Methotrexate

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.

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 ).

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.

Smaller studies

Smaller studies have also demonstrated efficacy of MTX in psoriasis. Flystrom and colleagues compared the short-term effectiveness of MTX to cyclosporine (CsA) in a randomized, controlled trial. A total of 37 patients with plaque psoriasis were treated with MTX using an initial dose of 7.5 mg/wk, maximum dose of 15 mg/wk, and 5 mg/d of folic acid supplementation. The primary endpoint was PASI-75 response at 12 weeks, which was achieved in 58% using MTX. There was a statistically significant difference in efficacy that was greater in the CsA treatment group. Heydendael and colleagues conducted a randomized, controlled trial also comparing MTX to CsA. A total of 43 patients were treated with MTX using an initial dose of 15 mg/wk, maximum dose of 22.25 mg/wk, and no folic acid supplementation. Fourteen MTX patients experienced elevated liver enzymes and were excluded from the study. At 16 weeks, approximately 60% of these patients achieved a PASI-75; however, no significant difference in efficacy was found between MTX and CsA treatment groups. Akhyani and colleagues compared the efficacy and safety of mycophenolate mofetil (MMF) and MTX in the treatment of chronic plaque psoriasis. Eighteen patients were administered MTX using an initial dose of 7.5 mg/wk. Following 12 weeks of treatment, patients in the MTX group achieved a PASI-75 of 53.3%. No significant differences in efficacy were found between MTX and MMF. Ranjan and colleagues compared the therapeutic efficacy of MTX at 15 to 20 mg/wk versus hydroxycarbamide at 3 to 4.5 g/wk. The primary endpoint was percentage reduction of baseline PASI scores over 12 weeks. The mean percentage reduction in the MTX group was 77.28 ± 28 and 48.47 ± 26.53 in the hydroxycarbamide group. A greater percentage of patients in the MTX group demonstrated greater than 75% reduction in the PASI scores than hydroxycarbamide (66.66% and 13.33%, respectively). A systematic review investigated MTX for psoriasis in 7 different trials and found that MTX 7.5 mg was less efficacious that CsA 3 mg, and MTX 15 mg was equally as efficacious as CsA 2.5 mg and fumaric acid ester. MTX 7.5–25 mg was less efficacious than both adalimumab and infliximab.

The data from these clinical trials and small studies suggest that MTX therapy for psoriasis is generally effective if the side effects are tolerable. Week 12 may represent an appropriate time for dermatologists to decide whether MTX is improving psoriasis or should be discontinued for alternative options. Additional randomized, controlled clinical studies in patients with psoriasis are needed to explore the efficacy profile of MTX and to validate the current prescribing guidelines.

Efficacy in reduction of immunogenicity

Immunogenicity refers to the ability of therapeutic protein products to stimulate an immune response, specifically, the development of antidrug antibodies (ADAs). These antibodies act by neutralizing or binding to therapeutic protein products, and their presence is often concerning for impending biologic failure. Moreover, ADAs can trigger potentially dangerous immune-complex AEs, such as serum sickness, bronchospasm, thromboembolic events, and Arthus and infusion reactions. Emerging evidence suggests that concomitant administration of disease-modifying anti-rheumatic drugs (DMARDs) such as MTX with biologic therapy can reduce the effects of biologic-associated immunogenicity. Administration of MTX in the context of biologic therapy may decrease ADAs’ formation in a dose-dependent manner, thus improving drug survival, protecting drug efficacy, and promoting better patient outcomes.

The data for MTX for the reduction of immunogenicity are promising, yet are largely established in patients with RA. Biologics indicated for the treatment of moderate-to-severe plaque psoriasis, etanercept, infliximab, adalimumab, ustekinumab, secukinumab, and ixekizumab, all pose the risk of immunogenicity, but few studies exist that investigate the value of the MTX-biologic combination in this population. Lecluse and colleagues conducted a prospective observational cohort study assessing ADAs in 29 patients receiving adalimumab for plaque psoriasis over 24 weeks. Thirteen of 29 patients (45%) developed ADAs; interestingly, none of their 3 patients who received concomitant MTX therapy developed ADAs. In a follow-up study, Menting and colleagues extended this cohort to 80 patients, including the original 29 patients. The long-term consequences of ADA after 24 weeks of adalimumab treatment were assessed and ADA concentrations were collected at baseline and at 12, 24, and 52 weeks. Overall, 39 of 90 (49%) patients developed ADAs. Three of 8 (37.5%) patients receiving concomitant MTX (2.5–20 mg/wk) at the start of therapy developed low titers of ADA. Thus, concomitant treatment with MTX did not significantly reduce ADAs in this study. The investigators possibly attribute their results to the small sample size of patients administered MTX with biologics.

Chiu and colleagues found that MTX can decrease immunogenicity in adalimumab-treated patients. Titers of ADAs were collected from 53 patients with psoriasis vulgaris who had been treated with adalimumab for at least 12 weeks. Fifty-five percent of patients initiated MTX 10 ± 3.2 mg weekly (range 5–15 mg weekly) at the start of adalimumab therapy, whereas 45% of patients started MTX 5 ± 9.2 months after biologic treatment. Lower titers of ADAs were found in patients administered MTX in comparison to adalimumab monotherapy ( P <.05). Interestingly, no difference in ADAs was found between patients treated with greater than 7.5 mg MTX versus less than 7.5 mg MTX. Investigators concluded that early initiation of MTX during biologic therapy might reduce the risk of developing ADAs later on, although this difference was marginally significant.

The addition of MTX, even after the development of ADA, could provide a safe and effective strategy to maintain biologic efficacy. Present literature suggests that MTX is potentially efficacious in reducing ADAs; however, the number of patients studied is limited, and this data should be interpreted with caution. The efficacy of concomitant MTX therapy with biologics needs further research and larger prospective trials with greater sample sizes necessary to validate coadministration of MTX with biologics.

Efficacy in psoriatic arthritis

Various therapies, including corticosteroids, DMARDs, and biologic DMARDs, exist to target the pain, inflammation, joint destruction, and ensuing debilities affiliated with PsA. After nonsteroidal anti-inflammatory drugs (NSAIDs), MTX is one of the most widely used DMARDs. Despite its widespread use for the management of PsA, there are very few placebo-controlled studies that have investigated its effectiveness. Furthermore, the existing clinical trials provide insufficient or conflicting evidence regarding its value in the synovitis and inflammation associated with PsA.

Recent evidence from controlled clinical trials suggests that MTX is not efficacious for PsA; however, the significant limitations of these studies hamper conclusive results. The Methotrexate in Psoriatic Arthritis study, a multicenter placebo-controlled trial involving 221 subjects with PsA, reported that MTX therapy has little to no disease-modifying effect. Subjects were randomized to receive either MTX or placebo for 6 months. MTX was initiated at 7.5 mg/wk, increased to 10 mg/wk at week 4, and 15 mg/wk at week 8. Sixty-seven of the 109 MTX subjects and 61 of 112 placebo subjects completed the study. Investigators observed no statistical improvement with the primary endpoint, Psoriatic Arthritis Response Criteria, as well as the American College of Rheumatology (ACR20) and 28-joint disease activity score. Conversely, the Tight Control of Psoriatic Arthritis study, a multicenter, open-label, randomized, controlled trial involving 206 subjects with PsA reported the beneficial effects of MTX in PsA. Patients received MTX either as tight control protocol or as standard care, with 104 subjects receiving a mean dose of greater than 15 mg/wk. At 12 weeks, improvements in multiple clinical outcomes were demonstrated. A higher proportion of patients receiving greater than 15 mg/wk achieved ACR20, ACR50, and PASI75.

In addition, large-scale registries, including the NOR-DMARD Norwegian registry and the University of Toronto PsA registry, and several observational studies report substantial improvements with MTX in joint disease in isolated and combination therapy. The paucity of clinical trial information and confounding results among different studies that evaluate the efficacy of MTX in PsA largely contributes to the lack of understanding.

Safety

MTX has higher chance of serious side effects owing to its systemic drug distribution and drug action. Patients should be well informed of the signs and symptoms of these AEs before beginning MTX therapy. The most important side effects are hepatotoxicity, myelosuppression, and pulmonary fibrosis. Systematic review of data receiving long-term low-dose MTX indicated that 33% progress to liver disease. The safety data from certain randomized, controlled clinical trials have provided important information regarding MTX use in psoriasis.