Rheumatol Int DOI 10.1007/s00296-012-2633-8

SHORT COMMUNICATION

Safety and efficacy of mizoribine in patients with connective tissue diseases other than rheumatoid arthritis Ryo Rokutanda • Mitsumasa Kishimoto • Sachiko Ohde Hisanori Shimizu • Atsushi Nomura • Yasuhiro Suyama Yuri Ohara • Kenichi Yamaguchi • Masato Okada

• •

Received: 16 March 2012 / Accepted: 15 December 2012 Ó Springer-Verlag Berlin Heidelberg 2012

Abstract The objective of this study was to examine the safety and efficacy of mizoribine (MZR), an inhibitor of inosine monophosphate dehydrogenase, in patients with connective tissue diseases (CTDs) other than rheumatoid arthritis. We identified all patients who had ever been treated with MZR for CTDs at our institution during the period from January 2001 to May 2011. A retrospective review of medical records was performed to evaluate safety and efficacy of MZR. A total of 63 patients (13 induction and 50 maintenance therapy with MZR) were included. During 70.2 patient-years of follow-up, only one patient required discontinuation of MZR due to an adverse event. Doses of PSL were significantly decreased at last follow-up in both the induction (45.2 ± 15.6 vs. 8.4 ± 5.7 mg/day, p \ 0.01) and the maintenance group (12.4 ± 7.6 vs. 9.3 ± 6.4 mg/day, p \ 0.01). MZR appears to be a safe and well-tolerated steroid-sparing agent in patients with CTDs. Keywords Treatment

Autoimmune diseases  B cells  T cells 

R. Rokutanda (&)  M. Kishimoto  H. Shimizu  Y. Suyama  Y. Ohara  K. Yamaguchi  M. Okada Division of Allergy and Rheumatology, St. Luke’s International Hospital, 9-1 Akashi-cho, Chuo-ku, Tokyo 104-8560, Japan e-mail: [email protected] S. Ohde Center for Clinical Epidemiology, St. Luke’s Life Science Institute, Tokyo, Japan A. Nomura Department of Rheumatology, Chubu Rosai Hospital, Nagoya, Japan

Introduction Connective tissue diseases (CTDs) are a heterogeneous group of autoimmune disorders characterized by inflammatory and fibrotic tissue injury. Because of growing concern about toxicity of long-term corticosteroid (CS) therapy, several immunosuppressive agents have been used in CTD treatment as steroid-sparing agents [1]. In fact, a recent quality indicator set for systemic lupus erythematosus recommends the use of steroid-sparing agents to reduce dose of CS to \10 mg/day [2]. However, like CS, these agents also have potential toxicities and carry risks of adverse events. Mizoribine (MZR) is an immunosuppressive agent which is similar to mycophenolate mofetil (MMF) in its inhibitory effect on inosine monophosphate dehydrogenase, a rate-limiting enzyme in the de novo pathway of nucleic acid synthesis [3]. The immunosuppressive effect has been suggested to be due to the inhibition of lymphocyte proliferation [4]. While MMF is well known for its efficacy against autoimmune diseases such as lupus nephritis, it is approved only for organ transplantations in Japan. MZR was first isolated from the culture media of Eupenicillium brefeldianum M-2166 in 1974 in Japan. Since MZR was first approved for use in renal transplantation patients, it has been thought to be safe and well tolerated as compared with other immunosuppressants, and recent studies have demonstrated its usefulness in the treatment of rheumatoid arthritis (RA) [5], systemic lupus erythematosus (SLE) [6], nephrotic syndrome [7], and immunoglobulin A nephropathy [8]. However, few studies have examined the safety and efficacy of MZR in various other connective tissue diseases. Therefore, we conducted this study to assess experiences with treating various CTDs by MZR. Our primary

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objective was to evaluate the safety and tolerability of using MZR in a heterogeneous sample of patients with various CTDs. A secondary objective of this study was to examine the impact of MZR on treating CTDs.

Methods Subjects We identified all patients who had ever been treated with MZR for CTDs at our institution during the period from January 2001 to May 2011. All patients who received MZR primarily for their CTDs at least 14 days and returned to our institution for more than one follow-up visit were included in this study. Each subject satisfied criteria for a specific diagnosis [9–12]. Data collection and analysis Medical records were retrospectively reviewed to identify the main clinical features in terms of the efficacy and safety of MZR. Collected data included age, sex, race, type of CTD, time since diagnosis of CTD, previous treatment, and the reason for starting MZR. For the safety evaluation, information about adverse events, duration of therapy, and reasons for stopping MZR were also recorded. To categorize the purposes of adding MZR to CS therapy, patients who received high doses of PSL (prednisolone, 0.5 mg/kg/ day or more) were defined as the induction therapy group, while those who received relatively low doses of PSL (\0.5 mg/kg/day) were defined as the maintenance therapy group. Longitudinal changes in the PSL doses were analyzed in each patient group.

19–79 years), and the mean time from diagnosis of CTD to the start of MZR was 5.9 ± 6.8 years. Eleven patients were male and 52 were female. The main clinical manifestations observed at the time of starting MZR are detailed in Table 1. The mean starting dose of MZR was 125.0 ± 42.7 mg/ day with a PSL dose of 19.2 ± 16.5 mg/day, and the follow-up period was 407 ± 417 days. The induction therapy group included 13 patients, while the other 50 patients belonged to the maintenance therapy group. The reasons for adding MZR to maintenance therapy were to reduce the CS dose in 29 cases, disease recurrences in 15, and intolerance to prior agents in 6. Doses of PSL were significantly

Table 1 Characteristics of analyzed patients Dataa No. of females/males (female %) Age at MZR initiation (mean ± SD years)

49.0 ± 16.5

Time since CTDs diagnosis (mean ± SD years)

5.9 ± 6.8

Diagnosis of CTDs Systemic lupus erythematosus

34 (54.0)

Sjo¨gren syndrome

6 (9.5)

ANCA-associated vasculitis

5 (7.9)

IgG4-related disease

5 (7.9)

Polymyositis/dermatomyositis

4 (6.3)

Giant cell arteritis

2 (3.2)

Polymyalgia rheumatica

2 (3.2)

Takayasu arteritis

2 (3.2)

Eosinophilic fasciitis

1 (1.6)

Cogan’s syndrome

1 (1.6)

Mixed connective tissue disease

1 (1.6)

Reasons for adding MZR during maintenance therapy (n = 50)

Statistics

For reduction of PSL doses

29 (58.0)

Recurrence

15 (30.0)

Intolerance to prior agent

Data are presented as counts or means with SDs. Doses of PSL at MZR initiation and last visit were compared using paired t tests. All statistical analyses were performed using SPSS 15.0 J (Tokyo, Japan). We considered p values of \0.05 to be statistically significant.

125 ± 42.7

Duration on MZR follow-up (mean ± SD days)

400 ± 417

Dose of PSL at MZR initiation (mean ± SD mg/day)

19.4 ± 16.5

Dose of PSL at last visit (mean ± SD mg/day)

9.4 ± 7.2

Discontinue MZR for any reason

Results

123

6 (12.0)

Dose of MZR at initiation (mean ± SD mg/day)

Lack of efficacy

During this period, 63 patients in total were treated with MZR in our institution. All but 4 were Japanese. The patient population comprised 34 with SLE, 6 with Sjo¨gren syndrome (SS), 5 with ANCA-associated vasculitis, 5 with IgG4-related disease, and 13 with CTDs. Mean patient age at the time of starting MZR was 49.8 ± 16.5 years (range

52/11 (82.5)

16 (25.4) 8 (12.7)

Archiving remission

2 (3.2)

Lost to follow-up

2 (3.2)

Patient’s preference

1 (1.6)

Unknown

1 (1.6)

Adverse effect

1 (1.6)

Death

1 (1.6)

MZR mizoribine, CTDs connective tissue diseases, ANCA anti-neutrophilic cytoplasmic antibody, IgG immunoglobulin, PSL prednisolone a

Except where indicated otherwise, values indicate the number (%) of patients

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Fig. 1 Longitudinal changes in the mean PSL doses of total and 2 patient groups. Doses of PSL were significantly decreased at last visit in total patients and both the induction therapy group and maintenance therapy group. PSL prednisolone, MZR mizoribine

decreased at last follow-up in both the induction (45.2 ± 15.6 vs. 8.4 ± 5.7 mg/day, p \ 0.01) and the maintenance group (12.4 ± 7.6 vs. 9.3 ± 6.4 mg/day, p \ 0.01, Fig. 1). Twenty-three patients had received at least one other immunomodulatory agent prior to starting MZR. During 70.2 patient-years of follow-up, only two adverse events were identified: one was stomatitis which resulted in stopping MZR, and the other was leukocytopenia which improved with MZR dose reduction. During the observational period, 16 patients discontinued MZR for various reasons. The reasons for discontinuation of treatment were lack of improvement/worsening of CTDs in 50.0 % (8/16 patients), withdrawal after achieving remission in 12.5 % (2/16 patients), and loss to follow-up in 12.5 % (2/16 patients, Table 1). During the study period, one patient died from colon cancer that had been detected several years before initiating MZR.

Discussion In this retrospective study, MZR showed good tolerability when used for treatment of various CTDs. Among the 63 patients, only one case discontinued MZR because of an adverse event during 70.2 patient-years of follow-up. Additionally, MZR achieved to reduce the mean doses of CS to \10 mg/day in both induction and maintenance therapy. To the best of our knowledge, this is one of the

largest studies showing the safety and efficacy of MZR in rheumatic diseases and is unique in that the subjects suffered from a variety of autoimmune diseases. MZR was investigated in various Japanese institutions during the period from 1978 to 1982, and in 1984, it was approved by the Japanese Ministry of Health, Labour and Welfare as a drug indicated for the prevention of rejection in renal transplantation. Since then, it has been approved for the treatment of lupus nephritis (1990), RA (1992), and primary nephritic syndrome (1995). In treating these diseases, MZR has often been combined with CS and/or other immunosuppressants, and its clinical safety and efficacy have been well documented [3]. Recent randomized controlled trial with childhood-onset lupus showed that survival without flare was significantly longer in patients treated by MZR combined with CS than in patients with CS only [13]. As for SS, one multicenter open-label clinical trial, 59 patients with SS treated by MZR demonstrated a significant improvement in the salivary function and patients’ assessment of sicca symptoms [14]. However, with the exception of several reports on a small number of patients, there have been few studies examining the use of MZR for other autoimmune diseases. In fact, to the best of our knowledge, this is the largest study showing the safety and efficacy of MZR for various CTDs other than RA. The low frequency of serious side effects of MZR may be attributable to its pharmacological characteristics. MZR is metabolized to its monophosphate form by adenosine kinase and, similar to MMF, competitively inhibits inosine monophosphate dehydrogenase and guanosine monophosphate synthase, enzymes required for de novo synthesis of guanine nucleotides from inosine monophosphate [15, 16]. Purine synthesis in lymphocytes depends exclusively on the de novo pathway. Thus, MZR strongly inhibits the proliferation of lymphocytes, but rarely affects that of other cells, in which a salvage pathway is used for purine synthesis. Uptake of MZR into nucleic acids does not occur because phosphorylation ceases at the level of monophosphates [17, 18]. Therefore, it is less likely for MZR to produce carcinogenicity, as reported for other immunosuppressants. Although MZR has the similar mechanism of action with MMF, its anti-viral activity, such as against cytomegalovirus, makes MZR preferable as add-on therapy on high-dose CS [19]. This study has several limitations. First, patients were treated at the primary rheumatologist’s discretion, introducing potential selection bias. This likely had a significant impact on the disease severity distribution of the patients included in the analysis. In addition, uniform criteria for utilization of CS or other immunosuppressants were not employed. Accordingly, it was difficult to evaluate the precise effects of MZR in this study. While the data

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reported herein are encouraging, they must be interpreted in the context of these limitations. Prospective clinical trials are needed to confirm our observations. In conclusion, MZR appears to be safe and well tolerated in patients with CTDs. In addition, MZR can be an effective steroid-sparing agent when combined with corticosteroids. Conflict of interest I declare that I have no conflict of interest in connection with this paper.

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