Guidelines of care for the management of psoriasis and psoriatic arthritis

Transcription

1 FROM THE ACADEMY Guielines of care for the management of psoriasis an psoriatic arthritis Section 4. Guielines of care for the management an treatment of psoriasis with traitional systemic agents Alan Menter, MD, Chair, a Neil J. Korman, MD, PhD, b Craig A. Elmets, MD, c StevenR.Felman,MD,PhD, Joel M. Gelfan, MD, MSCE, e Kenneth B. Goron, MD, f AliceB.Gottlieb,MD,PhD, g John Y. M. Koo, MD, h Mark Lebwohl, MD, i HenryW.Lim,MD, j Abby S. Van Voorhees, MD, k Karl R. Beutner, MD, PhD, l an Reva Bhushan, PhD m Dallas, Texas; Clevelan, Ohio; Birmingham, Alabama; Winston-Salem, North Carolina; Philaelphia, Pennsylvania; Chicago an Schaumburg, Illinois; Boston, Massachusetts; San Francisco an Palo Alto, California; New York, New York; an Detroit, Michigan Psoriasis is a common, chronic, inflammatory, multisystem isease with preominantly skin an joint manifestations affecting approximately 2% of the population. In this fourth of 6 sections of the guielines of care for psoriasis, we iscuss the use of traitional systemic meications for the treatment of patients with psoriasis. Treatment shoul be tailore to meet iniviual patients nees. We will iscuss in etail the efficacy an safety, an offer recommenations for the use of the 3 most commonly use, an approve, traitional systemic agents: methotrexate, cyclosporine, an acitretin. We will also briefly iscuss the available ata for the use of azathioprine, fumaric aci esters, hyroxyurea, leflunomie, mycophenolate mofetil, sulfasalazine, tacrolimus, an 6-thioguanine in psoriasis. ( J Am Aca Dermatol 2009;61: ) DISCLAIMER Aherence to these guielines will not ensure successful treatment in every situation. Furthermore, these guielines shoul not be eeme inclusive of From the Baylor University Meical Center, Dallas a ; Murough Family Center For Psoriasis, Department of Dermatology, University Hospitals Case Meical Center, Clevelan b ; Department of Dermatology, University of Alabama at Birmingham c ; Department of Dermatology, Wake Forest University School of Meicine, Winston-Salem ; Department of Dermatology an Center for Clinical Epiemiology an Biostatistics, University of Pennsylvania e ; Division of Dermatology, Evanston Northwestern Healthcare an Department of Dermatology, Northwestern University, Fienberg School of Meicine, Chicago f ; Tufts Meical Center, Tufts University School of Meicine, Boston g ; Department of Dermatology, University of CaliforniaeSan Francisco h ; Department of Dermatology, Mount Sinai School of Meicine, New York i ; Department of Dermatology, Henry For Hospital, Detroit j ; Department of Dermatology, University of Pennsylvania k ; Anacor Pharmaceuticals Inc, Palo Alto, CA, Department of Dermatology, University of California, San Francisco l ; an American Acaemy of Dermatology, Schaumburg. m Funing sources: None. The authors conflict of interest/isclosure statements appear at the en of the article. Reprint requests: Reva Bhushan, PhD, 930 E Woofiel R, Schaumburg, IL rbhushan@aa.org. Publishe online June 4, /$36.00 ª 2009 by the American Acaemy of Dermatology, Inc. oi: /j.jaa Abbreviations use: AAD: American Acaemy of Dermatology AST: aspartate aminotransferase BUN: serum urea nitrogen CBC: complete bloo cell CSA: cyclosporine FDA: Foo an Drug Aministration MMF: mycophenolate mofetil PASI: Psoriasis Area an Severity Inex PPD: purifie protein erivative PUVA: psoralen plus ultraviolet A SCC: squamous cell carcinoma TB: tuberculosis UV: ultraviolet all proper methos of care nor exclusive of other methos of care reasonably irecte to obtaining the same results. The ultimate jugment regaring the propriety of any specific therapy must be mae by the physician an the patient in light of all the circumstances presente by the iniviual patient. SCOPE This fourth section will cover the management an treatment of psoriasis with traitional systemic therapies. METHOD A work group of recognize psoriasis experts was convene to etermine the auience an scope of 451

2 452 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 the guieline, an ientify clinical questions to structure the primary issues in iagnosis an management iscusse in American Acaemy of Dermatology (AAD) psoriasis guielines section 1 an 2. 1,2 Work group members complete a isclosure of commercial support. An evience-base moel was use an evience was obtaine using a search of the MEDLINE atabase spanning the years 1960 through Only English-language publications were reviewe. The available evience was evaluate using a unifie system calle the Strength of Recommenation Taxonomy evelope by eitors of the US family meicine an primary care journals (ie, American Family Physician, Family Meicine, Journal of Family Practice,anBMJ USA). This strategy was supporte by a ecision of the Clinical Guielines Task Force in 2005 with some minor moifications for a consistent approach to rating the strength of the evience of scientific stuies. 3 Evience was grae using a 3- point scale base on the quality of methoology as follows: I. Goo-quality patient-oriente evience. II. Limite-quality patient-oriente evience. III. Other evience incluing consensus guielines, opinion, or case stuies. Clinical recommenations were evelope on the best available evience table in the guieline. These are ranke as follows: A. Recommenation base on consistent an gooquality patient-oriente evience. B. Recommenation base on inconsistent or limite-quality patient-oriente evience. C. Recommenation base on consensus, opinion, or case stuies. In those situations where ocumente eviencebase ata are not available, we have use expert opinion to generate our clinical recommenations. Prior guielines on psoriasis were also evaluate. This guieline has been evelope in accorance with the AAD Aministrative Regulations for Evience-base Clinical Practice Guielines, which inclue the opportunity for review an comment by the entire AAD membership an final review an approval by the AAD Boar of Directors. GENERAL PRINCIPLES In the past, conventional systemic psoriasis therapiesemethotrexate, cyclosporine (CSA), an acitretinewere use when psoriasis was too extensive for topical therapy or refractory to topical therapy an phototherapy. Although a minimum boy surface area, eg, 10%, has been traitionally use as a prerequisite to starting a systemic therapy for psoriasis, a subset of patients with limite isease have ebilitating symptoms. For example, although severe psoriasis of the palms an soles or severe scalp psoriasis affects less than 5% of the boy 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 change the treatment of psoriasis, giving us aitional therapeutic options that are potentially less toxic to the liver, kineys, an bone marrow an are not teratogenic. Nevertheless, traitional systemic therapies continue to play an important role in the treatment of psoriasis with their oral route of aministration an low cost (compare with biologics) making them an important treatment option in the appropriate patient. Methotrexate is the most commonly prescribe traitional systemic therapy worlwie for psoriasis. Detaile guielines concerning its osing an monitoring in patients with psoriasis have recently been publishe by the National Psoriasis Founation. 4 It is noteworthy that the rheumatology guielines for the use of methotrexate 5 are less stringent than those in ermatology, especially in the monitoring of hepatotoxicity. The ifference in this monitoring may be that patients with psoriasis with more severe isease are more likely to be obese than patients with rheumatoi arthritis, an thus be more prone to have unerlying nonalcoholic steatohepatitis. Methotrexate can be ramatically effective with even the most severe cases of psoriasis. The potential role of pharmacogenetic testing to improve our ability to preict the efficacy an safety of methotrexate suggests the possibility of personalizing the use of methotrexate in the years ahea. 6 Methotrexate has been use in combination with all of the approve biologic agents for psoriasis. The greatest experience is with tumor necrosis factor inhibitors. Methotrexate has been use to suppress antiboies against the two monoclonal tumor necrosis factor inhibitors, aalimumab an infliximab. 7 It is not known whether the use of methotrexate an biologics causes aitive immunosuppression as this combination has primarily been stuie in patients without psoriasis, an the iffering baseline risks associate with these iseases make this istinction uncertain. CSA is one of the most effective treatments available for psoriasis. 8 However, when use in the longer term (3-5 years), a significant proportion of patients will evelop some egree of glomerulosclerosis. 9 Publishe guielines in the Unite States therefore limit its use to 1 year, 8

3 JAM ACAD DERMATOL VOLUME 61, NUMBER 3 Menter et al 453 whereas in the Unite Kingom it is allowe for 2 years. 10 In patients with severe flares of psoriasis, CSA frequently inuces a rapi remission. Reboun flares of psoriasis after iscontinuation of systemic sterois or efalizumab can be prevente or rapily controlle with CSA 11 or methotrexate. Of the systemic therapies, acitretin is the least effective as monotherapy an it is therefore often use in conjunction with ultraviolet (UV) B or psoralen plus UVA (PUVA) phototherapy. Stuies performe in the 1980s emonstrate that etretinate, the pro-rug of acitretin, is particularly effective in patients with palm an sole psoriasis. 12 Because acitretin is not immunosuppressive, it has also been use in combination with biologic therapies. Acitretin s major sie effect is its teratogenicity, an its use is, therefore, limite to male an female patients of nonchilbearing potential. At high oses, it may be associate with significant mucocutaneous effects along with hair loss, an although it can occasionally be ose at 50 mg aily, most clinicians use oses between 10 an 25 mg per ay. Because of the known organ toxicities of traitional systemic agents, the concept of rotational therapy was evelope so that patients coul rotate from one agent to the other or to phototherapy or photochemotherapy to minimize total cumulative ose an thereby limit toxicity. 13 With the avent of biologic therapies, an their reuction in incience of major organ toxicity, rotational therapy is less commonly use. 13 To minimize the toxicity of any therapy, proper patient selection an appropriate monitoring are crucial. The ecision to aminister methotrexate, CSA, acitretin, or any other traitional therapy must be iniviualize. Every patient nees to be carefully evaluate with reference to isease severity, quality of life, an general meical an psychologic status. METHOTREXATE Oral methotrexate is an effective treatment for psoriasis being initially use more than 50 years ago. Methotrexate competitively inhibits the enzyme ihyrofolate reuctase, thus ecreasing the synthesis of folate cofactors neee to prouce nucleic acis. Because the effects of methotrexate are most ramatic on rapily iviing cells, it was originally thought that its beneficial effects in psoriasis were a result of the inhibition of epiermal proliferation. 14 However, it is now known that there is little effect on epiermal cells, but there is significant inhibition of the proliferation of lymphoi tissue at concentrations of methotrexate that are typically achieve with lowose weekly methotrexate. 15 These finings support the concept that the therapeutic effect of low-ose methotrexate in psoriasis is a result of its effects on the immune system. 16 Methotrexate was approve by the Foo an Drug Aministration (FDA) in 1972 for the treatment of severe, recalcitrant, isabling psoriasis. Because methotrexate was introuce before the acceptance of ranomize clinical trials as the stanar by which to juge rug efficacy, there are no large high-quality stuies emonstrating its safety an efficacy, an clinical experience with methotrexate is much greater than the ocumentation of its safety an efficacy in clinical stuies. For these reasons, methotrexate guielines, which were originally written in an have since been upate on numerous occasions (most recently in ), provie expert-base stanars for the use of methotrexate in the treatment of psoriasis. Efficacy Three well-esigne stuies that evaluate the efficacy of methotrexate were recently performe. Heyenael et al 18 compare the efficacy an safety of methotrexate with CSA in a stuy that ranomize 88 patients to receive either meication without a placebo group. The primary en point of Psoriasis Area an Severity Inex (PASI) 75 at 16 weeks was 60% for methotrexate an 71% for CSA (no statistical ifference). Twelve of 44 patients in the methotrexate group roppe out because of elevate liver function test results (it shoul be note that no folic aci supplementation was given in this stuy), whereas only one patient in the CSA group roppe out (because of elevate bilirubin). 18 Flytstrom et al 19 compare methotrexate with CSA in the treatment of 84 patients with psoriasis in a 12-week stuy that also i not inclue a placebo arm. These authors use a ifferent en point, namely a mean PASI change from baseline, which was 72% for CSA compare with 58% for methotrexate. Although CSA was statistically more effective than methotrexate, 12 patients in the CSA group an 4 patients in the methotrexate group roppe out seconary to laboratory abnormalities an withrawn consents before initiation of treatment. 19 Saurat et al 20 performe the first ouble-blin, placebo-controlle stuy of methotrexate, esigne to compare the safety an efficacy of aalimumab, methotrexate, an placebo in 250 patients. After 16 weeks of treatment, PASI 75 improvement was 19% for placebo, 36% for methotrexate, an 80% for aalimumab. For those patients in the methotrexate arm of the stuy, methotrexate was initiate at a low weekly osage of 7.5 mg for 2 weeks, followe by 10 mg weekly for 2 weeks, an then 15 mg for 4 weeks. Thereafter, an increase in the osage of methotrexate was permitte epening on the response an the presence or absence of

4 454 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 toxicities. After 8 weeks, if patients in the methotrexate arm ha achieve a PASI 50 response, no further increase in methotrexate osage was allowe. After 16 weeks, when the mean methotrexate ose was 19 mg, these patients were crosse over to receive aalimumab; it shoul be note that patients in the methotrexate arm were still showing clinical improvement at the time of crossover, suggesting that the results of this stuy may have unerestimate the efficacy of methotrexate. 20 Furthermore, the placebo response rate of 19% is ramatically higher than is seen in a clinical trial of this type, raising oubt about the valiity of this stuy. Dosage Methotrexate is generally given as a single weekly oral ose, given as a tablet or occasionally as a carefully measure parenteral solution given orally (0.1 ml of a 25 mg/ml multiose vial is equivalent to a 2.5-mg oral tablet). The parenteral solution of methotrexate is less costly than tablets. Intramuscular aministration is helpful when there is gastrointestinal intolerance to oral osing or if there are concerns regaring patient compliance. Subcutaneous injection is equally effective an can be self-aministere at home. Doses are usually starte at low levels to minimize sie effects an then graually increase to achieve efficacy. Many practitioners give a single test ose of 2.5 or 5 mg to evaluate for significant bonemarrow suppression in susceptible patients. Although there are no establishe maximum or minimum osages of methotrexate, weekly osages usually range from 7.5 to 25 mg. All osing scheules shoul be ajuste to the iniviual patient an the osage raise or reuce to obtain or maintain aequate isease control or minimize sie effects. After an increase in methotrexate ose, it may take up to 4 weeks for a clinical response to occur. Some patients can be graually tapere off treatment an restarte when the psoriasis recurs. It is important to minimize the total cumulative ose of methotrexate while maintaining isease control an meication tolerance. Folate supplementation Although the majority of experts recommen that all patients treate with methotrexate receive folate supplementation (1-5 mg/ given aily except the ay of methotrexate), others will a folate only if a patient evelops gastrointestinal sie effects or early bone-marrow toxicity as manifeste by an increase mean corpuscular volume. In patients who evelop bone-marrow toxicity or gastrointestinal sie effects while on folate, increasing the ose of folate may be helpful. Although a literature review of these ata, largely erive from the rheumatoi arthritis literature, suggests that low-ose folate supplementation may reuce the hematologic, gastrointestinal, an hepatic sie effects of methotrexate without ecreasing the efficacy, 21 one small controlle stuy in patients with psoriasis using folic aci at 5 mg aily suggeste that there may be a slight ecrease in efficacy. 22 However, the methoology of this latter stuy has been questione. 23 The optimal osage of folic aci is still to be etermine. Toxicity Common an generally minor toxicities of methotrexate inclue nausea, anorexia, stomatitis, an fatigue that most often occur at the time of methotrexate aministration. These effects may be minimize by aministering methotrexate by intramuscular or subcutaneous injection, splitting the ose, folate supplementation, or by aministering the ose with foo or at betime. The major toxicities that are of greatest concern in patients treate with methotrexate are myelosuppression, hepatotoxicity, an pulmonary fibrosis. Of 164 possible methotrexate-associate fatalities, 67 were cause by myelosuppression, 30 were cause by pulmonary fibrosis, an 8 were cause by hepatotoxicity. 24 Pulmonary fibrosis is one of the more severe manifestations of methotrexate toxicity an must be rule 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 rheumatoi arthritis Because methotrexate has not been stuie in large ouble-blin placebo-controlle trials of the type that have been routinely use to etermine the safety an efficacy of the biologic agents, less common averse effects have not been carefully evaluate. Recent reports suggest that treatment with methotrexate may be associate with some of the risks similar to those of the biologic agents, although to ate these reports have occurre almost exclusively in patients with rheumatoi arthritis Hepatitis, reactivation of tuberculosis (TB), an lymphoma, especially the B- cell type that is commonly associate with Epstein- Barr virus infection, have all been reporte in patients being treate with methotrexate These observations suggest that practitioners nee to maintain a high inex of suspicion for these infections in patients being treate with methotrexate. Hematologic The major risk factors for hematologic toxicity are avance age, renal impairment, the absence of folate supplementation, rug interactions, an

5 JAM ACAD DERMATOL VOLUME 61, NUMBER 3 Menter et al 455 Table I. Risk factors for hematologic toxicity from methotrexate Renal insufficiency Avance age Lack of folate supplementation Methotrexate osing errors Drug interactions Hypoalbuminemia Greater than moerate alcohol intake Aapte with permission from Kalb et al. 4 meication errors (Table I). Most of the literature concerning myelosuppression with methotrexate erives from the experience in patients with rheumatoi arthritis. Although the relative risk of myelosuppression in patients with psoriasis compare with patients with rheumatoi arthritis is unknown, the literature suggests that significant myelosuppression is rare in appropriately monitore patients with psoriasis who have no risk factors for hematologic toxicity. The practice of using a single test ose of methotrexate erives from the esire to ensure that severe myelosuppression oes not occur. The test ose is typically 2.5 or 5 mg with a complete bloo cell (CBC) count evaluate 5 to 6 ays later, to ensure that myelosuppression has not occurre before increasing to the full weekly osage. Although the use of a test ose oes not guarantee that patients will not experience myelosuppression, it is manatory in patients with a ecrease glomerular filtration rate or other significant risk factors for hematologic toxicity. 32 Pancytopenia can rarely occur with the use of low-ose weekly methotrexate, even after single oses of methotrexate It can occur at any time uring treatment; in all cases, however, there were ientifie risk factors, particularly impaire renal function, meication errors, or use of concomitant meications, especially sulfonamie-base. 32,36 As pancytopenia may occur as long as 4 to 6 weeks after increasing the methotrexate osage, more frequent monitoring is suggeste with osage increases. Hepatotoxicity Hepatotoxicity is a well-known sie effect of methotrexate. Recent stuies, however, emonstrate that hepatic fibrosis an cirrhosis are consierably less common than initially reporte. 37,38 Rheumatologists traitionally eem the liver biopsy as unnecessary, particularly in healthy patients. Thus, ermatology guielines are stricter as hepatic toxicity is greater in patients with psoriasis than in patients with rheumatoi arthritis. 27 Table II. Risk factors for hepatotoxicity from methotrexate History of or current greater than moerate alcohol consumption (methotrexate toxicity is associate with a history of total lifetime alcohol intake before methotrexate therapy; the exact amount of alcohol that leas to risk is unknown an iffers from person to person) Persistent abnormal liver chemistry stuy finings History of liver isease incluing chronic hepatitis B or C Family history of inheritable liver isease Diabetes mellitus Obesity History of significant exposure to hepatotoxic rugs or chemicals Hyperlipiemia Aapte with permission from Kalb et al. 4 The pathologic features of methotrexate-inuce liver toxicity resemble nonalcoholic steatohepatitis, the pattern of liver histology observe in people who are obese, hyperlipiemic, or iabetic. Methotrexate likely aggravates preexisting nonalcoholic steatohepatitis, suggesting that patients with psoriasis at greatest risk while receiving methotrexate are those with iabetes, with obesity, or who collectively meet the criteria for metabolic synrome in aition to those who rink alcohol. 39,40 Recent stuies suggest that when evaluating patients for methotrexate treatment, risk factors incluing alcohol intake, obesity, hyperlipiemia, iabetes, previous exposure to liver toxins, an hepatitis nee to be consiere. 40,41 Recently upate methotrexate guielines from the National Psoriasis Founation 4 suggest that patients be ivie into two groups, those with risk factors for hepatotoxicity from methotrexate (Table II) an those without. Patients with no risk factors for methotrexate-inuce hepatotoxicity shoul be juge by the American College of Rheumatology criteria for monitoring methotrexate. These criteria inclue an evaluation of liver chemistries every 1 to 3 months with the nee for a liver biopsy only if 5 of 9 aspartate aminotransferase (AST) levels are elevate uring a 12-month perio or if there is a ecline in the albumin (in patients with normal nutritional status) below normal in the setting of well-controlle isease (Table III). This approach has been valiate in patients with rheumatoi arthritis an has also emonstrate a ecrease in the number of liver biopsies. 42 Furthermore, ata suggest that 3.5 to 4.0 g instea 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

6 456 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 Table III. Monitoring for hepatotoxicity in patients with no risk factors for hepatotoxicity No baseline liver biopsy Monitor LFT results monthly for the first 6 mo an then every 1-3 mo thereafter / For elevations \2-fol upper limit of normal: repeat in 2-4 wk / For elevations [2-fol but \3-fol upper limit of normal: closely monitor, repeat in 2-4 wk, an ecrease ose as neee / For persistent elevations in 5/9 AST levels uring a 12-mo perio or if there is a ecline in the serum albumin below the normal range with normal nutritional status, in a patient with well-controlle isease, a liver biopsy shoul be performe Consier liver biopsy after g total cumulative osage or Consier switching to another agent or iscontinuing therapy after g total cumulative osage or Consier continuing to follow up accoring to above guielines without biopsy Aapte 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 Consier the use of a ifferent systemic agent Consier elaye baseline liver biopsy (after 2-6 mo of therapy to establish meication efficacy an tolerability) Repeate liver biopsies after approximately g of methotrexate Aapte with permission from Kalb et al. 4 normal liver chemistry results, history, an physical examination finings, the ecision about whether or not to unergo a liver biopsy shoul be mae on an iniviual basis. Choices for patients who have accumulate 3.5 to 4.0 g of methotrexate (whether from continuous or intermittent methotrexate osing) inclue performing a liver biopsy, switching to another therapy, or following the above guielines an continuing to monitor without a biopsy unless 5 of 9 AST levels are elevate. If the first liver biopsy specimen reveals normal results, repeate liver biopsy woul be ictate by the guielines in Table III. Patients with one or more risk factors for hepatotoxicity nee be followe up with the more stringent guielines (Table IV). If the risk-benefit analysis for a patient with such risk factors favors the use of methotrexate, then this patient shoul have a liver biopsy performe at or near the beginning of methotrexate therapy. As some patients will iscontinue methotrexate within 2 to 6 months because of averse effects or lack of clinical effectiveness, it is sensible to postpone the early treatment liver biopsy until after this initial perio. There is little to no evience to suggest that a several-month perio of methotrexate treatment will cause clinically significant liver isease. In patients with risk factors for liver isease, a repeate biopsy shoul be performe at a cumulative ose of 1.0 to 1.5 g. In patients with persistent significant abnormalities in liver chemistry values, a liver biopsy is also inicate. The liver biopsy in these patients at higher risk shoul be repeate with every aitional 1.0 to 1.5 g of methotrexate. Serum assays for liver fibrosis are now wiely accepte an recommene in Europe as a means of eliminating or ecreasing the nee for liver biopsies. Measurement of the amino-terminal peptie of procollagen III is the most use marker. One stuy using the amino-terminal peptie of pro-collagen III assay emonstrate a 7-fol reuction in the number of liver biopsies by the use of this assay. 45 The aminoterminal peptie of pro-collagen III assay is generally not available in the Unite States. New evelopments such as magnetic resonance elastography 46 an the enhance liver fibrosis panel 47 coul likewise further reuce the nee for liver biopsies in the future. FibroSpect, II (Prometheus Laboratories, San Diego, CA) an FibroSure (LabCorp, Burlington, NC) tests for liver fibrosis, although unproven to ai in the iagnosis of methotrexate-inuce fibrosis, are available in the Unite States an coul be consiere as possible alternatives for patients in whom liver biopsy is technically ifficult or contrainicate. Pregnancy Methotrexate is an abortifacient an a teratogen. It is FDA pregnancy category X an is contrainicate in women attempting to conceive. Methotrexate-inuce fetal abnormalities inclue cariac, skeletal, an central nervous system efects. 48 Women of chilbearing potential who are sexually active an are being treate with methotrexate must use contraception. Although the critical perio of methotrexate

7 JAM 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 reporte at all times of exposure to methotrexate. Conversely, numerous first-trimester pregnancies with exposure to large oses of methotrexate (primarily for the treatment of leukemia) have resulte in live births with no congenital or evelopmental problems. 49 Because methotrexate is wiely istribute in maternal tissues an may persist in the liver for up to 3 months after exposure, 50 it is appropriate for women to wait 3 months after iscontinuing methotrexate before attempting to conceive a chil. Male fertility Methotrexate is not mutagenic but spermatogenesis stuies in rats suggest that it may be toxic to cells unergoing ivision. 51 In human beings, there is controversy regaring the effect of methotrexate on spermatogenesis 52 ; the teratogenicity of methotrexate in fetus fathere by men who are on methotrexate is unclear because of a lack of ata. Although some stuies suggest that methotrexate treatment may result in severe, yet reversible, oligospermia espite normal hormone levels, 53 other stuies reveal no changes in spermatogenesis an sperm counts. 54,55 One cycle of spermatogenesis requires 74 ays thus it is appropriate for male patients to wait 3 months after iscontinuing methotrexate before attempting to conceive a chil to allow for the methotrexate effects to be eliminate. PEDIATRIC USE Methotrexate is FDA-approve for the treatment of psoriasis in aults an for juvenile rheumatoi arthritis. Although there are only a few reports on the use of methotrexate for the treatment of peiatric psoriasis, 56 the use of methotrexate in chilren for several ifferent ermatologic an rheumatologic conitions has been recently reviewe. 57 In general, low-ose weekly methotrexate is well tolerate in chilren. Primary sie effects seen in chilren inclue abnormal liver function test results, stomatitis, an gastrointestinal irritation. When interpreting the ata for the use of methotrexate in chilren, it is important to be aware that the majority of the publishe stuies erive from the rheumatology literature where patients are often treate with concomitant oral corticosterois. These authors suggeste that most peiatric patients can be monitore for hepatotoxicity accoring to the rheumatologic liver biopsy guielines recommene for aults without risk factors. Drug interactions Numerous meications may interact with methotrexate by a variety of mechanisms that can result Table V. Meications that may increase methotrexate toxicity Nonsteroial anti-inflammatory rugs Antibiotics Others Salicylates Trimethoprim/ Barbiturates sulfamethoxazole Naproxen Sulfonamies Colchicine Ibuprofen Penicillins Dipyriamole Inomethacin Minocycline Ethanol Phenylbutazone Ciprofloxacin Phenytoin Sulfonylureas Furosemie Thiazie-iuretics Aapte with permission from Kalb et al. 4 in elevate rug levels, thereby increasing the risk for methotrexate toxicity (Table V). After absorption, methotrexate bins to serum albumin. Salicylates, sulfonamies, iphenylhyantoin, an antibiotics incluing penicillin, minocycline, chloramphenicol, an trimethoprim may ecrease the bining of methotrexate to albumin leaing to increase serum levels of methotrexate. Several other meications incluing colchicine, CSA, probeneci, salicylates, an sulfonamies may lea to ecrease renal tubular excretion leaing to ecrease renal elimination of methotrexate an increase serum levels. Given the hepatotoxicity of methotrexate, caution shoul be use when prescribing this rug to patients taking other potentially hepatotoxic agents incluing alcohol, statins, leflunomie, retinois, azathioprine, an minocycline. Although some nonsteroial anti-inflammatory rugs may lea to elevation of serum methotrexate levels, incluing ibuprofen, salicylates, an naproxen 58 other nonsteroial anti-inflammatory rugs such as ketoprofen, flurbiprofen, piroxicam, an meloxicam, 59,60 as well as lumiracoxib, rofecoxib (which is no longer available), an celecoxib o not. Other interactions can occur with methotrexate with most of the clinically relevant contrainications being summarize in Table VI. INITIATION AND MONITORING Before initiating therapy with methotrexate, patients shoul have a thorough history an physical examination, reviewing alcohol intake, possible exposure to hepatitis B or C, an family history of liver isease. Laboratory tests, incluing a CBC count with ifferential, creatinine, liver function tests incluing albumin an bilirubin shoul be obtaine for baseline levels. Screening for hepatitis B an C shoul be

8 458 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 Table VI. Relative contrainications for the use of methotrexate Abnormalities in renal function may require a marke reuction in the ose as 85% of methotrexate is renally excrete Abnormalities in liver functionelft results shoul be followe up an all elevations require careful monitoring Hepatitis, active or recurrent Greater than moerate alcohol consumptionealthough there are few ata to support specific limits on alcohol consumption, some physicians require patients to completely refrain from alcohol whereas others allow aily alcohol intake; a history of alcoholism is particularly worrisome if there is baseline liver amage Concomitant use of hepatotoxic rugsemore frequent monitoring of LFT results shoul be consiere Active infectious isease, particularly chronic infections that are likely to be worsene by immunosuppressive effects of methotrexate (eg, active untreate tuberculosis or acquire immunoeficiency synrome); methotrexate shoul be withhel uring acute infections Current use of other immunosuppressive agents Conception shoul be avoie uring methotrexate treatment an afterwar for at least 3 mo in men an 3 ovulatory cycles in women Recent vaccination with a live vaccine Obesity (boy mass inex [ 30) Diabetes mellitus Unreliable patient Aapte with permission from Kalb et al. 4 LFT, Liver function test. consiere when there is evience of viral hepatitis such as elevate liver function test results. In regar to testing for TB, some experts recommen a baseline purifie protein erivative (PPD) test or other screening test for latent TB, particularly if the patient s history inicates risk. Although some argue that this is not the stanar of care, the Centers for Disease Control an Prevention Worl Wie Web site recommenations for TB suggest that patients on immunosuppressive rugs shoul be consiere for a pretreatment PPD. 64 The National Psoriasis Founation consensus statement also recommens screening for latent TB infection in all patients with psoriasis who will be treate with systemic or biologic immunosuppressive agents. 65 Pretreatment liver biopsy shoul only be performe in patients who have abnormal liver function test results, chronic hepatitis, an a history of greater than moerate alcohol intake efine as one rink/ for female patients or anyone oler than 65 years an two rinks/ for men younger than 65 years. 66 A chest raiograph is important for patients with unerlying pulmonary isease. Contraception issues, as iscusse earlier, shoul be aresse. Ongoing laboratory stuies shoul inclue a CBC count every 2 to 4 weeks for the first few months, then every 1 to 3 months, epening on leukocyte count an patient s stability. Some suggest that laboratory stuies be performe on the fifth to sixth ay of the weekly methotrexate cycle, to etect the leukopenia nair, an because liver chemistry values may be elevate 1 to 2 ays after a ose of methotrexate. Patients with risk factors for hematologic toxicity (Table I) nee closer monitoring, particularly at the onset of therapy an after increasing the osage of methotrexate. Patients with significant renal impairment are at risk even after single oses of methotrexate, an these patients require careful monitoring by obtaining bloo counts before the secon ose. A significant reuction in leukocyte or platelet counts necessitates reuction or temporary iscontinuation of methotrexate therapy. Folinic aci (leucovorin) is the antiote for the hematologic toxic effects of methotrexate. When an overose of methotrexate is suspecte or there a worrisome ecrement in the leukocyte, platelet, or re cell count, folinic aci (at 10 mg/m 2 ) shoul be aministere. Because the effectiveness of folinic aci in counteracting the hematologic toxicity of methotrexate ecreases as the time interval between methotrexate aministration an folinic aci treatment increases, folinic aci shoul be given immeiately with subsequent oses given every 6 hours. 4 The frequency of bloo count monitoring may be slowly ecrease over time as long as there is no toxicity or changes in the meical history. Serum urea nitrogen (BUN) an creatinine shoul be obtaine at 2- to 3-month intervals. For those patients with normal values, who may be at risk for ecrease renal function, such as the elerly or those with a ecrease muscle mass, a glomerular filtration rate shoul be calculate. Liver chemistries incluing alanine aminotransferase, AST, alkaline phosphatase, an serum albumin levels shoul be performe every 4 weeks (more frequent liver chemistry monitoring shoul be performe in lieu of an initial liver biopsy for patients with hepatic risk factors) (Table II). More frequent liver chemistry

9 JAM ACAD DERMATOL VOLUME 61, NUMBER 3 Menter et al 459 Table VII. Recommenations for methotrexate Inication: severe, recalcitrant, isabling psoriasis that is not aequately responsive to other forms of therapy Dosing: methotrexate is aministere as a weekly single oral ose Doses can be increase graually until an optimal response is achieve; total ose shoul not orinarily excee 30 mg/wk; oses shoul be reuce to the lowest possible amount of rug neee to achieve aequate control of psoriasis with concomitant topical therapy A test ose of mg is recommene Duration of osing Treatment can be continue for as long as is necessary provie there are no meaningful signs of liver or bone-marrow toxicity with aequate monitoring; folic aci supplementation 1-5 mg aily by mouth, except for the ay of methotrexate osing, reuces the frequency of sie effects Therapeutic results In the only placebo-controlle trial of methotrexate for psoriasis, 36% of patients treate with 7.5 mg/wk orally, increase as neee up to 25 mg/wk, reache PASI 75 after 16 wk Absolute contrainications Pregnancy Nursing mothers Alcoholism Alcoholic liver isease or other chronic liver isease Immunoeficiency synromes Bone-marrow hypoplasia, leukopenia, thrombocytopenia, or significant anemia Hypersensitivity to methotrexate Relative contrainications Abnormalities in renal function Abnormalities in liver function Active infection Obesity Diabetes mellitus Toxicity Elevate LFT results Minor elevations of LFT results are common; if elevation excees 23 normal, must check more frequently; if excees 33 normal, consier ose reuction; if excees 53 normal, iscontinue Anemia, aplastic anemia, leukopenia, thrombocytopenia Interstitial pneumonitis Ulcerative stomatitis Nausea, vomiting, iarrhea Malaise or fatigue Chills an fever Dizziness Decrease resistance to infection GI ulceration an bleeing Photosensitivity ( raiation recall ) Alopecia Drug interactions Hepatotoxic rugs: eg, barbiturates Acitretin has been use successfully in combination with methotrexate espite the potential for hepatotoxicity from both meications Drugs that interfere with renal secretion of methotrexate: eg, sulfamethoxazole, NSAIDs, an penicillins Folic aci antagonists: eg, trimethoprim Liver biopsy Patients at low riskeat baseline, not necessary First biopsy: g; subsequent biopsies to be consiere after 1.5 g Patients at high risk incluing history of iabetes, obesity, abnormal LFT results, excessive EtOh ingestion, chronic liver isease, family history of heritable liver isease Consier baseline biopsy or at 6 mo with subsequent biopsies after g Baseline monitoring History an physical examination CBC an platelet counts Continue

10 460 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 Table VII. Cont BUN, creatinine, an LFTs Liver biopsy is only inicate in patients with a history of significant liver isease Pregnancy test an test for HIV in selecte patients Consier PPD Consier chest raiograph if patient has unerlying pulmonary isease Ongoing monitoring CBC an platelet counts at varying intervals (initially every 2-4 wk for first few months an then every 1-3 mo epening on osage ajustments, symptoms, an previous CBC count results) LFTs at monthly intervals, BUN, creatinine every 2-3 mo epening on osage ajustments, symptoms, an previous bloo test results Pregnancy test if inicate Consier liver biopsy in patients at high risk incluing history of iabetes, obesity, abnormal LFT results, excessive EtOh ingestion, chronic liver isease, family history of heritable liver isease For those without risk factors, consier liver biopsy in patients with cumulative oses of more than g methotrexate For patients without risk factors, consier repeate liver biopsies after each subsequent 1.5-g osage, base on LFT results, risk factors (eg, iabetes an obesity) or in consultation with a hepatologist The aminoterminal peptie of procollagen III is use in Europe (but is generally not available in the Unite States) as a test for hepatic fibrosis, reucing the nee for frequent liver biopsies Pregnancy: category X; men an women consiering conception shoul be off methotrexate for 3 mo before attempting to conceive; shoul pregnancy ensue before this time perio, consier genetic counseling Nursing: mothers receiving methotrexate shoul not breast-fee Peiatric use: methotrexate is approve for the treatment of juvenile rheumatoi arthritis; low-ose methotrexate has been use effectively an safely in chilren for a variety of ermatologic an rheumatologic isorers Psoriatic arthritis: although there are only two small controlle trials evaluating methotrexate for psoriatic arthritis that are inaequately powere to assess clinical benefit, 176,177 methotrexate is often use as the primary agent to treat psoriatic arthritis BUN, Serum urea nitrogen; CBC, complete bloo cell; EtOh, alcohol; GI, gastrointestinal; LFT, liver function test; NSAIDS, nonsteroial antiinflammatory rugs; PASI, Psoriasis Area an Severity Inex; PPD, purifie protein erivative. monitoring is also inicate when the osage is increase or if the patient is taking concomitant hepatotoxic meications. If a significant persistent abnormality in liver chemistry evelops, methotrexate therapy shoul be withhel for 1 to 2 weeks an then liver chemistry tests shoul be repeate, with liver chemistry values likely to return to normal in 1 to 2 weeks. If significantly abnormal liver chemistry values persist for 2 to 3 months, a liver biopsy shoul be consiere if continuation of methotrexate therapy is esire. The extent of fibrosis on liver biopsy specimen ictates whether methotrexate may be continue. It is pruent to iscontinue methotrexate if a patient refuses to unergo a liver biopsy. More frequent monitoring of both laboratory stuies an liver histology is necessary if other hepatotoxic meications are use along with methotrexate. (Please see above section on hepatotoxicity for guiance on the use of liver biopsies in the monitoring of patients being treate with methotrexate.) CONTRAINDICATIONS Methotrexate is absolutely contrainicate in pregnancy or nursing an in patients with cirrhosis or who have significant anemia, leukopenia, or thrombocytopenia. Relative contrainications to the use of methotrexate for the treatment of psoriasis are numerous an are inclue in Table VI. Methotrexate shoul not be use in combination with trimethoprim/sulfamethoxazole (Septra [Hoffmann-La Roche Inc, Roche, Nutley, NJ], Bactrim [Monarch Pharmaceuticals Inc, Bristol, TN]) because of increase methotrexate toxicity. Although the combination is contrainicate in official labeling, methotrexate can be use in combination with acitretin when necessary with appropriate hepatic monitoring. 67 Recommenations for the use of methotrexate are shown in Table VII. The strength of recommenations for the treatment of psoriasis using methotrexate is shown in Table VIII. CYCLOSPORINE CSA is a highly effective an rapily acting systemic agent for the treatment of psoriasis. Discovere in 1970 an originally use as an immunosuppressive agent in organ transplantation, it was first shown to be effective for psoriasis in CSA inuces immunosuppression by inhibiting the first phase of T-cell activation. It bins to cyclophillin,

11 JAM ACAD DERMATOL VOLUME 61, NUMBER 3 Menter et al 461 Table VIII. The strength of recommenations for the treatment of psoriasis using traitional systemic therapies Agent Strength of recommenation Level of evience References Methotrexate* B II Cyclosporine* B II 18,71-75,77,78 Acitretin* B II 108, ,115,117,118,121 Azathioprine C III 149,150 Fumaric aci esters y B I 152,153 Hyroxyurea C III Leflunomie z B II 163 Mycophenolate mofetil C III 166,167 Sulfasalazine z B II 168 Tacrolimus z B II Thioguanine C III The reaer is avise not to use this table alone for ecision making regaring the choice of traitional systemic therapies. *Although methotrexate, cyclosporine, an acitretin are all Foo an Drug Aministration approve for the treatment of psoriasis an have been use for many years by ermatologists with goo to excellent results, the quality of the evience supporting their use is as liste. y The fumaric aci esters stuies are well-esigne placebo-controlle trials but because this treatment is not approve in the Unite States, it has been given strength of recommenation of B with a level I of evience. z Although there are placebo-controlle trials evaluating the use of leflunomie, sulfasalazine, an tacrolimus in the treatment of psoriasis requiring systemic therapy, the quality of the evience supporting their use is not very convincing. with the resulting CSA/cyclophillin complex bining to an inhibiting the enzyme calcineurin, leaing to blockae of signal transuction pathways that are epenent on the transcription factor, nuclear factor of activate T cells. This blockae leas to lower levels of multiple inflammatory cytokines incluing interleukin-2 an interferon gamma, thus inhibiting T-cell activation. 69,70 Despite the recent evelopment of multiple new therapeutic moalities, CSA remains an important option in treating psoriasis. CSA is very useful in crisis management, as a brige to other therapies, an in the rapi treatment of psoriasis unresponsive to other moalities, ie, as interventional therapy. EFFICACY Numerous clinical trials have emonstrate the efficacy of CSA in psoriasis. The original stuies evaluating CSA s efficacy in psoriasis provie evience that psoriasis is a T-celleriven immunologic isorer rather than a isorer of altere keratinocyte growth an ifferentiation. CSA given at 2.5 to 5 mg/kg/ for 12 to 16 weeks leas to rapi an ramatic improvement in psoriasis in up to 80% to 90% of patients When ose at 3 mg/kg/, CSA leas to a PASI 75 response in 50% to 70% of patients an a PASI 90 response in 30% to 50% of patients. 76 Short-term treatment with CSA is an attractive metho of treatment with minimal toxicities in healthy patients. In an open, multicentere, ranomize trial of up to 12 weeks of intermittent courses of CSA either tapere or abruptly stoppe in the treatment of psoriasis uring the course of 1 year, 400 patients were ranomize to two groups: abrupt iscontinuation of CSA or graual tapering by 1 mg/kg/ weekly until cessation. Relapse patients were retreate with CSA. 74 In all, 400, 259, 117, an 26 patients require 1, 2, 3, an 4 aitional treatment courses, respectively. The meian time to relapse was 109 ays in the patients who abruptly stoppe CSA an 113 ays for patients who were tapere off therapy; a statistically significant ifference of unclear clinical significance. Short, intermittent courses of CSA were generally well tolerate, however, 8% of patients iscontinue the stuy because of averse events, incluing those relate to increase creatinine an hypertension. Several stuies have evaluate the efficacy of long-term CSA in the treatment of psoriasis. In a stuy of 217 patients treate for 6 to 30 months with CSA at 1.25, 2.5, or 5.0 mg/kg/, 12.5% of patients were successfully maintaine on 1.25 mg/kg/ without loss of efficacy. 77 In another stuy of 181 patients with severe isease initially treate with an inuction phase of CSA, 86% of responers were treate with a 6-month maintenance phase in which they were assigne to either CSA 3.0, 1.5, or 0 mg/kg/. In all, 42% of the patients on 3 mg/kg/ of CSA relapse compare with 84% of those who were given placebo. 78 DOSAGE Although the package insert suggests osing CSA base on ieal boy weight, 79 we have foun that obese patients often require osing base on their

12 462 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 actual weight. CSA microemulsion is consiere to have a superior pharmacokinetic profile to the regular preparation. CSA shoul be aministere at a consistent time of the ay an in relation to meals to ecrease the intrainiviual bloo level variations. The CSA solution can be mixe with milk or orange juice but not with grapefruit juice, because this can increase plasma CSA concentrations by inhibiting the cytochrome P450 metabolism of CSA. The initial aily ose of CSA is 2.5 to 3 mg/kg in two ivie oses. It is generally recommene to maintain this stable ose for 4 weeks, an then increase the osage at increments of 0.5 mg/kg/ until isease control is achieve. Although the package insert recommens that the maximal aily osage shoul be 4 mg/kg/, 79 the customary maximum psoriasis ose is 5 mg/kg/. Another approach to osing of CSA use in patients with more severe isease is to initiate treatment at the highest osage, typically 5 mg/kg/, with stepwise ecreases after aequate isease control is achieve. TOXICITY CSA s most serious sie effects are nephrotoxicity an hypertension. These two toxicities are thought to be meiate by CSA s vasoconstrictive effects on renal arterioles. 80 Although reversible changes in the kiney may be relate to this vascular effect, long-term therapy frequently leas to permanent scarring with subsequent loss of renal function. 81 Because of these concerns, CSA is a rug that requires careful patient selection an subsequent monitoring to be use safely. Therefore, a careful assessment of psoriasis isease severity is critical when assessing the risk-benefit ratio of treatment with CSA. Patients with psoriasis taking CSA may be at increase risk of eveloping cutaneous squamous cell carcinomas (SCCs) particularly those with a history of more than 200 PUVA treatments. 80 A history of treatment with PUVA puts patients at significantly greater risk for the evelopment of nonmelanoma skin cancers when using CSA. For example, the risk of SCC in patients with a history of PUVA an any use of CSA is similar to the risk of SCC in patients with psoriasis who have receive greater than 200 PUVA treatments. 82 The incience of internal malignancies in patients with psoriasis treate with CSA was not significantly increase as compare with the general population (patients with \2 years of treatment with CSA [stanar incience ratio 1.2; 95% confience interval ], patients with [2 years of treatment with CSA [stanar incience ratio 1.7; 95% confience interval ]) 83 ; however, this stuy i not have appropriate statistical power to rule out a potentially important increase risk in internal malignancies. 83 Elevation of serum triglyceries ([750 mg/l) may occur as many as in 15% of patients with psoriasis treate with CSA, 79 whereas hypercholesterolemia ([300 mg/l) occurs in less than 3% of patients. 79 Importantly, these changes in lipi levels are reversible after CSA is iscontinue. Testing for TB shoul be consiere before initiating treatment with CSA. A TB skin test result with greater than 5 mm of inuration is consiere positive an is the test use most frequently. A newer, more specific test for latent TB infection is the QuantiFERON TB Gol test (Cellestis, Carnegie, Victoria, Australia), which measures whole bloo interferon gamma. This is especially useful in patients with a history of BCG immunization. 65 Nephrotoxicity Patients must be carefully monitore for nephrotoxicity with monthly serum creatinine levels an yearly glomerular filtration rates in patients who are maintaine on therapy for greater than 1 year. 84 The package insert recommens that patients with elevations of serum creatinine greater than 25% of baseline on two occasions (separate by 2 weeks) shoul have a 25% to 50% ecrease in their osage of CSA. After lowering the osage of CSA, the serum creatinine shoul be followe up every other week for 1 month. If the creatinine level oes not ecrease to within 25% of the patient s baseline creatinine level, the CSA ose shoul be ecrease by another 25% to 50%. If after these changes, the creatinine continues to remain greater than 25% above baseline, CSA shoul be iscontinue. This cutoff of 25% above baseline for ecreasing the CSA osage is lower than the more commonly use 30% cutoff in clinical practice. Furthermore, many experts use a stepwise ose reuction of approximately 1 mg/kg/ in place of a percentage of the initial ose. The length of CSA treatment correlates with the evelopment of nephrotoxicity. It is the opinion of the authors that intermittent treatment with 12-week courses of CSA significantly reuces the risk of renal toxicity compare with ongoing therapy. In all, 19% to 24% of patients on short-term treatment will evelop nephrotoxicity, largely reversible on cessation of CSA. 74,75,85 Patients treate continuously for more than 2 years have a significantly higher risk of eveloping irreversible renal amage. 9,86,87 In one stuy, elevations of creatinine greater than 30% of baseline were foun in 71% of patients who ha been treate with CSA for an average of 4.5 years. In the majority of these patients, creatinine levels

13 JAM ACAD DERMATOL VOLUME 61, NUMBER 3 Menter et al 463 stabilize but i not return to baseline levels after the CSA osage was ecrease. 9,86 Hypertension Hypertension is another common sie effect of CSA therapy that often resolves in patients treate with short courses of CSA. CSA-inuce hypertension occurs more commonly in oler patients. 9 Patients who evelop hypertension (measure on two separate occasions) an who have no history of hypertension shoul have their CSA ose reuce by 25% to 50%. If the bloo pressure oes not normalize after lowering the ose on several occasions, the package insert recommens stopping CSA. Another approach, avocate by Griffiths et al, 10 is to continue CSA as long as the hypertension is appropriately treate an monitore. Calcium channel blockers are the preferre treatment for CSA-inuce hypertension because of their effect on smooth muscle vasoilation, with israipine an amloipine preferre because neither agent alters CSA levels. Other options for treating hypertension inclue beta blockers an angiotensin-converting enzyme inhibitors. The use of thiazie iuretics shoul be avoie as they can lea to increase nephrotoxicity when combine with CSA. 88 Potassium-sparing iuretics shoul also not be use as they act synergistically with CSA to cause hyperkalemia. In the past, hypertension was efine as a bloo pressure of either greater than 140/90 mm Hg or greater than 160/90 mm Hg an this level was use as a reference point in the early stuies of CSA. Accoring to the 2003 guielines publishe by the Joint National Committee on the Prevention, Detection, Evaluation, an Treatment of High Bloo Pressure, 89 prehypertension is efine as 120 to 139/80 to 89 mm Hg, stage 1 hypertension is 140 to 159/90 to 99 mm Hg, an stage 2 hypertension is above 160/100 mm Hg. As all stages of hypertension or prehypertension put patients at increase risk for the evelopment of cariovascular isease, the ecision of when to initiate treatment for hypertension an when to iscontinue treatment with CSA will epen on the iniviual situation. Thus, careful, regular, an correct monitoring of bloo pressure in all patients unergoing CSA therapy is essential as elevations in bloo pressure frequently pre-ate changes in serum creatinine. 90 Other toxicities The most common cutaneous sie effect of CSA is hypertrichosis, occurring in about 6% of patients, 8 usually a more significant issue in women with arker hair. 91 Heaache occurs in 15% of patients treate with CSA, paresthesia in 7%, an musculoskeletal pain in 5%. 8 Rare inciences of pseuotumor cerebri in young patients taking concomitant tetracyclines for acne have been note. Other neurologic sie effects inclue tremor, asthenia, an fatigue. 91 Psychiatric sie effects have also been reporte. 8 Patients with a history of seizures shoul be mae aware that CSA can lower the seizure threshol. 8 Gingival hypertrophy, commonly seen in patients with transplantation treate with CSA, occurs rarely in patients with psoriasis. Pulmonary an respiratory symptoms incluing cough, rhinitis, an yspnea occur in about 5% of patients. 8 Gastrointestinal sie effects inclue abominal pain, which may resolve after a few ays, nausea, vomiting, an iarrhea. 91 As hypomagnesemia an hyperuricemia may occur, magnesium an uric aci levels shoul be monitore at regular intervals. Pregnancy The majority of the information about CSA s safety uring pregnancy erives from stuies of patients treate with CSA for the prevention of organ transplant rejection. In these stuies, CSA was given along with systemic sterois, azathioprine, or mycophenolate mofetil (MMF) an some series inclue patients treate with tacrolimus rather than CSA. In one stuy of 67 pregnancies after renal transplantation, preterm labor occurre in more than 40% of the pregnancies an fetal growth retaration in nearly 20%. Perinatal mortality occurre in approximately 10% of patients. Pregnancy outcome was better in those cases in which the mother was not treate with CSA. Prematurity an low birth weight have also been reporte in pregnancies after liver transplantation. 92 In these stuies, the pregnancy-relate complications are unlikely to be solely attributable to CSA, as these patients ha many complications an comorbiities of organ transplantation an they were also being treate with many other meications. There have been no specific birth efects linke to CSA in registries of patients with transplantation. 93 However, in one series of 61 pregnancies in 53 patients treate with CSA plus other rugs, a single infant was born with a club foot an another infant was born with a large facial hemangioma. 94 Because CSA is nephrotoxic, its effect on kiney function in chilren of women treate with CSA uring pregnancy is important to assess. Animal stuies suggest some concern that has not been borne out by the limite human experience. Rabbit kits expose to 10 mg/kg/ of CSA from ay 14 to ay 18 of gestation were born with renal ysfunction,

14 464 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 Table IX. Meications that may interfere with cyclosporine Meications that increase cyclosporine levels Antifungals: ketoconazole, itraconazole, fluconazole, vorinconazole Diuretics: furosemie, thiazies, carbonic anhyrase inhibitors Calcium channel antagonists: iltiazem, nicaripine, verapamil Corticosterois: high-ose methylprenisolone Antiemetics: metoclopramie Antibiotics: macrolies, fluoroquinolones Antiarrhythmics: amioarone Antimalarials: hyroxychloquine, chloroquine Anti-HIV rugs: ritonavir, ininavir, saquinavir, nelfinavir SSRIs: fluoxetine, sertraline Meications that ecrease cyclosporine levels Antibiotics: nafcillin, rifabutin, rifampin, rifapentine Antiepileptics: carbamazepine, phenytoin, phenobarbital, valproic aci Somatostatin analogues: octreotie Tuberculostatics: rifampicin Retinois: bexarotene St John wort: Hypericum perforatum Others: octreotie, ticlopiine, bosentan Meications that may increase the risk of renal toxicity NSAIDs: iclofenac, naproxen, sulinac, inomethacin Antifungals: amphotericin-b, ketoconazole Antibiotics: ciprofloxacin, vancomycin, gentamycin, tobramycin, trimethoprim Alkylating agents: melphalan Others: H2 histamine antagonists, tacrolimus Meications whose levels increase when taken concomitantly with cyclosporine Calcium channel blockers: iltiazem, nicaripine, verapimil Erectile ysfunction rugs: silenafil, taalafil, varenafil Statins: atorvastatin, lovastatin, simvastatin Benzoiazepines: miazolam, triazolam Others: prenisolone, igoxin, colchicine, igoxin, iclofenac, bosentan It is strongly recommene that an up-to-ate pharmaceutical reference be consulte whenever concomitant meication is use uring cyclosporine therapy. NSAIDS, Nonsteroial anti-inflammatory rugs; SSRI, selective serotonin reuptake inhibitor. hypertension that worsene with age, an progressive chronic renal insufficiency in aulthoo. 95 However, chilren expose in utero to CSA have shown no evience of renal amage as they grow. 96 The FDA has ranke CSA as pregnancy category C; ie, shoul be use uring pregnancy only if the potential benefit justifies the potential risk to the fetus. Although CSA oes not appear to have mutagenic or teratogenic effects, increase prenatal an postnatal mortality an reuce fetal weight have been foun in animal stuies an there has been an increase risk of premature birth in babies expose to CSA in utero. 97 PEDIATRIC USE CSA is FDA-approve for the treatment of psoriasis in aults. Although there is limite literature on the use of CSA for the treatment of peiatric psoriasis, a recent review of its use in chilren with several ifferent ermatologic an rheumatologic conitions suggests that the sie effect profile of CSA in chilren is similar to that seen in aults. 57 DRUG INTERACTIONS CSA is metabolize by the cytochrome P450 3A4 system. Macrolies, antifungals, an calcium channel blockers thus increase CSA levels, whereas anticonvulsants, rifamycins, an griseofulvin ecrease CSA levels. Foos that contain grapefruit juice increase levels of CSA by inhibiting cytochrome P450 enzymes in the intestinal wall, whereas St John Wort may ecrease CSA concentrations. In patients who have severe liver isease, CSA metabolism may be ecrease, leaing to higher rug levels. Although heavy alcohol intake increases CSA levels, mil to moerate alcohol consumption has little effect. 101 CSA is also an inhibitor of cytochrome P450 3A4 with levels of other interacting rugs such as calcium channel blockers, erectile ysfunction rugs, an statins being increase. Reports of serious rhabomyolysis occurring in patients who are concurrently treate with CSA together with a Statin have been escribe. 102 Certain rugs potentiate the renal toxicity of CSA incluing aminoglycosies an nonsteroial anti-inflammatory rugs an these shoul be restricte as shoul meications that elevate potassium levels. Many other interactions can occur with CSA an some of the most clinically relevant contrainications are summarize in Table IX. Given the long list of possible rug interactions, a thorough rug history must be obtaine from all patients before initiating treatment with CSA an patients shoul be eucate regaring the introuction of new rugs while taking CSA. INITIATION AND MONITORING Before initiating therapy with CSA, patients shoul have a thorough history an physical examination, reviewing possible exposure to TB an hepatitis B or C, an family history of kiney isease. A thorough history an physical examination with bloo pressure ocumentation shoul be obtaine before starting CSA therapy. 8,10 Because of the critical importance of accurate measurement of baseline renal function, serum

15 JAM ACAD DERMATOL VOLUME 61, NUMBER 3 Menter et al 465 creatinine shoul be measure on two separate occasions. Some even suggest 3 separate measurements of creatinine taking the average of the 3 as the baseline creatinine level. Other laboratory stuies shoul inclue BUN, urinalysis, CBC count, magnesium, potassium, uric aci, lipis, liver enzymes, an bilirubin. Patients shoul be evaluate for factors that might increase their risk of nephrotoxicity incluing obesity, 87 increase age, 9 concomitant use of nephrotoxic rugs (Table IX), an iabetes. It is important to iscuss appropriate contraception (see prior section on pregnancy an cyclosporine). Appropriate monitoring for patients on CSA is important for the prevention of averse events. After starting CSA, patients shoul be monitore with every-other-week bloo pressure, BUN, an creatinine measurements, along with monthly levels of CBC count, uric aci, potassium, lipis, liver enzymes, serum bilirubin, an magnesium. After 3 months of every-other-week monitoring of bloo pressure, BUN, an creatinine, monthly monitoring of these parameters can be institute. Although the package insert recommens everyother-week monitoring of bloo pressure, BUN, an creatinine for the first 3 months, many authors transition to monthly monitoring of these parameters after 6 to 8 weeks provie there are no ongoing abnormalities. 8,10,91 Monitoring of CSA bloo levels is generally unnecessary in the oses use to treat patients with psoriasis. 103 However, patients who are taking greater than 3 mg/kg/ of CSA over the long term, are being treate with other meications that may alter CSA metabolism, or have liver isease that might put them at risk for unpreictable rug metabolism, may require monitoring of CSA bloo levels. Although practitioners shoul attempt to avoi long-term continuous CSA treatment, it may occasionally be the only option available for patients with severe, recalcitrant isease, necessitating a nephrology consultation to assist with management of CSA-associate nephrotoxicity. Elevations of serum creatinine shoul be manage as escribe above with ecrease osage an re-evaluations. In aition, most other laboratory stuies shoul be obtaine monthly. Vaccinations given concomitantly with CSA may be less effective. Stuies in patients with transplantation taking CSA have shown inconsistent effectiveness of the influenza vaccine Because of the immunosuppression in patients treate with CSA, kille vaccines may prevent severe infection an their aministration appears to be safe. CONTRAINDICATIONS Hypersensitivity to CSA, a history of systemic malignancy (except for nonmelanoma skin cancer), uncontrolle hypertension, renal insufficiency, prior treatment with PUVA, an uncontrolle infections are all contrainications for use of CSA. Live vaccinations are contrainicate uring CSA therapy. CSA shoul be use with extreme caution in the elerly, immunoeficient, an obese population; in patients who have previously receive PUVA therapy; an in pregnancy. Furthermore, care shoul be taken when using other meications that may interact with CSA. 8 Recommenations for the use of CSA are shown in Table X. The strength of recommenations for the treatment of psoriasis using CSA is shown in Table VIII. RETINOIDS The oral retinois are vitamin-a erivatives that have been use to treat psoriasis since the early 1980s. Although their exact mechanism of action in the treatment of psoriasis is not completely unerstoo, retinois are known to moulate epiermal proliferation an ifferentiation an to have immunomoulatory an anti-inflammatory activity. Etretinate was the first retinoi introuce for the treatment of severe psoriasis an replace in 1988 by acitretin, the active metabolite of etretinate. EFFICACY The efficacy of acitretin is ose epenent. The results of several clinical trials suggest that acitretin monotherapy is somewhat less effective than other traitional systemic agents; however, hea-to-hea trials woul be necessary to confirm these conclusions. In patients with chronic plaque psoriasis, various ifferent osages have been use in clinical trials Of patients treate with 50 mg/ of acitretin over 8 weeks of treatment, 23% achieve PASI In another stuy, after 12 weeks of treatment with acitretin, the mean PASI improvement was between 70% an 75%. 116 In another stuy, 59 patients were treate with 20 mg per ay of acitretin with ose increases of 10 mg every 2 weeks up to a final ose of 70 mg. Clearance or marke improvement was achieve by 41% of the patients; however, 36% of patients roppe out of the stuy, mostly because of retinoi-relate averse events. 117 Acitretin may be use as an effective maintenance therapy. Thus, after 6 an 12 months of continuous treatment, 75% an 88%, respectively, of patients with chronic plaque psoriasis reache PASI In patients with pustular psoriasis, rapi an impressive responses may be seen with acitretin. In

16 466 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 Table X. Recommenations for cyclosporine Inication: ault, nonimmunocompromise patients with severe, recalcitrant psoriasis Severe is efine by the FDA as extensive or isabling plaque psoriasis Recalcitrant is efine by the FDA as those patients who have faile to respon to at least one systemic therapy or in patients for whom other systemic therapies are contrainicate, or cannot be tolerate Some guielines suggest use of cyclosporine in moerate to severe psoriasis Efficacy observe in erythroermic psoriasis, generalize pustular psoriasis, an palmoplantar psoriasis Dosing: mg/kg/ in two ivie oses/ Dose ajustments ownwar (by mg/kg) when clearance is achieve or when hypertension or ecrease renal function test results are observe Duration of osing Optimally use as interventional therapy; may be repeate at intervals after a rest perio US approval: 1 y continuous treatment; non-us approval: 2 y continuous treatment Short-term results At 3 an 5 mg/kg/, 36% an 65%, respectively, achieve a clear or almost clear result after 8 wk After 8-16 wk, 50%-70% of patients achieve PASI 75 Long-term results Not recommene because of toxicities Rapi relapse after abrupt iscontinuation of cyclosporine Contrainications Concomitant PUVA or UVB, methotrexate or other immunosuppressive agents, coal tar, history of [200 PUVA treatments or raiation therapy Abnormal renal function Uncontrolle hypertension Malignancy Hypersensitivity to cyclosporine Avoi live vaccinations Caution with major infection an poorly controlle iabetes Toxicity Renal impairment Acute Chronic (increasing glomerular fibrosis with increasing uration of treatment with higher osages) Hypertension Malignancies Cutaneous Lymphoproliferative Heaache, tremor, paresthesia Hypertrichosis Gingival hyperplasia Worsening acne Nausea/vomiting/iarrhea Myalgias Flu-like symptoms Lethargy Hypertriglyceriemia Hypomagnesemia Hyperkalemia Hyperbilirubinemia Increase risk of infection May increase risk of cancer Drug interactions (see Table VIII) Inucers/inhibitors of cytochrome P450 3A4 St John Wort ecreases cyclosporine concentration Cyclosporine may reuce clearance of igoxin, colchicine, prenisolone, statins (increase risk of rhabomyolysis) Potassium-sparing iuretics cause hyperkalemia Thiazie iuretics increase nephrotoxicity Kille vaccines may have ecrease efficacy Live vaccination is contrainicate Continue

17 JAM ACAD DERMATOL VOLUME 61, NUMBER 3 Menter et al 467 Table X. Cont Grapefruit juice NSAIDs Baseline monitoring History an physical examination Bloo pressure 3 2 BUN an Cr 3 2 Urinalysis Consier PPD LFTs, CBC count, lipi profile, magnesium, uric aci, an potassium Pregnancy test if inicate Ongoing monitoring Every other week uring initial 3 mo, thereafter at 1-mo intervals: bloo pressure, BUN, an Cr Monthly CBC count, LFTs, lipi profile, magnesium, uric aci, an potassium Pregnancy testing if inicate Pregnancy: category C; lower birth weight an shorter uration of pregnancy reporte in patients with transplantation; appears not to be teratogenic in patients with transplantation Nursing: mothers receiving cyclosporine shoul not breast-fee Peiatric use: transplantation recipients as young as 1 y have been treate with no unusual averse events; although safety an efficacy of cyclosporine for chilren \ 18 y with psoriasis has not been establishe, it may be consiere in this patient population with severe psoriasis Psoriatic arthritis: there are stuies emonstrating the efficacy of cyclosporine for psoriatic arthritis 178,179 BUN, Serum urea nitrogen; CBC, complete bloo cell; Cr, creatinine; FDA, Foo an Drug Aministration; LFT, liver function test; NSAIDS, nonsteroial anti-inflammatory rugs; PASI, Psoriasis Area an Severity Inex; PUVA, psoralen plus ultraviolet A; UV, ultraviolet. generalize pustular psoriasis, acitretin has been shown to be effective in 84% of patients. 119 Patients with erythroermic psoriasis can be successfully treate with etretinate, the pro-rug of acitretin. 120 Because of a lack of significant immunosuppression, acitretin is generally consiere effective an the treatment of choice in HIV-positive patients with severe psoriasis. 121 DOSAGE Acitretin response is relatively slow with a 3- to 6- month perio require to achieve a maximal response. Appropriate osing must take into account the balance among safety, tolerability, an efficacy as many patients may not tolerate the higher osages of acitretin to achieve optimal efficacy. For these reasons, the combination of retinois an UV light therapy may be consiere where feasible an appropriate. SAFETY Several potential averse effects have been associate with acitretin but these can generally be minimize by appropriate patient selection, careful osing, an monitoring. Teratogenicity is the most important safety issue. Acitretin is FDA pregnancy category X (highly unsafe uring pregnancy, with the risk of use outweighing any possible benefit). The use of any ose of acitretin uring pregnancy may lea to numerous malformations, incluing cariovascular, ocular, auitory, central nervous system, craniofacial, an skeletal, with the greatest risk occurring between the thir an sixth weeks of gestation. 122 Although the half-life of acitretin is 49 hours, acitretin may transform either spontaneously, or as a result of alcohol ingestion, into etretinate, which has a half-life of 168 ays. Base on this long half-life, it can take up to 3 years for etretinate to be eliminate from the boy. The minimum amount of alcohol consumption for this conversion to take place is not known an inavertent exposure to alcohol-containing proucts is ifficult to avoi. For these reasons, acitretin is contrainicate in women who plan to become pregnant or who fail to use aequate contraception for 3 years after iscontinuing acitretin. Uner almost every circumstance, acitretin shoul not be use in women of chilbearing potential. Mucocutaneous sie effects of acitretin occur in almost all patients to varying egrees an may inclue cheilitis, ryness of the eyes, nasal an oral mucosa, epistaxis, xerosis, brittle nails, hair loss, an burning or sticky skin. A less commonly seen cutaneous sie effect is retinoi ermatitis, in which erythematous scaly patches with very superficial fissuring of skin may occur; this may mimic unstable psoriasis. Periungual pyogenic granulomas may occur uring long-term use of acitretin. 112,123 The most common laboratory abnormality seen in patients treate with acitretin is hyperlipiemia, with

18 468 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 as many as 25% to 50% of patients experiencing increases in serum triglyceries. 124 Rare cases of pancreatitis, incluing fatal fulminant pancreatitis have been reporte. 125 Patients who are maintaine on acitretin over long perios of time an whose triglyceries are chronically elevate may be at increase risk for atherosclerosis an may warrant therapy with triglycerie-lowering therapy. 126 The risk for eveloping hyperlipiemia is increase in the setting of iabetes mellitus, obesity, an increase alcohol intake. 127 Lifestyle change to prevent/reuce hyperlipiemia shoul be encourage in patients with psoriasis who are being treate with oral retinois. Elevations of transaminases occur in 13% to 16% of patients treate with acitretin. 123 A liver biopsy stuy i not reveal a significant risk for liver toxicity in patients treate with acitretin. 128 Severe increases of liver function test results are rare, but may inicate toxic hepatitis inuce by acitretin. 129 Diffuse iiopathic hyperostosis has rarely been reporte as a sie effect of systemic retinois. It is characterize by egenerative sponylosis, arthritis of the vertebral articulations, an synesmophytes of the vertebral spine, an extra spinal bones with bone spur formation. 130 Occasionally severe hyperostosis may also be inuce. 131 Whether or not acitretin inuces osteoporosis has been the subject of controversy, 132,133 with the risk possibly highest in those receiving high-ose retinois for long time perios. Pseuotumor cerebri-like symptoms an signs have been observe uring acitretin usage. Decrease color vision an impairment of night vision may also occur. Although muscle an joint symptoms may occur uring acitretin treatment, they are selom a significant problem. DRUG INTERACTIONS Drug interactions may be relevant, particularly rugs that interfere with cytochrome P450 metabolism, such as CSA an rugs that compete for plasma protein bining such as phenytoin. Acitretin has been reporte to potentiate the glucose-lowering effect of glibenclamie. Because of the risk of hypervitaminosis A, concomitant aministration of vitamin A an/or other oral retinois with acitretin must be avoie. COMBINATION TREATMENT Enhance clinical response an a possible reuction of sie effects are the goals of combination therapy. Combination regimens of traitional treatments were reviewe in A consensus conference on the treatment of acitretin in combination with UVB or PUVA etermine that the combination enhances efficacy an limits the treatment frequency, uration, an cumulative oses, resulting in a more effective, better-tolerate, more convenient, an perhaps safer treatment. 135 Broaban UVB in combination with acitretin is highly effective as compare with monotherapy with acitretin This combination also increase safety as lower cumulative UVB exposure an lower oses of acitretin were neee to achieve clinical improvement. A 74% improvement in psoriasis severity score was shown in patients treate with acitretin 50 mg/ plus broaban UVB as compare with 35% with broaban UVB only, or to 42% with acitretin only. 138 Another stuy showe a similar efficacy with acitretin (35 mg/) for 4 weeks followe by a combination of broaban UVB plus acitretin (25 mg/), with the meian cumulative ose of broaban UVB to achieve 75% improvement being 41% lower for the combination as compare with UVB monotherapy. 139 The preferre scheule is acitretin monotherapy for 2 weeks followe by the aition of phototherapy. In patients alreay receiving UVB phototherapy but having a suboptimal response, acitretin ose at 25 mg/ may be ae. 128 In this scenario, it is pruent to ecrease the UVB ose by 30% to 50% for 1 week to minimize the propensity of UVBinuce erythema in skin expose to oral retinois. The UVB ose can then be increase graually as tolerate by the patient. The combination of narrowban UVB an acitretin is highly effective in patients whose psoriasis is ifficult to control, resulting in an improvement of at least 75% of the severity score in 72.5% of such patients. 140 The combination of acitretin an PUVA is more effective compare with monotherapy with either acitretin or PUVA alone The efficacy of this combination is also evient from the reuce cumulative UVA osage an the reuce number of PUVA sessions, implying an increase safety as compare with PUVA monotherapy. In theory, the anticancer potential of oral retinois may also a to their safety As with UVB therapy, acitretin is given for 14 ays before instituting PUVA treatment. When PUVA monotherapy appears to be insufficient, acitretin can be ae with appropriate reuction of the UVA ose by 30% to 50%. In patients who have receive of PUVA treatment, subsequent therapy with CSA increases the risk for eveloping SCCs. 80 On the other han, acitretin, when combine with PUVA therapy, consierably ecreases the incience of SCC. 148

19 JAM ACAD DERMATOL VOLUME 61, NUMBER 3 Menter et al 469 INITIATION AND MONITORING Before initiating therapy with acitretin, patients shoul have a thorough history an physical examination. Pretreatment laboratory stuies shoul inclue pregnancy testing; lipi stuies to evaluate for hypertriglyceriemia an hypercholesterolemia; an liver an renal function tests. If, espite acitretin s teratogenicity, it is consiere for use in a woman of chilbearing potential, then baseline an monthly pregnancy testing is appropriate. Monitoring for patients on acitretin is important for the prevention of averse events. After starting acitretin, patients shoul be monitore with everyother-week lipi profiles an liver enzymes. After 8 weeks of every-other-week monitoring, monitoring of lipi profiles an liver enzymes every 6 to 12 weeks can be institute. CBC count an renal function test results shoul be obtaine every 3 months. Recommenations for the use of acitretin are shown in Table XI. The strength of recommenations for the treatment of psoriasis using acitretin is shown in Table VIII. SECOND TIER SYSTEMIC AGENTS Although methotrexate, CSA, an acitretin are the traitional systemic therapies use in the treatment of psoriasis, it is occasionally necessary to consier treatment with alternative agents because of treatment-resistant isease or multiple intolerable averse events. In these clinical scenarios, it may be reasonable to consier therapy with other systemic agents. The level of evience supporting the use of these agents is of lesser quality than the more commonly use agents. AZATHIOPRINE Azathioprine, a purine analogue that blocks purine synthesis, is a commonly use immunosuppressive agent. Approve for use in renal transplantation an rheumatoi arthritis, azathioprine has been use off label for many years in the treatment of the autoimmune blistering iseases an atopic ermatitis. Although there are no ranomize trials for azathioprine in psoriasis, a few reports suggest beneficial results. The largest stuy was an openlabel one that inclue 29 patients ose at 100 to 300 mg of azathioprine aily. Of 29 patients, 19 benefite, with 13 of 19 patients showing greater than 75% improvement an 6 of 19 showing greater than 50% improvement, although the scale use to measure improvement was not specifie. 149 In another open-label stuy of 10 patients with severe psoriasis treate with azathioprine, 5 of 10 showe at least 25% improvement with the scale use to measure improvement again not specifie. 150 Averse effects of azathioprine may inclue leukopenia, anemia, thrombocytopenia, or pancytopenia. As 1 in 300 patients have an inherite eficiency in thiopurine methyltransferase that leas to an increase risk of eveloping myelotoxicity, thiopurine methyltransferase levels shoul be measure before commencing therapy. Liver toxicity manifeste by elevations in serum transaminases an alkaline phosphatase can occur. Gastrointestinal symptoms incluing nausea, vomiting, an iarrhea are relatively common an pancreatitis has rarely been reporte. The osage of azathioprine ranges from 0.5 up to 3 mg/kg, an is etermine by the results of thiopurine methyltransferase testing. Azathioprine works slowly with its onset of action generally requiring at least 6 to 8 weeks. Recommenations for the use of azathioprine are shown in Table XII. The British guielines for the use of azathioprine, publishe in 2004, coul also be consiere. 151 The strength of recommenations for the treatment of psoriasis using azathioprine is shown in Table VIII. FUMARIC ACID ESTERS Fumaric aci esters (also known as fumarates) are a mixture of imethylfumarate along with monoethylfumarate salts. Although fumarates are commonly use in Northern Europe, particularly in German-speaking countries an the Netherlans, for the treatment of patients with moerate to severe psoriasis, they are not approve in the Unite States. Fumarates appear to function by inhibiting T lymphocytes an shifting the cytokine profile from a T-helper 1 to a T-helper 2 phenotype. Several wellesigne ranomize stuies of fumarates emonstrate mean PASI improvement rates of between 50% an 80% after 12 to 16 weeks of treatment when ose initially at one pill aily of Fumaerm (containing 120 mg of imethylfumarate, 87 mg of calcium monoethylfumarate, 5 mg of magnesium monoethylfumarate, an 3 mg of zinc monoethylfumarate) an escalate as tolerate up to 6 pills aily The most common averse effect of the fumarates are gastrointestinal symptoms, incluing gastric an esophageal pain as well as nausea an vomiting, which may occur in over two thirs of patients. 156 These effects can be mitigate by initiating therapy with fumarates at a low ose an graually increasing the ose. About one thir of patients evelop flushing that tens to subsie with ongoing therapy. A mil lymphopenia is almost always present but appears to be of little consequence. 157 Serious, but reversible renal sie effects have been sporaically reporte, 158 but these events are not believe to be relate to

20 470 Menter et al JAM ACAD DERMATOL SEPTEMBER 2009 Table XI. Recommenations for acitretin Inication: FDA approve for aults with severe plaque type psoriasis Dosing: mg/ given as a single ose Lower oses ( # 25 mg/) often use to minimize sie effects, especially in combination regimens When acitretin is ae to UV, light ose shoul be reuce by 30%-50% Short-term results Efficacy rates not well efine but are high, base on stuies of high osages that are poorly tolerate Efficacy rates when use in combination with phototherapy are higher Long-term results Not reporte Contrainications Acitretin is a potent teratogen an must be avoie in women of chilbearing potential Severely impaire liver or kiney function Chronic abnormally elevate bloo lipi values Toxicity Cheilitis Alopecia Xerosis, pruritus Xerophthalmia, night blinness Dry mouth Paronychia Paresthesias Heaache, pseuotumor cerebri Nausea, abominal pain Joint pain Myalgia Hypertriglyceriemia Abnormal LFT results Drug interactions Etretinate can be forme with concurrent ingestion of acitretin an ethanol Acitretin may potentiate glucose-lowering effect of glibenclamie May interfere with the contraceptive effect of microose progestin minipill 180 Acitretin an methotrexate can both cause hepatotoxicity, therefore they shoul be combine with caution Acitretin may reuce the protein bining of phenytoin Acitretin an tetracyclines can both increase intracranial pressure; their combine use shoul be avoie Concomitant aministration of vitamin A an other oral retinois with acitretin shoul be avoie Baseline monitoring History an physical examination Lipi profile, CBC count, LFTs, renal function tests Pregnancy test if inicate Ongoing monitoring LFTs, lipi profile at 2-wk intervals for the first 8 wk, then every 6-12 wk CBC count, renal function tests every 3 mo Pregnancy test if inicate Pregnancy: category X Nursing: mothers receiving acitretin shoul not breast-fee Peiatric use: the safety an efficacy of acitretin in chilren with psoriasis is not establishe; high-ose, long-term oral retinoi use has been associate with ossification of interosseous ligaments an tenons of the extremities, skeletal hyperostoses, ecreases in bone mineral ensity, an premature epiphyseal closure Psoriatic arthritis: generally thought to be ineffective for psoriatic arthritis CBC, Complete bloo cell; FDA, Foo an Drug Aministration; LFT, liver function test; UV, ultraviolet. fumarates an have not been observe in any of the controlle trials. Recommenations for the use of fumaric aci esters are shown in Table XIII. The strength of recommenations for the treatment of psoriasis using fumaric aci esters is shown in Table VIII. HYDROXYUREA Hyroxyurea is an antimetabolite use in the treatment of certain cancers an hematologic conitions. It has been use in the treatment of psoriasis for more than 30 years an is thought to work by inhibiting DNA replication. Although there are no