Management options for low-dose methotrexate-induced oral ulcers: A systematic review

Oral ulcers caused by methotrexate (MTX) at low doses are a known side effect of this drug. Although increasingly more patients are medicated with MTX, these painful ulcers, without traumatic origin and resistant to any type of treatment, are not usually identified by health professionals as a side effect of the medication.

In the absence of a consensus protocol for the effective treatment of oral lesions produced by MTX, the objective of this article was to review and analyse the information from articles related to oral ulcers produced by low-dose MTX and to record the clinical management performed and the MTX dose given to the patient. Data sources - Medline, Web of Science, and Cochrane Library. Participants - Patients treated with low-dose MTX (less than 25 mg/week). Interventions - Management of oral lesions caused by MTX. Study eligibility criterion, study appraisal and synthesis method: An initial search was carried out in the aforementioned databases with the terms 'methotrexate AND oral OR ulcer'. The search was carried out using both medical subject heading (MeSH) terms and a free search between January 2003 and January 2018. Of the results obtained, two independent researchers analysed abstracts that met the search criteria, that is, those that mentioned oral ulcers produced by MTX at low doses. Next, both researchers read the complete article and determined whether it met the following inclusion criteria: written in English, specified the dose of MTX prescribed for the patient and specified the protocol of action for the ulcers. A third investigator acted as a mediator in cases of dispute. Agreement was calculated using Cohen's kappa coefficient, with a k value of 0.82. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guide for systematic reviews was used.

The initial search resulted in a total of 66 articles, of which 30 were selected to assess their inclusion in this study. Finally, 16 met the inclusion criteria. Using the Pierson and Newcastle-Ottawa scales and Bradford Hill criteria modified for studies of case series and "in relation to a case", 2 were rated as high quality, 2 were rated as low quality and 12 were rated as medium quality. The limitations of this study are based on the fact that all of the articles available to carry out the systematic review were "in relation to a case or series of cases", with the heterogeneity of data that this implies.

Evidence on the management of oral ulcers in the oral cavity produced by MTX at low doses is scarce due to the heterogeneity of data and the measures adopted in the selected studies. Therefore, it seems that this management is relegated to the perception of the clinician rather than to a specific protocol of action. Studies with a longer follow-up duration and larger sample size are needed to guide different health professionals on the management of these lesions.