Although not licensed for systemic lupus erythematosus (SLE), cyclophosphamide (CYC) has become over the last two decades the most widely prescribed cytotoxic drug for lupus nephritis (LN). A PubMed search using ‘lupus nephritis and cyclophosphamide’ as key words identifies not less than 454 papers on the topic. This should, however, not disguise the fact that its use is still controversial and that many issues remain debated, such as the timing and length of treatment, the route of administration and the ideal dosage. In this review, the different CYC regimes on the basis of the results of prospective randomized trials performed in LN patients is discussed.
Chabner BA , Allegra CJ , Curt GA , Calabresi P.Antineoplastic agents. In Hardman JG , Limbird LE , Molinoff PB , Ruddon RW , Gilman AG eds. Goodman and Gilman’s The Pharmacological Basis of Therapeutics. Ninth Edition, New York: McGraw-Hill , 1996: 1233-1287.
2.
Donadio JV Jr , Holley KE , Ferguson RH , Illstrup DM.Progressive lupus glomerulonephritis. Treatment with prednisone and combined prednisone and cyclophosphamide . Mayo Clin Proc1976; 51: 484-494 .
3.
Donadio JV Jr , Holley KE , Ferguson RH , Illstrup DM.Treatment of diffuse proliferative lupus nephritis with prednisone and combined prednisone and cyclophosphamide . N Engl J Med1978; 299: 1151-1155 .
4.
Fauci AS , Haynes BF , Katz P , Wolff SM.Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years . Ann Intern Med1983; 98: 76-85 .
5.
Chan TM , Li FK , Wong RW , Wong KL , Chan KW , Cheng IK.Sequential therapy for diffuse proliferative and membranous lupus nephritis: cyclophosphamide and prednisolone followed by azathioprine and prednisolone . Nephron1995; 71: 321-327 .
6.
Mok CC , Ho CT , Siu YPet al.Treatment of diffuse proliferative lupus glomerulonephritis: a comparison of two cyclophosphamide-containing regimens . Am J Kidney Dis2001; 38: 256-264 .
7.
Adu D , Pall A , Luqmani RAet al.Controlled trial of pulse versus continuous prednisolone and cyclophosphamide in the treatment of systemic vasculitis . Q J Med1997; 90: 401-409 .
8.
Yee CS , Gordon C , Dostal Cet al.EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis . Ann Rheum Dis2003; 63: 525-529 .
9.
Balow JE , Boumpas DT , Fessler BJ , Austin HA III.Management of lupus nephritis . Kidney Int1996; 49(suppl. 53): S88-S92 .
10.
Austin HA III , Klippel JH , Balow JEet al.Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs . N Engl J Med1986; 314: 614-619 .
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 Rheum1991; 34: 945-950 .
12.
Boumpas DT , Austin HA III , Vaughan EMet al.Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis . Lancet1992; 340: 741-745 .
13.
Gourley MF , Austin HA III , Scott Det al.Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial . Ann Intern Med1996; 125: 549-557 .
14.
Illei GC , Austin HA , Crane Met al.Combination therapy with pulse cyclophosphamide plus pulse methylprednisolone improves long-term renal outcome without adding toxicity in patients with lupus nephritis . Ann Intern Med2001; 135: 248-257 .
15.
Grootscholten C , Bijl M , Ligtenberg Get al.Is azathioprine an alternative for cyclophosphamide in the treatment of patients with proliferative lupus nephritis? Two-year results of the Dutch lupus nephritis study I . Ann Rheum Dis2004; 63(suppl. 1): 112-112 .
16.
Illei GC , Takada K , Parkin Det al.Renal flaresare common inpatientswith severe proliferative lupus nephritis treated with pulse immunosuppressive therapy: long-term followup of a cohort of 145 patients participating in randomized controlled studies . Arthritis Rheum2002; 46: 995-1002 .
17.
Fraenkel L , Bogardus S , Concato J.Patient preferences for treatment of lupus nephritis . Arthritis Rheum (Arthritis Care & Research)2002; 47: 421-428 .
18.
Boumpas DT , Austin HA III , Vaughan EM , Yarboro CH , Klippel JH , Balow JE.Risk for sustained amenorrhea in patients with systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy . Ann Intern Med1993; 119: 366-369 .
19.
Mok CC , Lau CS , Wong RW.Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy . Arthritis Rheum1998; 41: 831-837 .
20.
Takada K , Arefayene M , Desta Zet al.Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis . Arthritis Rheum2004; 50: 2202-2210 .
21.
McCune WJ , Somers EC , Ognenovski V , Christman G.Use of leuprolide acetate for ovarian protection during cyclophosphamide therapy of women with severe SLE: a case control study . Arthritis Rheum2001; 44(suppl.): S387-S387 .
22.
Blumenfeld Z , Shapiro D , Shteinberg M , Avivi I , Nahir M.Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy . Lupus2000; 9: 401-405 .
23.
Dooley MA , Hogan S , Jennette C , Falk R , for the Glomerular Disease Collaborative Network . Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans . Kidney Int1997; 51: 1188-1195 .
24.
Houssiau FA , D’Cruz DP , Haga HJ , Hughes GR.Short course of weekly low-dose intravenous pulse cyclophosphamide in the treatment of lupus nephritis: a preliminary study . Lupus1991; 1: 31-35 .
25.
D’Cruz D , Cuadrado MJ , Mujic Fet al.Immunosuppressive therapy in lupus nephritis . Clin Exp Rheumatol1997; 15: 275-282 .
26.
Haga HJ , D’Cruz D , Asherson R , Hughes GR.Short term effects of intravenous pulses of cyclophosphamide in the treatment of connective tissue disease crisis . Ann Rheum Dis1992; 51: 885-888 .
27.
Houssiau FA , Vasconcelos C , D’Cruz Det al.Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide . Arthritis Rheum2002; 46: 2121-2131 .
28.
Houssiau FA , Vasconcelos C , D’Cruz Det al.Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from the long-term follow-up of the Euro-Lupus Nephritis Trial . Arthritis Rheum2004; in press.
29.
El Hachmi M , Jadoul M , Lefebvre C , Depresseux G , Houssiau FA.Relapses of lupus nephritis: incidence, risk factors, serology and impact on outcome . Lupus2003; 12: 692-696 .
30.
Jayne D , Passweg J , Marmont Aet al.European Group for Blood and Marrow Transplantation; European League Against Rheumatism Registry: Autologous stem cell transplantation for systemic lupus erythematosus . Lupus2004; 13: 168-176 .
31.
Petri M , Jones RJ , Brodsky RA.High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus . Arthritis Rheum2003; 48: 166-173 .
32.
Chan TM , Li FK , Tang CSet al.Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group . N Engl J Med2000; 343: 1156-1162 .
33.
Hu W , Liu Z , Chen Het al.Mycophenolate mofetil vs cyclophosphamide therapy for patients with diffuse proliferative lupus nephritis . Chin Med J (Engl)2002; 115: 705-709 .
34.
Ginzler EM , Aranow C , Buyon Jet al.A multicenter study of mycophenolate mofetil (MMF) vs. intravenous cyclophosphamide (IVC) as induction therapy for severe lupus nephritis (LN) . Arthritis Rheum2003; 48(suppl.): S647-S647 .
35.
Contreras G , Pardo V , Leclercq Bet al.Sequential therapies for proliferative lupus nephritis . N Engl J Med2004; 350: 971-980 .
36.
Leandro MJ , Edwards JC , Cambridge G , Ehrenstein MR , Isenberg DA.An open study of B lymphocyte depletion in systemic lupus erythematosus . Arthritis Rheum2002; 46: 2673-2677 .
37.
Anolik JH , Campbell D , Felgar REet al.The relationship of Fc gamma RIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus . Arthritis Rheum2003; 48: 455-459 .
38.
Finck BK , Linsley PS , Wofsy D.Treatment of murine lupus with CTLA4Ig . Science1994; 265: 1225-1225 .
