K.C. Smith, MD FRCPC
Niagara Falls, Ontario, Canada
If methotrexate were introduced as a new drug today, it would be hailed as a major advance in the management of psoriasis, as well as for a number of other conditions. Because the patent on methotrexate expired decades ago, this medication has not recently received the attention it deserves. When patients are properly screened and educated about the correct use of methotrexate, and appropriately monitored during treatment, this drug is a safe, inexpensive, well-tolerated and effective medication for the control of psoriasis.
psoriasis, methotrexate, systemic therapy
In 1951 Gubner1 reported improvement in psoriatics treated with the folate antagonist aminopterin, but clinical use was limited by mucosal and GI side-effects. In 1958, Edmundson and Guy2 reported good control of psoriasis with amethopterin, or methotrexate (MTX), an analog of aminopterin.
MTX can produce a number of side-effects, particularly GI and liver toxicities. However, administrator of folic acid has been shown to reduce or eliminate the GI distress sometimes associated with MTX, and does not interfere with its efficacy4. Several different dosage schedules have been reported to be effective. The author finds 10mg of folic acid (Leucovorin), by contrast, reduces the efficacy of MTX5, and should be administrated as an antidote in cases of MTX overdose.
Studies in animals demonstrated that MTX toxicity was more closely related to duration of contact with tissues than with total dose, and in 1963, Berlin3 suggested that an intermittent dosage schedule might improve the therapeutic index. The current practice in dermatology is to administer MTX as a single dose once a week, or in three divided doses 12 hours apart is safer, and there are occasional reports of serious or lethal toxicity when patients mistakenly take MTX every 12 hours, every day of the week.
Mechanism of Action
MTX is one of the most effective systemic therapies for psoriasis, but the mechanism of action is not completely understood. The proliferating lymphoid cells THP-1 (macrophages) and MOLT-4 (T-cells) are over 1000 times more sensitive to MTX than keratinocytes at the concentrations seen in vivo with once-weekly therapy6. Low-dose MTX also promotes the intracellular accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) by inhibiting AICAR transformylase. Under conditions of cell injury, AICAR increases the release of the autocoid adenosine, a potent anti-inflammatory agent7.
Patient Selection and Management
The best candidates for treatment with MTX are those patients who, in addition to lacking contraindications to methotrexate, are honest, reliable, and realistic. Patients must be willing to avoid alcohol consumption while taking methotrexate, and should be willing to continue topical medications to reduce the dose of methotrexate required to obtain an adequate degree of control of their psoriasis.
Patients should be instructed to obtain ALL of their medication from a SINGLE pharmacy, to reduce the chances of drug interaction. A letter should be sent to every physician who is caring for the patient, informing them that MTX is being started, and a copy of all bloodwork should be ordered for each treating physician. Patients who do not have a family doctor should not be offered methotrexate unless your office is set up to deal with bloodwork abnormalities, regardless of whether you are available. Patients who do not cooperate with the regular bloodwork necessary for the safe use of this drug should be waned firmly, and a letter about this warning should be sent to each of the patient’s doctors. If non-cooperation continues, MTX must be stopped. Documentation about the patient’s history with regard to MTX, whether MTX was well tolerated, and the cumulative dose of this drug is important.
It is also important to document the justification for offering to prescribe MTX (e.g., the extent and location of the psoriasis, and the impact the psoriasis is having on the patient’s life, employment and relations with others).
Prior to starting MTX, patients must be educated about the precautions necessary for the safe use. Discuss the need for contraception with women who are candidates for treatment with methotrexate. Women must avoid pregnancy while taking this drug and for 3 months after stopping it because it has been associated with teratogenicity. There is no evidence that MTX has any adverse effect on spermatogenesis or fertility in men at the doses used in dermatology, and men should be reassured about this.
Prior to starting MTX, and from time to time during treatment, a list of the patient’s prescription and non-prescription medications (including “natural” or herbal remedies) should be reviewed, and the patient again cautioned to avoid alcohol consumption. Laboratory studies prior to starting MTX should include CBC, SGOT, alkaline phosphatase, bilirubin, creatinine, serum albumin, and hepatitis B and C serology. As well, HIV-1 should be checked in those at risk for HIV. However, MTX has been used successfully to treat psoriasis in HIV infected patients8. CBC and SGOT should be repeated twice a month for the first two months of treatment, then monthly while the patient is taking MTX. The SGPT should NOT be tested. It is frequently elevated when there is no clinical problem, leading to an unacceptable number of “false alarms.”
Hepatitis in low-dose therapy is not common seen, and may be more common in patients receiving combination therapy with etretinate, in those with heavy alcohol consumption, or in those with a higher total cumulative dose of methotrexate. Some drugs that can affect the toxicity of MTX are listed in Table 1. Liver biopsy is generally not performed prior to starting MTX in otherwise healthy patients. However, each prescription for this drug should be recorded in a flow chart, and when the total dose reaches 1.5gm, the patient should be referred to a gastroenterologist for consideration of a liver biopsy. As a general rule, a liver biopsy is not performed in healthy, young, non-obese, non-diabetic patients who have normal liver function studies. Patients should return to the gastroenterologist for reassessment each time the total dose of MTX increases by 1.5gm.
The Roenigk classification of liver biopsies (Grades 1-4)9 has been criticized because it was adapted from a classification system developed many years ago for use in primary biliary cirrhosis here portal inflammation is the major feature. For this reason, it is not an ideal classification tool for assessing MTX toxicity, which tends to produce entrilobular changes.
The starting dose of MTX in an adult is usually in the range of 10-15mg at bedtimes, once a week. Improvement in psoriasis is usually seen within 4-8 weeks. The dose may be increased to 25mg once a week if necessary. Topical medications and UVB or PUVA are usually continued in order to reduce the long-term need for MTX. Phototoxicity associated with MTX has been reported, but is very rare in clinical practice, and MTX is often used successfully with UVB or PUVA.
When a patient has improved to a satisfaction degree, the dose of MTX can be adjusted each week within a specified range (e.g., between 2.5-15mg once a week), as necessary. This is done in order to maintain adequate (but not necessarily perfect) control of the psoriasis, and often allows for a lower cumulative dose of MTX than would be the case if the patient was maintained on a fixed dose, e.g., 15mg once a week.
The successful use of “rotational therapy” (e.g., switching every 3-6 months between several treatments including methotrexate, cyclosporine, acitretin and PUVA) depends on many variables, including the patient’s finances, ability to attend on a regular basis for UV light treatment, underlying medical conditions, and medications. The increased complexity and cost of rotational therapy is sometimes justified by the reduced long-term load on any one organ system:
- Methotrexate – liver damage
- Cyclosporine – altered kidney function
- PUVA – skin
- Acitretin – elevated lipids
Methotrexate is an effective medication for the control of psoriasis. When patients are properly screened and educated about the correct use of this drug, and appropriately monitored during treatment, MTX is often very safe, simple to use, inexpensive, and well-tolerated.
Table 1: Drugs that may effect the toxicity of methotrexate
- Gubner R. Effect of “aminopterin” on epithelial tissues. Arch Dermatol Syphilol 64: 688-699 (1951).
- Edmundson EF, Guy WB: Treatment of psoriasis with folic acid antagonists. Arch Dermatol 78: 200-203 (1958).
- Berlin NI (Moderator). Folic acid antagonists: effects on the cell and the patient. Combined clinical staff conference at the National Institutes of Health. Ann Intern Med 59:931-956 (1963)
- Morgan SL, Baggott JE, Vaughn WH, et al. The effect of folic acid supplementation on the toxicity of low-dose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 33:9-18 (1990).
- Guzzo C. Folic acid supplementation with methotrexate therapy: what benefit if any? J Am Acad Dermatol 31 (4):689 (1994 Oct.)
- Jeffes EWB III, McCullough JL, Pittelkow MR, et al. Methotrexate therapy of psoriasis: differential sensitivity of proliferating lymphoid and epithelial cells to cytotoxic and growth-inhibitory effects of methotrexate. J Invest Dermatol 104 (2): 183-8 (1995 Feb).
- Cronstein BN, Naime D, Ostad E. The anti-inflammatory mechanism of methotrexate. Increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest 92(6):2675-82 (1993 Dec).
- Maurer TA, Zackheim HS, Tuffanelli L, Berger TG. The use of methotrexate for treatment of psoriasis in patients with HIV infection. J Am Acad Dermatol 31 (2 Pt 2):372-5 (1994 Aug).
- Roenigk HH Jr, Auerbach R, Maibach HI and Weinstein GD. Methotrexate in psoriasis: Revised guidelines. J Am Acad Dermatol 19 (1 Pt 1):145-56 (1988 Jul).