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

Journal name:
Nature Reviews Rheumatology
Volume:
10,
Pages:
23–34
Year published:
DOI:
doi:10.1038/nrrheum.2013.145
Published online

Abstract

Despite rapid accumulation of knowledge about complex immune dysregulation in systemic lupus erythematosus (SLE) and major primary lupus syndromes, and a plethora of promising new treatments reaching preclinical and early clinical studies, advanced-phase trials of new biologic agents have repeatedly failed to achieve their clinical end points. It is possible that none of these agents work, but the accuracy of this suggestion is as unclear as the case for efficacy, owing to issues in the design of studies and the opacity of the data that have resulted. Disease heterogeneity and complexity might be a hurdle that is simply too high to overcome by existing methodological approaches, and the way forward to interpretable trial results remains unclear. Nonetheless, well-characterized patterns of immune pathology are shared by substantial subsets of patients, and selective targeting of one or more relevant immune system molecules seems to offer the promise of safer and more effective treatments. Evolution dictates a more personalized approach to therapy and trial design, but this option seems challenging in the current economic, regulatory and scientific environment. This Review addresses these concerns by considering the progress of some of the investigational treatments targeting key physiological abnormalities in lupus.

References

  1. Lo, M. S. & Tsokos, G. C. Treatment of systemic lupus erythematosus: new advances in targeted therapy. Ann. NY Acad. Sci. 1247, 138152 (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, 10251027 (2010).
  3. Niewold, T. B. Interferon α as a primary pathogenic factor in human lupus. J. Interferon Cytokine Res. 31, 887892 (2011).
  4. Davidson, A. The rationale for BAFF inhibition in systemic lupus erythematosus. Curr. Rheumatol. Rep. 14, 295302 (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, 721731 (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, 39183930 (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, 222233 (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, 12151226 (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, 30773087 (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, S962S963 (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), ii56ii61 (2013).
  14. Crispin, J. C., Hedrich, C. M. & Tsokos, G. C. Gene-function studies in systemic lupus erythematosus. Nat. Rev. Rheumatol. 9, 476484 (2013).
  15. Gonzalez-Navajas, J. M., Lee, J., David, M. & Raz, E. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 12, 125135 (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, 280289 (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, 543551 (2007).
  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, 871882 (2012).
  20. Knight, J. S. & Kaplan, M. J. Lupus neutrophils: 'NET' gain in understanding lupus pathogenesis. Curr. Opin. Rheumatol. 24, 441450 (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, 210221 (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, 19051913 (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, 10111021 (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, 447456 (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].
  27. US National Library of Medicine. ClinicalTrials.gov [online].
  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, 27542761 (1995).
  30. Hansen, K. E., Arnason, J. & Bridges, A. J. Autoantibodies and common viral illnesses. Semin. Arthritis Rheum. 27, 263271 (1998).
  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, 325329 (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, 482487 (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, 35863592 (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, 357364 (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, 25802589 (2004).
  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, 3343 (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, 391397 (2008).
  43. Vital, E. M. et al. B cell biomarkers of rituximab responses in systemic lupus erythematosus. Arthritis Rheum. 63, 30383047 (2011).
  44. Merrill, J. et al. Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER). Lupus 20, 709716 (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, 11681178 (2009).
  46. Furie, R. A. et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 61, 11431151 (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, 13431349 (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, 20582066 (2011).
  49. Crispin, J. C., Kyttaris, V. C., Terhorst, C. & Tsokos, G. C. T cells as therapeutic targets in SLE. Nat. Rev. Rheumatol. 6, 317325 (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, 19601966 (2007).
  51. Sidiropoulos, P. I. & Boumpas, D. T. Lessons learned from anti-CD40L treatment in systemic lupus erythematosus patients. Lupus 13, 391397 (2004).
  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, 32513258 (2002).
  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, 719727 (2003).
  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, 15771583 (2010).
  55. US National Library of Medicine. ClinicalTrials.gov [online].
  56. Wofsy, D., Hillson, J. L. & Diamond, B. Abatacept for lupus nephritis: alternative definitions of complete response support conflicting conclusions. Arthritis Rheum. 64, 36603665 (2012).
  57. US National Library of Medicine. ClinicalTrials.gov [online].
  58. US National Library of Medicine. ClinicalTrials.gov [online].
  59. Giacomini, P. S. & Bar-Or, A. Laquinimod in multiple sclerosis. Clin. Immunol. 142, 3843 (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].
  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, 15791588 (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, 1624 (2011).
  66. Willis, M. A. & Cohen, J. A. Fingolimod therapy for multiple sclerosis. Semin. Neurol. 33, 3744 (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, 349362 (2011).
  68. US National Library of Medicine. ClinicalTrials.gov [online].
  69. Schall, N. et al. Peptide-based approaches to treat lupus and other autoimmune diseases. J. Autoimmun. 39, 143153 (2012).
  70. Monneaux, F. et al. Selective modulation of CD4+ T cells from lupus patients by a promiscuous, protective peptide analog. J. Immunol. 175, 58395847 (2005).
  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, 339347 (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, 33753383 (2011).
  75. Kurzeja, M., Rudnicka, L. & Olszewska, M. New interleukin-23 pathway inhibitors in dermatology: ustekinumab, briakinumab, and secukinumab. Am. J. Clin. Dermatol. 12, 113125 (2011).
  76. Li, J., Wang, X., Zhang, F. & Yin, H. Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases. Pharmacol. Ther. 138, 441451 (2013).
  77. Aringer, M. & Smolen, J. S. Therapeutic blockade of TNF in patients with SLE—promising or crazy? Autoimmun. Rev. 11, 321325 (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, 983994 (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, 41424150 (2007).
  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, 547555 (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, 257270 (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, 493503 (2012).
  86. Mozes, E. & Sharabi, A. A novel tolerogenic peptide, hCDR1, for the specific treatment of systemic lupus erythematosus. Autoimmun. Rev. 10, 2226 (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, 24702480 (2008).
  88. Mosca, M., Baldini, C. & Bombardieri, S. LJP-394 (abetimus sodium) in the treatment of systemic lupus erythematosus. Expert Opin. Pharmacother. 8, 873879 (2007).
  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, 306307 (2009).
  90. Smith, K. G. & Clatworthy, M. R. FcγRIIB in autoimmunity and infection: evolutionary and therapeutic implications. Nat. Rev. Immunol. 10, 328343 (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, 542552 (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, 112 (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, 304314 (2012).
  94. Llorente, L. et al. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum. 43, 17901800 (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, 20862092 (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, 523529 (2011).
  97. Tagoe, C. & Putterman, C. JAK2 inhibition in murine systemic lupus erythematosus. Immunotherapy 4, 369372 (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, 281288 (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, 776780 (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, 29832988 (2006).
  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, 29372946 (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, 656661 (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, 804810 (2010).
  104. US National Library of Medicine. ClinicalTrials.gov [online].
  105. US National Library of Medicine. ClinicalTrials.gov [online].
  106. US National Library of Medicine. ClinicalTrials.gov [online].
  107. US National Library of Medicine. ClinicalTrials.gov [online].
  108. US National Library of Medicine. ClinicalTrials.gov [online].
  109. US National Library of Medicine. ClinicalTrials.gov [online].
  110. US National Library of Medicine. ClinicalTrials.gov [online].
  111. US National Library of Medicine. ClinicalTrials.gov [online].
  112. US National Library of Medicine. ClinicalTrials.gov [online].
  113. US National Library of Medicine. ClinicalTrials.gov [online].
  114. US National Library of Medicine. ClinicalTrials.gov [online].
  115. US National Library of Medicine. ClinicalTrials.gov [online].
  116. US National Library of Medicine. ClinicalTrials.gov [online].
  117. US National Library of Medicine. ClinicalTrials.gov [online].
  118. US National Library of Medicine. ClinicalTrials.gov [online].
  119. US National Library of Medicine. ClinicalTrials.gov [online].
  120. US National Library of Medicine. ClinicalTrials.gov [online].
  121. US National Library of Medicine. ClinicalTrials.gov [online].
  122. US National Library of Medicine. ClinicalTrials.gov [online].
  123. US National Library of Medicine. ClinicalTrials.gov [online].
  124. US National Library of Medicine. ClinicalTrials.gov [online].
  125. US National Library of Medicine. ClinicalTrials.gov [online].
  126. US National Library of Medicine. ClinicalTrials.gov [online].
  127. US National Library of Medicine. ClinicalTrials.gov [online].
  128. US National Library of Medicine. ClinicalTrials.gov [online].

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Author information

Affiliations

  1. Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, MS 22, Oklahoma City, OK 73104, USA.

    • Aikaterini Thanou
  2. Clinical Pharmacology Research Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, MS 22, Oklahoma City, OK 73104, USA.

    • Joan T. Merrill

Contributions

A. Thanou researched data for the article and wrote the first draft of the manuscript. J. T. Merrill expanded the content of the article and reviewed/edited the manuscript before submission.

Competing interests statement

A. Thanou declares that she has received a one-year research grant from RDRCC for funding of a clinical trial of dipyridamole in the treatment of lupus. J. T. Merrill declares that she has received speaking, consulting and/or training fees from Abbott/Abbvie, Amgen, Argos, Astellas, Baxter, Biogen Idec, Bristol Myers Squibb, Cephalon, DSMB, Dynavax, Eisai, EMD Serono, Genentech/Roche, HGS/GlaxoSmithKline, Idera, InCyte, Kirin, Lilly, Macrogenics, MedImmune/AstraZeneca, Neovacs, Novo Nordisk, Ono, Parexel, Pfizer, Questcor, RPS, Takeda and UCB, and has participated in clinical trial adjudication for DSMB.

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Author details

  • Aikaterini Thanou

    Aikaterini Thanou is a clinical assistant member at the Arthritis and Clinical Immunology Research Program of the Oklahoma Medical Research Foundation, Oklahoma City, USA, where she is involved in the study of novel biologic agents for systemic lupus erythematosus (SLE). She has applied novel trial designs to cohort and investigator-initiated interventional trials in order to increase the discrimination of end points useful for treatment development in this heterogeneous disease.

  • Joan T. Merrill

    Joan T. Merrill is a member of the Oklahoma Medical Research Foundation and Head of the Clinical Pharmacology Research Program at that institution. She has participated in more than 30 clinical studies for SLE since 1993 and has more than 150 publications in the field. She is the Medical Director of the Lupus Foundation of America and the Principal Investigator of the BOLD (Biomarkers of Lupus Disease) study, which is evaluating the mechanistic impact of background immunosuppressants commonly used in interventional SLE trials.

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