Rheumatology International

, Volume 31, Issue 6, pp 757–763

Single center prospective study of tacrolimus efficacy and safety in the treatment of various manifestations in systemic lupus erythematosus

Authors

  • Katsuya Suzuki
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
  • Hideto Kameda
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
  • Koichi Amano
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
  • Hayato Nagasawa
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
  • Hirofumi Takei
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
  • Eiko Nishi
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
  • Ayumi Okuyama
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
  • Kensei Tsuzaka
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
    • Division of Rheumatology/Clinical Immunology, Department of Medicine, Saitama Medical CenterSaitama Medical University
    • Division of Rheumatology/Clinical Immunology, Department of Internal MedicineKeio University
Original Article

DOI: 10.1007/s00296-010-1366-9

Cite this article as:
Suzuki, K., Kameda, H., Amano, K. et al. Rheumatol Int (2011) 31: 757. doi:10.1007/s00296-010-1366-9

Abstract

The aim of this study was to prospectively evaluate the efficacy and safety of tacrolimus (TAC) in various manifestations of systemic lupus erythematosus (SLE) patients in daily clinical practice. Each of the 21 TAC-treated patients with SLE in our care over 2 years was enrolled in this open-label trial. Patients were administered TAC at a dosage of 1–6 mg once daily, followed up for 24 weeks. Efficacy and safety were evaluated utilizing clinical and laboratory findings. As treatment targets, TAC was preferentially used with oral corticosteroid administration for mild active manifestations such as arthritis, skin eruptions, or asymptomatic nephritis. In efficacy, the mean value of the SLE disease activity index was significantly reduced to 4.1, 2.7, 1.8, and 1.2 (N = 21, 20, 16 and 13) at 0, 4, 12, and 24 weeks, respectively. In eight cases, treatment was discontinued within 24 weeks due to insufficient effects (6 cases) and side effects (2 cases). Non-serious side effects were observed in only five cases (23.8%) over 24 weeks. TAC can be considered both effective and safe for the treatment of various manifestations of SLE.

Keywords

TacrolimusSystemic lupus erythematosusT cell

Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by an aberrant production of autoantibodies and immune complexes [13]. While corticosteroids (CS) and immunosuppressants are widely used for treatment, thereby creating a certain effect toward a higher rate of induction and maintenance therapy, more than a few resistant cases have been experienced. A new treatment has been strongly sought in the clinical setting [4].

Tacrolimus (TAC) is a relatively new type of medication that induces an immunosuppressive effect, specifically inhibiting the calcineurin pathway in T cells and reducing accompanying inflammatory cytokine production [57]. TAC has been approved for worldwide use in organ transplantation [811] and for treating autoimmune diseases, including myasthenia gravis [12]. In 2004, the use of TAC for the treatment of rheumatoid arthritis (RA) had been approved in Canada and Japan. A great deal of clinical evidence was accumulated, including our reports on RA [1316]. More recently, in 2006, TAC was approved for lupus nephritis with intolerance to be the previously normal treatment in Japan, first in the world. However, its efficacy and safety for various manifestations of SLE have not been clearly investigated. We have prospectively evaluated the efficacy and safety of TAC in SLE, focusing especially on various lupus manifestations beyond nephritis in the clinical setting; this report forms the basis for the appropriate practical use of TAC in various conditions of SLE.

Patients and methods

This study is a single-center open-label prospective 24-week observational study which took place from April 2005 to March 2007 in a typical clinical practice. Twenty-one SLE patients, fulfilling the American College of Rheumatology’s 1997 revised criteria for the classification of SLE [17] were enrolled. They all exhibited a resistance to or intolerance to other treatments, or potential difficulties with other treatments were foreseen because of anticipated complications. Patients were administered TAC at a dose of 1–3 mg (with the exception of 6 mg in one case) once a day in the evening for 24 weeks. The use of other drugs in combination was not restricted in any way.

Disease activity and clinical responses were evaluated utilizing the SLE disease activity index (SLEDAI) [18] at 0, 4, 12, and 24 weeks. The final efficacy evaluation of TAC was assessed by satisfying all of the following criteria: (1) a decrease of SLEDAI at 24 weeks from week 0 (baseline), (2) the continuation of TAC at 24 weeks, and (3) no increase of CS and no addition of immunosuppressive drugs. Safety was evaluated by examining clinical signs and symptoms in combination with laboratory findings, including the following: complete blood counts, general biochemistry and serum glucose, urinalysis, chest X-ray, and appropriate additional tests in cases of suspected adverse events. Each physician involved with this study decided independently on the continuation or discontinuation and the dosage adjustments of TAC.

Blood concentrations of TAC at 12 h after administration were measured at 4 weeks after starting the TAC regimen, with the exception of three cases; these levels were used for determining dose adjustments of TAC. After 4 weeks, they were measured if necessary.

For statistical analysis, we utilized a paired t test for the comparison of two groups and a non-repeated ANOVA test for the comparison of multiple groups. A P value of <0.05 was considered statistically significant (*P < 0.05, **P < 0.01).

Results

Patient background

Twenty-one SLE patients were enrolled in this study. Summarized demographics and baseline characteristics of all cases are shown in Table 1. The mean age was 34.8 years and 20 patients were females. Regarding subtypes of the disease, 24% of the patient had renal involvement. A few cases of syndromes overlapping with other collagen vascular diseases, including RA, were enrolled and all of them were used for lupus manifestations and evaluated. Regarding causes of administration, 16 cases of recurrences of disease, 4 cases of maintenance therapy-seeking for reduction of CS amounts, and only one case of first induction were included. Most cases had previously only used CS with the mean dose (± standard deviation) being prednisone at 13.4 ± 8.3 mg/day. Immunosuppressants, such as cyclosporine A (CyA), had also previously been used in eight cases.
Table 1

Summarized demographics and baseline characteristics of 21 SLE cases

Number of cases

21

Age (mean ± SD, range)

34.8 ± 11.4 (16–75)

Sex (male/female)

1/20

Subtype of disease

Renal 5

Non-renal 16

Cause of administration

First induction 1

Recurrence 16 (insufficient 14, side effects 2)

Maintenance 4 (for reduction of CS amount 4)

Just previous treatment

CS 20 (PSL 13.4 ± 8.3 (2–35) mg/day)

IS 8 (CyA 6, CPA 1, MZB 1)

IVIG 1

Disease activity index (SLEDAI) at start

4.2 ± 2.0 (1–8)

Target manifestation

Arthritis 8, skin eruption 5, nephropathy 5

Immunological abnormality 4, cytopenia 1

Alopecia 1, myositis 1

Combination therapy at start (mean ± SD)

CS 21 [PSL: 13.3 ± 7.9 (mg/day)]

IS 1 (CPA 1)

Dose of TAC at start (mean ± SD, range)

2.5 ± 1.0 (1–6)

CS Corticosteroids, CPA cyclophosphamide, CyA cyclosporin A, IS immunosuppressant, IVIG intravenous immunoglobulin, MZB mizoribine, SLEDAI SLE disease activity index, TAC tacrolimus

Mean scores of SLEDAI at baseline were 4.2 ± 2.0. The disease activity of enrolled patients was mild to moderate. Target manifestations of TAC treatments were diverse, including arthritis in 8; skin eruptions in 5; nephropathy in 5; immunological abnormalities in 4; and cytopenia, alopecia, and myositis in one case. All cases used CS in combination with TAC from the onset and the mean dose of predonisone was 13.3 ± 7.9 mg/day, almost equal to that prior to the start of TAC treatments. Only one case was orally concomitant with cyclophosphamide (CPA). The mean dose of TAC from the start was 2.5 ± 1.0 mg/day.

Efficacy

As a result of efficacy assessments, changes in SLEDAI scores in all cases are shown (Fig. 1a). Mean SLEDAI scores improved significantly at each of 4, 12, and 24 weeks from baseline in continuing cases. TAC continuation rates at 4, 12, and 24 weeks are shown (Fig. 1b). In the 13 cases that continued for 24 weeks, mean CS amounts were successfully reduced at 24 weeks compared with baseline (Fig. 1c). Only one of those 13 cases required an increase of CS at 24 weeks (Table 2). Although there was no significant difference in CS amounts between at start and at 24 weeks in those 13 cases, in the sub group of patients except one exacerbated case, there were significant differences (P < 0.05) by paired t test.
https://static-content.springer.com/image/art%3A10.1007%2Fs00296-010-1366-9/MediaObjects/296_2010_1366_Fig1_HTML.gif
Fig. 1

Efficacy and safety of tacrolimus in 21 SLE cases. a Time courses of SLEDAI scores after start of tacrolimus are shown. Mean values and standard deviations of SLEDAI and the number of assessed patients are also indicated. b Continuation rates (%) of tacrolimus at 0, 4, 12, and 24 weeks are shown. c Corticosteroid amounts at 0 and 24 weeks in all 13 cases that received 24 weeks of tacrolimus. Mean amounts and standard deviations of prednisolone amounts for the 13 cases are also indicated. d Time courses of serum anti-dsDNA antibody titers after start of tacrolimus are shown. Mean values and standard deviations of the titers and number of assessed patients are also indicated. Normal range of serum anti-dsDNA antibody titers is below 20 IU/ml in our laboratory. e Time courses of serum creatinine after start of tacrolimus are shown. Mean values and standard deviations of the values and the number of assessed patients are also indicated. Normal range of serum creatinine is from 0.4 to 1.1 mg/dl in our laboratory. *P < 0.05 and **P < 0.01, respectively

Table 2

List of detailed information on the TAC treatment for various manifestations

Case #

Age/sex

Major target manifestations

Initial dose of TAC (mg/day)

SLEDAI

CS amount

Efficacy assessment

At start

At 24 weeks

At start

At 24 weeks

At 24 weeks

SLE1

28/F

Immunological abnormality

2

4

2

5

5

Effective

SLE2

30/F

Arthritis

3

6

10

Insufficient (discontinue)

SLE3

34/F

Arthritis

3

4

0

10

9

Effective

SLE4

30/F

Arthritis

1.5

4

5

10

30

Insufficient (continue)

SLE5

37/F

Arthritis, alopecia

2

6

2

13

8

Effective

SLE6

71/F

Arthritis, proteinuria

1

8

0

13

12

Effective

SLE7

34/F

Skin eruption

3

4

0

10

8

Effective

SLE8

21/F

Skin eruption

3

2

2

5

5

Insufficient (continue)

SLE9

44/F

Cytopenia

2

1

3

20

10

Insufficient (continue)

SLE10

42/F

Skin eruption

2

2

2

10

7

Insufficient (continue)

SLE11

36/F

Immunological abnormality

2

2

10

Adv. events (discontinue)

SLE12

48/M

Proteinuria

2

6

10

Insufficient (discontinue)

SLE13

28/F

Immunological abnormality

3

6

0

30

8

Effective

SLE14

29/F

Skin eruption

2

2

0

20

3

Effective

SLE15

38/F

Proteinuria

2

4

10

Insufficient (continue)

SLE16

16/F

Proteinuria, cytopenia

6

6

8

Adv. events (discontinue)

SLE17

31/F

Immunol. abnormality, arthritis

2

4

5

Insufficient (discontinue)

SLE18

41/F

Arthritis

3

8

0

20

13

Effective

SLE19

23/F

Proteinuria

2

4

0

12.5

12.5

Effective

SLE20

30/F

Arthritis

3

4

5

Insufficient (discontinue)

SLE21

41/F

Skin eruption

3

2

16

Insufficient (discontinue)

Adv. events Adverse events, CS corticosteroid, ILD interstitial lung disease, SLEDAI SLE disease activity index

The mean titer amounts of anti-dsDNA antibodies, as a representative indicator of immunological parameters reflecting disease activity, were also reduced at 12 and 24 weeks compared with baseline (Fig. 1d).

In all cases, we also assessed efficacy by the last observation carried forward (LOCF). Ten of 21 cases (47.6%) satisfied efficacy criteria for mild to moderate disease activity, including various manifestations of SLE patients at 24 weeks.

We searched predictors for the continuation or the effectiveness, but there were no significant differences in age, sex, major target organ, initial dose of TAC, SLEDAI (at start) and CS, between those two groups.

Safety

Physician-determined definitive or undeniable adverse drug reactions relating to TAC were observed in five cases (23.8%) over 24 weeks (Table 3). Three of these cases were symptomatic events in the gastrointestinal tract, including epigastric discomfort, nausea, and diarrhea. Cervical lymphadenopathy was observed in one case. Finger tremors were observed in one case, although this had previously appeared with CyA treatment in the patients, and the physician continued TAC. In the four other cases, treatments were stopped at the onset of the events. None of the cases were considered to be serious and each was completely ameliorated by appropriate countermeasures [drug discontinuation (4) or careful observation (1)]. In four of five cases (80%), these events occurred within 2 months.
Table 3

Definitive or undeniable adverse events relating to tacrolimus in 21 SLE cases

Case #

Age/sex

Adverse events

Dose of TAC at event (mg/day)

Blood conc. of TAC at event (ng/ml)

Onset (M)

Type

Measures

Outcomes

SLE4

30/F

2

Epigastric discomforts

Stop

Improved and restart

1.5

1.4

SLE8

21/F

1

Diarrhea

Continue

Improved

3

ND

SLE11

36/F

4

Finger tremor

Stop

Discontinue

2

ND

(previously appeared in CyA treatment)

SLE16

16/F

2

Nausea

Stop

Improved and restart in lower dose

6

38.0

SLE21

41/F

1

Cervical lymphadenopathy

Stop

Improved and restart

3

6.1

Blood conc. Blood concentration, ND no data

In three of the above five cases, the blood concentration levels of TAC were measured at the adverse events. In two cases, the levels were below 10 ng/ml, but in the one case that was administered 6 mg/day, the level was 38.0 ng/ml and highly elevated at the time of the adverse events. Nausea turned out to be caused by high concentrations of TAC. After TAC was disrupted, this symptom improved and TAC was restarted at a lower dose.

Mean serum creatinine levels at 0, 4, 12, and 24 weeks were 0.68 ± 0.24, 0.66 ± 0.23, 0.73 ± 0.27, and 0.67 ± 0.17, respectively. There were no statistically significant differences (i.e. non-repeated measures of ANOVA) among the four groups (Fig. 1e).

Blood concentration

Blood concentration levels of TAC were measured in 18 cases, with the exception of 3 cases (SLE8, 11, and 20), and correlations of initial doses with blood concentration levels of TAC are shown in Fig. 2a. The mean concentration of 18 cases was 4.3 ± 2.4 ng/ml. The mean concentration of TAC in four dose groups (<2, 2, 3, and 6 mg/day) was 1.9 ± 0.7 (N = 2), 3.7 ± 1.8 (N = 9), 5.1 ± 1.8 (N = 6), and 10.6 ± 0.0 ng/ml (N = 1), respectively. Blood concentration levels were basically dose-dependent, but these levels had a wide range in each individual patient within the same dose groups. There were positive correlations (R2 = 0.52) and statistically significant differences (P = 0.0006).
https://static-content.springer.com/image/art%3A10.1007%2Fs00296-010-1366-9/MediaObjects/296_2010_1366_Fig2_HTML.gif
Fig. 2

Correlation between initial dose of TAC and blood concentration of TAC or change of SLEDAI. a Correlation between initial dose of TAC and blood concentration of TAC is shown (N = 18). b Correlation between initial dose of TAC and change of SLEDAI is shown (N = 18). Closed circles show each patient. The linear regression equations (including 95% confidence interval and 95% prediction interval) are also indicated as solid and dashed lines, respectively

On the other hand, no significant correlation was observed between the blood concentration levels of TAC, the dose of TAC (Fig. 2b), and SLEDAI improvement at 4 weeks from base line. Only in the 6 mg/day administration case was a high concentration level of TAC (10.2 ng/ml) observed, without any signs or symptoms. In this case, the medication was continued for 2 months, nausea appeared, and then TAC was discontinued as described in the earlier subsection on safety.

Discussion

In this report, we have demonstrated that TAC is both effective and safe in the treatment of various manifestations of SLE patients in a clinical setting. In our case series, for nearly half of the patients, 10 of 21 cases (47.6%), TAC was effective for mild to moderate disease activity, including various manifestations of SLE at 24 weeks without an increase of CS. Moreover, regarding safety, non-serious side effects were observed in only five cases (23.8%) over 24 weeks. The results of our prospective study support the finding that TAC is a new, effective agent for treating SLE.

While various immune response abnormalities were identified in SLE patients, especially aberrant and persistent T cell abnormalities, involving signal transduction defects, have been recognized as important factors in disease formation in the most recent decade [3]. Thus, a T cell blockade is considered to be quite reasonable as a potential therapeutic target for SLE.

Upon reviewing past reports of TAC treatment for SLE, a case series on three refractory SLE was first described by Duddridge and Powell [19]. Two of three cases were well-controlled and previous persistent vasculitis had been resolved; other features of active disease were controlled. The third patient’s vasculitis had not improved significantly after 2 months of treatment, and TAC was discontinued because of nephrotoxicity. Second, a case series on the successful usage of TAC in eight SLE cases, including six patients with refractory nephritis and two with anti-phospholipid syndrome, had been reported [20]. After that, several successful reports on TAC’s efficacy for nephritis [2127], nephropathy after kidney transplantation for SLE [28, 29], pediatric lupus nephritis [30], lupus cystitis [31], and neuromyelitis optica [32], were accumulated. Topical use of TAC, which had been approved for atopic dermatitis, had also begun to be tried for cutaneous lesions in lupus [3336]. A few clinical studies on TAC for collagen vascular diseases other than RA have also been reported [3740].

In designing our study, all patients at a specific period were involved, to avoid selection bias, which is different from many of the aforementioned case series. Patients were assigned according to the decisions of the involved physicians, as opposed to assignation by randomization. Our study focused on the real-world ordinary practice of TAC treatments for SLE; thus a full randomization study was not well suited to our purposes, nor would it have been suitable for our investigation into the optimization of efficacy and safety for all patients. Each physician carefully determined the dosage of TAC upon considering multiple factors for every individual patient, such as disease activity, complications, age, and renal function.

Looking for the patient background in our study, age and sex were typical for lupus patients, and baseline disease activity was mild to moderate; however, many cases were refractory for CS or recurrent with therapeutic difficulty. In daily clinical practice, we often encounter such cases of being refractory to multiple immunosuppressive agents with an intermediate dose of CS. Although we unwillingly increased CS for such cases in the past, in more than a few cases complications were forced due to CS. For the blind alley cornered patients with a mild flare of disease, such as arthritis, skin eruption, or immunological abnormalities, TAC was effective. Drop-out rate may not be low simply; however, the rate itself strongly depends on multiple factors, such as patient background, study protocol, existance of alternative choice and objective symptoms.

Although we think therapeutic effects should be basically dose dependent, the reason why dose dependency was not statically clear might be considered to be number of cases, heterogeneous group, and narrow declined distribution of TAC dose. We were able to confirm a drug response for these manifestations at 4 weeks, the same as in our report on RA [16]. Our results also indicate that it possesses steroid-sparing effects and makes a good combination partner in a subgroup of patients that responded well to the therapy. However, for severe manifestations, including cytopenia, current doses of TAC were not enough to improve their activities. Higher doses of TAC might be effective for induction, maintenance, or prevention of relatively severe disease manifestations in some cases. Longer observation and a double-blind, randomized controlled trial might be needed for dealing with this problem.

Regarding safety, TAC was generally considered to be safe except in the high-dose case, where we used it while paying special attention to renal toxicity, gastrointestinal dysfunction, glucose intolerance, and infection. Live vaccine, CyA, bosentan, and potassium-sparing diuretics are prohibited to use concomitant with TAC. Furthermore, we should be also careful to use TAC with following drugs such as macrolides, antifungal azoles, some of calcium channel blockers because of possibility of increase in blood concentration [16, 22, 23, 41]. A lower incidence of adverse events than in past clinical reports may be due to an appropriate and flexible dose regimen. From a safety perspective, it is important to consider dosages of TAC for each individual.

On the measurement of blood concentrations of TAC in SLE patients, current recognition and proposed new practice guidelines were garnered from our previous and current studies are as follows: (1) basically, efficacy is dose dependent, but individual differences exist and we should be checking that the concentration is in an appropriate range, at least once, soon after initial administration; (2) especially in the case of (a) liver and/or renal dysfunction, (b) an increase of dose in elderly patients, (c) more than 3 mg/day administration, and/or (d) a combination with drugs interacting with TAC, the monitoring of blood concentration levels is efficacious for preventing serious adverse events caused by an increased concentration; (3) it is difficult to predict the initial clinical response, drug concentration, and independent adverse events.

As a suggestion for further studies, it is necessary to establish evidence for the following: (1) appropriate applicants for the treatment of TAC; (2) appropriate dose, methods, periods, and blood concentration levels to maximize effect and minimize side effects for each manifestation; (3) sensitive indicators of monitoring and assessment methods for the treatment; and (4) long-term efficacy and safety, and contribution to prognosis.

In conclusion, TAC can be considered both effective and safe for treating various manifestations in SLE patients. For mild disease activation of SLE, it could become one of the new pragmatic options. However, for severe active conditions, its efficacy is considered to be limited at current dose settings and usage.

Conflict of interest statement

None.

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