Current immunotherapy in multiple sclerosis

Current immunotherapy in multiple sclerosis

KHURRAM BASHIR1 and JOHN N WHITAKER1±3

Departments of 1Neurology and the 2Center for Neuroimmunology, University of Alabama at Birmingham,and 3Neurology and Research Services, Birmingham Veterans Medical Center, Birmingham, Alabama,United States of America

Summary The underlying pathophysiology of multiple sclerosis is presumed to be autoimmune in nature.Attempts to ®nd an e�ective treatment for this common disease of the central nervous system have primarily

focused on immune-mediated therapies, both immunosuppressive and immunomodulatory. The wide variety ofimmunological abnormalities detected in multiple sclerosis and its animal model, experimental allergicencephalomyelitis, has prompted the testing of a diverse array of drugs to be used for treatment. Recent

successes in the treatment of relapsing-remitting multiple sclerosis with interferon b and glatiramer acetate haverenewed interest in and raised expectations for the e�ective control of this neurological disorder. Improvedmethodology in clinical trials, the development of surrogate markers and the availability of novel therapies bode

well for more rapid advances.

Key words: glatiramer acetate, glucocorticoids, immunomodulatory agents, immunosuppressive agents, inter-feron, multiple sclerosis.

Introduction

Multiple sclerosis (MS) is an organ-speci®c, autoimmune,demyelinating disease of the central nervous system

(CNS).1 As described elsewhere in this issue, MS is pre-sumed to be initiated by a cell-mediated immune processinvolving activated CD4+ Th1 cells that recognize a CNS

myelin antigen. These cells cross the blood±brain barrierand start a speci®c immune reaction which subsequentlyattracts a variety of non-speci®c cells. Cytokine inductionand release, antibody production, and activation of micro-

glia and astrocytes ensue.2 While remyelination may occur,it is usually not complete, and multiple bouts ultimatelylead to oligodendrocyte, myelin and axonal loss. The pro-

cess of remission then fails, and progression and disabilityresult. The major strategies for treating the tissue injury inMS have focused on limiting demyelination, but newer

avenues including induction of remyelination and im-provement in nerve conduction by demyelinated ®bres arealso being explored.

Given this presumed autoimmune basis, immunophar-

macological therapies have been the mainstay of MStreatment. Therapeutic attempts have been made to alter orblock the various steps conceived to occur in the in¯am-

matory and immunological pathways. The perceived needfor therapeutic agents that reach the lesion in situ in CNS,the inability to initiate treatment prior to the onset of CNS

damage, and the uncertainty of the speci®c immuno-pathogenesis, are viewed as obstacles to advancing e�ectivetreatment. Nonetheless, signi®cant therapeutic advances

have recently been made. The initial agents provided broad

and relatively non-speci®c immunosuppression. Lately, the

focus has shifted to therapies that are more selective. Whilethis focused approach has resulted in more selective mod-ulation of the immune system, the generation of epitope

non-speci®city during an immune response may render ahighly selective immunotherapy ine�ective.2

Most of the early clinical trials using immunosuppressive

agents had limitations of heterogeneous trial design, lack ofrandomization, absence of placebo group, di�erences indemographic characteristics of study and control popula-

tions, concomitant therapy with a variety of immunosup-pressive and immunomodulating agents, uncertain surro-gate markers of disease activity, relatively small doses of thestudy drug, small sample size or high dropout rates. For

these reasons as well as the unpredictable natural course ofMS, most drugs tested (Table 1) have either no or, at best,uncertain bene®t. Improvements in clinical trial design,

availability of cranial magnetic resonance imaging (MRI)and a clearer consensus about the subpopulations of MShave increased the likelihood of identifying e�ective treat-

ments.3 An international survey4 led to the current clinicalclassi®cation of MS into four main groups: relapsing-re-mitting (RR), secondary-progressive (SP), primary-pro-

gressive (PP) and progressive-relapsing (PR). Thisclassi®cation permits a more homogeneous grouping ofpatients for determining natural history as well as responseto experimental therapies. The new drugs for the treatment

of MS, all approved since 1993, have been for RR-typeonly. There are no treatments of proven bene®t for PP- orSP-MS patients. The account which follows will emphasize

the currently used e�ective treatments.

Interferon

Interferons (IFN) are cytokines with antiviral, anti-prolif-erative and immunomodulating properties. They are

Correspondence: Professor John N Whitaker, Department of

Neurology,University ofAlabama atBirminghamJT 1205, 625 19th

Street, South Birmingham, Alabama 35233-7340 USA.

Email: <[email protected]>

Received 27 October 1997; accepted 27 October 1997.

Immunology and Cell Biology (1998) 76, 55±64

divided into two types: type one includes alpha (a) and beta(b) interferons, while type 2 is the gamma (c) interferon.5

IFNc induces MHC class II antigen expression on thesurface of APC and, thus, acts as an activator of the im-

mune system.5 Initially, the level of IFNc was thought to bedecreased in the CNS of MS patients. The ensuing pilottrial to assess its safety and e�cacy in MS demonstrated an

unexpected marked increase in the relapse rate.6,7 Eighteenpatients, with a baseline mean relapse rate of 1.42 relapsesper patient per year, were randomized to receive three dif-

ferent doses of IFNc for 4 weeks. The mean relapse rate inthese patients increased to 4.67 relapses per patient per yearwhile on IFNc therapy. It decreased to 1.0 relapses/patient

per year in the 12±20 month period following the discon-tinuation of treatment with apparently no long-term detri-mental e�ects. The negative result of this trial provided animportant clue in the understanding of the pathogenesis of

MS, and research to de®ne the precise role of IFNc in thisprocess continues.

Interferon a and b are both type 1 interferons with the

same receptor, similar e�ects and a high degree of homo-logy.5 Trials using various natural and recombinant IFNa

preparations for the treatment of MS have yielded mixedresults. In a randomized, placebo-controlled pilot trial of

IFNa in 20 patients with RR-MS there was a modest re-duction in the rate and severity of relapses and the rate ofproduction of IFNc.8 Stabilization of disease activity on

MRI scans was also noted. These e�ects were reversible, asnoted in the follow-up report, with the return of all markersof disease activity to baseline after discontinuation of

treatment.9 This supported the hypothesis that the observedchanges were indeed the result of IFNa therapy. Studies aretoo limited to clearly de®ne the role of this agent in MStherapy.

Interferon b

IFNb was the ®rst drug to be approved by the UnitedStates Food and Drug Administration (US-FDA) for the

treatment of MS. The mechanisms underlying the e�ec-tiveness of IFNb are still not completely known. However,there are several hypotheses, including:5±12

(1) Down-regulation/inhibition of the synthesis or ac-tivity of IFNc, T cell proliferation and function, antibodydependent T cell toxicity, or the actions of TNFa andother cytokines.

(2) Induction/augmentation of T suppressor cell func-tion, or of IL-10 activity.

(3) Possible alteration of the response of the body's im-

mune system to viral infections.

Interferon b-1b

IFNb-1b is a non-glycosylated, human recombinant inter-

feron expressed in E. coli. The pilot trial with recombinantIFNb-1b and its follow-up results demonstrated a trendtowards a decrease in the relapse rate in RR-MS.13,14 A

multicentre, randomized, double-blind trial of IFNb-1bcompared two di�erent doses of this drug (1.6 millioninternational units (MIU) and 8 MIU) against placebo, alladministered subcutaneously on alternate days.15 The high

dose was set on the basis of patient tolerance to a singleinjection. A total of 372 ambulatory RR-MS patients withExpanded Disability Status Scale (EDSS) score of 5.5 or

less were enrolled. This study demonstrated a signi®cantimprovement in the rate of relapses with treatment (0.84relapses/year in the 8 MIU group vs 1.17 relapses/year in

the 1.6 MIU group vs 1.27 relapses/year in the placebogroup). The proportion of patients remaining relapse-freeat the end of 2 years (29.03% in the 8 MIU group vs 18.4%

in the 1.6 MIU group vs 14.6% in the placebo group), andthe median time to ®rst relapse (295 days in the 8 MIUgroup vs 180 days in the 1.6 MIU group vs 153 days in theplacebo group) also favoured the high-dose treatment

group. The severity of relapses was also reduced with8 MIU dose treatment. Cranial MRI data demonstrated asigni®cantly reduced lesion burden in the high-dose treat-

ment group compared with placebo at 3 years (medianchange in lesion area: )118.9 mm2 in the 8 MIU group vs+198.7 mm2 in the placebo group).16 A subgroup of pa-

tients (n � 52) underwent serial cranial MRI scans every 6weeks. Analysis of data from this cohort of patients

Table 1 Pharmacological therapies for multiple sclerosis

Established

bene®t

Possible

bene®t

Uncertain

bene®t

RR-MS IFNb-1b Cladribine Mitoxantrone

Acyclovir mAb to T cell subsets

IFNb-1a Cyclosporin

Glatiramer

acetate

IVIG

TPE

Cytokines

Levamisole

SP-MS Methotrexate* Cyclosporin

IFNb-1a Azathioprine

IFNb-1bTacrolimus (FK 506)

TLI

Mitoxantrone

Cladribine

IVMP

Mizoribine

mAb to T cell subsets

Roquinimex (Linomide)

IVIG

TPE

Levamisole

Cytokines

MS

relapse

IVMP

ACTH

Anti-integrin antibodies

Prednisone

*Upper extremity function only. Incomplete human testing due to cardiovascular toxicity.

ACTH, adrenocorticotrophic hormone; IFN, interferon; IVIG,

intravenous immunoglobulins; IVMP, intravenous methylpredni-

solone; mAb, monoclonal antibodies; RR-MS, relapsing-remitting

multiple sclerosis; SP-MS, secondary-progressive multiple sclerosis;

TLI, total lymphoid irradiation; TPE, therapeutic plasma ex-

change.

56 K Bashir and JN Whitaker

revealed that the bene®cial treatment e�ect was statisticallysigni®cant for both 1.6 MIU and 8 MIU treatment groups.

Although the trial was not powered for long-term results,there were trends for salutary e�ects on relapse reductionand MRI parameters persisting for 5 years.17 IFNb-1b had

no signi®cant e�ect on the progression of disease.Subsequent to the publication of this trial, the appear-

ance and accurate quanti®cation of neutralizing antibodies

(NAb) among treated patients became a concern.17 Amongthe patients treated with 8 MIU, the rate of development ofNAb was 31% at 1 year, 38% at 2 years and it persisted at38% after 3 years. The development of NAb resulted in

reduced e�ectiveness with the relapse rate and MRI deter-minations in NAb-positive patients in the 8 MIU groupsimilar to those in the placebo group. Neutralizing anti-

bodies appeared in both the high- and low-dose treatmentgroups with approximately equal frequency. There is noknown adverse e�ect of these NAb on the progression of

disease. Because of the uncertain validity of the assay ofNAb and the limited study of their consequences, clinicaldecisions based on the presence or absence of NAb cannotyet be made with con®dence. Common side±e�ects of

IFNb-1b therapy were lymphopaenia, anaemia, alanineaminotransferase abnormalities, injection site reactions,depression, and ¯u-like symptoms. The ¯u-like symptoms

decreased over time, with the complaint of fever, malaise ormyalgias noted in 52% of the patients at the beginning oftreatment and in only 8% after 1 year. The incidence of

depression remained high in the high-dose treatment groupafter 5 years (11.1% in the 8 MIU-group, 5.5% in the1.6 MIU group and 5.1% in the placebo group).17,18

Interferon b-1a

IFNb-1a is a recombinant, fully glycosylated interferonthat appears to be identical to the human native interferon.IFNb-1a (6 MIU per week) was compared to placebo in a

multicentre, double-blind, randomized trial involving 301patients.12 The dose and timing of administration werebased on the serum level of b2-microglobulin. The study

population included ambulatory RR-MS patients. IFNb-1adecreased the relapse rate (0.67 relapses/year in the treat-ment group vs 0.82 relapses/year in the placebo group) in

those patients who had mild disability with EDSS scores of1.0±3.5. This e�ect was more pronounced for the subgroupthat was treated for a full 2 years (0.61 relapses/year in the

treatment group vs 0.90 relapses/year in the placebo group).The time from the onset of therapy to the development of®rst relapse was not di�erent between the two groups. Themost signi®cant observation was that treatment with IFNb-1a reduced the rate of acquisition of disability. The prob-ability of developing sustained progression was 21.1% inthe treatment group and 33.3% in the placebo group in

the cohort of patients who completed 2 years of therapy.The degree of worsening in EDSS score from baseline wasalso reduced in the IFNb-1a group compared with the

placebo group (+0.25 vs+0.74). Additional analysis of thedata from this trial demonstrated that the probability ofattaining sustained progression (worsening by ³ 1 point onEDSS for ³ 6 months) was 21.9% in the IFNb-1a group

and 34.9% in the placebo group, a reduction of 37% with

treatment at 2 years.19 This reduction in probability ofsustained progression compared to placebo remained sig-

ni®cant when de®ned as worsening of ³ 1 point on EDSSfor ³ 12 months (61% reduction compared with placebo) orworsening of ³ 2 points for ³ 6 months (67% reduction

compared to placebo). In addition, while only 1% of thepatients in the IFNb-1a group reached an EDSS score of³ 6.0 (requiring unilateral assistance to walk 100 m), this

level of disability was noted in 7% of the placebo-treatedpatients. Serial MRI studies using gadolinium enhancementshowed a bene®cial treatment e�ect which was signi®cant at1 year but not at 2 years. This outcome was probably due to

the small sample size. This trial is unique in that for the ®rsttime a treatment modality was de®nitively shown to fa-vourably a�ect progression of disability in RR-MS. It

should be noted that, in comparison to other clinical trialsin MS, the placebo group showed an increased rate ofprogression. The risk of developing NAb to IFNb-1a was

22% after 2 years of therapy.12 A level of ( ³ 20 was asso-ciated with reduced e�ectiveness and this level was noted inless than 10% of the patients at 1 year in an open-labeltrial.20 Adverse e�ects seen with IFNb-1a therapy were

similar to those noted with IFNb-1b and included ¯u-likesymptoms, asthenia, chills, fever, anaemia, depression, in-jection site reactions, and menstrual disturbances. There are

fewer injection site reactions when compared to IFNb-1b,probably due to the fact that IFNb-1a is injected weeklyand intramuscularly. No increase in risk of depression was

noted, again possibly a result of the lower dose used.Overall, the incidence of side e�ects was low with IFNb-1atherapy. In fact, the trial was terminated early because of a

smaller than expected drop-out rate.

Glatiramer acetate

Glatiramer acetate is an acetate salt of a random polymerof four amino acids, L-alanine, L-lysine, L-glutamic acidand L-tyrosine at a molar ratio of 4.2 : 3.4 : 1.4 : 1.0, res-

pectively.21 Its underlying mechanism of action is unknownat present. It is similar in charge to, and shares some cross-reactivity with myelin basic protein (MBP). Pretreatmentwith glatiramer acetate is known to decrease the incidence

and severity of experimental autoimmune encephalomy-elitis (EAE) in experimental models.21 The postulatedmechanisms of action include desensitization, enhanced

production of antigen-speci®c suppressor T cells, inhibitionof MBP-speci®c e�ector T cells, and competition for thepeptide-binding site of the MHC class II antigen.5,21,22

Initial trials demonstrated the safety but did not con-vincingly prove the e�cacy of glatiramer acetate in thetreatment of MS.22,23 A 2 year multicentre, placebo-con-

trolled phase three trial of glatiramer acetate in 251 patientswith RR-MS demonstrated a bene®cial treatment e�ect.21

There was signi®cant reduction in relapse rate (0.59 re-lapses/year in the treatment group vs 0.84 relapses/year in

the placebo group), percentage of patients remaining re-lapse free at 2 years (78.4% in the treatment group vs75.4% in the placebo group) and median time to ®rst re-

lapse (287 days in the treatment group vs 198 days in theplacebo group). There was a trend, but no signi®cant prooffor lessening progression. Only 27 patients in this study

Current immunotherapy in multiple sclerosis 57

underwent serial gadolinium-enhanced cranial MRIscans,24 and a bene®cial e�ect could not be demonstrated.

Side e�ects noted with glatiramer acetate are mild and in-frequent, and include injection site reaction, chest pain, as-thenia, infection, pain, arthralgia, anxiety and hypertonia. It

also produces a peculiar systemic reaction in about 15% ofpatients with ¯ushing, chest tightness, and palpitationswhich usually resolves spontaneously in less than 30 min.

Comments on IFNb-1b, IFNb-1a and glatiramer acetate

The three drugs currently available for use in RR-MS are

IFNb-1b (Betaseron,Ò Berlex Laboratories), IFNb-1a(Avonex,Ò Biogen Inc.) and glatiramer acetate (Copax-one,Ò Teva Marion Partners). Di�erences in their structure,

dose, treatment schedule, monitoring parameters, e�ects onclinical course and adverse e�ects should be noted (Ta-ble 2). Di�erent trial designs, patient populations and pri-mary end-points make a direct comparison of these agents

arbitrary and `unscienti®c'. Still, in the absence of com-parative trial data, clinicians are faced with the question ofwhich drug to use in a given clinical setting. The main ad-

vantages of IFNb-1b are the longer duration of clinicalexperience with this agent and the higher dose used (8 MIUevery other day). Also, the bene®cial e�ect on MRI disease

activity has been most clearly demonstrated and with apresumed long duration only for IFNb-1b. IFNb-1a hasfewer side e�ects probably because of its relatively smaller

dose (6 MIU/week), and it is the only agent demonstratedto slow the progression of disability. In addition, the inci-dence of NAb appears to be lower with IFNb-1a therapycompared to IFNb-1b. Pending further studies, either agent

may be considered for treatment in RR-MS, with IFNb-1a

usually preferred in those who show mild progressive dis-ability and those less willing to accept the adverse e�ects.

The development of NAb with IFNb therapy and subse-quent loss of therapeutic e�ectiveness requires furtherstudy. Guidelines for the requirements for NAb testing and

interpretation of the test results in patients on IFNb-1b havebeen published.25 The place of glatiramer acetate is unclear,but it may be best for patients who develop NAb to IFNb or

those unable to tolerate either preparation of IFNb becauseof adverse e�ects. The side e�ects with glatiramer acetatetherapy are uncommon and, when they do occur, are usu-ally mild. It rarely causes laboratory test abnormalities.

Precisely de®ned subgroups of patients in whom a givenagent will be most bene®cial are still not known.

Glucocorticoids

Glucocorticoids and adrenocorticotrophic hormone(ACTH) have been the mainstay of therapy for the man-

agement of acute MS relapse for years. The mechanism ofaction of glucocorticoids is multifaceted. They inhibit T cellproliferation, suppress cytokine production and activity,

restore the blood±brain barrier and alter axonal transmis-sion.10,26 ACTH was evaluated in a multicentre, random-ized, double-blind, placebo-controlled trial.27 Utilizing the

Kurtzke Disability Status Scale (DSS), this trial was thebeginning of the e�ort to devise suitable clinical trials ofMS. The e�ect of ACTH (40 U twice daily for 7 days; 20 U

twice daily for 4 days; and 20 U daily for 3 days) wascompared with placebo for the treatment of relapse in 197patients. The bene®t of ACTH was statistically signi®cantat weeks 2 and 4 but not at weeks 1 and 3. ACTH treatment

resulted in more rapid recovery. Had the trial been con-

Table 2 Immunomodulating therapies available for multiple sclerosis

BetaseronÒ15 AvonexÒ12,19 CopaxoneÒ21

Source Escherichia coli Chinese hamster ovary cells Random polymer of four

amino acids*

Glycosylated No Yes NA

Type of MS Relapsing-remitting Relapsing-remitting Relapsing-remitting

Dose 0.25 mg (8 MIU) 30 lg (6 MIU) 20 mg

Route Subcutaneous Intramuscular Subcutaneous

Frequency Every other day Once a week Every day

Relapse rate (% reduction) Decreased (34%) Decreased (18%) Decreased (30%)

Relapse severity Decreased Not studied Not studied

Disability progression No e�ect Decreased No e�ect

Acute lesions on MRI Decreased Decreased Not known

MRI lesion burden Decreased No e�ect Not known

NAb to IFNb Present Present Absent

E�ect of NAb Decreased e�cacy Decreased e�cacy

(at a level of ³ 20)

NA

Laboratory abnormalities Common Rare None

Monitoring CBC, LFT (every 3 months) CBC, LFT (every 6 months) None

Adverse e�ects Flu-like symptoms. Injection

site reactions. Depression

Flu-like symptoms Injection site reactions.

Systemic reaction

*L-glutamic acid, L-alanine, L-lysine and L-tyrosine. Laboratory abnormalities with IFNb-1b, although common, are rarely clinically signi®cant. CBC, complete blood count; LFT, liver

function tests; NA, not applicable; NAb, neutralizing antibodies; MS, multiple sclerosis; MRI, magnetic resonance imaging.


tinued longer than 4 weeks, it is likely that the di�erencebetween the two study groups would have diminished or

even disappeared.Intravenous methylprednisolone (IVMP) was shown to

be e�ective in the treatment of a relapse, with recovery

being more rapid and consistent than that seen withACTH.28,29 Results of the Optic Neuritis Treatment Trial30

have been extrapolated, by neurologists, to all MS associ-

ated relapses. This trial demonstrated that a regimen ofIVMP (1000 mg/day for 3 days) followed by oral predni-sone (1mg/kg per day for 11 days) led to an acceleratedrecovery of visual de®cit. Patients with visual function

equal to or worse than 20/40 at the time of entry into thestudy seemed to gain maximum bene®t. After 6 monthsthere was no signi®cant di�erence in visual acuity between

the IVMP and placebo groups. Oral prednisone (1mg/kgper day for 14 days) provided no bene®t over placebo. Anunanticipated ®nding was that during the 6±24 month pe-

riod following treatment, the risk of recurrent optic neuritisin either eye was increased with oral prednisone (13% in theIVMP group vs 27% in the prednisone group vs 15%in the placebo group). These results should be interpreted

with the understanding that this study was not designed toassess the e�ect of glucocorticoids on MS relapses and thatthe IVMP group was unblinded and lacked a placebo

control. The use of IVMP for the treatment of optic neuritisprobably reduced the risk of development of MS during the2-year period following therapy.31 The risk of being diag-

nosed with clinically de®nite MS during this period was7.5% in the IVMP group, 14.7% in the prednisone groupand 16.7% in the placebo group. Another study, utilizing

serial gadolinium-enhanced MRI, suggested that treatmentof patients with a course of IVMP followed by a prednisonetaper (no dose speci®ed) reduces the number of new lesionsduring a 6-month follow-up period (1.5 new lesions/scan

with treatment vs 2.25 lesions/scan without treatment).32

The total number of lesions (mean 3.42 for scans in treat-ment group vs 3.48 for all scans) was similar in the two

groups, as was the total lesion area (15.9 mm2 per lesionwith treatment vs 14.8 mm2 per lesion without treatment).Oral prednisone is substituted for ACTH and IVMP for the

management of MS relapse by some clinicians mainly be-cause of its easier route and reduced expense of adminis-tration. Data substantiating its equivalent bene®t in acuterelapse have been presented33,34 but are not strongly per-

suasive. Chronic therapy with glucocorticoids has failed todemonstrate a bene®cial e�ect on either the progression ofdisability, or the rate of relapses.27,35,36 Common side ef-

fects of glucocorticoid therapy are hypertension, glucoseintolerance, obesity, cushingoid appearance, osteoporosis,aseptic bone necrosis, cataracts, metallic taste, burning

sensation in the external genitalia, irritability, mood changeand insomnia.

Other pharmacological agents

Cyclosporin

Cyclosporin is a fungus-derived immunosuppressive agentthat suppresses production and activity of cytokines, and

inhibits proliferation and alters function of T cells.37,38

In a multicentre, placebo-controlled trial in progressive

MS (primary and secondary not designated), cyclosporinshowed a trend to delay the time to wheelchair con®ne-ment.39 There was a signi®cant di�erence in the mean

change in DSS score compared to the baseline with treat-ment. There was no di�erence in the other clinical, imagingand laboratory end-points studied. A high dropout rate

(44% in the cyclosporin group vs 32% in the placebogroup) was noted in this trial secondary to adverse e�ectsand lack of recognized bene®t. Another double-blind, pla-cebo-controlled trial of cyclosporin in 80 patients with RR-

and progressive MS was conducted at two centres.40 Therewas a reduction in the rate and severity of relapses and atrend towards delay in disease progression at only one of

the two centres. This di�erence in outcomes was possiblythe result of di�erences in patient populations, cyclosporindoses and examiner's assessment between the two centres.

Nephrotoxicity and hypertension are the most serious andfrequent adverse e�ects.

Cyclophosphamide

Cyclophosphamide interferes with the synthesis and func-tion of DNA via alkylation. It can reverse the course of

EAE when given either before or after the onset of symp-toms.5 Multiple trials have been conducted to study thee�ect of cyclophosphamide in RR- and progressive MS

without providing clinical evidence for a clear therapeuticadvantage.41±43 There may be a role for combined therapywith intravenous cyclophosphamide and IVMP in rapidly

progressive MS.44

Methotrexate

Methotrexate (MTX) is a dihydrofolate reductase inhibitorthat enhances T suppressor cell activity and cytokine-inhibitor production, and suppresses B cell function and

cytokine release.37 A randomized, double-blind trial com-pared MTX (7.5 mg/week) with placebo in 60 patients withboth PP- and SP-MS.45 Methotrexate showed a modest

bene®t in the tests of upper extremity function at the end of2 years. The proportion of patients that did not progressover 2 years was 48.4% in the MTX group and 17.2% in

the placebo group. The maximal bene®t seemed to occurrelatively early in therapy (®rst 3±6 months) and in patientswith moderately severe disability (EDSS scores of 6.0±6.5).

It probably is more e�ective in SP disease compared withPP disease. Data from 35 patients who underwent cranialMRI scans every 6 weeks demonstrated a marginal bene®tin total lesion area in favour of MTX.46 Prolonged use of

MTX causes serious hepatotoxicity, pulmonary ®brosis,bone marrow suppression and teratogenesis.10,47

Azathioprine

Azathioprine is a purine analogue, commonly used at adose of 1mg/kg for its `steroid-sparing' e�ect. It suppresses

the function of NK cells, and alters both CD8+ T cell and


B cell activity.37,48 A number of studies have evaluated thee�cacy and safety of azathioprine in MS. The results of ®ve

double-blind and two single-blind randomized controlledtrials involving a total of 793 patients with progressive MSwere included in a meta-analysis.49 The di�erence in mean

EDSS score between the azathioprine and the placebogroups was )0.22 at 2 years and )0.24 at 3 years. The oddsratio of being relapse free with azathioprine treatment was

1.51 at 1 year and 2.04 at 2 years. These results have beencriticized on the basis of inadequate azathioprine dosesused in these trials as well as the use of total white cell countas a surrogate marker for the e�cacy of azathioprine.50

Despite this meta-analysis demonstrating that the risk ofrelapse was reduced by half over 2 years, the bene®t isprobably only marginal. The major side e�ects include

gastrointestinal, haematological and hepatic toxicity.10,48

Another potential risk of long-term therapy is cancer, inparticular non-Hodgkin lymphoma and skin cancer. This

risk of secondary malignancy in MS patients treated withazathioprine appears to be minimal.51,52

Cladribine

Cladribine (2-chlorodeoxyadenosine) is a selective anti-lymphocytic drug that is incorporated in the nuclear DNAand kills lymphocytes by apoptosis (programmed celldeath).5,37 A double-blind, placebo-controlled trial of

cladribine was conducted in 51 patients with progressiveMS (PP- or SP- not designated).53 This study was initiallydesigned to be a 2-year, double-blind, cross-over trial. The

results were reported at 1 year when the primary end-point,which was neurological improvement, was concluded tohave been met. There was either stabilization or improve-

ment noted on the clinical neurological rating scales in95.8% of the patients in the cladribine group (n � 24)compared with 69.6% of patients in the placebo group(n � 23). The calculated white matter damage on cranial

MRI and intrathecal oligoclonal band concentration werealso reported to be better in the cladribine group. Neitherthe method for quanti®cation of MRI nor the CSF changes

was based on a validated method. The results of the cross-over period in the second year essentially con®rmed the®ndings of the initial report.54 A double-blind, placebo-

controlled trial of subcutaneous cladribine at a lower dose(0.07 mg/kg per day for 5 days/month for 6 months) in 52RR-MS demonstrated a modest bene®cial e�ect on the rate

and severity of relapses and on the development of newgadolinium-enhanced lesions.55 In an open-labelled trial,subcutaneous cladribine failed to delay the progression ofdisability in 19 patients with progressive MS.56 Serious

complications associated with this agent are bone marrowsuppression53 and viral infections.54

Tacrolimus (FK 506)

Tacrolimus (FK 506) is a macrolide antibiotic which issimilar to cyclosporin in its mechanism of action and bio-logical properties. A preliminary trial of tacrolimus (started

at 0.15 mg/kg and then dose adjusted to maintain targetserum level) in SP-MS demonstrated no e�ect on the pro-gression of disease but its toxicity pro®le was reasonable.57

Total lymphoid irradiation

Total lymphoid irradiation (TLI) leads to lymphocyte

death in both the dividing and the resting phases of the cellcycle.58 It preferentially suppresses CD4+ lymphocytescompared to CD8+ cells.59 These e�ects can persist for

years, thus, possibly providing an advantage in chronicdiseases like MS. Initial trials of TLI in progressive MSdemonstrated a signi®cant delay in disease progression with

treatment.60 Further studies demonstrated no clear bene-®t.61 The immunosuppressive e�ect of TLI is suggested tobe enhanced by addition of low-dose steroids.62 The com-plications of TLI include pericarditis, premature coronary

artery disease, hyposplenism, sepsis, secondary cancer, andgonadal dysfunction.

Mitoxantrone

Mitoxantrone is a strong immunosuppressant that in anopen-label small trial failed to show bene®t in 13 patientswith progressive MS.63 Larger trials are in progress. It was

reported to delay disease progression and reduce gadolini-um-enhanced lesions on MRI in hyperactive MS.64 Its useis limited by serious haematological and cardiac toxicity.

6-Mercaptopurine

6-Mercaptopurine is an immunosuppressive agent that in-hibits multiple enzymes in the purine metabolism pathwaysand prevents antibody production.37 Azathioprine (discus-

sed earlier) was designed as a pro-drug for 6-mercapto-purine and has similar biological e�ects with a bettertoxicity pro®le. There is no apparent role for 6-mercap-

topurine in MS therapy.

Mizoribine

Mizoribine is an imidazole nucleoside antibiotic which is

viewed to have e�ects similar to azathioprine. The results ofpreliminary trials of mizoribine in MS seem encourag-ing.65,66 Its use in MS, for the most part, has been limited toJapan where a multicentre, double-blind clinical trial is in

progress.

15-Deoxyspergualin

15-Deoxyspergualin is a synthetic analogue of the antibiotic

spergualine. It interferes with B cell di�erentiation, cyto-toxic T cell activity and antigen presentation by theAPC.37,67 A phase three trial of 15-deoxyspergualin in MS

patients failed to demonstrate a bene®cial e�ect. Severegastrointestinal and haematological toxicity prohibits long-term therapy with this agent.67

Oral bovine myelin

Oral bovine myelin induces immune tolerance and sup-presses T cell activity. A double-blind, randomized trial in30 MS patients reported a trend towards decreased relapse


rate with treatment.68 Preliminary results of a multicentretrial in RR-MS did not reveal a favourable e�ect on either

the rate of relapses or the progression of disease. Detailedresults from this trial are awaited.

Monoclonal and polyclonal antibodies

Monoclonal and polyclonal antibodies are currently underinvestigation for their potential role in the treatment of MS.These antibodies may be directed against T cell subpopu-

lations (CD3+ or CD4+), T cell receptor (TCR) or itscomponent peptides, lymphocyte and endothelial cell sur-face adhesion molecules, or the costimulatory molecules.

Some of these agents are discussed elsewhere in this volume.The concerns with the use of antibody therapy are the se-vere complications including neurological worsening,69,70

and the production of anti-idiotypes (anti-antibodies)against these antibodies by the host.71

Therapeutic plasma exchange

Therapeutic plasma exchange (TPE) non-selectively re-moves blood components that are either known to be or arepotentially pathogenic such as antibodies, immune com-

plexes, and complement.72 The role of TPE in the man-agement of MS is uncertain and lacks documented bene®t.Primary di�culties in interpreting the results of trials

evaluating TPE stem from the use of concomitant immu-nosuppressive therapy and trial design.

Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) is pooled human IgGthat is presumed to alter the immune system by variousmechanisms, among the most interesting of which is its

potential for inducing CNS remyelination.5,37,72 A fewsmall trials of IVIG in MS suggested a salutary e�ect on therate and severity of relapses, disability progression andimprovement of visual acuity.73,74 Other trials failed to

con®rm these ®ndings.75 A recent double-blind, placebo-controlled trial in 148 patients with RR-MS demonstrated abene®cial e�ect on relapse rate and disability progression.76

Anecdotal reports of marked improvement in CNS de-myelinating illness with IVIG77 warrant further study.

Lymphocytophoresis

Lymphocytophoresis or leukophoresis reduces the numberof T cells and this, in turn, lowers the serum levels of an-tibodies and immune complexes.47 There is no convincing

evidence that it is bene®cial in MS.78

Roquinimex

Roquinimex enhances NK cell activity and alters synthesisof cytokines.37 Initial trials in RR- and SP-MS demon-strated a bene®cial e�ect on disability progression and MRI

disease activity.79,80 Its oral route of administration alsoo�ered a highly desirable advantage. An international,

phase 3, multicentre, placebo-controlled trial was under-taken in 1996 in RR- and SP-MS patients. This trial was

terminated in April 1997 because of unexpected seriouscardiovascular toxicity in the treated group.

Sulfasalazine

Sulfasalazine is an anti-in¯ammatory agent that inhibitsantibody production, NK cell activity and cytokine release(especially TNFa).81 Despite encouraging early results, a

recent placebo-controlled trial of oral sulfasalazine failed todemonstrate a signi®cant e�ect in retarding the progressionof disability in patients with mild RR- or progressive MS.82

Levamisole

Levamisole is an anthelminthic drug that enhances theimmune responsiveness to antigenic stimuli.47 In two smalltrials it demonstrated a marginal bene®t on relapse rate in

RR-MS and on disability progression in SP-MS.83,84 It hasalso been reported to worsen MS.85

Isoprinosine

Isoprinosine is an inosine derivative with mild antiviral andT cell stimulant activities.47 Initial small trials demonstrateda trend towards bene®t with treatment, especially in RR-

MS.86,87 A recent double-blind, placebo-controlled trial in52 patients with RR- and progressive MS failed to dem-onstrate a treatment e�ect.88

Acyclovir

Acyclovir is an antiviral agent commonly used for thetreatment of herpes simplex infections. In a randomized,double-blind, placebo-controlled trial of acyclovir (800 mg

three times a day) in 60 patients with RR-MS, there was a34% reduction in the annual relapse rate with treatment(1.03 relapses/year in the treated group and 1.57 relapses/

year in the placebo group).89 The di�erence in the relapserates for the 2 years prior to the study and the 2 years whileon acyclovir treatment was signi®cant. This data was

available for only 19 of the 30 patients in the treatmentarm. There was no e�ect noted on the progression of dis-ability. Further research on the value of acyclovir or relatedcompounds in the treatment of MS is warranted.

Conclusion

Recent advances have enabled the clinical neuroimmunol-ogists to o�er relatively e�ective treatment for RR-MS withacceptable toxicity. The treatment of relapses of establisheddisease with short-term, high-dose IVMP with or without

an oral prednisone taper is now standard therapy. Patientswith RR-MS or relapses on a background of SP-MS shouldbe treated with IFNb-1b, IFNb-1a or glatiramer acetate.

The relative advantages and disadvantages of therapy withthese agents will remain controversial until a direct com-parison is performed, possibly as part of a trial of combi-


nation therapy. The treatment of progressive disease re-mains unsatisfactory. Although methotrexate may improve

upper extremity function in SP-MS, its bene®cial e�ect islimited. There is no proven treatment for PP disease. Allother drugs should be considered experimental at present.

The goal of ®nding a more rational therapy for thetreatment of MS continues to motivate immunologists. Anideal immunopharmacological agent can be de®ned as `one

that could be given over a short-term period to achievelong-term unresponsiveness to the desired antigen, withoutimpairing the response to the infectious agents'.90 Althoughconsiderable progress in the treatment of RR-MS has been

made in the last 5 years, none of the current therapeuticagents meets all these criteria. The possibility of combina-tion immunosuppressive therapy for RR-, SP- or PP-MS, as

has been successful for certain neoplastic disorders, awaitsfurther advancements in trial design and the availability ofsurrogate markers.

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Current immunotherapy in multiple sclerosis