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Methotrexate related cutaneous adverse drug reactions: a systematic literature review

  • Mohammed Zuber ORCID logo , Harikrishna ORCID logo , Vidhyashree ORCID logo , Manik Chhabra ORCID logo , Rajesh Venkataraman ORCID logo , Sathish Kumar ORCID logo and Muhammed Rashid ORCID logo EMAIL logo
Published/Copyright: October 27, 2021
Journal of Basic and Clinical Physiology and Pharmacology
From the journal Journal of Basic and Clinical Physiology and Pharmacology Volume 33 Issue 5

Abstract

Objectives

Recently, there is an increased number of reports being published on Methotrexate (MTX) related cutaneous manifestations. We aimed to identify and critically appraise descriptive studies describing the MTX related skin manifestations, treatment approach, and their outcomes.

Methodology

An extensive literature search was performed in the PubMed, Embase, and Scopus databases from inception to April 2021 without any restrictions along with the bibliographic search of included studies, grey literature search, and a snowball search was performed in Google and Google Scholar to identify the relevant literature. Descriptive studies reporting MTX related cutaneous manifestations were considered for the review. The study selection, data extraction, and quality assessment were conducted by two independent reviewers and any disagreements were settled by consensus with the third reviewer.

Results

31 out of 8,365 descriptive studies including 38 patients (22 females and 16 males) aged between 12 and 78 years prescribed for the management of rheumatoid arthritis, ankylosing spondylitis, and psoriasis were included in this review. Toxic epidermal necrolysis (TEN), papular eruption, vasculitis, erosions of psoriasis, ulcerated psoriatic plaques, local reactions, keratinocyte dystrophy, erythema multiforme, drug rash with eosinophilia and systemic symptoms, Steven Johnson syndrome and photosensitive dermatitis were the majority of MTX induced cutaneous reactions. Immediate withdrawal of MTX, providing appropriate care with anti-inflammatory, topical steroids, and supplementation with folic acid were reported to be effective for the management of the MTX related cutaneous manifestations.

Conclusions

Clinicians and healthcare professionals should be aware of possible acute cutaneous drug reactions induced by MTX to avoid further consequences and fatal conditions. Immediate withdrawal of MTX and supportive care were reported as an efficacious therapeutic management of acute cutaneous drug reactions.

PROSPERO Registration number

CRD42020220038.

Keywords: adverse effect; case report; cutaneous reaction; methotrexate; skin manifestation; systematic review
Corresponding author: Muhammed Rashid, Assistant Professor, Department of Pharmacy Practice, Sri Adichunchanagiri College of Pharmacy, Adichunchanagiri University, BG Nagara, Nagamangala, Karnataka, 571448, India, Mobile: +91-9886880633, E-mail:

  1. Research funding: We did not receive any funding for conducting this systematic literature review.

  2. Author contributions: Conceptualization: Muhammed Rashid (MR), Mohammed Zuber (MZ); Study design: MR, MZ, Harikrishna (H); Literature search: MR, MZ, AH; Study Selection & Data Extraction: MZ, AH, Vidhyashree (V); Quality Assessment: MR, MZ; Manuscript original drafting: MR, MZ, H, V; Editing: MR, Manik Chhabra (MC); Manuscript review and revising: MR, Rajesh Venkataraman; Sathish Kumar; Guarantor: MR. All authors reviewed, discussed, and agreed to their individual contributions ahead of this time. Also all authors agreed their position in author listing.

  3. Competing interests: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.

Appendix 1: Detailed search strategy used in various databases

Appendix 1A: PubMed search strategy

Search Query Items found
#1 Methotrexate [MeSH Terms] 38,119
#2 ((((((((((((Amethopterin) OR Methotrexate, (D)-Isomer) OR Methotrexate, (DL)-Isomer) OR Mexate) OR Methotrexate Sodium) OR Sodium, Methotrexate) OR Methotrexate, Sodium Salt) OR Methotrexate, Disodium Salt) OR Methotrexate Hydrate) OR Hydrate, Methotrexate) OR Methotrexate, Dicesium Salt) OR Dicesium Salt Methotrexate) 24,511
#3 #1 OR #2 47,736
#4 Skin Manifestations [MeSH Terms] 72,767
#5 (((Manifestation, Skin) OR Manifestations, Skin) OR Skin Manifestation) 97,829
#6 Exanthema [MeSH Terms] 7,657
#7 ((((Skin Rash) OR Rash, Skin) OR Rash) OR Exanthem) 34,148
#8 Stevens-Johnson Syndrome [MeSH Terms] 5,340
#9 (((((((((((((((((((((((((((((((((Stevens Johnson Syndrome) OR Stevens-Johnson Syndrome Toxic Epidermal Necrolysis Spectrum) OR Stevens Johnson Syndrome Toxic Epidermal Necrolysis Spectrum) OR Toxic Epidermal Necrolysis Stevens-Johnson Syndrome Spectrum) OR Toxic Epidermal Necrolysis Stevens Johnson Syndrome) OR Toxic Epidermal Necrolysis Stevens Johnson Syndrome Spectrum) OR Toxic Epidermal Necrolysis Stevens-Johnson Syndrome) OR Stevens Johnson Syndrome Toxic Epidermal Necrolysis) OR Stevens-Johnson Syndrome Toxic Epidermal Necrolysis) OR Mycoplasma-Induced Stevens-Johnson Syndrome) OR Mycoplasma Induced Stevens Johnson Syndrome) OR Stevens-Johnson Syndrome, Mycoplasma-Induced) OR Syndrome, Mycoplasma-Induced Stevens-Johnson) OR Mycoplasma-Induced Stevens Johnson Syndrome) OR Drug-Induced Stevens Johnson Syndrome) OR Drug Induced Stevens Johnson Syndrome) OR Drug-Induced Stevens-Johnson Syndrome) OR Drug-Induced Stevens-Johnson Syndromes) OR Stevens-Johnson Syndrome, Drug-Induced) OR Stevens-Johnson Syndromes, Drug-Induced) OR Epidermal Necrolysis, Toxic) OR Epidermal Necrolyses, Toxic) OR Necrolyses, Toxic Epidermal) OR Necrolysis, Toxic Epidermal) OR Toxic Epidermal Necrolyses) OR Toxic Epidermal Necrolysis) OR Scalded Skin Syndrome, Nonstaphylococcal) OR Lyell’s Syndrome) OR Lyell Syndrome) OR Lyell’s Syndromes) OR Syndrome, Lyell’s) OR Syndromes, Lyell’s) OR Nonstaphylococcal Scalded Skin Syndrome) 7,241
#10 Drug Eruption [MeSH Terms] 23,746
#11 (((((((((((((((((((((((((Drug Eruption) OR Eruption, Drug) OR Eruptions, Drug) OR Dermatitis Medicamentosa) OR Dermatitis, Adverse Drug Reaction) OR Morbilliform Drug Reaction) OR Drug Reaction, Morbilliform) OR Drug Reactions, Morbilliform) OR Morbilliform Drug Reactions) OR Reaction, Morbilliform Drug) OR Reactions, Morbilliform Drug) OR Maculopapular Exanthem) OR Exanthem, Maculopapular) OR Exanthems, Maculopapular) OR Maculopapular Exanthems) OR Morbilliform Exanthem) OR Exanthem, Morbilliform) OR Exanthems, Morbilliform) OR Morbilliform Exanthems) OR Maculopapular Drug Eruption) OR Drug Eruption, Maculopapular) OR Drug Eruptions, Maculopapular) OR Eruption, Maculopapular Drug) OR Eruptions, Maculopapular Drug) OR Maculopapular Drug Eruptions) 30,496
#12 ((((((((((((Dermatitis, Contact, Allergic) OR Dermatitis, Allergic Eczematous) OR Allergic Eczematous Dermatitides) OR Allergic Eczematous Dermatitis) OR Dermatitides, Allergic Eczematous) OR Eczematous Dermatitides, Allergic) OR Eczematous Dermatitis, Allergic) OR Allergic Contact Dermatitis) OR Allergic Contact Dermatitides) OR Contact Dermatitides, Allergic) OR Contact Dermatitis, Allergic) OR Dermatitides, Allergic Contact) 17,658
#13 (((((((Fasciitides, Necrotizing) OR Necrotizing Fasciitides) OR Necrotizing Fasciitis) OR Fascitis, Necrotizing) OR Fascitides, Necrotizing) OR Necrotizing Fascitides) OR Necrotizing Fascitis) 5,129
#14 #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 1,75,014
#15 #3 AND #14 1063

Appendix 1B: Scopus search strategy

Search Query Items found
#1 ‘methotrexate’ 2,88,441
#2 “Amethopterin” OR “Methotrexate Sodium” OR “Sodium, Methotrexate” OR “Methotrexate, Sodium Salt” OR “Methotrexate, Disodium Salt” OR “Methotrexate Hydrate” OR “Hydrate, Methotrexate” OR “Methotrexate, Dicesium Salt” OR “Dicesium Salt Methotrexate” 3,978
#3 #1 OR #2 2,89,709
#4 “skin manifestations” OR “exanthema” OR “stevens-johnson syndrome” OR “toxic epidermal necrolysis” OR “SJS” OR “TEN” OR “drug eruption” OR “maculopapular drug eruptions” OR “morbilliform exanthems” OR “dermatitides” OR “necrotizing fasciitis” 20,71,644
#5 “cutaneous adverse drug reactions” OR “cutaneous adverse drug effects” OR “adverse cutaneous drug reactions” OR “adverse cutaneous drug effects” OR “cutaneous toxicity” OR “skin toxicity” 33,280
#6 #4 OR #5 20,95,438
#7 #3 AND #6 30,886
#8 TITLE-ABS-KEY (“Case Report” OR “Case Series”) 26,64,768
#9 #7 AND #8 3,211
#10 #9 AND AND (EXCLUDE (DOCTYPE , “re”) OR EXCLUDE (DOCTYPE , “cp”) OR EXCLUDE (DOCTYPE , “ch”) OR EXCLUDE (DOCTYPE, “sh”) OR EXCLUDE (DOCTYPE, “tb”)) 2,787

Appendix 1C: Embase search strategy

Appendix 2: Quality assessment

Study Id Level of evidence (OCEBM) Methodological quality assessment (Murad et al. [20])
Score Quality
Goerttler et al. [21] 4 8 Good
Pearce et al. [23] 4 7 Good
Wong et al. [24] 4 5 Moderate
Edward et al. [25] 5 7 Good
Salgüero et al. [26] 5 6 Good
Priego-Recio et al. [27] 5 6 Good
Borman et al. [28] 5 5 Moderate
Simonart et al. [29] 5 5 Moderate
Jeurissen et al. [15] 5 3 Moderate
Mebazaa et al. [30] 5 8 Good
Singal et al. [16] 5 6 Good
Behera et al. [31] 5 5 Moderate
Omoregie et al. [32] 5 6 Good
Teraki et al. [33] 5 8 Good
Thami et al. [34] 5 7 Good
Gupta et al. [35] 5 6 Good
Kurian et al. [36] 5 5 Moderate
Al-Saffar et al. [37] 5 6 Good
Tekur et al. [38] 5 6 Good
Torner et al. [39] 5 5 Moderate
Lewis HA et al. [22] 4 5 Moderate
Kazlow et al. [40] 5 4 Moderate
Hsu et al. [41] 5 4 Moderate
Riquelme-Mc Loughlin et al. [42] 5 6 Good
Skrek et al. [43] 5 5 Moderate
Borcea et al. [44] 5 7 Good
Arora et.al. [45] 5 7 Good
Reed et al. [46] 5 6 Good
Alaya et al. [47] 5 7 Good
Sako et al. [48] 5 7 Good
Blanes et al. [49] 5 6 Good

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Received: 2021-06-04
Accepted: 2021-10-01
Published Online: 2021-10-27

© 2021 Walter de Gruyter GmbH, Berlin/Boston

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  17. Alpha2-antiplasmin deficiency affects depression and anxiety-like behavior and apoptosis induced by stress in mice
  18. Modern gold standard of cardiac output measurement – A simplified bedside measurement of individual oxygen uptake in the cath lab
  19. Electrical vestibular nerve stimulation (VeNS): a follow-up safety assessment of long-term usage
  20. Psychological impact of abnormally invasive placenta: an underestimated and hidden morbidity
  21. Limited diagnostic value of questionnaire-based pre-participation screening algorithms: a “risk-exposed” approach to sports activity
  22. Predictors of abdominal pain severity in patients with constipation-prevalent irritable bowel syndrome
https://doi.org/10.1515/jbcpp-2021-0165
Keywords for this article
adverse effect; case report; cutaneous reaction; methotrexate; skin manifestation; systematic review

Articles in the same Issue

  1. Frontmatter
  2. Editorial
  3. Circulating tumor cells in bladder cancer: a new horizon of liquid biopsy for precision medicine
  4. Minireview
  5. PCSK9 and LRP6: potential combination targets to prevent and reduce atherosclerosis
  6. Reviews
  7. The complex relationship between physical activity and diabetes: an overview
  8. Methotrexate related cutaneous adverse drug reactions: a systematic literature review
  9. Long-term use of proton pump inhibitors adversely affects minerals and vitamin metabolism, bone turnover, bone mass, and bone strength
  10. An update on the physiologic changes during pregnancy and their impact on drug pharmacokinetics and pharmacogenomics
  11. Original Articles
  12. Apelin-13 protects human neuroblastoma SH-SY5Y cells against amyloid-beta induced neurotoxicity: Involvement of anti oxidant and anti apoptotic properties
  13. Are hypertensive patients with history of coronary artery disease at risk for silent lower extremity artery disease?
  14. The effect of long-term ketogenic diet on serum adiponectin and insulin-like growth factor-1 levels in mice
  15. Increase in cardioprotective SUR2A does not alter heart rate and heart rate regulation by physical activity and diurnal rhythm
  16. Effect of ascorbic acid supplementation on pulmonary functions in healthy adults: a randomized controlled pilot study
  17. Alpha2-antiplasmin deficiency affects depression and anxiety-like behavior and apoptosis induced by stress in mice
  18. Modern gold standard of cardiac output measurement – A simplified bedside measurement of individual oxygen uptake in the cath lab
  19. Electrical vestibular nerve stimulation (VeNS): a follow-up safety assessment of long-term usage
  20. Psychological impact of abnormally invasive placenta: an underestimated and hidden morbidity
  21. Limited diagnostic value of questionnaire-based pre-participation screening algorithms: a “risk-exposed” approach to sports activity
  22. Predictors of abdominal pain severity in patients with constipation-prevalent irritable bowel syndrome
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