Age-Related Lymphocyte Output During Disease-Modifying Therapies for Multiple Sclerosis

Patients with multiple sclerosis exhibit the same qualitative and quantitative changes in immune system cells observed in aging. In the last 20 years, multiple sclerosis patients have shown an increase in life expectancy and average age, but clinical trial inclusion criteria typically exclude patients over the age of 55 years. Therefore, disease-modifying therapies are likely administered to patients older than those enrolled in clinical trials.

In order to investigate whether disease-modifying therapies for multiple sclerosis induce modifications to the immune system that may have (super)additive effects resulting in an acceleration of immunosenescence, we quantified the number of T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs). These molecules are contained in new T and B lymphocytes released by the thymus and bone marrow and are considered molecular age-related markers.

The markers of aging were measured by a multiplex quantitative real-time PCR assay in 122 patients who had started therapy with interferon-beta (IFN-β), fingolimod, alemtuzumab, or natalizumab. Samples were obtained before the therapy and at 6 and 12 months of treatment. Comparisons between the variables were performed by a non-parametric statistical analysis.

In therapy-naive patients, a significant and direct correlation was found between a lower number of newly produced T and B cells and older age. Although disease-modifying therapies induced different changes (both increases and decreases) in the production of new T and B lymphocytes, 12 months of therapy with IFN-β or natalizumab did not affect the correlations found at baseline between the release of lymphocytes containing TRECs or KRECs and age. On the contrary, in patients treated with alemtuzumab, both correlations were lost, while in fingolimod-treated patients, only the correlation between TRECs and age disappeared.

This observational study indicated that different age-related changes of the new T and B lymphocyte production could be one of the reasons for the emergence, in the real-world setting, of adverse events not otherwise observed in clinical trials; thus, caution is advised when choosing disease-modifying therapies for multiple sclerosis patients.