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

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.     

Mizoribine for the treatment of lupus nephritis in children and adolescents

AIM: 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. CONCLUSION: 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.     

Implication of the peak serum level of mizoribine for control of the serum anti-dsDNA antibody titer in patients with lupus nephritis

AIM: Mizoribine (MZR) is a novel selective inhibitor of inosine monophosphatase dehydrogenase that was developed in Japan. We previously reported the efficacy and safety of oral MZR pulse therapy, which is associated with elevated peak serum MZR levels, in selected patients with lupus nephritis. However, only limited information is available as yet on the optimal peak serum level of MZR that would yield an enhanced clinical efficacy without serious toxicity in patients with lupus nephritis. METHODS: A total of 11 patients with clinically stable lupus nephritis treated with oral MZR pulse therapy combined with low-dose prednisolone were enrolled in the cross-sectional study. The peak serum concentrations of MZR (as determined by HPLC) and the serum anti-dsDNA antibody titers (as determined by ELISA) were examined in the patients in order to evaluate the correlation between these two parameters. The correlation between the dose of MZR (mg/kg) administered orally as a single daily dose and the peak serum level of the drug was also examined. In two of the patients, serial measurements of the changes in the peak serum levels of MZR and anti-dsDNA titers could be conducted over 10 months. RESULTS: A significant inverse correlation (r = -0.596, p = 0.0116) was observed between the peak serum levels of MZR and the serum anti-dsDNA antibody titers in the study participants, while the dose of prednisolone remained unchanged. The peak level of MZR in the serum was significantly correlated with the single dose of MZR (r = 0.509, p = 0.0371). In the two patients in whom serial measurements were conducted, the first patient who showed a peak serum MZR level of less than 2.5-3.0 microg/ml eventually developed an increase of the serum anti-dsDNA titer with hypocomplementemia and proteinuria. On the other hand, in the second patient who showed a peak serum MZR level in excess of 4.0 microg/ml, persistently low serum anti-dsDNA titers with normocomplementemia were observed. CONCLUSION: Although this study is only a preliminary study conducted on a small sample, we speculate from the results that a peak serum level of MZR of at least more than 2.5-3.0 mirog/ml is necessary to achieve satisfactory clinical efficacy of the drug for the treatment of lupus nephritis. Further study is needed to confirm these preliminary findings.     

Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis

AIM: Mizoribine (MZR) is a purine antimetabolic immunosuppressant agent that has few little severe adverse events. We studied whether maintenance therapy with MZR and prednisolone (PSL) in severe proliferative lupus nephritis patients could improve immunity, reduce proteinuria, prevent renal relapse, and reduce steroid dose. METHOD: Long-term maintenance therapy with MZR and PSL was evaluated in ten patients with biopsy-proven proliferative lupus nephritis. Patients with severe lupus nephritis, who had proteinuria of 0.5 g or more even after treatments with plasma exchange and/or pulse methyl prednisolone, were recruited. MZR at an average dose of 140 +/- 10 (100 - 200) mg was administered two to three times/day in combination with PSL. The average period for the MZR maintenance therapy was 89.7 +/- 5.5 (70 - 126) months. Urine protein excretion, serum hemolytic complement activity (CH50), C3, serum creatinine, general and biochemical blood examinations, anti-ds-DNA antibody were collected at each monthly medical examination. RESULTS: All patients were females, mean age 43.0 +/- 3.3 years. A significant decrease in proteinuria was noted two years after the combination therapy (p = 0.0016). Five patients experienced lupus nephritis relapse. Patients who did not experience relapses had their MZR combination therapy initiated earlier (p = 0.037) when compared with the patients who experienced relapses. Serum creatinine levels remained unchanged in all patients throughout treatment and follow-up, even during renal relapses. Levels of C3 and CH50 normalized as proteinuria decreased. None of the patients developed serious side effects during MZR treatment. A significant steroid-sparing effect was observed three years after initiating MZR (p = 0.0025). CONCLUSION: From our long-term observation, maintenance therapy with low-dose PSL combined with MZR can eliminate proteinuria and have steroid-sparing effect. Early initiation of the therapy can protect against renal relapses among severe proliferative lupus nephritis patients without serious side effects.     

Long-term intermittent pulse therapy with mizoribine attenuates histologic progression in young patients with severe lupus nephritis: report of two patients

Mizoribine (MZR), a novel selective inhibitor of inosine monophosphate dehydrogenase in the de novo pathway, whose mode of action is very similar to that of mycophenolate mofetil, has been successfully applied without serious adverse effects for the treatment of renal diseases. We have previously reported the efficacy and safety of a new MZR treatment regimen, namely, oral MZR intermittent pulse therapy, which we examined based on the observation that it might show superior efficacy to the conventional daily low-dose MZR regimen on account of the higher peak serum MZR levels, in selected patients with lupus nephritis. Two Japanese patients with severe lupus nephritis (WHO class IV-G) who were administered long-term intermittent MZR pulse therapy, and in whom pre- and post-treatment renal biopsies were reported. Post-treatment renal biopsy confirmed the marked attenuation of histologic progression by the treatment. These clinical observations may lend further support, from the histologic standpoint, to the efficacy of long-term MZR intermittent pulse therapy for selected patients with active lupus nephritis.     

Maintenance therapy with mycophenolate mofetil for children with severe lupus nephritis after low-dose intravenous cyclophosphamide regimen

Although recent studies on adults with lupus nephritis indicate that mycophenolate mofetil (MMF) may be effective in maintaining remission for patients who previously received short-term intravenous cyclophosphamide (IVCY) induction therapy, the experience with the new immunosuppressive agent in children with severe lupus nephritis has not been as satisfactory thus far. To assess the efficacy and safety of maintenance therapy with MMF, we prospectively analyzed four patients with biopsy-proven severe lupus nephritis (three girls, one boy; mean age 12 years; two with class IIIA, two with class IVG(A); mean duration of lupus nephritis 7 months) receiving MMF for at least 6 months after induction treatment. These patients had been treated previously with 6 months of low-dose IVCY combined with oral mizoribine and steroids for induction, followed by therapy with MMF adjusted to maintain predose mycophenolic acid (C0-MPA) levels at 2-5 mcg/ml. Mean follow-up after staring MMF was 27.5 months (range 6-41). The mean MMF dose required was 405 +/- 49 mg/m(2) per 12 h, which maintained mean C0-MPA levels of 3.3 +/- 0.41 mcg/ml. No patient experienced renal flares during maintenance therapy with MMF, which permitted a significant reduction in mean prednisolone dose from 11.9 +/- 1.3 to 3.9 +/- 2.6 mg/day (P = 0.003). No significant gastrointestinal or hematologic side effects of MMF were noted. This preliminary study demonstrates that maintenance therapy with MMF after a low-dose IVCY regimen appears to be a promising intervention without adverse effects in children with severe lupus nephritis. These data should be confirmed by a prospective randomized multicenter clinical trial.     

免疫吸附治疗狼疮性肾炎的临床观察

目的 观察免疫吸附治疗狼疮性肾炎的临床疗效.方法 选择2007年7月至2010年7月狼疮性肾炎患者29例,均有明显的血尿、尿蛋白每天＞2.0 g,血肌酐(306.28±0.12)μmol.其中14例狼疮性肾炎患者采用DNA280免疫吸附柱进行血液净化治疗,免疫吸附治疗2次,每次2 h,同时按疗程给与小剂量泼尼松(0.5 mg·kg-1·d-1)及间断环磷酰胺(6～8 g)静脉冲击治疗.另外15例患者应用传统治疗方法,给予大剂量的泼尼松(1 mg·kg-1·d-1)及间断环磷酰胺静脉冲击治疗作为对照组并进行比较.结果 免疫吸附治疗组患者好转率为79%,对照组好转率为56%,两组比较差异有统计学意义(P＜0.01).结论 免疫吸附能有效地控制狼疮性肾炎,明显改善狼疮性肾炎患者的肾功能.

Abstract：

Objective immunoadsorption treatment of lupus nephritis clinical efficacy. Methods from July 2007 to July 2010 29 patients with lupus nephritis, have significant hematuria, urinary protein per day＞ 2.0 g, serum creatinine (306.28 ± 0.12) μmol. 14 patients with lupus nephritis were treated with DNA280 immunosorbent column and blood purification therapy, immunoadsorption therapy 2 times 2 h, while treatment given by a small dose of prednisone (0.5 mg·kg-1·d-1) and intermittent cyclophosphamide (CTX, 6-8 g) intravenous pulse therapy. Another 15 patients were treated with conventional therapy, high dose of prednisone (1 mg · kg-1 · d-1) and CTX intermittent intravenous pulse therapy as a control group and compared. Results improved in patients treated with immunoadsorption was 78.57% in the control group improvement was 56.25% (P ＜ 0.01). Conclusion The adsorption can effectively control the immune lupus nephritis, lupus nephritis significantly improved renal function.     

Effect of methylprednisolone pulse therapy in patients with lupus nephritis assessed by WHO morphologic classification

To determine indications for treatment with high-dose intravenous methylprednisolone pulse therapy in lupus nephritis, we retrospectively assessed the response to pulse therapy over oral prednisolone administration in 120 biopsy proven lupus nephritis patients according to WHO morphologic classification. In the pulse group, 1 g of methylprednisolone was administered on three consecutive days and oral steroid therapy (40-30 mg) was started. In many occasions in treating class III and IV-b, repeated pulse therapy was performed. In control oral prednisolone group, middle-dose steroid therapy (50-30 mg) was started. In patients with minor glomerular abnormalities and mesangial lupus nephritis, rapid improvement of serological activities was observed in pulse group assessed by serum complement level, anti-DNA antibodies, and anti-nuclear antibodies. In patients with focal lupus nephritis, rapid rise in serum complement level and fall in proteinuria was observed in the pulse group. In patients with diffuse proliferative lupus nephritis with active necrotizing lesions, faster rise in serum complement level and proteinuria were observed in the pulse group. In patients with membranous lupus nephritis there was no significant difference between two groups. In comparison with the effect of pulse therapy among each morphologic class, the rise of serum complement level was slowest in class IV-b. Both group of IV-b and V manifested nephrotic syndrome and by pulse therapy the decrease in urinary protein was faster and more significant in class IV-b compared with class V. No significant adverse effect of methylprednisolone was observed during about 150 times of pulse therapy. Bacterial, viral infections such as herpes zoster and fungal infections were observed in pulse group as often as control group.     

Beneficial and adverse effects of high-dosage MZR therapy in the management of children with frequently relapsing nephrotic syndrome

BACKGROUND: Long-term therapy of mizoribine (MZR 2-5 mg/kg/day) has been reported in the management of children with frequently relapsing nephrotic syndrome(FRNS). It had minimum adverse effects, however, MZR therapy does not sufficiently suppress the relapse of FRNS. Previous reports suggested that modification of MZR therapy with a total dosage and administration schedule may improve the therapeutic effect. To elucidate the issue, we retrospectively evaluated the efficacy and safety of high-dose MZR therapy for children with FRNS. METHODS: The subjects comprised 13 affected children with FRNS (9 boys and 4 girls: median age of 11.7 years, ranging from 7.8 to 20.1 years). They were divided into a high dose group (MZR 7-10 mg/kg/ day; Max 400 mg) and a low dose group (MZR 4-6 mg/kg/day). We compared the therapeutic benefits between both groups, including the incidence of relapse(times/year) and daily dosages of prednisolone (PSL, mg/kg/day). The Wilcoxon test was used for statistical analysis. We also evaluated the relationship between the therapeutic effects and serum concentration of MZR two hours after the administration. RESULTS: The low dose and high-dose groups were well matched in terms of baseline characteristics. After the initiation of MZR, beneficial therapeutic effects ensued in the high-dose group (incidence of relapse: 3.61 vs. 1.59 times/year before and after the therapy, p < 0.05), daily dosages of PSL (0.65 vs. 0.29 mg/kg/day before and after therapy, p<0.001), but did not occur in the low-dose group(3.97 vs. 2.84 times/year; 0.84 vs. 0.53 mg/kg/day, n. s.). All patients with a serum MZR concentration of over 3 microg/ml had relapses less than three times a year. One patient in the high-dose group and the other in the low-dose group showed hyperuricemia, and responded well to medical treatment. No other adverse effect was observed. CONCLUSIONS: High-dose MZR therapy in the management for FRNS may provide more beneficial effects without significant adverse effects.     

Cinacalcet is efficacious in pediatric dialysis patients

Secondary hyperparathyroidism (high-turnover bone disease, or HTBD) is manifested by elevated parathyroid hormone (PTH) levels. Control of HTBD may be achieved by maintaining low serum phosphorous levels and administering vitamin D therapy, although some patients continue to exhibit high PTH levels. We report the results of the efficacy of the calcimimetic cinacalcet in six hemodialysis (HD) and three peritoneal dialysis (PD) pediatric patients with HTBD, age 14.5 +/- 1.0 (range 7.5-17.5) years. Six patients received 30 mg/day, one required 60 mg/day, and two received 120 mg/day. Treatment with cinacalcet resulted in a 61% decline in intact PTH (iPTH) levels (1,070 +/- 171.5 pretreatment to 417.6 +/- 97.8 posttreatment pg/ml, p = 0.005). Serum alkaline phosphatase also declined (561.8 +/- 169.6 U/L pretreatment to 390.3 +/- 110.3 U/L posttreatment pg/ml). During therapy, serum calcium (p = 0.9) and phosphorous (p = 0.9) levels, calcium-phosphorous product (p = 0.8), systolic blood pressure (BP) (p = 1.0), diastolic BP (p = 0.8), and hemoglobin (p = 0.9) remained unchanged. The dose of oral calcitriol for the three patients on PD while receiving cinacalcet trended downward (0.8 +/- 0.2 pretreatment vs. 0.5 +/- 0.0 mug/day posttreatment pg/ml), as did the dose of paracalcitol for those receiving HD (6.6 +/- 2.3 pretreatment vs. 4.3 +/- 1.7 micrograms/day posttreatment pg/ml). We conclude that short-term treatment with the calcimimetic cinacalcet is efficacious in adolescent dialysis patients.     

Pharmacokinetics of mycophenolate mofetil for autoimmune disease in children

This study describes the pharmacokinetics of mycophenolate mofetil (MMF) in 15 pediatric patients with vasculitis and connective tissue disease involving the kidney. Patients included 10 with systemic lupus erythematosus (SLE), 1 with antiphospholipid antibody syndrome, 2 with Wegener granulomatosis, and 1 each with Goodpasture syndrome, Henoch-Sch?nlein-associated nephritis, and 1 with severe tubulointerstitial nephritis and uveitis. All patients were treated with steroids and additional therapy prior to treatment with MMF, which was administered for a median of 491 days. Mean starting dose of MMF was 974+/-282 mg/m(2 )in two divided doses. Pharmacokinetic monitoring of the active compound of MMF, mycophenolic acid (MPA), was performed using an EMIT assay. The mean MPA AUC after a median of 39 days was 61.8+/-31.0 micro gxh/ml, median time to maximum concentration was 60 min, and mean maximum concentration was 18.5+/-8.4 micro g/ml. At last follow-up, mean MMF dose was 900+/-341 mg/m(2) per day, and mean trough MPA concentration was 3.1+/-1.1 (range 0.6-4.6) micro g/ml. Therapy was effective in inducing remission in 4 of 9 patients with active disease. Only 1 of the 5 other patients relapsed. All 6 patients with controlled disease maintained remission. There were few side effects: one episode each of diarrhea and leukocytopenia and two viral infections. We conclude that MMF at 900 mg/m(2) per day appears to be effective in these patients.     

Intravenous cyclophosphamide therapy in patients with steroid-resistant lupus nephritis]

We evaluated short term clinical effects of intravenous cyclophosphamide (iv CyP) therapy performed by every three month in 7 patients with steroid-resistant lupus nephritis. Significant improvements were observed in daily urinary protein excretion (3.1 to 0.83 g/day), creatinine clearance (65.4 to 95.3 ml/min), CH 50 levels (20.8 to 37.4 U/ml), and anti-DNA antibody titer (26.6 to 7.0 U/ml). In addition, the mean daily dose of prednisolone (PSL) could be markedly reduced from 38.6 mg to 13.9 mg at the final observation. Two patients suffered from Herpes Zoster infection at a few months after ivCyP therapy, however this incidence were not considered as critical side effect which reached to the discontinuation of this therapy. We concluded that ivCyP therapy by every three months were safety and achieved beneficial clinical effects on steroid-resistant lupus nephritis as far as short observation. On the contrary, the long term effect of this mode of therapy is to be defined.     

Studies on the outcome of lupus nephritis according to long-term treatment employing different modes of immunotherapy.

The outcome of long-term treatment of lupus nephritis under different immunotherapies, together with the factors affecting the outcome of lupus nephritis, was studied. A total of 212 lupus nephritis patients were classified into 5 groups according to their different modes of treatment: (1) initial dose of prednisolone (PSL) below 39 mg/day, (2) initial dose of PSL above 40 mg/day, (3) pulse therapy and steroids, (4) steroids and immunosuppressants, and (5) combination therapy of plasmapheresis with other therapies. The outcome of lupus nephritis was evaluated into 5 grades. As a result, the complete remission rate of lupus nephritis was 9.4%. The 5-year survival rates increased with all modes of treatment. However, it was impossible to identify which mode of therapy could bring about the highest rate of remission. Decreases in extrarenal involvement and low complement levels were observed together with increases in IgM anti-DNA antibodies among the lupus nephritis patients with remission.     

免疫吸附治疗重症活动性狼疮肾炎的临床观察

目的观察免疫吸附治疗重症活动性狼疮肾炎的临床疗效。方法选择应用免疫吸附治疗的15例重症狼疮肾炎患者,肾活检病理类型为Ⅳ型（n=10）和Ⅴ＋Ⅳ型（n=5）。观察吸附治疗前、后抗核抗体、抗双链DNA抗体、补体C3、血沉、疾病活动指数评分、血肌酐的变化情况,同时观察不良反应。结果与治疗前相比,患者治疗后抗核抗体、抗双链DNA抗体、血沉降低,补体C3升高,疾病活动指数评分、血肌酐降低（P〈0．01或P〈0．05）。1例患者脱离透析,随访半年后血肌酐稳定在350μmol／L左右。1例在免疫吸附治疗时出现过敏反应。结论免疫吸附治疗能较好的清除狼疮肾炎患者体内的多种自身抗体,使患者疾病活动指数评分下降,肾功能好转,是治疗狼疮肾炎的一种特异性强、疗效可靠、安全的方法。     

The treatment of severe lupus nephritis

Summary: The treatment of lupus nephritis involves two distinct phases of management: (i) induction therapy of acute severe disease; and (ii) maintenance treatment of chronic, sometimes relapsing disease. Since the introduction of effective immunosuppression, first with corticosteroids and then with cytotoxic agents in addition, the prognosis for lupus nephritis has improved greatly, especially that of more severe disease, whose prognosis now matches that of milder forms. There is now good evidence that the addition of a cytotoxic agent to corticosteroids improves both histological evolution and the development of renal failure, but both the choice of cytotoxic agent and the route of administrations remain controversial. Although the use of intravenous cyclophosphamide at intervals is popular, the long term outcome using azathioprine is as good and the drug is less toxic, particularly in relation to gonadal function and pregnancy. Therefore, we prefer to use induction with oral cyclophosphamide for 12 weeks, followed by azathiorpine therapy. the dose and route of corticosteroid in the acute phase is likewise controversial: high dose intravenous methylprednisolone perhaps has the advantage of lower side-effects than high dose oral corticosteroids. Controlled trials of plasma exchange have so far failed to reveal any benefits in the acute phase of lupus. Newer forms of immunosuppression using biological reagents against the immune reaction show promise, but their use is still experimental.     

Induction therapy with low-dose intravenous cyclophosphamide, oral mizoribine, and steroids for severe lupus nephritis in children

Although immunosuppressive regimens of corticosteroids combined with high-dose intravenous cyclophosphamide (IVCY) have been reported to suppress the activity of lupus nephritis, there is controversy regarding its application for children and adolescents, because of its potential toxicity including gonadal dysfunction. On the basis of the recent finding that a low-dose IVCY regimen for induction therapy in adult lupus nephritis effectively achieves renal remission comparable with that achieved with a conventional high-dose IVCY regimen, we treated two children with severe lupus nephritis by low-dose (fixed dose of 500 mg m^–2, cumulative dose 3 g m^–2, approximately one-fourth of the conventional high-dose IVCY regimen) IVCY and oral mizoribine (5 mg kg^–1 day^–1) and steroids (3 methylprednisolone pulse followed by oral prednisolone). They responded well to this regimen, showing remarkable improvement in both histological and clinical manifestations in a short period of time. From these findings we suggest that the new low-dose IVCY regimen may be as effective as the conventional high-dose IVCY regimen, without significant adverse effect, for induction therapy in children with severe lupus nephritis (class III or IV).     

Efficacy of low-dose leflunomide in lupus nephritis: A multi-center prospective study

Objective To investigate the efficacy of leflunomide combined with prednisone in the induction therapy of proliferative lupus nephritis (LN). Methods A prospective, multicenter, randomized controlled clinical trial was conducted in patients with biopsy-proved proliferative lupus nephritis recruited from 15 renal centers from 2013 to 2015. Patients were randomized to two groups. Oral leflunomide or intravenous cyclophosphamide was given to patients in each group. Both groups received a tapering course of oral prednisone therapy. All patients were followed up for 24 weeks. The blood biochemistry, urine index, clinical curative effect and adverse reaction were recorded and analyzed statistically. Results A total of 100 patients were enrolled in this clinical trial, including 48 patients in leflunomide group and 52 patients in cyclophosphamide group. After 24 weeks, the overall response rate was 79% (95%CI 67%-90%) in the leflunomide group and 69% (95%CI 56%-82%) in the cyclophosphamide group. 23% (95%CI 11%-35%) of patients in leflunomide group showed complete remission compared with 27% (95%CI 24%-30%) in cyclophosphamide group (P=0.35). The levels of 24-hr urine protein excretion, SLEDAI and anti-dsDNA antibody titers were decreased in patients treated with leflunomide group after 24-weeks treatment. And the levels of serum albumin and complement 3 after treatment were significantly higher compared with these before treatment. There was also no significant difference in changes of 24-hr urine protein excretion, SLEDAI score, anti-dsDNA antibody titers, serum albumin and complement C3 levels after treatment between two groups. Incidence of adverse events did not differ between the leflunomide and cyclophosphamide group. Conclusions Leflunomide combined with prednisone showed same efficacy compared with cyclophosphamide as induction therapy for lupus nephritis. Leflunomide might be an useful medicine in the induction therapy of lupus nephritis.     

Mizoribine oral pulse therapy for steroid-dependent nephrotic syndrome

There have been reports of the use of mizoribine (MZB) oral pulse therapy for the treatment of systemic lupus erythematosus. We report its efficacy in a 9-year-old girl with steroid- and cyclosporine-dependent nephrotic syndrome (NS). The patient experienced relapses of NS when prednisolone was tapered to 20 mg/day after discontinuing cyclosporine due to biopsy proven toxicity. When methylprednisolone pulse therapy combined with prednisolone therapy (40 mg/day) failed to result in a complete remission after 3 weeks, oral MZB pulse therapy (total dose of 500 mg, 10 mg/kg per day in three divided daily doses twice a week) was given. This therapy was continued for 9 months and resulted in complete remission of the NS for 6 months despite the discontinuation of prednisolone. The serum concentration of MZB was above 2.5 g/ml for about 10 h (from 3 h after the first dose of MZB to 2 h after the final dose). Thus, our results suggest that this regimen may be effective for patients with steroid-dependent NS.     

Sarcoid tubulo-interstitial nephritis: long-term outcome and response to corticosteroid therapy

Sarcoidosis is a chronic relapsing multi-systemic disorder characterized by the development of non-caseating granulomas. Granulomatous tubulo-interstitial nephritis is an uncommon manifestation of this condition. We identified 39 patients with sarcoidosis and renal disease from a single center of whom 17 patients had biopsy-proven tubulo-interstitial nephritis. They were analyzed with respect to demographic and clinical features, including response to corticosteroids and length of follow-up. They all presented with significant renal impairment. At presentation the mean+/-s.d. estimated glomerular filtration rate (eGFR) was 26.8+/-14 ml/min by modification of diet in renal disease (MDRD) equation 7. With treatment there was a significant improvement in renal function with eGFR 49.6+/-5.2 ml/min (P<0.01) at 1 year, and 47.9+/-6.8 ml/min (P<0.05) at the last review. The median follow-up was 84 months (range 6-284 months). Patients with chronic kidney disease (CKD) 3, the mean eGFR was 38.30+/-2.4 ml/min at presentation and 60.2+/-7.4 ml/min at 1 year (P=0.02) and in CKD 4 it improved from 19+/-2 to 38+/-6.6 ml/min at 1 year (P<0.05). After the 1st year, the change in eGFR was +0.8 ml/min/year for CKD 3 and -2 ml/min/year for CKD 4 (P<0.05). Three patients ceased their therapy either due to complications or poor compliance and experienced a worsening of renal function which was then reversed on re-commencing corticosteroids. Corticosteroids are effective in advanced tubulo-interstitial nephritis due to sarcoidosis. Long-term treatment is necessary to preserve renal function and to delay the onset of end-stage renal disease.     

Up-regulated MHC-class II expression and gamma-IFN and soluble IL-2R in lupus nephritis.

Expression of MHC-class II molecules (HLA-DR and -DQ), serum gamma-interferon (gamma-IFN) and soluble interleukin-2 receptor (sIL-2R) levels were studied in 35 Japanese patients with lupus nephritis (LN) to clarify intraglomerular cellular activation and cytokine involvement in human LN. In 11 normal kidney specimens, HLA-DR(Ia1) was noted in glomerular tufts, but HLA-DQ was either not or was faintly detected in glomeruli by the indirect immunofluorescence technique. HLA-DR and -DQ were observed mainly on the surface of glomerular endothelial cells in 100% and 50% of 28 lupus kidney specimens except for necrotic or sclerotic lesions. HLA-DQ was expressed in a high incidence of 67%, 86% in patients with proliferative LN (WHO Class III-IV) and active lesions, respectively. Serum gamma-IFN and sIL-2R levels were 1.2 +/- 0.2 U/ml and 190 +/- 24 U/ml (mean +/- SEM; N = 30) in normal controls, and elevated in patients with proliferative LN (4.1 +/- 1.0 U/ml, 383 +/- 81 U/ml, N = 25), especially with active lesions (6.2 +/- 1.5 U/ml, 500 +/- 110 U/ml, N = 14). Overall, glomerular lesions such as HLA-DQ expression, the activity index and leukocyte infiltration correlated positively with serum gamma-IFN levels (r = 0.55; P less than 0.01 for HLA-DQ, r = 0.68; P less than 0.001 for activity index, r = 0.38; P less than 0.05 for leukocyte infiltration), but not with serum sIL-2R levels, anti-DNA antibody titers and CH50 titers.(ABSTRACT TRUNCATED AT 250 WORDS)