1Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX USA
2Department of Dermatology, The University of Texas Medical Branch at Galveston, Galveston, TX USA
Methotrexate has been used for over half a century to treat a wide spectrum of skin conditions. It is a valuable steroid sparing agent, preventing protracted steroid courses and their undesirable side effects. While many alternative therapies exist and continue to emerge to treat these dermatologic conditions, the long history, affordability, and relative safety associated with methotrexate ensure its enduring utility. Further, ongoing research focusing on the pharmacogenetic properties of the drug may allow for more effective and targeted therapeutic strategies.
amethopterin, methotrexate, MTX, skin disease
Dermatologists have employed the antineoplastic agent methotrexate (MTX, amethopterin) for over 6 decades to treat a variety of skin conditions (Table 1), most prominently psoriasis. MTX is often used as a steroid sparing agent in dermatologic patients requiring prolonged steroid courses. The long history of use chronicled in the literature elucidates MTX’s efficacy, toxicity and relative safety, and portends to its ongoing utility. Recently, there has been a trend towards biologic therapy for several dermatologic conditions, placing the future of MTX treatment in jeopardy. However, MTX is significantly less expensive and novel studies in pharmacogenomics may allow a more personalized approach to its use. The following is a general review of MTX, focusing on its application in dermatologic diseases.
|Table 1. Dermatologic conditions treated with methotrexate|
MTX is a folic acid analogue that irreversibly binds to dihydrofolate reductase (DHFR), inhibiting the formation of reduced folates, which are essential cofactors for many enzymes. Consequently, the amounts of available purines, thymidylic acid, methionine, and serine decrease, ultimately impairing DNA, RNA, and protein synthesis.1-4 The maximum cytoxic effects are S-phase specific.1-3
The anti-inflammatory properties of MTX are likely explained by intracellular accumulation of AICAR, 5-amino-1-β-Dribofuranosyl- imidazole-4-carboxamide (from MTX inhibition of aminoimidazole-carboxamide ribonucleoside transformylase), which leads to increased extracellular and intracellular adenosine. This inhibits neutrophil chemotaxis and adherence, superoxide anion formation, and secretion of proinflammatory cytokines. Furthermore, MTX becomes polyglutamated intracellularly, favoring retention secondary to the increased negative charge. These active metabolites are much longer acting than the parent drug.1-4
MTX has multiple drug interactions; therefore, prior to initiating therapy, a thorough review of the patient’s medications is essential. For instance, MTX binds albumin and is excreted primarily by the kidney. Thus, medications that displace MTX from albumin (i.e., acetylsalicylic acid, barbiturates, sulfonamides, tetracylines, and sulfonylureas) or interfere with its renal secretion and clearance (i.e., probenacid, penicillin, and nonsteroidal anti-inflammatory drugs) may result in toxicity. Other drugs that enhance the antifolate effect like trimethoprimsulfamethoxazole and sulfonamides increase bone marrow toxicity and are contraindicated during MTX therapy.1,2,4,5
The most commonly reported side effects are mild and include gastrointestinal complaints, such as nausea, vomiting, and diarrhea. Hematologic complications are the major cause of death with therapy, and manifest as anemia, leukopenia, thrombocytopenia, or pancytopenia. Renal insufficiency, increased mean corpuscular volume, age, and drug interactions are risks. Hepatotoxicity is also a concern so the drug should be avoided in current or previous liver disease. Patients should be counseled to avoid alcohol and have routine monitoring of liver function.1,2,4 Monitoring for liver toxicity is discussed below. The drug predisposes patients to opportunistic infections as it is immunosuppressive. Idiosyncratic pneumonitis is a rare but dangerous complication. Dermatologic effects have been reported, including alopecia and toxic epidermal necrolysis (TEN). In psoriatics, a combination of long-term ultraviolet light therapy and MTX increases their squamous carcinoma risk.1,2,4 At high doses the drug can precipitate in the renal tubules causing damage. Adequate hydration and alkalinization of the urine help prevent this adverse effect.
Folic acid supplementation can reduce complications and folinic acid (leucovorin) can be used for rescue if significant pancytopenia occurs, since it bypasses the inhibited DHFR.1,2,4 Dose dividing (i.e., one-third of the dose given 12 hours apart) or parenteral or intramuscular administration are other options for managing side effects.2,4
MTX is a potent teratogen and abortifacient; thus, it is contraindicated in pregnancy. In general, women and men (MTX can lead to genetic aberrations in sperm) should avoid conception for at least 3 months after discontinuation of therapy and women should not breastfeed.1,2,4
Pre-methotrexate Screening and Monitoring
In general, the literature regarding pre-treatment screening and monitoring reflect the treatment protocol for psoriasis. Patients should be questioned about current medications and all contraindications to therapy (i.e., desire for pregnancy and current or past alcohol abuse). Initial laboratory testing should include a CBC with differential, renal function tests (BUN, creatinine), unrinalysis, liver function tests (LFT) (e.g., AST, ALT, alkaline phosphatase, bilirubin, and albumin), hepatitis serology (HBV and HCV), and HIV, TB, and pregnancy tests in at risk individuals.2,4 The patient’s blood counts and liver and renal function tests should be monitored throughout treatment. Initially done weekly and then with dose changes, the interval between blood tests can increase once the therapy has stabilized.1,2,4
Regarding liver fibrosis screening, various guidelines are available.6-10 Recently, Paul et al. compiled the available evidence and garnered expert opinion, publishing optimal dosing recommendations, conditions predisposing to hepatic fibrosis, and guidelines for screening for development of hepatic fibrosis in Europe.9 Additionally, Menter et al. have standardized guidelines for physicians in the United States. These include a liver biopsy typically performed after a cumulative dose of 3.5-4 g, with subsequent biopsies after each additional administration of 1-1.5 g. If risk factors including personal or family history of liver disease, excessive alcohol consumption, obesity, diabetes, or abnormal LFTs are present, then a baseline biopsy may be indicated.10 A serum assay for PIIINP (type III procollagen N-terminal peptide, a marker of fibrosis) reduces the need for liver biopsies.1,2,4,8,9,11 Though currently not widely offered, it should be used where available. Overall, the monitoring route a physician chooses to follow should be based on the condition treated, anticipated therapy duration, and availability of the tests.
The dose of MTX must be individualized. It is available in 2.5 mg tablets and 12.5 or 25 mg/mL solutions. Although it is typically given orally, it can be administered subcutaneously (SC), intramuscularly (IM), or intravenously (IV) to avoid gastrointestinal upset. A small test dose (2.5-5 mg) is advisable to screen for patients who may be hypersensitive. If blood work is stable after 1 week, subsequent doses may be incrementally increased (usually by 2.5-7.5 mg) with the ultimate goal of controlling disease at the lowest dose feasible. Typically, dermatologic conditions require 7.5-20 mg weekly. In certain populations, such as the elderly, 2.5 mg may be adequate. Others may require up to 30 mg or more. Daily folic acid supplementation of 1-5 mg is standard but still debatable.1,2,11
Psoriasis and Palmoplantar Pustulosis
The most frequent use for MTX worldwide is psoriasis, a common, chronic, recurring inflammatory disease with a strong genetic component.1 MTX is widely used for psoriatic erythroderma, psoriatic arthritis, acute pustular psoriasis, and extensive plaque psoriasis.4,12 Because the condition is lifelong, physicians must consider treatment cost. Although monitoring associated with MTX is expensive, the drug itself is affordable. In addition, cost analysis studies suggest MTX is overall more cost-effective than biologics.13 One retrospective study revealed 81% of 113 patients treated with MTX (maximum 15 mg/week) achieved prolonged improvement (mean duration of therapy was 8 years and 11 months), though 73% experienced side effects, which necessitated discontinuation in 29%.14 A similar review demonstrated only 6% of 157 patients exhibited a poor response to oral or IV MTX (7.5- 40 mg/week), while 94% showed moderate to good benefit with a mean treatment duration of 237 weeks. A total of 61% of patients experienced side effects, with 20% discontinuing therapy.15
Palmoplantar pustulosis is characterized by recurrent pruritic and painful sterile pustules, crusts, erythema, and scaling of volar surfaces. Only 8 of 25 patients improved with oral MTX (25 mg/ week) for 2 months, but in responders the onset of effect was evident within 2 weeks.16
Pityriasis Rubra Pilaris (PRP)
PRP is a rare papulosquamous eruption, classically presenting suddenly in adults with craniocaudally progressing small circumscribed follicular keratoses with accompanying palmoplantar keratoderma. The keratoses may evolve into salmon-colored, scaling plaques with characteristic islands of sparing. Erythroderma may develop. PRP is associated with infection (especially HIV), malignancy, and rheumatologic conditions.17-20 An early study demonstrated only 17 of 42 patients responded to MTX.18 Another report recognized that adding MTX (5-30 mg/week) to oral retinoids over 16 weeks increased the response by over 50% in 8 of 11 patients, but the combination may lead to increased hepatotoxicity.19 Furthermore, a review by Dicken of 8 patients described benefits from low dose MTX (10-25 mg/week) for 6 months.20
This systemic granulomatous disease affects a multitude of organ systems including the skin. Highest prevalence is found amongst African American women in their third to fourth decade. In an open study, skin lesions cleared in 12 of 16 patients treated with oral MTX (25 mg/week).21 In a retrospective analysis of 50 patients who completed at least 2 years of oral MTX (average 10 mg/week), 16 of 17 patients with cutaneous involvement responded favorably.22 While it may take up to 6 months to be effective, MTX has successfully demonstrated steroid sparing properties and may be particularly useful in treating the cutaneous manifestations of sarcoidosis.21-23
DM is an autoimmune disease manifesting as proximal muscle weakness from an inflammatory myositis with elevated creatine kinase and skin disease characterized by a heliotrope rash, shawl sign, Gottron’s papules, and mechanic’s hands. Patients also exhibit systemic signs such as fever, malaise, and weight loss. DM is more common in women and is associated with underlying malignancy in adults.24-26 A retrospective study of cutaneous responses in steroid resistant DM concluded 8 of 11 (73%) patients exhibited significant improvement in skin lesions with SC MTX (5-25 mg/week). Interestingly, the nonresponders had less inflammation on histology, indicating inhibition of lymphocyte migration might be a primary mechanism of utility in DM.25 Another study of 13 patients demonstrated complete to moderate clearing of cutaneous manifestations with oral MTX (2.5-30 mg/week). All patients were able to either discontinue or reduce their steroid dose.26
Cutaneous Lupus Erythematosus (CLE)
Lupus erythematosus is an autoimmune inflammatory condition characterized by a host of autoantibodies that may target any organ system. The skin is frequently involved and manifestations range from the classic malar rash to papular or urticarial type lesions. Scarring results in the chronic discoid form. A retrospective study cited improvement in 42 of 43 CLE patients (98%) treated with IV or oral MTX (7.5-25 mg/week) for 2-67 months.27
Bullous pemphigoid (BP) typically afflicts the elderly and is characterized by large, tense, subepidermal bullae with a predilection for the axillae, trunk, flexor forearms, thighs, and groin, leaving large denuded areas after rupture. The pathophysiology is related to anti-hemidesmosomal immunoglobulin G (IgG) antibodies, which result in dermoepidermal junction separation, complement factor C3 deposition, and an associated inflammatory infiltrate rich in eosinophils.28-31 A retrospective study showed 8 of 34 patients resistant to traditional therapy improved with the addition of oral MTX (average 5-10 mg/week) for 1 month, allowing a reduction in steroid dose.29 In addition, a prospective study of oral MTX (5-12.5 mg/week) in 11 geriatric patients who failed to respond to potent topical steroids demonstrated decreased disease activity after less than a month.30 Additionally, a prospective study of 18 patients utilized whole-body clobetasol for 2-3 weeks combined with oral or IM MTX (7.5-10 mg/week) reported all subjects responded to the induction regimen. Remission with MTX monotherapy (7.5-12.5 mg/week) occurred in 17 of 18 (94%) patients, which eventually allowed a treatment hiatus (mean of almost 7 months) in 13 of the subjects.31 A likely underlying mechanism of MTX’s efficacy in BP is that it induces apoptosis of eosinophils.32
Mucous membrane pemphigoid is an autoimmune subepidermal bullous disease characterized by chronic inflammation that progresses to scarring. A retrospective review examined 17 patients with ocular cicatricial pemphigoid (OCP) and druginduced OCP, 14 of which were treated with oral MTX (5-25 mg/ week) as first-line therapy. After an average treatment duration of 15 months, MTX controlled or suppressed conjunctival inflammation in 15 of 17 patients, facilitating improved or preserved visual acuity.33
Linear IgA bullous dermatosis is an acquired autoimmune vesiculobullous disease targeting skin and mucous membranes. Groups of curved blisters and urticarial plaques are typical. The diagnosis hinges on IgA immunofluorescence in the basement membrane zone. One case highlights a female geriatric patient who failed treatments with dapsone, sulphapyridine, sulphamethoxypyridazine, azathioprine, colchicine, and prednisolone alone or in combination. She finally responded to MTX (7.5-10 mg/week) plus prednisolone, and the steroid dose was eventually quartered. The disease remained quiescent under this regimen for 18 months until drug-induced hepatitis required MTX discontinuation.34
Pemphigus is an autoimmune blistering disease that affects the skin (antidesmoglein 1 antibodies) as well as mucous membranes (antidesmoglein 3 antibodies). Conventionally, it is divided into three subtypes: vulgaris, foliaceus, and paraneoplastic.35-37 MTX’s efficacy was recognized early, but physicians avoided use for years because of associated toxicity. However, this observation is likely attributable to the high doses that were first used.35 One study reported MTX (25-50 mg/week) in combination with prednisone was effective in 42 of 53 patients.36 More recently, MTX (maximized at 10-17.5 mg/week) in 9 patients in combination with prednisone permitted discontinuation of steroids in 6 of 9 patients after 6 months. Disease flared within 7-55 days after stopping MTX.37
Benign familial chronic pemphigus, or Hailey-Hailey disease, is an autosomal dominant condition with recurring vesicles and erosions in flexural surfaces precipitated by inherent friction in these areas. One patient treated with IM MTX (15 mg/week) cleared after 1 month of therapy; however, the disease recurred within 2 months of MTX cessation.38
Cutaneous T-cell lymphoma, or mycosis fungoides (MF), is a rare malignant T lymphocyte proliferative disease that typically presents in older males and follows an indolent course. Treatment aims at controlling the symptoms and slowing progression. One retrospective study extols the use of oral, IM, or most commonly SC MTX (5-125 mg/week) in 29 patients with erythrodermic MF. Over 50% of patients achieved complete (41%) or partial (17%) response. Median response duration was 31 months and median survival was 8.4 years.39
Pityriasis lichenoides et varioliformis acuta (PLEVA), or Mucha- Habermann disease, presents as a sudden onset of erythematous macules, papules, and papulovesicles in children or young adults that appear in patches from a few to over 100 lesions. The course is variable, but spontaneous resolution can occur in as little as a few weeks. Six patients given oral MTX (7.5-20 mg/week) all experienced rapid clearance, but prompt recurrence was often seen upon discontinuation of therapy.40
Pityriasis lichenoides chronica (PLC) affects children and presents as multiple erythematous, scaly macules and flat papules with slow evolution that last months. The overall disease course is years as relapses are common. Three severe cases of PLC treated with oral or IM MTX (25 mg/week) quickly responded, but 2 patients relapsed upon discontinuation.41
Lymphomatoid papulosis (LyP) is a rare skin disorder that usually occurs in adults and presents with papulonecrotic or papulonodular lesions in various developmental stages on their trunk and extremities. Individual LyP lesions often self-heal within 3 months, but the total disease duration may last years. The disorder is associated with malignant cutaneous lymphomas, particularly MF, but has an excellent prognosis. Patients with multiple lesions or residual scarring may elect treatment with MTX. One review illustrated satisfactory long-term control in 39 of 45 patients with oral, IM, or SC MTX (10-60 mg/week with subsequent increases in administration intervals up to every 4 weeks). The authors proposed a protocol of establishing an effective 10-25 mg weekly dose with successive increases in the dosing interval to maintain control while minimizing untoward effects.42
Atopic dermatitis (AD), or eczema, is a common, chronic, and relapsing disease with worldwide prevalence. It is hallmarked by dry skin, excessive pruritus, and acute flares. The cause of AD is genetic and has been linked to epidermal barrier dysfunction from filaggrin mutations resulting in increased transepidermal water loss, secondary inflammation, and frequent skin infections.43,44 Physical exam reveals eczematous patches and plaques, and lichenification is common.44 In a 24 week trial, oral MTX (average of 15 mg/week) improved symptoms in 52% of 11 patients, with 8 of 9 subjects exhibiting lasting improvement 12 weeks after drug cessation.45 A retrospective study examining 20 patients revealed 75% experienced improvement at 3 months with oral MTX (7.5-25 mg/week).46 Another retrospective study concluded 16 of 20 subjects responded to oral or IM MTX (7.5-25 mg/ week) within 2 weeks to 3 months. The authors noted a 43.5% improvement in patients’ quality of life.47 An additional study reported 9 patients (100%) responded to oral MTX (10-20 mg/ week) within 3-7 weeks, with 6 subjects achieving full remission by 3 months.48 Additionally, in a case series involving 5 geriatric patients, oral MTX (5-10 mg/week) effectively controlled the disease in 80% of patients even after eventual dose reduction to 2.5 mg/week.49 While an abundance of therapeutic approaches are available, MTX is emerging as a viable systemic treatment option to induce and maintain remission.43-49
Pompholyx or dyshidrotic eczema is a pruritic, vesicular rash found on glabrous surfaces. In 5 patients with recalcitrant disease, oral MTX (12.5-22.5 mg/week) allowed dose reduction or elimination of oral steroids.50
In reviewing the literature, evidence of the benefits of MTX in other dermatologic disorders is often restricted to case reports or case series. The rarity of these diseases likely precludes more robust studies. However, a cursory review does reveal that MTX is often used alone or in conjunction with other standard therapies.
Behcet’s disease is a systemic vasculitis comprised of oral and genital aphthae, uveitis, arthritis, and various skin lesions. Two cases cleared with oral MTX (15-20 mg/week).51 Further, cutaneous polyarteritis nodosa typically presents as livedo reticularis with nodules and ulcerations of the lower extremities. All 3 patients in a case series benefited with oral MTX (5-20 mg/ week).51
Morphea, or localized scleroderma, is a connective tissue disease resulting in fibrotic reactions and cicatrization that can be disfiguring and disabling.52-53 Nine of 10 pediatric patients treated with oral or SC MTX (7.5-20 mg/week), in addition to corticosteroids in 8 of these individuals, responded within 2 to 13 months, with a median response time of 3 months.2 Additionally, 6 of 9 adults with widespread morphea in a 24-week prospective trial benefited from oral MTX (initial 15 mg/week, adjusted to 7.5-25 mg/week).53
Eosinophilic fasciitis, or Shulman’s syndrome, is characterized by a symmetric woody induration of the extremities, usually sparing the hands and feet, has been linked to vigorous exercise. One individual resistant to corticosteroids improved with the addition of IM MTX (15 mg/week), allowing a reduction in steroid therapy.54
Lichen myxedematous presents clinically as fleshy or erythematous papules and plaques that may appear shiny and usually affect the arms, face, and neck. In severe cases, the infiltration of the skin by mucin-producing fibroblasts may restrict movement such as opening of the mouth. Sclerodactyly, Raynaud’s phenomenom, and esophageal dysmotility may accompany the systemic form, scleromyxedema, mimicking systemic sclerosis. An associated serum IgG gammopathy with scleromyxedema often distinguishes these entities. When proximal muscle weakness is present, muscle biopsy specimens often display vacuolar change and lack the chronic inflammatory cell infiltrates observed in other myopathies like dermatomyositis and polymyositis. Two of 3 reported cases of scleromyxedema myopathy responded to IV MTX. The more recent case utilized MTX at an initial dose of 5 mg/week with incremental increases to 30 mg/week in combination with oral steroids.55
Lichen planus is an extraordinarily pruritic papulosquamous condition associated with hepatitis C and many drugs (e.g., thiazide diuretics, antimalarials, and phenothiazines). It can be erosive and painful when lesions affect the oral cavity. Ten of 18 patients with oral lichen planus achieved greater than 75% clearance after treatment with MTX (2.5-12.5 mg/week).56
Keratoacanthomas (KAs) are distinct neoplasms. Classified in the spectrum of squamous cell carcinomas, these tumors swiftly evolve into firm, dome-shaped, crateriform masses with the potential for spontaneous involution. In cases when excision is deemed imprudent, intralesional MTX can be effective.57,58 Following 1-2 injections of 5-37.5 mg MTX (total 5-50 mg), 9 patients with solitary KAs exhibited complete tumor clearance in 2-4 weeks without recurrence up to 6 years later.57 Another case series of 6 patients with solitary KAs demonstrated partial tumor regression within 10 days and complete resolution within 1.5-5.7 weeks of intralesional MTX (1-4 doses of 12.5-25 mg totaling 12.5-62.5 mg).58
Pyoderma gangrenosum (PG) presents as enlarging pustules that form ulcers with dusky, undermined borders. At least half of cases are associated with a systemic disorder and therapy aimed at the underlying disease tends to improve the PG. Overall, PG is a stubborn disease to treat, often demanding high dose systemic steroids. One patient’s disease was undetectable after 2 months of oral MTX (7.5-15 mg/week), allowing tapering of high dose prednisone. Of note, one relapse occurred in this patient that resolved with prednisone, but at a dose reduction of one-third than previously required to control the disease.59
Multicentric reticulohistiocystosis is rare and characterized by destructive, symmetric polyarthritis and slow-growing skincolored, tan, or erythematous papules and nodules with a predilection for the hands. The skin and synovia are infiltrated by histiocytes and multinucleated giant cells with an eosinophilic, ground glass cytoplasm. Oral MTX (15-20 mg/week) has benefited at least 3 individuals with this devastating condition.60
The clinical triad of conjunctivitis, nongonococcal urethritis, and oligoarthritis associated with human leukocyte antigen B27 (HLA-B27) is referred to as reactive arthritis, formerly Reiter syndrome. Circinate balanitis and keratoderma blennorrhagica are the classic dermatologic lesions. Eighteen of 20 patients experienced dramatic improvement in their skin lesions within 2 weeks of receiving oral or parenteral MTX (10-50 mg/week).61
Relapsing polychondritis is a rare, idiopathic, painful, and potentially fatal condition linked to HLA-DR4. Manifestations include recurrent inflammation of cartilage and other connective tissues affecting the eyes, inner ears, kidneys, nerves, heart, skin, and blood vessels. While corticosteroids are the mainstay of treatment, MTX (average 17.5 mg/week) reduced the steroid burden in 23 of 31 patients.62
Mycobacterium leprae affects the skin and peripheral nerves in Hansen’s disease (leprosy). Anesthetic hypopigmented macules and erythematous papules, nodules, or plaques are typical features of skin lesions. A spectrum of presentations exists (from tuberculoid to lepromatous) dictated by cell-mediated immunity. Additionally, immune-mediated leprosy reactions may occur at any time regardless of treatment stage.63-64 MTX (5-7.5 mg/week) allowed discontinuation of steroids after 2 months and resulted in marked improvement in the skin lesions within 6 months in a patient with a type I reaction (reversal reaction).63 Further, oral MTX (7.5-15 mg/week) permitted corticosteroid reduction in 1 patient with a type II reaction (erythema nodosum leprosum).64
The precise pharmacokinetic, pharmocodynamic, and pharmacogenetic properties of MTX are still being pursued with a particular emphasis on predicting efficacy and the potential for adverse responses. For instance, one study revealed rheumatoid arthritis patients with higher levels of glutamylation of MTX have better results,65 though a smaller study in psoriatics did not reproduce this finding.66
Multiple reports have investigated how genetic variations correlate with MTX’s therapeutic response and adverse outcomes.67-74 Some of these pharmacokinetic and hereditary differences may be quantifiable with simple urine or blood testing.65,75,76 While this evidence is preliminary, the associations established or refuted between therapeutic response and toxicity indicate a future where treatment may be individually directed.77 Perhaps one day a comprehensive genetic index will be developed to predict and maximize outcomes.
Methotrexate is an effective and relatively safe treatment for multiple dermatologic conditions. Though many alternative options exist and continue to emerge, the long history, affordability, and ongoing research are harbingers of its enduring therapeutic value. Also, with new biologic therapies, long-term safety data is currently lacking. Investigations focusing on the pharmacogenetic properties of methotrexate may allow for more effective and targeted therapeutic strategies.
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