Efficacy and safety of tacrolimus therapy for lupus nephritis: a systematic review of clinical trials

Abstract

The aim of this study was to assess the efficacy and safety of tacrolimus for the treatment of lupus nephritis (LN). A systematic review of clinical trials on tacrolimus in LN was conducted. Seven studies met the review inclusion criteria. Two studies were case-control studies, and five studies were open-label trials. One randomized controlled trial (RCT) found that tacrolimus significantly improved lupus nephritis disease activity index (LNDAI) as compared with a placebo, but no difference was observed between these two groups in terms of treatment-related adverse events. The other case-control study compared tacrolimus with standard protocols of oral cyclophosphamide or azathioprine for the treatment of membranous LN and found that efficacies were similar. All five open-label prospective studies concluded that tacrolimus is safe and effective as an induction and maintenance therapy for LN or for the treatment of LN with persistent proteinuria that failed to respond to prednisolone and immunosuppressants. In conclusion, this systematic review shows that tacrolimus may be effective as an induction and maintenance therapy for LN or as a treatment for LN with persistent proteinuria despite gold standard treatment. However, further RCTs are needed to compare tacrolimus with standard regimens for the treatment of LN.

Keywords

lupus nephritis systematic review tacrolimus

Introduction

Systemic lupus erythematosus (SLE) is a prototypic human autoimmune disease, and a disorder of generalized autoimmunity of unknown etiology, and is characterized by intense inflammation and multiple organ damage.¹ Renal involvement occurs in up to 60% of patients with SLE, and lupus nephritis (LN) remains a predominant cause of morbidity and mortality.² Although cyclophosphamide (CYC) regimens improve renal outcomes as compared with steroids alone, and have long been considered a gold standard for inducing renal remission and preventing renal flares, their toxicities raise a number of concerns.³ Furthermore, their benefits continue to be tempered by significant drug-related toxicities, such as an increased risk of infection and ovarian toxicity.⁴

Tacrolimus (Prograf, FK506) is a macrolide calcineurin inhibitor that has been used for prophylactic purposes for rejection reaction after organ transplantation.⁵ Tacrolimus is a potent inhibitor of human T cell proliferation, and does so by inhibiting the intranuclear translocations of cytoplasmic nuclear factors in activated T cells by binding to tacrolimus-binding proteins in T lymphocytes and inhibiting calcineurin.⁶ This inhibition of calcineurin leads to a reduction in antigen-stimulated interleukin-2 (IL-2) T cell production and interferon-γ, tumor necrosis factor-α, and IL-2 receptor expression on T cells.⁷ Furthermore, the immunosuppressive effect of tacrolimus is 30 to 100 times greater in vitro than cyclosporine, and is 10 to 20 times greater in vivo.⁸ Moreover, because of its effects on T cell activation, on the pathogenesis of SLE and LN, and its immunomodulatory effect, tacrolimus is expected to have clinical benefits.

Several clinical trials have attempted to evaluate the efficacy and safety of tacrolimus in LN.⁹ ^– ¹⁵ The aim of the present study was to assess the efficacy and safety of tacrolimus in LN by systematically reviewing clinical data.

Methods

Identification of eligible studies and data extraction

We performed a literature search to identify clinical trials that examined tacrolimus therapy for LN. Literature searches were performed using MEDLINE (up to July 2010) and the Cochrane Controlled Trials Register (up to July 2010). The following key words and subject terms were used in the searches: ‘lupus nephritis’ and ‘tacrolimus’. All references in studies identified were reviewed to identify additional works not included in the electronic databases. Clinical trials were included if they met the following criteria: 1) the study examined tacrolimus as an induction or maintenance therapy for LN, and 2) the study was of patients with biopsy-proven LN. Unpublished studies and retrospective studies were excluded.

Results

Studies included in the systematic review

Seven studies met the systematic review inclusion criteria.⁹ ^– ¹⁵ These seven studies involved a total of 115 patients treated with tacrolimus and 54 controls. Two studies were case-control studies, and five were open-label trials. Relevant features of the studies included in the meta-analysis are provided in Tables 1 and 2. Follow-up periods ranged from 6 to 24 months.

Table 1

Characteristics of the studies included in this systematic review of tacrolimus therapy in lupus nephritis

Study^Ref	Number enrolled		Study type	Country (ethnicity)	Subject	Follow-up period (months)	Results
Study^Ref	T	C	Study type	Country (ethnicity)	Subject	Follow-up period (months)	Results
Miyasaka et al., 2009⁹	28	35	RCT	Japan (Asian)	LN (III–V) with persistent proteinuria on glucocorticoid ≥10 mg/day for at least 8 weeks	6	Tacrolimus was a safe and effective addition to glucocorticoid therapy
Szeto et al., 2008¹⁰	18	19	CC	China (Asian)	Membranous LN with nephritic syndrome	12	Tacrolimus was safe and effective treatment for membranous LN
Lee et al., 2010¹¹	9	NA	OL	Korea (Asian)	Diffuse proliferative LN refractory to IV CYC plus steroid pulses	12	Tacrolimus was an effective for refractory to the standard regimen for diffuse proliferative LN
Uchino et al., 2010¹²	23	NA	OL	Japan (Asian)	LN (III–V) with persistent proteinuria despite treatment with corticosteroids and/or immunosuppressants	6	Tacrolimus was safe and effective as maintenance therapy
Tanaka et al., 2009¹³	11	NA	OL	Japan (Asian)	LN (III–V) treated with prednisolone combined with cytotoxic agents	24	Tacrolimus was safe and effective
Asamiya et al., 2009¹⁴	17	NA	OL	Japan (Asian)	LN (III–V) after induction treatment	12	Tacrolimus was safe and effective as maintenance therapy
Mok et al., 2005¹⁵	9	NA	OL	China (Asian)	Active diffuse proliferative LN	6	Tacrolimus was effective for induction treatment of diffuse proliferative LN

T: tacrolimus group, C: control group, NA: not available, RCT: randomized controlled trial, CC: case control study, OL: open-label study, LN: lupus nephritis, AZA: azathioprine, CYC: cyclophosphamide, IV: intravenous.

Table 2

The studies included in this systematic review of tacrolimus therapy in lupus nephritis

Study^Ref	Tacrolimus dose	Tacrolimus level (mean ± SD)	Primary end point or efficacy	Relapse or flare rate (%)	Adverse effects
Miyasaka et al., 2009⁹	3 mg/day vs. placebo	4.35 ± 1.53 ng/ml	Daily proteinuria, urinary RBC count, Cr, C3, anti-dsDNA, Lupus Nephritis Disease Activity Index (LNDAI)	NC	All AEs: Tacrolimus (92.9%) vs. placebo (80.0%) (p = 0.277). M/F: infection 57.1% vs. 57.1%
Szeto et al., 2008¹⁰	0.1–0.2 mg/kg per day for 6 months followed by AZA vs. CYC or AZA	Dose adjustment with the target level of 3–8 ng/ml	Change in 24-hour urinary protein excretion. CR, PR	Tacrolimus (22.2%) vs. control (57.9%) (p = 0.027)	Tacrolimus vs. control: infection (3 vs. 2), elevated liver enzymes (1 vs. 1), dyspepsia (8 vs. 0), tremor (2 vs 0), Angio-edema (1 vs. 0)
Lee et al., 2010¹¹	0.1 mg/kg per day, adjusted by drug monitoring	4–10 ng/ml	U-pro/U-creat ratio, Cr, C3, C4, anti-dsDNA, SLEDAI	Treatment failure (1 case)	Hyperglycemia (1 case), Cr increased (1), hand tremor (7), presyncope (1)
Uchino et al., 2010¹²	2–3 mg/day	4.03 ± 1.49 ng/ml	U-pro/U-creat ratio, Cr, C3, C4, CH50, anti-dsDNA	NC	UTI (1 case), salivary gland infection (10), Herpes simplex (1), tremor (1), fatigue (1), hypertension (1), Cr increased (1), hemoglobin decreased (1)
Tanaka et al., 2009¹³	3 mg/day (0.04–0.075 mg/kg)	1.5–7.5 ng/ml	U-pro/U-creat ratio, Cr, C3, C4, CH50, anti-dsDNA, ECLAM	No response (1 case)	Acute bronchitis (4 cases), Herpes zoster (6)
Asamiya et al., 2009¹⁴	3 mg/day (0.06 ± 0.01 mg/kg)	3.9 ± 2.1 ng/ml	U-pro/U-creat ratio, Cr, C3, C4, CH50, anti-dsDNA	No	Bacterial meningitis (1 case), Herpes zoster (1), glucose metabolism disorder (1), tremor (1), Cr increased (1)
Mok et al., 2005¹⁵	0.1 mg/kg per day for 2 months followed by 0.06 mg/kg/day	5.9 ± 2.5–11.7 ± 4.9 ng/ml	Daily proteinuria, Cr, C3, anti-dsDNA, SLEDAI	NC	Alopecia (2 cases), transient hyperglycemia (2), tremor (1), Cr increased (1)

SD: standard deviation, NC: no comment, AEs: adverse effects, M/F: most frequent, LNDAI: calculated as the total of the scores of five parameters (daily urinary protein excretion, urinary RBC count, serum creatinine, anti-dsDNA antibody, and the complement (C3) level), CR: complete response, defined as 24-h urinary protein excretion <0.5 g/day, normal urinary sediment, normal serum albumin and estimated GFR (glomerular filtration rate) ≤15% above baseline, PR: partial remission, defined as urinary protein excretion 0.5–2.9 g/day, serum albumin ≥30 g/L and stable renal function, U-pro/U-creat ratio: urinary protein/creatinine ratio, Cr: creatinine, UTI: urinary tract infection, AE: adverse effects, ECLAM: European Consensus Lupus Activity Measurement index, SLEDAI: Systemic Lupus Erythematosus Disease Activity Index.

The efficacy and safety of tacrolimus in case-control studies

Of the two case-control studies,^9,10 one was a randomized controlled trial (RCT).⁹ This RCT was a placebo-controlled double-blind multicenter study, and was undertaken to evaluate the efficacy and safety of tacrolimus in patients with persistent nephritis on glucocorticoid for LN. The lupus nephritis disease activity index (LNDAI) decreased by 32.9 ± 31.0% (mean ± SD) in the tacrolimus group and increased by 2.3 ± 38.2% in the placebo group. However, the two groups were similar in terms of treatment-related adverse events. The case-control study conducted by Szeto et al.¹⁰ compared tacrolimus with standard protocols of oral cyclophosphamide (CYC) or azathioprine (AZA) for the treatment of membranous LN. After 24 weeks of treatment, complete and partial remission rates were 38.9% and 44.4% respectively in the tacrolimus group, and 36.8% and 57.9% in the control group (p = 0.5). However, the tacrolimus group showed significantly faster proteinuria resolution than the control group (p = 0.032). No serious adverse effect occurred in the tacrolimus group.

The efficacy and safety of tacrolimus for LN in open-label studies

Five open-label prospective studies were conducted for the treatment of LN.¹¹ ^– ¹⁵ Lee et al.¹¹ conducted a study to determine the efficacy and safety of tacrolimus as an alternative therapeutic option in patients with refractory diffuse proliferative LN. Tacrolimus (0.1 mg/kg per day) was administered for 1 year with dosage adjustment. Seven of the nine patients achieved a complete clinical response, which was defined as stabilization in the disease activity markers and serum creatinine level with reduction of ≥50% in U-prot/U-creat ratio, two patients showed complete remission with U-prot/U-creat ratio <0.2, but one experienced treatment failure. No serious adverse effects were observed. The study by Uchino et al.¹² was a multi-center open-label prospective 6-month observational study in LN patients with persistent proteinuria. The urinary protein/creatinine ratio (U-prot/U-creat ratio) at baseline was 2.52 ± 2.89 and decreased to 2.11 ± 3.01 after treatment for 2 months (p < 0.05). The U-prot/U-creat ratio continued to decrease significantly until 6 months (1.43 ± 2.43) (p < 0.05). None of the patients developed an adverse reaction requiring study discontinuation. The study by Tanaka et al.¹³ was an open-label trial on once daily tacrolimus (3 mg/day; 0.04–0.075 mg/kg) in young patients with pediatric-onset, long-standing LN. The U-prot/U-creat ratio gradually decreased after treatment commencement and dropped significantly at 24 months after the start of treatment. Complete responses were achieved in eight patients (73%) and partial responses in two patients (18%), but the remaining patient showed no response. ‘Complete response’ was defined as an improvement in the European Consensus Lupus Activity Measurement (ECLAM) index (a decrease of ≥50% compared with the baseline value) as well as improvements in all the remaining outcome parameters). ‘Partial response’ was defined as an improvement in the ECLAM index, but not in all the other outcome parameters. ‘No response’ included the stabilization or worsening of the ECLAM index as well as the other outcome parameters. No serious adverse effects were observed. The study by Asamiya et al.¹⁴ examined the efficacy and safety of tacrolimus for maintenance treatment in 17 patients with LN. The U-prot/U-creat ratio significantly decreased from 1.14 ± 1.74 at baseline to 0.23 ± 0.47 after 1 year (p < 0.05). Adverse effects were observed in five cases, but no relationship was found between the incidences’ adverse effects and blood tacrolimus levels. The mean tacrolimus blood concentration was 3.9 ± 2.1 ng/ml. The study carried out by Mok et al.¹⁵ reported preliminary evidence regarding the use of tacrolimus as an induction therapy in nine patients with diffuse proliferative LN. After 6 months of treatment, complete and partial responses were achieved by six (67%) and two (22%) patients, respectively. Complete response was defined as stabilization or improvement in serum creatinine level with reduction of proteinuria to <1 g/day, improvement in C3 level and complete resolution of active urinary casts. Partial response was defined as stabilization or improvement in serum creatinine level with reduction of proteinuria. No response referred to deterioration of serum creatinine level, an increase in proteinuria, or a reduction in proteinuria. Two patients developed transient hyperglycemia, but no serious adverse effects were observed.

Meta-analysis of open-label studies showed U-prot/U-creat ratio, serum C3 level and anti-dsDNA antibody titer were improved after treatment with tacrolimus (standardized mean differences (SMD) 1.143, 95% confidence interval (CI) 0.407 to 1.879, p = 0.002; −0.583, 95% CI −0.928 to −0.238, p = 0.001; 0.362, 95% CI −0.000 to 0.725, p = 0.050, respectively), but serum Cr level was not significantly changed after treatment with tacrolimus (SMD −0.371, 95% CI −0.790 to 0.047, p = 0.082).

Discussion

In the present review, we systematically reviewed the clinical data produced by studies that examined the use of tacrolimus for the treatment of LN.⁹ ^– ¹⁵ Case-control studies^9,10 and open-label studies¹¹ ^– ¹⁵ showed that tacrolimus is effective, well tolerated, and safe for induction and maintenance therapy in LN and that it has no serious adverse effects.

The treatment of LN consists of intense remission induction therapy, followed by long-term and less intense maintenance therapy.¹⁶ The standard regimen used for remission induction includes prednisolone combined with CYC as a daily oral or intravenous pulse therapy. Furthermore, the efficacy and safety of mycophenolate mofetile (MMF) for LN therapy has also been reported.¹⁷ With regard to maintenance therapy, pulse CYC has been recommended, and MMF and AZA are also considered good options.¹⁶ Persistent proteinuria, despite the resolution of acute lupus flares, is a common phenomenon. Furthermore, resistance to conventional immunosuppressive agents is a major risk factor and results in renal function deterioration and a poor prognosis.

Although aggressive cytotoxic therapy is needed for the induction of remission in LN, long-term cytotoxic therapy can have serious side effects, such as myelotoxicity and gonadal toxicity, and it increases the risk of secondary malignancy.³ Accordingly, alternative treatment options, such as calcineurin inhibitors, have been investigated as induction and maintenance therapies in LN.

Like cyclosporine, tacrolimus is classified as a calcineurin inhibitor, and as compared with cyclosporine, tacrolimus appears to be more potent in terms of preventing transplant rejection, and has fewer hypertensive and other adverse effects.⁵ Furthermore, although the nephrotoxicity of calcineurin inhibitor remains a major concern, tacrolimus was found to be well tolerated in studies.⁹ ^– ¹⁵

The present meta-analysis has several shortcomings that require consideration. First, the number of incorporated studies was small as were the sample sizes in these studies. Second, the follow-up period was short, and in most studies was no more than 12 months. Third, the five open-label studies had uncontrolled designs, and thus did not produce evidence regarding the specific effects of tacrolimus.¹¹ ^– ¹⁵ Furthermore, only two case-control studies containing one RCT were included in the analysis.^9,10 Fourth, clinical heterogeneity is an issue with respect to study type, subject, LN class, tacrolimus dosage, and follow-up duration. For example, one study was on induction therapy,¹⁵ another on maintenance therapy,¹⁴ and the others addressed treatment for LN with persistent proteinuria despite treatment.¹¹ ^– ¹³ Tacrolimus dose varied from tacrolimus 2 mg/kg per day to 0.2 mg/kg per day, and the follow-up period ranged from 6 to 24 months. Nonetheless, all seven studies revealed that tacrolimus is effective and safe for the treatment of LN.

In conclusion, our systematic review of clinical studies indicates that tacrolimus is effective as an induction and maintenance therapy in LN or as a treatment for LN with persistent proteinuria despite treatment. Further evaluations are required regarding the long-term use and effects of tacrolimus.

Footnotes

Funding

This study was supported by the Korea Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (grant number A080588).

Conflict of interest statement

None declared.

References

Harley

Kelly

Kaufman

. Unraveling the genetics of systemic lupus erythematosus. Springer Semin Immunopathol 2006; 28: 119–130.

Waldman

Appel

. Update on the treatment of lupus nephritis. Kidney Int 2006; 70: 1403–1412.

Austin

3rd Klippel

Balow

. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986; 314: 614–619.

Petri

. Cyclophosphamide: new approaches for systemic lupus erythematosus. Lupus 2004; 13: 366–371.

Kelly

Burckart

Venkataramanan

. Tacrolimus: a new immunosuppressive agent. Am J Health Syst Pharm 1995; 52: 1521–1535.

Kino

Hatanaka

Miyata

. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987; 40: 1256–1265.

Tocci

Matkovich

Collier

. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 1989; 143: 718–726.

Wiederrecht

Lam

Hung

Martin

Sigal

. The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci 1993; 696: 9–19.

Miyasaka

Kawai

Hashimoto

. Efficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study. Mod Rheumatol 2009; 19: 606–615.

10.

Szeto

Kwan

Lai

. Tacrolimus for the treatment of systemic lupus erythematosus with pure class V nephritis. Rheumatology (Oxford) 2008; 47: 1678–1681.

11.

Lee

Joo

. Tacrolimus is an alternative therapeutic option for the treatment of refractory lupus nephritis. Lupus 2010; 19: 974–980.

12.

Uchino

Tsukamoto

Nakashima

. Tacrolimus is effective for lupus nephritis patients with persistent proteinuria. Clin Exp Rheumatol 2010; 28: 6–12.

13.

Tanaka

Oki

Tsuruga

Yashiro

Hanada

Ito

. Management of young patients with lupus nephritis using tacrolimus administered as a single daily dose. Clin Nephrol 2009; 72: 430–436.

14.

Asamiya

Uchida

Otsubo

Takei

Nitta

. Clinical assessment of tacrolimus therapy in lupus nephritis: one-year follow-up study in a single center. Nephron Clin Pract 2009; 113: c330–336.

15.

Mok

Tong

Siu

. Tacrolimus for induction therapy of diffuse proliferative lupus nephritis: an open-labeled pilot study. Kidney Int 2005; 68: 813–817.

16.

Lee

Woo

Choi

Song

. Induction and maintenance therapy for lupus nephritis: a systematic review and meta-analysis. Lupus 2010; 19: 703–710.

17.

Moore

Derry

. Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Res Ther 2006; 8: R182–R182.