CoChat
Sign Up
Cited by 197Sphingolipid Metabolism and SignalingLysosomal Storage Disorders ResearchMultiple Sclerosis Research Studies

Targeting sphingosine-1-phosphate signaling in immune-mediated diseases: beyond multiple sclerosis

Open access
Pérez-Jeldres, Tamara, Alvarez-Lobos, Manuel, Rivera-Nieves, Jesús·2021·Drugs
DOI 10.1007/s40265-021-01528-8PMC PMC8116828
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1007/s40265-021-01528-8

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • S1P is involved in HDL function and neuroinflammation through regulation of gene expression in the nucleus and alteration in the functioning of various immune cells.

    “The signaling lipid S1P is involved in high-density lipoprotein (HDL) function (44) and neuroinflammation through the regulation of gene expression in the nucleus and alteration in the functioning of various immune cells (45).”

    From Nuclear SphK2/S1P signaling is a key regulator of ApoE production and Aβ uptake in astrocytes (2024) · cites this paper as [45]

    The Intracellular Targets of S1P section (page unavailable) describes S1P’s effects on nuclear gene transcription, and the S1P Receptors section describes its effects on several immune-cell types. The cited paper does not clearly establish that these mechanisms specifically drive neuroinflammation. HDL function is attached to citation 44, not this source’s citation 45. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 131

  1. [1]Kunkel GT Maceyka M Milstien S Spiegel S Targeting the sphingosine-1-phosphate axis in cancer, inflammation and beyond Nat Rev Drug Discov. 2013 12 9 688 702 23954895 PMC3908769
  2. [2]Park SJ Im DS Sphingosine 1-phosphate receptor modulators and drug discovery Biomol Ther (Seoul). 2017 25 1 80 90 28035084 PMC5207465
  3. [3]Peyrin-Biroulet L Christopher R Behan D Lassen C Modulation of sphingosine-1-phosphate in inflammatory bowel disease Autoimmun Rev. 2017 16 5 495 503 28279838
  4. [4]Chun J Giovannoni G Hunter SF Sphingosine 1-phosphate receptor modulator therapy for multiple sclerosis: differential downstream receptor signalling and clinical profile effects Drugs 2021 81 2 207 231 33289881 PMC7932974
  5. [5]Tsai HC Han MH Sphingosine-1-phosphate (S1P) and S1P signaling pathway: therapeutic targets in autoimmunity and inflammation Drugs 2016 76 11 1067 1079 27318702
  6. [6]Stepanovska B Huwiler A Targeting the S1P receptor signaling pathways as a promising approach for treatment of autoimmune and inflammatory diseases Pharmacol Res. 2020 154 104170 30776422
  7. [7]Cartier A Hla T Sphingosine 1-phosphate: lipid signaling in pathology and therapy Science 2019 366 6463 eaar5551 31624181 PMC7661103
  8. [8]Currò D Pugliese D Armuzzi A Frontiers in drug research and development for inflammatory bowel disease Front Pharmacol. 2017 8 400 28690543 PMC5481609
  9. [9]Argollo M Furfaro F Gilardi D Modulation of sphingosine-1-phosphate in ulcerative colitis Expert Opin Biol Ther. 2020 20 4 413 420 32093531
  10. [11]Proia RL Hla T Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy J Clin Invest. 2015 125 4 1379 1387 25831442 PMC4409021
  11. [12]Aoki M Aoki H Ramanathan R Hait NC Takabe K Sphingosine-1-phosphate signaling in immune cells and inflammation: roles and therapeutic potential Mediators Inflamm. 2016 2016 8606878 26966342 PMC4761394
  12. [13]Olesch C Ringel C Brüne B Weigert A Beyond immune cell migration: the emerging role of the sphingosine-1-phosphate receptor S1PR4 as a modulator of innate immune cell activation Mediat Inflamm. 2017 2017 6059203 PMC5564090 28848247
  13. [14]Park ES Choi S Shin B Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction J Biol Chem. 2015 290 15 9660 9673 25716317 PMC4392267
  14. [15]Wang T Wang J K63-linked polyubiquitination of IRF1: an essential step in the IL-1 signaling cascade Cell Mol Immunol. 2014 11 5 407 409 24793404 PMC4197205
  15. [16]Harikumar KB Yester JW Surace MJ K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5 Nat Immunol. 2014 15 3 231 238 24464131 PMC3976678
  16. [17]Blaho VA Hla T An update on the biology of sphingosine 1-phosphate receptors J Lipid Res. 2014 55 8 1596 1608 24459205 PMC4109755
  17. [18]Spiegel S Milstien S Grant S Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy Oncogene 2012 31 5 537 551 21725353 PMC3356932
  18. [19]Hait NC Allegood J Maceyka M Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate Science 2009 325 5945 1254 1257 19729656 PMC2850596
  19. [20]Hait NC Maiti A The role of sphingosine-1-phosphate and ceramide-1-phosphate in inflammation and cancer Mediat Inflamm. 2017 2017 4806541 PMC5705877 29269995
  20. [21]Alvarez SE Harikumar KB Hait NC Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2 Nature 2010 465 7301 1084 1088 20577214 PMC2946785
  21. [22]Nielsen OH Li Y Johansson-Lindbom B Coskun M Sphingosine-1-phosphate signaling in inflammatory bowel disease Trends Mol Med. 2017 23 4 362 374 28283249
  22. [23]Pérez-Jeldres T Tyler CJ Boyer JD Targeting cytokine signaling and lymphocyte traffic via small molecules in inflammatory bowel disease: JAK inhibitors and S1PR agonists Front Pharmacol. 2019 10 212 30930775 PMC6425155
  23. [24]Karuppuchamy T Tyler CJ Lundborg LR Sphingosine-1-phosphate lyase inhibition alters the S1P gradient and ameliorates Crohn's-like ileitis by suppressing thymocyte maturation Inflamm Bowel Dis. 2020 26 2 216 228 31807751 PMC6943703
  24. [25]Liu G Yang K Burns S Shrestha S Chi H The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells Nat Immunol. 2010 11 11 1047 1056 20852647 PMC2958252
  25. [26]Garris CS Wu L Acharya S Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation Nat Immunol. 2013 14 11 1166 1172 24076635 PMC4014310
  26. [27]Cinamon G Matloubian M Lesneski MJ Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone Nat Immunol. 2004 5 7 713 720 15184895
  27. [28]Karuppuchamy T Behrens EH González-Cabrera P Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease Mucosal Immunol. 2017 10 1 162 171 27049060 PMC5053832
  28. [29]Blankenbach KV Schwalm S Pfeilschifter J Heringdorf DMZ Sphingosine-1-phosphate receptor-2 antagonists: therapeutic potential and potential risks Front Pharmacol. 2016 7 167 27445808 PMC4914510
  29. [30]Green JA Suzuki K Cho B The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement Nat Immunol. 2011 12 7 672 680 21642988 PMC3158008
  30. [31]Muppidi JR Schmitz R Green JA Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma Nature 2014 516 7530 254 258 25274307 PMC4267955
  31. [32]Wang W Graeler MH Goetzl EJ Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration FASEB J. 2005 19 12 1731 1733 16046470
  32. [33]Jenne CN Enders A Rivera R T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow J Exp Med. 2009 206 11 2469 2481 19808259 PMC2768857
  33. [34]van Doorn R Lopes Pinheiro MA Kooij G Sphingosine 1-phosphate receptor 5 mediates the immune quiescence of the human brain endothelial barrier J Neuroinflamm. 2012 9 133 PMC3425155 22715976
  34. [35]O'Sullivan C Schubart A Mir AK Dev KK The dual S1PR1/S1PR5 drug BAF312 (Siponimod) attenuates demyelination in organotypic slice cultures J Neuroinflamm. 2016 13 31 PMC4746808 26856814
  35. [36]Sukocheva OA Lukina E McGowan E Bishayee A Sphingolipids as mediators of inflammation and novel therapeutic target in inflammatory bowel disease Adv Protein Chem Struct Biol. 2020 120 123 158 32085881
  36. [37]Sugahara K Maeda Y Shimano K Amiselimod, a novel sphingosine 1-phosphate receptor-1 modulator, has potent therapeutic efficacy for autoimmune diseases, with low bradycardia risk Br J Pharmacol. 2017 174 1 15 27 27714763 PMC5221453
  37. [38]Piali L Birker-Robaczewska M Lescop C Cenerimod, a novel selective S1P1 receptor modulator with unique signaling properties Pharmacol Res Perspect. 2017 5 6 e00370 PMC5723703 29226621
  38. [39]Juif PE Kraehenbuehl S Dingemanse J Clinical pharmacology, efficacy, and safety aspects of sphingosine-1-phosphate receptor modulators Expert Opin Drug Metab Toxicol. 2016 12 8 879 895 27249325
  39. [40]Japtok L Kleuser B The role of sphingosine-1-phosphate receptor modulators in the prevention of transplant rejection and autoimmune diseases Curr Opin Investig Drugs. 2009 10 11 1183 1194 19876786
  40. [41]Salvadori M Budde K Charpentier B FTY720 versus MMF with cyclosporine in de novo renal transplantation: a 1-year, randomized controlled trial in Europe and Australasia Am J Transplant. 2006 6 12 2912 2921 17061999
  41. [42]Calabresi PA Radue EW Goodin D Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial Lancet Neurol. 2014 13 6 545 556 24685276
  42. [43]La Mantia L Tramacere I Firwana B Pacchetti I Palumbo R Filippini G Fingolimod for relapsing-remitting multiple sclerosis Cochrane Database Syst Rev. 2016 4 CD009371 27091121 PMC10401910
  43. [44]Baker KF Isaacs JD Novel therapies for immune-mediated inflammatory diseases: What can we learn from their use in rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, psoriasis, Crohn's disease and ulcerative colitis? Ann Rheum Dis. 2018 77 2 175 187 28765121
  44. [45]Khatri BO Pelletier J Kappos L Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing-Remitting Multiple Sclerosis (TRANSFORMS) Mult Scler Relat Disord. 2014 3 3 355 363 25876473
  45. [46]Ramos GP Papadakis KA Mechanisms of disease: inflammatory bowel diseases Mayo Clin Proc. 2019 94 1 155 165 30611442 PMC6386158
  46. [47]Uhlig HH Powrie F Translating immunology into therapeutic concepts for inflammatory bowel disease Annu Rev Immunol. 2018 36 755 781 29677472
  47. [48]Mizushima T Ito T Kishi D Therapeutic effects of a new lymphocyte homing reagent FTY720 in interleukin-10 gene-deficient mice with colitis Inflamm Bowel Dis. 2004 10 3 182 192 15290910
  48. [49]Huwiler A Zangemeister-Wittke U The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: Recent findings and new perspectives Pharmacol Ther. 2018 185 34 49 29127024
  49. [50]Deguchi Y Andoh A Yagi Y The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice Oncol Rep. 2006 16 4 699 703 16969482
  50. [51]Daniel C Sartory N Zahn N Geisslinger G Radeke HH Stein JM FTY720 ameliorates Th1-mediated colitis in mice by directly affecting the functional activity of CD4+CD25+ regulatory T cells J Immunol. 2007 178 4 2458 2468 17277153
  51. [52]Radi ZA Heuvelman DM Masferrer JL Benson EL Pharmacologic evaluation of sulfasalazine, FTY720, and anti-IL-12/23p40 in a TNBS-induced Crohn's disease model Dig Dis Sci. 2011 56 8 2283 2291 21374065
  52. [53]Montrose DC Scherl EJ Bosworth BP S1P1 localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity J Lipid Res. 2013 54 3 843 851 23296878 PMC3617958
  53. [54]Gonzalez-Cabrera PJ Brown S Studer SM Rosen H S1P signaling: new therapies and opportunities F1000Prime Rep. 2014 6 109 25580263 PMC4251414
  54. [55]Radeke H Stein J Van Assche G Rogler G Lakatos P Muellershausen F Moulin P Jarvis P Colin L Gergely P Kruis W A multicentre, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of the s1p receptor agonist KRP203 in patients with moderately active refractory ulcerative colitis Inflamm Intest Dis. 2020 5 4 180 190 33313070 PMC7706482
  55. [56]Lewis JD Chuai S Nessel L Lichtenstein GR Aberra FN Ellenberg JH Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis Inflamm Bowel Dis. 2008 14 12 1660 1666 18623174 PMC2597552
  56. [57]Baron JH Connell AM Lennard-Jones JE variation between observers in describing mucosal appearances in proctocolitis Br Med J. 1964 1 5375 89 92 14075156 PMC1812908
  57. [58]Lamb YN Ozanimod: first approval Drugs 2020 80 8 841 848 32385738
  58. [59]Hemperly A Sandborn WJ Vande CN Clinical pharmacology in adult and pediatric inflammatory bowel disease Inflamm Bowel Dis. 2018 24 12 2527 2542 29788338 PMC11187819
  59. [60]Scott FL Clemons B Brooks J Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity Br J Pharmacol. 2016 173 11 1778 1792 26990079 PMC4867749
  60. [61]Derfuss T Mehling M Papadopoulou A Bar-Or A Cohen JA Kappos L Advances in oral immunomodulating therapies in relapsing multiple sclerosis Lancet Neurol. 2020 19 4 336 347 32059809
  61. [62]Sandborn WJ Feagan BG Wolf DC Ozanimod induction and maintenance treatment for ulcerative colitis N Engl J Med. 2016 374 18 1754 1762 27144850
  62. [63]Sandborn WJ, Feagan BG, Hanauer S, et al. Long-term efficacy and safety of ozanimod in moderate-to-severe ulcerative colitis: results from the open-label extension of the randomized, phase 2 touchstone study [published online ahead of print, 2021 Jan 13]. J Crohns Colitis. 2021;jjab012. PMC8256627 33438008
  63. [65]Feagan BG Sandborn WJ Danese S Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study Lancet Gastroenterol Hepatol. 2020 5 9 819 828 32553149
  64. [66]Ferrante M Colombel JF Sandborn WJ Validation of endoscopic activity scores in patients with Crohn's disease based on a post hoc analysis of data from SONIC Gastroenterology 2013 145 5 978 986.e5 23954314
  65. [67]Best WR Becktel JM Singleton JW Kern F Jr Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study Gastroenterology 1976 70 3 439 444 1248701
  66. [68]Khanna R Zou G D'Haens G A retrospective analysis: the development of patient reported outcome measures for the assessment of Crohn's disease activity Aliment Pharmacol Ther. 2015 41 1 77 86 25348809
  67. [69]Geboes K Riddell R Ost A Jensfelt B Persson T Löfberg R A reproducible grading scale for histological assessment of inflammation in ulcerative colitis Gut 2000 47 3 404 409 10940279 PMC1728046
  68. [70]Pai RK Khanna R D'Haens GR Definitions of response and remission for the Robarts Histopathology Index Gut 2019 68 11 2101 2102 30366909
  69. [71]Al-Shamma H Lehmann-Bruinsma K Carroll C The selective sphingosine 1-phosphate receptor modulator etrasimod regulates lymphocyte trafficking and alleviates experimental colitis J Pharmacol Exp Ther. 2019 369 3 311 317 30872391
  70. [72]Sandborn WJ Peyrin-Biroulet L Zhang J Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis Gastroenterology 2020 158 3 550 561 31711921
  71. [73]Kashou AH, Goyal A, Nguyen T, Chhabra L. Atrioventricular block. In: StatPearls. Treasure Island: StatPearls Publishing; 2021. 29083636
  72. [74]Sugahara K Maeda Y Shimano K Amiselimod (MT-1303), a novel sphingosine 1-phosphate receptor-1 modulator, potently inhibits the progression of lupus nephritis in two murine SLE models J Immunol Res. 2019 2019 5821589 31930150 PMC6942851
  73. [75]Shimano K Maeda Y Kataoka H Amiselimod (MT-1303), a novel sphingosine 1-phosphate receptor-1 functional antagonist, inhibits progress of chronic colitis induced by transfer of CD4+CD45RBhigh T cells PLoS ONE 2019 14 12 e0226154 31805144 PMC6894856
  74. [76]Kappos L Arnold DL Bar-Or A Two-year results from a phase 2 extension study of oral amiselimod in relapsing multiple sclerosis Mult Scler. 2018 24 12 1605 1616 28911260 PMC6196590
  75. [77]A clinical study to investigate the effects of MT-1303 on patients with moderate to severe Chronic Plaque Psoriasis focusing on how safe, tolerable and effective in treating the above condition MT-1303 is. https://www.cochranelibrary.com/es/central/doi/10.1002/central/CN-01799880/full. Accessed 12 Apr 2021. · DOI
  76. [78]D’Haens G Danese S Hibi T Watanabe M Davies M 1005–a controlled trial of amiselimod, a selective S1P receptor modulator in Crohn's disease Gastroenterology 2019 156 S-217 10.1016/S0016-5085(19)37337-8 · DOI
  77. [82]Stephen H, O’Reilly T, Lester R, Slatkin N, Lee J, Franklin H, Bulawski A, Israel R. Safety of amiselimod in healthy subjects: results from a phase 1 randomized, double-blind, placebo-controlled study. Inflamm Bowel Dis (Abstract). 2021;27(Supplement_1):S1. 10.1093/ibd/izaa347.001 · DOI
  78. [83]Greb JE Goldminz AM Elder JT Psoriasis Nat Rev Dis Primers. 2016 2 16082 27883001
  79. [84]Bell M Foley D Naylor C Discovery of super soft-drug modulators of sphingosine-1-phosphate receptor 1 Bioorg Med Chem Lett. 2018 28 19 3255 3259 30143424 PMC6185871
  80. [85]Vaclavkova A Chimenti S Arenberger P Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial Lancet 2014 384 9959 2036 2045 25127208
  81. [86]Tokuyama M Mabuchi T New treatment addressing the pathogenesis of psoriasis Int J Mol Sci. 2020 21 20 7488 PMC7589905 33050592
  82. [87]Ryan C Menter A Ponesimod—a future oral therapy for psoriasis? Lancet 2014 384 9959 2006 2008 25127207
  83. [88]Juif PE Hoch M Vaclavkova A Krause A Bush J Dingemanse J Mitigation of initial cardiodynamic effects of the S1P1 receptor modulator ponesimod using a novel up-titration regimen J Clin Pharmacol. 2017 57 3 401 410 27558098
  84. [89]Jin J Xue N Liu Y A novel S1P1 modulator IMMH002 ameliorates psoriasis in multiple animal models Acta Pharm Sin B. 2020 10 2 276 288 32082973 PMC7016294
  85. [90]Kusari A Han AM Schairer D Eichenfield LF Atopic dermatitis: new developments Dermatol Clin. 2019 37 1 11 20 30466683
  86. [91]Smolen JS Aletaha D McInnes IB Rheumatoid arthritis Lancet 2016 388 10055 2023 2038 27156434
  87. [92]Mao-Draayer Y Sarazin J Fox D Schiopu E The sphingosine-1-phosphate receptor: a novel therapeutic target for multiple sclerosis and other autoimmune diseases Clin Immunol. 2017 175 10 15 27890706 PMC5315594
  88. [93]Zhao C Fernandes MJ Turgeon M Specific and overlapping sphingosine-1-phosphate receptor functions in human synoviocytes: impact of TNF-alpha J Lipid Res. 2008 49 11 2323 2337 18658144
  89. [94]Tsunemi S Iwasaki T Kitano S Imado T Miyazawa K Sano H Effects of the novel immunosuppressant FTY720 in a murine rheumatoid arthritis model Clin Immunol. 2010 136 2 197 204 20421177
  90. [95]Buzard DJ Kim SH Lopez L Discovery of APD334: design of a clinical stage functional antagonist of the sphingosine-1-phosphate-1 receptor ACS Med Chem Lett. 2014 5 12 1313 1317 25516790 PMC4265817
  91. [96]Jin J Ji M Fu R Sphingosine-1-phosphate receptor subtype 1 (S1P1) modulator IMMH001 regulates adjuvant- and collagen-induced arthritis Front Pharmacol. 2019 10 1085 31607926 PMC6761374
  92. [97]Fava A Petri M Systemic lupus erythematosus: diagnosis and clinical management J Autoimmun. 2019 96 1 13 30448290 PMC6310637
  93. [98]Taylor Meadows KR Steinberg MW Clemons B Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus PLoS ONE 2018 13 4 e0193236 29608575 PMC5880347
  94. [99]Little AJ Vesely MD Cutaneous lupus erythematosus: current and future pathogenesis-directed therapies Yale J Biol Med. 2020 93 1 81 95 32226339 PMC7087060
  95. [101]Hermann V Batalov A Smakotina S Juif PE Cornelisse P First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study Lupus Sci Med. 2019 6 1 e000354 31798918 PMC6861098
  96. [102]Strasser DS Froidevaux S Sippel V Preclinical to clinical translation of cenerimod, a novel S1P1 receptor modulator, in systemic lupus erythematosus RMD Open 2020 6 2 e001261 32917831 PMC7722385
  97. [103]Tanaka Y Kondo K Ichibori A Amiselimod, a sphingosine 1-phosphate receptor-1 modulator, for systemic lupus erythematosus: a multicenter, open-label exploratory study Lupus 2020 29 14 1902 1913 33115374
  98. [104]Gladman DD Ibañez D Urowitz MB Systemic lupus erythematosus disease activity index 2000 J Rheumatol. 2002 29 2 288 291 11838846
  99. [105]Moberly JB Ford DM Zahir H Pharmacological effects of CS-0777, a selective sphingosine 1-phosphate receptor-1 modulator: results from a 12-week, open-label pilot study in multiple sclerosis patients J Neuroimmunol. 2012 246 1–2 100 107 22465063
  100. [106]Xu J Gray F Henderson A Safety, pharmacokinetics, pharmacodynamics, and bioavailability of GSK2018682, a sphingosine-1-phosphate receptor modulator, in healthy volunteers Clin Pharmacol Drug Dev. 2014 3 3 170 178 27128606
  101. [107]Arvin AM Wolinsky JS Kappos L Varicella-zoster virus infections in patients treated with fingolimod: risk assessment and consensus recommendations for management JAMA Neurol. 2015 72 1 31 39 25419615 PMC5391035
  102. [108]Chong I Wang KY Lincoln CM Cryptococcal meningitis in a multiple sclerosis patient treated with fingolimod: a case report and review of imaging findings Clin Imaging. 2019 54 53 56 30544079
  103. [109]Urbano M Guerrero M Rosen H Roberts E Modulators of the sphingosine 1-phosphate receptor 1 Bioorg Med Chem Lett. 2013 23 23 6377 6389 24125884 PMC3926431
  104. [110]Juif PE Ufer M Dingemanse J Cardiodynamic interactions between two S1P1 receptor modulators in an experimental clinical setting: different pharmacokinetic properties as an opportunity to mitigate first-dose heart rate effects Int J Mol Sci. 2019 20 13 3232 PMC6651405 31266149
  105. [111]Al-Salama ZT Siponimod: first global approval Drugs 2019 79 9 1009 1015 31144287
  106. [113]Cohen JA Tenenbaum N Bhatt A Zhang Y Kappos L Extended treatment with fingolimod for relapsing multiple sclerosis: the 14-year LONGTERMS study results Ther Adv Neurol Disord. 2019 12 1756286419878324 31598139 PMC6763939
  107. [114]Benedetti MD Marangi A Bozzetti S HPV-related papillary squamous cell carcinoma of the tonsil during treatment with fingolimod Mult Scler Relat Disord. 2018 23 24 26 29734135
  108. [115]Yuza K Nagahashi M Shimada Y Upregulation of phosphorylated sphingosine kinase 1 expression in colitis-associated cancer J Surg Res. 2018 231 323 330 30278948
  109. [116]Khoei SG Sadeghi H Samadi P Najafi R Saidijam M Relationship between Sphk1/S1P and microRNAs in human cancers Biotechnol Appl Biochem. 2020 10.1002/bab.1922 32275078 · DOI
  110. [117]Sukocheva OA Furuya H Ng ML Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target Pharmacol Ther. 2020 207 107464 31863815
  111. [118]Cao M Ji C Zhou Y Sphingosine kinase inhibitors: a patent review Int J Mol Med. 2018 41 5 2450 2460 29484372
  112. [119]Pulkoski-Gross MJ Uys JD Orr-Gandy KA Novel sphingosine kinase-1 inhibitor, LCL351, reduces immune responses in murine DSS-induced colitis Prostaglandins Other Lipid Mediat. 2017 130 47 56 28377281 PMC5509055
  113. [120]Price MM Oskeritzian CA Falanga YT A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent murine model of allergic asthma J Allergy Clin Immunol. 2013 131 2 501 11.e1 22939756 PMC3563730
  114. [121]Shin SH Cho KA Hahn S Inhibiting sphingosine kinase 2 derived-sphingosine-1-phosphate ameliorates psoriasis-like skin disease via blocking Th17 differentiation of naïve CD4 T lymphocytes in mice Acta Derm Venereol. 2019 99 6 594 601 30834454
  115. [122]Huang WC Liang J Nagahashi M Sphingosine-1-phosphate phosphatase 2 promotes disruption of mucosal integrity, and contributes to ulcerative colitis in mice and humans FASEB J. 2016 30 8 2945 2958 27130484 PMC4970610
  116. [123]Shirakabe K Higashiyama M Furuhashi H Amelioration of colitis through blocking lymphocytes entry to Peyer's patches by sphingosine-1-phosphate lyase inhibitor J Gastroenterol Hepatol. 2018 10.1111/jgh.14092 29336057 · DOI
  117. [124]Degagné E Pandurangan A Bandhuvula P Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs J Clin Invest. 2014 124 12 5368 5384 25347472 PMC4348973
  118. [126]Donoviel MS Hait NC Ramachandran S Spinster 2, a sphingosine-1-phosphate transporter, plays a critical role in inflammatory and autoimmune diseases FASEB J. 2015 29 12 5018 5028 26324848 PMC4653056
  119. [127]Naz F Arish M Battling COVID-19 pandemic: sphingosine-1-phosphate analogs as an adjunctive therapy? Front Immunol. 2020 11 1102 32670273 PMC7326128
  120. [128]Foerch C Friedauer L Bauer B Wolf T Adam EH Severe COVID-19 infection in a patient with multiple sclerosis treated with fingolimod Mult Scler Relat Disord. 2020 42 102180 32408155 PMC7202802
  121. [129]Catanzaro M Fagiani F Racchi M Corsini E Govoni S Lanni C Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2 Signal Transduct Target Ther. 2020 5 1 84 32467561 PMC7255975
  122. [130]Comi G Hartung HP Bakshi R Williams IM Wiendl H Benefit-risk profile of sphingosine-1-phosphate receptor modulators in relapsing and secondary progressive multiple sclerosis Drugs 2017 77 16 1755 1768 28905255 PMC5661009
  123. [131]Brinkmann V Billich A Baumruker T Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis Nat Rev Drug Discov. 2010 9 11 883 897 21031003
  124. [132]Brossard P Derendorf H Xu J Maatouk H Halabi A Dingemanse J Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study Br J Clin Pharmacol. 2013 76 6 888 896 23594176 PMC3845312
  125. [133]David OJ Kovarik JM Schmouder RL Clinical pharmacokinetics of fingolimod Clin Pharmacokinet. 2012 51 1 15 28 22149256
  126. [134]Dash RP Rais R Srinivas NR Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator for autoimmune diseases: review of clinical pharmacokinetics and drug disposition Xenobiotica 2018 48 5 442 451 28489480
  127. [135]Boof ML van Lier JJ English S Fischer H Ufer M Dingemanse J Absorption, distribution, metabolism, and excretion of cenerimod, a selective S1P1 receptor modulator in healthy subjects Xenobiotica 2020 50 8 947 956 32105166
  128. [136]Juif PE Baldoni D Reyes M Pharmacokinetics, pharmacodynamics, tolerability, and food effect of cenerimod, a selective S1P1 receptor modulator in healthy subjects Int J Mol Sci. 2017 18 12 2636 PMC5751239 29211013
  129. [137]Gardin A Gray C Neelakantham S Siponimod pharmacokinetics, safety, and tolerability in combination with rifampin, a CYP2C9/3A4 inducer, in healthy subjects Eur J Clin Pharmacol. 2018 74 12 1593 1604 30105453
  130. [139]Hazel K O'Connor A Emerging treatments for inflammatory bowel disease Ther Adv Chronic Dis. 2020 11 2040622319899297 32076497 PMC7003169
  131. [140]Singh S Murad MH Fumery M Dulai PS Sandborn WJ First- and second-line pharmacotherapies for patients with moderate to severely active ulcerative colitis: an updated network meta-analysis Clin Gastroenterol Hepatol. 2020 18 10 2179 2191.e6 31945470 PMC8022894

Cited by

Sorted by citations

Authors
Pérez-Jeldres, T., Alvarez-Lobos, M., & Rivera-Nieves, J.
Affiliations
Pontificia Universidad Católica de Chile (CL)
ORCID
Venue
Drugs
Publisher
Springer Science and Business Media LLC
Published
2021-05-13
Volume
81
Issue
9
Pages
985-1002
ISSN
  • 0012-6667 (ISSN-L)
  • 1179-1950
DOI
10.1007/s40265-021-01528-8
PMC
PMC8116828
OpenAlex
W3162784420
Cited by
197
References
1
Citations by year
2026: 34 · 2025: 42 · 2024: 43 · 2023: 38 · 2022: 33 · 2021: 7
FWCI
3.25
Type
journal article
Language
en
Update notices
correction (2021-07-30)
Open access
Licence
Locations
  • Drugs (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Universidad de Chile (submittedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Veterans Affairs (I01 BX001051)
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (R21AI149636)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK108670, P30DK120515)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sphingolipid Metabolism and Signaling
  • Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
Keywords
sphingosine-1-phosphate, S1P receptor modulators, S1PR1, lymphocyte migration, multiple sclerosis, fingolimod, siponimod, ozanimod, ponesimod, etrasimod, inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus, psoriasis, COVID-19 pandemic, adverse drug reactions, first-dose effect, pharmacokinetics
MeSH terms
Animals, Pharmaceutical Preparations, Humans, Immune System Diseases, Lysophospholipids, Multiple Sclerosis, Sphingosine, Signal Transduction

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review