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REVIEW ARTICLE
Year : 2014  |  Volume : 15  |  Issue : 2  |  Page : 66-73

Review of systemic methotrexate therapy in pediatric dermatoses


Department of Dermatology, Dr. D. Y. Patil Medical College, Navi Mumbai, Maharashtra, India

Date of Web Publication27-Aug-2014

Correspondence Address:
Manjyot Gautam
Department of Dermatology, Dr. D. Y. Patil Medical College, Navi Mumbai, Maharshtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2319-7250.139501

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  Abstract 

Introduction: With increasing knowledge about limitations of systemic steroids, the use of steroid sparing agents is now being accepted by practicing dermatologists. Methotrexate (MTX) is a well accepted steroid sparing drug in adults with dermatological conditions. However, its use in pediatric dermatoses has not been the subject of many investigations.
Materials and Methods: We decided to do a computerized search for the use of MTX in pediatric dermatoses using terms like "pediatric,'' "MTX," "psoriasis,'' "pityriasis rubra pilaris (PRP)," "atopic dermatitis," "pityriasis lichenoides," "lichen planus," "juvenile dermatomyositis (JDMS)," "localized morphea," "systemic lupus erythematosus (SLE)," "vesiculo-bullous diseases," "alopecia areata," "vasculitis," "eosinophilic fasciitis," "urticaria," "sarcoidosis," "pompholyx" and "vitiligo vulgaris." All the articles were retrieved and classified into review articles, studies, double-blinded trials and case reports. The final data were then analyzed.
Results: It has been found that MTX has been increasingly used in psoriasis, PRP, pityriasis lichenoides, JDMS, SLE and sarcoidosis. However, its use in several other dermatoses is restricted to isolated case reports.
Conclusion: Children tolerate MTX better than adults. However, proper clinical and laboratory surveillance has to be maintained in patients on long term MTX.

Keywords: Pediatric dermatoses, systemic methotrexate, immunosuppressants


How to cite this article:
Gautam M, Nadkarni N, Patil S, Godse K, Agarwal S. Review of systemic methotrexate therapy in pediatric dermatoses. Indian J Paediatr Dermatol 2014;15:66-73

How to cite this URL:
Gautam M, Nadkarni N, Patil S, Godse K, Agarwal S. Review of systemic methotrexate therapy in pediatric dermatoses. Indian J Paediatr Dermatol [serial online] 2014 [cited 2020 Oct 20];15:66-73. Available from: https://www.ijpd.in/text.asp?2014/15/2/66/139501


  Introduction Top


Ever since its discovery in the treatment of psoriasis in 1951 by Gubner, [1] Methotrexate (amethopterin, MTX), folic acid antagonist, has been used for the treatment of a wide spectrum of dermatologic conditions. Although many new drugs, including biologics have emerged in the market as competitors of MTX, this drug remains a popular choice among the dermatologists, especially in developing countries like India, because of years of experience of using MTX, its cost-effectiveness and a good safety profile.

There is very limited data regarding the use of MTX in the treatment of pediatric skin diseases. Majority of the publications on its use in children are based on the rheumatology literature or on case reports. Hence, a review of its use in pediatric conditions would be especially relevant.


  Structure Top


Methotrexate is 4-amino- N10 methyl pteroylglutamic acid. It is structurally similar to folic acid, which is the natural substrate for the enzyme dihydrofolate reductase. MTX competitively inhibits this enzyme. [2]


  Pharmacology Top


Route Of Administration And Dosage

Methotrexate can be administered orally or parenterally (subcutaneous or intramuscular injections). Oral route is preferred in children because of the ease of administration and greater child comfort. Furthermore, there does not appear to be any advantage related to efficacy or safety with either the oral or parenteral method of administration. [3]

Orally, MTX can be given as a single once weekly dose, or a triple dosage schedule given at 12 h interval (based upon cell cycle kinetics studies). [4] Both the dosing schedules are equally effective. However, this latter method can cause confusion in the minds of the caregivers as well as patients and can lead to inadvertent over-dosage. Hence, we prefer to give a single weekly dose.

Parenteral route is preferred if there is gastrointestinal (GI) intolerance. [5],[6]

Pharmacokinetics

There is significant variability in absorption, with food probably decreasing absorption of MTX. [7] Maximum blood levels occur 1-2 h after absorption and 35-50% of the drug is bound to proteins. The drug is well-distributed throughout the body except in the brain. The primary active metabolite is a polyglutamate derivative, which has a long half-life. [8]

On an average, 50-90% of the drug is excreted in the urine within 24 h. A minor degree of entero-hepatic circulation occurs. [2]

Mechanism of Action

There are two types of action of MTX, the antiproliferative action (mediated by folate-dependent pathway) and anti-inflammatory action (due to increase in aminoimidazole carboxamide ribonucleoside [AICAR] levels). The folate-dependent action involves enzymes such as methionine synthetase (DNA methylation), thymidylate synthetase (pyrimidine synthesis) and transformylase (purine synthesis). Thus, DNA multiplication is inhibited at multiple sites. The drug is active only in the S-phase of the cell cycle. [9],[10]

The anti-inflammatory action can be due to folate dependent pathways or folate independent pathways. The inhibition of polyamines is thought to be contributory when MTX is given in low doses. In higher doses, the enzyme inhibited is AICAR transformylase. This leads to increase the amount of AICAR, which increases adenosine levels, and adenosine is a potent antiinflammatory compound, which inhibits chemotaxis, cytokine factors, including tumor necrosis factor-α and down-regulates intercellular adhesion molecule. [11]



Adverse Effects

In general, children tolerate MTX well. GI intolerance (nausea, vomiting, diarrhea, anorexia, stomatitis) is the most common side-effect and it usually responds to dose reduction. Leucopenia and transient elevation of liver enzymes are also commonly encountered. [12]

Serious side-effects are rare and include pulmonary toxicity, [13] and hepatoxicity [14] and lymphomas. [15] Risk factors for hepatotoxicity include obesity, moderate to heavy alcohol consumption, type II diabetes mellitus, past history of chronic hepatitis, significant exposure to hepatotoxic drugs, persistent abnormal liver enzymes, and hyperlipidemia. [14] However most of these risk factors are not relevant in children.

Reactivation of tuberculosis [16] and viral hepatitis [17] can occur.

Other adverse effects reported are alopecia, photosensitivity, hematologic toxicity, headache, dizziness, cognitive disability and attention disorders. [18] Renal toxicity has been reported with high dose MTX use for leukemias. [19]

Supplementation with folic or folinic acid has been proposed to reduce toxicity associated with MTX therapy. Studies have shown that folate supplementation is effective in reducing the frequency of MTX side-effects without influencing the therapeutic benefit. [20],[21]

Our system for folic acid supplementation is that we advise 5 mg folic acid once daily after lunch on all the days when MTX is not given.

Drug Interactions [2]



  • Nonsteroidal anti-inflammatory drugs decrease renal elimination of MTX thereby increasing its levels in the circulation
  • Phenytoin increases serum levels of MTX by displacing the drug from plasma proteins
  • Doxycycline, minocycline, tetracycline increase serum levels of MTX
  • Dapsone and sulfonamides inhibit dihyropteroate synthetase. When given along with MTX levels of dapsone and sulfonamides can increase thereby increasing the risk of hematologic toxicity
  • Trimethoprim inhibits dihydrofolate reductase, which can increase the levels of trimethoprim and increase risk of hematologic toxicity
  • Systemic retinoids when given along with MTX increase the risk of hepatotoxicity.



  Materials and methods Top


A Google scholar search was done using words "pediatric," "MTX," "psoriasis," "pityriasis rubra pilaris (PRP)," "atopic dermatitis," "pityriasis lichenoides," "lichen planus," "juvenile dermatomyositis (JDMS)," "localized morphea," "systemic lupus erythematosus (SLE)," "vesiculo-bullous diseases," "alopecia areata," "vasculitis," "eosinophilic fasciitis," "urticaria," "sarcoidosis," "pompholyx" and "vitiligo vulgaris." All the articles were retrieved and classified into review articles, studies, double-blinded trials and case reports. The final data was then analyzed and presented in a narrative fashion under each disease used in search parameter.


  Results Top


0Psoriasis

Methotrexate is considered to be the systemic drug of choice for the treatment of childhood psoriasis, [22] the indications being:

  • Extensive recalcitrant plaque type psoriasis (psoriasis area severity index [PASI] >10)
  • Erythroderma
  • Generalized pustular psoriasis of Von Zumbusch
  • Severe disabling palmoplantar psoriasis
  • Palmoplantar pustulosis
  • Psoriatic arthritis.


Kumar et al. first reported the successful use of MTX in seven children having severe disease. They all received MTX 0.2-0.4 mg/kg in a single weekly oral dose. The time required to control the disease varied from 6 to 10 weeks. The total duration of MTX therapy was 31-46 weeks. No significant side-effects were noted in any patient. [23]

Dogra et al. treated a 2-year-old child with generalized pustular psoriasis. [24]

Kaur et al. did a retrospective analysis of 29 children with refractory psoriasis who were treated with MTX. Twenty-two out of the 24 children with complete data demonstrated excellent response (>75% reduction in PASI) with no major side-effects. The mean time to control the disease (>50% reduction in PASI) was 5 weeks. [25]

Atopic Dermatitis

Various studies have demonstrated the beneficial effects of MTX in adult atopic dermatitis. [26],[27],[28],[29],[30] It has emerged as one of the systemic drugs of choice in adult atopic dermatitis. [30] However, there is limited data demonstrating its use in children and adolescents. There is a case report of a 5-year-old boy with generalized atopic dermatitis who failed treatment with cyclosporine. He responded well to MTX (7-5 mg/week) with >50% reduction in SCORAD score after 7 weeks of therapy without any adverse effects of the medication. [31] A recent multi-centric study from Egypt compared the safety and efficacy of low-dose MTX (7.5 mg/week) versus low dose cyclosporine (2.5 mg/kg/day) in 40 children with severe AD. At 12 weeks the groups were indistinguishable, in that about 50% improved in both groups. [32]

Pityriasis Rubra Pilaris

Methotrexate is considered as one of the first-line systemic therapies for the treatment of PRP. [33],[34] Improvement or clearing with MTX has been reported in both adults and children. [35],[36],[37],[38] Griffiths reported improvement in 17 out of 44 patients treated with MTX [35] whereas Dicken demonstrated significant improvement in all his 8 patients who received MTX (10-25 mg/week) for an average of 6 months. [36] Clayton reported success of combination therapy of MTX with oral retinoids in refractory PRP. [37] However, this combination should be used with caution as it increases the risk of liver toxicity. In juvenile PRP, Klein et al. recommend the use of MTX only in severe recalcitrant cases. [33]

Pityriasis Lichenoides

Methotrexate is indicated for the severe ulcero-necrotic form of the disease. Combination of MTX with systemic steroids or cyclosporine and antibiotics has induced remission even in life-threatening cases. [39],[40],[41],[42]

Lichen Planus

Methotrexate is often suggested in the treatment of acute generalized lichen planus as a steroid sparing agent, but there is no published data supporting its use in children. There are few published reports regarding the efficacy of MTX in generalized lichen planus in adults. Turan et al. used MTX (15-20 mg/week) in 11 patients with generalized lichen planus, 10 of whom were completely cured after the 1 st month. [43] Likewise, Farhad et al. also reported the efficacy of low dose MTX (7.5-10 mg/week) in patients with generalized lichen planus. [44] Some authors have used MTX in combination with topical agents like topical steroids, calcineurin inhibitors for the treatment of refractory type of erosive oral or genital lichen planus with good results. [45],[46]

Localized Scleroderma (Morphea)

Methotrexate is emerging as the most frequently used systemic agent in the treatment of localized scleroderma in children. Low dose MTX can be used in combination with systemic corticosteroids for the treatment of rapidly progressive, disabling types of localized scleroderma in children. MTX improves skin fibrosis by directly acting on the skin fibroblasts and through its antiinflammatory effects. Uziel et al. demonstrated the efficacy of combined MTX (0.3-0.6 mg/kg weekly) and pulsed IV methylprednisolone (30 mg/kg/day) on 3 consecutive days/month for 3 months in 10 children with localized scleroderma. [47]

Similarly, Weibel et al. also reported the beneficial effects of combination of systemic corticosteroids and MTX in 34 children with localized scleroderma. None of them developed any major side-effects. [48]

Christen-Zaech et al. reviewed 136 children with localized scleroderma, where 39 of them received MTX. Majority of these patients responded well to this therapy with marked reduction in the induration. [49] Another randomized, double-blind, placebo controlled trial of MTX (15 mg/m 2 /week for 12 months) demonstrated the efficacy and safety of MTX in the treatment of juvenile localized scleroderma. [50]

Juvenile Dermatomyositis

Methotrexate is the most widely accepted second-line agent of choice in the treatment of recalcitrant JDMS, where it can be used in conjunction with systemic steroids. [51],[52] This combination can induce an early remission which can be sustained for a longer time. It helps in rapid tapering of steroids and thereby reducing the complications of long term, high dose oral steroids. Al-Mayouf et al. (2000) suggested early introduction of MTX (within 6 weeks of diagnosis) along with systemic steroids to prevent the development of complications like calcinosis in patients with severe JDMS. [53]

A recent randomized controlled trial including 139 children with newly diagnosed JDMS has compared the efficacy of treatment regimens for JDMS and concluded that combined therapy with prednisolone and either cyclosporine or MTX is more effective than with prednisolone alone and the safety profile favors the combination with MTX as against cyclosporine. [54]

Systemic Lupus Erythematosus

Studies have shown the efficacy of MTX in the treatment of subacute cutaneous lupus erythematosus [55] and refractory cases of chronic cutaneous lupus erythematosus in adults. [56] However, such studies are lacking in children. Lehman et al. have suggested that the use of MTX in childhood SLE should be reserved for patients with severe nephritis who are resistant to cyclophosphamide or have relapsed with the same. [57]

Vesiculo-Bullous Disorders

Although MTX has been used as a steroid sparing agent in adults with blistering disorders like pemphigus vulgaris [58],[59] and bullous pemphigoid, [60],[61] there is no published data on its use in children, mainly because of the rarity of these disorders in the pediatric population. There is a single study on childhood pemphigus where Wananukul et al. have presented five children with pemphigus. MTX was given in combination with oral steroids as a steroid sparing agent to a child with pemphigus foliaceus who presented as erythroderma. [62]

Alopecia Areata

Beneficial effects of MTX are reported in adult alopecia areata. [63],[64] However, its efficacy in children with severe alopecia areata is variable. MTX can be considered for severe childhood alopecia areata where alternative therapies are contra-indicated.

Royer et al. reported >50% hair re-growth in 5 out of the 14 children (aged 8-18 years) with severe alopecia areata who were treated with MTX 15-25 mg/week). No serious side-effects were reported in any of them. [65]

Vasculitis

Rettig and Cron reported the efficacy of MTX as a steroid sparing agent in nonrenal, chronic Henoch-Schonlein purpura in a child. [66]

Methotrexate has also been used in the treatment of pediatric Wegener's granulomatosis. [67]

Chronic Refractory Urticaria

Although MTX (10-25 mg) is useful in chronic refractory urticaria, [68],[69],[70] there is no published data of its use in children.

Sarcoidosis

Methotrexate is the drug of choice in second-line treatment of sarcoidosis both in adults as well as in children. [71] It is reserved for the treatment of sarcoidosis refractory to systemic steroids, patients who have developed steroid-related adverse effects and in patients with severe organ failure .[61] . MTX (10-15 mg/week) can either be combined with systemic steroids or used as monotherapy. Various authors have reported improvement in skin lesions with MTX. However relapse may occur on stopping MTX, suggesting that MTX controls and does not cure the disease. [72],[73],[74]

Eosinophilic Fasciitis

Ortega-Loayza et al. reported progressive improvement in a 12-year-old girl with eosinophilic fasciitis who was treated with a combination of MTX, systemic steroids and physical therapy. [75]

Pompholyx

Low dose MTX can be used for the treatment of severe and recalcitrant dyshidrotic eczema [76],[77] but there is no published data in the pediatric population.

Vitiligo Vulgaris

Published data on the use of MTX in vitiligo vulgaris is lacking. Although Sandra et al. reported improvement in their 54-year-old female patient of unstable vitiligo in terms of cessation of development of new lesions as well as considerable repigmentation of existing vitiligo lesions, [78] Al Ghondi and Khurrum were unable to notice any change in the vitiligo lesions in all their 6 vitiligo patients who were treated with MTX (25 mg/week) for 6 months. [79]

Algorithm for Initiating and Monitoring Methotrexate [80]



  • Rule out absolute contra-indications (pregnancy in adolescent patients, significant anemia, leukopenia, thrombocytopenia)
  • Evaluate for relative contra-indications (renal and hepatic impairment, chronic infections or immunocompromised states, or significant alcohol consumption, significant drug interactions or recent vaccinations). If significant factors exist, consider alternative therapy
  • Evaluate laboratory parameters at baseline (full blood count, renal and liver function tests, baseline liver biopsy may be considered in patients with hepatic risk factors, X-ray chest and pregnancy test). If these are abnormal, clinical re-evaluation is indicated
  • Initiate therapy (we recommend a test dose of 2.5 mg of MTX)
  • If no major side-effects emerge, therapy is started with 0.2-0.3 mg/kg body weight/week in a single dose, after a major meal
  • Monitor treatment with following parameters:
  • Hematologic surveillance: Complete blood count and Platelet count weekly for first 2 weeks, 2 weekly for next month, then monthly or 3 monthly depending on the clinical picture. Consider stopping MTX if the white blood cells count reduces to <3500/mm 3 or platelet count reduces to <100,000/mm 3 . [2]
  • Hepatic surveillance: Liver chemistries like serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase and serum albumin every 4-8 weeks, more frequently if hepatic risk factors. Consider reducing the dose or stopping MTX if the serum enzymes increase to >2 times the baselin. [2]
  • Renal surveillance: Renal function test including glomerular filtration rate every 3 months.


Role of Liver Biopsy in Monitoring Methotrexate Therapy

Over the years, liver biopsy studies in children with Juvenile rheumatoid arthritis who have taken MTX in significant doses (up to 4000 mg/1.73 m 2) have failed to show significant fibrosis, thereby suggesting that potential for developing hepatotoxicity with long term use of MTX is minimum. [81]

According to American College of Rheumatology guidelines liver biopsy should be considered in patients with ≥40%abnormalities of the liver enzyme tests done in the course of a year. [82] In the absence of risk factors baseline liver biopsy is not indicated, however, patients with risk factors should be subjected to a baseline liver biopsy, which should be delayed till it is ascertained that MTX is effective and well-tolerated by the patient. [80] Serial biopsies may not be recommended when the initial biopsy is normal, enzymes are normal, or when the weekly dose is <15 mg. [80]

Role of Serum Type III pro-collagen aminopeptide in Monitoring Methotrexate Therapy

Various authors are now suggesting to replace liver biopsy by serum type III pro-collagen aminopeptide (PIIINP) for monitoring patients on long term MTX. They have found this test to be reliable for fibrinogenesis. [83],[84] A recent study showed that patients with repeatedly normal levels of PIIINP had a low risk of developing liver toxicity. However, in some other conditions causing fibrosis (e.g. systemic sclerosis and rheumatoid arthritis), PIIINP levels are falsely elevated. [85]

Methotrexate and Immunization in Children

There is no information on the indications, efficacy or risk of vaccination in children taking MTX. In the absence of specific guidelines, live vaccines should be avoided. [86]


  Conclusion Top


Antimetabolite therapy was avoided in children in the past. However, in recent times, antimetabolites including MTX are being increasingly used in children, both as steroid sparing and steroid alternative drug. MTX has been used specially in the treatment of diseases like complicated forms of psoriasis, atopic dermatitis, localized and linear morphea, pityriasis lichenoides and many other vesiculo-bullous and autoimmune diseases.

Children seem to tolerate MTX better than adults. However, as with adults, proper pre-treatment workup as well as regular follow-up investigations should be conducted. Role of liver biopsy in MTX is controversial. It is probable that it may not be required in the absence of any risk factors for hepatotoxicity. Role of PIIINP is yet to be properly evaluated.

 
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