IPR2023-00049
`
`
`
`Merck 2011
`
`TWi v Merck
`
`Merck 2011
`TWi v Merck
`IPR2023-00049
`
`

`

`
`
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`CHURCHILL
`LIVINGSTONE
`TLSEVIER
`
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`THE BRITISH LIBRARY
`SCIENCE TECHNOLOGY
`21
`FEE
`2006
`AND TENOVATION
`
`McAlpine’s
`FOURTH EDITION
`MULTIPLE SCLEROSIS
`
`Alastair Compston Php FRCP FMedSci
`Professor of Neurology, University of Cambridge, Cambridge, UK
`
`Christian Confavreux mp
`Professor of Neurology, Hopital Neurologique, Hospices Civils de Lyon and Universe Claude Bernard,
`lyon, France
`
`Hans Lassmann MD
`Professor of Neurvimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria
`
`lan McDonald php rrcp FMedsci
`Professor Cmeritus of Clinical Neurology, Institute of Neurology, University Calleqe London, .ondon, UK
`
`David Miller mp FRcp FRACP
`Professor of Clinical Neurology,Institute of Neurology, University College London, and Consultant
`Neurologist, National Hospital for Neurology and Neurosurgery, London, UK
`
`John Noseworthymp Frcec
`Professor and Chair, Department of Neurclogy, Mayo Clinic College of Medicine, Rochester, MN, USA
`
`Kenneth Smith php
`Professor of Neurophysiology and Head of Neuroinflammation Group, King’s College London Schoolof
`Medicine at Guy's, London, UK
`
`Hartmut Wekerle mp
`Professor andDirector, Max Planck institute of Neurobiology, Planegg-Martinstied, Gerrany
`
`
`
`
`
`
`
`
`
`
`
`
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`
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`

`

`Contents
`
`Preface to the fourth edition
`
`SECTION 1
`THE STORY OF MULTIPLE SCLEROSIS
`
`The story of multiple sclerosis
`1.
`Alastair Compston, Hans Lassmanni and Jan McDonald
`The evolving concept of multiple sclerosis
`Naming and classifying the disease: 1868-1983
`Clinical descriptions of multiple sclerosis: 1838-1915
`Personal accounts of multiple sclerosis: 1822-1598
`The social history of multiple sclerosis
`The pathogenesis andclinical anatomy of multiple
`sclerosis: 1849-1977
`The laboratory science of multiple sclerosis: 1913-1981
`Discovery of glia and remyelination: 1858-1983
`The aetiology of multiple sclerosis: 1883-1976
`Attitudes to the treatment of multiple sclerosis: 1809-1983
`
`SECTION 2
`THE CAUSE AND COURSE OF MULTIPLE SCLEROSIS
`
`
`
`The distribution of multiple sclerosis
`2
`Alastair Compston and Christian Confavretn
`The rationale for epidemiclogical studies in multiple
`sclerosis
`Definitions ancstatistics in epicemiology
`Strategies for epidemiological studies in multiple sclerosis
`The geography of multiple sclerosis
`Multip 2 scerosis in Scandinavia
`Multiple sclerosis in the United Kingdom
`Multiple sclerosis in the United States
`Multiple sclerosis in Canada
`Multiple sclerosis in Australia and New Zealand
`Multiple sclerosis in Continental Europe
`Multiple sclerosis in the Middle East
`Multiple sclerosis in Africa
`Multiple sclerosis in Asia and the Far Fast
`Multiple sclerosis in migrants
`Epidemics and clusters of multiple sclerosis
`The environmental factor in multiple sclerosis
`
`The genetics of multiple sclerosis
`3
`Alastair Compston and HartiWekerle
`Genetic analysis of multiple sclerosis
`Methods of genetic analysis
`Radial susceptibility
`
`THE BRITISH LIBRARY
`SCIENCE TECHNOLOGY
`2006
`71.
`FEE
`Aug
`Phi OVATEOR 176
`126
`136
`163
`
`vill
`
`1
`
`Gender differences in susceptibility
`Famiial multiple sclerosis
`Candidate genes in multiple sclerosis
`Systematic genome screening
`Lessons from genetic studies of experimental autoimmune
`encephalomyelitis
`Canclusion
`
`175
`180
`
`183
`
`133
`iy
`202
`209
`221
`228
`243
`269
`
`273
`
`273
`27/3
`276
`279
`28)
`284
`
`287
`
`The natural history of multiple sclerosis
`4
`Christian Confavreux and Alastair Comtpston
`Methadolagical considerations
`The outcome landmarks of multiple sclerosis: dependent
`variables
`The onset of multiple sclerosis
`The overall course of multiple sclerosis
`The prognosis in multio:e scleresis
`Survival
`in multiple sclerosis
`Disease mechanisms underlying the clinical course
`intercurrent life events
`Conclusion
`
`7\
`
`The origins of multiple sclerosis: a synthesis
`5
`AMastair Compston, Hartmut Wekerle and Jan McDonald
`Suminary of the problem
`The geography and phenotype of multiple sclerosis
`The environmental factor in multiple sclerosis
`Genetic susceptibility and multiple sclerosis
`Genetics and the European population
`Multiple sclerosis: an evolutionary hypothesis
`
`SECTION 3
`THE CLINICAL FEATURES AND DIAGNOSIS OF
`MULTIPLE SCLEROSIS
`
`The symptoms and signs of multiple sclerosis
`6
`lan McDonald and Alastair Compston
`Multipie sclerosis as a neurological illness
`Symptoms at onset of the disease
`Symptoms andsigns in the course of the disease
`Individual symptoms and signs
`Associated diseases
`Multiple sclerosis in childhood
`Conclusion
`
`100
`105
`
`113
`
`113
`114
`123
`
`The diagnosis of multiple sclerosis
`7
`David Miller, lan McDonald and Kenneth Smith
`Diagnostic criteria for multiple sclerosis
`Seiection of investigations
`
`347
`350
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`PAN
`
`53
`
`5
`san
`
`san
`-
`
`sy
`se,
`=
`i”
`_
`2
`.
`.
`we
`
`sag
`Fp
`:
`>
`593
`
`so
`596
`“
`son
`ion
`
`{ demyelination and tissue damage
`for multiple sclerosrs
`pathogenesis 0
`peripheral blood biomarkers
`and disease activity
`arke
`Markers of multiple sclerosis and disease activ ty ih
`cerebrospinal fluid
`12 The pathology of multiple sclerosis
`Hang Lassniaint and Partie Uekerle
`introduction
`Pathological classification of demyeknatiig diveases
`he demyctinated plaque
`immunopatholegy of wflarmmation
`Demyelinalion and oligodendroglia datnege
`Remyelination
`.
`Axonal pathology
`Grey matter pathology and cortical plaques
`Astroglial reaction
`a
`Abnormalities mn the ‘normal’ white matter Of patent,
`with multiple sclerosis
`Distribution of lesions in the nervous system
`ls there evidence for an infectious agent
`in the testo of
`multiple sclerosis?
`Dynamic evolution of mullivic sclerous patholouy
`Differences between acute, relapsing and progressive
`multiple sclerosis
`Molecular approaches to the study of the multiple scurosis
`lesion; profiling at ania protecrne
`iat
`iple sclerosis WHD OUner Gistases
`Association of multiple
`Conclusion
`
`E T
`
`603
`610
`
`a
`
`of multiple sclerosi
`i
`on
`13. The pathophysiology
`mult ples
`sis
`Kenneth Smith, fan MeDonald,
`Darid Miller andl Elans Lavsnueny
`Introduction
`a
`Methods for exploring the pathophysiology of
`multiple sclerosis
`Relapsing remitting multiple sclerosis: loss of function
`Relapsing-remitting multiple sclerosis: recovery af function
`and remission
`Physiological explanations for clinical symptomsin muiple
`sclerosis
`Permanent loss of function in the context of disease
`progression
`Conclusion
`
`6
`
`649
`see
`
`gg
`44 The pathogenesis of multiple sclerosis: a pandect
`Hans Lassmann, Kenneth Smith, Hartmut Wekerle and Alastair
`Compston
`Core featuresin the neuropathology of multiple sclerosis
`The pathophysiology of functional defictts and recavery
`The relation betweeninflammation and neurodegencration in
`multiple sclerosis
`The role of autoimmunity in roultiple sclerosis
`Complexity and heterogeneity 17 multiple sclerosis
`
`665
`656
`667
`
`661
`663
`
`SECTION 5
`THE TREATMENT OF MULTIPLE SCLEROSIS
`
`45 Care of the person with multiple sclerosis
`David Miller, Jolin Noseworthy cand Mastiir Couipstan
`
`669
`
`671
`
`Contents
`
`Magnetic “esonance imaging
`Cvoked potentials
`Examination of the cerebrospinal fluid
`A strategyfor the investigation of demyelinating disease
`Updating the McDonald diagnostic criteria and the prospect
`of future revisions
`
`The differential diagnosis of multiple sclerosis
`8
`David Miller and Alastatr Comipston
`The spectrum of disorders mimicking multiple sclerosis
`Diseases that may cause multiple lesions of the central
`nervous system andaiso oftenfollow a relapsing~
`remitting course
`Systematized central nervous system diseases
`isolated or monosymptomatic central nervous system
`syndromes
`Nen-organic symptoms
`Howaccurate is the ciagnosis of multiple sclerosis?
`
`3 Multiple sclerosis in the individual and in groups:
`a conspectus
`David Miller, lan McDonald and Alastatr Compston
`The typical case
`Isolated syndromes and their outcome: judicious use of
`investigations and critique of the new diagnostic criteria
`Comorbidity anc associated diseases
`Situations in whichalternative diagnoses should be
`considered
`Whento ignore ‘inconvenient’ laboratory results orclinical
`findings: taking the best pasition
`’Pathognomonic’ versus ‘unheard of” features of multiple
`sclerosis
`
`SECTION 4
`THE PATHOGENESIS OF MULTIPLE SCLEROSIS
`
`10 The neurobiology of muttiple sclerosis
`Alastair Compston, Hans Lassmann and Kenneth Smith
`Organization in the central nervous system
`Cell biology of the central nervous system
`Macroglial lineages in the rodent and human nervous
`system
`Interactions between glia and axons
`Demyelinatian
`Axon degeneration and recovery of function
`Remyclination
`
`11. The immunology of inflammatory demyelinating
`disease
`Tlaronut Wekerle anid bans Lassmrann
`Multiple sclerosis as an auloimmune cisease
`Immune responses: rate and adaptive
`T lymphocytes
`B lymphocytes
`Autoimmunity andself-tolerance in the central
`nervous system
`Regulation of central nervous system autoimmune
`responses
`Immune reactivity in the central nervous system
`
`vi
`
`351
`373
`380
`383
`
`386
`
`389
`
`389
`
`390
`413
`
`422
`435
`436
`
`439
`
`439
`
`Ad
`345
`
`445
`
`446
`
`446
`
`447
`‘
`449
`
`449
`450
`
`455
`463
`469
`477
`483
`
`49)
`
`Agi
`Ag2
`494
`5c4
`
`505
`
`524
`530
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`Contents
`
`
`
`
`
`HO
`
`Geneval approach to the care of people with
`multiple sclerosis
`The early stages of disease: minimal disability
`The middle stages of disease: moderate disability
`The later stages of disease: severe disability
`Guidelines for the management andinvestigationol
`multiple sclerosis
`Conclusion
`
`671
`673
`677
`679
`
`680
`681
`
`683
`
`16 Treatment of the acute relapse
`Jolin Noseworthy, Christian Confavrenx and Alastair Compston
`683
`The features of active multiple sclerosis
`686
`The treatment af relapses
`690
`Other approaches to the treatment of acute relapse
`692
`Treatment of acute optic neuritis
`Managementof otherisolated syndromes and acute
`disseminated encephalomyelitis
`Adverse effects
`Modeof action of corticosteoids
`Practice guidelines
`
`694
`695
`696
`699
`
`17. The treatment of symptoms in multiple sclerosis
`and the role of rehabilitation
`John Noseworthy, David Miller and Alastair Conpsion
`The generalprinciples of symptamacic treatment in
`multiple sclerosis
`Disturbances of autonomic function
`Mobility and gait disturbance
`Fatigue
`Disturbances of brainstem function
`Perturbations of nerve conduction
`Cognitive function
`Visual loss
`
`701
`
`701
`701
`712
`717
`718
`72)
`724
`725
`
`Rehabilitation in multiple sclerosis
`Conclusion
`
`18 Disease-modifying treatments in multiple sclerosis
`John Noseworthy, David Miller and Alastair Compston
`The aims of disease-modifying treatment
`The principles of evidence-based prescribing in
`multiple sclerosis
`The role at magnetic resonance imaging in clinical tnals
`Drugs that stimulate the immune response
`Drugs that nonspecifically suppress the immune respolse
`The beta interferons
`Molecules that inhibit T-cell-peptide binding
`Treatments that target T cells
`Agents inhibiting macrophages and thew mediators
`Recent miscellaneous treatments
`Postscript
`
`19 The person with multiple sclerosis: a prospectus
`Alastair Compston, David Miller and Joli Noscworthy
`A perspective on the recent history of therapeutic endeavour in
`multiple sclerosis
`Setting an agenda: the windowof therapeutic opportunity
`Prospects for the treatment of progressive multiple sclerosis
`Remyelination and axon regeneration
`Tailoring treatment to defined groups
`Postscript
`
`References
`
`Index
`
`726
`728
`
`729
`
`~ Ww©
`
`734
`736
`742
`755
`784
`79)
`800
`801
`802
`
`803
`803
`805
`806
`810
`810
`
`81]
`
`947
`
`
`
`
`
`
`
`
`
`
`
`

`

`SECTION FIVE THE TREATMENT OF MULTIPLE SCLEROSIS
`
`Disease-modifying treatments
`in multiple sclerosis
`
`John Noseworthy, David Miller and Alastair Compston
`
`18
`
`THE AIMS OF DISEASE-MODIFYING
`TREATMENT
`
`There have been many developments since we last reviewed the
`role of disease-modifying treatments in multiple sclerosis.
`Collectively, these represent progress but fall well short of a
`solution to the problem. Results of the pivotal interferon and
`glatiramer acetate trials led to approval of these treatments by
`licensing bodies throughout the world. For the first time, patients
`with multiple sclerosis had a treatment. This was welcome and
`fuelled further efforts to improve on the evidence for efficacy
`and indications for the timing, dose and duration of therapy.
`Increasingly sensitive diagnostic criteria, bolstered by serial mag-
`netic resonance imaging (MRI) studies (W.I. McDonald et al
`2001), now allow more rapid diagnosis and hence – in our cur-
`rent climate – earlier exposure to treatment. However, further
`work is needed on many strategic issues and points of detail:
`
`• Will early treatment make a difference?
`• Can sensitive clinical and MRI measures detect early
`favourable trends that predict long-term benefit?
`• Might the trials be made even shorter?
`• How early in any study should a monitoring committee con-
`clude with certainty that a trial is positive and recommend
`early termination with generalized access to the therapy?
`
`It is axiomatic that doctors want to make their patients better.
`Patients want to lead normal lives unencumbered by any physical,
`psychological or life-style baggage related to multiple sclerosis.
`As clinical scientists, we need to structure that pastoral position
`around concepts of the pathogenesis and strategies for what
`realistically can be achieved. Patients with multiple sclerosis
`need treatment before the onset of fixed disability. Throughout,
`we have argued that the clinical manifestations of multiple scle-
`rosis can be attributed to perivascular inflammation and the
`tissue injury with which it is inextricably linked. Since we last
`reviewed the subject in 1998, the diversity of mechanisms that
`injure nerve fibres throughout the illness and the contribution
`these processes make to the clinical course have been intensively
`studied. Concepts have been updated and revised. Thus, whilst
`we remain of the view that inflammation is pivotal to the
`destruction in parallel of axons and oligodendroglia, the inflam-
`matory process also triggers biological processes that increas-
`ingly contribute to tissue destruction. What position should the
`
`prescribing physician take on how and when to treat the person
`with multiple sclerosis? Our stance is pragmatic but informed by
`the neurobiology and neuroimmunology, and by the evidence
`from clinical trials.
`We structure this discussion around the formulation that,
`typically, the early clinical course of multiple sclerosis is marked
`by relapses from which symptomatic recovery is usually com-
`plete. Inflammation drives the process. Subsequent episodes may
`affect the same or different myelinated pathways. Before long,
`clinical deficits, which correlate with abnormalities in saltatory
`conduction of the nerve impulse, accumulate. These reflect loss
`of functional reserve in the adaptive capacity of the nervous
`system to make best use of surviving electrical activity, and the
`impoverished but detectable signals that reach the cortex or
`distant parts of major pathways. Then, inflammation wanes
`(without necessarily ceasing) and the relative contribution of
`cumulative axonal damage, amplified by loss of trophic support,
`makes an impact (Figure 18.1). Initially, the clinical course is
`intermittent in 80% of affected individuals but a high proportion
`do later enter the secondary progressive phase in which impair-
`ment, loss of ability, and impact on health-related quality of life
`are each affected. For these patients, disability is established in
`40% by 10 years, in 60% by 15 years and in 80% (that is 50% of
`all patients) by 25 years. It is the onset of secondary progression
`that gives multiple sclerosis the frightening reputation it has
`amongst affected individuals. Progression is the main factor
`distinguishing mild from severe forms of multiple sclerosis. In
`20% of patients, the disease progresses slowly from onset, most
`typically with predominant spinal involvement, and this form
`of multiple sclerosis is even more predictably disabling. The
`analysis that fully reversible deficits mainly result from inflamm-
`tion, oedema and the physiological action of cytokines whereas
`persistent symptoms and signs can be attributed to demyelina-
`tion and the initial wave of axonal damage with failure of
`recovery mechanisms, and that chronic progression is attribut-
`able to cumulative axon degeneration, has obvious implications
`for treatment.
`Immunological therapies are most likely to be effective in the
`inflammatory (relapsing–remitting and relapsing–persistent)
`phases. Conversely, it will be more difficult to influence pro-
`gression with immunotherapy. Any treatment that reduces the
`accumulation of disability, and inhibits or delays time to onset of
`the progressive phase, is most likely to have a clinically useful
`disease-modifying effect whether or not that treatment also
`
`729
`
`

`

`Course
`
`Relapsing–remitting
`
`Secondary progression
`
`Clinical threshold
`
`Brain volume
`
`Inflammation
`
`Axonal Loss
`
`Pathology
`
`1
`
`2
`
`Frequent inflammation
`Demyelination
`Axonal transection
`Plasticity and remyelination
`
`Continuing inflammation
`Persistent demyelination
`
`Infrequent inflammation
`Chronic axonal degeneration
`Gliosis
`
`3
`
`4
`
`5
`
`6
`
`Treatment
`strategies
`
`APC
`
`VCAM-1
`
`VLA-4
`
`ICAM-
`1/2
`LFA-3
`
`LFA-1
`
`CD2
`TCR
`CD4
`
`B7
`
`CD28
`(CTLA-4)
`
`1
`
`2
`
`Th
`
`T-cell
`
`IFN-γ
`
`Ag
`
`Class II
`APC
`
`Respiratory
`burst
`
`Fc receptor
`
`Microglia
`
`TNF-α
`
`Action on peripheral
`autoreactive T cell activation
`and/or migration
`
`Mitoxantrone
`Azathioprine
`Methotrexate
`Cyclophosphamide
`Paclitaxel
`Bone marrow transplantation
`Teriflunomide
`Aletuzamab (Campath-1H)
`Tysabri (anti-VLA4)
`Altered peptide ligand
`T-cell vaccination
`Mucosal tolerance
`
`Action on T-cell-microglial
`interaction in the CNS
`
`IFN-β
`Glatiramer acetate
`Gene therapy
`Cytokine therapies
`Metalloproteinase Inhibitors
`Macrophage inhibitors
`IFN-α
`
`Axon protection
`
`iv methylprednisolone
`Riluzole
`Anti-convulsant
`
`Type II astrocyte
`
`Myelin
`
`Oligodendrocyte
`
`Axon
`Anti-myelin
`antibody
`
`Reactive astrocyte
`
`Myelin
`
`Degenerate
`axon
`
`Action to promote repair
`
`Growth factors
`iv immunoglobulin
`Cell implantation
`
`Figure 18.1 The course, pathogenesis and treatment of multiple sclerosis. Course: the clinical phases of relapse with recovery, relapse
`with persistent deficits and progression depend mainly on the effect of inflammation, demyelination and axon degeneration, respectively.
`Disease activity is often presymptomatic and, later, not invariably expressed clinically. As inflammation wanes, brain volume reduces
`with accumulated axonal loss. Pathology: perivascular inflammation (panel 1) causes acute axonal transection (panel 2), and microglia-
`mediated removal of myelin (panel 3) with persistent demyelination despite some remyelination (panel 4); chronic lesions show further
`axonal loss (panel 5) and gliosis (panel 6). The scheme does not depict primary progressive multiple sclerosis in which there is significant
`axonal degeneration with or without a preceding inflammatory phase. Treatment strategies: target the phase of T-cell activation in the
`periphery or cell migration; interactions between the activated T cell and microglia in the central nervous system; and axon protection
`and remyelination. Adapted from Compston and Coles (2003). © 2003, with permission from Elsevier.
`
`730
`
`

`

`The aims of disease-modifying treatment
`
`5
`
`affects the number of new episodes or lesions detected by brain
`imaging. Therefore, it makes sense to deploy strategies for treat-
`ment that address this evolution of events – choosing those
`interventions that preferentially tackle (or, preferably, anticipate)
`the individual components so as to be maximially effective.
`Although much contemporary research in multiple sclerosis is
`appropriately directed at identifying disease-modifying treat-
`ments, many patients already make clear that merely aspiring to
`shape the future course of the disease is not sufficient. They
`want to get better. If repair is a matter of restoring structure and
`function, it follows that dealing with the rewriting of neurological
`history requires treatments that enhance plasticity and recon-
`struct the myelinated axon in its network of connectivity. Thus,
`repair involves applying the lessons of neurobiology to the
`problems of multiple sclerosis. It remains possible that enhanced
`remyelination will occur in an immunologically stable environ-
`ment. The experimental evidence already hints at this possibility
`(see Chapter 10). Remyelination may protect injured axons from
`further damage resulting from loss of trophic support. Con-
`versely, optimizing their growth factor environment may reduce
`the extent to which axons, already insulted, are affected by
`further exposure to inflammatory mediators. Conversely, it is
`logical to assume that sophisticated repair strategies will have a
`low dividend for success without first having available a treatment
`that reliably stabilizes the disease process. Just as the dichotomy
`of genes versus environment is a somewhat sterile aetiological
`debate, so too separating inflammatory and biological mecha-
`nisms of injury to the axon–glial unit is somewhat strained.
`But to go back a step, in Chapter 1 we reviewed the develop-
`ment of ideas concerning disease-modifying treatments in
`multiple sclerosis. The era prior to 1980, summarized by W.I.
`McDonald (1983), was empirical and largely uncluttered by
`serious concern about disease mechanisms. This period of intel-
`lectual freedom concerning the nature of multiple sclerosis
`provided ample opportunity for wild, and at times frivolous,
`approaches to treatment, some of which (rightly) gave the
`disease the bad therapeutic name from which it has not yet fully
`recovered. An important development in the treatment of mul-
`tiple sclerosis in the 1980s was the acceptance that therapeutic
`claims must adopt orthodox clinical trial methodology based on
`blinding (single or double), use of controls (preferably placebo
`but sometimes receiving best existing medical practice), matching
`groups at entry for potentially confounding variables, setting pri-
`mary outcome measures at the outset of the study and not
`trawling for the best result on completion, and considering power
`calculations during the planning stage. Working groups were
`convened to issue guidelines (see, for example, J.R. Brown et al
`1979; Weiss and Dambrosia 1983). The impact of papers labo-
`riously listing trial design tactics encouraged journal editors and
`referees to flex their methodological muscles – factors which
`undoubtedly led therapists to conform and resulted in the
`steady demise of therapeutic generalizations based on anecdote.
`The rubric ‘double-blind, randomized and placebo-controlled’
`became commonplace. Since progress in identifying useful
`treatments was disappointingly slow, through no fault of those
`who designed the studies, separate trials of many agents pro-
`liferated and none could be regarded as definitive. Patients
`violated protocols and left studies for open label treatments,
`making it necessary to sort those who completed studies from
`‘intention to treat’ cohorts. Commentators struggled to put
`
`their thoughts in order by cataloguing published material and
`seeking a best position on disparate data. Faced with too few
`studies involving sufficient numbers of patients from which to
`draw firm conclusions, the meta-analysis emerged as a device for
`‘seeing the wood for the trees’. Considered by some as scientific
`sophistry, this analytical procedure exposed the criticism of
`mixing chalk with cheese and creating statistical noise, not least
`because outcome measures in multiple sclerosis are an integral
`of up to three independent clinical features – acute events, per-
`sistent deficits, and progression – which contribute to impairment,
`loss of ability, autonomy and participation (formerly referred to
`as impairment, disability and handicap).
`Later, came the interim analysis – often used to stop trials
`either on the grounds of futility or issues of patient safety.
`Recent examples include studies of intravenous immunoglobulin
`designed to measure clinical recovery in multiple sclerosis and
`optic neuritis; trials of altered peptide ligands; the story of
`agents that have an impact on tumour necrosis factor-α (TNF-
`α); the glatiramer acetate study in primary progressive multiple
`sclerosis; and the use of oral glatiramer acetate (see below for
`more detailed discussion). However, the interim analysis has
`also recently been used increasingly to stop trials early on the
`basis of perceived efficacy, thereby allowing active treatment to
`be made immediately available for all patients without the dis-
`advantaged controls waiting for completion of the protocol. We
`have seen this happen repeatedly, dating from the first wave of
`pivotal trials in relapsing–remitting multiple sclerosis [the North
`American IFNβ-1a trial (Avonex)] and, subsequently, with trials
`in possible (CHAMPS) and secondary progressive multiple
`sclerosis (the European trial, SPECTRIMS) – all discussed
`below. More recently, trials have been reported and widely
`accepted as valid with as little as 6 months follow-up (for
`example, EVIDENCE). The lesson from the failed Mayo Clinic
`Canadian Sulfasalazine Trial that early benefit may wane with
`further blinded follow-up seems often to have been forgotten
`(Noseworthy et al 1998; Rudge 1999). Hence, we now have to
`provide wise counsel to a generation of patients, some treated
`immediately after an inaugural clinical episode (clinically isolated
`syndromes), others when the illness has been established for
`only a few years (early relapsing–remitting multiple sclerosis),
`and many long into the illness with advanced secondary pro-
`gressive disease – despite the lack of convincing evidence for
`protracted benefit – aiming to steer a course between managing
`their expectations and not shirking our responsibilities as clinical
`scientists.
`The concentration of clinical research on the evaluation of
`therapies that target the immune response in multiple sclerosis
`itself represents something of an advance, displacing hypotheses
`for the pathogenesis finding their expression in less rational
`clinical trials. We hope that those who contributed to these
`studies will accept our decision to concentrate on contemporary
`immunotherapy and applied neurobiology. Of course, we accept
`that some (or indeed many) of the agents which we have
`selected for detailed discussion may in time join those which we
`have placed on the well-stacked shelves of therapeutic history in
`multiple sclerosis.
`By the late 1980s, Noseworthy et al (1989b) were able to
`tabulate a large number of potential therapies which experienced
`investigators considered to be promising options for treatment.
`Many are still being evaluated but some degree of consensus on
`
`731
`
`

`

`5
`
`CHAPTER EIGHTEEN Disease-modifying treatments in multiple sclerosis
`
`the basis for treatment in multiple sclerosis has emerged in
`recent years. At first, physicians were cautious when considering
`the use of immunotherapy for multiple sclerosis even though
`many of the available medications had been used successfully in
`other inflammatory and autoimmune diseases. This caution was
`appropriate since a significant proportion of affected individuals
`remain free from disability despite having intermittent symptoms
`over several decades, and it is not possible to segregate indi-
`viduals destined to have benign forms of multiple sclerosis early
`in the course. In our opinion, however, the focus on treating
`secondary progressive multiple sclerosis held up progress for a
`generation. Since the late 1990s, that lesson has been clear. Wait
`until late and the contribution of anti-inflammatory therapy is
`so small as to not be cost effective. For many affected indi-
`viduals, this is a formula for disappointment leading to cynicism
`that, despite intense research, no useful progress is being made
`in understanding the disease. It seems clear that, in the context
`of disease progression, the focus should now be on neuroprotec-
`tive and biologically motivated approaches – alone or in combi-
`nation with immunotherapy. Treat early and the dividend may
`be greater but still the dilemma remains. Drugs that are partially
`effective may not sufficiently stabilize the disease processes
`whereas the more actively anti-inflammatories are likely to carry
`nontrivial adverse-effect profiles. As we wrote in the early
`1990s, the comprehensive management of multiple sclerosis is
`about both limiting and repairing the damage.
`Progress has been made in improving outcome measures in the
`assessment of treatments for multiple sclerosis. Totting up the
`number of acute events requires them to be reliably defined, but
`patients will understandably assign significance to transient
`alterations in symptoms, perhaps having explanations other than
`disease activity. Conversely, motivation and the hope of a thera-
`peutic effect will lead others to ignore clinical changes even
`though these are biologically meaningful. Periods of disease
`activity measured by high relapse rates tend to oscillate and,
`overall, slow with time so that a reduction in relapse rate per se
`is not necessarily impressive unless the placebo group has
`behaved less well and in keeping with the known natural history
`of the disease. The problems are even greater for the assessment
`of disability. There have probably been more critiques of the
`Expanded Disability Status Scale of Kurtzke (EDSS) (Kurtzke
`1983a)and related clinical outcome measures than clinical trials
`in multiple sclerosis. The problems are well known. The EDSS
`mixes activity with disability and ignores participation. It is
`excessively weighted towards the motor system. It is ordinal not
`linear. Patients tend to cluster in the lower and higher echelons
`and it is insensitive in the middle range. However, it survives
`and despite much squabbling has yet to be replaced by a better,
`fully validated and universally accepted system. In this context,
`we welcome the deliberations of a panel convened by the
`United States National Multiple Sclerosis Society to make recom-
`mendations for a comprehensive clinical outcome system
`applied u