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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
J AM ACAD DERMATOL
VOLUME 53, NUMBER 4
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
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
J AM ACAD DERMATOL
OCTOBER 2005
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)
J AM ACAD DERMATOL
VOLUME 53, NUMBER 4
Table I. Contd
No. of
pts
Disease
studied
113
RA
Slot
Prospective,
et al21
nonblinded
study
15
Trial
Design
RA and
PA
Outcomes measured
Results
Comments
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
J AM ACAD DERMATOL
OCTOBER 2005
Folic acid
Dosing
Comments
1 mg (oral) daily
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
J AM ACAD DERMATOL
VOLUME 53, NUMBER 4
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
J AM ACAD DERMATOL
OCTOBER 2005
11.
12.
13.
14.
15.
16.
17.
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J AM ACAD DERMATOL
VOLUME 53, NUMBER 4
DERMATOLOGY AS
SHE IS SPOKE
Dermatologic stenography