The effect of Sphingosine-1-phosphate receptor modulator treatment on leukocyte subsets across different clinical indications: A systematic review

Background: Sphingosine-1-phosphate receptor (S1PR) modulators are approved as a treatment for several autoimmune diseases. While their role on total leukocyte populations is well-studied, their effects on specific leukocyte subsets remain unclear. This systematic review describes the impact of various S1PR modulators on human leukocyte subpopulations. Methods: We conducted a systematic literature search through the databases PubMed, Medline, Embase, and Cochrane, up to the 25th of July 2024. Studies were included if they involved patients treated with S1PR modulators and provided data on leukocyte subsets. Among the exclusion criteria, were non-English articles, animal studies, and in vitro studies. Data extraction focused on changes in leukocyte subsets post-treatment. Results: Out of 1658 articles identified, 63 met the inclusion criteria. Fingolimod was the most frequently studied agent and displayed significant reductions in total T-cell counts. More specifically, CD4+ T-cells, including naïve and central memory populations were reduced. CD8+ T-cells also decreased, although the alterations of effector memory subsets were inconsistent. B-lymphocytes were generally attenuated. Innate immune cells showed variable responses, with most studies indicating a reduction or no change. Data on other S1PR modulators suggested similar trends. Conclusion: S1PR modulators primarily reduce T- and B-cell subpopulations, which are known to play a prominent role in immune-mediated inflammatory disorders. Further research is needed to fully elucidate the differential effects among drugs targeting specific isoforms of the S1PR, focusing on the lymph nodes or inflammatory tissue sites (e.g. intestinal mucosa and cerebrospinal fluid), to explore the exact clinical implications of these pharmacodynamic findings.