Azathioprine/methylprednisolone versus cyclophosphamide in proliferative lupus nephritis. A randomized controlled trial

Abstract

Until recently, intravenous cyclophosphamide pulses with oral corticosteroids were regarded standard therapy for proliferative lupus nephritis (LN). Azathioprine, a less toxic alternative, was never proven to be inferior. In the first Dutch lupus nephritis study (enrollment between 1995 and 2001), we randomized 87 proliferative LN patients to either cyclophosphamide pulses (750 mg/m(2), 13 pulses in 2 years) combined with oral prednisone (CY) or to azathioprine (2 mg/kg/day in 2 years) combined with intravenous pulses of methylprednisolone (3 x 3 pulses of 1000 mg) and oral prednisone (AZA). After a median follow-up of 5.7 years (interquartile range 4.1-7.2 years), doubling of serum creatinine was more frequent in the AZA group, although not statistically significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI): 0.8-20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI: 1.5-31.8). Creatinine and proteinuria at last visit did not differ between the two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still free of cyclophosphamide treatment. During the first 2 years, the frequency of remission was not different, but infections, especially herpes zoster virus infections (HZV) were more frequent in the AZA group. Parameters for ovarian function did not differ between the two groups. In conclusion, in this open-label randomized controlled trial, cyclophosphamide was superior to azathioprine with regard to renal relapses and HZV. At last follow-up, there were no differences in serum creatinine or proteinuria between the two groups. However, since our study lacked sufficient power, longer follow-up is needed to reveal putative differences.

Updates on the Treatment of Lupus Nephritis

“…In contrast, azathioprine as induction therapy for lupus nephritis has not proven as effective as intravenous cyclophosphamide, with more relapses and less long-term benefit than cytotoxic therapy. 28 Other agents have been explored in induction regimens, typically used in conjunction with MMF and/or steroids. Rituximab, an anti-CD20 monoclonal antibody that depletes B cells, is useful in inducing remissions in some patients with severe lupus nephritis, including those who have failed cyclophosphamide or MMF therapy.…”

Histologic deterioration and more flares: The case against azathioprine plus methylprednisolone in the treatment of proliferative lupus nephritis

“…In fact, the greater corticosteroid exposure in the AZA plus MP group could account for the increased incidence of infections in that group (2). It follows that the lesser efficacy of the AZA plus MP regimen might have been even more evident if the corticosteroid dosing in the 2 regimens were identical.…”

“…The study included Ͼ60% of all patients with biopsy-proven proliferative lupus nephritis in the Dutch Lupus Nephritis Study (2). The exclusion of patients with creatinine clearance rates Ͻ25 ml/minute can explain the rarity of crescents found on renal biopsy.…”

Infecciones en pacientes reumatológicos asociadas a corticosteroides y antagonistas del factor de necrosis tumoral α

“…La exposición a corticosteroides aumenta el riesgo de reactivación del virus varicela-zoster en la forma de herpes zoster 6,23,24 . La frecuencia de herpes zoster es aproximadamente tres veces superior a lo observado en otros pacientes con condiciones músculo-esqueléticas no inflamatorias y tiende a concentrarse poco después del diagnóstico pero no necesariamente se presenta en el momento de estar tomando fármacos inmunosupresores 25 .…”