Skip to main content

Advertisement

Log in

Clinical trials in lupus nephritis

  • Published:
Current Rheumatology Reports Aims and scope Submit manuscript

Abstract

Significant advances in the treatment of lupus nephritis have been made in the last 50 years, beginning with the use of high doses of corticosteroids. The addition of intravenous cyclophosphamide (IVC) to steroids, a regimen introduced by the National Institutes of Health, has become the standard of care therapy for severe active nephritis. However, not all patients respond to IVC, and among those who do, manifestations of toxicity (nausea, vomiting, alopecia, sterility, increased risk of infection, and increased risk of malignancy) are frequent. Despite successful induction and maintenance therapy with IVC, there is a relapse rate of more than 50% after 10 years. In recent years, new immunosuppressive agents have been studied as potential alternatives to IVC. The most promising of these appears to be mycofenolate mofetil, which is being evaluated in clinical trials. Biologic agents designed to interfere with the immunologic process leading to B- and T-lymphocyte activation are also being tested as alternative therapies in lupus nephritis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

  1. Pollak VE, Pirani CL, Schwartz FD: The natural history of the renal manifestations of systemic lupus erythematosus. J Lab Clin Med 1964, 63:537–550.

    PubMed  CAS  Google Scholar 

  2. Cathcart ES, Idelson BA, Scheinberg MA, et al.: Beneficial effects of methylprednisolone "pulse" therapy in diffuse proliferative lupus nephritis. Lancet 1976, 1:163–166.

    Article  PubMed  CAS  Google Scholar 

  3. Kimberly RP, Lockshin MD, Sherman RL, et al.: High-dose intravenous methylprednisolone pulse therapy in systemic lupus erythematosus. Am J Med 1981, 70:817–824.

    Article  PubMed  CAS  Google Scholar 

  4. Isenberg DA, Morrow WJW, Snaith ML: Methylprednisolone pulse therapy in the treatment of systemic lupus erythematosus. Ann Rheum Dis 1982, 41:347–351.

    Article  PubMed  CAS  Google Scholar 

  5. Liebling MR, McLaughlin K, Boonsue S, et al.: Monthly pulses of methylprednisolone in SLE nephritis. J Rheumatol 1982, 9:543–548.

    PubMed  CAS  Google Scholar 

  6. Feng PH, Jayaratnam FJ, Tock EPC, et al.: Cyclophosphamide in treatment of systemic lupus erythematosus: 7 years’ experience. BMJ 1973, 2:450–452.

    PubMed  CAS  Google Scholar 

  7. Donadio JV Jr, Holley KE, Ferguson RH, et al.: Progressive lupus glomerulonephritis. Treatment with prednisone and combined prednisone and cyclophosphamide. Mayo Clin Proc 1976, 51:484–494.

    PubMed  Google Scholar 

  8. Levey AS, Lan S-P, Corwin HL, et al.: Progression and remission of renal disease in the lupus nephritis collaborative study. Results of treatment with prednisone and short-term oral cyclophosphamide. Ann Intern Med 1992, 116:114–123.

    PubMed  CAS  Google Scholar 

  9. Dinant HJ, Decker JL, Klippel JH, et al.: Alternative modes of cyclophosphamide and azathioprine therapy in lupus nephritis. Ann Intern Med 1982, 96:728–736.

    PubMed  CAS  Google Scholar 

  10. Austin HA III, Klippel JH, Balow JE, et al.: Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986, 314:614–619.

    Article  PubMed  Google Scholar 

  11. Steinberg AD, Steinberg SC: Long-term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum 1991, 34:945–950. The results of the National Institutes of Health’s long-term experience with 111 patients with systemic lupus erythematosus randomized to one of four immunosuppressive regimens for active nephritis are reported. Cyclophosphamide was shown to have long-term benefits in the delay or prevention of end-stage renal disease compared with prednisone alone or with prednisone plus azathioprine.

    Article  PubMed  CAS  Google Scholar 

  12. Ortiz A, Gonzalez-Parra E, Alvarez-Costa G, et al.: Bladder cancer after cyclophosphamide therapy for lupus nephritis. Nephron 1992, 60:378–379.

    Article  PubMed  CAS  Google Scholar 

  13. Boumpas DT, Austin HA III, Vaughan EM, et al.: Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993, 119:366–369.

    PubMed  CAS  Google Scholar 

  14. Ciruelo E, dela Cruz J, Lopez I, et al.: Cumulative rate of relapse of lupus nephritis after successful treatment with cyclophosphamide. Arthritis Rheum 1996, 39:2028–2034. Despite successful initial treatment of lupus nephritis with cyclophosphamide, 11 of 48 patients had a relapse of active renal disease, with a cumulative rate of 25% at 5 years and 56% at 10 years. The time to relapse was related to the duration from the onset of nephritis to the initiation of Cytoxan therapy, but was not associated with the presence of hypertension, serum creatinine, urine protein excretion, WHO classification of renal biopsy, activity or chronicity index, route of cyclophosphamide administration, or total length of cyclophosphamide therapy.

    Article  PubMed  CAS  Google Scholar 

  15. Dooley MA, Hogan S, Jennette C, et al.: Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Kidney Int 1997, 51:1188–1195. Black race indicates a poor prognosis compared with white race for preservation of renal function after cyclophosphamide therapy. Racial differences in renal outcome were independent of age, lupus duration, hypertension, and activity or chronicity indices on renal biopsy.

    Article  PubMed  CAS  Google Scholar 

  16. Boumpas DT, Austin HA III, Vaughn EM, et al.: Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992, 340:741–745.

    Article  PubMed  CAS  Google Scholar 

  17. Sesso R, Monteiro M, Sato E, et al.: A controlled trial of pulse cyclophosphamide versus pulse methylprednisolone in severe lupus nephritis. Lupus 1994, 3:107–112.

    PubMed  CAS  Google Scholar 

  18. Gourley MF, Austin HA III, Scott D, et al.: Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis: a randomized, controlled trial. Ann Intern Med 1996, 125:549–557. The addition of monthly pulses of intravenous methylprednisolone to intravenous cyclophosphamide did not result in a statistically significant improvement in preservation of renal function or risk of relapse subsequent to induction of remission. The toxicities of steroids and cyclophosphamide were additive.

    PubMed  CAS  Google Scholar 

  19. Favre H, Miescher PA, Huang YP, et al.: Cyclosporin in the treatment of lupus nephritis. Am J Nephrol 1989, 9:57–60.

    PubMed  Google Scholar 

  20. Radhakrishnan J, Kunis CL, Agati VD, et al.: Cyclosporin treatment of lupus membranous nephropathy. Clin Nephropathol 1994, 42:147–154.

    CAS  Google Scholar 

  21. Dostal C, Tesai V, Rychlik I, et al.: Effect of 1 year cyclosporine A treatment on the activity and renal involvement of systemic lupus erythematosus: a pilot study. Lupus 1998, 7:29–36.

    Article  PubMed  CAS  Google Scholar 

  22. Hallegua D, Wallace DJ, Metzger AL, et al.: Cyclosporine for lupus membranous nephritis: experience with ten patients and review of the literature. Lupus 2000, 9:241–251.

    Article  PubMed  CAS  Google Scholar 

  23. Fu LW, Yang LY, Chen WP, et al.: Clinical efficacy of cyclosporin a neoral in the treatment of paediatric lupus nephritis with heavy proteinuria. Br J Rheumatol 1998, 37:217–221.Despite anecdotal series suggesting that cyclosporine is beneficial in steroid and cyclophosphamide-resistant lupus nephritis, this controlled trial in pediatric patients did not show a difference in efficacy between cyclosporine and intravenous cyclophosphamide plus methylprednisolone. Increased growth in the cyclosporinetreated patients may have been related to the absence of steroids in that arm of the protocol.

    Article  PubMed  CAS  Google Scholar 

  24. Dooley MA, Cosio FD, Nachman PH, et al.: Mycophenolate mofetil therapy in lupus nephritis: clinical observations. J Am Soc Nephrol 1999, 10:933–839. This uncontrolled series of 13 patients with lupus nephritis, 12 of whom did not respond to intravenous cyclophosphamide, suggests that myophenolate mofetil is effective particularly in diminishing proteinuria. Toxicity of this regimen was relatively mild.

    Google Scholar 

  25. Chan TM, Li FK, Tang CSO, et al.: Efficacy of mycophenolate mofetil in patients with diffuse proliferative nephritis. N Engl J Med 2000, 343:1156–1162. This is the first published controlled randomized study of mycophenolate mofetil versus cyclophosphamide administered orally in 42 patients with lupus nephritis. Both regimens had an equal and very high rate of complete response (81% vs 76%). There was not a significant difference in toxicity between the two regimens; however, there was a trend toward more infections in the cyclophosphamide group, with two deaths in that group and none in the mycophenolate mofetil group.

    Article  PubMed  CAS  Google Scholar 

  26. Boletis JN, Ioannidis JP, Boki KA, et al.: Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis [letter]. Lancet 1999, 354:569–570.

    Article  PubMed  CAS  Google Scholar 

  27. Levy Y, Sherer Y, George J, et al.: Intravenous immunoglobulin treatment of lupus nephritis. Semin Arthritis Rheum 2000, 29:321–327.

    Article  PubMed  CAS  Google Scholar 

  28. Euler HH, Harten P, Schwab UM, et al.: Long-term and treatment-free remission in severe systemic lupus erythematosus following synchronization of plasmapheresis with subsequent pulse cyclophosphamide: an update. Arthritis Rheum 2000, 43:S243.

    Article  Google Scholar 

  29. Wallace DJ, Goldfinger D, Pepkowitz SH, et al.: randomized controlled trial of pulse/synchronizaton cyclophosphamide/ apheresis for proliferative lupus nephritis. J Clin Apheresis 1998, 13:163–166.

    Article  PubMed  CAS  Google Scholar 

  30. Traynor AE, Schroeder J, Rosa RM, et al.: Treatment of severe systemic lupus erythematosus with high-dose chemotherapy and haemopoietic stem-cell transplantation: a phase I study. Lancet 2000, 356:701–707. High-dose chemotherapy followed by autologous stem cell transplantation is being considered for patients with catastrophic autoimmune diseases. The successful Northwestern University experience in seven patients with systemic lupus erythematosus is described here. Two patients who received the initial immunosuppressive regimen were unable to be transplanted because of fatal infections.

    Article  PubMed  CAS  Google Scholar 

  31. Petri M, Jones R, Brodsy R: High-dose immunoablative cyclophosphamide (HDIC) open-label trial: complete responders and durability of response. Arthritis Rheum 2000, 43:S241. It is possible that high-dose (200 mg/kg) cyclophosphamide therapy without subsequent stem cell rescue may result in long-term remission of severe active systemic lupus erythematosus. Eight patients with nephritis underwent this therapy in an uncontrolled trial, resulting in disease-free remissions lasting up to 2.75 years.

    Google Scholar 

  32. Alarcon-Segovia D, Tumlin J, Furie R, et al.: SLE trial shows fewer renal flares in LJP 394-treated patients with high-affinity antibodies to LJP 394: 90-05 trial results. Arthritis Rheum 2000, 43:S272. LJP 394 is a B-cell toleragen specifically designed to prevent production of anti-dsDNA antibodies in patients with systemic lupus erythematosus. In a randomized trial of LJP 394 compared with placebo in patients with a history of lupus nephritis, the pretreatment presence of high-affinity antibodies to LJP 394 was associated with prolongation of the time to relapse in patients treated with this agent, compared with those treated with placebo.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ginzler, E.M. Clinical trials in lupus nephritis. Curr Rheumatol Rep 3, 199–204 (2001). https://doi.org/10.1007/s11926-001-0019-0

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11926-001-0019-0

Keywords

Navigation