[Comparison of various cyclophosphamide treatment regimens on the course and outcome of lupus nephritis ].
BACKGROUND
Immunosuppressive drugs, particularly cyclophosphamide, are widely accepted as the treatment of choice for severe, proliferative lupus nephritis. However, there is no consensus with regard to: 1) the dose required for achieving control of disease activity; 2) duration of cyclophosphamide therapy after the achievement of treatment response; 3) treatment of lupus nephritis relapses [1-5]. In the Institute of Rheumatology, Belgrade, two regimens of intravenous cyclophosphamide have been introduced in the treatment of lupus nephritis patients years ago. The first has comprised the so called "small pulses" that have been used since 1985, and the second has been standard protocol with high doses of cyclophosphamide, accepted in 1990. Results of these follow-up studies were published previously [6-8].


OBJECTIVE
The aim of this study was to compare the efficacy of two regimens of intravenous pulse cyclophosphamide in the treatment of patients with severe lupus nephritis.


METHODS
We analyzed the results of two follow-up studies comprising patients with lupus nephritis, treated with cyclophosphamide: 1) 41 females treated with "small pulses", consisting of 400 mg of cyclophosphamide weekly at treatment onset, followed by the same dose fortnightly for the next three months, and finally on monthly basis for several months or years; 2) 33 patients (29 females and 4 males) treated with standard protocol consisting of "induction phase" with 6 monthly pulses of high doses (0.5-0.75 g/m2 body surface), followed by "maintenance phase" with quarterly pulses for additional 1-2 years. The evaluation of long-term treatment effects was based on remission/response rate [9], number of patients with renal failure, end-stage renal disease and death outcome.


RESULTS
Groups of patients were quite comparable with respect to their demographic and clinical data (Table 1). The only difference was much higher frequency of renal biopsy in "high dose" cyclophosphamide pulse (85% versus 32%), confirming the presence of proliferative lupus nephritis. Cummulative dose of cyclophosphamide and treatment duration were not significantly different between treatment groups. At the end of the follow-up, distributions of favorable (remission/response) and unfavorable outcome was similar (p = 0.831; Mann-Whitney U test), as well as dynamics of remission achieving (p = 0.068; Log-rank test), cummulative renal survival (p = 0.129; Log-rank test) and patient survival (p = 0.577; Log-rank test).


CONCLUSIONS
Similar efficacy of two different cyclophosphamide regimens in our patients with lupus nephritis was not surprising considering that cummulative cyclophosphamide doses and treatment duration were similar obtaining similar control of disease. During induction phase of treatment, patients on small pulses have received even higher cummulative dose of cyclophosphamide. Aggressive immunosuppressive treatment with cyclophosphamide has significantly ameliorated the outcome of lupus nephritis. In different studies, rate of assessed clinical response is 60-80 [13-17]. Significant proportion (42%) of patients who achieved partial remission, as well as complete remission, developed flare of renal disease several months after the end of the treatment, necessitating restarting of pulse cyclophosphamide therapy. The results of our study were in accordance with those results, especially with results of Mosca et al. [18] who have applied the duration of treatment similar to ours in high pulse regimen.


CONCLUSIONS
Treatment response did not differ between two different cyclophosphamide regimens (small pulses and standard high doses protocol), but standard protocol seemed to be more comfortable for patients. We recommend standard protocol for patients with biopsy proved proliferative lupus nephritis as a gold treatment standard. However, sustained remission of proliferative lupus nephritis is a goal that still remains to be achieved.
Petrović
Radimila
R
Institute of Rheumatology, Belgrade. reumabeo@net.yu
Stojanović
Roksanda
R
Novicić-Sasić
Darinka
D
Dimitrijević
Jovan
J
Pavlović
Stevan
S
Stojković
Dragisa
D
Palić-Obradović
Dragana
D
Stevanović
Gordana
G
Prodanović
Slavica
S
D000293:Adolescent; D000328:Adult; D002648:Child; D003520:Cyclophosphamide / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D008181:Lupus Nephritis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D020551:Pulse Therapy, Drug
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide