Methotrexate in psoriasis: Consensus conference,☆☆,

https://doi.org/10.1016/S0190-9622(98)70508-0Get rights and content

Section snippets

INDICATIONS

Moderate to severe psoriasis, variably defined as patients with 20% or more involvement of body surface area or patients unresponsive to topical therapy, can be treated with several modalities including phototherapy, photochemotherapy (PUVA), retinoids, or methotrexate. This population comprises approximately 20% of patients with psoriasis in the United States.11 These guidelines are directed to the use of methotrexate in treatment of psoriasis. To minimize the toxicity of systemic therapy,

RELATIVE CONTRAINDICATIONS

The following are relative contraindications to the use of methotrexate for treatment of psoriasis:

  • Any abnormalities in renal function may require other therapy, or a marked reduction in the dose

  • Significant abnormalities in liver function

  • Pregnancy or nursing (absolute contraindications)

  • Male or female fertility (conception must be avoided during methotrexate therapy and afterward for at least 3 months in the male or one ovulatory cycle in the female)

  • Hepatitis, active or recent

  • Cirrhosis

  • Severe

PREMETHOTREXATE EVALUATION

The premethotrexate evaluation starts with the history and physical examination. Laboratory tests consist of the following studies: (1) complete blood cell count with differential and platelet count (quantitative); (2) renal function: serum creatinine, blood urea nitrogen, urinalysis, and creatinine clearance, particularly in elderly patients; (3) liver chemistry: AST (SGOT), ALT (SGPT), alkaline phosphatase, bilirubin, albumin, and hepatitis A, B and C serology test; (4) HIV antibody

Analysis and recommendations

A thorough history and physical examination will identify some patients with preexisting risk factors for liver disease. Liver chemistry tests will identify only some patients with existing liver disease. The most reliable test of liver damage remains needle biopsy of the liver. This should be performed by specially trained experienced physicians. In most studies examining patient populations with psoriasis before methotrexate treatment, fibrosis or cirrhosis has been found by liver biopsy in

Patients with no risk factors

In the absence of significant risk factors it is rare for life-threatening liver disease to develop with the first 1.0 to 1.5 gm of methotrexate. Therefore, if a physician is confident that significant risk factors are absent, a liver biopsy is not necessary until the patient has been treated with 1.0 to 1.5 gm of methotrexate.

Patients with risk factors

In patients with risk factors, it is advisable that a liver biopsy be done, when feasible, at or near the beginning of methotrexate therapy. A small percentage of

CONTINUING LABORATORY STUDIES

The following laboratory studies should be continued during the entire course of methotrexate therapy for psoriasis:

  • Complete blood cell count with differential and platelet count (quantitative) weekly for the first 2 weeks, then biweekly for the next month, and then approximately monthly depending on leukocyte count and stability of patient

  • Renal function studies: Determination of blood urea nitrogen and serum creatinine levels at 3- to 4-month intervals

  • Liver chemistries: Determination of ALT,

DECISION REGARDING LIVER BIOPSY DURING METHOTREXATE THERAPY

One of the most difficult issues that has persisted during the past 35 years of methotrexate usage has been the recognition of liver damage that occurs in a small percentage of patients; another issue has been the choice of how to test for this damage. The liver biopsy has been the most definitive test for severe liver disease, and many publications about patients with psoriasis have attempted to develop recommendations on the place of liver biopsy for the use of methotrexate safely over the

CLASSIFICATION OF LIVER BIOPSY FINDINGS

The following is a classification of pathologic changes that may be detected on liver biopsy. Recommendations concerning the continuation or discontinuation of methotrexate therapy are based on these pathologic changes.6 Interpretation should be done by persons with special competence in detecting drug-induced liver abnormalities. A connective tissue or reticular stain is required to identify fibrosis.

  • Grade I: Normal; fatty infiltration, mild; nuclear variability, mild; portal inflammation, mild

CLINICAL INTERPRETATION OF LIVER BIOPSY RESULTS

The decision regarding continuation or discontinuation of methotrexate therapy is made after liver biopsy. The following recommendations are based on liver abnormality:

  • 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 liver biopsy after approximately 6 months of methotrexate therapy. Alternative therapy should be considered.

  • Patients with grades IIIB and IV

Commonly used dosage schedules

The following two dosage schedules for methotrexate are commonly used:

  • Single weekly oral, intravenous, intramuscular or subcutaneous administration

  • Intermittent oral schedule of three divided doses over a 24-hour period each week (every 12 hours three times in 1 week).

The oral administration can be tablets or carefully measured parenteral solution (0.1 ml of 50 mg/2 ml parenteral solution is equivalent to 2.5 mg oral). According to the results of published studies, the two schedules have equal

FOLIC AND FOLINIC ACID SUPPLEMENTS

It has been suggested in studies on small numbers of patients that concomitant administration of folic acid (1 to 5 mg/day) reduces side effects such as nausea and megaloblastic anemia without diminishing the efficacy of methotrexate. Additional studies with folinic acid administered on days when methotrexate is not given also resulted in a reduction in side effects associated with methotrexate (e.g., nausea) without reducing its beneficial effects.14

ROTATIONAL THERAPY

All forms of therapy (phototherapy, photochemotherapy, methotrexate, oral retinoids) for moderate to severe psoriasis have varying degrees of long-term toxicity. To minimize long-term toxicity of any of these modalities when used as monotherapy, the rotational therapy concept recommends switching from one modality to another before reaching a cumulative toxic range.15 In the case of methotrexate the first concern of long-term liver toxicity is disease that may occur at approximately 1.0 to 1.5

COMBINATION THERAPIES

Although serious adverse drug reactions can occur when methotrexate is combined with other drugs, some drug combinations with methotrexate may have beneficial effects and reduce potential toxicity from both drugs.

Topical therapy should be encouraged in patients with psoriasis taking methotrexate to minimize the dosage. Patients tend to rely on methotrexate and forget about effective topical and intralesional corticosteroids, tars, vitamin D analogues, and even a full Goeckerman regimen for

OVERDOSAGE

Two leading causes of acute methotrexate toxicity are impaired renal function, which prevents excretion of normal doses of methotrexate, and concomitant administration of trimethoprim or trimethoprim-sulfamethoxazole (Bactrim, Septra, and generic).

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

ADVERSE REACTIONS TO METHOTREXATE IN DOSES USED TO TREAT PSORIASIS

The most commonly reported adverse reactions to the doses of methotrexate used in the treatment of psoriasis include malaise, gastrointestinal tract effects, headaches, and leukopenia. The severity of side effects is, in general, dose-related and related to renal and hematologic function. Adverse reactions reported during the use of methotrexate include the following:

  • 1.

    General fatigue: Headaches, chills and fever, dizziness

  • 2.

    Skin: Pruritus, pain, urticaria, mild reversible alopecia, ecchymosis,

DRUG INTERACTIONS

The use of any drug in addition to methotrexate should be carefully evaluated. Potentially interacting drugs are listed in Table IV

. Drugs that may interact with methotrexate to increase toxicity

MechanismDrugs*
Decreased renal elimination of methotrexateNephrotoxins (e.g., amino-glycosides, cyclosporine)
Salicylates
Phenylbutazone
Sulfonamides
Probenecid
Cephalothin
Penicillins
Colchicine
Many nonsteroidal antiinflammatory drugs (e.g., naproxen, ibuprofen, etc.)
Additive or synergistic toxicity

First page preview

First page preview
Click to open first page preview

References (18)

There are more references available in the full text version of this article.

Cited by (333)

  • Nano-enabled topical delivery of anti-psoriatic small molecules

    2021, Journal of Drug Delivery Science and Technology
  • Hepatotoxicity of Dermatologic Drug Therapy

    2020, Comprehensive Dermatologic Drug Therapy, Fourth Edition
  • Methotrexate

    2020, Comprehensive Dermatologic Drug Therapy, Fourth Edition
View all citing articles on Scopus

Reprints not available from the authors.

☆☆

J Am Acad Dermatol 1998;38:478-85.

0190-9622/98/$5.00 + 0  16/1/87611

View full text