Australasian Journal of Dermatology (2012) 53, 1–18 doi: 10.1111/j.1440-0960.2011.00839.

REVIEW ARTICLE

The use of methotrexate in dermatology: a review ajd_839 1..18

Sarah Shen1, Tim O’Brien,1 Lei Mee Yap,1 H Miles Prince2 and Christopher J McCormack1,3
1
Department of Dermatology, St Vincent’s Hospital, and Departments of 2Haematology and 3Surgical Oncology,
Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia

added to our knowledge of ways to further optimise its

ABSTRACT
Methotrexate is a synthetic folic acid analogue valued
for both its anti-proliferative and anti-inflammatory
properties. Considered one of the original immune-
modifying agents, it is used widely for the treatment
of steroid-recalcitrant inflammatory diseases. While
there are abundant studies documenting its efficacy
in rheumatic diseases, the use of methotrexate for
dermatological conditions, with the exception of pso-
riasis, has yet to be comprehensively explored. This
two-part review firstly outlines current data concern-
ing the pharmacology of methotrexate, including its
mechanism of action, side-effect profile and recom-
mended therapeutic approach, and, secondly, exam-
ines the emerging evidence for methotrexate’s
efficacy in a wide range of cutaneous disorders.
therapeutic benefit while predicting and curtailing its
toxicities.
PART A: PHARMACOLOGY AND
THERAPEUTIC APPROACHES
Pharmacology
Route of administration and dosage Methotrexate can be
administered orally, subcutaneously or intramuscularly. In
1971 two different dosage regimens were proposed by
Weinstein and colleagues:2 a single, once weekly dose and a
triple dosage schedule given at 12 h intervals with the latter
regimen based upon cell cycle kinetic studies.3 The two
dosing schedules are deemed to be equally effective.

Key words: adverse reactions, mechanism of Abbreviations:

action, methotrexate, pharmacology, psoriasis, AD atopic dermatitis
treatment guidelines. ADD American Academy of Dermatology
AICAR aminoimidazole-carboxamide-ribonucleoside
ALP alkaline phosphatase
ALT alanine aminotransferase
ASP aspartate aminotransferase
INTRODUCTION BMT betamethasone
CLE cutaneous lupus erythematosus
More than half a century has passed since methotrexate was CU chronic urticaria
first introduced into the therapeutic armamentarium for DM dermatomyositis
skin diseases. Its use in dermatology was the result of a eGFR estimated glomerular filtration rate
chance finding in 1951 when Gubner noted the rapid clear- GA granuloma annulare
ing of psoriatic skin lesions in cancer patients undergoing GAR glycinamide ribonucleotide
HIV human immunodeficiency virus
treatment with the anti-metabolic drug aminopterin.1 This
IL interleukin
led to the development of the more stable and less toxic LyP lymphomatoid papulosis
derivative, methotrexate. While it is mainly used to treat MF mycosis fungoides
psoriasis, benefit is seen in a myriad array of skin condi- MTX methotrexate
tions, including vasculitic connective tissue, blistering and NB-UVB narrow-band ultraviolet B
lymphoproliferative diseases. Ongoing research concerning NSAID nonsteroidal anti-inflammatory drugs
PASI psoriasis area severity index
its mechanism of action and pharmacogenetics has also
PIIINP serial serum type III procollagen aminopeptide
PL pityriasis lichenoides
PLEVA pityriasis lichenoides et varioliformis acuta
PRP pityriasis rubra pilaris
Correspondence: Dr Sarah Shen, St Vincent’s Hospital, 41 Victoria PUVA psoralen plus ultraviolet A
Parade, Fitzroy, Vic. 3065, Australia. Email: sshenwq@gmail.com RA rheumatoid arthritis
Sarah Shen, BMedSci, MBBS. Tim O’Brien, FACD. Lei Mee Yap, SCLE subacute cutaneous lupus erythematosus
FACD. H. Miles Prince, FRACP. Christopher J McCormack, FACD. UVB ultraviolet B
Submitted 17 September 2011; accepted 17 September 2011.

© 2011 The Authors

Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
2 S Shen et al.
Parenteral administration is advocated when there is gas-
trointestinal intolerance.4–7 One randomised double-blind
controlled study comparing oral to subcutaneous adminis-
tration of methotrexate in 375 rheumatoid arthritis (RA)
patients did not reveal any statistical difference in clinical
efficacy or tolerability.8
Pharmacokinetics Significant variation is seen in the bio-
availability of oral methotrexate although inter-patient dif-
ferences are considerable. There is also a dose-dependent
and saturable intestinal absorption variation, with increas-
ing variability in absorption with doses higher than 15 mg.9
There is conflicting evidence as to whether the bioavailabil-
ity of methotrexate is affected by the presence of food, with
some denying10,11 while others confirming a decrease in
absorption.7
In the circulation, approximately 35-50% of the drug is
bound to albumin. Maximum blood levels of methotrexate
occur 1–2 h after administration.9 Intracellular poly-
glutamate derivative is the primary active metabolite.
Hepatic oxidation forms 7-hydroxylmethotrexate, a minor
metabolite. The serum half-life is 6–7 h for methotrexate
but much longer for polyglutamate derivatives. A total of
50–90% of the drug is excreted unchanged in the urine after
24 h. It is filtered by the glomeruli and undergoes bidirec-
tional transport in the proximal renal tubule. Enterohepatic
recirculation occurs to a minor degree.9,12
Mechanism of action Methotrexate is a folate antagonist
that was originally conceived as an anti-malignancy drug.
Its primary metabolite polyglutamate competitively inhi-
bits dihyrofolate reductase, preventing the reduction of
folate cofactors. This results in the inhibition of thymidy-
late synthesis, thereby preventing pyrimidine synthesis.
Other folate-dependent enzymes inhibited by polygluta-
mate include aminoimidazole-carboxamide-ribonucleoside
(AICAR) transformylase. The inhibition of AICAR impairs
purine synthesis. The methylation of homocysteine to
methionine is also inhibited, thereby affecting the synthesis
of polyamines such as spermidine and spermine. The drug
is cell cycle specific and is active only in the S phase of the
cycle. Its anti-proliferative action at high doses is clinically
employed in the treatment of malignancy. Methotrexate
depletes the intracellular stores of activated folate and thus
disrupts cell replication. This leads to the inhibition of epi-
dermal cell proliferation, although lymphoid and macroph-
age cell lines have been shown to be affected by the
cytotoxic and growth inhibitory effects of methotrexate to a
greater degree.13
At low doses, methotrexate has potent anti-inflammatory
actions that appear to be mediated via pathways separate
from folate antagonism. The inhibition of polyamines is
thought to contribute to its anti-inflammatory effects.14
Recent studies have focused on its effects on adenosine as
critical to its anti-inflammatory properties.15–17 The inhibi-
tion of AICAR transformylase not only prevents one of the
final stages of de novo purine synthesis but leads to
increased levels of AICAR, which in turn results in a net
© 2011 The Authors
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
increase in intracellular and extracellular adenosine.
Adenosine is a purine nucleoside that is regarded as an
endogenous anti-inflammatory compound. By binding to
specific cell surface receptors, it has been shown to have
potent anti-inflammatory effects on a number of different
target cells. It inhibits the oxidative burst in neutrophils and
monocytes, prevents leukocyte chemotaxis and inhibits
monocyte and macrophage secretion of multiple cytokines,
including tumor necrosis factor-alpha, interleukin (IL)-10
and IL-12. Adenosine downregulates the expression of
adhesion molecules, including L-selectin, B2-integrin and
CD11b, resulting in the potent inhibition of polymorpho-
nuclear chemotaxis and adherence. In addition, adenosine
receptors are found on endothelial cells, another possible
target for adenosine’s anti-inflammatory effects (Fig. 1).
However, the anti-inflammatory role of adenosine has been
questioned18 and knowledge of methotrexate’s mechanism
of action is continuing to expand with recent research
implicating the production of reactive oxygen species.19 The
mechanism of action of methotrexate is illustrated in
Figure 1.
Adverse effects
Data regarding methotrexate’s adverse effects is primarily
derived from its use in RA, psoriasis and psoriatic arthritis
(PA). Potential methotrexate toxicities are summarised in
Table 1.
Constitutional Commonly reported adverse events of the
medication include nausea, anorexia, fatigue and malaise,
usually occurring around initiation of therapy. These side
effects are, in general, dose dependent and may be mini-
mised by taking the medication several hours before
bedtime and by folic acid administration.
Haematological Haematological toxicities are rare in the
absence of potential risk factors for developing myelosup-
pression such as renal insufficiency, increased mean cell
volume, older age, concomitant illnesses or infections,
hypoalbuminemia, drug overdose or drug interaction
(Table 2).20,21 In a 22-year retrospective study of 157 psoria-
sis patients on long-term low-dose methotrexate (15 mg
weekly), myelosuppression occurred in 10–20% of the
patients, manifesting as macrocytic anaemia, leucopenia,
thrombocytopenia or pancytopenia.22 Though rare, pancy-
topenia can occur at any time during therapy, therefore
close haematological monitoring is warranted. Cytopenia
usually improves after dose reduction or the withdrawal of
therapy.21,23
Gastrointestinal Nausea and vomiting often accompany
therapy. Diarrhoea and stomatitis may also occur. These
side effects are dose dependent and respond to folate
supplementation.24 Hepatotoxicity, including fibrosis and
cirrhosis, is a recognised adverse effect in patients on long-
term methotrexate for psoriasis.25 Fibrotic changes can
occur in the presence of normal liver function tests.26 Risk
 Methotrexate in dermatology 3

Folic Acid

Dihydrofolate AICAR AICAR

Dihydrofolate reductase MTX AICAR Transformylase

Tetrahydrofolate
Adenosine

Methionine synthase Thymidylate synthase GAR Transformylase Formyl AICAR

Downregulation of pro-inflammatory cytokines

DNA methylation Pyrimidine synthesis Purine synthesis Inhibition of apoptosis
Inhibition of polymorph chemotaxis

Figure 1 Schematic diagram of mechanism of action of methotrexate. The anti-proliferative actions of methotrexate (MTX) are mediated
via the inhibition of folate-dependent pathways. The anti-inflammatory actions are thought to be due to the upregulation of adenosine
resultant from the increase in the level of aminoimidazole-carboxamide-ribonucleoside (AICAR). GAR, glycinamide ribonucleotide.

factors for hepatotoxicity include Type 2 diabetes, alcohol
consumption and obesity and viral hepatitis B and C
(Table 3).27 The incidence of liver toxicity is significantly
higher in psoriasis patients than in those with RA; this dif-
ference between the groups has been attributed to the
higher rate of alcoholism, diabetes and hyperlipidae-
mia in the former.28,29 The histopathological features of
methotrexate-induced liver toxicity were found to resemble
those of non-alcoholic steatohepatitis, a pattern of liver his-
tology observed in obese, diabetic and hyperlipidaemic
patients.30,31 Histopathological changes secondary to meth-
otrexate use were graded by Roenigk in 1988 (Table 4);32 a
system of classification shown to have clinical utility.33
Studies utilising this system of classification have yielded
markedly varied frequency of liver fibrosis secondary
to methotrexate use (6–72%),31,34–37 thereby complicating
monitoring guidelines.
Oncogenic potential Methotrexate is a significant indepen-
dent risk factor for the development of squamous cell car-
cinoma in patients with severe psoriasis and this risk may
increase in psoriatics treated with psoralen plus ultraviolet
A (PUVA) therapy.38,39 Debate continues as to whether there
is an association between long-term methotrexate therapy
and the subsequent development of lymphomas.40,41 Reports
of methotrexate-induced lymphomas come primarily from
the rheumatology literature, with many identifying self-
resolving lymphomas upon therapy discontinuation,42–51 in
particularly Epstein–Barr virus-associated lymphomas.52–54
However, population-based studies looking at the use of
immunosuppressive agents, especially methotrexate, in the
treatment of RA and dermatomyositis (DM), did not defini-
tively demonstrate links with an increased risk of malig-
nancy.55,56 Furthermore, several small retrospective studies
revealed no added risk of lymphoproliferative disease in
patients with psoriasis.52 Nonetheless, a recent study, again
looking at the use of methotrexate in RA, showed a 50%
increase in risk of malignancy relative to the general popu-
lation with a threefold increase in melanoma, a fivefold
increase in non-Hodgkin lymphoma and a nearly threefold
increase in lung cancer.57
Reproductive toxicity Methotrexate is both an abortifacient
and a teratogen. While the critical period of exposure to the
drug is thought to be between 6 to 8 weeks after conception,
foetal abnormalities, which include cardiac, skeletal and
central nervous system defects, have been reported at all
times of exposure.58 Methotrexate is also secreted in small
amounts in breast milk, with the effects on infants
unknown.59 In men, methotrexate impedes spermatogen-
esis and has also shown potential for causing mutagenesis.60
Infections Opportunistic infections and the reactivation of
TB61 and hepatitis62 are reported in patients on low-dose
methotrexate. In patients with RA on methotrexate, these
infections seem to be more common than in those treated
with azathioprine, cyclophosphamide or cyclosporine.

© 2011 The Authors

Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
4 S Shen et al.

Table 1 Side effects of methotrexate Table 3 Risk factors for hepatotoxicity

Constitutional Type 2 diabetes mellitus

Nausea Obesity
Fatigue History of or current greater than moderate alcohol consumption
Malaise Persistent abnormal liver chemistry study findings
Anorexia History of liver disease including chronic hepatitis B or C
Gastrointestinal History of significant exposure to hepatotoxic drugs or chemicals
Nausea Hyperlipidemia
Diarrhoea
Stomatitis
Hepatotoxicity
Haematological
Table 4 Classification of liver biopsy findings
Cytopenia
Pulmonary Class I Normal
Pneumonitis Fatty infiltration, mild
Pulmonary fibrosis Nuclear variability, mild
Reproductive Portal inflammation, mild
Teratogenicity Class II Fatty infiltration, moderate to severe
Oligospermia Nuclear variability, moderate to severe
Oncogenic potential Portal tract expansion, portal tract inflammation and
Epstein-related lymphoma necrosis, moderate to severe
Squamous cell carcinoma Class IIIA Fibrosis, mild
Mucocutaneous Class IIIB Fibrosis, moderate to severe
Mucositis Class IV Cirrhosis
Photosensitivity
Radiation-recall reactions
Drug hypersensitivity reactions
Diffuse non-inflammatory alopecia
Infections of concomitant haematopoietic and gastrointestinal toxici-
Opportunistic ties.65 Two types of cutaneous ulceration induced by meth-
TB reactivation otrexate in patients with psoriasis have been described.
Hepatitis Type 1 involves the painful erosion of psoriatic plaques
Neurological
which can take place shortly after initiation of the treatment
Headache
Dizziness
or in the setting of dose alteration and drug interaction.66
Fatigue This can be mistaken as an exacerbation of the condition
Mood alterations itself. Type 2 describes ulceration in diseased skin, which
has a variable correlation with treatment duration and thus
may be overlooked as evidence of methotrexate toxicity.67,68
Alopecia, hyperpigmentation, ultraviolet burn recall and
Table 2 Risk factors for haematological toxicity toxic epidermal necrolysis also have been reported.9
Renal insufficiency
Advanced age Neurological toxicity Headaches, dizziness, fatigue and
Lack of folate supplementation mood alterations usually occur at drug initiation and are
Methotrexate dosing errors
dose dependent. However, they can also result from chronic
Drug interactions
Hypoalbuminemia use.21
Greater than moderate alcohol intake
Cardiac toxicity Methotrexate elevates the level of
homocysteine by inhibiting methionine synthase. Hyper-
Methotrexate is considered to be safe in the setting of
homocysteinemia is associated with an increased risk of
human immunodeficiency virus, given there is close moni-
cardiovascular disease, leading to the concern that meth-
toring of patients for signs of infection,63 although its use in
otrexate may secondarily increase the risk of cardiovas-
this group of patients remains controversial.
cular disease.69 However, methotrexate may in fact have
protective effects against cardiovascular disease as its anti-
Pulmonary toxicity Idiosyncratic acute pneumonitis and inflammatory properties may counteract elevated homocys-
slowly progressive pulmonary fibrosis are more commonly teine levels.70 In addition, folic acid administration is
seen in RA patients than in psoriatics taking methotrexate believed to abrogate the deleterious effects of methotrexate
but they can be life-threatening.64 A respiratory work-up is on homocysteine.71
warranted if pulmonary symptoms develop.
Others Low-dose methotrexate may contribute to the
Mucocutaneous toxicity Mucositis can occur in patients development of stress fractures of long bone. One study
without adequate folate supplementation and in the setting reported on three patients on low-dose methotrexate with a

© 2011 The Authors

Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
 Methotrexate in dermatology 5

Table 5 Drugs that may interact with methotrexate (MTX) to be at risk for pulmonary toxicities. Obtaining hepatitis
increase toxicity serologies prior to therapy initiation is not routine; however
Mechanism Drugs
viral titres should be tested if there is clinical suspicion.
Figure 2 illustrates the algorithm of pre-therapy evaluation
Decreased renal Nephrotoxins and subsequent monitoring recommendations, as based on
elimination of MTX Salicylates
the American Academy of Dermatology (ADD) 2009 guide-
Nonsteroidal anti-inflammatories
Pharmacological Trimethoprim-sulfamethazole lines of care for the management of psoriasis and PA.
enhancement of MTX Ethanol
toxic effects Phenylbutazone
Reduced tubular secretion Salicylates Monitoring of therapy
Sulfonamides
Probenecid Hepatic surveillance Monitoring liver toxicity is a point of
Cephalothin ongoing contention amongst clinicians. Hepatic surveil-
Penicillins lance is complicated by the fact that the risk of hepato-
Colchicine toxicity is not well established for many dermatological
Displacement of MTX Salicylates
diseases. Current guidelines are based on data gathered
from plasma protein Probenecid
binding Barbiturates from the use of methotrexate in psoriasis and RA, two large
Phenytoin but different patient groups. Serial liver biopsies are recom-
Intracellular Probenecid mended in psoriatics on long-term methotrexate therapy,
accumulation of MTX Dipyridamole especially when the cumulative dose exceeds 1.5 g.32,79–81
Hepatotoxicity Retinoids The basis for the recommendations has been reports of
significant but difficult to quantify risks of fibrosis and cir-
rhosis coupled with the poor correlation observed between
enzymatic levels and histopathological findings.25,37,82
triad of osseous pain, radiological osteoporosis and distal The guidelines for monitoring of treatment set by the
tibial stress fractures.72 Anaphylactoid reactions have been ADD in 200979 are based upon the stratification of patient
reported after low-dose methotrexate and can occur during risk. In the absence of certain risk factors, a baseline biopsy
initial exposure.73 is not recommended. Serial biopsies may not be required in
the absence of deranged liver enzymes levels and when the
initial baseline biopsy is normal, or when the weekly dose of
Paediatric use
the drug is 15 mg or less. The presence of risk factors for
Low-dose methotrexate is generally well tolerated in chil- hepatotoxicity mandates close monitoring, although one
dren for the treatment of psoriasis,74 with primary side should consider delaying a liver biopsy to ascertain medi-
effects relating to stomatitis, gastrointestinal intolerance cation efficacy and tolerability.81
and hepatotoxicity. However, most of the published data on Serial serum type III procollagen aminopeptide (PIIINP)
its use in children thus far derive from the rheumatology as a test for fibrinogenesis has been promoted as a
literature. It is suggested that most children can be moni- reliable83–86 and cost-effective87 monitoring tool in place of
tored for hepatotoxicity in accordance to the rheumatologi- a liver biopsy. A recent 10-year retrospective study of 70
cal liver biopsy guidelines recommended for adults without patients with psoriasis who were taking methotrexate
risk factors.75 showed that the presence of repeatedly normal levels of
PIIINP correlated to a minimal risk of developing liver tox-
icity.36 Based on the data, a British group has proposed the
Drug interactions and contraindications Manchester guidelines (Table 6) as a means of reducing the
Numerous medications may interact with methotrexate by a need for a liver biopsy in patients with psoriasis. The limi-
variety of mechanisms that can result in elevated drug tations of this set of guidelines relate to the fact that PIIINP
levels, thereby increasing the risk of toxicity,76–78 as sum- levels may be elevated in inflammatory conditions other
marised in Table 5. Absolute and relative contraindications than hepatic fibrosis. It is frequently elevated in RA patients
to methotrexate are listed in Figure 2. in the absence of hepatic damage and is therefore not a
useful marker in this group.87

INITIATION OF THERAPY
Thorough history taking and physical examination includ-
ing the clarification of disease severity, previous therapies,
contraindications to methotrexate and risk factors for devel-
oping potential toxicities, along with laboratory tests,
including a full blood count with differential, renal function,
liver function tests including albumin and bilirubin consti-
tute a baseline work-up. A chest radiograph is important for
patients with underlying pulmonary disease or deemed to
Haematological surveillance After methotrexate treatment
has been initiated, it is necessary to monitor regularly for
haematological toxicity. The first repeat laboratory check
should be within a 2-week period for patients without risk
factors. Patients with risk factors for haematological toxicity
(Table 2) need closer monitoring, particularly at the onset of
therapy and after increasing the dosage of methotrexate.79 A
significant reduction in red cell, leukocyte or platelet counts
necessitates the reduction or temporary discontinuation of

© 2011 The Authors

Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
6 S Shen et al.

CLINICAL EVALUATION

Absolute contraindication? Yes

Pregnancy Therapy contraindicated
Signficant anaemia, leukopenia or thrombocytopenia
No

Relative contraindications?
Renal insufficiency
Hepatic impairment
Chronic infection or immunosuppressed state (e.g TB, HIV) Yes
Heavy alcohol consumption Consider alternative therapy
Patient unreliability
Obesity
No Diabetes mellitus
Recent vaccination
Drug interactions (e.g. NSAIDS, see Table IV)

LABORATORY EVALUATION

Baseline Investigations:
Full blood examination
Renal function test Abnormal
Liver function test Clinical re-evaluation
Normal (Consider baseline liver biopsy in patients with signficant hepatic risk factors, see Table VI)
Pregnancy test
Chest X-ray

INITITATION OF THERAPY

MONITORING OF TREATMENT

Haematologic Surveillance
Complete blood cell count and platelet count weekly for the first 2 weeks, then 2 weekly
for next month, followed by monthly surveillance depending on the clinical picture

Renal Surveillance
Renal function tests including eGFR at every 2 to 3 months interval
Abnormal
Normal Hepatic Surveillance Clinical re-evalution
Liver chemistries: ALT, AST, ALP, and serum albumin every 4 to 8 weeks with more
frequent liver function monitoring required for patients with hepatic risk factors, see
Table VI.

Pregnancy Test (if indicated)

Women of childbearing age who are sexually active must take contraception. Men and
women considering conception should be off MTX for 3 months before attempting to
coneive.

Continue therapy

Figure 2 An algorithm for suggested pre-methotrexate evaluation and the subsequent monitoring of treatment. The monitoring schedule
is based on the 2009 American Academy of Dermatology guidelines for use of methotrexate (MTX) in psoriasis.81 ALT, alanine aminotrans-
ferase; ALP, alkaline phosphatase; ASP, aspartate aminotransferase; eGFR, epidermal growth factor receptor; HIV, human immunodeficiency
virus; NSAID, nonsteroidal anti-inflammatory drugs.

© 2011 The Authors

Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
 Methotrexate in dermatology
Table 6 Comparison of guidelines for monitoring of hepatoxicity
American Academy of Dermatology guidelines
Low-risk patients:
• Liver biopsy every 1 to 1.5 g of therapy in low-risk patients
• After a cumulative dose of 4 g, biopsy after each 1 g of therapy
High-risk patients:
• Consider alternative treatment
• Consider delayed baseline liver biopsy (after 2–6 months of
therapy, to establish medication’s efficacy and tolerability) in
at-risk patients.
• Repeat liver biopsy after every 0.5–1 g of therapy
After abnormal biopsy results:
• For histological grades IIIA, repeat every 6 months; consider
alternative therapy
• For histological grades IIIB and IV, discontinue therapy
PIIINP, serial serum type III procollagen aminopeptide
methotrexate therapy and may warrant the administration
of folinic acid, leucovorin, the antidote to methotrexate.76
Renal surveillance Regular monitoring of renal function is
essential in preventing toxicities, particularly bone marrow
toxicity. The glomerular filtration rate should be calculated
for those patients who have normal blood urea nitrogen and
creatinine levels but are at risk for renal insufficiency, such
as the elderly or those with a decreased muscle mass.79,81
Pulmonary surveillance The use of methotrexate in RA has
been associated with TB reactivation.61 The Center for
Disease Control and Prevention recommends screening for
latent TB infection in all patients with psoriasis who will be
treated with systemic or biological immunosuppressive
agents.88
Reproduction Pregnancy and lactation are both absolute
contraindications for therapy.79,81,89,90 A delay of at least
3 months between drug cessation and conception is recom-
mended.90,91 Men taking methotrexate should avoid conceiv-
ing during therapy and for 3 months after cessation of
therapy.81
Folate supplementation
Folate supplementation is shown to reduce gastrointestinal,
haematological and hepatotoxic adverse effects without
compromising efficacy.92 The current consensus statement
from the ADD strongly recommends folate supplementa-
tion with methotrexate therapy.81 However, there are still
varying opinions regarding the indications and dosing
regimen for folate supplementation, pointing to the need for
a more comprehensive set of guidelines. A survey of a 153
British dermatologists revealed that three-quarters use
folate supplementation in patients on methotrexate for pso-
riasis, one-quarter of this group use it for all patients on
therapy while the remainder use folate only in certain cir-
cumstances, namely, in patients with macrocytosis.93 Duhra
examined 78 psoriatic patients who were receiving low-
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
7
Manchester guidelines
• Baseline PIIINP level (if possible)
• Repeat PIIINP levels every 2–3 months while on therapy
Indications for considering liver biopsy:
• Pretreatment PIIINP >8.0 mg/L
• At least three abnormal PIIINP levels (>4.2 mg/L) over a
12-month period
• Elevated PIIINP level above 8.0 mg/L in two consecutive
samples
Indications for considering withdrawal of therapy:
• Elevated PIIINP level >10.0 m g/L in three consecutive samples
in a 12-month period
dose, once-weekly oral methotrexate therapy. Of these
patients 25 (32%) experienced gastrointestinal symptoms
that were reduced by folate supplementation.24 The combi-
nation of methotrexate with folic acid was examined in two
randomised controlled studies in psoriasis.94,95 In both
studies, folate supplementation reduced clinical efficacy but
improved tolerability. One large placebo-controlled study of
RA patients compared folinic acid with folic acid.96 No dif-
ference was evident between the two agents; both folate
supplementation regimens reduced liver toxicity but
appeared to have no effect on the other adverse effects of
methotrexate.
PART B: CLINICAL USE
The use of methotrexate in dermatology predates the era of
randomised control trials. Despite the relatively sparse
quantity of high-quality data concerning its efficacy in the
literature, monotherapy and combination therapy with
methotrexate continue to be widely used to treat a vast
array of skin disorders. Table 7 summarises the clinical use
of methotrexate in dermatology. Designations of levels of
evidence are adapted from the National Health and Medical
Research Council evidence hierarchy.167
Inflammatory dermatoses
Psoriasis Methotrexate is indicated in the symptomatic
control of severe, recalcitrant and disabling psoriasis not
responsive to topical therapy, examples of which are listed
in Table 8168. One of the earliest placebo-controlled trials
was designed to test the efficacy of methotrexate for PA. In
addition to improving arthritic symptoms, a significant
improvement in psoriasis was observed.169 Subsequent
studies confirmed its effectiveness for both psoriasis170,171
and PA at doses similar to those used for the former, with
diminished doses being possible for maintenance.172,173 A
significant reduction in psoriatic nail dystrophy was also
seen.174
Six randomised blinded trials investigated the use of
methotrexate in plaque-type psoriasis, comparing its
© 2011 The Authors
 8

© 2011 The Authors

Table 7 Data on the clinical use of methotrexate in dermatology

Highest level Case series and Clinical Total number of Number of patients
Diseases Specific conditions of evidence† retrospective studies (n) trials (n) patients treated responsive to treatment

Papulosquamous Psoriasis II (see Tables 9 and 10)

Pityriasis rubra pilaris IV 897–105 0 53 25
Pityriasis lichenoides IV 2106,107 0 9 9
Pityriasis lichenoides et varioliformis IV 3108–110 0 6 6
acuta
Allergic/immunological Chronic urticaria IV 3111–113 0 22 18
Dermatitic Atopic dermatitis III 6114–119 1120 72 64
Blistering Pemphigus vulgaris IV 6121–126 0 116 96
Pemphigus foliaceous IV 3121,122,127 0 20 15
Bullous pemphigoid IV 5128–132 0 62 59
Ocular cicatricial pemphigoid IV 1133 0 17 15
Connective tissue Localised scleroderma III 3134–136 3137–139 124 110
Dermatomyositis (cutaneous IV 3140–142 0 25 22
manifestation)
Cutaneous lupus IV 7143–149 1147 77 70
Vasculitic Cutaneous leukocytoclastic vasculitis IV 1150 0 1 1
S Shen et al.

Rheumatoid vasculitis IV 2151,152 0 9 9

Lupus vasculitis III 0 2147,153 4 3
Behcet’s disease IV 1154 0 2 2
Polyarteritis nodosa IV 4154–157 0 18 16
Granulomatous Cutaneous sarcoidosis IV 4158–161 0 40 35

Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists

Granuloma annulare IV 1162 0 1 1
Lymphoproliferative Lyphomatoid papillomatosis and CD30+ IV 3107,163,164 0 49 43
(Ki-1) Anaplastic large-cell
lymphoma
Mycosis fungoides III 1165 1166 78 30
Level of evidence†
I A systematic review of level II studies
II A randomised control trial
III A non-randomised control trial or an open prospective study
IV A retrospective study or case series/report
†
Levels of evidence in efficacy adapted from the National Health and Medical Research Council guidelines.
 Methotrexate in dermatology
Table 8 Indications for use of methotrexate in psoriasis169
• Psoriatic erythroderma
• Moderate to severe psoriatic arthritis
• Acute pustular psoriasis, von Zumbusch’s type
• Localised pustular psoriasis
• Psoriasis that affects certain areas of the body, causing
significant emotional distress, social and economic
disadvantage
• Lack of response to topical therapy, phototherapy, psoralen plus
ultraviolet A and retinoids
• Extensive psoriasis involving more than 20% of body surface
efficacy with various other immunosuppressive agents,
including mycophenolate mofetil,175 cyclosporine,176–178
hydroxyurea179 and fumarates.180 A review of systemic com-
bination therapy for psoriasis and PA was conducted by
Jensen and colleagues in 2010.181 Studies have examined the
efficacy of methotrexate in combination with betametha-
sone,182 ultraviolet B (UVB),183 PUVA184 and the biological
agent etanercept.185 A combined therapy with cyclosporine186
and alefacept187 for psoriatic arthritis was examined in two
randomised control trials. Data from these recent studies are
summarised in Tables 9 and 10.
The treatment of pustular variants of psoriasis with meth-
otrexate has been previously reported,188 and its efficacy has
been demonstrated in combination therapies with retin-
oids189,190 and colchicine.190,191 Although combination therapy
may allow dosage and subsequent toxicity to be reduced, the
potential for carcinogenesis, with methotrexate and photo-
therapy,192 and hepatitis, with methotrexate and retinoids,193
demands that such treatments be applied judiciously.
Reduced doses of methotrexate are effective in control-
ling psoriasis in the elderly, probably as a consequence of
decreased renal clearance.194 Patients older than 80 years
have been adequately controlled on only 2.5 mg of methotr-
exate per week.195 Discretion should be exercised when
using methotrexate – some residual areas of psoriasis can
be accepted to prevent relative overtreatment and the com-
plete clearance of psoriasis should not be the primary goal
of treatment.
Pityriasis rubra pilaris (PRP) An initial published report of
methotrexate treatment for PRP in 1964 was, in fact, of a
treatment failure,97 but multiple authors have subsequently
described clinical improvement or clearing with methotr-
exate treatment in both adult and paediatric patients.98–104
Dicken treated eight patients with methotrexate for an
average of 6 months, all of whom showed significant
improvement on 10 to 25 mg per week, given as a single
dose or three doses at 12-h intervals.98 Griffiths however
reported a lower response rate; combining his own patients
with those in the literature, he reported that 17 of 44
patients had improved on methotrexate.104 A total of 53
cases were reported with 28 patients responsive to treat-
ment. Low-dose methotrexate also resulted in a dramatic
improvement in a case of PRP-induced bilateral lower
eyelid cicatricial ectropion.105
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
9
Pityriasis lichenoides (PL) and pityriasis lichenoides et
varioliformis acuta (PLEVA) PL encompasses a wide spec-
trum of clinical presentations and is notoriously difficult to
treat. Methotrexate’s efficacy in its treatment has been
documented only in case studies. Cornelison and colleagues
in 1972 described the use of low-dose methotrexate
(ranging from 7.5 to 20 mg) in the treatment of six patients
with PL.106 Since then, additional cases have been
published.107
Improvement with methotrexate for PLEVA, both as lone
and combination therapy and in the setting of resistance to
first-line therapies, has been documented. An adolescent
with febrile ulceronecrotic PLEVA responded to a combina-
tion therapy of phototherapy and methotrexate.108 Four ado-
lescents with severe progressive PLEVA unresponsive to
erythromycin, tetracycline and prednisolone responded to
methotrexate 2.5 mg given every 12 h for three doses.109
Similarly, the remission of septic ulceronecrotic PLEVA was
reported in an 8-year old girl treated with a combination of
methotrexate and cyclosporine after her failure to respond
to 2 weeks of steroid therapy.110
Chronic urticaria (CU) Methotrexate is used in recalci-
trant CU. In a recent retrospective review of 16 patients with
steroid-dependent chronic urticaria treated with methotr-
exate, 10 patients had chronic idiopathic urticaria, includ-
ing three with associated delayed-pressure urticaria; four
patients had urticarial vasculitis and two patients had idio-
pathic angioedema without weals. All were unresponsive to
antihistamines and second-line agents except prednisolone.
Improvement was seen in 12 patients, with a complete
clearance of disease seen in two. The dose to achieve a
steroid-sparing effect was 10–15 mg weekly.111 Godse tested
45 patients with chronic idiopathic urticaria with the autolo-
gous serum skin test for autoantibodies, 12 of whom
achieved a positive result and out of the 12, four patients
were recalcitrant to treatment with oral antihistamines.
Methotrexate in the cumulative dose of 10 mg orally weekly
was given. A clinical improvement was seen in all four
patients.112 Gach and colleagues described two patients with
recalcitrant chronic urticaria whose disease was controlled
with methotrexate.113
Atopic dermatitis (AD) Treatment with methotrexate was
found to be more effective in adult onset AD than in child-
hood onset, although the reasons for this remain unclear.
Like many other skin conditions bar psoriasis, evidence is
sparse, despite suggestions that treatment with methotrex-
ate for AD should parallel that of psoriasis.114 Several case
series and retrospective studies have demonstrated the effi-
cacy and safety of treatment with low-dose methotrexate for
moderate-to-severe AD in adults who were unresponsive
to topical treatments, antihistamines and at least one of
the second-line treatments.114–118 Egan and colleagues119
reported successful treatment with methotrexate of five
patients with severe pompholyx. One open-label prospec-
tive study evaluated 12 patients with AD, eight of whom
achieved sustained clinical improvement. Methotrexate
© 2011 The Authors
 10

Table 9 Methotrexate (MTX) monotherapy for plaque psoriasis

© 2011 The Authors

Duration of
No. of treatment
References patients† Treatment groups Treatment dosing (weeks) Clinical evaluation

S. Fallah Arani 51 (1) MTX (n = 25, mean age 41, (1) MTX: 5–15 mg weekly 12 At 12 weeks the mean PASI decreased from 14.5 to
et al., 2011180 mean PASI 14.5) (2) Fumarate: 30–720 mg daily 6.7 in the MTX group and from 18.1 to 10.5 in the
MTX vs fumarate (2) Fumarate (n = 26, mean age fumarate group. Partial remission (PASI 75) was
43, mean PASI 18.1) achieved in 6 (24%) of the MTX group and 5
(19%) of the fumarate group.
Difference in PASI between the two groups was not
statistically significant.
Akhyani et al., 32 (1) MTX (n = 15, mean age = 46, (1) MTX: 7.5–20 mg weekly 12 At 12 weeks a PASI 75 response was observed in 11
2010175 mean PASI 16.5) (2) MMF: 2 g daily (73.3%) patients in the MTX-treated group
MTX vs (2) MMF (n = 17, mean age 40, compared to 10 (58.8%) in the MMF group.
mycophenolate mean PASI 17.4) Difference in PASI between the two groups was not
mofetil (MMF) statistically significant.
Flytström et al., 68 (1) MTX (n = 37, mean age 48, (1) MTX: 7.5–15 mg weekly 12 At 12 weeks a PASI 75 response was achieved by 9
2008176 mean PASI 14.1) (2) Cyclosporine: 3–5 mg/kg (24%) patients from the MTX group and 18 (58%)
MTX vs (2) Cyclosporine (n = 31, mean daily patients from the cyclosporine group.
cyclosporine age 45, mean PASI 15.5) Difference in PASI between the two groups was
statistically significant.
S Shen et al.

Ranjan et al., 30 (1) MTX (n = 15, mean age 44.9, (1) MTX: 15 mg weekly 12 At week 12, 10 (66.7%) patients from the
2007179 mean PASI 15.2) (increased by 5 mg at week MTX-treated group achieved PASI 75 while 2
MTX vs (2) Hydroxyurea (n = 15, mean 4 if PASI 25 was not reached) (13.3%) patients from the hydroxyurea group
hydroxyurea age 40.7, mean PASI 14.0) (2) Hydroxyurea: 2–3 g weekly achieved similar results.
(increased by 1.5 g at week 4 Difference in PASI between the two groups was

Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists

if PASI 25 was not reached) statistically significant.
Heydendael et al., 85 (1) MTX (n = 43, mean age 42, (1) MTX: 15–22.5 mg weekly 16 At week 16, 17 patients (40%) in the MTX group and
2003177 mean PASI 13.4) (2) Cyclosporine: 3–5 mg/kg 14 patients (33%) in the cyclosporine group had
MTX vs (2) Cyclosporine (n = 42, mean daily an almost complete remission (PASI 90).
cyclosporine age 38, mean PASI 14.0) Difference in PASI between the two groups was not
statistically significant.
Sandhu et al., 30 (1) MTX (n = 15, mean age, (1) MTX: 0.5 mg/kg weekly 12 At week 12, a PASI 75 response was achieved by all
2003178 mean PASI) (2) Cyclosporine: 3 mg/kg 15 patients from the MTX group and from 14
MTX vs (2) Cyclosporine (n = 15, mean (increased by 1 mg/kg after patients from the cyclosporine group.
cyclosporine age, mean PASI) 2 weeks of treatment) Difference in PASI between the two groups was not
The patients’ weight was not statistically significant.
specified.
†
Numbers of patients included in the primary analysis. PASI, psoriasis area severity index
 Table 10 Randomised studies on methotrexate (MTX) combination therapy for psoriasis and psoriatic arthritis†

No. of
References patients‡ Diagnosis Treatment groups Treatment Regimen Results

Gupta and Gupta, 40 Plaque psoriasis 36 (1) MTX + BMT (n = 28, mean End-point for clearance = PASI (1) Remission period of a mean of 91.8 days for
2007182 Erythrodermic 4 age 38.1) 90–100 combination therapy, time to clearance was
MTX with (2) MTX only (n = 12, mean age (1) MTX 15 mg weekly and BMT mean 27.1 day
betamethasone 43.1) 3 mg weekly (2) Remission period of a mean of 20.3 days for
(BMT) (2) MTX 15 mg weekly lone therapy
Time to disease clearance days was mean
33.1 day
Findings were statistically significant.
Asawanonda and 24 Plaque psoriasis (1) MTX + NB-UVB Duration of Treatment = 24 weeks (1) 10 out of 11 patients who received MTX/NB
Nateetongrungsak, (n = 11, mean age 40.3, mean End-point for clearance = PASI 90 UVB achieved clearance (PASI 90). The
2006183 PASI 18.05) (1) MTX 15 mg/week + NB-UVB 3 median time to clear in the MTX/NB UVB
MTX with (2) Placebo + NB-UVB treatments/week from week 4 group was 4 weeks. At the end of the
narrow-band (n = 13, mean age 47.6, mean (2) Placebo + NB-UVB 3 treatments/ treatment period, in the MTX-NB UVB group
ultraviolet B PASI 14.61) week from week 4 the median PASI score was 0.31
(2) 5 of 13 patients in the placebo-NB UVB
achieved clearance. In the placebo-NB UVB
group the median PASI was 4.62 at treatment
completion.
Findings were statistically significant.
Fraser et al., 2005186 72 Psoriatic arthritis (1) MTX + cyclosporine Duration of treatment = 12 months (1) Reduction of Mean PASI score 2 at baseline to
MTX with (n = 38, mean age 46.8, mean (1) MTX (dose unspecified) + 0.8 at 12 months
Cyclosporine PASI 2) cyclosporine 2.5 mg/kg daily (2) Reducation of Mean PASI 2.2 at baseline to
(2) MTX + placebo with dose increase to 4 mg/kg 1.9 at 12 months
(n = 34, mean age 47.1, PASI 2.2) daily over 12 weeks In the active but not the placebo arm there were
(2) MTX (dose not specified) + significant improvements in swollen joint
placebo count, mean 11.7 to 6.7, synovitis was reduced
by 33% in active group and 6% in placebo
group.
Methotrexate in dermatology

Shehzad et al., 60 Plaque psoriasis (1) PUVA only (n = 20, mean End-point for clearance = PASI 75 (1) Mean PASI reduction to 8.9, mean clearance
2004184 age, mean PASI 34.25) (1) PUVA 4 treatments weekly time 5.5 weeks
MTX with Psoralen (2) MTX only (n = 20, mean age, (2) MTX 10 mg weekly (2) Mean PASI reduction to 9, mean clearance
Ultraviolet A mean PASI 34.6) (3) MTX 10 mg weekly + PUVA 4 time 8 weeks
(3) PUVA + MTX (n = 20, mean treatments weekly (3) Mean PASI reduction to 8.5, mean clearance
age, mean PASI 33.75) time 2.5 weeks
Findings were statistically significant.
Zachariae et al., 59 Plaque psoriasis (1) Etanercept + tapering dose Duration of treatment = 24 weeks PASI 75 at both 12 weeks (28% vs 55%) and
2008185 of MTX (n = 28, mean age) (1) Etanercept + MTX 7.5–25 mg/ 24 weeks (32% vs 70%) was significantly better
MTX with (2) Combination therapy week tapered and discontinued for combination therapy.
Etanercept throughout study (n = 31, at week 4 Findings were statistically significant.
mean age) (2) Combination therapy
throughout the study
Mease et al., 2006187 285 Psoriatic arthritis (1) Alefacept + MTX (1) Alefacept + MTX 10–25 mg/ PASI 50 response 53% in combination group vs
MTX with Alefacept (n = 123, mean age) week 17% in placebo group
(2) Placebo + MTX (2) Placebo + MTX 10–25 mg/week Findings were statistically significant.
(n = 162, mean age) Some patients received additional
prednisolone 10 mg/day
†
Adapted from Jensen et al.181 ‡Indicates number of patients randomised for the study; the actual number subsequently analysed are stated in the treatment groups.
11

© 2011 The Authors

Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
BMT, betamethasone; PASI, psoriasis area severity index; PUVA, psoralen and ultraviolet A; NB-UVB, narrow-band ultraviolet B; SF-36, 36-item short form health survey.
12 S Shen et al.
was started at a dose of 10 mg with an incremental increase
of 2.5 mg weekly until a therapeutic effect was achieved.120
Blistering disorders A recent retrospective analysis of the
English medical literature concluded that methotrexate is
an effective and well-tolerated steroid-sparing immuno-
modulatory agent for pemphigoid and pemphigus.196 In
total, 13 case series have detailed its efficacy.121–132,197 The
available data on 116 patients with pemphigus vulgaris
demonstrated a clinical improvement in 96 (83%)of the
patients.121–126 In patients with severe to moderately severe
pemphigus vulgaris, methotrexate may be a useful mainte-
nance therapy once control is achieved with steroid therapy,
while allowing a lowering of the corticosteroid dose.121–124
Methotrexate generally has a delayed, beneficial effect on
oral lesions, whereas the cutaneous lesions usually respond
more rapidly.124–126 Improvement was observed in 15 out of
20 patients with pemphigus foliaceous treated with meth-
otrexate.121,122,127 It appears that methotrexate is more ben-
eficial in patients with bullous pemphigoid. An analysis of
the data on 62 patients with bullous pemphigoid found a
clinical improvement in 59 patients (95%).128–132 McCluskey
and colleagues133 reported that 15 out of 17 patients with
ocular cicatricial pemphigoid responded to methotrexate at
the dose of 5–25 mg weekly as a systemic monotherapy or in
combination with corticosteroids.
Localised scleroderma The selection of treatment moda-
lities for localised scleroderma, otherwise known as
morphea, remains controversial. The clinical utility of
methotrexate for this uncommon collagen vascular disease
has been documented in three retrospective studies134–136
and three open-label prospective studies,137–139 with a total of
124 patients treated of whom 110 (88.7%) responded to
treatment. Methotrexate, usually prescribed in combination
with i.v. pulse methylprednisolone, has been indicated for
the acute and deep form of this disease.198 A response
to single therapy has been seen in widespread deep
morphea.139
Combined therapy with corticosteroid and methotrexate
can be the first-line treatment for severe localised sclero-
derma if there are systemic manifestations, such as
extremities contractures and anchylosis or if it affects extra-
cutaneous structures such as fat, muscle, fascia or bone
involvement.135 A benefit was also seen in the acute form in
a paediatric group with oral methotrexate for maintenance
therapy and i.v. methylprednisolone pulse for induction.137 A
large retrospective review showed that methotrexate, given
to 39 out of the 136 children studied, lessened the indura-
tion, violaceous colouration and sometimes the soft-tissue
loss in all treated patients, except one with morphea pro-
funda and three with Parry Romberg syndrome.134
Dermatomyositis DM is an inflammatory myopathy com-
bined with characteristic cutaneous findings that are often
difficult to treat as they may have a discordant response
to therapy from the muscle disease, and can continue to
© 2011 The Authors
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
be refractory to treatment after muscle weakness has
resolved.199 Methotrexate in doses of 2.5 to 30 mg weekly
has been found effective for clearing cutaneous dis-
ease.140,141 A subset of DM, amyopathic dermatomyositis
(ADM) is characterised by classic cutaneous signs of DM
with little or no myositis and its response to methotrexate
was reported in two patients in a retrospective review.142
Cutaneous lupus erythematosus (CLE) Therapy with meth-
otrexate has been primarily used in patients with refractory
subacute cutaneous lupus erythematosus (SCLE)143–147,200
and discoid lupus erythematosus (DLE).146,148,149,201 In a ret-
rospective analysis, 12 patients with different subtypes of
CLE were treated with weekly low-dose methotrexate in a
dose of 10–25 mg orally or i.v..146 Six of these patients
achieved complete remission, four achieved partial remis-
sion and two patients did not respond. A recent study of 43
patients with different subtypes of recalcitrant CLE145
reported improvement in 42 (98%) of patients receiving
low-dose methotrexate, administered either orally or i.v..
Patients with SCLE and localised DLE showed greater
improvement than those with disseminated DLE. The i.v.
route was better tolerated than oral administration
although in a follow-up study, i.v. methotrexate administra-
tion was changed to subcutaneous application in 15 of
the 43 CLE patients with good tolerance and comparable
efficacy.200
Vasculitides The self-limiting nature of most forms of cuta-
neous vasculitis means there is minimal evidence for the
benefit of many therapeutic modalities. Reported cases
describe the efficacy of low-dose methotrexate (5–20 mg
weekly) in refractory Behcet’s disease and cutaneous pol-
yarteritis nodosa.154–157 Two open prospective studies have
demonstrated its efficacy in lupus vasculitis. Wilson and
colleagues147 described two patients with lupus vasculitis,
both of which responded to low-dose oral methotrexate.
Gansauge and colleagues153 reported a resolution in six out
of nine patients. Methotrexate has been associated with
drug-induced vasculitis;202 however, in patients with RA,
methotrexate does not alter the incidence of rheumatoid
vasculitis.203 Methotrexate has been used to treat refractory
cases of vasculitic cutaneous ulceration with RA, with the
potential advantage of benefiting other manifestations
of the disease.151,152 Upchurch and colleagues described
the effective use of low-dose intramuscular methotrexate
(15 mg once weekly) in one case of leukocytoclastic vascu-
litis associated with RA.150
Cutaneous sarcoidosis Methotrexate is effective in steroid-
resistant cutaneous sarcoidosis. Despite supporting data
derived principally from uncontrolled open-label studies,
the drug has been suggested to be the treatment of choice
for steroid recalcitrant sarcoidal ulcers.158,159 Veien and
Brodthagen160 reported the clearance of skin lesions in 12 of
16 patients treated with methotrexate at an initial weekly
dose of 25 mg tapered to a maintenance dose of 5 to 15 mg
 Methotrexate in dermatology
weekly. Webster and colleagues159 reported the results of
three patients with cutaneous sarcoidosis treated with 15 to
22.5 mg methotrexate weekly, with all three experiencing
improvement over 6 to 9 months. Lower and Baughman
investigated the prolonged use of methotrexate in sarcoido-
sis by following the course of 50 patients who received at
least 2 years of therapy at 10 mg methotrexate weekly. Of
the 17 patients with skin involvement, 16 improved with
methotrexate.161 Relapse is common after the discontinua-
tion of treatment, suggesting that, like anti-malarials, meth-
otrexate controls but does not cure the disease.158,161,204
Granuloma annulare (GA) GA is an idiopathic dermatosis
clinically manifested as well-defined annular skin-coloured
to erythematous papules and plaques with histological find-
ings of granulomatous inflammation, collagen degenera-
tion and mucin deposition. As yet there has been only one
case report detailing the benefit of methotrexate in treating
recalcitrant GA. Oral methotrexate 15 mg weekly was given
to a 67-year old woman with treatment-resistant dissemi-
nated GA. Six weeks after commencing therapy, most of her
lesions had resolved and the remainder had partially
regressed.162
Lymphoproliferative disorders
Lymphomatoid papulosis (LyP) and other primary cut-
aneous CD30+ lymphoproliferative disorders The man-
agement of LyP and other variants of primary cutaneous
CD30+ lymphoproliferative disorders range from simple
observation to aggressive systemic chemotherapy. Observa-
tions concerning treatment have been limited to individual
patients or small series of patients. Methotrexate is known
to be effective in LyP,107,163 but its role in the long-term
management of LyP has not been established. A retrospec-
tive study reviewed the 20-year experience of methotrexate
in the treatment of 45 patients with LyP and CD30+ lym-
phoma and borderline expressions of cutaneous CD30+
lymphoproliferative disease. During induction of methotr-
exate therapy the patients received maximum doses
ranging from 10 to 60 mg weekly (median, 20 mg weekly).
Clinical improvement usually occurred quickly; typically at
doses of 15 to 20 mg weekly, and satisfactory long-term
control was achieved in 39 (87%) patients with mainte-
nance doses given at once to twice weekly intervals. After
methotrexate was discontinued, 10 patients remained free
of CD30+ lesions for from 2 years to almost 20 years. The
observation that long-lasting complete remissions occurred
after a relatively short course of methotrexate in some
patients raises the possibility that high-dose methotrexate
therapy, possibly combined with leucovorin rescue, might
provide more than suppressive therapy in selected cases but
such an approach is not commonly used.164
Mycosis fungoides (MF) Low-dose methotrexate is com-
monly used in the treatment of cutaneous T-cell lymphoma,
although documentation is sparse. Its efficacy has never
been compared to other commonly used systemic agents
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
13
such as alkylating agents, retinoids or histone deacetylase
inhibitors.205 Low-dose oral methotrexate has been shown
to be effective in patients with erythrodermic MF and
refractory MF. In a study of 69 patients with refractory MF,
an overall response rate was seen in 23 (33%) patients with
a complete response rate seen in eight (12%) patients.165
Topical methotrexate using a topical gel formulation had
some efficacy but has not been developed further.166
FUTURE DIRECTIONS
Ongoing research concerning methotrexate’s mechanism
of action and naturally occurring genetic polymorphisms in
its enzymatic pathways may soon offer greater sophistica-
tion and precision in the utilisation of this long-employed
drug. It has been demonstrated that certain genetic poly-
morphisms in the adenosine pathway are predictive of a
better response to methotrexate therapy in RA.206,207 Further-
more, a genetic analysis may enable clinicians to identify
patients at risk for a particular adverse effect.208
With the currently established treatment guidelines for
methotrexate therapy based mainly on experiences in
psoriasis and RA, the clinical utility of methotrexate in
the treatment armamentarium for various inflammatory
and lymphoproliferative skin conditions demands further
examination.
REFERENCES
1. Gubner RS. Introduction of antifolics in psoriasis. A twenty-five
year retrospect of antineoplastic agents in nonmalignant
disease. Cutis 1979; 23: 425–8.
2. Weinstein GD, Frost P. Methotrexate for psoriasis. A new
therapeutic schedule. Arch. Dermatol. 1971; 103: 33–8.
3. Weinstein GD, Goldfaden G, Frost P. Methotrexate. Mecha-
nism of action on DNA synthesis in psoriasis. Arch. Dermatol.
1971; 104: 236–43.
4. Mainman H, McClaren E, Heycock C et al. When should we
use parenteral methotrexate? Clin. Rheumatol. 2010; 29:
1093–8.
5. Hamilton RA, Kremer JM. Why intramuscular methotrexate
may be more efficacious than oral dosing in patients with RA.
Br. J. Rheumatol. 1997; 36: 86–90.
6. Wegrzyn J, Adeleine P, Miossec P. Better efficacy of methotr-
exate given by intramuscular injection than orally in patients
with rheumatoid arthritis. Ann. Rheum. Dis. 2004; 63: 1232–4.
7. Godfrey C, Sweeney K, Miller K et al. The population pharma-
cokinetics of long-term methotrexate in rheumatoid arthritis.
Br. J. Clin. Pharmacol. 1998; 46: 369–76.
8. Braun J, Kästner P, Flaxenberg P et al. Comparison of the
clinical efficacy and safety of subcutaneous versus oral admin-
istration of methotrexate in patients with active rheumatoid
arthritis: results of a six-month, multicenter, randomized,
double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;
58: 73–81.
9. Olsen EA. The pharmacology of methotrexate. J. Am. Acad.
Dermatol. 1991; 25: 306–18.
10. Swierkot J, Szechiński J. Methotrexate in rheumatoid arthritis.
Pharmacol. Rep. 2006; 58: 473–92.
11. Oguey D, Kölliker F, Gerber NJ et al. Effect of food on the
bioavailability of low-dose methotrexate in patients with rheu-
matoid arthritis. Arthritis Rheum. 1992; 35: 611–14.
12. Bleyer WA. The clinical pharmacology of methotrexate: new
applications of an old drug. Cancer 1978; 41: 36–51.
© 2011 The Authors
14 S Shen et al.
13. Chan ES, Cronstein BN. Methotrexate – how does it really
work? Nat. Rev. Rheumatol. 2010; 6: 175–8.
14. Nesher G, Moore TL, Dorner RW. In vitro effects of methotr-
exate on peripheral blood monocytes: modulation by folinic
acid and S-adenosylmethionine. Ann. Rheum. Dis. 1991; 50:
637–41.
15. Cronstein BN, Naime D, Ostad E. The antiinflammatory
mechanism of methotrexate. Increased adenosine release at
inflamed sites diminishes leukocyte accumulation in an in vivo
model of inflammation. J. Clin. Invest. 1993; 92: 2675–82.
16. Montesinos MC, Desai A, Cronstein BN. Suppression of inflam-
mation by low-dose methotrexate is mediated by adenosine
A2A receptor but not A3 receptor activation in thioglycollate-
induced peritonitis. Arthritis Res. Ther. 2006; 8: R53.
17. Haskó G, Cronstein BN. Adenosine: an endogenous regulator
of innate immunity. Trends Immunol. 2004; 25: 33–9.
18. Andersson SE, Johansson LH, Lexmüller K et al. Anti-arthritic
effect of methotrexate: is it really mediated by adenosine? Eur.
J. Pharm. Sci. 2000; 9: 333–43.
19. Phillips DC, Woollard KJ, Griffiths HR. The anti-inflammatory
actions of methotrexate are critically dependent upon the pro-
duction of reactive oxygen species. Br. J. Pharmacol. 2003; 138:
501–11.
20. al-Awadhi A, Dale P, McKendry RJ. Pancytopenia associated
with low dose methotrexate therapy. A regional survey. J.
Rheumatol. 1993; 20: 1121–5.
21. Wollina U, Ständer K, Barta U. Toxicity of methotrexate treat-
ment in psoriasis and psoriatic arthritis – short- and long-term
toxicity in 104 patients. Clin. Rheumatol. 2001; 20: 406–10.
22. Van Dooren-Greebe RJ, Kuijpers AL, Mulder J et al. Methotr-
exate revisited: effects of long-term treatment in psoriasis. Br.
J. Dermatol. 1994; 130: 204–10.
23. Lim AY, Gaffney K, Scott DG. Methotrexate-induced pancy-
topenia: serious and under-reported? Our experience of 25
cases in 5 years. Rheumatology (Oxford) 2005; 44: 1051–5.
24. Duhra P. Treatment of gastrointestinal symptoms associated
with methotrexate therapy for psoriasis. J. Am. Acad. Dermatol.
1993; 28: 466–9.
25. Nyfors A. Liver biopsies from psoriatics related to methotrex-
ate therapy. 3. Findings in post-methotrexate liver biopsies
from 160 psoriatics. Acta Pathol. Microbiol. Scand. A 1977; 85:
511–18.
26. Zachariae H, Søgaard H, Heickendorff L. Methotrexate-
induced liver cirrhosis. Clinical, histological and serological
studies – a further 10-year follow-up. Dermatology 1996; 192:
343–6.
27. Auerbach R. Psoriasis symposium. Methotrexate. Semin. Der-
matol. 1992; 11: 23–9.
28. Kremer JM, Alarcón GS, Lightfoot RW et al. Methotrexate for
rheumatoid arthritis. Suggested guidelines for monitoring
liver toxicity. American College of Rheumatology. Arthritis
Rheum. 1994; 37: 316–28.
29. Whiting-O’Keefe QE, Fye KH, Sack KD. Methotrexate and his-
tologic hepatic abnormalities: a meta-analysis. Am. J. Med.
1991; 90: 711–16.
30. Langman G, Hall PM, Todd G. Role of non-alcoholic steato-
hepatitis in methotrexate-induced liver injury. J. Gastroen-
terol. Hepatol. 2001; 16: 1395–401.
31. Rosenberg P, Urwitz H, Johannesson A et al. Psoriasis patients
with diabetes type 2 are at high risk of developing liver fibrosis
during methotrexate treatment. J. Hepatol. 2007; 46: 1111–18.
32. Roenigk HH, Auerbach R, Maibach HI et al. Methotrexate in
psoriasis: revised guidelines. J. Am. Acad. Dermatol. 1988; 19:
145–56.
33. Berends MA, van Oijen MG, Snoek J et al. Reliability of the
Roenigk classification of liver damage after methotrexate
treatment for psoriasis: a clinicopathologic study of 160 liver
biopsy specimens. Arch. Dermatol. 2007; 143: 1515–19.
© 2011 The Authors
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
34. Robinson JK, Baughman RD, Auerbach R et al. Methotrexate
hepatotoxicity in psoriasis. Consideration of liver biopsies at
regular intervals. Arch. Dermatol. 1980; 116: 413–15.
35. Themido R, Loureiro M, Pecegueiro M et al. Methotrexate
hepatotoxicity in psoriatic patients submitted to long-term
therapy. Acta Derm. Venereol. 1992; 72: 361–4.
36. Zachariae H, Heickendorff L, Søgaard H. The value of amino-
terminal propeptide of type III procollagen in routine screen-
ing for methotrexate-induced liver fibrosis: a 10-year
follow-up. Br. J. Dermatol. 2001; 144: 100–3.
37. Malatjalian DA, Ross JB, Williams CN et al. Methotrexate hepa-
totoxicity in psoriatics: report of 104 patients from Nova Scotia,
with analysis of risks from obesity, diabetes and alcohol con-
sumption during long term follow-up. Can. J. Gastroenterol.
1996; 10: 369–75.
38. Stern RS, Laird N. The carcinogenic risk of treatments for
severe psoriasis. Photochemotherapy Follow-up Study. Cancer
1994; 73: 2759–64.
39. Zumtobel U, Schwarze HP, Favre M et al. Widespread cutane-
ous carcinomas associated with human papillomaviruses 5, 14
and 20 after introduction of methotrexate in two long-term
PUVA-treated patients. Dermatology 2001; 202: 127–30.
40. Maruani A, Wierzbicka E, Machet MC et al. Reversal of multi-
focal cutaneous lymphoproliferative disease associated with
Epstein-Barr virus after withdrawal of methotrexate therapy
for rheumatoid arthritis. J. Am. Acad. Dermatol. 2007; 57: S69–
71.
41. Georgescu L, Quinn GC, Schwartzman S et al. Lymphoma in
patients with rheumatoid arthritis: association with the disease
state or methotrexate treatment. Semin. Arthritis Rheum. 1997;
26: 794–804.
42. Williams CA, Bloch DA, Sibley J et al. Lymphoma and luekemia
in rheumatoid arthritis: are they associated with azathioprine,
cyclophosphamide, or methotrexate? J. Clin. Rheumatol. 1996;
2: 64–72.
43. Shiroky JB, Frost A, Skelton JD et al. Complications of immu-
nosuppression associated with weekly low dose methotrexate.
J. Rheumatol. 1991; 18: 1172–5.
44. Viraben R, Brousse P, Lamant L. Reversible cutaneous lym-
phoma occurring during methotrexate therapy. Br. J. Derma-
tol. 1996; 135: 116–18.
45. Kamel OW, van de Rijn M, Weiss LM et al. Brief report: revers-
ible lymphomas associated with Epstein-Barr virus occurring
during methotrexate therapy for rheumatoid arthritis and der-
matomyositis. N. Engl. J. Med. 1993; 328: 1317–21.
46. Tournadre A, D’Incan M, Dubost JJ et al. Cutaneous lymphoma
associated with Epstein-Barr virus infection in 2 patients
treated with methotrexate. Mayo Clin. Proc. 2001; 76: 845–8.
47. Ellman MH, Hurwitz H, Thomas C et al. Lymphoma developing
in a patient with rheumatoid arthritis taking low dose weekly
methotrexate. J. Rheumatol. 1991; 18: 1741–3.
48. Usman AR, Yunus MB. Non-Hodgkin’s lymphoma in patients
with rheumatoid arthritis treated with low dose methotrexate.
J. Rheumatol. 1996; 23: 1095–7.
49. Mariette X, Cazals-Hatem D, Warszawki J et al. Lymphomas in
rheumatoid arthritis patients treated with methotrexate: a
3-year prospective study in France. Blood 2002; 99: 3909–15.
50. Baird RD, van Zyl-Smit RN, Dilke T et al. Spontaneous remis-
sion of low-grade B-cell non-Hodgkin’s lymphoma following
withdrawal of methotrexate in a patient with rheumatoid
arthritis: case report and review of the literature. Br. J. Hae-
matol. 2002; 118: 567–8.
51. Bachman TR, Sawitzke AD, Perkins SL et al. Methotrexate-
associated lymphoma in patients with rheumatoid arthritis:
report of two cases. Arthritis Rheum. 1996; 39: 325–9.
52. Paul C, Le Tourneau A, Cayuela JM et al. Epstein-Barr virus-
associated lymphoproliferative disease during methotrexate
therapy for psoriasis. Arch. Dermatol. 1997; 133: 867–71.
 Methotrexate in dermatology
53. Chai C, White WL, Shea CR et al. Epstein Barr virus-associated
lymphoproliferative-disorders primarily involving the skin. J.
Cutan. Pathol. 1999; 26: 242–7.
54. Hirose Y, Masaki Y, Okada J et al. Epstein-Barr virus-
associated B-cell type non-Hodgkin’s lymphoma with concur-
rent p53 protein expression in a rheumatoid arthritis patient
treated with methotrexate. Int. J. Hematol. 2002; 75: 412–
15.
55. Airio A, Pukkala E, Isomäki H. Elevated cancer incidence in
patients with dermatomyositis: a population based study. J.
Rheumatol. 1995; 22: 1300–3.
56. Moder KG, Tefferi A, Cohen MD et al. Hematologic malignan-
cies and the use of methotrexate in rheumatoid arthritis: a
retrospective study. Am. J. Med. 1995; 99: 276–81.
57. Buchbinder R, Barber M, Heuzenroeder L et al. Incidence of
melanoma and other malignancies among rheumatoid arthri-
tis patients treated with methotrexate. Arthritis Rheum. 2008;
59: 794–9.
58. Lloyd ME, Carr M, McElhatton P et al. The effects of methotr-
exate on pregnancy, fertility and lactation. QJM 1999; 92: 551–
63.
59. Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs
in pregnancy and lactation. Semin. Arthritis Rheum. 2005; 35:
112–21.
60. Morris LF, Harrod MJ, Menter MA et al. Methotrexate and
reproduction in men: case report and recommendations. J. Am.
Acad. Dermatol. 1993; 29: 913–16.
61. Binymin K, Cooper RG. Late reactivation of spinal tuberculosis
by low-dose methotrexate therapy in a patient with rheuma-
toid arthritis. Rheumatology (Oxford) 2001; 40: 341–2.
62. Gwak GY, Koh KC, Kim HY. Fatal hepatic failure associated
with hepatitis B virus reactivation in a hepatitis B surface
antigen-negative patient with rheumatoid arthritis receiving
low dose methotrexate. Clin. Exp. Rheumatol. 2007; 25: 888–9.
63. Maurer TA, Zackheim HS, Tuffanelli L et al. The use of meth-
otrexate for treatment of psoriasis in patients with HIV infec-
tion. J. Am. Acad. Dermatol. 1994; 31: 372–5.
64. Phillips TJ, Jones DH, Baker H. Pulmonary complications fol-
lowing methotrexate therapy. J. Am. Acad. Dermatol. 1987; 16:
373–5.
65. Kalantzis A, Marshman Z, Falconer DT et al. Oral effects of
low-dose methotrexate treatment. Oral Surg. Oral Med. Oral
Pathol. Oral Radiol. Endod. 2005; 100: 52–62.
66. Pearce HP, Wilson BB. Erosion of psoriatic plaques: an early
sign of methotrexate toxicity. J. Am. Acad. Dermatol. 1996; 35:
835–8.
67. Lawrence CM, Dahl MG. Two patterns of skin ulceration
induced by methotrexate in patients with psoriasis. J. Am.
Acad. Dermatol. 1984; 11: 1059–65.
68. Kazlow DW, Federgrun D, Kurtin S et al. Cutaneous ulceration
caused by methotrexate. J. Am. Acad. Dermatol. 2003; 49:
S197–8.
69. Dierkes J, Westphal S. Effect of drugs on homocysteine con-
centrations. Semin. Vasc. Med. 2005; 5: 124–39.
70. Prodanovich S, Prodanowich S, Ma F et al. Methotrexate
reduces incidence of vascular diseases in veterans with pso-
riasis or rheumatoid arthritis. J. Am. Acad. Dermatol. 2005; 52:
262–7.
71. Kremer JM. Toward a better understanding of methotrexate.
Arthritis Rheum. 2004; 50: 1370–82.
72. Zonneveld IM, Bakker WK, Dijkstra PF et al. Methotrexate
osteopathy in long-term, low-dose methotrexate treatment for
psoriasis and rheumatoid arthritis. Arch. Dermatol. 1996; 132:
184–7.
73. Alkins SA, Byrd JC, Morgan SK et al. Anaphylactoid reactions to
methotrexate. Cancer 1996; 77: 2123–6.
74. Kumar B, Dhar S, Handa S et al. Methotrexate in childhood
psoriasis. Pediatr. Dermatol. 1994; 11: 271–3.
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
15
75. Dadlani C, Orlow SJ. Treatment of children and adolescents
with methotrexate, cyclosporine, and etanercept: review of the
dermatologic and rheumatologic literature. J. Am. Acad. Der-
matol. 2005; 52: 316–40.
76. Bangert CA, Costner MI. Methotrexate in dermatology. Derma-
tol. Ther. 2007; 20: 216–28.
77. Evans WE, Christensen ML. Drug interactions with methotr-
exate. J. Rheumatol. Suppl. 1985; 12 (Suppl 12): 15–20.
78. Lester RS. Methotrexate. Clin. Dermatol. 1989; 7: 128–35.
79. Kalb RE, Strober B, Weinstein G et al. Methotrexate and pso-
riasis: 2009 National Psoriasis Foundation Consensus Confer-
ence. J. Am. Acad. Dermatol. 2009; 60: 824–37.
80. Guidelines for management of patients with psoriasis. Work-
shop of the Research Unit of the Royal College of Physicians of
London; Department of Dermatology, University of Glasgow;
British Association of Dermatologists. BMJ 1991; 303: 829–35.
81. Roenigk HH, Auerbach R, Maibach H et al. Methotrexate in
psoriasis: consensus conference. J. Am. Acad. Dermatol. 1998;
38: 478–85.
82. Weinstein GD. Methotrexate. Ann. Intern. Med. 1977; 86: 199–
204.
83. Boffa MJ, Smith A, Chalmers RJ et al. Serum type III pro-
collagen aminopeptide for assessing liver damage in
methotrexate-treated psoriatic patients. Br. J. Dermatol. 1996;
135: 538–44.
84. Zachariae H, Søgaard H, Heickendorff L. Serum aminotermi-
nal propeptide of type III procollagen. A non-invasive test for
liver fibrogenesis in methotrexate-treated psoriatics. Acta
Derm. Venereol. 1989; 69: 241–4.
85. Zachariae H, Aslam HM, Bjerring P et al. Serum aminotermi-
nal propeptide of type III procollagen in psoriasis and psoriatic
arthritis: relation to liver fibrosis and arthritis. J. Am. Acad.
Dermatol. 1991; 25: 50–3.
86. Mitchell D, Smith A, Rowan B et al. Serum type III procollagen
peptide, dynamic liver function tests and hepatic fibrosis in
psoriatic patients receiving methotrexate. Br. J. Dermatol.
1990; 122: 1–7.
87. Chalmers RJ, Kirby B, Smith A et al. Replacement of routine
liver biopsy by procollagen III aminopeptide for monitoring
patients with psoriasis receiving long-term methotrexate: a
multicentre audit and health economic analysis. Br. J. Derma-
tol. 2005; 152: 444–50.
88. Mazurek GH, Villarino ME, CDC. Guidelines for using the
QuantiFERON-TB test for diagnosing latent mycobacterium
tuberculosis infection. Centers for Disease Control and Pre-
vention. MMWR Recomm. Rep. 2003; 52: 15–18.
89. Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and
pregnancy. Semin. Oncol. 1989; 16: 337–46.
90. Menter A, Korman NJ, Elmets CA et al. Guidelines of care for
the management of psoriasis and psoriatic arthritis: section 4.
Guidelines of care for the management and treatment of pso-
riasis with traditional systemic agents. J. Am. Acad. Dermatol.
2009; 61: 451–85.
91. Donnenfeld AE, Pastuszak A, Noah JS et al. Methotrexate expo-
sure prior to and during pregnancy. Teratology. 1994; 49:
79–81.
92. Strober BE, Menon K. Folate supplementation during methotr-
exate therapy for patients with psoriasis. J. Am. Acad. Derma-
tol. 2005; 53: 652–9.
93. Kirby B, Lyon CC, Griffiths CE et al. The use of folic acid
supplementation in psoriasis patients receiving methotrexate:
a survey in the United Kingdom. Clin. Exp. Dermatol. 2000; 25:
265–8.
94. Chládek J, Simková M, Vanecková J et al. The effect of folic
acid supplementation on the pharmacokinetics and pharma-
codynamics of oral methotrexate during the remission-
induction period of treatment for moderate-to-severe plaque
psoriasis. Eur. J. Clin. Pharmacol. 2008; 64: 347–55.
© 2011 The Authors
16 S Shen et al.
95. Salim A, Tan E, Ilchyshyn A et al. Folic acid supplementation
during treatment of psoriasis with methotrexate: a random-
ized, double-blind, placebo-controlled trial. Br. J. Dermatol.
2006; 154: 1169–74.
96. van Ede AE, Laan RF, Rood MJ et al. Effect of folic or folinic
acid supplementation on the toxicity and efficacy of methotr-
exate in rheumatoid arthritis: a forty-eight week, multicenter,
randomized, double-blind, placebo-controlled study. Arthritis
Rheum. 2001; 44: 1515–24.
97. Lamar LM, Gaethe G. Pityriasis rubra pilaris. Arch. Dermatol.
1964; 89: 515–22.
98. Dicken CH. Treatment of classic pityriasis rubra pilaris. J. Am.
Acad. Dermatol. 1994; 31: 997–9.
99. Anderson FE. Pityriasis rubra pilaris treated with methotrex-
ate. Aust. J. Dermatol. 1966; 8: 183–5.
100. Brown J, Perry HO. Pityriasis rubra pilaris. Treatment with
folic acid antagonists. Arch. Dermatol. 1966; 94: 636–8.
101. Parish LC, Woo TH. Pityriasis rubra pilaris in Korea. Treatment
with methotrexate. Dermatologica 1969; 139: 399–403.
102. Knowles WR, Chernosky ME. Pityriasis rubra pilaris. Pro-
longed treatment with methotrexate. Arch. Dermatol. 1970;
102: 603–12.
103. Hanke CW, Steck WD. Childhood-onset pityriasis rubra pilaris
treated with methotrexate administered intravenously. Cleve.
Clin. Q. 1983; 50: 201–3.
104. Griffiths WA. Pityriasis rubra pilaris. Clin. Exp. Dermatol. 1980;
5: 105–12.
105. Durairaj VD, Horsley MB. Resolution of pityriasis rubra pilaris-
induced cicatricial ectropion with systemic low-dose methotr-
exate. Am. J. Ophthalmol. 2007; 143: 709–10.
106. Cornelison RL, Knox JM, Everett MA. Methotrexate for the
treatment of Mucha–Habermann disease. Arch. Dermatol.
1972; 106: 507–8.
107. Lynch PJ, Saied NK. Methotrexate treatment of pityriasis
lichenoides and lymphomatoid papulosis. Cutis 1979; 23:
634–6.
108. López-Estebaranz JL, Vanaclocha F, Gil R et al. Febrile ulcero-
necrotic Mucha–Habermann disease. J. Am. Acad. Dermatol.
1993; 29: 903–6.
109. Rasmussen JE. Mucha–Habermann’s disease. Arch. Dermatol.
1979; 115: 676–7.
110. Herron MD, Bohnsack JF, Vanderhooft SL. Septic, CD-30 posi-
tive febrile ulceronecrotic pityriasis lichenoides et variolifor-
mis acuta. Pediatr. Dermatol. 2005; 22: 360–5.
111. Perez A, Woods A, Grattan CE. Methotrexate: a useful steroid-
sparing agent in recalcitrant chronic urticaria. Br. J. Dermatol.
2010; 162: 191–4.
112. Godse K. Methotrexate in autoimmune urticaria. Indian J. Der-
matol. Venereol. Leprol. 2004; 70: 377.
113. Gach JE, Sabroe RA, Greaves MW et al. Methotrexate-
responsive chronic idiopathic urticaria: a report of two cases.
Br. J. Dermatol. 2001; 145: 340–3.
114. Lyakhovitsky A, Barzilai A, Heyman R et al. Low-dose meth-
otrexate treatment for moderate-to-severe atopic dermati-
tis in adults. J. Eur. Acad. Dermatol. Venereol. 2010; 24:
43–9.
115. Zoller L, Ramon M, Bergman R. Low dose methotrexate
therapy is effective in late-onset atopic dermatitis and idio-
pathic eczema. Isr. Med. Assoc. J. 2008; 10: 413–14.
116. Goujon C, Bérard F, Dahel K et al. Methotrexate for the treat-
ment of adult atopic dermatitis. Eur. J. Dermatol. 2006; 16:
155–8.
117. Shaffrali FC, Colver GB, Messenger AG et al. Experience with
low-dose methotrexate for the treatment of eczema in the
elderly. J. Am. Acad. Dermatol. 2003; 48: 417–19.
118. Balasubramaniam P, Ilchyshyn A. Successful treatment of
severe atopic dermatitis with methotrexate. Clin. Exp. Derma-
tol. 2005; 30: 436–7.
© 2011 The Authors
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
119. Egan CA, Rallis TM, Meadows KP et al. Low-dose oral meth-
otrexate treatment for recalcitrant palmoplantar pompholyx. J.
Am. Acad. Dermatol. 1999; 40: 612–14.
120. Weatherhead SC, Wahie S, Reynolds NJ et al. An open-label,
dose-ranging study of methotrexate for moderate-to-severe
adult atopic eczema. Br. J. Dermatol. 2007; 156: 346–51.
121. Jablonska S, Chorzelski T, Blaszczyk M. Immunosuppressants
in the treatment of pemphigus. Br. J. Dermatol. 1970; 83: 315–
23.
122. Piamphongsant T, Sivayathorn A. Pemphigus: combined treat-
ment with methotrexate and prednisone. J. Med. Assoc. Thai.
1975; 58: 171–6.
123. Lever WF, Schaumburg-Lever G. Immunosuppressants and
prednisone in pemphigus vulgaris: therapeutic results
obtained in 63 patients between 1961 and 1975. Arch. Derma-
tol. 1977; 113: 1236–41.
124. Lever WF. Methotrexate and prednisone in pemphigus vul-
garis. Therapeutic results obtained in 36 patients between
1961 and 1970. Arch. Dermatol. 1972; 106: 491–7.
125. Mashkilleyson N, Mashkilleyson AL. Mucous membrane mani-
festations of pemphigus vulgaris. A 25-year survey of 185
patients treated with corticosteroids or with combination of
corticosteroids with methotrexate or heparin. Acta Derm.
Venereol. 1988; 68: 413–21.
126. Smith TJ, Bystryn JC. Methotrexate as an adjuvant treatment
for pemphigus vulgaris. Arch. Dermatol. 1999; 135: 1275–6.
127. Rivitti EA, Camargo ME, Castro RM et al. Use of methotrexate
to treat pemphigus foliaceus. Int. J. Dermatol. 1973; 12: 119–
22.
128. Downham TF, Chapel TA. Bullous pemphigoid:therapy in
patients with and without diabetes mellitus. Arch. Dermatol.
1978; 114: 1639–42.
129. Paul MA, Jorizzo JL, Fleischer AB et al. Low-dose methotrexate
treatment in elderly patients with bullous pemphigoid. J. Am.
Acad. Dermatol. 1994; 31: 620–5.
130. Dereure O, Bessis D, Guillot B et al. Treatment of bullous
pemphigoid by low-dose methotrexate associated with short-
term potent topical steroids: an open prospective study of 18
cases. Arch. Dermatol. 2002; 138: 1255–6.
131. Bara C, Maillard H, Briand N et al. Methotrexate for bullous
pemphigoid: preliminary study. Arch. Dermatol. 2003; 139:
1506–7.
132. Kjellman P, Eriksson H, Berg P. A retrospective analysis of
patients with bullous pemphigoid treated with methotrexate.
Arch. Dermatol. 2008; 144: 612–16.
133. McCluskey P, Chang JH, Singh R et al. Methotrexate therapy
for ocular cicatricial pemphigoid. Ophthalmology 2004; 111:
796–801.
134. Christen-Zaech S, Hakim MD, Afsar FS et al. Pediatric
morphea (localized scleroderma): review of 136 patients. J.
Am. Acad. Dermatol. 2008; 59: 385–96.
135. Weibel L, Sampaio MC, Visentin MT et al. Evaluation of meth-
otrexate and corticosteroids for the treatment of localized scle-
roderma (morphoea) in children. Br. J. Dermatol. 2006; 155:
1013–20.
136. Fitch PG, Rettig P, Burnham JM et al. Treatment of pediatric
localized scleroderma with methotrexate. J. Rheumatol. 2006;
33: 609–14.
137. Kreuter A, Gambichler T, Breuckmann F et al. Pulsed high-
dose corticosteroids combined with low-dose methotrexate in
severe localized scleroderma. Arch. Dermatol. 2005; 141: 847–
52.
138. Uziel Y, Feldman BM, Krafchik BR et al. Methotrexate and
corticosteroid therapy for pediatric localized scleroderma. J.
Pediatr. 2000; 136: 91–5.
139. Seyger MM, van den Hoogen FH, de Boo T et al. Low-dose
methotrexate in the treatment of widespread morphea. J. Am.
Acad. Dermatol. 1998; 39: 220–5.
 Methotrexate in dermatology
140. Kasteler JS, Callen JP. Low-dose methotrexate administered
weekly is an effective corticosteroid-sparing agent for the
treatment of the cutaneous manifestations of dermatomyositis.
J. Am. Acad. Dermatol. 1997; 36: 67–71.
141. Zieglschmid-Adams ME, Pandya AG, Cohen SB et al. Treat-
ment of dermatomyositis with methotrexate. J. Am. Acad. Der-
matol. 1995; 32: 754–7.
142. el-Azhary RA, Pakzad SY. Amyopathic dermatomyositis: retro-
spective review of 37 cases. J. Am. Acad. Dermatol. 2002; 46:
560–5.
143. Kuhn A, Specker C, Ruzicka T et al. Methotrexate treatment for
refractory subacute cutaneous lupus erythematosus. J. Am.
Acad. Dermatol. 2002; 46: 600–3.
144. Böhm L, Uerlich M, Bauer R. Rapid improvement of subacute
cutaneous lupus erythematosus with low-dose methotrexate.
Dermatology 1997; 194: 307–8.
145. Wenzel J, Brähler S, Bauer R et al. Efficacy and safety of meth-
otrexate in recalcitrant cutaneous lupus erythematosus:
results of a retrospective study in 43 patients. Br. J. Dermatol.
2005; 153: 157–62.
146. Boehm IB, Boehm GA, Bauer R. Management of cutaneous
lupus erythematosus with low-dose methotrexate: indication
for modulation of inflammatory mechanisms. Rheumatol. Int.
1998; 18: 59–62.
147. Wilson K, Abeles M. A 2 year, open ended trial of methotrexate
in systemic lupus erythematosus. J. Rheumatol. 1994; 21:
1674–7.
148. Bottomley WW, Goodfield MJ. Methotrexate for the treatment
of discoid lupus erythematosus. Br. J. Dermatol. 1995; 133:
655–6.
149. Goldstein E, Carey W. Discoid lupus erythematosus: successful
treatment with oral methotrexate. Arch. Dermatol. 1994; 130:
938–9.
150. Upchurch KS, Heller K, Bress NM. Low-dose methotrexate
therapy for cutaneous vasculitis of rheumatoid arthritis. J. Am.
Acad. Dermatol. 1987; 17: 355–9.
151. Williams HC, Pembroke AC. Methotrexate in the treatment of
vasculitic cutaneous ulceration in rheumatoid arthritis. J. R.
Soc. Med. 1989; 82: 763.
152. Espinoza LR, Espinoza CG, Vasey FB et al. Oral methotrexate
therapy for chronic rheumatoid arthritis ulcerations. J. Am.
Acad. Dermatol. 1986; 15: 508–12.
153. Gansauge S, Breitbart A, Rinaldi N et al. Methotrexate in
patients with moderate systemic lupus erythematosus (exclu-
sion of renal and central nervous system disease). Ann. Rheum.
Dis. 1997; 56: 382–5.
154. Jorizzo JL, White WL, Wise CM et al. Low-dose weekly meth-
otrexate for unusual neutrophilic vascular reactions: cutane-
ous polyarteritis nodosa and Behçet’s disease. J. Am. Acad.
Dermatol. 1991; 24: 973–8.
155. Boehm I, Bauer R. Low-dose methotrexate controls a severe
form of polyarteritis nodosa. Arch. Dermatol. 2000; 136: 167–9.
156. Schartz NE, Alaoui S, Vignon-Pennamen MD et al. Successful
treatment in two cases of steroid-dependent cutaneous pol-
yarteritis nodosa with low-dose methotrexate. Dermatology
2001; 203: 336–8.
157. Quintana G, Matteson EL, Fernández A et al. Localized
nodular vasculitis: a new variant of localized cutaneous pol-
yarteritis nodosa? Clin. Exp. Rheumatol. 2004; 22: S31–4.
158. Lower EE, Baughman RP. The use of low dose methotrexate in
refractory sarcoidosis. Am. J. Med. Sci. 1990; 299: 153–7.
159. Webster GF, Razsi LK, Sanchez M et al. Weekly low-dose meth-
otrexate therapy for cutaneous sarcoidosis. J. Am. Acad. Der-
matol. 1991; 24: 451–4.
160. Veien NK, Brodthagen H. Cutaneous sarcoidosis treated with
methotrexate. Br. J. Dermatol. 1977; 97: 213–16.
161. Lower EE, Baughman RP. Prolonged use of methotrexate for
sarcoidosis. Arch. Intern. Med. 1995; 155: 846–51.
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
17
162. Plotner AN, Mutasim DF. Successful treatment of disseminated
granuloma annulare with methotrexate. Br. J. Dermatol. 2010;
163: 1123–4.
163. Lange Wantzin G, Thomsen K. Methotrexate in lymphomatoid
papulosis. Br. J. Dermatol. 1984; 111: 93–5.
164. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effec-
tive therapy for lymphomatoid papulosis and other primary
cutaneous CD30-positive lymphoproliferative disorders. J. Am.
Acad. Dermatol. 1996; 34: 470–81.
165. Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose meth-
otrexate to treat mycosis fungoides: a retrospective study in 69
patients. J. Am. Acad. Dermatol. 2003; 49: 873–8.
166. Demierre MF, Vachon L, Ho V et al. Phase 1/2 pilot study of
methotrexate-laurocapram topical gel for the treatment of
patients with early-stage mycosis fungoides. Arch. Dermatol.
2003; 139: 624–8.
167. NHMRC. A Guide to the Development, Implementation and
Evaluation of Clinical Practice Guidelines. Canberra: National
Health and Medical Research Council, Commonwealth of Aus-
tralia, 1999.
168. Roenigk HH Jr, Auerbach R, Maibach H et al. Methotrexate for
psoriasis: consensus conference. J. Am. Acad. Dermatol. 1998;
38: 478–85.
169. Black RL, O’Brien WM, Vanscott EJ et al. Methotrexate therapy
in psoriatic arthritis; double-blind study on 21 patients. JAMA
1964; 189: 743–7.
170. Nyfors A, Brodthagen H. Methotrexate for psoriasis in weekly
oral doses without any adjunctive therapy. Dermatologica
1970; 140: 345–55.
171. Jeffes EW, Weinstein GD. Methotrexate and other chemo-
therapeutic agents used to treat psoriasis. Dermatol. Clin.
1995; 13: 875–90.
172. Zachariae H, Zachariae E. Methotrexate treatment of psoriatic
arthritis. Acta Derm. Venereol. 1987; 67: 270–3.
173. Kragballe K, Zachariae E, Zachariae H. Methotrexate in pso-
riatic arthritis: a retrospective study. Acta Derm. Venereol.
1983; 63: 165–7.
174. Nyfors A. Benefits and adverse drug experiences during long-
term methotrexate treatment of 248 psoriatics. Dan. Med. Bull.
1978; 25: 208–11.
175. Akhyani M, Chams-Davatchi C, Hemami MR et al. Efficacy and
safety of mycophenolate mofetil vs. methotrexate for the treat-
ment of chronic plaque psoriasis. J. Eur. Acad. Dermatol.
Venereol. 2010; 24: 1447–51.
176. Flytström I, Stenberg B, Svensson A et al. Methotrexate vs.
ciclosporin in psoriasis: effectiveness, quality of life and safety.
A randomized controlled trial. Br. J. Dermatol. 2008; 158: 116–
21.
177. Heydendael VM, Spuls PI, Opmeer BC et al. Methotrexate
versus cyclosporine in moderate-to-severe chronic plaque
psoriasis. N. Engl. J. Med. 2003; 349: 658–65.
178. Sandhu K, Kaur I, Kumar B et al. Efficacy and safety of
cyclosporine versus methotrexate in severe psoriasis: a study
from north India. J. Dermatol. 2003; 30: 458–63.
179. Ranjan N, Sharma NL, Shanker V et al. Methotrexate versus
hydroxycarbamide (hydroxyurea) as a weekly dose to treat
moderate-to-severe chronic plaque psoriasis: a comparative
study. J. Dermatolog. Treat. 2007; 18: 295–300.
180. Fallah Arani S, Neumann H, Hop WC et al. Fumarates vs. meth-
otrexate in moderate to severe chronic plaque psoriasis: a
multicentre prospective randomized controlled clinical trial.
Br. J. Dermatol. 2011; 164: 855–61.
181. Jensen P, Skov L, Zachariae C. Systemic combination treatment
for psoriasis: a review. Acta Derm. Venereol. 2010; 90: 341–9.
182. Gupta R, Gupta S. Methotrexate-betamethasone weekly oral
pulse in psoriasis. J. Dermatolog. Treat. 2007; 18: 291–4.
183. Asawanonda P, Nateetongrungsak Y. Methotrexate plus nar-
rowband UVB phototherapy versus narrowband UVB photo-
© 2011 The Authors
18 S Shen et al.
therapy alone in the treatment of plaque-type psoriasis: a
randomized, placebo-controlled study. J. Am. Acad. Dermatol.
2006; 54: 1013–18.
184. Shehzad T, Dar NR, Zakria M. Efficacy of concomitant use of
PUVA and methotrexate in disease clearance time in plaque
type psoriasis. J. Pak. Med. Assoc. 2004; 54: 453–5.
185. Zachariae C, Mørk NJ, Reunala T et al. The combination of
etanercept and methotrexate increases the effectiveness of
treatment in active psoriasis despite inadequate effect of meth-
otrexate therapy. Acta Derm. Venereol. 2008; 88: 495–501.
186. Fraser AD, van Kuijk AW, Westhovens R et al. A randomised,
double blind, placebo controlled, multicentre trial of combina-
tion therapy with methotrexate plus ciclosporin in patients
with active psoriatic arthritis. Ann. Rheum. Dis. 2005; 64: 859–
64.
187. Mease PJ, Gladman DD, Keystone EC et al. Alefacept in com-
bination with methotrexate for the treatment of psoriatic
arthritis: results of a randomized, double-blind, placebo-
controlled study. Arthritis Rheum. 2006; 54: 1638–45.
188. Collins P, Rogers S. The efficacy of methotrexate in psoriasis –
a review of 40 cases. Clin. Exp. Dermatol. 1992; 17: 257–60.
189. Vanderveen EE, Ellis CN, Campbell JP et al. Methotrexate and
etretinate as concurrent therapies in severe psoriasis. Arch.
Dermatol. 1982; 118: 660–2.
190. Rosenbaum MM, Roenigk HH. Treatment of generalized pus-
tular psoriasis with etretinate (Ro 10-9359) and methotrexate.
J. Am. Acad. Dermatol. 1984; 10: 357–61.
191. Horiguchi M, Takigawa M, Imamura S. Treatment of general-
ized pustular psoriasis with methotrexate and colchicine. Arch.
Dermatol. 1981; 117: 760.
192. Fitzsimons CP, Long J, MacKie RM. Synergistic carcinogenic
potential of methotrexate and PUVA in psoriasis. Lancet 1983;
1: 235–6.
193. Gollnick HP. Oral retinoids – efficacy and toxicity in psoriasis.
Br. J. Dermatol. 1996; 135 (Suppl 49): 6–17.
194. Bonifati C, Carducci M, Mussi A et al. Recognition and treat-
ment of psoriasis. Special considerations in elderly patients.
Drugs Aging 1998; 12: 177–90.
195. Fairris GM, Dewhurst AG, White JE et al. Methotrexate dosage
in patients aged over 50 with psoriasis. BMJ 1989; 298: 801–2.
196. Gürcan HM, Ahmed AR. Analysis of current data on the use of
methotrexate in the treatment of pemphigus and pemphigoid.
Br. J. Dermatol. 2009; 161: 723–31.
© 2011 The Authors
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
197. Heilborn JD, Ståhle-Bäckdahl M, Albertioni F et al. Low-dose
oral pulse methotrexate as monotherapy in elderly patients
with bullous pemphigoid. J. Am. Acad. Dermatol. 1999; 40:
741–9.
198. Sapadin AN, Fleischmajer R. Treatment of scleroderma. Arch.
Dermatol. 2002; 138: 99–105.
199. Villalba L, Adams EM. Update on therapy for refractory der-
matomyositis and polymyositis. Curr. Opin. Rheumatol. 1996; 8:
544–51.
200. Huber A, Tüting T, Bauer R et al. Methotrexate treatment in
cutaneous lupus erythematosus: subcutaneous application is
as effective as intravenous administration. Br. J. Dermatol.
2006; 155: 861–2.
201. Picco P, Gattorno M, Buoncompagni A et al. A case of paediat-
ric discoid lupus erythematosus evolving into SLE. Clin. Exp.
Rheumatol. 1998; 16: 620.
202. ten Holder SM, Joy MS, Falk RJ. Cutaneous and systemic mani-
festations of drug-induced vasculitis. Ann. Pharmacother. 2002;
36: 130–47.
203. Kaye O, Beckers CC, Paquet P et al. The frequency of cutane-
ous vasculitis is not increased in patients with rheumatoid
arthritis treated with methotrexate. J. Rheumatol. 1996; 23:
253–7.
204. Badgwell C, Rosen T. Cutaneous sarcoidosis therapy updated.
J. Am. Acad. Dermatol. 2007; 56: 69–83.
205. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fun-
goides and Sézary syndrome. Blood 2009; 114: 4337–53.
206. Wessels JA, Kooloos WM, De Jonge R et al. Relationship
between genetic variants in the adenosine pathway and
outcome of methotrexate treatment in patients with recent-
onset rheumatoid arthritis. Arthritis Rheum. 2006; 54: 2830–9.
207. Dervieux T, Wessels JA, van der Straaten T et al. Gene-gene
interactions in folate and adenosine biosynthesis pathways
affect methotrexate efficacy and tolerability in rheumatoid
arthritis. Pharmacogenet. Genomics 2009; Epub ahead of print.
208. Kooloos WM, Wessels JA, van der Kooij SM et al. Optimaliza-
tion of the clinical pharmacogenetic model to predict methotr-
exate treatment response: the influence of the number of
haplotypes of MTHFR 1298A-677C alleles on probability to
respond. Ann. Rheum. Dis. 2009; 68: 1371.