To the Editor:
Methotrexate (MTX) is an inexpensive and readily available medication that is used off-label for many inflammatory skin conditions in pediatric patients, with substantial variation in dosing and monitoring. To support optimal management of pediatric inflammatory skin diseases with low-dose MTX, a 27-member expert committee convened to establish evidence-based, consensus-driven guidelines.1 Five major subjects were assessed: 1) indications and contraindications, 2) dosing, 3) interactions with immunizations and medications, 4) adverse effects, and 5) monitoring. An executive summary is presented below. Open access to the full-length guildlines is available; see Seigfried et al. Pediatr Dermatol. 2023 Sep-Oct;40(5):789–808.1
The committee included pediatric and general dermatologists, pediatric rheumatologists, and participants from industry and patient advocacy groups. An extensive literature search was initiated in July 2019 using keywords from clinical questions developed for each of the 5 subjects. Preliminary consensus statements were drafted based on the available literature and expert opinions from the committee. An online survey platform and modified Delphi process were conducted to achieve consensus, predefined as ≥70% of participants rating a statement as 7–9 on a 0–9 Likert scale. The Strength of Recommendation Taxonomy (SORT) system2 was used to rate the strength of recommendations and quality of available data.
Forty-six recommendations reached consensus, including:
Lack of FDA approval does not preclude the clinical decision to prescribe MTX to pediatric patients with inflammatory skin disease.
MTX is useful for treating pediatric patients with morphea, psoriasis, dermatomyositis, atopic dermatitis, lupus, sarcoidosis, and alopecia areata, and for prevention of neutralizing antibodies associated with biologic therapy. The committee recognized other conditions that can be effectively treated with MTX supported by limited clinical data and personal experience.
While dosing based on either weight or body surface area can been used, weight-based dosing was recommended for ease of calculation in clinical practice.
There was agreement on a maximum maintenance dose of 1 mg/kg, up to 25 mg/week; however, consensus was not achieved about an optimal starting dose, corresponding to the wide dosing range reported in the literature.
MTX can be administered orally or subcutaneously, but the parenteral route likely enhances bioavailability and may increase efficacy.
An initial “test dose” (<7.5 mg) of MTX in not needed for pediatric patients with inflammatory skin disease.
Consider the impact of MTX on immunization and co-administered medications; multiple specific recommendations were made in this category.
Although MTX is generally well tolerated, it is important to counsel patients and caregivers about potential adverse effects, most commonly gastrointestinal. Daily supplementation with 1 mg/day oral folic acid can minimize gastrointestinal discomfort.
Tables 1 includes a selection of key consensus statements addressing dosing, interactions and adverse effects. Table 2 lists specific recommendations for monitoring patients on MTX.
Table 1.
Key consensus statements to guide MTX use for inflammatory skin disease in children
| Recommendation | Respondent agreement, % | SORTa |
|---|---|---|
|
| ||
| Dosing | ||
| While both weight-based dosing and body surface area-based dosing have been used for MTX in pediatric patients, weight-based dosing may be easier to calculate and has been safely used in many studies. | 88 | AI |
| Maximum dose of MTX in published studies varies widely, but for inflammatory skin disease the maximum dose is considered 1 mg/kg, not exceeding 25 mg/week. | 92 | CIII |
| Parenteral administration of MTX likely results in higher bioavailability and may increase efficacy. | 88 | CIII |
| Test doses are not necessary for pediatric patients starting low-dose MTX for inflammatory skin disease. | 85 | CIII |
| Onset of MTX effect is often 8–12 weeks for atopic dermatitis, psoriasis, and lichen planus, but may be closer to 12–16 weeks for alopecia areata and morphea. Time to maximal effect may be longer. | 92 | CIII |
| MTX can be discontinued abruptly without adverse effects, other than risk of disease worsening. | 88 | CIII |
| The rate of taper should be based on disease severity, risk of disease worsening, and/or patient and parent/caregiver preference. | 80 | CIII |
| Interactions | ||
| Concomitant use of MTX and trimethoprim/sulfamethoxazole is not contraindicated. | 75 | CIII |
| NSAIDs or salicylates can be given concurrently with low-dose MTX in children with normal renal function. | 84 | BII |
| Adverse Effects | ||
| Drug-related adverse effects of MTX including gastrointestinal effects, oral mucositis, fatigue, and headache are typically mitigated with folic acid supplementation. | 92 | BII |
| The use of folic acid is recommended during treatment with MTX, and daily dosing of 1 mg/day is recommended over once-weekly dosing for most patients. | 92 | CIII |
| The following information is pertinent in any patient on MTX with elevated liver enzymes: recent symptoms of viral illness, MTX dosing within 24 hours prior to phlebotomy, recent administration of other medications (eg, acetaminophen), recent alcohol consumption. | 96 | CIII |
| MTX should be temporarily discontinued when liver enzymes lab results are ≥3× ULN for 2 consecutive months. | 92 | CIII |
| Discontinue or decrease the dose of MTX if total white blood cell count is <3×109/L, absolute neutrophil count is <10×109/L, or platelet count is <100,000/L. | 92 | CIII |
| Counseling and mitigation strategies regarding the risks of fetal loss and teratogenicity should be discussed and implemented for individuals of childbearing potential taking MTX. | 100 | BII |
Table 2.
Recommendations to guide MTX monitoring for inflammatory skin disease in children
| Recommendation | Respondent agreement, % | SORTa |
|---|---|---|
|
| ||
| Baseline laboratory monitoring for all patients using MTX should include: • Complete blood count • White blood cell differential • Alanine aminotransferase • Aspartate aminotransferase • Serum creatinine |
92–100 | CIII |
| Ongoing laboratory monitoring should be done after 1st month and then every 3 to 4 months: • Complete blood count • White blood cell differential • Alanine aminotransferase • Aspartate aminotransferase • Serum creatinine |
75–88 | CIII |
| Baseline pregnancy testing should be performed for all patients of childbearing potential who are sexually active and not using contraception. | 88 | BII |
| Tuberculosis testing is only recommended for patients at risk for exposure. | 83 | CIII |
| Labs should be repeated sooner than usual for liver enzyme elevations 2–3x ULN. | 100 | CIII |
| Liver biopsy is not indicated for routine monitoring of pediatric patients taking low-dose MTX. | 96 | BII |
| Pulmonary function tests are only indicated for patients with pulmonary symptoms. | 100 | CIII |
MTX, methotrexate. NSAID, nonsteroidal anti-inflammatory drug.
The Strength of Recommendation Taxonomy (SORT) system2 was used to rate the strength of each recommendation as: A) recommendation based on consistent and good quality patient-oriented evidence; B) recommendation based on inconsistent or limited-quality patient-oriented evidence; or C) recommendation based on consensus, opinion, case studies, or disease-oriented evidence. The quality of available data upon which each recommendation was based was rated as: I) good-quality patient-oriented evidence (ie, measures outcomes that matter to patients: morbidity, mortality, symptom improvement, cost reduction, and quality of life); II) limited-quality patient-oriented evidence; or III) other evidence, including consensus guidelines, usual practice, opinion, disease-oriented evidence (ie, measures intermediate, physiologic, or surrogate endpoints that may or may not reflect improvements in patient outcomes), and case series for studies of diagnosis, treatment, prevention, or screening.
Even in the era of targeted therapies, MTX continues to play an important role in the management of inflammatory skin diseases. These consensus-based recommendations are intended to inform dosing, monitoring, and mitigation of potential side effects of MTX for treatment of pediatric inflammatory skin disease.
Acknowledgments
The authors would like to thank Jennifer C Jaworski, MS, BCMAS, CMPP, Umar Sheikh, MD, and Rita Sieracki, MLS for their contributions to this work. The authors would also like to thank the Pediatric Dermatology Research Alliance (PeDRA) Best Practices Task Force for their review of the manuscript.
Funding
This work was supported by a generous grant from the Pediatric Dermatology Research Alliance (PeDRA), with additional funding from the National Eczema Association (NEA) and the National Psoriasis Foundation (NPF). Funding sources had no influence on the content of the guidelines beyond several authors being members of the funding sources and review and approval of the final document by the Pediatric Dermatology Research Alliance (PeDRA) Best Practices Task Force.
Footnotes
Disclaimer: This publication has been reviewed by FDA and determined not to be consistent with the Agency’s views or policies. It reflects only the views and opinions of the authors.
Patient Consent: Not applicable
Conflicts of Interest
All potential conflicts of interest are reported below. Conflicts of interest were collected via the ICMJE form for Disclosure of Potential Conflicts of Interest (https://www.icmje.org/disclosure-of-interest/), transcribed into text, and reviewed by each author. None of the potential conflicts of interest were considered to have a possible influence on development of the recommendations.
Heather Brandling-Bennett has served as principal investigator for Lilly.
Elaine Siegfried has received consulting fees from AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica; has received honoraria from Regeneron, Sanofi Genzyme, and Verrica; has served on data safety monitoring boards for LEO Pharma, Novan, Pfizer, and UCB; participated in contracted research for AI Therapeutics; served as principal investigator for Janssen, and her institution has received fees related to clinical trials from Janssen, Lilly, Pierre Fabre, Regeneron, and Verrica and in support of a 2020–2021 pediatric dermatology fellowship from Pfizer.
Lisa Arkin has received consulting fees from Abbvie, Regeneron, and Verrica.
Adelaide Hebert has received research grants (paid to UTHealth McGovern Medical School) from LEO Pharma, Mayne Pharma, UCB, GSK, Ortho Dermatolgics, Amgen, Arcutis, AbbVie, and Pfizer; has received honoraria from Pfizer, Arcutis, UCB, Verrica, LEO Pharma, Novan, Incyte, Janssen, Mayne Pharma, and Castle Creek Bioscience; and has served on drug safety monitoring boards for Ortho Dermatologics, GSK, and Sanofi Regeneron.
Kelly Cordoro has served as a member of a scientific steering committee for Celgene.
Megan Curran has served as an advisory board member for Novartis, receiving honoraria.
Austin Dalrymple has served as an advisory board member for Novartis.
Carsten Flohr is chief investigator of the UK National Institute for Health Research-funded TREAT (ISRCTN15837754, EudraCT 2015–002013-29) and SOFTER (Clinicaltrials.gov: NCT03270566) trials as well as the UK-Irish Atopic Eczema Systemic Therapy Register (A-STAR; ISRCTN11210918) and a principal investigator in the European Union (EU) Horizon 2020-funded BIOMAP Consortium (http://www.biomap-imi.eu/). He also leads the EU Trans-Foods Consortium. His department has received funding from Sanofi-Genzyme and Pfizer for host-microbiome research.
Ken Gordon has received personal fees from AbbVie, Almirall, Amgen, BMS, Dermavant, Dermira, Lilly, Janssen, Kyowa Hakko Kirin, LEO Pharma, Novartis, Pfizer, Sun Pharma, and UCB and grants from BMS, Lilly, and UCB.
Alan Irvine has received person fees from AbbVie, LEO Pharma, Lilly, Novartis, and Sanofi/Regeneron, and has received a grant from the UK National Institute for Health Research (research arm of the UK Department of Health) as co-principal investigator of a clinical trial comparing MTX with cyclosporine in children with severe atopic dermatitis.
A. Yasmine Kirkorian has received honoraria from Verrica.
Irene Lara-Corrales has served as an advisory board member for Ipsen, LEO Pharma, Lilly, Novartis, Pfizer, and Sanofi Genzyme; as a consultant for AbbVie, Avicanna, Janssen, Johnson & Johnson, Loreal, Pfizer, Pierre Fabre, Sanofi Genzyme, and Valeant; as a speaker for AbbVie, Amgen, Novartis, and Sanofi Genzyme; and has served as a site investigator for AbbVie, Clementia Pharmaceuticals, Janssen, Lilly, and, Mayne Pharma.
Jill Lindstrom has received consulting fees from AbbVie, AnaptysBio, Arena Pharmaceuticals, Aristea, Incyte, and Priovant.
Amy S. Paller has served as an investigator for AbbVie, Applied Pharma Research, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, Regeneron, and UCB; Consultant for Aegerion Pharma, Azitra, BioCryst, Boehringer-Ingelheim, Bristol Myers Squibb, Castle Creek, Eli Lilly, Janssen, Krystal, LEO Pharma, Novartis, Regeneron, Sanofi/Genzyme, Seanergy, TWI Biotechnology, and UCB, and on the data safety monitoring board for AbbVie, Abeona, Catawba, Galderma, and InMed.
Wendy Smith Begolka has served as an advisory board member for Incyte and Pfizer, and has received a grant from Pfizer.
Wynnis Tom has served as a site investigator for clinical trials for Janssen, Regeneron, Incyte, Pfizer, Dermira, Eli Lilly, and AbbVie, and has been on data safety committees for LEO Pharma.
Abby Van Voorhees has received research grants from AbbVie, Celgene, and Lilly; has served as an advisory board member for BMS, Boehringer Ingelheim, Celgene, Novartis, and UCB; and had received consulting fees from Amgen.
Ruth Ann Vleugels has received consulting fees from AbbVie, Pfizer, and Priovant.
Lara Wine Lee has received consulting fees from AbbVie and Krystal Biotech; served as an investigator for AbbVie, Amryt, Arcutis, BMS, Castle Creek Biosciences, Celgene, Galderma, Incyte, Janssen, Kiniksa, Lilly, Mayne Pharma, Novartis, Pfizer, Regeneron, Sanofi Genzyme, Target Pharma, Trevi Therapeutics, and UCB; and has served as an advisory board member for Lilly, Novartis, Pfizer, and Regeneron.
Olivia Davies has received a fellow stipend from Pediatric Dermatology Research Alliance (PeDRA).
Elaine Siegfried has received consulting fees from AbbVie, Boehringer Ingelheim, Incyte, LEO Pharma, Novan, Novartis, Pierre Fabre, Pfizer, Regeneron, Sanofi Genzyme, UCB, and Verrica; has received honoraria from Regeneron, Sanofi Genzyme, and Verrica; has served on data safety monitoring boards for LEO Pharma, Novan, Pfizer, and UCB; participated in contracted research for AI Therapeutics; served as principal investigator for Janssen, and her institution has received fees related to clinical trials from Janssen, Lilly, Pierre Fabre, Regeneron, and Verrica and in support of a 2020–2021 pediatric dermatology fellowship from Pfizer.
Yvonne Chiu, Jeffrey Callen, Leslie Castello-Soccio, Dominic Co, Diane Hanna, Susan Kim, and Melissa Reyes have no conflicts to disclose.
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