Skin therapy tettert lM)
`v. 6, no. 3 (2000 )
`General Collection
`Wt SKSQQP
`Received: 01-16-2001
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`
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`
` K.C. Smitl
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`Dunn-u mmuur u mm
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`
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`Niagara Flis‘
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`-11 ‘_.
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`
` «is.urrosritttnnnin)
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`MEDICINE
`
`ABSTRACT
`
`KEY WORDS: psoriasis. iitetitotrertite, systemic therapy
`
`Uniethotrextite were introduced (it ct tteivdrttg today, it would be hailed" as (t major advance in tire titriiiogeirieirt of
`psoriasis. as weli as for it another of other conditions. Because tire patent on iiieiitoiremte expired decades ago, this
`medication has not recently received the attention it deserves. When patients are properly screened and educated about the
`correct use ofiiretiiotrerote. and appropriately irioiiitored during ti'etitiiieiti. this drug is (i so e. inexpensive, tvcli-tolcroteti
`rind effective riiedicntioti for the count)! ofpsoritisis.
`
`
`
`
`
`In |95l Girbnei" reported improvement in psoriatiCs treated with
`the I'oiatc antagonist nminopteiin. hut clirtical rise was limited by
`mucosal and GI sidevel't'ects. In [958. Ediittrndson and Guy1
`reported good control of psoriasis witlt aruelliopter'in. or
`iriettrotrcxatc lMTX), an analog of aiiiinopterin.
`
`MTX can produce a number of side-effects. particiiiarly GI and
`liver toxicities. However. administration of [hire acid has been
`shown to reduce or eliminate the GI distress sonrctintcs iISSOCIEIItitI
`
`with MTX, and does not interfere with its efficacy." Several
`dil'l'ci'enl dosage schedules have been reported to be el’l‘cctivc. The
`author finds llinrg of folic acid po once a week with MTX
`{regardiess ol' the dosage of MTX) is both simple and effective
`Folinic acid chticovoi'in). by contrast. reduces the efficacy of
`MTX". and should be administered as an antidote in crises of
`MTX overdose.
`
`Studies in animals denurnstralcd that MTX toxicity was more
`closely related to duration of contact with tissues than with total
`dose. and in 1963. Berlin1 suggested that an intermittent dosage
`schedule might improve the therapeutic index, The current
`practice in dermatology is to administer MTX as a single dose
`once a week. or in three divided doses i2 hotirs apart. to reduce
`GI discomfort. There is no evidence that three divided doses 12
`
`hours apart is safer. and there are occasional reports of serious or
`lethal toxicity when patients mistakenly take MTX every I?
`hour's. everyday of the week.
`
`Mechanism ofAction
`
`leTX is one of the most effective systemic therapies for psoriasis.
`but the mechanism of action is not completely understood. The
`proliferating lymphoid cells THF-l (macrophages) and MOLT-d
`[T-cclis) are over 1000 times more sensitive to MTX than
`keratinocytcs at the concentrations seen iit vivo with oncc~weekly
`therapy!l Low-dose MTX also promotes the intracellular
`accumulation of S-trniinoiinidazolc-tl-carboitamide ribonuclcotide
`tAlCAR) by inhibiting AICAR transformylasc. Under conditions
`of cell injury. AICAR increases the release of the autocoid
`adcttosiitc. a potent tintiiriilantmatory agent?
`
`Patient Selection and Management
`
`The best candidates for treatment with MTX are those patients
`who, in addition to lacking contraindications to ntcthott'cxate,
`arc hottest. reliable and realistic. Patients artist be willing to
`avoid alcohol consumption while taking methoirexate. and
`should be willing to continue topical medications to reduce the
`dose of ineiliotrexate required to obtain an adequate degree oi
`control ol' their psoriasis.
`
`Patients should be instructed to obtain ALL of their medications
`from a SINGLE pharmacy. to reduce the chances of drug
`interaction. A letter should be sent to every physician who is
`caring for the patient. informing them that Mix is being started.
`
`
`I;I)I'lUR; Stuart .\l-.tdrliii ASSUL'JM E ElIl'iUII [lirtvr'rtttlitiitttl]: Ilngrr Ilcgrccf. l'alhnlic Uiiivcnity. Lclivcn: ASSI)(‘I.\'I'E EDITOR li'arrada}: Jason Ilircrs
`y.
`IN'I MINE] IEI)t'[IJli: llancy ltr‘i MANAGING L'l)|'['fll7.: l’cuclopr: (
`Allan [EDITORIAL ADVISUIW IIIMIID: Kenneth .\. .\ririll_ llclli Israel Hospital ii Harvard Medical School. Boston;
`\\"iliu:I Forth" llcrgicltl. (‘Icvclalitl Clinic. ('lcvclil
`III IL ISM. Uri
`
`
`
`I
`tyol'Airrsturduiu. Nasturtium: [itrrtri Lhrisloplrc
`
`irir-crsirjts-llarltltliriik. Kiel; llicltartl L. llrilrsrnr
`Icilical University
`til‘Sorrtlt I‘irt‘irliriir. ('liarlcslur'i: lion
`3. F
`Iski. Un
`'hool tirML‘lllEllIL‘. Iloitoli‘. W. Andrew I). Gr'l'l't is. St. Johns liislitulc
`ton Altilniina. llirniinghnnr Barbara a. [:i'lcliresl. Hinton L'nivch )
`
`
`.
`rtitiiin
`Irlitya K. Cup
`. linivcri
`iri'l'orrrnln. 'lirron‘
`i ('oltnnhia. Vilitt'ntlvcr: M' rli Letitith Mount Sinai Medical Center. New York:
`
`
`
`
`
`Universi y ol‘ [’cnrnylv.
`iii. Philadelphia; Ilcltrnnl I. Mar arch, Unru
`ty Ell-(:Jlilbnll'll Ilursntt
`til. San Francisco: Larry E. Millikan. Tulane University Medical Center. New Orleans:
`
`
`ii: Uriivmititts Berlin. Uiiir'c
`- ii a. Kvio University School ril‘hluliclne. Tokyo: Constantin Ii. Urfirrros. T
`' " sklitlilvttint Bcrijtirniu i-‘rtrtrliiin. Berlin; Stephen 1.. Sucks. Viririac Clinic
`
`Sea-rim. \“tiricuru-er: .tlrrn It. Slinliin. SUNT lliurlllr Suit-rice: ('t-iiiur. timisldyn: Slcplicn it
`re. thin-unity ol'Trnni Medical Branch. (intrusion: John Tot-titers. University nl'illir'liigira. Ann Arbor:
`Klaus Wolll. Uriivenity riiVirmra. Vienna
`atthe NLM and m 3y be
`Eu than US Copyright Laws
`
`
`
`and a copy of alt bloodwork should be ordered for each treating
`
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`physician. Patients who do not have a family doctor should not be
`offered methotrexate unless your office is set up to deal with
`bloodwork abnormalities, regardless of whether you are available.
`Patients who do not cooperate with the regular bloodwork
`necessary for the safe use of this drug should be warned firmly,
`and a letter about this warning should be sent to each of the
`patient's doctors. If non-cooperation continues, MTX must be
`stopped. Documentation about the patient‘s history with regard to
`MTX, whether MTX was well tolerated, and the cumulative dose
`of this drug is important.
`
`It is also important to document the justification for offering to
`prescribe MTX (e.g., the extent and location of the psoriasis, and
`the impact the psoriasis is having on the patient‘s life,
`employment and relations with others).
`
`Patient Information
`
`Prior to starting MTX, patients must be educated about the
`precautions necessary for the safe use. Discuss the need for
`contraception with women who are candidates for treatment with
`methotrcxate. Women must avoid pregnancy while taking this drug
`and for 3 months after stopping it because it has been associated
`with teratogenicity. There is no evidence that MTX has any
`adverse effect on spermatogenesis or fertility in men at the doses
`used in dermatology, and men should be reassured about this.
`
`Management
`
`Prior to starting MTX, and from time to time during treatment, a
`list of the patient’s prescription and non-prescription medications
`(including "natural" or herbal remedies) should be reviewed, and
`the patient again cautioned to avoid atcolrol consumption.
`Laboratory studies prior to starting MTX should include CBC,
`SGOT, alkaline phosphatase, bilirubin, creatinine, serum albumin,
`and hepatitis B and C serology. As well, HIV-l should be checked
`in those at risk for HIV. However, MTX ltas been used
`Successfully to treat psoriasis in HIV infected patiertts.as CBC and
`SGOT should be repeated twice a month for the first two months
`of treatment, then monthly while the patient is taking MTX. The
`
`SGP’I‘ should NOT be tested. it is frequently elevated when there
`is no clinical problem, leading to an unacceptable number of
`“false alarms".
`
`The Roenigk classilication of liver biopsies (Grades 1-4)‘J has
`been criticized because it was adapted from a classification
`
`system developed many years ago for use in primary biiiary
`cirrhosis where portal inflammation is the major feature. For this
`reason, it is not an ideal classification tool for assessing MTX
`toxicity, which tends to produce centrilobniar changes.
`
`
`
`The starting dose of MTX in an adult is usually in the range of
`lO—ISrng at bedtime, once a week. Improvement in psoriasis is
`usually seen within 4-8 weeks. Tire dose may be increased to
`25mg once a week if necessary. Topical medications and UVB or
`PUVA are usually continued in order to reduce the long-term need
`for MTX. Phototosicity associated with MTX has been reported,
`but is very rare in clinical practice, and MTX is often used
`successfully with UVB or PUVA.
`
`When a patient has impmved to a satisfactory degree, the dose of
`MTX can be adjusted each week within a specified range (e.g..
`between 2.5- lSmg once a week), as necessary. This is done in
`order to maintain adequate (but not necessarily perfect) control of
`the psoriasis, and often allows for a lower cumulative dose of
`
`
`Larisa/stagnant . I '
`Drug
`
`increased hepatotoxicity of MTX
`
`0 Alcohol
`' Etretinate
`
`
`
`Hepatitis in low-dose therapy is not commonly seen, and may be
`tnore common in patients receiving corubination therapy with
`etretinatc, in those with heavy alcohol consumption, or in those
`with a higher total cumulative dose of methotrexate. Some drugs
`that can affect the toxicity of MTX are listed in Table l. Liver
`biopsy is generally not performed prior to starting MTX in
`otherwise healthy patients. However, each prescription for this
`drtrg should be recorded in a flow chart, and when the total dose
`reaches 1.5grn, the patient should be referred to a
`gastroenterologist for consideration of a liver biopsy. As a general
`rule, a liver biopsy is not performed in healthy. young, tron—obese,
`non-diabetic patients who have normal liver function studies.
`Patients should return to the gastroenterologist for reassessment
`each time the total dose of MTX increases by [.5grn.
`
`
`
`' Sulfonamides
`Increased effects and toxicity of MTX
`- Other antineoplastics
`' Folinic acid (Leucovorin)‘(nsed as antidote for overdose)
`- NSAIDS
`
`Reversal of MTX action
`
`Decreased renal elimination
`
`Increased antifolate effect
`
`Decreased MTX effect
`
`' Aspirin
`' Probenecid
`
`' Cyclosporin
`' Other nephrotoxins
`
`° Phenytoin
`
`- \leomycin [oral] with oral MTX
`
`Table 1: Drugs that may effect the toxicity of methotrexate
`
`This material was copied
`Skin Therapy Lertaemwrfaflmtflndrfin- Vof.6 No. 3
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`Subject US Copyright Laws
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`cotttfttttcdfl‘flttt page 2
`MTX than would be the case if the patient was maintained on a
`fixed dose. e.g.. 15mg once a week.
`
`Rotational Ther'apy
`
`The successful use of “rotational therapy" (e.g., switching every
`3-6 months between several treatments including methotrexate,
`
`cyclosporine, acitretin and PUVA) depends on many variables.
`including the patient’s finances, ability to attend on a regular basis
`for UV light treatment, underlying medical Conditions, and
`medications. The increased complexity and cost of rotational
`therapy is sometimes justified by the reduced long-term load on
`any one organ system:
`
`' Vlethotrexate — liver damage
`
`° Cyclosporine — altered kidney function
`' PUVA — skin
`
`- Acitrctin — elevated lipids.
`
`Conclusion
`
`Methotrexate is an effective medication for the control of
`
`psoriasis. When patients are properly screened and educated about
`the correct use of this drug, and appropriately monitored during
`
`treatment, MTX is often very safe, simple to use. inexpensive,
`and well~tolerated
`
`References
`l. Gtrbner R. Effect of "aminopterin" on epithelial tissues. Arch Domingo! Sipttilot
`{2-12638-(199 (I951).
`31. Edmundson WF, Guy WIS: Treatment of psoriasis with Folic acid antagonists. Arch
`Der ttttttnt “2200-2113 (I953).
`3. Berlin N! (Moderator). Folic acid antagonists: effects on the cell and the patient.
`Combined clinical statl' conference at the National Institutes of l tealth. (inn Intent
`Med 59:9] t-‘JSfi (I‘Jt'fi).
`4, Morgan SL, Bagged IE, Vaughn Wll, ct al. The etfect of little acid
`supplementation on the toxicity of low-dose titcihotreitatc in patients with
`rheumatoid arthritis. Arthritis Rtrerrirr 33:9-18 (199m.
`5. Guzzo C, liutic acid supplementation with ntelhotresate therapy: what benefit if
`any? J dirt r‘lcttd' Dcrrnrrt'ot “(4)1689 (I994 Oct).
`Jeffes EWLt Ill. McCullough JL. Pittelkotv MR. or at. Melttotresate therapy of
`psoriasis: differential sensitivity of proliferating lymphoid and epithelial cells to
`cytotoxic and grutht-ilthihitory effects of melhotresate. J Invest Dct'trrrttol'
`1040): IBM {1995 Feb).
`7. Cronstein BN. Naime D. Grant! E. The atttiirtflammatory mechanism of
`methotreitalc. Increased adenosine release at inflamed sires diminishes leukocyte
`accumulation in an ill vivo model of inilannnation. J Clin Fttl‘t'i't93lfi):15T5-33
`(1993 Dec).
`ti. MattrerTA, Zucklreim HS, Tut'l'nneili L. Berger TO. The use ofmetltotrcxate for
`treatment of psoriasis in patients with Ith infection. J IIIHI tit‘ttrt Derturttoi' 3H1 I’l
`3072—5 [I994 Aug}.
`ltoenigk l-lll Jr. Auerhnch R, Maibach ill and Weinstein GD. Metltotrcttatc in
`psoriasis: Revised guidelines. J Artir‘lcrtrt Dcrtrrrrtol' 19H Pt I):|45-56 (I988 Jul),
`
`(1.
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`IJ.
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`
`US FDA Advisory Committee Recommends
`Approval for Tocrolimus Ointment
`The US FDA Dermotologic ond Ophthalmic Advisory Committee recommended in November 2000, that Fuiisowo's Protopr'c
`Ointment ltocrolimus] be approved For the treatment of moderatoto-sevcre otopic dermatitis in children and adults.
`
`Atopic dermatitis, or eczema, is on increasingly common pruritic dermatosis thot is believed to be triggered by an imbalance
`in the immune system. Tocroiimus is the first of a new generation of topical immunomodulotors that bring about clinical
`improvement by modulating the patients immune response and is the first to be recommended For approval by the FDA.
`
`FUiisowq presented date: from clinical studies conducted worldAWide, in which children and adults were treated For l2
`weeks to 1 your. The US clinical trials were double'blind, placebo controlled, and patients were rondomized to apply
`either 0.03% tocrolimus, 0.1% tocrolimus or placebo twice daily. Both concentrations oi Protopr'c significantly improved or
`completely cleared the signs and symptoms 0F otopic dermatitis in 32/3 oi the patients.
`The Committee recommended the 0. l % concentration to treat adults. The tower 0.03% concentration was recommended
`tor children, and For odults who are undergoing long-term intermittent therapy, and are intolerant of, or are not
`ode uotcly responsive to, conventional treatment. Protopi‘c was not recommended as o first-line therapy. Committee
`mom ers Felt that patients should begin with treatments that have well characterized sototycproliles, e.g., corticosteroids.
`Tocroiirnus is steroid Free and provides o welcome addition For the management of otopic
`ermotitis, since many patients,
`as well as parents, are lootho/olroid to use corticosteroids.
`
`Skin burning and itching associated with the application of Protopic was reported, however, these events seemed to
`decrease as the disease improved1 The effects of ultraviolet light on skin treated with Protopt'c are not known. Marty
`committee members expressed concern about this and recommended that patients using Protopt'c should use soie sun
`practices to ovoid exposure to natural or ortilicictl sunlight.
`
`Fuiisowo put forward 0 New Drug Submission to Canada’s Therapeutics Products Program [TPF‘] [formerly HPBOItowo] in
`July 2000, For this product, and phase III clinical trials are underway. In Japan Protopr'c 0. I% was approved in l999. A
`decision by the FDA is expected in the next 6-8 weeks.
`
`JUST ANNOUNCED! On December 8, 2000, the US FDA granted approval of this topical immunomodulotor in the
`recommended concentrations for the treatment oi otopic dermatitis. Next issue {volume 6, Issue 4] Topicol Tucrolimus,
`SJ. Frankel and F. Kerdel.
`
`This materialwas copied
`Skin Therapy hem: Wendflnafihlrt Mmfdtn - Vat. 6 No. 3
`Subject US Copyright Laws
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