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The transitional phase of multiple sclerosis: Characterization and conceptual framework

      Highlights

      • A heterogeneous gradual transition from RRMS to SPMS is supposed to exist.
      • Exhausting compensatory mechanisms may be a common feature of the transition.
      • Clinically, diffuse deterioration in cognitive, motor and autonomous functions becomes apparent.
      • Smoldering lesions, cortical and gray matter pathology, and retinal layer degeneration are potential imaging markers.
      • Study concepts on immunotherapy of transitional MS should capture patients early in the process.

      Abstract

      The conversion of relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS) cannot be defined by a sharp threshold determined by event-based measures, but rather represents a gradual process. In consequence, there may exist a transitional phase between RRMS and clearly established SPMS. So far, transitional MS has been poorly characterized in terms of patient properties, course of disease and therapeutic interventions that may delay conversion to SPMS. Furthermore, the pathogenesis of transitional MS is incompletely understood, and no definitive imaging or laboratory test informs when exactly a patient has entered the transitional MS phase. Here we review the current knowledge and evidence characterizing the transitional phase of MS and propose potential designs and criteria for a prospective clinical study in patients with transitional MS.

      Keywords

      Abbreviations:

      9HPT (9-hole peg test), BVMT-R (brief visuospatial memory test-revised), CGI (clinical global impression), CHI3L1 (chitinase-3-like protein 1), CNS (central nervous system), CSF (cerebrospinal fluid), EDSS (expanded disability status scale), FSMC (fatigue scale for motor and cognitive functions), FSS (functional systems scale), GCIPL (combined ganglion cell and inner plexiform layer), GFAP (glial fibrillary acid protein), HADS (hospital anxiety and depression Scale), LCSLC (low contrast Sloan letter chart), MRI (magnetic resonance imaging), MS (multiple sclerosis), MSIS-29 (multiple sclerosis impact scale-29), MSFC (multiple sclerosis functional composite), NfL (neurofilament light chain), OCT (optical coherence tomography), PASAT (paced auditory serial addition test), PIRA (progression independent of relapse activity), PPMS (primary progressive multiple sclerosis), pRNFL (peripapillary retinal nerve fiber layer), RMS (relapsing multiple sclerosis), RRMS (relapsing-remitting multiple sclerosis), SDMT (symbol digit modalities test), SF-36 (short form 36), SPMS (secondary progressive multiple sclerosis), TREM-2 (triggering receptor expressed on myeloid cells-2), T25FW (timed 25-foot walk), 2MWT (2-minutes walking test), TUG (timed up and go test)

      1. Introduction

      Multiple sclerosis (MS) is characterized by highly heterogeneous disease courses in individual patients that may represent a continuum of gradually different disease phenotypes. With the exception of primary progressive MS (PPMS), most patients experience an initial phase dominantly characterized by recurrent relapses (RRMS). Their symptoms are fully or partially reversible and may contribute to accumulation of disability. In parallel, clinicians may observe disability progression independent of relapse activity (PIRA) which gradually takes over, thus resulting in secondary progressive MS (SPMS). A period of gradual conversion between RRMS and SPMS, i.e. a “transitional” phase of MS, is supposed to exist. While a number of published therapeutic studies have included patients with relapsing MS, a term that comprises RRMS and SPMS with superimposed relapses, no clinical studies have been performed that specifically address the transitional phase of the disease so far.

      2. Disease progression in MS

      2.1 Classification of MS stages

      In the 2013 update of the MS disease classification, disease activity as measured by clinical relapses, new or enhancing lesions on brain or spinal cord magnetic resonance imaging (MRI), or ongoing progression of disability were introduced as modifiers of the two core MS phenotypes, relapsing-remitting (RRMS) and progressive MS (PPMS, SPMS) (
      • Lublin FD
      • et al.
      Defining the clinical course of multiple sclerosis: the 2013 revisions.
      ). Generally, differences between phenotypes are rather qualitative than quantitative, often precluding sharp delineations. Clinically, progressive MS and as such SPMS is defined by the accumulation of disability without relation to relapses as opposed to relapse-associated worsening, which may be fully or partially reversible.
      Progressive MS is defined as a steadily increasing, objectively documented neurological dysfunction or disability without unequivocal recovery, while fluctuations and phases of stability, superimposed relapses and MRI activity may occur. The predominant sign of SPMS is increasing motor dysfunction, independently from relapse-associated deterioration. While this may be influenced operationally by the use of the EDSS in the definition of SPMS, it is consistent with the concept of a neurodegenerative length-dependent axonopathy as a central component of progressive MS (
      • Giovannoni G
      • et al.
      Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.
      ).

      2.2 Clinical predictors of conversion to SPMS

      According to natural history studies, 30-50% of untreated RRMS patients convert to SPMS within 10-15 years after disease onset, while 80% reach the progressive stage at 20 years (
      • Weinshenker BG
      • et al.
      The natural history of multiple sclerosis: a geographically based study. I. Clinical course and disability.
      ). Data from observational studies in more contemporary cohorts have suggested a shift towards a slower progression rate and conversion to SPMS (
      • Tremlett H
      • Paty D
      • Devonshire V
      Disability progression in multiple sclerosis is slower than previously reported.
      ,
      • Tedeholm H
      • et al.
      Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs.
      ). A low percentage of patients will never convert to SPMS and may represent a group with so-called “benign” MS (
      • Skoog B
      • et al.
      A representative cohort of patients with non-progressive multiple sclerosis at the age of normal life expectancy.
      ). Based on a large sample of patients with 5 years follow-up after progression, the following criteria for an early diagnosis of SPMS were identified (
      • Lorscheider J
      • et al.
      Defining secondary progressive multiple sclerosis.
      ): EDSS ≥4.0, pyramidal FSS ≥2, disability progression confirmed after ≥3 months by 1.0 (previous EDSS ≤5.5) or by 0.5 points (previous EDSS ≥6.0). Clinical predictors of an earlier transition to SPMS remain controversial and may include male sex, older age at MS onset, higher number of relapses early in disease course, poor recovery from first (
      • Confavreux C
      • Vukusic S
      • Adeleine P
      Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process.
      ) and subsequent relapses (
      • Novotna M
      • et al.
      Poor early relapse recovery affects onset of progressive disease course in multiple sclerosis.
      ), overall MS disease duration (
      • Scalfari A
      • et al.
      Onset of secondary progressive phase and long-term evolution of multiple sclerosis.
      ) and early treatment with injectable therapies versus highly effective immunomodulatory drugs during the RRMS phase (
      • Brown JWL
      • et al.
      Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis.
      ).
      While higher age at RRMS onset is a predictor of a shorter latency to SPMS, patients with younger age at onset still develop SPMS earlier in their life. Males convert to SPMS more rapidly than women (mean difference: 4 years) and are younger at conversion to SPMS (mean difference: 3 years). Males and females reach an EDSS of 8.0 at the same mean age (
      • Tremlett H
      • Zhao Yinshan
      • Devonshire V
      Natural history of secondary-progressive multiple sclerosis.
      ). Motor and/or sphincter symptoms at MS onset were identified as dominant predictors of SPMS (
      • Bergamaschi R
      • et al.
      Early prediction of the long term evolution of multiple sclerosis: the Bayesian Risk Estimate for Multiple Sclerosis (BREMS) score.
      ,
      • Bergamaschi R
      • et al.
      BREMSO: a simple score to predict early the natural course of multiple sclerosis.
      ). Moreover, a more rapid disability trajectory is associated with an increased risk of SPMS (
      • Fambiatos A
      • et al.
      Risk of secondary progressive multiple sclerosis: a longitudinal study.
      ). To predict the risk of conversion to SPMS, a nomogram employing gender, calendar year of birth, first-recorded EDSS, age at the first EDSS evaluation and age at disease onset was constructed (
      • Manouchehrinia A
      • et al.
      Predicting risk of secondary progression in multiple sclerosis: A nomogram.
      ).
      Worsening of ambulation, cognition, balance, muscle strength, visual symptoms, bladder symptoms and fatigue were identified by patients and physicians to be related to the transition from RRMS to early SPMS (
      • Ziemssen T
      • et al.
      A mixed methods approach towards understanding key disease characteristics associated with the progression from RRMS to SPMS: physicians’ and patients’ views.
      ). However, no specific symptom definitively indicated progression to SPMS for the individual patient.

      3. The concept and clinical assessment of transitional MS

      As the conversion to SPMS cannot be defined as a sharp threshold defined by event-based measures but rather takes place as a gradual process, there may exist an interim period of several years duration between RRMS and clearly established SPMS. Currently, SPMS represents a retrospective diagnosis. Clinically, “transitional MS” is a prequel of SPMS with signs of incipient progression during a variable duration of time before SPMS is unequivocally diagnosed. In a study involving 123 MS patients, the mean duration of diagnostic uncertainty between RRMS and SPMS was 2.9 years, and in 70% of the cases, the diagnosis of SPMS was only established when an EDSS of ≥6.0 was reached (
      • Katz Sand I.
      Classification, diagnosis, and differential diagnosis of multiple sclerosis.
      ).
      The inability to more precisely capture the onset of SPMS may in part be due to the limitations inherent to the EDSS itself which include: non-linear characteristics with the shortest timespan spent in the range of 3.0–5.0, emphasis on lower limb motor function, low sensitivity to cognitive and upper limb changes in advanced MS, high inter-rater variability, particularly in the lower ranges of the scale (1.0–3.5), and partly subjective evaluation (bowel and bladder function, ambulation). Of note, an EDSS increase confirmed at 3- and 6-month intervals overestimates the percentage of patients with permanent increase in disability (at 5 years) by 30% and 26%, respectively (
      • Kalincik T
      • et al.
      Defining reliable disability outcomes in multiple sclerosis.
      ). Thus, a preferable instrument for clinical assessment may be the well-standardized MSFC (the z-score of 9HPT (hand function), 25-foot Walk (ambulation) and PASAT3 (cognition), which is based entirely on objective components, and shows high intra- and inter-rater reliability. A deterioration by 0.5 points in the total score or by 20% in the single components can predict subsequent EDSS change (
      • Cohen JA
      • et al.
      Intrarater and interrater reliability of the MS functional composite outcome measure.
      ). The use of MSFC in longitudinal studies is impeded by repetition effects of the PASAT (
      • Solari A
      • et al.
      The multiple sclerosis functional composite: different practice effects in the three test components.
      ), which may be mitigated by replacing it with the SDMT that also has shown a higher sensitivity. Thus, the modified MSFC, which may allow for more sensitive detection of cognitive decline and upper extremity motor dysfunction, may be a preferable composite instrument of tracking progression versus EDSS (
      • López-Góngora M
      • Querol L
      • Escartín A
      A one-year follow-up study of the symbol digit modalities test (SDMT) and the paced auditory serial addition test (PASAT) in relapsing-remitting multiple sclerosis: an appraisal of comparative longitudinal sensitivity.
      ).
      Operationally, transitional MS may be defined as confirmed MSFC progression in a relapse-free interval independent of EDSS progression. However, the following questions would have to be answered: can a meaningful change in the modified MSFC (total score or components) confirmed after a predefined time period (e.g. 6 months) predict the subsequent conversion to SPMS better than the EDSS or despite a stable EDSS value?
      Novel rater-independent measuring tools (e.g. based on sensor technologies and mobile applications) allow for continuous objective monitoring of patient mobility, gait patterns, action range, dexterity, sleep patterns and selected cognitive functions in daily life. As an example, Flachenecker et al. (
      • Flachenecker F
      • Gaßner H
      • Hannik J
      • et al.
      Objective sensor-based gait measures reflect motor impairment in multiple sclerosis patients: Reliability and clinical validation of a wearable sensor device [published online ahead of print, 2019 Dec 23].
      ) used sensor-based gait analysis to support the clinical assessment of walking abnormalities and identified stride length at the individual maximum speed as a sensitive discriminator. These tools may thus provide sensitive early indicators of ongoing relapse-independent progression and could be integrated in the definition of study endpoints in transitional MS.

      4. Diagnostic findings associated with transitional MS

      4.1 Cognition and fatigue

      In general, cognitive problems are increasingly prevalent in MS over time (
      • Achiron A
      • et al.
      Modeling of cognitive impairment by disease duration in multiple sclerosis: a cross-sectional study.
      ,
      • Kister I
      • Bacon TE
      • et al.
      Natural history of multiple sclerosis symptoms.
      ) and over the stages from onset to RRMS to SPMS (
      • Potagas C
      • et al.
      Cognitive impairment in different MS subtypes and clinically isolated syndromes.
      ). Moderate-to-severe fatigue and lower grade depression show an increase with disease duration (). Yet, some patients are able to withstand a considerable disease burden without significant cognitive impairment, an observation that underlines the concept of cognitive reserve (
      • Santangelo G
      • et al.
      Cognitive reserve and neuropsychological performance in multiple sclerosis: a meta-analysis.
      ). Studies on specific cognitive and neuropsychiatric impairments applicable to the transitional phase of MS are virtually absent. In a first attempt to identify potential cognitive profiles related to disease stages, a study form the Netherlands compared RRMS, SPMS and PPMS (
      • Huijbregts
      • et al.
      Differences in cognitive impairment of relapsing remitting, secondary, and primary progressive MS.
      ). When controlling for age and gender, it turned out that overall RRMS patients performed cognitively better than the progressive group. However, RRMS patients performed worse than matched healthy control subjects, with processing speed, visual memory and executive function showing significant performance differences.
      These findings indicate that cognitive profiling according to disease courses obviously poses a challenge since the target cognitive domains are already affected in RRMS patients and just increasing in severity over time. With respect to the transitional phase, it is of interest that SPMS patients differed from RRMS patients most significantly in visuospatial short-term memory and learning. This may be regarded as the most sensitive cognitive change parameter to discriminate between RRMS and SPMS but also between SPMS and PPMS, as confirmed by recent data (
      • Renner A
      • Baetge SJ
      • Filser M
      • Ullrich S
      • Lassek C
      • Penner IK
      Characterizing cognitive deficits and potential predictors in multiple sclerosis: a large nationwide study applying brief international cognitive assessment for multiple sclerosis in standard clinical care.
      ).

      4.2 CNS pathology

      Neuropathologically, no abrupt change in phenotype is observed when patients enter the progressive phase of MS. White and grey matter lesions as well as neuroaxonal degeneration evolve continuously (
      • Stadelmann C
      • et al.
      Myelin in the central nervous system: structure, function, and pathology.
      ,
      • Schirmer L
      • et al.
      Axonal loss and neurofilament phosphorylation changes accompany lesion development and clinical progression in multiple sclerosis.
      ). In line with fewer enhancing lesions in MRI and less relapses, macrophage-rich actively demyelinating lesions become increasingly rare with time (
      • Frischer JM
      • et al.
      Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque.
      ). An exhaustion of neuronal compensatory mechanisms may be linked to the time point when disease progression becomes clinically apparent. In contrast to later stages of disease, in transitional MS, many lesions may still show signs of macrophage activation, demyelination, and axonal damage at the lesion edge, and thus active ongoing pathology which is potentially amenable to therapeutic intervention (
      • Faissner S
      • et al.
      Progressive multiple sclerosis: from pathophysiology to therapeutic strategies.
      ).

      4.3 Magnetic resonance imaging characteristics

      MRI is the most important surrogate marker to monitor MS disease activity, but no standardized imaging measures of progressive MS are currently established. Conventional MRI parameters (number/load of T2 and gadolinium-enhancing lesion) appear to be unable to predict the risk of conversion to SPMS (
      • Manouchehrinia A
      • et al.
      Predicting risk of secondary progression in multiple sclerosis: a nomogram.
      ). Still, early focal inflammatory disease activity and spinal cord lesions may represent predictors of very long-term disease outcomes (over 15 years) in RRMS (
      • Brownlee WJ
      • et al.
      Early imaging predictors of long-term outcomes in relapse-onset multiple sclerosis.
      ). Cortical lesions that may be found even in early MS display both numerical and volumetric increase with disease evolution from RRMS towards SPMS. The cortical lesion volume correlates with increasing EDSS and more severe cognitive impairment (
      • Roosendaal SD
      • et al.
      Accumulation of cortical lesions in MS: relation with cognitive impairment.
      ). Long-term longitudinal studies found a higher number and volume of cortical lesions, early loss of cortical thickness and loss of cerebellar cortical volume as significant predictors of a conversion to SPMS (
      • Scalfari A
      • et al.
      The cortical damage, early relapses, and onset of the progressive phase in multiple sclerosis.
      ). As a novel marker, atrophy of existing lesions may be more common in progressive MS than in RRMS (
      • Dwyer MG
      • et al.
      Atrophied brain lesion volume: a new imaging biomarker in multiple sclerosis.
      ). In a longitudinal study over 4 years, gray matter atrophy was a predictor of progression, while white matter atrophy was unrelated (
      • Fisher E
      • et al.
      Gray matter atrophy in multiple sclerosis: a longitudinal study.
      ). Along that line, spinal cord gray matter atrophy may also represent an early marker of SPMS (
      • Schlaeger R
      • et al.
      Spinal cord gray matter atrophy correlates with multiple sclerosis disability.
      ). The progressive disease course was significantly associated with a reduced spinal cord area independent of the spinal cord lesion number. According to a model of disease evolution (
      • Leray E
      • et al.
      Evidence for a two-stage disability progression in multiple sclerosis.
      ,
      • Rocca MA
      • et al.
      Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage.
      ), RRMS is dominated by white matter pathology, while gray matter damage is compensated by remyelination and plasticity. As these mechanisms become exhausted, gray matter pathology takes over (
      • Roosendaal SD
      • et al.
      Accumulation of cortical lesions in MS: relation with cognitive impairment.
      ,
      • Calabrese M
      • et al.
      The changing clinical course of multiple sclerosis: a matter of gray matter.
      ), inducing a gradual transition towards irreversibly progressive disability, i.e. SPMS. In transitional MS, intermediate imaging findings should be expected. Higher numbers of new and enlarging cortical lesions, incipient gray matter and cortical atrophy as well as atrophied lesions may provide indicators of transitional MS. The development and validation of an MRI score to measure changes typical for transitional MS is an obvious, but still challenging approach to detect early secondary progression.

      4.4 Biomarkers

      Biomarkers identifying MS patients at risk of conversion to SPMS, would be highly useful if they enable early intervention with the potential of better long-term outcomes. Preferred candidates include markers of axonal destruction and intracerebral inflammation. Ideally, these would be serum markers easily accessible by blood sampling. However, levels of CNS target molecules in blood are often very low down to the femtomolar range, requiring highly sensitive techniques, e.g. single molecule array (SIMOA), for valid detection (
      • Disanto G
      • Barro C
      • Benkert P
      • et al.
      Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis.
      ).
      Neurofilament light chain (NfL) is a cytoplasmic protein highly prevalent in myelinated axons (
      • Gaetani L
      • et al.
      Neurofilament light chain as a biomarker in neurological disorders.
      ). It is released in the cerebrospinal fluid (CSF) and blood upon axonal damage and has been under investigation as a disease marker in a number of neurodegenerative conditions. NfL serum levels have been shown to be elevated in SPMS versus RRMS patients prior to study treatment. Consistently, NfL levels show a modest positive correlation with change of EDSS over time and the rate of brain atrophy (
      • Kuhle J
      • et al.
      Serum neurofilament is associated with progression of brain atrophy and disability in early MS.
      ). However, NfL is not an inflammation-independent marker of neurodegeneration. While it proved to be highly sensitive, it is not specific for MS-related processes, and individual thresholds have not yet been prospectively determined.
      Glial fibrillary acidic protein (GFAP) is the main astrocyte intermediary filament and upregulated during activation. In the CSF, GFAP is elevated in SPMS versus RRMS patients and correlates with EDSS. GFAP levels may predict the rate of EDSS worsening over 8 to 10 years (
      • Linker RA
      • et al.
      Proteome profiling in murine models of multiple sclerosis: identification of stage specific markers and culprits for tissue damage.
      ,
      • Malmeström C
      • et al.
      Neurofilament light protein and glial fibrillary acidic protein as biological markers in MS.
      ). However, no evident information benefit was found versus NfL measured in serum. In the near future, also serum data on GFAP levels will become available via the SIMOA technique.
      Chitinase 3-like I (CHI3L1) protein, which is secreted by activated macrophages, showed elevated levels in the CSF of patients with progressive MS in a moderate-sized cohort study (
      • Cantó E
      • et al.
      Chitinase 3-like 1: prognostic biomarker in clinically isolated syndromes.
      ). Yet, CHI3L1, which can also be measured in serum, may prove useful as a marker of innate immune activation, a pathological hallmark of progressive MS. A recent article describes the combined elevation of CHI3L1 and NfL in CSF preceding diagnosis of clinical progression in RRMS patients, potentially identifying a subset of RRMS patients that may benefit from timely intervention (
      • Gil-Perotin S
      • et al.
      Combined cerebrospinal fluid neurofilament light chain protein and chitinase-3 like-1 levels in defining disease course and prognosis in multiple sclerosis.
      ).
      While a range of interesting biomarkers with promising data are under investigation, it should be noted that any predictive potential has essentially been shown on the population level rather than in individual patients. Thus, their usefulness for routine clinical purposes, particularly in transitional MS, remains to be established.

      4.5 Retinal optic coherence tomography

      Retinal optic coherence tomography (OCT) provides a simple noninvasive diagnostic procedure to analyze axonal and neuronal degeneration (
      • Petzold A
      • et al.
      Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis.
      ). Recent studies have reproducibly shown on a group level that the peripapillary retinal nerve fiber layer (pRNFL) thickness (a measure of axonal degeneration) in eyes without optic neuritis correlates with MS disease duration, EDSS score, brain atrophy and cognitive impairment, while the combined ganglion cell inner plexiform layer (GCIPL) thickness (a measure of neuronal degeneration) correlates with EDSS and progression of disability (
      • Petzold A
      • et al.
      Retinal layer segmentation in multiple sclerosis: a systematic review and meta-analysis.
      ).
      MS subtypes may be discriminated by pRNFL thickness in eyes without prior optic neuritis, which tends to be more strongly reduced in patients with progressive MS. This finding may indicate that axonal loss is a more prominent feature of progressive versus relapsing MS (
      • Bjartmar C
      • Trapp BD.
      Axonal degeneration and progressive neurologic disability in multiple sclerosis.
      ). Moreover, optic neuritis-independent pRNFL and GCIPL thinning are prognostic markers for future EDSS progression (
      • Martinez-Lapiscina EH
      • et al.
      Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study.
      ,
      • Knier B
      • et al.
      Association of retinal architecture, intrathecal immunity, and clinical course in multiple sclerosis.
      ,
      • Zimmermann HG
      • et al.
      Association of retinal ganglion cell layer thickness with future disease activity in patients with clinically isolated syndrome.
      ). In a recent study in patients with progressive MS, pRNFL was thinner in SPMS vs. PPMS. pRNFL evolution correlated with EDSS, and similar results were obtained for GCIPL
      • Guerrieri S
      • et al.
      Optical coherence tomography and visual evoked potentials in progressive multiple sclerosis..
      These results suggest a stronger involvement of the visual system in SPMS versus PPMS, while neurodegeneration appears to occur at the same rate in SPMS and PPMS.
      The IMSVISUAL consortium investigated the potential of pRNFL thickness as a biomarker of disease progression in a large multicenter cohort (
      • Martinez-Lapiscina EH
      • et al.
      Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study.
      ). In patients with a pRNFL thickness of ≤88 μm the risk of disability worsening during 1-3 years of follow-up was doubled, with a further risk increase in the fourth and fifth year. In a cohort of early RRMS patients, those with baseline GCIPL volume of <2 mm3 in the absence of optic neuritis had a more than six-fold increased risk of EDSS progression in the following three years (
      • Knier B
      • et al.
      Association of retinal architecture, intrathecal immunity, and clinical course in multiple sclerosis.
      ). Since the predictive value of OCT has only been shown on the population and not on the individual level, the usefulness for routine clinical purposes, particularly in transitional MS, remains to be established.

      5. Disease-modifying therapy to prevent progression

      5.1 Are immunotherapies for the transitional phase of MS feasible?

      The primary goal of any proposed treatment for patients in the transitional phase, is preventing, delaying or at least slowing the accumulation of disability. However, pathophysiological and clinical findings support the notion that the disease process becomes gradually less amenable to immunomodulatory drugs because of (i) the declining contribution of peripheral mechanisms of immune cell activation, (ii) the decrease of immune cell migration to the CNS, (iii) formation of lymphoid aggregates in the meninges, (iv) chronic microglia activation, and (v) accumulation of irreversible neurodegeneration.
      Neurologists tend to continue ongoing immune therapies into the perceived transitional phase even though the relative efficacy of the available drugs has not been adequately studied in this stage and the risk-benefit ratio becomes less favorable. It has been shown that higher-efficacy immunotherapies (natalizumab, fingolimod, dimethyl fumarate, alemtuzumab, cladribine, rituximab and mitoxantrone) reduce the risk of disability outcomes in the EDSS 3-6, 4-6 and 6-6.5 epochs compared to lower-efficacy therapies or no therapy (
      • Lizak N
      • et al.
      Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis.
      ). Interestingly these immunotherapies slowed progression also in patients with few relapses (median: 0 relapses in the 6-6.5 epoch), which gives a rationale for immunomodulation in transitional MS. Randomized controlled trials of immunotherapy specifically designed for the transitional phase of MS are currently lacking.

      5.2 Lessons from studies in established progressive MS

      Many studies that tested immune therapies in patients with definitive SPMS or PPMS failed to demonstrate clinically relevant efficacy. For most compounds, the observed effects are generally more pronounced in younger patients with remaining inflammatory disease activity as evidenced by contrast enhancing lesions on MRI or superimposed relapse activity (for overview on trials performed for individual substances, see Table 1).
      Table 1Designs and results of placebo-controlled therapeutic studies in patients with progressive MS.
      DrugConditionMain clinical resultTrialsLicensing status in progressive MS (EU)
      Glatiramer acetateSPMSTrend to reduction of disability progressionPhase III PROMiSe (
      • Wolinsky JS
      PROMiSe trial study group. The PROMiSe trial: baseline data review and progress report.
      )
      Not licensed
      NatalizumabSPMSNo reducedeed risk of EDSS and multicomponent progression Reduced 9HPT progressionPhase III ASCEND (
      • Kapoor R
      • et al.
      Effect of natalizumab on disease progression in secondary progressive multiple sclerosis (ASCEND): a phase 3, randomised, double-blind, placebo-controlled trial with an open-label extension.
      )
      Not licensed
      Interferon beta-1a/-1bSPMSTime to progression:

      3 studies negative, 2 positive
      Phase III

      European IFNB

      North-American IFNB

      SPECTRIMS (
      Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-Beta-1a in MS (SPECTRIMS) Study Group
      Randomized controlled trial of interferon- beta-1a in secondary progressive MS: clinical results.
      )

      IMPACT

      NORDIC
      Approved for SPMS with relapses
      MitoxantroneSPMS

      PMS
      Reduction of disability progression

      Improvement in composite endpoint (5 clinical measures incl. EDSS, ambulation index, time to first treated relapse)
      Phase III

      MITOX

      MIMS
      Approved for highly active RRMS associated with rapidly evolving disability, in patients for whom no alternative treatments are available
      FingolimodPPMSNo reduced risk of disability progressionPhase III

      INFORMS (
      • Lublin F
      • et al.
      Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial [published correction appears in Lancet. 2017 Jan 21;389(10066):254].
      )
      Not licensed
      OcrelizumabPPMSReduced risk of disability progressionPhase III

      ORATORIO (
      • Montalban X
      • et al.
      Ocrelizumab versus placebo in primary progressive multiple sclerosis.
      )
      Approved for PPMS with signs of inflammatory activity
      SiponimodSPMSReduced risk of disability progressionPhase III

      EXPAND (
      • Kappos L
      • et al.
      Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study [published correction appears in Lancet. 2018 Nov 17;392(10160):2170].
      )
      Approved for SPMS with signs of inflammatory activity
      CladribineRMSReduced risk of disability progressionPhase III

      CLARITY (
      • Cook S
      • et al.
      Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.
      )

      Approved for relapsing forms of MS with signs of inflammatory activity
      OpicinumabRRMS, SPMSPrimary endpoint missed (multicomponent endpoint)Phase II

      SYNERGY (
      • Cadavid D
      • et al.
      Safety and efficacy of opicinumab in patients with relapsing multiple sclerosis (SYNERGY): a randomised, placebo-controlled, phase 2 trial.
      )
      Phase III trial ongoing
      IbudilastPPMS, SPMSMRI: reduced loss of brain parenchymal fractionPhase II (
      • Fox RJ
      • et al.
      Phase 2 Trial of Ibudilast in progressive multiple sclerosis.
      )
      Phase III trial ongoing
      Alpha lipoic acidSPMSReduced loss of brain volumePhase II (
      • Spain R
      • et al.
      Lipoic acid in secondary progressive MS. A randomized controlled pilot trial.
      )
      Phase II trial ongoing
      Simvastatin

      SPMSImproved SF-36 physical componentPhase II

      MS-STAT (
      • Chan D
      • et al.
      Effect of high-dose simvastatin on cognitive, neuropsychiatric, and health-related quality-of-life measures in secondary progressive multiple sclerosis: secondary analyses from the MS-STAT randomised, placebo-controlled trial.
      )
      Not licensed
      As a common feature, these studies used time-to-event endpoints as their primary efficacy criteria, facilitating the detection of significant differences between treatment arms. However, the more meaningful question of the magnitude of long-term benefits achieved by these therapies remains to be answered. This may be achieved post hoc by responder analyses or by using continuous quantitative measures.
      The absent or at best moderate effects of currently available therapies tested for progressive MS may indicate that patients were included too late in the process of transition to SPMS. This notion support efforts to (i) more timely identify patients at risk of progression, and (ii) investigate novel promising therapies in patients who are in the transitional phase before SPMS is unequivocally reached.

      6. Proposed patient characteristics and endpoints of a prospective study in transitional MS

      As transitional MS is not a sufficiently defined entity, an interventional study aiming specifically at this population appears currently unfeasible. A prospective observational clinical study should aim at gathering data that allow a more thorough characterization of transitional MS and estimate treatment effects of potentially promising therapies. The selection of patients eligible should aim at the exclusion of patients with early MS and pure RRMS on the one hand, and established progressive MS on the other. Criteria and design for a putative study in a transitional MS are summarized in Table 2.
      Table 2Criteria and design for a putative prospective observational study in patients with transitional MS.
      Patient baseline characteristics
      MS disease duration≥ 4 years
      Number of previous relapses≥ 2
      EDSS score3.0 to 5.0
      Relapse-independent increase of disabilityEDSS increment of ≥0.5 points over the previous year or ≥1 point over the previous 2 years; both with confirmation after ≥ 3 months
      Radiographic characteristics≥1 of the following: ≥1 cortical lesion(s), evidence of cortical atrophy and/or smoldering lesions
      Disease activity during previous 2 years≥ 1 clinical relapse or ≥ 1 new or enlarging T2 lesion on MRI
      Study procedures
      Duration of follow-up≥ 3 years
      Timing of clinical visitsAt baseline, every 6 months and as clinically appropriate
      Parameters to be documented at study visits
      Performed at baseline, every 6 months and as clinically appropriate.
      MS treatment(s)Type, dosage, timing, duration
      Disability statusClinician global impression (CGI)

      Overall disability (EDSS)

      Hand-arm function (9HPT)

      Walking ability (T25FW, 2MWT, TUG)

      Cognition (SDMT, BVMT-R)

      Vision (LCSLC)
      Neuropsychiatric aspects and quality of lifeFatigue (FSMC)

      Depression (HADS)

      MS specific quality of life (MSIS-29)

      General quality of life (SF-36)
      Brain MR imagingT2 hyperintense lesions

      Gadolinium-enhancing lesions

      T1 hypointense lesions

      Smoldering lesions

      Total brain volume

      Cortical volume

      Gray matter volume

      (cortical/subcortical)

      Connectivity parameters
      Retinal OCTpRNFL

      GCIPL
      Molecular biomarkers in serumNfL

      CHI3L1

      GFAP
      1 Performed at baseline, every 6 months and as clinically appropriate.

      7. Conclusion

      While a range of drugs is available that quite effectively control the types of MS dominated by relapse activity, halting MS disability progression over the long-term disease course is the next challenge in MS therapy. So far, therapeutic trials in patients with established SPMS have shown disappointing or at best modest benefits. Therefore, preventing or delaying the conversion to SPMS during the transitional phase appears a worthwhile approach. Due to a different preponderance of immune-mediated mechanisms, study concepts involving immunotherapies should capture patients early in the transition.

      Declaration of Competing Interest

      IK received compensation for activities with Alexion, Bayer, Biogen, Chugai, Celgene, IQVIA, Merck, Mylan, Novartis, Sanofi Genzyme, Roche; as well as research support from Chugai and Diamed.
      IA received received compensation for activities with Roche, Alexion, Santhera as well as research support from Diamed.
      JH reports a grant for OCT research from the Friedrich-Baur-Stiftung and Merck, personal fees and non-financial support from Merck, Alexion, Novartis, Roche, Santhera, Biogen, Heidelberg Engineering, Sanofi Genzyme and non-financial support of the Guthy-Jackson Charitable Foundation, all outside the submitted work. JH is (partially) funded by the German Federal Ministry of Education and Research (Grant Numbers 01ZZ1603[A-D] and 01ZZ1804[A-H] (DIFUTURE)).
      CL received a research grant by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis (KKNMS), grant no.01GI1601I, received consulting and speaker's honoraria from Biogen Idec, Bayer Schering, Daiichi Sanykyo, Merck, Novartis, Sanofi, Genzyme and TEVA.
      IKP received honoraria for speaking at scientific meetings, serving at scientific advisory boards and consulting activities from Adamas Pharma, Almirall, Bayer, Biogen, Celgene, Desitin, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. She received research support from the German MS Society, Celgene, Novartis, Roche and Teva.
      CS received compensation for activities with Bayer, Biogen, Merck, Novartis and Roche as well as research support from Novartis and MedDay.
      RAL received compensation for activities with Bayer, Biogen, Celgene, Merck, Novartis, Sanofi Genzyme, and Roche; as well as research support from Biogen, Merck and Novartis.

      Financial support

      Development of this manuscript was supported by Merck.

      Author contributions

      All authors have read, commented on the manuscript and approved the final manuscript.

      Acknowledgments

      Medical writing and editorial support, under the direction of the authors, was provided by Markus Fischer, PhD (Fischer BioMedical Wissenschaftskommunikation, Germany) funded by Merck, according to Good Publication Practice guidelines. The authors were responsible for all content and editorial decisions, and received no honoraria related to the development of this publication.

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