Long-term mizoribine intermittent pulse therapy for young patients with flare of lupus nephritis

Abstract

Mizoribine (MZR) is a novel purine synthesis inhibitor that was developed in Japan. We previously reported the efficacy and safety of oral MZR intermittent pulse therapy, which is associated with elevated peak serum MZR levels, in selected patients with lupus nephritis. However, the efficacy and safety of long-term MZR intermittent pulse therapy (administered for over 24 months) in lupus nephritis patients at high risk for relapse has not yet been reported. Our study included five patients with a long history of systemic lupus erythematosus (SLE), including four patients with proliferative lupus nephritis (WHO class IV) and one patient with WHO class II lupus nephritis, in whom remission had been achieved through treatment with high-dose corticosteroids combined with cytotoxic agents. For the most recent flares, all the patients were treated with MZR intermittent pulse therapy without increase in the dose of corticosteroids. MZR was administered at 5-10 mg/kg per day (up to 500 mg) as a single daily dose on two days of the week (Monday and Thursday) for over 24 months. Concomitantly administered corticosteroid dose was gradually reduced or continued unchanged. At presentation, the urinary protein excretion, serum complement hemolytic activity (CH50) and serum anti-dsDNA antibody titer were 1.7+/-1.0 g/day, 16.6+/-3.8 U/mL (normal, 23-46 U/mL) and 143.7+/-151.1 IU/mL (normal,<12.0 IU/mL), respectively. At the latest observation point, after a mean interval of 31 months (24-34 months) after the initiation of MZR pulse therapy, the urinary protein excretion and serum anti-dsDNA antibody titer were significantly decreased (0.3+/-0.2 g/day and 18.5+/-19.1 IU/mL, respectively; P<0.05), and the serum CH50 value had returned to within normal range (33.6+/-7.8 U/mL, P<0.05). Despite the reduced minimum dose of prednisolone required to maintain clinical remission at the time of the post-treatment evaluation after MZR pulse therapy as compared with that at the time of the pretreatment evaluation (9.0+/-4.5 vs. 17.5+/-7.9 mg/day; P=0.0656), the calculated flare rate was significantly decreased (0.15+/-0.2 vs. 0.6+/-0.11 times per year; P<0.05). The serum creatinine level remained within normal range in all the study participants. Furthermore, the platelet count increased following the MZR pulse therapy in two patients who had suffered from chronic thrombocytopenia. No serious adverse effects were observed. From the view point of the balance between suppression of disease activity and the adverse effects of treatment, we believe that long-term MZR pulse therapy may be the treatment of choice in selected patients with lupus nephritis at high risk for relapse. However, this was only a pilot study conducted on a small number of subjects, without a control group. Further studies to confirm the long-term efficacy and safety of oral MZR intermittent pulse therapy in larger numbers of patients are needed.