-
Acta Clin Croat 2009; 48:349-353
TREATMENT OF MULTIPLE SCLEROSIS
Marija Bosnjak-Pasic', Branka Vidrih', Snjeiana Miskov' and Vida
Demarin'
Review
-Un iversity Department of Neurology, Reference Center for
Neurovascular Disorders and Reference Centerfor Headache of the
Ministry of Health and Social Welfare of the Republic of
Croatia,
Sestre milosrdnice University Hospital, Zagreb, Croatia,
-Universny Department of Psychiatry,Sestre milosrdnice University
Hospital, Zagreb, Croatia
SUMMARY - Multiple sclerosis is an autoimmune inflammatory
demyelinating disease of thecentral nervous system, characterized
by multifocal inflammatory destruction of myelin, axonaldamage and
loss of oligodendrocytes. The disease is carried through two
stages: inflammatory anddegenerative. The most common form of
disease in approximately 85%of the cases is RRMS
(relap-sing-remitting form). The treatment ofMS is devided into:
treatment of the acute phase of illness,prevention of new relapses
and disease progression, and symptomatic treatment. Most of the
chan-ges in treatment of multiple sclerosis and most of the news in
recent years concerning new drugsare used in the treatment of
progression of the disease and prevention of disease relapses. Some
ofthese drugs are registrated in most Europian countries and USA,
and others are in various stagesof research.
Key words: Multiple sclerosis - therapy; Immunosuppressive
agents - therapeutic use; Interferon, beta- therapeutic use
Introduction
Multiple sclerosis (MS) is an autoimmune inflam-matory
demyelinating disease of the central nervoussystem characterized by
multifocal inflammatory de-struction of myelin, axonal damage and
loss of oli-godendrocytes. In the pathogenesis of the
disease,activated T-lymphocytes are involved, causing en-dothelial
changes in the blood-brain barrier, secretinginflammatory mediators
and stimulating the cascadeof inflammation. In the disease
development, inter-feron gamma plays a significant role; it is
producedin activated T-cel1 lymphocytes (THI class) and ac-tivates
macrophages to protease and tumor necrosisfactor (TNF) production,
which in turn destroy oli-godendrocytes, leading to the onset and
progressionof the disease.
Correspondence to: MariJa Boinjae-Pasic, MD, University
De-partment of Neurology, Sestre milosrdnice University
Hospital,Vinogradska c. 29, HR-l0000 Zagreb, CroatiaE-mail:
marijabosnjakpasicei'net.hr
The most common form of disease, found in ap-proximately 85% of
cases is the relapsing-remittingform (RRMF). The treatment of MS is
divided intotreatment of the acute phase of the disease,
preventionof new relapses and disease progression, and symp-tomatic
treatment'.
Treatment ofMultiple Sclerosis
In newly diagnosed patients and in the stage ofacute
exacerbation or disease relapses, we apply cor-ticosteroids as
'pulse corticosteroid therapy' usingmethylprednisolone
(Solumedrolv'") intravenously500-1000 mg/day in 250 mL saline
solution in shortinfusions (30-45 minutes) for 5 days. Along with
cor-ticosteroids, histamine blockers (H2 receptors, ran-itidine),
acetazolamide and potassium replacementtherapy are administered for
three weeks. The corti-costeroid side effects are hirsutism,
osteoporosis, acne,cataract, hypertension, duodenal ulcer,
psychosis, andblood glucose impairment. Contraindications for
the
349
-
Marfja Bosnjak-Pastcer al.
use of corticosteroids are active inflammatory disease,poorly
regulated diabetes and psychosis.
The patients in the acute stage of the disease thatdo not
respond to corticosteroid therapy can be treat-ed with
plasmapheresis, i.e. seven successive plasma-pheresis procedures
every other day or intravenous im-munoglobulins (IVIg) at a dose of
0.4 g/kg daily for5 days. Side effects of immunoglobulin therapy
maybe related to their intravenous administration, dosageor
transmission of infectious agents (e.g., hepatitis Cvirus) and
prions. The most important side effects as-sociated with the
intravenous administration of im-munoglobulins include headache,
fever, shivering, Ia-cial flushing, back pain, and anaphylactic
shock as themost severe one. Side effects associated with dosageof
intravenously administered immunoglobulins arehematologic
(neutropenia and lymphopenia, and in-creased plasma viscosity),
dermatologic (rash, eczemaand urticaria), aseptic meningitis and
renal (tubular)damage2,3.
Immunomodulators and immunosuppressants areused in the
prevention of the disease relapse. Since1993, the immunomodulatory
therapy with inter-ferons that change the natural course of the
diseasein MS patients has been used in the prophylactictreatment of
disease exacerbation. The mechanismof action of interferons is not
fully understood, butthey are known to have antiviral,
immunomodula-tory and antiproliferative effects. They increase
thenumber and activation of CD 8 suppressor cells,their count being
reduced in MS patients, inhibit-ing the secretion of interferon
gamma, which favorsthe development and progression of the disease,
andinhibits the interferon gamma-induced expression ofMHC class II
antigen at glial cells. They also lead tolymphotoxin (LT) and TNF
decrease, which impairsoligodendrocyte function and promotes
astrogliosisthat reduces the possibility for activated immunecells
to cross the blood-brain barrier and increasesTH2 cytokines,
interleukin 4 (IL-4) and IL-10 byfavoring their production as well
as the productionof transforming growth factor beta (TGF beta) in
Thelper cells.
In the world, recombinant beta interferons areused in the
treatment of MS. The glycolyzed formis interferon la, which is
similar to natural humaninterferon beta (Rebif", Merck-Serono and
Avon-
350
Treatment of multiple sclerosis
ex, Biogen Idee), was registered in Europe, Canadaand the USA in
1998. The non-glycolyzed form isinterferon beta 1b (Betaserorr",
Berlex Laborato-ries, Betaferon, Bayer-Schering AG, and
Extavia,Novartis)!". There was a number of important clini-cal
trials that tested and compared the efficacy ofthese interferons in
the treatment of patients suffer-ing from various forms of MS,
primarily in patientswith RRMS, according to the frequency of drug
us-age (once a week, three times a week, or every otherday), the
length of drug usage (one year, two years,or several years), the
way of administration (subcu-taneously, s.c., or intramuscularly,
i.m.), drug dos-age, and disability at the beginning and at the
endof drug administration on the EDSS scale (scale ofdisability
ofMS patients in which disability is scoredfrom 0 for normal
neurologic status to 10 for death).The efficacy of each beta
interferon was assessed bythe number of relapses, disease
progression, reduc-tion of disability on EDSS scale by 1 point,
reduc-tion in the number of active demyelinating lesionson magnetic
resonance (MR), and reduction in theextent of lesions on MRI during
drug administra-tion. The best known clinical studies were as
follows:the first multicenter, randomized, double blind, pla-cebo
controlled study from 1993 in RRMS patients(comparison of
interferon beta 1b and placebo);PRISMS study (comparison of two
different dosesof beta interferon 1 a ~ Rebif> 22 mcg (6 MIU)
s.c.three times a week and Rebif> 44 mcg (12 MIU)s.c. three
times a week)'; SPECTRIMS (SecondaryProgressive Efficacy Clinical
Trial in MS); ETOMS(Early Treatment ofMultiple Sclerosis with
Rebif"),EVIDENCE (Evidence for Interferon Dose
Effect:European-North American Comparative Efficacytrials,
comparative study of Efficacy of Rebif> andAvonex"); and OWIMS
(comparison of Rebif> ina dose of 22 mcg s.c. and 44 mcg s.c.
once a week).The latest studies, some ofwhich are still in
progress,are INCOMIN (Independent Comparison oflnter-ferons,
following up patients treated with interferonbeta 1 b 250 mcg every
other day s.c. and interferonbeta 1 a 30 mcg i.m. once a week,
showing the morefrequent usage to be more efficient); BEYOND
(astudy with a twofold dose of interferon beta 1 b, Be-taferone",
which is still in the second phase); andBENEFIT (Betaferone? in
Newly Emerging mul-
Acta Clin Croat, Vol. 48, No.3, 2009
-
Marfja Bosnjak-Pastcer al.
tiple sclerosis For Initial Treatment), with initial
ad-ministration of interferon beta 1 b, Beraferone", innewly
detected patients in comparison with placebo.The latest study the
three-year results of which havebeen published this year showed the
use of interferonbeta 1 b, Beraferone", in the early stages of the
dis-ease, in comparison with placebo, to delay the timeto
clinically definitive form of disease (CDMS), tosignificantly
reduce the number of relapses and dis-ability, and to increase the
quality of life in patients.Meta-analysis of randomized placebo
controlledstudies of interferons in patients with RRMS (pub-lished
during the 1993-2002 period) using the Co-chrane Collaboration
method has shown them tomildly reduce the number of patients with
diseaseexacerbation in the first year of treatment, with un-certain
clinical efficacy after the first year of inter-feron
administration; additional studies on the longterm use of
recombinant forms of beta interferon andcost-effect analysis are
necessary>".
The quality of MS treatment with interferon betawas assessed in
the Q.UASIMS study that included510 centers in 11 countries and
compared treatmentwith different interferon beta preparations. This
studyshowed similar efficacy of all beta interferons avail-able,
being administered either as initial or follow uptherapy for
RRMS7-18
In Croatia, there are strict criteria concerning in-dications
and contraindications for the treatment withinterferon beta.
Treatment with interferon beta maybe related to the occurrence of
neutralizing antibod-ies. Immunologic studies have shown that
neutral-izing antibodies can extend biological lifetime of
cy-tokines and have beneficial effect. The occurrence
ofneutralizing antibodies with the use of interferon maybe related
to the loss ofefficiency. Side effects of inter-feron beta are
'flue-like' symptoms, skin lesions at thesite of application,
elevated liver enzymes, depression,and allergies. Anemia may be
present with the use ofAvonex'> and cytopenia with
Betaseronw.
Among other medications used in therapy of MS,mention should be
made of the immunomodulatorCopaxonc" (glatiramer acetate) in a
dosage of 20mg s.c. once a day", which is on the Croatian
Insti-tute for Health Insurance list since September 2006,along
with immunosuppressants (Novartone, mitox-antron hydrocloride in a
dosage of 8-12 mg/m- i.v.,Azatioprine'P Imuran", cyclophosphamide
Cytoxan",
Acta Clin Croat, Vol. 48, No.3, 2009
Treatment of multiple sclerosis
cyclosporine A and methotrexate). Currently, highestexpectations
are put on therapy with mitoxantronehydrochloride, a synthetic
anaplastic agent with anti-inflammatory effect. This medication is
prescribedfor SPMS, and has been confirmed to reduce
clinicalsymptoms and lesion activity on MRI. The dosage
ofmedication is cumulative, and because of its cardio-toxicity it
has a strictly limited total life dose of up to120-140 mg
i.v.'.
Additionally, full irradiation of lymphatic nodescan be
performed over a 5-6 weeks.
Recently, new studies on the use of stem celltransplantation in
the treatment of severe forms ofMS (SPMS and PPMS) are emerging.
This form oftreatment has been previously administered for
otherautoimmune diseases such as systemic sclerosis andrheumatoid
arthritis'V''.
Monoclonal antibodies (Mabs) that also belong tothe class of
biotechnological medications show prom-ising results in the
treatment of autoimmune and in-flammatory diseases such as MS.
Since they enableselective modulation of defined molecules, they
are anattractive therapeutic option.
For different types ofMS, a large number ofmono-clonal
antibodies are currently studied: anti Til, antiT12, anti T 4, anti
CD3, anti CD4, anti CD 25, antiCD20, and widely known anti CD52
(alemtuzumab),clinical studies of which are in progress21,22 . One
ofthe monoclonal antibodies, anti alpha 4 integrin (na-talizumab,
Tysabri"), is already registered in Americaand Europe for the
treatment of rapidly progressiveforms of MS. Studies which confirm
its efficacy areAFFIRM (compares efficiency of Tysabri'" 300 mgi.v.
every four weeks vs. placebo every four weeks) andSENTINEL
(Tysabri'" in recommended dose is addedto therapy with Avonex'>
in half of all patients, whilein the other half placebo is combined
with Avonex'>for 120 weeks). Patients that received Tysabri'"
had asignificantly lower number and frequency of diseaserelapses,
reduced disability and lower number of ac-tive lesions on
MR23-25.
Today, orally administered drugs for use in MS arealso
investigated, the best known of which is cladrib-ine
(2-chloro-2-deoxyadenosine, CdA), a syntheticpurine analog''- As
for symptomatic treatment, themanagement of spasticity, slackness,
dysfunction ofmiction, equilibrium, vertigo, tremor, pain and
moodchanges is of highest importance.
351
-
Marfja Bosnjak-Pastcer al.
Conclusion
Due to the large number of clinical studies of newdrugs for MS,
it appears optimistic to expect a dis-covery of increasingly
effective medications for MStherapy. Research is directed towards
enhancement ofcurrently available medications (new formulations
ofdrugs already in use, e.g., beta interferon la, which isless
immunogenic, pegylated interferon beta prepara-tions that have
better pharmacokinetic properties andcan be administered less
often), improved possibili-ties of administration (by improving
auto injectors),research of oral drugs, usage of combination of
drugs,and better collaboration between patients and phy-sicians,
which is also very important for successfultreatment.
References1. Choffion M. Mechanisms of action for treatments in
multiple
sclerosis. Biodrugs 2005;19:299-3082. Isaacs A, Lindemann J.
Virus interference. The interferon.
Proc R Soc Lond (BioI) 1957;147;258-673. Iz rada struene grupe
za lijekove Ministarstva zdravstva Re-
publike Hrvatske. Pharmaca 1997;35:49-604. The IFNB MS Study
Group.Interferon beta -Ib is effective in
RRlVIS: clinical results of a multicentre, randomized,
double-blind, plecebo-controlled trial. Neurology
1993;43:665-61
5. Filippini G, Munari L, Incorvaia B, Ebers GC, Polman C,DAmico
R. Interferons in relapsing rmitting multiple scle-rosis: a
systematic review. Lancet 2003;361:545-52
6. ShariefMK. Dose and frequency of administration of
inter-feron-beta affect its efficacy in multiple sclerosis. Clin
drugInvestig 2003;23:551-9
7. The PRISMS Study Group (Prevention of Relapses and
Dis-ability by Interferon Beta-la Subcutaneously in
MultipleSclerosis). Randomised double-blind placebo controlled
studyof interferon beta-la in relapsing/remitting multiple
sclerosis. Lancet 1988;352:1498-504
8. Jacobs LD, Cookfair DL, Rudick RA. Results of a phase
IIItrialof intramuscular recombinant beta interferon as
treat-mentof mul tiple sclerosis. Ann NeuroI1994;36:256 ???
9. Jacobs LD, Cookfair DL, Rudick RA. Intramuscular
inter-feron-beta la for a disease progression in relapsing
multiplesclerosis. Ann NeuroI1996;39:258-94
10. IFNB MS Study Group. Interferon beta-lb is effective in
re-lapsing-remitting multiple sclerosis. I MRI analysis results ofa
multicentre, randomized, double-blind, placebo-controlledtrial.
Neurology 1993;43:662-667
11. Kappos L. New aspects in the treatment of multiple
sclerosiswith interferon beta
lb.]NeuroI2004;251(SuppI4):IV/l;DOI10.1007/00415-004-1401-4
352
Treatment of multiple sclerosis
12. Durelli L. Is multiple sclerosis a disease that requires
frequentbeta interferon dosing? ] Neurol 2004;251(Suppl 4):
IV/13-IV/24;DOI10.1007/00415-004-1404-1
13. Comi G, Filippi M, BarkhofF, Durelli L, Edan G, Fernan-dez 0
et al. Effect of early interferon treatment on conver-sion to
definite multiple sclerosis: a randomised study. Lancet2001;
357;1576-82
14. Galetta SL. The Controlled High Risk Avonex
MultipleSclerosis Trial (CHAlVIPS study). J
Neuroophthalmol2001;21;292-5
15. Kappos L, Polman CH , Freedman MS, Edan G, HartungHP, Miller
DH et al. Treatment with interferon beta-lbdelays conversion t
clinically definite and McDonald MSin patients with clinically
isolated syndromes. Neurology2006;67;1242-9
16. Kappos L, Freedman MS, Polman CH, Edan G, HartungHP, Miller
DH et al. Effect of early versus delayed interferonbeta-lb
treatment on disability after a first clinical event sug-gestive of
multiple sclerosis:a 3-year follow-up analysis of theBENEFIT study.
Lancet 2007;370;389-97
17. Johnson KP, Brooks BR, Cohen ]A, Ford CC, Goldstein],Lisak
RP et al. Extended use ofglatiramer acetat (Copaxone)is well
tolerated and maintains its clinical effect on multiplesclerosis
relapse rate and degree of disability. Copolymer 1Multiple
Sclerosis Study Group. Neurology 1998;50:701-8
18. Tyndall A, Saccardi R. Haematopoetic stem cell
transplanta-tion in the treatment of severe autoimune
disease;results fromphase IIII studies, prospective randomized
trials and futuredirection.Br Soc Immunol Clin Exp
ImmunoI2005;141:1-9
19. Mancardi GL. Autologus haematopoetic stem cell
transplan-tation. neurol sci 2005;26:S19.
20. Hohlfeld R, Wekerle H. Drug insight: using
monocvlonalantibodies to treat multiple sclerosis. Nature Clin
Pract Neu-mI2005;1;34-44
21. O'Leary S, Beavin], Bishop C, Capolino L, Greinel e, Hud-son
E. Practical guidelines for administering natalizumab:anursing
perspective. Int MS Care 2007;9:1-8
22. Cannella B, Raine CS. The adhesion molecule and cytokine
pro-file of multiple sclerosis lesions. Ann
NeuroI1995;37:424-35
23. Tysabri" (nataliz.umab) (package insert). Cambridge,
MA:Biogen Idee, Inc. 2006
24. Yednock TA, Cannon C, Fritz LC, Sanchez-Madrid F,Steinman L,
Karin N. Prevention of experimental autoim-mune encephalomyelitis
by antibodies against alpha 4 beta 1integrin. Nature
1992;356:63-6
25. Polman CH, O'Connor PW, Havrdova E, Hutchinson M,Kappos L,
Miller DH et al. A randomized, placebo- con -trolled trial of
natalizumab for relapsing multiple sclerosis. NEngl] M,d
2006;354;899-910
26. Post-hos analysis of the AFFIRM study. Cambridge, MA:Biogen
Idee, Inc. 2005
27. Sipe lC. Cladribine for multiple sclerosis: review and
currentstatus. Expert Rev Neurother 2005;5:721-7
Acta Clin Croat, Vol. 48, No.3, 2009
-
Marfja Bosnjak-Pastcer al.
Sazetak
LIJECENJE MULTIPLE SKLEROZE
M. Bosnjalc-Pasi/, B. Vidrih, S. Miskov i V Demarin
Treatment of multiple sclerosis
Multipla skleroza (MS) je upalna autoimuna demijelinizacijska
bolest sredrsnjega iiveanog sustava obiljeiena multifo-kalnom
upalnom destrukcijom mijelina, ostecenjem aksona i gubitkom
oligodendrocita. Bolest se odvija kroz dvije faze,upalnu i
degenerativnu. NajcdCi oblik bolesti, u otprilike 85% slucajeva je
RRMS (relapsno-remitentni oblik).
Lijecenje MS dijeli se na lqecenje akutne faze bolesti,
prevenciju novih recidiva i progresije bolesti te
simptomatskohjecenje. Posljednjih godina najvrse promjena i novih
lijekova u lqecenju multiple skleroze rabi se u lqecenju odnosno
spr-jecavanju progresije bolesti te prevenciji recidiva bolesti.
Neki od tih lijekova su registrirani u vecini europskih zemalja i
uAmerici, a drugi su u razlicitim fazama istraiivanja.
Kljucne rijeci: Multipla skleroza ~ terapiJa;Imunosupresivi ~
terapiJskaprimjena; Interferon, beta ~ terapiJskaprimjena
Acta Clin Croat, Vol. 48, No.3, 2009 353
Acta 3-2009 book 1_Page_127Acta 3-2009 book 1_Page_128Acta
3-2009 book 1_Page_129Acta 3-2009 book 1_Page_130Acta 3-2009 book
1_Page_131