Associations Between Contrast-Enhancing Lesions and MS Disease Spectrums Raise Questions

Marcus W. Koch, MD

An analysis of 4 large, well-characterized, randomized controlled trials that featured different disease courses of multiple sclerosis (MS) showed inconsistencies with the association of age and the presence of contrast enhancing lesions (CELs), further confirming the general phenomenon within the disease space.

Lead author Marcus W. Koch, MD, assistant professor of clinical neurosciences, Hotchkiss Brain Institute, University of Calgary, and colleagues investigated this association using trial data from CombiRx (NCT00211887; n = 1008), a trial in relapsing-remitting MS (RRMS); ASCEND (NCT01416181; n = 889), a trial in secondary progressive MS (SPMS); and 2 primary progressive MS trials PROMISE (n = 943) and INFORMS (NCT00731692; n = 970). Each of the trials observed included gadolinium enhanced cranial MRI scans at the beginning and throughout the trial. The first scan was selected before treatment initiation for the entire trial cohorts, and the 1-year follow-up scan of the treatment arm for analysis.

CEL occurrence differed between datasets according to disease courses, with 39.6% of CombiRx participants having CELs, followed by ASCEND participants with 23.9%, and PROMISE and INFORMS participants with 14% and 12.8%, respectively. Age was divided at baseline into 5 categories: up to 30 years, 31 to 40 years, 41 to 50 years, 51 to 60 years, and older than 60 years. In all datasets, the distribution of CELs by disease course was largely preserved throughout the age groups, with an almost linear decrease in the percentage of participants with advancing age.

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After 1 year of experimental treatment, CEL occurrence was meaningfully reduced in all trial datasets. Less pronounced reductions were observed in CombiRx and PROMISE, which used the platform treatments interferon beta and glatiramer acetate. In these trials, the percentage of CEL occurrence was reduced to about half of the baseline percentage after 1 year of treatment (CombiRx: 39.6% to 14.8%; PROMISE: 14% to 7.6%).

In INFORMS, investigators observed a reduction from 12.8% to 3.3% in CEL occurrence after a year’s worth of fingolimod (Gilenya; Novartis) treatment. As for ASCEND, almost all CELs were abolished in patients treated with natalizumab (Tysabri; Biogen), from 23.9% to 1%. Notably, the almost linear decrease of CEL occurrence with advancing age was preserved in CombiRx, PROMISE, and INFORMS after 1 year of treatment.

"It should be kept in mind, however, that ASCEND was a negative trial and that natalizumab treatment, despite its impressive effect on CEL occurrence, could not prevent the steady functional decline the participants experienced in this trial over the observation period," Koch et al noted, continuing that this lack of functional outcome effects support the hypothesis that SPMS disease progression is not driven by focal inflammatory demyelination, though their findings indicate its presence. "The hypotheses about the nature of this pathophysiology range from a different form of inflammation to the idea that multiple sclerosis may be primarily a neurodegenerative disease in which inflammation is an early reaction to neurodegenerative processes," they added.

A significantly greater number of participants who had CEL at baseline also had CEL at follow-up compared to those without CELs at baseline. In CombiRx, 27% of participants with CELs at baseline also had CELs at follow-up, compared to only 7% of participants without CELs at baseline being CEL positive at follow-up (chi-square, P <.0001). This trend continued for PROMISE (21% vs 5%; P <.0001) and INFORMS (14 vs 2%; P <.0001) but was inconclusive in ASCEND due to the low number of CELs at 1 year follow-up.

Multivariate logistic regression modeling indicated that age is the only baseline characteristic associated with the risk of CELs at baseline, with higher age associated with a lower risk of CELs. The strength of the association of age and CEL occurrence was similar between trial datasets, with ORs between 0.94 and 0.96 per year increasing age and comparable 95% CIs between trial datasets.

Disease duration was not significantly associated with CELs in any of the models. Higher Expanded Disability Status Scale (EDSS) score at baseline was associated with a higher risk of CELs at baseline in PROMISE, but none of the other datasets (OR per EDSS point increase, 1.20 [95% CI, 1.03-1.41]).

Koch et al noted several limitations to the findings. "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," they wrote.

REFERENCE
Koch MW, Mostert J, Zhang, Y, et al. Association of age with contrast-enhancing lesions across the multiple sclerosis disease spectrum. Neurology. Published online August 10, 2021. doi: 10.1212/WNL.0000000000012603