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`research-article2017
`
`729455 MSJ0010.1177/1352458517729455Multiple Sclerosis JournalH Lassmann44444455555555555555555555555555555555555555555555555555555555555555555555544444555555555555555555555555555555555555555555555555555 MSM
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`11111111111010100100010000000.11110.111771111111117777777777777777/1777777/7777 /77/11337/7/77/113353133523355352552224452222454244424458242444585858858555551755511517717177711777777277777297727729472994552944555554555555Multiple Sclerosis JournMulMultiple Sclerosis JournMultiple Sclerosis MuMMMMuMMMM le Sclerosis Journltiple Sclerosis Journe Sclerosis Journultiple Sclerosis Journul e Sclerosis Jople Sclerosis Journee Sclerosisle Sclerosis JournSclerosis Journos Jois ossis Journis JosiSclerosis JouS si JouurrnnalH LassmannalH LassmannalH LassmannalH LassmannalH LaaalHH LassmannalH LassmannH LasLLH L nnnassmans an
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`Multiple Sclerosis Journal
`
`2017, Vol. 23(12) 1593 –1599
`
`DOI: 10.1177/
`https://doi.org/10.1177/1352458517729455
`1352458517729455
`https://doi.org/10.1177/1352458517729455
`
`© The Author(s), 2017.
`Reprints and permissions:
`http://www.sagepub.co.uk/
`journalsPermissions.nav
`
`Correspondence to:
`H Lassmann
`Center for Brain Research,
`Medical University of
`Vienna, Spitalgasse 4,
`A-1090 Wien, Austria.
`hans.lassmann@
`meduniwien.ac.at
`
`Hans Lassmann
`Center for Brain Research,
`Medical University of
`Vienna, Wien, Austria
`
`MULTIPLE
`SCLEROSIS MSJ
`JOURNAL
`
`Advancing Trial Design in Progressive Multiple Sclerosis
`
`Targets of therapy in progressive MS
`
`Hans Lassmann
`
`Abstract: Highly effective anti-inflammatory therapies have so far been developed for patients with
`relapsing/remitting multiple sclerosis, which also show some benefits in the early progressive stage
`of the disease. However, treatment options for patients, who have entered the progressive phase, are
`still limited. Disease starts as an inflammatory process, which induces focal demyelinating lesions in
`the gray and white matter. This stage of the disease dominates in the relapsing phase, extends into the
`early stages of progressive disease, and can be targeted by current anti-inflammatory treatments. In
`parallel, inflammation accumulates behind a closed or repaired blood brain barrier, and this process
`peaks in the late relapsing and early progressive stage and then declines. Some data suggest that this
`process may be targeted by immune ablation and hematopoietic stem cell transplantation. In the late
`stage, inflammation may decline to levels seen in age-matched controls, but age and disease burden–
`related neurodegeneration ensues. Such neurodegeneration affects the damaged brain and spinal cord,
`in which functional reserve capacity is exhausted, giving rise to further disability progression. Anti-
`inflammatory treatments are unlikely to be beneficial in this stage of the disease, but neuroprotective
`and repair-inducing strategies may still be effective.
`
`Keywords: Multiple sclerosis, inflammation, neurodegeneration, treatment
`
`Date received: 4 July 2017; accepted: 7 July 2017
`
`Introduction
`Anti-inflammatory and immunomodulatory thera-
`pies are highly effective in the early relapsing stage
`of multiple sclerosis (MS), but with few exceptions
`they have failed to show a beneficial effect, when
`patients entered the progressive stage. For this rea-
`son a widely held concept is that MS starts as an
`inflammatory disease, but is driven at later stages
`by neurodegeneration, which develops indepen-
`dently from inflammatory mechanisms. This view
`in part contradicts neuropathological experience,
`which shows that inflammation, defined by T- and
`B-cell infiltrates, is invariably associated with
`active demyelination and tissue injury in the pro-
`gressive stage of the disease.1 In this short review,
`we discuss
`the neuropathological differences
`between relapsing and progressive MS, the current
`knowledge of pathophysiological mechanisms driv-
`ing tissue injury in progressive MS, and the impli-
`cations of these findings for currently established
`and future treatments of patients.
`
`Neuropathological features distinguishing
`relapsing from progressive MS
`The neuropathological changes in the brain of patients
`with relapsing or progressive MS are essentially simi-
`lar. Inflammation, signified by the presence of T and B
`lymphocytes, is present, and this is associated with the
`formation and/or expansion of focal lesions of primary
`demyelination in the white and gray matter and with
`neurodegeneration in the plaques and in normal-
`appearing white and gray matter. Focal lesions are
`characterized by profound astrocytic scar formation
`and a variable extent of axonal loss and remyelination.
`However, the relative incidence of different lesion fea-
`tures changes with time of disease evolution.2 New
`focal white matter lesions dominate the pathological
`picture of early MS, and many of the plaques are in the
`active stage of demyelination. In contrast, in the pro-
`gressive stage, new active lesions become rare, but
`many of the focal lesions display a rim of activated
`microglia at the border and some macrophages with
`recent myelin degradation products. This suggests
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`Multiple Sclerosis Journal 23(12)
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`slow expansion of pre-existing lesions.3 In addition,
`cerebral and cerebellar cortical demyelination, which
`is present but sparse in the early stage of MS, becomes
`very prominent in the progressive stage, reaching in
`some extreme examples an extent of up to 90%.4–6 In
`addition, profound diffuse pathology is present in the
`normal-appearing white and gray mater, which con-
`sists of small perivenous inflammatory infiltrates, sur-
`rounded by small rims of demyelination, diffuse
`astrocytic gliosis as well as diffuse microglia activa-
`tion and axonal degeneration.4,7 Neuronal loss is pro-
`nounced in cortical lesions,8 and the extent of diffuse
`pathology in the normal-appearing white matter cor-
`relates better with the extent of cortical than white
`matter demyelination.4 Diffuse neurodegeneration in
`the gray as well as the white matter seems to be driven
`in part by the inflammatory process in the leptomenin-
`ges as well as by anterograde and retrograde degenera-
`tion resulting from axonal loss in focal lesions.9,10
`
`Inflammatory infiltrates in MS are dominated by CD8+
`T lymphocytes, CD20 positive B cells, and immuno-
`globulin-producing plasma cells.1,11,12 CD8+ T cells, B
`cells, and plasma cells show clonal expansion, which
`indicates their activation by specific cognate antigen(s)
`within the central nervous system (CNS).13,14 CD8+ T
`cells dominate the inflammatory reaction not only in
`MS but also in most other inflammatory diseases in
`the human CNS, in particular in virus-induced
`encephalitides. In contrast, B cells are enriched within
`MS lesions and the B cell/monocyte ratio in the cere-
`brospinal fluid (CSF) correlated with the severity of
`disease progression.15 The patterns of inflammation
`are similar between relapsing and progressive MS,
`although the global extent of lymphocytic inflamma-
`tion is higher in acute or relapsing MS in comparison
`to progressive MS.1 Phenotypic characterization of B
`cells in MS lesions has so far not been performed but
`in the CSF short-lived plasmablasts dominate.16 CD8+
`T cells express markers of either activated cytotoxic T
`cells (granzyme B expression17) or of tissue-resident
`effector memory T cells. A major difference between
`acute/relapsing MS and progressive MS is that in the
`former, the lymphocytic infiltration is associated with
`profound blood–brain barrier damage, while in the
`progressive stage, inflammation is at least partly com-
`partmentalized in the brain behind an intact (possibly
`repaired) blood–brain barrier.18
`
`Active tissue injury, consistent of demyelination,
`axonal transsection, and neuronal degeneration, is
`associated with profound microglia activation.19,20 In
`addition, however, microglia is already partly activated
`toward a pro-inflammatory phenotype in the normal
`white matter of controls, and this is even more the case
`
`in the normal-appearing white matter of MS patients.21
`Global pro-inflammatory microglia activation increases
`with age of controls and with age and disease duration
`in MS patients. In areas of active tissue injury, micro-
`glia are dominantly activated into a pro-inflammatory
`phenotype, expressing functional markers for oxidative
`activation, phagocytosis, and antigen presentation. In
`active lesions of acute and relapsing MS, the lesions
`are additionally infiltrated by recruited macrophages,
`which contribute to about 60% of the global mac-
`rophage population in the lesions.21 In response to
`myelin phagocytosis, these macrophages convert to an
`intermediate phenotype, co-expressing pro- and anti-
`inflammatory markers.22 This coincides with the induc-
`tion of remyelination in the lesions. This is different in
`slowly expanding lesions of progressive MS, where
`active tissue injury is mainly associated with pro-
`inflammatory microglia
`activation, macrophage
`recruitment is sparse, and expression of anti-inflamma-
`tory markers is minimal to absent.21
`
`Perivascular and meningeal inflammation may occur
`as lymphocytic aggregates, which may show features
`of tertiary lymph follicles.23 One of their prominent
`features is the high content of B lymphocytes. Although
`they are already present in the earliest stages of MS,24
`their number and incidence increase with disease dura-
`tion, reaching highest levels at the early phase of pro-
`gressive disease.4–6 Patients who have such follicle-like
`inflammatory aggregates in the meninges have a more
`aggressive progressive disease, reduced life expec-
`tancy, and in pathology more profound cortical (sub-
`pial) demyelination and diffuse brain injury in the
`normal-appearing white and gray matter.25
`
`The inflammatory process appears to die out in late
`stages of progressive MS. In such patients, lympho-
`cytic infiltrates are reduced to very low levels, similar
`to those seen also in age-matched controls. Active
`demyelination is absent in the brain of these patients,
`but there is a low level of ongoing (axonal) neurode-
`generation, which too is similar to that present in age-
`matched controls.1
`
`Mechanisms of demyelination and tissue injury
`A broad spectrum of different mechanisms of immune-
`mediated tissue injury has been identified in experimen-
`tal models, which were suggested to be relevant for MS
`pathogenesis.26 Many of these mechanisms are however
`shared between different inflammatory brain diseases,
`which do not show the MS typical features of inflam-
`matory primary demyelination with relative axonal
`sparing. Comparing active MS lesions at different
`stages of their evolution and with other inflammatory or
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`Figure 1. Pathological substrates of MS in different disease stages.
`WM: white matter, GM: gray matter.
`
`non-inflammatory diseases, a dominant pathway of tis-
`sue injury appeared, which involves microglia activa-
`tion, their production of reactive oxygen and nitric
`oxide species, and profound oxidative injury of oligo-
`dendrocytes, axons, and neurons, in particular when
`they show changes of initial damage or cell death.27,28
`Mitochondria are particularly vulnerable in conditions
`of oxidative injury and it is, thus, not surprising to see
`extensive mitochondrial damage in active stages of
`demyelination and neurodegeneration29,30 and a chronic
`mitochondrial dysfunction due to mutations and dele-
`tions of mitochondrial DNA in progressive MS.31 The
`consequence of mitochondrial injury is energy defi-
`ciency, best described by the terms histotoxic or virtual
`hypoxia.32 Downstream consequences of oxidative
`injury, mitochondrial damage, and energy deficiency
`are endoplasmic reticulum stress and neurodegenera-
`tion due to ionic imbalance, excitotoxicity, and intracel-
`lular calcium accumulation.33
`
`These mechanisms are very prominent in the MS
`brain and apparently initiated by the chronic inflam-
`matory process. However, quite similar mechanisms
`also play a role in brain aging, age-related neurode-
`generative diseases, and vascular diseases. The latter
`is particularly important, since recent data from
`pathology and imaging indicate that MS lesions may
`arise at any sites of the brain, but persistent lesions
`with extensive axonal loss and lack of repair mainly
`accumulate in brain areas with low vascular perfusion
`and oxygen tension.10,34 Thus, age-related neurode-
`generation, low vascular perfusion in the normal
`brain, and vascular co-morbidities in aging patients
`amplify tissue damage and neurodegeneration in MS.
`
`Finally, the normal human brain progressively accu-
`mulates iron with aging, and this global iron accumu-
`lation appears to be amplified in MS patients.35 Iron
`mainly accumulates in myelin and oligodendrocytes,
`
`and oligodendrocyte death in MS lesions liberates
`iron from the intracellular stores. Free divalent iron
`potentiates oxidative injury through the formation of
`highly reactive hydroxyl radicals. Thus, iron-related
`neurodegeneration is an additional factor, which
`amplifies tissue injury and neurodegeneration in the
`progressive stage of MS.
`
`The evolution of brain damage in MS may
`require stage-dependent therapeutic strategies
`Overall, on the basis of pathology, MS can be roughly
`categorized into three different disease stages (Figure
`1): an initial (early stage) of brain injury driven by sys-
`temic inflammation, a second stage of compartmental-
`ized inflammation in the brain and spinal cord, and a
`last phase of inflammation independent, but age and
`disease burden–related neurodegeneration. It is likely,
`but not yet formally, proven that all stages of the dis-
`ease are triggered by the initial inflammatory response
`and, thus, effective anti-inflammatory treatment in
`early MS should reduce or even abrogate progression
`in the subsequent disease stages. In addition, it has to
`be acknowledged that there is no strict separation of
`these disease stages but that the respective pathoge-
`netic mechanisms in part act in parallel (Figure 1).
`
`Early inflammatory stage
`The first stage of inflammation driven by the systemic
`immune reaction gives rise to new focal lesions domi-
`nantly located in the white matter. This dominates in
`patients in the early relapsing/remitting stage of the dis-
`ease but extends into the early stages of (primary and sec-
`ondary) progressive MS. In the latter patients, disease
`progression may still be associated with some clinical
`disease activity and/or the appearance of some contrast-
`enhancing lesions in magnetic resonance imaging (MRI).
`Anti-inflammatory or immunomodulatory treatment is
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`Multiple Sclerosis Journal 23(12)
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`effective in such patients with progressive disease, and
`recent trials show that this is also associated with a mod-
`erate reduction of disability progression (ocrelizumab;36
`siponimod: Novartis release on BAF312).
`
`Compartmentalized inflammation in progressive
`MS
`A dominant feature of the pathology of progressive
`MS is the presence of a compartmentalized inflam-
`matory response, where T cells, B cells, and plasma
`cells are trapped within the brain and spinal cord
`behind a closed or repaired blood–brain barrier. This
`gives rise to large inflammatory (follicle-like) aggre-
`gates in the meninges and large perivascular spaces,
`associated with active cortical demyelination, slow
`expansion of pre-existing white matter lesions, and
`diffuse injury of the normal-appearing white and
`gray matter. Although trapped inflammation builds
`up already in the early stage of the disease, it reaches
`its peak in the late relapsing and early progressive
`phase. The therapeutic strategy in this stage of the
`disease should be the blockade of the inflammatory
`response within the CNS. To be effective, respective
`anti-inflammatory drugs have to reach the inflamma-
`tory response behind a closed blood–brain barrier.
`Thus, most of the current biological drugs (such as
`antibodies) will not reach their specific target in the
`brain
`in sufficient concentrations. Furthermore,
`blockade of leukocyte recruitment from lymphatic
`tissue or their migration through the blood brain bar-
`rier, which can be achieved by sphingosine phos-
`phate receptor or α4 integrin blockade,37,38 is unlikely
`to be effective, when the immune cells are already
`within the CNS compartment. Since T cells in the
`lesions in progressive MS show only a low degree of
`activation and a very low rate of proliferation, classi-
`cal immunosuppressive treatments are not a prime
`therapeutic option, even when they can get access to
`the brain. Furthermore, as discussed above, a major
`population of CD8+ T cells within the lesions of pro-
`gressive MS displays a phenotype of tissue-resident
`effector memory cells. To become tissue-resident
`cells such T lymphocytes downregulate their expres-
`sion of sphingosine phosphate receptors39 and thus,
`they can also no longer be targeted by drugs like fin-
`golimod or siponimod. Unfortunately, so far, very lit-
`tle is known about strategies to therapeutically target
`tissue-resident T or B lymphocytes. Whether intrath-
`ecal elimination of T and/or B cells slows disease
`progression is currently unclear.
`
`However, immune ablation with subsequent bone mar-
`row (stem cell) transplantation may have an effect on
`compartmentalized inflammation in the brain. It has
`
`been applied in patients with severe progressive dis-
`ease, and the therapeutic effects seem to be more pro-
`nounced compared to conventional immunosuppressive
`or immunomodulatory treatments.40,41 Furthermore,
`aggressive immune ablation uses a combination of
`drugs, which have the potential to get access to the
`CNS through the blood brain barrier, shown by a short-
`term increase in brain atrophy, possibly due to direct
`cytotoxic actions.42 Neuropathological studies on a
`very small number of patients showed a profound
`reduction of the inflammatory response, but there was
`some residual inflammation and microglia activation
`associated with persistent demyelination or neurode-
`generation.43 However, these neuropathological data
`mainly came from patients, who died early after
`immune ablation and bone marrow transplantation, and
`data on the long-term effects of this treatment on
`inflammation in the brain and spinal cord are sparse.
`Despite these caveats, new MRI data indicate that after
`the acute phase following immune ablation and bone
`marrow transplantation, the rate of brain atrophy
`declines to levels seen in age-matched controls.40
`
`Late stage of progressive MS
`In the last stage of MS, progressive neurodegeneration
`occurs even in the absence of an overt inflammatory
`response.1 The disease mechanisms in this stage of the
`disease seem to be similar to those in brain aging, but
`they occur in a brain and spinal cord, which is already
`damaged beyond the stage of functional compensa-
`tion.10,33 Since microglia activation, oxidative injury,
`mitochondrial damage, and subsequent “virtual
`hypoxia” are important amplification factors of neuro-
`degeneration in chronic inflammation as well as aging,
`these neurodegenerative mechanisms are important
`drivers of disease in all stages of MS. Therapeutic goal
`for this stage of the disease (or this type of injury)
`should be both the induction of functional improve-
`ment and the reduction of the speed of neurodegenera-
`tion. Thus, a treatment trial may have highly ambitious
`goals, such as the rate of patients with short-term clini-
`cal improvement and long-term halt of disease pro-
`gression. This has recently been shown in a small
`controlled trial in patients treated with high-dose bio-
`tin,44 which seems to counteract the state of energy
`deficiency in “virtual hypoxia.” In addition, some data
`suggest that the progression of neurodegeneration may
`be ameliorated by simvastation45 and siponimod
`(Novartis press release on BAF312). The mechanisms
`behind the effects of the latter drugs in MS are not
`fully understood at present.
`
`An alternative strategy is the stimulation of remy-
`elination and repair either through pharmacological
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`Figure 2. Therapeutic strategies in different stages of MS evolution.
`
`transplantation.
`through cell
`approaches or
`Remyelination in demyelinated lesions may result
`in functional improvement and in neuroprotection,
`as shown in experimental animals.46 However, the
`reasons for remyelination failure in MS lesions are
`highly complex and not only involve the loss of oli-
`godendrocyte progenitor cells or their blockade of
`differentiation into myelinating cells, which are
`mechanisms that can be targeted pharmacologically
`or by cell transplantation. Important additional fac-
`tors are recurrent inflammatory demyelination in
`remyelinated areas,47,48 extensive loss and func-
`tional impairment of axons in chronic demyelinated
`lesions,49 and impairment of the regenerative
`capacity due to age-related factors and vascular
`comorbidities.10 Furthermore, spontaneous remy-
`elination occurs in MS patients and lesions, its
`extent being variable in different patients and
`dependent upon lesion location.50,51 It is thus
`expected that therapies stimulating remyelination
`will only be effective in combination with anti-
`inflammatory treatments and in lesions, which
`still contain sufficient axons to be remyelinated.
`Furthermore, paraclinical markers, which deter-
`mine the extent of spontaneous and treatment-
`induced remyelination and which define the reasons
`for remyelination failure, are urgently required for
`the design of respective clinical trials.
`
`Conclusion
`In this review, it is discussed that treatment targets are
`different in different stages of disease evolution in
`MS patients (Figure 2). However, it is important to
`consider that the mechanisms, which dominate in a
`given disease stage are also involved in the other
`stages. For pragmatic reasons, it may be useful in
`clinical trials to define the effect of anti-inflammatory
`versus neuroprotective treatments in those disease
`stages, where the respective mechanisms dominate,
`
`but when a positive treatment effect is proven, it is
`likely that they are also in part effective during other
`disease stages.
`
`Acknowledgements
`This review is part of a special issue derived from the
`5th Focused ECTRIMS Workshop, “Advancing Trial
`Design in Progressive Multiple Sclerosis,” held in
`Rome, Italy, on 9–10 March 2017. The authors
`acknowledge the contributions of workshop attendees.
`
`Declaration of Conflicting Interests
`The author(s) declared no potential conflicts of inter-
`est with respect to the research, authorship, and/or
`publication of this article.
`
`Funding
`The author(s) received no financial support for the
`research, authorship, and/or publication of this article.
`
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