Sarah Shen1, Tim O’Brien,1 Lei Mee Yap,1 H Miles Prince2 and Christopher J McCormack1,3
1Department 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
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.
Key words: adverse reactions, mechanism of action, methotrexate, pharmacology, psoriasis, treatment guidelines.
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.
AD atopic dermatitis
ADD American Academy of Dermatology
ALP alkaline phosphatase
ALT alanine aminotransferase
ASP aspartate aminotransferase
More than half a century has passed since methotrexate was first introduced into the therapeutic armamentarium for skin diseases. Its use in dermatology was the result of a chance finding in 1951 when Gubner noted the rapid clear- ing of psoriatic skin lesions in cancer patients undergoing treatment with the anti-metabolic drug aminopterin.1 This led to the development of the more stable and less toxic derivative, methotrexate. While it is mainly used to treat psoriasis, benefit is seen in a myriad array of skin condi- tions, including vasculitic connective tissue, blistering and lymphoproliferative diseases. Ongoing research concerning its mechanism of action and pharmacogenetics has also
NB-UVB NSAID PASI PIIINP
cutaneous lupus erythematosus chronic urticaria dermatomyositis
estimated glomerular filtration rate granuloma annulare
glycinamide ribonucleotide human immunodeficiency virus interleukin
lymphomatoid papulosis mycosis fungoides methotrexate
narrow-band ultraviolet B nonsteroidal anti-inflammatory drugs psoriasis area severity index
serial serum type III procollagen aminopeptide
PL pityriasis lichenoides
PLEVA pityriasis lichenoides et varioliformis acuta
Correspondence: Dr Sarah Shen, St Vincent’s Hospital, 41 Victoria Parade, Fitzroy, Vic. 3065, Australia. Email: [email protected]
Sarah Shen, BMedSci, MBBS. Tim O’Brien, FACD. Lei Mee Yap, FACD. H. Miles Prince, FRACP. Christopher J McCormack, FACD.
Submitted 17 September 2011; accepted 17 September 2011.
pityriasis rubra pilaris psoralen plus ultraviolet A rheumatoid arthritis
subacute cutaneous lupus erythematosus ultraviolet B
© 2011 The Authors
Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists
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
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.
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
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.
Table 1 Side effects of methotrexate Constitutional
Nausea Fatigue Malaise Anorexia
Gastrointestinal Nausea Diarrhoea Stomatitis Hepatotoxicity Haematological Cytopenia
Table 3 Risk factors for hepatotoxicity Type 2 diabetes mellitus
History of or current greater than moderate alcohol consumption Persistent abnormal liver chemistry study findings
History of liver disease including chronic hepatitis B or C
History of significant exposure to hepatotoxic drugs or chemicals Hyperlipidemia
Table 4 Classification of liver biopsy findings
Pulmonary Pneumonitis Pulmonary fibrosis Reproductive Teratogenicity Oligospermia Oncogenic potential
Fatty infiltration, mild Nuclear variability, mild Portal inflammation, mild
Fatty infiltration, moderate to severe Nuclear variability, moderate to severe
Portal tract expansion, portal tract inflammation and
necrosis, moderate to severe
Squamous cell carcinoma Mucocutaneous Mucositis
Drug hypersensitivity reactions Diffuse non-inflammatory alopecia Infections
Opportunistic TB reactivation Hepatitis Neurological Headache Dizziness Fatigue
Table 2 Risk factors for haematological toxicity Renal insufficiency
Lack of folate supplementation Methotrexate dosing errors Drug interactions Hypoalbuminemia
Greater than moderate alcohol intake
Methotrexate is considered to be safe in the setting of human immunodeficiency virus, given there is close moni- toring of patients for signs of infection,63 although its use in this group of patients remains controversial.
Pulmonary toxicity Idiosyncratic acute pneumonitis and slowly progressive pulmonary fibrosis are more commonly seen in RA patients than in psoriatics taking methotrexate but they can be life-threatening.64 A respiratory work-up is warranted if pulmonary symptoms develop.
Mucocutaneous toxicity Mucositis can occur in patients without adequate folate supplementation and in the setting
Class IIIA Fibrosis, mild
Class IIIB Fibrosis, moderate to severe
Class IV Cirrhosis
of concomitant haematopoietic and gastrointestinal toxici- ties.65 Two types of cutaneous ulceration induced by meth- otrexate in patients with psoriasis have been described. Type 1 involves the painful erosion of psoriatic plaques which can take place shortly after initiation of the treatment or in the setting of dose alteration and drug interaction.66 This can be mistaken as an exacerbation of the condition 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 toxic epidermal necrolysis also have been reported.9
Neurological toxicity Headaches, dizziness, fatigue and mood alterations usually occur at drug initiation and are dose dependent. However, they can also result from chronic use.21
Cardiac toxicity Methotrexate elevates the level of homocysteine by inhibiting methionine synthase. Hyper- homocysteinemia is associated with an increased risk of cardiovascular disease, leading to the concern that meth- otrexate may secondarily increase the risk of cardiovas- cular disease.69 However, methotrexate may in fact have protective effects against cardiovascular disease as its anti- inflammatory properties may counteract elevated homocys- teine levels.70 In addition, folic acid administration is believed to abrogate the deleterious effects of methotrexate on homocysteine.71
Others Low-dose methotrexate may contribute to the development of stress fractures of long bone. One study reported on three patients on low-dose methotrexate with a
Table 5 Drugs that may interact with methotrexate (MTX) to increase toxicity
be at risk for pulmonary toxicities. Obtaining hepatitis serologies prior to therapy initiation is not routine; however
Mechanism Decreased renal
elimination of MTX Pharmacological
enhancement of MTX toxic effects
Reduced tubular secretion
Displacement of MTX from plasma protein binding
Intracellular accumulation of MTX
Nonsteroidal anti-inflammatories Trimethoprim-sulfamethazole Ethanol
Phenylbutazone Salicylates Sulfonamides Probenecid Cephalothin Penicillins Colchicine Salicylates Probenecid Barbiturates Phenytoin Probenecid Dipyridamole Retinoids
viral titres should be tested if there is clinical suspicion. Figure 2 illustrates the algorithm of pre-therapy evaluation and subsequent monitoring recommendations, as based on the American Academy of Dermatology (ADD) 2009 guide- lines of care for the management of psoriasis and PA.
Monitoring of therapy
Hepatic surveillance Monitoring liver toxicity is a point of ongoing contention amongst clinicians. Hepatic surveil- lance is complicated by the fact that the risk of hepato- toxicity is not well established for many dermatological diseases. Current guidelines are based on data gathered from the use of methotrexate in psoriasis and RA, two large but different patient groups. Serial liver biopsies are recom- mended in psoriatics on long-term methotrexate therapy, especially when the cumulative dose exceeds 1.5 g.32,79–81 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 tibial stress fractures.72 Anaphylactoid reactions have been reported after low-dose methotrexate and can occur during initial exposure.73
Low-dose methotrexate is generally well tolerated in chil- dren for the treatment of psoriasis,74 with primary side effects relating to stomatitis, gastrointestinal intolerance and hepatotoxicity. However, most of the published data on its use in children thus far derive from the rheumatology literature. It is suggested that most children can be moni- tored for hepatotoxicity in accordance to the rheumatologi- cal liver biopsy guidelines recommended for adults without risk factors.75
Drug interactions and contraindications
Numerous medications may interact with methotrexate by a variety of mechanisms that can result in elevated drug levels, thereby increasing the risk of toxicity,76–78 as sum- marised in Table 5. Absolute and relative contraindications to methotrexate are listed in Figure 2.
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
The guidelines for monitoring of treatment set by the ADD in 200979 are based upon the stratification of patient risk. In the absence of certain risk factors, a baseline biopsy 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 the drug is 15 mg or less. The presence of risk factors for hepatotoxicity mandates close monitoring, although one should consider delaying a liver biopsy to ascertain medi- cation efficacy and tolerability.81
Serial serum type III procollagen aminopeptide (PIIINP) as a test for fibrinogenesis has been promoted as a reliable83–86 and cost-effective87 monitoring tool in place of a liver biopsy. A recent 10-year retrospective study of 70 patients with psoriasis who were taking methotrexate 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 Manchester guidelines (Table 6) as a means of reducing the need for a liver biopsy in patients with psoriasis. The limi- tations of this set of guidelines relate to the fact that PIIINP levels may be elevated in inflammatory conditions other than hepatic fibrosis. It is frequently elevated in RA patients in the absence of hepatic damage and is therefore not a useful marker in this group.87
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
Absolute contraindication? Yes
Signficant anaemia, leukopenia or thrombocytopenia
Relative contraindications? Renal insufficiency Hepatic impairment
Chronic infection or immunosuppressed state (e.g TB, HIV)
Heavy alcohol consumption Patient unreliability
Consider alternative therapy
Diabetes mellitus Recent vaccination
Drug interactions (e.g. NSAIDS, see Table IV)
Baseline Investigations: Full blood examination Renal function test
Liver function test
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 function tests including eGFR at every 2 to 3 months interval
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.
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.
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
•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
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 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-
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
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
Table 8 Indications for use of methotrexate in psoriasis169
•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
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
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
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
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
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
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
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.
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