Methotrexate: Understanding the risk in psoriasis patients

Sirs,

Low-dose methotrexate is an effective systemic therapy for moderate-to-severe psoriasis and has become a commonly prescribed systemic medication for psoriasis. Though effective, methotrexate is associated with morbidity and mortality. In practice, the majority of the adverse effects are mild and transient, including changes in blood counts, elevation of serum transaminases, and gastrointestinal intolerance However, the risk of sub-clinical hepatic fibrosis and cirrhosis has led some clinicians to recommend liver biopsy at 1.5 g of cumulative methotrexate ([1]). Other well-documented though rare adverse effects include acute pneumonitis, pancytopenia and serious infections.

Using PubMed and PubMed MeSH searches, we identified 125 deaths in 66 reports which cited methotrexate as at least a contributing factor in patient mortality from 1965 to 2005 ([2-65]). Forty-four of these cases occurred in the US. The majority of the patients were female (69%) with an average age of 61.8 years (23 months to 91 years). A mean cumulative dose of 750.3 mg methotrexate was calculated for 59 patients for which such dosing information was available. A total of 107 of the 125 patients had either rheumatoid arthritis or psoriasis. Myelosuppression was the cause of death in 43% of the cases, and pneumonitis in 17% (Table I). In three cases, medication mistakes occurred: one patient received methotrexate by mistake and two others took more than was prescribed. However, dosages remained within low-dose levels. There were 50 cases where concomitant medications were reported: corticosteroids (n = 26), NSAIDS (n = 18), and antibiotics (n = 9).

Table I. Adverse events of methotrexate therapy resulting in death.

Fatal adverse event	Number of deaths (%)
Myelosuppression	53 ([42])^a
Pneumonitis	22 ([18])^a
Infectious	13 ([10])^a
Hepatic insufficiency	12 ([10])
Lymphoma	11 ([9])
Toxic epidermal necrolysis	3 ([2])
Renal insufficiency	4 ([3])
Other	7 ([6])

^aAcute toxicity – within 1 month of initiation: myelosuppression ([8]), pneumonitis ([1]), infectious ([1]).

Data from the 2001 and 2002 National Ambulatory Medical Care Survey (NAMCS) reveal 390 000 visits where methotrexate was mentioned and psoriasis or psoriatic arthritis was coded. Acknowledging multiple visits by individual patients, we estimate there are 40 000 patients who take methotrexate for psoriasis and a death rate of 1.2 per 100 000 psoriasis patients treated annually with methotrexate.

Under-reporting may be common, but even if our calculated death rate of 1.2/100 000 psoriasis patients treated with methotrexate per year is incorrect by a factor of 10, deaths related to methotrexate are rare, though not zero. Route of administration and, in particular, dosing, likely play a role in these cases, though that information was not always available. For comparison, according to the Physician's Desk Reference, metformin (Glucophage), a highly prescribed drug in the US, is associated with lactic acidosis at a rate of 3 per 100 000 people. Estimating a 40% mortality rate in cases of lactic acidosis, metformin has a mortality rate of approximately 1.2 per 100 000 events as well.

Methotrexate, with its efficacy and low cost, has an important role in the treatment of moderate-to-severe psoriasis. The drug's benefit in selected psoriasis patients outweighs its low morbidity and mortality. Awareness of methotrexate's adverse effects, guidelines for its use, and proper patient education may reduce future fatalities. Finally, methotrexate should continue to be utilized in appropriate populations with careful patient education, timely follow-up, and systematic laboratory monitoring.

Acknowledgements

Funding/conflicts of interest: The Center for Dermatology Research is supported by an unrestricted educational grant from Galderma Laboratories, Inc. Dr Feldman has received research, speaking and/or consulting support from Connetics, Centocor, Roche, Amgen, Biogen, and Genentech.