Fewer Relapses in Active Secondary Progressive MS With High-Efficacy Therapies

High-efficacy therapies were superior in reducing relapses in people with active secondary progressive multiple sclerosis (SPMS) but not in people with inactive disease, an observational study showed.

In people with active SPMS, high-efficacy therapies led to less frequent relapses than low-efficacy therapies (HR 0.7, P=0.006), reported Tomas Kalincik, MD, PhD, of the University of Melbourne in Australia, and co-authors. In patients with inactive SPMS, there was no evidence for a difference in relapse frequency between groups (HR 0.8, P=0.39).

There also was no evidence for a difference in the risk of disability progression, the researchers wrote in Neurology.

Most people with MS are diagnosed initially with relapsing remitting MS (RRMS). More than half eventually transition to SPMS, a slow, steady worsening of disease with or without relapses.

High-efficacy medications can treat early MS aggressively by preventing relapses and modifying progression, but it’s unclear whether they help when RRMS transitions to secondary progressive disease, Kalincik noted.

“Our study finding that high-efficacy therapies are superior to low-efficacy therapies only in reducing relapses in people with active secondary progressive MS provides valuable guidance for neurologists when choosing the most effective therapies for people with this form of MS,” Kalincik said in a statement.

“When the goal is to alleviate ongoing relapse activity, more potent therapy is justified,” he said. “But when the goal is to limit disability progression in secondary progressive MS, both types of drugs show comparable effectiveness.”

“The finding of no impact on progression is disappointing, yet not entirely surprising,” noted Ruth Dobson, PhD, of Queen Mary University London in England, and Amber Salter, PhD, MPH, of UT Southwestern Medical Center in Dallas, in an accompanying editorial.

When this study started, participants already had clinical evidence of progression, so the researchers addressed “whether highly effective anti-inflammatory treatments halt, rather than prevent, progression,” Dobson and Salter wrote. “This work thus indirectly supports the notion that treating this cohort of patients will require therapies targeted at both inflammation and neurodegeneration (i.e., dual therapy), potentially at a relatively early disease stage.”

Kalincik and colleagues evaluated 1,000 patients treated with high- or low-efficacy therapies after SPMS onset in MSBase and OFSEP, two large observational cohorts, accounting for therapeutic lag. Data were extracted in December 2019.

High-efficacy therapies were natalizumab (Tysabri), alemtuzumab (Lemtrada), mitoxantrone, ocrelizumab (Ocrevus), rituximab (Rituxan), cladribine (Mavenclad), and fingolimod (Gilenya).

Low-efficacy treatments were interferon beta, glatiramer acetate (Copaxone), and teriflunomide (Aubagio). To distinguish clearly between high- and low-efficacy groups, dimethyl fumarate (Tecfidera) was excluded. Siponimod (Mayzent), a new therapy approved in 2019 that showed potential to mitigate long-term disability in SPMS, also was not included.

The researchers defined baseline as the first start of treatment after SPMS onset. They estimated therapeutic lag — the time it takes for treatment to have a clinical effect — for each patient based on demographic and clinical characteristics. The investigators classified patients as having active SPMS if they had a relapse or physician-reported neuroradiological disease activity in the 2 years before they started study therapy. All other patients were classified as having inactive SPMS.

In total, 510 participants had active disease and 490 had inactive MS. The groups were matched on propensity of receiving high- versus low-efficacy treatment. Each group had about 71% women and an average age around 46.

Disability was assessed with the Expanded Disability Status Scale (EDSS). Relapses were defined as new symptoms or exacerbation of existing symptoms for at least 24 hours in the absence of concurrent illness or fever, and occurring at least 30 days after a previous relapse.

The high- and low-efficacy cohorts showed no difference in cumulative hazards of confirmed disability progression in either the active (HR 1.1, 95% CI 0.8-1.5) or inactive SPMS (HR 1.3, 95% CI 0.9-1.8) groups. There was no difference in the proportion of patients free from disability progression in either the active (HR 0.9, 95% CI 0.7-1.2) or inactive (HR 1.2, 95% CI 0.7-1.8) groups.

The researchers also looked at the proportion of patients requiring a wheelchair (EDSS of 7 or higher) as a secondary outcome and found no difference based on treatment allocation.

Large registry studies are not free from bias, Dobson and Salter noted. While propensity score matching can reduce the effect of confounding, “it inevitably leads to the exclusion of data from unmatched individuals,” the editorialists wrote. “By selecting samples that allow the calculation of potential therapeutic lag, further selection bias may inadvertently be introduced.”

Treatments were combined into high- and low-efficacy groups to maximize analytical power and it’s possible individual therapies may have an effect on disability outcomes, Kalincik and co-authors acknowledged. In addition, because a significant number of participants, especially in the inactive group, did not have imaging in the 2 years before baseline, some participants without MRI may have been classified incorrectly as inactive.