Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Challenges in bringing the bench to bedside in drug development for sle

Key Points

  • Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder that can involve any organ system, most commonly joints, skin and kidneys.

  • The hallmark of SLE is a diverse but characteristic set of autoantibodies that can bind to both intracellular and extracellular structures.

  • Current management of SLE is not evidence-based; many drugs remain unapproved by the FDA for lupus, understudied and substandard with regard to optimal administration, dosing and monitoring.

  • Current models of lupus pathogenesis have provided a theoretical framework for understanding how heterogenous genetic defects might combine in various ways to increase susceptibility to SLE in different individuals.

  • Targeted immune therapies raise both hopes and concerns for SLE patients. Further development of targeted immune-modulating therapies will lead to safer and more specific treatments for SLE; however, caution is advised in a population already at increased risk for thrombosis, vasculitis and atherosclerosis.

Abstract

It is now widely accepted that the current standard of care for systemic lupus erythematosus (SLE) patients is inadequate. There has not been a new medication approved for this disease in thirty years. Attempts to develop and test new drugs have been ongoing since the mid-1990s, but have encountered formidable obstacles. Current models for lupus pathogenesis have provided a theoretical framework for understanding how heterogeneous genetic defects might combine in various ways to increase susceptibility to SLE in different individuals, and could have important implications for new drug development. With the current burst of drug discovery and increased public awareness of SLE, the impetus to overcome these obstacles has never been greater.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Immune system in SLE.

Similar content being viewed by others

References

  1. Boumpas, D. T. et al. Systemic lupus erythematosus: emerging concepts. Part 1: renal, neuropsychiatric, cardiovascular, pulmonary, and hematologic disease. Ann. Intern. Med. 122, 940–950 (1995). A review article on the pathogenesis, diagnosis and management of dermatological and joint manifestations of SLE.

    Article  CAS  PubMed  Google Scholar 

  2. Boumpas, D. T. et al. Systemic lupus erythematosus: emerging concepts. Part 2: dermatologic and joint disease, the antiphospholipid antibody syndrome, pregnancy and hormonal therapy, morbidity and mortality, and pathogenesis. Ann. Intern. Med. 123, 42–53 (1995). A review article on the pathogenesis, diagnosis and management of visceral manifestations of SLE.

    Article  CAS  PubMed  Google Scholar 

  3. Tan, E. M. et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 25, 1271–1277 (1982). This paper describes the 1982 revised classification criteria for SLE.

    Article  CAS  PubMed  Google Scholar 

  4. Hochberg, M. C. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 40, 1725 (1997). Provides an updated version of the 1982 revised classification criteria for SLE.

    Article  CAS  PubMed  Google Scholar 

  5. Mohan, C., Yu, Y., Morel, L., Yang, P. & Wakeland, E. K. Genetic dissection of SLE pathogenesis: Sle3 on murine chromosome 7 impacts T cell activation, differentiation, and cell death. J. Immunol. 162, 6492–6502 (1999).

    CAS  PubMed  Google Scholar 

  6. Morel, L. et al. Multiplex inheritance of component phenotypes in a murine model of lupus. Mamm. Genome. 10, 176–181 (1999).

    Article  CAS  PubMed  Google Scholar 

  7. Alarcon-Riquelme, M. E. & Prokunina, L. Finding genes for SLE: complex interactions and complex populations. J. Autoimmun. 21, 117–120 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Namjou, B. et al. Stratification of pedigrees multiplex for systemic lupus erythematosus and for self-reported rheumatoid arthritis detects a systemic lupus erythematosus susceptibility gene (SLER1) at 5p15. 3. Arthritis Rheum. 46, 2937–2945 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Tsao, B. P. et al. Linkage and interaction of loci on 1q23 and 16q12 may contribute to susceptibility to systemic lupus erythematosus. Arthritis Rheum. 46, 2928–2936 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Olson, J. M. et al. A genome screen of systemic lupus erythematosus using affected-relative-pair linkage analysis with covariates demonstrates genetic heterogeneity. Genes Immun. 3 (Suppl. 1), S5–S12 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Arbuckle, M. R., Reichlin, M., Harley, J. B. & James, J. A. Shared early autoantibody recognition events in the development of anti-Sm B/B' in human lupus. Scand. J. Immunol. 50, 447–455 (1999).

    Article  CAS  PubMed  Google Scholar 

  12. James, J. A. & Harley, J. B. A model of peptide-induced lupus autoimmune B cell epitope spreading is strain specific and is not H-2 restricted in mice. J. Immunol. 160, 502–508 (1998).

    CAS  PubMed  Google Scholar 

  13. Kammer, G. M., Laxminarayana, D. & Khan, I. U. Mechanisms of deficient Type I protein kinase A activity in lupus T lymphocytes. Int. Rev. Immunol. 23, 225–244 (2004).

    Article  CAS  PubMed  Google Scholar 

  14. Takeuchi, T., Tsuzaka, K. & Abe, T. Altereed expression of the T cell receptor–CD3 complex in sle. Int. Rev. Immunol. 23, 273–291 (2004).

    Article  CAS  PubMed  Google Scholar 

  15. Grammer, A. C. & Lipsky, P. E. B cell abnormalities in systemic lupus erythematosus. Arthritis Res. Ther. 5 (Suppl. 4), S22–27 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kim, S. J., Gershov, D., Ma, X., Brot, N. & Elkon, K. B. Opsonization of apoptotic cells and its effect on macrophage and T cell immune responses. Ann. NY Acad. Sci. 987, 68–78 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Ravirajan, C. T., Pittoni, V. & Isenberg, D. A. Apoptosis in human autoimmune diseases. Int. Rev. Immunol. 18, 563–589 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Grodzicky, T. & Elkon, K. B. Apoptosis: a case where too much or too little can lead to autoimmunity. Mt Sinai J. Med. 69, 208–219 (2002).

    PubMed  Google Scholar 

  19. Baumler, C., Kim, G. O. & Elkon, K. B. Growth regulation of activated lymphocytes: defects in homeostasis lead to autoimmunity and/or lymphoma. Rev. Immunogenet. 2, 283–290 (2000).

    CAS  PubMed  Google Scholar 

  20. Kay, M. M. & Goodman, J. Immunoregulation of cellular lifespan: physiologic autoantibodies and their peptide antigens. Cell. Mol. Biol. 49, 217–243 (2003).

    CAS  PubMed  Google Scholar 

  21. Gardner-Thorpe, J., Ito, H., Ashley, S. W. & Whang, E. E. Autoantibody-mediated inhibition of pancreatic cancer cell growth in an athymic (nude) mouse model. Pancreas. 27, 180–189 (2003).

    Article  PubMed  Google Scholar 

  22. Stafford, H. A., Anderson, C. J. & Reichlin, M. Unmasking of anti-ribosomal P autoantibodies in healthy individuals. J. Immunol. 155, 2754–2761 (1995).

    CAS  PubMed  Google Scholar 

  23. Bouvet, J. P. et al. Induction of natural autoantibody activity following treatment of human immunoglobulin with dissociating agents. J. Autoimmun. 16, 163–172 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Rahman, A. Autoantibodies, lupus and the science of sabotage. Rheumatology (Oxford) 43, 1326–1336 (2004).

    Article  CAS  Google Scholar 

  25. Crow, M. K. & Kirou, K. A. Interferon-α in systemic lupus erythematosus. Curr. Opin. Rheumatol. 16, 541–547 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Illei, G. G., Tackey, E., Lapteva, L. & Lipsky, P. E. Biomarkers in systemic lupus erythematosus. I. General overview of biomarkers and their applicability. Arthritis Rheum. 50, 1709–1720 (2004). The first part of a review article on the biomarkers that can be used to predict prognosis, characterize disease activity and guide therapy in SLE patients.

    Article  CAS  PubMed  Google Scholar 

  27. Illei, G. G., Tackey, E., Lapteva, L. & Lipsky, P. E. Biomarkers in systemic lupus erythematosus: II. Markers of disease activity. Arthritis Rheum. 50, 2048–2065 (2004). The second part of a review article on the biomarkers that can be used to predict prognosis, characterize disease activity and guide therapy in SLE patients.

    Article  CAS  PubMed  Google Scholar 

  28. Badsha, H. & Edwards, C. J. Intravenous pulses of methylprednisolone for systemic lupus erythematosus. Semin. Arthritis Rheum. 32, 370–377 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Kang, I. & Park, S. H. Infectious complications in SLE after immunosuppressive therapies. Curr. Opin. Rheumatol. 15, 528–534 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Barr, R. G. et al. Prognosis in proliferative lupus nephritis: the role of socio-economic status and race/ethnicity. Nephrol. Dial. Transplant. 18, 2039–2046 (2003).

    Article  PubMed  Google Scholar 

  31. Cortes-Hernandez, J. et al. Predictors of poor renal outcome in patients with lupus nephritis treated with combined pulses of cyclophosphamide and methylprednisolone. Lupus 12, 287–296 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. Isenberg, D. & Leckie, M. J. Biological treatments for systemic lupus erythematosus. Scand. J. Rheumatol. 31, 187–191 (2002).

    Article  CAS  PubMed  Google Scholar 

  33. Bogdanovic, R. et al. Lupus nephritis in childhood: a review of 53 patients followed at a single center. Pediatr. Nephrol. 19, 36–44 (2004).

    Article  PubMed  Google Scholar 

  34. Gladman, D. D. Indicators of disease activity, prognosis, and treatment of systemic lupus erythematosus. Curr. Opin. Rheumatol. 6, 487–492 (1994).

    Article  CAS  PubMed  Google Scholar 

  35. Gladman, D. D. et al. Sensitivity to change of 3 systemic lupus erythematosus disease activity indices: international validation. J. Rheumatol. 21, 1468–1471 (1994).

    CAS  PubMed  Google Scholar 

  36. Hay, E. M. et al. The BILAG index: a reliable and valid instrument for measuring clinical disease activity in systemic lupus erythematosus. Q. J. Med. 86, 447–458 (1993).

    CAS  PubMed  Google Scholar 

  37. Gladman, D. D. et al. Crosscultural validation and reliability of 3 disease activity indices in systemic lupus erythematosus. J. Rheumatol. 19, 608–611 (1992).

    CAS  PubMed  Google Scholar 

  38. Bencivelli, W. et al. Disease activity in systemic lupus erythematosus: report of the Consensus Study Group of the European Workshop for Rheumatology Research. III. Clin. Exp. Rheumatol. 10, 549–554 (1992).

    CAS  PubMed  Google Scholar 

  39. Ward, M. M., Marx, A. S., Barry, N. N. Comparison of the validity and sensitivity to change of 5 activity indices in systemic lupus erythematosus. J. Rheumatol. 27, 664–670 (2000).

    CAS  PubMed  Google Scholar 

  40. Corzillius, M., Fortin, P. & Stucki, G. Responsiveness and sensitivity to change of SLE disease activity measures. Lupus 8, 655–9 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Brunner, H. I., Feldman, B. M., Bombardier, C. & Silverman, E. D. Sensitivity of the Systemic Lupus Erythematosus Disease Activity Index, British Isles Lupus Assessment Group Index, and Systemic Lupus Activity Measure in the evaluation of clinical change in childhood-onset systemic lupus erythematosus. Arthritis Rheum. 42, 1354–1360 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Stoll, T. et al. Consistency and validity of patient administered assessment of quality of life by the MOS SF-36; its association with disease activity and damage in patients with systemic lupus erythematosus. J. Rheumatol. 24, 1608–1614 (1997).

    CAS  PubMed  Google Scholar 

  43. Stoll, T., Stucki, G., Malik, J., Pyke, S. & Isenberg, D. A. Association of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index with measures of disease activity and health status in patients with systemic lupus erythematosus. J. Rheumatol. 24, 309–313 (1997).

    CAS  PubMed  Google Scholar 

  44. Baechler, E. C. et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc. Natl Acad. Sci. USA. 100, 2610–2615 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Nagy, G., Brozik, M., Tornoci, L. & Gergely, P. Diagnostic value of combined evaluation of neopterin and anti-DNA antibody levels for assessment of disease activity in systemic lupus erythematosus. Clin. Exp. Rheumatol. 18, 699–705 (2000).

    CAS  PubMed  Google Scholar 

  47. Mollnes, T. E. et al. Complement activation in patients with systemic lupus erythematosus without nephritis. Rheumatology (Oxford) 38, 933–940 (1999).

    Google Scholar 

  48. Nagy, G. et al. Usefulness of detection of complement activation products in evaluating SLE activity. Lupus 9, 19–25 (2000).

    Article  CAS  PubMed  Google Scholar 

  49. Horak, P. et al. Clinical utility of selected disease activity markers in patients with systemic lupus erythematosus. Clin. Rheumatol. 20, 337–344 (2001).

    Article  CAS  PubMed  Google Scholar 

  50. Belmont, H. M., Buyon, J., Giorno, R. & Abramson, S. Up-regulation of endothelial cell adhesion molecules characterizes disease activity in systemic lupus erythematosus. The Shwartzman phenomenon revisited. Arthritis Rheum. 37, 376–383 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Stohl, W. et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 48, 3475–3486 (2003).

    Article  PubMed  Google Scholar 

  52. Stohl, W. SLE — systemic lupus erythematosus: a BLySful, yet BAFFling, disorder. Arthritis Res. Ther. 5, 136–138 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kawasaki, A., Tsuchiya, N., Fukazawa, T., Hashimoto, H. & Tokunaga, K. Analysis on the association of human BLYS (BAFF, TNFSF13B) polymorphisms with systemic lupus erythematosus and rheumatoid arthritis. Genes Immun. 3, 424–429 (2002).

    Article  CAS  PubMed  Google Scholar 

  54. Roschke, V. et al. BLyS and APRIL form biologically active heterotrimers that are expressed in patients with systemic immune-based rheumatic diseases. J. Immunol. 169, 4314–4321 (2002).

    Article  CAS  PubMed  Google Scholar 

  55. Seshasayee, D. et al. Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity. 18, 279–288 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Baker, K. P. et al. Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum. 48, 3253–3265 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Swaak, A. J., Hintzen, R. Q., Huysen, V., van den Brink, H. G. & Smeenk, J. T. Serum levels of soluble forms of T cell activation antigens CD27 and CD25 in systemic lupus erythematosus in relation with lymphocytes count and disease course. Clin. Rheumatol. 14, 293–300 (1995).

    Article  CAS  PubMed  Google Scholar 

  58. Font, J. et al. Elevated soluble CD27 levels in serum of patients with systemic lupus erythematosus. Clin. Immunol. Immunopathol. 81, 239–243 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Stojanovich, L., Stojanovich, R., Kostich, V. & Dzjolich, E. Neuropsychiatric lupus favourable response to low dose i. v. cyclophosphamide and prednisolone (pilot study). Lupus 12, 10–15 (2003).

    Article  Google Scholar 

  60. Zonana-Nacach, A., Barr, S. G., Magder, L. S. & Petri, M. Damage in systemic lupus and its association with corticosteroids. Arthritis Rheum. 43, 1801–1808 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Fisher, D. E. & Bickel, W. H. Corticosteroid-induced avascular necrosis. A clinical study of seventy-seven patients. Bone Joint Surg. Am. 53, 859–873 (1971).

    Article  CAS  Google Scholar 

  62. Tam, L. S., Gladman, D. D., Hallett, D. C., Rahman, P. & Urowitz, M. B. Effect of antimalarial agents on the fasting lipid profile in systemic lupus erythematosus. J. Rheumatol. 27, 2142–2145 (2000).

    CAS  PubMed  Google Scholar 

  63. Borba, E. F. & Bonfa, E. Longterm beneficial effect of chloroquine diphosphate on lipoprotein profile in lupus patients with and without steroid therapy. J. Rheumatol. 28, 780–785 (2001).

    CAS  PubMed  Google Scholar 

  64. Lakshminarayanan, S., Walsh, S., Mohanraj, M. & Rothfield, N. Factors associated with low bone mineral density in female patients with systemic lupus erythematosus. J. Rheumatol. 28, 102–108 (2001).

    CAS  PubMed  Google Scholar 

  65. Levy, R. A. et al. Hydroxychloroquine (HCQ) in lupus pregnancy: double-blind and placebo-controlled study. Lupus 10, 401–404 (2001).

    Article  CAS  PubMed  Google Scholar 

  66. Steinberg, A. D. et al. Cyclophosphamide in lupus nephritis: a controlled trial. Ann. Intern. Med. 75, 165–171 (1971).

    Article  CAS  PubMed  Google Scholar 

  67. Flanc, R. S. et al. Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am. J. Kidney Dis. 43, 197–208 (2004). A systematic review of randomized controlled trials, which assessed the benefits and harm of current treatments for diffuse proliferative lupus nephritis.

    Article  CAS  PubMed  Google Scholar 

  68. Miller, J. J., Williams, G. F. & Leissring, J. C. Multiple late complications of therapy with cyclophosphamide, including ovarian destruction. Am. J. Med. 50, 530–535 (1971).

    Article  PubMed  Google Scholar 

  69. Brook, C. G. & Evans, P. R. Psychosis in systemic lupus erythematosus (SLE) and the response to cyclophosphamide. Proc. R. Soc. Med. 62, 912 (1969).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Bardana, E. J. Jr, Porter, G. A., Pirofsky, B., Gourley, R. T. & Bayrakci, C. Azathioprine in steroid-insensitive nephropathy. Am. J. Med. 49, 789–800 (1970).

    Article  PubMed  Google Scholar 

  71. Drinkard, J. P. et al. Azathioprine and prednisone in the treatment of adults with lupus nephritis. Clinical, histological, and immunological changes with therapy. Medicine (Baltimore) 49, 411–432 (1970).

    Article  CAS  Google Scholar 

  72. El Hachmi, M., Jadoul, M., Lefebvre, C., Depresseux, G. & Houssiau, F. A. Relapses of lupus nephritis: incidence, risk factors, serology and impact on outcome. Lupus 12, 692–696 (2003).

    Article  CAS  PubMed  Google Scholar 

  73. Chan, T. M. et al. Treatment of membranous lupus nephritis with nephrotic syndrome by sequential immunosuppression. Lupus 8, 545–551 (1999).

    Article  CAS  PubMed  Google Scholar 

  74. Contreras, G. et al. Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 350, 971–980 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Mok, C. C., Ho, C. T., Chan, K. W., Lau, C. S. & Wong, R. W. Outcome and prognostic indicators of diffuse proliferative lupus glomerulonephritis treated with sequential oral cyclophosphamide and azathioprine. Arthritis Rheum. 46, 1003–1013 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Abu-Shakra, M. & Shoenfeld, Y. Azathioprine therapy for patients with systemic lupus erythematosus. Lupus 10, 152–153 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Armenti, V. T. et al. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin. Transpl. 1, 121–130 (2002).

    Google Scholar 

  78. Remer, C. F., Weisman, M. H. & Wallace, D. J. Benefits of leflunomide in systemic lupus erythematosus: a pilot observational study. Lupus 10, 480–483 (2001).

    Article  CAS  PubMed  Google Scholar 

  79. Sato, E. I. Methotrexate therapy in systemic lupus erythematosus. Lupus 10, 162–164 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Hu, W. et al. Cyclosporine A in treatment of membranous lupus nephropathy. Chin. Med. J. 116, 1827–1830 (2003).

    CAS  PubMed  Google Scholar 

  81. Dammacco, F. et al. Cyclosporine-A plus steroids versus steroids alone in the 12-month treatment of systemic lupus erythematosus. Int. J. Clin. Lab. Res. 30, 67–73 (2000).

    Article  CAS  PubMed  Google Scholar 

  82. Merrill, J. T. Regulation of the vasculature: clues from lupus. Curr. Opin. Rheumatol. 14, 504–509 (2002).

    Article  CAS  PubMed  Google Scholar 

  83. Fabbri, P., Cardinali, C., Giomi, B. & Caproni, M. Cutaneous lupus erythematosus: diagnosis and management. Am. J. Clin. Dermatol. 4, 449–465 (2003).

    Article  PubMed  Google Scholar 

  84. Traynor, A. E. et al. Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study. Lancet. 356, 701–707 (2000).

    Article  CAS  PubMed  Google Scholar 

  85. Hashimoto, N. et al. Autologous hematopoietic stem cell transplantation for refractory antiphospholipid syndrome causing myocardial necrosis. Bone Marrow Transplant. 33, 863–866 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Merrill, J. T. Dehydroepiandrosterone, a sex steroid metabolite in development for systemic lupus erythematosus. Expert Opin. Investig. Drugs 12, 1017–1025 (2003).

    Article  CAS  PubMed  Google Scholar 

  87. Petri, M. A. et al. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 46, 1820–1829 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Chang, D. M., Lan, J. L., Lin, H. Y. & Luo, S. F. Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 46, 2924–2927 (2002).

    Article  CAS  PubMed  Google Scholar 

  89. Ding, L., Zhao, M., Zou, W., Liu, Y. & Wang, H. Mycophenolate mofetil combined with prednisone for diffuse proliferative lupus nephritis: a histopathological study. Lupus 13, 113–118 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Li, L., Wang, H. & Lin, S. Mycophenolate mofetil treatment for diffuse proliferative lupus nephritis: a multicenter clinical trial in China. Zhonghua Nei Ke Za Zhi. 41, 476–479 (2002).

    PubMed  Google Scholar 

  91. Contreras, G. et al. Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 350, 971–80 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Harzallah, K. et al. Efficacy of mycophenolate mofetil on recurrent glomerulonephritis after renal transplantation. Clin. Nephrol. 59, 212–216 (2003).

    Article  CAS  PubMed  Google Scholar 

  93. Zhao, M. et al. Clinical observations of mycophenolate mofetil therapy in refractory primary nephrotic syndrome. Nephrology 8, 2–10 (2003).

    Article  Google Scholar 

  94. Buratti, S., Szer, I. S., Spencer, C. H., Bartosh, S. & Reiff, A. Mycophenolate mofetil treatment of severe renal disease in pediatric onset systemic lupus erythematosus. J. Rheumatol. 28, 2103–2108 (2001).

    CAS  PubMed  Google Scholar 

  95. Coutts, S. M., Plunkett, M. L., Iverson, G. M., Barstad, P. A. & Berner, C. M. Pharmacological intervention in antibody mediated disease. Lupus 5, 158–159 (1996).

    Article  CAS  PubMed  Google Scholar 

  96. Merrill, J. T. LJP 1082: a toleragen for Hughes syndrome. Lupus 13, 335–338 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Weisman, M. H., Bluestein, H. G., Berner, C. M. & de Haan, H. A. Reduction in circulating dsDNA antibody titer after administration of LJP 394. J. Rheumatol. 24, 314–318 (1997).

    CAS  PubMed  Google Scholar 

  98. Wallace, D. J. & Tumlin, J. A. LJP 394 (abetimus sodium, Riquent) in the management of systemic lupus erythematosus. Lupus 13, 323–327 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Spertini, F. et al. Idiotypic vaccination with a murine anti-dsDNA antibody: phase I study in patients with nonactive systemic lupus erythematosus with nephritis. J. Rheumatol. 26, 2602–2608 (1999).

    CAS  PubMed  Google Scholar 

  100. Grammer, A. C. et al. Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154-CD40 interactions. J. Clin. Invest. 112, 1506–1520 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Harigai, M. et al. Responsiveness of peripheral blood B cells to recombinant CD40 ligand in patients with systemic lupus erythematosus. Lupus 8, 227–233 (1999).

    Article  CAS  PubMed  Google Scholar 

  102. Uhm, W. S. et al. Cytokine balance in kidney tissue from lupus nephritis patients. Rheumatology (Oxford) 42, 935–938 (2003).

    Article  CAS  Google Scholar 

  103. Kuroiwa, T., Schlimgen, R., Illei, G. G. & Boumpas, D. T. Monocyte response to Th1 stimulation and effector function toward human mesangial cells are not impaired in patients with lupus nephritis. Clin. Immunol. 106, 65–72 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Kato, K. et al. The soluble CD40 ligand sCD154 in systemic lupus erythematosus. J. Clin. Invest. 104, 947–955 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Higuchi, T. et al. Cutting edge: ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune disease. J. Immunol. 168, 9–12 (2002).

    Article  CAS  PubMed  Google Scholar 

  106. Quezada, S. A. et al. Distinct mechanisms of action of anti-CD154 in early versus late treatment of murine lupus nephritis. Arthritis Rheum. 48, 2541–2554 (2003).

    Article  CAS  PubMed  Google Scholar 

  107. Kairaitis, L. et al. Blockade of CD40-CD40 ligand protects against renal injury in chronic proteinuric renal disease. Kidney Int. 64, 1265–1272 (2003).

    Article  CAS  PubMed  Google Scholar 

  108. Wang, X. et al. Effects of anti-CD154 treatment on B cells in murine systemic lupus erythematosus. Arthritis Rheum. 48, 495–506 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Kalled, S. L., Cutler, A. H. & Burkly, L. C. Apoptosis and altered dendritic cell homeostasis in lupus nephritis are limited by anti-CD154 treatment. J. Immunol. 167, 1740–1747 (2001).

    Article  CAS  PubMed  Google Scholar 

  110. Brams, P. et al. A humanized anti-human CD154 monoclonal antibody blocks CD154-CD40 mediated human B cell activation. Int. Immunopharmacol. 1, 277–294 (2001).

    Article  CAS  PubMed  Google Scholar 

  111. Huang, W. et al. The effect of anti-CD40 ligand antibody on B cells in human systemic lupus erythematosus. Arthritis Rheum. 46, 1554–1562 (2002).

    Article  CAS  PubMed  Google Scholar 

  112. Davis, J. C. Jr, Totoritis, M. C., Rosenberg, J., Sklenar, T. A. & Wofsy, D. Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J. Rheumatol. 28, 95–101 (2001).

    CAS  PubMed  Google Scholar 

  113. 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).

    Article  CAS  PubMed  Google Scholar 

  114. 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).

    Article  CAS  PubMed  Google Scholar 

  115. Leandro, M. J., Edwards, J. C., Cambridge, G., Ehrenstein, M. R. & Isenberg, D. A. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum. 46, 2673–2677 (2002).

    Article  PubMed  Google Scholar 

  116. Anolik, J. H. et al. The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus. Arthritis Rheum. 48, 455–459 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Weide, R., Heymanns, J., Pandor, F. A. & Koppler, H. Successful long-term treatment of systemic lupus erythematosus with rituximab maintenance therapy. Lupus 12, 779–782 (2003).

    Article  CAS  PubMed  Google Scholar 

  118. Anolik, J., Sanz, I. & Looney, R. J. B cell depletion therapy in systemic lupus erythematosus. Curr. Rheumatol. Rep. 5, 350–356 (2003).

    Article  PubMed  Google Scholar 

  119. Eisenberg, R. SLE — rituximab in lupus. Arthritis Res. Ther. 5, 157–159 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Kneitz, C., Wilhelm, M. & Tony, H. P. Effective B cell depletion with rituximab in the treatment of autoimmune diseases. Immunobiology 206, 519–527 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Shanafelt, T. D., Madueme, H. L., Wolf, R. C. & Tefferi, A. Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and Evans syndrome. Mayo Clin. Proc. 78, 1340–1346 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Zaja, F. et al. B-cell compartment as the selective target for the treatment of immune thrombocytopenias. Haematologica. 88, 538–546 (2003).

    PubMed  Google Scholar 

  123. Cate, R. et al. Anti-CD20 monoclonal antibody (rituximab) for refractory autoimmune thrombocytopenia in a girl with systemic lupus erythematosus. Rheumatology (Oxford) 43, 244 (2004).

    Article  Google Scholar 

  124. Saito, K. et al. Successful treatment with anti-CD20 monoclonal antibody (rituximab) of life-threatening refractory systemic lupus erythematosus with renal and central nervous system involvement. Lupus 12, 798–800 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Fra, G. P., Avanzi, G. C. & Bartoli, E. Remission of refractory lupus nephritis with a protocol including rituximab. Lupus 12, 783–787 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Janeway, C., Travers, P., Walport, M. & Capra, J. D. Immunobiology: The immune System in Health and Disease 4th edn (Current Biology, London, 1999).

    Google Scholar 

Download references

Acknowledgements

The authors would like to thank T. Roehrig for her technical assistance with the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Doruk Erkan.

Ethics declarations

Competing interests

J.T.M. and J.P.B. have served as consultants for many of the companies who are directly or indirectly developing new products for SLE, including all of those mentioned in this article. They have not received more than US $5,000 in honoraria or other payments from any individual company within the past 5 years.

Related links

Related links

DATABASES

Entrez Gene

BLyS

CD27

CD40

CD154

VCAM1

OMIM

SLE 

American College of Rheumatology

Glossary

AUTOANTIBODY

Antibody against patients' own cellular antigens.

TH2 CELLS

A subset of CD4 cells that are mainly involved in stimulating B cells.

POLYCLONAL

Multiple clones with diverse specificity.

APOPTOSIS

Programmed cell death.

CYTOKINES

Proteins produced by cells to interact with other cells.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Merrill, J., Erkan, D. & Buyon, J. Challenges in bringing the bench to bedside in drug development for sle. Nat Rev Drug Discov 3, 1036–1046 (2004). https://doi.org/10.1038/nrd1577

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1577

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing