Title: Guidelines of care for the management of psoriasis and psoriatic arthritis
Abstract: Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this fourth of 6 sections of the guidelines of care for psoriasis, we discuss the use of traditional systemic medications for the treatment of patients with psoriasis. Treatment should be tailored to meet individual patients' needs. We will discuss in detail the efficacy and safety, and offer recommendations for the use of the 3 most commonly used, and approved, traditional systemic agents: methotrexate, cyclosporine, and acitretin. We will also briefly discuss the available data for the use of azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil, sulfasalazine, tacrolimus, and 6-thioguanine in psoriasis. Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In this fourth of 6 sections of the guidelines of care for psoriasis, we discuss the use of traditional systemic medications for the treatment of patients with psoriasis. Treatment should be tailored to meet individual patients' needs. We will discuss in detail the efficacy and safety, and offer recommendations for the use of the 3 most commonly used, and approved, traditional systemic agents: methotrexate, cyclosporine, and acitretin. We will also briefly discuss the available data for the use of azathioprine, fumaric acid esters, hydroxyurea, leflunomide, mycophenolate mofetil, sulfasalazine, tacrolimus, and 6-thioguanine in psoriasis. Adherence to these guidelines will not ensure successful treatment in every situation. Furthermore, these guidelines should not be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. The ultimate judgment regarding the propriety of any specific therapy must be made by the physician and the patient in light of all the circumstances presented by the individual patient. This fourth section will cover the management and treatment of psoriasis with traditional systemic therapies. A work group of recognized psoriasis experts was convened to determine the audience and scope of the guideline, and identify clinical questions to structure the primary issues in diagnosis and management discussed in American Academy of Dermatology (AAD) psoriasis guidelines section 1 and 2.1Menter A. Gottlieb A. Feldman S.R. Van Voorhees A.S. Leonardi C.L. Gordon K.B. et al.Guidelines of care for the management of psoriasis and psoriatic arthritis, section 1: overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics.J Am Acad Dermatol. 2008; 58: 826-850Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, 2Gottlieb A. Korman N.J. Gordon K.B. Feldman S.R. Lebwohl M. Koo J.Y. et al.Guidelines of care for the management of psoriasis and psoriatic arthritis, section 2: psoriatic arthritis; overview and guidelines of care for treatment with an emphasis on the biologics.J Am Acad Dermatol. 2008; 58: 851-864Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar Work group members completed a disclosure of commercial support. An evidence-based model was used and evidence was obtained using a search of the MEDLINE database spanning the years 1960 through 2008. Only English-language publications were reviewed. The available evidence was evaluated using a unified system called the Strength of Recommendation Taxonomy developed by editors of the US family medicine and primary care journals (ie, American Family Physician, Family Medicine, Journal of Family Practice, and BMJ USA). This strategy was supported by a decision of the Clinical Guidelines Task Force in 2005 with some minor modifications for a consistent approach to rating the strength of the evidence of scientific studies.3Ebell M.H. Siwek J. Weiss B.D. Woolf S.H. Susman J.L. Ewigman B. et al.Simplifying the language of evidence to improve patient care: Strength of recommendation taxonomy (SORT): a patient-centered approach to grading evidence in medical literature.J Fam Pract. 2004; 53: 111-120PubMed Google Scholar Evidence was graded using a 3-point scale based on the quality of methodology as follows:I.Good-quality patient-oriented evidence.II.Limited-quality patient-oriented evidence.III.Other evidence including consensus guidelines, opinion, or case studies. Clinical recommendations were developed on the best available evidence tabled in the guideline. These are ranked as follows:A.Recommendation based on consistent and good-quality patient-oriented evidence.B.Recommendation based on inconsistent or limited-quality patient-oriented evidence.C.Recommendation based on consensus, opinion, or case studies. In those situations where documented evidence-based data are not available, we have used expert opinion to generate our clinical recommendations. Prior guidelines on psoriasis were also evaluated. This guideline has been developed in accordance with the AAD “Administrative Regulations for Evidence-based Clinical Practice Guidelines,” which include the opportunity for review and comment by the entire AAD membership and final review and approval by the AAD Board of Directors. In the past, conventional systemic psoriasis therapies–methotrexate, cyclosporine (CSA), and acitretin–were used when psoriasis was too extensive for topical therapy or refractory to topical therapy and phototherapy. Although a minimum body surface area, eg, 10%, has been traditionally used as a prerequisite to starting a systemic therapy for psoriasis, a subset of patients with limited disease have debilitating symptoms. For example, although severe psoriasis of the palms and soles or severe scalp psoriasis affects less than 5% of the body surface area, the significant negative affect on the quality of life of the patient makes a systemic approach to treatment appropriate. In recent years, biologics have changed the treatment of psoriasis, giving us additional therapeutic options that are potentially less toxic to the liver, kidneys, and bone marrow and are not teratogenic. Nevertheless, traditional systemic therapies continue to play an important role in the treatment of psoriasis with their oral route of administration and low cost (compared with biologics) making them an important treatment option in the appropriate patient. Methotrexate is the most commonly prescribed traditional systemic therapy worldwide for psoriasis. Detailed guidelines concerning its dosing and monitoring in patients with psoriasis have recently been published by the National Psoriasis Foundation.4Kalb R.E. Strober B. Weinstein G. Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation consensus conference.J Am Acad Dermatol. 2009; 60: 824-837Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar It is noteworthy that the rheumatology guidelines for the use of methotrexate5Ritchlin CT, Kavanaugh A, Gladman DD, Mease PJ, Helliwell P, Boehncke WH, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis doi:10.1136/ard.2008.094946. Published online October 24, 2008.Google Scholar are less stringent than those in dermatology, especially in the monitoring of hepatotoxicity. The difference in this monitoring may be that patients with psoriasis with more severe disease are more likely to be obese than patients with rheumatoid arthritis, and thus be more prone to have underlying nonalcoholic steatohepatitis. Methotrexate can be dramatically effective with even the most severe cases of psoriasis. The potential role of pharmacogenetic testing to improve our ability to predict the efficacy and safety of methotrexate suggests the possibility of personalizing the use of methotrexate in the years ahead.6Warren R.B. Chalmers R.J. Griffiths C.E. Menter A. Methotrexate for psoriasis in the era of biological therapy.Clin Exp Dermatol. 2008; 33: 551-554Crossref PubMed Scopus (20) Google Scholar Methotrexate has been used in combination with all of the approved biologic agents for psoriasis. The greatest experience is with tumor necrosis factor inhibitors. Methotrexate has been used to suppress antibodies against the two monoclonal tumor necrosis factor inhibitors, adalimumab and infliximab.7Atzeni F. Sarzi-Puttini P. Autoantibody production in patients treated with anti-TNF.Expert Rev Clin Immunol. 2008; 4: 275-280Crossref PubMed Scopus (9) Google Scholar It is not known whether the use of methotrexate and biologics causes additive immunosuppression as this combination has primarily been studied in patients without psoriasis, and the differing baseline risks associated with these diseases make this distinction uncertain. CSA is one of the most effective treatments available for psoriasis.8Lebwohl M. Ellis C. Gottlieb A. Koo J. Krueger G. Linden K. et al.Cyclosporine consensus conference: with emphasis on the treatment of psoriasis.J Am Acad Dermatol. 1998; 39: 464-475Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar However, when used in the longer term (3-5 years), a significant prop- ortion of patients will develop some degree of glomerulosclerosis.9Lowe N.J. Wieder J.M. Rosenbach A. Johnson K. Kunkel R. Bainbridge C. et al.Long-term low-dose cyclosporine therapy for severe psoriasis: effects on renal function and structure.J Am Acad Dermatol. 1996; 35: 710-719Abstract Full Text PDF PubMed Scopus (58) Google Scholar Published guidelines in the United States therefore limit its use to 1 year,8Lebwohl M. Ellis C. Gottlieb A. Koo J. Krueger G. Linden K. et al.Cyclosporine consensus conference: with emphasis on the treatment of psoriasis.J Am Acad Dermatol. 1998; 39: 464-475Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar whereas in the United Kingdom it is allowed for 2 years.10Griffiths C.E. Dubertret L. Ellis C.N. Finlay A.Y. Finzi A.F. Ho V.C. et al.Cyclosporin in psoriasis clinical practice: an international consensus statement.Br J Dermatol. 2004; 150: 11-23Crossref PubMed Google Scholar In patients with severe flares of psoriasis, CSA frequently induces a rapid remission. Rebound flares of psoriasis after discontinuation of systemic steroids or efalizumab can be prevented or rapidly controlled with CSA11Carey W. Glazer S. Gottlieb A.B. Lebwohl M. Leonardi C. Menter A. et al.Relapse, rebound, and psoriasis adverse events: an advisory group report.J Am Acad Dermatol. 2006; 54: S171-S181Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar or methotrexate. Of the systemic therapies, acitretin is the least effective as monotherapy and it is therefore often used in conjunction with ultraviolet (UV) B or psoralen plus UVA (PUVA) phototherapy. Studies performed in the 1980s demonstrated that etretinate, the pro-drug of acitretin, is particularly effective in patients with palm and sole psoriasis.12White S.I. Marks J.M. Shuster S. Etretinate in pustular psoriasis of palms and soles.Br J Dermatol. 1985; 113: 581-585Crossref PubMed Google Scholar Because acitretin is not immunosuppressive, it has also been used in combination with biologic therapies. Acitretin's major side effect is its teratogenicity, and its use is, therefore, limited to male and female patients of nonchildbearing potential. At high doses, it may be associated with significant mucocutaneous effects along with hair loss, and although it can occasionally be dosed at 50 mg daily, most clinicians use doses between 10 and 25 mg per day. Because of the known organ toxicities of traditional systemic agents, the concept of rotational therapy was developed so that patients could rotate from one agent to the other or to phototherapy or photochemotherapy to minimize total cumulative dose and thereby limit toxicity.13Menter M.A. See J.A. Amend W.J. Ellis C.N. Krueger G.G. Lebwohl M. et al.Proceedings of the Psoriasis Combination and Rotation Therapy Conference; Deer Valley, UT; October 7-9, 1994.J Am Acad Dermatol. 1996; 34: 315-321Abstract Full Text PDF PubMed Scopus (50) Google Scholar With the advent of biologic therapies, and their reduction in incidence of major organ toxicity, rotational therapy is less commonly used.13Menter M.A. See J.A. Amend W.J. Ellis C.N. Krueger G.G. Lebwohl M. et al.Proceedings of the Psoriasis Combination and Rotation Therapy Conference; Deer Valley, UT; October 7-9, 1994.J Am Acad Dermatol. 1996; 34: 315-321Abstract Full Text PDF PubMed Scopus (50) Google Scholar To minimize the toxicity of any therapy, proper patient selection and appropriate monitoring are crucial. The decision to administer methotrexate, CSA, acitretin, or any other traditional therapy must be individualized. Every patient needs to be carefully evaluated with reference to disease severity, quality of life, and general medical and psychologic status. Oral methotrexate is an effective treatment for psoriasis being initially used more than 50 years ago. Methotrexate competitively inhibits the enzyme dihydrofolate reductase, thus decreasing the synthesis of folate cofactors needed to produce nucleic acids. Because the effects of methotrexate are most dramatic on rapidly dividing cells, it was originally thought that its beneficial effects in psoriasis were a result of the inhibition of epidermal proliferation.14Weinstein G.D. Frost P. Methotrexate for psoriasis: a new therapeutic schedule.Arch Dermatol. 1971; 103: 33-38Crossref PubMed Google Scholar However, it is now known that there is little effect on epidermal cells, but there is significant inhibition of the proliferation of lymphoid tissue at concentrations of methotrexate that are typically achieved with low-dose weekly methotrexate.15Jeffes III, E.W. McCullough J.L. Pittelkow M.R. McCormick A. Almanzor J. Liu G. et al.Methotrexate therapy of psoriasis: differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and growth-inhibitory effects of methotrexate.J Invest Dermatol. 1995; 104: 183-188Crossref PubMed Google Scholar These findings support the concept that the therapeutic effect of low-dose methotrexate in psoriasis is a result of its effects on the immune system.16Saporito F.C. Menter M.A. Methotrexate and psoriasis in the era of new biologic agents.J Am Acad Dermatol. 2004; 50: 301-309Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar Methotrexate was approved by the Food and Drug Administration (FDA) in 1972 for the treatment of severe, recalcitrant, disabling psoriasis. Because methotrexate was introduced before the acceptance of randomized clinical trials as the standard by which to judge drug efficacy, there are no large high-quality studies demonstrating its safety and efficacy, and clinical experience with methotrexate is much greater than the documentation of its safety and efficacy in clinical studies. For these reasons, methotrexate guidelines, which were originally written in 197217Roenigk Jr., H.H. Maibach H.I. Weinstein G.D. Use of methotrexate in psoriasis.Arch Dermatol. 1972; 105: 363-365Crossref PubMed Google Scholar and have since been updated on numerous occasions (most recently in 20094Kalb R.E. Strober B. Weinstein G. Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation consensus conference.J Am Acad Dermatol. 2009; 60: 824-837Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar), provide expert-based standards for the use of methotrexate in the treatment of psoriasis. Three well-designed studies that evaluated the efficacy of methotrexate were recently performed. Heydendael et al18Heydendael V.M. Spuls P.I. Opmeer B.C. de Borgie C.A. Reitsma J.B. Goldschmidt W.F. et al.Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis.N Engl J Med. 2003; 349: 658-665Crossref PubMed Scopus (251) Google Scholar compared the efficacy and safety of methotrexate with CSA in a study that randomized 88 patients to receive either medication without a placebo group. The primary end point of Psoriasis Area and Severity Index (PASI) 75 at 16 weeks was 60% for methotrexate and 71% for CSA (no statistical difference). Twelve of 44 patients in the methotrexate group dropped out because of elevated liver function test results (it should be noted that no folic acid supplementation was given in this study), whereas only one patient in the CSA group dropped out (because of elevated bilirubin).18Heydendael V.M. Spuls P.I. Opmeer B.C. de Borgie C.A. Reitsma J.B. Goldschmidt W.F. et al.Methotrexate versus cyclosporine in moderate-to-severe chronic plaque psoriasis.N Engl J Med. 2003; 349: 658-665Crossref PubMed Scopus (251) Google Scholar Flytstrom et al19Flytstrom I. Stenberg B. Svensson A. Bergbrant I.M. Methotrexate vs cyclosporin in psoriasis: effectiveness, quality of life and safety.a randomized controlled trial. Br J Dermatol. 2008; 158: 116-121Google Scholar compared methotrexate with CSA in the treatment of 84 patients with psoriasis in a 12-week study that also did not include a placebo arm. These authors used a different end point, namely a mean PASI change from baseline, which was 72% for CSA compared with 58% for methotrexate. Although CSA was statistically more effective than methotrexate, 12 patients in the CSA group and 4 patients in the methotrexate group dropped out secondary to laboratory abnormalities and withdrawn consents before initiation of treatment.19Flytstrom I. Stenberg B. Svensson A. Bergbrant I.M. Methotrexate vs cyclosporin in psoriasis: effectiveness, quality of life and safety.a randomized controlled trial. Br J Dermatol. 2008; 158: 116-121Google Scholar Saurat et al20Saurat J.H. Stingl G. Dubertret L. Papp K. Langley R.G. Ortonne J.P. et al.Efficacy and safety results from the randomized controlled comparative study of adalimumab vs methotrexate vs placebo in patients with psoriasis (CHAMPION).Br J Dermatol. 2008; 158: 558-566Crossref PubMed Scopus (247) Google Scholar performed the first double-blind, placebo-controlled study of methotrexate, designed to compare the safety and efficacy of adalimumab, methotrexate, and placebo in 250 patients. After 16 weeks of treatment, PASI 75 improvement was 19% for placebo, 36% for methotrexate, and 80% for adalimumab. For those patients in the methotrexate arm of the study, methotrexate was initiated at a low weekly dosage of 7.5 mg for 2 weeks, followed by 10 mg weekly for 2 weeks, and then 15 mg for 4 weeks. Thereafter, an increase in the dosage of methotrexate was permitted depending on the response and the presence or absence of toxicities. After 8 weeks, if patients in the methotrexate arm had achieved a PASI 50 response, no further increase in methotrexate dosage was allowed. After 16 weeks, when the mean methotrexate dose was 19 mg, these patients were crossed over to receive adalimumab; it should be noted that patients in the methotrexate arm were still showing clinical improvement at the time of crossover, suggesting that the results of this study may have underestimated the efficacy of methotrexate.20Saurat J.H. Stingl G. Dubertret L. Papp K. Langley R.G. Ortonne J.P. et al.Efficacy and safety results from the randomized controlled comparative study of adalimumab vs methotrexate vs placebo in patients with psoriasis (CHAMPION).Br J Dermatol. 2008; 158: 558-566Crossref PubMed Scopus (247) Google Scholar Furthermore, the placebo response rate of 19% is dramatically higher than is seen in a clinical trial of this type, raising doubt about the validity of this study. Methotrexate is generally given as a single weekly oral dose, given as a tablet or occasionally as a carefully measured parenteral solution given orally (0.1 mL of a 25 mg/mL multidose vial is equivalent to a 2.5-mg oral tablet). The parenteral solution of methotrexate is less costly than tablets. Intramuscular administration is helpful when there is gastrointestinal intolerance to oral dosing or if there are concerns regarding patient compliance. Subcutaneous injection is equally effective and can be self-administered at home. Doses are usually started at low levels to minimize side effects and then gradually increased to achieve efficacy. Many practitioners give a single test dose of 2.5 or 5 mg to evaluate for significant bone-marrow suppression in susceptible patients. Although there are no established maximum or minimum dosages of methotrexate, weekly dosages usually range from 7.5 to 25 mg. All dosing schedules should be adjusted to the individual patient and the dosage raised or reduced to obtain or maintain adequate disease control or minimize side effects. After an increase in methotrexate dose, it may take up to 4 weeks for a clinical response to occur. Some patients can be gradually tapered off treatment and restarted when the psoriasis recurs. It is important to minimize the total cumulative dose of methotrexate while maintaining disease control and medication tolerance. Although the majority of experts recommend that all patients treated with methotrexate receive folate supplementation (1-5 mg/d given daily except the day of methotrexate), others will add folate only if a patient develops gastrointestinal side effects or early bone-marrow toxicity as manifested by an increased mean corpuscular volume. In patients who develop bone-marrow toxicity or gastrointestinal side effects while on folate, increasing the dose of folate may be helpful. Although a literature review of these data, largely derived from the rheumatoid arthritis literature, suggests that low-dose folate supplementation may reduce the hematologic, gastrointestinal, and hepatic side effects of methotrexate without decreasing the efficacy,21Strober B.E. Menon K. Folate supplementation during methotrexate therapy for patients with psoriasis.J Am Acad Dermatol. 2005; 53: 652-659Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar one small controlled study in patients with psoriasis using folic acid at 5 mg daily suggested that there may be a slight decrease in efficacy.22Salim A. Tan E. Ilchyshyn A. Berth-Jones J. Folic acid supplementation during treatment of psoriasis with methotrexate: a randomized, double-blind, placebo-controlled trial.Br J Dermatol. 2006; 154: 1169-1174Crossref PubMed Scopus (49) Google Scholar However, the methodology of this latter study has been questioned.23Brownell I. Strober B.E. Folate with methotrexate: big benefit, questionable cost.Br J Dermatol. 2007; 157: 213Crossref PubMed Scopus (5) Google Scholar The optimal dosage of folic acid is still to be determined. Common and generally minor toxicities of methotrexate include nausea, anorexia, stomatitis, and fatigue that most often occur at the time of methotrexate administration. These effects may be minimized by administering methotrexate by intramuscular or subcutaneous injection, splitting the dose, folate supplementation, or by administering the dose with food or at bedtime. The major toxicities that are of greatest concern in patients treated with methotrexate are myelosuppression, hepatotoxicity, and pulmonary fibrosis. Of 164 possible methotrexate-associated fatalities, 67 were caused by myelosuppression, 30 were caused by pulmonary fibrosis, and 8 were caused by hepatotoxicity.24MacDonald A. Burden A.D. Noninvasive monitoring for methotrexate hepatotoxicity.Br J Dermatol. 2005; 152: 405-408Crossref PubMed Scopus (28) Google Scholar Pulmonary fibrosis is one of the more severe manifestations of methotrexate toxicity and must be ruled out in patients presenting with new pulmonary symptoms such as cough; however, this complication is much less common in patients with psoriasis than in patients with rheumatoid arthritis.25Belzunegui J. Intxausti J.J. De Dios J.R. Lopez-Dominguez L. Queiro R. Gonzalez C. et al.Absence of pulmonary fibrosis in patients with psoriatic arthritis treated with weekly low-dose methotrexate.Clin Exp Rheumatol. 2001; 19: 727-730PubMed Google Scholar, 26Kremer J.M. Toward a better understanding of methotrexate.Arthritis Rheum. 2004; 50: 1370-1382Crossref PubMed Scopus (102) Google Scholar, 27Helliwell P.S. Taylor W.J. Treatment of psoriatic arthritis and rheumatoid arthritis with disease modifying drugs–comparison of drugs and adverse reactions.J Rheumatol. 2008; 35: 472-476PubMed Google Scholar Because methotrexate has not been studied in large double-blind placebo-controlled trials of the type that have been routinely used to determine the safety and efficacy of the biologic agents, less common adverse effects have not been carefully evaluated. Recent reports suggest that treatment with methotrexate may be associated with some of the risks similar to those of the biologic agents, although to date these reports have occurred almost exclusively in patients with rheumatoid arthritis.28Binymin K. Cooper R.G. Late reactivation of spinal tuberculosis by low-dose methotrexate therapy in a patient with rheumatoid arthritis.Rheumatology (Oxford). 2001; 40: 341-342Crossref PubMed Google Scholar, 29Clarke L.E. Junkins-Hopkins J. Seykora J.T. Adler D.J. Elenitsas R. Methotrexate-associated lymphoproliferative disorder in a patient with rheumatoid arthritis presenting in the skin.J Am Acad Dermatol. 2007; 56: 686-690Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 30Gwak G.Y. Koh K.C. Kim H.Y. Fatal hepatic failure associated with hepatitis B virus reactivation in a hepatitis B surface antigen-negative patient with rheumatoid arthritis receiving low dose methotrexate.Clin Exp Rheumatol. 2007; 25: 888-889PubMed Google Scholar, 31Maruani A. Wierzbicka E. Machet M.C. Abdallah-Lotf M. de Muret A. Machet L. Reversal of multifocal cutaneous lymphoproliferative disease associated with Epstein-Barr virus after withdrawal of methotrexate therapy for rheumatoid arthritis.J Am Acad Dermatol. 2007; 57: S69-S71Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Hepatitis, reactivation of tuberculosis (TB), and lymphoma, especially the B-cell type that is commonly associated with Epstein-Barr virus infection, have all been reported in patients being treated with methotrexate.23Brownell I. Strober B.E. Folate with methotrexate: big benefit, questionable cost.Br J Dermatol. 2007; 157: 213Crossref PubMed Scopus (5) Google Scholar, 24MacDonald A. Burden A.D. Noninvasive monitoring for methotrexate hepatotoxicity.Br J Dermatol. 2005; 152: 405-408Crossref PubMed Scopus (28) Google Scholar, 25Belzunegui J. Intxausti J.J. De Dios J.R. Lopez-Dominguez L. Queiro R. Gonzalez C. et al.Absence of pulmonary fibrosis in patients with psoriatic arthritis treated with weekly low-dose methotrexate.Clin Exp Rheumatol. 2001; 19: 727-730PubMed Google Scholar, 26Kremer J.M. Toward a better understanding of methotrexate.Arthritis Rheum. 2004; 50: 1370-1382Crossref PubMed Scopus (102) Google Scholar These observations suggest that practitioners need to maintain a high index of suspicion for these infections in patients being treated with methotrexate. The major risk factors for hematologic toxicity are advanced age, renal impairment, the absence of folate supplementation, drug interactions, and medication errors (Table I). Most of the literature concerning myelosuppression with methotrexate derives from the experience in patients with rheumatoid arthritis. Although the relative risk of myelosuppression in patients with psoriasis compared with patients with rheumatoid arthritis is unknown, the literature suggests that significant myelosuppression is rare in appropriately monitored patients with psoriasis who have no risk factors for hematologic toxicity.Table IRisk factors for hematologic toxicity from methotrexate• Renal insufficiency• Advanced age• Lack of folate supplementation• Methotrexate dosing errors• Drug interactions• Hypoalbuminemia• Greater than moderate alcohol intakeAdapted with permission from Kalb et al.4Kalb R.E. Strober B. Weinstein G. Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation consensus conference.J Am Acad Dermatol. 2009; 60: 824-837Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Open table in a new tab Adapted with permission from Kalb et al.4Kalb R.E. Strober B. Weinstein G. Lebwohl M. Methotrexate and psoriasis: 2009 National Psoriasis Foundation consensus conference.J Am Acad Dermatol. 2009; 60: 824-837Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar The practice of using a single test dose of methotrexate derives from the desire to ensure that severe myelosuppression does not occur. The test dose is typically 2.5 or 5 mg with a complete blood cell (CBC) count evaluated 5 to 6 days later, to ensure that myelosuppression has not occurred before increasing to the full weekly dosage. Although the use of a test dose does not guarantee that patients will not experience myelosuppression, it is mandatory in patients with a decreased glomerular filtration rate or other significant risk factors for hematologic toxicity.32Gutierrez-Urena S. Molina J.F. Garcia C.O. Cuellar M.L. Espinoza L.R. Pancytopenia secondary to methotrexate therapy in rheumatoid arthritis.Arthritis Rheum. 1996; 39: 272-276Crossref PubMed Scopus (104) Google Scholar Pancytopenia can rarely occur with the use of low-dose weekly methotrexate, even after single doses of methotrexate.33Cohen P.R. Schulze K.E. Nelson B.R. Pancytopenia after a single intradermal infiltration of methotrexate.J Drugs Dermatol. 2005; 4: 648-651PubMed Google Scholar, 34Jih D.M. Werth V.P. Thrombocytopenia after a single test dose of methotrexate.J Am Acad Dermatol. 1998; 39: 349-351Abstract Full Text Full Text PDF PubMed Google Scholar, 35Preet Singh Y. Aggarwal A. Misra R. Agarwal V. Low-dose methotrexate-induced pancytopenia.Clin Rheumatol. 2007; 26: 84-87Crossref PubMed Scopus (14) Google Scholar It can occur at any time during treat
Publication Year: 2009
Publication Date: 2009-09-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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