FROM THE ACADEMY
`
`Guidelines of care for the management of psoriasis
`and psoriatic arthritis
`
`Section 4. Guidelines of care for the management and treatment of
`psoriasis with traditional systemic agents
`
`Alan Menter, MD, Chair,a Neil J. Korman, MD, PhD,b Craig A. Elmets, MD,c Steven R. Feldman, MD, PhD,d
`Joel M. Gelfand, MD, MSCE,e Kenneth B. Gordon, MD,f Alice B. Gottlieb, MD, PhD,g John Y. M. Koo, MD,h
`Mark Lebwohl, MD,i Henry W. Lim, MD,j Abby S. Van Voorhees, MD,k Karl R. Beutner, MD, PhD,l and
`Reva Bhushan, PhDm
`Dallas, Texas; Cleveland, Ohio; Birmingham, Alabama; Winston-Salem, North Carolina; Philadelphia,
`Pennsylvania; Chicago and Schaumburg, Illinois; Boston, Massachusetts; San Francisco and
`Palo Alto, California; New York, New York; and Detroit, Michigan
`
`Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint
`manifestations affecting approximately 2% of the population. In this fourth of 6 sections of the guidelines of
`care for psoriasis, we discuss the use of traditional systemic medications for the treatment of patients with
`psoriasis. Treatment should be tailored to meet individual patients’ needs. We will discuss in detail the efficacy
`and safety, and offer recommendations for the use of the 3 most commonly used, and approved, traditional
`systemic agents: methotrexate, cyclosporine, and acitretin. We will also briefly discuss the available data for
`the use of azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil, sulfasalazine,
`tacrolimus, and 6-thioguanine in psoriasis. ( J Am Acad Dermatol 2009;61:451-85.)
`
`DISCLAIMER
`Adherence to these guidelines will not ensure
`successful treatment in every situation. Furthermore,
`these guidelines should not be deemed inclusive of
`
`From the Baylor University Medical Center, Dallasa; Murdough
`Family Center For Psoriasis, Department of Dermatology, Uni-
`versity Hospitals Case Medical Center, Clevelandb; Department
`of Dermatology, University of Alabama at Birminghamc;
`Department of Dermatology, Wake Forest University School
`of Medicine, Winston-Salemd; Department of Dermatology and
`Center for Clinical Epidemiology and Biostatistics, University of
`Pennsylvaniae; Division of Dermatology, Evanston Northwestern
`Healthcare and Department of Dermatology, Northwestern
`University, Fienberg School of Medicine, Chicagof; Tufts Medical
`Center, Tufts University School of Medicine, Bostong; Depart-
`ment of Dermatology, University of CaliforniaeSan Franciscoh;
`Department of Dermatology, Mount Sinai School of Medicine,
`New Yorki; Department of Dermatology, Henry Ford Hospital,
`Detroitj; Department of Dermatology, University of Pennsylva-
`niak; Anacor Pharmaceuticals Inc, Palo Alto, CA, Department of
`Dermatology, University of California, San Franciscol; and Amer-
`ican Academy of Dermatology, Schaumburg.m
`Funding sources: None.
`The authors’ conflict of interest/disclosure statements appear at
`the end of the article.
`Reprint requests: Reva Bhushan, PhD, 930 E Woodfield Rd, Schaumburg,
`IL 60173. E-mail: rbhushan@aad.org.
`Published online June 4, 2009.
`0190-9622/$36.00
`ª 2009 by the American Academy of Dermatology, Inc.
`doi:10.1016/j.jaad.2009.03.027
`
`Abbreviations used:
`
`American Academy of Dermatology
`AAD:
`aspartate aminotransferase
`AST:
`serum urea nitrogen
`BUN:
`complete blood cell
`CBC:
`cyclosporine
`CSA:
`Food and Drug Administration
`FDA:
`MMF: mycophenolate mofetil
`PASI:
`Psoriasis Area and Severity Index
`PPD:
`purified protein derivative
`PUVA: psoralen plus ultraviolet A
`SCC:
`squamous cell carcinoma
`TB:
`tuberculosis
`UV:
`ultraviolet
`
`all proper methods of care nor exclusive of other
`methods of care reasonably directed to obtaining the
`same results. The ultimate judgment regarding the
`propriety of any specific therapy must be made by
`the physician and the patient in light of all the
`circumstances presented by the individual patient.
`
`SCOPE
`This fourth section will cover the management
`and treatment of psoriasis with traditional systemic
`therapies.
`
`METHOD
`A work group of recognized psoriasis experts was
`convened to determine the audience and scope of
`
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`the guideline, and identify clinical questions to
`structure the primary issues in diagnosis and man-
`agement discussed in American Academy of
`Dermatology (AAD) psoriasis guidelines section
`1 and 2.1,2 Work group members completed a
`disclosure of commercial support.
`An evidence-based model was used and evidence
`was obtained using a search of the MEDLINE data-
`base spanning the years 1960 through 2008. Only
`English-language publications were reviewed.
`The available evidence was evaluated using a uni-
`fied system called the Strength of Recommendation
`Taxonomy developed by editors of the US family
`medicine and primary care journals (ie, American
`Family Physician, Family Medicine, Journal of Family
`Practice, and BMJ USA). This strategy was supported by
`a decision of the Clinical Guidelines Task Force in 2005
`with some minor modifications for a consistent ap-
`proach to rating the strength of the evidence of
`scientific studies.3 Evidence was graded using a 3-
`point scale based on the quality of methodology as
`follows:
`
`I. Good-quality patient-oriented evidence.
`II. Limited-quality patient-oriented evidence.
`III. Other evidence including consensus guidelines,
`opinion, or case studies.
`
`Clinical recommendations were developed on the
`best available evidence tabled in the guideline.
`These are ranked as follows:
`A. Recommendation based on consistent and good-
`quality patient-oriented evidence.
`B. Recommendation based on inconsistent or lim-
`ited-quality patient-oriented evidence.
`C. Recommendation based on consensus, opinion,
`or case studies.
`
`In those situations where documented evidence-
`based data are not available, we have used expert
`opinion to generate our clinical recommendations.
`Prior guidelines on psoriasis were also evaluated.
`This guideline has been developed in accordance
`with the AAD ‘‘Administrative Regulations
`for
`Evidence-based Clinical Practice Guidelines,’’ which
`include the opportunity for review and comment by
`the entire AAD membership and final review and
`approval by the AAD Board of Directors.
`
`GENERAL PRINCIPLES
`In the past, conventional systemic psoriasis ther-
`apiesemethotrexate,
`cyclosporine
`(CSA),
`and
`acitretinewere used when psoriasis was too exten-
`sive for topical therapy or refractory to topical ther-
`apy and phototherapy. Although a minimum body
`
`surface area, eg, 10%, has been traditionally used as a
`prerequisite to starting a systemic therapy for psori-
`asis, a subset of patients with limited disease have
`debilitating symptoms. For example, although severe
`psoriasis of the palms and soles or severe scalp
`psoriasis affects less than 5% of the body surface
`area, the significant negative affect on the quality of
`life of the patient makes a systemic approach to
`treatment appropriate.
`In recent years, biologics have changed the treat-
`ment of psoriasis, giving us additional therapeutic
`options that are potentially less toxic to the liver,
`kidneys, and bone marrow and are not teratogenic.
`Nevertheless, traditional systemic therapies continue
`to play an important role in the treatment of psoriasis
`with their oral route of administration and low cost
`(compared with biologics) making them an impor-
`tant treatment option in the appropriate patient.
`Methotrexate is the most commonly prescribed
`traditional systemic therapy worldwide for psoriasis.
`Detailed guidelines concerning its dosing and mon-
`itoring in patients with psoriasis have recently been
`published by the National Psoriasis Foundation.4 It is
`noteworthy that the rheumatology guidelines for the
`use of methotrexate5 are less stringent than those in
`dermatology, especially in the monitoring of hepa-
`totoxicity. The difference in this monitoring may be
`that patients with psoriasis with more severe disease
`are more likely to be obese than patients with
`rheumatoid arthritis, and thus be more prone to
`have
`underlying
`nonalcoholic
`steatohepatitis.
`Methotrexate can be dramatically effective with
`even the most severe cases of psoriasis. The potential
`role of pharmacogenetic testing to improve our
`ability to predict the efficacy and safety of metho-
`trexate suggests the possibility of personalizing
`the use of methotrexate in the years ahead.6
`Methotrexate has been used in combination with
`all of the approved biologic agents for psoriasis.
`The greatest experience is with tumor necrosis factor
`inhibitors. Methotrexate has been used to suppress
`antibodies against the two monoclonal tumor necro-
`sis factor inhibitors, adalimumab and infliximab.7 It is
`not known whether the use of methotrexate and
`biologics causes additive immunosuppression as this
`combination has primarily been studied in patients
`without psoriasis, and the differing baseline risks
`associated with these diseases make this distinction
`uncertain.
`the most effective treatments
`CSA is one of
`available for psoriasis.8 However, when used in the
`longer
`term (3-5 years), a significant prop-
`ortion of patients will develop some degree of
`glomerulosclerosis.9 Published guidelines in the
`its use to 1 year,8
`United States therefore limit
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`Menter et al 453
`
`whereas in the United Kingdom it is allowed for 2
`years.10 In patients with severe flares of psoriasis,
`CSA frequently induces a rapid remission. Rebound
`flares of psoriasis after discontinuation of systemic
`steroids or efalizumab can be prevented or rapidly
`controlled with CSA11 or methotrexate.
`Of the systemic therapies, acitretin is the least
`effective as monotherapy and it is therefore often
`used in conjunction with ultraviolet (UV) B or
`psoralen plus UVA (PUVA) phototherapy. Studies
`performed in the 1980s demonstrated that etretinate,
`the pro-drug of acitretin, is particularly effective in
`patients with palm and sole psoriasis.12 Because
`acitretin is not immunosuppressive, it has also been
`used in combination with biologic therapies.
`Acitretin’s major side effect is its teratogenicity, and
`its use is, therefore,
`limited to male and female
`patients of nonchildbearing potential. At high doses,
`it may be associated with significant mucocutaneous
`effects along with hair loss, and although it can
`occasionally be dosed at 50 mg daily, most clinicians
`use doses between 10 and 25 mg per day.
`Because of the known organ toxicities of tradi-
`tional systemic agents,
`the concept of rotational
`therapy was developed so that patients could rotate
`from one agent to the other or to phototherapy or
`photochemotherapy to minimize total cumulative
`dose and thereby limit toxicity.13 With the advent of
`biologic therapies, and their reduction in incidence
`of major organ toxicity, rotational therapy is less
`commonly used.13
`To minimize the toxicity of any therapy, proper
`patient selection and appropriate monitoring are
`crucial. The decision to administer methotrexate,
`CSA, acitretin, or any other traditional therapy must
`be individualized. Every patient needs to be carefully
`evaluated with reference to disease severity, quality
`of life, and general medical and psychologic status.
`
`METHOTREXATE
`Oral methotrexate is an effective treatment for
`psoriasis being initially used more than 50 years ago.
`Methotrexate competitively inhibits the enzyme
`dihydrofolate reductase, thus decreasing the synthe-
`sis of folate cofactors needed to produce nucleic
`acids. Because the effects of methotrexate are most
`dramatic on rapidly dividing cells, it was originally
`thought that its beneficial effects in psoriasis were a
`result of the inhibition of epidermal proliferation.14
`However, it is now known that there is little effect on
`epidermal cells, but there is significant inhibition of
`the proliferation of lymphoid tissue at concentrations
`of methotrexate that are typically achieved with low-
`dose weekly methotrexate.15 These findings support
`the concept that the therapeutic effect of low-dose
`
`methotrexate in psoriasis is a result of its effects on
`the immune system.16 Methotrexate was approved
`by the Food and Drug Administration (FDA) in 1972
`for the treatment of severe, recalcitrant, disabling
`psoriasis. Because methotrexate was introduced be-
`fore the acceptance of randomized clinical trials as
`the standard by which to judge drug efficacy, there
`are no large high-quality studies demonstrating its
`safety and efficacy, and clinical experience with
`methotrexate is much greater than the documenta-
`tion of its safety and efficacy in clinical studies. For
`these reasons, methotrexate guidelines, which were
`originally written in 197217 and have since been
`updated on numerous occasions (most recently in
`20094), provide expert-based standards for the use of
`methotrexate in the treatment of psoriasis.
`
`Efficacy
`Three well-designed studies that evaluated the
`efficacy of methotrexate were recently performed.
`Heydendael et al18 compared the efficacy and safety
`of methotrexate with CSA in a study that randomized
`88 patients to receive either medication without a
`placebo group. The primary end point of Psoriasis
`Area and Severity Index (PASI) 75 at 16 weeks was
`60% for methotrexate and 71% for CSA (no statistical
`difference). Twelve of 44 patients in the methotrex-
`ate group dropped out because of elevated liver
`function test results (it should be noted that no folic
`acid supplementation was given in this study),
`whereas only one patient in the CSA group dropped
`out (because of elevated bilirubin).18 Flytstrom
`et al19 compared methotrexate with CSA in the
`treatment of 84 patients with psoriasis in a 12-week
`study that also did not include a placebo arm. These
`authors used a different end point, namely a mean
`PASI change from baseline, which was 72% for CSA
`compared with 58% for methotrexate. Although CSA
`was statistically more effective than methotrexate, 12
`patients in the CSA group and 4 patients in the
`methotrexate group dropped out secondary to lab-
`oratory abnormalities and withdrawn consents be-
`fore initiation of treatment.19 Saurat et al20 performed
`the first double-blind, placebo-controlled study of
`methotrexate, designed to compare the safety and
`efficacy of adalimumab, methotrexate, and placebo
`in 250 patients. After 16 weeks of treatment, PASI 75
`improvement was 19% for placebo, 36% for metho-
`trexate, and 80% for adalimumab. For those patients
`in the methotrexate arm of the study, methotrexate
`was initiated at a low weekly dosage of 7.5 mg for 2
`weeks, followed by 10 mg weekly for 2 weeks, and
`then 15 mg for 4 weeks. Thereafter, an increase in the
`dosage of methotrexate was permitted depending on
`the response and the presence or absence of
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`toxicities. After 8 weeks, if patients in the metho-
`trexate arm had achieved a PASI 50 response, no
`further increase in methotrexate dosage was al-
`lowed. After 16 weeks, when the mean methotrexate
`dose was 19 mg, these patients were crossed over to
`receive adalimumab; it should be noted that patients
`in the methotrexate arm were still showing clinical
`improvement at the time of crossover, suggesting
`that the results of this study may have underesti-
`mated the efficacy of methotrexate.20 Furthermore,
`the placebo response rate of 19% is dramatically
`higher than is seen in a clinical trial of this type,
`raising doubt about the validity of this study.
`
`Dosage
`Methotrexate is generally given as a single weekly
`oral dose, given as a tablet or occasionally as a
`carefully measured parenteral solution given orally
`(0.1 mL of a 25 mg/mL multidose vial is equivalent to a
`2.5-mg oral tablet). The parenteral solution of meth-
`otrexate is less costly than tablets. Intramuscular
`administration is helpful when there is gastrointesti-
`nal intolerance to oral dosing or if there are concerns
`regarding patient compliance. Subcutaneous injec-
`tion is equally effective and can be self-administered
`at home. Doses are usually started at low levels to
`minimize side effects and then gradually increased to
`achieve efficacy. Many practitioners give a single test
`dose of 2.5 or 5 mg to evaluate for significant bone-
`marrow suppression
`in
`susceptible patients.
`Although there are no established maximum or
`minimum dosages of methotrexate, weekly dosages
`usually range from 7.5 to 25 mg. All dosing schedules
`should be adjusted to the individual patient and the
`dosage raised or reduced to obtain or maintain
`adequate disease control or minimize side effects.
`After an increase in methotrexate dose, it may take up
`to 4 weeks for a clinical response to occur. Some
`patients can be gradually tapered off treatment and
`restarted when the psoriasis recurs. It is important to
`minimize the total cumulative dose of methotrexate
`while maintaining disease control and medication
`tolerance.
`
`Folate supplementation
`Although the majority of experts recommend that
`all patients treated with methotrexate receive folate
`supplementation (1-5 mg/d given daily except the
`day of methotrexate), others will add folate only if a
`patient develops gastrointestinal side effects or early
`bone-marrow toxicity as manifested by an increased
`mean corpuscular volume. In patients who develop
`bone-marrow toxicity or gastrointestinal side effects
`while on folate, increasing the dose of folate may be
`
`helpful. Although a literature review of these data,
`largely derived from the rheumatoid arthritis litera-
`ture, suggests that low-dose folate supplementation
`may reduce the hematologic, gastrointestinal, and
`hepatic side effects of methotrexate without decreas-
`ing the efficacy,21 one small controlled study in
`patients with psoriasis using folic acid at 5 mg daily
`suggested that there may be a slight decrease in
`efficacy.22 However, the methodology of this latter
`study has been questioned.23 The optimal dosage of
`folic acid is still to be determined.
`
`Toxicity
`Common and generally minor toxicities of meth-
`otrexate include nausea, anorexia, stomatitis, and
`fatigue that most often occur at the time of metho-
`trexate administration. These effects may be
`minimized by administering methotrexate by intra-
`muscular or subcutaneous injection, splitting the
`dose, folate supplementation, or by administering
`the dose with food or at bedtime. The major toxicities
`that are of greatest concern in patients treated with
`methotrexate are myelosuppression, hepatotoxicity,
`and pulmonary fibrosis. Of 164 possible methotrex-
`ate-associated fatalities, 67 were caused by myelo-
`suppression, 30 were caused by pulmonary fibrosis,
`and 8 were caused by hepatotoxicity.24 Pulmonary
`fibrosis is one of the more severe manifestations of
`methotrexate toxicity and must be ruled out
`in
`patients presenting with new pulmonary symptoms
`such as cough; however, this complication is much
`less common in patients with psoriasis than in
`patients with rheumatoid arthritis.25-27
`Because methotrexate has not been studied in large
`double-blind placebo-controlled trials of the type that
`have been routinely used to determine the safety and
`efficacy of the biologic agents, less common adverse
`effects have not been carefully evaluated. Recent
`reports suggest
`that
`treatment with methotrexate
`may be associated with some of the risks similar to
`those of the biologic agents, although to date these
`reports have occurred almost exclusively in patients
`with rheumatoid arthritis.28-31 Hepatitis, reactivation of
`tuberculosis (TB), and lymphoma, especially the B-
`cell type that is commonly associated with Epstein-
`Barr virus infection, have all been reported in patients
`being treated with methotrexate.23-26 These observa-
`tions suggest that practitioners need to maintain a high
`index of suspicion for these infections in patients
`being treated with methotrexate.
`
`Hematologic
`The major risk factors for hematologic toxicity are
`advanced age, renal
`impairment, the absence of
`folate supplementation, drug interactions, and
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`Menter et al 455
`
`Table I. Risk factors for hematologic toxicity from
`methotrexate
`
`Table II. Risk factors for hepatotoxicity from
`methotrexate
`
`d Renal insufficiency
`d Advanced age
`d Lack of folate supplementation
`d Methotrexate dosing errors
`d Drug interactions
`d Hypoalbuminemia
`d Greater than moderate alcohol intake
`
`Adapted with permission from Kalb et al.4
`
`medication errors (Table I). Most of the literature
`concerning myelosuppression with methotrexate
`derives from the experience in patients with rheu-
`matoid arthritis. Although the relative risk of myelo-
`suppression in patients with psoriasis compared with
`patients with rheumatoid arthritis is unknown, the
`literature suggests that significant myelosuppression
`is rare in appropriately monitored patients with
`psoriasis who have no risk factors for hematologic
`toxicity.
`The practice of using a single test dose of metho-
`trexate derives from the desire to ensure that severe
`myelosuppression does not occur. The test dose is
`typically 2.5 or 5 mg with a complete blood cell (CBC)
`count evaluated 5 to 6 days later, to ensure that
`myelosuppression has not occurred before increasing
`to the full weekly dosage. Although the use of a test
`dose does not guarantee that patients will not expe-
`rience myelosuppression, it is mandatory in patients
`with a decreased glomerular filtration rate or other
`significant risk factors for hematologic toxicity.32
`Pancytopenia can rarely occur with the use of
`low-dose weekly methotrexate, even after single
`doses of methotrexate.33-35 It can occur at any time
`during treatment; in all cases, however, there were
`identified risk factors, particularly impaired renal
`function, medication errors, or use of concomitant
`medications, especially sulfonamide-based.32,36 As
`pancytopenia may occur as long as 4 to 6 weeks after
`increasing the methotrexate dosage, more frequent
`monitoring is suggested with dosage increases.
`
`Hepatotoxicity
`Hepatotoxicity is a well-known side effect of
`methotrexate. Recent studies, however, demon-
`strated that hepatic fibrosis and cirrhosis are consid-
`erably less common than initially reported.37,38
`Rheumatologists traditionally deem the liver biopsy
`as unnecessary, particularly in healthy patients.
`Thus, dermatology guidelines are stricter as hepatic
`toxicity is greater in patients with psoriasis than in
`patients with rheumatoid arthritis.27
`
`d History of or current greater than moderate alcohol
`consumption (methotrexate toxicity is associated with a
`history of total lifetime alcohol intake before
`methotrexate therapy; the exact amount of alcohol that
`leads to risk is unknown and differs from person to
`person)
`d Persistent abnormal liver chemistry study findings
`d History of liver disease including chronic hepatitis B or C
`d Family history of inheritable liver disease
`d Diabetes mellitus
`d Obesity
`d History of significant exposure to hepatotoxic drugs or
`chemicals
`d Hyperlipidemia
`
`Adapted with permission from Kalb et al.4
`
`The pathologic features of methotrexate-induced
`liver toxicity resemble nonalcoholic steatohepatitis,
`the pattern of liver histology observed in people who
`are obese, hyperlipidemic, or diabetic. Methotrexate
`likely aggravates preexisting nonalcoholic steatohe-
`patitis, suggesting that patients with psoriasis at
`greatest risk while receiving methotrexate are those
`with diabetes, with obesity, or who collectively meet
`the criteria for metabolic syndrome in addition to
`those who drink alcohol.39,40 Recent studies suggest
`that when evaluating patients for methotrexate treat-
`ment, risk factors including alcohol intake, obesity,
`hyperlipidemia, diabetes, previous exposure to liver
`toxins, and hepatitis need to be considered.40,41
`Recently updated methotrexate guidelines from
`the National Psoriasis Foundation4 suggest that pa-
`tients be divided into two groups, those with risk
`factors for hepatotoxicity from methotrexate (Table
`II) and those without. Patients with no risk factors for
`methotrexate-induced hepatotoxicity should be
`judged by the American College of Rheumatology
`criteria for monitoring methotrexate. These criteria
`include an evaluation of liver chemistries every 1 to 3
`months with the need for a liver biopsy only if 5 of 9
`aspartate aminotransferase (AST) levels are elevated
`during a 12-month period or if there is a decline in
`the albumin (in patients with normal nutritional
`status) below normal in the setting of well-controlled
`disease (Table III). This approach has been validated
`in patients with rheumatoid arthritis and has also
`demonstrated a decrease in the number of liver
`biopsies.42 Furthermore, data suggest that 3.5 to 4.0 g
`instead of 1.0 to 1.5 g of cumulative methotrexate
`may be a more appropriate time frame for the first
`liver biopsy in patients without preexisting risk
`factors for hepatotoxicity.39,43,44 In patients with
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`Table III. Monitoring for hepatotoxicity in patients with no risk factors for hepatotoxicity
`
`d No baseline liver biopsy
`d Monitor LFT results monthly for the first 6 mo and then every 1-3 mo thereafter
`/ For elevations \2-fold upper limit of normal: repeat in 2-4 wk
`/ For elevations [2-fold but \3-fold upper limit of normal: closely monitor, repeat in 2-4 wk, and decrease dose as
`needed
`/ For persistent elevations in 5/9 AST levels during a 12-mo period or if there is a decline in the serum albumin below
`the normal range with normal nutritional status, in a patient with well-controlled disease, a liver biopsy should be
`performed
`d Consider liver biopsy after 3.5-4.0 g total cumulative dosage
`or
`d Consider switching to another agent or discontinuing therapy after 3.5-4.0 g total cumulative dosage
`or
`d Consider continuing to follow up according to above guidelines without biopsy
`
`Adapted with permission from Kalb et al.4
`AST, Aspartate aminotransferase; LFT, liver function test.
`
`Table IV. Monitoring for hepatotoxicity in patients
`with risk factors for hepatotoxicity
`
`d Consider the use of a different systemic agent
`d Consider delayed baseline liver biopsy (after 2-6 mo of
`therapy to establish medication efficacy and tolerability)
`d Repeated liver biopsies after approximately 1-1.5 g of
`methotrexate
`
`Adapted with permission from Kalb et al.4
`
`normal liver chemistry results, history, and physical
`examination findings, the decision about whether or
`not to undergo a liver biopsy should be made on an
`individual basis. Choices for patients who have
`accumulated 3.5 to 4.0 g of methotrexate (whether
`from continuous or intermittent methotrexate dos-
`ing) include performing a liver biopsy, switching to
`another therapy, or following the above guidelines
`and continuing to monitor without a biopsy unless 5
`of 9 AST levels are elevated. If the first liver biopsy
`specimen reveals normal results, repeated liver bi-
`opsy would be dictated by the guidelines in Table III.
`Patients with one or more risk factors for hepato-
`toxicity need be followed up with the more stringent
`guidelines (Table IV). If the risk-benefit analysis for a
`patient with such risk factors favors the use of
`methotrexate, then this patient should have a liver
`biopsy performed at or near the beginning of meth-
`otrexate therapy. As some patients will discontinue
`methotrexate within 2 to 6 months because of
`adverse effects or lack of clinical effectiveness, it is
`sensible to postpone the early treatment liver biopsy
`until after this initial period. There is little to no
`evidence to suggest that a several-month period of
`methotrexate treatment will cause clinically signifi-
`cant liver disease. In patients with risk factors for
`
`liver disease, a repeated biopsy should be performed
`at a cumulative dose of 1.0 to 1.5 g. In patients with
`persistent significant abnormalities in liver chemistry
`values, a liver biopsy is also indicated. The liver
`biopsy in these patients at higher risk should be
`repeated with every additional 1.0 to 1.5 g of
`methotrexate.
`Serum assays for liver fibrosis are now widely
`accepted and recommended in Europe as a means of
`eliminating or decreasing the need for liver biopsies.
`Measurement of the amino-terminal peptide of pro-
`collagen III is the most used marker. One study using
`the amino-terminal peptide of pro-collagen III assay
`demonstrated a 7-fold reduction in the number of
`liver biopsies by the use of this assay.45 The amino-
`terminal peptide of pro-collagen III assay is generally
`not available in the United States. New develop-
`ments such as magnetic resonance elastography46
`and the enhanced liver fibrosis panel47 could like-
`wise further reduce the need for liver biopsies in the
`future. FibroSpect, II (Prometheus Laboratories, San
`Diego, CA) and FibroSure (LabCorp, Burlington, NC)
`tests for liver fibrosis, although unproven to aid in
`the diagnosis of methotrexate-induced fibrosis, are
`available in the United States and could be consid-
`ered as possible alternatives for patients in whom
`liver biopsy is technically difficult or contraindicated.
`
`Pregnancy
`Methotrexate is an abortifacient and a teratogen. It
`is FDA pregnancy category X and is contraindicated in
`women attempting to conceive. Methotrexate-in-
`duced fetal abnormalities include cardiac, skeletal,
`and central nervous system defects.48 Women of
`childbearing potential who are sexually active and
`are being treated with methotrexate must use contra-
`ception. Although the critical period of methotrexate
`
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`J AM ACAD DERMATOL
`VOLUME 61, NUMBER 3
`
`Menter et al 457
`
`exposure is thought to be between 6 to 8 weeks after
`conception, fetal abnormalities have been reported at
`all times of exposure to methotrexate. Conversely,
`numerous first-trimester pregnancies with exposure to
`large doses of methotrexate (primarily for the treat-
`ment of leukemia) have resulted in live births with no
`congenital or developmental problems.49 Because
`methotrexate is widely distributed in maternal tissues
`and may persist in the liver for up to 3 months after
`exposure,50 it is appropriate for women to wait 3
`months after discontinuing methotrexate before at-
`tempting to conceive a child.
`
`Male fertility
`Methotrexate is not mutagenic but spermatogen-
`esis studies in rats suggest that it may be toxic to
`cells undergoing division.51 In human beings, there
`is controversy regarding the effect of metho-
`trexate on spermatogenesis52; the teratogenicity of
`methotrexate in fetus fathered by men who are on
`methotrexate is unclear because of a lack of data.
`Although some studies suggest that methotrexate
`treatment may result
`in severe, yet
`reversible,
`oligospermia despite normal hormone levels,53
`other studies reveal no changes in spermatogenesis
`and sperm counts.54,55 One cycle of spermatogen-
`esis requires 74 days thus it is appropriate for male
`patients to wait 3 months after discontinuing meth-
`otrexate before attempting to conceive a child to
`allow for the methotrexate effects to be eliminated.
`
`PEDIATRIC USE
`Methotrexate is FDA-approved for the treatment of
`psoriasis in adults and for juvenile rheumatoid arthri-
`tis. Although there are only a few reports on the use of
`methotrexate for the treatment of pediatric psoriasis,56
`the use of methotrexate in children for several different
`dermatologic and rheumatologic conditions has been
`recently reviewed.57 In general,
`low-dose weekly
`methotrexate is well tolerated in children. Primary
`side effects seen in children include abnormal liver
`function test results, stomatitis, and gastrointestinal
`irritation. When interpreting the data for the use of
`methotrexate in children, it is important to be aware
`that the majority of the published studies derived from
`the rheumatology literature where patients are often
`treated with concomitant oral corticosteroids. These
`authors suggested that most pediatric patients can be
`monitored for hepatotoxicity according to the rheu-
`matologic liver biopsy guidelines recommended for
`adults without risk factors.
`
`Drug interactions
`Numerous medications may interact with meth-
`otrexate by a variety of mechanisms that can result
`
`Table V. Medications that may increase
`methotrexate toxicity
`
`Nonsteroidal
`anti-inflammatory
`drugs
`
`Antibiotics
`
`Others
`
`Salicylates
`
`Trimethoprim/
`sulfamethoxazole
`Sulfonamides
`Naproxen
`Penicillins
`Ibuprofen
`Minocycline
`Indomethacin
`Phenylbutazone Ciprofloxacin
`
`Barbiturates
`
`Colchicine
`Dipyridamole
`Ethanol
`Phenytoin
`Sulfonylureas
`Furosemide
`Thiazide-diuretics
`
`Adapted with permission from Kalb et al.4
`
`in elevated drug levels, thereby increasing the risk
`for methotrexate toxicity (Table V). After absorp-
`tion, methotrexate binds
`to serum albumin.
`Salicylates, sulfonamides, diphenylhydantoin, and
`antibiotics including pen