Age impacts inflammatory demyelination across all MS disease courses

The correlation between age and contrast-enhancing lesions “is a general phenomenon” across the MS spectrum of disease, according to an analysis of four large, randomized controlled trials published in Neurology.

The analysis of these trials suggested that “a natural ‘mellowing’ of focal inflammatory disease activity” with age occurs across the MS disease spectrum, according to the researchers, an idea that has “some support” in the literature.

“Several studies showed that [contrast-enhancing lesion] frequency decreases with age, a finding that is in keeping with the observation that relapses decrease with age and disease duration, and with the general idea that inflammatory disease activity in MS is more pronounced in younger, and less prevalent in older people,” the researchers wrote. “However, these studies were dominated by patients with [relapsing-remitting MS], and it is less clear whether the observed association of age and [contrast-enhancing lesions] occurrence is present across all MS disease courses.”

Marcus W. Koch, MD, PhD, associate professor of neurology in the department of clinical neurosciences and the Hotchkiss Brain Institute at the University of Calgary, and colleagues examined data from four large, randomized controlled trials in RRMS, secondary progressive MS and primary progressive MS to determine the relationship between age and the presence of contrast-enhancing lesions at baseline and after 1 year of experimental treatment.

The trials included CombiRx (n = 1,008), ASCEND (n = 889), PROMISE (n = 943) and INFORMS (n = 970), according to the study results. Patients with RRMS in CombiRx, a multicenter phase 3 trial, received interferon beta plus placebo (25%), glatiramer acetate plus placebo (25%) or a combination of the two agents (50%) “so that all included participants received a form of immunomodulatory treatment.” The multicenter phase 3 trials ASCEND and PROMISE examined the efficacy of natalizumab treatment in SPMS and glatiramer acetate in PPMS, respectively. INFORMS, another phase 3 multicenter trial, analyzed the efficacy of fingolimod among patients with PPMS.

All trials included gadolinium-enhanced cranial MRI scans taken at baseline and throughout the trial. The researchers selected the first scan before treatment started for all trial cohorts and the 1-year follow-up scan of the treatment arm for their analyses, according to the study results. They then established the number of patients with contrast-enhancing lesions on these scans.

Koch and colleagues found that the rate of contrast-enhancing lesions at baseline differed between the datasets according to the disease course, where 39.6% of patients in CombiRx, 23.9% of patients in ASCEND, 14% of patients in PROMISE and 12.3% of patients in INFORMS had contrast-enhancing lesions. The dissemination according to disease course “was largely preserved within each age group,” according to the study results. The researchers observed “an almost linear decrease” in the number of participants with contrast-enhancing lesions with advancing age.

Following 1 year of experimental treatment, the number of contrast-enhancing lesions decreased in all trial datasets, according to the study results, and were “almost absent” in ASCEND. The researchers found that the reduction in contrast-enhancing lesions with advancing age was preserved in CombiRx, PROMISE and INFORMS after 1 year of treatment.

Koch and colleagues also examined the relationship between the baseline factors of age, disease duration, sex and expanded disability status score and contrast-enhancing lesions at baseline using multivariable binary logistic regression models. They found that age was the only factor related to the risk for contrast-enhancing lesions at baseline across all datasets, where increased age correlated with a reduced risk for contrast-enhancing lesions (OR for having contrast-enhancing lesions at baseline per year increase in age: CombiRx = 0.96 [95% CI, 0.95-0.98], ASCEND = 0.94 [95% CI, 0.92-0.97], PROMISE = 0.94 [95% CI, 0.91-0.96] and INFORMS = 0.97 [95% CI, 0.94-0.99]).

“While our investigation shows that the effect of aging on focal inflammatory demyelination is present in all MS disease courses, we caution against comparing between these datasets and against generalizing the findings from these datasets to the general clinical population of people with MS. Clinical trials always include a selected subgroup of the real-world population of people with MS and are often enriched for activity to increase or enhance the occurrence of outcome events,” the researchers wrote. “Our findings should be replicated in real-world datasets, ideally in population-based cohorts including people with all subtypes of MS.”