Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide

For the treatment of proliferative lupus nephritis, long-term cyclophosphamide (CY) regimens are efficacious, however, at the expense of substantial toxicity. In the last decade, sequential regimens of short-term CY induction followed by either mycophenolate mofetil (MMF) or azathioprine (AZA) maintenance have shown to be efficacious and safe reducing the long-term exposure to CY. In a maintenance study including predominantly Hispanics and African-Americans, the patients who received MMF and AZA maintenance had a higher cumulative probability of remaining free of the composite of death or chronic renal failure (CRF) compared to quarterly intravenous CY (IVCY) maintenance (89% in MMF, 80%, in AZA and 45% in IVCY). Likewise, MMF and AZA maintenance were associated with significantly lower incidence of severe infections (2% in each MMF or AZA, and 25% in IVCY), sustained amenorrhea (6% in MMF, 8% in AZA, and 32% in IVCY), and hospitalizations (one hospital-days per patient-year in each MMF or AZA, and 10 in IVCY). In a European induction study including predominantly Caucasians, patients who received any of two sequential regimens, low dose versus high dose IVCY induction both followed by AZA maintenance, had a high cumulative probability of remaining free of treatment failure (84% in low dose IVCY and 80% in high dose IVCY; treatment failure defined as a composite of free of corticosteroid resistant flare, nephrotic syndrome, doubling creatinine, and persistent elevated creatinine). Low dose IVCY and high dose IVCY induction were associated with low incidence of sustained amenorrhea (4% in each group) and severe infections (11% in low dose and 22% in high dose IVCY induction). Of interest, most of the severe infection episodes occurred while patients were receiving IVCY induction. Finally an Asian study demonstrated that patients with proliferative lupus nephritis could be effectively treated with short-term oral CY induction followed by AZA maintenance. The cumulative probability of complete remission was 76%. The relapse rate was only 11%. The incidence of permanent amenorrhea and infection were 8% and 33%, respectively. None of the Asian patients had an increase in serum creatinine level to double the baseline value. Maintenance therapies with MMF or AZA following short-term CY induction in a sequential regimen are efficacious and safe for the treatment of high-risk patients with proliferative lupus nephritis.     

Induction therapies for class IV lupus nephritis with non-inflammatory necrotizing vasculopathy: mycophenolate mofetil or intravenous cyclophosphamide

The presence of renal noninflammatory necrotizing vasculopathy (NNV) is often associated with a severe form of lupus nephritis (LN), which is unresponsive to standard therapy. We conducted a 6-month randomized, prospective, open-label trial comparing mycophenolate mofetil (MMF) (1.5-2.0 g/day) with monthly i.v. cyclophosphamide (CTX) (0.75-1.0 g/m2) as induction therapy for class IV LN with NNV. The primary and second end points were complete remission (CR) and partial remission (PR), respectively. Of 20 patients recruited, nine were randomly assigned to MMF and 11 to CTX. The baseline characteristics between groups were not significant. CR was achieved in four patients (44.4%) receiving MMF and in none of the patients receiving CTX (P = 0.026). PR was achieved in two patients (22.2%) in the MMF group and three patients (27.2%) in the CTX group. The total remission rate (CR + PR) in the MMF and CTX group was 66.6 and 27.2%, respectively (P = 0.17). MMF was more effective than i.v. CTX in reducing proteinuria and haematuria. Adverse events were significantly less frequent with MMF than with CTX (P = 0.028). MMF was superior to i.v. CTX in inducing CR of LN with NNV and had a more favourable safety profile.     

霉酚酸酯治疗Ⅳ型狼疮性肾炎伴非炎症坏死性血管病变的初步临床观察

目的比较霉酚酸酯(MMF)与间断环磷酰胺(CTX)静脉冲击疗法对Ⅳ型狼疮性肾炎(LN)伴非炎症坏死性血管病变(NNV)的疗效。方法20例系统性红斑狼疮患者经肾活检确诊为Ⅳ型LN伴间质NNV,分别采用激素联合MMF(MMF组,n=9)或激素联合CTX静脉冲击疗法(CTX组,n=11),MMF剂量1.5~2.0g/d,;CTX剂量为0.75~1g/m2.BSA,每月静脉滴注一次。两组患者基础病情相似,比较两组治疗6个月的临床疗效和不良反应。临床疗效分为完全缓解[尿蛋白定量<0.4g/24h,尿红细胞(RBC)计数<10万/ml,无管型及白细胞尿,血清白蛋白≥35g/L,血肌酐(SCr)正常]和部分缓解(尿蛋白下降超过基础值50%且<2g/24h,尿红细胞计数及SCr下降超过基础值50%,血浆白蛋白≥30g/L)。结果MMF失访1例,CTX组失访2例。诱导治疗6月MMF组3例(37.5%)完全缓解,而CTX组无一例完全缓解,P=0.08,部分缓解例数分别为MMF组3例(37.5%)和CTX组3例(33.3%)。尿RBC<10万/ml比例MMF组高于CTX组(75%vs0,P<0.01)。尿蛋白转阴(尿蛋白定量<0.4g/24h)比例MMF组亦高于CTX组(62.5%vs11.1%,P<0.05)。治疗前MMF组5例、CTX组6例SCr增高,治疗6月两组均有1例SCr未降至正常。MMF组1例(12.5%)并发带状疱疹,CTX组5例(55.5%)发生不良反应,包括胃肠道症状(3例),白细胞减少(1例),肝酶升高(1例)。结论激素联合MMF对伴NNV病变的Ⅳ型LN近期疗效优于CTX,但需要扩大病例数长期随访,并探索更为有效的治疗方法。     

High‐dose cyclophosphamide versus monthly intravenous cyclophosphamide for systemic lupus erythematosus: A prospective randomized trial

Objective

Monthly intravenous (IV) cyclophosphamide for 6 months has been the standard induction regimen for lupus nephritis, followed by a maintenance regimen of quarterly infusions for 2 years. We undertook this study to compare the efficacy and safety of the standard regimen versus a high‐dose IV cyclophosphamide regimen.

Methods

We performed a prospective randomized trial comparing monthly IV cyclophosphamide at 750 mg/m² body surface area for 6 months followed by quarterly IV cyclophosphamide for 2 years (traditional treatment) against high‐dose IV cyclophosphamide (50 mg/kg daily for 4 days) (high‐dose treatment). Entry criteria included renal lupus, neurologic lupus, or other organ system involvement with moderate‐to‐severe activity.

Results

Fifty‐one patients were randomized; 3 withdrew before treatment and 1 committed suicide after 2 months of high‐dose treatment. Twenty‐two had renal lupus, 14 had neurologic lupus, and 11 had other organ involvement. The outcome measure was the Responder Index for Lupus Erythematosus (complete response, partial response, no change, or worsening). At 6 months (the end of induction), 11 of 21 patients (52%) in the high‐dose treatment group had a complete response compared with 9 of 26 patients (35%) in the traditional treatment group (P = 0.13). At the final visit (30 months), 10 of 21 patients (48%) in the high‐dose treatment group had a complete response compared with 13 of 20 patients (65%) who continued with traditional treatment (P = 0.13). Six patients crossed over from traditional treatment to high‐dose treatment because of lack of response, and 3 of those patients became complete responders.

Conclusion

There was not strong evidence that monthly IV cyclophosphamide and high‐dose IV cyclophosphamide differed in complete or in any (complete or partial) response to induction or maintenance therapy. However, nonresponders to monthly IV cyclophosphamide can sometimes be rescued with high‐dose IV cyclophosphamide.

     

激素联合赛可平和他克莫司治疗狼疮性肾炎的前瞻性临床研究

目的:前瞻性观察激素联合赛可平(MMF)和他克莫司(FK506)(多靶点组)诱导治疗狼疮性肾炎(LN)的疗效及安全性,并与激素联合环磷酰胺静脉冲击疗法(IV-CYC)进行比较。方法:79例经肾活检确诊的IV型、Ⅴ+Ⅳ型和Ⅴ+Ⅲ型LN患者随机分为多靶点组(n=45)和IV-CYC组(n=34)。两组患者均先使用甲泼尼龙静脉冲击治疗后口服泼尼松。多靶点组中MMF(杭州中美华东制药有限公司)治疗剂量1g/d,MMF血药浓度(MPA-AUC0～12h)目标值为20～30mg·h/L;FK506(杭州中美华东制药有限公司)剂量4mg/d,FK506谷浓度维持4～7ng/ml。IV-CYC组CYC剂量0.5～0.75g/m2BSA,每月1次。诱导治疗疗程6～9个月。疗效主要指标为完全缓解率(定义为尿蛋白<0.4g/24h,血清白蛋白≥35g/L,血清肌酐正常,无肾外活动),比较两组的临床疗效和不良反应。结果:多靶点组[女39例,男6例,平均年龄(25.1±9.3)岁]与IV-CYC组[女30例,男4例,平均年龄(30.4±8.9)岁]的基础临床指标和病理类型无统计学差异。诱导6月(53.3%vs29.4%P<0.05)和9月(62.2%vs42.6%,P<0.05)的完全缓解率多靶点组均显著高于IV-CYC组。多靶点组Ⅴ+Ⅳ型的完全缓解率显著高于IV-CYC组(50.0%vs16.7%,P<0.05),Ⅴ+Ⅲ型的完全缓解率也高于IV-CYC(54.5%vs22.2%,P>0.05)。IV型LN两组缓解率无差异。多靶点组总不良反应发生率低于IV-CYC(31.1%vs70.6%,P<0.01),其中多靶点组的主要不良反应为高血压(11.1%)和带状疱疹(6.7%),IV-CYC组的主要不良反应为胃肠道反应(23.5%)、白细胞减少(13.7%)和皮肤感染(8.8%)。两组分别有2例和1例并发肺部感染,无一例死亡。结论:激素联合赛可平和他克莫司组成的多靶点疗法治疗LN的疗效优于CYC静脉冲击疗法,尤其对Ⅴ+Ⅳ型疗效更为显著且不良反应发生率低。多靶点疗法的临床疗效和对远期预后的影响还需要多中心和长期随访的临床研究。     

Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: Results of a multicenter,prospective, open‐label clinical trial

Objective

The recurrence rate of anti‐SSA/Ro–associated congenital heart block (CHB) is 17%. Sustained reversal of third‐degree block has never been achieved. Based on potential reduction of maternal autoantibody titers as well as fetal inflammatory responses, intravenous immunoglobulin (IVIG) was evaluated as preventive therapy for CHB.

Methods

A multicenter, prospective, open‐label study based on Simon's 2‐stage optimal design was initiated. Enrollment criteria included the presence of anti‐SSA/Ro antibodies in the mother, birth of a previous child with CHB/neonatal lupus rash, current treatment with ≤20 mg/day of prednisone, and <12 weeks pregnant. IVIG (400 mg/kg) was given every 3 weeks from week 12 to week 24 of gestation. The primary outcome was the development of second‐degree or third‐degree CHB.

Results

Twenty mothers completed the IVIG protocol before the predetermined stopping rule of 3 cases of advanced CHB in the study was reached. CHB was detected at 19, 20, and 25 weeks; none of the cases occurred following the finding of an abnormal PR interval on fetal Doppler monitoring. One of these mothers had 2 previous children with CHB. One child without CHB developed a transient rash consistent with neonatal lupus. Sixteen children had no manifestations of neonatal lupus at birth. No significant changes in maternal titers of antibody to SSA/Ro, SSB/La, or Ro 52 kd were detected over the course of therapy or at delivery. There were no safety issues.

Conclusion

This study establishes the safety of IVIG and the feasibility of recruiting pregnant women who have previously had a child with CHB. However, IVIG at low doses consistent with replacement does not prevent the recurrence of CHB or reduce maternal antibody titers.

     

Immunosuppressive therapy in lupus nephritis: The Euro‐Lupus Nephritis Trial,a randomized trial of low‐dose versus high‐dose intravenous cyclophosphamide

Objective

Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low‐dose IV CYC prescribed as a remission‐inducing treatment, followed by azathioprine (AZA) as a remission‐maintaining treatment.

Methods

In this multicenter, prospective clinical trial (the Euro‐Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high‐dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low‐dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent‐to‐treat analyses were performed.

Results

Followup continued for a median of 41.3 months in the low‐dose group and 41 months in the high‐dose group. Sixteen percent of those in the low‐dose group and 20% of those in the high‐dose group experienced treatment failure (not statistically significant by Kaplan‐Meier analysis). Levels of serum creatinine, albumin, C3, 24‐hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low‐dose group and 54% of the high‐dose group (not statistically significant). Renal flares were noted in 27% of the low‐dose group and 29% of the high‐dose group. Although episodes of severe infection were more than twice as frequent in the high‐dose group, the difference was not statistically significant.

Conclusion

The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission‐inducing regimen of low‐dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high‐dose regimen.

     

Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial,a randomized trial of low-dose versus high-dose intravenous cyclophosphamide

OBJECTIVE: Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment. METHODS: In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed. RESULTS: Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant. CONCLUSION: The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen.     

Liraglutide is effective and well tolerated in combination with an oral antidiabetic drug in Japanese patients with type 2 diabetes: A randomized, 52‐week,open‐label,parallel‐group trial

Introduction

The safety and efficacy of liraglutide in combination with an oral antidiabetic drug (OAD) compared with combination of two OADs were assessed in Japanese patients with type 2 diabetes.

Materials and Methods

This was a 52‐week, open‐label, parallel‐group trial in which patients whose type 2 diabetes was inadequately controlled with a single OAD (glinide, metformin, α‐glucosidase inhibitor or thiazolidinedione) were randomized 2:1 to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group; n = 240) or pretrial OAD in combination with an additional OAD (additional OAD group; n = 120). The primary outcome measure was the incidence of adverse events (AEs).

Results

Overall, 86.3% of patients in the liraglutide group and 85.0% of patients in the additional OAD group experienced AEs; these were similar in nature and severity. Adverse event rates were 361 and 331 per 100 patient‐years of exposure, respectively. Confirmed hypoglycemia was rare (seven episodes in two patients on liraglutide, and two in two patients on additional OAD). There were no reported pancreatitis events, and no unexpected safety signals were identified. Mean reductions in glycosylated hemoglobin were significantly greater in the liraglutide group than the additional OAD group [estimated mean treatment difference −0.27% (95% confidence interval (CI) −0.44, −0.09; P = 0.0026)]; reductions in mean fasting plasma glucose levels were also greater with liraglutide [estimated mean difference −5.47 mg/dL (−0.30 mmol/L; 95% CI: −10.83, −0.10; P = 0.0458)].

Conclusions

Liraglutide was well tolerated and effective as combination therapy with an OAD in Japanese patients with type 2 diabetes.     

A phase II prospective open‐label escalating dose trial of recombinant interleukin‐11 in mild von Willebrand disease

Summary. von Willebrand factor (VWF) is a multimeric glycoprotein that mediates platelet adhesion and is decreased in von Willebrand disease (VWD). 1‐8 deamino‐d‐ arginine vasopressin (DDAVP), the most common treatment for VWD, is limited by tachyphylaxis and inconvenience, and in 20% of the patients, unresponsiveness. Recombinant human interleukin‐11 (rhIL‐11), a gp‐130 signalling cytokine with haematopoietic and anti‐inflammatory activity, increases VWF antigen and its activity in heterozygous VWF^+/? mice and dogs. To determine the biological efficacy and safety of rhIL‐11 in non‐bleeding human subjects with mild VWD, we conducted a phase II prospective open‐label trial of rhIL‐11 at 10, 25 and 50 μg kg^?1 subcutaneously (s.c.), given daily for 7 days in nine subjects with mild VWD. VWF and factor VIII (FVIII) levels increased gradually and progressively after s.c. rhIL‐11, which was sustained through 7 days of dosing to 1.5‐ to 3‐fold over baseline. Following intravenous DDAVP, 0.3 μg kg^?1, on day 7 there was a further boost in VWF and FVIII levels, suggesting that the mechanism of rhIL‐11 differs from that of DDAVP. Platelet VWF mRNA expression measured by quantitative PCR increased from two‐ to eightfold over baseline, suggesting that the mechanism of rhIL‐11 effect may be upregulation of VWF mRNA. VWF and FVIII levels returned to baseline by day 14. rhIL‐11 was well tolerated with less than grade‐1 hypertension, hypokalaemia and fluid retention. Recombinant IL‐11 increases VWF levels in humans with mild VWD, justifying future clinical trials to determine its potential in preventing or reducing bleeding in this patient population.     

Subject‐driven titration of biphasic insulin aspart 30 twice daily is non‐inferior to investigator‐driven titration in Chinese patients with type 2 diabetes inadequately controlled with premixed human insulin: A randomized,open‐label,parallel‐group,multicenter trial

Aims/Introduction

The present study was to compare the efficacy and safety of subject‐driven and investigator‐driven titration of biphasic insulin aspart 30 (BIAsp 30) twice daily (BID).

Materials and Methods

In this 20‐week, randomized, open‐label, two‐group parallel, multicenter trial, Chinese patients with type 2 diabetes inadequately controlled by premixed/self‐mixed human insulin were randomized 1:1 to subject‐driven or investigator‐driven titration of BIAsp 30 BID, in combination with metformin and/or α‐glucosidase inhibitors. Dose adjustment was decided by patients in the subject‐driven group after training, and by investigators in the investigator‐driven group.

Results

Eligible adults (n = 344) were randomized in the study. The estimated glycated hemoglobin (HbA_1c) reduction was 14.5 mmol/mol (1.33%) in the subject‐driven group and 14.3 mmol/mol (1.31%) in the investigator‐driven group. Non‐inferiority of subject‐titration vs investigator‐titration in reducing HbA_1c was confirmed, with estimated treatment difference −0.26 mmol/mol (95% confidence interval −2.05, 1.53) (–0.02%, 95% confidence interval –0.19, 0.14). Fasting plasma glucose, postprandial glucose increment and self‐measured plasma glucose were improved in both groups without statistically significant differences. One severe hypoglycemic event was experienced by one subject in each group. A similar rate of nocturnal hypoglycemia (events/patient‐year) was reported in the subject‐driven (1.10) and investigator‐driven (1.32) groups. There were 64.5 and 58.1% patients achieving HbA_1c <53.0 mmol/mol (7.0%), and 51.2 and 45.9% patients achieving the HbA_1c target without confirmed hypoglycemia throughout the trial in the subject‐driven and investigator‐driven groups, respectively.

Conclusions

Subject‐titration of BIAsp 30 BID was as efficacious and well‐tolerated as investigator‐titration. The present study supported patients to self‐titrate BIAsp 30 BID under physicians’ supervision.     

28‐week,randomized, multicenter,open‐label,parallel‐group phase III trial to investigate the efficacy and safety of biphasic insulin aspart 70 thrice‐daily injections vs twice‐daily injections of biphasic insulin aspart 30 in patients with type 2 diabetes

Aims/Introduction: An insulin analogue formulation with a 7:3 ratio of rapid‐acting and intermediate‐acting fractions, biphasic insulin aspart 70 (BIAsp70) was developed to supplement basal insulin between meals and mimic the physiological pattern of postprandial insulin secretion. Materials and Methods: We carried out a randomized, open‐label study to compare the efficacy and safety profiles of BIAsp70 and an insulin analogue formulation with a 3:7 ratio of rapid‐acting and intermediate‐acting fractions (BIAsp30) in type 2 diabetes mellitus patients. Patients were randomized and received either thrice‐daily BIAsp70 (n = 145) or twice‐daily BIAsp30 (n = 144) for 28 weeks. The primary end‐point was glycated hemoglobin (HbA_1c) after 16 weeks of treatment. Results: Non‐inferiority of BIAsp70 vs BIAsp30 was confirmed and superiority was established with a between‐group difference (BIAsp70–BIAsp30) in HbA_1c after 16 weeks of treatment of ?0.35% (95% CI: ?0.51 to ?0.19; P < 0.0001 for superiority). The mean postprandial glucose increment (19.96 vs 54.35 mg/dL; P < 0.0001) and M‐value (12.99 vs 17.94; P < 0.0001) at 16 weeks were smaller in the BIAsp70 group than in the BIAsp30 group, and were maintained at 28 weeks. Pre‐breakfast glucose (157.9 vs 140.7 mg/dL), total insulin dose (46.8 vs 38.1 U/day) and weight gain (+1.94 vs 1.23 kg) at week 28 were greater in the BIAsp70 group. Incidence of nocturnal hypoglycemia was significantly lower with BIAsp70 vs BIAsp30 (1.23 vs 3.21 events/subject year; P = 0.0002) at week 28. Conclusions: Thrice‐daily BIAsp70 was superior to twice‐daily BIAsp30 in terms of HbA_1c change, with less variation in daytime plasma glucose profiles. BIAsp70 was well tolerated, with a lower incidence of nocturnal hypoglycemia vs BIAsp30. This trial was registered with ClinicalTrial.gov (no. NCT00318786). (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00015.x, 2010)