Folate supplementation during methotrexate

therapy for patients with psoriasis

Bruce E. Strober, MD, PhD, and Kavita Menon, BA
New York, New York
Methotrexate is a folate antagonist that is a well-established therapy for autoimmune and inflammatory
conditions. In some patients, methotrexate is associated with significant side effects and toxicity. Folate
supplementation is often used to ameliorate methotrexate-associated side effects and toxicities. We sought
to demonstrate that folate supplementation during methotrexate therapy reduces both toxicity and side
effects without compromising efficacy. A MEDLINE search of the search terms methotrexate, folic acid,
folinic acid, and leucovorin was performed and literature relevant to the use of folates as a supplement
to methotrexate was reviewed. According to studies reviewed, the use of folate supplements in patients
treated with methotrexate reduces the incidence of hepatotoxicity and gastrointestinal intolerance without
impairing the efficacy of methotrexate. Both folic acid and folinic acid are equally effective; however, folic
acid is more cost effective. It must be noted that there are relatively few studies that have addressed folate
supplementation with the use of methotrexate for the treatment of psoriasis. After examining the available
data from the literature and drawing from clinical experience, we advise folate supplementation for every
patient who receives methotrexate. ( J Am Acad Dermatol 2005;53:652-9.)

ethotrexate is considered among the most

effective treatments for rheumatoid arthritis, moderate to severe psoriasis, and other
autoimmune and inflammatory conditions. Lowdose weekly methotrexate has been proven to be
well tolerated over extended treatment periods.
Nevertheless, adverse side effects (ie, gastrointestinal
symptoms, mucosal ulceration) and systemic toxicities (ie, bone marrow suppression and hepatotoxicity) may hinder extended use of the drug. Because
long-term use of methotrexate is associated with
hepatotoxicity, frequent evaluation of liver function
tests and periodic liver biopsy are recommended
during therapy.1,2
Several studies have shown that supplementing
methotrexate therapy with either folic acid or folinic
acid (leucovorin)a synthetic form of reduced
folatecan reduce methotrexate toxicity (specifically, hepatotoxicity and gastrointestinal side effects)
without lowering its efficacy and thus allowing
for its continued use.3-11 Despite its success with

controlling methotrexate toxicity, the use of folates

is not consistently advocated in the dermatology
literature.

METHODS
A MEDLINE search using the terms methotrexate, folic acid, folinic acid, and leucovorin was
performed for the period January 1966 to December
2004. Literature relevant to the use of folates as
a supplement to methotrexate was reviewed. Only
studies involving patients with psoriasis, psoriatic
arthritis, rheumatoid arthritis, or juvenile idiopathic
arthritis were assessed. Patients in the studies had
been undergoing methotrexate therapy for at least
4 weeks with either folic acid, folinic acid, or placebo
supplementation. Studies that included patients receiving concomitant medications with methotrexate
for the treatment of psoriasis, psoriatic arthritis,
rheumatoid arthritis, or juvenile idiopathic arthritis
were excluded from this analysis.

MECHANISM OF ACTION
From the Departments of Dermatology and Dermatopharmacology, New York University School of Medicine.
Funding sources: None.
Conflicts of interest: None identified.
Reprint requests: Bruce E. Strober, MD, PhD, 560 First Ave, TCH158, New York, NY 10016. E-mail: b_strober@hotmail.com.
0190-9622/$30.00
2005 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2005.06.036

652

Methotrexate inhibits the reduction of folate

cofactors by binding intracellularly to dihydrofolate
reductase, preventing the conversion of dihydrofolate to tetrahydrofolate.2 Tetrahydrofolate acts as a
single-carbon transfer source in the production of
thymidylate, a necessary component of purine synthesis.12 Folates are also involved in the conversion of serine to glycine.2 In high doses, as used in
cancer chemotherapy, methotrexate depletes the

Strober and Menon 653

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Table I. Summary of studies on folate supplementation

Trial

Design

No. of
pts

Duhra3

Prospective,
open-label
study

78

Shiroky
et al4

Multicenter,
randomized, double-blind,
placebocontrolled
study

92

Morgan
et al5

Randomized,
doubleblind,
placebocontrolled
study

79

Ravelli
et al9

Retrospective,
noncontrolled
study

43

Suzuki
Retrospective 66, 14
et al10
review of
66 pts and
prospective
study of 14
pts w/ high
serum ALT

Disease
studied

Psoriasis

Outcomes measured

Frequency, severity,
dose-relationship of GI
symptoms from MTX
therapy; response to
folic acid suppl
RA
Relief of side effects (oral
ulcers, GI symptoms,
transaminase elevations)
from MTX tx w/ concurrent use of folinic acid.
Efficacy and disease activity assessed and evaluated by physicians and
pts global assessment
of disease activity, joint
tenderness and swelling
indices, morning stiffness, grip strength, 50-ft
walking time, and HAQ
disability index
RA
Effect of low- and highdose folic acid on toxicity and efficacy in pts on
low-dose MTX; efficacy
measured by changes in
joint swelling, joint
tenderness and pain
indices, physician and pt
global assessments, grip
strength, ESR, modified
HAQ
Juvenile No. of episodes of
hepatotoxicity (increase
idioin serum transaminase
pathic
levels), GI toxicity and
arthritis
disease flare per pt-year
of MTX tx before and
after folinic acid suppl

RA

Results

Comments

GI symptoms occurred Folate suppl

controlled GI sympin 32% of pts; symptoms w/o compromistoms relieved by MTX
(no statistics available) ing efficacy (no formal
evaluation of efficacy)
Mean weekly dose
Almost 50% fewer
of MTX at week 52 was
side effects in folinic
higher in folinic
acidetreated pts
acidetreated group
(17.3% vs 32.2%;
(13.6 vs 12.0 mg;
P \ .001); efficacy
P = .22); 22 pts
was unimpaired and
withdrew because
disease activity
of side effects, 17 of
remained similar
whom were receiving
placebo (P \ .01)

A composite
68% of pts
toxicity score was used
experienced some
toxicity; toxicity scores to measure adverse
events; toxicities
were greater in plaincluded alopecia,
cebo group than in
the 2 folic acid groups nausea, GI intolerance,
diarrhea, rash, elevated
(P = .001); no statistical difference between liver enzyme/creatinine
the 2 folic acid groups; levels, cytopenias
efficacy was similar in
all 3 groups (P [ .5)
Efficacy was
Mean No. of episodes
per pt-year of hepato- evaluated by assessing
toxicity and GI toxicity frequency of episodes
of disease flare and
decreased from 2.30
to 0.32 (P \ .001) and clinical remission
before and after folinic
from 1.09 to 0.29
(P = .002), respectively acid suppl; folinic acid
did not impair MTX
efficacy as episodes
of disease flare were
unchanged before and
after folinic acid suppl
Authors recommend that
ALT levels
Effect of folate
folic acid be given
suppl on serum ALT and decreased in all pts
when side effects
RA activity in 14 pts with w/in 3 mo; 11 pts
of folate deficiency
showed no change in
high serum ALT. RA
(" AST/ALT) occur
RA activity; 3 pts
activity measured by
during MTX tx
dropped out because
ESR, CRP, and joint
of exacerbation of RA
indices

654 Strober and Menon

J AM ACAD DERMATOL
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Table I. Contd
Trial

Design

No. of
pts

Disease
studied

75

RA

Multicenter,
randomized, double-blind,
placebocontrolled
study

434

RA

Hoekstra Multicenter,
et al7
randomized, double-blind,
placebocontrolled
study

411

RA

Joyce
Double-blind,
et al23
placebocontrolled
study

27

RA

Tishler
Prospective,
et al24
noncontrolled,
nonblinded
study

Griffith
Prospective,
et al11
randomized, double-blind,
placebocontrolled
study

van Ede
et al6

RA and
PA

Outcomes measured

Results

Comments

Although placebo
More pts concluded
Toxicity and efficacy
group had statistically
study early in the
after stopping folic
significant decreases in
placebo group (46%
acid suppl in RA pts
disease activity in a
vs 21%; P = .02); 3 pts
established on MTX
few variables, results
in placebo group
and cessation of MTX
were not clinically
discontinued because
because of inefficacy
significant
of oral ulcers, nausea,
or toxicity. Efficacy
and vomiting;
measured by Ritchie
increased incidence
index, pts and
of nausea in placebo
physicians global
group (45% vs 7%)
assessment
38% of placebo, 17% of In addition to
Frequency of MTX
hepatotoxicity, there
folic acid group, and
withdrawal due to
were no consistent
12% of folinic acid
adverse events and efdifferences in toxicity
group withdrew from
ficacy and toxicity of
among the 3 groups;
study because of
MTX. Efficacy of tx and
final MTX doses were
toxicity. Differences
disease activity mealower in placebo
between placebo
sured by ESR, pts
group (P \ .02)
group and folic acid
assessment of pain,
and folinic acid groups
number of tender and
were statistically
swollen joints, physisignificant (P \ .001
cians and pts global
for both comparisons);
assessments of disease
ALTs were statistically
activity, and pts ashigher in placebo
sessment of physical
group (P \ .0001); no
function. Arthritis Imsignificant differences
pact Measurement
in disease activity.
Scales used to measure
among the 3 groups
functional capacity.
Folate suppl decreased The higher MTX
Toxicity, final dose,
doses attained in the
hepatotoxicity
and efficacy of MTX
folate groups were
(P \ .001), which
w/ or w/o folates
likely due to decreased
occurred in 26% of
(folic acid and
toxicity in these pts
placebo and 4% of
folinic acid)
compared with
folate group; final
placebo and
dose of MTX was
decreased withdrawal
17.6 mg/wk in folate
from toxicity (52 in
group and 15.0 mg/wk
placebo group vs 30
in placebo group
in folate group)
(P \ .001)
This exacerbation
Folinic acid group
Toxicity and
was attributed to
showed worsening in
efficacy after folinic
timing of dose
Ritchie index (P \ .01),
acid suppl during
(2 h after MTX) and
pain (P \ .05), global
MTX tx
size of dose (twice
joint score (P \ .05),
dose of MTX)
ESR (P \ .05); toxicity
did not differ between
the 2 groups
Toxicity and
Folinic acid relieved
Exacerbations can be
efficacy after folinic
MTX-related nausea;
attributed to timing of
acid suppl during
pt experienced
folinic acid dose, 4-6 h
MTX tx
worsening of morning
after MTX dose.
stiffness, Ritchie index,
pts and physicians
subjective assessment
of pain, ESR (P \ .05)

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Table I. Contd
No. of
pts

Disease
studied

van Ede Multicenter,

et al19
doubleblind,
placebocontrolled
study

113

RA

Slot
Prospective,
et al21
nonblinded
study

15

Trial

Design

RA and
PA

Outcomes measured

Results

Comments

Folic acid can

Mean plasma
Homocysteine
relieve MTX-related
homocysteine level
levels before and after
hyperhomoafter treatment
treatment w/ MTX and
cysteinemia
increased in placebo
folates or placebo
group by 3.6 mol/L
(95% CI, 1.7 to 5.6) and
decreased in folic acid
group by
2.7 mol/L
(95% CI,
1.4 to
4.0)
and folinic acid group
by
1.6 (95% CI,
0.1
to
3.0)
Given increased
Plasma
Plasma
cardiovascular risk
homocysteine
homocysteine levels
associated w/ elevated
increased from 12.3 6
after MTX tx alone
plasma homocysteine,
3.4 mol/L at baseline
followed by addition
folic acid suppl is
to 14.6 6 5.8 mol/L
of folic acid suppl
recommended to
during MTX tx
relieve MTX-related
(P \ .05); w/ addition
hyperhomoof folic acid to MTX tx,
cysteinemia.
plasma homocysteine
levels decreased to
10.3 6 3.0 mol/L.

ALT, Alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation
rate; GI, gastrointestinal; HAQ, Health Assessment Questionnaire; MTX, methotrexate; PA, psoriatic arthritis; pt(s), patient(s); RA, rheumatoid
arthritis; suppl, supplementation; tx, therapy; w/, with; w/o, without.

intracellular stores of activated folate and thus disrupts DNA, RNA, and protein synthesis.
In low doses, as used in the treatment of psoriasis, psoriatic arthritis, and rheumatoid arthritis,
methotrexate has anti-inflammatory effects.14-17
Once absorbed, methotrexate is metabolized to
polyglutamate derivatives that are potent inhibitors
of a number of folate-dependent enzymes, including 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase.13,14,16 The inhibition
of AICAR transformylase leads to the accumulation
of AICAR, which subsequently inhibits adenosine
deaminase and adenosine monophosphate deaminase, resulting in increased concentrations of adenosine.14,16 Adenosine acts as an anti-inflammatory
agent by mediating cytokine secretion in macrophages and neutrophils and the expression of adhesion molecules including L-selecting, b2-integrin,
and CD11b.14,16 In addition, adenosine regulates
inflammation by binding to one or more of 4 known
receptors (A1, A2a, A2b, and A3). Of these receptors,
the A2a receptor has been shown to have the greatest
anti-inflammatory effects.14 From this perspective,
methotrexate augments the amount of adenosine, an
endogenous anti-inflammatory compound.

The mechanism by which folates bypass methotrexate toxicity is unclear. Folinic acid was designed
to circumvent dihydrofolate reductase inhibition
and reduce toxicity. Folinic acid is metabolized to
the 10-formyl-tetrahydrofolate, a cofactor used by
AICAR transformylase; it relieves methotrexate inhibition of this enzyme. Folinic acid may also compete
with methotrexate for transport into the cell and thus
interfere with the cellular uptake of methotrexate.14
It is believed that both folic acid and folinic acid
correct a state of folate deficiency.5

TOXICITY
Methotrexate treatment can cause multiple systemic side effects. Gastrointestinal side effects are the
most frequent, and the nausea, vomiting, and diarrhea that accompany therapy are often dose related.
Hepatotoxicity is assessed by monitoring transaminase levels and with periodic liver biopsies, although
transaminase levels sometimes can be unreliable, as
shown in a study of biopsy-proven fibrosis/cirrhosis
secondary to methotrexate, in which 35% of those
patients evaluated had normal liver transaminase
levels.12,18 Some physicians perform baseline liver
biopsies in those patients with a history of liver

656 Strober and Menon

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OCTOBER 2005

Table II. Recommendations for folate

supplementation
Supplement

Folic acid

Dosing

Comments

1 mg (oral) daily

Dose on day of MTX

administration, also
Folinic acid Weekly, 5 mg (oral) Consider using if
folic acid not ame(leucovorin) every 12 h 3 3
doses only, w/ first liorating laboratory
dose 24 h after last abnormalities (LFT
elevations) and
dose of weekly
symptoms of MTX
MTX
toxicity
LFT, Liver function test; MTX, methotrexate; w/, with.

disease or other risk factors for hepatotoxicity including age, obesity, alcohol intake, and diabetes.
Biopsies are generally recommended after a cumulative dose of 1 to 1.5 g of methotrexate and depend
on the individual patient. In most patients, liver
function tests are repeated every 4 to 8 weeks.2,12
Methotrexate can also cause stomatitis, alopecia, and
bone marrow suppression that results in leukopenia,
thrombocytopenia, or pancytopenia. Methotrexate
treatment can lead to increased plasma homocysteine concentrations, an independent risk factor for
cardiovascular disease.19-22
Do folates reduce methotrexate-induced
toxicity without lowering efficacy?
Folates alleviate gastrointestinal and liver toxicity,
allowing patients to continue methotrexate therapy.
Duhra3 followed up 78 patients with psoriasis who
were receiving low-dose, once-weekly, oral methotrexate therapy. Thirty-two percent of these patients
experienced gastrointestinal symptoms that were
greatly reduced with folic acid supplementation.
Importantly, Duhra stated that the efficacy of methotrexate in the treatment of psoriasis was not compromised, but this article is not clear as to whether
concomitant antipsoriatic therapies were allowed
during the observation period.
Studies in the rheumatologic literature examining
folic acid and folinic acid supplementation are more
extensive (see Table I).4-11 Methotrexate is a first-line
agent in the treatment of rheumatoid arthritis.
Shiroky et al4 conducted a randomized, doubleblind, placebo-controlled trial involving 92 patients
with rheumatoid arthritis receiving 2.5 to 5.0 mg
of folinic acid subsequent to a weekly oral dose of
methotrexate, ranging from 7.5 to 30.0 mg for
52 consecutive weeks. Folinic acid significantly
reduced gastrointestinal side effects and serum
transaminase levels without lowering efficacy. In a
similar randomized, double-blind, placebo-controlled

study, Morgan et al5 followed 79 patients with

rheumatoid arthritis receiving methotrexate who
were given placebo or either 5 or 27.5 mg of folic
acid weekly. Toxicity was lower in patients in
both folic acid groups compared with the placebo
group, and the efficacy of methotrexate remained
unaffected.
The withdrawal of folates in patients established
on methotrexate and folic acid therapy has been
shown to cause a recurrence of side effects, including nausea, vomiting, and mouth ulcers. Griffith
et al11 asked 75 patients receiving methotrexate
(\20 mg weekly) and folic acid (5 mg daily) to discontinue folic acid; they randomized the patients
into one of two groups: placebo or 5 mg folic acid
daily. The placebo group reported more nausea,
vomiting, mouth ulcers, and breaks from methotrexate therapy. Methotrexate efficacy in both groups
was unaffected.
Folate supplementation also decreases plasma
homocysteine levels and thus the risk for arterial
vascular disease.19,21,22 van Ede et al19 measured
plasma homocysteine levels in 113 patients with
rheumatoid arthritis before the initiation of methotrexate therapy. Patients were given either folic
acid, folinic acid, or placebo to supplement their
regimen and were observed for 48 weeks. Patients
receiving methotrexate with placebo were found
to have elevated plasma homocysteine levels. Both
folic acid and folinic acid reduced plasma homocysteine levels without interfering with methotrexate
efficacy.

EFFECTS ON THE BONE MARROW

Although liver function test abnormalities and side
effects related to methotrexate therapy are ameliorated by folate supplementation, the specific effects
on bone marrow suppression (ie, cytopenias) are less
well characterized. Shiroky et al4 evaluated hematologic events and observed no significant hematologic
abnormalities in either the placebo or folinic acid
groups. Morgan et al5 included the evaluation of
hematologic events as part of a larger composite
toxicity score, which was decreased in the folic acid
group. Griffith et al11 noted that two patients withdrew from the study because of neutropenia; both
patients were in the placebo group. Nevertheless, the
data on this issue are thinner, and therefore further
evaluation is necessary to determine a protective
effect of folic acid on the bone marrow.

IS FOLIC ACID BETTER THAN

FOLINIC ACID?
Folic acid and folinic acid, when compared with
each other, have been found to be equally effective

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in lowering methotrexate toxicity, particularly gastrointestinal side effects and hepatotoxicity.6,7 In

a 48-week, randomized, double-blind, placebocontrolled study, patients with active rheumatoid
arthritis receiving methotrexate were treated with
1 mg folic acid daily or 2.5 mg of folinic acid weekly.6
Both folate supplementation regimens reduced the
incidence of elevated liver enzyme levels during
methotrexate therapy. Differences with regard to
adverse events and toxicities between the two
groups were statistically insignificant. The efficacy
of methotrexate was unchanged. Additionally, supplementation with folates allowed 83% of patients
to continue using methotrexate at 48 weeks, compared with only 62% of those receiving methotrexate
alone.
However, one study of folinic acid, at a dose of 15
mg weekly for the treatment of rheumatoid arthritis
showed reduced methotrexate efficacy and exacerbation of the rheumatoid arthritis.23 This exacerbation was attributed not only to the timing of the
dose2 hours after the weekly methotrexate dose
but also the size of the dose (twice the dose of the
methotrexate). In another study, 15 mg of folinic acid
was administered for 3 consecutive days beginning 4
to 6 hours after a 7.5- to 12.5-mg dose of methotrexate. Although nausea was prevented, worsening of
disease occurred in all patients.24 In other studies
that show no reduction of methotrexate efficacy in
the setting of folinic acid supplementation, folinic
acid was given 24 hours after methotrexate administration.4,25 Therefore the exact timing of folinic acid
supplementation may play a large role in maintaining the therapeutic benefit of methotrexate. Varying
the dose and timing of folic acid does not appear to
affect methotrexate efficacy.13
A meta-analysis of 7 trials of either folic acid or
folinic acid supplementation in lowering methotrexate toxicity in patients with rheumatoid arthritis
shows that folic acid reduces mucosal and gastrointestinal side effects by 79%, whereas folinic acid
lowered toxicity by 43%, a difference that is statistically insignificant.26 No consistent differences were
found in disease activity when comparing both
folates, implying that either approach to folate supplementation does not affect treatment efficacy.
Biochemically, folinic acid may have a greater
effect in reducing methotrexate efficacy.5 Increased
levels of urinary 5-aminoimidazole-4 carboxamide
(AICA), a metabolite of AICAR, indicate the inhibition of AICAR transformylase and have been correlated with reduced disease activity in patients with
rheumatoid arthritis and psoriasis.5,27 Increased urinary levels of adenosine in psoriasis patients has also
been linked to reduced disease activity.27 Folinic

acid normalized AICA values in a study of 40 patients

with rheumatoid arthritis who received 6 weeks of
methotrexate therapy and who were randomized to
receive either folic acid or folinic acid.5 After the first
6 weeks, 24-hour urinary AICA levels were elevated,
compared with baseline levels. Adenosine excretion
was not affected by either supplement.
Folic acid is significantly less expensive than
folinic acid. A 1-mg tablet of folic acid costs $0.08
($0.56 per week).28 A weekly dose of 15-mg folinic
acid costs approximately $10.28 A cost-benefit analysis of both folates that factored in both medical
and nonmedical costs demonstrated no statistically
significant differences between the two folates.8
Nevertheless, when only total medical costs were
examined, the cost was lower for folic acid.8
Therefore, because of its lower cost and comparable
efficacy, folic acid is recommended as the first-line
folate supplement. However, folinic acid remains the
first choice in the treatment of methotrexate overdose or acute hematologic toxicity.13

CONCLUSION
The use of folates increases the likelihood of
efficacious long-term, tolerable, and toxicity-free
therapy for patients receiving methotrexate. Primarily shown in studies of rheumatoid arthritis, folates
reduce adverse effects and toxicities without affecting efficacy. Because folinic acid has a substantially
higher cost without a significant advantage in preventing methotrexate-related side effects, folic acid
should be prescribed as a first-line supplement to
patients receiving methotrexate for the treatment of
psoriasis. The beneficial effects of folic acid are not
depen-dent on timing; therefore it can be given every
day, including the day of methotrexate administration. Folinic acid should be considered in circumstances in which folic acid appears to be ineffective
in enhancing both the tolerability and safety of
methotrexate. The use of folinic acid should consider the timing of its administration because dosing
folinic acid too close (within 24 hours) to the administration of methotrexate may hinder efficacy (see
dosing recommendations in Table II). The limitation
of our analysis is the sparse information on the use
of folate supplementation in psoriasis patients. In
fact, we could only identify one study by Duhra that
evaluated psoriasis patients receiving folates during
methotrexate therapy; although this study did not
illustrate any impact of supplementation on treatment efficacy, the author did not formally describe
this analysis.3 In a recent comparison between the
efficacy and tolerability of cyclosporine and methotrexate for the treatment of psoriasis, approximately 25% of the methotrexate-treated subjects

658 Strober and Menon

J AM ACAD DERMATOL
OCTOBER 2005

had elevations in liver enzyme levels over the course

of 16 weeks of therapy. In this study patients did not
receive folate supplementation while receiving
methotrexate (V. M. R. Heydendael, written communication, May 2005).29
Rheumatoid arthritis and psoriasis share many
pathophysiologic similarities and have been shown
to respond to similar therapies; therefore it is logical
to assume that the data derived from studies
of rheumatoid arthritis relate similarly to psoriasis
and psoriatic arthritis. Given the current data on
rheumatoid arthritis, methotrexate therapy with
folate supplementation may allow for a safer, efficacious, and better-tolerated therapeutic experience
for patients with psoriasis and psoriatic arthritis.
Future randomized, controlled trials in psoriasis patients may ultimately prove this contention. In summary, both on the basis of our interpretation of the
available data and clinical experience, our practice is
to prescribe folate supplementation for every patient
who receives methotrexate.

11.

12.
13.

14.
15.

16.

17.
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SHE IS SPOKE

Dermatologic stenography

What I dictated: keratoacanthoma

What got typed: carried away canthoma
What my colleague dictated: lichen sclerosis et atrophicus
What got typed: Likened sclerosis at the tropicus
Mark C. Valentine, MD
Everett, Washington
doi:10.1016/j.jaad.2005.05.025