Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: A randomized, double-blind, placebo-controlled trial

Joel M. Kremer, Mark C. Genovese, Grant W. Cannon, Jacques R. Caldwell, John J. Cush, Daniel E. Furst, Michael E. Luggen, Ed Keystone, Michael H. Weisman, William M. Bensen, Jeffrey L. Kaine, Eric M. Ruderman, Patricia Coleman, David L. Curtis, Elliot J. Kopp, Seth M. Kantor, Jonathan Waltuck, Herbert B. Lindsley, Joseph A. Markenson, Vibeke StrandBruce Crawford, Indra Fernando, Karen Simpson, Joan M. Bathon

Research output: Contribution to journalArticle

298 Citations (Scopus)

Abstract

Background: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. Objective: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. Design: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. Setting: 20 centers in the United States and Canada. Patients: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. Intervention: Leflunomide or matching placebo added to existing methotrexate therapy. Measurements: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. Results: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. Conclusions: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

Original languageEnglish (US)
Pages (from-to)726-733
Number of pages8
JournalAnnals of internal medicine
Volume137
Issue number9
DOIs
StatePublished - Nov 5 2002
Externally publishedYes

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leflunomide
Methotrexate
Rheumatoid Arthritis
Placebos
Therapeutics
Antimetabolites
Antirheumatic Agents
Rheumatology
Canada

ASJC Scopus subject areas

  • Internal Medicine

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Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate : A randomized, double-blind, placebo-controlled trial. / Kremer, Joel M.; Genovese, Mark C.; Cannon, Grant W.; Caldwell, Jacques R.; Cush, John J.; Furst, Daniel E.; Luggen, Michael E.; Keystone, Ed; Weisman, Michael H.; Bensen, William M.; Kaine, Jeffrey L.; Ruderman, Eric M.; Coleman, Patricia; Curtis, David L.; Kopp, Elliot J.; Kantor, Seth M.; Waltuck, Jonathan; Lindsley, Herbert B.; Markenson, Joseph A.; Strand, Vibeke; Crawford, Bruce; Fernando, Indra; Simpson, Karen; Bathon, Joan M.

In: Annals of internal medicine, Vol. 137, No. 9, 05.11.2002, p. 726-733.

Research output: Contribution to journalArticle

Kremer, JM, Genovese, MC, Cannon, GW, Caldwell, JR, Cush, JJ, Furst, DE, Luggen, ME, Keystone, E, Weisman, MH, Bensen, WM, Kaine, JL, Ruderman, EM, Coleman, P, Curtis, DL, Kopp, EJ, Kantor, SM, Waltuck, J, Lindsley, HB, Markenson, JA, Strand, V, Crawford, B, Fernando, I, Simpson, K & Bathon, JM 2002, 'Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate: A randomized, double-blind, placebo-controlled trial', Annals of internal medicine, vol. 137, no. 9, pp. 726-733. https://doi.org/10.7326/0003-4819-137-9-200211050-00007
Kremer, Joel M. ; Genovese, Mark C. ; Cannon, Grant W. ; Caldwell, Jacques R. ; Cush, John J. ; Furst, Daniel E. ; Luggen, Michael E. ; Keystone, Ed ; Weisman, Michael H. ; Bensen, William M. ; Kaine, Jeffrey L. ; Ruderman, Eric M. ; Coleman, Patricia ; Curtis, David L. ; Kopp, Elliot J. ; Kantor, Seth M. ; Waltuck, Jonathan ; Lindsley, Herbert B. ; Markenson, Joseph A. ; Strand, Vibeke ; Crawford, Bruce ; Fernando, Indra ; Simpson, Karen ; Bathon, Joan M. / Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate : A randomized, double-blind, placebo-controlled trial. In: Annals of internal medicine. 2002 ; Vol. 137, No. 9. pp. 726-733.
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abstract = "Background: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. Objective: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. Design: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. Setting: 20 centers in the United States and Canada. Patients: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. Intervention: Leflunomide or matching placebo added to existing methotrexate therapy. Measurements: The primary efficacy variable was the rate of achievement of 20{\%} improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. Results: In the leflunomide and placebo groups, 46.2{\%} and 19.5{\%} of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1{\%} in the leflunomide group and 24.8{\%} in the placebo group), as were the overall incidences of adverse events (89.2{\%} vs. 89.5{\%}, respectively). Adverse events were predominantly mild or moderate. Conclusions: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.",
author = "Kremer, {Joel M.} and Genovese, {Mark C.} and Cannon, {Grant W.} and Caldwell, {Jacques R.} and Cush, {John J.} and Furst, {Daniel E.} and Luggen, {Michael E.} and Ed Keystone and Weisman, {Michael H.} and Bensen, {William M.} and Kaine, {Jeffrey L.} and Ruderman, {Eric M.} and Patricia Coleman and Curtis, {David L.} and Kopp, {Elliot J.} and Kantor, {Seth M.} and Jonathan Waltuck and Lindsley, {Herbert B.} and Markenson, {Joseph A.} and Vibeke Strand and Bruce Crawford and Indra Fernando and Karen Simpson and Bathon, {Joan M.}",
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T1 - Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate

T2 - A randomized, double-blind, placebo-controlled trial

AU - Kremer, Joel M.

AU - Genovese, Mark C.

AU - Cannon, Grant W.

AU - Caldwell, Jacques R.

AU - Cush, John J.

AU - Furst, Daniel E.

AU - Luggen, Michael E.

AU - Keystone, Ed

AU - Weisman, Michael H.

AU - Bensen, William M.

AU - Kaine, Jeffrey L.

AU - Ruderman, Eric M.

AU - Coleman, Patricia

AU - Curtis, David L.

AU - Kopp, Elliot J.

AU - Kantor, Seth M.

AU - Waltuck, Jonathan

AU - Lindsley, Herbert B.

AU - Markenson, Joseph A.

AU - Strand, Vibeke

AU - Crawford, Bruce

AU - Fernando, Indra

AU - Simpson, Karen

AU - Bathon, Joan M.

PY - 2002/11/5

Y1 - 2002/11/5

N2 - Background: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. Objective: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. Design: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. Setting: 20 centers in the United States and Canada. Patients: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. Intervention: Leflunomide or matching placebo added to existing methotrexate therapy. Measurements: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. Results: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. Conclusions: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

AB - Background: Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate. Objective: To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis. Design: 24-week, multicenter, randomized, double-blind, placebo-controlled trial. Setting: 20 centers in the United States and Canada. Patients: Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months. Intervention: Leflunomide or matching placebo added to existing methotrexate therapy. Measurements: The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis. Results: In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate. Conclusions: Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

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