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Rheumatology Advance Access originally published online on November 1, 2005
Rheumatology 2006 45(4):441-444; doi:10.1093/rheumatology/kei172
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© The Author 2005. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Safety of tacrolimus, an immunosuppressive agent, in the treatment of rheumatoid arthritis in elderly patients

S. Kawai and K. Yamamoto1

Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine and 1 Department of Allergy and Rheumatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

Correspondence to: S. Kawai, Division of Rheumatology, Department of Internal Medicine, Toho University School of Medicine, 6-11-1 Omori-Nishi, Ota-ku Tokyo 143-8541, Japan. E-mail: skawai{at}med.toho-u.ac.jp


   Abstract
Top
 Abstract
Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objective. To prospectively evaluate the safety of tacrolimus in active rheumatoid arthritis (RA) in elderly patients with insufficient response to disease-modifying antirheumatic drugs (DMARDs).

Methods. Fifty-seven patients aged ≥65 yr with RA for ≥6 months were enrolled in an open-label, non-controlled study. All DMARDs were discontinued and tacrolimus was administered orally once daily after the evening meal for 28 weeks. Tacrolimus, initiated at 1.5 mg/day, was increased to 3 mg/day after 6 weeks if no abnormal changes developed. Existing NSAID and oral corticosteroid (≤7.5 mg/day prednisolone equivalent) therapy could be continued during the study. Safety was evaluated as clinical symptoms, abnormal changes in laboratory values and the development of infection. Treatment response was determined using the American College of Rheumatology (ACR) criteria for improvement. Whole blood concentrations of tacrolimus 12 h after administration were measured by high-performance liquid chromatography and tandem mass spectrometry.

Results. Clinical adverse events developed in 25 patients (46.3%). Abnormal changes in laboratory values occurred in 25 patients (46.3%). Ten patients (18.5%) developed infection. An ACR20 response was achieved by 50.0% of efficacy-evaluable patients and ACR20 success rates (the proportion of patients achieving ACR20 response and completing the study) was 46.3%. The ACR50 response rate was 18.5% of evaluable patients. Mean blood concentration of tacrolimus was 3.3 and 5.3 ng/ml in patients receiving 1.5 and 3.0 mg daily, respectively. No relationship between its concentration and adverse reactions was observed.

Conclusion. In elderly patients with insufficient response to DMARD therapy, tacrolimus at 1.5–3.0 mg/day is safe and well-tolerated and provides clinical benefit.

KEY WORDS: Rheumatoid arthritis, Tacrolimus, DMARDs, Immunosuppressant, Elderly


   Introduction
Top
 Abstract
 Introduction
Patients and methods
 Results
 Discussion
 References
 
Tacrolimus targets T cells and causes immunosuppression by selective mechanisms; in T cells, tacrolimus/tacrolimus-binding protein complex further binds to calcineurin to inhibit the translocation of cytoplasmic nuclear factors into the nucleus, thereby inhibiting the expression of cytokines such as IL-2, IL-3, IL-4, interferon-{gamma} and TNF-{alpha} [1, 2]. Clinical studies of tacrolimus for rheumatoid arthritis (RA) were conducted in Japan in patients aged 20–64 yr and in the USA in patients aged 18–70 yr to estimate the optimal dosage of tacrolimus in the treatment of RA [3, 4]. In both studies, tacrolimus was shown to be optimally effective against RA at a dosage of 3 mg/day. The objective of the present study was to evaluate the safety of tacrolimus in elderly Japanese patients with RA who had had an insufficient response to DMARDs. Because elderly patients often have impaired organ functions and are more susceptible to drug toxicity than younger patients, tacrolimus was initiated at 1.5 mg/day in all patients and was increased to 3 mg/day in patients who met the dose escalation criteria.


   Patients and methods
Top
 Abstract
 Introduction
 Patients and methods
Results
 Discussion
 References
 
Patients
This study involved patients aged 65 yr or more in whom RA had been diagnosed at least 6 months previously, according to the American Rheumatism Association 1987 Revised Criteria for Disease Classification [5]. Patients had previously reported an insufficient response to treatment with at least one disease-modifying antirheumatic drug (DMARD) and had currently active RA, defined as (i) erythrocyte sedimentation rate (ESR) ≥30 mm/h or C-reactive protein (CRP) ≥1.0 mg/dl; (ii) at least 6 of 48 joints assessed as tender or painful with pressure; and (iii) at least 3 of 46 joints assessed as swollen. Exclusion criteria included renal dysfunction (serum creatinine ≥1.0 mg/dl or more than the upper limit of normal), hepatic dysfunction, hyperkalaemia, presence or history of cardiac disorders, presence or history of pancreatitis or diabetes mellitus, presence or history of malignancies, severe infection, and severe drug allergy. Also excluded from the study were those who had received intra-articular, intramuscular or intravenous (but not topical) treatment with more than two NSAIDs or started oral corticosteroid therapy less than 4 weeks before enrolment, and those who were currently on oral corticosteroids (≥7.5 mg prednisolone equivalent daily).

Study protocol
The Institutional Review Board at each study site approved the protocol, and all patients gave written informed consent prior to any study-related procedures.

Patient eligibility was confirmed during a 1- to 4-week screening period during which patient characteristics (age, medical history, complications, etc.), concomitant therapy, disease activity, blood pressure, body weight, haematology, blood chemistry, urinalysis, immunology and ECG were assessed. DMARDs were discontinued without a washout period, and treatment with tacrolimus was initiated at 1.5 mg/day. Tacrolimus was taken after the evening meal. The dose of tacrolimus could be increased to 3 mg/day after 6 weeks if, in the investigator's opinion, the treatment was well tolerated and the following predetermined criteria for dose escalation were met: (i) a serum creatinine level less than the standard value, which had not increased by >0.3 mg/dl compared with baseline; (ii) a fasting plasma glucose level <110 mg/dl and glycosylated haemoglobin (HbA1c) <5.9%; and (iii) a tacrolimus blood concentration (about 12 h after administration) <20 ng/ml.

Whole blood concentrations of tacrolimus were measured by high-performance liquid chromatography and tandem mass spectrometry. Blood samples were taken 12 ± 4 h after tacrolimus administration.

Criteria for evaluation
Safety was evaluated in terms of adverse events, including clinical symptoms, abnormal changes in laboratory values, and development of infection. Treatment response (ACR20) was determined using the American College of Rheumatology (ACR) definition for improvement [6]. The ACR50 response was defined as 50% improvement using the ACR definition. The ACR20 success rate was defined as the proportion of patients achieving ACR20 and completing 28 weeks of therapy.

Statistical methods
All data were collected and monitored in accordance with the regulations of the Ministry of Health, Labour and Welfare in Japan. Data analysis was performed by statisticians at Astellas Pharma, Tokyo, Japan (formerly Fujisawa Pharmaceutical, Osaka, Japan). Data are expressed as the mean ± S.D. Data obtained at each specified time were compared with those obtained at baseline using Wilcoxon's signed ranks test. The significance level was P<0.05, using two-sided tests. In addition, 95% confidence intervals (CIs) of ACR20 and ACR50 response rates were calculated.


   Results
Top
 Abstract
 Introduction
 Patients and methods
 Results
Discussion
 References
 
Patient characteristics
This study enrolled 57 patients who received at least one dose of tacrolimus. Forty-four patients completed 28 weeks of tacrolimus treatment and 13 patients discontinued treatment prematurely. Reasons for treatment discontinuation were adverse events (n = 7), a lack of response to treatment (n = 3) and other reasons (n = 3). Safety and efficacy were evaluated in 54 patients, 46 of whom were female. The mean age of participants was 70.2 ± 3.8 yr and the mean duration of RA was 162.7 ± 140.7 months. Twenty-four patients increased their dose (to more than 2.0 mg/day), 25 patients received 1.5 mg/day throughout 28 weeks and five patients decreased their dose because of adverse events.

Safety
Safety was assessed in 54 patients. Table 1 shows all adverse events reported during the study. Forty-two clinical adverse events occurred in 25 patients (46.3%). Skin and appendage disorders were the most frequent, with 11 events reported; six events were classified as gastrointestinal system disorders, and five events were classified as affecting the body as a whole, general disorders or affecting the nervous system (Table 1). All of the clinical adverse events except a case with vertigo and a case with gastrointestinal disorder were observed at least more than 2 weeks after tacrolimus treatment. Most clinical adverse events were transient and mild or moderate in severity.


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  		TABLE 1. Incidence of adverse events

 
Abnormal changes in laboratory values occurred in 25 patients (46.3%). Abnormal changes included increased blood urea nitrogen (n = 11; 20.4%), increased creatinine (n = 8; 14.8%), increased urinary N-acetyl-3ß-D-glucosaminidase (n = 5; 9.3%), increased ß2-microglobulin (n = 5; 9.3%), decreased lymphocyte levels (n = 3; 5.6%) and increased levels of leucocytes, monocytes, alkaline phosphatase, serum glucose and HbA1c in two patients each (3.7%). All of the abnormal changes in laboratory values were observed at least 2 weeks after tacrolimus treatment. Most of the abnormal changes in laboratory values resolved.

The incidence of infection was 18.5% (n = 10). Common cold or ’flu was the most frequent, with seven events reported, and three events were classified as upper airway infection. Infections resolved in nine patients who continued to take tacrolimus, and resolved in one patient after tacrolimus was withdrawn.

Two patients developed five serious adverse events that may have been related to tacrolimus (increased glycaemia and HbA1C, allergic angiitis, elevated neutrophil count and decreased lymphocyte count). These adverse events were observed more than 2 weeks after tacrolimus treatment, and resolved after tacrolimus was withdrawn.

Three clinical adverse events, two abnormal changes in laboratory values and five infections occurred after increasing the dose of tacrolimus.

Creatinine values in patients who increased tacrolimus dosage were examined using scattergram analysis, but no trend towards an increase was identified in these patients (data not shown).

Treatment response
The ACR20 response rate was 50.0% (95% CI 36.1–63.9%). In the subgroup analysis based on changing dose, the ACR20 response rate was 45.8% in patients whose dose was increased to ≥2.0 mg/day and 53.3% in the group maintained on ≤1.5 mg/day.

The overall ACR20 success rate was 46.3% (95% CI 32.6–60.4%). The ACR50 response rate was 18.5% (95% CI 9.3–31.4%). The efficacy of tacrolimus treatment was highly significant for all individual ACR component scores compared with baseline (P<0.001) (Table 2).


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  		TABLE 2. Mean ± S.D. change from baseline to end of treatment for individual ACR component scores in elderly patients receiving tacrolimus for 28 weeks

 
Tacrolimus whole blood concentration
When the patients were administered a dose of 1.5 or 3.0 mg, the mean blood concentration of tacrolimus (about 12 h after administration) was 3.3 ± 1.8 (n = 37) or 5.3 ± 2.0 (n = 8) ng/ml, respectively. For patients administered 1.5 mg/kg, the mean blood concentration of tacrolimus in patients who developed adverse reactions was 2.9 ± 1.4 (n = 20) ng/ml, whereas that in patients who did not develop any adverse reactions was 3.8 ± 2.2 (n = 17) ng/ml.


   Discussion
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
References
 
This study involved elderly patients (aged ≥65 yr), who are generally at increased risk of developing adverse drug reactions compared with non-elderly individuals. This is considered to be primarily due to delayed elimination of drugs (via the renal route) with ageing and other pharmacokinetic alterations that increase systemic exposure to drugs (e.g. changes in volume of distribution and hepatic metabolism) [7]. As a safety precaution, tacrolimus was initiated at 1.5 mg/day in all patients and increased up to 3 mg/day only in patients who met the dose escalation criteria. As a result, almost half of patients remained on 1.5 mg/day.

Based on the experience with tacrolimus in transplant recipients [8, 9] and the results of the Japanese and US clinical studies in RA patients [3, 4], renal dysfunction appears to be a concern in patients receiving tacrolimus. In the present study, renal dysfunction was indicated by increased serum creatinine in eight patients and increased blood urea nitrogen in 11 patients and led to discontinuation of tacrolimus in two of these patients. However, the serum creatinine data obtained in 24 patients whose dose of tacrolimus was increased (≥2.0 mg/day) showed no significant increase after dose escalation.

Of the patients treated with tacrolimus in this study, two developed the common cold and one developed oesophageal candidiasis that required discontinuation of the drug. Patients recovered from all these episodes of infection. Since tacrolimus is usually administered to RA patients at doses lower than those recommended in transplant recipients, infection is likely to be less of a safety concern with the use of tacrolimus in the treatment of RA, as suggested by previous studies [3, 4, 10, 11].

The mean blood concentration of tacrolimus in patients with adverse reactions was not different from that in patients without adverse reactions. We did not find a clear relationship between the blood concentration of tacrolimus and adverse reactions in this study. It has been reported previously that the blood concentration of tacrolimus correlates closely to adverse events in renal transplant recipients [9]; higher incidences of adverse events were observed in their patients with higher tacrolimus blood concentrations (≥10 ng/ml). The lack of correlation between the blood concentration of tacrolimus and adverse reactions in this study may be due to the small sample size and/or lower blood concentrations of tacrolimus.

In summary, tacrolimus is safe and well-tolerated and provides clinical benefit for elderly RA patients who have an insufficient response to DMARDs. A useful strategy in this patient group is to initiate tacrolimus treatment at 1.5 mg/day and increase the dose to 3 mg/day, while closely monitoring for the development of adverse events. It is recommended that caution be exercised when administering the drug to patients with impaired renal function and that dose reduction is considered in the event of an increase in serum creatinine.
Figure 1


   Acknowledgments
 
We thank the members of this study group as follows: Fuminori Hirano (Asahikawa Medical College, Hokkaido, Japan); Tadao Mitsui (Aichi Medical University, Aichi, Japan); Isao Hirose (Showa University School of Medicine, Fujigaska Hospital, Kanagawa, Japan); Naoto Mitsuki (Fujisawa City Hospital, Kanagawa, Japan); Hitoaki Okazaki (Jichi Medical School, Tochigi, Japan); Akira Murasawa (Niigata Prefectural Senami Hospital, Niigata, Japan); Hiroshi Inoue (Inoue Hospital, Gunma, Japan); Mikio Matsuura (Tokyo Metropolitan Fuchu Hospital, Tokyo, Japan); Isao Saikawa (Karatsu Red Cross Hospital, Saga, Japan); Reiji Masago (Seirei Hamamatsu General Hospital, Shizuoka, Japan); Seiji Tsuboi (Shizuoka Kousei Hospital, Shizuoka, Japan); Hiroyuki Fujioka (Kobe University Graduate School of Medicine, Hyogo, Japan); Kiyoshi Takasugi (Dohgo Spa Hospital, Ehime, Japan); Eiichi Suematsu (National Hospital Organization Kyushu Medical Center, Fukuoka, Japan); Jun Koide (Jiseikai/Kami-Itabashi Hospital, Tokyo, Japan); Shinichi Yoshino (Nippon Medical School, Tokyo, Japan); Shunsei Hirohata (Teikyo University School of Medicine, Tokyo, Japan); Tetsu Hosoi (Yamada Red Cross Hospital, Mie, Japan); Toru Suguro (Toho University School of Medical, Tokyo, Japan); Tomoyuki Hashimoto (Hakodate Central General Hospital, Hokkaido, Japan); Masahiro Yamamura (Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan); Michio Minami (Hokkaido Orthopedics Memorial Hospital, Hokkaido, Japan). This study was funded by a grant from Astellas Pharma, Tokyo, Japan (formerly Fujisawa Pharmaceutical, Osaka, Japan).

S.K. and K.Y. are medical/clinical consultants to Astellas Pharma, Tokyo, Japan (formerly Fujisawa Pharmaceutical, Osaka, Japan).


   References
Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

  1. Kino T, Hatanaka H, Miyata S et al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo) 1987;40:1256–65.[Medline]
  2. Kelly PA, Burckart GJ, Venkataramanan R. Tacrolimus: a new immunosuppressive agent. Am J Health Syst Pharm 1995;52:1569–71.[Medline]
  3. Kondo H, Abe T, Hashimoto H et al. Efficacy and safety of tacrolimus (FK506) in treatment of rheumatoid arthritis: a randomized, double blind, placebo controlled dose-finding study. J Rheumatol 2004;31:243–51.[Abstract/Free Full Text]
  4. Furst DE, Saag K, Fleischmann MR et al. Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study. Arthritis Rheum 2002;46:2020–8.[CrossRef][Medline]
  5. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.[Web of Science][Medline]
  6. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995;38:727–35.[Web of Science][Medline]
  7. Ishizaki T. Change of physiological function and pharmacokinetics with aging: change of pharmacodynamic reactions. J Integr Med 2003;13:914–20.
  8. Opelz G. Effect of immunosuppressive therapy on graft half-life projections. The Collaborative Transplant Study. Transplant Proc 1999;31:31S–33S.[Medline]
  9. Böttiger Y, Brattström C, Tyden G, Sawe J, Groth CG. Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients. Br J Clin Pharmacol 1999;48:445–8.[CrossRef][Web of Science][Medline]
  10. Yocum DE, Furst DE, Kaine JL et al. Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial. Arthritis Rheum 2003;48:3328–37.[CrossRef][Web of Science][Medline]
  11. Yocum DE, Furst DE, Bensen WG et al. Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience. Rheumatology 2004;43:992–9.[Abstract/Free Full Text]
Submitted 7 June 2005; revised version accepted 23 September 2005.
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