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Therapeutics

An extended course of pulse cyclophosphamide preserved renal function and reduced the rate of exacerbations in patients with severe lupus nephritis

ACP J Club. 1993 May-June;118:86. doi:10.7326/ACPJC-1993-118-3-086


Source Citation

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 Sep 26;340:741-5.


Abstract

Objective

To evaluate the efficacy of pulse methylprednisolone and pulse cyclophosphamide in the long-term management of lupus nephritis and to determine whether the efficacy and toxicity of short and long courses of pulse cyclophosphamide differ.

Design

Randomized controlled trial.

Setting

{Referral-based government hospital}.*

Patients

65 patients (mean age 30 y, 60 women) with systemic lupus erythematosus and severe lupus nephritis (defined by a nephritic urine sediment and impaired renal function with a creatinine clearance between 25 to 80 mL/min). Exclusion criteria were previous cytotoxic drug therapy for > 10 weeks, active infections, insulin-dependent diabetes, previous malignancy, or pregnancy. No patients were lost to follow-up.

Intervention

Patients were allocated to 1 of 3 treatment groups: intravenous infusion of methylprednisolone 1.0 g/m2 body surface area over 30 minutes, initially in 3 daily doses, followed by monthly single doses for 6 months (n = 25); single monthly intravenous infusions of cyclophosphamide, 0.5 to 1.0 g/m over 60 minutes for 6 months (n = 20); or single monthly infusions of cyclophosphamide, 0.5 to 1.0 g/m2 over 60 minutes for 6 months, followed by single quarterly doses (0.5 to 1.0 g/m2) for 2 more years (n = 20). All patients were treated concomitantly with prednisone.

Main outcome measures

Renal insufficiency defined as sustained doubling (for > 1 mo) of serum creatinine over the lowest value reached during the study period; exacerbations of lupus nephritis or severe systemic lupus.

Main results

After 3 years, the cumulative probability of doubling serum creatinine was > 40% in patients receiving pulse methylprednisolone compared with < 10% in patients receiving a long course of cyclophosphamide (P = 0.04). The methylprednisolone and the short-course cyclophosphamide groups did not differ for renal insufficiency. After completion of the monthly phase of treatment, the cumulative probability of exacerbations in patients on short-course cyclophosphamide was > 50% after 3 years compared with < 10% in those receiving long-course cyclophosphamide (P = 0.006).

Conclusions

Monthly cyclophosphamide for 6 months followed by quarterly pulse cyclophosphamide for 2 more years was more effective than 6 months of pulse methylprednisolone in preserving renal function in patients with severe lupus nephritis. This long course of cyclophosphamide also reduced the rate of exacerbations when compared with cyclophosphamide for 6 months.

Source of funding: Federal government.*

For article reprint: Dr. D.T. Boumpas, Arthritis and Rheumatism Branch, National Institute of Arthritis and Muscuskeletal and Skin Diseases, National Institutes of Health, Building 10, Room 95209, Bethesda, MD 20892-1828, USA. FAX 301-402-0765.

*Information supplied by author.


Commentary

The study by Boumpas and colleagues compared methylprednisolone with parenteral cyclophosphamide treatment because nonrandomized studies have described benefits with bolus methylprednisolone in lupus nephritis, especially in patients with recent antecedent deteriorated renal function (1), and because an alternative to cytotoxic therapy in systemic lupus erythematosus is desirable. However, National Institutes of Health (NIH) trials since 1973 have shown that treatment with parenteral cyclophosphamide plus oral prednisone is superior to prednisone alone, and the current trial found that cyclophosphamide preserves renal function better than methylprednisolone.

Before generalizing this finding to other settings, at least 3 factors should be considered. First, patients with persistent responses to therapy with prednisone alone may be underrepresented at the NIH because it is a tertiary referral center to which the least responsive cases are likely to be referred. Second, success in managing hypertension and hypocomplementemia are important to preserving renal function, and the study did not document that the intervention and control groups were managed equally well in this respect. Third, the patients were entered into the trials between 1981 and 1986, before the widespread use of renal-sparing medications such as angiotensin-converting enzyme inhibitors. Thus, allowing this study to sound the death knell of bolus methylprednisolone therapy in lupus nephritis could be premature. Combinations of cytotoxic agents plus methylprednisolone could prove superior to treatment with either one alone; the results of a further NIH study have shown a trend favoring combination therapy with cyclophosphamide and methylprednisolone (2).

This study shows that a longer term of cyclophosphamide is more effective than a shorter term. This and other similar studies may justify inclusion of the terms "induction," "consolidation," and "maintenance" therapy in the lexicon of rheumatologists.

H. Michael Belmont, MD
Hospital for Joint DiseasesNew York, New York, USA


References

1. Kimberly R, Lockshin M, Sherman R, et al. High-dose intravenous methylprednisolone pulse therapy in systemic lupus erythematosus. Am J Med. 1981; 70:817-23.

2. Gourley MF, Austin HA 3rd, Scott D, et al. Methylprednisolone and cyclophosphamide, alone or in combination, in patients with lupus nephritis. A randomized, controlled trial. Ann Intern Med. 1996;125:549-57.