Sphingosine 1-Phosphate Modulation in Inflammatory Bowel Diseases: Keeping Lymphocytes Out of the Intestine

Inflammatory bowel diseases (IBDs) are chronic and disabling conditions that, uncontrolled, lead to irreversible bowel damage and associated comorbidities. Despite the new era of biological therapies, IBDs remain not curative. The treatment purpose is to induce endoscopic remission, reduce the progression of the disease and improve the quality of life. Optimal and early treatment could enable the prevention of their complications. Small molecules, administrated as oral agents, have the capacity of overcoming the limitations of biologic agents (i.e., parenteral administration, rapidity of action and primary and secondary non-responsiveness). Of special interest are results from the use of oral sphingosine 1-phosphate (S1P) receptor modulators (ozanimod, etrasimod, fingolimod and laquinimod), based on S1P activities to target lymphocyte recirculation in the mucosa, acting as immunosuppressive agents. Most S1P modulators are reported to be safe and effective in the treatment of both UC and CD. High and satisfactory rates of clinical remission as well as endoscopic improvement and remission can be achieved with these molecules. Safety alarms remain rather low, although the S1P binding to two of its G protein-coupled receptors, 2 and 3 (S1PR2 and S1PR3), may be associated with cardiovascular risks. Cost-effectiveness studies and head-to-head trials are needed to better define their place in therapy. This review summarizes these emerging data published by PubMed and EMBASE databases and from ongoing clinical trials on the safety and efficacy of selectivity of S1P modulators in the treatment of IBD.