Mizoribine for the treatment of lupus nephritis in children and adolescents.
OBJECTIVE
The optimal treatment for lupus nephritis in the pubertal age group is still unclear. We therefore retrospectively evaluated the efficacy and safety of mizoribine (MZR), a novel selective inhibitor of inosine monophosphatase dehydrogenase, developed in Japan for the treatment of lupus nephritis in pubertal patients, because MZR has been reported to have relatively less clinically toxicity than conventionally used drugs.


METHODS
Over the past 12 years, we have treated 20 children with newly diagnosed, biopsy-proven lupus nephritis at our hospital. Of these, 10 patients who received a 2-year course of MZR in combination with prednisolone (PSL) as initial maintenance therapy and who could be observed for at least two years after the commencement of the MZR treatment, were enrolled in this study. MZR was given orally at the dose of 4 - 5 mg/kg per day in two divided doses. Changes in the clinical parameters, such as the urinary protein excretion, serum anti-dsDNA antibody titer, serum hemolytic complement activity (CH50) and serum creatinine, and in the frequency of disease flares defined as persistent worsening of those clinical parameters, were examined pre- and posttreatment for comparison, and the steroid-sparing effect of MZR was analyzed.


RESULTS
As induction therapy, all the patients had received high-dose oral PSL or intravenous methylprednisolone pulse therapy. Five female patients who were diagnosed to have proliferative lupus nephritis (WHO class III or IV) were scheduled to receive an 8-week course of oral cyclophosphamide (CPA) combined with high-dose steroids prior to the commencement of MZR, but CPA needed to be discontinued in four of these patients because of clinical drug toxicity. The clinical parameters showed significant improvement after the 2-year treatment with MZR combined with PSL, as compared to the pretreatment values (mean urinary protein excretion: 1.6+/-1.9 g/day vs.0.1 +/-0.1 g/day, serum CH50 value: 12.6+/-5.4 U/ml vs. 34.5+/-7.7 U/ml, serum anti-dsDNA antibody titer: 141.8+/-128.2 IU/ml vs. 18.5+/-17.7 IU/ml, respectively (p <0.01)). The serum creatinine remained normal. Although the daily dose of the concomitantly administered PSL to maintain clinical remission could be decreased significantly in all the study participants (39.5+/-1.6 mg/day vs. 6.8+/-5.1 mg/day, p < 0.01), two patients developed flares while on treatment, which were successfully treated by transiently increasing the dose of PSL. The MZR therapy could be completed in all of the patients without significant clinical toxicity being reported. At their most recent follow-up (mean 4.3 years), none of the 10 patients had renal insufficiency, and complete remission without any need for further medication had been achieved in two patients.


CONCLUSIONS
Although this case series is without controls, maintenance therapy with MZR administered in combination with PSL may be beneficial and clinically less toxic in at least a proportion of pubertal patients with lupus nephritis.
Tanaka
H
H
Department of Pediatrics, Hirosaki University School of Medicine, Hirosaki, Japan. hirotana@cc.hirosaki-u.ac.jp
Tsugawa
K
K
Tsuruga
K
K
Suzuki
K
K
Nakahata
T
T
Ito
E
E
Waga
S
S
D000293:Adolescent; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D002648:Child; D003404:Creatinine / Q000097:blood; D003520:Cyclophosphamide / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D008181:Lupus Nephritis / Q000188:drug therapy*; D008297:Male; D011239:Prednisolone / Q000008:administration & dosage; D012189:Retrospective Studies; D012263:Ribonucleosides / Q000008:administration & dosage / Q000627:therapeutic use*; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D003520:Cyclophosphamide; D011239:Prednisolone; D003404:Creatinine