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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
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every 2 weeks to target dose of 0.25 mg every other day.
2
Interferon beta-1a
a. Avonex: 30 µg administered intramuscularly once
weekly or 7.5 µg once weekly to reduce flulike side
effects, increasing dose in increments of 7.5 µg once
weekly till target dose of 30 µg a week is reached.
b. Rebif: Target dose either 22 or 44 µg administered
subcutaneously three times weekly.
3
c. Plegridy: A pegylated version of Avonex that
allows for longer-lasting binding to interferon
receptor sites; thus, this only needs to be
administered subcutaneously twice monthly. Initial
dose 63 µg on day 1, 94 µg on day 15. Maintenance
125 µg every 14 days beginning on day 29.
4
Oral Therapies
Aubagio (Teriflunomide)
As the active metabolite of leflunomide, it acts as an
immunomodulatory agent by inhibiting pyrimidine synthesis
and disrupts T cells from interacting with antigen-presenting
cells. 5 It is approved for the treatment of relapsing forms of
MS in adults and is available in 7- and 14-mg doses. No
titration is needed. Side effects include hair thinning,
abdominal pain, diarrhea, and often soft stools. Liver enzymes
have to be monitored monthly for the first 6 months and then
periodically thereafter. Aubagio can cause increased blood
pressure, and although this is not considered a contraindication
for use of the drug, patients with a history of high blood
pressure should be monitored closely. 5 If a patient needs to
stop the drug abruptly because of tolerability issues or
pregnancy considerations, an elimination procedure can be
undertaken with the use of cholestyramine or activated
charcoal to quickly decrease serum levels of Aubagio.
5
Pediatric use is being evaluated in clinical trials.
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Gilenya (Fingolimod)
This is a sphingosine 1-phosphate receptor modulator
indicated and approved for the treatment of relapsing forms of
MS. 6 It binds to sphingosine receptors to block the egress of
lymphocytes (B cells, central memory and naïve T cells) from
lymphoid tissue, reducing the number of lymphocytes in
peripheral blood. Gilenya does not destroy lymphocytes but
does sequester them in lymphoid tissue; thus, CBC testing will
demonstrate lymphopenia, often with absolute lymphocyte
counts below 0.2 × 109/L. 7 This is an expected finding. Within
8 weeks of discontinuation of fingolimod, lymphocyte counts
usually return to the normal range, but CD4 and CD8 central
memory cells decrease and remain decreased over time. It was
recently approved for pediatric use.
There are some concerns relating to fingolimod adverse
reactions that should be noted by the internist. Bradycardia
and atrioventricular (AV) block can occur. Six-hour first-dose
electrocardiogram (EKG) monitoring is required for Gilenya
for monitoring of bradycardia and risk of first-degree AV
block at the initiation of dosing and at the 6-hour mark, along
with hourly blood pressure and heart rate monitoring.
6
Ophthalmological evaluation before the first dose, 3 to
4 months after therapy initiation, and yearly thereafter for
macular edema is also required.
There is an increased risk of macular edema if the patient has
underlying diabetes or uveitis. If noted, macular edema is
reversed once Gileny is discontinued. 7 Gilenya can elevate
liver enzymes; thus, patients need to have liver enzymes
monitored periodically. Progressive multifocal
leukoencephalopathy (PML) cases have been reported with
Gilenya, not thought to be related to lymphopenia. 8 The age
of the patient may play a role in increased PML risk. Other
opportunistic infections also have occurred; these include
pulmonary tuberculosis (TB), asymptomatic pulmonary
cryptococcus, and cutaneous cryptococcus, and also a case of
disseminated cryptococcus, ocular and cerebral toxoplasmosis,
visceral leishmaniasis, Kaposi sarcoma, and Merkel cell
carcinoma.
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Respiratory and herpetic infections also can occur. If patients
have frequent herpetic infections, they may not be ideal
candidates for Gilenya use; however, there can be
consideration of maintaining the patient on low-dose acyclovir
or famvir while on Gilenya. Drug-drug interactions between
Gilenya and other medications that have the potential to
prolong QT interval have to be considered. The following is
not an exhaustive list but includes some of the more frequently
used classes of drugs that can prolong QT interval and should
be avoided with Gilenya use 6 :
Antimicrobials: Levofloxacin, ciprofloxacin,
erythromycin, ketoconazole, azithromycin, chloroquine,
clarithromycin, fluconazole, moxifloxacine, pentamidine
Antidepressants: Amitriptyline, desipramine,
imipramine, fluoxetine, sertraline, venlafaxine,
escitalopram, citalopram
Antipsychotics: Haloperidol, quetiapine,
chlorpromazine, thioridazine
Others: Sumatriptan, zolmitriptan, methadone,
ondansetron, propofol, donepezil, droperidol
Antiarrhythmics: Amiodarone, quinidine, procainamide
Tecfidera (Dimethyl Fumarate)
Tecfidera is indicated for relapsing forms of MS. It is a twicedaily oral medication, recommended usually to be taken with
breakfast and dinner. In the 2-year DEFINE trial, comparing
Tecfidera with placebo, there was a 49% relative risk
reduction of relapses compared with placebo. 9 Taking
Tecfidera with food decreases flushing and abdominal pain.
Flushing and abdominal pain seen with Tecfidera are most
common within the first month of use and then significantly
decrease thereafter. Non-enteric-coated aspirin before dosing
also decreases flushing. CBC with differential and liver
function tests (LFTs) should be drawn before Tecfidera use
and repeated at least every 6 months. If someone has a serious
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infection, then it is important to hold treatment with Tecfidera
until infection is resolved.
In the clinical trials, mean lymphocyte counts decreased about
30% during the first year of treatment. If lymphocyte count is
less than 500 and persists greater than 6 months, then the drug
should be discontinued. Repeat lymphocyte testing should be
performed until counts return to normal. Tecfidera should not
be used during pregnancy or breastfeeding. If anyone does
become pregnant while taking Tecfidera, she should
discontinue treatment and enroll in
Tecfiderapregnancyregistry.com. Increased LFTs have been
observed with Tecfidera, and because of this it is important to
check LFTs periodically, on average every 6 months. Tecfidera
may cause liver injury. PML cases have been seen with
Tecfidera and seem to be associated with lower lymphocyte
counts. Infections other than PML appear to be rare with
Tecfidera.
Monoclonal Antibodies (Infusion
Therapies)
Lemtrada (Alemtuzumab)
This is a monoclonal antibody given in two treatment cycles.
Year 1 it is administered 5 days in a row and then year 2,
3 days in a row. Lemtrada targets the CD52 molecule
expressed on T and B leukocytes. Because intravenous
administration of Lemtrada causes lysis of these cells, infusion
reactions can occur as a result of these cells being depleted,
causing cytokine release syndrome. Pretreatment with steroids
and antihistamines helps to decrease these reactions. Once the
immune system starts to reconstitute, secondary autoimmunity
can occur. Monthly CBC with differential to monitor for
autoimmune thrombocytopenia, and urinalysis and serum
creatinine to monitor for Goodpasture syndrome, is required
monthly up to 4 years after the last infusion. The urine protein
to creatinine ratio needs to be obtained before starting the drug
and at periodic intervals up to 48 months after last infusion.
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Thyroid function testing is required every 3 months. Human
immunodeficiency virus testing before starting the drug is also
required by the US Food and Drug Administration (FDA).
Hepatitis B and hepatitis C carriers who receive Lemtrada may
be at risk of irreversible liver damage relative to potential
virus reactivation. Yearly skin examination is also required
because of increased risk of melanoma. Annual HPV
screening is recommended for women. Before starting
Lemtrada the following tests are recommended:
TB screen
Varicella zoster titer
CBC with differential
Urinalysis
Thyroid function profile
Serum creatinine
Urine protein to creatinine ratio
If a woman is of childbearing potential, it is important to make
sure that she is not pregnant before initiating treatment.
Contraceptive therapy is recommended, and patients should
not try to get pregnant for at least 6 months after Lemtrada
infusion. Anyone who has any active infection should not
proceed with the infusion but should wait until the infection is
cleared before treating. Tattoos also should be avoided for at
least 8 weeks after infusion to help prevent infection.
Acyclovir must be given at the start of treatment and
continued for at least 2 months. If the CD4 count is still below
200 at that time, acyclovir needs to be continued until the
count is 200 or above. Regarding lymphopenia, even though
repopulation of cells occurs, 20% of patients had below
normal lymphocyte counts after 12 months. The following are
certain infections and other safety precautions with Lemtrada
that should be recognized:
Acute acalculous cholecystitis was seen in eight patients
who received Lemtrada for relapsing MS. Seven
developed acute acalculous cystitis during or shortly after
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receiving Lemtrada, and one person developed it 6 to
7 weeks after infusion. Frequency of this risk is estimated
at 0.2%
10
Acute coronary syndrome is possible. A young
otherwise healthy woman developed cardiac ischemia
midway through a Lemtrada infusion. The mechanism
may have been related to increased endothelial and
myocyte membrane permeability and vasodilation via
cytokine release syndrome and could lead to an increased
demand and ischemia of the myocardium. This
underscores the need for monitoring of vital signs during
infusion and vigilance for potential cardiac events. EKG
monitoring at this point is not required but may be up to
the discretion of the treating neurologist
11
Listeria was first reported with Lemtrada use in
2008.Dietary precautions are important to emphasize to
patients, particularly avoiding uncooked meats and fish,
unpasteurized soft cheeses, dairy products, and juices for
at least 4 months after infusion. The risk of Listeria
meningitis is the highest in the first month after each
Lemtrada cycle. However, owing to the concern that
patients may not follow dietary precautions, preventive
treatment with sulfamethoxazole-trimethoprim is now
recommended in the United Kingdom. If it is unlikely
that the patient will be compliant with diet, cotrimoxazole 960 mg three times weekly for 1 month is
recommended. If patients are adherent to following a
Listeria-free diet, another treatment option is 8 days of
amoxicillin 1 g three times daily or co-trimoxazole
960 mg twice daily, which would eliminate Listeria
colonization before treatment
Hemophagocytic lymphohistiocytosis occurred in two
patients treated with Lemtrada for leukemia, but this was
not seen in MS
Pulmonary nocardia beijingensis infection
Pneumonitis
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Ischemic and hemorrhagic stroke and cervicocephalic
arterial dissection is a rare but serious complication that
can occur shortly after Lemtrada use. Health care
providers need to advise patients at every Lemtrada
infusion to seek emergency medical attention if they have
symptoms of numbness, or weakness, visual symptoms,
sudden difficulty with walking or balance, or sudden
severe headache or neck pain
12
Ocrevus (Ocrelizumab)
Ocrevus is a B cell–directed humanized monoclonal antibody,
targeting the CD20 antigen expressed on mature B cells. It is
the first FDA-approved therapy for primary progressive MS
and FDA approved for relapsing forms of MS. It targets pro-B
cells in the bone marrow but spares CD20-negative plasma
cells that produce antibodies. The main effect of the anti-CD
20 therapy seems to maintain adequate antibody levels but
reduces antigen presenting and cytokine secreting functions of
B cells. Compared with rituximab, Ocrevus has a higher
capacity for direct, antibody-dependent cell toxicity.
In the OPERA study comparing ocrelizumab with interferon
beta-1a, the infection rate was 58.4% in the Ocrevus-treated
group and 52.4% in the interferon beta-1a group. Main
infections noted were upper respiratory tract infections and
nasopharyngitis. Most infections were considered mild to
moderate. There were no deaths related to infection in
OPERA, which analyzed relapsing patients, and in the
ORATORIO study, which analyzed progressive patients and
compared ocrelizumab with placebo, there were two deaths,
due to pneumonia, one of which was aspiration pneumonia,
not thought to be related to ocrelizumab. Since ocrelizumab
has been FDA approved there have been six cases of PML
reported all in patients who had transitioned to Ocrevus from
Tysabri who were John Cunningham virus (JCV) antibody
positive. Ocrevus can cause reactivation of hepatitis B
infection, and hepatitis panel is required before its use.
Tysabri (Natalizumab)
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Tysabri is the first monoclonal antibody approved to treat
relapsing MS. The mechanism of action includes blocking
alpha4 integrin on lymphocytes, decreasing trafficking of
lymphocytes into the central nervous system. There are risks
of infection when using Tysabri that should be noted. Patients
who are taking Tysabri and have positive JCV antibodies have
a higher risk of developing PML. The risk is higher for
patients who are JCV antibody positive who have been taking
Tysabri for longer than 2 years and have been on prior
immunosuppressive therapy. Besides being able to detect if a
patient is JCV antibody positive, the clinician can use the JCV
index to know the exact titer level. For those taking Tysabri
for 25 to 36 months without prior immunosuppressive use, the
PML risk is 0.2/1000 in those with index of 0.9 or less,
0.3/1000 with index of 0.9 to 1.5, and 3/1000 in those with
index greater than 1.5.
Herpes infections have also been reported with natalizumab.
13
An important point to keep in mind is that PML can be
mistaken for relapse activity or worsening of underlying MS
symptoms and may not be recognized. Sometimes the only
change that is noticed is cognitive change or altered mental
status, and MRI may be the only way that early changes of
PML may be noted, so consistent monitoring and being alert to
any change in behavior or function are important. Clinical
trials studying extended interval dosing of natalizumab from
every 28 days to every 6 weeks to possibly maintain efficacy
and decrease risk of PML are ongoing.
Rituxan (Rituximab)
Rituximab is a chimeric monoclonal antibody directed against
the CD 20 antigen on B cells (the epitope is different from that
of Ocrevus). It is not FDA approved for MS but has been used
particularly for patients who have failed other MS therapies
and is the standard of care for the treatment of neuromyelitis
optica. 14 It is used for the treatment of B cell lymphoma,
lymphoproliferative disorders, rheumatoid arthritis, and
systemic lupus erythematosus refractory to other treatments.
Many of the infections seen with rituximab have occurred in
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the setting of its use in the treatment of patients with
rheumatoid arthritis where it was used in combination with
other immunosuppressive therapies, for example,
cyclophosphamide or methotrexate. It varies also from
ocrelizumab in that rituximab has a greater effect on
complement-dependent cytotoxicity than ocrelizumab.
Dalfampridine (Ampyra)
Dalfampridine is not a DMT but is a treatment that is often
used as an adjunct for patients who are experiencing walking
difficulties. It is a potassium channel blocker that helps to
improve conduction along demyelinated nerve fibers.
Approximately 33% to 40% of patients are positive responders
to the drug, measured in clinical trials by improvement in 25foot timed walking speed. On average, patients who were
positive responders had an approximately 25% improvement
in walking speed. This correlated with clinically meaningful
quality-of-life measures. The main concern with Ampyra is
that patients need to have a creatinine clearance rate above 50.
The standard dose is 10 mg twice daily, taken 12 hours apart.
Seizures can be a side effect of the medication. A decrease in
the creatinine clearance or taking the drug too close together
could increase levels of dalfampridine within the blood stream.
So What Will the Future Hold?
Progress is still being made to develop new DMT for the
patient with MS. Many potential DMT that are in clinical trials
show great potential for future treatment. The following are
several of the agents currently in clinical trials:
Ofatumumab (subcutaneous anti-CD20-directed
monoclonal antibody) for relapsing forms of MS
Ublituximab (intravenous anti-CD20 monoclonal
antibody)
Cladribine, FDA approved March 2019, oral agent,
purine antimetabolite, considered cytotoxic. It is
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administered in two oral yearly treatment courses,
causing prolonged lymphopenia. It will generally be
recommended for patients who have either tolerability or
efficacy failure with prior DMT. It is also contraindicated
in patients with chronic infections, HIV, current
malignancy and TB. It should not be used during
pregnancy or breastfeeding.
40
Ozanimod, siponimod (these are both more selective
S1P1 receptor agonists). Siponimod recently received
FDA approval for use in relapsing and active secondary
progressive patients
Biotin (vitamin B7) is a water-soluble vitamin, currently
in phase 3 trial; high-dose biotin 100 mg three times daily
for progressive MS. Early studies have shown
improvement in slowing disability progression
Ibudilast—oral phosphodiesterase-4 and 10 inhibitor
showed slowing of whole brain atrophy and may be a
future treatment for progressive disease
Therapeutic approaches using autologous hematopoietic
stem cells and mesenchymal stem cells are being
investigated in clinical trials as MS treatments. To date,
the best success has been seen in younger patients with
highly active disease. Helpful websites for patients to get
information on stem cell research are http://www.iscr.org
and http://www.celltherapysociety.org
15
Diets to help modulate the gut microbiome and vaccine
targeting EBV are also being studied
Vaccinations
Vaccinations play an important role in public health by
prevention of communicable illnesses.16 Benefits of long-term
preventive immunity often outweigh risks associated with the
vaccine. Infections can often worsen MS symptoms, so
vaccinations that help in the prevention of febrile illnesses can
decrease infections and minimize relapse risk.17 Generally,
inactivated vaccines that have killed viral components have a
low risk versus benefit.16 Even with these considerations,
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