CHAPTER 61 TRADITIONAL DMARDS 965
Malignancies
The induction of malignancies by MTX is a concern, and
several studies have examined this question with conflict-
ing conclusions. Recently, reports of lymphoma in MTX-
treated patients with RA have appeared. Because the
incidence of lymphoma is already increased in patients with
RA,118 these reports are difficult to interpret. The case for a
causative role of MTX has been strengthened, however,
because a number of these cases have been B cell lympho-
mas of the type commonly seen in association with immu-
nosuppression (associated with Epstein-Barr virus) and that
may regress after discontinuation of MTX.119,120 Subse-
quently, lack of a causal relationship between MTX treat-
ment and the development of lymphoma has been seen in
two large series of RA patients—one prospective study118
and one retrospective study.121 The potential benefits of
MTX for most RA patients thus far outweigh these statisti-
cally small risks.122
Miscellaneous
Methotrexate Flu. Patients taking MTX may describe
flulike symptoms shortly after taking their weekly dose.
Nausea, low-grade fevers, myalgias, and chills are the most
common signs of the so-called MTX flu. These side effects
usually respond to supplementation with folic acid, decreas-
ing the dose, switching from oral to parenteral administra-
tion, or changing the time of the dose (so that the patient
takes MTX right before going to bed).
Nodulosis. The development of, or increase in, the
number or size of rheumatoid nodules has been reported
to occur in patients with RA treated with MTX, with a
prevalence of as much as 8%.123 This may occur in rheuma-
toid factor–negative patients, and in those in whom the
synovitis is under excellent control. The mechanism of this
nodule formation has been suggested to be the result of an
increase in adenosine, which appears to promote nodule
formation.124 Conversely, nodules have been reported to
decrease during MTX therapy.
Vasculitis. Despite efficacy in the treatment of the cuta-
neous vasculitis associated with RA, leukocytoclastic vas-
culitis has also been attributed to MTX therapy.125
Fertility, Pregnancy, and Lactation
MTX does not seem to adversely affect female fertility but
can cause reversible sterility in men.126 Women and men
should discontinue MTX for at least 3 months before
attempting to conceive because of its large distribution
and long half-life in the liver. Folic acid supplementation
is essential before conception. MTX is included in the
FDA Pregnancy Category X and is contraindicated during
pregnancy. Women of childbearing age who are consid-
ered for MTX therapy should receive extensive counsel-
ing regarding teratogenic risk and should be placed and
maintained on adequate contraception, before therapy
is begun. Toxicities include fetal abnormalities such as
“aminopterin syndrome” (multiple craniofacial, limb,
and CNS abnormalities)127 and embryonic or fetal loss,
and MTX at high doses (1 mg/kg) is an effective abortifa-
cient. MTX is also contraindicated during lactation be-
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cause small amounts are excreted in breast milk (see
Table 61-1).
Toxicity Monitoring
The American College of Rheumatology (ACR) has
recently revised recommendations for the use of DMARDs,
and these serve as an excellent resource.128 Toxicities that
require monitoring include myelosuppression, hepatotoxic-
ity, and pulmonary toxicity. Baseline evaluation should
include a complete blood count (CBC) with platelets,
hepatitis B and C serology in high-risk patients, liver
transaminases, and creatinine. Although these guidelines
make no recommendations on the need for a baseline
chest radiograph, this is a reasonable approach. Liver biop-
sies are not routinely recommended before MTX is initi-
ated. The rare patients whom one wants to treat with
MTX despite abnormalities in screening laboratory or
other significant risk factors may require liver biopsy before
MTX is initiated. In addition, biopsies are recommended
only in those patients who continue to have enzyme
abnormalities and for whom continuation of MTX therapy
is contemplated.
Monitoring for toxicity should be done every 2 to
12 weeks and is based on the duration of therapy, with
more frequent monitoring provided earlier in the course
of treatment. Systems review and physical examination
should include monitoring for symptoms or signs of myelo-
suppression (fever, infection, bruising, and bleeding), pul-
monary toxicity (shortness of breath, cough, rales), GI
intolerance (nausea, vomiting, diarrhea), and lymphade-
nopathy. Laboratory parameters that should be followed
include a CBC with platelets, liver transaminases, and cre-
atinine (Table 61-2).
It is important to consider vaccination status in any
patient who is going to use MTX. RA patients have an
increased incidence of death from pneumonia,129 and
MTX may reduce the immune response to pneumococcal
antigen.130 Thus any patient in whom MTX is going to
be used should first receive the pneumococcal vaccina-
tion, with booster as appropriate. Vaccinations for hepati-
tis B virus for at-risk patients and yearly influenza vaccines
are recommended as well. Caution should be exercised
when administering live virus vaccinations to patients
on MTX.
Drug Interactions and Contraindications
Drug Interactions
Drugs that are known hepatotoxins, such as SSZ, lefluno-
mide, and azathioprine, may potentiate liver toxicity when
used in combination. Organic acids such as sulfonamides,
salicylates, NSAIDs, penicillin G, piperacillin, and proben-
ecid competitively inhibit tubular secretion, and this delays
MTX clearance.131 MTX also undergoes distal tubular reab-
sorption, which may be enhanced by the addition of
hydroxychloroquine (HCQ)132 and blocked by the addition
of folic acid.131 Drugs that affect renal function should be
used with caution because of the renal clearance of MTX
and, therefore, the increased risk of MTX toxicity that
could occur because of decreased clearance.
966 PART 8 PHARMACOLOGY OF ANTI-RHEUMATIC DRUGS

TABLE 61-2 Safety Monitoring

Monitoring Interval
<3 Months of 3-6 Months of Drug >6 Months of
Baseline Drug Therapy* Therapy* Drug Therapy* Contraindications
MTX CBC, LFT, Cr, HBV, Every 2-4 wk Every 8-12 wk Every 8-12 wk Active infection, symptomatic
HCV; vaccinate: pulmonary disease, WBC <3000/mm3,
influenza, Plt <50,000/mL3, CrCl <30 mL/min,
Pneumococcus, history of myelodysplasia or recent
HBV lymphoproliferative disorder, LFT >2
× ULN, acute or chronic HBV or HCV,
pregnancy, lactation
Leflunomide CBC, LFT, Cr, HBV, Every 2-4 wk Every 8-12 wk Every 8-12 wk Active infection
HCV; vaccinate: WBC <3000/mm3, Plt <50,000/mL3,
influenza, history of myelodysplasia or recent
Pneumococcus, lymphoproliferative disorder, LFT >2
HBV × ULN, acute or chronic HBV or HCV,
pregnancy, lactation
Sulfasalazine CBC, LFT, Cr; Every 2-4 wk Every 8-12 wk Every 8-12 wk Sulfa allergy, Plt <50,000/mL3, LFT >2 ×
vaccinate: ULN, acute HBV/HCV, some classes
influenza, of chronic HBV/HCV
Pneumococcus
Hydroxychloroquine CBC, LFT, Cr; None None None History of vision changes attributed to
complete 4-aminoquinolone derivatives, some
ophthalmologic classes of untreated HBV/HCV
examination
within 1 year

*Monitoring at <3, 3-6, and >6 mo need only include CBC, LFT, and Cr.
CBC, Complete blood count; Cr, creatinine; CrCl, creatinine clearance; HBV, hepatitis B; HCV, hepatitis C; LFT, liver function test; Plt, platelets; ULN, upper
limit of normal; WBC, white blood cell count.
From Saag K, Geng G, Patkar N: American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying
anti-rheumatic drugs in rheumatoid arthritis. Arthritis Rheum 59:762–784, 2008.

Several of the aforementioned drugs deserve special LEFLUNOMIDE

mention. TMP-SMX should be avoided or used with
extreme caution because of possible hematologic toxicity
with MTX. Mechanisms for this toxicity include an additive
anti-folate effect from TMP, decreased MTX clearance
because of inhibition of tubular secretion by SMX, and
altered MTX plasma protein binding. NSAIDs are com-
monly used in patients with RA as adjunctive therapy.
NSAIDs may increase MTX levels by displacing MTX from
plasma proteins and limiting tubular secretion. Despite lack
of a significant pharmacokinetic or clinical interaction
between low-dose MTX and a variety of NSAIDs,133 vigi-
lance for MTX toxicity should increase whenever NSAID
dosages are changed in patients on stable weekly doses of
MTX. Low doses of aspirin used for cardiovascular prophy-
laxis are not likely to be of concern. Furthermore, proben-
ecid should be avoided because it inhibits tubular secretion
of MTX.
Contraindications
MTX should not be used in patients with severe renal,
pulmonary, or hepatic impairment, pre-existing bone
marrow suppression, alcoholic liver disease, and pregnancy
or breastfeeding. Ongoing or active infection is also a con-
traindication. In most cases, patients who desire to continue
drinking alcohol should not be treated with MTX. Mild to
moderate renal insufficiency is a relative contraindication,
and use of MTX in these patients may require more vigilant
toxicity monitoring (Table 61-3).
KEY POINTS
Leflunomide reversibly inhibits dihydroorotate
dehydrogenase.
Loading doses often are not used in clinical practice because
of gastrointestinal toxicity.
Because of enterohepatic recirculation, leflunomide has a
very long half-life.
Leflunomide is absolutely contraindicated in pregnancy, and
levels must be checked with a washout protocol if needed
before conception.
Vigilance must be used for hepatotoxicity.
Leflunomide, an isoxazole derivative, is a synthetic DMARD
approved for the treatment of RA. It emerged from a specific
anti-inflammatory drug development program and has
potent immunomodulatory effects.
Chemical Structure
Leflunomide is a low-molecular-weight isoxazole compound
and is chemically unrelated to any previous immuno-
suppressant. Leflunomide is a pro-drug and is rapidly and
completely converted to its active metabolite, the malono-
nitriloamide A77 1726. A77 1726 is also known as terifluno -
mide (Figure 61-4).

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 CHAPTER 61 TRADITIONAL DMARDS 967

TABLE 61-3 Methotrexate, Leflunomide, Sulfasalazine, and Anti-malarials: Summary of Mechanism of Action, Efficacy, and Toxicity
Proposed Mechanism of Action Efficacy Toxicity
Methotrexate Inhibition of ATIC→↑ Adenosine RA Nausea
Inhibition of TYMS→↓ Pyrimidine synthesis LGL/Felty’s syndrome Hepatotoxicity
Inhibition of DHFR→↓ Transmethylation reactions JIA Bone marrow suppression
PsA Pneumonitis
SLE MTXflu
Vasculitis
Leflunomide Inhibition of DHODH→↓ Pyrimidine synthesis RA Hepatotoxicity
Inhibition of tyrosine kinase→↓ Cell signal SLE Diarrhea
transduction PsA Weight loss
Sulfasalazine Inhibition of arachidonic acid cascade RA Nausea
Inhibition of ATIC→↑ Adenosine JIA Headache
Multiple cellular effects Ankylosing spondylitis Leukopenia
Systemic effects via MALT PsA Rash
Reactive arthritis
Anti-malarials ↑ pH of subcellular vesicles→Interference with Ag RA Nausea
Hydroxychloroquine processing and cell-mediated cytotoxicity SLE Rash
Chloroquine Discoid lupus Neuromyopathy
APS Retinopathy
Sjögren’s syndrome

Ag, Antigen; APS, anti-phospholipid syndrome; ATIC, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase; DHFR, dihydrofolate
reductase; DHODH, dihydroorotate dehydrogenase; JIA, juvenile idiopathic arthritis; LGL, large granular lymphocyte; MALT, mucosa-associated lymphoid
tissue; MTX, methotrexate; PsA, psoriatic arthritis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; TYMS, thymidylate synthetase; ↑, increased;
↓, decreased; →, indicates the result.

the active metabolite (A77 1726) achieved in patients, its

Leflunomide major effect appears to be reversible inhibition of the
enzyme dihydroorotate dehydrogenase (DHODH), which
results in inhibition of pyrimidine synthesis; (2) at higher
CO NH CF3 concentrations, A77 1726 also inhibits tyrosine kinases,
interfering with cell signal transduction.135
Activation of T cells results in progression from the
N
resting phase (G0) to the G1 phase, where ribonucleotides
O
are synthesized, and then to the S phase, where cellular
CH3 DNA is replicated in preparation for mitosis. T cell activa-
tion requires significant increases in de novo pyrimidine and
OH– purine biosynthesis. Sensors such as proto-oncogenes (p53)
O and checkpoints (cyclins C and D) in this pathway monitor
the level of nucleotide pools and prevent damaged cells
NH C C C N from replicating.135
Ribonucleotide uridine monophosphate (rUMP) is a
precursor for the formation of pyrimidine nucleotides and
F3C
CH3
thus is essential for both RNA and DNA synthesis. The
OH
steps in de novo rUMP synthesis are seen in Figure 61-5. A
Active metabolite: A77 1726 critical step in this pathway is the generation of dihydro-
orotate in the cytoplasm with subsequent diffusion into
the mitochondria, where the enzyme DHODH is located.
Figure 61-4 Leflunomide is rapidly and completely metabolized to its DHODH converts dihydro-orotate to orotate, and the latter
active metabolite, A77 1726. diffuses back into the cytoplasm and is subsequently con-
verted to rUMP and, ultimately, to RNA and DNA.
The first postulated mechanism of action of leflunomide
consists of inhibition of DHODH by A77 1726, which
Actions of Leflunomide lowers orotate levels and leads to a decrease in rUMP and
subsequent nucleotide synthesis, resulting in T cell cycle
As with MTX, the precise mechanism of action responsible arrest. This mechanism of action has been substantiated by
for the effects of leflunomide in rheumatic disease is not experimental evidence. In vitro mitogen-stimulated activa-
completely understood.134 Leflunomide is immunomodula- tion of T cells is blocked by levels of A77 1726 that inhibit
tory, with the net effect being a reduction in activated T DHODH, and this inhibition can be reversed by the addi-
lymphocytes. Its two in vitro mechanisms of action vary tion of uridine, suggesting that A77 1726 works by disrup-
depending on concentration: (1) At the concentration of tion of pyrimidine biosynthesis.136,137 Further, the only

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968 PART 8 PHARMACOLOGY OF ANTI-RHEUMATIC DRUGS
ATP + Glutamine
Carbamyl phosphate
synthetase II
Carbamoyl
phosphate
Carbamoyl
aspartate
Dihydroorotate
Dihydroorotate
dehydrogenase
Dihydroorotate
Coenzyme Q
MITOCHONDRIA
Figure 61-5 The active metabolite of leflunomide, A77 1726, blocks the conversion of dihydroorotate to orotate within the mitochondria. ATP,
Adenosine triphosphate; dTMP, 2-deoxythymidylate; dUMP, 2-deoxyuridylate; rUDP, ribonucleotide diphosphate; rUMP, ribonucleotide uridine mono-
phosphate; rUTP, ribonucleotide triphosphate.
enzyme inhibited by A77 1726 in this pathway, at concen-
tration obtained in vivo, is DHODH.138
Evidence also exists to support that inhibition of
DHODH produces an arrest of lymphocytes in the G1 phase
of the cell cycle.139 If the level of ribonucleotides, including
rUMP, falls below a critical point, cytoplasmic p53 activa-
tion occurs, and p53 will translocate to the nucleus and
initiate cellular arrest by ultimately preventing transcrip-
tion of cyclins D and E. In cultures of human T cells, A77
1726 depletes rUMP pools and results in an accumulation
of nuclear p53 with resultant cell cycle arrest.140 In compari-
son, treatment of cell lines lacking p53 with A77 1726 does
not cause a G1 phase arrest.141
Resting lymphocytes maintain ribonucleotide require-
ments largely through salvage pathways and are essentially
unaffected by leflunomide.142 Active, or autoimmune, lym-
phocytes rely on the de novo pathway and are affected by
leflunomide. During the course of treatment with this slow-
acting agent, autoimmune lymphocytes should be removed
progressively.135
At higher concentrations, A77 1726 inhibits phosphory-
lation of tyrosine kinases that are critical for cell growth and
differentiation of activated cells.143,144 This inhibition has
been proposed to partially or completely explain the anti-
proliferative effects of leflunomide; however, it is unclear
whether concentrations sufficient to achieve this effect are
obtained in vivo.
Several other additional anti-inflammatory properties of
leflunomide have been noted. Leflunomide has the ability
to block the activation of nuclear factor-κB (NF-κB),145
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RNA DNA
rUTP dTMP
rUDP dUMP
rUMP
Orotidine
monophosphate
A77 1726
Orotate
which regulates the expression of genes important in inflam-
matory processes, including those seen in inflammatory
arthritis.146 Ex vivo and in vitro studies in humans have
shown that both leflunomide and MTX inhibit neutrophil
chemotaxis, which may decrease the recruitment of inflam-
matory cells into the joints.44 Leflunomide also decreases
the ratio of MMP-1 to TIMP-1.44 Finally, leflunomide
alters the synthesis of cytokines by augmenting the immu-
nosuppressive cytokine-transforming growth factor-β1 and
suppressing the immunostimulatory cytokine IL-2.147
Pharmacology
Absorption and Bioavailability
The GI tract and the liver rapidly and completely convert
ingested leflunomide into A77 1726. Food does not inter-
fere with absorption. Circulating A77 1726 is highly bound
(>99%) to plasma proteins, predominantly albumin. Its
plasma concentration is linearly correlated with a single oral
dose over a range of 5 to 25 mg; steady state is reached in
7 weeks after daily dosing.148
Distribution and Half-Life
A77 1726 has a half-life of approximately 2 weeks (mean,
15.5 days),148 with a low apparent volume of distribution.
A77 1726 undergoes enterohepatic recirculation. In healthy
individuals, 90% of leflunomide is excreted by 28 days,148
but some may be present for much longer periods.

Elimination
In healthy individuals, the proportions excreted by the
kidney and the gut are nearly equal. Because detectable A77
1726 may be present in the body months or years later, the
ability to rapidly and effectively eliminate A77 1726 with
cholestyramine is important. Oral administration of chole-
styramine, 8 g three times daily for 11 days, can lower the
apparent half-life of A77 1726 to 1 to 2 days.149 Further-
more, activated charcoal, 50 g every 6 hours, can reduce
plasma levels by 50% within 24 hours.149
Indications
Rheumatoid Arthritis. Leflunomide was first shown to be
safe and effective in treating RA in a placebo-controlled,
dose-ranging, 6-month trial.148 Two pivotal trials, one in
Europe and one in the United States, have compared
leflunomide with SSZ and MTX. The European trial had
three treatment arms: leflunomide (20 mg/day after a
loading dose), SSZ (increased to 2 g/day), and placebo.150
In this trial, both leflunomide and SSZ were superior to
placebo in terms of swollen and tender joint counts, as
well as physicians’ and patients’ overall assessments. It is
important to note that both the leflunomide and SSZ
groups reported significant effects on slowing of radio-
graphic progression of disease compared with placebo. The
U.S. trial compared patients treated with leflunomide
(20 mg/day after a loading dose), MTX (7.5 to 15 mg/wk),
or placebo.151 Again, both active drugs were found to be
superior to placebo but not different from each other.
Both leflunomide and MTX also slowed radiographic pro-
gression of disease compared with the placebo group.
Another trial compared leflunomide (20 mg/day with
loading) with MTX (10 to 15 mg/wk) in a 1-year trial
with a 1-year extension.152 In this trial, MTX was shown
to be statistically superior to leflunomide for the clinical
outcomes measured, as well as the rate of radiographic
progression after 2 years.
Other Rheumatic Diseases. Leflunomide has been
reported to be effective in treating systemic lupus erythe-
matosus. In a randomized, controlled trial, leflunomide was
more effective than placebo in improving markers of lupus
disease activity, and was safe and well tolerated.153 A sub-
sequent small, prospective, open-label trial of patients
with lupus nephritis unresponsive to conventional ther-
apy showed that leflunomide was efficacious and well
tolerated.154
Leflunomide has been shown to be effective in treating
PsA and psoriasis when compared with placebo.155 In an
open-label trial of AS, leflunomide was shown to be effec-
tive in treating peripheral arthritis, but axial symptoms did
not improve.156
Both an open-label trial157 and a randomized, controlled
clinical trial158 have shown the efficacy of leflunomide in
maintaining remission in granulomatosis with polyangiitis
after successful induction with cyclophosphamide. In the
latter trial, leflunomide was superior to MTX in preventing
relapse.
Leflunomide is also safe and effective in patients with
juvenile idiopathic arthritis (JIA) who did not respond to
or could not tolerate MTX.159
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CHAPTER 61 TRADITIONAL DMARDS 969
Dose and Drug Administration
Leflunomide is available in oral tablets at doses of 10, 20,
and 100 mg. Oral leflunomide is rapidly metabolized to A77
1726, which has a very long half-life; therefore the standard
recommendation is to start therapy with a loading dose of
100 mg daily for 3 days, then switch to the standard main-
tenance dose of 20 mg daily. Despite this recommendation,
many clinicians no longer prescribe a loading dose because
it is believed to increase the drug’s GI toxicity.160 Also, it is
common practice to decrease the dose to 10 mg daily if
toxicity occurs, or if complete control of the disease can be
maintained. Because of its long half-life, some clinicians
give leflunomide less often (three to five times per week).
Geriatric Patients
No pharmacokinetic studies specific to geriatric patients
have been done for leflunomide; hence dosing recommen-
dations are the same as for the general population. No
clinical experience in patients with renal insufficiency has
been reported, so those patients should be monitored care-
fully. See Table 61-1.
Pediatric Patients
Although not approved in the United States to treat
patients with JIA, leflunomide is used off-label for this con-
dition at a dose of 10 to 20 mg/day. This dosing is often
based on a patient’s body weight. A recently published
example of dosing by body weight is as follows: A patient
weighing less than 20 kg receives 10 mg every other day, a
patient weighing more than 20 kg but less than 40 kg
receives 10 mg/day, and a patient weighing more than 40 kg
receives 20 mg/day.161 See Table 61-1.
Toxicity
For major controlled trials that have used leflunomide at a
dose of 20 mg/day, the incidence of adverse events that
resulted in trial withdrawal are shown in Table 61-4.
Leflunomide-associated withdrawals (19%) were more fre-
quent than those associated with MTX (14%), were similar
in frequency to those associated with SSZ (19%), but were
more frequent than those associated with placebo treatment
(8%).
Gastrointestinal and Hepatic Side Effects
The most common side effect that limits the use of lefluno-
mide is diarrhea, which responds to dose reduction and may
TABLE 61-4 Leflunomide Trial Withdrawals for Adverse
Events
No. of Patients Withdrawals
Leflunomide 816 154 (19%)
Methotrexate 680 94 (14%)
Sulfasalazine 133 25 (19%)
Placebo 210 16 (8%)
970 PART 8 PHARMACOLOGY OF ANTI-RHEUMATIC DRUGS
be less common if the loading dose is not used. Abdominal
pain, dyspepsia, and nausea from leflunomide appear to be
slightly increased versus placebo rates.
Liver toxicity can occur in association with leflunomide
administration. Data from a large U.S. cohort of RA and
PsA patients show that elevations in ALT/AST levels
greater than 1 × ULN occurred in 17% and elevations
greater than 2 × ULN occurred in 1% to 2% of patients
taking leflunomide. Leflunomide given in combination with
MTX resulted in ALT/AST elevations greater than 1 ×
ULN in 31% and greater than 2 × ULN in 5% of patients.
Furthermore, this change in transaminases was more com-
monly seen in patients with PsA.109 The European Agency
for Evaluation of Medicinal Products (EMEA) reported 296
patients with hepatic abnormalities and 15 patients with
liver failure and death while taking leflunomide.162,163 The
FDA reviewed adverse event reports between August 2002
and May 2009, and found 49 cases of severe liver injury, 14
of which resulted in death.164 Most patients with hepatotox-
icity have risk factors, including concomitant administra-
tion of another hepatotoxic agent or underlying liver
disease.
Cardiovascular Side Effects
Hypertension has consistently been reported to occur more
frequently in leflunomide-treated compared with placebo-
treated patients.150,151 Additionally, elevation of cholesterol
levels has been reported in association with leflunomide
use.165 Both of these effects should be monitored because of
the excess cardiovascular mortality reported in patients
with RA.
Miscellaneous
Dermatologic. Skin rashes have been reported, most com-
monly occurring between the second and fifth months of
treatment and necessitating discontinuation of the drug.
Severe skin reactions such as Stevens-Johnson syndrome or
toxic epidermal necrolysis require leflunomide washout with
cholestryramine.
An increased incidence of alopecia has been reported in
clinical trials in association with leflunomide treatment.
Pulmonary. Recent reports have suggested that leflu-
nomide can cause interstitial lung disease (ILD), usually
within 3 months of starting therapy. Patients with pre-
existing ILD are at highest risk for this potentially fatal
complication.166,167
Hematologic. Rare cases of pancytopenia have been
reported in post-marketing surveillance, primarily in
patients with known risk factors for blood dyscrasias. An
increased risk of lymphoproliferative disorders has not been
associated with leflunomide.
Weight Loss. Significant weight loss has also been
reported to occur in patients taking leflunomide.168
Fertility, Pregnancy, and Lactation
Leflunomide is rated Pregnancy Category X. Animal studies
have demonstrated substantial teratogenic and embryole-
thal effects with small doses of leflunomide. Therefore
women of childbearing potential should be strongly coun-
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seled about this, and leflunomide should not be prescribed
for women who are not practicing reliable birth control
methods. A pregnancy test should be considered before
therapy is initiated. Leflunomide excretion in milk is
unknown; therefore nursing mothers should not receive
leflunomide.
It is critically important to note that the active metabo-
lite of leflunomide (A77 1726), largely because of its entero-
hepatic circulation, may remain in the body for years.
Therefore, if a woman who has previously received lefluno-
mide wishes to become pregnant, A77 1726 levels should
be measured. Active elimination of leflunomide from the
body should be considered for levels above 0.02 mg/L. This
can be achieved by the oral administration of cholestyr-
amine for 11 days (8 g, three times daily).169 Before preg-
nancy is attempted, verification of levels below 0.02 mg/L
should be confirmed on two separate occasions, at least 14
days apart, and the woman should then wait an additional
three full menstrual cycles.170 Patients may require more
than one course of cholestyramine to achieve this level.
Although no data exist, men wishing to father children
should undergo the same washout procedure as women
and should wait an additional 3 months after the second
drug plasma level is verified to be below 0.02 mg/L (see
Table 61-1).
Toxicity Monitoring
Similar to MTX, the ACR has published guidelines on the
initiation and monitoring of leflunomide treatment.128
Patients taking leflunomide should have a baseline CBC
and liver enzyme monitoring, including AST, ALT, and
albumin. Serum creatinine measurement is important
because leflunomide is partially eliminated by the kidney.
The frequency of monitoring depends on the duration of
therapy (see Table 61-2). More frequent monitoring may
be warranted if concomitant immunosuppressive agents,
such as MTX, are given. If patients experience significant
toxicity, a washout procedure is indicated to more rapidly
eliminate the drug. Caution should be exercised when
live virus vaccinations are administered to patients on
leflunomide.
Drug Interactions and Contraindications
Drug Interactions
Cholestyramine interferes with enterohepatic recycling of
leflunomide, resulting in lower serum concentrations. Con-
comitant use with hepatotoxic agents, including MTX,
increases the risk of liver toxicity, and leflunomide must be
used with caution and monitored judiciously. Rifampin may
increase the serum concentration of A77 1726. Leflunomide
may potentiate warfarin therapy.
Contraindications
Leflunomide should not be used in patients with impaired
liver function, severe renal impairment, bone marrow dys-
plasia, severe immunodeficiency, severe hypoproteinemia,
or known hypersensitivity to the drug. The liver is involved
in enterohepatic recirculation and biliary excretion; thus

leflunomide use in liver disease is contraindicated. In renal
insufficiency, the levels of circulating A77 1726 do not
appear to be increased, but the component of free A77 1726
is increased. Leflunomide is contraindicated in the setting
of serious infection and should be discontinued in patients
with new or worsening pulmonary symptoms or rash. Leflu-
nomide is absolutely contraindicated in pregnancy and
breastfeeding (see Table 61-1).
SULFASALAZINE
KEY POINTS
Sulfasalazine (SSZ) has anti-microbial and anti-inflammatory
properties, but the exact mechanism of action is unknown.
SSZ is commonly used as part of combination therapy for RA.
Gastrointestinal intolerance is a common side effect.
Although rare, surveillance for leukopenia is important early
in the course of the treatment.
SSZ was the first agent to be synthesized specifically for
rheumatoid arthritis in 1938, by Professor Nanna Svartz of
Stockholm, in collaboration with the Swedish pharmaceu-
tical company Pharmacia. The prevailing notion at that
time was that RA was caused by infection, and SSZ was
designed with both anti-inflammatory and anti-bacterial
properties.
Chemical Structure
Salicylazosulfapyridine (SASP), now known as sulfasalazine,
is a conjugate of the anti-inflammatory 5-aminosalicylic
acid (5-ASA or mesalamine) and the anti-bacterial sulfa-
pyridine joined by an azo bond (Figure 61-6). The abbrevia-
tion SASP is still in use as an alternative to SSZ.
SULFASALAZINE
HOOC
HO N N SO2 NH
N immune response. In vitro, SSZ, but not sulfapyridine or
Colonic bacteria
HOOC
HO NH2 H2N SO2 NH
N
5-Aminosalicylic acid Sulfapyridine
Figure 61-6 Sulfasalazine and its major metabolites.
booksmedicos.org
CHAPTER 61 TRADITIONAL DMARDS 971
Actions of Sulfasalazine
Despite more than 7 decades of use, the mechanism of
action of SSZ in rheumatic disease still is not fully eluci-
dated. When SSZ was designed, its anti-microbial proper-
ties were thought to be fundamentally important in the
successful treatment of RA, which was postulated to be an
enteropathic arthropathy. Through alteration of gut flora,
SSZ may downregulate the immune response leading to
inflammatory arthritis. Although this hypothesis has never
been disproved, this mechanism of action has fallen out of
favor for several reasons. To date, no conclusive evidence
has been found for an infectious cause of RA, other sulfon-
amides have failed to result in clinical improvement, and a
relationship between gut flora and clinical response to SSZ
is lacking.171 Currently, SSZ is presumed to work via anti-
inflammatory and immunomodulatory effects.
SSZ has been demonstrated in vitro to possess multiple
anti-inflammatory properties. First, SSZ weakly inhibits the
pro-inflammatory effects of the arachidonic acid cascade,
with a slight inhibitory effect on prostaglandin E2 synthe-
tase activity,172 as well as lipoxygenase products.173 SSZ also
downregulates neutrophil chemotaxis, migration, and pro-
teolytic enzyme production and degranulation,174,175 and
inhibits neutrophil activation by decreasing the flux of
second messengers involved in intra-cellular signal trans-
duction.176 Neutrophil migration to sites of inflammation
can be downregulated by adenosine. SSZ inhibits folate-
dependent enzymes, including AICAR transformylase
(ATIC) and DHFR, resulting in increased adenosine release
into the extra-cellular milieu.177 Gadangi and colleagues
confirmed that SSZ, similar to MTX, modulates inflamma-
tion via increased adenosine release.178 This effect appears
to be the result solely of SSZ because sulfapyradine and
5-ASA are inactive. SSZ is a more potent inhibitor of ATIC
than MTX.
SSZ also possesses multiple immunomodulatory proper-
ties. In vitro, SSZ inhibits T cell proliferation, natural killer
cell activity, and B cell activation, with resultant declines
in immunoglobulin synthesis and RF production.171 In all of
these systems, sulfapyridine and 5-ASA are less active than
SSZ. Cytokine profiles are also altered by SSZ, resulting
in inhibition of the T cell cytokines IL-2179 and IFN-γ,180
and the monocyte/macrophage cytokines IL-1, TNF, and
IL-6.181,182 NF-κB is a key transcription factor that when
active mediates the transcription of key cytokines, adhesion
molecules, and chemokines essential to mounting an
5-ASA, inhibits NF-κB translocation to the nucleus.183
SSZ, more so than sulfapyridine, inhibits endothelial cell
proliferation and angiogenesis, which likely contributes to
the synovitis of RA.184 The synovial fibroblast also plays a
key role in the pathogenesis of RA, and SSZ inhibits fibro-
blast proliferation and metalloproteinase synthesis.185
Finally, SSZ inhibits the formation of osteoclasts and may
be anti-resorptive in RA.186
The active moiety of SSZ is controversial. The parent
compound, SSZ, appears to have the most biologic activity
when compared with sulfapyridine and 5-ASA. However,
the SSZ levels needed in vitro to see the anti-inflammatory
and immunomodulatory effects are far greater than those
obtained in vivo. No demonstrable relationship has been