Methotrexate: Role of Treatment in Skin Disease
Alex C. Holliday, MD1; Megan N. Moody, MD, MPH2; Alma Berlingeri-Ramos, MD2
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.
- Palmoplantar pustulosis
- Pityriasis rubra pilaris
- Cutaneous sarcoidosis
- Cutaneous lupus erythematosus
- Bullous pemphigoid
- Mucous membrane pemphigoid
- Linear IgA bullous dermatosis
- Hailey-Hailey disease
- Cutaneous T-cell lymphoma
- Pityriasis lichenoides et varioliformis acuta
- Pityriasis lichenoides chronica
- Lymphomatoid papulosis
- Atopic dermatitis
- Behcet's disease
- Cutaneous polyarteritis nodosa
- Eosinophilic fasciitis
- Lichen myxedematous
- Lichen planus
- Solitary keratoacanthoma
- Pyoderma gangrenosum
- Multicentric reticulohistiocystosis
- Reactive arthritis
- Relapsing polychondritis
- Leprosy reactions
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.
- Dutz JP, Ho VC. Immunosuppressive agents in dermatology: an update. Dermatol Clinic. 1998 Apr;16(2):235-50.
- Bangert CA, Costner MI. Methotrexate in dermatology. Dermatol Ther. 2007 Jul-Aug;20(4):216-28.
- Genestier L, Paillot R, Quemeneur L, et al. Mechanisms of action of methotrexate. Immunopharmacology. 2000 May;47(2-3):247-57.
- Boffa MJ, Chalmers RJG. Methotrexate for psoriasis. Clin Exp Dermatol. 1996 Nov;21(6):399-408.
- Andersen WK, Feingold DS. Adverse drug interactions clinically important for the dermatologist. Arch Dermatol. 1995 Apr;131(4):468-73.
- American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002 Feb;46(2):328-46.
- Roenigk HH Jr, Auerback R, Maibach H, et al. Methotrexate in psoriasis: consensus conference. J Am Acad Dermatol. 1998 Mar;38(3):478-85.
- Chalmers RJG, Kirby B, Smith A, et al. Replacement of routine liver biopsy by procollagen III aminopeptide for monitoring patients with psoriasis receiving long-term methotrexate therapy: a multi-center audit and routine and health economic analysis. Br J Dermatol. 2005 Mar;152(3):444-50.
- Paul C, Gallini A, Maza A, et al. Evidence-based recommendations on conventional systemic treatment in psoriasis: systemic review and expert opinion of a panel of dermatologists. J Eur Acad Dermatol Venereol. 2011 May;25(Suppl 2):2-11.
- Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009 Sep;61(3):451-85.
- Warren RB, Chalmers RJG, Griffiths CEM, et al. Methotrexate for psoriasis in the era of biological therapy. Clin Exp Dermatol. 2008 Aug;33(5):551-4.
- Ghaffar SA, Clements SE, Griffiths CEM. Modern management of psoriasis. Clin Med. 2005 Nov-Dec;5(6):564-8.
- Beyer V, Wolverton SE. Recent trends in systemic psoriasis treatment costs. Arch Dermatol. 2010 Jan;146(1):46-54.
- Van Dooren-Greebe RJ, Kuijpers AL, Mulder J, et al. Methotrexate revisited: effects of long-term treatment in psoriasis. Br J Dermatol. 1994 Feb;130(2): 204-10.
- Haustein UF, Rytter M. Methotrexate in psoriasis: 26 years' experience with low-dose long-term treatment. J Eur Acad Dermatol Venereol. 2000 Sep;14(5):382-8.
- Thomsen K. Pustulosis palmaris et plantaris treated with methotrexate. Acta Dermatol Venereol. 1971;51(5):397-400.
- Klein A, Landthaler M, Karrer S. Pityriasis rubra pilaris: a review of diagnosis and treatment. Am J Clin Dermatol. 2010;11(3):157-70.
- Griffiths WAD. Pityriasis rubra pilaris. Clin Exp Dermatol. 1980 Mar;5(1):105-12.
- Clayton BD, Jorizzo JL, Hichcock MG, et al. Adult pityriasis rubra piiaris: a 10-year case series. J Am Acad Dermatol. 1997 Jun;36(6 Pt 1):959-64.
- Dicken CH. Treatment of classic pityriasis rubra pilaris. J Am Acad Dermatol. 1994 Dec;31(6):997-9.
- Veien NK, Brodthagen H. Treatment of sarcoid with methotrexate. Br J Dermatol. 1977 Aug;97(2):213-6.
- Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med. 1995 Apr;155(8):846-51.
- Baughman RP, Lower EE. A clinical approach to the use of methotrexate for sarcoidosis. Thorax. 1999 Aug;54(8):742-6.
- Sato S, Kuwana M. Clinically amyopathic dermatomyositis. Curr Opin in Rheumatol. 2010 Nov;22(6):639-43.
- Hornung T, Ko A, Tuting T, et al. Efficacy of low-dose methotrexate in the treatment of dermatomyositis skin lesions. Clin Exp Dermatol. 2012 Mar;37(2):139-42.
- Kasteler JS, Callen JP. Low-dose methotrexate administered weekly is an effective corticosteroid-sparing agent for the treatment of the cutaneous manifestations of dermatomyositis. J Am Acad Dermatol. 1997 Jan;36(1): 67-71.
- Wenzel J, Brähler S, Bauer R, et al. Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients. Br J Dermatol. 2005 Jul;153(1):157-62.
- Korman NJ. Bullous pemphigoid. Dermatol Clin. 1993 Jul;11(3):483-98.
- Paul MA, Jorizzo JL, Fleischer AJ, et al. Low-dose methotrexate treatment in elderly patients with bullous pemphigoid. J Am Acad Dermatol. 1994 Oct;31(4):620-5.
- Heilborn JD, Ståhle-Bäckdahl M, Albertioni F, et al. Low-dose oral pulse methotrexate as monotherapy in elderly patients with bullous pemphigoid. J Am Acad Dermatol. 1999 May;40(5 Pt 1):741-9.
- Dereure O, Bessis D, Guillot B, et al. Treatment of bullous pemphigoid by low-dose methotrexate associated with short-term potent topical steroids: an open prospective study of 18 cases. Arch Dermatol. 2002 Sep;138(9):1255-6.
- Dahlman-Ghozlan K, Ortonne JP, Bahadoran P, et al. Low-dose oral methotrexate induces apoptosis of tissue eosinophils in bullous pemphigoid. Acta Derm Venereol. 2008;88(3):219-22.
- McCluskey P, Chang JH, Singh R, et al. Methotrexate therapy for ocular cicatricial pemphigoid. Opthalmology. 2004 Apr;111(4):796-801.
- Burrows NP, Jones RR. Methotrexate and cyclosporine are of value in the treatment of adult linear IgA disease. J Dermatol Treat. 1992 Jan;3(1):31-3.
- Lever WF, Goldberg HS. Treatment of pemphigus vulgaris with methotrexate. Arch Dermatol. 1969 Jul;100(1):70-8.
- Mashkilleyson N, Mashkilleyson AL. Mucous membrane manifestations of pemphigus vulgaris. A 25-year survey of 185 patients treated with corticosteroids or with combination of corticosteroids with methotrexate or heparin. Acta Derm Venereol. 1988;68(5):413-21.
- Smith TJ, Bystryn JC. Methotrexate as an adjuvant treatment for pemphigus vulgaris. Arch Dermatol. 1999 Oct;135(10):1275-6.
- Fairris GM, White JE, Leppard BJ, et al. Methotrexate for intractable benign familial chronic pemphigus. Br J Dermatol. 1986 Nov;115(5):640.
- Zackheim HS, Kashani-Sabet M, Hwang ST. Low dose methotrexate to treat erythrodermic cutaneous T cell lymphoma: Results in twenty-nine patients. J Am Acad Dermatol. 1996 Apr;34(4):626-31.
- Cornelison RL, Knox JM, Everett MA. Methotrexate for the treatment of Mucha-Habermann disease. Arch Dermatol. 1972 Oct;106(4):507-8.
- Lynch PJ, Saied NK. Methotrexate treatment of pityriasis lichenoides and lymphomatoid papulosis. Cutis. 1979 May;23(5):634-6.
- Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective therapy for lymphomatoid papulosis and other primary cutaneous CD30-positive lymphoproliferative disorders. J Am Acad Dermatol. 1996 Mar;34(3):470-81.
- Walling HW, Swick BL. Update on the management of chronic eczema: new approaches and emerging treatment options. Clin Cosmet Invest Dermatol. 2010 Jul;28(3):99-117.
- Deleuran MS, Vestergaard C. Therapy of severe atopic dermatitis in adults. J Dtsch Dermatol Ges. 2012 Jun;10(6):399-406.
- Weatherhead S, Wahie S, Reynolds N, et al. An open-label, dose-ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol. 2007 Feb;156(2):346-51.
- Goujon C, Bérard F, Dahel K, et al. Methotrexate for the treatment of adult atopic dermatitis. Eur J Dermatol. 2006 Mar-Apr;16(2):155-8.
- Lyakhovitsky A, Barzilai A, Heyman R, et al. Low-dose methotrexate treatment for moderate-to-severe atopic dermatitis in adults. J Eur Acad Dermatol Venereol. 2010 Jan;24(1):43-9.
- Zoller L, Ramon M, Bergman R. Low dose methotrexate therapy is effective in late-onset atopic dermatitis and idiopathic eczema. Isr Med Assoc J. 2008 Jun;10(6):413-4.
- Shaffrali FC, Colver GB, Messenger AG, et al. Experience with low-dose methotrexate for the treatment of eczema in the elderly. J Am Acad Dermatol. 2003 Mar;48(3):417-9.
- Egan CA, Rallis TM, Meadows KP, et al. Low-dose oral methotrexate treatment for recalcitrant palmoplantar pompholyx. J Am Acad Dermatol. 1999 Apr;40(4):612-14.
- Jorizzo JL, White WL, Wise CM, et al. Low-dose weekly methotrexate for unusual neutrophilic vascular reactions: cutaneous polyarteritis nodosa and Behcet's disease. J Am Acad Dermatol. 1991 Jun;24(6 Pt 1):973-8.
- Uziel Y, Feldman BM, Krafchik BR, et al. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr. 2000 Jan;136(1):91-5.
- Seyger MMB, van der Hoogen FHJ, de Boo T, et al. Low-dose methotrexate in the treatment of widespread morphea. J Am Acad Dermatol. 1998 Aug; 39(2 Pt 1):220-5.
- Pouplin S, Daragon A, Le LX. Treatment of eosinophilic fasciitis with methotrexate. J Rheumatol. 1998 Mar;25(3):606-7.
- Helfrich DJ, Walker ER, Martinez AJ, et al. Scleromyxedema myopathy: case report and review of the literature. Arthritis Rheum. 1988 Nov;31(11):1437-41.
- Torti DC, Jorizzo JL, McCarty MA. Oral lichen planus: a case series with emphasis on therapy. Arch Dermatol. 2007 Apr;143(4):511-15.
- Melton JL, Nelson BR, Stough DB, et al. Treatment of keratoacanthomas with intralesional methotrexate. J Am Acad Dermatol. 1991 Dec;25(6 Pt 1):1017-23.
- Cuesta-Romero C, de-Grado-Pena J. Intralesional methotrexate in solitary kertatoacanthoma. Arch Dermatol. 1998 Apr;134(4):513-4.
- Teitel AD: Treatment of pyoderma gangrenosum with methotrexate. Cutis. 1996 May;57(5):326-8.
- Franck N, Amor B, Ayral X, et al: Multicentric reticulohistiocytosis and methotrexate. J Am Acad Dermatol. 1995 Sep;33(3):524-5.
- Lally EV, Ho G Jr. A review of methotrexate therapy in Reiter syndrome. Semin Arthritis Rheum. 1985 Nov;15(2):139-45.
- Trentham DF, Le CH. Relapsing polychondritis. Ann Intern Med. 1998 Jul;129(2):114-22.
- Biosca G, Casallo S, López-Vélez R. Methotrexate treatment for type 1 (reversal) leprosy reactions. Clin Infect Dis. 2007 Jul;45(1):e7-9.
- Kar BR, Babu R. Methotrexate in resistant ENL. Int J Leprosy. 2004 Dec;72(4):480-2.
- Dervieux T, Lein DO, Marcelletti J. HPLC Determination of erythrocyte methotrexate polyglutamates after low-dose methotrexate therapy in patients with rheumatoid arthritis. Clin Chem. 2003 Oct;49(10):1632-41.
- Hroch M, Chladek J, Simkova M. A pilot study of pharmacokinetically guided dosing of oral methotrexate in the initial phase of psoriasis treatment. J Eur Acad Dermatol Venereol. 2008 Jan;22(1):19-24.
- Warren R, Griffiths C. The potential of pharmacogenetics in optimizing the use of methotrexate for psoriasis. Br J Dermatol. 2005 Nov;153(5):869-73.
- Weisman M, Furst D, Park G, et al. Risk genotypes in folate-dependent enzymes and their association with methotrexate-related side effects in rheumatoid arthritis. Arthritis Rheum. 2006 Feb;54(2):607-12.
- Wessels J, Kooloos W, De Jonge R, et al. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2006 Sep;54(9):2830-9.
- Campalani E, Arenas M, Marinaki A, et al. Polymorphisms in folate, pyrimidine, and purine metabolism are associated with efficacy and toxicity of methotrexate in psoriasis. J Invest Dermatol. 2007 Aug;127(8):1860-7.
- Warren R, Smith RL, Campalani E, et al. Genetic variation in efflux transporters influences outcome to methotrexate therapy in patients with psoriasis. J Invest Dermatol. 2008 Aug;128(8):1925-9.
- Warren R, Smith RL, Campalani E, et al. Outcomes of methotrexate therapy for psoriasis and relationship to genetic polymorphisms. Br J Dermatol. 2009 Feb;160(2):438-41.
- Xiao H, Xu J, Zhou X, et al. Associations between the genetic polymorphisms of MTHFR and outcomes of methotrexate treatment in rheumatoid arthritis. Clin Exp Rheumatol. 2010 Sep-Oct;28(5):728-33.
- Chandran V, Siannis F, Rahman P, et al. Folate pathway enzyme gene polymorphisms and the efficacy and toxicity of methotrexate in psoriatic arthritis. J Rheumatol. 2010 Jul;37(7):1508-12.
- Hendel J, Nyfors A. Pharmacokinetics of methotrexate in erythrocytes in psoriasis. Eur J Clin Pharmacol. 1984;27(5):607-10.
- Baggott JE, Morgan SL, Sams WM, et al. Urinary adenosine and aminoimidazolecarboxamide excretion in methotrexate-treated patients with psoriasis. Arch Dermatol. 1999 Jul;135(7):813-7.
- Hebert HL, Ali FR, Bowes J, et al. Genetic susceptibility to psoriasis and psoriatic arthritis: implications for therapy. Br J Dermatol. 2012 Mar;166(3):474-82.
In this issue:
- Dermatitis Herpetiformis
- Methotrexate: Role of Treatment in Skin Disease
- Update on Drugs and Drug News - March-April 2013