j.jaad.2005.06.036

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Folate supplementation during methotrexatetherapy 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. Folatesupplementation is often used to ameliorate methotrexate-associated side effects and toxicities. We soughtto demonstrate that folate supplementation during methotrexate therapy reduces both toxicity and sideeffects 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 supplementto methotrexate was reviewed. According to studies reviewed, the use of folate supplements in patientstreated with methotrexate reduces the incidence of hepatotoxicity and gastrointestinal intolerance withoutimpairing the efficacy of methotrexate. Both folic acid and folinic acid are equally effective; however, folicacid is more cost effective. It must be noted that there are relatively few studies that have addressed folatesupplementation with the use of methotrexate for the treatment of psoriasis. After examining the availabledata 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.)

Methotrexate is considered among the mosteffective treatments for rheumatoid arthri-tis, moderate to severe psoriasis, and other

autoimmune and inflammatory conditions. Low-dose weekly methotrexate has been proven to be well tolerated over extended treatment periods.Nevertheless, adverse side effects (ie, gastrointestinal

symptoms, mucosal ulceration) and systemic toxic-ities (ie, bone marrow suppression and hepatotox-icity) may hinder extended use of the drug. Becauselong-term use of methotrexate is associated withhepatotoxicity, frequent evaluation of liver functiontests and periodic liver biopsy are recommendedduring therapy.1,2

Several studies have shown that supplementingmethotrexate therapy with either folic acid or folinicacid (leucovorin)—a synthetic form of reducedfolate—can reduce methotrexate toxicity (specifi-cally, hepatotoxicity and gastrointestinal side effects)

without lowering its eff icacy and thus allowingfor its continued use.3-11 Despite its success with

controlling methotrexate toxicity, the use of folatesis not consistently advocated in the dermatology literature.

METHODS A MEDLINE search using the terms ‘‘methotrex-

ate,’’ ‘‘folic acid,’’ ‘‘folinic acid,’’ and ‘‘leucovorin’’ wasperformed for the period January 1966 to December2004. Literature relevant to the use of folates asa supplement to methotrexate was reviewed. Only studies involving patients with psoriasis, psoriaticarthritis, rheumatoid arthritis, or juvenile idiopathicarthritis were assessed. Patients in the studies hadbeen undergoing methotrexate therapy for at least4 weeks with either folic acid, folinic acid, or placebosupplementation. Studies that included patients re-ceiving concomitant medications with methotrexatefor the treatment of psoriasis, psoriatic arthritis,

rheumatoid arthritis, or juvenile idiopathic arthritis were excluded from this analysis.

MECHANISM OF ACTIONMethotrexate inhibits the reduction of folate

cofactors by binding intracellularly to dihydrofolatereductase, preventing the conversion of dihydrofo-late to tetrahydrofolate.2 Tetrahydrofolate acts as asingle-carbon transfer source in the production of thymidy late, a necessary component of purine syn-thesis.12 Folates are also involved in the conver-sion of serine to glycine.2 In high doses, as used in

cancer chemotherapy, methotrexate depletes the

From the Departments of Dermatology and Dermatopharmacol-

ogy, New York University School of Medicine.

Funding sources: None.

Conflicts of interest: None identified.

Reprint requests: Bruce E. Strober, MD, PhD, 560 First Ave, TCH-

158, New York, NY 10016. E-mail: [email protected].

0190-9622/$30.00

ª 2005 by the American Academy of Dermatology, Inc.

doi:10.1016/j.jaad.2005.06.036

652

mailto:[email protected]



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Table I. Summary of studies on folate supplementation

Trial Design

No. of

pts

Disease

studied Outcomes measured Results Comments

Duhra3 Prospective,

open-label

study

78 Psoriasis Frequency, severity,

dose-relationship of GI

symptoms from MTXtherapy; response to

folic acid suppl

GI symptoms occurred

in 32% of pts; symp-

toms relieved by MTX(no statistics available)

Folate suppl

controlled GI symp-

toms w/o compromis-ing efficacy (no formal

evaluation of efficacy)

Shiroky

et al4Multicenter,

random-

ized, dou-

ble-blind,

placebo-

controlled

study

92 RA Relief of side effects (oral

ulcers, GI symptoms,

transaminase elevations)

from MTX tx w/ concur-

rent use of folinic acid.

Efficacy and disease ac-

tivity assessed and eval-

uated by physician’s and

pt’s global assessment

of disease activity, joint

tenderness and swelling

indices, morning stiff-ness, grip strength, 50-ft

walking time, and HAQ

disability index

Almost 50% fewer

side effects in folinic

acidetreated pts

(17.3% vs 32.2%;P \ .001); efficacy

was unimpaired and

disease activity

remained similar

Mean weekly dose

of MTX at week 52 was

higher in folinic

acidetreated group

(13.6 vs 12.0 mg;P = .22); 22 pts

withdrew because

of side effects, 17 of

whom were receiving

placebo (P \ .01)

Morgan

et al5Randomized,

double-

blind,

placebo-

controlled

study

79 RA Effect of low- and high-

dose folic acid on toxic-

ity 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, modifiedHAQ

68% of pts

experienced some

toxicity; toxicity scores

were greater in pla-

cebo group than in

the 2 folic acid groups

(P = .001); no statisti-

cal difference between

the 2 folic acid groups;

efficacy was similar inall 3 groups (P [ .5)

A composite

toxicity score was used

to measure adverse

events; toxicities

included alopecia,

nausea, GI intolerance,

diarrhea, rash, elevated

liver enzyme/creatinine

levels, cytopenias

Ravelli

et al9Retrospective,

noncon-

trolled

study

43 Juvenile

idio-

pathic

arthritis

No. of episodes of

hepatotoxicity (increase

in serum transaminase

levels), GI toxicity and

disease flare per pt-year

of MTX tx before and

after folinic acid suppl

Mean No. of episodes

per pt-year of hepato-

toxicity and GI toxicity

decreased from 2.30

to 0.32 (P \ .001) and

from 1.09 to 0.29

(P = .002), respectively

Efficacy was

evaluated by assessing

frequency of episodes

of disease flare and

clinical remission

before and after folinic

acid suppl; folinic acid

did not impair MTX

efficacy as episodes

of disease flare were

unchanged before and

after folinic acid supplSuzuki

et al10Retrospective

review of

66 pts and

prospective

study of 14

pts w/ high

serum ALT

66, 14 RA Effect of folate

suppl on serum ALT and

RA activity in 14 pts with

high serum ALT. RA

activity measured by

ESR, CRP, and joint

indices

ALT levels

decreased in all pts

w/in 3 mo; 11 pts

showed no change in

RA activity; 3 pts

dropped out because

of exacerbation of RA

Authors recommend that

folic acid be given

when side effects

of folate deficiency

(" AST/ALT) occur

during MTX tx

J A M A CAD DERMATOL

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Table I. Cont’d

Trial Design

No. of

pts

Disease

studied Outcomes measured Results Comments

Griffith

et al11Prospective,

random-

ized, dou-ble-blind,

placebo-

controlled

study

75 RA Toxicity and efficacy

after stopping folic

acid suppl in RA ptsestablished on MTX

and cessation of MTX

because of inefficacy

or toxicity. Efficacy

measured by Ritchie

index, pts’ and

physician’s global

assessment

More pts concluded

study early in the

placebo group (46%vs 21%; P = .02); 3 pts

in placebo group

discontinued because

of oral ulcers, nausea,

and vomiting;

increased incidence

of nausea in placebo

group (45% vs 7%)

Although placebo

group had statistically

significant decreases indisease activity in a

few variables, results

were not clinically

significant

van Ede

et al6Multicenter,

random-

ized, dou-

ble-blind,

placebo-

controlledstudy

434 RA Frequency of MTX

withdrawal due to

adverse events and ef-

ficacy and toxicity of

MTX. Efficacy of tx and

disease activity mea-sured by ESR, pt’s

assessment of pain,

number of tender and

swollen joints, physi-

cian’s and pt’s global

assessments of disease

activity, and pt’s as-

sessment of physical

function. Arthritis Im-

pact Measurement

Scales used to measure

functional capacity.

38% of placebo, 17% of

folic acid group, and

12% of folinic acid

group withdrew from

study because of

toxicity. Differencesbetween placebo

group and folic acid

and folinic acid groups

were statistically

significant (P \ .001

for both comparisons);

ALTs were statistically

higher in placebo

group (P \ .0001); no

significant differences

in disease activity.

among the 3 groups

In addition to

hepatotoxicity, there

were no consistent

differences in toxicity

among the 3 groups;

final MTX doses werelower in placebo

group (P \ .02)

Hoekstraet al7

Multicenter,random-

ized, dou-

ble-blind,

placebo-

controlled

study

411 RA Toxicity, final dose,and efficacy of MTX

w/ or w/o folates

(folic acid and

folinic acid)

Folate suppl decreasedhepatotoxicity

(P \ .001), which

occurred in 26% of

placebo and 4% of

folate group; final

dose of MTX was

17.6 mg/wk in folate

group and 15.0 mg/wk

in placebo group

(P \ .001)

The higher MTXdoses attained in the

folate groups were

likely due to decreased

toxicity in these pts

compared with

placebo and

decreased withdrawal

from toxicity (52 in

placebo group vs 30

in folate group)

Joyce

et al23Double-blind,

placebo-

controlledstudy

27 RA Toxicity and

efficacy after folinic

acid suppl duringMTX tx

Folinic acid group

showed worsening in

Ritchie index (P \

.01),pain (P \ .05), global

joint score (P \ .05),

ESR (P \ .05); toxicity

did not differ between

the 2 groups

This exacerbation

was attributed to

timing of dose(2 h after MTX) and

size of dose (twice

dose of MTX)

Tishler

et al24Prospective,

noncon-

trolled,

nonblinded

study

7 RA and

PA

Toxicity and

efficacy after folinic

acid suppl during

MTX tx

Folinic acid relieved

MTX-related nausea;

pt experienced

worsening of morning

stiffness, Ritchie index,

pt’s and physician’s

subjective assessment

of pain, ESR (P \ .05)

Exacerbations can be

attributed to timing of

folinic acid dose, 4-6 h

after MTX dose.


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in lowering methotrexate toxicity, particularly gas-trointestinal side effects and hepatotoxicity.6,7 Ina 48-week, randomized, double-blind, placebo-controlled study, patients with active rheumatoidarthritis receiving methotrexate were treated with1 mg folic acid daily or 2.5 mg of folinic acid weekly.6

Both folate supplementation regimens reduced theincidence of elevated liver enzyme levels duringmethotrexate therapy. Differences with regard toadverse events and toxicities between the twogroups were statistically insignificant. The efficacy of methotrexate was unchanged. Additionally, sup-plementation with folates allowed 83% of patientsto continue using methotrexate at 48 weeks, com-pared with only 62% of those receiving methotrexatealone.

However, one study of folinic acid, at a dose of 15mg weekly for the treatment of rheumatoid arthritis

showed reduced methotrexate efficacy and exacer-bation of the rheumatoid arthritis.23 This exacerba-tion was attributed not only to the timing of thedose—2 hours after the weekly methotrexate dose— but also the size of the dose (twice the dose of themethotrexate). In another study, 15 mg of folinic acid was administered for 3 consecutive days beginning 4to 6 hours after a 7.5- to 12.5-mg dose of methotrex-ate. Although nausea was prevented, worsening of disease occurred in all patients.24 In other studiesthat show no reduction of methotrexate efficacy inthe setting of folinic acid supplementation, folinic

acid was gi ven 24 hours after methotrexate admin-istration.4,25 Therefore the exact timing of folinic acidsupplementation may play a large role in maintain-ing the therapeutic benefit of methotrexate. Varyingthe dose and timing of folic acid does not appear toaffect methotrexate efficacy.13

A meta-analysis of 7 trials of either folic acid orfolinic acid supplementation in lowering methotrex-ate toxicity in patients with rheumatoid arthritisshows that folic acid reduces mucosal and gastroin-testinal side effects by 79%, whereas folinic acidlowered toxicity b y 43%, a difference that is statisti-

cally insignificant.26

No consistent differences werefound in disease activity when comparing bothfolates, implying that either approach to folate sup-plementation does not affect treatment efficacy.

Biochemically, folinic acid may have a greatereffect in reducing methotrexate efficacy.5 Increasedlevels of urinary 5-aminoimidazole-4 carboxamide(AICA), a metabolite of AICAR, indicate the inhibi-tion of AICAR transformylase and have been corre-lated with reduced disease activit y in patients withrheumatoid arthritis and psoriasis.5,27 Increased uri-nary 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 toreceive either folic acid or folinic acid.5 After the first6 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 thanfolinic acid. A 1-mg tablet of folic acid costs $0.08($0.56 per week).28 A weekly dose of 15-mg folinicacid costs approximately $10.28 A cost-benefit analysis of both folates that factored in both medicaland nonmedical costs demonstrated no statisticall y significant differences between the two folates.8

Nevertheless, when only total medical costs wereexamined, the cost was lower for folic acid.8

Therefore, because of its lower cost and comparableefficacy, folic acid is recommended as the first-line

folate supplement. However, folinic acid remains thefirst choice in the treatment of methotrexate over-dose or acute hematologic toxicity.13

CONCLUSIONThe use of folates increases the likelihood of

efficacious long-term, tolerable, and toxicity-freetherapy for patients receiving methotrexate. Primar-ily shown in studies of rheumatoid arthritis, folatesreduce adverse effects and toxicities without affect-ing efficacy. Because folinic acid has a substantially higher cost without a significant advantage in pre-

venting methotrexate-related side effects, folic acidshould be prescribed as a first-line supplement topatients receiving methotrexate for the treatment of psoriasis. The beneficial effects of folic acid are notdepen-dent on timing; therefore it can be given every day, including the day of methotrexate administra-tion. Folinic acid should be considered in circum-stances in which folic acid appears to be ineffectivein enhancing both the tolerability and safety of methotrexate. The use of folinic acid should con-sider the timing of its administration because dosingfolinic acid too close (within 24 hours) to the admi-

nistration of methotrexate may hinder efficacy (seedosing recommendations in Table II). The limitationof our analysis is the sparse information on the useof folate supplementation in psoriasis patients. Infact, we could only identify one study by Duhra thatevaluated psoriasis patients receiving folates duringmethotrexate therapy; although this study did notillustrate any impact of supplementation on treat-ment efficac y, the author did not formally describethis analysis.3 In a recent comparison between theefficacy and tolerability of cyclosporine and metho-trexate for the treatment of psoriasis, approxi-

mately 25% of the methotrexate-treated subjects



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had elevations in liver enzyme levels over the courseof 16 weeks of therapy. In this study patients did notreceive folate supplementation while receivingmethotrexate (V. M. R. Heydendael, written commu-nication, May 2005).29

Rheumatoid arthritis and psoriasis share many pathophysiologic similarities and have been shownto respond to similar therapies; therefore it is logicalto assume that the data derived from studiesof rheumatoid arthritis relate similarly to psoriasisand psoriatic arthritis. Given the current data onrheumatoid arthritis, methotrexate therapy withfolate supplementation may allow for a safer, effica-cious, and better-tolerated therapeutic experiencefor patients with psoriasis and psoriatic arthritis.Future randomized, controlled trials in psoriasis pa-tients may ultimately prove this contention. In sum-mary, both on the basis of our interpretation of the

available data and clinical experience, our practice isto prescribe folate supplementation for every patient who receives methotrexate.

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DERMATOLOGY AS 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



http://www.drugstore.com/pharmacy/prices/drugprice.asp?ndc=00143124810&trx=1Z5006









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