REVIEW
`
`Methotrexate and psoriasis: 2009 National Psoriasis
`Foundation Consensus Conference
`
`Robert E. Kalb, MD,a Bruce Strober, MD, PhD,b Gerald Weinstein, MD,d and Mark Lebwohl, MDc
`Buffalo and New York, New York; and Irvine, California
`
`Background: Methotrexate remains a valuable option for the treatment of psoriasis. This report will
`summarize studies regarding the use of methotrexate since the last guidelines were published in 1998.
`
`Objective: A task force of the National Psoriasis Foundation Medical Board was convened to evaluate
`treatment options. Our aim was to achieve a consensus on new updated guidelines for the use of
`methotrexate in the treatment of psoriasis.
`
`Methods: Reports in the literature were reviewed regarding methotrexate therapy.
`
`Results: A consensus was achieved on use of methotrexate in psoriasis including specific recommenda-
`tions on dosing and monitoring. The consensus received unanimous approval from members of the
`Medical Board of the National Psoriasis Foundation.
`
`Limitations: There are few evidence-based studies on the treatment of psoriasis with methotrexate. Many
`of the reviewed reports are for the treatment of rheumatoid arthritis.
`
`Conclusions: Methotrexate is a safe and effective drug for the treatment of psoriasis. Appropriate patient
`selection and monitoring will significantly decrease the risks of side effects. In patients without risk factors
`for hepatic fibrosis, liver biopsies may not be indicated or the frequency of liver biopsies may be markedly
`reduced. ( J Am Acad Dermatol 2009;60:824-37.)
`
`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 con-
`cerning its efficacy and side effects are sparse.
`Monotherapy and combination therapy with metho-
`trexate continue to be widely used in dermatology
`primarily in psoriasis and psoriatic arthritis, and for
`diseases as varied as sarcoidosis, dermatomyositis,
`and pyoderma gangrenosum.1-3
`The treatment of psoriasis has changed dramati-
`cally in the past decade. There has been an explosion
`
`of basic research and clinical research. Five biologic
`agents—alefacept, efalizumab, etanercept,
`inflixi-
`mab, and adalimumab—have been approved by
`the Food and Drug Administration (FDA) for the
`treatment of psoriasis. A sixth biologic agent, uste-
`kinumab, 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
`
`From the Departments of Dermatology: State University of New York
`at Buffalo, School of Medicine and Biomedical Science, Buffaloa;
`New York University School of Medicineb; The Mount Sinai School
`of Medicine, New Yorkc; and University of California at Irvine.d
`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, con-
`sultant, and/or
`investigator
`for Abbott, Amgen, Astellas,
`
`Genentech, Centocor, and Wyeth. Dr Weinstein has been an
`investigator for Abbott Labs, Amgen, Genentech, and Cento-
`cor. Dr Lebwohl has received consulting fees, speaking fees,
`and/or honoraria from Abbott, Amgen, Astellas, Centocor,
`Genentech, Stiefel and Novartis.
`Reprint requests: Mark Lebwohl, MD, 5 E 98th St, 5th Floor, New
`York, NY 10029. E-mail: Lebwohl@aol.com.
`0190-9622/$36.00
`ª 2008 by the American Academy of Dermatology, Inc.
`doi:10.1016/j.jaad.2008.11.906
`
`824
`
`Medac Exhibit 2042
`Koios Pharmaceuticals v. Medac
`IPR2016-01370
`Page 00001
`
`

`

`J AM ACAD DERMATOL
`VOLUME 60, NUMBER 5
`
`Kalb et al 825
`
`Abbreviations used:
`
`ACR:
`ALT:
`AST:
`CDC:
`
`American College of Rheumatology
`alanine aminotransferase
`aspartate aminotransferase
`Centers for Disease Control and
`Prevention
`Food and Drug Administration
`FDA:
`nonalcoholic steatohepatitis
`NASH:
`NSAID: nonsteroidal anti-inflammatory drug
`PASI:
`Psoriasis Area and Severity Index
`PIIINP:
`aminoterminal peptide of procollagen III
`PPD:
`purified protein derivative
`PUVA:
`psoralen plus ultraviolet A
`
`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 pso-
`riasis 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 dis-
`ease, 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.
`treatment of
`Methotrexate was approved for
`rheumatoid arthritis in 1988 and guidelines pub-
`lished 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 rou-
`tine 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 sever-
`ity, quality of life, and general medical and psycho-
`logical status.
`
`METHOTREXATE EFFICACY IN PSORIASIS
`Three recent blinded studies have been published
`concerning the efficacy of methotrexate in psoriasis.
`Heydendael et al6 compared methotrexate to cyclo-
`sporine without a placebo arm. There were approx-
`imately 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 abnor-
`mally elevated liver function tests, although no folic
`acid supplementation was given to the enrolled
`patients. The mean dose of methotrexate at the
`primary end point was not
`stated. Flytstrom,
`Stenberg, and Svensson7 also compared methotrex-
`ate to cyclosporine without a placebo arm. Eighty-
`four patients were randomized and 68 were included
`in the analysis. The mean PASI change from baseline
`was 72% in the cyclosporine group and 58% in the
`methotrexate arm. Cyclosporine was statistically
`more effective, but more patients dropped out
`from this arm. The mean dose of methotrexate at
`the primary end point was not stated. Saurat et al8
`reported a double-blind, controlled study of metho-
`trexate versus adalimumab in 250 patients. A placebo
`arm was also included; therefore this was the first
`placebo-controlled analysis of methotrexate for the
`treatment of psoriasis. The primary end point of PASI
`75 achievement at 16 weeks was 19% for the placebo
`arm, 36% for the methotrexate group, and 80% for
`the adalimumab group. The methotrexate was dosed
`7.5 mg for the first 2 weeks, 10 mg for the next 2,
`15mg for the next 4, and could be slowly increased
`thereafter depending on the response and the pres-
`ence or absence of
`laboratory abnormalities.
`Importantly,
`if, after week 8, a subject receiving
`methotrexate had achieved a PASI 50 response, no
`
`Page 00002
`
`

`

`826 Kalb et al
`
`J AM ACAD DERMATOL
`MAY 2009
`
`subject’s methotrexate
`increase in that
`further
`dose was allowed. After 16 weeks, the mean meth-
`otrexate dose was 19 mg. This group was then
`crossed over to receive adalimumab, although the
`response to methotrexate was still increasing and the
`maximum response may not have been reached.
`These two issues suggest that this study may have
`underestimated the true efficacy of methotrexate in
`psoriasis.
`
`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 eleva-
`tion warrants closer monitoring
`3. Hepatitis, active or recurrent
`4. Cirrhosis
`5. Excessive current alcohol consumption—there
`are few data to support specific limits on alco-
`hol consumption. Some physicians advise pa-
`tients
`to refrain from alcohol
`altogether,
`whereas others allow as much as two drinks
`per day. A history of alcoholism is problematic
`if there is evidence of liver damage.
`6. Concomitant use of hepatotoxic drugs (see drug
`interactions below)—more frequent monitoring
`of liver function tests may be necessary.
`7. Active infectious disease, especially chronic in-
`fections likely to be exacerbated by methotrex-
`ate’s immunosuppressive effects—for example,
`active untreated tuberculosis or advanced HIV
`infection. During acute infections, methotrexate
`can be temporarily withheld.
`8. Immunosuppressed state; this does not apply to
`patients receiving treatment with other agents,
`such as biologic therapies.
`9. Conception should be avoided during metho-
`trexate therapy and afterward for at
`least 3
`months in the male or one ovulatory cycle in
`the female.
`10. Recent vaccination, especially with live vaccine
`11. Obesity (body mass index greater than 30)
`12. Diabetes mellitus
`13. Unreliable patient
`
`The following are absolute contraindications to
`the use of methotrexate for psoriasis:
`
`1. Pregnancy or nursing
`
`2. Significant anemia,
`cytopenia
`
`leukopenia, or
`
`thrombo-
`
`Circumstances may arise in which the contraindi-
`cations must be waived such as when benefits can be
`expected to outweigh the risks of methotrexate
`therapy in an individual patient. For example, if an
`obese, diabetic patient needed short-term metho-
`trexate therapy, it might be reasonable to prescribe
`short-term methotrexate
`despite
`the
`relative
`contraindications.
`
`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 con-
`sist of the following studies:
`
`1. Complete blood cell count and platelet count
`2. Renal function tests (blood urea nitrogen and
`serum creatinine); calculated glomerular filtra-
`tion rate or creatinine clearance when indicated;
`the Cockroft and Gault formula10 can be used to
`estimate the creatinine clearance in adults:
`
`F or men : Estimated creatinine clearance
`¼ ð140 Age ðyrsÞÞ 3 Body Weight ðkgÞ
`divided by ð72 3 Serum Creatinine
`ðmg=dlÞÞ
`
`F or women : Estimated creatinine clearance
`¼ Above formula 3 0:85
`
`3. Liver chemistry (alanine aminotransferase [ALT ],
`aspartate aminotransferase [AST ], alkaline phos-
`phatase, bilirubin, albumin); hepatitis B and C
`serology tests when indicated. While some ex-
`perts advocate hepatitis serologies in all patients
`before methotrexate therapy, others do not ob-
`tain viral titers unless there is additional evidence
`of viral hepatitis, such as elevated liver function
`tests.
`4. Pregnancy test, if indicated in a woman of child-
`bearing potential
`5. HIV antibody determination in patients at risk for
`HIV infection
`6. Some experts recommend a baseline purified
`protein derivative (PPD) test or other screening
`
`Page 00003
`
`

`

`J AM ACAD DERMATOL
`VOLUME 60, NUMBER 5
`
`Kalb et al 827
`
`the
`tuberculosis, particularly if
`for latent
`test
`patient’s history indicates risk. Some argue that
`this is not explicitly the standard of care, but the
`Centers of Disease Control and Prevention (CDC)
`Web site recommendations on tuberculosis sug-
`gest that any patient about to start immunosup-
`pressive drugs should be considered for a
`pretreatment PPD.11
`7. Consider baseline liver biopsy in patients with a
`history of significant liver disease (see Hepato-
`toxicity section below).
`
`CONTINUING LABORATORY STUDIES
`The following laboratory studies should be con-
`tinued 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 in-
`creasing the dose, every 2 to 4 weeks for the first
`few months, then approximately every 1 to 3
`months, depending on leukocyte count and sta-
`bility of patient. Patients with risk factors for
`hematologic toxicity (Table I) need closer mon-
`itoring, particularly at the onset of therapy and
`after dosage increases.
`2. Renal function studies: blood urea nitrogen and
`serum creatinine levels at 2- to 3-month intervals.
`For those patients with normal values, who may
`be at risk for decreased renal function, a glo-
`merular filtration rate should be calculated. Most
`commercial laboratories now report this value
`for all patients.
`3. Liver chemistries: ALT, AST, alkaline phospha-
`tase, and serum albumin levels every 4 to 12
`weeks (more frequent liver chemistry monitoring
`in lieu of an initial liver biopsy for patients with
`hepatic risk factors, see Table I).
`4. Pregnancy test if indicated in women of child-
`bearing potential.
`5. More frequent monitoring may be required under
`certain circumstances, such as dosage changes or
`if there are concomitant medications.
`
`A significant reduction in leukocyte or platelet
`counts necessitates reduction or temporary discon-
`tinuation of methotrexate therapy. The maximum
`depression of the leukocyte count and platelet count
`usually occurs 7 to 10 days after a dose of metho-
`trexate. Immediate administration of folinic acid (20
`mg) orally or intravenously should be considered in
`cases of clinically significant leukopenia or throm-
`bocytopenia. Progressively increasing mean corpus-
`cular volume is common in patients on a regimen of
`methotrexate and signals the onset of macrocytic
`
`Table I. Risk factors for hematologic toxicity from
`methotrexate
`
`Renal insufficiency
`Advanced age
`Lack of folate supplementation
`Medication errors
`Drug interactions
`Hypoalbuminemia
`Excess alcohol intake
`Multiple concurrent medications
`
`anemia. Folic acid administered orally in dosages of
`1 to 5 mg per day may prevent or reverse this side
`effect. Folinic acid given orally at 5 mg for 3 doses
`every 12 hours, once weekly, with the first dose 12
`hours after the last dose of methotrexate is also
`acceptable. Both types of folic acid supplementation
`are available in a generic form and are relatively
`inexpensive.
`When liver chemistry tests are obtained, there
`should be at least a 5-day interval between the last
`methotrexate dose and the blood tests because liver
`chemistry values may be elevated 1 to 2 days after a
`dose of methotrexate. If a significant persistent
`abnormality in liver chemistry develops, methotrex-
`ate therapy should be withheld for 1 to 2 weeks and
`then the battery of liver chemistry tests should be
`repeated. Liver chemistry values should return to
`normal in 1 to 2 weeks. If significantly abnormal liver
`chemistry values persist for 2 to 3 months, a liver
`biopsy should be considered if continuation of
`methotrexate therapy is desired.
`
`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 gastrointesti-
`nal side effects in some patients. Since medication
`errors can be a significant problem with methotrex-
`ate, it is of utmost important to ensure that patients
`understand the proper dose schedule.12 Patients in
`the United Kingdom carry a ‘‘methotrexate card’’ for
`proper administration and to calculate the cumula-
`tive dose.13
`The multi-dose vial can also be used for physi-
`cian- or patient-administered subcutaneous or intra-
`muscular
`injections. A recent blinded study in
`
`Page 00004
`
`

`

`828 Kalb et al
`
`J AM ACAD DERMATOL
`MAY 2009
`
`patients with rheumatoid arthritis compared subcu-
`taneous and oral methotrexate. This study revealed
`greater efficacy in the subcutaneous group with
`equal tolerability.14 Some patients may have de-
`creased gastrointestinal side effects when switched
`to subcutaneous administration from the oral route.
`With the advent of biologic therapy, more patients
`are familiar with self injection techniques.
`When methotrexate therapy is initiated, many
`experts recommend a ‘‘test dose’’ be administered
`and repeat laboratory tests for hematologic effects
`checked in approximately 7 days. Some experts
`recommend a small dose, such as 5 mg, whereas
`others start at the anticipated dose, such as 15 mg.
`This test dose practice is mandatory in any patient
`with a decreased calculated glomerular filtration rate
`or other significant risk factors for hematologic
`toxicity15 (Table I). Using a test dose also provides
`an additional safeguard against rare, idiosyncratic
`reactions to methotrexate.
`Doses are usually started with lower initial levels
`to minimize side effects and adjusted to achieve
`clinical effectiveness. Recent studies with other sys-
`temic therapies for psoriasis suggest that a weight-
`based dosing schedule may be more effective,16 but
`there are no published weight-based studies for the
`treatment of psoriasis with methotrexate.
`While there is not an established maximum or
`minimum dose,
`the weekly single or triple oral
`dosages are ordinarily 7.5 to 25 mg/wk. Reported
`schedules have been to start at lower doses (eg, 7.5
`mg/wk) and gradually increased, whereas others
`recommend starting at the anticipated target dose
`(eg, 15 mg/wk).
`All schedules should be adjusted to the individual
`patient. Patients on any schedule should have the
`dosage raised or reduced to obtain or maintain
`adequate disease control. It can take 4 to 8 weeks
`to see a response to changes in methotrexate dose.
`Some patients can be gradually weaned off therapy
`and restarted if the disease flares. The goal is to both
`decrease the total cumulative dose and improve
`tolerability.
`
`FOLATE SUPPLEMENTATION
`Some experts recommend all patients receiving
`methotrexate should receive folate supplementa-
`tion. 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
`
`hours, once weekly, with the first dose 12 hours after
`the last dose of methotrexate. Folate supplementa-
`tion reduces hematologic, gastrointestinal, and he-
`patotoxic side effects without decreasing the
`efficacy.17 A recent report18 using folic acid 5 mg
`daily suggests there is a slight decrease in efficacy,
`but the study’s methodology has been questioned.19
`We believe that the benefits of folate supplementa-
`tion greatly outweigh a slight decrease in efficacy, if it
`exists.
`
`METHOTREXATE TOXICITY
`The use of methotrexate is restricted by the risk of
`organ toxicity. The 3 primary concerns are myelo-
`suppression, hepatotoxicity, and pulmonary fibrosis.
`Of the 164 possible methotrexate-associated fatali-
`ties 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 serious
`side effect.13 Pulmonary fibrosis is much less com-
`mon in psoriasis patients treated with methotrexate
`compared to patients with rheumatoid arthritis,
`which is the reason a chest x-ray is not part of the
`routine baseline studies. Fibrosis should be consid-
`ered, however, if pulmonary symptoms develop.21,22
`The hematologic and hepatotoxicity issues are dis-
`cussed below.
`Common minor adverse events include nausea,
`anorexia, stomatitis, fatigue, and malaise often at the
`time the medication is taken. Clinical experience
`suggests these side effects may be diminished by
`folate supplementation, administering the metho-
`trexate by intramuscular or subcutaneous injection,
`splitting the dose, or by administering the dose at
`bedtime.
`The advent of biologic therapy has prompted a
`more thorough study of patients with psoriasis. Side
`effects, such as reactivation of
`tuberculosis and
`hepatitis, and the development of lymphoma have
`been reported in trials of biologic agents and in
`postmarketing observations. Since methotrexate has
`never been subjected to the same scrutiny, such
`potential toxicities or adverse effects have not been
`considered. More recent reports suggest that meth-
`otrexate therapy may be associated with risks similar
`to those of other immunosuppressive treatments,
`although these reports almost exclusively involve
`patients with rheumatoid arthritis. Lymphoma, par-
`ticularly Epstein-Barr virus associated, and the reac-
`tivation of tuberculosis and hepatitis have all been
`reported.23-26 A recent study showed a 50% increased
`risk of malignancy relative to the general population
`
`Page 00005
`
`

`

`J AM ACAD DERMATOL
`VOLUME 60, NUMBER 5
`
`Kalb et al 829
`
`with a 3-fold increase in melanoma, 5-fold increase
`in non-Hodgkin lymphoma, and nearly 3-fold in-
`crease in lung cancer.27 In short, clinicians need to
`have a high index of suspicion for any patient
`receiving immunosuppressive therapy.
`In discussing the side effects of methotrexate, we
`should also point out new data regarding unantici-
`pated benefits. A protective effect against cardiovas-
`cular disease has been demonstrated.28 It should be
`emphasized that recent reports suggest that metho-
`trexate is an anti-inflammatory medication that may
`have beneficial cardiovascular effects in a subset of
`patients.29 From this perspective, the benefits of
`methotrexate therapy in many patients may out-
`weigh the risks.
`
`METHOTREXATE AND HEMATOLOGIC
`TOXICITY
`The primary risk factors reported for hematologic
`toxicity are renal impairment, advanced age, lack of
`folate supplementation, drug interactions, and medi-
`cation 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 mye-
`losuppression is rare in properly monitored psoriasis
`patients without risk factors for hematologic toxicity.
`While pancytopenia is a rare side effect with the
`use of low-dose weekly methotrexate, it may occur
`at any time during treatment, particularly in those
`with hematologic risk factors.30,31 Rarely, significant
`cytopenia has been reported, even after single doses
`of low-dose methotrexate.31-34 In all cases, however,
`there were significant risk factors, particularly im-
`paired renal function or medication errors.
`Since pancytopenia may occur at any time during
`methotrexate therapy,
`it
`is important
`to monitor
`complete blood cell counts regularly. Patients should
`regularly be reminded of the proper use of their
`therapy and possible medication interactions. In
`some of the reported cases, pancytopenia occurred
`4 to 6 weeks after the methotrexate dosage was
`increased, so more frequent monitoring is suggested
`with such dose changes.
`In the absence of hematologic risk factors, such as
`renal
`insufficiency, pancytopenia with low-dose
`weekly methotrexate is rare. After methotrexate
`treatment has been initiated, it is necessary to mon-
`itor regularly for hematologic toxicity. The first
`repeat laboratory check should be within a 2-week
`period for patients without risk factors. The glomer-
`ular filtration rate should be calculated for those
`patients who have normal blood urea nitrogen and
`
`creatinine levels but are at risk for renal insufficiency,
`such as the elderly or those with a decreased muscle
`mass. This frequency of laboratory monitoring may be
`slowly decreased over time (1- to 3-month intervals),
`provided there are no problems or changes in the
`medical history. Some experts believe that complete
`blood cell counts should be performed at least every 4
`weeks, though others reduce the frequency of mon-
`itoring in patients whose conditions are consistently
`stable. Patients with significant renal impairment are
`at a high risk even after single doses of methotrexate.
`These patients require careful monitoring. Initial lab-
`oratory checks should be obtained before the second
`dose. After any dose increases, laboratories should be
`checked before the next dose is administered.
`
`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 rheuma-
`tologists 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 psoriasis
`than in patients with rheumatoid arthritis. The re-
`duced hepatotoxicity among patients with rheuma-
`toid arthritis is in part related to the higher incidence
`of rheumatoid arthritis in women who consume less
`alcohol than men. Patients with psoriasis have a
`higher
`incidence
`of
`obesity,
`diabetes,
`and
`alcoholism.37
`The histopathologic features of methotrexate-
`induced liver toxicity resemble nonalcoholic steato-
`hepatitis (NASH),
`the pattern of
`liver histology
`observed in people who are obese, hyperlipidemic,
`or diabetic. In fact, psoriasis patients with risk factors
`for NASH may develop liver fibrosis at a lower
`cumulative methotrexate dose than those without
`risk factors. Methotrexate likely aggravates preexist-
`ing NASH, implying that patients with psoriasis at
`greatest risk while receiving methotrexate are those
`with diabetes, obesity, and those who drink alco-
`hol.38,39 The presence of these risk factors may
`represent inherent phenotypes of psoriatic patients
`that
`increase the risk of hepatotoxicity. If these
`studies were controlled for such confounding vari-
`ables, then the methotrexate-related liver injury rate
`in patients with psoriasis would most likely resemble
`that of patents with rheumatoid arthritis.38,40,41
`Recently published updates suggest that when eval-
`uating a patient for methotrexate treatment, risk
`factors
`such as alcohol consumption, obesity,
`
`Page 00006
`
`

`

`830 Kalb et al
`
`J AM ACAD DERMATOL
`MAY 2009
`
`Table II. Risk factors for hepatic toxicity from
`methotrexate
`
`Table III. Monitoring for hepatotoxicity in low-risk
`patients
`
`History of or current alcohol consumption*
`Persistent abnormal liver chemistry studies
`History of liver disease, including chronic hepatitis B or C
`Family history of inheritable liver disease
`Diabetes mellitus
`Obesity
`History of significant exposure to hepatotoxic drugs or
`chemicals
`Lack of folate supplementation
`Hyperlipidemia
`
`*Methotrexate toxicity is associated with a history of total lifetime
`alcohol intake before methotrexate therapy. The exact amount of
`alcohol that confers risk is unknown and differs among persons.
`
`hyperlipidemia, diabetes, previous exposure to liver
`toxins, and hepatitis should be considered.39,42 In
`short,
`the clinical scenario of each patient must
`dictate the necessity of the liver biopsy.
`The updated guidelines suggest
`that patients
`being considered for methotrexate therapy be di-
`vided into two groups based on their risk factors for
`liver injury (Table II). Patients with no risk factors for
`liver injury likely have a low risk of fibrosis that is
`similar to that of RA patients; therefore the ACR
`criteria for monitoring methotrexate are applied to
`these patients by some experts. Specifically, every 1-
`to 3-month evaluation of liver chemistries with liver
`biopsy performed if 5 of 9 serum AST levels are
`elevated over a 12-month period or if there is a
`decline in the serum albumin (in the context of
`normal nutritional status) below the normal range in
`the setting of well-controlled disease (Table III). This
`approach was validated and displayed a safe reduc-
`tion in the number of biopsies performed.5,43 Other
`recent data suggest that 3.5 to 4.0 g instead of 1.0 to
`1.5 g of cumulative methotrexate should prompt the
`first liver biopsy in patients without preexisting risk
`factors for hepatotoxicity.38,44,45 In the presence of
`normal findings on liver chemistry tests, history, and
`physical examination, the decision to perform or
`omit liver biopsies for low-risk patients receiving
`methotrexate should be made on a case-by-case
`basis after consideration of the relative risk. Options
`for such patients who reach a cumulative dose of 3.5
`to 4.0 g include following the ACR guidelines and
`continuing to monitor without a biopsy, performing
`the first biopsy at this 3.5- to 4.0-g level, or stopping
`or switching methotrexate to another therapy if
`possible. If this first liver biopsy shows no significant
`abnormalities in these low-risk patients, repeat liver
`biopsies would be dictated by following the ACR
`guidelines shown in Table III.
`
`No baseline liver biopsy
`Monitor liver function tests monthly for the first 6 months
`and then every 1 to 2 months thereafter.
`/ For minor elevations (\2-fold upper limit of normal),
`repeat in 2 to 4 weeks.
`/ For moderate elevations ([2-fold but \3-fold upper
`limit of normal), closely monitor, repeat in 2 to 4
`weeks, and dose reductions as necessary.
`/ For persistent elevations in 5 of 9 AST levels over a
`12-month period or if there is a decline in serum
`albumin with normal nutritional status below the
`normal range in the setting of well-controlled
`disease, liver biopsy should be performed.
`Consider continuing to follow according to above ACR
`guidelines without biopsy
`Or
`Consider liver biopsy after 3.5 to 4.0 g total cumulative
`dosage
`
`Or
`Consider switching to another agent or discontinuing
`therapy after 3.5 to 4.0 g total cumulative dosage.
`
`ACR, American College of Rheumatology; AST, serum aspartate
`aminotransferase.
`
`There is consensus that those patients with one or
`more risk factors for hepatic fibrosis should be
`followed with the previously published more strin-
`gent guidelines (Table IV). If a patient has significant
`risk factors, then the first consideration should be the
`feasibility of using a different systemic agent. If the
`risk/benefit consideration for an individual patient
`with such risk factors favors the use of methotrexate,
`then it is advisable that a liver biopsy be done, when
`feasible, at or near the beginning of methotrexate
`therapy. A small p