Treatman of MS

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

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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-

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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


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",



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.

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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.

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Sazetak

LIJECENJE MULTIPLE SKLEROZE

M. Bosnjalc-Pasi/, B. Vidrih, S. Miskov i V Demarin


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

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Treatman of MS

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