MULTIPLE SCLEROSIS IN 2018

Targeting progression in multiple sclerosis — an update

In 2018, the distinguishing pathological features of white matter lesions in patients with progressive multiple sclerosis (MS) were refined, and serological and MRI biomarkers of clinical worsening and evolution to progressive MS were identified. We also saw therapeutic advances in progressive MS with the emergence of new neuroprotective strategies and putative markers of neurodegeneration.

Key advances

  • A pathological study showed that substantial white matter lesion activity, in the form of mixed active–inactive, smouldering and slowly expanding lesions, persists and correlates with disease severity in patients with long-standing progressive multiple sclerosis (MS)1.

  • Levels of serum neurofilament light chain, a marker of neuroaxonal damage, were found to be higher in progressive MS than in relapsing MS, to correlate with current and future clinical disability, and to predict accelerated brain and spinal cord atrophy4.

  • In patients with relapse-onset MS, a high cortical lesion count at disease onset predicted conversion to secondary progressive MS5, and in patients with primary progressive MS, baseline grey matter damage was predictive of clinical worsening after 15 years6.

  • Integration of MRI measures into the clinical evaluation of patients with MS would allow earlier prognostication of long-term clinical outcomes6, leading to possible improvements in treatment decision-making and optimization of overall costs.

  • In a phase II trial in patients with progressive MS, ibudilast treatment was associated with slower progression of brain atrophy but also had some adverse effects10; this study provides the impetus for future trials of neuroprotection in progressive MS.

Identification of the mechanisms associated with disease progression and improved prediction of clinical evolution are among the main unmet needs in multiple sclerosis (MS) research. In 2018, we witnessed several major advances in understanding the progression of MS, with new findings on pathology, biomarkers, prognosis and treatment.

A pathological study examined 7,562 lesions from 182 clinically well-documented brain donors with relatively long disease duration (mean 29 years): 56 with primary progressive MS (PPMS), 100 with secondary progressive MS (SPMS), 14 with relapsing–remitting MS (RRMS) and 12 with an undetermined clinical course1. The researchers analysed the heterogeneity of lesion activity and its relationship to disease course and severity. Compared with patients who had RRMS, those with progressive MS had a higher lesion load and a higher proportion of mixed active–inactive lesions, which helped to explain their greater disease severity (that is, a shorter time to reach an Expanded Disability Status Scale (EDSS) score of 6).

The demonstration of substantial inflammatory and demyelinating lesion activity even after long-standing disease in patients with progressive MS highlights the need for in vivo biomarkers that can be used to identify these types of lesions, as they might aid prognostication and provide a target for future treatments. These mixed active–inactive lesions include the ‘smouldering’ and ‘slowly expanding’ lesions with borders of ongoing demyelination, axonal injury, microglial activation and inflammatory activity that were described in previous pathological studies2. The current state of knowledge about these lesions includes their frequency in progressive MS phenotypes, their association with more severe disease status and their increased prevalence with age2 (peaking at ~47 years), suggesting that their measurement could aid identification of patients who are transitioning from relapsing to progressive MS. Consistent with the idea that remyelination capacity in the brain decreases with age and disease duration, patients with progressive MS (in particular, those with PPMS) had a lower proportion of remyelinated lesions1 than did patients with RRMS. This finding should be taken into consideration when planning trials of remyelinating therapies in patients with progressive MS.

Serum neurofilament light chain (sNfL) has been proposed as a biomarker of neuroaxonal injury in several diseases, including MS3. In 2018, a study of 259 patients with MS and 259 healthy controls with 6.5-year clinical and MRI follow-up confirmed that quantification of sNfL in MS is clinically informative4. In particular, sNfL levels were significantly higher in progressive than in relapsing MS. Furthermore, sNfL levels correlated with the severity of disability and, together with T2 lesion volume, predicted EDSS worsening in the subsequent year. An analysis of the relationship between sNfL levels and several MRI measures showed that sNfL levels are influenced by inflammatory activity, as reflected in enhancing lesions, new T2 lesions and T2 lesion volume. Most interestingly, high sNfL levels predicted accelerated atrophy of the brain and spinal cord, even in the absence of inflammatory activity. Overall, these results suggest a link between elevated sNfL levels and an increased risk of clinical deterioration, as a consequence of neurodegeneration, over the medium term. The practical implications of these findings might include the use of more aggressive therapies or a rapid switch to a different treatment in patients with high sNfL levels.

“results suggest a link between elevated sNfL levels and an increased risk of clinical deterioration”

Important advances in understanding progression have also been made by applying MRI in long-term prognostic studies of relapse-onset5 MS and PPMS6. A clinical and MRI follow-up study assessed 219 patients with RRMS at clinical onset and, on average, 7.9 years later5. The study demonstrated that extensive cortical damage at disease onset and during the first 2 years of disease monitoring, as assessed by the number and volume of cortical lesions and cortical atrophy, was associated with a higher relapse rate during the study and more rapid onset of a progressive phase. Most importantly, a high cortical lesion count at disease onset predicted conversion to SPMS, and the number of lesions correlated with the speed of conversion (on average 4 years earlier in patients with ≥7 cortical lesions than in those with 1–3 lesions). None of the patients without cortical lesions at baseline evolved to SPMS. Combined with data from patients with clinically isolated syndromes, which suggest that cortical lesions are specific to MS and are associated with the accrual of more severe disability7, these findings support the development of standardized MRI sequences for the assessment of cortical lesions in clinical practice.

“a high cortical lesion count at disease onset predicted conversion to SPMS”

The importance of grey matter involvement for long-term prognosis was also confirmed by a 15-year follow-up study of 49 patients with PPMS6. An MRI model that included diffusion tensor measures of grey matter damage at baseline and measures of neurodegeneration — namely, formation of new T1-hypointense lesions and changes in brain volume — during the first 15 months of follow-up allowed the prediction of long-term disability in 77.6% of the patients. In contrast to previous studies of PPMS with a shorter follow-up8 (5 years), spinal cord atrophy was not associated with clinical deterioration, suggesting that the processes leading to accrual of disability evolve over time.

Integration of the aforementioned MRI model with clinical measures allowed patients with PPMS who were at risk of long-term clinical worsening to be identified 4 years earlier than was possible with clinical assessment alone6. Early prognostication is of paramount importance now that treatments for progressive MS, such as ocrelizumab and siponimod9, are emerging. A trial published in 2018 indicated that ibudilast, an inhibitor of macrophage migration factor, several cyclic nucleotide phosphodiesterases and Toll-like receptor 4, has a neuroprotective effect in progressive MS10. In this phase II, placebo-controlled, randomized trial involving 255 patients with PPMS or SPMS, progression of brain atrophy over a 2-year period was 48% slower in patients treated with ibudilast than in those treated with placebo, although the drug was associated with increased rates of gastrointestinal adverse effects, headache and depression. Whether this effect on MRI measures of neurodegeneration will translate into clinical benefits over the long term is currently unknown.

“Early prognostication is of paramount importance now that treatments for progressive MS … are emerging”

In conclusion, 2018 has seen unprecedented advances in our understanding of progression in MS, resulting from the identification of stage-specific pathological processes, in addition to serum and MRI biomarkers. We now need to take steps to move these measures closer towards clinical use in order to improve patient management.

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Correspondence to Maria A. Rocca.

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M.A.R. has received speaker’s honoraria from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva, Merck Serono and Roche and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. M.F. has received compensation for consulting services and/or speaking activities from Biogen Idec, Merck Serono, Novartis and Teva Pharmaceutical Industries, and receives research support from Biogen Idec, Merck Serono, Novartis, Teva Pharmaceutical Industries, Roche, the Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla and ARiSLA (Fondazione Italiana di Ricerca per la SLA).

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Rocca, M.A., Filippi, M. Targeting progression in multiple sclerosis — an update. Nat Rev Neurol 15, 62–64 (2019). https://doi.org/10.1038/s41582-018-0127-3

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