MULTIPLE SCLEROSIS (MS)


























  • †Optic nerve lesions in a patient presenting with optic neuritis cannot be used in fulfilling the McDonald criteria. Symptomatic and asymptomatic MRI lesions can be considered in the determination of dissemination in space or time.
  • DIS - dissemination in space
  • DIT - dissemination in time
  • Reference [2]
2017 McDonald Criteria for Diagnosing MS
# of clinical attacks MRI lesions with objective clinical findings† Additional diagnostic criteria necessary for MS diagnosis
≥ 2 ≥ 2 None
≥ 2 1 along with clear-cut historical evidence of a previous attack involving a lesion in a distinct anatomical location None
≥ 2 1 One of the following:
  • DIS on MRI
  • DIS demonstrated by clinical attack implicating a different CNS site
1 ≥ 2 One of the following:
  • DIT on MRI
  • Presence of CSF-specific oligoclonal bands
1 1 DIS on MRI and one of the following:
  • DIT on MRI
  • Presence of CSF-specific oligoclonal bands
  • Symptomatic and asymptomatic MRI lesions may be considered
  • Reference [2]
2017 McDonald Criteria for Diagnosing Primary Progressive MS
Primary progressive MS can be diagnosed in patients with 1 year of progressive disability (retrospectively or prospectively determined) independent of clinical relapse who meet two of the following criteria:
  • One or more T2-hyperintense lesions characteristic of MS in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial
  • Two or more T2-hyperintense spinal cord lesions
  • Presence of CSF-specific oligoclonal bands




  • Reference [2]
MS differential
Condition Comment
Acute disseminated encephalomyelitis
  • Mainly seen in children; rare in adults
  • Marked by grey and white matter lesions on MRI
  • Clinical symptoms are similar to MS but also include encephalopathy (mental status changes)
Neuromyelitis optica spectrum disorder
  • Marked by optic neuritis (typically bilateral) and transverse myelitis that is longitudinally extensive (> 3 vertebral segments) involving the central cord
  • Female predisposition (9:1) and more common in Asian/African
  • 70% of affected patients are positive for aquaporin 4 antibody (AQP4-IgG)
Neurosarcoidosis
  • Marked by cranial nerve involvement (including optic nerve), myelopathy, and meningeal enhancement
  • Other findings consistent with sarcoidosis
CNS vasculitis
  • Marked by headache, mental status changes, and/or focal neurological deficits
  • Lesions of the grey and white matter often with evidence of microhemorrhage
  • May be positive for serum anti-neutrophil cytoplasmic antibodies (ANCA)
CNS hypoxic events
  • Strokes and other CNS events that lead to hypoxia/ischemia
  • Depending on the area, may cause white matter lesions
Susac's syndrome
  • Marked by vision and hearing loss and mental status changes
  • Corpus callosum (snowball lesions) and white and grey matter lesions
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)
  • Marked by migraines, strokes, dementia, and psychiatric problems
  • Testing for NOTCH3 gene mutation and/or skin biopsies with distinct pathology
Connective tissue diseases
Neuro-Behcet's disease
  • Marked by large brainstem lesions in patients with a history of oral and genital ulcers and intraocular inflammation
  • HLA-B5 testing may be helpful
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS)
  • Marked by gadolinium-enhancing lesions within the brainstem and cerebellum
  • Symptoms include ataxia, double vision, and slurred speech
Fabry's disease
  • Rare genetic lipid metabolism disorder
  • Symptoms include stroke events and vertigo
  • GLA enzyme activity or gene testing



  • Reference [1,2,3,4,5,7]
Clinical Course and Prognostic Factors of MS and Related Syndromes
Radiologically isolated syndrome
  • About 34% of patients with radiologically isolated syndrome will go on to develop clinically isolated syndrome or MS (typically relapsing-remitting) over the next 5 years
  • Male sex, younger age (< 37 years), multiple CNS lesions, gadolinium-enhancing lesions, CSF-specific oligoclonal bands, abnormal visual evoked potentials, and/or presence of infratentorial/spinal cord lesions are all factors that may be associated with a higher risk of developing MS
  • Spinal cord lesions and male sex increase the risk of developing primary progressive MS
Clinically isolated syndrome
  • In studies lasting up to 20 years, 65 - 80% of patients with a clinically isolated syndrome and an abnormal baseline MRI have gone on to be diagnosed with MS
  • Male sex, younger age (< 37 years), multiple CNS lesions, gadolinium-enhancing lesions, CSF-specific oligoclonal bands, abnormal visual evoked potentials, and/or presence of infratentorial/spinal cord lesions are all factors that may be associated with a higher risk of developing MS
  • The presence of ≥ 10 brain lesions on MRI is strongly associated with progression to MS
Relapsing-remitting MS
  • Most common type of MS accounting for 85 - 90% of cases. Throughout the disease, women have higher relapse rates than men.
  • About 15 - 30% of patients with relapsing-remitting MS will go on to develop secondary progressive MS, although treatment with disease-modifying drugs lowers the risk to around 11% over a ten-year period
  • Older age (> 37 years) at diagnosis, male sex, greater disability at baseline, and a higher degree of brain atrophy are associated with a greater risk of developing progressive disability
  • Short interval between first and second attacks and higher number of lesions at clinical onset are associated with greater risk for long-term disability
Primary progressive MS
  • Accounts for 10 - 15% of patients diagnosed with MS
  • Typically presents at an older age (mean age of onset is 40 years) and men and women are affected equally
  • Older age (> 37 years) at diagnosis, male sex, greater disability at baseline, and a higher degree of brain atrophy are associated with a greater risk of developing progressive disability
  • Motor impairment is the predominant form of progressive disability, but ataxia, visual impairment, and cognitive dysfunction may also be progressive
Secondary progressive MS
  • Typically occurs after a 10 - 15 year course of relapsing-remitting MS. Occurs more frequently in women than men.
  • About 15 - 30% of patients with relapsing-remitting MS will go on to develop secondary progressive MS, although treatment with disease-modifying drugs lowers the risk to around 11% over a ten-year period
  • Motor impairment is the predominant form of progressive disability, but ataxia, visual impairment, and/or cognitive dysfunction may also be progressive



Clinically Isolated Syndrome (CIS) Treatment Recommendations
AAN recommendations
  • Multiple trials have confirmed that treating CIS with disease-modifying therapies (DMTs) is associated with a significant delay in second clinical relapse or new brain MRI-detected lesions in people with a first demyelinating event who are considered to be at high risk for MS on the basis of brain MRI-detected lesions
  • Clinicians should discuss the benefits and risks of treatment for people with CIS who have ≥ 2 brain lesions that have imaging characteristics consistent with MS
  • After discussing the risks and benefits, clinicians should prescribe treatment to people with a single clinical demyelinating event and two or more brain lesions characteristic of MS who decide they want this therapy. There is insufficient evidence to recommend a specific therapy.
  • For patients who are not being treated, annual imaging with close follow-up is recommended for at least 5 years [9]

EAN/ECTRIMS recommendations
  • Offer interferon or glatiramer acetate to patients with CIS and an abnormal MRI with lesions suggestive of MS who do not fulfil criteria for MS [10]

Studies in CIS

  • †Definition of highly active MS varies by trial. In one trial, the following criteria were used: ≥ 2 relapses in the prior year with ≥ 1 gadolinium-enhancing lesion on MRI. In another trial, ≥ 2 relapses in the past year or ≥ 3 relapses in the past 2 years was used. [11,12]
Relapsing-remitting MS Treatment Recommendations
AAN recommendations
  • Clinicians should offer disease-modifying therapies (DMTs) to people with relapsing forms of MS with recent clinical relapses or MRI activity
  • Clinicians should prescribe alemtuzumab, fingolimod, or natalizumab to people with highly active MS†
  • Clinicians may recommend azathioprine or cladribine for people with relapsing forms of MS who do not have access to approved DMTs
  • Annual imaging with close follow-up for at least 5 years may be recommended for patients who are not on DMTs, have not had relapses in the preceding two years, and do not have active new MRI lesion activity on recent imaging [9]

EAN/ECTRIMS recommendations
  • Offer early treatment with DMTs in patients with active relapsing-remitting MS as defined by clinical relapses and/or MRI activity (active lesions, contrast-enhancing lesions; new or unequivocally enlarging T2 lesions assessed at least annually)
  • Choice of DMT will depend on the following factors: patient characteristics and comorbidities, disease severity/activity, drug safety profile, drug accessibility
  • Use one of the following drugs: interferon beta-1b, interferon beta-1a SQ or IM, peginterferon beta-1a, glatiramer acetate, teriflunomide, dimethyl fumarate, cladribine, fingolimod, daclizumab, natalizumab, ocrelizumab and alemtuzumab [10]

Expert opinion recommendations
  • Initial therapy - patients with average active MS†
    • Dimethyl fumarate
    • Teriflunomide
    • Interferon beta
    • Glatiramer acetate
  • Initial therapy - patients with highly active MS†
    • Natalizumab
    • Fingolimod
    • Alemtuzumab
    • Daclizumab [3]

Primary Progressive MS Treatment Recommendations
AAN recommendations
  • Clinicians should offer ocrelizumab to people with primary progressive MS who are likely to benefit from this therapy unless there are risks of treatment that outweigh the benefits [9]

EAN/ECTRIMS recommendations
  • Consider treatment with ocrelizumab for patients with primary progressive MS [10]

Studies in primary progressive MS

Secondary Progressive MS Treatment Recommendations
AAN recommendations
  • The AAN does not make specific recommendations for secondary progressive MS [9]

EAN/ECTRIMS recommendations
  • Consider treatment with interferon beta-1a (subcutaneously) or interferon beta-1b in patients with active secondary progressive MS taking into account, in discussion with the patient, the dubious efficacy, as well as the safety and tolerability profile of these drugs
  • Consider treatment with mitoxantrone in patients with active secondary progressive MS taking into account, in discussion with the patient, the efficacy and specifically the safety and tolerability profile of this agent
  • Consider treatment with ocrelizumab or cladribine for patients with active secondary progressive MS [10]

Monitoring Therapy Recommendations
AAN recommendations
  • Patients not being treated with DMTs
    • For patients who are not being treated with DMTs, annual imaging with close follow-up is recommended for at least 5 years [9]
  • Patients being treated with DMTs
    • Clinicians should recognize that relapses or new MRI-detected lesions may develop after initiation of a DMT and before the treatment becomes effective in people with MS who are using DMTs. Consequently, many clinicians obtain new baseline MRI three to six months after initiating DMTs to monitor from a treated baseline.

EAN/ECTRIMS recommendations
  • When monitoring treatment response in patients treated with DMTs, perform a standardized reference brain MRI usually within 6 months of treatment onset and compare it with a further brain MRI performed typically 12 months after starting treatment. Adjust the timing of both MRIs, taking into account the DMTs typical onset of treatment effect and disease activity.
  • The preferred measure of treatment response to DMTs is the appearance of new or unequivocally enlarging T2 lesions supplemented by gadolinium-enhancing lesions
  • When monitoring treatment safety, perform MRI according to the following:
    • Low risk of PML: annually
    • High risk of PML (JCV+, natalizumab for ≥ 18 months): every 3 - 6 months and when switching drugs [10]

Therapy Failure / Intolerance Recommendations
AAN recommendations
  • General recommendations
    • Clinicians should discuss switching from one DMT to another in people with MS who have been using a DMT long enough for the treatment to take full effect and are adherent to their therapy when they experience one or more relapses, two or more unequivocally new MRI-detected lesions, or increased disability on examination, over a one-year period of using a DMT
    • Switching to a DMT with a different mechanism or efficacy profile may be beneficial
    • Alemtuzumab, natalizumab, fingolimod, and ocrelizumab may have higher efficacy when compared to previously approved self-injectable DMTs [9]
  • Natalizumab recommendations
    • Clinicians should discuss switching to a DMT with a lower PML risk in patients with MS taking natalizumab who are or become JCV antibody positive, especially with an index of above 0.9 while on therapy
    • Clinicians should check for natalizumab antibodies in people with MS who have infusion reactions before subsequent infusions, or in people with MS who experience breakthrough disease activity with natalizumab use. Clinicians should switch DMTs in people with MS who have persistent natalizumab antibodies.
    • Physicians must counsel people with MS considering natalizumab discontinuation that there is an increased risk of MS relapse or MRI-detected disease activity within six months of discontinuation
    • Physicians and people with MS choosing to switch from natalizumab to fingolimod should initiate treatment within eight to 12 weeks after natalizumab discontinuation (for reasons other than pregnancy or pregnancy planning) to diminish the return of disease activity [9]
  • Cancer while receiving DMTs
    • If a patient with MS develops a malignancy while using a DMT, clinicians should promptly discuss switching to an alternate DMT, especially for people with MS using azathioprine, methotrexate, mycophenolate, cyclophosphamide, fingolimod, teriflunomide, alemtuzumab, or dimethyl fumarate [9]
  • Serious infections while receiving DMTs
    • People with MS who develop serious infections potentially linked to their DMT should switch DMTs (does not pertain to PML management in people with MS using DMT [9]

EAN/ECTRIMS recommendations
  • Offer a more efficacious drug to patients treated with interferon or glatiramer acetate who show evidence of treatment failure
  • When treatment with a highly efficacious drug is stopped, either due to inefficacy or safety concerns, consider starting another highly efficacious drug
  • In treatment decisions, consider the possibility of resumed disease activity or even rebound when stopping treatment, particularly with natalizumab

Expert opinion recommendations for relapsing-remitting MS

    Step 1
    • For patients who do not achieve therapeutic goals on their initial therapy, consider switching to one of the following:
      • Natalizumab
      • Fingolimod
      • Alemtuzumab
      • Mitoxantrone - due to side effects, should only be used as a last resort
    Step 2
    • For patients who fail Step 1, consider the following:
      • Rituximab
      • Ofatumumab
      • Stem cell transplant [3]

Stopping Therapy Recommendations
AAN recommendations
  • Clinically-isolated syndrome
    • There is insufficient evidence to make a recommendation in regards to the risk/benefit of stopping therapy in patients with CIS who are being treated with DMTs [9]
    • In CIS treatment studies (see CIS treatment above), patients were typically treated for 2 - 3 years
  • Relapsing-remitting MS
    • No randomized controlled trials have directly addressed the question of whether, when, or why to discontinue DMTs in an individual with relapsing-remitting MS who has no evidence of relapses or disability progression and has stable brain imaging. The natural history of untreated relapsing-remitting MS is for relapses and disability accumulation to occur.
    • In a randomized controlled trial of 175 individuals taking natalizumab who had been relapse free for one year and had no gadolinium-enhanced lesions on MRI, participants were randomized to continue natalizumab use, switch to placebo, or switch to other therapies. Relapses occurred in 4% of those continuing natalizumab use and in 15 - 29% of those in other treatment arms over 24 weeks. An observational study comparing outcomes in individuals who did or did not stop DMT after a period of at least five years without relapses found a similar risk of relapses between the groups but an increased risk of disability progression among those who stopped DMT. Younger age and lower Expanded Disability Status Scale (EDSS) scores were significant predictors of relapse (clinical or MRI) after treatment discontinuation.
    • Clinicians should advocate that people with MS who are stable (that is, no relapses, no disability progression, stable imaging) on DMT should continue their current DMT unless the patient and physician decide a trial off therapy is warranted [9]
  • Secondary progressive MS
    • People with secondary progressive MS who have relapses or active MRI-detected new lesion formation benefit from DMT
    • No randomized controlled trials have directly addressed the question of whether or when to discontinue DMTs in people with secondary progressive MS. Clinical trials have not evaluated the benefits of DMT in individuals with secondary progressive MS who are nonambulatory with respect to other clinically relevant domains, including vision, cognition, and upper limb function
    • Among individuals with secondary progressive MS (those with and those without clinical relapses) for at least two years at the time of treatment withdrawal, an EDSS ≥ 6 was associated with a 50% lower risk of relapses or MRI-detected activity after treatment discontinuation
    • Clinicians should assess the likelihood of future relapse in individuals with secondary progressive MS by assessing patient age, disease duration, relapse history, and MRI-detected activity (e.g., frequency, severity, time since most recent relapse or gadolinium-enhanced lesion).
    • Clinicians may advise discontinuation of DMT in people with secondary progressive MS who do not have ongoing relapses (or gadolinium-enhanced lesions on MRI activity) and have not been ambulatory (EDSS ≥ 7) for at least two years [9]

EAN/ECTRIMS recommendations
  • Consider continuing a DMT if a patient is stable (clinically and on MRI) and shows no safety or tolerability issues [10]

Pregnancy Recommendations
AAN recommendations
  • Relapse risk is reduced during pregnancy and increases in the postpartum period (3 - 6 months)
  • Clinicians should counsel women to stop their DMT before conception for planned pregnancies unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy
  • Clinicians should discontinue DMTs during pregnancy if accidental exposure occurs, unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy
  • Clinicians should not initiate DMTs during pregnancy unless the risk of MS activity during pregnancy outweighs the risk associated with the specific DMT during pregnancy [9]

EAN/ECTRIMS recommendations
  • Advise all women of childbearing potential that the only DMT that has a FDA pregnancy category rating of "B" is glatiramer acetate
  • For women planning a pregnancy, if there is a high risk of disease reactivation, consider using interferon or glatiramer acetate until pregnancy is confirmed. In some very specific (active) cases, continuing this treatment during pregnancy could also be considered.
  • For women with persistent high disease activity, it would generally be advised to delay pregnancy. For those who, despite this advice, still decide to become pregnant or have an unplanned pregnancy, consider the following:
    • Treatment with natalizumab throughout pregnancy may be considered after full discussion of potential implications
    • Treatment with alemtuzumab could be an alternative therapeutic option for planned pregnancy in very active cases, provided that a 4-month interval is strictly observed from the latest infusion until conception [10]
Fatigue

Spasticity

Oscillopsia

Gait disturbance

Tremor

Bladder dysfunction

Sexual dysfunction

Bowel dysfunction

Mood and cognition

Pain



Interferon Beta (Betaseron®, Avonex®, Plegridy®, Rebif®, Extavia®)

Dosage forms | Maintenance dosing
  • Avonex® (interferon beta-1a) - prefilled syringe | 30 mcg IM once weekly
  • Plegridy® (peginterferon beta-1a) - prefilled pen | 125 mcg SQ every 14 days
  • Rebif® (interferon beta-1a) - prefilled syringe | 22 - 44 mcg SQ three times a week
  • Betaseron® (interferon beta-1b) - injection kit | 0.25 mg SQ every other day
  • Extavia® (interferon beta-1b) - injection kit | 0.25 mg SQ every other day

FDA-approved indication - Relapsing-remitting MS
Efficacy
Lab monitoring
  • CBC and blood chemistries including liver function tests (CMP) at 1, 3, and 6 months following initiation of therapy and periodically thereafter

Mechanism of action
  • Interferon beta is a naturally occurring protein that binds to receptors on human cells. Receptor binding induces the expression of a number of proteins that lead to the enhancement of suppressor T-cell activity, reduction of pro-inflammatory cytokine production, down-regulation of antigen presentation, and inhibition of lymphocyte trafficking into the central nervous system.

Common side effects
NOTE: Data is from the Betaseron PI. Only side effects that occurred at an incidence ≥ 10% are listed.

Side effect Placebo
(N=965)
Betaseron
(N=1407)
Lymphocytes count decreased (<1500/mm3) 66% 86%
Injection site reaction 26% 78%
Flu-like symptoms (complex) 37% 57%
Asthenia 48% 53%
Headache 43% 50%
Pain 35% 42%
Hypertonia 33% 40%
Fever 19% 31%
Myalgia 14% 23%
Insomnia 16% 21%
Rash 15% 21%
Chills 9% 21%
Incoordination 15% 17%
Abdominal pain 11% 16%
Absolute neutrophil count decreased (< 1500/mm3) 5% 13%
White blood cell count decreased (<3000/mm3) 4% 13%
ALT increased
(SGPT > 5 times baseline)
4% 12%
Peripheral edema 10% 12%
Urinary urgency 8% 11%
Skin disorder 8% 10%


Precautions / Contraindications
  • Pregnancy - category C
  • Decreased white blood cells - may increase risk or worsen. Monitor CBC.
  • Hepatic injury - may increase risk or worsen. Monitor liver functions.
  • Depression - may increase risk or worsen
  • Congestive heart failure - may worsen
  • Thrombotic microangiopathy - cases of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura and hemolytic uremic syndrome have been reported with interferon beta products
  • Autoimmune disorders - rare cases of autoimmune disorders including idiopathic thrombocytopenia, hyper- and hypothyroidism, autoimmune hepatitis, and drug-induced lupus have been reported
  • Seizures - may precipitate or worsen
  • Anaphylaxis and allergic reactions - rare cases have been reported
  • Liver disease - may cause liver toxicity. Use caution and monitor liver functions.
  • Kidney disease - manufacturer makes no recommendation

Glatiramer Acetate Copaxone®)

Dosage forms | Maintenance dosing
  • Copaxone® (glatiramer acetate) - 20 mg and 40 mg prefilled syringe | 20 mg SQ once daily or 40 mg SQ three times a week
  • Generic: Glutopa®

FDA-approved indication - Relapsing-remitting MS
Efficacy
Lab monitoring
  • None

Mechanism of action
  • Activates glatiramer acetate-specific suppressor T-cells in the periphery

Common side effects
NOTE: Only side effects that occurred at an incidence of ≥ 10% are listed

Side effect Copaxone 20 mg/mL
(N=563)
Placebo
(N=564)
Injection Site Erythema 43% 10%
Injection Site Pain 40% 20%
Infection 30% 28%
Injection Site Pruritus 27% 4%
Injection Site Mass 26% 6%
Asthenia 22% 21%
Pain 20% 17%
Vasodilatation 20% 5%
Injection Site Edema 19% 4%
Rash 19% 11%
Nausea 15% 11%
Influenza 14% 13%
Dyspnea 14% 4%
Chest Pain 13% 6%
Anxiety 13% 10%
Back Pain 12% 10%


Precautions / Contraindications
  • Pregnancy - category B
  • Lipoatrophy - up to 2% of patients
  • Skin necrosis - rare events have been reported
  • Immunosuppression - may suppress the immune response
  • Kidney disease - has not been studied
  • Liver disease - manufacturer makes no recommendation

Dimethyl Fumarate (Tecfidera®)

Dosage forms | Maintenance dosing
  • Tecfidera® (dimethyl fumarate) - 120 mg and 240 mg capsule | 240 mg twice a day

FDA-approved indication - Relapsing-remitting MS
Efficacy
Lab monitoring
  • CBC before therapy, 6 months after starting therapy, and every 6 - 12 months as indicated
  • Liver function tests before starting therapy and during therapy as clinically indicated

Mechanism of action
  • Activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway. Nrf2 activation leads to a reduction in the release of inflammatory cytokines, and it also has antioxidant effects.

Common side effects
NOTE: Only side effects that occurred at an incidence ≥ 2% higher than placebo are listed

Side effect Tecfidera
(N=769)
Placebo
(N=771)
Flushing 40% 6%
Abdominal pain 18% 10%
Diarrhea 14% 11%
Nausea 12% 9%
Vomiting 9% 5%
Pruritus 8% 4%
Rash 8% 3%
Albumin urine present 6% 4%
Erythema 5% 1%
Dyspepsia 5% 3%
ALT increased 4% 2%
Lymphopenia 2% <1


Precautions / Contraindications
  • Pregnancy - risk unknown
  • Anaphylaxis and angioedema - has occurred after first dose and at any time during therapy
  • PML - rare cases have been reported, particularly in patients with lymphopenia (< 0.5x10⁹/L) for > 6 months
  • Lymphopenia - mean lymphocyte count decreases by an average of 30% during first year of therapy; consider changing therapy for lymphopenia (< 0.5x10⁹/L) lasting ≥ 6 months
  • Liver toxicity - cases have been reported; check liver function tests before therapy and when indicated
  • Kidney disease - has not been studied
  • Liver disease - has not been studied. Cases of liver toxicity have been reported.

Teriflunomide (Aubagio®)

Dosage forms | Maintenance dosing
  • Aubagio® (teriflunomide) - 7 mg and 14 mg tablet | 7 - 14 mg once daily

FDA-approved indication - Relapsing-remitting MS
Efficacy
Lab monitoring
  • Liver function tests before starting therapy. Monitor ALT at least monthly for 6 months after starting therapy and as clinically indicated thereafter.
  • CBC before starting therapy and as clinically indicated
  • Pregnancy test before starting therapy. Teriflunomide is contraindicated in pregnancy.
  • TB testing before starting therapy. For patients testing positive, treat prior to therapy.

Mechanism of action
  • Teriflunomide inhibits dihydroorotate dehydrogenase (DD), a mitochondrial enzyme involved in de novo pyrimidine synthesis. DD inhibition suppresses the proliferation of autoreactive B and T cells and promotes a shift towards anti-inflammatory cytokines. Teriflunomide is an active metabolite of the drug leflunomide that is used to treat rheumatoid arthritis.

Common side effects

Side effect Aubagio 14 mg
(N=1002)
Placebo
(N=997)
Headache 16% 15%
Increase in ALT 15% 9%
Diarrhea 14% 8%
Alopecia 13% 5%
Nausea 11% 7%
Paresthesia 9% 7%
Arthralgia 6% 5%
Neutropenia 6% 2%
Hypertension 4% 2%


Precautions / Contraindications
  • Pregnancy - Category X; DO NOT USE
  • Severe liver disease - DO NOT USE
  • Coadministration with leflunomide - DO NOT COMBINE
  • Hepatotoxicity - in trials, ALT > 3 X ULN occurred in 6.2% of patients (14 mg dose); elevations occurred mostly during first year of treatment, and half returned to normal without discontinuation; consider stopping therapy for ALT > 3 X ULN
  • Bone marrow suppression - WBCs decrease by 15% on average and platelets decrease by 10% on average during therapy
  • Serious infections - may increase risk
  • Tuberculosis (TB) - test for TB before starting therapy. If positive, treat before starting therapy.
  • Malignancy - may increase risk, particularly lymphoproliferative disorders
  • Hypersensitivity and serious skin reactions - anaphylaxis and serious skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported
  • Peripheral neuropathy - has been seen in up to 2% of patients
  • Increase in blood pressure - average increase in SBP of 2 - 3 mmHg seen in trials
  • Interstitial lung disease - rare cases have been reported
  • Drug interactions - teriflunomide is a CYP2C8 inhibitor, CYP1A2 weak inducer, OATP1B1/1B3 inhibitor, BCRP inhibitor, and OAT3 inhibitor | Rosuvastatin - do not exceed 10 mg when given with teriflunomide
  • Liver disease
    • Mild to moderate (Child-Pugh A/B) - no dose adjustment
    • Severe (Child-Pugh C) - DO NOT USE
  • Kidney disease - no dose adjustment necessary

Natalizumab (Tysabri®)

Dosage forms | Maintenance dosing
  • Tysabri® (natalizumab) - 300 mg vial | 300 mg IV every 4 weeks

FDA-approved indication - Relapsing-remitting MS
Efficacy
Lab monitoring
  • John Cunningham virus (JCV) antibody testing to help determine the risk of PML
  • Liver function tests and CBC when indicated

Mechanism of action
  • Tysabri is a recombinant humanized IgG4ϰ monoclonal antibody that binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils. Tysabri inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s). Inhibiting this interaction prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. The therapeutic mechanism of Tysabri in MS may be through the inhibition of leukocyte migration across the blood-brain-barrier.

Common side effects
NOTE: Only side effects occurring at an overall incidence ≥ 5% are listed

Side effect Natalizumab
(N=627)
Placebo
(N=312)
Headache 38% 33%
Fatigue 27% 21%
Urinary tract infection 21% 17%
Arthralgia 19% 14%
Depression 19% 16%
Lower respiratory tract infection 17% 16%
Pain in extremity 16% 14%
Rash 12% 9%
Gastroenteritis 11% 9%
Abdominal discomfort 11% 10%
Diarrhea 10% 9%
Vaginitis 10% 6%
Tooth infections 9% 7%
Urinary frequency 9% 7%
Herpes 8% 7%
Tonsillitis 7% 5%
Dermatitis 7% 4%
Vertigo 6% 5%
Chest discomfort 5% 3%
Other hypersensitivity reactions 5% 2%
Muscle cramps 5% 3%
Irregular menstruation 5% 4%


Precautions / Contraindications
  • Pregnancy - risk unknown
  • Concomitant immunosuppressants - DO NOT COMBINE
  • Progressive multifocal leukoencephalopathy (PML) - Tysabri increases the risk of PML which has a mortality rate of > 20%. Symptoms of PML progress over days to weeks and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. Risk is increased by longer duration of therapy (especially > 2 years), prior treatment with immunosuppressants, and the presence of anti-JCV antibodies. Risk of PML by JC antibody index and length of therapy are presented in the tables below. Providers must be enrolled in the Tysabri CD TOUCH program in order to prescribe Tysabri.

  • †Estimates are for patients with no prior immunosuppressant use
  • Reference [9]
Risk of PML in patients using natalizumab for 25 - 36 months†
anti-JCV index PML risk
< 0.9 0.2/1000
0.9 - 1.5 0.3/1000
> 1.5 3/1000
  • Imm = immunosuppressants
  • Examples of immunosuppressants include mitoxantrone, azathioprine, methotrexate, cyclophosphamide, and mycophenolate mofetil
  • Reference [Manufacturer's PI]
Risk of PML in patients who are anti-JCV antibody positive
Length of Tysabri exposure No prior Imm Prior Imm use
1 - 24 months < 1/1000 1/1000
25 - 48 months 3/1000 12/1000
49 - 72 months 6/1000 13/1000
  • Stopping therapy - for patients who stop natalizumab, there is an increased risk of MS relapse in the first 6 months. Initiating fingolimod within 8 - 12 weeks may reduce risk.
  • Herpes infections - increases risk of herpes encephalitis, meningitis, and retinitis
  • Hepatotoxicity - cases of acute hepatitis and liver failure have occurred
  • Hypersensitivity reactions/antibody formation - hypersensitivity reactions including anaphylaxis have occurred. Reactions are more common in patients who develop natalizumab antibodies. Check for natalizumab antibodies in patients who have infusion reactions or experience decreased efficacy. Natalizumab should be discontinued in patients with persistent antibodies.
  • Serious infections - Tysabri may increase the risk of serious infections including invasive fungal infections, bacterial infections, viral infections, and others
  • Increase in blood counts - Tysabri increases circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Levels return to normal when Tysabri is discontinued.
  • Decrease in hemoglobin - Tysabri induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dl) that are frequently transient
  • Vaccines - patients may receive non-live vaccines. Do not give live or attenuated vaccines.
  • Liver disease - has not been studied
  • Kidney disease - has not been studied

Fingolimod (Gilenya®)

Dosage forms | Maintenance dosing
  • Gilenya® (fingolimod) - 0.25 mg and 0.5 mg capsule | 0.5 mg once daily (adults and children ≥ 88 lbs (40kg)); 0.25 mg once daily (children < 88 lbs (40kg))

FDA-approved indication - Relapsing-remitting MS in patients ≥ 10 years old
Efficacy
Lab/other monitoring
  • Obtain baseline ECG
  • CBC before starting therapy and as clinically indicated
  • Liver function tests before starting therapy and as clinically indicated. Most increases in liver enzymes occur within 9 months of starting therapy.
  • Eye exam at baseline, 3 - 4 months after starting therapy, and as clinically indicated for visual changes
  • Patients without a healthcare professional confirmed history of chickenpox or without documentation of a full course of vaccination against varicella should be tested for antibodies to varicella before initiating therapy. For non-immune patients, Varicella vaccine should be given and treatment postponed 1 month.

Mechanism of action
  • Fingolimod is metabolized by sphingosine kinase to the active metabolite, fingolimod-phosphate. Fingolimod-phosphate is a sphingosine 1-phosphate receptor modulator, and binds with high affinity to sphingosine 1-phosphate receptors 1, 3, 4, and 5. Fingolimod-phosphate blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood.

Common side effects

Side effect Fingolimod 0.5 mg
(N=783)
Placebo
(N=773)
Headache 25% 24%
Liver transaminase elevations 15% 4%
Nausea 13% 12%
Diarrhea 13% 10%
Cough 12% 11%
Influenza 11% 8%
Sinusitis 11% 8%
Abdominal pain 11% 10%
Back pain 10% 9%
Pain in extremity 10% 7%
Dyspnea 9% 7%
Bronchitis 8% 5%
Hypertension 8% 4%
Lymphopenia 7% < 1%
Migraine 6% 4%
Vision blurred 4% 2%
Bradycardia 3% 1%
Alopecia 3% 2%
Blood triglycerides increased 3% 1%
Skin papilloma 3% 2%


Precautions / Contraindications
  • Pregnancy - risk unknown
  • Recent (within 6 months) cardiovascular disease (CVD) - DO NOT USE. CVD includes myocardial infarction, unstable angina, stroke, TIA, decompensated heart failure requiring hospitalization or Class III/IV heart failure.
  • Heart block - DO NOT USE. Heart block includes Mobitz Type II second-degree or third-degree AV block or sick sinus syndrome, unless patient has a functioning pacemaker.
  • Prolonged QTc interval (≥ 500 msec) - DO NOT USE
  • Concomitant Class Ia or Class III antiarrhythmic drugs - DO NOT USE
  • Bradycardia - fingolimod may slow the heart rate. In adult trials, symptomatic bradycardia following the first dose was reported in 0.6% of patients. Heart rate monitoring for 6 hours after the first dose is recommended in all patients. Continued monitoring is recommended when indicated.
  • Liver injury - fingolimod may cause an increase in liver enzymes. In adult trials lasting up to 2 years, increase in liver enzymes > 3 X ULN occurred in 14% of fingolimod-treated patients and 3% of placebo-treated patients. Most elevations occurred within 9 months of starting therapy.
  • AV block - fingolimod may cause AV conduction delays. In adult trials, first-degree AV block was reported in 5% of patients and second-degree (Mobitz Type I) AV block was seen in 4% of patients. The conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours of treatment.
  • Infections - fingolimod may increase risk of infections. In trials, serious infections occurred in 2.3% of fingolimod-treated patients and 1.6% of placebo-treated patients.
  • Progressive multifocal leukoencephalopathy (PML) - cases of PML have been reported in patients receiving fingolimod. Symptoms of PML progress over days to weeks and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.
  • Macular edema - fingolimod may cause macular edema. Obtain an eye exam at baseline, 3 - 4 months after starting therapy, and as clinically indicated. In trials, macular edema occurred in 0.5% of fingolimod-treated patients and 0.4% of placebo-treated patients. Most cases occurred within 4 months of starting therapy. Patients with a history of uveitis and/or diabetes have a higher risk.
  • Posterior Reversible Encephalopathy Syndrome (PRES) - rare cases of PRES have been reported in fingolimod-treated patients. Symptoms of PRES include sudden onset of severe headache, altered mental status, visual disturbances, and seizure.
  • Respiratory effects - fingolimod may cause a slight decrease in respiratory function. In adult trials lasting up to 2 years, the reduction from baseline in FEV₁(% predicted) was 2.8% in fingolimod-treated patients and 1.0% in placebo-treated patients.
  • Severe increase in disability upon discontinuation - severe increases in disability upon discontinuing fingolimod have been reported. The increases generally occurred within 12 weeks of stopping therapy.
  • Blood pressure increase - in adult trials, fingolimod caused an average increase in SBP/DBP of 3 mmHg/2 mmHg
  • Skin cancer - in adult trials, the risk of basal cell carcinoma (2% vs 1% for placebo) and melanoma was increased in fingolimod-treated patients
  • Effect after stopping therapy - fingolimod remains in the system for up to 2 months upon discontinuation. Consider risks of starting new therapy and continued side effects/precautions when stopping.
  • Hypersensitivity reactions - hypersensitivity reactions, including rash, urticaria, and angioedema have been reported
  • Leukopenia - fingolimod causes a dose-dependent reduction in peripheral lymphocyte count to 20 – 30% of baseline values
  • Vaccines - response to all vaccines will be attenuated. Do not give live or attenuated vaccines during and for up to 2 months after discontinuation of therapy.
  • Kidney disease - exposure to drug and metabolites is increased. No dosage adjustment is recommended, although it has not been studied extensively.
  • Liver disease
    • Mild to moderate (Child-Pugh A/B) - no dose adjustment
    • Severe (Child-Pugh C) - use caution. Monitor closely.

Drug interactions
  • QT-prolonging drugs - use caution when combining
  • Ketoconazole - ketoconazole increases fingolimod levels 1.7-fold. Use caution.
  • Immunosuppressants including steroids - consider risk of immunosuppression/infection when combining, and the overlap of effects that may occur when changing therapies
  • Drugs that slow the heart rate - use caution and monitor effects when combining with other drugs that slow the heart rate (e.g. beta blockers, diltiazem, verapamil, clonidine, digoxin)

Alemtuzumab (Lemtrada®)

Dosage forms | Maintenance dosing
  • Lemtrada® (alemtuzumab) - 12 mg vial | 12 mg/day IV for 2 treatment courses: First course: 12 mg/day on 5 consecutive days (60 mg total dose); Second course: 12 mg/day on 3 consecutive days (36 mg total dose) administered 12 months after the first course; Subsequent courses: 12 mg per day on 3 consecutive days (36 mg total dose) as needed at least 12 months after the last dose

FDA-approved indication - Relapsing-remitting MS; Because of its safety profile, the use of alemtuzumab should generally be reserved for patients who have had an inadequate response to two or more drugs
Efficacy
Lab/other monitoring
  • Before therapy
    • Complete any necessary immunizations at least 6 weeks prior to treatment
    • Determine whether patients have a history of varicella or have been vaccinated for varicella zoster virus (VZV). If not, test the patient for antibodies to VZV and consider vaccination for those who are antibody-negative. Postpone treatment with LEMTRADA until 6 weeks after VZV vaccination
    • Perform tuberculosis screening according to local guidelines
    • Consider hepatitis B and C screening in high-risk patients
    • Instruct patients to avoid potential sources of Listeria monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry)
    • Inspect skin for melanoma
    • Measure CBC, serum creatinine, liver function tests, TSH, urinalysis with urine cell counts, urine protein to creatinine ratio prior to treatment
  • During therapy and for 48 months after the last dose
    • CBC monthly
    • Serum creatinine monthly
    • Urinalysis with urine cell counts monthly
    • TSH every 3 months
    • Liver function tests periodically
    • Yearly skin exams to monitor for melanoma

Mechanism of action
  • Alemtuzumab is a recombinant humanized IgG1 kappa monoclonal antibody directed against the cell surface glycoprotein, CD52. CD52 is a cell surface antigen present on T and B lymphocytes, natural killer cells, monocytes, and macrophages. Following cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis. After alemtuzumab treatment, B cells recover within 7 months, but T cells do not reach the lower limit of normal before the second treatment.

Common side effects

Side effect Lemtrada
(N=811)
Interferon beta-1a
(N=389)
Rash 53% 6%
Headache 52% 23%
Pyrexia 29% 9%
Nasopharyngitis 25% 19%
Nausea 21% 9%
Urinary tract infection 19% 8%
Fatigue 18% 13%
Insomnia 16% 15%
Upper respiratory tract infection 16% 13%
Herpes viral infection 16% 3%
Urticaria 16% 2%
Pruritus 14% 2%
Thyroid gland disorders 13% 3%
Fungal infection 13% 4%
Arthralgia 12% 9%
Pain in extremity 12% 9%
Back pain 12% 8%
Diarrhea 12% 6%
Sinusitis 11% 8%
Oropharyngeal pain 11% 5%
Paresthesia 10% 8%
Dizziness 10% 5%
Abdominal pain 10% 5%
Flushing 10% 4%
Vomiting 10% 3%
Cough 9% 4%
Chills 9% 3%
Dysgeusia 8% 7%
Influenza 8% 6%
Dermatitis 8% 5%
Dyspepsia 8% 4%
Blood in urine 8% 3%
Dyspnea 8% 1%
Tachycardia 8% 1%
Anxiety 7% 6%
Muscular weakness 7% 6%
Bronchitis 7% 4%
Chest discomfort 7% 2%
Muscle spasms 6% 5%
Myalgia 6% 5%
Decrease in CD4 lymphocytes 6% 2%
Decrease in CD8 lymphocytes 6% 2%


Precautions / Contraindications
  • Pregnancy - risk unknown
  • HIV - DO NOT USE. Lowers CD4 count.
  • Autoimmunity - Treatment with alemtuzumab can result in the formation of autoantibodies and increase the risk of serious autoimmune mediated conditions. In clinical studies, thyroid disorders (36.8%), immune thrombocytopenia (2%), glomerulonephropathies (0.3%) vitiligo (0.3%), autoimmune hemolytic anemia (0.3%), autoimmune pancytopenia (0.2%), undifferentiated connective tissue disorders (0.2%), type 1 diabetes (0.2%), rheumatoid arthritis (0.1%), retinal pigment epitheliopathy (0.1%), and acquired hemophilia A (anti-Factor VIII antibodies) (0.1%) have occured in alemtuzumab-treated patients. Guillain-Barré syndrome has been reported in postmarketing use. Chronic inflammatory demyelinating polyradiculoneuropathy has been reported in the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL), as well as other autoimmune disorders, generally at higher and more frequent doses than recommended in MS. Autoantibodies may be transferred from the mother to the fetus during pregnancy. A case of transplacental transfer of anti-thyrotropin receptor antibodies resulting in neonatal Graves' disease occurred after alemtuzumab treatment in the mother.
  • Infusion Reactions - Alemtuzumab causes cytokine release syndrome which can cause serious infusion reactions. In studies, 92% of alemtuzumab-treated patients experienced infusion reactions. In some patients, infusion reactions were reported more than 24 hours after alemtuzumab infusion. Serious reactions including anaphylaxis occurred in 3% of patients. In trials, patients were premedicated with 1,000 mg of methylprednisolone for the first 3 days of each alemtuzumab treatment course.
  • Stroke and Cervicocephalic Arterial Dissection - cases have been reported within 3 days of alemtuzumab administration
  • Malignancies - in trials, thyroid cancer and melanoma occured in 0.3% of alemtuzumab-treated patients. Lymphoma and lymphoproliferative disorders have also been reported.
  • Immune Thrombocytopenia - Immune thrombocytopenia (ITP) occurred in 2% of alemtuzumab-treated patients in MS trials (controlled and open-label extension). Nadir platelet counts ≤20,000 cells per microliter as a result of ITP occurred in 2% of all alemtuzumab-treated patients in clinical studies in MS. ITP has been diagnosed more than 3 years after the last dose.
  • Glomerulonephropathies Including Anti-Glomerular Basement Membrane Disease - glomerular nephropathies occurred in 0.3% of alemtuzumab-treated patients in MS clinical studies. Cases of anti-GBM disease have been diagnosed up to 40 months after the last dose of alemtuzumab. Symptoms of nephropathy may include edema, hematuria, change in urine color, decreased urine output, fatigue, dyspnea, and hemoptysis. For urine dipstick results of 1+ protein or greater, measure the urine protein to creatinine ratio. For urine protein to creatinine ratio greater than 200 mg/g, increase in serum creatinine greater than 30%, or unexplained hematuria, perform further evaluation for nephropathies. Increased serum creatinine with hematuria or signs of pulmonary involvement of anti-GBM disease (e.g., hemoptysis, exertional dyspnea) warrant immediate evaluation. Early detection and treatment of nephropathies may decrease the risk of poor outcomes.
  • Thyroid Disorders - thyroid disorders including hyper/hypothyroidism, Grave's disease, autoimmune thyroiditis, and goiter occurred in 36.8% of alemtuzumab-treated patients in MS clinical studies (controlled and open-label extension). Newly diagnosed thyroid disorders have occurred more than 7 years after the first alemtuzumab dose.
  • Other Autoimmune Cytopenias - autoimmune cytopenias including neutropenia (0.1%), hemolytic anemia (0.3%), and pancytopenia (0.2%) occurred in alemtuzumab-treated patients in MS clinical studies.
  • Infections - In MS trials lasting up to 2 years, infections occurred in 71% of alemtuzumab-treated patients compared to 53% of interferon beta-1a-treated patients. Infections that occurred more often in alemtuzumab-treated patients than interferon beta-1a patients included nasopharyngitis, urinary tract infection, upper respiratory tract infection, sinusitis, herpetic infections, influenza, and bronchitis. Serious infections occurred in 3% of patients treated with alemtuzumab as compared to 1% of patients treated with interferon beta-1a. Herpes virus infections (16%) and oral and vaginal candidiasis (12%) infections occurred frequently in alemtuzumab-treated patients. Screen for TB before treatment and consider screening for hepatitis B and C in high-risk individuals. Treat patients with TB before initiating therapy.
  • Listeria monocytogenes infections - Listeria monocytogenes infections (e.g., meningitis, encephalitis, sepsis, and gastroenteritis), including fatal cases of Listeria meningoencephalitis, have occurred in alemtuzumab-treated patients. Listeria infections have occurred as early as 3 days after treatment and up to 8 months after the last alemtuzumab dose. Advise patients to avoid or adequately heat foods that are potential sources of Listeria monocytogenes (e.g., deli meat, dairy products made with unpasteurized milk, soft cheeses, or undercooked meat, seafood, or poultry). Initiate these Listeria precautions prior to starting alemtuzumab treatment.
  • Alemtuzumab antibodies - in trials, anti-alemtuzumab antibodies were detected in up to 83% of patients. Antibody development had no clear effect on clinical outcomes, total lymphocyte count, or adverse events.
  • Autoimmune hepatitis - cases of autoimmune hepatitis has been reported in patients receiving alemtuzumab
  • Acute Acalculous Cholecystitis - in controlled clinical studies, 0.2% of alemtuzumab-treated MS patients developed acute acalculous cholecystitis, compared to 0% of patients treated with interferon beta-1a. Time to onset of symptoms ranged from less than 24 hours to 2 months after alemtuzumab infusion.
  • Pneumonitis - in clinical trials, 0.5% alemtuzumab-treated patients had pneumonitis of varying severity
  • Live vaccines - do not administer live vaccines during therapy, after therapy, or in the 6 weeks before therapy.
  • Kidney disease - alemtuzumab may cause glomerular nephropathies. Use caution in patients with kidney disease
  • Liver disease - alemtuzumab has been associated with cases of autoimmune hepatitis

Ocrelizumab (Ocrevus®)

Dosage forms | Maintenance dosing
  • Ocrevus® (ocrelizumab) - 300 mg vial | First dose: 300 mg IV; Second dose: 300 mg IV 2 weeks later; Subsequent doses: 600 mg IV every 6 months

FDA-approved indication - Relapsing-remitting MS and primary progressive MS
Efficacy
Lab/other monitoring
  • Before therapy
    • Hepatitis B screening

Mechanism of action
  • Ocrelizumab is a recombinant humanized monoclonal antibody directed against CD20-expressing B-cells
  • The precise mechanism by which ocrelizumab exerts its therapeutic effects in multiple sclerosis is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ocrelizumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.

Common side effects
Side effect Ocrevus 600 mg IV every 24 weeks
(N=825)
Rebif 44 mcg SQ 3 times a week
(N=826)
Upper respiratory tract infections 40% 33%
Infusion reactions 34% 10%
Depression 8% 7%
Lower respiratory tract infections 8% 5%
Back pain 6% 5%
Herpes virus- associated infections 6% 4%
Pain in extremity 5% 4%


Precautions / Contraindications
  • Pregnancy - risk unknown
  • Hepatitis B infection - DO NOT GIVE. Ocrelizumab is contraindicated in patients with active HBV confirmed by positive results for HBsAg and anti-HBV tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.
  • Infusion Reactions - In trials, up to 40% of ocrelizumab-treated patients experienced infusion reactions including pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, and tachycardia. Observe patients for at least 1 hour after infusion. Reactions may occur up to 24 hours after infusion. Premedicate with an antihistamine and 100 mg of methylprednisolone (or an equivalent corticosteroid) IV 30 minutes prior to each infusion to reduce the frequency and severity of infusion reactions
  • Infections - In RR MS trials, 58% of ocrelizumab-treated patients experienced one or more infections compared to 52% of interferon beta-treated patients. Ocrelizumab increased the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. Ocrelizumab was not associated with an increased risk of serious infections in MS patients.
  • Progressive Multifocal Leukoencephalopathy (PML) - no cases of PML were identified in ocrelizumab clinical trials, but JC virus infection resulting in PML has been observed in patients treated with other anti-CD20 antibodies
  • Vaccines - do not administer live vaccines during therapy and until B-cell repletion. Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ocrelizumab for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ocrelizumab for non-live vaccines. In infants of mothers exposed to ocrelizumab during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19+ B-cells. You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but should consider assessing vaccine immune responses.
  • Malignancies - ocrelizumab may increase the risk of malignancy. In trials, breast cancer occurred more frequently in ocrelizumab-treated patients (6 of 781) than in interferon beta- and placebo-treated patients (0 of 668).
  • Decreased immunoglobulins - ocrelizumab may decreased total immunoglobulins with the greatest decline seen in IgM levels. Following treatment, the proportion of ocrelizumab-treated patients reporting IgG, IgA, and IgM levels below the LLN at 96 weeks was 1.5%, 2.4%, and 16.5%, respectively.
  • Decreased neutrophils - In a PP MS clinical trial, decreased neutrophil counts occurred in 13% of ocrelizumab-treated patients compared to 10% in placebo-treated patients.
  • Ocrelizumab antibodies - in trials, anti-ocrelizumab antibodies developed in ∼ 1% of patients. It is unknown if antibody production is associated with adverse events or decreased efficacy.
  • Liver disease - contraindicated in hepatitis B infection. Patients with mild hepatic impairment were included in clinical trials. No significant change in the pharmacokinetics was observed.
  • Kidney disease - patients with mild renal impairment were included in clinical trials. No significant change in the pharmacokinetics was observed.

Mitoxantrone

Dosage forms | Maintenance dosing
  • Mitoxantrone - 2 mg/ml vial | 12 mg/m² given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months

FDA-approved indication - Relapsing-remitting MS and secondary progressive MS
Efficacy
Lab/other monitoring
  • Before therapy
    • CBC and liver function tests
    • Pregnancy test
    • ECG and cardiac ECHO
  • Before each dose
    • CBC and liver function tests
    • Pregnancy test
    • ECG and cardiac ECHO
  • After therapy
    • Cardiac ECHO annually

Mechanism of action
  • Mitoxantrone intercalates into DNA through hydrogen bonding causing crosslinks and strand breaks. Mitoxantrone also interferes with RNA and is a potent inhibitor of topoisomerase II, an enzyme responsible for uncoiling and repairing damaged DNA. It has a cytocidal effect on both proliferating and nonproliferating cultured human cells, suggesting lack of cell cycle phase specificity.
  • Mitoxantrone has been shown in vitro to inhibit B cell, T cell, and macrophage proliferation and impair antigen presentation, as well as the secretion of interferon gamma, TNFα, and IL-2

Common side effects
Side effect Placebo
(N=64)
Mitoxantrone 12 mg/m²
(N=62)
Nausea 20% 76%
Alopecia 31% 61%
Menstrual disorder 26% 61%
Amenorrhea 3% 43%
Upper respiratory tract infection 52% 53%
Urinary tract infection 13% 32%
Stomatitis 8% 19%
Leukopenia 0% 19%
Arrhythmia 8% 18%
Diarrhea 11% 16%
Gamma-GT increased 3% 15%
Urine abnormal 6% 11%
ECG abnormal 3% 11%
Constipation 6% 10%
Back pain 5% 8%
SGOT increased 8% 8%
Sinusitis 2% 6%
Low granulocytes 2% 6%
Anemia 2% 6%
SGPT increased 3% 5%
Headache 5% 6%


Precautions / Contraindications
  • Pregnancy - DO NOT USE. Category D. Teratogenic.
  • Cardiotoxicity - Congestive heart failure (CHF), potentially fatal, may occur either during therapy with mitoxantrone or months to years after termination of therapy. Cardiotoxicity risk increases with cumulative mitoxantrone dose and may occur whether or not cardiac risk factors are present. Presence or history of cardiovascular disease, radiotherapy to the mediastinal/pericardial area, previous therapy with other anthracyclines or anthracenediones, or use of other cardiotoxic drugs may increase this risk. MS patients with a baseline LVEF below the lower limit of normal should not be treated with mitoxantrone. MS patients should be assessed for cardiac signs and symptoms by history, physical examination and ECG prior to each dose. Additional doses of mitoxantrone should not be administered to MS patients who have experienced either a drop in LVEF to below the lower limit of normal or a clinically significant reduction in LVEF during mitoxantrone therapy. MS patients should not receive a cumulative mitoxantrone dose greater than 140 mg/m². MS patients should undergo yearly quantitative LVEF evaluation after stopping mitoxantrone to monitor for late occurring cardiotoxicity. In cancer patients, the risk of symptomatic CHF was estimated to be 2.6% for patients receiving up to a cumulative dose of 140 mg/m²
  • Secondary leukemia - mitoxantrone therapy in patients with MS and in patients with cancer increases the risk of developing secondary acute myeloid leukemia. Publications describe leukemia risks of 0.25% to 2.8% in cohorts of patients with MS treated with mitoxantrone and followed for varying periods of time. This leukemia risk exceeds the risk of leukemia in the general population. The most commonly reported types were acute promyelocytic leukemia and acute myelocytic leukemia
  • Liver disease - patients who have hepatic impairment should ordinarily not be treated with mitoxantrone. In patients with severe hepatic impairment, the AUC is more than three times greater than the value observed in patients with normal hepatic function.
  • Kidney disease - mitoxantrone pharmacokinetics in patients with renal impairment are unknown