Meta-analysis of the Age-Dependent Efficacy of Multiple Sclerosis Treatments

Abstract

ObjectiveTo perform a meta-analysis of randomized, blinded, multiple sclerosis (MS) clinical trials, to test the hypothesis that efficacy of immunomodulatory disease-modifying therapies (DMTs) on MS disability progression is strongly dependent on age.MethodsWe performed a literature search with pre-defined criteria and extracted relevant features from 38 clinical trials that assessed efficacy of DMTs on disability progression. We fit a linear regression, weighted for trial sample size, and duration, to examine the hypothesis that age has a defining effect on the therapeutic efficacy of immunomodulatory DMTs.ResultsMore than 28,000 MS subjects participating in trials of 13 categories of immunomodulatory drugs are included in the meta-analysis. The efficacy of immunomodulatory DMTs on MS disability strongly decreased with advancing age (R2 = 0.6757, p = 6.39e−09). Inclusion of baseline EDSS did not significantly improve the model. The regression predicts zero efficacy beyond approximately age 53 years. The comparative efficacy rank derived from the regression residuals differentiates high- and low-efficacy drugs. High-efficacy drugs outperform low-efficacy drugs in inhibiting MS disability only for patients younger than 40.5 years.ConclusionThe meta-analysis supports the notion that progressive MS is simply a later stage of the MS disease process and that age is an essential modifier of a drug efficacy. Higher efficacy treatments exert their benefit over lower efficacy treatments only during early stages of MS, and, after age 53, the model suggests that there is no predicted benefit to receiving immunomodulatory DMTs for the average MS patient.

Genetic model of MS severity predicts future accumulation of disability

“…MS‐DSS (Weideman et al., ) is assigned by a statistical model using gradient boosting machines. MS‐DSS includes disability measured by a highly sensitive CombiWISE (Kosa et al., ), mathematically adjusted for the efficacy of administered treatments using a published formula (Weideman, Tapia‐Maltos, Johnson, Greenwood, & Bielekova, ), the amount of CNS‐tissue destruction measured by the Combinatorial MRI Scale of CNS Tissue Destruction (COMRIS‐CTD) (Kosa et al., ), and additional features of lower variable importance, including demographic data. The model uses the following cross‐sectional data, listed in order of statistical importance: (1) therapy‐adjusted CombiWISE divided by patient age (CombiWISE/age); (2) CombiWISE; (3) COMRIS‐CTD; (4) time to first therapy, which measures the delay (in years) from disease onset to initiation of treatment; (5) difference in therapy‐adjusted and measured CombiWISE, which reflects the variant of the disease that is treatable by current immunomodulatory treatments; (6) age, and (7) family history of MS. MS‐DSS, the modeling outcome in the current study, is automatically calculated from user‐inputted raw data via a web interface (https://bielekovalab.shinyapps.io/msdss).…”

Treating multiple sclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pandemic

“…11 Severe COVID-19 infections are more common in older adults (aged >60 years) with a higher case fatality rate. 6 Treatment decisions in this age group should be individualized, taking into account other comorbidities that increase the risk of death (cardiorespiratory disease and diabetes) 6 and the more modest benefits of diseasemodifying treatment in older patients 12 and/or those with progressive forms of MS. Pregnant women should follow general health advice during the COVID-19 pandemic, with no special considerations.…”

An argument for broad use of high efficacy treatments in early multiple sclerosis

“…48 A meta-analysis of MS clinical trials found a larger reduction in relapses and MRI damage in a younger patient group, with a lack of difference between treated and untreated patients seen in patients older than age 40.5 years. 49 A population-based cohort in the United Kingdom found that patients (n = 104) treated initially with highly effective therapy had a lower mean change in EDSS at 5 years and a higher median time to sustained accumulation of disability than those treated with moderately effective therapies (n = 488). This effect persisted after adjustment for covariates including age and sex.…”