ABSTRACT
Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.
Subject(s)
Immune System Diseases/drug therapy , Immune System Diseases/metabolism , Lysophospholipids/metabolism , Multiple Sclerosis/drug therapy , Multiple Sclerosis/metabolism , Pharmaceutical Preparations/administration & dosage , Signal Transduction/drug effects , Sphingosine/analogs & derivatives , Animals , Humans , Sphingosine/metabolismABSTRACT
Immune-mediated inflammatory diseases (IMIDs) of the joints, gut and skin are treated with inhibitors of inflammatory cytokines. These cytokines are involved in the pathogenesis of coronavirus disease 2019 (COVID-19). Investigating anti-SARS-CoV-2 antibody responses in IMIDs we observe a reduced incidence of SARS-CoV-2 seroconversion in IMID patients treated with cytokine inhibitors compared to patients receiving no such inhibitors and two healthy control populations, despite similar social exposure. Hence, cytokine inhibitors seem to at least partially protect from SARS-CoV-2 infection.