Treatment of systemic lupus erythematosus: New therapeutic avenues and blind alleys

Nature Reviews Rheumatology

Volumn 10, Issue 1, 2014, Pages 23-34

  Thanou, Aikaterini ^a   Merrill, Joan T ^a  

^a OKLAHOMA MEDICAL RESEARCH FOUNDATION   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2 AMINO 2 [2 [4 (3 BENZYLOXYPHENYLTHIO) 2 CHLOROPHENYL]ETHYL] 1,3 PROPANEDIOL; ABATACEPT; ABR 215757; AZATHIOPRINE; B CELL ACTIVATING FACTOR; BELIMUMAB; BLISIBIMOD; EPRATUZUMAB; FORIGERIMOD; INTERFERON; LAQUINIMOD; METHOTREXATE; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; OCRELIZUMAB; PAQUINIMOD; PLACEBO; RITUXIMAB; RONTALIZUMAB; SIFALIMUMAB; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; B LYMPHOCYTE; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG MEGADOSE; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; HUMAN; IMMUNOPATHOGENESIS; INNATE IMMUNITY; LUPUS ERYTHEMATOSUS NEPHRITIS; MULTICENTER STUDY (TOPIC); MULTIPLE SCLEROSIS; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; SLEDAI; SYSTEMIC LUPUS ERYTHEMATOSUS; T LYMPHOCYTE; TREATMENT DURATION;

ADAPTIVE IMMUNITY; HUMANS; IMMUNITY, INNATE; IMMUNOTHERAPY; INTERFERONS; LUPUS ERYTHEMATOSUS, SYSTEMIC; SIGNAL TRANSDUCTION;

EID: 84891160297     PISSN: 17594790     EISSN: 17594804     Source Type: Journal    
DOI: 10.1038/nrrheum.2013.145     Document Type: Review

References (128)

1. Lo, M. S. & Tsokos, G. C. Treatment of systemic lupus erythematosus: new advances in targeted therapy. Ann. NY Acad. Sci. 1247, 138-152 (2012).
2. Bruce, I. N., Gordon, C., Merrill, J. T. & Isenberg, D. Clinical trials in lupus: what have we learned so far? Rheumatology (Oxford) 49, 1025-1027 (2010).
3. Niewold, T. B. Interferon α as a primary pathogenic factor in human lupus. J. Interferon Cytokine Res. 31, 887-892 (2011).
4. Davidson, A. The rationale for BAFF inhibition in systemic lupus erythematosus. Curr. Rheumatol. Rep. 14, 295-302 (2012).
5. Kalunian, K. et al. Efficacy and safety of rontalizumab (anti-interferon α) in SLE subjects with restricted immunosuppressant use: results of a randomized, double-blind, placebo-controlled phase 2 study. Arthritis Rheum. 64, S1111 (2012).
6. Navarra, S. V. et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial. Lancet 377, 721-731 (2011).
7. Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 63, 3918-3930 (2011).
8. Merrill, J. T. et al. Efficacy and safety of rituximab in moderately to severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 62, 222-233 (2010).
9. Rovin, B. H. et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 64, 1215-1226 (2012).
10. Merrill, J. T. et al. The efficacy and safety of abatacept in patients with non life threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 62, 3077-3087 (2010).
11. Furie, R. et al. Efficacy and safety of abatacept over 12 months in patients with lupus nephritis: results from a multicenter, randomized, double-blind, placebo-controlled phase II/III study. Arthritis Rheum. 63, S962-S963 (2011).
12. Thanou, A. & Merrill, J. T. Top. 10 things to know about lupus activity measures. Curr. Rheumatol. Rep. 15, 334 (2013).
13. Rullo, O. J. & Tsao, B. P. Recent insights into the genetic basis of systemic lupus erythematosus. Ann. Rheum. Dis. 72 (Suppl. 2), ii56-ii61 (2013).
14. Crispin, J. C., Hedrich, C. M. & Tsokos, G. C. Gene-function studies in systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 476-484 (2013).
15. Gonzalez-Navajas, J. M., Lee, J., David, M. & Raz, E. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 12, 125-135 (2012).
16. Munoz, L. E., Lauber, K., Schiller, M., Manfredi, A. A. & Herrmann, M. The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat. Rev. Rheumatol. 6, 280-289 (2010).
17. Baccala, R., Hoebe, K., Kono, D. H., Beutler, B. & Theofilopoulos, A. N. TLR-dependent and TLR-independent pathways of type I interferon induction in systemic autoimmunity. Nat. Med. 13, 543-551 (2007). (Pubitemid 46828489)
18. Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011).
19. Liu, Z. & Davidson, A. Taming lupus - a new understanding of pathogenesis is leading to clinical advances. Nat. Med. 18, 871-882 (2012).
20. Knight, J. S. & Kaplan, M. J. Lupus neutrophils: 'NET' gain in understanding lupus pathogenesis. Curr. Opin. Rheumatol. 24, 441-450 (2012).
21. Lichtman, E. I., Helfgott, S. M. & Kriegel, M. A. Emerging therapies for systemic lupus erythematosus - focus on targeting interferon-α. Clin. Immunol. 143, 210-221 (2012).
22. Merrill, J. T. et al. Safety profile and clinical activity of sifalimumab, a fully human anti-interferon α monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann. Rheum. Dis. 70, 1905-1913 (2011).
23. Petri, M. et al. Sifalimumab, a human anti interferon α monoclonal antibody, in systemic lupus erythematosus: a phase 1 randomized controlled, dose-escalation study. Arthritis Rheum. 65, 1011-1021 (2013).
24. Lauwerys, B. R. et al. Down-regulation of interferon signature in systemic lupus erythematosus patients by active immunization with interferon α-kinoid. Arthritis Rheum. 65, 447-456 (2013).
25. Tcherepanova, I., Curtis, M., Sale, M., Miesowicz, F. & Nicolette, C. Results of a randomized placebo controlled phase IA study of AGS 009, a humanized anti inteferon α monoclonal antibody in subjects with systemic lupus erythematosus. Ann. Rheum. Dis. 71, 536 (2012).
26. US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT01031836?term=NCT01031836&rank=1.
27. US National Library of Medicine. ClinicalTrials.gov [online], http://www.clinicaltrials.gov/ct2/show/NCT00657189?term=NCT00657189&rank=1.
28. Gronwall, C., Vas, J. & Silverman, G. J. Protective roles of natural IgM antibodies. Front. Immunol. 3, 66 (2012).
29. Stafford, H. A., Anderson, C. J. & Reichlin, M. Unmasking of anti-ribosomal P autoantibodies in healthy individuals. J. Immunol. 155, 2754-2761 (1995).
30. Hansen, K. E., Arnason, J. & Bridges, A. J. Autoantibodies and common viral illnesses. Semin. Arthritis Rheum. 27, 263-271 (1998). (Pubitemid 28176232)
31. Marin, G. G., Cardiel, M. H., Cornejo, H. & Viveros, M. E. Prevalence of antinuclear antibodies in 3 groups of healthy individuals: blood donors, hospital personnel, and relatives of patients with autoimmune diseases. J. Clin. Rheumatol. 15, 325-329 (2009).
32. Lu, T. Y. et al. A retrospective seven-year analysis of the use of B cell depletion therapy in systemic lupus erythematosus at University College London Hospital: the first fifty patients. Arthritis Rheum. 61, 482-487 (2009).
33. Catapano, F., Chaudhry, A. N., Jones, R. B., Smith, K. G. & Jayne, D. W. Long-term efficacy and safety of rituximab in refractory and relapsing systemic lupus erythematosus. Nephrol. Dial. Transplant. 25, 3586-3592 (2010).
34. Diaz-Lagares, C. et al. Efficacy of rituximab in 164 patients with biopsy-proven lupus nephritis: pooled data from European cohorts. Autoimmun. Rev. 11, 357-364 (2012).
35. Reddy, V., Jayne, D., Close, D. & Isenberg, D. A. B cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design. Arthritis Res. Ther. 15, S2 (2013).
36. Looney, R. J. et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum. 50, 2580-2589 (2004). (Pubitemid 39062719)
37. Mei, H. E., Schmidt, S. & Dorner, T. Rationale of anti-CD19 immunotherapy: an option to target autoreactive plasma cells in autoimmunity. Arthritis Res. Ther. 14 (Suppl. 5), S1 (2012).
38. Mysler, E. F. et al. Efficacy and safety of ocrelizumab, a humanized antiCD20 antibody, in patients with active proliferative lupus nephritis (LN): results from the randomized, double-blind phase III BELONG study. Arthritis Rheum. 62, S607 (2010).
39. Thanou-Stavraki, A. & Sawalha, A. H. An update on belimumab for the treatment of lupus. Biologics 5, 33-43 (2011).
40. Wallace, D. J. et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-202760.
41. Furie, R. A. et al. Effects of blisibimod, a sucutaneous inhibitor of B cell activating factor, in patients with SLE. Ann. Rheum. Dis. 72 (Suppl. 3), 90 (2013).
42. Fillatreau, S., Gray, D. & Anderton, S. M. Not always the bad guys: B cells as regulators of autoimmune pathology. Nat. Rev. Immunol. 8, 391-397 (2008). (Pubitemid 351595221)
43. Vital, E. M. et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum. 63, 3038-3047 (2011).
44. Merrill, J. et al. Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER). Lupus 20, 709-716 (2011).
45. Wallace, D. J. et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum. 61, 1168-1178 (2009).
46. Furie, R. A. et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 61, 1143-1151 (2009).
47. van Vollenhoven, R. F. et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann. Rheum. Dis. 71, 1343-1349 (2012).
48. Kyttaris, V. C., Zhang, Z., Kampagianni, O. & Tsokos, G. C. Calcium signaling in systemic lupus erythematosus T cells: a treatment target. Arthritis Rheum. 63, 2058-2066 (2011).
49. Crispin, J. C., Kyttaris, V. C., Terhorst, C. & Tsokos, G. C. T cells as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 317-325 (2010).
50. Kyttaris, V. C., Wang, Y., Juang, Y. T., Weinstein, A. & Tsokos, G. C. Increased levels of NF ATc2 differentially regulate CD154 and IL 2 genes in T cells from patients with systemic lupus erythematosus. J. Immunol. 178, 1960-1966 (2007). (Pubitemid 46154669)
51. Sidiropoulos, P. I. & Boumpas, D. T. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 13, 391-397 (2004). (Pubitemid 38788502)
52. Kalunian, K. C., Davis, J. C. Jr, Merrill, J. T., Totoritis, M. C. & Wofsy, D. Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 3251-3258 (2002). (Pubitemid 35453534)
53. Boumpas, D. T. et al. A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum. 48, 719-727 (2003). (Pubitemid 36302008)
54. Robles-Carrillo, L. et al. Anti-CD40L immune complexes potently activate platelets in vitro and cause thrombosis in FCGR2A transgenic mice. J. Immunol. 185, 1577-1583 (2010).
55. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01093911?term=NCT01093911&rank=1.
56. Wofsy, D., Hillson, J. L. & Diamond, B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis Rheum. 64, 3660-3665 (2012).
57. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00774852?term=NCT00774852&rank=1.
58. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00094380?term=NCT00094380&rank=1.
59. Giacomini, P. S. & Bar-Or, A. Laquinimod in multiple sclerosis. Clin. Immunol. 142, 38-43 (2012).
60. Hahn, B. H., Wong, M., Lourenco, E. & Skaggs, B. Laquinimod (LAQ) is equivalent to mycophenolate mofetil (MMF) in preventing and suppressing murine lupus nephritis and has greater effects on myeloid/monocyte/macrophage cells. Arthritis Rheum. 64, S1032 (2012).
61. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01085084?term=NCT01085084&rank=1.
62. Jayne, D. et al. A randomized controlled study of laquinimod in active lupus nephritis patients in combination with standard of care. Ann. Rheum. Dis. 72, 164 (2013).
63. Bengtsson, A. A. et al. Pharmacokinetics, tolerability, and preliminary efficacy of paquinimod (ABR 215757), a new quinoline 3 carboxamide derivative: studies in lupus-prone mice and a multicenter, randomized, double-blind, placebo-controlled, repeat-dose, dose-ranging study in patients with systemic lupus erythematosus. Arthritis Rheum. 64, 1579-1588 (2012).
64. Bengtsson, A. et al. An exploratory study to evaluate changes in disease activity and biomarkers during treatment with ABR 215757 in patients with mild active systemic lupus erythematosus (SLE). Ann. Rheum. Dis. 70, 316 (2011).
65. Chi, H. Sphingosine 1 phosphate and immune regulation: trafficking and beyond. Trends Pharmacol. Sci. 32, 16-24 (2011).
66. Willis, M. A. & Cohen, J. A. Fingolimod therapy for multiple sclerosis. Semin. Neurol. 33, 37-44 (2013).
67. Sun, Y. et al. FTY720-induced conversion of conventional Foxp3- CD4+ T cells to Foxp3+ regulatory T cells in NOD mice. Am. J. Reprod. Immunol. 66, 349-362 (2011).
68. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01294774?term=NCT01294774&rank=1.
69. Schall, N. et al. Peptide-based approaches to treat lupus and other autoimmune diseases. J. Autoimmun. 39, 143-153 (2012).
70. Monneaux, F. et al. Selective modulation of CD4+ T cells from lupus patients by a promiscuous, protective peptide analog. J. Immunol. 175, 5839-5847 (2005). (Pubitemid 41508068)
71. Zimmer, R., Scherbarth, H. R., Rillo, O. L., Gomez-Reino, J. J. & Muller, S. Lupuzor/P140 peptide in patients with systemic lupus erythematosus: a randomised, double-blind, placebo-controlled phase IIb clinical trial. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2012-202460.
72. Zimmer, R., Wallace, D. J. & Muller, S. Randomized, double-blind, placebo-controlled studies of P140 peptide in mannitol (Lupuzor) and trehalose (Forigerimod) in patients with SLE. Arthritis Rheum. 64, S1110 (2012).
73. Ronnblom, L. & Elkon, K. B. Cytokines as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 339-347 (2010).
74. Jones, S. A., Scheller, J. & Rose-John, S. Therapeutic strategies for the clinical blockade of IL 6/gp130 signaling. J. Clin. Invest. 121, 3375-3383 (2011).
75. Kurzeja, M., Rudnicka, L. & Olszewska, M. New interleukin 23 pathway inhibitors in dermatology: ustekinumab, briakinumab, and secukinumab. Am. J. Clin. Dermatol. 12, 113-125 (2011).
76. Li, J., Wang, X., Zhang, F. & Yin, H. Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases. Pharmacol. Ther. 138, 441-451 (2013).
77. Aringer, M. & Smolen, J. S. Therapeutic blockade of TNF in patients with SLE - promising or crazy? Autoimmun. Rev. 11, 321-325 (2012).
78. Fleischmann, R. M. et al. Evidence of peripheral B cell depletion in subjects with controlled systemic lupus erythematosus (SLE) following subcutaneous administration of SBI 087. Arthritis Rheum. 62, S1154 (2010).
79. Czuczman, M. S. & Gregory, S. A. The future of CD20 monoclonal antibody therapy in B cell malignancies. Leuk. Lymphoma 51, 983-994 (2010).
80. Shaw, M. et al. The effects of repeated doses of briobacept (BR3-Fc) in patients with rheumatoid arthritis. Ann. Rheum. Dis. 67, 87 (2008).
81. Dall'Era, M. et al. Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis Rheum. 56, 4142-4150 (2007). (Pubitemid 350262342)
82. Pena-Rossi, C. et al. An exploratory dose-escalating study investigating the safety, tolerability, pharmacokinetics and pharmacodynamics of intravenous atacicept in patients with systemic lupus erythematosus. Lupus 18, 547-555 (2009).
83. Ginzler, E. M. et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res. Ther. 14, R33 (2012).
84. Seavey, M. M., Lu, L. D., Stump, K. L., Wallace, N. H. & Ruggeri, B. A. Novel, orally active, proteasome inhibitor, delanzomib (CEP 18770), ameliorates disease symptoms and glomerulonephritis in two preclinical mouse models of SLE. Int. Immunopharmacol. 12, 257-270 (2012).
85. Ichikawa, H. T. et al. Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells. Arthritis Rheum. 64, 493-503 (2012).
86. Mozes, E. & Sharabi, A. A novel tolerogenic peptide, hCDR1, for the specific treatment of systemic lupus erythematosus. Autoimmun. Rev. 10, 22-26 (2010).
87. Cardiel, M. H. et al. Abetimus sodium for renal flare in systemic lupus erythematosus: results of a randomized, controlled phase III trial. Arthritis Rheum. 58, 2470-2480 (2008).
88. Mosca, M., Baldini, C. & Bombardieri, S. LJP 394 (abetimus sodium) in the treatment of systemic luus erythematosus. Expert Opin. Pharmacother. 8, 873-879 (2007). (Pubitemid 46736459)
89. Merrill, J. T. & Buyon, J. P. Connective tissue diseases: What does the death of Riquent hold for the future of SLE? Nat. Rev. Rheumatol. 5, 306-307 (2009).
90. Smith, K. G. & Clatworthy, M. R. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat. Rev. Immunol. 10, 328-343 (2010).
91. Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 62, 542-552 (2010).
92. Yeilding, N. et al. Development of the IL 12/23 antagonist ustekinumab in psoriasis: past, present, and future perspectives - an update. Ann. NY Acad. Sci. 1263, 1-12 (2012).
93. Gordon, K. B. et al. A phase III, randomized, controlled trial of the fully human IL 12/23 mAb briakinumab in moderate to severe psoriasis. J. Invest. Dermatol. 132, 304-314 (2012).
94. Llorente, L. et al. Clinical and biologic effects of anti interleukin 10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum. 43, 1790-1800 (2000).
95. Deng, G. M., Liu, L., Bahjat, F. R., Pine, P. R. & Tsokos, G. C. Suppression of skin and kidney disease by inhibition of spleen tyrosine kinase in lupus-prone mice. Arthritis Rheum. 62, 2086-2092 (2010).
96. Ichinose, K., Juang, Y. T., Crispin, J. C., Kis-Toth, K. & Tsokos, G. C. Suppression of autoimmunity and organ pathology in lupus-prone mice upon inhibition of calcium/calmodulin-dependent protein kinase type IV. Arthritis Rheum. 63, 523-529 (2011).
97. Tagoe, C. & Putterman, C. JAK2 inhibition in murine systemic lupus erythematosus. Immunotherapy 4, 369-372 (2012).
98. Deng, J., Huo, D., Wu, Q., Yang, Z. & Liao, Y. A meta-analysis of randomized controlled trials comparing tacrolimus with intravenous cyclophosphamide in the induction treatment for lupus nephritis. Tohoku J. Exp. Med. 227, 281-288 (2012).
99. Barikbin, B., Givrad, S., Yousefi, M. & Eskandari, F. Pimecrolimus 1% cream versus betamethasone 17-valerate 0.1% cream in the treatment of facial discoid lupus erythematosus: a double-blind, randomized pilot study. Clin. Exp. Dermatol. 34, 776-780 (2009).
100. Fernandez, D., Bonilla, E., Mirza, N., Niland, B. & Perl, A. Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum. 54, 2983-2988 (2006). (Pubitemid 44497779)
101. Lai, Z. W. et al. N acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 64, 2937-2946 (2012).
102. Stirzaker, R. A. et al. Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice. Lupus 21, 656-661 (2012).
103. Ando, S. et al. FTY720 exerts a survival advantage through the prevention of end-stage glomerular inflammation in lupus-prone BXSB mice. Biochem. Biophys. Res. Commun. 394, 804-810 (2010).
104. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01559090?term=NCT01559090&rank=1.
105. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01438489?term=NCT01438489&rank=1.
106. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01753193?term=NCT01753193&rank=1.
107. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01622348?term=NCT01622348&rank=1.
108. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00368264?term=NCT00368264&rank=1.
109. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00797784?term=NCT00797784&rank=1.
110. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00447265?term=NCT00447265&rank=1.
111. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00539838?term=NCT00539838&rank=1.
112. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01408576?term=NCT01408576&rank=1.
113. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01262365?term=NCT01262365&rank=1.
114. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01261793?term=NCT01261793&rank=1.
115. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01196091?term=NCT01196091&rank=1.
116. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01205438?term=NCT01205438&rank=1.
117. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01395745?term=NCT01395745&rank=1.
118. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00624338?term=NCT00624338&rank=1.
119. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01169857?term=NCT01169857&rank=1.
120. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00774943?term=NCT00774943&rank=1.
121. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01273389?term=NCT01273389&rank=1.
122. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01689025?term=NCT01689025&rank=1.
123. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00818948?term=NCT00818948&rank=1.
124. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01164917?term=NCT01164917&rank=1.
125. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01597050?term=NCT01597050&rank=1.
126. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01781611?term=NCT01781611&rank=1.
127. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT00779194?term=NCT00779194&rank=1.
128. US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/NCT01085097?term=NCT01085097&rank=1.