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


METHODS
24-week, multicenter, randomized, double-blind, placebo-controlled trial.


METHODS
20 centers in the United States and Canada.


METHODS
Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months.


METHODS
Leflunomide or matching placebo added to existing methotrexate therapy.


METHODS
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.
Kremer
Joel M
JM
The Center for Rheumatology, LLP, 1367 Washington Avenue, Suite 101, Albany, NY 12206, USA. jkremer@joint-docs.com
Genovese
Mark C
MC
Cannon
Grant W
GW
Caldwell
Jacques R
JR
Cush
John J
JJ
Furst
Daniel E
DE
Luggen
Michael E
ME
Keystone
Ed
E
Weisman
Michael H
MH
Bensen
William M
WM
Kaine
Jeffrey L
JL
Ruderman
Eric M
EM
Coleman
Patricia
P
Curtis
David L
DL
Kopp
Elliot J
EJ
Kantor
Seth M
SM
Waltuck
Jonathan
J
Lindsley
Herbert B
HB
Markenson
Joseph A
JA
Strand
Vibeke
V
Crawford
Bruce
B
Fernando
Indra
I
Simpson
Karen
K
Bathon
Joan M
JM
D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000627:therapeutic use*; D000963:Antimetabolites / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D004185:Disability Evaluation; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use*; D000077339:Leflunomide; D008111:Liver Function Tests; D008297:Male; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D010919:Placebos; D011788:Quality of Life; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000963:Antimetabolites; D007555:Isoxazoles; D010919:Placebos; D000077339:Leflunomide; D008727:Methotrexate