NIJMEGEN, The Netherlands—Histologic data from the Dutch Working Party on Systemic Lupus Erythematosus (SLE) have ended the hope that azathioprine (AZA) plus methylprednisolone (MP) might be an effective and less toxic alternative to pulse CYC for the treatment of proliferative lupus nephritis. This study, which included serial renal biopsies at baseline and at 2 years also showed that renal biopsy is not likely to help clinicians identify patients at high risk for renal failure, lead author Cecile Grootscholten, MD, reports in the March issue of Arthritis & Rheumatism.¹

In an accompanying editorial, Tak Mao Chan, MD, with the department of medicine at the University of Hong Kong, writes, "[T]he report by Grootscholten et al provides important histologic follow-up data that indicate inferior outcomes following treatment with AZA compared with CYC, and the histologic results paralleled worsening renal function. Although the exact mechanisms leading to these differences in outcome with the 2 treatment regimens remains speculative, excessive relapses and subclinical immune-mediated inflammation were probably contributory factors."²

Randomized, prospective study

Dr. Grootscholten, at Radboud University Nijmegen Medical Center, and colleagues enrolled 87 patients with biopsy-proven lupus nephritis. Patients were randomized to 2 years of treatment with either pulse CYC (6 intravenous 750 mg/m²  pulses at 4-week intervals, then 7 pulses at 12-week intervals) plus prednisone (1 mg/kg/day for 4 weeks tapered to 10 mg/day after 6 months) or AZA (2 mg/kg/day) plus pulse MP (9 intravenous 1-gm pulses in 2 months) and oral prednisone (20 mg/day tapered to 10 mg/day over 5 months). "The first Dutch Lupus Nephritis Study was initiated with the goal of seeking a less toxic alternative to pulse CYC therapy," the authors write.

Unfortunately, the 2-year follow-up showed no difference in the changes in median activity index, but the AZA patients had a significantly larger increase in the median chronicity index than did the CYC group. "These results indicate that, although both CYC and AZA are effective in reducing active lesions in lupus nephritis, progression of chronic lesions is more effectively halted by CYC," Dr. Grootscholten et al report.

Patients in the AZA group were five times as likely to reach the primary study endpoint (doubling of the serum creatinine level, but not necessarily sustained) as those in the CYC group (relative risk 5.2, 95% CI 1.1-25.2, P = .004). Renal relapses were also significantly more frequent in the AZA group (relative risk 4.9, 95% CI 1.6-15, P = .006).

Repeat renal biopsies were performed on 39 of the 87 patients at 2 years. The authors note that these patients "were representative of the overall group, both at entry and at 2-year follow up." The repeat renal biopsies did not yield information that would help identify patients at risk of developing end-stage renal disease.

Histopathology did confirm the superiority of the CYC regimen, showing fewer completely sclerosed glomeruli, less tubular atrophy, and a significantly lower increase in the chronicity index.

"[F]or time to doubling of the serum creatinine level, treatment failure, or relapse, treatment [group] was the only predictive factor. At the time of repeat biopsy, however, none of the 2-year parameters, including treatment, could predict the occurrence of doubling of the serum creatinine level, treatment failure, relapse, or time to these events," the investigators report.

The Dutch researchers also note that although the results of this study indicate that 2 years of CYC is more effective at preventing renal relapse and chronic lesions, other data "suggests that long-term renal function in patients receiving AZA plus MP is comparable with that in patients treated with CYC. Therefore, for selected patients with proliferative lupus nephritis who wish to avoid the gonadal toxicity of CYC, treatment with AZA plus MP can be an alternative."

Dr. Chan cautions that since about 70% of the patients in this study were Caucasian, the results may not be applicable to African Americans, who are at increased risk for renal fibrosis, transforming growth factor β1 hyperexpression, and inferior renal survival compared with other ethnic groups. "Therefore, the AZA plus MP regimen does not appear appropriate for high-risk groups such as African Americans," he writes.

Dr. Chan also sees a possible usefulness for serial biopsies. He would like to see data from biopsies performed later in the course of follow-up, and he points out that the presence of extensive chronic damage seen on biopsy "can alert the clinician to avoid treatment with nephrotoxic agents such as calcineurin inhibitors."

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References

1. Grootscholten C, Bajema IM, Florquin S, et al. Treatment with cyclophosphamide delays the progression of chronic lesions more effectively than does treatment with azathioprine plus methylprednisolone in patients with proliferative lupus nephritis. Arthritis Rheum. 2007;56:924-937.
2. Chan TM. Histologic deterioration and more flares: the case against azathioprine plus methylpredisolone in the treatment of proliferative lupus nephritis. Arthritis Rheum. 2007;56:702-704.