Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience
D. E. Yocum,
D. E. Furst1,
,
W. G. Bensen2,
F. X. Burch3,
M. A. Borton4,
L. J. Mengle-Gaw5,
B. D. Schwartz5,
W. Wisememandle3 and
Q. A. Mekki4 on behalf of the Tacrolimus RA Study Group
University of Arizona, Tucson, AZ, 1 Virginia Mason Research Center, Seattle, WA, USA, 2 St Joseph Hospital/McMaster University, Toronto, ON; Canada, 3 NorthEast San Antonio Rheumatology Associates, San Antonio, TX, 4 Fujisawa Healthcare, Inc., Deerfield, IL, 5 The Camden Group, St Louis, MO, USA.
Correspondence to: M. A. Borton. E-mail: mary_ann_borton{at}fujisawa.com
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Abstract
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Objective. To evaluate the long-term safety of tacrolimus 3 mg/day in patients with rheumatoid arthritis (RA).
Methods. Patients with active RA who had discontinued all DMARDs for at least 2 weeks and had at least five tender/painful joints and three swollen joints, and required DMARD treatment in the opinion of the investigator, were enrolled into this open-label long-term safety trial. In addition, patients who had completed at least 3 months of treatment with tacrolimus 2 mg/day, tacrolimus 3 mg/day or placebo in a Phase III double-blind efficacy trial were allowed to roll over into this study. This latter group of patients did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. All patients enrolled received tacrolimus 3 mg/day in addition to their current regimen of NSAIDs and corticosteroids.
Results. 896 patients received at least one dose of tacrolimus 3 mg. The median duration of treatment was 359 days. 145 patients (16.2%) withdrew from the study for adverse events possibly or probably related to tacrolimus, 33 patients (3.7%) withdrew from the study for adverse events unrelated to tacrolimus and 112 (12.5%) withdrew for lack of efficacy. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. 529 patients (59%) experienced an adverse event that was possibly or probably related to tacrolimus; the most common were diarrhoea (14.6%), nausea (10.3%), tremor (9.0%), headache (8.7%), abdominal pain (7.9%), dyspepsia (7.6%), increased creatinine (6.8%) and hypertension (5.4%). Twenty-four patients (2.7%) experienced serious adverse events possibly or probably related to study drug; the most common were pneumonia (0.6%), hyperglycaemia (0.3%), gastroenteritis (0.2%), pancreatitis (0.2%) and diabetes mellitus (0.2%). The mean creatinine level increased from 67±19 µmol/l (0.76±0.22 mg/dl) at baseline to 75±26 µmol/l (0.85±0.30 mg/dl) (P<0.0001) at end of treatment. 351 (40.3%) of the 872 patients for whom creatinine levels were available at both baseline and during treatment had
30% increase from baseline in serum creatinine during the study, either related or unrelated to tacrolimus, with 73 patients (8.4%) having creatinine levels exceeding the normal range. At end of treatment, 177 patients (20.3%) had a
30% increase from baseline in creatinine. Serum creatinine remained within the normal range throughout the trial in approximately 90% of patients. At the end of treatment, the ACR20, ACR50 and ACR70 response rates were 38.4%, 18.6% and 9.0% respectively. Over 26% of patients had at least a 70% improvement in both swollen and painful/tender joints.
Conclusion. This study demonstrates that tacrolimus was safe and well-tolerated and provided clinical benefit over a period of at least 12 months.
KEY WORDS: Rheumatoid arthritis, Tacrolimus, DMARD, Immunosuppressant, FK506, Prograf
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Introduction
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Rheumatoid arthritis (RA) is a chronic autoimmune disorder which requires early diagnosis and aggressive treatment to minimize the morbidity associated with its progression [1, 2]. Disease-modifying anti-rheumatic drugs (DMARDs) and biological modifiers have been used to accomplish these objectives [310]. A common prominent feature of these agents is their immunosuppressive properties.
Tacrolimus (Prograf®, FK506), an orally available macrolide calcineurin inhibitor, is an immunomodulatory and anti-inflammatory agent [1118]. It diminishes the ability of calcineurin to dephosphorylate and translocate the nuclear factor of activated T cells (NF-AT) that initiates gene transcription for the synthesis of inflammatory cytokines such as tumour necrosis factor-
(TNF-
), interleukin-2 (IL-2), and interferon-
(IFN-
). Because of these properties, tacrolimus is used to prevent rejection of organ transplants and has been studied as a treatment for RA. Recently, tacrolimus was reported to be safe and efficacious in a Phase II 6-month double-blind trial of RA patients who had failed methotrexate therapy [19], a Phase III 6-month double-blind efficacy study of tacrolimus as monotherapy in RA patients who had failed one or more DMARDs and a 6-month open-label safety trial of tacrolimus and methotrexate combination therapy in patients with RA who had had a partial response to methotrexate [20, 21]. Tacrolimus has a lower molecular weight and is 100-fold more potent in inhibiting T-cell proliferation than cyclosporin, another calcineurin inhibitor with documented efficacy in treating patients with RA [5, 18].
The open-label 12-month study reported here was undertaken to determine the long-term safety of tacrolimus as monotherapy in patients with RA.
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Methods
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Patients
The 12-month open-label long-term safety study began on 5 August 1999 and ended on 28 May 2002. It enrolled 896 patients at 82 sites in the United States and Canada. Eligible patients were at least 16 years of age, had rheumatoid arthritis by American College of Rheumatology (ACR) criteria [22] for at least 6 months, were ACR functional class IIII by revised criteria [23], and required DMARD treatment in the opinion of the investigator. Because this study was primarily designed to evaluate the long-term safety of tacrolimus with efficacy as a secondary objective, complete washout of previously used DMARDs was not required. Patients enrolling directly into the study had to be off all DMARDs (including leflunomide) only for a minimum of 2 weeks. Following the 2-week DMARD washout period, these patients had to have at least five tender/painful joints and three swollen joints at the time of study entry. Patients who had participated in the double-blind efficacy study [21] for at least 3 months and rolled over into the long-term safety study
did not have to fulfil any joint count requirements prior to entry into the long-term safety study, provided that no more than 14 days had elapsed between the end of their participation in the double-blind study and screening for the long-term safety study. Non-steroidal anti-inflammatory drugs (NSAIDs) and oral corticosteroids were allowed, with dose adjustments as determined by the investigator. In addition, intra- and peri-articular steroid injections were allowed without restriction, but the injected joints were excluded from all subsequent joint count assessments. Patients with moderate or severe liver disease, creatinine >1.5 times the upper limit of normal (ULN), haemoglobin <9.0 mg/dl, white blood cell (WBC) count <3000 cells/mm3, or platelet count <100 000 platelets/mm3 were excluded.
The institutional review board at each study site approved the protocol, and all patients gave written informed consent prior to any study-related procedures, consistent with the principles of the Declaration of Helsinki.
Study protocol
Patients participating in the long-term safety study were recruited from two populations: patients who enrolled directly into the study and patients who had participated in the double-blind RA efficacy study [21] for at least 3 months and were eligible to roll over into the long-term safety study. The 585 patients who directly enrolled in the long-term safety study and the 100 patients who received placebo in the double-blind efficacy study [21] comprised the de novo group of 685 patients. The 2 mg rollover group (103 patients) and 3 mg rollover group (108 patients) from the double-blind RA efficacy trial [21] had received tacrolimus 2 mg/day or tacrolimus 3 mg/day, respectively, for at least 3 months in that trial. All patients enrolled in the long-term safety study received tacrolimus 3 mg/day. Efficacy and safety were analysed on the basis of exposure to tacrolimus 3 mg/day; therefore, patients in the 3 mg rollover group who received the study drug could have had up to 18 months exposure to 3 mg/day of tacrolimus (up to 6 months in the double-blind efficacy trial [21] and up to 12 months in the long-term safety trial). All other patients had up to 12 months exposure to tacrolimus 3 mg/day. Safety assessments were performed at week 2 and at months 1, 2, 3, 4.5, 6, 7.5, 9, 10.5 and 12 and were based on physical examinations, the incidence of treatment-emergent adverse events and the results of clinical laboratory tests [with an emphasis on creatinine, blood urea nitrogen (BUN), glucose and haemoglobin A1C (HbA1c) because of the previous experience in transplant patients where tacrolimus use was associated with changes in these laboratory values]. Patients who exhibited an increase in serum creatinine of
40% from the baseline visit, or
30% from the previous visit, that was clinically significant in the investigator's opinion had the test repeated in 1 week, and if the elevation persisted, had the study drug withheld for up to 14 days. If the test remained elevated after the study drug was withheld, the patient was withdrawn from the study. The assignment of any abnormal laboratory parameter as an adverse event was left to the discretion of each investigator. A serious adverse event (SAE) was defined as an adverse event (AE) occurring at any dose that resulted in any of the following outcomes: death, life-threatening AE, persistent or significant disability or incapacity, in-patient hospitalization or prolongation of existing hospitalization, congenital abnormality or birth defect or an important medical event. Efficacy was assessed at months 3, 6, 9 and 12 using the ACR definitions of improvement (ACR20, ACR50 and ACR70 response) [24]. ACR20, ACR50 and ACR70 responses were defined as
20%,
50% and
70% improvement, respectively, in tender or painful joint count and swollen joint count, and
20%,
50% or
70% improvement, respectively, in three of the following five parameters: patient's assessment of pain on a 100-mm visual analogue scale (VAS), patient's global assessment of disease activity on a 100-mm VAS, physician's global assessment of disease activity on a 100-mm VAS, patient's assessment of physical function (based on the modified Health Assessment Questionnaire) and an acute-phase reactant [erythrocyte sedimentation rate (ESR) by the Westergren method or C-reactive protein (CRP)]. A Data Safety Monitoring Board (DSMB) monitored the study for issues which could impact upon the safety of patients.
Tacrolimus levels and modification of treatment
While trough levels of tacrolimus were monitored during the studies, they were not used for patient management. Tacrolimus was either held or discontinued based on treatment-emergent adverse events or a rise in creatinine levels.
Statistical analysis
Safety and efficacy analyses were performed on the full analysis set, consisting of all patients who received at least one dose of the study drug.
The primary efficacy endpoint was ACR20 response at the end of treatment. Secondary endpoints were ACR20, ACR50 and ACR70 response rates at months 3, 6, 9 and 12; ACR50 and ACR70 response rates at the end of treatment; and per cent change from baseline for the individual ACR components at the end of treatment. For patients who had been in the tacrolimus 2 mg and tacrolimus 3 mg groups in the double-blind efficacy study [21] and who had rolled over into the long-term safety study, change from baseline was calculated using the baseline evaluation in the double-blind efficacy study; for patients who had been in the placebo group in the double-blind efficacy study and who had rolled over into the long-term safety study, change from baseline was calculated using the baseline evaluation in the long-term safety study. Ninety per cent confidence intervals around the difference between baseline and treatment values were constructed for the primary and secondary endpoints. For serum creatinine and blood pressure, a single-sample t-test was used to assess whether the change from baseline to end of treatment was different from zero. Statistical significance was P<0.05.
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Results
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Demographics, baseline characteristics and disposition
896 patients received at least one dose of the study drug. The demographics and baseline characteristics are shown in Table 1. Of the 896 patients who received at least one dose of tacrolimus, 489 (54.6%) completed the study, 178 (19.9%) withdrew for an adverse event, 112 (12.5%) withdrew for lack of efficacy and 117 (13.1%) withdrew for administrative reasons (withdrawal of consent, non-compliance with protocol, discovery of pre-existing eligibility failure, loss to follow-up, moved away, withdrawn by the investigator, extreme stiffness and final visit conducted 1 month early) (Fig. 1). At baseline, 471 patients (52.6%) were taking corticosteroids at an average dose of 7.64 mg of prednisone or its equivalent, 723 patients (80.7%) were taking NSAIDs and 689 (76.9%) had been taking DMARDs during the previous 2 yr. The mean number of DMARDs taken by the study population at any time prior to the study was 1.58, with a range of 0 to 7. Fifty-four patients who had received 3 mg/day tacrolimus in the double-blind efficacy trial [21] and rolled over from that study completed a total of 18 months of 3 mg/day tacrolimus therapy. The median duration of treatment with 3 mg/day of tacrolimus for all patients was 359 days.
Safety
Overall, 651 patients had
6 months, 497 patients
12 months and 54 patients had 18 months of exposure to 3 mg/day tacrolimus, including up to 6 months of exposure in the double-blind efficacy trial. Median trough tacrolimus levels were approximately 2 to 3 ng/ml, and tacrolimus did not accumulate over the course of the study. Common (
5%) adverse events are listed in Table 2. The overall incidence of adverse events was similar in patients less than 65 years of age and
65 years of age. The first appearance of adverse events over time is shown in Table 3. No adverse event with an incidence >0.7% appeared for the first time after the first 3 months of treatment with 3 mg tacrolimus. The percentage of patients experiencing an adverse event of hypertension or increased creatinine was relatively constant after the initial 3-month period, and was approximately 12.5% for hypertension and 11.5% for increased creatinine. Common (
5%) adverse events considered possibly or probably related to tacrolimus were diarrhoea in 131 patients (14.6%), nausea in 92 patients (10.3%), tremor in 81 patients (9.0%), headache in 78 patients (8.7%), abdominal pain in 71 patients (7.9%), dyspepsia in 68 patients (7.6%), creatinine increased in 61 patients (6.8%) and hypertension in 48 patients (5.4%). 145 patients (16.2%) with an adverse event that was possibly or probably related to tacrolimus withdrew from the study. An additional 33 patients (3.7%) withdrew from the study for an adverse event that was unrelated to tacrolimus. Adverse events causing withdrawal, whether related or unrelated to tacrolimus, occurring in four or more patients are shown in Table 4.
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TABLE 4. Summary of treatment-emergent adverse events causing withdrawal in at least four patients who received at least one dose of the study drug
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A total of 108 patients (12.1%) experienced one or more treatment-emergent serious adverse events during the study period; 24 patients (2.7%) experienced one or more serious adverse event considered possibly or probably related to study drug (Table 5). One patient died during the study period. This patient had pneumonia, respiratory failure, sepsis and acute renal failure. The death was not considered to be related to the study drug.
91.6% of the 872 patients for whom creatinine data were available both at baseline and during treatment had creatinine levels below or within the normal range throughout the study. The mean (±S.D.) creatinine levels at baseline and at the end of treatment were 67±19 µmol/l (0.76±0.22 mg/dl) and 75±26 µmol/l (0.85±0.30 mg/dl) respectively for these 872 patients (P<0.0001). Maximum increases in creatinine of
30% from baseline at any time during treatment occurred in 351/872 (40.3%) of all patients, with the incidence of such increases decreasing to 20.3% (177/872) by the end of treatment (Table 6). Of those patients who experienced an increase from baseline in creatinine of
30%, 240/393 (61.1%) of patients had a documented subsequent return to baseline creatinine values, with a mean time to return of 52.8 days. (Additional patients may also have returned to baseline creatinine values, but, if so, their return was not documented.) Sixty-two patients had creatinine levels between 124 and 168 µmol/l (1.4 and 1.9 mg/dl) at any time during the study, and 11 patients had creatinine values of >168 µmol/l (>1.9 mg/dl); 10 of these latter 11 patients returned to creatinine levels of <168 µmol/l (<1.9 mg/dl) within 1 month post-treatment; the eleventh patient had the maximum creatinine level at the end of treatment and had no post-treatment creatinine value documented.
For all patients, the mean (±S.D.) systolic blood pressure was 128.5±16.8 mmHg at baseline and 129.7±17.5 mmHg at the end of treatment (P = 0.0796). The mean (±S.D.) diastolic blood pressure was 78.3±9.2 mmHg at baseline and 79.5±9.3 mmHg at the end of treatment (P = 0.0009). While statistically significant, this change in diastolic blood pressure was not considered clinically significant. Hypertension was reported as a treatment-emergent adverse event for 82 (9.2%) patients (42 patients with a history of hypertension and 40 patients with no history of hypertension). These events were considered possibly or probably related to tacrolimus for 27 (3.0%) patients.
Diabetes was reported as a treatment-emergent adverse event for nine patients with no previous history of diabetes, and was considered possibly related to tacrolimus for three (0.3%). Diabetes was also reported as an adverse event for seven patients with a previous history of diabetes, and was considered possibly related to tacrolimus in one (0.1%) and probably related in one (0.1%).
Tremor was experienced by 94 patients (10.5%), and was considered to be possibly or probably related to tacrolimus in 81 patients (9.0%). The majority of the tremors were mild or moderate in severity; three severe events were reported.
At some time during the study, 23 patients experienced a BUN >14.28 mmol/l (>40 mg/dl); 145 patients experienced an elevated glucose >84 mmol/l (>150 mg/dl) and 192 patients experienced an elevated HbA1C >0.065 (>6.5%).
Efficacy
The overall ACR20 response at the end of treatment was 38.4%. The ACR20 response was higher among patients who had previously received tacrolimus therapy in the double-blind study (46.4%) [21] than among the de novo patients (35.9%) (Table 7). ACR20, ACR50 and ACR70 response rates generally increased with time on treatment (Fig. 2). The overall ACR50 and ACR70 responses at the end of treatment for all patients were 18.6 and 9.0% respectively (Table 7).

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FIG. 2. ACR responders over the course of treatment for all patients: diamonds, ACR20; squares, ACR50; triangles, ACR70. Per cent ACR responders based on last observation carried forward (LOCF) analysis. Patients with no on-treatment efficacy evaluation were considered failures for calculating ACR response rates at all visits. The denominator for determining ACR responder rates at months 0, 3, 6, 9 and 12 is all patients enrolled in the long-term safety study who received the study drug (896 patients). The denominator for determining ACR responder rates at months 15 and 18 is patients who received tacrolimus 3 mg in the double-blind efficacy trial [21], and rolled over into the long-term safety study (108 patients).
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The percentage of patients achieving
20,
50 or
70% improvement in ACR component scores and the per cent change from baseline for individual ACR component scores at the end of treatment are shown in Table 8. The percentages were generally comparable between the de novo and rollover groups (data not shown). Of note, approximately 60% of patients achieved
20% improvement, approximately 40% of patients achieved
50% improvement and approximately 25% of patients achieved
70% improvement for swollen joint counts, tender/painful joint counts and the physician's global assessment of disease activity. Moreover, the largest per cent changes from baseline were seen for these three components. This pattern of greater response in these three parameters is consistent with the results of two double-blind efficacy studies and an open-label study [1921]. Despite the allowance of unlimited joint injections with corticosteriods, only 145 patients (16.2%) required joint injections during the study, further reinforcing the substantial improvement in joint counts. The percentages of patients achieving
20%,
50% and
70% improvement in most individual ACR responder components generally increased with time on treatment (data not shown).
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Discussion
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The 12-month open-label long-term safety study reported here demonstrates the safety and efficacy of tacrolimus as monotherapy for rheumatoid arthritis, with documented maintenance of the response for up to 18 months.
The adverse events seen were generally similar in nature to those that had previously been reported in trials of tacrolimus in patients who had received liver or kidney transplants [25]. However, the incidences of adverse events, including the adverse events of hypertension, tremor, diabetes and increased creatinine, previously identified as safety concerns with tacrolimus in transplant studies, were generally notably lower in the rheumatoid arthritis patients receiving 3 mg tacrolimus for up to 18 months than the incidences seen in transplant patients (9.2% vs. 3850%, 10.5% vs. 4856%, <5% vs. 24% and 7.4% vs. 2445% respectively) [25]. Moreover, a number of adverse events, including insomnia, paraesthesia, oliguria, hyperkalaemia, hypokalaemia, hyperglycaemia, hypomagnesaemia, hypophosphataemia, anaemia, and peripheral oedema, seen with an incidence of at least 15% in trials of tacrolimus in liver and/or kidney transplant patients, were seen in less than 5% of RA patients treated with tacrolimus. The lower incidence of these adverse events in the RA population is almost certainly the result of the lower dose used to treat rheumatoid arthritis (3 mg/day) than that needed to prevent transplant rejection (0.10.2 mg/kg/day). In addition, there was no increase in the initial incidence of adverse events seen with longer duration of treatment. Thus, tacrolimus appears to be generally well tolerated by RA patients, with the appearance of new treatment-emergent adverse events decreasing with time on treatment.
A comparison of the incidence of adverse events, including hypertension, tremor, abdominal pain and hypertrichosis, reported in RA patients treated with macrolide calcineurin inhibitors, demonstrates a generally similar or lower incidence in patients treated with 3 mg/day tacrolimus for up to 18 months in the tacrolimus study reported here (9.2%, 10.5%, 14.2% and 0% respectively) compared with patients treated with 2.55 mg/day cyclosporin for up to 6 months in four trials (825%, 713%, 15% and 1519% respectively) [26]. A comparison of the incidence of creatinine increased
30% from baseline in these same two populations of RA patients shows an incidence of 40% for tacrolimus in the trial reported here versus 3948% for cyclosporin [26]. For tacrolimus, however, it is important to note that despite the 40% incidence of
30% increase from baseline creatinine, approximately 90% of patients in the current tacrolimus study maintained creatinine levels below or within the normal range (44124 µmol/l) (0.51.4 mg/dl) throughout their participation in this study. Thus, while tacrolimus appears to possess at least as good a safety profile as cyclosporin in RA patients, both creatinine and blood pressure need to be routinely monitored for any RA patients treated with tacrolimus.
The efficacy results seen for all patients in this open-label study demonstrate that over 38% of patients achieved an ACR20, while 18.6 and 9% of patients respectively achieved an ACR50 and ACR70 with tacrolimus as monotherapy. Moreover, the responses were seen by 3 months and were maintained for as long as 18 months. In particular, for patients who received 3 mg tacrolimus in the double-blind efficacy study [21] and rolled over into the long-term safety study, the ACR20, ACR50 and ACR70 response rates at the month 18 visit at the end of the long-term study were 46.3%, 20.4% and 15.7% respectively, underscoring that the responses were maintained over time. It is noteworthy that while only approximately 40% of patients achieved
20% in the subjective measures of patient's assessment of pain, patients global assessment of disease activity and the mHAQ, approximately 60% of patients achieved at least
20% improvement in the ACR components of tender and swollen joints and physician's global assessment. In addition, in contrast to cyclosporin, which does not elicit improvement in ESR [5, 27], tacrolimus treatment resulted in an improvement in both CRP and ESR. No radiographic data were available for this study to allow assessment of structural damage. Although ACR responder rates with tacrolimus may not be as robust as those observed in other recent RA studies [710], patients who do respond appear to respond well.
In summary, tacrolimus at 3 mg/day as monotherapy was safe and well-tolerated for up to 18 months in patients with RA. The incidence of known macrolide calcineurin inhibitor-associated adverse events previously identified in trials of tacrolimus for the prophylaxis of transplant rejection generally occurred at notably lower rates than in the studies of tacrolimus in transplant patients, and at lower rates than in the studies of cyclosporin in RA patients. ACR response rates were maintained for up to 18 months, the longest time a patient could have been exposed to 3 mg/day in combined tacrolimus studies. For patients who respond to tacrolimus, tacrolimus is an effective and well-tolerated oral therapy for RA.
L. J. Mengle-Gaw and B. D. Schwartz are medical/clinical consultants to Fujisawa Healthcare, Inc. W. Wisemandle, Q. A. Mekki and M. A. Borton are employed by Fujisawa Healthcare, Inc.
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Acknowledgments
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This study was funded by a grant from Fujisawa Healthcare, Inc, Deerfield, IL.
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Notes
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Present address: UCLA, Los Angeles, CA, USA. 
Tacrolimus RA Study Group: Victor Arboleda, MD (Clearwater, FL); Andrew Baldassare, MD (St Louis, MO); Herbert S. B. Baraf, MD (Wheaton, MD); Richard K. Bath, MD (Cincinnati, OH); Scott Baumgartner, MD (Spokane, WA); Gary E. Bayliss, MD (Salem, VA); William G. Bensen, MD (Hamilton, Ontario, Canada); Joel A. Block, MD (Chicago, IL); Eugene Boling, MD (Upland, CA); Stephen A. Bookbinder, MD (Ocala, FL); Jeffrey E. Booth, MD (Sandy, UT); Alan Brodsky, MD (Dallas, TX); Francis X. Burch, MD (San Antonio, FL); Jacques Caldwell, MD (Daytona Beach, FL); Andrew Chalmers; MD (Vancouver, British Columbia, Canada); Alfred Cividino, MD (Hamilton, Ontario, Canada); Stanley Cohen, MD (Dallas, TX); Robert Deaver Collins, Jr, MD (Jackson, MS); John J. Condemi, MD (Rochester, NY); Atul Deodhar, MD (Portland, OR), Charles Derus, MD (Aurora, IL); Frederick Dietz, MD (Rockford, IL); John E. Ervin, MD (Kansas City, MO); Luis R. Espinoza, MD (New Orleans, LA); Robert Emil Ettlinger, MD (Tacoma, WA); John J. Fahey, MD (Milwaukee, WI); Pamela G. Freeman, MD (Orlando, FL); Daniel E. Furst, MD
(Seattle, WA); Barry Getzoff, DO (Philadelphia, PA); Geoffrey S. Gladstein, MD (Stamford, CT); Oscar S. Gluck, MD (Phoenix, AZ); Marc A. Goldberg, MD (Passaic, NJ); Allan Goldman, MD (Milwaukee, WI); Warren E. Greth, MD (West Reading, PA); Barry Gruber, MD (East Setauket, NY); Joseph Habros, MD (Scottsdale, AZ); E. Robert Harris, MD (Whittier, CA); David Helfrich, MD (Pittsburgh, PA); Gerald Yount Ho, MD (Anaheim, CA); Michele Hooper, MD (Beachwood, OH); Eric R. Hurd, MD (Dallas, TX); Richard Hymowitz, MD (Medford, NJ); Thomas Irvin, MD (Tacoma, WA); Christopher G. Jackson, MD (Salt Lake City, UT); Leslie W. Jackson, MD (Tacoma, WA); Jeffrey Kaine, MD (Sarasota, FL); Joji Kappes, MD (Portland, OR); Edward Keystone, MD (Toronto, Ontario, Canada); Alan J. Kivitz, MD (Duncansville, PA); Karen S. Kolba, MD (Santa Maria, CA); Tom Matthew Kovaleski, MD (Little Rock, AR); Gunnar Kraag, MD (Ottawa, Ontario, Canada); Bryan G. Laura, MD (Evansville, IN); Richard L. Lautzenheiser, MD (Indianapolis, IN); John L. Lawson, MD (Washington, DC); George Chau-Chen Liang, MD (Chicago, IL); Jeffrey D. Lieberman, MD (Decatur, GA); Mitchell B. Lowenstein, MD (Palm Harbor, FL); William Makarowski, MD (Erie, PA); David Mandel, MD (Mayfield Village, OH); James I. McMillen, MD (Camp Hill, PA); Jerry Allen Molitor, MD, PhD (Seattle, WA); Michael J. Noss, MD (Cincinnati, OH); Howard L. Offenburg, MD (Gainesville, FL); Douglas C. Owens, MD (Greer, SC); Jeffrey S. Peller, MD (Rome, GA); Charles Pritchard, MD (Willow Grove, PA); Louis Ricca, MD (St Petersburg, FL); Daniel H. Rosler, MD (Milwaukee, WI); Joel Rutstein, MD (San Antonio, TX); Marshall R. Sack, MD (Austin, TX); P. Anthony Saway, MD (Birmingham, AL); Michael Schweitz, MD (West Palm Beach, FL); Yvonne Sherrer, MD (Ft Lauderdale, FL); James Kenneth Smith, Jr, MD (Portland, OR); David G. Stainbrook, Jr, DO (Columbus, OH).; Jon T. Stevenson, MD (Spokane, WA); Kyle W. Strader, MD (Raleigh, NC); Din-On Sun, DO (Orlando, FL); James D. Taborn, MD (Kalamazoo, MI); Nehemiah T. Tan, MD (Decatur, IL); Elizabeth Tindall, MD (Portland, OR); Daniel Wallace, MD (Los Angeles, CA); Nathan Wei, MD (Frederick, MD); Craig Wiesenhutter, MD (Coeur dAlene, ID); David E. Yocum, MD (Tucson, AZ). 
Patients eligible for the double-blind efficacy study had to be at least 16 years of age, have rheumatoid arthritis by ACR criteria for at least 6 months, be ACR functional class IIII by revised criteria, have demonstrated, in the opinion of the investigator, either resistance to or intolerance of one or more DMARDs (DMARD resistance was defined as continued active rheumatoid arthritis despite receiving a therapeutic dose of a specific DMARD for a duration of time typically sufficient to elicit a therapeutic response; DMARD intolerance was defined as the inability or unwillingness of the patient to continue therapy due to an adverse drug experience), be off all DMARDs for at least 4 to 12 weeks (dependent on the DMARD), and, following the DMARD washout, have at least 10 tender/painful joints and seven swollen joints at study entry, with no more than 30% variance in the tender/painful joint count from 1 week prior to study entry. Concomitant therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and oral corticosteroids (
10 mg/day of prednisone or its equivalent) was permitted, provided that NSAID doses were stable for at least 2 weeks, and oral corticosteroid doses were stable for at least 4 weeks prior to study entry, and that these doses were continued throughout the study. 
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Submitted 29 September 2003;
revised version accepted 14 January 2004.