A number of recent studies have provided important insights on the pathophysiology, clinical course and treatment of secondary-progressive multiple sclerosis (SPMS). SPMS is generally characterized as a progressive accumulation of disability after an initial relapsing course; further modifiers are active disease (relapses and/or new MRI lesions) with or without progression, not active with progression and not active and no progression (stable disease) (Lublin et al. Neurology 2014;83:278-286).
In clinical practice, a U.S. chart review reported that most neurologists diagnosed SPMS based on progressive disability accumulation independent of relapse activity, with disability progression confirmed at six months (Naismith et al. AAN 2020; abstract 007). MS specialists were more likely to characterize SPMS as active compared to general neurologists (73% vs. 59%).
The average age at onset is 45 years + 10 years, with the transition to SPMS typically lasting about five years (Coyle P. CMSC 2020). Risk factors for the development of SPMS include older age, longer disease duration, a more rapid disability trajectory and a greater number of relapses in the previous year (Fambiatos et al. Mult Scler 2020;26:79-90).
Ongoing disease activity is a common finding during the secondary-progressive phase and appears to have prognostic value. A Mayo Clinic analysis reported that 29.5% of SPMS patients continued to have relapses after progression onset (Paz Soldan et al. Neurology 2015;84:81-88). Of particular importance was that relapses after progression onset was an independent risk factor for reaching EDSS 6.0 (hazard ratio 1.37). The authors estimated that ongoing relapses after progressive MS onset shortened the time to EDSS 6.0 by two years.
During the course of SPMS, a recent finding is the development of focal white matter lesions that are not due to transmigration of inflammatory cells across the blood-brain barrier (Mahsa Dadar et al. Mult Scler 2020; epublished March 23, 2020). A three-year follow-up of 589 SPMS patients found that diffuse abnormal white matter consolidated into focal white matter lesions over time. An increasing focal white matter lesion volume was correlated with a worsening EDSS score. This suggests the need to target diffuse white matter abnormalities early in progression to slow the evolution of progressive tissue damage.
Siponimod, a sphingosine 1-phosphate receptor-1,5 modulator, was recently approved in Canada for the treatment of active SPMS based on the results of the EXPAND trial, which demonstrated a 21% reduction in 3-month confirmed disability progression with siponimod relative to placebo (Kappos et al. Lancet 2018;391:1263-1273). The drug sequesters pathogenic lymphocyte subsets in secondary lymphoid tissue. Siponimod has recently been shown to downregulate genes involved in T and B cell activation and receptor signalling, resulting in a reduction in CD4+ and CD8+ T cells and B cells, and enrichment of the regulatory T (Treg) and B (Breg) cell pool (Wu et al. JCI Insight 2020;5:e134251).
New data were presented at the European Academy of Neurology virtual congress. Siponimod crosses the blood-brain barrier (Bigaud et al. EAN 2020; EPR1152) and two analyses reported on the effect of the drug on CNS tissue. In the EXPAND MRI substudy, siponimod had a significant effect on the magnetization transfer ratio (MTR), a marker of myelin density, in normal-appearing white matter, with complete suppression of MTR decline at 24 months (Arnold et al. EAN 2020; EPR1147). Treatment was also associated with improvement in MTR recovery in new lesions; the authors noted that this finding was consistent with promotion of remyelination.
A separate analysis reported significant reductions with siponimod versus placebo in cortical grey-matter atrophy and thalamic atrophy at months 12 and 24. Benefits on GM and thalamic atrophy were also observed in the subgroups of patients aged >45 years (cGM 58% reduction, thalamic atrophy 31% reduction at month 24), higher EDSS score (EDSS >6) (64% and 43% reduction, respectively), non-active disease (71% and 58%, respectively) and prior DMT use (65% and 44%, respectively) (Vermersch et al. EAN 2020; EPR3098).
A post-hoc analysis of the EXPAND dataset examined treatment effects in the subgroup with active disease (n=779), defined as relapses in the two years prior to screening and/or one or more Gd+ lesions at baseline (Gold et al. EAN 2020; EPR2118). There was a significant reduction in time to 3-month and 6-month confirmed disability progression (31% and 37%, respectively) with siponimod versus placebo. Moreover, siponimod increased the chance of improved cognitive processing speed by 51% and reduced the risk of sustained cognitive worsening by 28%.
Conversely, siponimod also reduced the risk of disability progression in non-relapsing patients in the EXPAND cohort, according to an analysis presented at the Consortium of MS Clinics (CMSC) annual meeting (Cree et al. CMSC 2020; abstract DXT10). In the subgroup of patients who were relapse-free in the 1 year prior to entry, there was a 25% reduction in 6-month confirmed disability progression with siponimod versus placebo.
Also noteworthy were the results from the EXPAND extension study (Kappos et al. EAN 2020; abstract EPR2128). For patients on continuous siponimod, an estimated 59% had no 6-month confirmed disability worsening and 68% had no confirmed cognitive worsening on SDMT (>4 points) up to month 48. The risk of 6-month CDP was reduced 22% with continuous siponimod versus delayed treatment (placebo/siponimod arm). The authors concluded that the benefits of siponimod in slowing physical and cognitive impairment are sustained for up to five years.