Most pivotal disease-modifying treatment (DMT) trials miss an opportunity to evaluate and understand sex differences. There seem to be unexplored sources of bias in observational and interventional studies. Greater attention is warranted to evaluate sex-specific experiences, especially with regard to safety and side effects. Issues around childbearing, lactation, and the use of exogenous hormones also need to be more fully addressed.
These statements were argued by Dr Riley Bove (Weil Institute for the Neurosciences, USA) in an invited lecture at the MSVirtual2020 . Sex differences in MS risk and course are well documented and well known. The female:male ratio is about 3:1. Overall, men and women tend to reach disability milestones at a similar age, despite numerous differences in the disease course. For example, men tend to be older at diagnosis, have more often a progressive onset of MS, have a lower relapse rate (with a greater proportion of motor relapses), and experience more rapid disability progression in relapsing-onset MS. In women, the risk of developing adverse health outcomes is nearly double compared to men. After the menopause, women may experience increased disability progression, but also less inflammatory activity. Many gaps in scientific knowledge surround this age group, including the effectiveness of hormone supplementation in stabilizing symptoms or even offering neuroprotection.
Despite known differences, even drugs with substantial sex differences in absorption, metabolism and excretion have had no sex-specific dosage recommendations in their labels. In the major clinical trials, evaluation of sex differences in enrollment characteristics, DMT efficacy, and/or side effects are incomplete . Possible confounders in observational studies that have been inadequately addressed are bias in reporting relapses, and not accounting for MS type and duration when evaluating progression. Recommended steps for reporting sex differences in future trials include, at a minimum: to give attention to statistical power and to pharmacokinetics and pharmacodynamics, and harmonization of baseline characteristics, evaluation of efficacy and safety, and consideration of sex-specific experiences or risks.
Dr Bove also addressed pregnancy and lactation. Ethical concerns complicate proper research in this area. An example of an ethical approach in research is to evaluate transfer of DMT into breast milk without exposing the infant. Obviously, DMT selection in women of childbearing potential is very important, including the issue of whether and when to discontinue a DMT, and how to avoid rebound risk. Dr Bove added that there is mounting evidence that B-cell-depleting agents support disease control surrounding pregnancy, as B-cell depletion can extend well beyond drug elimination.
- Bove R, et al. MSVIRTUAL2020, PS12.01.
- Houtchens MK & Bove R. Front Neuroendocrinol. 2018;50:123-34.