Gestational Diabetes Mellitus ............................ 1591
`
`First, Do No Harm (Pending Prior Approval) 1627
`
`Selective Screening for
`
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`C.D. N AYLOR, M. SER�IER, E. CHEN,
`AND 0. FARINE
`
`The
`ew England
`Journa of Medicine
`
`Established in 1812 as THE NEW E NGi.AN D JOURNAL O F MEDIC I NE A N D SURGERY
`
`VOLUME 337
`
`NOVEMBER 27, 1997
`
`NUMBER 22
`
`ORIGINAL ART ICLES
`
`
`Cardiacpr0pl1ylactic Use of Implanted
`MASSACHUSETTS GENERAL HOSPITAL
`
`A 59-Year-Old Man with Anorexia, Weight Loss,
`
`
`Defibrillators in Patients at High Risk
`
`for Ventricular Arrhythmias after
`
`
`
`
`
`and a Mediastinal Mass ...................................... 1612.
`
`
`
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`R.P. MACDERMOTT AND F.M. GllAE�IE·COOK
`J.T. BIGGER, JR.
`
`Coronary-Artery Bypass Graft Surgery ........... 1569
`
`CASE RECOR OS OF THE
`
`in Sickle Cell Anemia ............................................ 1584
`
`
`
`Sickle Cell Disease and the Endotheliwn ........... 1623
`
`
`
`Screening for Gestational Diabetes Mellitus ..... 1625
`
`EOITOR IALS
`A Comparison of Antiarrhythmic-Drug
`
`1621
`
`
`Clinical Trials of Implantable Defibrillators
`
`Therapy with Implantable Defibrillators
`R.J. MrERIIURG AND A. CASTELLANOS
`in Patients Resuscitated from
`
`Near-Fatal Ventricular Arrhythmias ................. 1576
`
`
`
`
`
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`R.H. LUIIIN
`
`TH E ANTIARRHYTHMICS V ERSUS I �11'1.A:--:TARLE
`
`DEFIIIRILLATORS (I\ VI 0) )N\'ESTIG,\TORS
`
`
`
`
`M.F. GREiiNE
`Grculating Activated Endothelial Cells
`
`
`
`
`
`OCCASIONAL NOTES
`A.SoLOVEY AND OTHERS
`
`
`
`A. PRUCHNICKI
`
`CORR ESPONOENCE
`
`
`Prednisone and Aspirin in Women
`with Recurrent Fetal Loss ........................................ r629
`
`
`Brief Report: A Family with Hypogonadotropic
`
`
`
`Antiphospholipid Antibodies, Annexin V,
`
`
`Hypogonadism and Mutations in the
`
`
`
`
`
`and Pregnancy Loss ................................................... 1630
`
`Gonadotropin-Releasing Hormone
`
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`Plasma Homocysteine Levels and Mortality
`
`
`Receptor .................................................................... 1597
`
`
`
`
`in Patients with Coronary Artery Disease .............. 1631
`N.DE Roux AND OTHERS
`
`
`
`
`Fungal Sinusitis .............................................................. 1633
`
`Interferon Alfa-2b and Cytarabine
`in Chronic Myelogenous Leukemia ......................... 1634
`
`
`
`IMAGES IN CLINICAL MEOICINE
`
`
`
`
`
`
` 1635 ...... ...... ...... ...... .. ........... Is Psychoanalysis Science? ........
`
`
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`Peliosis Hepatis ........................................................... 1603
`
`
`
`
`False Positive Dipstick Test for Malaria ...................... 1635
`E.WALTER AND J. M0CKEL
`
`Malaria Acquired 13 Times in Two Years in Germany 1636
`
`'BOOK REV! EWS ....................................................... 1637
`
`
`
`
`
`REVIEW ARTICLE
`
`
`
`NOTICES ..................................................................... 1639
`
`Drug Therapy: Management of
`
`
`
`Multiple Sclerosis ................................................... 1604
`CORRECTION
`
`All·tmm-Rctinoic Acid in Acute Promyclocytic
`
`R.A. RUDICK, J .A. COHEN,
`1639
`
`
`I,cukcmia .................................................................
`B.WEJNSTOCK·GUTnlAN, R.P. Kl:--:KEL,
`
`
`lNl'ORMATION FOR AUTHORS ......................... 1640
`AND R.M. RANSOH0FF
`
`
`
`MEDICAL Socrnn· ··rci, 1997, hJ TH" MASS,ICIHJShTTS
`
`
`
`
`
`T►11= Nrw Es<.;LA�n Iota.SAi. or ME01c1:-..:1:. (ISSN 002�-4793) i) puhlishcd weekly
`
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`f,om cditori3l otlic<"s .it l 0 Sh:ntuck Street. no�con, M,\ 02115-C,094. Suln(ription price:
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`m:lilins offic..·c�. SI 19 00 per p.·3r. P..:riodic.·31s post.sgc p:iid :ir Boston 3nd :u 3dditioml
`
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`
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`This material may be protected by Copyright law(Title 17 U.S. Code)
`The New England Journal of Medicine
`
`
`
` |
`
`tients with relapsing—remitting multiple sclerosis. As
`a result of these advances,effective therapies are now
`available, andclinical trials of other promising thera-
`pies are under way.
`DISEASE CHARACTERISTICS
`RELATED TO TREATMENT DECISIONS
`
`The goal of therapy in patients with multiple sele-
`rosis is to prevent relapses and progressive worsening
`of the disease. Spontancous recovery is rare when
`neurologic deficits have persisted for longer than six
`months, and there are no known therapies that pro-
`mote regeneration and reverse fixed neurologic deé
`icits. Therefore, disease-modifying therapy should
`be considered before neurologic deficits have per-
`sisted longer than six months. Decisions in individ-
`ual patients should be based both onthe course of
`the patient’s disease and on the probability of severe
`disabling disease.
`A standardized nomenclature to describe the
`course of multiple sclerosis (Table 1) was developed
`by consensus.!? The most common pattern at onset
`is relapsing—remitting disease, but it becomes sec-
`ondary progressive disease over time in more than 50
`percent ofpatients. Approximately 10 percent of pa-
`tients have primary progressive multiple sclerosis.
`They tend to be olderat onset (40 to 60 years ofage)
`and commonly have a progressive myelopathy. Pa-
`tients with primary progressive multiple sclerosis
`have fewer gadolinium-enhanced lesions on cranial
`MRI scans and fewer inflammatory changes in ccre-
`brospinal fluid than patients with secondary progres-
`sive multiple sclerosis.!* Progressive relapsing multi-
`ple sclerosis is a very uncommonpattern ofdisease.
`The vast majority of patients have relapsing—remit-
`ting multiple sclerosis during the early years and sec-
`ondary progressive multiple sclerosis later. Patients
`with relapsing—remitting multiple sclerosis have the
`best responses to treatment, whereas patients with
`progressive disease are less responsive to treatment.
`Disease-modifying therapy should be considered
`early in the course for patients with an unfavorable
`prognosis. The unfavorable prognostic markers relat:
`ed to more rapid worsening ofdisease that are listed
`in Table 2 can be used to select patients for treat
`ment.!922 Patients who have multiple cranial MRI le
`sions at the time of their first symptoms are much
`morelikely to have major disability later on.2* There|
`fore, in addition totheclinical features, the finding®
`on cranial MRIareusefulin selecting patients for @
`ly treatment. Approximately 10 percent of patien®
`have relatively benign disease, however, so not evelY
`patient should receive disease-modifying therapy.
`
`
`
`Drug Therapy
`
`ALASTAIR J.J. Woop, M.D., Editor
`
`MANAGEMENT OF MULTIPLE
`SCLEROSIS
`
`Ricuarb A. Rupick, M.D., JEFFREY A. CoHen, M.D.,
`BiaNcA WEINSTOCK-GUTTMAN, M.D.,
`Revere P. KINKEL, M.D.,
`AND RICHARD M. RANsoHoFF, M.D.
`
`ULTIPLE SCLEROSISis a common dis-
`
`Me ofthe central nervous system affect-
`
`ing approximately 1 million young adults,
`mostly women, worldwide.! It
`is characterized by
`episodic neurologic symptoms that ar often fol-
`lowedbyfixed neurologic deficits, increasing disabil-
`ity, and medical, socioeconomic, and physical decline
`over a period of 30 to 40 years.
`For most of the 20th century, multiple sclerosis
`was considered untreatable. In 1982,
`the Multiple
`Sclerosis Society of Canada and the National Multiple
`Sclerosis Society of the United States sponsored the
`first
`international workshop on therapeutic trials.*
`This workshop served to usher in an era of activism
`and optimism that has substantially replaced wide-
`spread therapeutic nihilism and skepticism about the
`feasibility of clinical trials in multiple sclerosis.
`There have been a number of important advances
`since the international workshop.*+ The Expanded
`Disability Status Scale achieved widespread use as a
`single measure of the severity of multiple selerosis.5
`Magnetic resonance imaging (MRI) was invented,
`applied to multiple sclerosis,® and quickly established
`as a sensitive marker of the pathologic process. Large
`multicenter clinical
`trials were completed,?7!* and
`monographsonclinical trials were published.!5!6 The
`Food and Drug Administration (FDA) approved in-
`terferon beta-la (Avonex, Biogen, Cambridge, Mass.),
`interferon beta-lb (Betaseron, Berlex Laboratories,
`Richmond, Calif), and glatiramer acetate (Copax-
`onc, Teva Marion Partners, Kansas City, Mo.) for pa-
`
`From the Mellen Center for Multiple Sclerosis Trearment and Research,
`Department of Neurology, Cleveland Clinic Foundation, Cleveland, OH
`44106, where reprint requests should be addressed to Dr, Rudick,
`©1997, Massachusetts Medical Society.
`
`1604
`
`November 27, 1997
`
`

`

`DRUG THERAPY
`
`TasLe 1. CLINICAL CATEGORIES OF MULTIPLE SCLEROSIS.
`
`Disease CATEGORY
`
`DEFINITION
`
`
`
`DESIGN OF CLINICAL TRIALS
`
`pelation between TreatmentStrategies and Pathogenesis
`Various lines of research support the hypothesis
`that multiple sclerosis is an autoimmuneprocess oc-
`curring in genetically susceptible personsafter an en-
`yironmental exposure. The geographic heterogeneity
`of the disease and the widely varying prevalence rates
`in different ethnic populations suggestinterplay be-
`tween environmental and genetic factors. The obser-
`yation that commonviralinfections can precipitate
`relapses led to the concept that viruses can trigger
`autoimmune demyelination in susceptible persons.?*
`No specific pathogen hasbeenreliably linked to mul-
`tiple sclerosis, however, so none of the current treat-
`ment approaches are targeted at microbial patho-
`gens. The children ofpatients with multiple sclerosis
`have an increased risk (30-fold to 50-fold) of multi-
`ple sclerosis.?° Studies of twins and adopted children
`suggest that the increased risk is largely genetic.*¢
`Candidate-gene and whole-genome screening sug-
`pests that multiple weakly acting genes interact to
`determine therisk of multiple sclerosis.2729
`Mostcurrent therapeutic approaches are based on
`the hypothesis that multiple sclerosis is an organ-
`specific autoimmunedisease. Inoculation of suscep-
`tible animals with myelin proteinsresults in a relaps-
`ing-remitting, inflammatory, demyelinating central
`nervous system disease called experimental autoim-
`mune encephalomyelitis. Experimental autoimmune
`encephalomyelitis can be transferred to unimmu-
`nized animals through activated T cells that recog-
`nize small fragments of myelin proteins.%° These
`pathogenic T cells use a restricted array of genes for
`T-cell—-antigen receptors. Molecularstrategies that in-
`terrupt the interaction between myelin protein pep-
`tides and pathogenic T-cell receptors are effective in
`acute experimental autoimmune encephalomyelitis.3!
`Human T cells that recognize myelin antigens also
`have restricted use ofT-cell receptors, prompting at-
`tempts to eliminate pathogenic T cells with antibod-
`i€s or vaccination.32 To date, however, evidence of a
`unique immunologic abnormality in patients with
`multiple sclerosis is lacking. In particular, T cells that
`recognize myelin can be isolated with similar fre-
`quencies from patients with multiple sclerosis and
`normal subjects. Furthermore, as autoimmune dis-
`Cases progress, self-peptides are released from the
`target organ, increasing thediversity of the T-cell re-
`sponse. This phenomenon, termed “epitope spread-
`ing,” occurs in animals with chronic experimental
`dutoimmune encephalomyelitis44 and in patients
`With multiple sclerosis?® and may limit simple treat-
`Ment strategies based on blocking the recognition
`Of autoantigen.
`The lesions of multiple sclerosis resemble those in-
`duced by delayed hypersensitivity, containing inflam-
`Matory cytokines, activated T cells, and mononuclear
`
`Relapsing-remitting
`
`Secondary progressive
`
`Episodes of acute worsening with recovery and
`a stable course between relapses
`Gradual neurologic deterioration with or with-
`out superimposed acute relapses in a patient
`who previously had relapsing-remitting mul-
`tiple sclerosis
`Gradual, nearly continuous neurologic deterio-
`ration from the onset of symptoms
`Gradual neurologic deterioration from the on-
`set of symptoms but with subsequent super-
`
`imposed relapses
`
`Primaryprogressive
`
`Progressive relapsing
`
`
`
`TaBLe 2. PROGNOSTIC MARKERS THAT PREDICT
`More SEVERE MULTIPLE SCLEROSIS.
`
`Progressive discase from the onset of symptoms
`Motorand cerebellar signs at presentation to neurologist
`Shortinterval betweenthe first two relapses
`Poorrecovery from relapse
`Multiple cranial lesions on T,-weighted MRI atpresentation
`
`phagocytes.**37 These elements, shown in Figure 1,
`are all potential targets for intervention. Function-
`related T-cell surface molecules can be down-regulat-
`ed with antibodies. Cytokine-based therapies, such as
`those involving soluble receptors for tumor necrosis
`factor @ or immunosuppressive cytokines such as
`transforming growth factor 6 orinterleukin-10, may
`potentially be effective. The inflammation ofthe cen-
`tral nervous system mayalso besensitive to interven-
`tion directed against leukocyte and cerebrovascular
`endothelial adhesion molecules or chemokines, which
`mediate the migration of leukocytes into the central
`nervoussystem. In both multiple sclerosis and exper-
`imental autoimmune encephalomyelitis, myelin anti-
`bodies are concentrated in the central nervous sys-
`tem, and demyelinating antibodies in experimental
`autoimmuneencephalomyelitis synergize with T-cell—
`effector mechanisms.*” Pathogenic antibodies are also
`potential therapeutic targets.
`
`Controlled Clinical Trials
`
`Therapeutic advances in multiple sclerosis are de-
`pendentonclinical trials because of the highly vari-
`able and unpredictable course of the disease and the
`difficulty in precisely measuring neurologic disability.
`The ExpandedDisability Status Scale, the most wide-
`ly used outcome measure in clinical trials of multiple
`sclerosis, is an ordinal rating scale ranging from 0 to
`10, in increments of 0.5, with higherscorcs reflecting
`increasing severity. The fact that there is a single
`score for each patient at each time point makes study
`design andstatistical analysis relatively simple, but
`
`Volume 337 Number 22
`
`1605
`
`

`

`
`The New England Journal of Medicine
`
`\
`
`Systemic |
`Circulation
`oe
`
`v
`
`Recruitmentofcells
`
`Central Ne rious
`System
`
`ri
`
`Myelin injury
`
`Astrocyte
`
` Blood-Brain
`Barrier
`
`
`
`
`
`
`Chemokines <@—
`
`
`
`Microglia
`
`
`
` superantigens,
`mimicry, or u
`mechani.
`
`Activation of
`endothelium
`
`
`
`Autoreactive
`T cell
`
`Antigen-presentingcell
`
`
`
`
`
`
`
`Figure 1. Pathogenesis of Multiple Sclerosis.
`Circulating autoreactive T cells are activated by stimulation with superantigens,8 molecular mimicry,3 or unknown mechanisms.
`Onceactivated, these autoreactive cells traverse the blood-brain barrier to enter the central nervous system. Perivascular antigen-
`presenting cells provide the signals necessary to result in the activation and clonal expansion of these autoreactive T cells and the —
`secretion of proinflammatory cytokines by them. The cytokines, including tumor necrosis factor and interferon-y, induce astrocytes _
`and leukocytes to secrete chemokines” and stimulate the expression of adhesion molecules by endothelial cells. Activated micro-
`glia and macrophages damage myelin internodes.*' Proinflammatory cytokines may directly inhibit nerve conduction, leading to —
`neurologic dysfunction. Immunosuppressive cytokines (not shown) inhibit the inflammatory process, leading to neurologic recov
`ery. The putative mechanismsofaction of the therapeutic effects of interferon beta, as indicated by the numbers,include inhibition
`of the proliferation of autoreactive T ceils (1); inhibition of the expression of major-histocompatibility-complex class |] molecules,”
`leading to reduced antigen presentation within the central nervous system (2); inhibition of metalloproteases,**5 leading to re-
`duced migration af T cells into and through the central nervous system (3); and induction of immunosuppressive cytokines,“ lead-
`ing to resolution of the inflammatory process (4).
`
`the minimal changes in scores for some patients over
`long intervals and the subjectivity in making theclin-
`ical ratings limit the value of the scale. The usefulness
`of the Expanded Disability Status Scale has been im-
`proved bythe addition of a definition of treatment
`failure as sustained worsening of a clinically impor-
`tant amount.4* Aneffort is under way to develop im-
`proved clinical outcome measures,” which could de-
`crease the required sample sizes or shorten the
`duration of multiple sclerosis trials.
`Serial MRI studies have shown that newgadolin-
`ium-enhancedlesions are 5 to 10 times as common
`
`
`
`1606
`
`November 27, 1997
`
`as clinical relapses.*° Preliminary evidence of the ¢
`ficacy of treatments on the basis of MRI findings:
`will probably serve as the basis for firture trials, and
`all will include serial MRI as an important secondary
`outcome measure.
`
`|
`
`RELAPSING MULTIPLE SCLEROSIS
`
`Corticosteroids
`
`Corticosteroids are the mainstay of treatment fot
`acute relapses of multiple sclerosis. Corticosteroi
`have immunomodulatory and antiinflammatory &
`
`
`
`
`
`

`

`DRUG THERAPY
`
`»cts that restore the blood-brain barrier, reduce
`pdema, and may possibly improve axonal conduc-
`ron. Corticosteroid therapy shortens the duration
`of the relapse and accelerates recovery, but whether
`the Overall degree of recovery is improved or the
`jong-termcourse is altered is not known.5!*3 Corti-
`gropin was demonstrated to help recovery from re-
`japse,>? but it has beenlargely replaced by high-dose
`jntravenous methylprednisolone, because the latter
`has 4 More rapid onsct ofaction, produces more
`consistent benefits, and has fewerside effects.525+
`for moderate-to-severe relapses, 1000 mg of meth-
`ylprednisolone per day by intravenous infusion for
`3 to.5 days followed by 60 mg oforal prednisone
`per day, with tapering of the dose over a period of
`}2 days, accelerates neurologic recovery.
`In the Optic Neuritis TreatmentTrial, 457 patients
`with acute optic neuritis were randomly assigned to
`receive 1000 mg ofintravenous methylprednisolone
`per day for 3 days followed by 1 mg of oral predni-
`sone per kilogram of body weight per day for 11
`days; 1 mg of oral prednisone per kilogram per day
`for 14 days; or oral placebo. Therate of recovery of
`vision was significantly faster in the intravenous-
`methylprednisolone group, with the greatest bene-
`fits in patients with visual acuity of 20/50 or worse
`at entry,? but there were no significant differences
`between groups in visual outcome at six months.
`Prednisone therapy increased the risk of new epi-
`sodes of optic neuritis in either eye, and intravenous
`methylprednisolone reduced by approximately 50
`percenttherisk of an attack leading to the diagnosis
`ofmultiple sclerosis during the two-year follow-up.*°
`This effect was most evident in patients at highest
`tisk for subsequent relapse — those with multicen-
`tric brain lesions on MRIat entry into the study. Af
`ter three years, differences between the treatment
`groups were no longersignificant,5° suggesting that
`intravenous methylprednisolone delayed but did not
`stop the developmentof multiple sclerosis after op-
`tic neuritis. These results have led to the widespread
`use of intravenous methylprednisolone for patients
`With optic neuritis and abnormalfindings on MRI
`of the brain. The results also renewed debate over
`whether intravenous methylprednisolone has long-
`term benefits for patients with multiple sclerosis. A
`dinical
`trial
`is under way to determine whether
`Pulsed doses of intravenous methylprednisolone giv-
`€n every other month slow disease progression in
`Patients with moderatedisability and secondary pro-
`gressive multiple sclerosis.
`
`Interferon Beta
`_Interferon beta is the treatment ofchoice for pa-
`"ents with relapsing-remitting multiple sclerosis.
`Woforms of recombinantinterferon beta — la and
`— have been approved by the FDA and Europe-
`0 regulatory agencies. Interferon beta-la is a glyco-
`
`|
`
`
`
`sylated, recombinant mammalian-cell product, with
`an amino-acid sequence identical to that of natural
`interferon beta. Interferon beta-1b is a nonglycosy-
`lated recombinant bacterial-cell product in which
`serine is substituted for cysteine at position 17.
`Interferon beta-1b was tested in a multicentertrial
`involving 372 patients with relapsing—remitting mul-
`tiple sclerosis and mild-to-moderate disability. Treat-
`ment consisted of either 8 million units (250 wg) or
`1.6 million units (50 4g) of interferon beta-1b or pla-
`cebo given by subcutaneousinjection every other day
`for up tofive years. As compared with treatment with
`placebo, treatment with the higher dose reduced the
`relapse rate by 31 percent, increased the proportion
`of patients who were relapse-free (27 percent vs. 17
`percent), and reduced bya factor of 2 the numberof
`patients who had moderate and severe relapses.’
`There was no difference in the proportion ofpatients
`in whom disability increased or in changes in the dis-
`ability scores between treatment groups. Thepatients
`in the placebo group had a meanincrease of 17 per-
`centin the area of the lesions on T,-weighted MRI at
`three years, as compared with a mean decrease of
`6 percent in the patients given high-dose interferon
`beta-1b. There wasalso a significant reduction in dis-
`ease activity, defined as the finding of new or enlarg-
`ing lesionsin serial MRIs.5? The MRI findingsin this
`study were pivotal in obtaining FDA approval forin-
`terferon beta-1b andinitiated the era in which MRI
`hasa key role in assessing therapeutic responsesin pa-
`tients with multiple sclerosis.
`Interferon beta-la was tested in a multicentertrial
`involving 301 patients with relapsing—remitting mul-
`tiple sclerosis and mild-to-moderatedisability. Treat-
`ment consisted of weekly intramuscular injections
`(6 million units [30 4g]) or placebo for up to two
`years.258 The principal outcome was the length of
`time to the progression ofdisability, defined as a de-
`crease from baseline ofat least 1.0 point on the Ex-
`panded Disability Status Scale that persisted for at
`least six months. Treatment with interferon beta-la,
`as compared with placebo,significantly lowered the
`probability ofprogression ofdisability” and of severe
`disability.5° In addition, patients treated with inter-
`feron beta-la for two years had a reduction of 32
`percent in the annual rate of relapse, and|had fewer
`gadolinium-enhanced lesions on MRI. The favor-
`able effect of interferon beta-la on gadolinium-
`enhancedlesions, confirmedin a separate study with
`interferon beta-1b,suggests that interferon beta
`inhibits new lesion formation.
`Both types ofinterferon beta are usually well tol-
`erated. The most commonside effects are influenza-
`like symptoms for 24 to 48 hours after each injec-
`tion, and these usually subside after two to three
`monthsoftreatment. Injection ofinterferon beta-1b
`causes redness, tenderness, swelling, and occasional-
`ly, necrosis at the injection site. Interferon beta-1b
`
`Volume 337 Number 22
`
`1607
`
`

`

`The New England Journal of Medicine
`
`
`
`Taste 3. IMPORTANT UNRESOLVED QUESTIONS
`RELATED TO INTERFERON BETA THERAPY IN PATIENTS
`WITH RELAPSING-REMITTING MULTIPLE SCLEROSIS.
`
`Whenshould therapy be started?
`Howlong should therapy be continued?
`Can the dose be individualized to achieve maximal therapeu-
`tic benefit?
`
`Whatare the therapeutic mechanisms of action of the drug?
`Whatare the long-termbenefits?
`Which preparation ofinterferon betais clinically superior?
`
`if the therapeutic effect could be monitoredeasily.
`The best preparation of interferon beta and the
`long-term benefits of such therapy remain controver.
`sial. Both interferon beta-la and interferon beta-]
`reduce the relapse rate and discase activity on MRI,
`but interferon beta-la appears to be bettertolerated,
`In addition, interferon beta-]a results in less progres-
`sion ofdisability,” suggesting that long-term therapy
`will lessen the eventual impact of the disease.
`Glatiramer Acetate
`
` better methods to individualize treatment, particularly
`
`Glatiramer acetate is a mixture of random syn-
`thetic polypeptides composed of 1.-alanine, L-glutam-
`can also causeslight elevations in serum aminotrans-
`ferase concentrations, leukopenia, or anemia, and a
`ic acid, L-lysine, and L-tyrosine in a molar ratio of
`6.0:1.9:4.7:1.0. It was synthesized as an immuno-
`few patients have become depressed or have had
`chemical mimic of myclin basic protein, a putative
`worsening of preexisting depression, Interferon beta-
`Lb-neutralizing activity was detected in serum sam-
`autoantigen in multiple sclerosis. After glatiramer
`acetate was found to inhibit experimental autoim-
`ples from 38 percent of patients by the third year of
`treatment®! and correlated with decreased efficacy of
`mune encephalomyelitis, a small trial suggested efti-
`cacy in patients with relapsing—remitting multiple
`therapy.Serum interferon beta-la—neutralizing ac-
`tivity was found less often — in 14 percent of pa-
`sclerosis. It was subsequently tested inatrial involy-
`ing 251 patients with relapsing-remitting multiple
`tients after one year and 22 percent after two years.”
`Althoughinterferon beta therapy is effective, im-
`sclerosis and mild-to-moderate disability. Treatment
`portant questions remain (Table 3). A risk—benefit
`consisted ofdaily subcutaneous injections of 20 mg
`analysis must be done in each patient. The cost of
`of glatiramer acetate or placebo for nwo years.!4 The
`therapy, currently approximately $8,000 to $10,000
`annualized relapse rate, the primary end point, was”
`per year, and the uncertain long-term risks may out-
`29 percent
`lower in the glatiramer acetate group,
`and the proportion of patients who did not have a
`weigh the benefits in patients with mild multiple scle-
`relapse was higher (34 percent vs. 27 percent). A
`rosis and a favorable prognosis. Whether long-term
`therapy should be started at the time of the first at-
`greater proportion ofpatients in the glatiramerace-
`tack and what constitutes the optimal duration of
`tate group had an improvementof1.0 point or more
`in their score on the Expanded Disability Status Scale
`therapy are not known. In a study of recombinant
`(25 percent vs. 15 percent), and fewer had worsening.
`interferon alfa-2a (Roferon-A, Hoftmann—LaRoche,
`Nutley, N.J.) in patients with relapsing—-remitting
`of disability (21 percent vs. 29 percent). The most
`commonside effect was mild reactions at the injec-
`multiple sclerosis, relapse occurred when therapy was
`stopped after six months,suggesting the need for
`tion site, which occurred in 90 percent of patients
`given glatiramer acetate; 15 percent had briefepi-
`more prolonged therapy. Thefinal report from the in-
`terferon beta-]b study®! suggested that patients con-
`sodesofflushing, chest tightness, shortness of breath,
`palpitations, and anxiety after one or more inject
`tinued to respond to treatmentforfive years, a finding
`tions. Scrum antibodies to glatiramer acctate also_
`that supports the value of long-term therapy, but the
`developed, but the presence ofthese antibodies had
`high dropout rate (greater than 50 percent) may
`have biased the results in favor of long-term therapy.
`noeffect on the clinical benefit. MRI scans, which
`were obtained at only oneofthe studysites, showed
`Specific indications to stop therapy were steady pro-
`gression ofdisability over a period of six months or
`little change over the course of the study.”
`Glatiramer acetate was approved by the FDA i”
`treatment with three courses of corticotropin or cor-
`1996. It represents an alternative to interferon bet
`ticosteroids for acute relapses during a one-year pe-
`therapy for patients with relapsing-remitting miulu-
`riod. The appearanceof serum interferon beta—neu-
`ple sclerosis and may be mostuseful for patients wh?
`tralizing antibodies should promptalternative therapy,
`becomeresistant to interferon beta trearment owing
`particularly in patients with disease progression.®
`The variable biologic response to interferon beta
`to serum interferon beta—neutralizing activity.
`suggests that the dose could be individualized. Side
`effects of the interferon beta-1b correlate with body-
`surface area,®! but there are no established methods to
`individualize the dose for maximal efficacy. Figure 1
`showsthe putative sites of action ofinterferon beta in
`patients with multiple sclerosis. Clarifying the mecha-
`nisms most closely linked to efficacy might lead to
`
`Azathioprine
`Azathioprine, a purine analogue, depresses path
`cell-mediated and humoral immunity. A meta-analy”
`sis of five randomized, double-blind, placebo-co!™
`trolled trials supported the conclusion that oral a?
`thioprine (2 to 3 mg per kilogram per day) reduce
`
`1608 - November 27, 1997
`
`

`

`DRUG THERAPY
`
`
`
`‘ye rate of relapse in multiple sclerasis® but has no
`i
`aect on the progression ofdisability. The concern
`at prolonged azathioprine therapy may increase the
`ik Of non-Hodgkin’s lymphomaor skin cancer®
`yas not confirmed in a case-control study.” Azathi-
`aprine should be considered in patients with relaps-
`ig-remitting multiple sclerosis who do not respond
`jo therapy with interferon beta or glatiramer acetate.
`arathioprine may be useful in patients with Devic’s
`disease,’! a variant of multiple sclerosis affecting the
`optic Nerves and cervical spinal cord, or in those with
`current inflammatory myelitis.72
`
`Intravenous ImmuneGlobulin
`[Intravenous immuneglobulin has been used suc-
`cessfully in neuroimmunologic disorders, including |
`acute and chronic inflammatory demyelinating poly-
`|
`radiculopathy and myasthenia gravis, but its role in
`tients with multiple sclerosis is not yet clear. In a
`gudy of 150 patients with relapsing-remitting mul-
`tiple sclerosis who were treated with intravenous im-
`mune globulin (150 to 200 mg per kilogram per
`month.) or placebo for twoyears, there was less wor-
`ning in the scores on the Expanded Disability Sta-
`tus Scale in the group given immuneglobulin, but
`the differences between groups were small. The
`numberofrelapses and the annual relapse rate were
`also lower in the immune globulin group. However,
`the treating physicians were aware of the treatment
`assignment, which could have biased the results.
`PROGRESSIVE MULTIPLE SCLEROSIS
`
`|
`
`
`
`Investigators have only recently made a clinical
`distinction between secondary progressive multiple
`sclerosis and primary progressive multiple sclerosis,
`aid most studies have not distinguished between
`these two formsof chronic progressive multiple scle-
`tosis. Treatment for chronic progressive multiple
`sclerosis has usually consisted ofnonspecificimmune |
`suppression and has been of only moderate benefit.
`Methotrexate
`
`|
`
`Methotrexate inhibits dihydrofolate reductase. Low-
`dose oral methotrexate is relatively nontoxic and ef-
`fective in rheumatoid arthritis and psoriasis, presum-
`ably by inhibiting both cell-mediated and humoral
`‘munityor as a result of its antiinflammatoryeffects.
`Sixty ambulatory patients with chronic progressive
`Multiple sclerosis and moderate-to-severe disability
`Were treated with methotrexate (7.5 mg weekly) or
`placebo for two years.?3 As compared with placebo,
`Methotrexate significantly reduced sustained worsen-
`ig, according to a composite measure of outcome
`that included the Expanded Disability Status Scale,
`** Ambulation Index,74 and two tests of arm func-
`n. The methotrexate-treated patients had less dis-
`Sse progression, and patients with secondary pro-
`Bessive multiple sclerosis benefited most.737* The
`
`clinical benefits were considered moderate, but
`toxicity was minimal. Because there are no nontoxic
`alternative treatments for patients with chronic
`progressive multiple sclerosis, low-dose oral metho-
`trexate should be considered for those with progres-
`sive deterioration.
`
`Cyclophosphamide
`Cyclophosphamideis an alkylating agent with po-
`tent cytotoxic and immunosuppressive effects.
`In
`several controlled but unblindedtrials, high-dose in-
`travenous cyclophosphamide with or without subse-
`quent booster injections was effective in patients
`with chronic progressive multiple sclerosis.7+7°77 How-
`ever, onetrial failed to demonstrate benefit.!° In this
`trial, the examining neurologist was unaware of the
`treatment assignments, and the patients wore bath-
`ing caps to mask the alopecia induced by cyclophos-
`phamide. Cyclophosphamide has many side effects
`in addition to alopecia, including nausea and vomit-
`ing, hemorrhagic cystitis,
`leukopenia, myocarditis,
`infertility, and pulmonary interstitial fibrosis. Treat-
`ment with cyclophosphamide may be most appro-
`priate for patients with rapidly progressive disease
`who do notrespondtoless toxic alternatives such as
`methotrexate.78
`
`Cyclosporine
`Cyclosporine is a potent immunosuppressive drug
`that inhibits several steps in the activation ofT cells.
`Ina multicenter U.S. study, 550 patients with chronic
`progressive multiple sclerosis were given oral cyclo-