No treatments appeared to lower disability accrual rate

High-efficacy treatments reduced relapses to a greater extent than low-efficacy treatments in patients with active secondary progressive multiple sclerosis (SPMS), an observational cohort analysis showed.

In active SPMS, the hazard ratio for the outcome of less frequent relapses for high-versus low-efficacy therapy was 0.7 (P=0.006), reported Tomas Kalincik, MD, PhD, of the University of Melbourne in Australia, and co-authors in Neurology.

No evidence for a difference in relapse rate for those with inactive SPMS was observed. There also was no difference between high- and low-efficacy treatment groups in disability progression.

“The treatment of patients with SPMS has been disappointing, with both high- and low-efficacy therapies generally failing to reduce the rate of disability accrual,” Kalincik and colleagues wrote.

The study defined high-efficacy medications as natalizumab, alemtuzumab, mitoxantrone, ocrelizumab, rituximab, cladribine, and fingolimod. Low-efficacy medications consisted of interferon β, glatiramer acetate, and teriflunomide. To create a clear distinction between high- and low-efficacy groups, the researchers excluded dimethyl fumarate from their analysis. Siponimod, which was approved in 2019 for active secondary progressive disease and other forms of MS, was also excluded.

The researchers extracted longitudinal data in December 2019 from 1,000 patients with SPMS (510 active, 490 inactive) in two observational cohorts: the international MSBase registry and the OFSEP registry in France. Disability was gauged with the Expanded Disability Status Scale (EDSS) at baseline and two or more visits 6 or more months apart following an estimated therapeutic lag (between treatment beginning and the anticipated start of any salutary effects).

Patients were matched on their propensity of receiving high- versus low-efficacy therapy to balance baseline characteristics between groups, leaving 80% of the active and 71% of the inactive SPMS cohorts in the final analysis.

Active SPMS was defined by relapse or imaging evidence of active disease (new or enlarging T2 or Gd+ lesions) in the 2 years prior to beginning study therapy. Disability progression was defined as an increase in EDSS of 1.5 steps for those with baseline EDSS of 0 (no disability); 1 step from an EDSS of 1 to 5.5; and 0.5 step from baseline EDSS of 6 or higher, confirmed over 6 or more months in the absence of a relapse in the 30 days before updated EDSS evaluation.

Of 1,000 patients identified by investigators as objectively having SPMS, more than half (n=565) were physician-identified as having relapsing-remitting MS.

Comparing high- and low-efficacy cohorts, the researchers found:

  • No difference in cumulative confirmed disability progression for high- and low-efficacy cohorts for active (HR 1.1, 95% CI 0.8-1.5) or inactive SPMS (HR 1.3, 95% CI 0.9-1.8).
  • No difference in the proportion of patients free from disability progression in the active (HR 0.9, 95% CI 0.7-1.2) or inactive SPMS (HR 1.2, 95% CI 0.7-1.8).

“By using an early, data-driven definition of SPMS, the authors were able to include a substantial number of patients who still had a physician diagnosis of relapsing remitting MS,” noted Ruth Dobson, MA, MRCP of the Queen Mary University in London, England, and Amber Salter, PhD, MPH, of UT Southwestern Medical Center in Dallas, in an accompanying editorial.

“Despite the earlier SPMS categorization used in this study, these patients already had clinical evidence of progression at the time of initiation on the treatment under investigation; thus [the authors] address whether highly effective anti-inflammatory treatments halt, rather than prevent progression,” the editorialists 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.”

Disease-modifying therapy (DMT) is often used in patients classified as having SPMS based on evidence that those with active disease—implying inflammation and relapses—may experience benefit of improved disability progression. A 2020 observational study defining SPMS according to the objectively-based Lorscheider definition found disability outcome benefit in SPMS patients with active relapses.

“Both the evidence from clinical trials and registry data suggest that immunotherapy is warranted in patients with active SPMS,” Kalincik and colleagues noted. “Whether high-efficacy therapy is superior to low-efficacy therapy in achieving these benefits is uncertain. A delayed onset of treatment effect, termed therapeutic lag, may obscure therapeutic benefits if not accounted for particularly in cohorts enriched for patients with higher disability scores.”

In the current study, the active SPMS group was about 72% female, with mean age of about 45 and SPMS duration of 1.80 and 1.88 years for the high- and low-efficacy groups respectively. The inactive SPMS group was 71% female, with mean age of about 47 and SPMS duration of 1.78 and 1.90 years for the high- and low-efficacy groups respectively.

“The finding of no impact on progression is disappointing, yet not entirely surprising,” the editorialists observed. “Previous studies in patients with clinician-defined progressive disease have found similar.”

The study has several limitations, Dobson and Salter noted. Despite propensity score matching to balance baseline differences in treatment groups, ascertainment bias and reverse causation may have confounded results. In addition, imaging was available in over half of patients with active SPMS treated with active therapy but in less than a quarter of those with inactive disease, but MRI findings were used to define active inflammatory disease.

“It may well be that at least some of those without MRI were incorrectly classified as inactive; in both real-world studies and routine clinical practice patients do not have MRI at defined timepoints, and so these limitations must be recognized,” the editorialists wrote.

  1. High-efficacy treatments reduced relapses to a greater extent than low-efficacy treatments in patients with active secondary progressive multiple sclerosis (SPMS), an observational cohort analysis showed.

  2. No evidence for a difference in relapse rate for those with inactive SPMS was observed. There also was no difference between high- and low-efficacy treatment groups in disability progression.

Paul Smyth, MD, Contributing Writer, BreakingMED™

This study was supported by the EDMUS Foundation and NHMRC.

Kalincik served on scientific advisory boards for Roche, Sanofi-Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi-Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research support from Biogen.

Dobson and Salter reported no conflicts of interest.

Cat ID: 36

Topic ID: 82,36,730,36,192,925