Key points

Introduction

Methotrexate (MTX) is a well-established systemic treatment for moderate-to-severe psoriasis and psoriatic arthritis (PsA). The US Food and Drug Administration (FDA) first approved the use of MTX for the treatment of severe, recalcitrant, disabling psoriasis in 1972. Today, approximately 20,000 to 30,000 psoriatic patients in the United States receive MTX treatment yearly.

MTX is the mainstay of treatment in rheumatoid arthritis (RA), and the rheumatologic literature thoroughly describes its safety profiles, which include the common side effects of nausea, loss of appetite, vomiting, and diarrhea, and more severe adverse effects (AEs) of bone marrow, pulmonary, and hepatic toxicity. Greater knowledge of MTX and its effect on patients with RA has promoted conscientious use of this medication in patients battling with moderate-to-severe plaque psoriasis. Dermatologists have expanded indications for prescribing MTX to other forms of severe psoriasis, including PsA, erythrodermic psoriasis, acute and localized forms of pustular psoriasis, nail psoriasis, psoriasis that is recalcitrant to alternative treatments, and/or psoriasis that significantly impacts a patient’s economic or psychological well-being and does not respond appropriately to retinoid, phototherapy, or psoralen and UV-A therapy. There are many off-label uses of MTX, such as scleroderma, dermatomyositis, alopecia areata, and others. In addition to psoriasis and RA, MTX is FDA approved for use in malignant neoplastic diseases, including gestational choriocarcinoma, chorioadenoma destruens, hydatidiform mole, acute lymphocytic leukemia, meningeal leukemia, mycosis fungoides, non-Hodgkin lymphomas as well as cancers of the head and neck, breast, and lung, but doses for malignancies are much higher than those used for dermatologic indications.

Physicians caring for patients with psoriasis taking MTX are faced with the challenge of identifying optimal therapeutic doses, while managing adverse side effects. Appropriate use of MTX requires a gradual increasing of dosages paired with careful patient management. Several guidelines on MTX dosing regimens have been published and are largely based on expert opinions, although administration strategies vary widely.

MTX is manufactured as oral tablets or intramuscular, intravenous, or intra-arterial injections. The tablet form is 2.5 mg MTX disodium, whereas the injection is 25 mg/mL MTX sodium. The recommended starting dose schedule for psoriasis is a once-weekly, low-dose schedule of either a single oral, intramuscular, or intravenous 7.5- to 15-mg per week dose until adequate response is achieved or a divided oral dose schedule 2.5 mg at 12-hour intervals for a total of 3 doses ( Fig. 4.1 ). Some physicians recommend a test dose as low as 5 mg for the first week of treatment. Dosages should be adjusted to the individual patient (ie, reduced doses for decreased renal function, the elderly patient, or persons with low body mass index vs greater doses for those with extensive, intractable disease), while avoiding higher doses. MTX can be used for long-term management of plaque psoriasis and should be continued until optimal clinical responses are achieved. There is not an established maximum dose, although many use 25 to 30 mg as a maximum. Following improvement of lesions, dosages are typically tapered to the lowest effective dose and may be continued long term with adequate monitoring owing to the risk of toxicity. MTX should be kept in an area that is not readily accessible to children. Tablets and injection vials should be stored in areas with little heat or moisture, adequate light protection, and room temperatures 59°F to 86°F (15°C to 30°C). Special care should be taken not to freeze injection vials.

MTX dosing regimen for psoriasis.

( From Czarnecka-Operacz M, Sadowska-Przytocka A. The possibilities and principles of methotrexate treatment of psoriasis—the updated knowledge. Postepy Dermatol Alergol 2014;31:392–400.)

Mechanism of action

MTX is a folate antagonist that interferes with de novo purine synthesis by inhibiting the enzyme dihydrofolate reductase. This critical enzyme is responsible for converting dihydrofolate to tetrahydrofolate, and its inhibition lowers the synthesis of DNAs, particularly purines and thymidylate. For this reason, MTX effectively hinders cellular replication ( Fig. 4.2 ).

MTX mechanism of action.

The exact mechanism of action of MTX in the treatment of moderate-to-severe plaque psoriasis is not fully understood. Traditionally, the antiproliferative role of MTX was assumed to be most effective against the rapidly proliferating psoriatic epidermis. Inhibition of DNA synthesis during the S phase of the cell cycle would theoretically decrease epithelial cell production and parallel keratinization rates of normal skin.

However, this long-standing theory has been disproven. Novel concepts emphasize this drug’s immune modulatory properties that downgrade the psoriasis inflammatory cascade by promoting apoptosis and suppressing intracellular adhesion molecule expression of T cells involved in the pathogenesis of psoriasis. In addition, MTX inhibits neutrophil chemotaxis and reduces levels of tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1). These ideas represent fundamental advances in the understanding of the pathogenesis and treatment of psoriasis in the last decade, and further studies are needed to better elucidate its immune activity.

Efficacy

There is a scant amount of evidence regarding the efficacy of MTX in plaque psoriasis, despite its former widespread usage. Much of the existing drug data is primarily derived from trials involving patients with RA. To date, large randomized, controlled trials, such as the CHAMPION, RESTORE, M10-255, and a few smaller trials, have been conducted to evaluate the efficacy and safety of MTX for the treatment of plaque psoriasis. Table 4.1 provides a summary of these trials, including their comparative interventions, primary endpoints, and outcomes.

CHAMPION

The CHAMPION trial was a phase 3, placebo-controlled study that was the first to compare oral MTX to adalimumab and placebo for the treatment of psoriasis. The study enrolled 271 patients from 28 different sites across Europe and Canada and randomized them in a 2:2:1 ratio to receive MTX, adalimumab, or placebo for 16 weeks. Oral MTX was dosed at 7.5 mg at week 0, increased to 10 mg/wk at week 2, and finally 15 mg/wk at week 4. Patients who achieved Psoriasis Area and Severity Index (PASI) 50 by week 8 were maintained on the 15-mg/wk dose, and those who did not were increased to 20 mg/wk. Any patient not achieving PASI-50 by week 12 was increased to a maximum study dose of 25 mg/wk. Efficacy was defined as achieving a PASI 75 response after 16 weeks of treatment. Patients with prior exposure to TNF antagonists were excluded. The trial demonstrated greater PASI-75 scores for adalimumab (79.6%) to oral MTX (35.5%) and placebo (18.9%) for the treatment of plaque psoriasis. Further analysis of the CHAMPION trial suggests that week 12 may be a crucial time period to decide whether a patient should continue MTX treatment or change to a different medication. Fig. 4.3 demonstrates the efficacy data of the CHAMPION trial.

Efficacy data of CHAMPION trial.