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Rheumatology Advance Access originally published online on August 27, 2008
Rheumatology 2008 47(11):1678-1681; doi:10.1093/rheumatology/ken335
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis

C.-C. Szeto1, B. C.-H. Kwan1, F. M.-M. Lai2, L.-S. Tam1, E. K.-M. Li1, K.-M. Chow1, W. Gang1 and P. K.-T. Li1

1Department of Medicine and Therapeutics and 2Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China.

Correspondence to: C.-C. Szeto, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. E-mail: ccszeto{at}cuhk.edu.hk


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. The treatment of pure membranous (class V) lupus nephropathy remains unsatisfactory. We studied the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE.

Methods. We recruited 18 consecutive SLE patients (tacrolimus group) with recently confirmed biopsy-proven class V lupus nephritis. They were treated with a tailing dose of oral prednisolone and tacrolimus 0.1–0.2 mg/kg/day for 6 months, followed by maintenance prednisolone and AZA. The rate of resolution of proteinuria and SLEDAI were compared with 19 historical controls treated with oral cyclophosphamide or AZA (control group). All patients were followed for 12 months.

Results. Baseline clinical characteristics were comparable between the groups. For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). However, tacrolimus group had faster resolution of proteinuria than the control group by the general linear model with repeated measures (P = 0.032). At 12 weeks, proteinuria was reduced by 76.2 ± 17.0% for the tacrolimus group and 47.1 ± 51.1% for the control group (P = 0.028). Serial change in renal function and SLEDAI score did not differ between the groups. During the study period, four patients of the tacrolimus group, and 11 of the control group, developed lupus flare (P = 0.027). There was no serious adverse effect in the tacrolimus group.

Conclusions. A 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. The long-term effect and optimal regimen of tacrolimus require further study.

KEY WORDS: Systemic lupus erythematosus, Lupus nephritis, Calcineurin inhibitor


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Glomerulonephritis is one of the major disease manifestations of SLE [1, 2]. A number of randomized controlled trials and meta-analysis have demonstrated that patients with proliferative lupus nephritis could be effectively treated with corticosteroid together with immunosuppressive drugs (for example, cyclophosphamide or mycophenolate) [3–5]. On the other hand, the treatment of membranous lupus nephropathy, a subset that carries a high morbidity, remains unsatisfactory [6]. Traditionally, patients with membranous nephropathy secondary to SLE should be treated early with angiotensin antagonists to minimize proteinuria [1, 6, 7]. In patients with protracted nephrotic syndrome, consideration should be given to therapies including corticosteroids with or without cytotoxic agents [1, 6, 7]. However, toxicity is a major concern with this regimen.

Cyclosporin has been found to be effective in reducing proteinuria in patients with primary membranous nephropathy [8–10] and proliferative lupus nephritis [11]. However, the efficacy of cyclosporin in the treatment of membranous nephropathy secondary to SLE is controversial [1, 12, 13], and proteinuria usually increases after the drug is stopped. Nevertheless, this observation suggests the possible benefit of immunosuppressive therapy targeted against the calcineurin pathway of T-helper cells in the treatment of primary membranous nephropathy. Since tacrolimus has a more potent immunosuppressive effect than cyclosporin in vitro [14, 15] it has been used successfully in the rescue therapy of renal allograft rejection refractory to cyclosporin [16, 17] as well as primary membranous nephropathy [18, 19]. Recent studies also found that tacrolimus is effective in treating active systemic lupus and proliferative lupus nephritis [20–22] and possibly resistant class V lupus nephritis [23]. The objective of the present study is to examine the efficacy and safety of tacrolimus in the treatment of membranous nephritis secondary to SLE.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
Patient selection
This was an open-label study approved jointly by the Chinese University of Hong Kong—New Territories East Cluster Clinical Research Ethics Committee (ClinicalTrials.gov ID NCT00125307 [ClinicalTrials.gov] ). From July 2004 to December 2006, we recruited consecutive patients with biopsy-proven pure class V (membranous) nephritis secondary to SLE in the Divisions of Nephrology and Rheumatology, Prince of Wales Hospital, Hong Kong (the tacrolimus group). We also reviewed consecutive patients with biopsy-proven pure class V lupus nephritis treated in our centre from January 2002 to June 2004 by standard protocols (see subsequently) as historic controls (the control group).

All patients fulfilled the revised ACR criteria for SLE and had biopsy-proven membranous nephropathy secondary to SLE within 4 weeks of recruitment, with the presence of: (i) nephrotic syndrome with proteinuria (>3 g/day) and serum albumin <30 g/dl, with or without active urinary sediments; (ii) age over 18 yrs with informed consent; and (iii) female patients of child-bearing age and male patients agreed to maintain effective birth control practice during the study. We excluded patients with abnormal liver function tests, hepatitis B surface antigen or hepatitis C antibody-positive, diabetes mellitus, and a history of allergy or intolerance to macrolide antibiotics or tacrolimus.

Treatment regimen
After written informed consent according to the Declaration of Helsinki, study eligibility was determined at a screening visit and confirmed at a qualifying visit 2 weeks later. Baseline assessments included a review of the medical history, physical examination, physician-scored SLEDAI, and the damage index from the SLICC. The 24-h urinary protein excretion rate was determined 2 weeks and 1 day before tacrolimus treatment was initiated. The determinations were averaged to provide a baseline urinary protein excretion rate. Glomerular filtration rate (GFR) was estimated by a standard equation validated in Chinese [24].

After the baseline evaluation, prednisolone 30 mg/day was started. The dosage of prednisolone was tapered by 5 mg every 2 weeks until 20 mg/day; then by 5 mg every 4 weeks until 10 mg/day; then by 2.5 mg every 4 weeks until 5 mg/day for the rest of the study period. Tacrolimus was started at daily dose of 0.1–0.2 mg/kg/day in two divided doses for 6 months. Tacrolimus was administered at the same time each morning and evening. All patients were advised to take tacrolimus at least 1 h before the meal or 2 h after the meal. After 6 months of treatment, tacrolimus was stopped and AZA was added at a dose of 1.5 mg/kg/day as maintenance therapy. For the control group, patients were treated with standard protocols of steroid plus oral cyclophosphamide [25] or AZA [26] as decided by individual clinician.

Patient management
Clinical and laboratory evaluations was assessed biweekly for 4 weeks, then monthly until 6 months (when tacrolimus was stopped), and then 2-monthly until the end of 12 months. Clinical evaluations included blood pressure, body weight, routine urinalysis and SLEDAI scoring. The presence of oedema was documented clinically by a semi-quantitative scale. Laboratory tests include 24-h urine for proteinuria and creatinine clearance, as well as blood tests for complete blood counts, serum electrolytes, urea, creatinine, liver enzymes, fasting sugar, amylase, complement levels and anti-ds-DNA antibody (using Crithidia luciliae as substrate) were performed during every clinic visit. Fasting total cholesterol, LDL-cholesterol and triglyceride were taken at baseline and at the end of 1, 3, 6 and 12 months. All patients received angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. Additional anti-hypertensive therapy was added as needed to keep the target blood pressure <140/80 mmHg.

Tacrolimus level and dose adjustment
While the patient was receiving tacrolimus, blood samples (1 ml) were collected during every clinic visit for the determination of whole blood tacrolimus level before the morning dose of immunosuppressive medication was administered. Dose adjustment was done with the target level of 3–8 ng/ml. Change in tacrolimus dose was generally made in steps of 25% of the original dose.

Outcome measures
The primary end-point was the change in 24-h urinary protein excretion. Therapeutic response was determined at 12 and 24 weeks. Complete remission was defined as 24-h urinary protein excretion <0.5 g/day, normal urinary sediment, normal serum albumin and estimated GFR ≤15% above baseline. Partial remission was defined as urinary protein excretion 0.5–2.9 g/day, serum albumin ≥30 g/l and stable renal function.

Secondary end-point was the change in renal function, SLEDAI score and the development of lupus flare (renal or non-renal). We followed the criteria of lupus flare and specific organ system involvement as outlined by Schiffenbauer and Simon [27]. In short, a lupus flare was defined as an increase in SLEDAI ≥3, including both clinical and biochemical parameters. Major lupus flare was defined as an increase in SLEDAI ≥12; or new or worse cerebral lupus, vasculitis, nephritis, myositis, platelet count <60 x 109/l, haemolytic anaemia with haemoglobin <7 g/dl; or requiring ≥0.5 mg/kg/day prednisolone; or new immunosuppressive therapy.

Any infectious episodes and other potential side-effects of tacrolimus were recorded. Potential adverse events were assessed by using open-ended questions at each study visit. Patients were withdrawn from the study for death, doubling of baseline serum creatinine level, pregnancy, severe cardiac toxicity with clinically significant arrhythmia or ischaemic cardiac events, neurotoxicity with severe impairment of motor functions or signs of clinically significant impairment of mental status, other intolerable adverse events (e.g. vesicular or bulbous skin rash), significant non-compliance with the protocol or the desire of the patient to withdraw from the study for any reason.

Statistical analysis
Statistical analysis was performed by SPSS for Windows software version 11.5 (SPSS Inc., Chicago, IL, USA). All data are expressed as mean ± S.D. unless otherwise specified and analysed on intention-to-treat basis. Data were compared by Student's t-test or chi-square test as appropriate. The effects of treatment group on the serial change in proteinuria, estimated GFR and SLEDAI score were compared by general linear model for repeated measures, followed by Student's t-test for post hoc comparison. A P-value of <0.05 was considered significant. All probabilities were two-tailed.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
We recruited 18 patients for the tacrolimus group, and reviewed 19 patients for the control group. The baseline demographic and clinical data are summarized in Table 1. Five patients of the control group were treated with the sequential oral cyclophosphamide regimen, and the other 14 with the combination regimen of corticosteroid and AZA. Baseline characteristics of the two groups were essentially similar, except that the tacrolimus group had a slightly higher histological activity index in renal biopsy, and a trend of more proteinuria than the control group (Table 1). One patient of the tacrolimus group withdrew consent and declined follow-up after 2 weeks of treatment.


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  		TABLE 1. Baseline demographic and clinical data

 
Proteinuria and clinical response
The serial change in proteinuria of the two groups is summarized in Fig. 1. There was a significant effect of tacrolimus treatment on the reduction in proteinuria with time by the general linear model with repeated measures (P = 0.032). Post hoc analysis showed that the tacrolimus group had more rapid resolution of proteinuria than the control group at 2, 4, 8 and 12 weeks. At 12 weeks, proteinuria was reduced by 76.2 ± 17.0% for the tacrolimus group and 47.1 ± 51.1% for the control group (P = 0.028). For the tacrolimus group, the complete and partial remission rates were 27.8 and 50.0%, respectively at 12 weeks; for the control group, they were 15.8 and 47.4%, respectively (overall chi-square test, P = 0.5). At 24 weeks, the complete and partial remission rates were 38.9 and 44.4% respectively for the tacrolimus group, and 36.8 and 57.9% respectively for the control group (overall chi-square test, P = 0.5).


Figure 1
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  		FIG. 1. Serial trend of proteinuria during the study period. Whisker-box plot. The boxes indicate median, 25th and 75th percentile; whisker caps indicate 5th and 95th percentile; circles indicate outliers (white, tacrolimus group; grey, control group).

 
Renal function, lupus activity and disease flare
There was no significant difference in the renal function between the two groups throughout the follow-up period (general linear model with repeated measures, P = 0.7) (Fig. 2). Similarly, the difference in SLEDAI score between the two groups throughout the follow-up period did not reach statistical significance (general linear model with repeated measures, P = 0.2) (Fig. 3).


Figure 2
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  		FIG. 2. Serial trend of estimated GFR during the study period. White circles denote tacrolimus group; grey circles denote control group. Error bars denote S.D.

 

Figure 3
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  		FIG. 3. Serial trend of SLEDAI during the study period. Whisker-box plot. The boxes indicate median, 25th and 75th percentile; whisker caps indicate 5th and 95th percentile; circles indicate outliers (white, tacrolimus group; grey, control group).

 
During the study period, 4 patients (22.2%) of the tacrolimus group and 11 (57.9%) of the control group developed lupus flare (chi-square test, P = 0.027). All flares of the tacrolimus group developed after 24 weeks of the study, while 3 of the 11 flares in the control group developed within 24 weeks of initial therapy (Fisher's exact test, P = 0.23). None of the patients in the tacrolimus group, but two (10.5%) in the control group developed major lupus flare (Fisher's exact test, P = 0.5).

Adverse effects
In general, tacrolimus was well tolerated. The adverse effects are summarized in Table 2. Dyspepsia was the most common adverse effect reported, although all cases improved with symptomatic treatment. There were three minor infections in the tacrolimus group; none required hospital admission.


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  		TABLE 2. Summary of adverse effects

 

   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
In the present study, we found that a 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr.

Although apparently somewhat better than conventional cytotoxic therapy, our result on tacrolimus was in fact similar to the previous report on sequential oral cyclophosphamide [25], which showed an overall response rate of 90% and relapse rate of 40% in 4 yrs, and AZA [26], which had an overall response rate of 89% and relapse rate of 19%. It could be argued that the control group of our study had unexpectedly poor clinical response—resulting in a result that apparently favoured tacrolimus. Nonetheless, our data showed, to the very least, that tacrolimus was at least as effective as conventional therapy, with a reasonable safety profile. Our result agreed with the previous pilot study on tacrolimus [23]; the rate of resolution of proteinuria and lupus activity was also similar to the previous study on proliferative lupus nephritis [22]. Previous study on CSA, another calcineurin inhibitor, showed a substantially higher overall (complete plus partial) response rate than our study (95% vs 77.8%), presumably because of the higher effective dose [13]. It should be noted, however, that one-third of the patients relapsed after CSA was stopped [13]. In comparison, around 22% of our patients relapsed within 6 months after tacrolimus therapy was completed, but the number of subjects was small for both studies.

The dosage of tacrolimus we used was similar to previous studies on lupus nephritis [22, 23] as well as primary membranous nephropathy [19], but somewhat lower than that usual for kidney allograft recipients. It remains possible that a higher dosage may result in greater therapeutic efficacy, but one would also expect more frequent adverse effect.

In general, tacrolimus—at the dose range that we used—was well tolerated and side-effects were usually minor. It should be noted that comparison of the adverse events between the two groups of our study is not appropriate because data on adverse events of the control group were collected retrospectively by chart review, while that of the tacrolimus group by prospective follow-up and direct questioning during every clinic visit.

There are a number of limitations for our study. First, it was not a randomized control trial. Although most of the baseline parameters were highly comparable between the two groups, there were small differences in the pre-treatment proteinuria and histological activity index. It could be argued that most of the control group were treated with AZA, which may not be as effective as cyclophosphamide. Nonetheless, previous studies did not show obvious difference in the response rate between the two regimens [25, 26], and both are still regarded as reasonable options in a recent recommendation [7]. In addition, the number of cases that we recruited during the study and historical control periods are similar, suggesting that selection bias should not have been a severe problem in our study.

Another important limitation is the relatively short follow-up period. In essence, our patients were monitored for 6 months after tacrolimus was stopped. It should be noted, however, that a previous study on cyclosporin showed that patients often relapsed soon after calcineurin inhibitor was stopped [13]. We believe that the risk of relapse after 6 months of stopping tacrolimus is more related to the maintenance regimen and intrinsic characteristics (for example, genetics) of individual patients. Unfortunately, the optimal maintenance regimen for lupus nephritis remains controversial [28]. Theoretically, a longer course of tacrolimus may keep the patient free from relapse longer. However, nephrotoxicity is a real concern. Although many patients were still receiving a moderate to high dose of steroid at 12 weeks, we report primarily the response rate at this time-point because many of the patients in the control arm were treated with oral cyclophosphamide for 12 weeks.

In summary, we found that a 6-month course of tacrolimus is a safe and effective treatment of pure class V (membranous) lupus nephritis. As compared with conventional cytotoxic treatment, tacrolimus possibly results in a faster resolution of proteinuria, and a lower risk of lupus flare within 1 yr. However, the long-term effect and optimal regimen of tacrolimus require further study.

Formula


   Acknowledgements
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
We thank Lee Wai Ching and Lorraine Tseung for their clerical support.

Funding: Astellas Pharma Hong Kong Co., Ltd. donated the study medication for this work. This study was otherwise supported by the CUHK research accounts 6901031 and 7101215.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 29 April 2008; revised version accepted 14 July 2008.
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