British Journal of Dermatology
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Volume 160, Issue 3, Pages 622-628
Published Online: 20 Oct 2008
EPIDEMIOLOGY AND HEALTH SERVICES RESEARCH
Effect of folic or folinic acid supplementation on
methotrexate-associated safety and efficacy in
inflammatory disease: a systematic review
S. Prey and C. Paul
Department of Dermatology, Paul Sabatier University and Purpan Hospital, 31 059 Toulouse cedex 9, France
Correspondence to Sorilla Prey.
E-mail: prey.s@chu-toulouse.fr
Conflicts of interest
None declared.
KEYWORDS
folic acid • folinic acid • methotrexate • psoriasis
ABSTRACT
Background Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for
more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis.
Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal
tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation.
Objectives We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with
methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the
efficacy of methotrexate.
Methods Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in
patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study
selection, assessment of methodological quality, data extraction and analysis were carried out by two independent
researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each
subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic.
Results Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were
257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The
statistical analysis showed a significant reduction of 35·8% of hepatic side-effects induced by methotrexate for
patients with supplementation with folic or folinic acid (95% confidence interval −0·467 to −0·248). There was no
statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of
supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately
due to a low incidence of these events in the population studied. We were unable to analyse the effect of
supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not
comparable.
Conclusions Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated
with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the
latter promotes its use.
Accepted for publication 14 July 2008
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1365-2133.2008.08876.x About DOI
ARTICLE TEXT
Methotrexate is a standard treatment for several inflammatory disorders, particularly rheumatoid arthritis, psoriasis
and chronic juvenile arthritis. Methotrexate is a dihydrofolate reductase inhibitor which prevents the multiplication of
rapidly dividing cells.1 Some authors suggest that the toxicity of this drug is a result of folate depletion. The main
limitations of methotrexate therapy are represented by adverse reactions which are seen in 5–35% of patients at
5 years.2,3 The most common are myelosuppression, gastrointestinal manifestations (nausea, vomiting, mouth
sores, loss of appetite), hair loss, malaise and elevated liver enzymes.
The development of methotrexate treatment in psoriasis was largely empirical and controlled trials investigating the
appropriate dose and risk factors for toxicity are lacking. Supplementation with folic or folinic acid has been
advocated to reduce side-effects associated with methotrexate therapy.4,5 In dermatology, folic acid
supplementation is not given routinely by all dermatologists in patients receiving methotrexate. According to a
European survey, only 32% of dermatologists used folic acid supplementation in all patients on methotrexate. 6 This
percentage rose to 58% in a more recent evaluation made in 2004 to the entire consultant membership (n = 531) of
the British Association of Dermatologists.7 It has been shown that patients with severe psoriasis often have folic
acid depletion. Such depletion may be associated with an increase in their cardiovascular risk through
hyperhomocysteinaemia.8 The purpose of this systematic review was to assess the evidence regarding the efficacy
of folic or folinic acid supplementation to prevent methotrexate-associated adverse reactions in the treatment of
inflammatory diseases. In addition, we sought to investigate the potential effect of folic acid supplementation on
methotrexate efficacy.
Materials and methods
Search methods for identification of studies
Electronic searches
The Cochrane Skin Group Specialized Trials Register, Cochrane Controlled Trials Register, MEDLINE and
EMBASE were searched using the strategy developed by Dickersin et al. in 1994.9 We searched using the term
'methotrexate' combined with 'folic acid', 'folinic acid', 'leucovorin', 'toxicity' and 'side effects' for the period 1990–
2007. Publications considered as relevant were randomized controlled trials (RCTs) and meta-analyses.
Handsearching
Reference lists of all the trials selected through the electronic search were manually searched to identify additional
trials.
Criteria for considering studies for this review
Types of studies
RCTs and clinical controlled trials comparing folic or folinic acid supplementation with placebo for patients treated
with methotrexate for inflammatory disease.
Types of participants
Only studies involving patients with rheumatoid arthritis or psoriasis with or without arthritis were assessed. Studies
including patients with concomitant systemic medications that may affect the outcome of the inflammatory disorders
were excluded from this analysis.
Types of intervention
All groups: methotrexate (oral or parenteral) at a dose level of at least 7·5 mg per week.
Intervention group: folic or folinic acid.
Control group: placebo.
Duration of treatment in double-blind phase: at least 12 weeks.
Methodological quality
The methodological quality of the studies was assessed by two reviewers using a quality scale. 10 The studies
approved had to be double-blinded RCTs. All of them had to contain enough detail in their data to make a metaanalysis. When data were missing, the authors were contacted. When no answer was given, these trials were
removed from the statistical analysis.
Description of studies
In total, nine relevant studies were found by performing an electronic search. These studies were conducted
between 1988 and 2007. Six of these trials were included in this review: all were RCTs, and their characteristics are
summarized in Table 1.11–16 Five trials were performed with patients treated for rheumatoid arthritis, and one with
patients treated for psoriasis (with or without arthritis).
Table 1 References to trials included in this review
Reference
(first author
and year)
Interventions
No.
patients,
condition
Follow
up
Salim (2006)11
Double-blind RCT: placebo
vs. folic acid 5 mg daily
22, psoriasis
12 weeks
van Ede
(2001)12
Double-blind RCT: placebo
vs. folic acid 1 mg daily;
placebo vs. folinic acid
2·5 mg weekly
Double-blind RCT: placebo
vs. folic acid 5 mg daily
411, RA
48 weeks
75, RA
30 months
Griffith
(2000)13
Results
Same side-effects except no data about liver
toxicity; lower efficacy of methotrexate
(higher PASI, DLQI, VAS score)
Supplementation reduces liver toxicity, but
not gastrointestinal or mucosal side-effects;
same efficacy with lower doses of
methotrexate in placebo group
More withdrawals because of nausea in
placebo group
Weinblatt
(1993)14
Shiroky
(1993)15
Morgan
(1990)16
Double-blind RCT: placebo
vs. folinic acid 1 mg weekly
Double-blind RCT: placebo
vs. folinic acid 2·5–5 mg
weekly
Double-blind RCT: placebo
vs. folic acid 1 mg daily
16, RA
8 weeks
No differences in efficacy
92, RA
52 weeks
32, RA
24 weeks
Lower hepatic, gastrointestinal and mucosal
toxicity with folinic acid; no differences in
efficacy
Lower toxicity score with folic acid; no
differences in efficacy
RCT, randomized controlled trial; RA, rheumatoid arthritis; PASI, Psoriasis Area and Severity Index; DLQI, Dermatology
Life Quality Index; VAS, visual analogue scale.
Three trials evaluated the effect of supplementation with folic acid (dose ranging from 1 to 5 mg per day, 5–7 days a
week), two investigated the effect of supplementation with folinic acid (dose ranging from 1 to 5 mg per week), and
one evaluated the effect of both treatments vs. placebo.12 This RCT was included in the evaluation of the effect of
both folic and folinic acid supplementation in the meta-analysis.12
We had to estimate the number of adverse events reported in the trial of Shiroky et al.,15 as these results were
given by visit, and not by patient. As a consequence, we compiled the mean number of adverse events by visit as
an estimate of the incidence of adverse events during the study in each group.
The data from the poster by Pinarbasi et al.17 could not be extracted and this small study was excluded from the
analysis. The study by Morgan et al. performed in 199418 could not be analysed, because details of each sideeffect, which resulted in the toxicity score, were not given by the authors. The study by Hanrahan and Russell 19
could not be included because it is a cross-over study, with a short follow-up of their patients (4 weeks of treatment)
which is not long enough. The aim of this study was to demonstrate a diminution of side-effects for patients who
already had these side-effects at the beginning of the study. Characteristics of excluded studies are summarized in
Table 2.
Table 2 References to studies excluded in this review
Reference
(first author
and year)
Interventions
Pinarbasi
(2007)17
No. patients,
condition
Follow
up
RCT: placebo vs. folic acid
5 mg daily for 5 days
42, psoriasis
Unknown
Strober
(2005)21
Whittle
(2001)20
Review
Psoriasis + RA
Ortiz (1998)4
Meta-analysis of 11 trials
307, RA
Morgan
(1994)18
Double-blind RCT: placebo
vs. folic acid 5 mg weekly;
placebo vs. folic acid 27·5 mg
weekly
Double-blind, cross-over
RCT: placebo vs. folinic acid
20 mg weekly
79, RA
Hanrahan
(1988)19
Review: folic acid 5 mg
weekly
13, RA
Results
Lower haematological and mucosal
toxicity with folic acid; no differences
in efficacy (PASI)
Folic acid reduces side-effects without
affecting efficacy
Folic acid reduces homocysteine level,
cardiovascular risk and hepatic and
gastrointestinal side-effects
Reduction of gastrointestinal or
mucosal side-effects (folic acid 79%,
folinic acid 42%, NS); no differences
in disease activity
12 months Lower gastrointestinal and mucosal
toxicity with folic acid
supplementation; no differences in
efficacy; no ITT
4 weeks
No differences in terms of incidence of
nausea
RCT, randomized controlled trial; RA, rheumatoid arthritis; PASI, Psoriasis Area and Severity Index; NS, not significant;
ITT, intent to treat.
We also found a meta-analysis performed by Ortiz et al. and published in the Cochrane databases,4,5 and two
reviews on the topic of folic or folinic acid supplementation. 20,21
Statistical analysis
All analyses were performed by using the statistical software Meta-analysis Version 1.2.0 (Tecnopharma, Osaka,
Japan, 2004). Absolute risk reductions (ARRs) were calculated with the pooled random effect model. Results are
given with 95% confidence intervals (CIs).
Results
Effects of supplementation on reducing side-effects
Gastrointestinal side-effects
The number of patients having diarrhoea, nausea and abdominal pain was assessed in all trials. Supplementation
with folic and folinic acid was associated with a slight reduction of the incidence of gastrointestinal side-effects
which was not significant (ARR = −0·086, 95% CI −0·188 to 0·016; Fig. 1).
Fig 1. Comparison of supplementation vs. placebo,
outcome gastrointestinal side-effects.
[Normal View ]
Mucosal and cutaneous side-effects
To assess the effect of supplementation on the risk of mucosal and cutaneous side-effects, we calculated in each
study the number of cases of mouth ulceration, stomatitis, rash and alopecia. There was a trend for a reduction in
the risk of mucosal and cutaneous side-effects in patients receiving folic or folinic acid (ARR = −0·072, 95% CI
−0·181 to 0·037; Fig. 2).
Fig 2. Comparison of supplementation vs. placebo,
outcome mucocutaneous side-effects.
[Normal View ]
Haematological side-effects
Few cases of haematological complications were reported during these RCTs (neutropenia, lymphopenia,
anaemia). The incidence was 2·10% in the placebo group and 2·15% in the supplementation group. With these
limitations in mind, there was no significant reduction of haematological complications in patients receiving
supplementation (ARR = 0·004, 95% CI −0·018 to 0·026; Fig. 3).
Fig 3. Comparison of supplementation vs. placebo,
outcome haematological side-effects.
[Normal View ]
Hepatic side-effects
We considered as abnormal alanine aminotransferase values greater than twice the upper limit of normal levels.
Folic and folinic acid supplementation significantly reduced the risk of liver enzyme elevation in patients treated with
methotrexate (ARR = −0·358, 95% CI −0·467 to −0·248; Fig. 4a). The effect was seen in patients treated both with
folic acid (ARR = −0·309, 95% CI −0·512 to −0·105; Fig. 4b) and with folinic acid (ARR = −0·389, 95% CI −0·568 to
−0·209; Fig. 4c).
Fig 4. (a) Comparison of all supplementation vs. placebo,
outcome hepatic side-effects. (b) Comparison of
supplementation with folic acid vs. placebo, outcome
hepatic side-effects. (c) Comparison of supplementation
with folinic acid vs. placebo, outcome hepatic side-effects.
[Normal View ]
Effects of supplementation on methotrexate efficacy
Rheumatoid arthritis
Because of the heterogeneity of parameters of evaluation, pooling of all data is precluded (Table 3). If we
considered the results of each study, folic or folinic acid supplementation had little influence on the efficacy of
methotrexate in patients with rheumatoid arthritis. However, in three studies a lower dose of methotrexate was
required to obtain a clinical response in the placebo group. The difference between doses of methotrexate was
significant in one of the three trials.12,15,18
Table 3 Effect of supplementation on efficacy of methotrexate
Reference (first
author and year)
Rheumatoid arthritis
van Ede (2001)12
Griffith (2000)13
Morgan (1994)18
Weinblatt (1993)14
Shiroky (1993)15
Morgan (1990)16
Hanrahan (1988)19
Psoriasis
Pinarbasi (2007)17
Salim (2006)11
Methotrexate dosage lower in placebo group: 14·5/18·0/16·4 mg weekly (P < 0·001) for
placebo/folic acid/folinic acid groups
Less disease activity in placebo group (NS): Ritchie index 6·79/10·03 (P = 0·04); patient's global
assessment 39·75/54·37 (P = 0·02); doctor's global assessment 28·67/41·88 (P = 0·01)
Improvement of the swelling index in 68/78/78% of patients (placebo/low dose/high dose);
methotrexate dosage lower in placebo group: 8·5/9·4/9·6 mg weekly (P = 0·27)
Same efficacy
Same efficacy in disease activity; HAQ disability −0·70/−0·45 for placebo/folinic acid groups
(P = 0·05); methotrexate dosage lower in placebo group: 12·0/13·6 mg weekly (P = 0·22)
Same efficacy
Same efficacy
Same efficacy on PASI
Better PASI (12 weeks), VAS score and DLQI in the placebo group (P < 0·05)
NS, not significant; HAQ, Health Assessment Questionnaire; PASI, Psoriasis Area and Severity Index; VAS, visual
analogue scale; DLQI, Dermatology Life Quality Index.
Psoriasis
Two trials evaluated the effect of folic acid supplementation for patients with psoriasis. The dose was 5 mg daily,
every day11 or 5 days per week.17 The first trial performed in 22 patients showed that the clinical outcome,
evaluated using three different scores (Psoriasis Area and Severity Index, visual analogue scale and Dermatology
Life Quality Index) was significantly more favourable in patients not receiving supplementation. 11 However, the
effect size was relatively small, so these results should be interpreted with caution. The second trial in 42 patients
did not show any difference in outcome between the two groups. 17 We are therefore not able to conclude whether
folic acid supplementation reduces the efficacy of methotrexate for treating psoriasis.
Discussion
This systematic review shows that folic or folinic acid supplementation significantly reduces the incidence of hepatic
side-effects of methotrexate (ARR = −0·358, 95% CI −0·467 to −0·248). There was no statistical difference for
mucocutaneous and gastrointestinal side-effects. The effect on haematological side-effects could not be assessed
accurately due to low incidence of these events in the population studied.
It is unclear whether folic or folinic acid supplementation is associated with a reduction of the efficacy of
methotrexate. Some data suggest that patients receiving supplementation may need higher doses of
methotrexate.11,12 Previous studies have shown that the anti-inflammatory effect of methotrexate, especially in
psoriasis or rheumatoid arthritis, is not exclusively related to folate metabolism. Other mechanisms may be
involved, such as the inhibition of aminoimidazole carboxamide ribonucleotide transformylase, which induces the
accumulation of adenosine, a potent anti-inflammatory agent.22 The effect of supplementation on the risk of
methotrexate long-term side-effects (i.e. liver fibrosis) has not been assessed. As liver fibrosis is associated with
high cumulative exposure to methotrexate, the role of folic or folinic acid supplementation to prevent liver fibrosis
deserves further study. This may be especially relevant for patients with psoriasis, who have a high risk of
developing liver fibrosis in the presence of comorbidities such as diabetes, obesity and alcohol consumption. 23
There is a high level of uncertainty regarding the nature of supplementation and the dose. There is no evidence that
folinic acid is more effective than folic acid although definite evidence is still lacking. The dose of folic/folinic acid
supplementation to be used has not been prospectively defined. There was a high level of heterogeneity between
trials, the dose varying from 5 to 27·5 mg of folic acid per week, and 1 to 5 mg of folinic acid per week. The trial of
van Ede et al., which compared the efficacy of supplementation with folic acid 1 mg daily vs. folinic acid 2·5 mg
weekly vs. placebo, did not show any significant difference between the two modalities of supplementation. 12 Only
one trial compared two doses of folic acid, and showed that a high dose of folic acid (27·5 mg weekly) was not
more effective than a low dose of 5 mg weekly.18
We conclude that low-dose folic supplementation is associated with a reduction of hepatic side-effects of
methotrexate (ARR 35·8%) and therefore can be recommended in clinical practice. Under folic supplementation a
higher dose of methotrexate may be required to obtain clinical efficacy in some patients.
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