ms current therapies

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Hindawi Publishing CorporationScienti1047297caVolume 983090983088983089983091 Article ID 983090983092983097983089983088983089 983089983089 pageshttpdxdoiorg983089983088983089983089983093983093983090983088983089983091983090983092983097983089983088983089

Review ArticleCurrent and Future Therapies for Multiple Sclerosis

Alireza Minagar

Department of Neurology Louisiana State University Health Sciences Center 983089983093983088983089 Kings Highway Shreveport LA 983095983089983089983091983088 USA

Correspondence should be addressed to Alireza Minagar aminaglsuhscedu

Received 983089983097 December 983090983088983089983090 Accepted 983089983091 January 983090983088983089983091

Academic Editors P Annunziata D Franciotta and L remolizzo

Copyright copy 983090983088983089983091 Alireza Minagar Tis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

With the introduction o intereron-983089b in 983089983097983097983091 as the 1047297rst FDA-approved treatment or multiple sclerosis the era o treatment o this incurable disease began and its natural course was permanently changed Currently seven differenttreatments or patientswithmultiple sclerosis with differentmechanisms o action and dissimilar side effect pro1047297les exist Tese medications include intereron-983089a intramuscular (Avonex) intereron-983089a subcutaneous (Rebi) intereron-983089b subcutaneous (BetaseronExtavia) glatirameracetate (Copaxone) natalizumab (ysabri) 1047297ngolimod (Gilenya) teri1047298unomide (Aubagio) and mitoxantrone (Novantrone) Inaddition a large number o clinical trials are being conducted to assess the saety and efficacy o various experimental agents inpatients with multiple sclerosis including alemtuzumab dimethyl umarate laquinimod rituximab daclizumab and cladribine Inthis paper the author presents a concise and comprehensive review o present and potential treatments or this incurable disease

1 Introduction

Multiple sclerosis (MS) is an immune-mediated demyelinat-ing disease o the human central nervous system (CNS)which causes neurological disability in young adults [983089 983090]Presently the etiology and cure or MS remain unknownMS develops in individuals who are genetically susceptibleollowing exposure to an unidenti1047297ed environmental agentExtensive epidemiological studies indicate that genetic ac-tors play a signi1047297cant role in the development o MS [983089 983091 983092]In addition certain environmental actors such as exposureto or inection with certain viruses such as Epstein-Barr viruslow serum vitamin D levels and smoking may contribute to

the development o MSMS is commonly a disabling disease and remains the

leading cause o acquired neurological disability in youngadults individuals between 983089983093 to 983092983093 years [983093] Te peak age o onset is 983090983097 years and similar to other immune-mediated diseases in most orms o MS emales outnumberthe males MS affects both white and gray matters o the CNS(whole brain disease) and its underlying neuropathology leads to loss o myelinoligodendrocyte complex as well asneuronal and axonal degeneration (demyelination versusneurodegeneration) [983094]

Clinically MS presents with our relatively distin-guishable patters relapsing remitting (RRMS) secondary

progressive (SPMS) primary progressive (PPMS) andrelapsing progressive (RPMS) Te most common clinicalphenotype o MS RRMS may initiate with a single uni-or multiocal demyelinating attack reerred to as clinically isolated syndrome (CIS) [983095] Tis 1047297rst attack is usually ollowed by similar or different orms o relapses in timePatients may recover rom these attacks completely orpartially with or without treatment Te majority o MSpatients initially present with relapsing-remitting orm o MS which is characterized by more neuroin1047298ammation thanneurodegeneration [983096] Tis concept clinically maniestswith relapses and ormation o new MRI lesions particularly contrast-enhancing 983089-weighted lesions Over the course o

years each relapse may leave the patient with some residualdisability which slowly accumulates leading to permanentdisability Within 983089983088 years rom the initial diagnosis mostpatients with RRMS enter the secondary progressive (SPMS)orm o MS which presents with less in1047298ammation andmore neurodegeneration [983097] Clinically patients with SPMSpresent with progression o neurological disability Primary progressive MS is the least requent orm o MS and isrecognized by the absence o the relapses and progressivedeterioration o neurological status rom the onset scarcity o the neuroin1047298ammation within the CNS and paucity o clinical relapses [983097 983089983088] Patients with PPMS usually donot demonstrate signi1047297cant recovery rom the progressive



983090 Scienti1047297ca

disease Unlike patients with RRMS male and emaleindividuals are equally affected by PPMS

Currently MS remains an incurable condition Howevera number o treatments with varying efficacy and adverseeffect pro1047297les have been approved by the FDA Tese med-ications include beta-intererons glatiramer acetate ysabri

Gilenya and mitoxantrone Very recently a new diseasemodiying agent teri1047298unomide (Aubagio) was approved by the FDA or treatment o relapsing orms o MS

2 Beta-Interferons

Beta-intererons which include two orms o intereron-983089a(IFN-983089a) and intereron-983089b [IFN-983089b] are type 983089 interer-ons and approved by the FDA or treatment o MS and CISTree different ormulations o beta-intererons which existor treatment o MS consist o low dose IFN-983089a (Avonex) (983091983088micrograms intramuscular once weekly) high disease IFN-983089a [Rebi] (983090983090 and 983092983092 micrograms subcutaneously threetimes weekly) and IFN-

983089b (Betaseron) (983096983088983088983088983088983088983088 units 983090983093983088

micrograms subcutaneously alternate day injection) Due tothe difference in requency o administration and the utilizeddose Avonex is known as ldquolow doserdquo -intereron whileRebi and Betaseron are recognized as ldquohigh doserdquo Tesethree beta-intereron ormulations along with glatirameracetate are recognized as 1047297rst-line disease modiying agentsor treatment o MS [983089983089] Te mechanisms o action o beta-intererons are discussed and then their clinical trials andside effects will be presented in the order o their approvalin the US

3 Beta-Interferons Mechanisms of Action

While detailed mechanism(s) o the therapeutic actions o the -intererons remains incompletely understood theirbene1047297cial impact in MS patients may stem rom their anti-in1047298ammatory properties as well as their effects on theendothelial cells o the blood brain barrier It has beendemonstrated that IFN- decreases antigen presentation [983089983090]has potential modulatory effects on costimulatory moleculespresent on dendritic and other cells [983089983091 983089983092] suppressesprolieration o the T983089 cells and increases expression o IL-983089983088 (a major anti-in1047298ammatory cytokine) [983089983093] and shifsthe in1047298ammatory environment rom proin1047298ammatory toanti-in1047298ammatory [983089983094 983089983095] IFN- as a class does impactthe endothelial cells and block the disintegrating effects

o the IFN-1038389 on cerebral endothelial cells [983089983096] decreaseplasma endothelial microparticles which act as promoters o transendothelial migration o the activated leukocytes [983089983097]protect endothelial cells rom apoptosis induced by serumrom MS patients [983090983088] and decrease the expression o matrixmetalloproteinases which participate in disruption o thesubendothelial matrix [983090983089 983090983090]

4 Beta-Interferons Clinical Trials

In 983089983097983097983091 IFN-983089b (BetaseronExtavia) was the 1047297rst immun-omodulatory agent approved by the FDA or the treatmento patients with RRMS [983090983091 983090983092] and it is also approved

or treatment o patients with SPMS who still experiencerelapses [983090983093] Utilizing recombinant DNA technology IFN-983089b is produced by Escherichia coli [983090983094] Te dosage o IFN-983089b is 983090983093983088 1103925g subcutaneously every other day

A number o clinical trials have assessed the efficacy andsaety o IFN-983089b in patients with MS [983090983091 983090983092] In 983089983097983097983091 during

a phase 983091 double-blind placebo-controlled clinical trialIFN-983089b was evaluated in a cohort o 983091983095983090 patients with MShaving an EDSS score o 983088983088ndash983093983093 and who had experienced atleast two relapses in the two years prior to study initiationStudy subjects were randomly treated with placebo or IFN-983089b (983093983088983088 or 983090983093983088 1103925g subcutaneously once every other day)or 983090983092 months Based on the results o this initial studyutilization o IFN-983089b in MS reduced clinical relapse ratein both treatment groups compared to the placebo (higherdose versus placebo 907317 = 00001 lower dose compared toplacebo 907317 = 001) In addition patients who were treatedwith the higher dose o IFN-983089b compared to those treatedwith the lower dose showed more decrease in their clinicalrelapse rate (907317 = 00086) which in turn indicated a doseeffect MR neuroimaging results also revealed reduction o 983090-weighted active lesions (higher dose IFN-983089b comparedto placebo 907317 = 00089 lower dose IFN-983089b compared toplacebo 907317 = 004) Te number o new 983090-weighted lesionsdecreased (higher dose IFN-983089b versus placebo 907317 = 00026lower dose compared to placebo 907317 = 003) so did the MRIburden o the disease (higher dose IFN-983089b compared toplacebo 907317 lt 0001 lower dose compared to the placebo907317 = 004) During this trial treatment o MS patients withIFN-983089b did not show any superior effect over placebo onprogression o disability

Another study addressed the long-term saety and effi-cacy o IFN-983089b in the treatment o MS patients withRRMS During this multicenter open-label observationalstudy which was conducted or up to 983089983094 years cross-sectionaldata rom the participants in the pivotal trial o IFN-983089bwas utilized [983090983095] Te 1047297ndings o this study indicated thatearly and uninterrupted long-term therapy o MS patientswith IFN-983089b was acceptable since the decrease in the relapserate stayed similar to the initial study In addition longerperiod treatment o patients with RRMS with IFN-983089b wasassociated with slowing o progression o disability [983090983096]

Frequent side effects o IFN-983089b consist o 1047298u-likesymptoms headache injection site reactions asthenia lym-phopenia elevated hepatic enzymes and pain Less com-monly encountered but more serious adverse events include

depression with suicidal ideation injection site necrosis andinection which indicate discontinuation o therapy

Interestingly a recently published study on IFN-983089b by Goodin et al [983090983097] assessed the effect o this medicationon survival rate o a randomized cohort o MS patient 983090983089years ollowing the initiation o the pivotal IFN-983089b trialTe study subjects were randomized to receive either theactive drug-IFN-983089b 983090983093983088 1103925g subcutaneously once every otherday or placebo Based on the results o this study study subjects who were treated with IFN-983089b demonstrated asigni1047297cant decrease in all-cause mortality over the 983090983089-yearperiod compared to placebo recipients (907317 = 00173) Teauthors concluded that early therapy o MS patients with



Scienti1047297ca 983091

IFN-983089b is associated with increased survival in initially untreated patients with RRMS

5 Interferon-1a (Rebif)

Tis preparation o IFN-983089a is manuactured by DNA tech-

nology and by the Chinese hamster ovarian cells Rebi iscommercially available at two doses 983090983090 1103925g and 983092983092 1103925g andis administered subcutaneously three times weekly IFN-983089a (Rebi) was approved in 983090983088983088983090 in the US or treatmento RRMS patients when its superiority over Avonex (theother approved orm o IFN-983089a) was demonstrated in thecontext o the EVIDENCE trial [983091983088] Te EVIDENCE trialwas a randomized multicenter comparative clinical study that assessed and compared the saety and efficacy o IFN-983089a (983092983092 1103925g subcutaneously three times weekly) over IFN-983089a (983091983088 1103925g intramuscular once weekly) in 983094983095983095 patients withRRMS Te study evaluators were blinded to treatment andperormed neurological and neuroimaging examinations

Te primary goal o this trial consisted o the proportion o the patients who were relapse ree at 983090983092 weeks and the majorMRIoutcomewas thenumber o active lesions per patient perscan at 983090983092 weeksBased on the results o thiscomparative trialafer 983090983092 weeks 983095983092983097 o patients who were treated with IFN-983089a 983092983092 1103925g three times weekly stayed relapse-ree comparedwith 983094983091983091 o those who were treated with IFN-983089a 983091983088 1103925gonce weekly Te odds ratio or staying ree rom relapse was983089983097 (983097983093 CI 983089983091ndash983090983094 907317 = 00005) at 983090983092 weeks and 983089983093 (983097983093 CI983089983089 to 983090983089 907317 = 0009) at 983092983096 weeks in avor o IFN-983089b 983092983092 1103925gthree times weekly reatment o MS patients with IFN-983089a983092983092 1103925g three times weekly was associated with ewer MR activelesions (907317 lt 0001 at983090983092 and 983092983096 weeks)compared tothose whowere treated with IFN-983089a983091983088 1103925g once weekly reatment withhigh dose high requency IFN-983089a was associated with moreinjection reactions more cases o asymptomatic elevation o hepatic enzymes and a higher incidence o the developmento neutralizing antibodies

A previous study the PRISMS clinical trial (preventiono relapses and disability by intereron -983089a subcutaneously in multiple sclerosis) [983091983089] assessed the effects o IFN-983089ain patients with relapsing-remitting MS Tis randomizeddouble-blind placebo-controlled trial which led to theapproval o the subcutaneous orm o IFN-983089a or patientswith relapsing-remitting MS compared IFN-983089a (SC) 983090983090micrograms versus 983092983092 micrograms three times weekly andplacebo over a period o two years Te study participants

( = 560) were MS patients with an EDSS score between 983089983088and 983093983088 and at least two exacerbations in the two years priorto the initiation o the clinical trial Te outcome measureso this clinical trial consisted o relapse rate progression o disability and MRI activity Neurological examination wasperormed once every three months with MRI o brainperormed twice per year Analysis was based on intentionto treat Afer the conclusion o this trial data was availableon 983093983091983091 o the patients Analysis o the collected data revealedthat the relapse rate was signi1047297cantly lower at 983089983090 and 983090983092months with both doses o IFN-983089a compared with placebo(mean number per subject 983089983096983090 or 983090983090 1103925g group and 983089983095983091or 983092983092 1103925g versus 983090983093983094 or placebo) Te time to 1047297rst relapse

was lengthened by 983091 and 983093 months in the 983090983090 1103925g and 983092983092 1103925ggroups respectively and the proportion o the relapse-reepatients was signi1047297cantly increased (907317 lt 005) reatmentwith IFN-983089a delayed progression in disability and loweredaccumulated disability during the clinical trial reatment o MS patients with both doses o IFN-983089a had positive impact

on accumulation o burden o disease and number o activelesions on brain MR imaging compared to patients receivingplacebo Te investigators concluded that treatment o MSpatients with IFN-983089a was well tolerated and effective interms o relapse rate de1047297ned disability and all MR outcomemeasures in a dose-dependent manner

Like other beta-intererons side effects o IFN-983089a(Rebi) include 1047298u-like syndrome injection site pain and red-ness hematological and hepatic abnormalities and depres-sion Rarely skin at the injection site becomes inected andnecrotic

6 Interferon-1a (Avonex)

Intereron-983089a (Avonex) was approved by the FDA in 983089983097983097983094or the treatment o patients with relapsing orm o MSand similar to Rebi it is made by Chinese hamster ovariancells Te FDA approval o this medication ollowed theresults obtained rom a clinical trial which was designedby the Multiple Sclerosis Collaborative Research Group(MSCRG) [983091983090ndash983091983092] During this phase 983091 multicenter double-blind placebo-controlled clinical trial 983091983088983089 patients withRRMS were randomized to be treated with IFN-983089a (983091983088 Mgintramuscularly once weekly) or placebo or 983090983092 monthsTe patientsrsquo EDSS scores were between 983089983088 and 983091983093 andeach patient had experienced at least two relapses in thethree years prior to study initiation Te clinical trial was

discontinued earlier than originally designed and only 983093983095o patients 1047297nished the two-year length o the study Many conclusions were drawn based on this group o the patientswho were treated with two years o IFN-983089aandnotthewholegroup which would have included all participants Afer 983090983092months treatment o MS patients with IFN-983089a (Avonex)was associated with an effect on the primary endpoint o the trial the progression rate o at least 983089983088 point on theEDSS compared to placebo In addition treatment o MSpatients with IFN-983089a decreased relapse rate by 983089983096 or thetotal group and 983091983090 or those who 1047297nished the 983090983092-monthmedication course o the trial Te most requent side effectso Avonex include 1047298u-like symptoms with headache ever

chills atigue and vomiting Other less common side effectsconsist o depression suicidal ideation or deterioration o psychiatric disorders Elevated liver enzymes have also beenreported

7 Glatiramer Acetate

Glatiramer acetate (GA) (also known as Cop-983089 and Copax-one) is a synthetic polymer o random sequences o ournaturally occurring amino acids (L-tyrosine L-glutamateL-alanine and L-lysine) and is used as one o the 1047297rstline disease-modiying agents or the treatment o patientwith RRMS Experimental work has demonstrated that GAsuppresses experimental allergic encephalomyelitis (EAE)



983092 Scienti1047297ca

[983091983093 983091983094] GA does not have any biological receptors in thehuman body and its exact mechanism o action remainsunknown However it is believed that GA acts by bindingto the major histocompatibility complex class II moleculescompeting with the other MS putative antigen(s) such asmyelin basic protein or binding to these molecules andto the

speci1047297c receptors located on the surace o the lymphocytes[983091983095]Clinical efficacy o GA in the treatment o patients with

MS has been assessed in the context o a number o clinicaltrials One initial phase 983090 clinical trial o GA in patientswith relapsing MS demonstrated a 983095983094 reduction in relapserate with GA treatment [983091983096] Another multicenter placebo-controlled phase 983091 clinical trial showed that treatment o MSpatients with GA was associated with reduction o relapserate by one third with a signi1047297cant number o study subjectsremaining relapse ree [983091983097] Other clinical trials addressedthe effects o GA on MRI parameters [983092983088 983092983089] Based onthe results o these studies lesion burden measured by MRI demonstrated improvement in GA-treated MS patientsand GA decreased the requency o new contrast-enhancinglesions as well as lesion load compared to baseline values

Side effects o GA include sel-limited eeling o chesttightness 1047298ushing anxiety dyspnea and palpitation Flu-likesymptoms which commonly occur afer the injection o -intererons do not happen with GA injections and treatmento MS with GA is not associated with leucopenia depressionor elevated hepatic enzymes

8 Mitoxantrone

Mitoxantrone (also known as Novantrone) is an antineo-plastic drug structurally related to anthracyclines such as

doxorubicin and daunorubicin Mitoxantrone has immuno-suppressive and immunomodulatory eatures Mitoxantroneintercalates with DNA which in turn leads to single- anddouble stranded breaks It also suppresses DNA repairby inhibiting the topoisomerase II Mitoxantrone exertsimmunosuppressive effects on prolierating cells such as Band lymphocytes decreases secretion o IFN-1038389 NF-and IL-983090 and also induces apoptosis o B lymphocytes andmonocytes [983092983090ndash983092983093] Mitoxantrone possesses dangerous andlie-threatening adverse effects including cardiotoxicity inboth cancerand MS patients [983092983094ndash983092983097] treatment-relatedacutemyelogenous leukemia and gonadal dysunction [983093983088ndash983093983090]While mitoxantrone is a very effective immunosuppressant

with many toxic side effects its utilization has signi1047297cantly decreased due to the introduction o other potent and lessdangerous medications such as natalizumab

9 Natalizumab

Natalizumab (ysabri) is a humanized anti-integrin mono-clonal antibody utilized in treating patients with RRMS [983093983091983093983092] andulcerative colitis [983093983093] Tis anti-adhesion monoclonalantibody targets the 983092-chain o 983092983089 integrin [983093983092 983093983094] whichis also recognized as very late activating antigen-983092 (VLA-983092) [983093983094] All leukocytes except or neutrophils express VLA-983092 on their surace which binds to the adhesion molecule

vascular adhesion molecule-983089 (VCAM-983089) on the surace o activated cerebral endothelial cells Binding o the activatedleukocyte to the in1047298amed endothelial cells is a crucial stepin transendothelial migration o leukocytes to the CNS Teconcept o ldquoanti-adhesion therapyrdquo or MS by utilizing amonoclonal antibody stems rom the original experiments

o Yednock et al [983093983095] on mice with EAE Tese investigatorsdemonstrated that treatment o animals with EAE with anti-VLA-983092 monoclonal antibody resulted in a signi1047297cant decreasein the accumulation o activated leukocytes within the CNS

A number o phase 983090 clinical trials have evaluated thesaetyo natalizumab [983093983091 983093983096] leading to many phase 983091 clinicaltrials Te clinical efficacy o natalizumab or the treatment o MS was assessed during two phase 983091 clinical trials AFFIRM[983093983097] and SENINEL [983094983088] During the AFFIRM trial 983097983090983092participants with relapsing MS who had experienced relapseswere treated with either natalizumab (983091983088983088 mg intravenously)or placebo once every 983090983096 days or 983090983092 months [983093983097] Te study participants who were treated with natalizumab had a 983094983096reduction in clinical relapse rate at 983089 year (907317 lt 0001)and a 983092983090 reduction in the rate o disability progressionat 983090983092 months (907317 lt 0001) reatment o MS patientswith natalizumab was associated with a 983097983090 reduction o contrast-enhancing lesions (907317 lt 0001) 983096983091 reduction o accumulation o new or enlarging 983090-weighted lesions anda 983095983094 decline in new 983089-weighted hypointense lesions (907317 lt0001)

During a second phase 983091 clinical trial (SENINEL)983089983089983095983089 MS patients with relapsing MS who had at least oneexacerbation in the year prior to the study while being treatedwith IFN-983089a (IM once weekly) were randomly assigned tobe treated with either natalizumab (983091983088983088 mg IV once every 983092 weeks) plus IFN-983089a or IFN-983089a plus placebo Te resultso this clinical trial indicated that combination therapy withIFN-983089a and natalizumab was associated with a reducedannualized relapse rate compared to treatment with IFN-983089aalone (983088983091983093 versus 983088983095983093 907317 lt 0001) as well as development o ewer new or expanding 983090-weighted lesions on brain MRI(907317 lt 0001) At month 983090983092 treatment o MS patients witha combination o IFN-983089a and natalizumab was associatedwith a 983090983092 decrease in the relative risk o sustained disability progression (907317 = 002) Currently natalizumab is utilized ortreatment o MS patients and is administered 983091983088983088mg IV onceevery 983090983096 days [983094983089]

Side effects o natalizumab include headache atiguearthralgia urinary tract inection lower respiratory inec-

tion gastroenteritis vaginitis diarrhea and hypersensitivity reactions An uncommon but potentially deadly side effecto treatment o MS patients with natalizumab is the develop-ment o an opportunistic inection o oligodendrocytes by JC

virus known as progressive multiocal leukoencephalopathy (PML) Clinically PML maniests with subacute progressivecognitive decline and ocal neurological de1047297cits and it isusually atal [983094983090 983094983091] As o November 983089 983090983088983089983090 there havebeen 983091983088983090 con1047297rmed cases o PML in MS patients treated withysabri since it became available again in 983090983088983088983094 Te risk o developing PML is higher in MS patients who are seropos-itive or JCV antibodies and those who have previously undergone immunosuppressive therapy with mitoxantrone



Scienti1047297ca 983093

methotrexate or azathioprine Currently serologic status o the MS patients or JC virus can be determined and this pieceo data may assist clinicians with their decision to continueor cease treatment o the MS patients with natalizumab MSpatients who are sero-negative or JCV antibodies should beretested every six months

It is important to bear in mind that while a de1047297nitivecure or MS remains elusive natalizumab is by ar one o themost potent drugs ever developed or treatment o relapsing-remitting MS and its utilization is associated with prolongedperiods o reedom rom disease (as evidence by absence o relapses o disability progression and o MRI evidence o disease activity) in most o the treated patients

10 Fingolimod

Fingolimod (FY 983095983090983088 currently marketed as Gilenya) isan oral sphingosine-983089-phosphate (S983089P) receptor modulatorapproved or treatment o MS in 983090983088983089983088 in North America Tismedication is utilized as a second-line drug S983089P receptors areexpressed by lymphoid and neural tissues Sphingosine-basedphospholipids are constituents o cell membranes and possesschemoattractive unction or the lymphoid cells Resting andB lymphocytes express elevatedlevels o S983089P receptor andlymphocyte exit rom the lymph nodes and thymus dependson the activity o this receptor [983094983092ndash983094983094]

Te efficacy o 1047297ngolimod in the treatment o MS hasbeen demonstrated in major clinical trials During onephase 983090 clinical trial (with a 983090-year extension) its efficacy or treatment o MS was compared to placebo [983094983095] TeRANSFORMS study was a 983089983090-month double-blind clinicaltrial in which 983089983090983097983090 patients with RRMS having a history o at least one relapse were randomized to oral 1047297ngolimod (983088983093or 983089983090983093 mg daily) or IFN-983089a 983091983088 1103925g IM once weekly [983094983096]Te primary goal o this study was to assess the annualizedrelapse rate and secondary end points included the numbero new or enlarged lesions on 983090-weighted MR imaging at983089983090 months as well as progression o disability sustained orat least three months O the initial participants a total o 983089983089983093983091 patients completed the study Te annualized relapse ratewas signi1047297cantly lower in patients in the two arms o theclinical trial who were treated with 1047297ngolimod-983088983090983088 in the983089983090983093 mg group (983097983093 con1047297dence interval 983088983089983094ndash983088983090983094) and 983088983089983094in the 983093 mg group o the study (983097983093 con1047297dence interval 983088983089983090ndash983088983090983089) compared to the group treated with IFN-983089a (983088983091983091 983097983093con1047297dence interval 983088983090983094ndash983088983092983090 907317 lt 0001)

A rare but signi1047297cant issue associated with the use o 1047297ngolimod is the development o the herpes zoster inec-tion and its associated neurological complications Varicella-zoster virus (VZV) is a neurotrophic and exclusively human

virus causing chicken pox (varicella) Once contracted the virus remains as a latent agent within the ganglionic neu-rons along the neuroaxis Based on available study datatwo cases o atal herpes virus amily inections occurredResults indicated that one patient with herpes simplex virusencephalitis died during the trial and another patient withprimary disseminated VZV inection died as well Teseherpes-related atal outcomes occurred during the clinicaltrial o 1047297ngolimod in MS patients who were treated with

a higher dose o the medication [983094983096] Tereore patients whoare not immunized against VZV should be vaccinated priorto initiation o therapy with 1047297ngolimod

Other practical considerations with clinical utilization o 1047297ngolimod particularly ollowing administration o the 1047297rstdose are bradycardia bradyarrhythmias and mild reduction

o orced expiratory volume in 983089 second Such side effectsstem rom the act that in addition to its presence onthe lymphocytes the sphingosine-phosphate receptor is alsoexpressed on other tissues such as atrial myocytes Due to thiseffect a 983094-hour observation period is advised once the 1047297rstdose o 1047297ngolimod is administered

11 Alemtuzumab

Alemtuzumab (also known as Campath-983089H) is a humanizedmonoclonal antibody which targets cell surace moleculeCD983093983090-a glycoprotein antigen expressed on the surace o mature lymphocytes and monocytes CD983093983090 is also expressedby other cells such as thymocytesand macrophages Howeverstem hematopoietic cells plasma cells and platelets do notexpress the CD983093983090 antigen [983094983097] Currently alemtuzumab isapproved by the FDA or treatment o B lymphocyte chroniclymphocytic leukemia Alemtuzumab depletes cells whichcarry CD983093983090 via different routes including complement-mediated lysis antibody-dependent cell toxicity and apopto-sis It has also been demonstrated that alemtuzumab inducesproduction o neurotrophic actors by the reconstitutedautoreactive lymphocytes [983095983088] One line o reasoning orutilization o alemtuzumab or treatment o MS rests on theconcept that with proound depletion o lymphocytes by thismonoclonal antibody the reconstituted pool o lympho-cytes will be devoid o autoreactive clones o lymphocyteswhich promote neuroin1047298ammation in the context o MS [983095983089]which in turn reduces CNS in1047298ammatory damage

Efficacy o alemtuzumab orthe treatmento MS has beenassessed through a number o clinical trials CAMMS983090983090983091 a983091983094-month phase 983090 rater-blinded trial included 983091983091983092 subjectswith RRMS whose disease duration was le983091 years Te study participants were randomized to annual intravenous cycles o alemtuzumab (983089983090 or 983090983092 mgday) versus IFN-983089a (983092983092 1103925g sub-cutaneously three times weekly) or the length o the clinicaltrial [983095983090] reatment with alemtuzumab was associated with asigni1047297cant reduction o annualized relapse rate compared toIFN-983089a (983088983089983088 versus 983088983091983094 907317 lt 0001) as well as signi1047297cantly decreased 983090-weighted lesion burden than IFN-983089a (907317 =

0005) [983095983090] Patients who were treated with alemtuzumabexperienced a signi1047297cantly lower rate o sustained disability accumulation versus IFN-983089a (983097983088 versus 983090983094983090 907317 lt 0001)as evidenced by improvements o the EDSS score Based onthe results o one planned post hoc analysis more patientswho were randomly treated with alemtuzumab had achievedsustained decrease in disability compared to those who weretreated with IFN-983089a (hazard ratio = 983090983094983089 983097983093 CI = 983089983093ndash983092983092907317 = 00004) [983095983091]

Recently the results o a phase 983091 clinical trial o alem-tuzumab in treatment o patients with RRMS were published[983095983092] Te 1047297rst study assessed the efficacy o alemtuzumab

versus IFN-983089a (Rebi) or patients with RRMS During this



983094 Scienti1047297ca

randomized controlled 983090-year trial 983089983096983095 o 983089983097983093 participantswho were randomized to IFN-983089a and 983091983095983094 o 983091983096983094 patientsallocated to alemtuzumab were included in the primary analyses Based on the results o this study 983095983093 (983092983088) patientsin the IFN-983089a group experienced relapses (983089983090983090 events) whileonly 983096983090 (983090983090) patients in the alemtuzumab group relapsed

(983089983089983097 events rate ratio 983088sdot983092983093 [983097983093 CI 983088sdot983091983090ndash983088sdot983094983091] 907317 lt 00001)corresponding to a 983093983092sdot983097 improvement with alemtuzumabTe authors concluded that the efficacy and saety pro1047297le o alemtuzumab in treatment o treatment-naıve MS patientssupports its utilization in these patients

12 Dimethyl Fumarate

Dimethyl umarate (BG983088983088983088983089983090) an ester derivative o umaricacid possesses immunomodulatory properties and is apotential oral treatment o MS BG-983089983090 has shown bene1047297cialeffects in treatment o EAE and may reduce transendothelialmigration o activated leukocytes through the blood brainbarrier along with neuroprotective effects via activation o antioxidative pathways [983095983093 983095983094]

Te efficacy o BG-983089983090 or treatment o MS was assessedduring DEFINE trial Tis clinical trial was a 983090-year phase983091 randomized double-blind placebo-controlled dose-comparison study o BG-983089983090 in 983089983090983091983092 patients during whichstudy subjects were randomized to two different doseso BG-983089983090 (either 983090983092983088 mg PO BID or 983090983092983088 mg PO ID) orto placebo Results o this clinical trial demonstrated thesuperior effect o both doses o BG-983089983090 over placebo insigni1047297cant reduction in the proportion o patients whorelapsed at 983090 years compared to placebo (907317 lt 00001) Bothdoses o BG-983089983090 were superior to placebo in reducing theannual relapse rate the number o new or newly enlarging983090-weighted hyperintense lesions and con1047297rmed disability progression [983095983095] Based on the results o the DEFINE studyBG-983089983090 had a saety pro1047297le comparable to placebo

One o the largest published studies on BG-983089983090 andrelapsing-remitting MS stems rom phase 983090 randomizeddouble-blind placebo-controlled dose-ranging study whichincluded 983090983093983095 participants with relapsing-remitting MS Testudy participants were randomly treated with oral placebo

versus BG-983089983090 983089983090983088 mg 983091983094983088 mg or 983095983090983088 mg orally daily or 983090983092weeks In the 983090983092-weeks extension phase o this trial study participants who were treated with placebo were switchedto BG-983089983090 983095983090983088 mg orally daily Te primary outcome o thisstudy wasthe total number o new contrast-enhancinglesions

on brain MR scans at weeks 983089983090 983089983094 and 983090983092 Other outcomesincluded cumulative number o new contrast-enhancinglesions new 983089-weighted hypointense lesions at 983090983092 weeksand annualized relapse rate According to the results o thisclinical trial treatment o MS patients with BG-983089983090 983090983092983088 mgorally three times daily was associated with 983094983097 decrease inthe mean total number o new contrast-enhancing lesionscompared to the placebo group (983089983092 versus 983092983093 907317 lt 00001)reatment with BG-983089983090 was also associated with a decreasein the number o new or expanding 983090-hyperintense lesions(907317 = 00006) and new 983089-weighted hypointense lesions (907317 =0014) compared to placebo In addition treatment o MSpatients with BG-983089983090 decreased the annualized relapse rate

by 983091983090 Adverse events o treatment with BG-983089983090 includedabdominal pain 1047298ushing and hot 1047298ush Dose-related eventsin recipients o BG-983089983090 consisted o headache atigue andeeling hot [983095983096]

wo recently published papers in the New EnglandJournal o Medicine have reported the efficacy o BG-983089983090 in

treatment multiple sclerosis [983095983097 983096983088] Te 1047297rst report by Foxetal[983095983097] (CONFIRM study) presents the results o a placebo-controlled phase 983091 clinical trial o BG-983089983090 or glatiramer acetatein patients with relapsing-remitting MS During this trial thestudy participants were randomized to BG-983089983090 at a dose o 983090983092983088 mg orally two or three times daily or placebo Te study also included glatiramer acetate as a comparator treatmentarm Te primary endpoint o the CONFIRM clinical trialwas the annualized relapserate during a periodo 983090983092 monthsTis clinical trial did not aim to assess the superiority orlack o superiority o oral BG-983089983090 against glatiramer acetateBased on the results obtained rom this clinical trial afer983090983092 months the annualized relapse rate was lower in MSpatients treated with BG-983089983090 twice every day (983088983090983090) threetimes daily (983088983090983088) and glatiramer acetate (983088983090983097) comparedto placebo (983088983092983088) (relative decreases two times daily BG-983089983090 983092983092 907317 lt 0001 three times daily BG-983089983090 983093983089 907317 lt0001 glatiramer acetate 983090983097 907317 = 001) Compared to theplacebo treatments with BG-983089983090 twice daily and BG-983089983090 threetimes daily as well as glatiramer acetate were associated witha signi1047297cant decrease in the numbers o new or expanding983090-weighted hyperintense lesions (all 907317 lt 0001) and new 983089-weighted hypointense lesions (907317 lt 0001 907317 lt 0001and 907317 lt 0002 resp) Adverse events were more commonin patients treated with active BG-983089983090 or glatiramer acetateand consisted o 1047298ushing and gastrointestinal events (BG-983089983090) or injection site reactions with glatiramer acetate Teadverse events did not include any opportunistic inectionsor malignant cancers reatment with BG-983089983090 is associatedwith low lymphocyte counts Te investigators concludedthat treatment o patients with relapsing-remitting MS withBG-983089983090 and glatiramer acetate caused signi1047297cant reductionin annualized relapse rate and improved neuroradiologic1047297ndings compared to the placebo

Te second paper published by Gold et al [983096983088] presentsthe results rom a phase 983091 placebo-controlled trial o oralBG-983089983090 or treatment o patients with relapsing MS Teinvestigators executed a randomized double-blind placebo-controlled study o oral BG-983089983090 in patients with MS Study participants were randomly assigned to treatment with oral

BG-983089983090 m at a dose o 983090983092983088 mg twice every day BG-983089983090 983090983092983088 mgthree times daily or placebo (DEFINE study) Te primary endpoint o the study consisted o the proportion o patientswho experienced one relapse within two years A numbero other aims included annualize relapse rate the timetowards con1047297rmed progression o disability and neuroimag-ing parameters Based on the results o this clinical trial theMS patients treated with BG-983089983090 experienced signi1047297cantly lessrelapses (noted in both BG-983089983090 dosing groups) compared topatients receiving placebo (983090983095 with BG-983089983090 two times daily and 983090983094 with BG-983089983090 three times daily compared to 983092983094 withplacebo 907317 lt 0001) Te annualized relapse rate afer 983090983092months was 983088983089983095 in the BG-983089983090 twice daily group 983088983089983097 in the



Scienti1047297ca 983095

BG-983089983090 three times daily group and983088983091983094 in the placebo-treatedarm o the study (907317 lt 0001 or the comparison o eachBG-983089983090 regimen with placebo) According to the results o this clinical trial the estimated proportion o patients withcon1047297rmed progression o disability was 983089983094 in the BG-983089983090twice daily arm 983089983096 in the BG-983089983090 three times daily group

and 983090983095 in the placebo-treated arm with signi1047297cant relativerisk reductions o 983091983096 with BG-983089983090 two times daily (907317 =0005) and 983091983092 with BG-983089983090 three times daily (907317 = 001)reatment o MS patients also signi1047297cantly decreased thequantity o contrast-enhancing lesions and new or expanding983090-weighted hyperintense lesion on brain MR (907317 lt 0001 orthe comparison o BG-983089983090 regimen versus placebo) reatmento MS patients with BG-983089983090 was associated with adverseevents such as abdominal pain nausea diarrhea loweredlymphocyte counts and increased hepatic transerases lev-els Te authors concluded that treatment o relapsing MSpatients with BG-983089983090 (both dosing regimens) signi1047297cantly decreased the number o relapses the annualize relapse rate

the rate o disability deterioration and the number o MRIlesions

13 Teriflunomide

eri1047298unomide (Aubagio) (a derivative o le1047298unomide) isan oral drug which binds to dihydro-orotate dehydroge-nase (DHODH) and reversibly inhibits it DHODH is amitochondrial membrane protein which is essential orpyrimidine synthesis [983096983089 983096983090] It is believed that such sup-pression o pyrimidine synthesis in rapidly prolieratingcells such as and B lymphocytes is responsible orthe immunomodulatory effects o teri1047298unomide [983096983091] Onepreliminary phase 983090 proo-o-concept randomized double-blind placebo-controlled clinical trial assessed the saety and efficacy o teri1047298unomide in MS patients with relapses[983096983092] Study participants were randomized to be treated witheither placebo teri1047298unomide 983095 mgdaily or teri1047298unomide983089983092 mgdaily According to the results o this study treatmento MS patients with teri1047298unomide was associated with areduction o combined unique active lesions per MRI scanduring the 983091983094-week treatment phase eri1047298unomide was well-tolerated by patients with relapsing MS Another randomizedclinical trial o oral teri1047298unomide or patients with relapsingMS assessed the annualized relapse rate and con1047297rmedprogression o disability in these patients [983096983093] (EMSOstudy) During this clinical trial 983089983088983096983096 MS patients 983089983096 to 983093983093

years o age with an EDSS score o 983088983088 to 983093983093 and at leastone relapse in the year or two relapses in the two yearsprior to study initiation were randomized to either placeboteri1047298unomide 983095 mgdaily or teri1047298unomide 983089983092 mgdaily or 983089983088983096weeks in a 983089 983089 983089 pattern Compared to placebo treatment o MS patients with teri1047298unomidewas associatedwith 983091983089983090 and983091983089983093 reduction in annualized relapse rate in the 983095 mgdaily and 983089983092 mgdaily treatment groups respectively (907317 lt 0001or both comparisons with placebo) In addition treatmento MS patients with teri1047298unomide (both doses) had a positiveimpact on MRI outcomes Signi1047297cant side effects occurringin patients treated with teri1047298unomide consisted o diarrheanausea hair thinning and mildly increased hepatic enzymes

14 Laquinimod

Laquinimod a derivative o linomide is an immunomod-ulatory agent which is used as a once-daily oral drugor treatment o MS While the exact therapeutic mecha-nism(s) o action o laquinimod in MS remains unknownit has been demonstrated that laquinimod promotes anti-in1047298ammatory cytokine pro1047297le in human peripheral bloodmononuclear cells [983096983094] In EAE model o MS laquinimoddecreased in1047298ammation demyelination and axonal injury [983096983095ndash983096983097]

Laquinimod has been assessed or treatment o MS in thecontext o one phase 983091 clinical trial During a 983090-year phase983091 randomized double-blind placebo-controlled clinical trial(ALLEGRO) 983089983089983088983094 patients with relapsing-remitting MS wererandomized to treatment with 983088983094 mg laquinimod once daily

versus placebo Te primary end point consisted o theannualized relapse rate during the 983090983092-month study while thesecondary end points were con1047297rmed disability progression

and the cumulative number o contrast-enhancing lesionsand new or enlarging lesions on 983090-weighted MR sequence[983097983088] reatment with laquinimod was associated with amodest decrease in annualized relapse rate versus placebo(983088983091983088 plusmn 983088983088983090 versus 983088983091983097 plusmn 983088983088983091 907317 = 0002) along with adecrease in the risk o con1047297rmed disability progression (983089983089

versus 983089983093983095 hazard ratio 983088983094983092 con1047297dence interval 983097983093 907317 =001) Te mean cumulative numbers o contrast-enhancinglesions and new or enlarging 983090-weighted lesions were lessin patients who received laquinimod In addition treatmento MS patients with laquinimod was associated with a 983091983091decrease in progression o brain atrophy compared to placebo(907317 lt 00001)

15 Rituximab

Rituximab (Rituxan) is a chimeric (humanmouse) mon-oclonal antibody with IgG983089 heavy-chain and kappa lightchain constant region sequences and mouse variable regionsequences which depletes CD983090983088+ B lymphocytes via cell-mediated and complement-dependent cytotoxic effects andpromotes apoptosis o these cells [983097983089] In 983089983097983097983095 the FDAapproved use o rituximab or the treatment o relapsing orreractory cases o low grade or ollicular CD983090983088+ B lympho-cyte non-Hodgkin lymphomas CD983090983088 antigen is a 983091983093 kDatransmembrane protein which is expressed by majority o

B lymphocytes in patients with non-Hodgkin lymphomasWhile normal B lymphocytes and its precursors expressthis antigen plasma cells lymphocytes and hematopoieticstem cells do not possess CD983090983088 antigen As a B lymphocytedepleting drug administration o rituximab leads to rapidabolition o CD983090983088+ B lymphocytes in the peripheral circu-lation [983097983090 983097983091] One phase 983090 clinical trial assessed efficacy o rituximab in patient with relapsing-remitting MS and resultso this study indicated that treatment o MS with rituximabwas associated with decline o contrast-enhancing lesions

versus placebo (minus983097983089 907317 lt 0001) as well as signi1047297cantreduction in risk or relapse (983090983088983091 versus 983092983088983088 907317 = 004)[983097983092]



983096 Scienti1047297ca

16 Daclizumab

Daclizumab (also recognized as Zenapax) is a humanizedmonoclonalantibody targeting the -subunit o IL-983090 receptorCD983090983093 on activated lymphocytes IL-983090 which is a lym-phocyte growth actor has a signi1047297cant task in beginningthe prolieration or clonal expansion o antigen-stimulated lymphocytes [983097983093] Tereore blocking the CD983090983093 on the acti-

vated lymphocytes downregulates prolieration o B and lymphocytes via reducing the secretion o pro-in1047298ammatory cytokines [983097983094 983097983095] Currently daclizumab is utilized alongwith other immunosuppressive drugs to circumvent renalgraf rejection [983097983096] Clinical studies o daclizumab in MSpatients indicate that its clinical efficacy is exerted via pro-duction o CD983093983094+ natural killer cells with regulatory unction[983097983097]

Daclizumab was assessed or treatment o MS in thecontext o two clinical trials During the 1047297rst multicenterplacebo-controlled trial (SELEC) a cohort o 983094983088983088 patientswith MS was randomized in a 983089 983089 983089 ratio to be treated

with daclizumab 983089983093983088 mg subcutaneously every 983092 weeksdaclizumab 983091983088983088 mg subcutaneously every 983092 weeks or placebo[983089983088983088] Te primary outcome o this study consisted o itseffect on annual relapse rate at 983089983090 months At one year theannual relapse rate or placebo was 983088983092983094 while it was 983088983090983089 ordaclizumab 983091983088983088 mg group and983088983090983091 mg ordaclizumab 983089983093983088 mggroup respectively (P 983088983088983088983089) A second phase II clinicaltrial (CHOICE) which included 983090983091983088 patients with activerelapsing-remitting MS already being treated with IFN-assessed the efficacy o daclizumab or the treatment o MSStudy participants were randomly assigned to be treatedwith add-on subcutaneous daclizumab 983090 mgkg once every 983090weeks subcutaneousdaclizumab 983089 mgkg once every 983092 weeks

or placebo or a period o 983090983092 weeks O these 983092983094 o patientswere on subcutaneous 983091983088 o IFN-983089a intramuscular and983090983092 on IFN-983089b subcutaneous Te primary endpoint o thisstudy was the total number o new or enlarged contrast-enhancing lesions which were detected between weeks 983096 and983090983092 Based on the results o this clinical trial both add-ondaclizumab groups had lower number o new or enlargedcontrast-enhancing lesions (983089983091983090 or high dose daclizumaband 983091983093983096 or low dose daclizumab) compared to the grouptreated with IFN- and placebo (983092983095983093) (907317 = 0004)

Based on the saety inormation obtained rom theCHOICE study inection rates were similar across all treat-ment groups However the incidence o cutaneous adverse

events was higher in the combined daclizumab groups com-pared to the placebo group A higher rate o grade-983091 or grade-983092 inections happened in patients who were treated withdaclizumab compared to the placebo group Patients whowere treated with daclizumab did not develop opportunisticinections and all inection resolved with treatment [983089983088983089]

17 Cladribine

Cladribine is a potent immunosuppressive agent Its activemetabolite suppresses DNA synthesis and repair whichin turn results in apoptosis o lymphocytes [983089983088983090] Duringa large clinical trial (CLARIY) cladribine was assessed

or the treatment o patients with relapsing-remitting MSWhile cladribine was ound to be effective or treatmento these patients certain concerns regarding its prolongedimmunosuppressiveeffects as well as increased risk orcancercaused the withdrawal o applications or marketing approvalin Europe and cessation o urther ollow-up development in

the United States

18 Concluding Remarks

Prior to 983089983097983097983091 there were no effective treatments or MSand most patients developed signi1047297cant disability and diseaseprogression a ew years rom disease onset However cur-rently there are at least 983096 FDA-approved treatments or MSand much effort and emphasis are placed on development o saer and orally available medications or treatment o MSWhile we are still ar rom 1047297nding a cure or MS small butpersistent steps are being taken in that direction and theuture looks bright or MS patients

References

[983089] J H Noseworthy C Lucchinetti M Rodriguez and B GWeinshenker ldquoMultiple sclerosisrdquo Te New England Journal of Medicine vol 983091983092983091 no 983089983091 pp 983097983091983096ndash983097983093983090 983090983088983088983088

[983090] F Luessi V Siffrin and F Zipp ldquoNeurodegeneration in multiplesclerosis novel treatment strategiesrdquo Expert Review of Neu-rotherapeutics vol 983089983090 no 983097 pp 983089983088983094983089ndash983089983088983095983095 983090983088983089983090

[983091] E M FrohmanM K Racke andC S RaineldquoMedical progressmultiple sclerosismdashthe plaque and its pathogenesisrdquo Te NewEngland Journal of Medicine vol 983091983093983092 no 983097 pp 983097983092983090ndash983097983093983093 983090983088983088983094

[983092] A Nylander and D A Ha1047298er ldquoMultiple sclerosisrdquo Journal of Clinical Investigation vol 983089983090983090 no 983092 pp 983089983089983096983088ndash983089983089983096983096 983090983088983089983090

[983093] G Disanto J M Morahan and S V Ramagopalan ldquoMultiplesclerosis risk actors and their interactionsrdquo CNS and Neuro-logical DisordersmdashDrug argets vol 983089983089 no 983093 pp 983093983092983093ndash983093983093983093 983090983088983089983090

[983094] L Crespy W Zaaraoui M Lemaire et al ldquoPrevalence o grey matter pathology in early multiple sclerosis assessed by magnetization transer ratio imagingrdquo PLoS ONE vol 983094 no 983097Article ID e983090983092983097983094983097 983090983088983089983089

[983095] D H Miller D Chard and O Ciccarelli ldquoClinically isolatedsyndromesrdquo Te Lancet Neurology vol 983089983089 no 983090 pp 983089983093983095ndash983089983094983097983090983088983089983090

[983096] E M Mowry ldquoNatural history o multiple sclerosis early prognostic actorsrdquo Neurologic Clinics vol 983090983097 no 983090 pp 983090983095983097ndash983090983097983090 983090983088983089983089

[983097] S Vukusicand C Conavreux ldquoNatural history o multiplescle-rosis risk actors and prognostic indicatorsrdquo Current Opinion inNeurology vol 983090983088 no 983091 pp 983090983094983097ndash983090983095983092 983090983088983088983095

[983089983088] F D Lublin ldquoClinical eatures and diagnosis o multiplesclerosisrdquo Neurologic Clinics vol 983090983091 no 983089 pp 983089ndash983089983093 983090983088983088983093

[983089983089] A P Borazanci M K Harris R N Schwendimann et al ldquoMul-tiple sclerosis clinical eatures pathophysiology neuroimagingand uture therapiesrdquo Future Neurology vol 983092 no 983090 pp 983090983090983097ndash983090983092983094 983090983088983088983097

[983089983090] B G W Arnason ldquoIntereron in multiple sclerosisrdquo Clinical Immunology and Immunopathology vol 983096983089 no 983089 pp 983089ndash983089983089 983089983097983097983094

[983089983091] Y M Huang N Stoyanova Y P Jin et al ldquoAltered phenotypeand unction o blood dendritic cells in multiple sclerosis are



Scienti1047297ca 983097

modulated by IFN- and IL-983089983088rdquo Clinical and Experimental Immunology vol 983089983090983092 no 983090 pp 983091983088983094ndash983091983089983092 983090983088983088983089

[983089983092] S Shapiro Y Galboiz N Lahat A Kinarty and A MillerldquoTe ldquoimmunological-synapserdquo at its APC side in relapsingand secondary-progressive multiple sclerosis modulation by intereron-rdquo Journal of Neuroimmunology vol 983089983092983092 no 983089-983090 pp983089983089983094ndash983089983090983092 983090983088983088983091

[983089983093] Y Zang J Hong R Robinson S Li V M Rivera and JZ Zhang ldquoImmune regulatory properties and interactions o Copolymer-I and -intereron 983089a in multiple sclerosisrdquo Journal of Neuroimmunology vol 983089983091983095 no 983089-983090 pp 983089983092983092ndash983089983093983091 983090983088983088983091

[983089983094] V Ozenci M Kouwenhoven N eleshova M Pashenkov SFredrikson and H Link ldquoMultiple sclerosis pro- and anti-in1047298ammatory cytokines and metalloproteinases are affecteddifferentially by treatment with IFN-rdquo Journal of Neuroim-munology vol 983089983088983096 no 983089-983090 pp 983090983091983094ndash983090983092983091 983090983088983088983088

[983089983095] V Ozenci M Kouwenhoven Y M Huang P Kivisakk andH Link ldquoMultiple sclerosis is associated with an imbalancebetween tumour necrosis actor-alpha (NF-)- and IL-983089983088-secreting blood cells that is corrected by intereron- (IFN-)treatmentrdquo Clinical and Experimental Immunology vol 983089983090983088 no983089 pp 983089983092983095ndash983089983093983091 983090983088983088983088

[983089983096] A Minagar A Long Ma et al ldquoIntereron (IFN)-983089a andIFN-983089b block IFN-1038389-induced disintegration o endothelial junction integrity and barrierrdquo Endothelium vol 983089983088 no 983094 pp983090983097983097ndash983091983088983095 983090983088983088983091

[983089983097] M Lowery-Nordberg E Eaton E Gonzalez-oledo et al ldquoTeeffects o high dose intereron-983089a on plasma microparticlescorrelation with MRI parametersrdquo Journal of Neuroin1047298amma-tion vol 983096 article 983092983091 983090983088983089983089

[983090983088] S Haghjooy Javanmard M Saadatnia V Homayouni et alldquoIntereron--983089b protects against multiple sclerosis-inducedendothelial cells apoptosisrdquo Frontiers in Bioscience (Elite Edi-tion) vol 983092 pp 983089983091983094983096ndash983089983091983095983092 983090983088983089983090

[983090983089] A Prat A Al-Asmi P Duquette and J P Antel ldquoLymphocytemigration and multiple sclerosis relation with disease courseand therapyrdquo Annals of Neurology vol 983092983094 no 983090 pp 983090983093983091ndash983090983093983094983089983097983097983097

[983090983090] A Minagar J S Alexander R N Schwendimann et alldquoCombination therapy with intereron -983089a and doxycycline inmultiple sclerosis an open-label trialrdquo Archives of Neurology vol 983094983093 no 983090 pp 983089983097983097ndash983090983088983092 983090983088983088983096

[983090983091] Te IFNB Multiple Sclerosis Study Group ldquoIntereron -983089bis effective in relapsing-remitting multiple sclerosis II MRIanalysis results o a multicenter randomized double-blindplacebo-controlled trialrdquo Neurology vol 983092983091 no 983092 pp 983094983093983093ndash983094983094983089983089983097983097983091

[983090983092] D W Paty and D K B Li ldquoIntereron -983089b is effective in

relapsing-remitting multiple sclerosis II MRI analysis resultso a multicenter randomized double-blind placebo-controlledtrialrdquo Neurology vol 983092983091 no 983092 pp 983094983094983090ndash983094983094983095 983089983097983097983091

[983090983093] D H Miller P D Molyneux G J Barker D G MacManus I FMoseley and K Wagner ldquoEffect o intereron-983089b on magneticresonance imaging outcomes in secondary progressive multi-ple sclerosis results o a European multicenter randomizeddouble-blind placebo-controlled trial European study groupon intereron-983089b in secondary progressive multiple sclerosisrdquo Annals of Neurology vol 983092983094 no 983094 pp 983096983093983088ndash983096983093983097 983089983097983097983097

[983090983094] D F Mark S D Lu A A Creasey R Yamamoto and L S LinldquoSite-speci1047297c mutagenesis o the human 1047297broblast intererongenerdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 983096983089 no 983089983096 pp 983093983094983094983090ndash983093983094983094983094 983089983097983096983092

[983090983095] L Kappos C Polman C Pozzilli A Tompson and F DahlkeldquoPlacebo-controlled multicentrerandomised trial o intereron-983089b in treatment o secondary progressive multiple sclerosisrdquoTe Lancet vol 983091983093983090 no 983097983089983091983097 pp 983089983092983097983089ndash983089983092983097983095 983089983097983097983096

[983090983096] G Ebers A raboulsee D Langdon D Goodin A KoniceznyandTe BetaseronBetaseronLF Study GroupldquoTe intereron-983089b 983089983094-year long-term ollow-up study the resultsrdquo in Proceed-ings of the 983093983096th Annual Meeting of the American Academy of Neurology pp 983088983089ndash983088983095983097 San Diego Cali USA 983090983088983088983094

[983090983097] D S Goodin A Reder G C Ebers et al ldquoSurvival in MS arandomized cohort study 983090983089 years afer the start o the pivotalIFN-983089b trialrdquo Neurology vol 983095983096 no 983089983095 pp 983089983091983089983093ndash983089983091983090983090 983090983088983089983090

[983091983088] H Panitch D S Goodin G Francis et al ldquoRandomizedcomparative study o intereron -983089atreatment regimens in MSTe evidence trialrdquo Neurology vol 983093983097 no 983089983088 pp 983089983092983097983094ndash983089983093983088983094983090983088983088983090

[983091983089] G C Ebers G Rice J Lesaux et al ldquoRandomised double-blind placebo-controlled study o intereron -983089a in relaps-ingremitting multiple sclerosisrdquo Te Lancet vol 983091983093983090 no 983097983089983091983097pp 983089983092983097983096ndash983089983093983088983092 983089983097983097983096

[983091983090] L D Jacobs D L Cookair R A Rudick et al ldquoIntramuscularintereron -983089a or disease progression in relapsing multiplesclerosisrdquo Annals of Neurology vol 983091983097 no 983091 pp 983090983096983093ndash983090983097983092 983089983097983097983094

[983091983091] R A Rudick D E Goodkin L D Jacobs et al et al ldquoImpacto intereron -983089a on neurologic disability in relapsing multiplesclerosisrdquo Neurology vol 983092983097 no 983090 pp 983091983093983096ndash983091983094983091 983089983097983097983095

[983091983092] J H Simon L D Jacobs M Campion et al et al ldquoMagneticresonance studies o intramuscular intereron -983089a or relapsingmultiple sclerosisrdquo Annals of Neurology vol 983092983091 no 983089 pp 983095983097ndash983096983095983089983097983097983096

[983091983093] D eitelbaum M Fridkis-Hareli R Arnon and M SelaldquoCopolymer 983089 inhibits chronic relapsing experimental allergicencephalomyelitis induced by proteolipid protein (PLP) pep-tides in mice and intereres with PLP-speci1047297c cell responsesrdquo

Journal of Neuroimmunology vol 983094983092 no 983090 pp 983090983088983097ndash983090983089983095 983089983097983097983094

[983091983094] Deitelbaum A Meshorer Hirsheld R Arnon andM SelaldquoSuppression o experimental allergic encephalomyelitis by asynthetic polypeptiderdquo European Journal of Immunology vol983089 no 983092 pp 983090983092983090ndash983090983092983096 983089983097983095983089

[983091983095] M Fridkis-Hareli D eitelbaum I Pecht R Arnon and MSela ldquoBinding o copolymer 983089 and myelin basic protein leadsto clustering o class II MHC molecules on antigen-presentingcellsrdquo International Immunology vol 983097 no 983095 pp 983097983090983093ndash983097983091983092 983089983097983097983095

[983091983096] M B Bornstein A Miller S Slagle et al et al ldquoA pilot trialo Cop 983089 in exacerbating-remitting multiple sclerosisrdquo Te NewEngland Journal of Medicine vol 983091983089983095 no 983095 pp 983092983088983096ndash983092983089983092 983089983097983096983095

[983091983097] K P Johnson B R Brooks J A Cohen et al ldquoExtended use o

glatiramer acetate (Copaxone) is well tolerated and maintainsits clinical effect on multiple sclerosis relapse rate and degree o disabilityrdquo Neurology vol 983093983095 no 983089983090 supplement pp S983092983094ndashS983093983091983090983088983088983089

[983092983088] G L Mancardi F Sardanelli R C Parodi et al ldquoEffect o copolymer-983089 on serial gadolinium-enhanced MRI in relapsingremitting multiple sclerosisrdquo Neurology vol 983093983088 no 983092 pp 983089983089983090983095ndash983089983089983091983091 983089983097983097983096

[983092983089] G Comi M Filippi and J S Wolinsky ldquoEuropeanCanadianmulticenter double-blind randomized placebo-controlledstudy o the effects o glatiramer acetate on magnetic resonanceimaging-measured disease activity and burden in patients withrelapsing multiple sclerosisrdquo Annals of Neurology vol 983092983097 no 983091pp 983090983097983088ndash983090983097983095 983090983088983088983089



983089983088 Scienti1047297ca

[983092983090] H Lenk U Muller and S anneberger ldquoMitoxantrone mech-anism o action antitumor activity pharmacokinetics efficacy in the treatment o solid tumors and lymphomas and toxicityrdquo Anticancer Research vol 983095 no 983094 pp 983089983090983093983095ndash983089983090983094983092 983089983097983096983095

[983092983091] L S Rosenberg M J Carvlin and R Krugh ldquoTe antitumoragent mitoxantrone binds cooperatively to DNA evidence orheterogeneity in DNA conormationrdquo Biochemistry vol 983090983093 no

983093 pp 983089983088983088983090ndash983089983088983088983096 983089983097983096983094

[983092983092] J M Fidler S Q DeJoy and J J Gibbons Jr ldquoSelectiveimmunomodulation by the antineoplastic agent mitoxantroneI Suppression o B lymphocyte unctionrdquo Journal of Immunol-ogy vol 983089983091983095 no 983090 pp 983095983090983095ndash983095983091983090 983089983097983096983094

[983092983093] B Bellosillo D Colomer G Pons and J Gil ldquoMitoxantronea topoisomerase II inhibitor induces apoptosis o B-chroniclymphocytic leukaemia cellsrdquo British Journal of Haematology vol 983089983088983088 no 983089 pp 983089983092983090ndash983089983092983094 983089983097983097983096

[983092983094] H P Hartung R Gonsette N Konig et al ldquoMitoxantronein progressive multiple sclerosis a placebo-controlled double-blind randomised multicentre trialrdquo Te Lancet vol 983091983094983088 no983097983091983093983088 pp 983090983088983089983096ndash983090983088983090983093 983090983088983088983090

[983092983095] R J Crossley ldquoClinical saety and tolerance o mitoxantronerdquoSeminars in Oncology vol 983089983089 no 983091 supplement 983089 pp 983093983092ndash983093983096983089983097983096983092

[983092983096] V Martinelli M Radaelli L Straffi M Rodegher andG ComildquoMitoxantrone bene1047297ts and risks in multiple sclerosis patientsrdquoNeurological Sciences vol 983091983088 supplement 983090 pp S983089983094983095ndashS983089983095983088983090983088983088983097

[983092983097] R G Ghalie G Edan M Laurent et al ldquoCardiac adverse effectsassociated with mitoxantrone (Novantrone) therapy in patientswith MSrdquo Neurology vol 983093983097 no 983094 pp 983097983088983097ndash983097983089983091 983090983088983088983090

[983093983088] C Cattaneo C Almici E Borlenghi M Motta andG Rossi ldquoAcase o acute promyelocytic leukaemia ollowing mitoxantronetreatmento multiplesclerosisrdquo Leukemia vol983089983095 no 983093pp983097983096983093ndash983097983096983094 983090983088983088983091

[983093983089] C Heesen M Bruegmann J Gbdamosi E Koch A Monchand C Buhmann ldquoTerapy-related acute myelogenous leukae-mia (t-AML) in a patient with multiple sclerosis treated withmitoxantronerdquo Multiple Sclerosis vol 983097 no 983090 pp 983090983089983091ndash983090983089983092 983090983088983088983091

[983093983090] J Bines D M Oleske and M A Cobleigh ldquoOvarian unctionin premenopausal women treated with adjuvant chemotherapy or breast cancerrdquo Journal of Clinical Oncology vol983089983092 no 983093 pp983089983095983089983096ndash983089983095983090983097 983089983097983097983094

[983093983091] D H Miller O A Khan W A Sheremata et al ldquoA controlledtrial o natalizumab or relapsing multiple sclerosisrdquo Te NewEngland Journal of Medicine vol 983091983092983096 no 983089 pp 983089983093ndash983090983091 983090983088983088983091

[983093983092] W A Sheremata A Minagar J S Alexander and VollmerldquoTe role o -983092 integrin in the aetiology o multiple sclerosiscurrent knowledge and therapeutic implicationsrdquo CNS Drugs

vol 983089983097 no 983089983089 pp 983097983088983097ndash983097983090983090 983090983088983088983093[983093983093] S Ghosh E Goldin F H Gordon et al ldquoNatalizumab or active

Crohnrsquos diseaserdquo Te New England Journal of Medicine vol 983091983092983096no 983089 pp 983090983092ndash983091983090 983090983088983088983091

[983093983094] B Engelhardt and L Kappos ldquoNatalizumab targeting 983092-inte-grins in multiple sclerosisrdquo Neurodegenerative Diseases vol 983093no 983089 pp 983089983094ndash983090983090 983090983088983088983095

[983093983095] A Yednock C Cannon L C Fritz F Sanchez-Madrid LSteinmann and N Karin ldquoPrevention o experimental autoim-mune encephalomyelitis by antibodies against 983092983089 integrinrdquoNature vol 983091983093983094 no 983094983091983094983092 pp 983094983091ndash983094983094 983089983097983097983090

[983093983096] N ubridy P O Behan R Capildeo et al ldquo Te effect o anti-983092 integrin antibody on brain lesion activity in MSrdquo Neurology vol 983093983091 no 983091 pp 983092983094983094ndash983092983095983090 983089983097983097983097

[983093983097] C H Polman P W OrsquoConnor E Havrdova et al ldquoA ran-domized placebo-controlled trial o natalizumab or relapsingmultiple sclerosisrdquo Te New England Journal of Medicine vol983091983093983092 no 983097 pp 983096983097983097ndash983097983089983088 983090983088983088983094

[983094983088] R A Rudick W H Stuart P A Calabresi et al ldquoNatalizumabplus intereron -983089a or relapsing multiple sclerosisrdquo Te NewEngland Journal of Medicine vol 983091983093983092 no 983097 pp 983097983089983089ndash983097983090983091 983090983088983088983094

[983094983089] R A Rudick and A Sandrock ldquoNatalizumab 983092-integrinantagonist selective adhesion molecule inhibitors or MSrdquoExpert Review of Neurotherapeutics vol 983092 no 983092 pp 983093983095983089ndash983093983096983088983090983088983088983092

[983094983090] M A Sahraian E W Radue A Eshaghi S Besliu andA Minagar ldquoProgressive multiocal leukoencephalopathy areview o the neuroimaging eatures and differential diagnosisrdquoEuropean Journal of Neurology vol 983089983097 no 983096 pp 983089983088983094983088ndash983089983088983094983097983090983088983089983090

[983094983091] P S Soslashrensen A Bertolotto G Edan et al ldquoRisk strati1047297cationor progressive multiocal leukoencephalopathy in patientstreated with natalizumabrdquo Multiple Sclerosis vol 983089983096 no 983090 pp983089983092983091ndash983089983093983090 983090983088983089983090

[983094983092] M MatloubianC G LoG Cinamon et al ldquoLymphocyteegressrom thymus and peripheral lymphoid organs is dependent onS983089P receptor 983089rdquo Nature vol 983092983090983095 no 983094983097983095983090 pp 983091983093983093ndash983091983094983088 983090983088983088983092

[983094983093] K Chiba ldquoFY983095983090983088 a new class o immunomodulator inhibitslymphocyte egress rom secondary lymphoid tissues and thy-mus by agonistic activity at sphingosine 983089-phosphate receptorsrdquoPharmacology and Terapeutics vol 983089983088983096 no 983091 pp 983091983088983096ndash983091983089983097983090983088983088983093

[983094983094] L Kappos J Antel G Comi et al ldquoOral 1047297ngolimod (FY983095983090983088)or relapsing multiple sclerosisrdquo Te New England Journal of Medicine vol 983091983093983093 no 983089983089 pp 983089983089983090983092ndash983089983089983092983088 983090983088983088983094

[983094983095] P OrsquoConnor G Comi X Montalban et al ldquoOral 1047297ngolimod(FY983095983090983088) in multiple sclerosis two-year results o a phase IIextension studyrdquo Neurology vol 983095983090 no 983089 pp 983095983091ndash983095983097 983090983088983088983097

[983094983096] J A Cohen F Barkho G Comi et al ldquoOral 1047297ngolimod orintramuscular intereron or relapsing multiple sclerosisrdquo TeNew England Journal of Medicine vol 983091983094983090 no 983093 pp 983092983088983090ndash983092983089983093983090983088983089983088

[983094983097] A Minagar J S Alexander M A Sahraian and R ZivadinovldquoAlemtuzumab and multiple sclerosis therapeutic applicationrdquoExpert Opinion on Biological Terapy vol 983089983088 no 983091 pp 983092983090983089ndash983092983090983097983090983088983089983088

[983095983088] J L Jones J M Anderson C L Phuah et al ldquoImprovement indisability afer alemtuzumab treatment o multiple sclerosis isassociated with neuroprotective autoimmunityrdquo Brain vol 983089983091983091no 983096 pp 983090983090983091983090ndash983090983090983092983095 983090983088983089983088

[983095983089] Moreau J Torpe D Miller et al ldquoPreliminary evidence

rom magnetic resonance imaging or reduction in diseaseactivity afer lymphocyte depletion in multiple sclerosisrdquo TeLancet vol 983091983092983092 no 983096983097983089983096 pp 983090983097983096ndash983091983088983089 983089983097983097983092

[983095983090] A J Coles D A S Compston K W Selmaj et al ldquoAlem-tuzumab vs intereron -983089a in early multiplesclerosisrdquo Te NewEngland Journalof Medicine vol 983091983093983097no 983089983095 pp 983089983095983096983094ndash983089983096983088983089 983090983088983088983096

[983095983091] A J Coles E Fox A Vladic et al ldquoAlemtuzumab versusintereron -983089a in early relapsing-remitting multiple sclerosispost-hoc and subset analyses o clinical efficacy outcomesrdquo TeLancet Neurology vol 983089983088 no 983092 pp 983091983091983096ndash983091983092983096 983090983088983089983089

[983095983092] JA CohenA JColes DL Arnoldet al ldquoAlemtuzumabversusintereron 983089a as 1047297rst-line treatment orpatients with relapsing-remitting multiple sclerosis a randomised controlled phase 983091trialrdquo Te Lancet vol 983091983096983088 no 983097983096983093983094 pp 983089983096983089983097ndash983089983096983090983096 983090983088983089983090



Scienti1047297ca 983089983089

[983095983093] D H Lee R A Linker and R Gold ldquoSpotlight on umaratesrdquoInternational MS Journal vol 983089983093 no 983089 pp 983089983090ndash983089983096 983090983088983088983096

[983095983094] D Moharregh-Khiabani R A Linker R Gold and M StangelldquoFumaric acid and its esters an emerging treatment or multiplesclerosisrdquo Current Neuropharmacology vol 983095 no 983089 pp 983094983088ndash983094983092983090983088983088983097

[983095983095] R Gold L Kappos A Bar-Or et al ldquoClinical efficacy o BG-983089983090 an oral therapy in relapsing-remitting multiple scle-rosis data rom the phase 983091 DEFINE trialrdquo in Proceedings of the 983093th Joint eriannial Congress of European and AmericasCommittees for reatment and Research in Multiple Sclerosis(ECRIMSACRIMS) Amsterdam Te Netherlands October983090983088983089983089

[983095983096] L Kappos R Gold DH Milleret al ldquoEfficacy andsaety ooralumarate in patients with relapsing-remitting multiple sclerosisa multicentre randomised double-blind placebo-controlledphase IIb studyrdquo Te Lancet vol 983091983095983090 no 983097983094983092983096 pp 983089983092983094983091ndash983089983092983095983090983090983088983088983096

[983095983097] R J Fox D H Miller J Phillips et al ldquoPlacebo-controlledphase 983091 study o oral BG-983089983090 or glatiramer in multiple sclerosisrdquoTe New England Journal of Medicine vol 983091983094983095 no 983089983090 pp 983089983088983096983095ndash983089983088983097983095 983090983088983089983090

[983096983088] R Gold L Kappos D L Arnold et al ldquoPlacebo-controlledphase 983091 study o oral BG-983089983090 or relapsing multiple sclerosisrdquo TeNew England Journal of Medicine vol 983091983094983095 no 983089983090 pp 983089983088983097983096ndash983089983089983088983095983090983088983089983090

[983096983089] A M Palmer ldquoeri1047298unomide an inhibitor o dihydroorotatedehydrogenase or the potential oral treatment o multiplesclerosisrdquo Current Opinion in Investigational Drugs vol 983089983089 no983089983089 pp 983089983091983089983091ndash983089983091983090983091 983090983088983089983088

[983096983090] J Killestein R A Rudick and C H Polman ldquoOral treatmentor multiple sclerosisrdquo Te Lancet Neurology vol 983089983088 no 983089983089 pp983089983088983090983094ndash983089983088983091983092 983090983088983089983089

[983096983091] M C Claussen and Korn ldquoImmune mechanisms o newther-

apeutic strategies in MSmdashteri1047298unomiderdquo Clinical Immunology vol 983089983092983090 no 983089 pp 983092983097ndash983093983094 983090983088983089983090

[983096983092] P W OrsquoConnor D Li M S Freedman et al ldquoA phase II study o the saety and efficacy o teri1047298unomide in multiple sclerosiswith relapsesrdquo Neurology vol 983094983094 no 983094 pp 983096983097983092ndash983097983088983088 983090983088983088983094

[983096983093] P OrsquoConnor J S Wolinsky C Conavreux et al ldquoRandomizedtrial o oral teri1047298unomide or relapsing multiple sclerosisrdquo TeNew England Journal of Medicine vol 983091983094983093 no 983089983092pp 983089983090983097983091ndash983089983091983088983091983090983088983089983089

[983096983094] P S Giacomini and A Bar-Or ldquoLaquinimod in multiplesclerosisrdquo Clinical Immunology vol 983089983092983090 no 983089 pp 983091983096ndash983092983091 983090983088983089983090

[983096983095] W Bruck and S S Zamvil ldquoLaquinimod a once-daily oraldrug in development or the treatment o relapsing-remittingmultiple sclerosisrdquo Expert Review of Clinical Pharmacology vol

983093 no 983091 pp 983090983092983093ndash983090983093983094 983090983088983089983090[983096983096] W Bruck and C Wegner ldquoInsight into the mechanism o

laquinimod actionrdquo Journal of the Neurological Sciences vol983091983088983094 no 983089-983090 pp 983089983095983091ndash983089983095983097 983090983088983089983089

[983096983097] C Wegner C Stadelmann R P ortner et al ldquoLaquinimodintereres with migratory capacity o cells and reduces IL-983089983095levels in1047298ammatory demyelination and acute axonal damagein mice with experimental autoimmune encephalomyelitisrdquo Journal of Neuroimmunology vol 983090983090983095 no 983089-983090 pp 983089983091983091ndash983089983092983091 983090983088983089983088

[983097983088] G Comi O Abramsky Arbizu et al ldquoOral laquinimod inpatients with relapsing-remitting multiple sclerosis 983091983094-week double-blind active extension o the multi-centre randomizeddouble-blind parallel-group placebo-controlled studyrdquo Multi- ple Sclerosis vol 983089983094 no 983089983089 pp 983089983091983094983088ndash983089983091983094983094 983090983088983089983088

[983097983089] D G Maloney ldquoAnti-CD983090983088 antibody therapy or B-cell lym-phomasrdquo Te New England Journal of Medicine vol 983091983094983094 no 983090983089pp 983090983088983088983096ndash983090983088983089983094 983090983088983089983090

[983097983090] D K Kitsos S siodras E Stamboulis and K I VoumvourakisldquoRituximab and multiple sclerosisrdquo Clinical Neuropharmacol-ogy vol 983091983093 no 983090 pp 983097983088ndash983097983094 983090983088983089983090

[983097983091] M S Weber Menge K Lehmann-Horn et al ldquoCurrenttreatment strategies or multiple sclerosismdashefficacy versus neu-rological adverse effectsrdquo Current Pharmaceutical Design vol983089983096 no 983090 pp 983090983088983097ndash983090983089983097 983090983088983089983090

[983097983092] S L Hauser E Waubant D L Arnold et al ldquoB-cell depletionwith rituximab in relapsing-remitting multiple sclerosisrdquo TeNew England Journal of Medicine vol 983091983093983096 no 983095 pp 983094983095983094ndash983094983096983096983090983088983088983096

[983097983093] R Malek ldquoTe biology o interleukin-983090rdquo Annual Review of Immunology vol 983090983094 pp 983092983093983091ndash983092983095983097 983090983088983088983096

[983097983094] H Gensicke D Leppert O Yaldizli et al ldquoMonoclonal anti-bodies and recombinant immunoglobulins or the treatment o multiple sclerosisrdquo CNS Drugs vol 983090983094 no 983089 pp 983089983089ndash983091983095 983090983088983089983090

[983097983095] R Martin ldquoHumanized anti-CD983090983093 antibody treatment with

daclizumab in multiple sclerosisrdquo Neurodegenerative Diseases vol 983093 no 983089 pp 983090983091ndash983090983094 983090983088983088983095

[983097983096] A Cuppoletti F Perez-Villa I Vallejos and E Roig ldquoExperi-ence with single-dose daclizumab in the prevention o acuterejection in heart transplantationrdquo ransplantation Proceedings vol 983091983095 no 983097 pp 983092983088983091983094ndash983092983088983091983096 983090983088983088983093

[983097983097] B Bielekova M Catalamo S Reichert-Scrivner et al ldquoRegu-latory CD983093983094bright natural killer cells mediate immunomodula-tory effectso IL-983090R -targetedtherapy (daclizumab) in multiplesclerosisrdquo Proceedings of the National Academy of Sciences of theUnited States of America vol 983089983088983091 no 983089983093 pp 983093983097983092983089ndash983093983097983092983094 983090983088983088983094

[983089983088983088] G Giovannoni R Gold K Selmaj et al ldquoA randomizeddouble-blind placebo-controlled study to evaluate the saety and efficacy o daclizumab HYP monotherapy in relapsing-

remitting multiple sclerosis primary results o the SELECtrialrdquo Multiple Sclerosis vol 983089983095 no 983089983088 pp S983093983088983095ndashS983093983090983092 983090983088983089983089

[983089983088983089] D Wynn M Kauman X Montalban et al ldquoDaclizumab inactive relapsing multiple sclerosis (CHOICE study) a phase983090 randomised double-blind placebo-controlled add-on trialwith intereron rdquo Te Lancet Neurology vol 983097 no 983092 pp 983091983096983089ndash983091983097983088 983090983088983089983088

[983089983088983090] C Gasperini and S Ruggieri ldquoEmerging oral drugs orrelapsing-remitting multiple sclerosisrdquo Expert Opinion onEmerging Drugs vol 983089983094 no 983092 pp 983094983097983095ndash983095983089983090 983090983088983089983089



Submit your manuscripts at

httpwwwhindawicom



983090 Scienti1047297ca

disease Unlike patients with RRMS male and emaleindividuals are equally affected by PPMS

Currently MS remains an incurable condition Howevera number o treatments with varying efficacy and adverseeffect pro1047297les have been approved by the FDA Tese med-ications include beta-intererons glatiramer acetate ysabri

Gilenya and mitoxantrone Very recently a new diseasemodiying agent teri1047298unomide (Aubagio) was approved by the FDA or treatment o relapsing orms o MS

2 Beta-Interferons

Beta-intererons which include two orms o intereron-983089a(IFN-983089a) and intereron-983089b [IFN-983089b] are type 983089 interer-ons and approved by the FDA or treatment o MS and CISTree different ormulations o beta-intererons which existor treatment o MS consist o low dose IFN-983089a (Avonex) (983091983088micrograms intramuscular once weekly) high disease IFN-983089a [Rebi] (983090983090 and 983092983092 micrograms subcutaneously threetimes weekly) and IFN-

983089b (Betaseron) (983096983088983088983088983088983088983088 units 983090983093983088

micrograms subcutaneously alternate day injection) Due tothe difference in requency o administration and the utilizeddose Avonex is known as ldquolow doserdquo -intereron whileRebi and Betaseron are recognized as ldquohigh doserdquo Tesethree beta-intereron ormulations along with glatirameracetate are recognized as 1047297rst-line disease modiying agentsor treatment o MS [983089983089] Te mechanisms o action o beta-intererons are discussed and then their clinical trials andside effects will be presented in the order o their approvalin the US

3 Beta-Interferons Mechanisms of Action

While detailed mechanism(s) o the therapeutic actions o the -intererons remains incompletely understood theirbene1047297cial impact in MS patients may stem rom their anti-in1047298ammatory properties as well as their effects on theendothelial cells o the blood brain barrier It has beendemonstrated that IFN- decreases antigen presentation [983089983090]has potential modulatory effects on costimulatory moleculespresent on dendritic and other cells [983089983091 983089983092] suppressesprolieration o the T983089 cells and increases expression o IL-983089983088 (a major anti-in1047298ammatory cytokine) [983089983093] and shifsthe in1047298ammatory environment rom proin1047298ammatory toanti-in1047298ammatory [983089983094 983089983095] IFN- as a class does impactthe endothelial cells and block the disintegrating effects

o the IFN-1038389 on cerebral endothelial cells [983089983096] decreaseplasma endothelial microparticles which act as promoters o transendothelial migration o the activated leukocytes [983089983097]protect endothelial cells rom apoptosis induced by serumrom MS patients [983090983088] and decrease the expression o matrixmetalloproteinases which participate in disruption o thesubendothelial matrix [983090983089 983090983090]

4 Beta-Interferons Clinical Trials

In 983089983097983097983091 IFN-983089b (BetaseronExtavia) was the 1047297rst immun-omodulatory agent approved by the FDA or the treatmento patients with RRMS [983090983091 983090983092] and it is also approved

or treatment o patients with SPMS who still experiencerelapses [983090983093] Utilizing recombinant DNA technology IFN-983089b is produced by Escherichia coli [983090983094] Te dosage o IFN-983089b is 983090983093983088 1103925g subcutaneously every other day

A number o clinical trials have assessed the efficacy andsaety o IFN-983089b in patients with MS [983090983091 983090983092] In 983089983097983097983091 during

a phase 983091 double-blind placebo-controlled clinical trialIFN-983089b was evaluated in a cohort o 983091983095983090 patients with MShaving an EDSS score o 983088983088ndash983093983093 and who had experienced atleast two relapses in the two years prior to study initiationStudy subjects were randomly treated with placebo or IFN-983089b (983093983088983088 or 983090983093983088 1103925g subcutaneously once every other day)or 983090983092 months Based on the results o this initial studyutilization o IFN-983089b in MS reduced clinical relapse ratein both treatment groups compared to the placebo (higherdose versus placebo 907317 = 00001 lower dose compared toplacebo 907317 = 001) In addition patients who were treatedwith the higher dose o IFN-983089b compared to those treatedwith the lower dose showed more decrease in their clinicalrelapse rate (907317 = 00086) which in turn indicated a doseeffect MR neuroimaging results also revealed reduction o 983090-weighted active lesions (higher dose IFN-983089b comparedto placebo 907317 = 00089 lower dose IFN-983089b compared toplacebo 907317 = 004) Te number o new 983090-weighted lesionsdecreased (higher dose IFN-983089b versus placebo 907317 = 00026lower dose compared to placebo 907317 = 003) so did the MRIburden o the disease (higher dose IFN-983089b compared toplacebo 907317 lt 0001 lower dose compared to the placebo907317 = 004) During this trial treatment o MS patients withIFN-983089b did not show any superior effect over placebo onprogression o disability

Another study addressed the long-term saety and effi-cacy o IFN-983089b in the treatment o MS patients withRRMS During this multicenter open-label observationalstudy which was conducted or up to 983089983094 years cross-sectionaldata rom the participants in the pivotal trial o IFN-983089bwas utilized [983090983095] Te 1047297ndings o this study indicated thatearly and uninterrupted long-term therapy o MS patientswith IFN-983089b was acceptable since the decrease in the relapserate stayed similar to the initial study In addition longerperiod treatment o patients with RRMS with IFN-983089b wasassociated with slowing o progression o disability [983090983096]

Frequent side effects o IFN-983089b consist o 1047298u-likesymptoms headache injection site reactions asthenia lym-phopenia elevated hepatic enzymes and pain Less com-monly encountered but more serious adverse events include

depression with suicidal ideation injection site necrosis andinection which indicate discontinuation o therapy

Interestingly a recently published study on IFN-983089b by Goodin et al [983090983097] assessed the effect o this medicationon survival rate o a randomized cohort o MS patient 983090983089years ollowing the initiation o the pivotal IFN-983089b trialTe study subjects were randomized to receive either theactive drug-IFN-983089b 983090983093983088 1103925g subcutaneously once every otherday or placebo Based on the results o this study study subjects who were treated with IFN-983089b demonstrated asigni1047297cant decrease in all-cause mortality over the 983090983089-yearperiod compared to placebo recipients (907317 = 00173) Teauthors concluded that early therapy o MS patients with



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8 Mitoxantrone




9 Natalizumab











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10 Fingolimod








11 Alemtuzumab








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13 Teriflunomide



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15 Rituximab






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16 Daclizumab








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13 Teriflunomide



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Scienti1047297ca 983089983089




































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13 Teriflunomide



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16 Daclizumab








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Scienti1047297ca 983093



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the United States



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983093 pp 983089983088983088983090ndash983089983088983088983096 983089983097983096983094




































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