Radhika Shah, MS, BS1; Crystal E. Nwannunu, BS2; Allison L. Limmer, BA, BS2; Ravi R. Patel, MD3; Uyen Ngoc Mui, MD3; Stephen K. Tyring, MD, PhD2,3

1Texas A&M University College of Medicine, Dallas, TX, USA
2Department of Dermatology, McGovern Medical School, The University of Texas Health Sciences Center, Houston, TX, USA
3Center for Clinical Studies, Houston, TX, USA

Conflict of interest:
All of the authors have no conflicts to declare for this work.

Abstract:
Methotrexate (MTX), an agent originally intended for anti-neoplastic use, has been successfully employed in the treatment of a variety of dermatologic conditions. In addition to its multiple clinical indications, variable dosing and modes of administration make it a viable option for patients of all ages and most comorbidities. MTX is a folate analog that antagonizes dihydrofolate reductase, thus inhibiting thymidylate synthesis and, ultimately, the production of pyrimidine. Depending on dosage, MTX can function as an anti-inflammatory agent, immunomodulator, or antimetabolite. Patients suffering from psoriasis have benefited from MTX in addition to those with atopic dermatitis, chronic urticaria, pemphigus vulgaris, bullous pemphigoid, cutaneous lupus erythematosus, cutaneous sarcoidosis, and mycosis fungoides. Although patients with these conditions can benefit from MTX treatment, the drug can cause adverse sequelae, including hematologic, pulmonary, gastrointestinal, and hepatic side effects. Therefore, the drug should be administered under careful physician supervision.

Key Words:
atopic dermatitis, methotrexate, psoriasis, psoriasis treatment

Introduction

Methotrexate (MTX), an agent originally intended for antineoplastic use, has been successfully employed in the treatment of a variety of dermatologic conditions. It can be administered orally, subcutaneously, or intramuscularly, and depending on its clinical indication, MTX can be given once weekly or on a triple-dose schedule at 12-hour intervals. The drug is a folate analog that antagonizes the enzyme dihydrofolate reductase. Inhibition of dihydrofolate reductase obstructs thymidylate synthesis and, ultimately, inhibits production of pyrimidine, an important nucleic acid base that gives rise to cytosine, thymine, and uracil. At a low dose, MTX acts as an anti-inflammatory agent and immunomodulator. At high doses, it acts as an antimetabolite. Given its mechanism of action, MTX can lead to many adverse events and should be used with caution. Along with nausea, anorexia, fatigue, and malaise, other systemic toxicities can occur, including hematologic, gastrointestinal, reproductive, pulmonary, cardiac, and neurologic complications. It is safe to use low-dose MTX in children, but it should be avoided in pregnant women. Drug interactions may occur and can increase the likelihood of MTX toxicity. For this reason, the American Academy of Dermatology (AAD) strongly recommends folate supplementation with MTX therapy.1 This review aims to briefly delineate established clinical indications for, as well as recent research regarding the utility of MTX in dermatology.

Clinical Indications

Psoriasis

One of MTX’s primary uses is in the treatment of moderate to severe psoriasis and psoriatic arthritis, as the drug acts as an antiinflammatory agent.1 In one randomized, double-blind, placebo-controlled study, 75% improvement was seen in the Psoriasis Area and Severity Index (PASI) score in 40% of patients treated with MTX.2 PASI 75 in 45.2% of patients treated with MTX was also reported by a meta-analysis of 11 studies.3 Based on several randomized, controlled trials (RCTs), a starting dose of 15 mg/ week and maximum dose of 25 mg/week is recommended in patients with psoriasis.4 In addition to monotherapy, MTX can be administered in combination with betamethasone, ultraviolet B (UVB) phototherapy, and etanercept to treat psoriasis. Pustular variants of psoriasis have also been treated with combination therapy of MTX with retinoids and colchicine. Due to decreased renal clearance in the elderly, lower doses are effective in treating this patient population. A dose of only 2.5 mg/week is adequate in controlling psoriasis for patients over 80 years of age.1

Chronic Urticaria (CU)

A recent retrospective review of 16 patients with steroid-dependent CU treated with MTX demonstrated improvement in 12 patients, with complete clearance of CU in 2 patients. A dose of 10-15 mg/week was administered to achieve a steroid-sparing effect.1,5 In a different study involving 45 patients with chronic idiopathic urticaria, of which 12 tested positive for autoantibodies, MTX was given in 10 mg/week doses to these patients, all of whom improved clinically.1,6 A different study performed in 2014 for the treatment of H1-antihistamine resistant chronic spontaneous urticaria involved 14 patients over the course of 12 weeks. Only 10 out of 14 patients completed the 12-week treatment, and no statistically significant difference in efficacy was observed between MTX treatment group and placebo group.7 Despite this finding, MTX is still commonly used to treat patients with CU, with several studies supporting its efficacy. However, additional confirmatory studies should be pursued. Serious side effects of MTX in patients with CU include bone marrow suppression and hepatitis.8

Atopic Dermatitis (AD)

MTX is an effective second- or third-line treatment option for AD in both adults and children.9 However, it has been shown to be more effective in adult-onset compared to childhood-onset AD.1 In one randomized, controlled trial that compared the efficacies of MTX versus azathioprine (AZA) in adults with severe AD, a SCORAD (SCORing Atopic Dermatitis) reduction of 42% was seen in patients treated with 10-22.5 mg/week of MTX. In a randomized clinical trial for children aged 8 to 14 years, a SCORAD reduction of 49% was demonstrated in those treated with 7.5 mg/week of MTX compared to a 45% reduction in those treated with cyclosporin A. MTX was usually well-tolerated, and the most common side effect in these studies was nausea.9 An open-label prospective study demonstrated that 8 out of 12 patients with AD achieved clinical improvement through a starting dose of 10 mg and incremental increase of 2.5 mg/week until a therapeutic effect was observed.1,10 Long-term risks include pulmonary fibrosis and hepatotoxicity.9

Blistering Disorders

Pemphigus Vulgaris

A retrospective chart review evaluated 23 patients with pemphigus vulgaris who were initially treated with prednisone before starting treatment with MTX.11 Results of this study revealed that 21 of the 23 patients (91%) experienced clinical improvement in blistering after MTX initiation.11 In addition to clinical improvement, these patients were able to reduce their dosage of prednisone, with 16 patients (70%) weaning off prednisone completely.11 It was reported that MTX had to be discontinued in 2 patients due to adverse effects.

Bullous Pemphigoid (BP)

MTX has been shown to be effective in controlling BP when combined with systemic steroids.12 A retrospective study was conducted to evaluate the efficacy and safety of MTX with standard prednisone treatment. Of the 138 participants included in the study, 98 were treated with MTX and received a median weekly dosage of 5-6 mg.12 Treatment groups included MTX only, MTX plus prednisone, prednisone only, and topical betamethasone gel. After 24 months, an estimated remission rate among treatments groups was 43%, 35%, 0% and 83%, respectively (p < 0.001).12 The adverse effects observed in this study, which resulted in cessation of MTX, included gastrointestinal (GI) irritation, anemia, transient alveolitis, and increased liver enzyme levels.12 Another study suggested a marked therapeutic effect with MTX use in BP patients suffering from secondary diseases such as diabetes and active peptic ulcers.13,14

Localized Scleroderma

Although the treatment selection for localized scleroderma is still controversial, MTX has been observed as an effective treatment modality.1,15 A comparative study was performed between two treatment groups: MTX and MTX plus corticosteroids with statistically significant (p = 0.02) differences in duration of sclerotic disease between treatment groups, 22-25 months and 12 months, respectively.15 Both groups received a median weekly dosage of 15 mg of MTX.15 Clinical assessment revealed that 81% of patients treated with MTX and all patients treated with MTX plus steroids showed clinical improvement of sclerotic skin.15 An additional study that evaluated juvenile patients specifically supported the efficacy and safety of MTX as a monotherapy.16 MTX was well-tolerated in these studies with reported side effects including infections, GI disturbance, and elevated liver enzymes.15,16

Cutaneous Lupus Erythematosus (CLE)

MTX is commonly used as a second-line treatment in patients with CLE who have contraindications or resistance to first-line agents and in patients with refractory subacute CLE, as well as discoid lupus erythematosus.1,17 A retrospective study was performed to analyze 12 patients refractory to first-line therapy who received MTX treatment.18 A median dosage of 10-25 mg of MTX was administered weekly.18 Ten of the 12 patients showed improvements of their cutaneous lesions within 6 weeks.18 Another study of 43 patients with recalcitrant CLE treated with MTX demonstrated improvement of cutaneous lesions in 98% of patients, with the best clinical improvement seen particularly in patients with subacute CLE.18 Discontinuation of treatment occurred in 7 patients who displayed severe side effects, however, the side effects resolved after cessation of MTX.18 Both studies supported the use of low dose MTX for management in refractory patients.17,18

Cutaneous Sarcoidosis (CS)

MTX is a widely employed second-line agent in the treatment of CS along with antimalarial drugs and tetracyclines.1,19 Secondline agents are useful especially if the patient needs to avoid or is resistant to glucocorticoids. However, studies evaluating the efficacy of MTX for CS are uncontrolled and small, with one study demonstrating efficacy in 80% of participants.1,19 MTX is given in doses of 10-25 mg/week for CS; once improvement is noted, the dose can be tapered to as low as 2.5 mg/week.1,20,21 Another study suggested that low-dose MTX (7.5 mg/week) as monotherapy for sarcoidosis was more effective for cutaneous than pulmonary lesions with no patients experiencing serious adverse events.22

Mycosis Fungoides (MF)

Literature regarding the use of MTX in treating cutaneous T-cell lymphoma has expanded in recent years. Low-dose MTX (up to 30 mg/week orally) is a viable first-line agent for advanced MF, with low toxicity compared to multiagent chemotherapy regimens and a mean period of 5 months until repeat treatment is required.23 Additionally, the combination of MTX with other systemic agents such as interferon-alpha and bexarotene may enhance efficacy in the treatment of advanced MF.24

Safety Considerations

Hepatotoxicity

One of the main concerns of MTX use in patients is hepatotoxicity. Several studies have shown that patients treated with MTX are at increased risk for developing hepatic adverse events such as elevated transaminase levels and fibrosis. The exact pathogenesis for this phenomenon is unclear, but it has prompted transaminase monitoring and use of liver biopsies to monitor patients at risk for hepatotoxicity through the Roenigk classification system, which progressively classifies changes from early fatty infiltration to varying degrees of fibrosis. Transaminase levels should be monitored every 2 weeks when initiating treatment or adjusting doses, and every 12 weeks once a stable dose is achieved. If transaminases are elevated, administration of MTX should be reduced, and further evaluation is needed to determine the source of elevation. In this case, a liver biopsy might be indicated; however, liver biopsies are rarely clinically indicated, due to its high sampling error rate of 20-30% and risk of morbidity and mortality.25 A relatively new non-invasive technology known as transient elastography (TE) has been more recently utilized to monitor liver fibrosis. TE uses an ultrasound transducer in order to measure shear wave speed to approximate stiffness in hepatic tissue.26 A study of 24 patients treated with a median dose of 1,635 mg of MTX for psoriasis who previously underwent liver biopsy showed that TE had good negative predictive value and accurately identified 88% of those without significant fibrosis.27 It has also been found that a higher prevalence of non-alcoholic fatty liver disease (NAFLD) exists in psoriatic patients treated with MTX compared with the general population. This can be explained by risk factors of NAFLD, including obesity and type II diabetes mellitus. The development of NAFLD in this population is the hepatic manifestation of metabolic syndrome, and treating these patients with MTX puts them at an even higher risk for hepatotoxicity.28 A possible explanation for MTX hepatotoxicity is a reduction of folate stores in the liver due to a local folate deficiency. For this reason, the AAD recommends 1-5 mg of daily folic acid supplementation for all MTX-treated patients.25,29 Although it was once thought that MTX use should be limited over one’s lifetime, if there are no signs of hepatotoxicity or bone marrow failure with regular monitoring, MTX therapy should not be withheld regardless of cumulative dose.30

Drug Interactions

MTX administration can pose a high risk for drug-drug interactions. Sulfa drugs such as trimethoprim-sulfamethoxazole (TMP-SMX) can interact with MTX and cause severe adverse effects by potentiating the inhibition of dihydrofolate reductase.31 This further impairs folate production, thus increasing risk for myelosuppression.32 A systemic analysis revealed that concurrent MTX and TMP-SMX use, occurring at remarkably low doses (5-15 mg/week), is a risk factor for pancytopenia.33 In addition, TMP-SMX and MTX are both nephrotoxic agents, and their combinative effects impair renal excretory function, which can lead to elevated drug levels. Caution is advised in patients with preexisting renal conditions.32

Concurrent use of nonsteroidal anti-inflammatory agents (NSAIDs) and MTX results in a proposed mechanism of competitive renal tubular excretion, leading to increased serum MTX levels.32 The use of high dose MTX with NSAIDs has been documented to cause adverse effects including myelosuppression, transaminitis and acute kidney injury. NSAIDs that commonly have the propensity to interact with MTX include indomethacin, diclofenac, ibuprofen, and high dose aspirin.32,33

When MTX is co-administered with antibacterial agents such as penicillin, there is a prolonged delay in clearance, causing increased serum MTX levels that can place a patient at risk of adverse effects including neutropenia, renal failure and mucositis.34 While administration of low dose MTX (7.5- 25 mg/day) poses a lower risk than dosing at antineoplastic levels (500 mg-1.2 g/m2/week), it is recommended that an alternate antibiotic be used to prevent these risk factors.34,35

Pregnancy

MTX, as a folate antagonist, disrupts DNA synthesis, DNA damage repair, and cellular replication.36 These properties can cause devastating birth defects for a developing fetus, including heart malformations, cleft palate, hypospadias, congenital diaphragmatic hernia, craniosynostosis, and even death.36,37 In fact, MTX is used for medical termination of pregnancy. A recent meta-analysis found that two doses of MTX was more effective than either one or multiple doses in the treatment of ectopic pregnancy.36 Therefore, MTX should be stopped at least 3 months prior to becoming pregnant and should not be used at any point during the pregnancy.37

Risk of Lymphoma

MTX, aside from being immunosuppressive, is also cytotoxic and can lead to a loss of cellular immune control of tumor proliferation.38 One prospective cohort study involving 1,380 patients treated for psoriasis found that high-dose exposure, defined as at least 36 months of MTX treatment, led to an increased risk of lymphoma. Patients in the cohort treated with MTX had a 7 times greater risk of lymphoma compared to those in the cohort with less exposure to MTX (IRR, 7.77).39

Conclusion

MTX has been an important agent in the management of dermatologic conditions for decades. Although first indicated for the treatment of psoriasis, MTX has been shown to be a successful treatment option for a wide array of skin diseases. As biologics become more widely prescribed and available, monitoring the combination of these drugs with MTX will be relevant; for example, etanercept and MTX co-administration has shown increased efficacy without an increase in adverse events when compared to etanercept alone in the treatment of psoriasis.40 Additionally, a recent study found that rates of non-basal cell skin cancers were 3 times higher in rheumatic patients treated with prolonged low-dose MTX versus placebo, an observation that warrants caution and further investigation.41

References



  1. Shen S, O’Brien T, Yap LM, et al. The use of methotrexate in dermatology: a review. Australas. J Dermatol. 2012 Feb;53(1):1-18.

  2. Kim WB, Jerome D, Yeung J. Diagnosis and management of psoriasis. Can Fam Physician. 2017 Apr;63(4):278-85.

  3. Kaushik SB, Lebwohl MG. Review of safety and efficacy of approved systemic psoriasis therapies. Int J Dermatol. 2019 Jun;58(6):649-58.

  4. Menting SP, Dekker PM, Limpens J, et al. Methotrexate dosing regimen for plaque-type psoriasis: a systematic review of the use of test-dose, startdose, dosing scheme, dose adjustments, maximum dose and folic acid supplementation. Acta Derm Venereol. 2016 Jan;96(1):23-8.

  5. Perez A, Woods A, Grattan CE. Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol. 2010 Jan;162(1):191-4.

  6. Godse K. Methotrexate in autoimmune urticaria. Indian J Dermatol Venereol Leprol. 2004 Nov-Dec;70(6):377.

  7. Holm JG, Ivyanskiy I, Thomsen SF. Use of nonbiologic treatments in antihistamine-refractory chronic urticaria: a review of published evidence. J Dermatolog Treat. 2018 Feb;29(1):80-97.

  8. Godse KV. Chronic urticaria and treatment options. Indian J Dermatol. 2009 54(4):310-2.

  9. Prezzano JC, Beck LA. Long-term treatment of atopic dermatitis. Dermatol Clin. 2017 Jul;35(3):335-49.

  10. Weatherhead SC, Wahie S, Reynolds NJ, et al. An open-label, dose-ranging study of methotrexate for moderate-to-severe adult atopic eczema. Br J Dermatol. 2007 Feb;156(2):346-51.

  11. Tran KD, Wolverton JE, Soter NA. Methotrexate in the treatment of pemphigus vulgaris: experience in 23 patients. Br J Dermatol. 2013 Oct;169(4):916-21.

  12. Kjellman P, Eriksson H, Berg P. A retrospective analysis of patients with bullous pemphigoid treated with methotrexate. Arch Dermatol. 2008 May;144(5):612-6.

  13. Heilborn JD, Stahle-Backdahl M, Albertioni F, et al. Low-dose oral pulse methotrexate as monotherapy in elderly patients with bullous pemphigoid. J Am Acad Dermatol. 1999 May;40(5 Pt 1):741-9.

  14. Downham TF 2nd, Chapel TA. Bullous pemphigoid: therapy in patients with and without diabetes mellitus. Arch Dermatol. 1978 Nov;114(11):1639-42.

  15. Kroft EB, Creemers MC, van den Hoogen FH, et al. Effectiveness, side-effects and period of remission after treatment with methotrexate in localized scleroderma and related sclerotic skin diseases: an inception cohort study. Br J Dermatol. 2009 May;160(5):1075-82.

  16. Zulian F, Martini G, Vallongo C, et al. Methotrexate treatment in juvenile localized scleroderma: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2011 Jul;63(7):1998-2006.

  17. Wenzel J, Brahler S, Bauer R, et al. Efficacy and safety of methotrexate in recalcitrant cutaneous lupus erythematosus: results of a retrospective study in 43 patients. Br J Dermatol. 2005 Jul;153(1):157-62.

  18. Boehm IB, Boehm GA, Bauer R. Management of cutaneous lupus erythematosus with low-dose methotrexate: indication for modulation of inflammatory mechanisms. Rheumatol Int. 1998 18(2):59-62.

  19. Mosam A, Morar N. Recalcitrant cutaneous sarcoidosis: an evidence-based sequential approach. J Dermatolog Treat. 2004 Dec;15(6):353-9.

  20. Lower EE, Baughman RP. The use of low dose methotrexate in refractory sarcoidosis. Am J Med Sci. 1990 Mar;299(3):153-7.

  21. Veien NK, Brodthagen H. Cutaneous sarcoidosis treated with methotrexate. Br J Dermatol. 1977 Aug;97(2):213-6.

  22. Isshiki T, Yamaguchi T, Yamada Y, et al. Usefulness of low-dose methotrexate monotherapy for treating sarcoidosis. Intern Med. 2013 52(24):2727-32.

  23. Hughes CF, Khot A, McCormack C, et al. Lack of durable disease control with chemotherapy for mycosis fungoides and Sezary syndrome: a comparative study of systemic therapy. Blood. 2015 Jan 1;125(1):71-81.

  24. Humme D, Nast A, Erdmann R, et al. Systematic review of combination therapies for mycosis fungoides. Cancer Treat Rev. 2014 Sep;40(8):927-33.

  25. Conway R, Carey JJ. Risk of liver disease in methotrexate treated patients. World J Hepatol. 2017 Sep 18;9(26):1092-100.

  26. Cheng HS, Rademaker M. Monitoring methotrexate-induced liver fibrosis in patients with psoriasis: utility of transient elastography. Psoriasis (Auckl). 2018 8:21-9.

  27. Berends MA, Snoek J, de Jong EM, et al. Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis. Liver Int. 2007 Jun;27(5):639-45.

  28. Shetty A, Cho W, Alazawi W, et al. Methotrexate hepatotoxicity and the impact of nonalcoholic fatty liver disease. Am J Med Sci. 2017 Aug;354(2):172-81.

  29. Strober BE, Menon K. Folate supplementation during methotrexate therapy for patients with psoriasis. J Am Acad Dermatol. 2005 Oct;53(4):652-9.

  30. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. J Am Acad Dermatol. 2009 Sep;61(3):451-85.

  31. Toivo TM, Mikkola JA, Laine K, et al. Identifying high risk medications causing potential drug-drug interactions in outpatients: A prescription database study based on an online surveillance system. Res Social Adm Pharm. 2016 Jul-Aug;12(4):559-68.

  32. Dong J, Bonomo L, Lebwohl M. Common adverse drug-drug interactions in dermatology: oral therapies. SKIN The Journal of Cutaneous Medicine. 2017;1(2):74-82. Available at: https://jofskin.org/index.php/skin/article/ view/18. Accessed: September 30, 2019.

  33. Bourre-Tessier J, Haraoui B. Methotrexate drug interactions in the treatment of rheumatoid arthritis: a systematic review. J Rheumatol. 2010 Jul;37(7):1416-21.

  34. Rochester CD. Drug interactions in dermatology. Are they just skin deep? US Pharm. 2007 Apr 17;32(4):HS29-39. Available at: https://www.uspharmacist. com/article/drug-interactions-in-dermatology. Accessed: September 30, 2019.

  35. Hansten PD, Horn JR. The top 100 drug interactions: a guide to patient management. 2006 edition. Freeland, WA: H&H Publications, LLP.

  36. Alur-Gupta S, Cooney LG, Senapati S, et al. Two-dose versus single-dose methotrexate for treatment of ectopic pregnancy: a meta-analysis. Am J Obstet Gynecol. 2019 Aug;221(2):95-108 e2.

  37. Dawson AL, Riehle-Colarusso T, Reefhuis J, et al. Maternal exposure to methotrexate and birth defects: a population-based study. Am J Med Genet A. 2014 Sep;164A(9):2212-6.

  38. Bewtra M, Lewis JD. Update on the risk of lymphoma following immunosuppressive therapy for inflammatory bowel disease. Expert Rev Clin Immunol. 2010 Jul;6(4):621-31.

  39. Stern RS. Lymphoma risk in psoriasis: results of the PUVA follow-up study. Arch Dermatol. 2006 Sep;142(9):1132-5.

  40. Zachariae C, Mork NJ, Reunala T, et al. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate effect of methotrexate therapy. Acta Derm Venereol. 2008 88(5): 495-501.

  41. Ridker PM, Everett BM, Pradhan A, et al. Low-dose methotrexate for the prevention of atherosclerotic events. N Engl J Med. 2019 Feb 21;380(8):752-62.


Purchase Article PDF for $1.99

STL Volume 24 Number 6
Purchase PDF for $2.79

RELATED ARTICLESMORE FROM THIS ISSUE