CLINICAL THERAPEUTICS® / VOL. 26, NO. 4, 2004
Leflunomide in the Treatment of Rheumatoid Arthritis
Edmund K. Li, FRCP, Lai-Shan Tam, MRCP (UK), and Brian Tomlinson, FRCP
Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong
ABSTRACT
Background: Current drug therapies for rheumatoid arthritis (RA), including nonsteroidal anti-inflammatory
drugs and disease-modifying antirheumatic drugs, help control inflammation but can cause significant toxicity.
Drugs are needed that are able to suppress inflammation and modify the underlying immune response with
improved tolerability. Leflunomide is an agent that affects the inflammatory process, particularly in RA.
Objective: This paper reviews the pharmacology of leflunomide, its approved use in RA, and the results of
major clinical trials, including adverse events.
Methods: Relevant trials were identified through a search of the English-language literature indexed on
EMBASE, MEDLINE, Current Contents, and the Cochrane Controlled Trials Register from January 1980 to
November 2003. Search terms were limited to leflunomide.
Results: In 3 large Phase III clinical trials (US301, MN301, and MN302), leflunomide had equivalent clinical
efficacy and tolerability to methotrexate and sulfasalazine and superior efficacy and tolerability compared with
placebo. In US301 (N = 482), the ACR (American College of Rheumatology) 20 response rate (proportion of
patients with ≥20% improvement from baseline in tender and swollen joint counts, patient’s assessment of pain,
patient’s and physician’s global assessment of disease activity, physical function, and acute-phase reactant value)
at 1 year was similar with leflunomide and methotrexate and significantly greater with both active treatments
than with placebo (52%, 46%, and 26%, respectively; both, P < 0.001). The efficacy of leflunomide was seen
early (after 4 weeks of treatment) and was sustained throughout the study. There was less radiographic damage
in both active-treatment groups compared with placebo (leflunomide, P ≤ 0.001; methotrexate, P = 0.02). In
MN301 (N = 358), the ACR20 response rate at 6 months was similar with leflunomide and sulfasalazine and significantly greater with both active treatments compared with placebo (55%, 56%, and 29%, respectively; both,
P < 0.001). Radiographic progression was also similar with leflunomide and sulfasalazine, both of which were
significantly superior to placebo (Larsen score, 0.42, 0.41, and 1.4; both, P < 0.001). An extension of this study
revealed maintenance of efficacy at 12 and 24 months. In MN302 (intent-to-treat population, N = 999), 50.5%
of patients in the leflunomide group were ACR20 responders at the end of 1 year, compared with 64.8% in the
methotrexate group (P < 0.001 vs leflunomide). After 2 years, ACR20 response rates were similar with leflunomide and methotrexate (64.3% and 71.7%). The overall safety profile of leflunomide appears promising,
although monitoring for elevations in liver enzymes and bone marrow suppression is recommended. The most
common drug-related adverse events associated with leflunomide in these clinical trials were diarrhea, abnormalities in liver enzymes, rash, and hypertension.
Accepted for publication January 23, 2004.
Printed in the USA. Reproduction in whole or part is not permitted.
Copyright © 2004 Excerpta Medica, Inc.
0149-2918/04/$19.00
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CLINICAL THERAPEUTICS®
Conclusions: In the trials reviewed, leflunomide
had approximately comparable clinical efficacy and
tolerability to methotrexate and sulfasalazine, and
was superior to placebo. The onset of treatment efficacy occurred more rapidly with leflunomide than
with other active treatments. (Clin Ther. 2004;26:
447–459) Copyright © 2004 Excerpta Medica, Inc.
Key words: clinical trial, leflunomide, rheumatoid
arthritis.
INTRODUCTION
Rheumatoid arthritis (RA) is an inflammatory condition that affects 1% of the population worldwide
and is associated with substantial morbidity and
mortality. Standard pharmacotherapies include nonsteroidal anti-inflammatory drugs (NSAIDs), which
reduce arachidonic acid products generated by
cyclooxygenase and have significant analgesic and
anti-inflammatory effects but are associated with
gastrointestinal intolerance, and disease-modifying
antirheumatic drugs (DMARDs), which improve
symptoms and disease progression with differing
degrees of efficacy and toxicity. Available therapies for
rheumatic diseases have been inadequate to control
inflammation without significant toxicity. Drugs are
needed that are able to suppress inflammation and
modify the underlying immune response with
improved tolerability.
For more than 2 decades, no new DMARDs were
introduced for the treatment of RA. The standard
DMARDs were auranofin, azathioprine, cyclophosphamide, cyclosporine, D-penicillamine, hydroxychloroquine, intramuscular gold, methotrexate, and
sulfasalazine. In 1999, 3 new agents—leflunomide,*
etanercept,† and infliximab‡—were approved for the
treatment of RA by the US Food and Drug Administration. Etanercept and infliximab are biologic
interventions that selectively block tumor necrosis
factor alpha (TNF-α). Etanercept is a recombinant
soluble TNF-Fc fusion protein available for subcutaneous injection, and infliximab is a chimeric
(mouse–human) anti-TNF monoclonal antibody for
*Trademark:
Arava® (Aventis Pharmaceuticals Inc., Bridgewater, New
Jersey).
†Trademark: Enbrel® (Amgen Inc., Thousand Oaks, California).
‡Trademark: Remicade® (Centocor, Inc., Malvern, Pennsylvania).
448
intravenous infusion. Recently, 2 additional agents
became available. Adalimumab§ is a fully humanized
monoclonal TNF-α antibody, available for subcutaneous administration, and anakinra?? is a humanized
monoclonal antibody and interleukin-1–receptor
antagonist, available for subcutaneous injection.
This article reviews the preclinical pharmacology,
pharmacokinetics, and mechanism of action of
leflunomide. The results of major clinical trials of its
use in RA, its efficacy compared with current treatments, and adverse events associated with its use are
summarized. Relevant trials were identified through
searches of the English-language literature indexed
on EMBASE, MEDLINE, Current Contents, and the
Cochrane Controlled Trials Register from January
1980 to November 2003. The search terms were limited to leflunomide.
PRECLINICAL PHARMACOLOGY
Leflunomide is a synthetic isoxazole derivative (N-[4trifluoro-methylphenyl]-5-methylisoxazol-4-carboxamide) that was first shown to have disease-modifying
properties in the 1980s in animal models of arthritis
and autoimmunity. Not only did it inhibit the inflammatory response in adjuvant arthritic rats, but it
improved the diminished proliferation of mitogeninduced lymphocytes in diseased animals.1 Although
leflunomide has no chemical relationship or mechanism of action in common with any of the conventional immunomodulatory drugs, it has demonstrated
prophylactic and therapeutic effects in experimental
models of chronic graft-versus-host disease.2 It has
also been used successfully to suppress the development of systemic lupus erythematosus in MRL/lpr
mice,3 adjuvant arthritis in the Lewis rat,1 and
proteoglycan-induced arthritis in genetically susceptible BALB/C mice,4 as well as to suppress the development of autoimmune diabetes in a mouse model.5
Other diseases in which leflunomide has shown benefit in the rat model include tubulointerstitial nephritis,6 glomerulonephritis induced by anti–basement
membrane antibody,7 and myasthenia gravis.8 Because
of its success in standard animal models of autoimmune disease, leflunomide was tested in patients with
RA and was reported to be effective in 1995.9
§Trademark: Humira™ (Abbott Laboratories, Abbott Park, Illinois).
??Trademark: Kineret™ (Amgen Inc.).
E.K. Li et al.
PHARMACOKINETICS
Leflunomide is almost completely absorbed from the
gastrointestinal tract and undergoes nonenzymatic
conversion in the intestinal mucosa and plasma (and
possibly during first pass through the liver) through
opening of the isoxazole ring to form the active
malononitrilamide metabolite A77 1726 (3 cyano-3hydroxy-N-[4-trifluronmethylphenyl] crotonamide).
A77 1726 is highly protein bound in plasma (99.5%),
predominantly to albumin, and is not dialyzable. It has
a low volume of distribution (0.13 L/kg at steady
state).10 Leflunomide’s half-life is ~15 days in humans.
It may take 2 to 3 weeks to reach steady-state plasma
concentrations after initiation of therapy with a loading
dose of 100 mg/d for 3 days, followed by a maintenance dose of 10 to 20 mg/d; without the loading dose,
it may take up to 2 months. Plasma concentrations of
A77 1726 are dose proportional after administration of
both loading and maintenance doses of leflunomide.
Mean (SD) steady-state plasma concentrations at 24
hours after receipt of maintenance doses of 5, 10, and
25 mg/d for 24 weeks were 8.8 (2.9), 18 (9.6), and 63
(36) µg/mL, respectively.9 Leflunomide is cleared by
hepatic metabolism, mainly to trifluoromethylaniline
(TFMA)–oxanillic acid, and by subsequent biliary
excretion, which may be affected by hepatic dysfunction. Based on the finding that the drug’s half-life can
be decreased to 1 to 2 days by the administration of
cholestyramine or activated charcoal, which prevent
reabsorption, it is likely that enterohepatic circulation
occurs. Leflunomide is excreted in almost equal proportions in the bile as A77 1726 and in the urine as
leflunomide glucuronide and TFMA–oxanillic acid.11
MECHANISMS OF ACTION
Two mechanisms of action have been described for
leflunomide in vitro. They are discussed in the following sections.
Inhibition of Dihydroorotate Dehydrogenase
Leflunomide’s unique mechanism of action in the
treatment of RA is its ability to selectively inhibit the
enzyme dihydroorotate dehydrogenase (DHODH), a
mitochondrial enzyme critical for de novo biosynthesis of pyrimidine ribonucleotides such as ribonucleotide uridine monophosphate (rUMP) and
ribonucleotide uridine triphosphate (Figure 1).
This enzyme is used by activated lymphocytes, rap-
idly proliferating cells involved in the pathogenesis
of RA.12,13 Blockade of pyrimidine synthesis resulting from a reduction in the pyrimidine nucleotide
pool interrupts T lymphocyte clonal expansion,
arresting the cell cycle between the G1 and S phases (Figure 2).
In the resting phase (G0) of lymphocytes and other
cell types (eg, hematopoietic cells, gastrointestinal
lining cells), the biosynthetic pathway for de novo
pyrimidine ribonucleotide synthesis is inactive and
can rely on the salvage pathway.11 However, in the
presence of antigenic signals, such as occur in
inflamed joints, T lymphocytes are stimulated to proliferate. Lymphocytes then progress from G0 to G1
and subsequently to S, with cellular DNA proliferation. Under these circumstances, lymphocytes must
accumulate sufficient amounts of nucleic acid precursors (pyrimidines and purines) to provide an energy
source for membrane biosynthesis and cell division.
The pyrimidine ribonucleotide pool (ie, uridine and
cytosine) expands roughly 8-fold,14 compared with
only 2-fold expansion of the purine ribonucleotide
pool (ie, adenosine and guanosine). After lymphocyte
activation, enzyme activity is increased in the salvage
pathway of pyrimidine synthesis but is unable to
meet the increased demand for pyrimidines; therefore, the de novo pathway occurring in the mid-G1
phase is used to meet this higher demand.
The basic step in de novo pyrimidine synthesis is
conversion of dihydroorotate to orotate by DHODH.
Orotate diffuses into the cytoplasm and is subsequently converted to rUMP by a multi-enzyme complex. rUMP functions in DNA and RNA synthesis, in
membrane biosynthesis, and as an energy source for
activated cells (Figure 1).14
Leflunomide’s inhibition of DHODH leads to a
reduction in the essential pyrimidine precursors (eg,
rUMP), causing arrest of the cell cycle at the G1 phase.
Indeed, when A77 1726 was added to mitogenstimulated human blood lymphocytes, the proportion of stimulated cells that progressed to the S phase
was markedly diminished,15 interrupting cell cycle
progression. The action of A77 1726 leads to lowered
levels of rUMP, which can result in a modification of
synovial high endothelial venules that permits homing of activated lymphocytes to the synovium.16
Through the lowering of rUMP, leflunomide may also
exert anti-inflammatory effects by inducing increased
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CLINICAL THERAPEUTICS®
Uridine triphosphate
ATP + glutamine
Carbamoyl phosphate synthetase
Uridine diphosphate
Uridine diphosphate
Carbamoyl phosphate
Uridine monophosphate
(rUMP)
Uridine monophosphate
(rUMP)
Carbamoyl aspartate
Uridine monophosphate
(rUMP)
Orotidine monophosphate
Orotidine monophosphate
Dihydroorotate
Orotate
Orotate
DHODH
Dihydroorotate
Orotate
Mitochondria
Figure 1. Outline of uridine synthesis. ATP = adenosine triphosphate; DHODH = dihydroorotate dehydrogenase; rUMP =
ribonucleotide uridine monophosphate.
synthesis of immunosuppressive cytokines such as
transforming growth factor beta (TGF-β).17
Tyrosine Kinase Inhibition and Other Actions
The other mechanism of action of leflunomide is
inhibition of tyrosine kinase.18 Tyrosine kinases are
essential for signal transduction, induction of cell
growth, and differentiation of activated cells.
Although A77 1726 inhibits the activity of tyrosine
kinase, the drug concentration required is considerably higher than that required for inhibition of
450
DHODH or than plasma concentrations generally
attained in patients with RA15; therefore, in terms of
immunomodulation, an effect on tyrosine kinase is
unlikely to be the primary antiproliferative action of
this drug.
Other possible secondary mechanisms of action of
leflunomide include inhibition of the activation of
nuclear factor κB, a potent mediator of several proinflammatory genes that is induced by TNF.19
Leflunomide also inhibits the expression of cell adhesion molecules, which facilitate cellular interactions
E.K. Li et al.
Stimulation of cell
T cell
G0
Preparation for S phase
De novo synthesis of
pyrimidine ribonucleotides
G1
Leflunomide
Replication of DNA
S
G2
Mitosis
M
M
M
Figure 2. Cell cycle progression from the G0 (resting) phase to mitosis (M) of activated lymphocytes. In the mid-G1 phase,
the pathway for de novo synthesis of ribonucleotides is upregulated. This process must provide sufficient pyrimidines (uridine, thymidine, cytidine) and purines (adenosine, guanosine) for the cell to progress from the G1 phase
to the S phase.
involved in antigen presentation, secretion of
cytokines, and production of matrix metalloproteinases that degrade articular cartilage and
bone.20–22 In vitro, leflunomide reduced oxygen freeradical production by human monocytes.23 It also
reduced neutrophil chemotaxis in vitro, resulting in a
rapid reduction in the number of neutrophils infiltrating the rheumatoid joint cavity.24 Augmentation
of the immunosuppressive cytokine TGF-β117 and
inhibition of cyclooxygenase-2 activity have also been
observed with leflunomide.25
CLINICAL TRIALS OF LEFLUNOMIDE
The clinical efficacy of leflunomide in RA was first
demonstrated in a German Phase II randomized,
double-blind, placebo-controlled trial involving 402
patients with active disease.9 Patients received
leflunomide 5, 10, and 25 mg/d or placebo for 6
months. Leflunomide 10 and 25 mg/d were found to
be effective based on improvements in both the
patient’s and physician’s global assessments (P < 0.05
vs placebo), accepted measures of response in clinical
trials of RA.
Since that study, there have been 3 multicenter,
randomized, double-blind, placebo-controlled Phase
III trials of leflunomide in the treatment of RA,
referred to as US301,26 MN301,27 and MN302.28 In
all 3 studies combined, 1838 patients were randomized to treatment and 816 received leflunomide.
Approximately 40% of patients had early RA, with a
451
CLINICAL THERAPEUTICS®
disease duration of <2 years; overall, the mean duration of disease was ~5 years. Almost 40% of patients
were DMARD naive. Treatment groups in the 3 trials
received leflunomide, methotrexate, or placebo,26
leflunomide or methotrexate,28 or leflunomide, sulfasalazine, or placebo.27 Patients randomized to receive
leflunomide were given a loading dose of 100 mg for
3 days, followed by a maintenance dose of 20 mg/d.
The results of these clinical trials are described in the
following sections (Table).
Leflunomide Versus Methotrexate and/or Placebo
US301, reported by Strand et al,26 was conducted
in the United States and Canada and involved 482
patients. Patients were randomized in a 3:3:2 ratio to
receive methotrexate 7.5 to 15 mg/wk, leflunomide
20 mg/d, or placebo. Among the clinical end points
was the ACR20 response rate, a standard measure
defined by the American College of Rheumatology
(ACR) as the proportion of patients with ≥20%
improvement from baseline in tender and swollen
joint counts, patient’s assessment of pain, patient’s and
physician’s global assessment of disease activity, physical function, and acute-phase reactant value.29 At 1 year,
the ACR20 response rate was 52% in the leflunomide
group, 46% in the methotrexate group, and 26% in
the placebo group (P < 0.001, both active treatments
vs placebo). Leflunomide showed efficacy after 4
weeks of treatment, and efficacy was sustained
throughout the study period. Radiographic analyses
demonstrated significantly less structural damage in
both active-treatment groups compared with placebo
(leflunomide, P ≤ 0.001; methotrexate, P = 0.02).
Based on these results, the study investigators considered leflunomide and methotrexate to have comparable efficacy. Furthermore, leflunomide was associated
with significantly greater patient-reported improvements versus methotrexate in scores on several categories of the Health Assessment Questionnaire (HAQ)
(P < 0.01) and the Medical Outcomes Study 36-Item
Short-Form Health Survey (SF-36) (P < 0.001). The
HAQ is an established questionnaire for assessing general function in adults, and the SF-36 was designed
for use in population surveys.
In an extension of this study to 2 years, Cohen et
al30 reported that efficacy was sustained in both
active-treatment groups and that leflunomide produced significantly greater improvements in physical
452
function over 2 years of treatment compared with
methotrexate (P = 0.005).
In MN302, reported by Emery et al,28 999 patients
with active RA were randomized to receive a loading
dose of leflunomide 100 mg/d for 3 days, followed
by leflunomide 20 mg/d, or methotrexate 7.5 to
15 mg/wk for 1 to 2 years. During the first year, 50.5%
(250/495) of patients in the leflunomide group were
ACR20 responders, compared with 64.8% (317/489)
in the methotrexate group (P < 0.001 vs leflunomide). ACR50 and ACR70 response rates were slightly but not significantly higher in the methotrexate
group. The overall improvement with methotrexate
in this study was 30% to 70% greater than that
reported by Strand et al in US301.26 Two possible
reasons were proposed for the greater efficacy of
methotrexate: first, folic acid supplementation in all
methotrexate recipients in US301 (compared with
<10% of patients in MN302) may have decreased the
efficacy of methotrexate; second, patients in US301
had a longer history of disease (6.5–7.0 y) compared
with those in MN302 (3.7–3.8 y).
After 2 years of treatment, however, there was no
statistically significant difference in ACR20 response
rates between the leflunomide and methotrexate
groups in MN302 (64.3% and 71.7%, respectively).28
Radiographic assessment using the Larsen score, an
index of bone and joint damage in the hands and feet,
indicated equivalent disease progression after 1 year
of treatment with leflunomide or methotrexate (mean
[SD], 1.25 [0.48] vs 1.29 [0.45]). After 2 years,
patients who received leflunomide had no further
increase in joint damage, and patients who received
methotrexate had a small improvement. The net
result was a small but nonsignificant treatment difference for change in radiographic scores between
active-treatment groups. However, in the absence of a
placebo group, the effect of treatment on disease progression cannot be clearly evaluated.
Leflunomide Versus Sulfasalazine and/or Placebo
MN301, reported by Smolen et al,27 was a 6-month
randomized, double-blind study conducted in
Europe, Australia, New Zealand, and South Africa.
Three hundred fifty-eight patients were randomized
to 1 of 3 treatment arms: a loading dose of leflunomide 100 mg/d for 23 days, followed by leflunomide
20 mg/d; sulfasalazine 0.5 g/d, titrated to 2 g/d at
E.K. Li et al.
Table. Summary of randomized control trials of leflunomide. In trials that included a placebo group, comparisons are
versus placebo; in trials without a placebo group, comparisons are versus the active comparator.
Mladenovic
et al9*
Smolen et al27†
LEF/PLA
LEF/PLA SSZ/PLA
LEF
MTX
LEF/PLA MTX/PLA
LEF
SSZ
LEF
MTX
100/102
133/92
501
498
182/118
80
76
98
101
6
6
12
24
Outcome measures
Tender joint count
Swollen joint count
Patient’s global assessment
Physician’s global assessment
Duration of morning stiffness
Pain score,VAS
ESR
CRP
ACR20
HAQ
SF-36
→
↑¶
↑¶
↑¶
→
↑¶
↑¶
↑¶
↑‡
NA
NA
↑‡
↑‡
↑\
↑\
↑††
↑‡
↑\
↑‡
↑‡
↑‡
NA
↑‡
↑‡
↑\
↑\
↑††
↑‡
↑††
↑‡
↑‡
↑‡
NA
↑§
↑‡
↑\
↑\
↑¶
↑¶
↑¶
↑¶
↑‡
↑¶
NA
→
↑#
→
↑**
→
→
↑‡
↑§§
→
→
NA
↑\
↑\
↑\
↑\
↑¶
↑‡‡
↑‡‡
↑\
↑‡
↑‡
↑\
Radiographic measures
Larsen score
Sharp score
NA
NA
↑‡
NA
↑‡
NA
→
NA
→
NA
NA
↑\
No. of patients
Duration of follow-up, mo.
133
Emery et al28†
Strand et al26†
182
12
Scott et al31†
Cohen et al30†
24
(ext. of
Smolen)
24
(ext. of
Strand)
↑\
↑\
↑\
↑\
→
↑‡‡
↑‡‡
↑\
↑\
↑‡‡
↑\
→
→
↑\
↑\
→
→
→
→
↑‡‡
↑‡‡
NA
↑¶
→
→
↑¶
↑¶
↑¶
→
→
→
↑¶
→
NA
↑\\
→
NA
NA
→
LEF = leflunomide; PLA = placebo; SSZ = sulfasalazine; MTX = methotrexate; → = no change versus PLA or other active treatment; ↑ = improvement;
VAS = visual analog scale; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; ACR20 = American College of Rheumatology 20 response rate
(proportion of patients with ≥20% improvement from baseline in tender and swollen joint counts, patient’s assessment of pain, patient’s and physician’s
global assessment of disease activity, physical function, and acute-phase reactant value); HAQ = Health Assessment Questionnaire; NA = not available; SF-36 =
Medical Outcomes Study 36-Item Short-Form Health Survey.
*With leflunomide 10 mg/d.
†With leflunomide 20 mg/d.
‡P < 0.001.
§P = 0.006.
\P = 0.001.
¶P = 0.005.
#P = 0.017.
**P = 0.015.
††P = 0.004.
‡‡P = 0.01.
§§P = 0.008.
\\P = 0.02.
week 4; or placebo. At 6 months, ACR20 response
rates were 55% for leflunomide, 56% for sulfasalazine, and 29% for placebo (P < 0.001, both
active treatments vs placebo). Leflunomide and sulfasalazine showed similar efficacy in retarding radiographic progression, as shown by changes in the
Larsen score for eroded joint count, and were significantly more effective than placebo (0.42, 0.41, and
1.4, respectively; P < 0.001). Leflunomide produced
an earlier response, with 31% of patients having an
ACR20 response at week 4, compared with 19% and
9% with sulfasalazine and placebo, respectively.
An extension of this study to 2 years reported by
Scott et al31 found maintenance of efficacy at 12 and
24 months. At 2 years, receipt of leflunomide was
associated with significant improvements versus sul453
CLINICAL THERAPEUTICS®
fasalazine in the physician’s global assessment (50%
vs 32%, respectively; P = 0.001), patient’s global
assessment (46% vs 30%; P = 0.001), ACR20
response rate (82% vs 60%; P < 0.01), and functional ability, as measured by HAQ score (–0.65 vs –0.36;
P = 0.01).32 Leflunomide was also significantly superior to sulfasalazine in terms of the more stringent
ACR50 response rate (52% vs 25%; P = 0.04).
Patients who had benefited from 2 years of
leflunomide treatment in MN30127 and MN30228
were invited to participate in an open-label extension study in which they would receive leflunomide
for up to 5 years.33 Among the 214 patients who
entered the extension study, the improvements in
ACR20, ACR50, and ACR70 response rates observed
at year 1 (72.9%, 48.3%, and 14.5%, respectively)
were maintained (69.2%, 43.0%, and 19.6%) for a
mean of 4.6 years. Improved functional ability, as
measured in terms of HAQ score (a change of –0.22
is considered clinically meaningful), was seen at year
1 (mean change, –0.6) and maintained through the
end of the study (mean change, –0.5 and –0.5,
respectively).
Combination Treatment with Leflunomide
and Methotrexate
The efficacy of leflunomide used in combination
with methotrexate has been assessed in 2 trials: an
open-label trial in 30 patients34 and a randomized,
double-blind, placebo-controlled trial in 263 patients
with RA.35 In both studies, leflunomide was added to
methotrexate in patients who had failed to respond to
methotrexate alone.
In the open-label trial,34 the combination of
leflunomide and methotrexate produced an improvement in the ACR20 response rate; the response rate
reached 53% (16/30 patients) at the end of 1 year,
which was considered to indicate therapeutic potential. The combination was generally well tolerated,
with the exception of an elevation in liver enzymes in
19 patients; in 68% (13) of these cases, levels of both
aspartate and alanine aminotransferase decreased to
<1.2 times the upper limit of normal by the end of
the study without a reduction in the dose of leflunomide. An analysis of methotrexate pharmacokinetic
parameters (ie, maximum plasma concentration, time to
maximum concentration, area under the concentrationtime curve) involving 11 of the 30 patients showed
454
no significant changes from baseline (before administration of leflunomide) at any time during leflunomide administration.
In the randomized, double-blind, placebocontrolled trial,35 46.2% (60/130) of patients in the
leflunomide/methotrexate group and 19.5% (26/133
patients) in the placebo/methotrexate group met
ACR20 response criteria at 24 weeks (P < 0.001).
ACR50 response rates in the leflunomide/methotrexate
and placebo/methotrexate groups were a respective
26.2% and 6.0% (P < 0.001), and ACR70 response
rates were 10.0% and 2.3% (P = 0.016).
These results suggest that in patients with active
RA, combination therapy with leflunomide and
methotrexate provides statistically significant and
clinically meaningful improvements compared with
the combination of placebo and methotrexate.
Furthermore, combination therapy appears to be an
alternative for patients who have an incomplete
response to methotrexate alone.
Comparative Efficacy of Leflunomide in
Meta-Analyses and Pooled Analyses
A study of pooled clinical efficacy data from 6 randomized controlled trials showed leflunomide to be
significantly better than placebo, with improvements
in ACR20 response rate roughly 2 times that with
placebo at both 6 months (relative benefit [RB] =
1.93; 95% CI, 1.51–2.47) and 12 months (RB = 1.99;
95% CI, 1.42–2.77).36 Other clinical measures of disease activity, functional measures, and radiographic
scores were also significantly better in leflunomide
recipients than in placebo recipients (all, P < 0.05).
In another analysis,30 leflunomide was not significantly superior to methotrexate on most outcome
measures, with the exception of scores on the modified HAQ (weighted mean difference, –0.14; 95% CI,
–0.25 to –0.03), Problem Elicitation Technique
scores (weighted mean difference, –3.5; 95% CI,
–5.62 to –1.38), and scores on the physical component of the SF-36 (weighted mean difference, –3.0;
95% CI, –5.41 to –0.59). When leflunomide was
compared with sulfasalazine,31 there were no statistically significant differences on most clinical outcomes, although leflunomide produced significantly
greater ACR20 response rates at 24 months compared
with sulfasalazine (RB = 1.37; 95% CI, 1.07–1.75).
The effects of leflunomide on retarding radiographic
E.K. Li et al.
deterioration were not significantly different from
those of sulfasalazine and methotrexate,37 although
the results of the study by Strand et al26 tended to
favor leflunomide over methotrexate, and the results
of the study by Emery et al28 favored methotrexate.
Thus, based on the available information, leflunomide is not superior to either methotrexate or sulfasalazine in delaying bone erosion or joint damage in
patients with RA.
SAFETY PROFILE
In a recent systematic review and meta-analysis,36 significantly fewer patients receiving leflunomide withdrew from treatment compared with those receiving
placebo (RR = 0.70; 95% CI, 0.59–0.83). Rates of
withdrawal were similar with leflunomide and sulfasalazine, but more patients discontinued leflunomide
than methotrexate (RR = 1.26; 95% CI, 1.08–1.48).
Adverse effects were more commonly reported with
leflunomide than with methotrexate (RR = 1.43; 95%
CI, 1.13–1.83) or placebo (RR, 2.73; 95% CI,
1.67–4.47), but occurred with a similar incidence in
the leflunomide and sulfasalazine groups (RR, 0.77;
95% CI, 0.45–1.33).
Another study showed a significantly lower rate of
discontinuations with methotrexate than with
leflunomide (P = 0.001), which had a similar rate to
sulfasalazine.38 However, the overall incidence of discontinuations due to adverse effects was lower with
leflunomide than with methotrexate or sulfasalazine;
discontinuations related to toxicity occurred significantly earlier with leflunomide and sulfasalazine than
with methotrexate (P < 0.001).
The most common adverse effect associated with
leflunomide treatment was diarrhea, reported in 17%
of patients.27 Diarrhea was usually transient or
responded to a decrease in the leflunomide dose.
Nausea occurred in 9.3% of patients, abdominal pain
in 4.6%, and vomiting in 2.8%. The frequency and
severity of these symptoms were highest during the
first 2 weeks of treatment and declined thereafter.
Postmarketing surveillance has revealed rare cases
of serious hepatic injury, sometimes with a fatal outcome. Most cases have occurred within 6 months of
starting therapy in patients with multiple risk factors
for hepatotoxicity (eg, liver disease, use of other
hepatotoxic drugs).39 There are also reports of elevations in aminotransferases in 15% of leflunomide
recipients, compared with 12% for methotrexate and
3% for placebo.26,27 Most of these elevations were <2
times the upper limit of normal and were transient or
resolved with dose reduction.11,26,28,40 An elevation
in transaminases >2 times the upper limit of normal
occurred in 2.3% to 11.0% of patients in Phase III trials,26 a similar rate to that seen when folate supplementation was added to methotrexate therapy.28
Three of 108 patients in one study had an elevation
in liver enzymes >3 times the upper limit of normal.40
Literature review revealed only a single case of severe
liver disease (early cirrhosis) in a patient who had
received the combination of leflunomide and
methotrexate.41 It was not possible, however, to state
whether the liver injury was the effect of either drug
alone or of the combination.
Liver enzymes must be checked at baseline and
monitored at monthly intervals during the first 6
months of leflunomide therapy. If values are stable,
monitoring is recommended every 6 to 8 weeks. If
values increase <2-fold, the dose should be decreased
to 10 mg/d. For persistent elevations 2 to 3 times the
upper limit of normal after dose reduction, liver biopsy is recommended if leflunomide therapy is to be
continued.42
As discussed earlier, the active metabolite of leflunomide is highly protein bound and is cleared by hepatic metabolism and biliary secretion. Use of leflunomide
is not recommended in patients with a history of
hepatitis, in those who consume large amounts of
alcohol,31,43 or in patients with hypoproteinemia or
impaired liver function caused by any stage of cirrhosis.
Several other adverse effects can occur with
leflunomide. Reversible alopecia or rash has been
reported in 8% of patients, and mild weight loss and
headache have been noted in some patients.27,28,44–46
Significant leukopenia or thrombocytopenia has not
been reported, with the exception of 20 cases of
leukopenia in 501 patients over a 2-year period in
one study28; none of the leukocyte counts were <2 2
109 white cells/L. Ten cases of pancytopenia have
been reported, in 9 of which the patient was taking
concomitant methotrexate therapy.47,48 Based on the
Naranjo probability scale, the relationship between
leflunomide and pancytopenia was probable in 1
case47 and possible in 9 others.48 For this reason, routine hematologic monitoring is suggested in patients
taking leflunomide and methotrexate.48 Bone marrow
455
CLINICAL THERAPEUTICS®
suppression is a concern, and interruption of therapy
may be necessary if a serious infection occurs.
Monitoring of the white blood cell count, platelets,
and hemoglobin is recommended at the same time
intervals as for liver enzyme monitoring.39
Apart from 1 case of nonfatal sepsis,26 no increases
in the incidence of opportunistic exogenous infections
such as Pneumocystis carinii pneumonia, uncontrolled
endogenous infections, or reactivation or dissemination of varicella zoster virus have been reported in the
literature.33 This lack of infections reflects the ability
of replicating cells in the gastrointestinal and
hematopoietic systems to meet their need for pyrimidine ribonucleotides for DNA synthesis through the
salvage pathways, independent of de novo nucleotide
pathways or DHODH. Unlike methotrexate, which
may cause hypersensitivity pneumonitis in 0.7% to
7.0% of patients,49 leflunomide has not been associated with pulmonary toxicity.33
Drug-related hypertension has been noted in
patients receiving leflunomide at an incidence ranging from 1.1% to 6.8%.26,28,40,50 In one study,50 30
patients receiving leflunomide had significant
increases in both systolic and diastolic blood pressure
(P < 0.05); the mechanism is unclear but may be
related to an increase in sympathetic drive. Another
possible mechanism for a blood pressure increase
with leflunomide may involve displacement of the
free fraction of concomitant diclofenac or ibuprofen
from protein binding, increasing the NSAID’s effect
on the distribution of renal blood flow and potentially increasing retention of salt and water.11
A pharmacokinetic study found that steady-state
concentrations of A77 1726 in plasma were not
affected by renal impairment or hemodialysis.51
Therefore, reduction of the leflunomide dose does
not appear to be necessary in patients with chronic
renal failure undergoing hemodialysis. Experience
with leflunomide in patients with renal impairment
is limited. Although leflunomide is not contraindicated, it should be used with caution in patients with
any degree of renal insufficiency, as the kidneys play
a role in excretion of the metabolite.35 One case of
glomerulonephritis leading to renal failure has been
reported in a patient with RA; antiglomerular basement membrane antibodies were detected shortly
after the initiation of leflunomide.52 Although
leflunomide’s exact role in this case of renal failure
456
was unknown, the close temporal relationship
between drug administration and the adverse event
suggest a causal association.
The incidence of rheumatoid vasculitis is not
increased with leflunomide compared with methotrexate. Nonetheless, vasculitis has been reported
in 2 patients receiving leflunomide, both of whom
died.53 Interestingly, leflunomide has been effective in
maintaining remission of Wegener’s granulomatosis.54
Leflunomide can potentiate the anticoagulant effect
of warfarin, resulting in an increase in the international normalized ratio of warfarin in patients taking warfarin. A77 1726 inhibits the cytochrome P450 (CYP)
2C9 isozyme and can increase the bioavailability of
drugs metabolized by this isozyme, such as warfarin,55
phenytoin, tolbutamide, and rifampicin (a nonspecific
CYP inducer). Leflunomide has no significant interactions with oral contraceptives, NSAIDs, or cimetidine.
Although no animal studies have been conducted
to evaluate potential fetal damage, leflunomide is
considered teratogenic, and its use is contraindicated
in women who are pregnant or who wish to become
pregnant.10 Before pregnancy is considered, plasma
concentrations of A77 1726 should be <0.2 mg/L on
2 occasions ≥14 days apart. In the event of pregnancy or toxicity, the elimination of leflunomide can be
hastened by administering cholestyramine 8 g TID
for 11 days. Leflunomide should not be used during
lactation, because it is not known whether leflunomide is excreted in breast milk. Similarly, use of
leflunomide is not recommended in men who wish to
father a child.26,45
There is no evidence of an increased incidence of
lymphoproliferative disorders or malignancies in
patients receiving leflunomide for RA.10 The incidence has been similar to that in patients receiving
methotrexate or sulfasalazine.
CONCLUSIONS
Leflunomide is a synthetic isoxazole derivative that acts
predominantly on activated lymphocytes and prevents
them from initiating the inflammatory processes that
lead to cartilage and bone destruction in RA. In the trials reviewed, leflunomide appeared to improve all clinical outcomes and to delay radiologic progression of
RA compared with placebo. After 5 years of treatment,
its efficacy and adverse-event profile were comparable
to those of sulfasalazine and methotrexate.
E.K. Li et al.
REFERENCES
1. Bartlett RR, Schleyerbach R. Immunopharmacological
profile of a novel isoxazol derivative, HWA 486, with
potential antirheumatic activity—I. Disease modifying
action on adjuvant arthritis of the rat. Int J Immunopharmacol. 1985;7:7–18.
2. Popovic S, Bartlett RR. The use of the murine chronic
graft vs host (CGVH) disease, a model for systemic
lupus erythematosus (SLE), for drug discovery. Agents
Actions. 1987;21:284–286.
3. Popovic S, Bartlett RR. Disease modifying activity of
HWA 486 on the development of SLE in MRL/1-mice.
Agents Actions. 1986;19:313–314.
4. Glant TT, Mikecz K, Bartlett RR, et al. Immunomodulation of proteoglycan-induced progressive polyarthritis by leflunomide. Immunopharmacology. 1992;
23:105–116.
5. Stosic-Grujicic S, Dimitrijevic M, Bartlett RR. A novel
immunomodulating agent—leflunomide inhibits experimental autoimmune diabetes in mice. Transplant Proc.
1996;28:3072–3073.
6. Thoenes GH, Sitter T, Langer KH, et al. Leflunomide
(HWA 486) inhibits experimental autoimmune tubulointerstitial nephritis in rats. Int J Immunopharmacol.
1989;11:921–929.
7. Ogawa T, Inazu M, Gotoh K, et al. Therapeutic effects
of leflunomide, a new antirheumatic drug, on
glomerulonephritis induced by the antibasement
membrane antibody in rats. Clin Immunol Immunopathol. 1991;61:103–118.
8. Vidic-Dankovic B, Kosec D, Damjanovic M, et al.
Leflunomide prevents the development of experimentally induced myasthenia gravis. Int J Immunopharmacol.
1995;17:273–281.
9. Mladenovic V, Domljan Z, Rozman B, et al. Safety and
effectiveness of leflunomide in the treatment of
patients with active rheumatoid arthritis. Results of a
randomized, placebo-controlled, phase II study.
Arthritis Rheum. 1995;38:1595–1603.
10. Leflunomide [package insert]. Bridgewater, NJ: Aventis
Pharmaceuticals Inc; 2000.
11. Fox RI, Herrmann ML, Frangou CG, et al. Mechanism
of action for leflunomide in rheumatoid arthritis. Clin
Immunol. 1999;93:198–208.
12. Cherwinski HM, McCarley D, Schatzman R, et al. The
immunosuppressant leflunomide inhibits lymphocyte
progression through cell cycle by a novel mechanism.
J Pharmacol Exp Ther. 1995;272:460–468.
13. Greene S, Watanabe K, Braatz-Trulson J, Lou L.
Inhibition of dihydroorotate dehydrogenase by the
immunosuppressive agent leflunomide. Biochem
Pharmacol. 1995;50:861–867.
14. Fairbanks LD, Bofill M, Ruckemann K, Simmonds HA.
Importance of ribonucleotide availability to proliferating T-lymphocytes from healthy humans. Disproportionate expansion of pyrimidine pools and contrasting effects of de novo synthesis inhibitors. J Biol
Chem. 1995;270:29682–29689.
15. Cherwinski HM, Cohn RG, Cheung P, et al. The
immunosuppressant leflunomide inhibits lymphocyte
proliferation by inhibiting pyrimidine biosynthesis.
J Pharmacol Exp Ther. 1995;275:1043–1049.
16. Fox RI. Mechanism of action of leflunomide in
rheumatoid arthritis. J Rheumatol Suppl. 1998;53:
20–26.
17. Cao WW, Kao PN, Aoki Y, et al. A novel mechanism of
action of the immunomodulatory drug, leflunomide:
Augmentation of the immunosuppressive cytokine,
TGF-beta 1, and suppression of the immunostimulatory cytokine, IL-2. Transplant Proc. 1996;28:3079–
3080.
18. Xu X, Blinder L, Shen J, et al. In vivo mechanism by
which leflunomide controls lymphoproliferative and
autoimmune disease in MRL/MpJ-lpr/lpr mice.
J Immunol. 1997;159:167–174.
19. Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent
nuclear factor–kappa B activation and gene expression.
J Immunol. 1999;162:2095–2102.
20. Deage V, Burger D, Dayer JM. Exposure of T lymphocytes to leflunomide but not to dexamethasone favors
the production by monocytic cells of interleukin-1
receptor antagonist and the tissue-inhibitor of metalloproteinases-1 over that of interleukin-1beta and metalloproteinases. Eur Cytokine Netw. 1998;9:663–668.
21. Ruckemann K, Fairbanks LD, Carrey EA, et al.
Leflunomide inhibits pyrimidine de novo synthesis in
mitogen-stimulated T-lymphocytes from healthy
humans. J Biol Chem. 1998;273:21682–21691.
22. Kraan MC, Reece RJ, Barg EC, et al. Modulation of
inflammation and metalloproteinase expression in synovial tissue by leflunomide and methotrexate in
patients with active rheumatoid arthritis. Findings
in a prospective, randomized, double-blind, paralleldesign clinical trial in thirty-nine patients at two centers. Arthritis Rheum. 2000;43:1820–1830.
457
CLINICAL THERAPEUTICS®
23. Schorlemmer HU, Kurrle R, Schleyerbach R.
Leflunomide’s active metabolite A77-1726 and its
derivatives, the malononitrilamides, inhibit the generation of oxygen radicals in mononuclear phagocytes.
Int J Immunother. 1998;14:213–222.
24. Kraan MC, de Koster BM, Elferink JG, et al. Inhibition
of neutrophil migration soon after initiation of treatment with leflunomide or methotrexate in patients
with rheumatoid arthritis: Findings in a prospective,
randomized, double-blind clinical trial in fifteen
patients. Arthritis Rheum. 2000;43:1488–1495.
25. Hamilton LC, Vojnovic I, Warner TD. A771726, the
active metabolite of leflunomide, directly inhibits the
activity of cyclo-oxygenase-2 in vitro and in vivo in a
substrate-sensitive manner. Br J Pharmacol. 1999;127:
1589–1596.
26. Strand V, Cohen S, Schiff M, et al, for the Leflunomide
Rheumatoid Arthritis Investigators Group. Treatment
of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Arch Intern Med.
1999;159:2542–2550.
27. Smolen JS, Kalden JR, Scott DL, et al, for the European
Leflunomide Study Group. Efficacy and safety of
leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: A double-blind,
randomised, multicentre trial. Lancet. 1999;353:
259–266.
28. Emery P, Breedveld FC, Lemmel EM, et al. A comparison of the efficacy and safety of leflunomide and
methotrexate for the treatment of rheumatoid arthritis.
Rheumatology (Oxford). 2000;39:655–665.
29. Felson DT, Anderson JJ, Boers M, et al. American
College of Rheumatology. Preliminary definition of
improvement in rheumatoid arthritis. Arthritis Rheum.
1995;38:727–735.
30. Cohen S, Cannon GW, Schiff M, et al, for the
Utilization of Leflunomide in the Treatment of
Rheumatoid Arthritis Trial Investigator Group. Twoyear, blinded, randomized, controlled trial of treatment
of active rheumatoid arthritis with leflunomide compared with methotrexate. Arthritis Rheum. 2001;44:
1984–1992.
31. Scott DL, Smolen JS, Kalden JR, et al. Treatment of
active rheumatoid arthritis with leflunomide: Two year
follow up of a double blind, placebo controlled trial
versus sulfasalazine. Ann Rheum Dis. 2001;60:913–923.
32. Kalden JR, Scott DL, Smolen JS, et al, for the European
Leflunomide Study Group. Improved functional ability
458
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
in patients with rheumatoid arthritis—longterm treatment with leflunomide versus sulfasalazine. J Rheumatol.
2001;28:1983–1991.
Kalden JR, Schattenkirchner M, Sorensen H, et al. The
efficacy and safety of leflunomide in patients with
active rheumatoid arthritis: A five-year followup study.
Arthritis Rheum. 2003;48:1513–1520.
Weinblatt ME, Kremer JM, Coblyn JS, et al.
Pharmacokinetics, safety, and efficacy of combination
treatment with methotrexate and leflunomide in
patients with active rheumatoid arthritis. Arthritis
Rheum. 1999;42:1322–1328.
Kremer JM, Genovese MC, Cannon GW, et al.
Concomitant leflunomide therapy in patients with
active rheumatoid arthritis despite stable doses of
methotrexate. A randomized, double-blind, placebocontrolled trial. Ann Intern Med. 2002;137:726–733.
Osiri M, Shea B, Robinson V, et al. Leflunomide for
the treatment of rheumatoid arthritis: A systematic
review and metaanalysis. J Rheumatol. 2003;30:
1182–1190.
Sharp JT, Strand V, Leung H, et al, for the Leflunomide
Rheumatoid Arthritis Investigators Group. Treatment
with leflunomide slows radiographic progression of
rheumatoid arthritis: Results from three randomized
controlled trials of leflunomide in patients with active
rheumatoid arthritis [published correction appears in
Arthritis Rheum. 2000;43:1345]. Arthritis Rheum.
2000;43:495–505.
Aletaha D, Stamm T, Kapral T, et al. Survival and effectiveness of leflunomide compared with methotrexate and
sulfasalazine in rheumatoid arthritis: A matched observational study. Ann Rheum Dis. 2003;62:944–
951.
2003 Safety alerts for drugs, biologics, medical devices,
and dietary supplements. Available at: http://www.fda.
gov/medwatch/SAFETY/2003/safety03.htm#arava.
Accessed November 23, 2003.
Smolen JS. Efficacy and safety of the new DMARD
leflunomide: Comparison to placebo and sulfasalazine
in active rheumatoid arthritis. Scand J Rheum Suppl.
1999;112:15–21.
Weinblatt ME, Dixon JA, Falchuk KR. Serious liver disease in a patient receiving methotrexate and leflunomide. Arthritis Rheum. 2000;43:2609–2611.
Sanders S, Harisdangkul V. Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J
Med Sci. 2002;323:190–193.
E.K. Li et al.
43. Kremer JM. Rational use of new and existing diseasemodifying agents in rheumatoid arthritis. Ann Intern
Med. 2001;134:695–706.
44. Herrmann ML, Schleyerbach R, Kirschbaum BJ.
Leflunomide: An immunomodulatory drug for the treatment of rheumatoid arthritis and other autoimmune diseases. Immunopharmacology. 2000;47:273–289.
45. Wallace CA. On beyond methotrexate treatment of
severe juvenile rheumatoid arthritis. Clin Exp Rheumatol.
1999;17:499–504.
46. Strand V. Approaches to the management of systemic
lupus erythematosus. Curr Opin Rheumatol. 1997;9:410–420.
47. Auer J, Hinterreiter M, Allinger S, et al. Severe pancytopenia after leflunomide in rheumatoid arthritis. Acta
Medica Austriaca. 2000;27:131–132.
48. Hill RL, Topliss DJ, Purcell PM. Pancytopenia associated with leflunomide and methotrexate. Ann Pharmacother. 2003;37:149.
49. Alarcon GS. Methotrexate: Its use for the treatment of
rheumatoid arthritis and other rheumatic disorders.
50.
51.
52.
53.
54.
55.
In: Koopman WJ, ed. Arthritis and Allied Conditions.
14th ed. Baltimore, Md: Williams & Wilkins; 2001:
743–768.
Rozman B, Praprotnik S, Logar D, et al. Leflunomide
and hypertension. Ann Rheum Dis. 2002;61:567–569.
Beaman JM, Hackett LP, Luxton G, Illett KF. Effect of
hemodialysis on leflunomide plasma concentrations.
Ann Pharmacother. 2002;36:75–77.
Bruyn GA, Veenstra RP, Halma C, Grond J. Antiglomerular basement membrane antibody–associated
renal failure in a patient with leflunomide-treated
rheumatoid arthritis. Arthritis Rheum. 2003;48:1164–
1165.
Bruyn GA, Griep EN, Korff KJ. Leflunomide for active
rheumatoid arthritis. Lancet. 1999;353:1883.
Gross WL. New concepts in treatment protocols for
severe systemic vasculitis. Curr Opin Rheumatol. 1999;
11:41–46.
Lim V, Pande I. Leflunomide can potentiate the anticoagulant effect of warfarin. BMJ. 2002;325:1333.
Address correspondence to: Edmund K. Li, FRCP, Department of Medicine & Therapeutics, The Chinese
University of Hong Kong, Prince of Wales Hospital, Hong Kong. E-mail: edmundli@cuhk.edu.hk
459