A multitarget therapy of mycophenolate mofetil and tacrolimus for lupus nephritis induction therapy led to almost twice as many complete remissions as did intravenous cyclophosphamide in an open-label, randomized, controlled trial.
“Because immune dysregulation is fundamental to pathogenesis of lupus nephritis, with both B and T cells involved in the development of the disease, it may be necessary to target multiple aspects of the immune response using combined immunosuppressants,” wrote Dr. Zhi-Hong Liu of Nanjing (China) University and her colleagues (Ann. Intern. Med. 2014 Nov. 11 [doi:10.7326/M14-1030]).
Dr. Zhihong Liu
Between April 2009 and June 2011, 368 adults aged 18-65 years from 26 renal centers in China were randomized to receive mycophenolate mofetil (MMF) and tacrolimus with a steroid or IV cyclophosphamide with a steroid for 24 weeks. A total of 362 received medication (6 did not receive their assigned cyclophosphamide treatment for unknown reasons), and 310 completed the whole 24-week course of treatment. All participants in the study had biopsy-proven lupus nephritis diagnosed within the previous 6 months and had not been previously treated with MMF, cyclophosphamide, tacrolimus, or high-dose methylprednisolone, nor had they had renal replacement therapy, plasmapheresis, or IV gamma globulin therapy in the previous 12 weeks.
All patients began by receiving IV methylprednisolone pulse therapy (0.5 g/day) for 3 days and then oral prednisone (0.6 mg/kg) daily for 4 weeks, with prednisone tapering to 10 mg/day for the remainder of the study period. Following methylprednisolone pulse therapy, the multitarget group received MMF (0.5 g twice daily) and tacrolimus (2 mg twice daily) while the comparison group received IV cyclophosphamide (initially 0.75 g/m2 body surface area, then adjusted to 0.5-1.0 g/m2).
Nearly half – 45.9% – of patients in the multitarget group achieved full remission, whereas 25.6% of patients receiving IV cyclophosphamide showed complete remission (P < .001). The investigators defined complete remission as a 24-hour urinary protein excretion of 0.4 g or less, the absence of active urine sediments, a serum albumin level of 35 g/L or greater, and normal serum creatinine.
Results on secondary endpoints also favored multitarget therapy. The percentage of patients who had an overall response to treatment (complete and partial remissions) was 83.5% for multitarget therapy and 63% for cyclophosphamide (P < .001). Multitarget therapy patients responded to treatment at a median of 8.9 weeks, compared with cyclophosphamide-treated patients at 13 weeks. The investigators defined partial response as a 50% or greater reduction in proteinuria and urine protein less than 3.5 g/24 hours, a serum albumin level of 30 g/L or higher, and a normal or 25% or lower increase in serum creatinine level from baseline.
After treatment, patients in the multitarget therapy group also had significantly better results on other secondary endpoints, including changes in urine protein, serum albumin, systemic lupus erythematosus disease activity score, and C3 levels.
Adverse events occurred among 50.3% of multitarget recipients and 52.5% of cyclophosphamide recipients. More patients who received multitarget therapy had a serious adverse event (7.2% vs. 2.8%, respectively), and more patients withdrew from the multitarget therapy group (5.5% vs. 1.7%), but there were no statistically significant differences between the groups for either comparison.
The study was supported by the National Basic Research Program of China and the National Key Technology R&D Programs. Information on disclosures was unavailable at the time of publication.