Patient Encounter Part 1

CN is a 28-year-old woman who complains of a 2-day history of weakness and tingling in her right arm and leg. These symptoms began over a 4-hour period. She also reports an episode 2 years ago of right eye pain and blurred vision that resolved over 1 month. She was diagnosed with optic neuritis at that time. Following an MRI, she is diagnosed with relapsing remitting MS today.

Why was her MS classified as relapsing remitting?

How would you treat the episode today?

Tests for Responsiveness. Antibodies to ^-interferons can reduce their clinical benefit. 1 Neutralizing antibodies develop 18 to 24 months after treatment begins.41 Neutralizing antibodies can form against any ^-interferon, but frequency and route of administration affect neutralizing antibody development: 28% to 47% for subcutaneous interferon ^-1b; 12% to 28% for subcutaneous interferon ^-1a; and 2% to 6% for intramuscular interferon ^-1a.

Issues surround neutralizing antibodies including standardization of the neutralizing antibody assay, testing recommendations, and treatment recommendations for

positive tests. Neutralizing antibodies may disappear even during continued treat-ment.43 Neutralizing antibodies exhibit cross-reactivity with other ^-interferons42

Table 29-3 Comparison of Disease-Modifying Therapies

Drug

Route__Frequency

Adverse Effect!

IllltT^IU" 0-1 J

InlLTfcon ¡5-1 b Ifletasercmh fflniül 44 iiKy

IM Wrtfjy

5tJ 3 m ptf yitrk

SQ Evcuy other day

FIuHlfi/j 61%

Anemia Wt Flj-lkt'

Injedkjri sue recelions Leukopenia lrintsminavi* 17-î79b Fbj-Ike Symptoms 00-71 Injection Lite reactors 50-KSï. AvI Ix-nij l^jun&rrml disifthir 17^ Leukopdna 10-16%

Inctejsttl aopmaWamlncKrirtSfiSfiisäftliiiiinc

(llatii nnie- acetate

Mltoantnme INiwantrone)

Mic/ilijuffLib

HyWlJiit

lî mgvVn'uplo IV

HO mrj/dn' imasiniurri litadric Lky.cj

MOmg.

Dally Injection Lite reacttoji MUfc

Sriienrtk: iwctun i

£v«y 3 nwnths Nijsea 7SAt

."iihyrl il iii.i CardiotCKkiO1 Alt>p?ciaÉIÇ() Meivtrual .Jhoni^K^i^.

Urinary (rjjc t inkttkjn AnnprKwrhea Jiflfi I riikiiixT'M 19%

y-GKiUmyl IrWUpipGlai* iitH-iBC1 Eveiy A nrets Headache ÎSSt

FilkiLf 27% A'thialgta t?% Urirwy cr^cf infection 20W M^t«!fy?iiii|ivity leacltod lew (tun fiorti Mi,. 40,46,*! 5ft

Table 29-4 Prevention or Treatment Strategies for P- Interferon Adverse Effects

Flu-Like Symptom»

Injtctl&n HtajtMtlan

La boratoi y flbn ormilltits*

Injett dcse in evening

Bnn^ FlKltjlKîn |H KTOm (empçrjluie teginal W-^doie Tot 2 weets toe injection, site prior to (he nroettion oi tWMffltflk [hen incrciSL'lP fluLati.' intLttknn sit« a, full doss

Lfce ¡bupmfien ¡00 mg Ih-îq«? jnd Jlievpe. use tyiioeortiiont cream on tand IÎhoursafiix ruction the

AH« natives lo iUjprofcn include Ï nec ionic: Tcmporduly discontinue;

«iiiiiiirKiiiiefT, ("«i^iscnti1 consult deinurokKMic; ilo ncn « wptJi tap«, and pentoxifylline corlicoslenoids hemcglcttr Iç:ï th*lft4g/dl ^L or 53 iTimcl/L) Whd<? bbod colli less than 1 k IOyimm,'<J«.-i lhan 3X TOVl)

Absolute neutfoohikou m less than 1.5 x 10'/mm'(k?ss Uwn I.ÏX107O

Plileltfi less 1h^n 75 >: lWrnn' Hera than 75 * ltm) Bilirubin graaier titan 25 (t baseline AST/ALT groat« lhan 5 x baseline Alfcilirt phosphiiw? flutter than 5 x biSiline

ALT, alanine amlroirnvsferase.: AlLaLpariait'aminotiansfeiase.

"At these threshold values, fl-lnterferon should be temporally discontinued an:l laboratory values monitored. From lieis. -10,

P-Interferons induce the expression of interferon-responsive genes, such as myxovirus-resistance-protein A (MxA). The ability of the patient to respond to ^-interferons can be determined l>y testing MxA gene expression. Lack of expression is associated with MS relapses.

Dosing and Administration. Dose, frequency, and route of administration differ between the ^-interferon products (Table 29-3). Dose-response curves have been observed with the ft-interferons. However, it is unknown if the total weekly dose or the frequency of administration is more important.39

Glatiramer Acetate

Pharmacology and Mechanism of Action. The mechanism of action of glatiramer acetate is unknown; the following properties have been observed:

• Binds to MHC class II, blocking the activation of T cells

• Activates Th2 cells, preventing inflammation

• Activated Th2 cells secrete brain-derived neurotrophic factor, which may be neuro-protective'

Efficacy. Glatiramer acetate reduces relapses by 28% each year compared to placebo. Additionally, relapses occur later compared to placebo (322 vs 219 days).45

Adverse Effects. Patients report pain, redness, itching, swelling, and bruising at injection sites (Table 29-3). Icing the injection site pre-and post-injection improves these reactions; topical anesthetics can also be used. Systemic reactions involve flushing, chest tightness, palpitations, anxiety, and shortness of breath. This reaction usually occurs within 30 minutes of the injection; recurrence is infrequent. Doses may be reduced by 75% for the week following the reaction, then increased by 25% per week to the full dose.46

Issues With Self-Injected Disease-Modifying Therapies

Adherence. Adherence to injectable medications is a significant problem; but there is no significant difference in rates of discontinuation between products (17%-41%).

Main reasons for discontinuation are adverse effects and lack of efficacy. Realistic ex-

pectations regarding therapy and higher educational levels improve adherence rates.

Choosing Therapy. There is no consensus on the best medication for initial therapy. Comparative ^-interferon trials indicate better efficacy with more frequent and/or higher dosing.39 This consideration must be balanced with neutralizing antibody development, patient acceptance, and tolerance.

Patient Education. Refer to Table 29-5 for key components of patient self-injection education.

Mitoxantrone

Pharmacology and Mechanism of Action. Mitoxantrone is an anthracenedione antineoplastic indicated for MS. The mechanisms of action thought to be important for MS are as shown below:

Table 29-5 Patient Education for Self-Injection

Keep all nonrefrigerated supplies together and out of the reach of children and pets

If refrigerated, allow medication to warm to room temperature

Wash hands thoroughly

Choose injection site, rotating among sites

Ice area to be injected for no more than 15 minutes, if desired

Clean injection site thoroughly with alcohol or soap and water

Administer injection

Ice injection site for no more than 15 minutes after injection, if desired

• Causes apoptosis in T and APCs, preventing initial T cell activation

• Inhibits DNA and RNA synthesis, decreasing the proliferation of T cells, B cells, and macrophages

• Decreases cytokine release, preventing inflammation

• Inhibits macrophages, preventing myelin degradation

Efficacy. Mitoxantrone is indicated for secondary progressive MS, progressive relapsing MS, and for patients with worsening relapsing remitting MS. It reduces the clinical attack rate and attack-related MRI outcome measures in patients with relapsing disease Because of »m potemia,,for ta*icMe, should be reserved for patients with rapidly advancing disease who have failed other therapies.26

Adverse Effects. Adverse effects are seen regularly in patients given mitoxantrone (Table 29-3). Bluish discoloration of the sclera and the urine often lasts 24 hours postinfusion.49 Transient leukopenia and neutropenia are common (nadir 10-14 days after the infusion); exposure to infectious individuals during this time should be avoided.49 Patients taking mitoxantrone should not receive live virus vaccines; other vaccines should be held for 4 to 6 weeks after a mitoxantrone dose.49 Amenorrhea may be permanent, an important consideration in women of child-bearing potential.

Arrhythmias may occur shortly after the drug is given. Cardiotoxicity is a serious, rare adverse effect of mitoxantrone. The incidence of congestive heart failure was 0.15% in patients with normal left ventricular ejection fraction and 2.18% in those who had asymptomatic left ventricular ejection fraction of less than 50% at baseline.49 Therefore, mitoxantrone should not be used in patients with baseline cardiomyopathy, even if asymptomatic. The risk of cardiotoxicity is dose related. The maximum lifetime dose of mitoxantrone is 140 mg/m (about 3 years of therapy).

Cyclooxygenase-2 inhibitors should be avoided in patients receiving mitoxantrone because of a potential for worsening cardiac toxicity. 9

Acute myelogenous leukemia occurred in 0.07% of mitoxantrone-treated patients.49 This acute leukemia appears within 2 to 4 years of initiating mitoxantrone and is generally responsive to standard antileukemic therapy.

Table 29-6 Monitoring Disease-Modifying Therapies

Therapy

Tetli

frequenty

0-lntEffeJoni

CBC, biliiubine*« trotyl«, AST, ALT, v-glutim^

Baseline, 12 wo^lhenevay i month:

[Avür^i

11 .iri'.ÎC'i ,r,r. .ïl^ilirii' plxjvpl i.ir.iw-

fietaseron, Rebif)

EDiS, MSFC, iwjinloqfc hislay ind examination

fvwy 3 tnorviht dixing the Iiü! year ol lherapy (hen every

Mlloxantrwie

CBC, bilnutiin. AST, ALI, afcaline ptvjspivata»,

Befafe each inhjsion

plavortironef

ppgnjncy Imt

ECG

Jtnelino

Ffto'aKliûQraiïi or N'-MCiA An

fWi^line iiirf pvrty 6-J7 rncfuh',; p< njr [o eaiTi irihrikvi afr^i

100 mg/ftr'

HSK, iwMoUypf hûTçiï .sud fxinilnjtcn

Evflry 3 mürafn dlïirii) rtw Fkfl yi.tr of ihifjpj; ihf n cvt^y

4 monlhs

{iLi[iiiimif .iL'M.iCr

LLJVi, MSIt, s'r^iin ikjc|i^ hüldy iild ttqnUpinlcn

Cyfly 3 merwhii di^int) [he (Vil yen uf ihwjpy ifvn ev&y

(Co pa m ne)

6 monthi

rJ^WliSurTklti

M5KT, "n-urulooi; hiSK-yOJid fiïjirtwrôn

he if i "twnhs du-iri^ rhL- fast ^jr tfcn eveiy

6 months

URL fir ?ifsrT»3tk3n lor K. v»kB

Al tjnsLl oifWVi npjicksgic ^ymptcrm not MKigeitivi: of MS

Ptemiuiion patient theckhl

friot (oevery infusion

innii H"JMÎ[ And reauthorization questional^

f vfry 6 rmirilhY.

ALI. alanine iiflirXïlrinsieriii: AV, Ml).*™-drniiyj[ijn%li?iartist, couineUtctXl CLxjîïI: C5f,«nefctoipinslihjitl Lim Laoarit)«! PiMhilil)1 Ûlarirt-Scak» Mi, niultipli «IphkK; MÏFt'., Multipfe Stferoslg Funrtlonjllfcifiipoilie; MLHiA^ multiple gaUe^ Af-quitrntwi.

ALI. alanine iiflirXïlrinsieriii: AV, Ml).*™-drniiyj[ijn%li?iartist, couineUtctXl CLxjîïI: C5f,«nefctoipinslihjitl Lim Laoarit)«! PiMhilil)1 Ûlarirt-Scak» Mi, niultipli «IphkK; MÏFt'., Multipfe Stferoslg Funrtlonjllfcifiipoilie; MLHiA^ multiple gaUe^ Af-quitrntwi.

Dosing and Administration Mitoxantrone is infused intravenously over 30 minutes to reduce the chance of cardiotoxicity.49 Mitoxantrone is administered every 3 months, if cardiac function and laboratory values are normal (Table 29-6).

Natalizumab

Pharmacology and Mechanism of Action. Natalizumab is a4-integrin antagonist indicated for relapsing forms of MS. Its postulated mechanism of action follows:

• Binds to a4P7 and a4P7 integrins, preventing migration of lymphocytes into the CNS and inflammation

• Inhibits binding of a4-positive leukocytes to fibronectin and osteopontin, decreasing the activation of leukocytes already within the CNS50

Efficacy. Treatment with natalizumab reduced relapses by 68% at 1 year and disability by 42% at 2 years compared to placebo.50

Adverse Effects. Adverse effects of natalizumab include infection, arthralgia, headache, and fatigue.50 Hypersensitivity reactions have been observed; symptoms may include itching, dizziness, fever, rash, hypotension, dyspnea, chest pain, and anaphyl-axis, usually within 2 hours of administration. A much more serious, but rare, adverse effect is progressive multifocal leukoencephalopathy (PML). PML, caused by the JC polyomavirus virus, is rapidly progressive and usually results in death or permanent disability. Shortly after natalizumab was introduced, three patients developed PML, leading to temporary withdrawal of the medicine. Natalizumab was reintroduced through a restricted distribution program. These concerns lead to the recommendation that natalizumab be reserved for patients with rapidly advancing disease who have failed other therapies. Specific recommendations are to avoid in patients with PML, HIV, immunodeficiency, or hematological malignancy; to carefully assess for immune compromise in patients previously treated with immunosuppres-sion or chemotherapy; and to perform a baseline cranial MRI for later comparison if new neurologic symptoms develop.51

Antinatalizumab antibodies develop in 9% to 12% of patients. If patients are persistently antibody-positive, relapse rates and disability increase; antibody develop-

ment is also associated with hypersensitivity reactions.

Dosing and Administration. Natalizumab should be used as monotherapy for MS.51 Natalizumab is administered 300 mg in 100 mL normal saline over a 1-hour IV infusion every 4 weeks. Patients have not been treated for more than 2 years with natalizumab.

Outcome Evaluation

• Assess periodically for changes in symptoms.

• In patients taking P-interferons with frequent relapses, testing for neutralizing antibodies and/or MxA gene expression may assist in choosing therapy.

• Monitor the patient for medication-specific adverse effects (Tables 29-3 and 29-6).

• Assess regularly for adherence with all components of therapy.

Symptomatic Therapies

MS patients develop many symptoms that require treatment. The symptoms most unique to MS are fatigue and spasticity. Other important symptoms such as urinary incontinence, pain, depression, cognitive impairment, and sexual dysfunction are discussed only briefly (refer to other chapters).

Fatigue

There are nonpharmacologic and pharmacologic strategies for decreasing the impact of fatigue on the lifestyle of MS patients (Table 29-7). Pharmacologic management of fatigue includes amantadine or stimulants; however, evidence of efficacy from randomized controlled trials is limited.

Spasticity

The goals of treating spasticity are patient-specific. For ambulatory patients, reducing spasticity may improve mobility. For bed-bound patients, treating spasticity may relieve pain and facilitate transfers and care. Physical therapy is a nonpharmacologic treatment for spasticity.10

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