Sustained Immunotherapy May Improve Secondary Progressive MS Disability Outcomes

Nathaniel Lizak, MBBS, staff doctor, Alfred Health

Nathaniel Lizak, MBBS

The findings of an observational cohort study of 1621 patients with secondary progressive multiple sclerosis (SPMS) from the international MSBase registry suggest that sustained immunotherapy was associated with improved disability outcomes in patients with disease activity.

All told, 661 (40.8%) of the patients had experienced superimposed relapse during SPMS. Of those, patients who received disease-modifying therapies (DMTs) accounted for a greater percent of time with a reduced Multiple Sclerosis Severity Score (MSSS) progression slope during SPMS. Per each 25% increase in the proportion of time receiving treatment, low-efficacy therapies (β&thinsp;=&thinsp;−0.025; 95% CI, −0.039 to −0.012; P&thinsp;<&thinsp;.001), medium-efficacy therapies (β&thinsp;=&thinsp;−0.022; 95% CI, −0.044 to −0.001; P&thinsp;=&thinsp;.06), and high-efficacy therapies (β&thinsp;=&thinsp;−0.034; 95% CI, −0.056 to −0.013; P&thinsp;=&thinsp;.002) were all observed with reduced slopes.

“In this study, the rate of disability progression after the onset of SPMS was not associated with the early disease course and treatment decisions. Relapses during SPMS were associated with accelerated disability progression and represent an accessible treatment target,” the study authors, including Nathaniel Lizak, MBBS, staff doctor, Alfred Health, wrote. “The study’s results suggest that inflammatory disease activity remains a substantial yet modifiable component of SPMS.”

Of the 1621 total patients included, 1103 (68.0%) were female, and the mean age at MS onset was 33.9 years (SD, 10.6). The mean MSSS progression slope during SPMS was −0.02 points per year (standard deviation [SD], 0.36).

Patient demographic characteristics, early treatment exposure, and early relapses were all not observed to be associated with disability progression in patients with SPMS. There was a single exception—an association between older age at MS onset and lower MSSS progression slope in those with superimposed relapses (β&thinsp;=&thinsp;−0.003; 95% CI, −0.005 to −0.001; P&thinsp;=&thinsp;.003).

Additionally, Lizak et al. conducted a complementary analysis, observing MSSS trajectories while stratifying patients by the proportion of time patients received treatment in addition to therapy exposure. The MSSS at time of conversion was different between the groups and continued to diverge afterward. Those with high exposure to DMTs (>90%) was distinct from the trajectory of patients with lower receipt of disease-modifying therapies (50% to 90%; and <50%). This was particularly true for those who experienced superimposed relapses, in which a decreasing MSSS slope was observed, compared to the more stable trajectory for those who did not experience relapses.

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The group noted that a number of prior studies have shown the difficulty in estimating future MS trajectories, which are influenced by possible rapid changes in disease activity and disability accumulation.

“Our finding of a lack of association between disease activity in the relapsing-remitting phase and disability accumulation during the secondary progressive phase is consistent with this interpretation,” Lizak et al. wrote. “Although this intraindividual variability in disease course makes any individual prognosis difficult, it also offers the possibility that MS with sufficient episodic inflammatory activity remains modifiable with immunotherapy at any stage of disease.”

For the full cohort, a higher annualized relapse rate (ARR) during SPMS was associated with an increase is the risk of becoming wheelchair dependent, defined as an EDSS score of 7.0 (hazard ratio [HR],&thinsp;1.87; 95% CI, 1.17—3.00; P&thinsp;=&thinsp;.009).Those with a greater proportion of time receiving DMTs during this period was observed to be associated with a reduced risk of progressing to an EDSS score of 7.0 for those who were experiencing relapse in SPMS. For each 25% increase in the proportion of SPMS time treated HRs were 0.78 (95% CI, 0.68—0.90; P&thinsp;<&thinsp;.001) for low-efficacy therapies, 0.73 (95% CI, 0.55—0.96; P&thinsp;=&thinsp;.03) for medium-efficacy therapies, 0.73 (95% CI,&thinsp;0.57—0.94; P&thinsp;=&thinsp;.02) for high-efficacy therapies.

Those who did not experience relapses during SPMS showed a similar association with medium-efficacy DMTs only (HR, 0.63; 95% CI, 0.44—0.89; P&thinsp;=&thinsp;.01).

The DMTs assessed included therapies taken during the 2 disease periods—relapsing MS (first 4 years after diagnosis) and SPMS (from SPMS conversion to last EDSS score)&mdash;in 3 categories: low efficacy, defined as interferon beta preparations, glatiramer acetate, and teriflunomide; medium efficacy, consisting of fingolimod, dimethyl fumarate, cladribine, and daclizumab; and high efficacy, which included natalizumab, mitoxantrone, alemtuzumab, autologous hematopoietic stem cell transplantation, ocrelizumab, and rituximab.

Interferon beta preparations (n = 1112; 79.7%) and glatiramer acetate (n = 280; 20.1%) consisted of the majority of the 1396 low-efficacy DMT exposures during the early relapsing MS period, and the majority of the 1163 exposures during SPMS (interferon beta: n = 793 [68.2%]; glatiramer acetate: n = 303 [26.1%]).

There were 74 exposures during early relapsing MS and 385 exposures during SPMS to medium-efficacy DMTs. Of those, fingolimod and dimethyl fumarate represented the majority in both the relapsing MS (fingolimod: n = 66 [89.2%]; dimethyl fumarate: n = 6 [8.1%]) and SPMS (fingolimod: n = 295 [76.6%]; dimethyl fumarate: n = 83 [21.6%]) periods. For the 171 relapsing MS and 411 SPMS exposures, natalizumab and mitoxantrone were the most common, accounting for 93 (54.4%) and 76 (44.4%) of relapsing MS and 285 (69.3%) and 105 (25.5%) of SPMS exposures, respectively.

“Although early active treatment during RRMS is associated with a delay in the onset of SPMS, the rate of disability accumulation once the secondary progressive phase has commenced is not substantially modified by early treatment decisions,” Lizak and colleagues concluded. “Notably, similar to PPMS, relapses during SPMS represent an accessible treatment target and a marker of likely response to immunotherapy. Thus, when inflammation exists in patients with progressive MS, treatment may be associated with a reduction in the rate of disability accumulation.”

REFERENCE

Lizak N, Malpas CB, Sharmin S, et al. Association of Sustained Immunotherapy With Disability Outcomes in Patients With Active Secondary Progressive Multiple Sclerosis. JAMA Neurol. Published online July 27, 2020. doi: 10.1001/jamaneurol.2020.2453.