Department of
`Veterans Affairs
`
`Journal of Rehabilitation Research and Development
`Vol. 39 No. 2, March/April 2002
`Pages 273-286
`
`Immunotherapy of multiple sclerosis—Current practice and
`future directions
`
`Mark J. Tullman, MD; Fred D. Lublin, MD; Aaron E. Miller, MD
`The Corinne Goldsmith Dickinson Centerfor Multiple Sclerosis, Mount Sinai Medical Center, 5 East 98th Street, Box
`1138, New York, NY 10029
`
`Abstract—Over the past decade, multiple sclerosis (MS) has
`becomea treatable neurological disease. This paper reviews
`the therapies that have been studied to treat MS and discusses
`various treatment approaches on the horizon. Immunosuppres-
`sive and immunomodulatory therapies have been shown to
`alter the long-term course of MS. Therapiesare currently avail-
`able for relapsing-remitting, secondary progressive, and pro-
`gressive relapsing disease. Although effective, these therapies
`have a modest impact on reduction in relapse rate and slowing
`of disease progression. Much work is needed to improve upon
`this modest effect and hopefully obtain a cure.
`
`immunomodulatory,
`disease-modifying agents,
`Key words:
`immunosuppressive, immunotherapy, multiple sclerosis, treatment.
`
`INTRODUCTION
`
`the first disease-modifying therapy was
`In 1993,
`approved in the United States for treatment of multiple
`sclerosis (MS). Since then four additional agents have
`been approved, solidifying MSasa treatable neurological
`disease. Therapy is now available for relapsing-remitting
`(RR), secondary progressive (SP), and progressive relaps-
`ing (PR) MS(see Figure). There are no proven therapies
`
`Address all correspondence and requests for reprints to Mark J. Tull-
`man, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis,
`Mount Sinai Medical Center, 5 East 98th Street, Box 1138, New York,
`NY 10029; email: gmtullman@aol.com.
`
`273
`
`for primary progressive MS (PPMS). Asdetailed in the
`following sections, the available therapies for MS are
`modest in their effect on reduction in relapse rate and
`slowing of progression of disease, but nevertheless,
`clearly effective. During the past decade, there have been
`many pilot and pivotaltrials in MS, allowing for incre-
`mental improvement in clinical trial design and imple-
`mentation. In addition to refining the clinical scales used
`to assess efficacy, employing many magnetic resonance
`imaging (MRI) metrics has allowed for more rapid
`assessmentof treatment effect and a better understanding
`of the underlying immunopathologic process of MS.
`Therapy for MS generally involves either disease-modi-
`fying agents (DMA) (ie., those that alter the long-term
`course of MS), treatments of acute exacerbations, or symp-
`tomatic therapies. The latter are beyond the scope ofthis
`paper. The DMA segregate into immunosuppressive thera-
`pies, characterized by relatively nonspecific down-regula-
`tionof immune function and immunomodulatory therapy,
`where the effects on the immune system are more targeted
`and usually less toxic. Currently,
`the best-studied agents
`have been immunomodulatory.
`
`TREATMENT OF ACUTE ATTACKS
`
`Corticosteroids have anti-inflammatory and immuno-
`suppressive effects. Although they likely do notalter the
`natural course of the disease, corticosteroids shorten the
`duration of an attack and hasten the time to recovery.
`
`Merck 2006
`Merck 2006
`Hopewell v Merck
`Hopewell v Merck
`IPR2023-00480
`IPR2023-00480
`
`JANET A. HAMILTON, RDR
`
`EXHIBIT At
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`MM Led
`DATE:
`ASR “AZ
`
`

`

`274
`
`Journal of Rehabilitation Research and DevelopmentVol. 39 No. 2 2002
`
`None3
`
` rent optic neuritis than were the patients in the other two
`
`Interferonf-1a,* Interferonf-1b, Glatiramer
`Acetate, Mitoxantrone?
`groups. Patients treated with IV steroidshada statistically
`significant lower rate of the subsequent development of
`SP|Mitoxantrone, Interferon f-1b+
`clinically definite MS over a 2-year period than did the
`Mitoxantrone
`patients in the other two groups (8). However,this effect
`was temporary and by the end of 3 years, no difference
`existed among the three groups (9).
`Corticosteroids are well tolerated by most patients
`with MS(10). The side effects of short-term pulse doses
`include behavioral disturbances, aseptic necrosis of bone,
`promotion of osteoporosis, risk of infection, and possibly
`peptic ulceration. The long-term risks of pulse doses of
`corticosteroids are unknown. Thus, the risks and benefits
`of corticosteroids need to be considered individually. It is
`perhaps best to treat patients with mild symptoms and
`signs that are not bothersome(e.g., mild sensory symp-
`toms) with a conservative approach.
`The only other treatment shown to be effective for
`acute relapses in MSis plasma exchange (PE). In a small,
`double-blind, placebo-controlled crossover trial by Wein-
`shenkeret al., patients with severe attacks of inflamma-
`tory demyelinating disease (all patients had hemiplegia,
`paraplegia, or tetraplegia) who failed to improveafter at
`least a 5-day course of high-dose parenteral corticoster-
`oid therapy were randomized to receive either seven
`treatments of PE or sham exchanges over 14 days (11).
`Morethan 40 percent ofpatients treated with PE had con-
`siderable improvement of their neurological deficits
`compared with approximately 6 percent of those patients
`This
`who
`received sham exchange.
`improvement
`occurred early during treatment and wassustained during
`6 months of follow-up. Those that responded were
`treated within an average of 40 days of onset of symp-
`toms. One patient improved after treatment was begun
`61 days after the onset of symptoms. The time from onset
`of symptomsto initiation of treatment was similar in
`those patients that responded to therapy and those that
`failed therapy.
`A reasonable approach to the treatment of acute
`relapses of MS would seem to be a 3- to 7- day course of
`high-dose intravenouscorticosteroid therapy. If a patient
`has significant residual disability after 7 days, a trial of
`PE maybe warranted.
`
`* Both 30 pg IM once weekly and 44-pg SC thrice weekly
`have been shownto be effective in RRMS.
`t Indicated in patients with worsening RRMS, despite treat-
`ment with interferon f or glatiramer acetate.
`{ Twostudies of interferon $—1b in patients with SPMS have
`yielded conflicting results in disease progression.
`8 Glatiramer acetate and mitoxantrone are currently being
`tested in PPMS.
`RR= relapsing-remitting
`SP = secondary progressive
`PR = progressive relapsing
`PP = primary progressive
`
`Figure.
`Successful therapeutic trials in MS by disease type.
`
`They have been the mainstay of treatment for acute exac-
`erbations in MS for more than 30 years (1-4). Whereas
`periodic pulse doses of intravenous (IV) methylpredniso-
`lone are not effective in preventing disability in patients
`with progressive MS, a recent phase II trial concluded
`that they do have an effect on disability in patients with
`RRMS(5,6).
`Although no consensus exists on optimal dose, route,
`or length of therapy, currently, patients with acute attacks
`are often treated with high-dose IV methylprednisolone
`(500—1,000 mg/day) for 3 to 5 days, followed by an oral
`prednisone taper. While some neurologists treat acute
`relapses with oral prednisone, the results of the Optic
`Neuritis Treatment Trial question this practice. In this
`multicenter, blinded, randomized, placebo-controlledtrial
`of acute unilateral optic neuritis, 457 patients were ran-
`domized to receive either oral placebo, oral prednisone
`(1 mg/kg) for 14 days or high-dose IV methylpredniso-
`lone for 3 days, followed by 11 days of an oral prednisone
`taper within 8 days of onset of visual symptoms (7).
`Although the vision in patients in the IV steroid- treated
`group improved more rapidly than those of the oral pred-
`nisone- or placebo-treated group, the visual acuity was
`similar in all three groups at 6 months. There was no dif-
`ference in the rate of recovery between the placebo- and
`oral prednisone-treated groups. However, patients treated
`with oral prednisone were more likely to develop recur-
`
`

`

`DISEASE-MODIFYING AGENTS
`
`Immunomodulatory Therapy
`There are four immunomodulatory agents, interferon
`f-la (Avonex and Rebif),
`interferon £-1b (Betaseron),
`and glatiramer acetate (Copaxone), approved by the Food
`and Drug Administration (FDA) for the treatment of
`RRMS(12-18).
`
`Interferon Beta
`
`The mechanism of action of interferon # (IFN 6) in
`MSis unknown. It has a wide range of effects on the
`immune cascade. Potential mechanisms include reduction
`in transport of T cells from the peripheral circulation into
`the central nervous system (CNS) through effects on
`adhesion molecules, chemokines, and matrix metallopro-
`teinases; inhibition of type 1] T-helper cell activation and
`augmentation of suppressor T cell function; and alter-
`ation of cytokine production to favor an anti-inflamma-
`tory state (19).
`Interferon f-1b (IFN f-1b) was the first treatment
`shown to have a favorable effect on the natural history of
`MS (12,13). It is produced in Escheria coli and differs
`from human IFN £ by two amino acids. Unlike human
`IFN £, IFN f-1b is not glycosylated. In 1993, the FDA
`approved IFN £-1b for the treatment of RRMS. This
`approval was based on results of a multicenter, double-
`blind, randomized, placebo-controlledtrial of 372 patients
`with a baseline Expanded Disability Status Scale (EDSS)
`of 0.0 to 5.5 who hadat least two relapses in the previous
`2 years (12,13,20). In this study, patients were randomized
`to receive either placebo, IFN $-1b 1.6 million interna-
`tional units (MIU) (50 yg), or IFN $-1b 8 MIU (250 pg)
`subcutaneously (SC) every other day for 2 years. The pri-
`mary end points of the study were a reduction in exacerba-
`tion rate and the percentage of patients
`remaining
`exacerbation free. At the end of 2 years, the group of
`patients treated with IFN £-1b 8 MIU had an exacerbation
`rate of 0.84 attacks a year compared with 1.27 attacks a
`year in the group treated with placebo,a statistically sig-
`nificant reduction of approximately 34 percent. At the end
`of 2 years, there was a significantly greater number of
`patients in the IFN-treated group who remained relapse
`free than in the placebo-treated group. However, when the
`study was extended, the difference was no longersignifi-
`cant after 3 years. Patients treated with the IFN-1b had a
`longer time to first and second relapse, fewer moderate to
`severe attacks, and required fewer hospitalizations. Con-
`
`TULLMAN etai. Immunotherapy of multiple sclerosis
`
`275
`
`firmed progression of disability had no significant differ-
`ence, as measured by an increase of one or more EDSS
`points that persisted for at least 3 months, between the
`IFNf-1b and placebo-treated groups. Patients treated with
`IFN f-1b had a significant reduction in MRI activity and
`burden of disease. The results of various outcome mea-
`sures including exacerbation rate and MRI disease burden
`favored the higher dose treatment group and provided evi-
`dence for a possible dose effect.
`Neutralizing antibodies (NAb) developed in approxi-
`mately 38 percent of the patients treated with IFN -1b
`after 2 years (with most developing during the first year
`of treatment) and were associated with a decreasein clin-
`ical and MRI efficacy (12,20). After 18 months,
`the
`relapse rate of the group ofpatients treated with IFNf-1b
`8 MIU who were NAbpositive was similar to the group
`of patients receiving placebo (21). However, over time,
`NAbdisappeared in the majority of patients, and Rice et
`al. have recently suggested that the measurement of NAb
`may havelittle clinical use and the treatment decisions
`should be made exclusively on clinical grounds (22).
`In the
`Independent Comparison of
`Interferon
`(INCOMIN)trial, IFN -1b 8 MIU given SC every other
`day and IFN f-la (Avonex) 6 MIU once weekly were
`compared in patients with RRMS (23). After 6 months
`of treatment with IFN,
`the two had similar clinical
`effects. However, after 1 year, IFN £-1b was superior in
`various unblinded clinical outcomes, including relapse
`rate and sustained EDSS progression. Similarly, MRI
`results (evaluated in a single-blind manner) favored the
`IFN f-1b-treated group. The recently presented 2-year
`results showeda similar outcome.
`
`IFN f-1b has also been shown effective in SPMS
`(24). In a multicenter, double-blind, randomized, placebo-
`controlled European trial, 718 patients with SPMS (EDSS
`3.0 to 6.5) were randomized to receive either IFN f-1b 8
`MIUorplacebo SC every other day for up to 3 years. The
`primary outcome was time to confirmed progression of
`disability measured by a sustained increase of at least 1.0
`point on the EDSS (0.5 point if the EDSS was 2 6.0). The
`mean follow-up for both groups was approximately 900
`days. In this study, the group treated with IFN/-1b had an
`approximate 22-percent reduction in the time to progres-
`sion with an average delay of 9 to 12 months. During the
`study period, nearly one-third fewer patients in the IFN-
`ib-treated group became wheelchair-bound compared
`with the placebo-treated group.In addition, patients in the
`IFN f-1b-treated group had a significant reduction in
`
`

`

`276
`
`Journal of Rehabilitation Research and Development Vol. 39 No. 2 2002
`
`relapse rate, had longer time to first relapse, required
`fewer hospitalizations, and had less steroid use. Positive
`results were also seen for MRI analysis (25). A second
`study of IFN £-1b in SPMS was performed in North
`America and was recently reported but not yet published
`(26). In this study, SPMSpatients were treated with either
`placebo, IFN $-1b 8 MIU SC every other day, or IFN /-
`1b 5 MIU/m?(this group received an average dose of 9.6
`MIU) subcutaneously every other day. As opposed to the
`European study, this study showed no effect on the pri-
`mary outcome assessment of time to confirmed progres-
`sion of disability. Similar to the European study, other
`outcome measures, such as reduction in relapse rate and
`MRI activity and lesion load,
`favored the treatment
`group.
`IFN f-1b is currently approved by the FDA in ambu-
`latory patients with RRMSto reduce the frequency of
`relapses. The usual dose is 8 MIU (250 ug) SC every
`other day.
`IFN £-la (Avonex) is produced in mammalian cell
`culture andis structurally identical to human IFN f. The
`pivotal trial of Avonex was a multicenter, double-blind,
`randomized, placebo-controlled trial of 311 patients who
`had RRMSwith a baseline EDSS of1.0 to 3.5 and hadat
`least two exacerbationsin the previous 3 years (14). These
`patients were randomized to receive Avonex 6 MIU
`(30 pg) or placebo via intramuscular (IM) injection once
`weekly. As opposed to the trials of the other interferons
`and glatiramer acetate, the primary outcome measure was
`time to sustained progression of at least 1.0 point on the
`EDSS. After 2 years, there was a significant treatment
`effect. Approximately 35 percent of patients in the pla-
`cebo-treated group had sustained progression ofdisability
`comparedwith approximately 22 percent ofpatients in the
`Avonex-treated group. Several clinical and MRI measures
`served as secondary outcome events. For patients who
`received Avonex for 2 years, the annual exacerbation rate
`was reduced by 32 percent from 0.9 to 0.61. However,
`intent to treat analysis only demonstrated an 18-percent
`reduction in relapse rate. There was a significant reduction
`in the mean numberand volumeof gadolinium-enhancing
`lesions in the Avonex-treated group. After 1 year, the MRI
`total volume of T2-weighted lesions was significantly
`reduced in the IFN-treated group. However, by the end of
`2 years, no significant difference existed between the two
`groups. Neutralizing antibodies developed in 22 percent of
`patients after 2 years.
`
`There is ongoing debate as to when to initiate pro-
`phylactic therapy in patients with MS. The current prac-
`tice guidelines from the National MS Society state that
`initiation of therapy with an immunomodulatory agent
`should begin as soon as possible following a definite
`diagnosis of MS and determination of a relapsing course
`(27). In the recent CHAMPSstudy, a multicenter, dou-
`ble-blind, randomized, placebo-controlled trial involving
`383 patients, it was shown that initiating treatment with
`Avonexat the time of a first clinical demyelinating event
`(optic neuritis,
`incomplete transverse myelitis, brain
`stem, or cerebellar syndrome) in patients with MRI evi-
`dence of prior subclinical demyelination (defined as two
`or more clinically silent lesions greater than 3 mm in
`diameter, one of which had to be periventricular or
`ovoid) is beneficial in reducing the probability of devel-
`oping clinically definite MS (28). Over 3 years, the rate
`of developing clinically definite MS was 44 percent
`lower in the group of patients treated with Avonex than
`the group of patients treated with placebo. However, at
`the end of 3 years, 50 percent of the placebo-treated
`patients did not have a second acute demyelinating event.
`Thus, although the course of MS is unpredictable, treat-
`ment may be unnecessary in a significant proportion of
`patients after a single clinical demyelinating event(i.e.,
`before a diagnosis ofclinically definite MS).
`Currently, the FDA has approved the Avonex form of
`IFN f-1a for relapsing forms of MSto slow the accumu-
`lation of disability and to reduce the rate of relapses. The
`approved dose is 6 MIU (30 yg) IM weekly.
`IFN f-la (Rebif) is produced in Chinese hamster
`ovary cells and is structurally identical to human IFN 8
`and Avonex. It was tested in Europe and Canada in a
`multicenter, double-blind,
`randomized, placebo-con-
`trolled study involving 560 patients with RRMS (EDSS
`0.0 to 5.0) with at least two relapses in the previous
`2 years (15,16). Patients were randomizedto receive pla-
`cebo, Rebif 6 MIU (22 1g), or Rebif 12 MIU (44 pg) SC
`three times a week for 2 years. The primary outcome
`measure of the number of relapses over 2 years was
`obtained with a reduction of 33 percent in the Rebif
`12 MIU-treated group and a 27 percent reduction in the
`Rebif 6 MIU-treated group. Patients in both treatment
`groups performed significantly better than the placebo
`group with respect to a number of moderate to severe
`relapses,
`time to first relapse, percentage of patients
`relapse free, percentage of patients requiring steroid use,
`and time to sustained progression of disability. MRI
`
`

`

`analysis revealed a significant decrease in disease burden
`and fewer gadolinium-enhancing lesions in both treat-
`ment groups compared to the placebo group. Similar to
`what was seen in the IFN £-1b RRMStrial, a dosing
`effect was suggested with the lower-dose treatment group
`having intermediate results in clinical and MRI out-
`comes. After 2 years, the study was extended an addi-
`tional 2 years with the placebo group crossed over and
`randomized to receive either IFN £-la 6 MIU or 12 MIU
`three times a week (29). The treatment effect on clinical
`and MRI measures was maintained during the study for
`both doses of Rebif, with the higher dose group receiving
`the most benefit. Results were superior for patients
`treated with Rebif for all 4 years than for patients in the
`crossover groups, suggesting that early treatment may be
`more beneficial. After 2 years, NAb developed in
`roughly 24 percent of the low-dose treatment group and
`12.5 percent of the high-dose treatment group, and their
`presence did not affect the mean numberofrelapses (15).
`After 4 years, the proportion of patients that developed
`persistent NAb wassimilar, but their presence was asso-
`ciated with reduced clinical and MRIefficacy (29).
`In the Evidence for Interferon Dose-Response: Euro-
`pean-North American Comparative Efficacy (EVIDENCE)
`trial, the two forms ofIFNf-1a (Avonex 6 MIU IM weekly
`versus Rebif 12 MIU three times per week) were compared
`in patients with RRMSin a multicenter, evaluator-blinded
`study (30). The 24-week data (the only results published
`thus far) demonstrated a superior effect of Rebif on relapse
`rate,
`time to first exacerbation, proportion of patients
`relapse-free, and steroid use. MRI outcomes also favored
`the Rebif-treated group.
`Rebif was also tested in SPMSin a multicenter, dou-
`ble-blind, randomized, placebo-controlled trial of 618
`patients (31,32). Although MRI outcomes and relapse
`rate in the Rebif-treated groups had positive results, the
`primary outcome measure of time to confirmed progres-
`sion ofdisability was not significantly prolonged.
`Based on the data from the EVIDENCEtrial, the
`FDA approved Rebif for use in RRMS in March 2002.
`The usual dose is 12 MIU (44 1g) three times per week.
`The main side effects of the interferons are flu-like
`symptoms, injection site reactions, and laboratory abnor-
`malities. The flu-like symptoms (e.g., fever, chills, and
`myalgia) usually occur several hours after injection and
`often resolve within 24 hours. They can be especially
`problematic in the first few weeks after the introduction
`of treatment and may lead to noncompliance and even
`
`TULLMANet al. Immunotherapy of multiple sclerosis
`
`277
`
`they generally
`discontinuation of the drug. However,
`resolve within a few months ofinitiation of therapy, and
`by the end of 1 year, such symptoms are reduced mark-
`edly (20). The flu-like symptoms can often be managed
`with nonsteroidal anti-inflammatory medications or ace-
`taminophen and/or a gradual increasing dose escalation.
`Interferon is frequently given at night to limit side effects
`during wakefulness. All the interferons have been associ-
`ated with injection site reactions that may be as mild as
`local rednessto rarely as severe as skin necrosis requiring
`surgical debridement. Skin necrosis is much less com-
`mon with Rebif than Betaseron (12,15). There have been
`no reports of skin necrosis associated with the use of
`Avonex. Injection site reactions can be reduced by proper
`injection preparation and technique.
`A mild increase in liver enzymes, thrombocytopenia,
`anemia, or leukopenia may be seen shortly after initiation
`of therapy with the various interferons and usually
`returns to near baseline by 4 months. However, labora-
`tory abnormalities may develop at any time during ther-
`apy. A complete blood count and liver function tests
`should be obtained before starting therapy and monitored
`during the course of treatment (4 to 6 weeksafter initiat-
`ing treatment, at 3 months, and every 3 to 6 months there-
`after). Patients taking other medications that can cause
`hepatotoxicity or myelosuppression require more careful
`laboratory monitoring.
`The interferons may possibly cause or worsen
`depressive symptoms (12,20,29). MS patients have a
`high prevalence of depression and suicidal
`ideation
`(33-35). Patients on interferon should be evaluated rou-
`tinely for symptoms of depression. IFN £-1b causes
`menstrual irregularities in some women. No drugs are
`known to interact with the interferons. They are con-
`traindicated in patients with hypersensitivity to the
`drug. Women whoare pregnant, trying to become preg-
`nant, or are lactating should not use interferons.
`
`Glatiramer Acetate (Copaxone)
`Glatiramer Acetate (GA) is a synthetic polypeptide
`composed of four amino acids, L-alanine, L-glutamic
`acid, L-lysine, and L-tyrosine. Its mechanism ofaction is
`unknown but may be related to its capability to enhance
`suppressor T cells or to act as an altered peptide ligand
`(36).
`In a pivotal multicenter, double-blind, randomized,
`placebo-controlled trial, 251 patients with RRMS with an
`EDSS of 0.0 to 5.0 and who had at least two relapses in
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`278
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`Journal of Rehabilitation Research and Development Vol. 39 No. 2 2002
`
`the previous 2 years were randomized to receive either
`placebo or GA 20 mg SC daily for 2 years (17). The pri-
`mary outcome measure of a reduction in relapse rate was
`achieved with a 29-percent reduction from 0.84 in the
`placebo-treated group to 0.59 in the GA-treated group.
`The sustained progression ofdisability had no significant
`difference (as defined by an increase ofat least 1.0 point
`on the EDSS maintained for more than 90 days) between
`the two groups. A subsequent MRI study demonstrated
`that when compared with placebo, GA significantly
`reduced the number of new T2-weighted and gadolin-
`ium-enhancing lesions
`(18). However,
`this
`effect
`occurred more slowly andless intensively than seen with
`IFNf, suggesting that GA exerts its beneficial effect by a
`different mechanism ofaction than IFNf. A large trial of
`GA in PPMSis currently underway (37).
`GAis generally well tolerated, and the most common
`side effects noted during thetrial were injection site reac-
`tions and a systemic reaction. The injection site reaction
`consisted of mild redness and induration at the injection
`site. There have been no reports of skin necrosis associ-
`ated with its use. An unpredictable, sporadic transient
`systemic reaction occurred in 15 percent of patients
`receiving GA in the trial. This reaction consisted of a
`combination of chest tightness, flushing, shortness of
`breath, palpitations, and anxiety. It occurred within min-
`utes of injection and wasself-limited, lasting for seconds
`to minutes and resolving spontaneously without sequelae.
`In most patients,
`it occurred only once. GA does not
`cause anemia, leukopenia, or liver enzyme abnormalities,
`and routine laboratory studies are not necessary. GA does
`not cause depressive symptoms. No drugs are knownto
`interact with GA. It is contraindicated in patients with
`hypersensitivity to the drug or to mannitol. Women who
`are pregnant or who are lactating should not use GA.
`Neutralizing antibodies do not develop against GA. GA
`is currently FDA approvedin patients with RRMSforthe
`reduction of relapses. The standard dose is 20 mg SC
`every day.
`Although they certainly are not a cure with a relapse
`reduction of approximately one-third, the DMA that have
`become available in the past decade have provided MS
`patients with hope for a brighter future. According to the
`National MS Society Disease Management Consensus
`Statement,
`therapy should be continued indefinitely,
`unless a benefit is clearly lacking, side effects are intoler-
`able, new data that reveal other reasons for cessation, or
`better therapy becomesavailable (27).
`
`IMMUNOSUPPRESSIVE THERAPIES
`
`Mitoxantrone (Novantrone)
`Mitoxantroneis a synthetic anthracendionethat inter-
`calates into deoxyribonucleic acid (DNA), producing
`cross- links and strand breaks. It also interferes with ribo-
`nucleic acid (RNA) synthesis. It is indicated to treat pain
`related to advanced hormone refractory prostate cancer
`and as initial therapy of acute nonlymphocytic leukemia.
`Several small randomized, controlled trials suggested
`that mitoxantrone may have a beneficial effect on clinical
`and MRI measures in patients with MS (38-40). These
`results were confirmed in a larger multicenter, observer-
`blind, randomized, placebo-controlled trial in patients
`with severe RRMS, SPMS, or PRMS (41,42). In this
`trial, 194 patients were randomized to receive placebo,
`mitoxantrone 5 mg/m?, or mitoxantrone 12 mg/m? intra-
`venously every 3 months for 2 years. A cohort of 110
`patients received annual MRIscans. Mitoxantronesignif-
`icantly reduced the mean change in EDSS; EDSS
`decreased by 0.12 and 0.23 in mitoxantrone 12 mg/m?
`and 5 mg/m? treated groups, respectively, and increased
`by 0.23 in patients in the placebo group. There were also
`significant differences favoring mitoxantrone on various
`clinical measures,
`including the number of relapses,
`ambulatory impairment, and proportion of patients with
`confirmed EDSSprogression. Patients in the higher dose
`mitoxantrone group had superior results in most out-
`comes. On MRI analysis, mitoxantrone significantly
`reduced the numberof gadolinium-enhancing lesions and
`the average number of new T2-weighted lesions.
`The major toxicities of mitoxantrone are bone-mar-
`row suppression and dose-related cardiotoxicity (reduced
`left ventricular ejection fraction (LVEF) and irreversible
`congestive heart failure (CHF)). Treatment with mitox-
`antrone is limited to a cumulative lifetime dose of
`140 mg/m? (2 to 3 years in most people). Evaluation of
`LVEF is
`recommended before therapy is
`initiated.
`According to the mitoxantrone product
`insert, MS
`patients with LVEFthat is less than 50 percent ordinarily
`should not receive mitoxantrone (43). Further assessment
`of LVEF is recommended in patients who develop symp-
`toms of CHF and before all doses in patients who have
`received a cumulative dose greater than 100 mg/m?. Other
`side effects include alopecia, nausea, menstrual irregular-
`ities, and elevated liver enzymes. A complete blood count
`and liver function tests should be monitored before each
`dose. Mitoxantrone is contraindicated in patients with
`
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`
`
`hypersensitivity to the drug. It should not be used during
`pregnancyor lactation.
`In 2000,
`the FDA approved mitoxantrone for the
`treatment of SPMS, PRMS,and worsening RRMS. The
`recommended dose is 12 mg/m? intravenously every
`3 months. This agent is currently being tested in PPMS
`(44).
`
`Azathioprine (Imuran)
`Azathioprine is an imidazolyl derivative of 6-mer-
`captopurine that impairs DNA and RNAsynthesis.It is
`used in a variety of autoimmune disorders,
`including
`myasthenia gravis. In a meta-analysis of seven random-
`ized, blind, controlled trials with 793 patients with all
`forms of MS, azathioprine was shown to significantly
`reduce relapse rate at 1, 2, and 3 years (45). At 1 year, the
`change in EDSS was similar in the treated and control
`groups. After 2 years, there was a trend toward slowing
`disease progression favoring the azathioprine-treated
`group. A small retrospective study analyzed MRI lesion
`load in patients with RRMS (46). This study compared
`two serial MRI scans (mean interval between scans was
`2.5 years) of patients treated with azathioprine and ste-
`roids after acute relapses with the scans of patients
`treated with steroids alone. A significant reduction in
`MRI lesion load was seen in the group treated with aza-
`thioprine and steroids.
`Toxicities of azathioprine include bone marrow sup-
`pression, nausea, vomiting, and liver enzyme elevations.
`Anincreased risk of cancer may possibly exist with long-
`term use of azathioprine (47). It should not be used dur-
`ing pregnancy.
`Overall, azathioprine has been shown to have a mod-
`est effect on relapses but no convincing effect on progres-
`sive disease. Despite this, azathioprine is probably the
`most common cytostatic agent used in progressive MS,
`based primarily on desperation and anecdotalreports.
`
`Cladribine (Leustatin)
`Cladribine
`is
`an adenosine deaminase-resistant
`purine-nucleoside analogue. It is an immunosuppressant
`that preferentially targets lymphocytes. It is used in the
`treatmentof hairy cell leukemia.
`Several small, randomized, double-blind, placebo-
`controlled studies suggested that cladribine may have a
`favorable effect on clinical and MRI outcomesin patients
`with RRMSand progressive MS (48-50). Subsequently,
`cladribine was studied in a larger, randomized, double-
`
`TULLMANet al. Immunotherapy of multiple sclerosis
`
`blind, placebo-controlled trial in patients with progres-
`sive MS (51). This poorly designed study did not demon-
`Strate any clinical benefit after 1 year but did show a
`marked reduction in gadolinium-enhancinglesions in the
`cladribine-treated group. Side
`effects of cladribine
`include
`long-term bone-marrow suppression,
`fever,
`fatigue, nausea, and diarrhea. It should not be used during
`pregnancy.
`
`Cyclophosphamide (Cytoxan)
`Cyclophosphamide is an alkylating agent with cyto-
`toxic and anti-inflammatory effects that is used to treat
`neoplastic and autoimmunedisorders. Several studies of
`cyclophosphamide in patients with MS haveyielded con-
`flicting results (52-54). Comparison betweentrials is
`always hazardous, and various induction protocols have
`been used, some with the addition of steroids and/orplas-
`mapheresis. The Canadian Cooperative Study provides
`the strongest evidencefor its lack of efficacy (55). In this
`multicenter, single-blind, placebo-controlled trial, 168
`patients with progressive MS were randomizedto receive
`intravenous cyclophosphamide and oral prednisone; oral
`cyclophosphamide, oral prednisone, and weekly PE; or
`placebo medications and sham exchange. Patients were
`followed for an average of 2.5 years. No significant dif-
`ferences existed between the three groupsin the primary
`outcome of progression of disease. Nevertheless, there
`are many anecdotes of success leading to use of this
`agent in desperate cases. Toxicities of cyclophosphamide
`include alopecia, nausea, vomiting, hemorrhagic cystitis,
`sterility, and malignancy. The drug is teratogenic and
`should not be used during pregnancy.
`
`Cyclosporine (Sandimmune)
`Cyclosporine is a cyclic polypeptide with potent
`immunosuppressive properties. It appears to suppress T-
`helper cells. Its main use is in transplant recipients. In a
`large multicenter, double-blind, placebo-controlled trial,
`557 patients with progressive MS were randomized to
`receive e