ReviewMethotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference
Introduction
Methotrexate was first used for the treatment of psoriasis over 50 years ago. Its use predates the age of randomized clinical trials. High-quality data concerning its efficacy and side effects are sparse. Monotherapy and combination therapy with methotrexate continue to be widely used in dermatology primarily in psoriasis and psoriatic arthritis, and for diseases as varied as sarcoidosis, dermatomyositis, and pyoderma gangrenosum.1, 2, 3
The treatment of psoriasis has changed dramatically in the past decade. There has been an explosion of basic research and clinical research. Five biologic agents—alefacept, efalizumab, etanercept, infliximab, and adalimumab—have been approved by the Food and Drug Administration (FDA) for the treatment of psoriasis. A sixth biologic agent, ustekinumab, has been recommended for approval; more novel agents are forthcoming. Methotrexate is much less costly than biologics, even when the costs of blood monitoring and liver biopsies are considered. Many insurance companies therefore require an inadequate response or intolerance to methotrexate as a prerequisite. These targeted biologic therapies are alternative treatment options to methotrexate in the long-term management of psoriasis, especially in patients with hematologic or hepatic side effects of methotrexate. Nevertheless, methotrexate remains a valuable therapeutic option for patients.
Methotrexate was approved by the FDA for psoriasis at the same time the initial guidelines were published in 1972. The listed indication was for the treatment of severe, recalcitrant, disabling psoriasis. Minimum body surface area was not specified in the approved indication, allowing treatment of patients with functional disability due to palmoplantar disease, recalcitrant scalp disease, or other limited but severe forms of psoriasis. The approved indication suggests lack of response to topical therapy and phototherapy, when available and practical. Methotrexate has been used to successfully treat plaque, guttate, pustular, and erythrodermic forms of psoriasis. It is interesting to note that the approval of methotrexate for psoriasis was not associated with double-blind, placebo-controlled trials that the FDA now requires for most drugs. The guidelines written by several dermatologists in 1972 have provided standards for the use of methotrexate for psoriasis. There have been updates on these guidelines; the most recent was published in 1998.4 The format and content of the 1998 guidelines were used as a template for this review, and two of the authors (G. W. and M. L.) participated in the writing of the 1998 guidelines. The contributions of Henry Roenigk, Howard Maibach, and Robert Auerbach to previous guidelines will have a positive lasting impact on this and future guidelines.
Methotrexate was approved for treatment of rheumatoid arthritis in 1988 and guidelines published by the American College of Rheumatology (ACR) differed from those of earlier dermatology guidelines by not requiring liver biopsy before methotrexate treatment. The requirement for a routine pretreatment liver biopsy was eliminated in the 1998 dermatology guidelines. In contrast to those of dermatology, the rheumatologic guidelines differ in their recommendations in monitoring for possible liver toxicity associated with methotrexate.5
This article reviews available data to achieve a consensus on new updated guidelines for the use of methotrexate in the treatment of psoriasis; it was reviewed by members of the Medical Board of the National Psoriasis Foundation and approved by unanimous vote. To minimize the toxicity of any therapy, proper patient selection and appropriate monitoring are crucial. The decision to administer methotrexate should be individualized. Each patient should be evaluated with reference to disease severity, quality of life, and general medical and psychological status.
Section snippets
Methotrexate efficacy in psoriasis
Three recent blinded studies have been published concerning the efficacy of methotrexate in psoriasis. Heydendael et al6 compared methotrexate to cyclosporine without a placebo arm. There were approximately 45 patients in each group. The primary end point of PASI (Psoriasis Area and Severity Index) 75 response at 12 weeks was 60% for methotrexate and 71% for cyclosporine. Fourteen of 45 patients in the methotrexate arm dropped out because of abnormally elevated liver function tests, although no
Contraindications
The following are relative contraindications to the use of methotrexate for the treatment of psoriasis:
- 1.
Any abnormalities in renal function may require another therapy or a marked reduction in the dose as 85% of methotrexate is excreted through the kidneys.
- 2.
Significant abnormalities in liver function—liver function tests must be followed and any elevation warrants closer monitoring
- 3.
Hepatitis, active or recurrent
- 4.
Cirrhosis
- 5.
Excessive current alcohol consumption—there are few data to support specific
Pre-methotrexate evaluation
The pre-methotrexate evaluation starts with the history and physical examination. The history should focus on psoriasis, psoriatic arthritis, response to prior therapies, and presence of contraindications to methotrexate. Physical examination should likewise focus on psoriasis, psoriatic arthritis, and signs of renal, hepatic, or infectious diseases.
A recent review offers useful guidelines in starting and continuing methotrexate.9 Laboratory tests consist of the following studies:
- 1.
Complete blood
Continuing laboratory studies
The following laboratory studies should be continued during the entire course of methotrexate therapy for psoriasis:
- 1.
Complete blood cell count and platelet count (quantitative) 7 to 14 days after starting or increasing the dose, every 2 to 4 weeks for the first few months, then approximately every 1 to 3 months, depending on leukocyte count and stability of patient. Patients with risk factors for hematologic toxicity (Table I) need closer monitoring, particularly at the onset of therapy and
Drug dose schedules
Methotrexate is typically given as a single weekly oral dose or in 3 doses at 12-hour intervals weekly. Oral administration can be in the form of a tablet or a carefully measured parenteral solution given orally (0.1 mL of a 25 mg/mL multi-dose vial is equivalent to a 2.5-mg oral tablet). The parenteral solution of methotrexate is less costly than the tablets. A single weekly dose will likely increase compliance. Dividing the dose can decrease minor gastrointestinal side effects in some
Folate supplementation
Some experts recommend all patients receiving methotrexate should receive folate supplementation. Some physicians will add folate only if patient issues occur such as gastrointestinal side effects or early bone marrow toxicity as manifested by an increased mean corpuscular volume. In patients already receiving folate, increasing the dose may also help in these situations. Options for folate supplementation include folic acid 1 mg daily or folinic acid given orally at 5 mg for 3 doses every 12
Methotrexate toxicity
The use of methotrexate is restricted by the risk of organ toxicity. The 3 primary concerns are myelosuppression, hepatotoxicity, and pulmonary fibrosis. Of the 164 possible methotrexate-associated fatalities reported to the United Kingdom Committee on the Safety of Medicines between 1969 and 2004, 67 were related to myelosuppression, 30 were due to pulmonary fibrosis, and 8 were due to liver toxicity.20 A more recent survey of UK dermatologists again emphasized myelosuppression as the most
Methotrexate and hematologic toxicity
The primary risk factors reported for hematologic toxicity are renal impairment, advanced age, lack of folate supplementation, drug interactions, and medication errors (see Table I). Much of the data regarding myelosuppression has been published in patients with rheumatoid arthritis. The relative risk of this side effect in patients with psoriasis compared to patients with rheumatoid arthritis is unknown. The published data suggest that clinically significant myelosuppression is rare in
Methotrexate and hepatotoxicity
New data prompt a re-evaluation of the most recent dermatology guidelines for performing liver biopsies in patients receiving methotrexate. Several studies have shown that methotrexate-associated hepatic fibrosis and cirrhosis are considerably less aggressive than initially reported.35, 36 Many rheumatologists deem the liver biopsy as unnecessary, particularly in healthy patients. The more stringent dermatology guidelines rest on the assertion that hepatic toxicity is greater in patients with
Clinical interpretation of liver biopsy results
In patients selected for a liver biopsy based on the conditions discussed above, the decision regarding continuation or discontinuation of methotrexate therapy is made after consideration of the biopsy results. The following recommendations are based on liver abnormalities using the Roenigk scale51 (Table V):
- •
Patients with grade I or II changes may continue to receive methotrexate therapy.
- •
Patients with grade IIIA change(s) may continue to receive methotrexate therapy, but should have a repeat
Combination therapies
The goal in combination therapy is to improve efficacy and decrease toxicity of each individual agent. In patients receiving a stable methotrexate dosage, the addition of a second agent may accomplish both. Since hepatotoxicity may be related to total cumulative dose, a decreased weekly dose would lead to a lower cumulative dose over time. The addition of methotrexate to a stable regimen of another systemic agent can also increase efficacy often at lower than normal weekly methotrexate doses.
Rotational therapies
Rotating different treatments for moderate to severe psoriasis is based on the concept that the duration of therapy may continue for many years, during which time significant risks of toxicity may accumulate. Examples include skin cancers after 200 PUVA treatments, hepatic fibrosis secondary to methotrexate, and renal disease from cyclosporine. Whether the long-term use of biologic agents in the treatment of psoriasis will lead to cumulative toxicity is unknown. Experience has proven that
Overdosage
The leading causes of acute methotrexate toxicity are impaired renal function (which prevents excretion of normal doses of methotrexate), medication errors, and the concomitant administration of trimethoprim or trimethoprim-sulfamethoxazole. Leucovorin calcium (citrovorum factor or folinic acid) is the only antidote for the hematologic toxic effects of methotrexate. When an overdose of methotrexate is suspected for any reason, including minimal renal compromise, the patient should be given
Effect of low-dose methotrexate on male fertility and spermatogenesis
Methotrexate is not mutagenic. It is toxic to cells undergoing division (ie, spermatogenesis).63 Methotrexate is often used in combination with other drugs in chemotherapeutic regimens; thus its effect on male fertility is uncertain.64 Its effects are usually reversible once the drug is withdrawn.
There is controversy regarding its effect on male spermatogenesis and fertility.65 Some studies support that methotrexate treatment may result in severe oligospermia in the face of normal hormone
Effect of low-dose methotrexate on pregnancy
Methotrexate is a known abortifacient and teratogen; it is FDA pregnancy category X. There are characteristic methotrexate-induced fetal abnormalities, including skeletal, cardiac, and central nervous system.72 Women of childbearing potential exposed to methotrexate should use an adequate form of contraception. Methotrexate is contraindicated in women attempting to conceive.
There is a significant amount of literature documenting fetal exposure to methotrexate. The critical period of exposure is
Methotrexate use in children
Methotrexate is FDA approved for the treatment of psoriasis in adults and for juvenile rheumatoid arthritis. The use of methotrexate in children for both dermatologic and rheumatologic indications was recently reviewed.85 In general, low-dose weekly methotrexate is well tolerated in this age group. The primary side effects were increased liver function tests, stomatitis, nausea, and vomiting, which usually reversed with temporary discontinuation of methotrexate. When interpreting this report,
Drug interactions
Many treatments interact with methotrexate by a variety of mechanisms that can result in elevated drug levels, thus creating the potential for methotrexate toxicity, including pancytopenia and death. There are numerous reports of fatal interactions with methotrexate. In one report, 70 cases of pancytopenia were reported, including 12 deaths, and drug interactions were a common underlying cause.27
Perhaps the most common offending drug is trimethoprim-sulfamethoxazole. The mechanism by which
Conclusion
Decades after its introduction, methotrexate remains an effective treatment in the therapeutic armamentarium of dermatologists. Despite the introduction of biologics, methotrexate is regularly used alone or in combination with biologics for the treatment of psoriasis, and it remains a valuable treatment option in many other dermatologic diseases.
Safe and effective use of methotrexate requires rational patient selection and, subsequently, fastidious and appropriate monitoring. Importantly, the
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Members of the Medical Advisory Board of the National Psoriasis Foundation are listed in the Appendix.
Funding sources: None.
Dr Kalb has received consulting fees or served as an investigator for Abbott, Amgen, Astellas, Centocor, Genentech, Stiefel, and Warner/Chilcott. Dr Strober has been a speaker, advisor, consultant, and/or investigator for Abbott, Amgen, Astellas, Genentech, Centocor, and Wyeth. Dr Weinstein has been an investigator for Abbott Labs, Amgen, Genentech, and Centocor. Dr Lebwohl has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, Astellas, Centocor, Genentech, Stiefel and Novartis.