Metoclopramide, ondansetron, dromperidone, antacids, H2
proton pump inhibitors, and antidiarrheals have been recommended to combat the GI
symptoms, and antihistamines have been used for flushing but no testing of these
approaches has been performed.
181 Lyphopenia occurs in about 2% of patients taking
dimethyl fumarate; however, mean lymphocyte count decreases by about 30% in the
first year of treatment and then stabilizes. Patients should have a complete blood
count at baseline and then annually.
aspirin 325 mg PO 30 minutes prior to dosing could be recommended. If she
experiences GI problems, those could be treated symptomatically.
CASE 57-1, QUESTION 7: C.B. continued on therapy with dimethyl fumarate. However, 1 year later, she
MRI shows several new, gadolinium-enhancing lesions. What therapy should be recommended for acute
treatment of C.B.’s current relapse? Would you change her maintenance therapy at this time?
Corticosteroids should be used to decrease the time to recover from acute
relapses. The most commonly used regimen is 500 to 1,000 mg intravenous
methylprednisolone daily for 3 to 5 days with or without a subsequent regimen of
tapering dose oral steroids for 1 to 3 weeks.
183 Comparison of oral and intravenous
corticosteroid treatment shows that there are no major differences in clinical
outcomes, and both treatments appear to be equally effective and safe.
recommended oral corticosteroid regimen is prednisone 1,250 mg daily every other
184 Some investigators have attempted to use corticosteroids on a
chronic basis, giving pulse doses of one or several days monthly; however, this type
of regimen does not affect disability progression and should not be
185 Because C.B. is already hospitalized, she should receive
methylprednisolone 1,000 mg intravenously daily for 3 days. If she were an
outpatient, either intravenous or oral steroid therapy could be recommended, but an
oral corticosteroid regimen would be more convenient.
As MS therapies become more effective, tolerance for relapses has decreased. No
evidence of disease activity (NEDA) is a composite measure that indicates that there
186 An expert panel was convened to help further clarify this
classification of NEDA. This group developed a multiple sclerosis decision model
(MSDM) which takes into consideration the domains of relapses, progression,
neuropsychology factors, and MRI findings.
187 Points are assigned for each of these
domains based on assessments, and users are guided to maintain therapy, closely
monitor, or change therapy. However, a number of assessments are required to assign
the points which may not be practical in many clinic settings. Percentages of patients
in clinical trials achieving NEDA status are between 28% and 42% over the first 2
years of therapy; however, this number appears to drop to around 8% after 7 years in
It appears that C.B. is failing treatment with dimethyl fumarate because she has
experienced two relapses within approximately 1 year and has substantial new lesion
formation on MRI; there are several alternatives at this point. C.B. could change to
another first-line therapy (β interferon, or teriflunomide) or she could begin therapy
with a second-line agent: mitoxantrone, natalizumab, or fingolimod. There are direct
comparator studies of first- and second-line agents (Table 57-8). Additionally, an
observational study has addressed the question of the efficacy of the second-line
therapies, natalizumab and fingolimod.
annualized relapse rate for those changed to natalizumab was reduced from 1.5 to 0.2
whereas the rate for those changed to fingolimod was reduced from 1.5 to 0.4 (p =
0.02). A careful discussion of the potential risks and benefits of each possible
treatment will ensure that the patient is well educated on the options and that an
appropriate selection is made.
adverse effects of fingolimod? What monitoring will be necessary?
In studies of fingolimod, 70.4% of patients remained relapse-free for 2 years
compared with 45.6% for those treated with placebo. At 1 year, 82.6% of
fingolimod-treated patients were relapse-free compared with 69.3% of those treated
with interferon β-1a intramuscularly. The annualized relapse rate was 0.16/year for
fingolimod, 0.40/year for placebo, and 0.33/year for interferon β-1a
92 C.B. should expect good suppression of her MS with fingolimod
Because S1P receptors (the targets of fingolimod therapy) are not confined to
lymphocytes, adverse effects of fingolimod may affect other body organs and tissues.
For example, a transient, dose-dependent reduction in heart rate can occur within 1
hour after the first fingolimod dose (bradycardia in 1.3%); first- and second-degree
atrioventricular block can also occur (0.1% and 0.2%, respectively).
with pre-existing sinus bradycardia or heart block without pacemakers should not be
given fingolimod. Other adverse effects include macular edema and a reduction in
91 Because the mechanism of action of fingolimod is to prevent
lymphocytes from circulating, there is a reduction in peripheral blood lymphocytes
and an increase in infections and, possibly, cancers.
91 This reduction in peripheral
blood lymphocytes is reversible within 4 to 8 weeks of discontinuation of
49 Fingolimod does not inhibit humoral immunity to infections.
Progressive multifocal leukoencephalopathy (PML) has been reported in patients
191 PML is caused by JC DNA polyomavirus (JCV) reactivation.
JCV then causes an infection of oligodendrocytes that is often fatal or causes
4 Dormant JCV infection is relatively common, with 50% to
86% of adults having antibodies to JCV. When a patient is immunosuppressed, JCV
192 PML is rapidly progressive and has a mortality rate of
193 Symptoms of PML include neurobehavioral, motor, language,
and cognitive changes; seizures; vision changes; hemiparesis; and tremor.
Notably, all of these symptoms could be mistaken for an MS relapse.
Baseline Testing and Monitoring Associated with Fingolimod
Varicella zoster immunity evaluation and vaccination, if needed
Ophthalmology evaluation for macular edema
Dermatologic evaluation for melanomas
Forced expiratory volume in 1 second (FEV1
) or full pulmonary function testing, if patient has history of asthma
or chronic obstructive pulmonary disease
Observe in clinical area for 6 hours after initial dose with monitoring of blood pressure and pulse
Ophthalmology evaluation at 4 months and as needed thereafter
Complete blood count every 6 months
Liver function tests every 6 months
Dermatologic evaluation as needed
Increases in liver enzymes (transaminase and bilirubin) have also been
92 Because fingolimod has a long half-life of 9 to 10 days, its
pharmacologic effects will still be present for up to 2 months after therapy is
196 Baseline testing and continued monitoring recommended with the use
of fingolimod is summarized in Table 57-9. Fingolimod should be given as
monotherapy, and the patient should not have had a relapse or have been treated with
corticosteroids within 30 days of starting treatment. If patients do not have an existing
history of varicella zoster infection or vaccination, vaccination evaluation should be
196 Rates of varicella infections are between 7 and 11/1,000 patientyears.
197 C.B. should wait for 30 days after her relapse and any corticosteroid
treatment before starting fingolimod. During this time, she can have baseline testing
before starting treatment. She should be educated on potential adverse effects and the
long-lasting pharmacologic effects of fingolimod that may persist for up to 2 months
after therapy is discontinued.
considering having another child. How should C.B. be counseled regarding fingolimod therapy during
It is well documented that the rate of relapses for women with MS decreases
during pregnancy, increases in the first 3 months after delivery, then returns to the
198 No treatment for MS is recommended for use during
pregnancy, and some therapies, such as mitoxantrone, require pregnancy tests before
each infusion. However, there are limited data regarding the exposure of fetuses to
some of the treatments for MS when given during early pregnancy. No increase in
spontaneous abortions or stillbirths was seen with glatiramer acetate or β
199–201 However, very few of these exposures were for the full term of
pregnancy. A report of 66 pregnancies in women taking fingolimod found fetal
abnormalities in 7.6%. In all of these cases, the exposure was in the first trimester.
Pregnancy is contraindicated during treatment with teriflunomide, with contraception
required for both women and men.
203 Eighty-nine pregnancies (70 in women exposed
to teriflunomide and 19 in partners of men exposed to teriflunomide) were reported
during clinical trials. Of these, 42 healthy live births, 31 induced abortions, and 14
spontaneous abortions were reported. It should be noted that in almost all cases,
teriflunomide was stopped and accelerated elimination procedures were undertaken
as soon as the pregnancy was known to minimize fetal exposure.
also contraindicated during pregnancy. Women should use adequate contraceptive
measures during treatment and for 4 months following treatment. Alemtuzumab can
cause thyroid disorders which, during pregnancy, can have serious adverse effects on
In general, MS therapy should be discontinued before conception. In the case of
C.B., she should be advised that she would need to discontinue fingolimod at least 2
months before conception and stay off the medication while pregnant. It is not known
whether fingolimod is excreted into the breast milk of nursing women.
the potential adverse effects of fingolimod on an infant’s immune system, she should
be advised either to not breast-feed or to abstain from taking fingolimod during
CASE 57-1, QUESTION 10: C.B. discontinued fingolimod, conceived approximately 4 months later, and
How should her fatigue be addressed?
Nonpharmacologic therapy such as stretching may help with C.B.’s spasticity. Her
symptoms are more generalized (involving the lower extremities) than localized, so
systemic therapy may be more beneficial than localized therapy such as splinting or
botulinum toxin injections (therapies that might be considered if only her toes were
131 Systemic therapies that may relieve spasticity include baclofen and
tizanidine; because both agents appear to be equally effective, neither agent is
preferred over the other for C.B.
Although fatigue is a common problem when caring for infants, C.B. also may be
experiencing fatigue related to her MS. She would likely benefit from
nonpharmacologic therapy such as avoiding sleep deprivation to the extent possible
and concentrating her infant care during the morning hours, enlisting more assistance
in the afternoon and evening. She should also be assessed for any symptoms of
QUESTION 1: N.R. is a 47-year-old woman who was diagnosed with relapsing-remitting MS 5 years ago.
How might this result assist in the recommendation of future therapy for N.R.?
Neutralizing antibodies develop in many patients given therapy for MS, including
β interferons, natalizumab, and alemtuzumab. Neutralizing antibodies are seen in up
to 44% of patients given interferon β.
93 Fewer patients given interferon β-1a
intramuscularly once weekly develop them than those given interferon β-1a
subcutaneously 3 times weekly or interferon β-1b subcutaneously every other day.
For patients with persistently high antibody titers, their relapse rates are also
93 With time, neutralizing antibodies often disappear.
Despite these observations, the indications for neutralizing antibody testing and the
interpretation of test results are areas of ongoing controversy. The Therapeutics and
Technology Assessment Subcommittee of the American Academy of Neurology has
issued the following statements regarding neutralizing antibodies to interferon β: (a)
treatment with interferon β is associated with the production of neutralizing
antibodies; (b) it is probable that neutralizing antibodies, especially in persistently
high titers, are associated with a reduction in the radiographic and clinical
effectiveness of treatment; (c) it is probable that the rate of neutralizing antibody
production is less with interferon β-1a compared with interferon β-1b treatment; (d)
it is probable that the seroprevalence of neutralizing antibodies is affected by one or
more of the following: formulation, dose, route of administration, or frequency of
administration of interferon β; and (e) there is insufficient information on the
utilization of neutralizing antibody testing to provide specific recommendations
regarding the indications for testing or interpretation of antibody titer results.
A panel of MS and neutralizing antibody experts was convened in 2009 to develop
practical recommendations. Some of their findings included are as follows: (a)
Persistently high titers might provide sufficient guidance to suggest stopping therapy
in a patient; however, with low or intermediate titers, additional information might
be needed to make a decision regarding therapy continuation; (b) different interferon
β products are associated with different rates of antibody formation; chemical
formulation, route of administration, and frequency of dosing appear to have an
effect; and different formulations of the same molecule may result in different
immunogenicity; and (c) to minimize assay variability, antibody measurements should
be done in laboratories that have fulfilled the criteria for validation of neutralizing
antibody assays, and interferon β-1a should be used in the assays to standardize the
207 Thus, there is continued discussion about the appropriate use of
neutralizing antibody assays for β interferons.
Antibodies also form to therapies for MS other than the β interferons. Up to 95%
of patients treated with glatiramer acetate have antibodies, but they do not appear to
change the efficacy of glatiramer acetate.
natalizumab and may affect treatment efficacy or increase the likelihood of
natalizumab infusion reactions. Many patients who express antibodies to natalizumab
do so within the first 6 months of treatment, but these antibodies often disappear with
continued treatment. Antibodies to natalizumab are more likely to persist if they
develop more than 6 months after treatment initiation.
associated with increased rates of relapse.
209 Neutralizing antibodies have been
detected with alemtuzumab, but they do not appear to affect efficacy.
N.R. has a high titer of neutralizing antibodies, and they appear to be associated
with a decline in efficacy of her interferon β-1b. Therefore, it would seem
appropriate to change therapy at this time. Options would include glatiramer acetate,
dimethyl fumarate, teriflunomide, alemtuzumab, mitoxantrone, natalizumab, or
fingolimod. Because of the potential for cross-reactivity of the neutralizing
antibodies to other β interferons, a change to another β interferon product would not
be expected to provide benefit.
CASE 57-2, QUESTION 2: N.R.’s interferon β-1b therapy was discontinued, and she was begun on
teriflunomide 14 mg PO daily. What monitoring will be required while taking this medicine?
Elevated ALT, alopecia, and diarrhea were seen in 10% to 20% of patients in
clinical trials and more commonly in patients treated with teriflunomide than with
203 White blood cell counts decrease by about 15% and platelets by about
10% during the first 6 weeks of teriflunomide treatment, and remain low throughout
the treatment. A CBC is recommended at baseline.
immunosuppression seen, patients should be monitored for infection, and patients
should not receive live virus vaccines while under the effects of teriflunomide.
Modest increases in blood pressure were also observed. Other required monitoring
includes baseline liver enzymes and bilirubin, blood pressure, and screening for
latent tuberculosis infection. The monitoring of ALT should occur monthly for the
first 6 months of therapy and periodically thereafter.
203 Teriflunomide rarely causes
the serious adverse effects of peripheral neuropathy, acute renal failure,
hyperkalemia, and bone marrow suppression.
101 Serious adverse effects are not
reported with teriflunomide, but those seen with the parent drug leflunomide are
Stevens–Johnson syndrome, interstitial lung disease, and hepatotoxicity.
Teriflunomide has a very long half-life of approximately 18 days.
it can take up to 3 months to achieve steadystate serum concentrations and a
proportionally long time to eliminate the medicine (8–24 months). In situations
requiring rapid elimination of teriflunomide (e.g., serious adverse effects, desired
pregnancy), accelerated elimination procedures are recommended. The
recommended accelerated elimination procedures are administration of
cholestyramine 8 g every 8 hours for 11 days or administration of activated charcoal
powder 50 g every 12 hours for 11 days. Verification of elimination should be
undertaken by two teriflunomide serum concentrations of <0.02 mcg/mL taken 2
Prior to N.R. starting teriflunomide, her immunization status should be carefully
checked and she should be screened for tuberculosis. If necessary, her immunizations
should be updated and any infectious diseases should be completely treated before
starting therapy. She should have a baseline CBC, liver enzymes, bilirubin, and
blood pressure. Monthly for the first 6 months, she should have blood drawn for
ALT. This would also be an opportune time to check blood pressure and screen for
Common adverse effects of mitoxantrone include nausea, menstrual abnormalities,
alopecia, upper respiratory and urinary tract infections, neutropenia, and a temporary
change to blue color in the urine and sclera.
210 Dose-related cardiotoxicity occurs
with mitoxantrone use, requiring an estimation of left ventricular ejection fraction
211 The dose of mitoxantrone for MS is 12 mg/m2 given as a 5- to
15-minute intravenous infusion every 3 months.
211 Cardiotoxicity limits the lifetime
dose of mitoxantrone to 140 mg/m2 or approximately 3 years of therapy. The most
common cardiotoxic effects are cardiomyopathy, decreased left ventricular ejection
fraction, and irreversible congestive heart failure.
210 Approximately 12% of patients
experience decreased left ventricular ejection fraction, and 0.4% exhibit congestive
212 Treatment-related acute leukemia may occur in 0.81% of
mitoxantrone-treated patients. Most cases of leukemia present during the first few
years of mitoxantrone therapy, and the development of leukemia may be dose
It appears that limiting the cumulative dose of mitoxantrone to <60 mg/m2
may reduce the risk of leukemia.
213 Recommended monitoring for patients taking
mitoxantrone is presented in Table 57-10. It should be noted that adherence to
mitoxantrone monitoring recommendations is low. In a review of 548 patients, 78%
had complete blood counts, 54% had liver function tests, 18% had left ventricular
ejection fraction determinations, and 10% of women had pregnancy tests before each
214 Because of the cardiac and leukemia concerns, mitoxantrone is rarely
Monitoring Required for Mitoxantrone Use
Left ventricular ejection fraction
Left ventricular ejection fraction yearly to monitor for late development of cardiotoxicity
Adverse effects of natalizumab include fatigue, liver dysfunction, infections,
hypersensitivity reactions, and infusion-related reactions.
reactions are IgE-mediated and occur within 2 hours of the start of the infusion.
Patients who exhibit HLA-DRB1*13 or HLA-DRB*14 are more likely to have
216 Genotyping may be helpful to identify these patients
prior to natalizumab prescribing. Symptoms include urticaria, dyspnea, and
circulatory, and vital sign changes. If these symptoms occur, the infusion should be
headache, dizziness, fatigue, nausea, sweats, and rigors. If this type of reaction
occurs, there is no need to discontinue therapy; the patient can be pretreated with
histamine type 1 and 2 receptor antagonists and acetaminophen.
PML caused the suspension of natalizumab sales shortly after its introduction.
Natalizumab was later reintroduced to the market with a limited distribution system
and extensive monitoring requirements.
From 2005 to 2009, 28 cases of PML in natalizumab-treated patients were
reported in addition to the three cases reported previously. During that period,
approximately 65,000 patients with MS were exposed to natalizumab. However, it
appears that PML risk is proportional to the duration of natalizumab exposure; one
case is reported per 1,000 patients in those who have received 24 or more
195 Overall, reporting appears to occur at a rate of one or two per month.
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