Multiple sclerosis (MS) historically has been defined by its clinical presentation and overt phenomenologic features. The ability to characterize any given disease properly is limited by the observational power of the scientific tools and methods available. Since the early stages of MS characterization, both acute neurologic changes (relapses) and slow worsening (progression) were recognized, and resulted in the clinical phenotypes we continue to use. Understanding of the pathophysiologic drivers of acute and progressive accumulation of MS disability has evolved. This has led to a biologically-based definition of disease progression which enables clinicians to tailor interventions in more effective and individualized ways by using biologically driven markers.1
In MS, clinical relapses and new or enhancing MRI lesions in the central nervous system (CNS) indicate acute inflammatory activity driven by autoreactive cells belonging to the peripheral adaptive immune system, whereas slow disease progression is believed to be secondary to a combination of persistent compartmentalized inflammation (most likely driven by myeloid cells of the innate immune system) and neurodegeneration in the CNS.2 Disability accumulation results from a combination of these processes in the form of incomplete recovery from an acute immune-mediated inflammatory event known as “relapse-associated worsening,” and functional decline resulting from persistent CNS inflammation and neurodegeneration is known as “smoldering-associated worsening,” although this term requires more precise characterization (see Figure 1 for a summary of the clinical manifestations of relapse-associated and smoldering-associated worsening). Although both processes contribute to the accumulation of physical and cognitive disability, it is now recognized that disease progression, and not acute inflammation, is the main driver of disability. Clinical worsening that occurs in those who are free of acute inflammatory activity is referred to as progression independent of relapse activity (PIRA).3 The concept of PIRA encapsulates progressive disease which occurs secondary to pathobiologic mechanisms other than acute inflammation. As such, characterization of true PIRA requires the use of surrogate markers of acute inflammation (eg, new or enhancing MRI activity) in addition to clinical relapses.
The progressive mechanism of disability accumulation is present from early stages of the disease and becomes more prominent as it reaches thresholds beyond the ability of biologic compensatory mechanisms that preserve or restore physical and cognitive functions. Research which elucidates the CNS-compartmentalized mechanisms that contribute to slower disease progression should lead to new therapeutic options for individuals with progressive MS.
The Challenge
Recent data support the recognition of MS as a disease spectrum with different mechanistic drivers that happen simultaneously—not sequentially—with variable representation in any given person.1,4 The clinical course and different phenotypes of MS depend on multiple conditioning factors, including the degree, location, and extent of acute and chronic inflammation and demyelination; secondary axonal and neuronal degeneration; mitochondrial injury and dysfunction; oxidative stress; remyelination failure; biological sex; race; genetics; comorbidities; health behaviors; social determinants of health; and timing, efficacy and persistence of disease modifying therapy use (see Figure 2).5 The variability of disease activity among individuals with MS emphasizes the importance of early identification of disability progression for the proper management of individuals with MS (eg, selection of appropriate treatments that target the processes responsible for progressive MS).
Clinical relapses and new T2 and enhancing T1 MRI lesions have been the dominant primary outcomes in MS clinical trials because they are identifiable by patients and clinicians. Consequently, the progression of disability has not been fully represented in MS clinical trials. Sustained disability accumulation at 3 and 6 months has been used in many studies as a marker of progression. This outcome is commonly based on the Expanded Disability Status Scale (EDSS), a scoring tool that has several shortcomings when striving for a comprehensive assessment of worsening disability. For example, vision, cognition, and upper-limb function are underrepresented. In addition, ambulation function is the main factor determining the score for values >4, resulting in the pyramidal system being overrepresented. Beyond these limitations, there are well-documented interrater and intrarater discrepancies.6
More useful disability outcome measures are needed to address an array of obstacles, including the heterogeneous manifestations of MS; the slow accrual of disability; the subclinical nature of early worsening; the confounding of functional changes induced by other factors,6 such as aging and comorbidities; the subjectivity of clinical evaluations; and the temporal gap between assessments. In addition, these outcome measures should consider the need for development of precision medicine in MS, whereby the individual’s unique genetic, environmental, proteomic, immunologic, neuroanatomic, and pathologic factors4,7 dictate the implementation of therapeutic strategies.
What Can Be Measured
It is paramount to increase the sensitivity of the means used in the identification of actionable changes. More likely than not, there will be no single test that will be able to assess the complex mechanisms and interactions resulting in progression of disability in MS. Achieving this goal requires continued development of tools in 3 categories that will eventually result in a singular individualized scoring reflective of the trajectory of any given case. Those categories include functional, anatomic, and biologic realms.8
Functional Assessment
Instruments measuring function evaluate motor, ambulation, and cognitive performance, and can leverage patient-reported outcomes to assess emotional status, quality of life, and wellbeing. An important feature of these assessments is the ease with which they can be implemented in clinical practice. Several of these assessments can be integrated into a single device for ease of administration, such as the Multiple Sclerosis Performance Test, which is tablet-based.9 To address some of the limitations associated with the EDSS, the Multiple Sclerosis Functional Composite introduced multidimensionality in a 3-component scale, including the Timed 25-Foot Walk Test for leg function and ambulation, the 9-Hole Peg Test for arm and hand function, and the Paced Auditory Serial Addition Test for cognitive function (see article by Mahmoudi et al on Treatment Response Assessment Tools for Relapsing Multiple Sclerosis elsewhere in this issue for more details regarding these assessment tools).
Early and frequent assessments can identify a functional trend, but these assessments can miss changes that occur between clinical visits as they are performed cross-sectionally. Digital technologies have the potential to monitor changes that occur between clinical visits, especially with the use of wearable devices that record multiple parameters on a continuous basis. Continuous assessment in the individual’s environment offers a more accurate evaluation of their specific challenges. In addition, many patient-reported outcomes can be obtained asynchronously through smart phones, tablets, or computers.
Anatomic Assessment
The ability to image the CNS and identify pathologic changes with MRI has improved the clinician’s ability to diagnose MS and assess the efficacy of MS treatments. The presence of new T2- and T1-enhancing lesions have been commonly used as an outcome in clinical trials. Those abnormalities represent acute focal inflammatory activity that correlates with the phenotypic relapsing form of the disease. Although baseline lesion burden, localization, and postcontrast enhancement are associated with later stages of progressive MS,10 they are difficult to quantify and have limited applicability. Volumetric analysis of both whole and regional brain atrophy correlates with worsening of motor and cognitive functions. There is growing interest in the use of thalamic and upper cervical cord measurements, as these distinct localized structures are more readily quantifiable in a reproducible manner.
There are specific MRI metrics that correlate with slow clinical worsening. Chronic active lesions, which can be identified through histopathologic studies and represent ongoing compartmentalized inflammation that persists once acute white matter inflammation resolves, are increasingly correlated with disease progression.11 These chronic active lesions can now be identified through MRI and positron emission tomography (PET) techniques, and include paramagnetic rim lesions (PRLs) in susceptibility-sensitive MRI sequences, slowly expanding lesions (SELs) on T1- and T2-weighted MRI sequences, and translocator protein (TSPO)–positive lesions on PET.12 PRLs have been identified in all MS clinical phenotypes, including very early stages, such as radiologically isolated syndrome, and are associated with higher physical and cognitive disability in cross-sectional studies. Longitudinal studies have found a predictive value of baseline number of PRLs for worsening disability and conversion to secondary progressive MS.13 SELs represent areas of preexisting T2 lesions that exhibit slow, constant, gradual, and radial expansion over time.12 Larger SEL volumes and higher proportions of T2 lesions identified as SELs predict disability worsening. PET has been used to demonstrate increased innate immune activity in the brain of individuals with MS when using ligands that bind to the 18-kDa TSPO, which is expressed on the outer mitochondria membrane of activated myeloid cells. PRLs have the most robust association with histopathologic changes.12
Optical coherence tomography (OCT) can also be leveraged to assess neurodegeneration in MS. Independent of the direct neuronal loss secondary to optic neuritis, the development of retinal atrophy correlates with total brain volume. Due to the unmyelinated nature of the retinal neurons, it is well suited for the identification of neuroaxonal degeneration without the confounding component of loss of myelin and remyelination.13 Using OCT to assess the peripapillary retinal nerve fiber layer (pRNFL) could be an indicator of subsequent worsening of neurologic disability, though additional research is needed to assess the correlation between OCT measurements and disease progression.14
Fluid Biomarkers
The use of proteomic indicators of pathobiologic processes may contribute to the clinician’s ability to identify specific factors causing disease progression in individuals with MS. Ideally, proteomic indicators should correlate with neuronal and myelin injury and repair, as well as peripheral and compartmentalized immune disease–specific activity. Neurofilament light (NfL) has been identified as a biomarker of MS because it reflects neuroaxonal loss—a central process in the pathobiology of MS. Neurofilaments are structural components of the neuronal cytoskeleton and are released during injury or disease, including active focal inflammation in MS. As such, they are a better indicator of acute inflammation associated with relapses and new MRI lesions and not necessarily of the lower-grade inflammation and neurodegeneration responsible for progressive disability, although persistence of NfL levels above normal values despite effective disease-modifying therapy use can represent subclinical disease activity.15,16 Better prediction of long-term outcomes can be achieved by combining NfL levels with other potential biomarkers that represent pathobiologic processes involved in MS disease progression, such as glial fibrillary acidic protein (GFAP) which is an intermediate filament of astrocytes. These astrocytes are damaged when innate immune disease mechanisms within the CNS condition diffuse inflammation and neurodegeneration. This is manifested clinically by disease progression, and measuring GFAP can be a marker of this process. As such, GFAP has been identified as a potentially useful biomarker for future PIRA.17
Conclusion
Recognition of the prominent role of neurodegeneration and compartmentalized inflammation caused by CNS immune cells on disability accumulation in individuals with MS requires continued action on 3 fronts: development of novel therapeutic approaches targeting this pathologic mechanism, elucidation of the biology of disease progression, and implementation of outcome measures that are sensitive to the recognition and monitoring of this aspect of the disease. Continued advancement in functional, anatomic, and fluid biomarkers is necessary, and will result in improved care, timely optimization of therapies, and better long-term outcomes.
