Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2745_Библиотеки_им_академика_М_И_Перельмана
.pdf
due to the preexisting disease or new diagnosis. Consider a
patient with diabetes who presents with sensory symptoms;
these may be related to diabetic neuropathy or MS disease
progression, and determining the origin of these symptoms is
critical for treatment.
Communication between neurologists and other medical
specialties may help to avoid drug-drug interactions and
adverse events such as hospitalization. As essential as it is to
make an accurate MS diagnosis and begin an appropriate
DMT, preventing and managing comorbidities can be equally
important in slowing the progression of disability. The greater
the number of comorbidities a patient has, the more likely they
are to switch from their first DMT therapy and less likely they
are to remain on DMT that may be most effective at
preventing MS progression.
20
Comorbidities Can Increase Mortality
Compared with the general population, mortality in MS is
increased, with a life expectancy on average 10 years shorter.
21
It stands to reason that the addition of comorbidities has the
potential to further decrease life expectancy. 21 One Canadian
study found ischemic heart disease, depression, diabetes, and
lung comorbidities to increase mortality in MS. 22 Managing
underlying comorbidities, treating depression and anxiety are
challenges often faced by internists caring for MS patients.
13
Counseling on smoking cessation is also often a challenge, but
very important as smoking has been shown to contribute to
disability progression.
Comorbidities Can Affect Disability
Several cross sectional studies have suggested that an increase
in comorbidities correlates to an increase in disability. For
example, one study examining cardiovascular risk scores in
MS found a direct relationship between the Framingham
General Cardiovascular Disease Risk Score and MS severity
scale. 23 The NARCOMS had suggested that increased
https://t.me/medicina_free
vascular comorbidities such as heart disease and diabetes
increased risk of walking difficulties.
16
Lifestyle Choices Affect Disease
Progression
Neurologists, MS specialists, and other nonneurological
specialists must coordinate to formulate a treatment approach,
the ultimate objective being overall wellness. Diet has proven
to play an important role in symptom severity and disability.
Diet and exercise have been associated with decreased
disability and also decrease in symptoms such as fatigue,
depression, and pain. 19 Maintaining a healthy diet can
contribute to the slowing of disease progression. A recent
study found an increase in lesions on MRI imaging in MS
patients with hyperlipidemia.
24,25
It is essential to encourage
and educate patients about the benefits of optimal health
behaviors, such as smoking cessation, maintaining a healthy
weight and physical activity benefits. Some of the health
measures important in MS management include smoking
cessation, normalizing vitamin D levels, maintaining healthy
body weight (with BMI < 25), encouraging a diet high in fruits
and vegetables and whole grains and low in sugar and red
meat, exercise, and social stimulation.
24,26
Smoking is
particularly injurious, given the effects it can have not only on
MS disability but many common comorbid vascular conditions
such as hypertension and heart disease. Identification of
comorbidities, increasing patient awareness of the severity and
need for treatment of these diseases, and coordinating with the
primary care doctor can have a positive impact on healthrelated outcomes. 27 An example of a patient case study where
interdisciplinary coordination improved overall level of
functioning is the following.
A 44-year-old woman, with a history of relapsing MS, who
although had been relapse free while being treated with
Tysabri, became John Cunningham virus antibody positive,
and decision was made to switch to rituximab. She was
experiencing severe frequent migraines, occurring at least 15
times monthly. She also had history of chronic low-back pain
https://t.me/medicina_free
which had led her to become dependent on narcotic
medications. Depression was also present in part due to
chronic pain and decreased ability to function. Sleep was
impaired and this was contributing to increase in day time
fatigue. She was unable to work. To best manage this patient, a
multipronged approach was necessary. She was switched to
rituximab for her DMT and has responded well. She has no
new MRI lesions or relapses. For her lower back pain,
physical therapy was recommended and she was also referred
to pain specialist who did try epidural injections to decrease
pain but what did eventually provide patient with significant
overall pain relief was the use of medicinal marijuana. She
was able to eliminate use of narcotics and other anticonvulsant
medications she had taken for pain relief such as gabapentin.
Magnesium supplement helped with nighttime cramping that
she experienced. She was referred to psychiatry who treated
her with low-dose venlafaxine for depression. Botox injections
have been used for chronic migraine, and these are
significantly improved. She has resumed part time work and is
also doing yoga, which has been beneficial for her back pain.
Regarding vaccinations, she received Shingrix first dose
4 weeks before rituximab infusion.
In the next chapter, we will have greater discussion of
vaccination use in MS patients and the various DMTs and their
monitoring requirements.
References
Olek MJ, Howard J. Treatment of Acute Exacerbations of Multiple Sclerosis in
Adults. In: Dashe JF , ed. Wolters Kluwer; 2018 (19).
https://www.uptodate.com/contents/treatment-of-acute-exacerbations-ofmultiple-sclerosis-in-adults?
search=multiple%20sclerosis%20relapse&source=search_result&selectedTitle=
1∼99&usage_type=default&display_rank=1. Accesed November 10, 2018.
Nielsen NM, Rostgaard K, Rasmussen S, et al. Cancer risk among patients with
multiple sclerosis: a population based register study. Int J Cancer.
2006;118:979-984.
Marrie RA, Reider N, Cohen J, et al. Systematic review of the incidence and
prevalence of cancer in multiple sclerosis. Mult Scler J. 2014;21(3):294-304.
Tysabri (Natalizumab). Biogen. 2018. https://www.tysabri.com/?cid=PPC-GGL-
TY.DTC.Tysabri_DTC_Branded_Phrase.Phrase-NA-
https://t.me/medicina_free
19104&gclid=EAIaIQobChMI5qr74aLV3gIVxFqGCh0oFAH4EAAYASAAEgI
1PPD_BwE&gclsrc=aw.ds. Accessed November 14, 2018.
Polman CH, O’Connor PW, Havrdova E, et al. A randomized, placebo-controlled
trial of natalizumab for relapsing multiple sclerosis. NEJM. 2006;354(9):899-
910.
Oconnor P, Comi G, Montalban X, et al. Oral fingolimod (FTY720) in multiple
sclerosis: two-year results of a phase II extension study. Neurology.
2009;72(1):73-79. doi:10.1212/01.wnl.0000338569.32367.3d.
Olek MJ. Disease-Modifying Treatment of Relapsing-Remitting Multiple Sclerosis
in Adults. In: Dashe JF , ed. Wolters Kluwer; 2018 (84).
https://www.uptodate.com/contents/disease-modifying-treatment-of-relapsingremitting-multiple-sclerosis-in-adults?
search=copaxone&source=search_result&selectedTitle=2∼15&usage_type=def
ault&display_rank=1. Accessed November 10, 2018.
Ocrevus (Ocrelizumab). Genentech. 2018. https://www.ocrevus.com/hcp.html?
cid=ocr_PS_MNOVMSH0396_14&c=MNOVMSH0396&gclid=EAIaIQobCh
MIzKuqaTV3gIVCVqGCh3jzgR0EAAYASAAEgLEdfD_BwE&gclsrc=aw.ds.
Accessed November 14, 2018.
Lemtrada (Alemtuzumab). Genzyme. 2018. https://www.lemtradahcp.com/?
s_mcid=ps-LP-google-BRinfo-BRsafety-BROfficialSite. Accessed November
14, 2018.
Gijsen R, Hoeymans N, Schellevis FG, Ruwaard D, Satariano WA, van Den Bos
GAM. Causes and consequences of comorbidity: a review. J Clin Epidemiol.
2001:54:661-674.
Marrie RA, Horvitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. Comorbidity,
socioeconomic status and multiple sclerosis. Mult Scler. 2008;14:1091-1098.
Marrie RA, Reider N, Cohen J, et al. A systematic review of the incidence and
prevalence of sleep disorders and seizure disorders in multiple sclerosis. Mult
Scler. 2015;21:342-349.
Marrie RA. Comorbidity in multiple sclerosis: implications for patient care. Nat
Rev Neurol. 2017;13:375-382.
Zhang T, Tremlett H, Leung S, et al. Examining the effects of comorbidities on
disease modifying therapies in multiple sclerosis. Neurology. 2016;86:1287-
1295.
Kowalec K, McKay K, Patten S, et al. Comorbidity increases the risk of relapse in
multiple sclerosis. Neurology. 2017;89:2455-2461.
Marrie RA, Rudick R, Horwitz R, et al. Vascular comorbidity is associated with
more rapid disability progression in multiple sclerosis: overview. Mult Scler.
2015:21(3):263-281.
Villani V, Prosperini L, De Giglio L, Pozzilli C, Salvetti M, Sette G. The impact of
interferon beta and natalizumab on comorbid migraine in multiple sclerosis.
Headache. 2012;52(7):1130-1135. doi: 10.1111/j.1526-4610.2012.02146.x.
PubMed PMID: 22486199.
Laroni A, Signori A, Maniscalco G, et al. Assessing association of comorbidities
with treatment choice, and persistence in MS. Neurology. 2017;89:2222-2229.
https://t.me/medicina_free
Feist KM, Fisk JD, Patten SB, et al. Comorbidity is associated with pain related
activity limitations in multiple sclerosis. Mult Scler Relat Disord. 2015;4:470-
476.
Fitzgerald KC, Tyry T, Salter A, et al. Diet quality is associated with disability and
symptom severity in multiple sclerosis. Neurology. 2017;90(1):e1-e11.
Thorman A, Sorenson P, Koch-Hendriksen N, Laursen B, Magyar M. Comorbidity
in MS is associated with diagnostic delays and increased mortality. Neurology.
2017;89:1668-1675.
Marrie RA, Elliott L, Marriott J, et al. Effect of comorbidity on mortality in
multiple sclerosis. Neurology. 2015;85:240-247.
Moccia M, Lanzillo R, Palladino R, et al. The Framingham cardiovascular risk
score in multiple sclerosis. Eur J Neurol. 2015;22(8):1176-1183. doi:
10.1111/ene.12720. PubMed PMID: 25912468.
Conway DS, Thompson NR, Cohen JA. Influence of hypertension, diabetes,
hyperlipedmia, and obstructive lung disease on multiple sclerosis disease
course. Mult Scler. 2017;23:277-285.
Weinstock-Guttman B, Ziavadinov R, Mahfooz N, et al. Serum lipid profiles are
associated with disability and MRI outcomes in multiple sclerosis. J
Neuroinflammation. 2011:8:127.
Fitzgerald KC, Tyry T, Salter A, et al. Diet quality is associated with disability and
symptom severity in multiple sclerosis. Neurology. 2018;90(1):e1-e11.
Moss BP, Rensel MR, Hersh CM. Wellness and the role of comorbidities in
multiple sclerosis. Neurotherapeutics. 2017;14:999-1017.
https://t.me/medicina_free
C H A P T E R 6
Internal Medicine II:
Disease-Modifying Therapies
and Adverse Effects
Mary Ann Picone Constantine J. Pella
Introduction
Disease-modifying therapies (DMTs) are at the forefront of
treatment for the progression of multiple sclerosis (MS). It is
important for the internist and nonneurologist to understand
the administration of DMTs and the adverse effects and
infection risks associated with some of the newer DMTs. For
more information on the mechanism of action of DMTs, please
refer to the Immunology chapter.
As you can see from Figure 6.1, there are multiple DMTs
available now with different mechanisms of actions. Table 6.1
shows the stratification of the different therapies organized by
efficacy. These are approved for relapsing forms of MS, and
ocrelizumab is approved also for primary progressive MS. The
challenge in choosing treatment is trying to do the best to
individualize treatment for a heterogeneous disease. Choosing
the optimal individualized treatment regimen involves
evaluating patient lifestyle, comorbidities, support system,
benefits and risks of treatment, timing of pregnancy, and
prognostic disease profile and encouraging the patient to have
realistic expectations of what the therapies can do. Although
none of the treatments are cures, the goal is to achieve as close
to what is referred to as NEDA, no evidence of disease
activity. This refers to no new activity noted on magnetic
resonance imaging (MRI), no relapses, and no clinical disease
https://t.me/medicina_free
progression. Considering the higher-efficacy agents available
today, there is a lower threshold to keep a patient on a therapy
that may be suboptimal. It is important that patients are
followed closely, particularly early on in the disease course
and when new therapies are initiated to monitor for efficacy
and adverse events. We have no biomarkers at present to
predict which patients will respond to a certain therapy;
however, neurofilament light protein is a proposed biomarker
for MS disease activity and treatment response. This is a
structural component of neurons and axons. Neurofilaments
are released into the cerebrospinal fluid (CSF) after axonal
injury. Levels increase during relapse, and initial CSF levels
may help to predict disease course. These are still
investigational at this point.
FIGURE 6.1 Time plot showing the evolution of different
disease-modifying therapies for the treatment of MS.
*Voluntary withdrawal from market announced March 2018.
Republished with permission of Intellisphere, LLC from Owens
GM. Managed care aspects of managing multiple sclerosis. Am J
Manag Care. 2013;19(16 Suppl):s307-s312; permission conveyed
through Copyright Clearance Center, Inc. See eBook for color
figure. **Recently received FDA approval March 2019.
TABLE 6.1
Various Disease-Modifying Treatments (DMTs) Stratified by Efficacy
DMT Route of
Administration
Dosage Monitoring Adverse Effects
Low Efficacy
https://t.me/medicina_free
DMT Route of
Administration
Dosage Monitoring Adverse Effects
Interferon-ß
(Betaseron,
Extavia,
Rebif,
Avonex,
Plegridy)
SC/IM Depends
on type of
interferon
therapy
Every 6 mo:
CBC, LFTs
Every
12 mo: TSH
Injection site
reaction, flulike
symptoms,
headache,
lymphopenia,
hepatotoxicity,
depression,
spasticity
Glatiramer
acetate
(Copaxone)
SC 20 mg/mL
daily
or
40 mg/mL
twice a
week
(∼48 h
apart)
–
Immediate
postinjection
reaction,
uncommon
idiosyncratic
reaction,
lipoatrophy
Teriflunomide
(Aubagio)
PO 7.0 and
14.0 mg
daily
Once per
month for
1st 6 months
LFTs
Every 6 mo:
CBC, LFTs
Diarrhea,
nausea,
alopecia, bone
marrow
suppression,
hepatotoxicity,
peripheral
neuropathy,
teratogenicity
Medium Efficacy
Dimethyl
fumarate
(Tecfidera)
PO Titrated up
from
120 mg
twice a day
to 240 mg
twice a day
Every 6 mo:
CBC, LFTs
Dyspepsia,
nausea,
vomiting,
abdominal pain,
diarrhea,
flushing, PML
Fingolimod
(Gilenya)
PO 0.5 mg
daily
In 3 mo:
repeat CBC
with diff,
LFTs,
Macula
Eval. Every
6 mo: LFTs,
CBC with
diff
Headache,
hypertension,
transaminitis,
lymphopenia,
HSV, macular
edema,
bradycardia,
PML,
dermatological
cancers
High Efficacy
https://t.me/medicina_free
DMT Route of
Administration
Dosage Monitoring Adverse Effects
Natalizumab
(Tysabri)
IV 300 mg
every 4 wk
Every 3
months,
CBC with
diff, LFTS.
Every 6 mo:
JCV Ab,
MRI. After
6 mo:
natalizumab
neutralizing
antibodies
Infusion
reactions,
hepatotoxicity,
PML, HSV,
encephalitis,
headache
Alemtuzumab
(Lemtrada)
IV 12 mg/d 5
consecutive
days
followed
by 12 mg/d
for 3
consecutive
days 1 y
later
Every 3 mo:
TSH.
Yearly skin
examination,
GYN, MRI
Secondary
autoimmunity,
infusion
reactions,
malignancies,
infections,
pneumonitis
Ocrelizumab
(Ocrevus)
IV 600 mg
every 6 mo
a
Hepatitis B
screen
before use,
yearly MRI
Infusion
reactions,
reactivation of
hepatitis B and
tuberculosis,
possible
malignancy,
PML, upper
respiratory
infections
Adapted with permission from Mahajan KR, Rae-Grant A. New American
Academy of Neurology Disease-Modifying Treatment Guidelines: Impact on
Clinical Practice. In: Practical Neurology. Bryn Mawr Communications III, LLC;
2018;17(6):22-27.
Patients are premedicated with IV solumedrol or an equivalent
corticosteroid and an antihistamine before the infusion.
APC, antigen presenting cells; BUN, blood urea nitrogen;
CBC, complete blood count; CNS, central nervous system; Cr,
creatinine; ECG, electrocardiography; GYN, gynecological
screening for HPV; HSV, herpes simplex virus; IM,
intramuscular; IV, intravenous; JCV, John Cunningham virus;
LFT, liver function test; MRI, magnetic resonance imaging;
OCT, optical coherence tomography; PML, progressive
multifocal leukoencephalopathy; PO, orally, dihydro-orotate
https://t.me/medicina_free
dehydrogenase; SC, subcutaneous; TSH, thyroid stimulating
hormone; UA, urine analysis.
Injections
Copaxone (Glatiramer Acetate)
This is an immunomodulator used for patients with relapsingremitting MS. It consists of the acetate salts of synthetic
polypeptides, containing four naturally occurring amino acids:
l-glutamic acid, l-alanine, l-tyrosine, and l-lysine. Designed to
mimic a protein in myelin, Copaxone binds to major
histocompatibility complex molecules and competes with
myelin antigens for T cells, which induces specific suppressor
cells of the T helper 2 (Th2) type that migrate to the brain
where they express the anti-inflammatory cytokines
interleukin 10 and transforming growth factor beta, in addition
to brain-derived neurotrophic factor. 1 Recent evidence
suggests that Copaxone directly inhibits dendritic cells and
monocytes, both of which are circulating antigen-presenting
cells. 7 There is no required blood work monitoring with
Copaxone.
Interferon
Interferons as a class need to have complete blood count
(CBC) with differential and liver function profile monitored
generally every 6 months. Depression has been reported with
interferons, although in clinical trials versus noninterferon
therapy, no increased risk of depression was noted in patients
treated with interferon. Flulike symptoms are the most
common side effects, but dose titration can help to mitigate
flulike symptoms. Injection-site reactions can also be seen,
particularly with subcutaneous injections. Seizures have also
been reported in patients given interferon therapy. Dosing with
interferons (for adults) varies based on the brand:
Interferon beta-1b (Betaseron, Extavia): Initial:
0.0625 mg every other day, increase dose by 0.0625 mg
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана