Ghadiri M, Fitz-Gerald L, Rezk A, Li R, Nyirenda M, Haegert D, Giacomini PS, Bar-Or A, Antel J.Reconstitution of the peripheral immune repertoire following withdrawal of fingolimod Mult Scler. 2017;23(9):1225-1232. doi: 10.1177/1352458517713147.
BACKGROUND:Following fingolimod cessation, immune reconstitution or lack thereof may have consequences for disease rebound or safety of commencing alternative therapies.
OBJECTIVE:To examine the degree and profile of peripheral blood lymphocyte reconstitution following fingolimod withdrawal.
METHODS: Total lymphocyte counts (TLC) and CD4+/CD8+ T-cell counts were measured in 18 multiple sclerosis (MS) patients pre-treatment, on fingolimod, and up to 8-9 months post-cessation. T-cell subsets were analyzed using flow cytometry.
RESULTS: At 2-week post-fingolimod cessation, TLC reconstitution was variable and not correlated with age, treatment duration, pre-, or on-treatment TLC. Despite normalization of TLC and CD4+:CD8+ ratios over months, naive subsets remained lower and effector memory subsets higher in frequency compared with pre-treatment. Drug-induced increases in ratios of regulatory to pathogenic Th17-containing central memory populations appeared to rapidly return to baseline.
CONCLUSION: Early peripheral lymphocyte reconstitution after fingolimod withdrawal remains partial and heterogeneous. Relative frequencies of circulating naive and memory T-cell subsets may not recover for many months, even when clinical laboratory tests have normalized. Analyzing specific components of the peripheral immune repertoire helps define the overall immune status of patients. To be determined is whether assessment of such immune measures will have implications for the timing and safety of commencing alternative therapies.
Fingolimod is a an immune-migration inhibition agent. This means that rebound can occur when cells come out of their niche where they are supposedly held by loss of sphingosine one phosphate receptor. However when you examine the blood you can not only see that some subset of white cell disappear from the blood, you can also see that in some individuals there is a loss of white blood cells. This study reiterates this issue and says that despite withdrawal of drug there are some people that do not reconstitute their immune system. This would perhaps suggest that fingolimod may be depleting immune stem cells/progenitors and so that people do not reconstitute properly. This is saying that there are actions other than simple blockade of migration and I may suggest that it can kill cells. We know this can happen as there is evidence in the literature,
The question is how common is this issue because if you do not reconstitute your immune system then you will be open to infections. That effector memory cells are more common is consistent with the mechanism as they do not express CCR7 which with Sphingosine-0ne-phosphate one receptor is used to allow naive and central memory T cells to exit lymphoid glands. Furthermore, when T cells reconstitute it is always the memory T cells that repopulate quicker than the naive T cells. However of concern there are a few individuals that do not reconstitute and this means that you may be at risk from infection.
So this leaves the problem how to transition from fingolimod. If you wait too long before starting the next treatment, rebound disease activity could occur. However, you may have heard the suggestion that a fingolimod-switch to alemtuzumab can mean that disease activity returns (in about 25%) of cases, because the fingolimod traps the cells in the lymph glands, I think it is bone-marrow, and alemtuzumab can't get to them an delete them. But because the antibody is quickly gone, the fingolimod keeps the cells away from the antibody. However,what if there is lack of lymphocytes if the depletion is long-term it will be problematical. We have seen people where the cell numbers, recover after use another immune depleter.