Safety of tacrolimus in patients with rheumatoid arthritis

Long-term experience

David E. Yocum, Daniel E. Furst, William G. Bensen, Francis X. Burch, Mary Ann Borton, L. J. Mengle-Gaw, B. D. Schwartz, W. Wisememandle, Q. A. Mekki, Victor Arboleda, Andrew Baldassare, Herbert S B Baraf, Richard K. Bath, Scott Baumgartner, Gary E. Bayliss, William G. Bensen, Joel A. Block, Eugene Boling, Stephen A. Bookbinder, Jeffrey E. Booth & 75 others Alan Brodsky, Francis X. Burch, Jacques Caldwell, Andrew Chalmers, Alfred Cividino, Stanley Cohen, Robert Deaver Collins, John J. Condemi, Atulya (Atul) Deodhar, Charles Derus, Frederick Dietz, John E. Ervin, Luis R. Espinoza, Robert Emil Ettlinger, John J. Fahey, Pamela G. Freeman, Daniel E. Furst, Barry Getzoff, Geoffrey S. Gladstein, Oscar S. Gluck, Marc A. Goldberg, Allan Goldman, Warren E. Greth, Barry Gruber, Joseph Habros, E. Robert Harris, David Helfrich, Gerald Yount Ho, Michele Hooper, Eric R. Hurd, Richard Hymowitz, Thomas Irvin, Christopher G. Jackson, Leslie W. Jackson, Jeffrey Kaine, Joji Kappes, Edward Keystone, Alan J. Kivitz, Karen S. Kolba, Tom Matthew Kovaleski, Gunnar Kraag, Bryan G. Laura, Richard L. Lautzenheiser, John L. Lawson, George Chau Chen Liang, Jeffrey D. Lieberman, Mitchell B. Lowenstein, William Makarowski, David Mandel, James I. McMillen, Jerry Allen Molitor, Michael J. Noss, Howard L. Offenburg, Douglas C. Owens, Jeffrey S. Peller, Charles Pritchard, Louis Ricca, Daniel H. Rosler, Joel Rutstein, Marshall R. Sack, P. Anthony Saway, Michael Schweitz, Yvonne Sherrer, James Kenneth Smith, David G. Stainbrook, Jon T. Stevenson, Kyle W. Strader, Din On Sun, James D. Taborn, Nehemiah T. Tan, Elizabeth Tindall, Daniel Wallace, Nathan Wei, Craig Wiesenhutter, David E. Yocum

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

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 openlabel 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 inio this study. This latter group of patients did not have td 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 longterm 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 ± 030 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.

Original languageEnglish (US)
Pages (from-to)992-999
Number of pages8
JournalRheumatology
Volume43
Issue number8
DOIs
StatePublished - Aug 2004
Externally publishedYes

Fingerprint

Tacrolimus
Rheumatoid Arthritis
Safety
Creatinine
Joints
Antirheumatic Agents
Therapeutics
Reference Values
Dyspepsia
Gastroenteritis
Tremor
Non-Steroidal Anti-Inflammatory Agents
Serum
Double-Blind Method
Hyperglycemia
Pancreatitis
Nausea
Abdominal Pain
Headache
Diarrhea

Keywords

  • DMARD
  • FK506
  • Immunosuppressant
  • Prograf
  • Rheumatoid arthritis
  • Tacrolimus

ASJC Scopus subject areas

  • Neuroscience(all)
  • Rheumatology

Cite this

Yocum, D. E., Furst, D. E., Bensen, W. G., Burch, F. X., Borton, M. A., Mengle-Gaw, L. J., ... Yocum, D. E. (2004). Safety of tacrolimus in patients with rheumatoid arthritis: Long-term experience. Rheumatology, 43(8), 992-999. https://doi.org/10.1093/rheumatology/keh155

Safety of tacrolimus in patients with rheumatoid arthritis : Long-term experience. / Yocum, David E.; Furst, Daniel E.; Bensen, William G.; Burch, Francis X.; Borton, Mary Ann; Mengle-Gaw, L. J.; Schwartz, B. D.; Wisememandle, W.; Mekki, Q. A.; Arboleda, Victor; Baldassare, Andrew; Baraf, Herbert S B; Bath, Richard K.; Baumgartner, Scott; Bayliss, Gary E.; Bensen, William G.; Block, Joel A.; Boling, Eugene; Bookbinder, Stephen A.; Booth, Jeffrey E.; Brodsky, Alan; Burch, Francis X.; Caldwell, Jacques; Chalmers, Andrew; Cividino, Alfred; Cohen, Stanley; Collins, Robert Deaver; Condemi, John J.; Deodhar, Atulya (Atul); Derus, Charles; Dietz, Frederick; Ervin, John E.; Espinoza, Luis R.; Ettlinger, Robert Emil; Fahey, John J.; Freeman, Pamela G.; Furst, Daniel E.; Getzoff, Barry; Gladstein, Geoffrey S.; Gluck, Oscar S.; Goldberg, Marc A.; Goldman, Allan; Greth, Warren E.; Gruber, Barry; Habros, Joseph; Harris, E. Robert; Helfrich, David; Ho, Gerald Yount; Hooper, Michele; Hurd, Eric R.; Hymowitz, Richard; Irvin, Thomas; Jackson, Christopher G.; Jackson, Leslie W.; Kaine, Jeffrey; Kappes, Joji; Keystone, Edward; Kivitz, Alan J.; Kolba, Karen S.; Kovaleski, Tom Matthew; Kraag, Gunnar; Laura, Bryan G.; Lautzenheiser, Richard L.; Lawson, John L.; Liang, George Chau Chen; Lieberman, Jeffrey D.; Lowenstein, Mitchell B.; Makarowski, William; Mandel, David; McMillen, James I.; Molitor, Jerry Allen; Noss, Michael J.; Offenburg, Howard L.; Owens, Douglas C.; Peller, Jeffrey S.; Pritchard, Charles; Ricca, Louis; Rosler, Daniel H.; Rutstein, Joel; Sack, Marshall R.; Saway, P. Anthony; Schweitz, Michael; Sherrer, Yvonne; Smith, James Kenneth; Stainbrook, David G.; Stevenson, Jon T.; Strader, Kyle W.; Sun, Din On; Taborn, James D.; Tan, Nehemiah T.; Tindall, Elizabeth; Wallace, Daniel; Wei, Nathan; Wiesenhutter, Craig; Yocum, David E.

In: Rheumatology, Vol. 43, No. 8, 08.2004, p. 992-999.

Research output: Contribution to journalArticle

Yocum, DE, Furst, DE, Bensen, WG, Burch, FX, Borton, MA, Mengle-Gaw, LJ, Schwartz, BD, Wisememandle, W, Mekki, QA, Arboleda, V, Baldassare, A, Baraf, HSB, Bath, RK, Baumgartner, S, Bayliss, GE, Bensen, WG, Block, JA, Boling, E, Bookbinder, SA, Booth, JE, Brodsky, A, Burch, FX, Caldwell, J, Chalmers, A, Cividino, A, Cohen, S, Collins, RD, Condemi, JJ, Deodhar, AA, Derus, C, Dietz, F, Ervin, JE, Espinoza, LR, Ettlinger, RE, Fahey, JJ, Freeman, PG, Furst, DE, Getzoff, B, Gladstein, GS, Gluck, OS, Goldberg, MA, Goldman, A, Greth, WE, Gruber, B, Habros, J, Harris, ER, Helfrich, D, Ho, GY, Hooper, M, Hurd, ER, Hymowitz, R, Irvin, T, Jackson, CG, Jackson, LW, Kaine, J, Kappes, J, Keystone, E, Kivitz, AJ, Kolba, KS, Kovaleski, TM, Kraag, G, Laura, BG, Lautzenheiser, RL, Lawson, JL, Liang, GCC, Lieberman, JD, Lowenstein, MB, Makarowski, W, Mandel, D, McMillen, JI, Molitor, JA, Noss, MJ, Offenburg, HL, Owens, DC, Peller, JS, Pritchard, C, Ricca, L, Rosler, DH, Rutstein, J, Sack, MR, Saway, PA, Schweitz, M, Sherrer, Y, Smith, JK, Stainbrook, DG, Stevenson, JT, Strader, KW, Sun, DO, Taborn, JD, Tan, NT, Tindall, E, Wallace, D, Wei, N, Wiesenhutter, C & Yocum, DE 2004, 'Safety of tacrolimus in patients with rheumatoid arthritis: Long-term experience', Rheumatology, vol. 43, no. 8, pp. 992-999. https://doi.org/10.1093/rheumatology/keh155
Yocum DE, Furst DE, Bensen WG, Burch FX, Borton MA, Mengle-Gaw LJ et al. Safety of tacrolimus in patients with rheumatoid arthritis: Long-term experience. Rheumatology. 2004 Aug;43(8):992-999. https://doi.org/10.1093/rheumatology/keh155
Yocum, David E. ; Furst, Daniel E. ; Bensen, William G. ; Burch, Francis X. ; Borton, Mary Ann ; Mengle-Gaw, L. J. ; Schwartz, B. D. ; Wisememandle, W. ; Mekki, Q. A. ; Arboleda, Victor ; Baldassare, Andrew ; Baraf, Herbert S B ; Bath, Richard K. ; Baumgartner, Scott ; Bayliss, Gary E. ; Bensen, William G. ; Block, Joel A. ; Boling, Eugene ; Bookbinder, Stephen A. ; Booth, Jeffrey E. ; Brodsky, Alan ; Burch, Francis X. ; Caldwell, Jacques ; Chalmers, Andrew ; Cividino, Alfred ; Cohen, Stanley ; Collins, Robert Deaver ; Condemi, John J. ; Deodhar, Atulya (Atul) ; Derus, Charles ; Dietz, Frederick ; Ervin, John E. ; Espinoza, Luis R. ; Ettlinger, Robert Emil ; Fahey, John J. ; Freeman, Pamela G. ; Furst, Daniel E. ; Getzoff, Barry ; Gladstein, Geoffrey S. ; Gluck, Oscar S. ; Goldberg, Marc A. ; Goldman, Allan ; Greth, Warren E. ; Gruber, Barry ; Habros, Joseph ; Harris, E. Robert ; Helfrich, David ; Ho, Gerald Yount ; Hooper, Michele ; Hurd, Eric R. ; Hymowitz, Richard ; Irvin, Thomas ; Jackson, Christopher G. ; Jackson, Leslie W. ; Kaine, Jeffrey ; Kappes, Joji ; Keystone, Edward ; Kivitz, Alan J. ; Kolba, Karen S. ; Kovaleski, Tom Matthew ; Kraag, Gunnar ; Laura, Bryan G. ; Lautzenheiser, Richard L. ; Lawson, John L. ; Liang, George Chau Chen ; Lieberman, Jeffrey D. ; Lowenstein, Mitchell B. ; Makarowski, William ; Mandel, David ; McMillen, James I. ; Molitor, Jerry Allen ; Noss, Michael J. ; Offenburg, Howard L. ; Owens, Douglas C. ; Peller, Jeffrey S. ; Pritchard, Charles ; Ricca, Louis ; Rosler, Daniel H. ; Rutstein, Joel ; Sack, Marshall R. ; Saway, P. Anthony ; Schweitz, Michael ; Sherrer, Yvonne ; Smith, James Kenneth ; Stainbrook, David G. ; Stevenson, Jon T. ; Strader, Kyle W. ; Sun, Din On ; Taborn, James D. ; Tan, Nehemiah T. ; Tindall, Elizabeth ; Wallace, Daniel ; Wei, Nathan ; Wiesenhutter, Craig ; Yocum, David E. / Safety of tacrolimus in patients with rheumatoid arthritis : Long-term experience. In: Rheumatology. 2004 ; Vol. 43, No. 8. pp. 992-999.
@article{dd39d5dc831b4a6bb83903227f482eeb,
title = "Safety of tacrolimus in patients with rheumatoid arthritis: Long-term experience",
abstract = "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 openlabel 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 inio this study. This latter group of patients did not have td 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 longterm 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 ± 030 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.",
keywords = "DMARD, FK506, Immunosuppressant, Prograf, Rheumatoid arthritis, Tacrolimus",
author = "Yocum, {David E.} and Furst, {Daniel E.} and Bensen, {William G.} and Burch, {Francis X.} and Borton, {Mary Ann} and Mengle-Gaw, {L. J.} and Schwartz, {B. D.} and W. Wisememandle and Mekki, {Q. A.} and Victor Arboleda and Andrew Baldassare and Baraf, {Herbert S B} and Bath, {Richard K.} and Scott Baumgartner and Bayliss, {Gary E.} and Bensen, {William G.} and Block, {Joel A.} and Eugene Boling and Bookbinder, {Stephen A.} and Booth, {Jeffrey E.} and Alan Brodsky and Burch, {Francis X.} and Jacques Caldwell and Andrew Chalmers and Alfred Cividino and Stanley Cohen and Collins, {Robert Deaver} and Condemi, {John J.} and Deodhar, {Atulya (Atul)} and Charles Derus and Frederick Dietz and Ervin, {John E.} and Espinoza, {Luis R.} and Ettlinger, {Robert Emil} and Fahey, {John J.} and Freeman, {Pamela G.} and Furst, {Daniel E.} and Barry Getzoff and Gladstein, {Geoffrey S.} and Gluck, {Oscar S.} and Goldberg, {Marc A.} and Allan Goldman and Greth, {Warren E.} and Barry Gruber and Joseph Habros and Harris, {E. Robert} and David Helfrich and Ho, {Gerald Yount} and Michele Hooper and Hurd, {Eric R.} and Richard Hymowitz and Thomas Irvin and Jackson, {Christopher G.} and Jackson, {Leslie W.} and Jeffrey Kaine and Joji Kappes and Edward Keystone and Kivitz, {Alan J.} and Kolba, {Karen S.} and Kovaleski, {Tom Matthew} and Gunnar Kraag and Laura, {Bryan G.} and Lautzenheiser, {Richard L.} and Lawson, {John L.} and Liang, {George Chau Chen} and Lieberman, {Jeffrey D.} and Lowenstein, {Mitchell B.} and William Makarowski and David Mandel and McMillen, {James I.} and Molitor, {Jerry Allen} and Noss, {Michael J.} and Offenburg, {Howard L.} and Owens, {Douglas C.} and Peller, {Jeffrey S.} and Charles Pritchard and Louis Ricca and Rosler, {Daniel H.} and Joel Rutstein and Sack, {Marshall R.} and Saway, {P. Anthony} and Michael Schweitz and Yvonne Sherrer and Smith, {James Kenneth} and Stainbrook, {David G.} and Stevenson, {Jon T.} and Strader, {Kyle W.} and Sun, {Din On} and Taborn, {James D.} and Tan, {Nehemiah T.} and Elizabeth Tindall and Daniel Wallace and Nathan Wei and Craig Wiesenhutter and Yocum, {David E.}",
year = "2004",
month = "8",
doi = "10.1093/rheumatology/keh155",
language = "English (US)",
volume = "43",
pages = "992--999",
journal = "Rheumatology (United Kingdom)",
issn = "1462-0324",
publisher = "Oxford University Press",
number = "8",

}

TY - JOUR

T1 - Safety of tacrolimus in patients with rheumatoid arthritis

T2 - Long-term experience

AU - Yocum, David E.

AU - Furst, Daniel E.

AU - Bensen, William G.

AU - Burch, Francis X.

AU - Borton, Mary Ann

AU - Mengle-Gaw, L. J.

AU - Schwartz, B. D.

AU - Wisememandle, W.

AU - Mekki, Q. A.

AU - Arboleda, Victor

AU - Baldassare, Andrew

AU - Baraf, Herbert S B

AU - Bath, Richard K.

AU - Baumgartner, Scott

AU - Bayliss, Gary E.

AU - Bensen, William G.

AU - Block, Joel A.

AU - Boling, Eugene

AU - Bookbinder, Stephen A.

AU - Booth, Jeffrey E.

AU - Brodsky, Alan

AU - Burch, Francis X.

AU - Caldwell, Jacques

AU - Chalmers, Andrew

AU - Cividino, Alfred

AU - Cohen, Stanley

AU - Collins, Robert Deaver

AU - Condemi, John J.

AU - Deodhar, Atulya (Atul)

AU - Derus, Charles

AU - Dietz, Frederick

AU - Ervin, John E.

AU - Espinoza, Luis R.

AU - Ettlinger, Robert Emil

AU - Fahey, John J.

AU - Freeman, Pamela G.

AU - Furst, Daniel E.

AU - Getzoff, Barry

AU - Gladstein, Geoffrey S.

AU - Gluck, Oscar S.

AU - Goldberg, Marc A.

AU - Goldman, Allan

AU - Greth, Warren E.

AU - Gruber, Barry

AU - Habros, Joseph

AU - Harris, E. Robert

AU - Helfrich, David

AU - Ho, Gerald Yount

AU - Hooper, Michele

AU - Hurd, Eric R.

AU - Hymowitz, Richard

AU - Irvin, Thomas

AU - Jackson, Christopher G.

AU - Jackson, Leslie W.

AU - Kaine, Jeffrey

AU - Kappes, Joji

AU - Keystone, Edward

AU - Kivitz, Alan J.

AU - Kolba, Karen S.

AU - Kovaleski, Tom Matthew

AU - Kraag, Gunnar

AU - Laura, Bryan G.

AU - Lautzenheiser, Richard L.

AU - Lawson, John L.

AU - Liang, George Chau Chen

AU - Lieberman, Jeffrey D.

AU - Lowenstein, Mitchell B.

AU - Makarowski, William

AU - Mandel, David

AU - McMillen, James I.

AU - Molitor, Jerry Allen

AU - Noss, Michael J.

AU - Offenburg, Howard L.

AU - Owens, Douglas C.

AU - Peller, Jeffrey S.

AU - Pritchard, Charles

AU - Ricca, Louis

AU - Rosler, Daniel H.

AU - Rutstein, Joel

AU - Sack, Marshall R.

AU - Saway, P. Anthony

AU - Schweitz, Michael

AU - Sherrer, Yvonne

AU - Smith, James Kenneth

AU - Stainbrook, David G.

AU - Stevenson, Jon T.

AU - Strader, Kyle W.

AU - Sun, Din On

AU - Taborn, James D.

AU - Tan, Nehemiah T.

AU - Tindall, Elizabeth

AU - Wallace, Daniel

AU - Wei, Nathan

AU - Wiesenhutter, Craig

AU - Yocum, David E.

PY - 2004/8

Y1 - 2004/8

N2 - 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 openlabel 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 inio this study. This latter group of patients did not have td 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 longterm 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 ± 030 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.

AB - 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 openlabel 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 inio this study. This latter group of patients did not have td 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 longterm 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 ± 030 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.

KW - DMARD

KW - FK506

KW - Immunosuppressant

KW - Prograf

KW - Rheumatoid arthritis

KW - Tacrolimus

UR - http://www.scopus.com/inward/record.url?scp=4344656186&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4344656186&partnerID=8YFLogxK

U2 - 10.1093/rheumatology/keh155

DO - 10.1093/rheumatology/keh155

M3 - Article

VL - 43

SP - 992

EP - 999

JO - Rheumatology (United Kingdom)

JF - Rheumatology (United Kingdom)

SN - 1462-0324

IS - 8

ER -