METHOTREXATE

By Gary M. White, MD

Note, this is a brief summary only and is meant to emphasize dermatologic aspects. More complete information, including the package insert and recent studies should be consulted before prescribing.


Methotrexate is a pill given for the treatment of moderate to severe psoriasis. It is usually very effective and well tolerated. The main potential serious side effect is on the liver. Patients who take it should drink very little to no alcohol.

Mechanism of Action

A folic acid antagonist which causes a block in the production of thymidylic acid with resultant inhibition of DNA synthesis. Probably, MTX works immunologically by reducing the participating T-cell population.

Dosing

Methotrexate is usually given once a week although it may be given in 3 divided doses over 24 hours. This triple dose regimen is often described as 111, 211, 222, etc. to refer to the number of pills take at each dose. A typical effective dose maintenance dose is 6-9 pills per week. A typical dosing schedule for initiation of methotrexate therapy is as follows:

One study showed that if after 4 weeks, the patient has not improved by at least 25% (PASI25), then the likelihood of success with methotrexate (PASI75 at week 16) is low [JAAD 2017;77;1030].

Subcutaneous MTX (e.g. 7.5-25 mg Q week) [J Drugs Dermatology 2016;15;345] may also be used and is helpful for patients who experience significant GI upset. There is also a 25 mg/cc solution for IM injection.

Half life

The half life of methotrexate is 3-15 hours. Within 4 days, the methotrexate has mostly cleared and the spike in LFTs has passed. Thus, dosing on Monday or Tuesday allows for (limited) alcohol consumption over the weekend that does not overlap liver toxicities.

Oral liquid

It is significantly cheaper to swallow the appropriate amount of IM solution (mixed with juice, water) than a pill. If the injectable solution is 50 mg/ 2cc, then each 0.1 cc is 2.5 mg.

Use in Children

In children with psoriasis, 0.2-0.7 mg/kg/week has been recommended. An initial test dose of 1.25 mg to 5 mg, followed in 1 week by laboratory monitoring is recommended. Conservative dose escalations of 1.25-5 mg/week are advised until therapeutic effect is obtained, followed by a slow taper to a beneficial maintenance dose.

The 2.5 mg scored tablet can be split or crushed and given with non-milk food.

Pregnancy Category X

Injection

In October 2013, the FDA approved Otrexup, subcutaneous MTX for once-weekly self-administration delivered with a single-dose, disposable auto injector for symptomatic control of severe recalcitrant, disabling psoriasis that is not adequately responsive to other forms of therapy in adults. The FDA also approved the use of Otrexup™ for treating adults with active, severe rheumatoid arthritis

Otrexup is available at 4 dosage strengths: 10 mg, 15 mg, 20 mg and 25 mg all per 0.4 ml.

Folic Acid Supplementation

Multiple studies have been done. It appears that folic acid supplementation reduces hepatotoxicity and GI side effects without reducing efficacy. Folic acid supplementation (eg 1 mg/day) has been recommended for all patients taking methotrexate [JAAD 2005:53;652]. In one study of children with psoriasis treated with mtx, folic acid supplementation daily was more protective than once weekly dosing [JAMA Derm 2017;153;1147].

Absorption

Food intake had no effect on absorption (J Rheumatol 1995;22;630).

MONITORING

Patients should have baseline CBC, LFTs, creatinine and a CXR (some get a PPD and hepatitis panel). A CBC is often obtained 1 week after an initial dose of 2.5-5.0 mg. Subsequent labs should be tailored to the situation but may be done at 2 weeks, 4 weeks and then every 3 months. One approach is a CBC and LFT's every 3 months and an albumin yearly. Labs should be obtained just before that week's dose (6-7 days after the previous dose) in order to miss the common post dosing rise in LFTs.

Higher baseline total serum calcium levels correlated with greater improvement of psoriasis treated with methotrexate [JAAD 2015 article in press].

Combination Therapy

Methotrexate had been combined with biologics for resistant psoriasis. Or it may be given for a flare during biologic monotherapy.

SIDE EFFECTS

Methotrexate Overdose

Oral methotrexate is taken once a week. Rarely, patients may accidentally take it daily. Severe side effects and even death may occur [Dermatology 2014;229:306–309]. See Methotrexate Induced Epidermal Necrosis

To prevent Methotrexate Induced Epidermal Necrosis, the following are recommended:

Liver Damage

Liver inflammation, fibrosis and cirrhosis may occur with longterm use of methotrexate. It is thus very important that patients be counseled to consume very little to no alcohol. Liver enzymes should be drawn routinely and the methotrexate stopped or referral to GI made for persistently abnormal values. Fibrospect blood test is now being used as a substitute for liver biopsy [JAMA Derm 2017;153;977]. If test comes back low, biopsy is often deferred. If intermediate or high, biopsy needs to be done.

Gastrointestinal effects

Nausea, vomiting, diarrhea may occur.

Mucosal ulceration

This may occur at high doses.

Severe Skin Reactions

Severe Allergic Reaction

Severe Organ Damage

Severe Opportunistic Infections

Teratogenicity

It has been recommended that men or women be off methotrexate for at least 4 months before conceiving.

Pneumonitis

This side effect is rare. It may occur early in therapy. The patient may present with fever, cough and exertional dyspnea. Alveolar and interstitial infiltrates are seen. Linear fibrosis, a ground glass appearance and enlarged lymph nodes may be seen.

Basal Cell and Squamous Cell Carcinoma

At least 3 gms of lifetime exposure was an independent risk factor for the development of SCC in one study [Cancer 1994;73;2759]. The use of methotrexate in patients with RA or IBD increased the incidence of NMSC--hazard ratio 1.60 [JAMA Derm 2016;152;164].

Methotrexate Osteopathy

Methotrexate osteopathy was initially recognized in children treated with high doses of MTX. It can however occur in patients treated with relatively low doses. Patients present typically with severe localized pain in one or both ankles and/or feet. Further investigation shows osteoporosis and compression fractures of the distal tibia. Helpful imaging studies include radiographs, technetium Tc99m scanning and MRI. Withdrawal of the methotrexate is the only treatment [AD 1996;132;184].

Reactivation Of Solar Erythema

Radiation recall described the phenomenon where the administration of methotrexate causes the appearance of redness and inflammation in exactly the same distribution as a prior sunburn. The prior sunburn was in a sense "recalled" [Photoderm Photoimm Photomed 1995;11;55]. Edema, vesiculation and bulla formation may occur. Of note, this reaction has not been reported to have occurred more than 5 days after UV light exposure.

Cutaneous Pseudolymphoma

Clinical presentation has included papulonodular ulcerations [ADDV 1995;122;521].

Lymphoma and Lymphoproliferative Disease

Lymphoma and Epstein-Barr virus associated lymphoproliferative disorders have recently been observed during low-dose MTX therapy. The typical presentation is fever, weight loss and lymph node enlargement.

Ulceration

Skin ulceration is an extremely uncommon side effect of methotrexate. It may occur in both psoriatics and non-psoriatics. Two types of ulceration have been described. Type 1 ulcerations occur in psoriatic plaques approximately 10 days after starting methotrexate therapy. Type 2 ulcers affect clinically uninvolved skin affected by other pathology (e.g. stasis dermatitis) in a variable duration after starting methotrexate.

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