SPMS pathogenesis and treatment


ECTRIMS Special Report

Secondary-progressive multiple sclerosis (SPMS) was an area of special interest at the recent European Committee for Treatment and Research in MS (ECTRIMS) annual meeting, held October 26-28 in Amsterdam, The Netherlands.

An analysis of European databases (N=10,238) underscored the importance of early diagnosis and treatment of SPMS (Pontieri et al. ECTRIMS 2022; O065). The study showed that treatment slowed early EDSS worsening in SPMS patients. However, a treatment benefit was not seen in the latter stages, presumably due to aging and the increasing predominance of neurodegenerative processes.

While neuroinflammation and neurodegeneration are seen as sequential processes that act somewhat independently, this view was challenged by a novel analysis of neurofilament-light chain (NfL) levels in ocrelizumab trials (Bar-Or et al. ECTRIMS 2022; P256). As a result of anti-inflammatory treatment effects, NfL, a marker of neuroaxonal damage, was no longer prognostic of confirmed disability progression (CDP). However, NfL levels after 48 weeks of treatment were prognostic of the long-term risk of CDP, suggesting that there is ongoing subclinical inflammation and neuroaxonal damage even in the absence of relapses and focal inflammatory lesions.

This observation may help to explain the findings of recent siponimod studies. A database analysis included patients with active and non-active SPMS (N=632, mean age 52.4 years), and showed that EDSS scores were stable or improved in 91% at two years (de las Heras et al. ECTRIMS 2022; P325). Similarly, in the real-world AMASIA study (N=584), EDSS scores were stable after one year of treatment with siponimod (Hoffmann et al. ECTRIMS 2022; P448). This effect was seen for all prior-DMT subgroups and across all age groups. For example, in the subgroup aged >50 years, the mean change from baseline was 0.1 EDSS points at one year (5.3 to 5.4). In the EXPAND extension study, the impact of siponimod on CDP risk was shown to be sustained for up to five years (Cree et al. Mult Scler 2022;28:1591-1605).

Also noteworthy was a real-world study in Germany (Regner-Nelke et al. Neurol Res Pract 2022;4:55). The cohort comprised 108 SPMS patients with a similar age at baseline (53.4 years) as the database analysis but with a longer duration of MS (mean 17.8 years) and higher baseline EDSS score (median 6.0). At 1 year, 64.8% had no change in EDSS score, of whom 21.4% showed disability improvement. The study also reported that in the subgroup with cognitive testing, SDMT and PASAT scores remained stable.

Cognitive outcomes from the phase IIIb EXCHANGE study were also reported at ECTRIMS (Fox et al. ECTRIMS 2022; EP1146). The study enrolled 163 patients (mean age 46.6 years) who were transitioning to SPMS. After initiating siponimod, there was a mean improvement in Processing Speed Test scores from baseline to day 168, although it should be noted that some of the improvement may be attributable to a practice effect. Clinical improvements were associated with increases in patient-reported satisfaction scores for treatment effectiveness (Cohan et al. ECTRIMS 2022; EP1145).

The benefits of S1PR modulators like siponimod are largely attributed to anti-inflammatory activity, including limiting the expression of pro-inflammatory Th17 cells (Raveney et al. ECTRIMS 2022; EP0939). However, several studies at ECTRIMS highlighted that these agents may also have a range of effects within the CNS.

Siponimod was shown to reduce the expression of pro-inflammatory markers in microglia in an animal model (Heitmann et al. ECTRIMS 2022; P132). A separate animal study demonstrated that siponimod downregulated MHC class II expression in microglia; this may indicate a reduced microglial response to pro-inflammatory CD4+ T cells (Husseini et al. ECTRIMS 2022; P318). A third animal study reported that siponimod exerted direct effects on oligodendrocytes that resulted in a reduction in demyelination and axonal injury; this protective effect was shown to be independent of the drug’s effects on T and B cells and appeared to be S1P5-dependent (Kipp et al. ECTRIMS 2022; P317; published as Behrangi et al. Proc Natl Acad Sci USA 2022;119:e2204509119).

The clinical impact of these potential CNS effects was reported in a recent analysis from the EXPAND trial (Arnold et al. Mult Scler 2022;28:1526-1540). The study found that siponimod reduced whole-brain and grey-matter atrophy at 1 and 2 years. The mean relative reduction in whole-brain atrophy with siponimod versus placebo was 49% at year 1 (-0.23 vs. -0.45), and 31% at year 2 (-0.62 vs. -0.92). Relative reduction in cortical GM volume loss with siponimod versus placebo was 102% at 1 year (+0.01 vs. -0.60), and 63% at 2 years (-0.39 vs. -1.04). There were also significant reductions in thalamic volume loss at both time points (50% year 1, 42% at year 2).

Moreover, siponimod improved brain tissue integrity and remyelination as shown by increases in magnetization transfer imaging (MTR); MTR was higher than baseline values at 2 years with siponimod versus placebo in normal-appearing brain tissue (+0.001 vs. -0.055), cortical GM (+0.008 vs. -0.046) and normal-appearing white matter (+0.010 vs. -0.056). The authors concluded that these findings are compatible with a direct effect of siponimod on neurodegenerative processes in the CNS.

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