Rheumatology Advance Access originally published online on March 10, 2004
Rheumatology 2004 43(8):992-999; doi:10.1093/rheumatology/keh155
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Rheumatology Vol. 43 No. 8 © British Society for Rheumatology 2004; all rights reserved
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Safety of tacrolimus in patients with rheumatoid arthritis: long-term experience
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
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
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 d’Alene, 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 I–III 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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