sclerosis
• Relapsing-remitting multiple sclerosis patients may also have a slowing of sustained disability progress
• A study showed that it is more effective compared with placebo in reducing the number of new or enlarging T2 lesions at 2 years in patients with relapsing-remitting multiple sclerosis 

Interferon beta-1a (Intramuscular and Subcutaneous) and 1b (Subcutaneous)

• Used to reduce frequency and severity of acute relapses in moderately active relapsing forms of multiple sclerosis
  • Interferon beta-1b is recommended as an option in patients with relapsing-remitting multiple sclerosis with ≥2 relapses in the last 2 years
• May consider use in any patient at risk for developing clinically definite multiple sclerosis (CDMS)
• There may be certain populations of patients who are better candidates for therapy than others but it is yet to be determined how to distinguish these patients
• Has been shown to reduce the attack rate (determined either clinically or by magnetic resonance imaging) in patients with multiple sclerosis or in patients who experienced an isolated syndrome and are at risk of developing clinically definite multiple sclerosis
• Can be a treatment option for patient with active secondary-progressive multiple sclerosis with continuing relapses
  • Has been shown to reduce disability progression at 3 and 6 months in patients with secondary-progressive multiple sclerosis based on 4 placebo-controlled clinical trials
  • Efficacy in reducing risk of relapse over 2 years in patients with secondary-progressive multiple sclerosis was demonstrated in a placebo-controlled clinical trial
• Reduce disease severity (determined by magnetic resonance imaging)
• May slow progress of disability
• Neutralizing antibodies (NAb) may develop and interfere with long-term efficacy of treatment

Mitoxantrone

• An antineoplastic agent
• Used in patients with worsening relapsing-remitting multiple sclerosis and secondary-progressive multiple sclerosis to reduce frequency of clinical relapse and reduce neurological disability
  • May be more effective in reducing risk of relapse and disability progression over 2 years in patients with worsening relapsing-remitting multiple sclerosis based on a placebo-controlled study
  • Has been shown to reduce risk of disability worsening in patients with secondary-progressive multiple sclerosis based on a placebo-controlled trial
• Should be reserved for patients with rapidly advancing disease who have failed other therapies
• Probably reduces attack rate in relapsing forms of multiple sclerosis
• A study showed that it is more effective than placebo in reducing the number of new lesions on T2 at 2 years in patients with relapsing-remitting multiple sclerosis
• Efficacy in reducing risk of disability progression over 2 years in patients with relapsing-remitting multiple sclerosis was seen in a placebo-controlled trial
• Toxic effects (eg cumulative dose cardiotoxicity) may outweigh benefit

Natalizumab

• Murine monoclonal antibody used as monotherapy to prevent relapses and delay progression of disability in relapsing-remitting multiple sclerosis
• Due to increased risk of progressive multifocal leukoencephalopathy (PML) in the use of Natalizumab, it is generally recommended for patients who had inadequate response to or inability to tolerate alternative multiple sclerosis therapy
• Recommended treatment option for patients with highly active disease or rapidly evolving severe relapsing-remitting multiple sclerosis
• Efficacy in decreasing the risk of at least 1 new or enlarging T2 lesion at 1 year and in reducing T2 lesion load at 2 years in patients with relapsing-remitting multiple sclerosis was shown in a placebo-controlled clinical trial

Ofatumumab

• A human anti-CD20 monoclonal antibody used in the treatment of relapsing forms of multiple sclerosis
• Studies have shown it to be as effective as Ocrelizumab with acceptable safety profile in the treatment of relapsing -remitting multiple sclerosis
• A recent study showed reduction in the relapse rate compared to Teriflunomide in adults with relapsing multiple sclerosis

Ozanimod

• A sphingosine 1-phosphate receptor modulator similar to Fingolimod
• Recently approved treatment for clinically isolated syndrome, relapsing-remitting multiple sclerosis, active secondary multiple sclerosis
• It was shown to be effective against placebo in reducing MRI lesion activity
• Has shown efficacy against interferon beta-1a in reducing brain volume loss, new or enlarging lesions on MRI in cases of relapsing-remitting multiple sclerosis 

Peginterferon beta-1a

• Treatment option for adults with relapsing-remitting multiple sclerosis
• Similar to treatment with Interferon beta-1a, it produces a significant relative reduction of annualized relapse rates and disability progression in multiple sclerosis 
• Has a more flexible dosing schedule compared to Interferon beta-1a 

Ponesimod

• A selective, rapidly reversible sphingosine 1-phosphate receptor modulator
• It has been recently approved for the use in the treatment of relapsing type of multiple sclerosis including clinically isolated syndrome, relapsing-remitting multiple sclerosis, and active secondary multiple sclerosis
• A placebo-controlled trial showed reduction in new MRI lesions and relapse rate
• It has decreased annual relapse rates compared to Teriflunomide

Siponimod

• A selective sphingosine1-phosphate receptor modulator that prevents lymphocyte from leaving the lymph nodes resulting in decreased infiltration of potentially auto-aggressive lymphocytes into the CNS 
• Used in the treatment of relapsing forms of multiple sclerosis, including CIS, highly active relapsing-remitting disease and active secondary-progressive disease in adults 
• A placebo-controlled trial of patients with secondary-progressive multiple sclerosis showed significant reduction in the proportion of patients with confirmed disability progression over 3 months compared to placebo as well as reduction in the annualized relapse rate

Teriflunomide

• An active metabolite of Leflunomide that acts on inhibiting the proliferation of activated T and B lymphocytes
• Treatment option for active relapsing-remitting multiple sclerosis patients whose disease is not highly active or rapidly evolving
• Studies show that administration of Teriflunomide significantly reduces relapse rate in patients with multiple sclerosis
• Efficacy in decreasing disability progression at 2 years in patients with relapsing-remitting multiple sclerosis was seen in 2 placebo-controlled clinical trials
• May be effective in decreasing risk of converting to multiple sclerosis in patients with CIS over 2 years as shown in a placebo-controlled clinical trial

Immune-Reconstitution Therapy (IRT)

• Provides extended efficacy during a short-course treatment

Alemtuzumab

• A monoclonal antibody that binds to CD52 antigen causing cell lysis
• Recommended as a treatment option for adult patients with active relapsing-remitting multiple sclerosis, including rapidly evolving aggressive disease
• Treatment option for patients who have responded inadequately to ≥2 disease-modifying treatment for relapsing-remitting multiple sclerosis
• Studies showed a decrease in the relapse rate and risk of sustained accumulation of disability in patients
• Studies have shown that it is more effective than Interferon beta-1a 44 mcg subcutaneously 3 times/week in decreasing risk of disability progression over 2 years in patients with relapsing-remitting multiple sclerosis

Cladribine

• An antineoplastic agent
• Recommended treatment option for patients with relapsing-remitting multiple sclerosis with high disease activity that have inadequate response to other disease-modifying treatment
• Can be a treatment option for patients with active secondary-progressive multiple sclerosis
• Studies showed that it is more effective than placebo in reducing rate of relapse and risk of relapse over 2 years in patients with relapsing-remitting multiple sclerosis
• Efficacy in decreasing risk of disability progression over 2 years was seen in a placebo-controlled clinical trial
• Found to significantly reduce gadolinium-enhanced lesions, active T2 lesions and combined unique lesions compared with placebo in patients with relapsing-remitting multiple sclerosis
• It may be effective in decreasing risk of converting to multiple sclerosis in patients with clinically isolated syndromes (CIS) over 3 years based on a placebo-controlled clinical trial

Ocrelizumab

• An anti-CD20 monoclonal antibody approved for treatment of relapsing or primary-progressive forms of multiple sclerosis
• First B-cell targeted therapy for adult patients with multiple sclerosis and first drug to gain US Food and Drug Administration (FDA) approval for primary-progressive multiple sclerosis
• Efficacy of Ocrelizumab for treatment of primary-progressive multiple sclerosis was seen in a placebo-controlled clinical trial that showed risk reduction in the portion of patients with 12-week confirmed disability progression
• Can be a treatment option for patients with active secondary-progressive multiple sclerosis
• Recommended treatment option for patients with highly active or rapidly evolving aggressive relapsing-remitting multiple sclerosis, or patients with active relapsing-remitting multiple sclerosis where Alemtuzumab is contraindicated or not suitable
• Efficacy of Ocrelizumab for treatment of relapsing forms of multiple sclerosis was seen in 2 randomized double-blind active comparator trials that showed reduced annualized relapse rates and reduced worsening of disability 
• In 2 studies it was found to be more effective than Interferon beta-1a 44 mcg in reducing risk of disability progression confirmed at 3 and 6 months over 2 years in patients with relapsing-remitting multiple sclerosis

Alternative Therapy

Azathioprine

• An imidazolyl derivative of Mercaptopurine which inhibits RNA and DNA synthesis
• May be a treatment option for patients with relapsing-remitting multiple sclerosis who do not have access to approved disease-modifying treatment
• Studies have shown it is more effective compared with beta Interferons in decreasing relapse rate

Cyclophosphamide

• An antineoplastic, alkylating agent that causes suppression of both cell-mediated and humoral immunity of the body
• Given in high-doses as  a third-line agent for refractory and aggressive relapsing-remitting multiple sclerosis
• Used off-label in cases of treatment failure or suboptimal responders to first- and second-line drugs for secondary progressive multiple sclerosis

Rituximab

• A chimeric anti-CD20 monoclonal antibody that acts on B cell lymphocytes 
• Off-label use has considerably increased after a phase 2 trial showed a reduction in the incidence of relapses clinically and reduction of new and/or active lesions radiologically in patients with relapsing-remitting multiple sclerosis 
• May be an option for highly active or rapidly evolving aggressive relapsing-remitting multiple sclerosis in places where other alternatives to therapy are unavailable or unaffordable

Relapse Treatment

• Goals: To reduce duration and severity of acute attacks, and reduce residual disability

Corticosteroids

• When used short-term, have been shown to speed functional recovery in patients with acute attacks of multiple sclerosis
  • Short-term use during attacks has not been shown to give any long-term functional benefit
• One study has shown that regular pulse glucocorticoids may be of long-term advantage to patients with relapsing-remitting multiple sclerosis, but more studies are needed
• Methylprednisolone is used to treat acute attacks and relapses of multiple sclerosis
  • Inhibits inflammatory cascades and the activation and invasion of T cells into the central nervous system
• Intravenous corticosteroids are preferred over oral corticosteroids because of increased risk of recurrent optic neuritis in oral steroids
• Corticotropin available as intramuscular or subcutaneous agent is an alternative for patients who cannot tolerate high-dose corticosteroids or who have poor venous access or prefer self-administration

Muscle Relaxants

• Along with physiotherapy, muscle relaxants are one of the mainstays of management of spasticity
• Eg Baclofen, Dantrolene, Eperisone, Tizanidine, Tolperisone
• These drugs act via different mechanisms:
  • Baclofen is thought to act at the spinal cord level but may have supraspinal sites of action and is a powerful neuronal depressant and may exert its inhibitory effects by acting as agonist at gamma aminobutyric acid (GABA) receptors
  • Dantrolene acts directly on the muscles, possibly by interfering with the release of calcium from muscular sarcoplasmic reticulum needed for contraction
  • Eperisone is a centrally acting muscle relaxant which may also have a vasodilator action
  • Tizanidine is a centrally acting relaxant and alpha-adrenergic agonist thought to act at spinal and supraspinal levels by inhibiting the presynaptic activity of excitatory interneurons
    • It may produce additive effects to Baclofen, allowing a reduction in the dosage of both drugs
  • Tolperisone is also a centrally acting muscle relaxant

Ginkgo Biloba

• Various evidences have shown that ginkgo biloba intake helps relieve fatigue but is ineffective for improvement of cognitive function

Magnetic Therapy

• Found effective in reducing fatigue in relapsing-remitting multiple sclerosis
• Further studies are needed to prove efficacy of magnetic therapy in reducing multiple sclerosis-related disabilities

Neurologic Deficit Rehabilitation

• Multidisciplinary assessment by experts
• Programs which are goal-oriented; needs of the individual will change over time so goals will need to be adjusted
• Comprehensive management will involve:
  • Input from a number of modalities
  • Patient education and provision of information
  • Therapy from many different disciplines, including drug therapy

Plasmapheresis

• Should be considered only in rare cases of severe relapse that have poor response to treatment with high-dose corticosteroids or do not respond to intravenous corticosteroids
• Not recommended for chronic primary-progressive multiple sclerosis or secondary-progressive multiple sclerosis

Reflexology

• May provide temporary reduction of multiple sclerosis-related paresthesia

• Patients tend to suffer from a range of symptoms
• Symptoms change over time; constant re-evaluation is needed
• Management needs to be individualized
• Consider the impact of treatment of one particular symptom on the other symptoms

Therapy Goals

• Improve function
• Ease discomfort
• Prevent secondary complications and disability