MS Speaks

Presented at the ACTRIMS conference in New Orleans, February 18-20, 2016:

Immunomodulatory therapy slows accumulation of disability in moderately advanced multiple sclerosis

Background:

Three large cohort studies have previously examined factors influencing disability accumulation in moderately advanced multiple sclerosis (MS), but arrived to contradictory results. The effect of therapy during this disease stage remains unclear.

Objectives:

To identify modifiers of disability trajectories in moderately advanced MS, including disease activity and immunomodulatory therapy during the early and moderately advanced stages of MS. We hypothesized that individual disability trajectories are not homogenous and can be predicted based on demographic and clinical characteristics.

Methods:

The epochs between Expanded Disability Status Scale (EDSS) steps 3-6, 4-6, and 6-6.5 were analyzed. Patients with relapse-onset multiple sclerosis, 6-month confirmed progression to the initial EDSS step (baseline), and ³12 [?] months pre-baseline follow-up were identified in MSBase, a large international observational multiple sclerosis cohort study.

Multivariable survival models examined the impact of relapse rate and proportion of time treated (prior to and during each epoch), age and disease duration at baseline, on progression to the outcome EDSS (6 or 6.5). Sensitivity analyses varying outcome definition and inclusion criteria were conducted.

Results:

For the 3-6, 4-6, and 6-6.5 epochs, 1,560, 1,504, and 1,231 patients were identified, respectively. Pre- and post-baseline disability trajectories showed large coefficients of variance (0.85-0.92 and 1.95-2.26, respectively) and did not correlate. Probability of reaching the outcome EDSS was not associated with pre-baseline variables, but was increased by higher relapse rates during each epoch (hazard ratios: 1.58-3.07; P<0.001). Greater proportion of each epoch treated with higher-efficacy therapies was associated with lower risk of the outcome EDSS (hazard ratios: 0.27-0.68; P²0.02). These results were confirmed by sensitivity analyses.

Conclusion:

Disease progression during moderately advanced multiple sclerosis is amnesic to prior disease activity. Lower relapse rates and greater persistence on higher-efficacy immunomodulatory therapy after reaching EDSS steps 3, 4, and 6 are associated with a decreased risk of accumulating further disability. These observations justify treatment even after moderately advanced disability has been attained.

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Authors:

Nathaniel Lizak
University of Melbourne
Monash University

Alessandra Lugaresi
MS Centre, Neuroscience, Imaging and Clinical Sciences, University ‘G. d’Annunzio’, Chieti, Italy

Raed Alroughani
Amiri Hospital, Kuwait City, Kuwait

Jeanette Lechner-Scott
Hunter Medical Research Institute

Mark Slee
Flinders University and Medical Centre

Vilija Jokubaitis
University of Melbourne
Royal Melbourne Hospital

Tim Spelman
University of Melbourne
Royal Melbourne Hospital

Helmut Butzkueven
University of Melbourne
Royal Melbourne Hospital
Box Hill Hospital, Monash University

Tomas Kalincik
University of Melbourne
Royal Melbourne Hospital

Multiple Sclerosis News Today (Magdalena Kegel, February 18, 2016) contains an article about this paper:

...In this session, Nathaniel Lizak from the University of Melbourne and Monash University, will present potentially important data on the effects of immunotherapies in disability progression. His talk is titled, “Immunomodulatory therapy slows accumulation of disability in moderately advanced multiple sclerosis.”

The research builds on data from the MSBase, a large international observational MS cohort study.

Three large previous studies have suggested that once disease trajectories reach a moderate stage — defined as the transition from Expanded Disability Status Scale (EDSS) phase three or four to six — the disease is at a new stage and driven by neurodegeneration. The implication is that once the disease reaches this phase, a therapy no longer has any effect on disease progression. The results of these earlier studies were, however, contradictory, and no analysis of variability had been performed.

The research team set out to investigate variability and predictability of the course of disability in moderately advanced MS. They also aimed to establish if it is possible to modify the accumulation of disability with immunomodulatory treatment.

Data was extracted from the MSBase and divided —relapse-onset MS patients into three groups based on their EDSS scores at a defined baseline. The researchers included data on patients who had reached an EDSS score of 3, 4, or 6, and analyzed patient data 12 months before this baseline through to outcome EDSS scores of 6 or 6.5. In total, 1,560 patients with EDSS scores of 3-6, 1,504 patients with scores 4-6, and 1,231 patients with scores 6-6.5 were included in the study.

Results showed that before and after the baseline time point, the course of disability was highly variable, and the researchers found no associations between pre- and post-baseline disability trajectories. They also noted that a higher rate of yearly relapses increased the risk of disability progression, and that inflammation is a key driver of disability in moderately advanced MS.

Also, patients who persisted shorter times on higher efficacy immunomodulatory treatment during each phase had an increased probability of reaching the outcome EDSS score. The team, however, could not prove these associations for the relapses and therapy before the baseline.

Higher efficacy therapies were defined as treatment with natalizumab (Tysabri), fingolimod (Gilenya), alemtuzumab (Lemtrada), dimethyl fumarate (Tecfidera), cladribine (Leustatin), rituximab (Rituxan), or mitoxantrone (Novantrone).

The study concludes that disability accumulation during moderately advanced MS is highly variable, and not dependent on how the disease developed at an earlier stage. The data also contradicts the practice of discontinuing treatment once MS patients have reached higher EDSS scores, by clearly showing that immunomodulatory treatment prevents disability accumulation.

The article can be seen here.