Azathioprine, the Cinderella in the treatment of lupus nephritis

Sir, With interest I read the contribution of Dr Joanne Bargman on the use of cyclophosphamide in the treatment of lupus nephritis [1]. Although not fully supported by the data, the i.v. pulses of cyclophosphamide became the gold standard for treatment of proliferative lupus nephritis. In several analyses [2,3], azathioprine gave at least comparable results as cyclophosphamide, but with a much better toxicity profile. Nevertheless, azathioprine became the forgotten Cinderella in this therapeutic scenery and was regarded as second-class treatment. The author then describes that, although it seemed appropriate, the use of azathioprine was not discussed at all in two major nephrology conferences she attended. So it was surprising to note that Dr Bargman did not discuss the only head to head comparison between i.v. cyclophosphamide and azathioprine [4,5]. This randomized controlled trial, comparing i.v. cyclophosphamide with three times three pulses of methylprednisolone and 2 mg/kg azathioprine, in the Netherlands in 87 patients with biopsy-proven proliferative lupus nephritis showed after a median follow-up of 77 months that the occurrence of partial or complete remissions was equal in both arms; non-sustained doubling of serum creatinine occurred more frequently in the AZA group (RR 5.2; 95% CI 1.1–25.2; P = 0.04) [5]; renal flares occurred more frequently in the AZA group (RR 4.9; 95%, CI 1.6–15.0; P 0.006); renal flares responded to intensivation of treatment in all patients; at the last follow-up, there were no differences between the groups in median serum creatinine (82 μmol/l; IQR: 74–108) and median proteinuria (0.3 g/24 h; IQR: 0.10– 0.72); in repeat biopsies after 2 years in both groups, the activity index decreased similarly, but the chronicity index decreased slightly in the CY group (2.8–3.0), but in the AZA group, this increase was larger (2.8–3.8; P = 0.05); at the last follow-up, 88% of the patients in the AZA group had been free of cyclophosphamide treatment and had therefore a better prognosis regarding fertility. These results show that azathioprine is not the first drug of choice for induction treatment in patients with lupus nephritis. However, if a patient chooses not to jeopardize fertility, azathioprine forms an alternative. Also, during pregnancy, azathioprine is relatively safe in contrast to mycophenolate mofetil (MMF) or cyclophosphamide, which are contraindicated. Therefore, azathioprine still has a (limited) place in the induction treatment of lupus nephritis. As maintenance treatment, azathioprine is probably a good choice. In the Euro-Lupus Trial, azathioprine started after 3 months gave comparable results as i.v. cyclophosphamide given for 1 year [6,7]. The upcoming results of the MAINTAIN-trial will give better insight into the comparison of azathioprine with MMF as maintenance treatment [8]. In a recent meta-analysis, the results of azathioprine and MMF during maintenance were comparable, although the number of patients in this analysis was rather low [9]. Conflict of interest statement. None declared.