Smouldering multiple sclerosis: the 'real MS'

Abstract

Using a philosophical approach or deductive reasoning, we challenge the dominant clinico-radiological worldview that defines multiple sclerosis (MS) as a focal inflammatory disease of the central nervous system (CNS). We provide a range of evidence to argue that the 'real MS' is in fact driven primarily by a smouldering pathological disease process. In natural history studies and clinical trials, relapses and focal activity revealed by magnetic resonance imaging (MRI) in MS patients on placebo or on disease-modifying therapies (DMTs) were found to be poor predictors of long-term disease evolution and were dissociated from disability outcomes. In addition, the progressive accumulation of disability in MS can occur independently of relapse activity from early in the disease course. This scenario is underpinned by a more diffuse smouldering pathological process that may affect the entire CNS. Many putative pathological drivers of smouldering MS can be potentially modified by specific therapeutic strategies, an approach that may have major implications for the management of MS patients. We hypothesise that therapeutically targeting a state of 'no evident inflammatory disease activity' (NEIDA) cannot sufficiently prevent disability accumulation in MS, meaning that treatment should also focus on other brain and spinal cord pathological processes contributing to the slow loss of neurological function. This should also be complemented with a holistic approach to the management of other systemic disease processes that have been shown to worsen MS outcomes.

Keywords: multiple sclerosis; progression independent of relapse activity; progressive multiple sclerosis; smouldering multiple sclerosis.

Figure 1.

Relapse-Associated Worsening (RAW) and Composite Progression Independent of Relapse Activity (PIRA) Definitions. This figure is based on Kappos et al. and is a schematic representation of RAW and PIRA, which are non-mutually exclusive drivers of confirmed disability accumulation (CDA) in both relapsing and progressive forms of MS. The baseline is the reference point for disability changes measured over time; in the context of clinical trials, this is the time of randomisation to study treatment, but in the context of the clinic, this would be the reference disability assessment visit from which subsequent changes are measured over time. The shaded areas represent the intervals around the neurological assessments that had to remain free of relapses to fulfil the criterion of independence from relapses (at initial event and confirmation points). Neurological assessments were scheduled to occur every 12 weeks, according to the protocol of the study; if a relapse occurred, there was one neurological assessment outside of the schedule, at a point corresponding to the leftmost point on the relapse triangle. EDSS, Expanded Disability Status Scale; IID, initially assessed increase of disability; MS, multiple sclerosis.

Figure 2.

Lublin 2013 multiple sclerosis phenotype descriptions for relapsing and progressive disease (based on Lublin et al.). *Activity determined by clinical relapses assessed at least annually and/or MRI activity (contrast-enhancing T1w lesions; new and/or unequivocally enlarging T2w lesions). ^#Progression measured by clinical evaluation, assessed at least annually. If assessments are not available, activity and progression are ‘indeterminate’. CIS, clinically isolated syndrome; d, days; PP, primary progressive; RRMS, relapsing-remitting multiple sclerosis; SP, secondary progressive; wk, weeks.

Figure 3.

The pathological drivers of smouldering MS. Apart from acute focal damage characterised by axonal transection and conduction block that occurs over days to weeks and causes relapse-associated worsening (RAW), there are delayed time-dependent processes that are responsible for smouldering MS. Demyelination and energy deficits are responsible for delayed worsening, which occurs over weeks to months. Whether this is dependent or independent of ongoing focal inflammation is a moot point. This is then followed by post-inflammatory neurodegenerative processes, which run their course over many years and include microglial and innate immune mediators, ongoing energy deficits, antibody-mediated damage, and possible viral infection. Finally, age-related neurodegenerative processes that are premature and accelerated are responsible for late-onset disability progression, which plays out over decades.

Figure 4.

Advanced MRI and PET imaging in smouldering MS. Exemplary paramagnetic hypointense rim lesion as shown by different advanced MRI maps: Quantitative Susceptibility Mapping (QSM) shows the characteristic paramagnetic rim, while 3D FLAIR and T1w MP2RAGE images show the characteristics of a destructive lesion. The Neurite Density Index (NDI) derived from the neurite orientation dispersion and density imaging (NODDI) model, along with the myelin water fraction (MWF) and qT1 image evidence a strong reduction in axonal density, myelin and overall microstructure, respectively. The image on the right visualises comprehensive TSPO-PET measurable microglial activity in focal lesional and perilesional areas in the brain of a 48-year-old female RRMS patient with an EDSS of 4.0 and disease duration of 12 years.

Figure 5.

Combination therapy trials and the holistic management of MS. In addition to effective anti-inflammatory therapies, add-on neuroprotective treatments to prevent further loss of damaged or vulnerable axons and remyelination and neurorestorative therapies are required to address the pathological drivers of smouldering MS. In parallel, a holistic approach to the management of MS is required to address factors that can affect brain health and potentially accelerate MS-related end-organ damage.