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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Literature search
  5. Methotrexate
  6. Conclusion
  7. References
  8. CPD questions
  9. Instructions for answering questions

Methotrexate (MTX) has remained the backbone of the treatment for moderate to severe psoriasis ever since its first use nearly half a century ago. Over the years, its high efficacy, low cost, relative ease of administration and usefulness in concomitant psoriatic arthritis have contributed in making MTX the drug of choice in managing severe psoriasis. Although the majority of patients achieve remission of disease activity with MTX, a significant proportion may experience mild and transient adverse effects. From time to time, various guidelines on the use of MTX have correctly and adequately stressed the need for strict monitoring of haematological and hepatic adverse events. Over the years, the safe total cumulative dose of MTX (above which the risk of developing liver fibrosis is significantly increased) has been raised. Simultaneously, there has been an increased emphasis on developing noninvasive tests such as scanning and serum biomarker assays for detecting early liver fibrosis, in order to obviate the need for liver biopsy. However, the recent discovery and subsequent proliferating use of biological response modifiers has gradually shifted the focus away from MTX, despite it still being the most commonly prescribed drug for psoriasis worldwide. The aim of this review is to present a detailed account of MTX therapy and its use in psoriasis, along with its current relevance in disease management in the evolving era of biological drugs.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Literature search
  5. Methotrexate
  6. Conclusion
  7. References
  8. CPD questions
  9. Instructions for answering questions

The discovery in the late 1940s of antifolate chemotherapy, using folic acid (FA) antagonists, was a landmark event in the history of chemotherapy, because a member of this class of drugs, aminopterin, was the first effective treatment for leukaemia.[1] Folic acid antagonists are also credited with producing the first cure of a solid tumour, choriocarcinoma.[2] In 1951, Gubner et al.[3] recognized aminopterin to be effective in the treatment of psoriasis. Thereafter, interest in and its derivative, methotrexate (MTX) proliferated rapidly among dermatologists, because of its efficacy in psoriasis and psoriatic arthritis (PsA). It was the significant anti-inflammatory action of MTX, rather than its cytotoxic action, which formed the basis of its use in various other dermatological diseases, including pityriasis rubra pilaris, dermatomyositis, lupus erythematosus, sarcoidosis, systemic sclerosis, morphoea, atopic dermatitis and immunobullous diseases.[4]

It is well accepted that there is currently no long-term cure for psoriasis, so the goals of management are to achieve initial control of the disease process, followed by maintenance of long-term remissions while minimizing treatment-related adverse effects (AEs).[5] The treatment has to be individualized, taking into consideration factors such as the extent of disease, anatomical location, effect on quality of life, concomitant presence of PsA or other medical illnesses, socioeconomic factors and compliance with treatment.[6] Despite the advent of several new systemic therapies, including acitretin, ciclosporin, phototherapy and biological response modifiers, MTX remains the gold standard for the treatment of moderate to severe psoriasis.

Literature search

  1. Top of page
  2. Summary
  3. Introduction
  4. Literature search
  5. Methotrexate
  6. Conclusion
  7. References
  8. CPD questions
  9. Instructions for answering questions

We performed an extensive literature search to collect evidence-based data on the use of MTX in psoriasis. The relevant literature published from 1960 to April 2012 was obtained from three bibliographical databases: PubMed, EMBASE and the Cochrane Library, using the keywords ‘methotrexate’, ‘FA antagonists’, ‘psoriasis’, ‘methotrexae in psoriasis’ or ‘treatment of psoriasis’. The search and selection of the literature was restricted to publications written in English, Dutch, German or French. In total, 1552 citations were screened. All clinical trials, randomized double-blind or single-blind controlled trials, open-label studies, retrospective studies, reviews, case reports and letters concerning the use of MTX in psoriasis were screened. Articles covering the use of MTX in psoriasis in all age groups were screened, and reference lists in the selected articles were scrutinized to identify other relevant articles that had not been found in the initial search. Articles without relevant information about MTX in general (e.g. its mechanism of action, pharmacokinetics and AEs), and its use in psoriasis in particular, were excluded. Clinical trials in which MTX was used for indications other than psoriasis vulgaris (PV), such as psoriatic arthritis, pustular and nail psoriasis, and other dermatological conditions, were not included in the analysis. In total, we found and analysed 39 clinical trials mentioning the use of MTX in psoriasis. Of these, 17 were prospective open-label studies, 14 were randomized clinical trials, and 7 were large retrospective studies. In addition, another 152 articles including various consensus conferences and other guidelines for MTX in psoriasis, were reviewed, as were case reports citing new AEs.

Methotrexate

  1. Top of page
  2. Summary
  3. Introduction
  4. Literature search
  5. Methotrexate
  6. Conclusion
  7. References
  8. CPD questions
  9. Instructions for answering questions

Pharmacokinetics

MTX (4-amino-N10-methyl pteroylglutamic acid) is structurally similar to FA. At doses of < 25 mg/m2, MTX is absorbed efficiently from the gastrointestinal tract, but at higher doses, absorption is erratic, and it should preferably be given parenterally. The mean absolute bioavailability ranges from 30% to 90%.[7] Following its absorption from the jejunum, ∼10% of the MTX undergoes first-pass metabolism in the liver, where it is converted to 7-hydroxy-MTX before achieving maximum plasma concentration after 0.75–2 h (Tmax).[8] Pharmacokinetic studies show that the relative bioavailability of oral MTX may be less than that achieved with parenteral administration, primarily because of the variable intestinal absorption and first-pass effect.[9] Around 50% of MTX is bound to plasma protein, and may be displaced by other drugs, including salicylates, tetracycline and phenytoin. Because MTX is cleared primarily by proximal tubular filtration, significant renal insufficiency can lead to reduction in overall MTX clearance from 84.6 to 2.8 mL/min/m2, and hence will require a dose adjustment to minimize toxicity.[10, 11] At the pharmacogenetic level, it has been found that polymorphisms in the dihydrofolate reductase (DHFR) are associated with MTX efficacy, although the results of various studies are not uniformly consistent.[12] The relative resistance to the effect of MTX has also been ascribed to impaired transport of MTX into cells,[13] decreased ability to synthesize MTX polyglutamate (MTX-PG),[14] and increased expression of drug efflux transporters of the multidrug resistance protein class. Because MTX has a structural similarity to FA, it enters the cell through the reduced folate carrier and forms MTX-PGs, which then cannot be transported extracellularly unless hydrolysed back to MTX monoglutamate by γ-glutamyl hydrolase. This accumulation of MTX-PG inside the cells allows a prolonged intracellular presence with once-weekly administration.

Mechanism of action in psoriasis

MTX and MTX-PG inhibit the enzymes DHFR and thymidylate synthase, as well as other enzymes involved in de novo purine synthesis. In this way, they deplete the intracellular reserve of fully reduced folates, and thus affect transmethylation reactions. Other immunosuppressant effects of the drug include the inhibition of T and B lymphocytes, suppression of proinflammatory cytokines, and inhibition of chemotaxis of neutrophils and monocytes. In addition, MTX decreases DNA synthesis and induces apoptosis in keratinocytes.[15, 16] Because the pathogenesis of psoriasis involves an aberrant T-cell response, the immune system is a possible target for the antipsoriatic effects of MTX.[17] MTX interferes with epidermal-cell kinetics, presumably through a temporary reduction in DNA synthesis.[18] It impairs complement C5a-induced skin response and leukotriene B4-induced intraepidermal penetration of granulocytes.[19] Recently, Meephansan et al.[20] reported that MTX significantly reduces serum levels of interleukin-22, a cytokine that promotes keratinocyte proliferation and dermal inflammation in psoriasis. Another novel mechanism of action is through reduction in the mRNA levels of peroxisome proliferator-activated receptor β/δ, a member of the nuclear hormone receptor superfamily that contributes to psoriasis pathogenesis.[21]

Owing to the inhibition of 5-aminoimidazole-4 carboxamide ribonucleoside (AICAR) transformylase, MTX induces the release of adenosine, which inhibits generation of oxygen free radicals by polymorphonuclear cells (PMNs), adhesion of PMNs, macrophage-induced modulation of tumour necrosis factor-α, and proliferation of lymphocytes, explaining the anti-inflammatory and immune modulatory effects of MTX.[22] Caffeine, a poorly selective adenosine receptor antagonist, blocks the anti-inflammatory effects of adenosine in vitro, and thus might interfere with the therapeutic actions of MTX.[23, 24] Adenosine may be responsible for some of the AEs associated with MTX, including hepatotoxicity, fatigue and somnolence; these may result from its action on A1 and A2B receptors, which stimulates hepatic steatosis,[25] and its action on A2A receptors plays a role in the development of hepatic fibrosis.

Indications in psoriasis

MTX can be used in patients with moderate to severe psoriasis, when the disease is not responding to topical treatments or phototherapy, or when other therapeutic agents are contraindicated in a given patient. In addition, it can be used in psoriatic erythroderma, moderate to severe PsA, generalized pustular psoriasis, and in cases where the disease affects certain areas of the body such as the hands and feet, interfering with normal function and activities, including employment.

Contraindications for use of methotrexate in psoriasis

MTX is absolutely contraindicated in pregnant or nursing women, and patients with severe liver or kidney disease, severe and/or active infectious disease (e.g. tuberculosis, pyelonephritis), severe anaemia, leucopenia or thrombocytopenia, excessive alcohol consumption, immunodeficiency, active peptic ulcer and significantly reduced lung function.[26] It may be given with caution (relative contraindications) to elderly or poorly compliant patients, or in patients with mild to moderate liver and kidney dysfunction or ulcerative colitis, or those with a history of hepatitis or malignancy, gastritis, diabetes mellitus and congestive cardiac failure.

Dosage and treatment schedule in psoriasis

In the 1960s, the oral dose of MTX used to treat psoriasis was 2.5 mg or 5.0 mg per day, usually for 5 consecutive days per week, or a weekly oral or intramuscular dose of 25 mg or 50 mg.[27] In 1971, Weinstein introduced a weekly oral schedule of three doses per 24 h once weekly, beginning with a schedule of 2.5 mg per dose and gradually increasing to 5 mg per dose.[28] The rationale for this was to obtain the maximum effect on the accelerated cell cycle of psoriatic lesions and to diminish toxicity, and this became established practice. The guidelines[29] on MTX dosage for psoriasis have been revised several times since 1972, most recently in 2009 (by both the American Academy of Dermatology (AAD)[26] and the European Academy of Dermatology and Venereology).[30] The recommended weekly single oral dose of MTX is 7.5–25 mg once weekly; however in the absence of any consensus on the optimum dose of MTX for psoriasis, there is a wide variation in prescribing patterns, thus resulting in variable or delayed therapeutic effects. The recommended baseline and follow-up monitoring procedures are given in Table 1.

Table 1. Baseline investigations and follow-up monitoring for methotrexate
MonitoringAAD guidelines[26]European guidelines[30]
  1. AAD, American Academy of Dermatology; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; PPD, purified protein derivative; PIIINP, amino terminal type III procollagen peptide.

BaselineComplete blood countComplete blood count
Pregnancy test 2 weeks before starting of treatment and at day 2 or 3 of a normal menstrual cyclePregnancy test 2 weeks before starting of treatment and at day 2 or 3 of a normal menstrual cycle
Liver function testLiver function test
Renal function testRenal function test
HIV testHBV/HCV test
Tuberculin skin test (PPD)PIIINP
 Serum albumin
 Urinary sediment
Follow-upComplete blood cell count weekly for the first 2 weeks, biweekly for the next few months, and then every 1–3 monthsRepeat complete blood cell count after first week, biweekly for the next 2 months, and then every 2–3 months

Liver function tests every 4–12 weeks

Renal function tests every 2–3 months

Liver and renal function tests and urine analysis biweekly for 2 months, and then every 2–3 months
 PIIINP levels every 3 months

Two dosage schedules for MTX are commonly used in psoriasis. The first is a single weekly administration of the drug, usually at 7.5–25 mg/week, which may be oral, intravenous, intramuscular or subcutaneous. The drug may be started at a lower dose (e.g. 7.5 mg/week) and then gradually increased, or may be given at full dose from the outset. However, in 2011, Montaudie et al.,[31] in their systematic review of MTX, concluded that response to MTX is dose-dependent, and recommended that the initial dose of MTX should be between 5 and 15 mg/week, with a rapid increase to a target dose of 15–25 mg/week over the next 4 weeks. According to these authors, 60% of patients achieve a 75% reduction in Psoriasis Area and Severity Score (PASI 75) within 16 weeks if the initial dose of MTX is 15 mg/week, but this decreases to 40% with an initial dose of 7.5 mg/week.

In India, most centres prefer to start MTX at a dose of 0.3–0.5 mg/kg/week, continue it till PASI 75 is achieved, and then gradually taper it down. Such a regimen gives good and rapid control of disease in the majority of the patients; however, because of the relatively high initial dose of MTX, the clinical and laboratory monitoring for any acute AEs has to be stringent. A number of large patient series with this high initial dose of MTX have consistently proven the effectiveness of the drug in providing rapid and near-complete resolution of disease, with no increased risk of AEs.[32-34] If myelosuppression is present, it usually reaches its maximum within 7–10 days. More frequent monitoring is carried out during the initial treatment and when increasing the dose. Alternatively, an intermittent oral schedule consists of three divided doses over a 24-h period each week (three doses with an interval of 12-h between them). Studies indicate that a single weekly oral dose of MTX has a favourable side-effect profile compared with an intermittent oral schedule.[35] Radmanesh et al.,[36] comparing weekly MTX (15 mg/week) with daily MTX (2.5 mg/day for 6 days/week), found the weekly regimen to be significantly more effective, with fewer AEs.

Folic-acid supplementation and methotrexate

It has been suggested that concomitant administration of FA (1–5 mg/day) reduces side-effects such as nausea and megaloblastic anaemia without diminishing the efficacy of MTX.[37] However, a recent meta-analysis, evaluating the effect of FA and folinic acid on the efficacy and AE profile of MTX, concluded that such supplementation does not significantly reduce the mucocutaneous and gastrointestinal side-effects of MTX, although the incidence of hepatic side-effects is significantly reduced. The effect on haematological AEs could not be assessed because of the small percentage of patients experiencing this AE.[38] Several studies have showen that homocysteine levels are increased in patients taking MTX, as a consequence of inhibition of a folate-dependent enzyme, methionine synthase. This hyperhomocysteinaemic state may be associated with a higher risk of atherosclerosis. Folate supplementation has been shown to lower homocysteine levels during low-dose MTX therapy, and thus prevent its cardiotoxic and atherogenic effects.[39] In addition, Micha et al.[40] suggested in a recent meta-analysis that MTX itself, by treating the inflammation in psoriasis, reduces the cardiovascular risk.

There are opposing views about the effect of FA supplementation on the therapeutic effect of MTX. When FA is given along with MTX, it results in a higher folate pool. A positive correlation has been shown between reduction in PASI and a higher ratio of mean MTX-PG concentration to red blood cell (RBC) folate concentration. Dervieux et al.[41] suggested that high folate status may interfere with MTX efficacy in rheumatoid arthritis. Higher RBC folate polyglutamate levels were associated with a larger number of tender and swollen joints, but not with worsening in the Physician Global Assessment disease score. Chladek et al.[42] conducted a randomized crossover study to evaluate the effects of supplementation with FA 20 mg/week during treatment of moderate to severe plaque psoriasis with oral MTX, and showed that patients on MTX monotherapy had a more rapid reduction in PASI compared with patients on the MTX–FA combination at the end of 32 weeks of treatment. Rheumatologists have recommended FA 5 mg/week, given at some time after oral MTX administration, although there is as yet no consensus on this protocol.[43] Montaudie et al.[31] suggested that FA 5 mg/day may be given for 1–3 days, starting 48 h after MTX ingestion.

Adverse effects

The toxicities of MTX have been classified as types A–D.[44]

  • Type A toxicities include gastrointestinal and bone-marrow toxicity. These are dose-dependent, and are related to the effects of folate antagonism on tissues with high rates of cell replication. Increase in mean corpuscular volume has been shown to be a predictor of haematological toxicity.[45]
  • Type B reactions are idiosyncratic, such as pneumonitis.[46]
  • Type C toxicity is related to long-term antifolate effects, and includes hepatoxicity and hyperhomocysteinaemia.
  • Type D effects are delayed effects that occur after discontinuation, such as effects on pregnancy and teratogenesis.[45]

The AEs commonly experienced with the doses of MTX used in the treatment of psoriasis include malaise, nausea, vomiting, glossitis, ulcerative stomatitis, headaches and leucopenia. Less often, pharyngitis, diarrhoea, vomiting and enteritis may occur. Other reported AEs include general fatigue, chills, fever and dizziness.[47] Mucocutaneous side-effects include pruritus, pain, urticaria, mild reversible alopecia, ecchymosis, acute ulcerations of psoriatic lesions, reactivation of phototoxic responses and rarely, toxic epidermal necrolysis-like dermatoses.[48] An increased incidence of cutaneous infections such as disseminated molluscum contagiousum has also been reported.[49] When given within a few days of ultraviolet (UV) irradiation, MTX may reactivate an acute sunburn response, also known as UV recall, photo recall or photodermatitis reactivation.[50] Myelosuppression caused by MTX may be life-threatening. Patients at increased risk of developing haematological toxicity are those who are elderly, have renal insufficiency, lack folate supplementation or are on concomitant medications that have significant drug interactions.[26] In cases of MTX toxicity, folinic acid (calcium leucovorin) should be instituted immediately at a dose of 20 mg (or 10 mg/m2) intravenously or intramuscularly. It should be repeated subsequently at 6-h intervals after measuring serum MTX levels until the serum MTX concentration is < 10−8 mol/L.

One of the major concerns with the long-term use of MTX is the associated risk of developing hepatic fibrosis, which has been estimated at approximately 4%.[26] Studies have shown that the only reliable method of detecting fibrosis is histological examination of liver biopsy material. Table 2 lists the various invasive and noninvasive methods that may be used to screen for presence of early liver fibrosis in patients on MTX. The AAD guidelines recommend a liver biopsy based on the presence of risk factors such as chronic alcoholism, previous liver disease, diabetes mellitus, obesity, hyperlipidaemia and concomitant use of hepatotoxic drugs.[26] The most recent AAD guidelines advocate a first liver biopsy after 3.5–4.0 g of the cumulative MTX dose has been given to patients without pre-existing risk factors for hepatotoxicity. In patients with one or more risk factors for hepatic toxicity, a liver biopsy should be performed at treatment initiation or within 2–6 months of starting treatment. Thereafter, it should be repeated after every 1–1.5 g of cumulative dose. According to European guidelines, the risk for hepatotoxicity increases further after a cumulative dosage of > 3 g MTX and/or > 100 g/week of alcohol consumption.[30] These guidelines advocate the use of amino terminal type III procollagen peptide (PIIINP) as a noninvasive tool for monitoring long-term hepatotoxicity, and liver biopsy may be considered in selected cases if PIIINP levels are persistently raised. PIIINP levels should be measured before starting MTX, and then every 3 months thereafter.[30] Chalmers et al.[51] conducted a multicentre audit over a 24-months period to compare healthcare costs and outcomes of two intervention groups (from centres in which serial PIIINP measurement was used to detect the risk of developing liver fibrosis) with those of two control groups (from centres that followed AAD guidelines). This audit showed that patients managed using serial PIIINP measurement and selective liver biopsy were not disadvantaged compared with those managed according to AAD guidelines. Vibration-controlled transient elastography (Fibroscan; Echosens, Paris, France) has recently been proposed as a measure of liver stiffness. This machine uses elastic waves of low audio frequency (50 Hz), whose propagation velocity depends on tissue elasticity, thus it can identify liver stiffness secondary to liver fibrosis. It is a reliable tool to detect both advanced liver fibrosis and early cirrhosis.[52, 53] Another new technique, the Controlled Attenuation Parameter (CAP; Echosens) has been shown to be very sensitive in detecting early steatosis.[54] Bray et al.[55] reported that transient elastography combined with PIIINP has the potential to reduce the number of liver biopsies required for safe MTX monitoring in patients with psoriasis (particularly for those with a body mass index of < 30 kg/m2). Montaudie et al.[31] proposed that a combination of fibrotests and fibroscans together with measurement of the PIIINP is an ideal method for monitoring liver toxicity.

Table 2. Various invasive and non invasive tests used for monitoring methotrexate (MTX) hepatotoxicity
TestInterpretationComments
  1. ALT, alanine aminotransferase; AST, aspartate aminotransferasee; DHS, dynamic hepatic scintigraphy; gp, glycoprotein; MRI, magnetic resonance imaging; PIIINP, amino terminal type III procollagen peptide; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase.

Liver biopsyGrade I: normal, mild fatty change/mild portal inflammationMTX can be safely given in patients showing changes up to grade II. For grade IIIa changes, continue MTX, but repeat biopsy every 6 months. MTX contraindicated for grades IIIb and IV
Grade II: moderate to severe of these changes
Grade III: fibrosis; mild in stage IIIa and moderate to severe in IIIb)
Grade IV: cirrhosis
PIIINPLiver biopsy if pretreatment PIIINP is > 8.0 μg/L, or is higher than the normal range of 1.7–4.2 μg/L in at least three samples in 1 year, or is > 8.0 μg/L in two consecutive samples Withdraw MTX if PIIINP is > 10.0 μg/L in at least three samples in 1 yearPIIINP monitoring is cost-effective, patient-friendly, and leads to a seven-fold decrease in the number of liver biopsies, thus avoiding liver biopsy complications. PIIINP is not specific for fibrosis of the liver, and can be raised in normal children and adolescents, and in patients with inflammatory arthritis or scleroderma
UltrasonographyMost common and easiest method for diagnosing non-alcoholic fatty liver diseaseLow inter-rater and intra-operator repeatability and low sensitivity limits
Transient elastographyNoninvasive, ultrasonography-based scan measuring liver stiffness. Has low interoperator variability, and is most accurate at discriminating cirrhosis from normalMost of the studies have been performed with patients with chronic liver diseases. The method needs to be validated in patients with psoriasis
MRIInsufficient data at presentInitial studies measured with a low field-strength MRI machine did not correlate with the histological findings of liver biopsies.
DHSHigh predictive value in early fibrosis, low predictive value in advanced fibrosisDHS holds promise for the detection of early MTX-induced hepatic damage
Other serum markers  
Direct markers: ALT, AST, γ-glutamyltranspeptidase, hyaluronic acid, apolipoprotein A1, bilirubin, haptogloblin, cholesterol, platelets and prothrombin time
Indirect markers: collagen IV, collagen VI, human cartilage gp39, laminin, MMP-2, tenascin, TIMP-1, undulin

MTX may lead to azotaemia, microscopic haematuria, cystitis, nephropathy, transient oligospermia, defective spermatogenesis/oogenesis, teratogenesis, menstrual dysfunction, reduced libido and erectile dysfunction.[56] Conception must be avoided by both sexes during MTX therapy and for at least 3 months afterwards.[26] Oligospermia associated with MTX use usually reverses after stopping treatment; however, its effect on conception when the father is taking MTX is less well established. The Berlin Institute for Clinical Teratology and Drug Risk Assessment During Pregnancy documented a single case of trisomy 16 among 58 pregnancies for which paternal exposure to MTX was present.[57] Ostensen et al.[58] reported two out of 11 men who received MTX at the time of conception had children with birth defects. In the light of the limited evidence to date, it may be advisable to limit the exposure to MTX of men who wish to father a child.

Effects of MTX on the nervous system include dizziness, blurred vision, visual field changes and acute depression. Rarely reported AEs include isolated sixth nerve damage, excessive drowsiness, hyperosmia and encephalopathy.[59-63] Development of pleural effusion and pulmonary nodules secondary to MTX usage has also been found.[64] The presence of MTX osteopathy in patients treated with low-dose MTX is reported,[65] although Rozin et al.[66] suggested that most patients treated with low-dose MTX have no increased risk of osteopathy. There are a few reports of medial tibial stress syndrome with the use of low-dose MTX.[67]

It has been suggested that immunosuppression resulting from MTX therapy could lead to increased rates of malignancy, although this has not been proven conclusively.[68] MTX does have the potential to cause chromosomal damage in vitro. There are multiple case reports of patients who developed malignancies during or after treatment with MTX. In 1989, Jensen reported the development of metastatic skin cancer during MTX therapy for psoriasis.[69] Although there are several sporadic case reports, the only neoplasms noted in larger series to be possibly increased in frequency are lymphoproliferative disorders. In 1975, Bailin retrospectively studied 205 patients with psoriasis who were treated with MTX, and found no increase in the rate of malignancy.[70] In a case-control study in 1982, Stern found no association between the development of cutaneous or noncutaneous malignancies in patients with psoriasis treated with MTX.[70] It was concluded that the risk for malignancies other than lymphoproliferative disorders is not increased with MTX. In 1983, Nysfors reported 10 malignancies among 248 patients with psoriasis treated with MTX who were followed up for at least 7 years.[72] Marcil et al.[73] in their study concluded that long-term use of MTX was associated with a lower risk of malignancy than either any ciclosporin or high-dose posoralen ultraviolet A. Recently, Buchbinder et al.[74] identified a 50% increased risk of malignancy in patients with rheumatoid arthritis using MTX, relative to the general population, with a three-fold increase in melanoma, a five-fold increase in non-Hodgkin lymphoma and a nearly three fold increase in lung cancer. There are few data on the use of MTX in patients with pre-existing malignancy. Strangfeld et al.[75] analysed the recurrence of malignancies in 122 patients with a previous history of cancer using the German Rheumatoid Arthritis-Observation of Biological Therapy (RABBIT) registry and found no significant increase in the incidence of new malignancies or recurrences after approximately 5 years of follow-up in patients treated with biological therapies. Persad et al.[76] found no such studies in the dermatolgical literature. Hence, it is prudent to work in close association with a medical oncologist when managing patients with severe psoriasis with long term immunosuppressive therapies.

Studies of methotrexate use in psoriasis

Although MTX has been in use in psoriasis for over half a century, there is a paucity of quality data supporting its use, because its efficacy was well established before randomized double-blind controlled trials became the benchmark for establishing the efficacy of a drug. MTX can be given as monotherapy or as combination therapy for psoriasis. Table 3 shows the various clinical studies in which MTX has been used as monotherapy in moderate to severe psoriasis.[30, 33, 77-92] The response to monotherapy is usually seen in 1–4 weeks, with at least 50% reduction in PASI in 70–80% of treated patients. MTX has also been combined with several other systemic or topical agents to decrease its total cumulative dose and hence its side-effects, and also to increase the efficacy of the treatment. The various clinical trials in which MTX has been used for moderate to severe psoriasis in combination with other topical and systemic therapies, are enlisted in Table 4,[34, 93-101] and those in combination with biological response modifiers are summarized in Table 5.[102-107]

Table 3. Efficacy of methotrexate (MTX) as monotherapy in moderate to severe psoriasis
ReferencesStudy designPatients, n Dose of MTXResults
  1. AE, adverse effects; MMF, mycophenolate mofetil; PASI, Psoriasis Area and Severity Index; RCT, randomized controlled trial; TCM, traditional Chinese medicine.

  2. a

    The authors used subjective and objective measures, including abolition of itching, reduction in scaling and clearance of lesions.

Schewach et al.[77] Open-label prospective study17Intramuscular 12.5–37.5 mg/weekMaximum response in 3 patients, good to moderate in 11 and minimal in 3
Baker et al.[78] Open-label prospective study1825 mg/weekClinical response was highly satisfactory in 11 (63%) and worthwhilea in 5 others
Weinstein et al.[27] Open-label study267.5 mg/week20/26 patients attained 75–100% improvement
Collins et al.[79] Retrospective study over 10 years40Initially 15 mg/week followed by 12.5 mg/weekMTX was particularly effective in controlling erythrodermic and generalized pustular psoriasis
van Dooren-Greebe et al.[80] Retrospective study over 22 years11315 mg/week81% of the patients had near clearance
van Dooren-Greebe et al.[81] Study of the effects of intermittent treatment on long-term treatment with low-dose oral MTX1015 mg/weekInterruption of long-term MTX treatment led to a substantial reduction in cumulative MTX dose
Haaustein et al.[82] Retrospective study over 26 years157< 15–20 mg/weekGood response seen in 76% of patients, moderate response in 18% and poor response in 6%
Kumar et al.[32] Retrospective study over 20 years2440.3–0.5 mg/kg/weekPASI 75 achieved in 88% of patients in 8.5 ± 5.1 weeks
Hyedendial [83] Comparison of efficacy and safety of weekly MTX with daily ciclosporin8815 mg/week (ciclosporin was 3 mg/kg/day)No significant difference between the two therapies
Sandhu et al.[33] Comparison of efficacy and safety of weekly MTX with daily ciclosporin300.5 mg/kg/week (ciclosporin was 3 mg/kg/day; increased to a maximum of 4 mg/kg/day)PASI 75 achieved in 5.3 weeks with MTX and 6.8 weeks with ciclosporin
Ranjan et al.[84] Open-label study to compare efficacy of hydroxyurea with MTX3015–20 mg/weekWeekly doses of hydroxyurea can be an alternative to MTX
Flytstorm et al.[85] RCT to compare efficacy of MTX with ciclosporin6815 mg/kg/week maximum (ciclosporin 3 mg/kg/day, increased to a maximum of 5 mg/kg/day)Mean PASI change from baseline at 12 weeks was 58% in the MTX group and 72% in the ciclosporin group
Saurat et al. (CHAMPION trial)[86] Noninferiority RCT2717.5–25 mg/weekPASI 75 achieved by 80% of patients in adalimumab group, 36% in the MTX group and 19% in the placebo group
Akhyani et al.[87] Open-label trial of MMF vs. MTX187.5–25 mg/weekNo significant differences in efficacy between the MTX and MMF groups
Reich et al.[88] Noninferiority RCT of adalimumab with MTX and placebo2707.5–25 mg/weekWith four times as many AE-free response days, adalimumab demonstrated a superior risk–benefit profile
Ho et al.[89] RCT to compare MTX with TCM6115 mg/weekMTX significantly better than TCM
Fallah et al.[90] RCT to compare MTX with fumarates6015 mg/weekNo significant differences in efficacy between MTX and fumaric acid groups
Barker et al.[91] Open-label RCT to compare infliximab with MTX86815–20 mg/weekInfliximab significantly better than MTX
Radmanesh et al.[36] RCT to compare MTX daily vs weekly dose2022.5 mg/day for 6 days/week or 15 mg/weekSignificantly better efficacy with weekly MTX, with fewer side- effects
Reich et al.[92] RCT to compare MTX with briakinumab3175–25 mg/weekBriakinumab significantly better than MTX
Table 4. Efficacy of methotrexate (MTX) in combination with other topical therapies and conventional systemic therapies in moderate to severe psoriasis
ReferencesStudy designPatients, n Dose of MTXResults
  1. AE, adverse effect; NBUVB, narrowband UVB; PsA, psoriatic arthritis; PUVA, psoralen ultraviolet A; RCT, randomized controlled trial; RDBPCT, randomized double-blind placebo-controlled trial; UV, ultraviolet.

Morrison et al.[93] Open-label study to assess effectiveness of MTX/PUVA combination3015 mg/week for 3 weeks, followed by MTX/PUVAClearance seen in 28/30 patients in 5.7 weeks, with 9.3 exposures to PUVA therapy
Paul et al.[94] Open-label study to assess efficacy of MTX/UVB combination2615 mg/week for 3 weeks followed by MTX/UVBThe combination of MTX and UVB allowed for clearing of psoriasis at relatively low doses of UVB and MTX
Clark et al.[95] Retrospective study to assess efficacy of MTX/ciclosporin combination in psoriasis1915 mg/weekCombination significantly better than monotherapy
de Jong et al.[96] RDBPCT comparing MTX with MTX/calcipotriol combination 15 mg/weekCombination was safe, effective and lowered cumulative dosage of MTX
Shehzad et al.[97] Open-label study comparing PUVA monotherapy vs. MTX monotherapy vs. MTX/PUVA combination6015 mg/weekClearance achieved in PUVA at 5.5 weeks, MTX at 8 weeks, PUVA/MTX at 2.5 weeks
Fraser et al.[98] RDBPCT to assess effectiveness of MTX/ciclosporin combination in PsA7215 mg/weekCombination significantly improved the signs of inflammation but not pain or quality of life.
Asawanonda[99] RCT to assess effectiveness of MTX/NB-UVB combination vs. NB-UVB2415 mg/week for 3 week followed by MTX/NB-UVBMTX pretreatment allowed clearance of psoriasis in fewer phototherapy sessions than when administered alone
Ayedin et al.[100] Prospective open-label study to assess efficacy of MTX/ciclosporin combination2010 mg/weekCombination significantly better than monotherapy
Lowenthal et al.[101] Retrospective data analysis to assess effectiveness of MTX/acitretin combination187.5–15 mg/weekWell tolerated and often effective; no new AEs
Mahajan et al.[34] RCT to assess effectiveness of MTX/NB-UVB combination vs. NB-UVB400.5 mg/kg/weekMTX/NB-UVB combination significantly better than NB-UVB alone
Table 5. Efficacy of methotrexate in combination with biologicals in moderate to severe psoriasis
ReferencesStudy designPatients, n Dose of MTXResults
  1. ACR, American College of Rheumatology; PsA, psoriatic arthritis; PASI, Psoriasis Area and Severity Index; RCT, randomized controlled trial; RDBPCT, randomized double-blind placebo-controlled trial.

Mease et al.[102] RDBPCT to assess effectiveness of MTX/alefacept combination with MTX in PsA18515 mg/weekAlefacept in combination with MTX may be an effective and safe treatment for PsA
Zachariae et al.[103] RCT to assess efficacy of MTX/etanercept combination vs. etanercept in psoriasis5915 mg/weekAddition of etanercept to MTX achieved significant improvement in psoriasis after 24 weeks
Yamauchi et al.[104] Open-label case series to assess effectiveness of MTX/etanercept combination in psoriasis615 mg/weekEtanercept therapy allowed tapering of MTX and sustained clinical responses in moderate to severe psoriasis
Drissen et al.[105] Retrospective study to assess effectiveness of MTX/etanercept combination in psoriasis1415 mg/weekAddition of MTX to etanercept improved its efficacy
Mease et al.[106] Open-label extension trial to assess effectiveness of MTX/alefacept combination with MTX in psoriasis16015 mg/week86 of 160 patients (54%)s achieved ACR 20, while 32% and 12%, respectively, achieved ACR 50 and ACR 70
Gottlieb et al.[107] RCT to assess effectiveness of MTX/etanercept combination vs. placebo and etanercept in psoriasis4787.5–15 mg/weekPASI 75 at week 24–77.3% with combination vs. 60.3% with monotherapy (P > 0.0001)

In a retrospective study by van Dooren-Greebe et al.,[81] 113 patients with severe psoriasis were treated with low-dose MTX over 22 years. The treatment resulted in prolonged clearance or near clearance in 81% of the patients, while 73% of the patients had side-effects, most frequently abnormal liver function tests, nausea and gastric symptoms. The maximum weekly dosage was 15 mg (Weinstein schedule), with the mean cumulative dose being 4.803 g. In another retrospective study, Kumar et al.[32] reviewed the data on 244 patients with psoriasis who were given once-weekly oral MTX at the full therapeutic dose (0.3–0.5 mg/kg/week) during the period 1981–2000. An improvement of > 75% occurred in 88% of patients in 8.5 ± 5.1 weeks, and only three patients had significantly abnormal liver-function tests. Liver biopsies were taken before (34 biopsies) and after (13 biopsies) MTX therapy, which showed grade I/II changes that were nonprogressive. These studies confirm the effectiveness of MTX monotherapy in moderate to severe psoriasis.

Comparing MTX with other therapies such as ciclosporin has shown conflicting results. Sandhu et al.[33] found MTX to provide a faster relief than ciclosporin, whereas Haydendial et al.[83] did not find any significant difference between the two agents. In a recent randomized controlled study comparing both of these agents, ciclosporin was found to be significantly more effective than MTX in treating psoriasis.[85]

With the increasing use of biological response modifiers in psoriasis and PsA, there is a need for comparisons of these agents with MTX. The CHAMPION trial [Comparative Study of Humira (Adalimumab) with Methotrexate with Placebo in Patients with Psoriasis])[86] can be considered a landmark study, as it evaluated the efficacy and safety of MTX versus a biological drug. At the end of the 16-week treatment period, PASI 75 was achieved by 80% patients in the adalimumab group, 36% patients in the MTX group and 19% patients in the placebo group, while PASI 100 was achieved by 17% patients receiving adalimumab, 7% patients receiving MTX and 2% patients receiving placebo. It was concluded that adalimumab showed superior efficacy compared with MTX and placebo. In the subanalysis of the CHAMPION trial, it was seen that PASI 75 was achieved by 70% patients who were early responders to MTX (i.e. those who achieved PASI 50 at week 8) and by 41% patients who were late responders to MTX (i.e. who achieved PASI 50 at week 12). Less than 5% of patients who were late nonresponders achieved PASI 75.[88] Hence, patients who do not respond to MTX by week 12 may be considered for alternative therapy. In another recent trial comparing subcutaneous briakinumab (a monoclonal antibody against the p40 molecule) and oral MTX, the former was found to be significantly superior to MTX in terms of efficacy, although the risk of infection and malignancy was also slightly higher.[90]

If the trials comparing biologicals and MTX are critically analysed, it is apparent that in all these trials, MTX was initially started at the lower dose, which was increased to a maximum of 15–25 mg/week only when there was an unsatisfactory response. Because the efficacy of MTX may be dose-dependent,[31] the low initial dose of MTX may be responsible for the relatively lower number of patients achieving PASI 75 at week 12. In Indian trials, MTX has shown excellent efficacy and faster response with few side-effects when given at a dose of 0.3–0.5 mg/kg/week, hence, a comparison of the biological therapies with the full therapeutic dose of MTX given from the outset may be warranted. Moreover, MTX is more cost-effective than biological therapies, which makes it a more favourable option, particularly in developing countries. Staidle et al.[108] reported MTX to be the cheapest of all the therapies studied for patients who achieved PASI 75.

MTX has also been used in combination with photochemotherapy and phototherapy, with encouraging results.[34, 92, 93, 96, 98] This combination leads to significant reduction in the dose and number of exposures to phototherapy, although a theoretical risk of increased carcinogenicity remains, hence, caution should be exercised when using this combination. Similarly, MTX has been successfully combined with ciclosporin, actretin and topical calcipotriol. Although MTX has been successfully combined with acitretin in managing psoriasis, such a combination is not routinely recommended because of the increased risk of liver toxicity.[101] If it is used, the dose of both MTX and acitretin should be reduced, and monitoring of liver functions should be more frequent. Similarly, MTX should not be combined with hydroxyurea, as both lead to myelosuppression. Yamauchi et al.[104] reported that addition of etanercept for six patients allowed the gradual cessation of MTX while maintaining the clinical results. Addition of MTX to etanercept therapy has now been shown to be significantly better than etanercept monotherapy.[107] This is not only because of their combined antipsoriatic effect, but also because MTX inhibits the formation of antibodies against etanercept.

Methotrexate in childhood psoriasis and in elderly patients

MTX has been used with good efficacy for extremes of ages, both in the paediatric and geriatric population. However, both populations pose special challenges.

The absorption and distribution of MTX are unchanged in elderly patients, but metabolism is decreased because of loss of liver mass, and renal clearance is prolonged due to reductions in renal mass, renal blood flow.[109] Overall toxicity, incidence and severity is not increased, but gastrointestinal, hepatic and haematological AEs are more common, especially in patients aged > 65 years.

MTX is considered an effective treatment option in moderate to severe childhood psoriasis, and meticulous use of MTX may prevent long-term or serious side-effects. The tolerability and efficacy of MTX in the treatment of childhood psoriasis has been documented in a few case series (Table 6). Kumar et al.[110] first reported the successful use of MTX in seven children (aged 3–16 years) with severe disease, and did not find any significant side-effects or biochemical and haematological alterations. Most of the studies have used MTX at a dose of 0.2–0.4 mg/kg/week. Dogra et al.[111] documented an excellent therapeutic outcome in a 2-year-old child with generalized pustular psoriasis. In a study of 24 children with severe psoriasis from India, response to treatment with oral MTX was excellent (> 75% decrease in PASI) in all but 2 patients. The mean time to control the disease, (i.e. to achieve PASI 50) was 5.1 weeks. Side-effects seen in nine children were mild, and included nausea, vomiting and loss of appetite.[112] Collin et al. reported 13 children with severe plaque-type psoriasis treated with low-dose (0.03–0.24 mg/kg, increased to 0.1–0.41 mg/kg) oral MTX once weekly; 11 responded, resulting in clearance of psoriasis, leaving small residual plaques. MTX was well tolerated except for abnormal liver-function tests in two patients.[113]

Table 6. Use of methotrexate in childhood psoriasis
ReferencesStudy designNo. of Patients, nDose of MTXResults
Kumar et al.[110]Open-label study 73.75–25 mg/weekMore than 75% clearance of lesions was seen in all patients in mean of 7.9 weeks
Kaur et al.[112]Open-label study240.2–0.4 mg/kg/weekPASI 75 achieved in 22/24 patients. PASI 50 achieved in a mean time of 5.1 weeks
Collin et al.[113]Open-label study130.03–0.41 mg/kg/weekClearance with minimal residual disease was achieved in 11/13 patients

Another area of ambiguity is the continuation of MTX during the perioperative period. The currently available data do not suggest a need to discontinue MTX because of surgery, and there is some evidence that treatment with MTX is safe before and after elective surgical procedures.[113] CH-1504, a new metabolically stable antifolate that lacks the toxic effects of MTX, has shown encouraging results in the treatment of rheumatoid arthritis in open-label studies.[115] Further investigations into the use of this agent in psoriasis may lead to a decrease in the incidence of AEs associated with antifolate chemotherapies, while maintaining the benefits.

Conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Literature search
  5. Methotrexate
  6. Conclusion
  7. References
  8. CPD questions
  9. Instructions for answering questions

MTX has been the standard treatment for treating moderate to severe psoriasis for over five decades. That it is efficacious in psoriasis is beyond doubt, and it is important to recognize that MTX will continue to be the mainstay of treatment for psoriasis in the present century, especially in developing countries, because of its cost-effectiveness. However, in view of the emerging therapeutic options, including biological therapies, the way forward is to combine the use of MTX with these newer therapies, thus improving the efficacy of the treatment.

Learning points

  • MTX has been the standard systemic therapy for psoriasis for over five decades, and is still considered the gold standard, even with the advent of biological drugs.
  • MTX is a very effective treatment for psoriasis vulgaris and other clinical forms of psoriasis when used at an adequate dose.
  • Its safety has been proven over decades of use, and monitoring is now improved by the development of newer non-invasive tests.
  • MTX is likely to remain a useful adjunctive therapy to newer treatment options such as biological drugs.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Literature search
  5. Methotrexate
  6. Conclusion
  7. References
  8. CPD questions
  9. Instructions for answering questions

CPD questions

  1. Top of page
  2. Summary
  3. Introduction
  4. Literature search
  5. Methotrexate
  6. Conclusion
  7. References
  8. CPD questions
  9. Instructions for answering questions

Learning objectives

To demonstrate current knowledge of the mechanism of action of methotrexate (MTX) in psoriasis, its indications and contraindications, important drug interactions/combinations, its adverse effects and how to monitor them while prescribing MTX.

Question 1

All the following are indications for starting methotrexate therapy in psoriasis except:

  1. Extensive psoriasis with Psoriasis Area and Severity Index (PASI) of > 10.
  2. Psoriatic erythroderma.
  3. Impetigo herpetiformis.
  4. The Von Zumbusch variant of pustular psoriasis.
  5. Psoriasis vulgaris with severe psoriatic arthritis.

Question 2

In which of the following situations is treatment with methotrexate not contraindicated?

  1. Concomitant human immunodeficiency virus infection.
  2. End-stage renal disease.
  3. Pregnancy.
  4. History of noncompliance.
  5. History of basal cell carcinoma.

Question 3

Methotrexate acts through all of the following mechanisms except:

  1. Inhibition of dihydrofolate reductase.
  2. Inhibition of thymidylate synthase.
  3. Inhibition of 5-aminoimidazole-4 carboxamide ribonucleotide (AICAR) transformylase.
  4. Reduction in the levels of peroxisome proliferator-activated receptor (PPAR)β/δ levels.
  5. Upregulation of interleukin-22 levels.

Question 4

Which of the following drugs is likely to produce a marked increase the incidence of hepatotoxic adverse effects when combined with methotrexate?

  1. Tumour necrosis factor-α antagonists.
  2. Ciclosporin.
  3. Hydroxyurea.
  4. Acitretin.
  5. Phototherapy.

Question 5

Which of the following is a promising non-invasive investigation for assessing liver fibrosis?

  1. Fibroscan.
  2. Fibrotests.
  3. Liver biopsy.
  4. Ultrasonography.
  5. Dynamic hepatic scintigraphy.

Instructions for answering questions

  1. Top of page
  2. Summary
  3. Introduction
  4. Literature search
  5. Methotrexate
  6. Conclusion
  7. References
  8. CPD questions
  9. Instructions for answering questions

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  • Read the article in print or online, paying particular attention to the learning points and any author conflict of interest disclosures
  • Reflect on the article
  • Register or login online at http://www.wileyhealthlearning.com/ced and answer the CPD questions
  • Complete the required evaluation component of the activity

Once the test is passed, you will receive a certificate and the learning activity can be added to your RCP CPD diary as a self-certified entry.