Vous êtes sur la page 1sur 18

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


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

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- increase in intracellular and extracellular adenosine.
trointestinal intolerance.4–7 One randomised double-blind Adenosine is a purine nucleoside that is regarded as an
controlled study comparing oral to subcutaneous adminis- endogenous anti-inflammatory compound. By binding to
tration of methotrexate in 375 rheumatoid arthritis (RA) specific cell surface receptors, it has been shown to have
patients did not reveal any statistical difference in clinical potent anti-inflammatory effects on a number of different
efficacy or tolerability.8 target cells. It inhibits the oxidative burst in neutrophils and
monocytes, prevents leukocyte chemotaxis and inhibits
monocyte and macrophage secretion of multiple cytokines,
Pharmacokinetics Significant variation is seen in the bio-
including tumor necrosis factor-alpha, interleukin (IL)-10
availability of oral methotrexate although inter-patient dif-
and IL-12. Adenosine downregulates the expression of
ferences are considerable. There is also a dose-dependent
adhesion molecules, including L-selectin, B2-integrin and
and saturable intestinal absorption variation, with increas-
CD11b, resulting in the potent inhibition of polymorpho-
ing variability in absorption with doses higher than 15 mg.9
nuclear chemotaxis and adherence. In addition, adenosine
There is conflicting evidence as to whether the bioavailabil-
receptors are found on endothelial cells, another possible
ity of methotrexate is affected by the presence of food, with
target for adenosine’s anti-inflammatory effects (Fig. 1).
some denying10,11 while others confirming a decrease in
However, the anti-inflammatory role of adenosine has been
absorption.7
questioned18 and knowledge of methotrexate’s mechanism
In the circulation, approximately 35-50% of the drug is
of action is continuing to expand with recent research
bound to albumin. Maximum blood levels of methotrexate
implicating the production of reactive oxygen species.19 The
occur 1–2 h after administration.9 Intracellular poly-
mechanism of action of methotrexate is illustrated in
glutamate derivative is the primary active metabolite.
Figure 1.
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 Adverse effects
50–90% of the drug is excreted unchanged in the urine after Data regarding methotrexate’s adverse effects is primarily
24 h. It is filtered by the glomeruli and undergoes bidirec- derived from its use in RA, psoriasis and psoriatic arthritis
tional transport in the proximal renal tubule. Enterohepatic (PA). Potential methotrexate toxicities are summarised in
recirculation occurs to a minor degree.9,12 Table 1.

Mechanism of action Methotrexate is a folate antagonist Constitutional Commonly reported adverse events of the
that was originally conceived as an anti-malignancy drug. medication include nausea, anorexia, fatigue and malaise,
Its primary metabolite polyglutamate competitively inhi- usually occurring around initiation of therapy. These side
bits dihyrofolate reductase, preventing the reduction of effects are, in general, dose dependent and may be mini-
folate cofactors. This results in the inhibition of thymidy- mised by taking the medication several hours before
late synthesis, thereby preventing pyrimidine synthesis. bedtime and by folic acid administration.
Other folate-dependent enzymes inhibited by polygluta-
mate include aminoimidazole-carboxamide-ribonucleoside
(AICAR) transformylase. The inhibition of AICAR impairs Haematological Haematological toxicities are rare in the
purine synthesis. The methylation of homocysteine to absence of potential risk factors for developing myelosup-
methionine is also inhibited, thereby affecting the synthesis pression such as renal insufficiency, increased mean cell
of polyamines such as spermidine and spermine. The drug volume, older age, concomitant illnesses or infections,
is cell cycle specific and is active only in the S phase of the hypoalbuminemia, drug overdose or drug interaction
cycle. Its anti-proliferative action at high doses is clinically (Table 2).20,21 In a 22-year retrospective study of 157 psoria-
employed in the treatment of malignancy. Methotrexate sis patients on long-term low-dose methotrexate (15 mg
depletes the intracellular stores of activated folate and thus weekly), myelosuppression occurred in 10–20% of the
disrupts cell replication. This leads to the inhibition of epi- patients, manifesting as macrocytic anaemia, leucopenia,
dermal cell proliferation, although lymphoid and macroph- thrombocytopenia or pancytopenia.22 Though rare, pancy-
age cell lines have been shown to be affected by the topenia can occur at any time during therapy, therefore
cytotoxic and growth inhibitory effects of methotrexate to a close haematological monitoring is warranted. Cytopenia
greater degree.13 usually improves after dose reduction or the withdrawal of
At low doses, methotrexate has potent anti-inflammatory therapy.21,23
actions that appear to be mediated via pathways separate
from folate antagonism. The inhibition of polyamines is Gastrointestinal Nausea and vomiting often accompany
thought to contribute to its anti-inflammatory effects.14 therapy. Diarrhoea and stomatitis may also occur. These
Recent studies have focused on its effects on adenosine as side effects are dose dependent and respond to folate
critical to its anti-inflammatory properties.15–17 The inhibi- supplementation.24 Hepatotoxicity, including fibrosis and
tion of AICAR transformylase not only prevents one of the cirrhosis, is a recognised adverse effect in patients on long-
final stages of de novo purine synthesis but leads to term methotrexate for psoriasis.25 Fibrotic changes can
increased levels of AICAR, which in turn results in a net occur in the presence of normal liver function tests.26 Risk

© 2011 The Authors


Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
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 However, population-based studies looking at the use of
consumption and obesity and viral hepatitis B and C immunosuppressive agents, especially methotrexate, in the
(Table 3).27 The incidence of liver toxicity is significantly treatment of RA and dermatomyositis (DM), did not defini-
higher in psoriasis patients than in those with RA; this dif- tively demonstrate links with an increased risk of malig-
ference between the groups has been attributed to the nancy.55,56 Furthermore, several small retrospective studies
higher rate of alcoholism, diabetes and hyperlipidae- revealed no added risk of lymphoproliferative disease in
mia in the former.28,29 The histopathological features of patients with psoriasis.52 Nonetheless, a recent study, again
methotrexate-induced liver toxicity were found to resemble looking at the use of methotrexate in RA, showed a 50%
those of non-alcoholic steatohepatitis, a pattern of liver his- increase in risk of malignancy relative to the general popu-
tology observed in obese, diabetic and hyperlipidaemic lation with a threefold increase in melanoma, a fivefold
patients.30,31 Histopathological changes secondary to meth- increase in non-Hodgkin lymphoma and a nearly threefold
otrexate use were graded by Roenigk in 1988 (Table 4);32 a increase in lung cancer.57
system of classification shown to have clinical utility.33
Studies utilising this system of classification have yielded
markedly varied frequency of liver fibrosis secondary Reproductive toxicity Methotrexate is both an abortifacient
to methotrexate use (6–72%),31,34–37 thereby complicating and a teratogen. While the critical period of exposure to the
monitoring guidelines. 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
Oncogenic potential Methotrexate is a significant indepen- times of exposure.58 Methotrexate is also secreted in small
dent risk factor for the development of squamous cell car- amounts in breast milk, with the effects on infants
cinoma in patients with severe psoriasis and this risk may unknown.59 In men, methotrexate impedes spermatogen-
increase in psoriatics treated with psoralen plus ultraviolet esis and has also shown potential for causing mutagenesis.60
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 Infections Opportunistic infections and the reactivation of
of methotrexate-induced lymphomas come primarily from TB61 and hepatitis62 are reported in patients on low-dose
the rheumatology literature, with many identifying self- methotrexate. In patients with RA on methotrexate, these
resolving lymphomas upon therapy discontinuation,42–51 in infections seem to be more common than in those treated
particularly Epstein–Barr virus-associated lymphomas.52–54 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
Haematological surveillance After methotrexate treatment
Thorough history taking and physical examination includ- has been initiated, it is necessary to monitor regularly for
ing the clarification of disease severity, previous therapies, haematological toxicity. The first repeat laboratory check
contraindications to methotrexate and risk factors for devel- should be within a 2-week period for patients without risk
oping potential toxicities, along with laboratory tests, factors. Patients with risk factors for haematological toxicity
including a full blood count with differential, renal function, (Table 2) need closer monitoring, particularly at the onset of
liver function tests including albumin and bilirubin consti- therapy and after increasing the dosage of methotrexate.79 A
tute a baseline work-up. A chest radiograph is important for significant reduction in red cell, leukocyte or platelet counts
patients with underlying pulmonary disease or deemed to 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 7

Table 6 Comparison of guidelines for monitoring of hepatoxicity

American Academy of Dermatology guidelines Manchester guidelines


Low-risk patients: • Baseline PIIINP level (if possible)
• Liver biopsy every 1 to 1.5 g of therapy in low-risk patients • Repeat PIIINP levels every 2–3 months while on therapy
• After a cumulative dose of 4 g, biopsy after each 1 g of therapy Indications for considering liver biopsy:
High-risk patients: • Pretreatment PIIINP >8.0 mg/L
• Consider alternative treatment • At least three abnormal PIIINP levels (>4.2 mg/L) over a
• Consider delayed baseline liver biopsy (after 2–6 months of 12-month period
therapy, to establish medication’s efficacy and tolerability) in • Elevated PIIINP level above 8.0 mg/L in two consecutive
at-risk patients. samples
• Repeat liver biopsy after every 0.5–1 g of therapy Indications for considering withdrawal of therapy:
After abnormal biopsy results: • Elevated PIIINP level >10.0 m g/L in three consecutive samples
• For histological grades IIIA, repeat every 6 months; consider in a 12-month period
alternative therapy
• For histological grades IIIB and IV, discontinue therapy

PIIINP, serial serum type III procollagen aminopeptide

methotrexate therapy and may warrant the administration dose, once-weekly oral methotrexate therapy. Of these
of folinic acid, leucovorin, the antidote to methotrexate.76 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
Renal surveillance Regular monitoring of renal function is
randomised controlled studies in psoriasis.94,95 In both
essential in preventing toxicities, particularly bone marrow
studies, folate supplementation reduced clinical efficacy but
toxicity. The glomerular filtration rate should be calculated
improved tolerability. One large placebo-controlled study of
for those patients who have normal blood urea nitrogen and
RA patients compared folinic acid with folic acid.96 No dif-
creatinine levels but are at risk for renal insufficiency, such
ference was evident between the two agents; both folate
as the elderly or those with a decreased muscle mass.79,81
supplementation regimens reduced liver toxicity but
appeared to have no effect on the other adverse effects of
Pulmonary surveillance The use of methotrexate in RA has methotrexate.
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 PART B: CLINICAL USE
treated with systemic or biological immunosuppressive The use of methotrexate in dermatology predates the era of
agents.88 randomised control trials. Despite the relatively sparse
quantity of high-quality data concerning its efficacy in the
Reproduction Pregnancy and lactation are both absolute literature, monotherapy and combination therapy with
contraindications for therapy.79,81,89,90 A delay of at least methotrexate continue to be widely used to treat a vast
3 months between drug cessation and conception is recom- array of skin disorders. Table 7 summarises the clinical use
mended.90,91 Men taking methotrexate should avoid conceiv- of methotrexate in dermatology. Designations of levels of
ing during therapy and for 3 months after cessation of evidence are adapted from the National Health and Medical
therapy.81 Research Council evidence hierarchy.167

Folate supplementation Inflammatory dermatoses


Folate supplementation is shown to reduce gastrointestinal, Psoriasis Methotrexate is indicated in the symptomatic
haematological and hepatotoxic adverse effects without control of severe, recalcitrant and disabling psoriasis not
compromising efficacy.92 The current consensus statement responsive to topical therapy, examples of which are listed
from the ADD strongly recommends folate supplementa- in Table 8168. One of the earliest placebo-controlled trials
tion with methotrexate therapy.81 However, there are still was designed to test the efficacy of methotrexate for PA. In
varying opinions regarding the indications and dosing addition to improving arthritic symptoms, a significant
regimen for folate supplementation, pointing to the need for improvement in psoriasis was observed.169 Subsequent
a more comprehensive set of guidelines. A survey of a 153 studies confirmed its effectiveness for both psoriasis170,171
British dermatologists revealed that three-quarters use and PA at doses similar to those used for the former, with
folate supplementation in patients on methotrexate for pso- diminished doses being possible for maintenance.172,173 A
riasis, one-quarter of this group use it for all patients on significant reduction in psoriatic nail dystrophy was also
therapy while the remainder use folate only in certain cir- seen.174
cumstances, namely, in patients with macrocytosis.93 Duhra Six randomised blinded trials investigated the use of
examined 78 psoriatic patients who were receiving low- methotrexate in plaque-type psoriasis, comparing its

© 2011 The Authors


Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
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 9

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

© 2011 The Authors


Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
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 be refractory to treatment after muscle weakness has
of 2.5 mg weekly until a therapeutic effect was achieved.120 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
Blistering disorders A recent retrospective analysis of the (ADM) is characterised by classic cutaneous signs of DM
English medical literature concluded that methotrexate is with little or no myositis and its response to methotrexate
an effective and well-tolerated steroid-sparing immuno- was reported in two patients in a retrospective review.142
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 Cutaneous lupus erythematosus (CLE) Therapy with meth-
demonstrated a clinical improvement in 96 (83%)of the otrexate has been primarily used in patients with refractory
patients.121–126 In patients with severe to moderately severe subacute cutaneous lupus erythematosus (SCLE)143–147,200
pemphigus vulgaris, methotrexate may be a useful mainte- and discoid lupus erythematosus (DLE).146,148,149,201 In a ret-
nance therapy once control is achieved with steroid therapy, rospective analysis, 12 patients with different subtypes of
while allowing a lowering of the corticosteroid dose.121–124 CLE were treated with weekly low-dose methotrexate in a
Methotrexate generally has a delayed, beneficial effect on dose of 10–25 mg orally or i.v..146 Six of these patients
oral lesions, whereas the cutaneous lesions usually respond achieved complete remission, four achieved partial remis-
more rapidly.124–126 Improvement was observed in 15 out of sion and two patients did not respond. A recent study of 43
20 patients with pemphigus foliaceous treated with meth- patients with different subtypes of recalcitrant CLE145
otrexate.121,122,127 It appears that methotrexate is more ben- reported improvement in 42 (98%) of patients receiving
eficial in patients with bullous pemphigoid. An analysis of low-dose methotrexate, administered either orally or i.v..
the data on 62 patients with bullous pemphigoid found a Patients with SCLE and localised DLE showed greater
clinical improvement in 59 patients (95%).128–132 McCluskey improvement than those with disseminated DLE. The i.v.
and colleagues133 reported that 15 out of 17 patients with route was better tolerated than oral administration
ocular cicatricial pemphigoid responded to methotrexate at although in a follow-up study, i.v. methotrexate administra-
the dose of 5–25 mg weekly as a systemic monotherapy or in tion was changed to subcutaneous application in 15 of
combination with corticosteroids. the 43 CLE patients with good tolerance and comparable
efficacy.200

Localised scleroderma The selection of treatment moda-


lities for localised scleroderma, otherwise known as Vasculitides The self-limiting nature of most forms of cuta-
morphea, remains controversial. The clinical utility of neous vasculitis means there is minimal evidence for the
methotrexate for this uncommon collagen vascular disease benefit of many therapeutic modalities. Reported cases
has been documented in three retrospective studies134–136 describe the efficacy of low-dose methotrexate (5–20 mg
and three open-label prospective studies,137–139 with a total of weekly) in refractory Behcet’s disease and cutaneous pol-
124 patients treated of whom 110 (88.7%) responded to yarteritis nodosa.154–157 Two open prospective studies have
treatment. Methotrexate, usually prescribed in combination demonstrated its efficacy in lupus vasculitis. Wilson and
with i.v. pulse methylprednisolone, has been indicated for colleagues147 described two patients with lupus vasculitis,
the acute and deep form of this disease.198 A response both of which responded to low-dose oral methotrexate.
to single therapy has been seen in widespread deep Gansauge and colleagues153 reported a resolution in six out
morphea.139 of nine patients. Methotrexate has been associated with
Combined therapy with corticosteroid and methotrexate drug-induced vasculitis;202 however, in patients with RA,
can be the first-line treatment for severe localised sclero- methotrexate does not alter the incidence of rheumatoid
derma if there are systemic manifestations, such as vasculitis.203 Methotrexate has been used to treat refractory
extremities contractures and anchylosis or if it affects extra- cases of vasculitic cutaneous ulceration with RA, with the
cutaneous structures such as fat, muscle, fascia or bone potential advantage of benefiting other manifestations
involvement.135 A benefit was also seen in the acute form in of the disease.151,152 Upchurch and colleagues described
a paediatric group with oral methotrexate for maintenance the effective use of low-dose intramuscular methotrexate
therapy and i.v. methylprednisolone pulse for induction.137 A (15 mg once weekly) in one case of leukocytoclastic vascu-
large retrospective review showed that methotrexate, given litis associated with RA.150
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- Cutaneous sarcoidosis Methotrexate is effective in steroid-
funda and three with Parry Romberg syndrome.134 resistant cutaneous sarcoidosis. Despite supporting data
derived principally from uncontrolled open-label studies,
the drug has been suggested to be the treatment of choice
Dermatomyositis DM is an inflammatory myopathy com- for steroid recalcitrant sarcoidal ulcers.158,159 Veien and
bined with characteristic cutaneous findings that are often Brodthagen160 reported the clearance of skin lesions in 12 of
difficult to treat as they may have a discordant response 16 patients treated with methotrexate at an initial weekly
to therapy from the muscle disease, and can continue to dose of 25 mg tapered to a maintenance dose of 5 to 15 mg

© 2011 The Authors


Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
Methotrexate in dermatology 13

weekly. Webster and colleagues159 reported the results of such as alkylating agents, retinoids or histone deacetylase
three patients with cutaneous sarcoidosis treated with 15 to inhibitors.205 Low-dose oral methotrexate has been shown
22.5 mg methotrexate weekly, with all three experiencing to be effective in patients with erythrodermic MF and
improvement over 6 to 9 months. Lower and Baughman refractory MF. In a study of 69 patients with refractory MF,
investigated the prolonged use of methotrexate in sarcoido- an overall response rate was seen in 23 (33%) patients with
sis by following the course of 50 patients who received at a complete response rate seen in eight (12%) patients.165
least 2 years of therapy at 10 mg methotrexate weekly. Of Topical methotrexate using a topical gel formulation had
the 17 patients with skin involvement, 16 improved with some efficacy but has not been developed further.166
methotrexate.161 Relapse is common after the discontinua-
tion of treatment, suggesting that, like anti-malarials, meth- FUTURE DIRECTIONS
otrexate controls but does not cure the disease.158,161,204
Ongoing research concerning methotrexate’s mechanism
of action and naturally occurring genetic polymorphisms in
Granuloma annulare (GA) GA is an idiopathic dermatosis its enzymatic pathways may soon offer greater sophistica-
clinically manifested as well-defined annular skin-coloured tion and precision in the utilisation of this long-employed
to erythematous papules and plaques with histological find- drug. It has been demonstrated that certain genetic poly-
ings of granulomatous inflammation, collagen degenera- morphisms in the adenosine pathway are predictive of a
tion and mucin deposition. As yet there has been only one better response to methotrexate therapy in RA.206,207 Further-
case report detailing the benefit of methotrexate in treating more, a genetic analysis may enable clinicians to identify
recalcitrant GA. Oral methotrexate 15 mg weekly was given patients at risk for a particular adverse effect.208
to a 67-year old woman with treatment-resistant dissemi- With the currently established treatment guidelines for
nated GA. Six weeks after commencing therapy, most of her methotrexate therapy based mainly on experiences in
lesions had resolved and the remainder had partially psoriasis and RA, the clinical utility of methotrexate in
regressed.162 the treatment armamentarium for various inflammatory
and lymphoproliferative skin conditions demands further
Lymphoproliferative disorders examination.

Lymphomatoid papulosis (LyP) and other primary cut-


REFERENCES
aneous CD30+ lymphoproliferative disorders The man-
agement of LyP and other variants of primary cutaneous 1. Gubner RS. Introduction of antifolics in psoriasis. A twenty-five
CD30+ lymphoproliferative disorders range from simple year retrospect of antineoplastic agents in nonmalignant
observation to aggressive systemic chemotherapy. Observa- disease. Cutis 1979; 23: 425–8.
tions concerning treatment have been limited to individual 2. Weinstein GD, Frost P. Methotrexate for psoriasis. A new
therapeutic schedule. Arch. Dermatol. 1971; 103: 33–8.
patients or small series of patients. Methotrexate is known
3. Weinstein GD, Goldfaden G, Frost P. Methotrexate. Mecha-
to be effective in LyP,107,163 but its role in the long-term nism of action on DNA synthesis in psoriasis. Arch. Dermatol.
management of LyP has not been established. A retrospec- 1971; 104: 236–43.
tive study reviewed the 20-year experience of methotrexate 4. Mainman H, McClaren E, Heycock C et al. When should we
in the treatment of 45 patients with LyP and CD30+ lym- use parenteral methotrexate? Clin. Rheumatol. 2010; 29:
phoma and borderline expressions of cutaneous CD30+ 1093–8.
5. Hamilton RA, Kremer JM. Why intramuscular methotrexate
lymphoproliferative disease. During induction of methotr-
may be more efficacious than oral dosing in patients with RA.
exate therapy the patients received maximum doses Br. J. Rheumatol. 1997; 36: 86–90.
ranging from 10 to 60 mg weekly (median, 20 mg weekly). 6. Wegrzyn J, Adeleine P, Miossec P. Better efficacy of methotr-
Clinical improvement usually occurred quickly; typically at exate given by intramuscular injection than orally in patients
doses of 15 to 20 mg weekly, and satisfactory long-term with rheumatoid arthritis. Ann. Rheum. Dis. 2004; 63: 1232–4.
control was achieved in 39 (87%) patients with mainte- 7. Godfrey C, Sweeney K, Miller K et al. The population pharma-
cokinetics of long-term methotrexate in rheumatoid arthritis.
nance doses given at once to twice weekly intervals. After
Br. J. Clin. Pharmacol. 1998; 46: 369–76.
methotrexate was discontinued, 10 patients remained free 8. Braun J, Kästner P, Flaxenberg P et al. Comparison of the
of CD30+ lesions for from 2 years to almost 20 years. The clinical efficacy and safety of subcutaneous versus oral admin-
observation that long-lasting complete remissions occurred istration of methotrexate in patients with active rheumatoid
after a relatively short course of methotrexate in some arthritis: results of a six-month, multicenter, randomized,
patients raises the possibility that high-dose methotrexate double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;
therapy, possibly combined with leucovorin rescue, might 58: 73–81.
9. Olsen EA. The pharmacology of methotrexate. J. Am. Acad.
provide more than suppressive therapy in selected cases but
Dermatol. 1991; 25: 306–18.
such an approach is not commonly used.164 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
Mycosis fungoides (MF) Low-dose methotrexate is com-
bioavailability of low-dose methotrexate in patients with rheu-
monly used in the treatment of cutaneous T-cell lymphoma, matoid arthritis. Arthritis Rheum. 1992; 35: 611–14.
although documentation is sparse. Its efficacy has never 12. Bleyer WA. The clinical pharmacology of methotrexate: new
been compared to other commonly used systemic agents applications of an old drug. Cancer 1978; 41: 36–51.

© 2011 The Authors


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

13. Chan ES, Cronstein BN. Methotrexate – how does it really 34. Robinson JK, Baughman RD, Auerbach R et al. Methotrexate
work? Nat. Rev. Rheumatol. 2010; 6: 175–8. hepatotoxicity in psoriasis. Consideration of liver biopsies at
14. Nesher G, Moore TL, Dorner RW. In vitro effects of methotr- regular intervals. Arch. Dermatol. 1980; 116: 413–15.
exate on peripheral blood monocytes: modulation by folinic 35. Themido R, Loureiro M, Pecegueiro M et al. Methotrexate
acid and S-adenosylmethionine. Ann. Rheum. Dis. 1991; 50: hepatotoxicity in psoriatic patients submitted to long-term
637–41. therapy. Acta Derm. Venereol. 1992; 72: 361–4.
15. Cronstein BN, Naime D, Ostad E. The antiinflammatory 36. Zachariae H, Heickendorff L, Søgaard H. The value of amino-
mechanism of methotrexate. Increased adenosine release at terminal propeptide of type III procollagen in routine screen-
inflamed sites diminishes leukocyte accumulation in an in vivo ing for methotrexate-induced liver fibrosis: a 10-year
model of inflammation. J. Clin. Invest. 1993; 92: 2675–82. follow-up. Br. J. Dermatol. 2001; 144: 100–3.
16. Montesinos MC, Desai A, Cronstein BN. Suppression of inflam- 37. Malatjalian DA, Ross JB, Williams CN et al. Methotrexate hepa-
mation by low-dose methotrexate is mediated by adenosine totoxicity in psoriatics: report of 104 patients from Nova Scotia,
A2A receptor but not A3 receptor activation in thioglycollate- with analysis of risks from obesity, diabetes and alcohol con-
induced peritonitis. Arthritis Res. Ther. 2006; 8: R53. sumption during long term follow-up. Can. J. Gastroenterol.
17. Haskó G, Cronstein BN. Adenosine: an endogenous regulator 1996; 10: 369–75.
of innate immunity. Trends Immunol. 2004; 25: 33–9. 38. Stern RS, Laird N. The carcinogenic risk of treatments for
18. Andersson SE, Johansson LH, Lexmüller K et al. Anti-arthritic severe psoriasis. Photochemotherapy Follow-up Study. Cancer
effect of methotrexate: is it really mediated by adenosine? Eur. 1994; 73: 2759–64.
J. Pharm. Sci. 2000; 9: 333–43. 39. Zumtobel U, Schwarze HP, Favre M et al. Widespread cutane-
19. Phillips DC, Woollard KJ, Griffiths HR. The anti-inflammatory ous carcinomas associated with human papillomaviruses 5, 14
actions of methotrexate are critically dependent upon the pro- and 20 after introduction of methotrexate in two long-term
duction of reactive oxygen species. Br. J. Pharmacol. 2003; 138: PUVA-treated patients. Dermatology 2001; 202: 127–30.
501–11. 40. Maruani A, Wierzbicka E, Machet MC et al. Reversal of multi-
20. al-Awadhi A, Dale P, McKendry RJ. Pancytopenia associated focal cutaneous lymphoproliferative disease associated with
with low dose methotrexate therapy. A regional survey. J. Epstein-Barr virus after withdrawal of methotrexate therapy
Rheumatol. 1993; 20: 1121–5. for rheumatoid arthritis. J. Am. Acad. Dermatol. 2007; 57: S69–
21. Wollina U, Ständer K, Barta U. Toxicity of methotrexate treat- 71.
ment in psoriasis and psoriatic arthritis – short- and long-term 41. Georgescu L, Quinn GC, Schwartzman S et al. Lymphoma in
toxicity in 104 patients. Clin. Rheumatol. 2001; 20: 406–10. patients with rheumatoid arthritis: association with the disease
22. Van Dooren-Greebe RJ, Kuijpers AL, Mulder J et al. Methotr- state or methotrexate treatment. Semin. Arthritis Rheum. 1997;
exate revisited: effects of long-term treatment in psoriasis. Br. 26: 794–804.
J. Dermatol. 1994; 130: 204–10. 42. Williams CA, Bloch DA, Sibley J et al. Lymphoma and luekemia
23. Lim AY, Gaffney K, Scott DG. Methotrexate-induced pancy- in rheumatoid arthritis: are they associated with azathioprine,
topenia: serious and under-reported? Our experience of 25 cyclophosphamide, or methotrexate? J. Clin. Rheumatol. 1996;
cases in 5 years. Rheumatology (Oxford) 2005; 44: 1051–5. 2: 64–72.
24. Duhra P. Treatment of gastrointestinal symptoms associated 43. Shiroky JB, Frost A, Skelton JD et al. Complications of immu-
with methotrexate therapy for psoriasis. J. Am. Acad. Dermatol. nosuppression associated with weekly low dose methotrexate.
1993; 28: 466–9. J. Rheumatol. 1991; 18: 1172–5.
25. Nyfors A. Liver biopsies from psoriatics related to methotrex- 44. Viraben R, Brousse P, Lamant L. Reversible cutaneous lym-
ate therapy. 3. Findings in post-methotrexate liver biopsies phoma occurring during methotrexate therapy. Br. J. Derma-
from 160 psoriatics. Acta Pathol. Microbiol. Scand. A 1977; 85: tol. 1996; 135: 116–18.
511–18. 45. Kamel OW, van de Rijn M, Weiss LM et al. Brief report: revers-
26. Zachariae H, Søgaard H, Heickendorff L. Methotrexate- ible lymphomas associated with Epstein-Barr virus occurring
induced liver cirrhosis. Clinical, histological and serological during methotrexate therapy for rheumatoid arthritis and der-
studies – a further 10-year follow-up. Dermatology 1996; 192: matomyositis. N. Engl. J. Med. 1993; 328: 1317–21.
343–6. 46. Tournadre A, D’Incan M, Dubost JJ et al. Cutaneous lymphoma
27. Auerbach R. Psoriasis symposium. Methotrexate. Semin. Der- associated with Epstein-Barr virus infection in 2 patients
matol. 1992; 11: 23–9. treated with methotrexate. Mayo Clin. Proc. 2001; 76: 845–8.
28. Kremer JM, Alarcón GS, Lightfoot RW et al. Methotrexate for 47. Ellman MH, Hurwitz H, Thomas C et al. Lymphoma developing
rheumatoid arthritis. Suggested guidelines for monitoring in a patient with rheumatoid arthritis taking low dose weekly
liver toxicity. American College of Rheumatology. Arthritis methotrexate. J. Rheumatol. 1991; 18: 1741–3.
Rheum. 1994; 37: 316–28. 48. Usman AR, Yunus MB. Non-Hodgkin’s lymphoma in patients
29. Whiting-O’Keefe QE, Fye KH, Sack KD. Methotrexate and his- with rheumatoid arthritis treated with low dose methotrexate.
tologic hepatic abnormalities: a meta-analysis. Am. J. Med. J. Rheumatol. 1996; 23: 1095–7.
1991; 90: 711–16. 49. Mariette X, Cazals-Hatem D, Warszawki J et al. Lymphomas in
30. Langman G, Hall PM, Todd G. Role of non-alcoholic steato- rheumatoid arthritis patients treated with methotrexate: a
hepatitis in methotrexate-induced liver injury. J. Gastroen- 3-year prospective study in France. Blood 2002; 99: 3909–15.
terol. Hepatol. 2001; 16: 1395–401. 50. Baird RD, van Zyl-Smit RN, Dilke T et al. Spontaneous remis-
31. Rosenberg P, Urwitz H, Johannesson A et al. Psoriasis patients sion of low-grade B-cell non-Hodgkin’s lymphoma following
with diabetes type 2 are at high risk of developing liver fibrosis withdrawal of methotrexate in a patient with rheumatoid
during methotrexate treatment. J. Hepatol. 2007; 46: 1111–18. arthritis: case report and review of the literature. Br. J. Hae-
32. Roenigk HH, Auerbach R, Maibach HI et al. Methotrexate in matol. 2002; 118: 567–8.
psoriasis: revised guidelines. J. Am. Acad. Dermatol. 1988; 19: 51. Bachman TR, Sawitzke AD, Perkins SL et al. Methotrexate-
145–56. associated lymphoma in patients with rheumatoid arthritis:
33. Berends MA, van Oijen MG, Snoek J et al. Reliability of the report of two cases. Arthritis Rheum. 1996; 39: 325–9.
Roenigk classification of liver damage after methotrexate 52. Paul C, Le Tourneau A, Cayuela JM et al. Epstein-Barr virus-
treatment for psoriasis: a clinicopathologic study of 160 liver associated lymphoproliferative disease during methotrexate
biopsy specimens. Arch. Dermatol. 2007; 143: 1515–19. therapy for psoriasis. Arch. Dermatol. 1997; 133: 867–71.

© 2011 The Authors


Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
Methotrexate in dermatology 15

53. Chai C, White WL, Shea CR et al. Epstein Barr virus-associated 75. Dadlani C, Orlow SJ. Treatment of children and adolescents
lymphoproliferative-disorders primarily involving the skin. J. with methotrexate, cyclosporine, and etanercept: review of the
Cutan. Pathol. 1999; 26: 242–7. dermatologic and rheumatologic literature. J. Am. Acad. Der-
54. Hirose Y, Masaki Y, Okada J et al. Epstein-Barr virus- matol. 2005; 52: 316–40.
associated B-cell type non-Hodgkin’s lymphoma with concur- 76. Bangert CA, Costner MI. Methotrexate in dermatology. Derma-
rent p53 protein expression in a rheumatoid arthritis patient tol. Ther. 2007; 20: 216–28.
treated with methotrexate. Int. J. Hematol. 2002; 75: 412– 77. Evans WE, Christensen ML. Drug interactions with methotr-
15. exate. J. Rheumatol. Suppl. 1985; 12 (Suppl 12): 15–20.
55. Airio A, Pukkala E, Isomäki H. Elevated cancer incidence in 78. Lester RS. Methotrexate. Clin. Dermatol. 1989; 7: 128–35.
patients with dermatomyositis: a population based study. J. 79. Kalb RE, Strober B, Weinstein G et al. Methotrexate and pso-
Rheumatol. 1995; 22: 1300–3. riasis: 2009 National Psoriasis Foundation Consensus Confer-
56. Moder KG, Tefferi A, Cohen MD et al. Hematologic malignan- ence. J. Am. Acad. Dermatol. 2009; 60: 824–37.
cies and the use of methotrexate in rheumatoid arthritis: a 80. Guidelines for management of patients with psoriasis. Work-
retrospective study. Am. J. Med. 1995; 99: 276–81. shop of the Research Unit of the Royal College of Physicians of
57. Buchbinder R, Barber M, Heuzenroeder L et al. Incidence of London; Department of Dermatology, University of Glasgow;
melanoma and other malignancies among rheumatoid arthri- British Association of Dermatologists. BMJ 1991; 303: 829–35.
tis patients treated with methotrexate. Arthritis Rheum. 2008; 81. Roenigk HH, Auerbach R, Maibach H et al. Methotrexate in
59: 794–9. psoriasis: consensus conference. J. Am. Acad. Dermatol. 1998;
58. Lloyd ME, Carr M, McElhatton P et al. The effects of methotr- 38: 478–85.
exate on pregnancy, fertility and lactation. QJM 1999; 92: 551– 82. Weinstein GD. Methotrexate. Ann. Intern. Med. 1977; 86: 199–
63. 204.
59. Temprano KK, Bandlamudi R, Moore TL. Antirheumatic drugs 83. Boffa MJ, Smith A, Chalmers RJ et al. Serum type III pro-
in pregnancy and lactation. Semin. Arthritis Rheum. 2005; 35: collagen aminopeptide for assessing liver damage in
112–21. methotrexate-treated psoriatic patients. Br. J. Dermatol. 1996;
60. Morris LF, Harrod MJ, Menter MA et al. Methotrexate and 135: 538–44.
reproduction in men: case report and recommendations. J. Am. 84. Zachariae H, Søgaard H, Heickendorff L. Serum aminotermi-
Acad. Dermatol. 1993; 29: 913–16. nal propeptide of type III procollagen. A non-invasive test for
61. Binymin K, Cooper RG. Late reactivation of spinal tuberculosis liver fibrogenesis in methotrexate-treated psoriatics. Acta
by low-dose methotrexate therapy in a patient with rheuma- Derm. Venereol. 1989; 69: 241–4.
toid arthritis. Rheumatology (Oxford) 2001; 40: 341–2. 85. Zachariae H, Aslam HM, Bjerring P et al. Serum aminotermi-
62. Gwak GY, Koh KC, Kim HY. Fatal hepatic failure associated nal propeptide of type III procollagen in psoriasis and psoriatic
with hepatitis B virus reactivation in a hepatitis B surface arthritis: relation to liver fibrosis and arthritis. J. Am. Acad.
antigen-negative patient with rheumatoid arthritis receiving Dermatol. 1991; 25: 50–3.
low dose methotrexate. Clin. Exp. Rheumatol. 2007; 25: 888–9. 86. Mitchell D, Smith A, Rowan B et al. Serum type III procollagen
63. Maurer TA, Zackheim HS, Tuffanelli L et al. The use of meth- peptide, dynamic liver function tests and hepatic fibrosis in
otrexate for treatment of psoriasis in patients with HIV infec- psoriatic patients receiving methotrexate. Br. J. Dermatol.
tion. J. Am. Acad. Dermatol. 1994; 31: 372–5. 1990; 122: 1–7.
64. Phillips TJ, Jones DH, Baker H. Pulmonary complications fol- 87. Chalmers RJ, Kirby B, Smith A et al. Replacement of routine
lowing methotrexate therapy. J. Am. Acad. Dermatol. 1987; 16: liver biopsy by procollagen III aminopeptide for monitoring
373–5. patients with psoriasis receiving long-term methotrexate: a
65. Kalantzis A, Marshman Z, Falconer DT et al. Oral effects of multicentre audit and health economic analysis. Br. J. Derma-
low-dose methotrexate treatment. Oral Surg. Oral Med. Oral tol. 2005; 152: 444–50.
Pathol. Oral Radiol. Endod. 2005; 100: 52–62. 88. Mazurek GH, Villarino ME, CDC. Guidelines for using the
66. Pearce HP, Wilson BB. Erosion of psoriatic plaques: an early QuantiFERON-TB test for diagnosing latent mycobacterium
sign of methotrexate toxicity. J. Am. Acad. Dermatol. 1996; 35: tuberculosis infection. Centers for Disease Control and Pre-
835–8. vention. MMWR Recomm. Rep. 2003; 52: 15–18.
67. Lawrence CM, Dahl MG. Two patterns of skin ulceration 89. Doll DC, Ringenberg QS, Yarbro JW. Antineoplastic agents and
induced by methotrexate in patients with psoriasis. J. Am. pregnancy. Semin. Oncol. 1989; 16: 337–46.
Acad. Dermatol. 1984; 11: 1059–65. 90. Menter A, Korman NJ, Elmets CA et al. Guidelines of care for
68. Kazlow DW, Federgrun D, Kurtin S et al. Cutaneous ulceration the management of psoriasis and psoriatic arthritis: section 4.
caused by methotrexate. J. Am. Acad. Dermatol. 2003; 49: Guidelines of care for the management and treatment of pso-
S197–8. riasis with traditional systemic agents. J. Am. Acad. Dermatol.
69. Dierkes J, Westphal S. Effect of drugs on homocysteine con- 2009; 61: 451–85.
centrations. Semin. Vasc. Med. 2005; 5: 124–39. 91. Donnenfeld AE, Pastuszak A, Noah JS et al. Methotrexate expo-
70. Prodanovich S, Prodanowich S, Ma F et al. Methotrexate sure prior to and during pregnancy. Teratology. 1994; 49:
reduces incidence of vascular diseases in veterans with pso- 79–81.
riasis or rheumatoid arthritis. J. Am. Acad. Dermatol. 2005; 52: 92. Strober BE, Menon K. Folate supplementation during methotr-
262–7. exate therapy for patients with psoriasis. J. Am. Acad. Derma-
71. Kremer JM. Toward a better understanding of methotrexate. tol. 2005; 53: 652–9.
Arthritis Rheum. 2004; 50: 1370–82. 93. Kirby B, Lyon CC, Griffiths CE et al. The use of folic acid
72. Zonneveld IM, Bakker WK, Dijkstra PF et al. Methotrexate supplementation in psoriasis patients receiving methotrexate:
osteopathy in long-term, low-dose methotrexate treatment for a survey in the United Kingdom. Clin. Exp. Dermatol. 2000; 25:
psoriasis and rheumatoid arthritis. Arch. Dermatol. 1996; 132: 265–8.
184–7. 94. Chládek J, Simková M, Vanecková J et al. The effect of folic
73. Alkins SA, Byrd JC, Morgan SK et al. Anaphylactoid reactions to acid supplementation on the pharmacokinetics and pharma-
methotrexate. Cancer 1996; 77: 2123–6. codynamics of oral methotrexate during the remission-
74. Kumar B, Dhar S, Handa S et al. Methotrexate in childhood induction period of treatment for moderate-to-severe plaque
psoriasis. Pediatr. Dermatol. 1994; 11: 271–3. psoriasis. Eur. J. Clin. Pharmacol. 2008; 64: 347–55.

© 2011 The Authors


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

95. Salim A, Tan E, Ilchyshyn A et al. Folic acid supplementation 119. Egan CA, Rallis TM, Meadows KP et al. Low-dose oral meth-
during treatment of psoriasis with methotrexate: a random- otrexate treatment for recalcitrant palmoplantar pompholyx. J.
ized, double-blind, placebo-controlled trial. Br. J. Dermatol. Am. Acad. Dermatol. 1999; 40: 612–14.
2006; 154: 1169–74. 120. Weatherhead SC, Wahie S, Reynolds NJ et al. An open-label,
96. van Ede AE, Laan RF, Rood MJ et al. Effect of folic or folinic dose-ranging study of methotrexate for moderate-to-severe
acid supplementation on the toxicity and efficacy of methotr- adult atopic eczema. Br. J. Dermatol. 2007; 156: 346–51.
exate in rheumatoid arthritis: a forty-eight week, multicenter, 121. Jablonska S, Chorzelski T, Blaszczyk M. Immunosuppressants
randomized, double-blind, placebo-controlled study. Arthritis in the treatment of pemphigus. Br. J. Dermatol. 1970; 83: 315–
Rheum. 2001; 44: 1515–24. 23.
97. Lamar LM, Gaethe G. Pityriasis rubra pilaris. Arch. Dermatol. 122. Piamphongsant T, Sivayathorn A. Pemphigus: combined treat-
1964; 89: 515–22. ment with methotrexate and prednisone. J. Med. Assoc. Thai.
98. Dicken CH. Treatment of classic pityriasis rubra pilaris. J. Am. 1975; 58: 171–6.
Acad. Dermatol. 1994; 31: 997–9. 123. Lever WF, Schaumburg-Lever G. Immunosuppressants and
99. Anderson FE. Pityriasis rubra pilaris treated with methotrex- prednisone in pemphigus vulgaris: therapeutic results
ate. Aust. J. Dermatol. 1966; 8: 183–5. obtained in 63 patients between 1961 and 1975. Arch. Derma-
100. Brown J, Perry HO. Pityriasis rubra pilaris. Treatment with tol. 1977; 113: 1236–41.
folic acid antagonists. Arch. Dermatol. 1966; 94: 636–8. 124. Lever WF. Methotrexate and prednisone in pemphigus vul-
101. Parish LC, Woo TH. Pityriasis rubra pilaris in Korea. Treatment garis. Therapeutic results obtained in 36 patients between
with methotrexate. Dermatologica 1969; 139: 399–403. 1961 and 1970. Arch. Dermatol. 1972; 106: 491–7.
102. Knowles WR, Chernosky ME. Pityriasis rubra pilaris. Pro- 125. Mashkilleyson N, Mashkilleyson AL. Mucous membrane mani-
longed treatment with methotrexate. Arch. Dermatol. 1970; festations of pemphigus vulgaris. A 25-year survey of 185
102: 603–12. patients treated with corticosteroids or with combination of
103. Hanke CW, Steck WD. Childhood-onset pityriasis rubra pilaris corticosteroids with methotrexate or heparin. Acta Derm.
treated with methotrexate administered intravenously. Cleve. Venereol. 1988; 68: 413–21.
Clin. Q. 1983; 50: 201–3. 126. Smith TJ, Bystryn JC. Methotrexate as an adjuvant treatment
104. Griffiths WA. Pityriasis rubra pilaris. Clin. Exp. Dermatol. 1980; for pemphigus vulgaris. Arch. Dermatol. 1999; 135: 1275–6.
5: 105–12. 127. Rivitti EA, Camargo ME, Castro RM et al. Use of methotrexate
105. Durairaj VD, Horsley MB. Resolution of pityriasis rubra pilaris- to treat pemphigus foliaceus. Int. J. Dermatol. 1973; 12: 119–
induced cicatricial ectropion with systemic low-dose methotr- 22.
exate. Am. J. Ophthalmol. 2007; 143: 709–10. 128. Downham TF, Chapel TA. Bullous pemphigoid:therapy in
106. Cornelison RL, Knox JM, Everett MA. Methotrexate for the patients with and without diabetes mellitus. Arch. Dermatol.
treatment of Mucha–Habermann disease. Arch. Dermatol. 1978; 114: 1639–42.
1972; 106: 507–8. 129. Paul MA, Jorizzo JL, Fleischer AB et al. Low-dose methotrexate
107. Lynch PJ, Saied NK. Methotrexate treatment of pityriasis treatment in elderly patients with bullous pemphigoid. J. Am.
lichenoides and lymphomatoid papulosis. Cutis 1979; 23: Acad. Dermatol. 1994; 31: 620–5.
634–6. 130. Dereure O, Bessis D, Guillot B et al. Treatment of bullous
108. López-Estebaranz JL, Vanaclocha F, Gil R et al. Febrile ulcero- pemphigoid by low-dose methotrexate associated with short-
necrotic Mucha–Habermann disease. J. Am. Acad. Dermatol. term potent topical steroids: an open prospective study of 18
1993; 29: 903–6. cases. Arch. Dermatol. 2002; 138: 1255–6.
109. Rasmussen JE. Mucha–Habermann’s disease. Arch. Dermatol. 131. Bara C, Maillard H, Briand N et al. Methotrexate for bullous
1979; 115: 676–7. pemphigoid: preliminary study. Arch. Dermatol. 2003; 139:
110. Herron MD, Bohnsack JF, Vanderhooft SL. Septic, CD-30 posi- 1506–7.
tive febrile ulceronecrotic pityriasis lichenoides et variolifor- 132. Kjellman P, Eriksson H, Berg P. A retrospective analysis of
mis acuta. Pediatr. Dermatol. 2005; 22: 360–5. patients with bullous pemphigoid treated with methotrexate.
111. Perez A, Woods A, Grattan CE. Methotrexate: a useful steroid- Arch. Dermatol. 2008; 144: 612–16.
sparing agent in recalcitrant chronic urticaria. Br. J. Dermatol. 133. McCluskey P, Chang JH, Singh R et al. Methotrexate therapy
2010; 162: 191–4. for ocular cicatricial pemphigoid. Ophthalmology 2004; 111:
112. Godse K. Methotrexate in autoimmune urticaria. Indian J. Der- 796–801.
matol. Venereol. Leprol. 2004; 70: 377. 134. Christen-Zaech S, Hakim MD, Afsar FS et al. Pediatric
113. Gach JE, Sabroe RA, Greaves MW et al. Methotrexate- morphea (localized scleroderma): review of 136 patients. J.
responsive chronic idiopathic urticaria: a report of two cases. Am. Acad. Dermatol. 2008; 59: 385–96.
Br. J. Dermatol. 2001; 145: 340–3. 135. Weibel L, Sampaio MC, Visentin MT et al. Evaluation of meth-
114. Lyakhovitsky A, Barzilai A, Heyman R et al. Low-dose meth- otrexate and corticosteroids for the treatment of localized scle-
otrexate treatment for moderate-to-severe atopic dermati- roderma (morphoea) in children. Br. J. Dermatol. 2006; 155:
tis in adults. J. Eur. Acad. Dermatol. Venereol. 2010; 24: 1013–20.
43–9. 136. Fitch PG, Rettig P, Burnham JM et al. Treatment of pediatric
115. Zoller L, Ramon M, Bergman R. Low dose methotrexate localized scleroderma with methotrexate. J. Rheumatol. 2006;
therapy is effective in late-onset atopic dermatitis and idio- 33: 609–14.
pathic eczema. Isr. Med. Assoc. J. 2008; 10: 413–14. 137. Kreuter A, Gambichler T, Breuckmann F et al. Pulsed high-
116. Goujon C, Bérard F, Dahel K et al. Methotrexate for the treat- dose corticosteroids combined with low-dose methotrexate in
ment of adult atopic dermatitis. Eur. J. Dermatol. 2006; 16: severe localized scleroderma. Arch. Dermatol. 2005; 141: 847–
155–8. 52.
117. Shaffrali FC, Colver GB, Messenger AG et al. Experience with 138. Uziel Y, Feldman BM, Krafchik BR et al. Methotrexate and
low-dose methotrexate for the treatment of eczema in the corticosteroid therapy for pediatric localized scleroderma. J.
elderly. J. Am. Acad. Dermatol. 2003; 48: 417–19. Pediatr. 2000; 136: 91–5.
118. Balasubramaniam P, Ilchyshyn A. Successful treatment of 139. Seyger MM, van den Hoogen FH, de Boo T et al. Low-dose
severe atopic dermatitis with methotrexate. Clin. Exp. Derma- methotrexate in the treatment of widespread morphea. J. Am.
tol. 2005; 30: 436–7. Acad. Dermatol. 1998; 39: 220–5.

© 2011 The Authors


Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
Methotrexate in dermatology 17

140. Kasteler JS, Callen JP. Low-dose methotrexate administered 162. Plotner AN, Mutasim DF. Successful treatment of disseminated
weekly is an effective corticosteroid-sparing agent for the granuloma annulare with methotrexate. Br. J. Dermatol. 2010;
treatment of the cutaneous manifestations of dermatomyositis. 163: 1123–4.
J. Am. Acad. Dermatol. 1997; 36: 67–71. 163. Lange Wantzin G, Thomsen K. Methotrexate in lymphomatoid
141. Zieglschmid-Adams ME, Pandya AG, Cohen SB et al. Treat- papulosis. Br. J. Dermatol. 1984; 111: 93–5.
ment of dermatomyositis with methotrexate. J. Am. Acad. Der- 164. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effec-
matol. 1995; 32: 754–7. tive therapy for lymphomatoid papulosis and other primary
142. el-Azhary RA, Pakzad SY. Amyopathic dermatomyositis: retro- cutaneous CD30-positive lymphoproliferative disorders. J. Am.
spective review of 37 cases. J. Am. Acad. Dermatol. 2002; 46: Acad. Dermatol. 1996; 34: 470–81.
560–5. 165. Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose meth-
143. Kuhn A, Specker C, Ruzicka T et al. Methotrexate treatment for otrexate to treat mycosis fungoides: a retrospective study in 69
refractory subacute cutaneous lupus erythematosus. J. Am. patients. J. Am. Acad. Dermatol. 2003; 49: 873–8.
Acad. Dermatol. 2002; 46: 600–3. 166. Demierre MF, Vachon L, Ho V et al. Phase 1/2 pilot study of
144. Böhm L, Uerlich M, Bauer R. Rapid improvement of subacute methotrexate-laurocapram topical gel for the treatment of
cutaneous lupus erythematosus with low-dose methotrexate. patients with early-stage mycosis fungoides. Arch. Dermatol.
Dermatology 1997; 194: 307–8. 2003; 139: 624–8.
145. Wenzel J, Brähler S, Bauer R et al. Efficacy and safety of meth- 167. NHMRC. A Guide to the Development, Implementation and
otrexate in recalcitrant cutaneous lupus erythematosus: Evaluation of Clinical Practice Guidelines. Canberra: National
results of a retrospective study in 43 patients. Br. J. Dermatol. Health and Medical Research Council, Commonwealth of Aus-
2005; 153: 157–62. tralia, 1999.
146. Boehm IB, Boehm GA, Bauer R. Management of cutaneous 168. Roenigk HH Jr, Auerbach R, Maibach H et al. Methotrexate for
lupus erythematosus with low-dose methotrexate: indication psoriasis: consensus conference. J. Am. Acad. Dermatol. 1998;
for modulation of inflammatory mechanisms. Rheumatol. Int. 38: 478–85.
1998; 18: 59–62. 169. Black RL, O’Brien WM, Vanscott EJ et al. Methotrexate therapy
147. Wilson K, Abeles M. A 2 year, open ended trial of methotrexate in psoriatic arthritis; double-blind study on 21 patients. JAMA
in systemic lupus erythematosus. J. Rheumatol. 1994; 21: 1964; 189: 743–7.
1674–7. 170. Nyfors A, Brodthagen H. Methotrexate for psoriasis in weekly
148. Bottomley WW, Goodfield MJ. Methotrexate for the treatment oral doses without any adjunctive therapy. Dermatologica
of discoid lupus erythematosus. Br. J. Dermatol. 1995; 133: 1970; 140: 345–55.
655–6. 171. Jeffes EW, Weinstein GD. Methotrexate and other chemo-
149. Goldstein E, Carey W. Discoid lupus erythematosus: successful therapeutic agents used to treat psoriasis. Dermatol. Clin.
treatment with oral methotrexate. Arch. Dermatol. 1994; 130: 1995; 13: 875–90.
938–9. 172. Zachariae H, Zachariae E. Methotrexate treatment of psoriatic
150. Upchurch KS, Heller K, Bress NM. Low-dose methotrexate arthritis. Acta Derm. Venereol. 1987; 67: 270–3.
therapy for cutaneous vasculitis of rheumatoid arthritis. J. Am. 173. Kragballe K, Zachariae E, Zachariae H. Methotrexate in pso-
Acad. Dermatol. 1987; 17: 355–9. riatic arthritis: a retrospective study. Acta Derm. Venereol.
151. Williams HC, Pembroke AC. Methotrexate in the treatment of 1983; 63: 165–7.
vasculitic cutaneous ulceration in rheumatoid arthritis. J. R. 174. Nyfors A. Benefits and adverse drug experiences during long-
Soc. Med. 1989; 82: 763. term methotrexate treatment of 248 psoriatics. Dan. Med. Bull.
152. Espinoza LR, Espinoza CG, Vasey FB et al. Oral methotrexate 1978; 25: 208–11.
therapy for chronic rheumatoid arthritis ulcerations. J. Am. 175. Akhyani M, Chams-Davatchi C, Hemami MR et al. Efficacy and
Acad. Dermatol. 1986; 15: 508–12. safety of mycophenolate mofetil vs. methotrexate for the treat-
153. Gansauge S, Breitbart A, Rinaldi N et al. Methotrexate in ment of chronic plaque psoriasis. J. Eur. Acad. Dermatol.
patients with moderate systemic lupus erythematosus (exclu- Venereol. 2010; 24: 1447–51.
sion of renal and central nervous system disease). Ann. Rheum. 176. Flytström I, Stenberg B, Svensson A et al. Methotrexate vs.
Dis. 1997; 56: 382–5. ciclosporin in psoriasis: effectiveness, quality of life and safety.
154. Jorizzo JL, White WL, Wise CM et al. Low-dose weekly meth- A randomized controlled trial. Br. J. Dermatol. 2008; 158: 116–
otrexate for unusual neutrophilic vascular reactions: cutane- 21.
ous polyarteritis nodosa and Behçet’s disease. J. Am. Acad. 177. Heydendael VM, Spuls PI, Opmeer BC et al. Methotrexate
Dermatol. 1991; 24: 973–8. versus cyclosporine in moderate-to-severe chronic plaque
155. Boehm I, Bauer R. Low-dose methotrexate controls a severe psoriasis. N. Engl. J. Med. 2003; 349: 658–65.
form of polyarteritis nodosa. Arch. Dermatol. 2000; 136: 167–9. 178. Sandhu K, Kaur I, Kumar B et al. Efficacy and safety of
156. Schartz NE, Alaoui S, Vignon-Pennamen MD et al. Successful cyclosporine versus methotrexate in severe psoriasis: a study
treatment in two cases of steroid-dependent cutaneous pol- from north India. J. Dermatol. 2003; 30: 458–63.
yarteritis nodosa with low-dose methotrexate. Dermatology 179. Ranjan N, Sharma NL, Shanker V et al. Methotrexate versus
2001; 203: 336–8. hydroxycarbamide (hydroxyurea) as a weekly dose to treat
157. Quintana G, Matteson EL, Fernández A et al. Localized moderate-to-severe chronic plaque psoriasis: a comparative
nodular vasculitis: a new variant of localized cutaneous pol- study. J. Dermatolog. Treat. 2007; 18: 295–300.
yarteritis nodosa? Clin. Exp. Rheumatol. 2004; 22: S31–4. 180. Fallah Arani S, Neumann H, Hop WC et al. Fumarates vs. meth-
158. Lower EE, Baughman RP. The use of low dose methotrexate in otrexate in moderate to severe chronic plaque psoriasis: a
refractory sarcoidosis. Am. J. Med. Sci. 1990; 299: 153–7. multicentre prospective randomized controlled clinical trial.
159. Webster GF, Razsi LK, Sanchez M et al. Weekly low-dose meth- Br. J. Dermatol. 2011; 164: 855–61.
otrexate therapy for cutaneous sarcoidosis. J. Am. Acad. Der- 181. Jensen P, Skov L, Zachariae C. Systemic combination treatment
matol. 1991; 24: 451–4. for psoriasis: a review. Acta Derm. Venereol. 2010; 90: 341–9.
160. Veien NK, Brodthagen H. Cutaneous sarcoidosis treated with 182. Gupta R, Gupta S. Methotrexate-betamethasone weekly oral
methotrexate. Br. J. Dermatol. 1977; 97: 213–16. pulse in psoriasis. J. Dermatolog. Treat. 2007; 18: 291–4.
161. Lower EE, Baughman RP. Prolonged use of methotrexate for 183. Asawanonda P, Nateetongrungsak Y. Methotrexate plus nar-
sarcoidosis. Arch. Intern. Med. 1995; 155: 846–51. rowband UVB phototherapy versus narrowband UVB photo-

© 2011 The Authors


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

therapy alone in the treatment of plaque-type psoriasis: a 197. Heilborn JD, Ståhle-Bäckdahl M, Albertioni F et al. Low-dose
randomized, placebo-controlled study. J. Am. Acad. Dermatol. oral pulse methotrexate as monotherapy in elderly patients
2006; 54: 1013–18. with bullous pemphigoid. J. Am. Acad. Dermatol. 1999; 40:
184. Shehzad T, Dar NR, Zakria M. Efficacy of concomitant use of 741–9.
PUVA and methotrexate in disease clearance time in plaque 198. Sapadin AN, Fleischmajer R. Treatment of scleroderma. Arch.
type psoriasis. J. Pak. Med. Assoc. 2004; 54: 453–5. Dermatol. 2002; 138: 99–105.
185. Zachariae C, Mørk NJ, Reunala T et al. The combination of 199. Villalba L, Adams EM. Update on therapy for refractory der-
etanercept and methotrexate increases the effectiveness of matomyositis and polymyositis. Curr. Opin. Rheumatol. 1996; 8:
treatment in active psoriasis despite inadequate effect of meth- 544–51.
otrexate therapy. Acta Derm. Venereol. 2008; 88: 495–501. 200. Huber A, Tüting T, Bauer R et al. Methotrexate treatment in
186. Fraser AD, van Kuijk AW, Westhovens R et al. A randomised, cutaneous lupus erythematosus: subcutaneous application is
double blind, placebo controlled, multicentre trial of combina- as effective as intravenous administration. Br. J. Dermatol.
tion therapy with methotrexate plus ciclosporin in patients 2006; 155: 861–2.
with active psoriatic arthritis. Ann. Rheum. Dis. 2005; 64: 859– 201. Picco P, Gattorno M, Buoncompagni A et al. A case of paediat-
64. ric discoid lupus erythematosus evolving into SLE. Clin. Exp.
187. Mease PJ, Gladman DD, Keystone EC et al. Alefacept in com- Rheumatol. 1998; 16: 620.
bination with methotrexate for the treatment of psoriatic 202. ten Holder SM, Joy MS, Falk RJ. Cutaneous and systemic mani-
arthritis: results of a randomized, double-blind, placebo- festations of drug-induced vasculitis. Ann. Pharmacother. 2002;
controlled study. Arthritis Rheum. 2006; 54: 1638–45. 36: 130–47.
188. Collins P, Rogers S. The efficacy of methotrexate in psoriasis – 203. Kaye O, Beckers CC, Paquet P et al. The frequency of cutane-
a review of 40 cases. Clin. Exp. Dermatol. 1992; 17: 257–60. ous vasculitis is not increased in patients with rheumatoid
189. Vanderveen EE, Ellis CN, Campbell JP et al. Methotrexate and arthritis treated with methotrexate. J. Rheumatol. 1996; 23:
etretinate as concurrent therapies in severe psoriasis. Arch. 253–7.
Dermatol. 1982; 118: 660–2. 204. Badgwell C, Rosen T. Cutaneous sarcoidosis therapy updated.
190. Rosenbaum MM, Roenigk HH. Treatment of generalized pus- J. Am. Acad. Dermatol. 2007; 56: 69–83.
tular psoriasis with etretinate (Ro 10-9359) and methotrexate. 205. Prince HM, Whittaker S, Hoppe RT. How I treat mycosis fun-
J. Am. Acad. Dermatol. 1984; 10: 357–61. goides and Sézary syndrome. Blood 2009; 114: 4337–53.
191. Horiguchi M, Takigawa M, Imamura S. Treatment of general- 206. Wessels JA, Kooloos WM, De Jonge R et al. Relationship
ized pustular psoriasis with methotrexate and colchicine. Arch. between genetic variants in the adenosine pathway and
Dermatol. 1981; 117: 760. outcome of methotrexate treatment in patients with recent-
192. Fitzsimons CP, Long J, MacKie RM. Synergistic carcinogenic onset rheumatoid arthritis. Arthritis Rheum. 2006; 54: 2830–9.
potential of methotrexate and PUVA in psoriasis. Lancet 1983; 207. Dervieux T, Wessels JA, van der Straaten T et al. Gene-gene
1: 235–6. interactions in folate and adenosine biosynthesis pathways
193. Gollnick HP. Oral retinoids – efficacy and toxicity in psoriasis. affect methotrexate efficacy and tolerability in rheumatoid
Br. J. Dermatol. 1996; 135 (Suppl 49): 6–17. arthritis. Pharmacogenet. Genomics 2009; Epub ahead of print.
194. Bonifati C, Carducci M, Mussi A et al. Recognition and treat- 208. Kooloos WM, Wessels JA, van der Kooij SM et al. Optimaliza-
ment of psoriasis. Special considerations in elderly patients. tion of the clinical pharmacogenetic model to predict methotr-
Drugs Aging 1998; 12: 177–90. exate treatment response: the influence of the number of
195. Fairris GM, Dewhurst AG, White JE et al. Methotrexate dosage haplotypes of MTHFR 1298A-677C alleles on probability to
in patients aged over 50 with psoriasis. BMJ 1989; 298: 801–2. respond. Ann. Rheum. Dis. 2009; 68: 1371.
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