Mizoribine as a safe and effective combined maintenance therapy with prednisolone for anti-neutrophil cytoplasmic antibody-associated vasculitis in a hemodialysis patient

Abstract

A 77-year-old man developed severe renal insufficiency due to proteinase 3 anti-neutrophil cytoplasmic antibody (PR3-ANCA)-associated vasculitis, and was started on hemodialysis (HD). Because his renal insufficiency appeared to be irreversible, he was maintained on oral prednisolone (PSL) at 5 mg/day. However, a disease flare-up with alveolar hemorrhage occurred. Serology revealed elevated levels of PR3-ANCA and C-reactive protein (CRP). The patient was given pulse therapy with a quarter dose of methylprednisolone (m-PSL) (250 mg, 3 days), followed by oral PSL at 15 mg/day. As a supplemental treatment, he was given 25 mg of mizoribine (MZR) immediately after each HD session. Subsequently, the levels of PR3-ANCA and CRP decreased, and the alveolar hemorrhage resolved. The dose of MZR to be given was determined by measuring the patient's serum concentrations of MZR at various time points after the HD session. The maintenance dose of MZR was finally set at 50 mg. At present, the oral PSL dosage has been tapered to 10 mg/day, and the patient has achieved a state of remission without any side effects.

Keywords: Hemodialysis; Mizoribine; Proteinase 3 anti-neutrophil cytoplasmic antibody-associated vasculitis; Pulmonary hemorrhage.

Fig. 1

Renal biopsy specimen in the current case. Light microscopic examination showed cellular crescents in 10 of 13 glomeruli (periodic acid-Schiff stain)

Fig. 2

Time courses of the patient’s PR3-ANCA and CRP levels. The levels decreased after induction therapy with m-PSL and oral PSL. However, the ANCA-associated vasculitis flared up after the PSL dose was decreased to 5 mg/day. The patient was then readmitted in July 2011. BALF analysis confirmed alveolar hemorrhage. m-PSL was administered at 250 mg/day for 3 days, followed by oral PSL at 15 mg/day. Two weeks later, a supplemental treatment of 25 mg MZR administered immediately after each HD session was initiated. The maintenance dose of MZR was finally set at 50 mg, after monitoring its serum concentration. These treatments relieved the patient’s symptoms, and the CT findings disappeared completely

Fig. 3

CT scan at the level of the upper lobe in July 2011. a Consolidation in the left upper lobe is apparent. b The CT scan performed 4 months later at the same level shows resolution of the consolidation

Fig. 4

Serum MZR concentrations after the oral administration of 25 and 50 mg of MZR, immediately following dialysis, measured at five time points: immediately after dialysis, 4 h after dialysis, 6 h after dialysis, 24 h after dialysis, and immediately before the next dialysis session (after 44.5 h). The patient’s dialysis conditions, which could influence the serum MZR concentration, were not changed during MZR therapy. The kinetics of the MZR were found to be adequately fitted by a one-compartment model to estimate its serum concentration. Therefore, we drew the kinetic curves using this model, employing higher intradialytic elimination rate constants that were calculated using the semi-log graph