Methotrexate-induced oral mucositis in patients with rheumatoid arthritis: A case series and literature review

Authors

  • Jeanine Fourie Department of Periodontics and Oral Medicine,  School of Dentistry, Faculty of Health Sciences, University of  Pretoria, South Africa.  https://orcid.org/0000-0002-8674-8145
  • Dean Laubscher Department of Periodontics and Oral Medicine,  School of Dentistry, Faculty of Health Sciences, University of  Pretoria, South Africa.  https://orcid.org/0009-0005-2106-8113
  • Thokozani Simelane Department of Periodontics and Oral  Medicine School of Dentistry, Faculty of Health Sciences, University  of Pretoria, South Africa

DOI:

https://doi.org/10.17159/sadj.v80i01.20071

Keywords:

Methotrexate (MTX), Disease-modifying anti-rheumatic drugs (DMARDs), Rheumatoid arthritis (RA), Anti-inflammatory

Abstract

Methotrexate is used as both an antineoplastic drug and disease-modifying anti-rheumatic drug. In both cases, methotrexate use may result in oral mucositis. Dentists are likely to manage patients with rheumatoid arthritis and should consider this adverse drug event when mouth ulcers are observed.

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References

1. Deeming GM, Collingwood J, Pemberton MN. Methotrexate and oral ulceration. Br Dent J. 2005;198(2):83-5.

2. Bykerk VP, Akhavan P, Hazlewood GS, Schieir O, Dooley A, Haraoui B, et al. Canadian Rheumatology Association recommendations for pharmacological management of rheumatoid arthritis with traditional and biologic disease-modifying antirheumatic drugs. J Rheumatol. 2012;39(8):1559-82.

3. Chamorro-Petronacci C, García-García A, Lorenzo-Pouso AI, Gómez-García FJ, Padín-Iruegas ME, Gándara-Vila P, et al. Management options for low-dose methotrexate-induced oral ulcers: A systematic review. Med Oral Patol Oral Cir Bucal. 2019;24(2):e181-e9.

4. Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2016;68(1):1-26.

5. Katsoulas N, Chrysomali E, Piperi E, Levidou G, Sklavounou-Andrikopoulou A. Atypical methotrexate ulcerative stomatitis with features of lymphoproliferative-like disorder: Report of a rare ciprofloxacin-induced case and review of the literature. J Clin Exp Dent. 2016;8(5):e629-e33.

6. Bedoui Y, Guillot X, Sélambarom J, Guiraud P, Giry C, Jaffar-Bandjee MC, et al. Methotrexate: An old drug with new tricks. Int J Mol Sci. 2019;20(20):5091.

7. Kalantzis A, Marshman Z, Falconer DT, Morgan PR, Odell EW. Oral effects of low-dose methotrexate treatment. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2005;100(1):52-62.

8. Torres RP, Santos FP, Branco JC. Methotrexate: Implications of pharmacogenetics in the treatment of patients with rheumatoid arthritis. ARP Rheumatol. 2022;1(3):225-9.

9. Chan ES, Cronstein BN. Methotrexate – how does it really work? Nat Rev Rheumatol. 2010;6(3):175-8.

10. Inoue K, Yuasa H. Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinet. 2014;29(1):12-9.

11. Horn HM, Tidman MJ. The clinical spectrum of dystrophic epidermolysis bullosa. Br J Dermatol. 2002;146(2):267-74.

12. Dervieux T, Furst D, Lein DO, Capps R, Smith K, Walsh M, et al. Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis. Arthritis Rheum. 2004;50(9):2766-74.

13. van Roon EN, van de Laar MA. Methotrexate bioavailability. Clin Exp Rheumatol. 2010;28(5 Suppl 61):S27-32.

14. Maksimovic V, Pavlovic-Popovic Z, Vukmirovic S, Cvejic J, Mooranian A, Al-Salami H, et al. Molecular mechanism of action and pharmacokinetic properties of methotrexate. Mol Biol Rep. 2020;47(6):4699-708.

15. Lopez-Olivo MA, Siddhanamatha HR, Shea B, Tugwell P, Wells GA, Suarez-Almazor ME. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2014;2014(6):Cd000957.

16. Mazaud C, Fardet L. Relative risk of and determinants for adverse events of methotrexate prescribed at a low dose: A systematic review and meta-analysis of randomized placebo-controlled trials. Br J Dermatol. 2017;177(4):978-86.

17. Dervisoglou T, Matiakis A. Oral ulceration due to methotrexate treatment: A report of 3 cases and literature review. Balkan J Dent Med. 2015;19:19-24.

18. Goodman SM, Cronstein BN, Bykerk VP. Outcomes related to methotrexate dose and route of administration in patients with rheumatoid arthritis: A systematic literature review. Clin Exp Rheumatol. 2015;33(2):272-8.

19. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer. 2004;4(4):277-84.

20. Sonis ST. Oral mucositis. Anticancer Drugs. 2011;22(7):607-12.

21. Lalla RV, Brennan MT, Gordon SM, Sonis ST, Rosenthal DI, Keefe DM. Oral mucositis due to high-dose chemotherapy and/or head and neck radiation therapy. J Natl Cancer Inst Monogr. 2019;2019(53):47-58.

22. Sonis ST. Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol. 2007;5(9 Suppl 4):3-11.

23. Hanakawa H, Orita Y, Sato Y, Uno K, Nishizaki K, Yoshino T. Large ulceration of the oropharynx induced by methotrexate-associated lymphoproliferative disorders. Acta Med Okayama. 2013;67(4):265-9.

24. Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis: A meta-analysis of randomized controlled trials. J Rheumatol. 1998;25(1):36-43.

25. Mori S, Hidaka M, Kawakita T, Hidaka T, Tsuda H, Yoshitama T, et al. Factors associated with myelosuppression related to low-dose methotrexate therapy for inflammatory rheumatic diseases. PLoS One. 2016;11(4):e0154744.

26. Yélamos O, Català A, Vilarrasa E, Roé E, Puig L. Acute severe methotrexate toxicity in patients with psoriasis: A case series and discussion. Dermatology. 2014;229(4):306-9.

27. Shrestha R, Ojha SK, Jha SK, Jasraj R, Fauzdar A. Methotrexate-induced mucositis: A consequence of medication error in a rheumatoid arthritis patient. Cureus. 2023;15(9):e46290.

28. Ajmani S, Preet Singh Y, Prasad S, Chowdhury A, Aggarwal A, Lawrence A, et al. Methotrexate-induced pancytopenia: A case series of 46 patients. Int J Rheum Dis. 2017;20(7):846-51.

29. Attar SM. Adverse effects of low-dose methotrexate in rheumatoid arthritis patients: A hospital-based study. Saudi Med J. 2010;31(8):909-15.

30. Yang Y, Liu Z, Chen J, Wang X, Jiao Z, Wang Z. Factors influencing methotrexate pharmacokinetics highlight the need for individualized dose adjustment: A systematic review. Eur J Clin Pharmacol. 2024;80(1):11-37.

31. Li W, Mo J, Yang Z, Zhao Z, Mei S. Risk factors associated with high-dose methotrexate-induced toxicities. Expert Opin Drug Metab Toxicol. 2024;20(4):263-74.

32. Colebatch AN, Marks JL, van der Heijde DM, Edwards CJ. Safety of nonsteroidal anti-inflammatory drugs and/or paracetamol in people receiving methotrexate for inflammatory arthritis: A Cochrane systematic review. J Rheumatol Suppl. 2012;90:62-73.

33. Uwai Y, Saito H, Inui K-i. Interaction between methotrexate and nonsteroidal anti-inflammatory drugs in organic anion transporter. Eur J Pharmacol. 2000;409(1):31-6.

34. Tao D, Wang H, Xia F, Ma W. Pancytopenia due to possible drug-drug interactions between low-dose methotrexate and proton pump inhibitors. Drug Healthc Patient Saf. 2022;14:75-8.

35. Yousef AM, Farhad R, Alshamaseen D, Alsheikh A, Zawiah M, Kadi T. Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia. Cancer Chemother Pharmacol. 2019;83(4):755-62.

36. Csordas K, Lauten A, Rüger A, Oehme F, Albrecht M, Sommer C, et al. Interactions of methotrexate with antirheumatic medications: A systematic review of the literature. Clin Rheumatol. 2022;41(12):3543-51.

37. Georgiou R, Aspri G, Skyrme-Jones R, Morrow N, Fernandes R, Ashby L, et al. Serum methotrexate concentrations and adverse events: A systematic review. Clin Rheumatol. 2019;38(7):1925-34.

38. Hahn T, Zhelnova E, Sucheston L, Demidova I, Savchenko V, Battiwalla M, et al. A deletion polymorphism in glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation. Biol Blood Marrow Transplant. 2010;16(6):801-8.

39. Ambrosone CB, Tian C, Ahn J, Kropp S, Helmbold I, von Fournier D, et al. Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study. Breast Cancer Res. 2006;8(4):R40.

40. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, et al. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer. 2004;100(9 Suppl):1995-2025.

41. World Health O. WHO handbook for reporting results of cancer treatment. Geneva: World Health Organization; 1979.

42. National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). U.S. Department of Health and Human Services; 2009 [updated June 2010]. Available from: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf.

43. Lalani R, Lyu H, Vanni K, Solomon DH. Low-Dose Methotrexate and Mucocutaneous Adverse Events: Results of a Systematic Literature Review and Meta-Analysis of Randomized Controlled Trials. Arthritis Care Res (Hoboken). 2020;72(8):1140-6.

44. Magdy E, Ali S. Stratification of methotrexate-induced oral ulcers in rheumatoid arthritis patients. Spec Care Dentist. 2021;41(3):367-71.

45. Ince A, Yazici Y, Hamuryudan V, Yazici H. The frequency and clinical characteristics of methotrexate (MTX) oral toxicity in rheumatoid arthritis (RA): a masked and controlled study. Clin Rheumatol. 1996;15(5):491-4.

46. Pedrazas CH, Azevedo MN, Torres SR. Oral events related to low-dose methotrexate in rheumatoid arthritis patients. Braz Oral Res. 2010;24(3):368-73.

47. Troeltzsch M, von Blohn G, Kriegelstein S, Woodlock T, Gassling V, Berndt R, et al. Oral mucositis in patients receiving low-dose methotrexate therapy for rheumatoid arthritis: report of 2 cases and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(5):e28-33.

48. Hocaoglu N, Atilla R, Onen F, Tuncok Y. Early-onset pancytopenia and skin ulcer following low-dose methotrexate therapy. Hum Exp Toxicol. 2008;27(7):585-9.

49. Rampon G, Henkin C, Jorge VM, Almeida HL Jr. Methotrexate-induced mucositis with extra-mucosal involvement after accidental overdose. An Bras Dermatol. 2018;93(1):155-6.

50. Nam JW. Perforation in Submucous Cleft Palate Due to Methotrexate-Induced Mucositis in a Patient With Rheumatoid Arthritis. J Craniofac Surg. 2018;29(3):772-3.

51. Horie N, Kawano R, Kaneko T, Shimoyama T. Methotrexate-related lymphoproliferative disorder arising in the gingiva of a patient with rheumatoid arthritis. Aust Dent J. 2015;60(3):408-11.

52. Omoregie FO, Ukpebor M, Saheeb BD. Methotrexate-induced erythema multiforme: a case report and review of the literature. West Afr J Med. 2011;30(5):377-9.

53. Alghamdi N, Albaqami A, Alharbi A. Atypical Presentation of Herpes Simplex Virus Infection in an Immunocompromised Patient. Cureus. 2023;15(4):e37465.

54. Warner J, Brown A, Whitmore SE, Cowan DA. Mucocutaneous ulcerations secondary to methotrexate. Cutis. 2008;81(5):413-6.

55. Scully C, Sonis S, Diz PD. Oral mucositis. Oral Dis. 2006;12(3):229-41.

56. Ahmed EM, Ali S, Gaafar SM, Rashed LM, Fayed HL. Evaluation of topical human platelet lysate versus topical clobetasol in management of methotrexate-induced oral ulceration in rheumatoid arthritis patients: randomized-controlled clinical trial. Int Immunopharmacol. 2019;73:389-94.

57. González-Moles MA, Scully C. Vesiculo-erosive oral mucosal disease--management with topical corticosteroids: (1) Fundamental principles and specific agents available. J Dent Res. 2005;84(4):294-301.

58. Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposals for guidelines. Scand J Rheumatol. 2001;30(3):129-34.

59. Shea B, Swinden MV, Tanjong Ghogomu E, Ortiz Z, Katchamart W, Rader T, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013;2013(5):Cd000951.

60. Schelzel G, Palicherla A, Tauseef A, Millner P. Low-dose methotrexate toxicity leading to pancytopenia: leucovorin as a rescue treatment. Proc (Bayl Univ Med Cent). 2024;37(2):339-43.

61. Dhir V, Sandhu A, Kaur J, Pinto B, Kumar P, Kaur P, et al. Comparison of two different folic acid doses with methotrexate – a randomized controlled trial (FOLVARI Study). Arthritis Res Ther. 2015;17(1):156.

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Published

2025-03-25

Issue

Vol. 80 No. 01 (2025): The South African Dental Journal

Section

Case Reports

License

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

How to Cite

Fourie, J., Laubscher, D., & Simelane, T. (2025). Methotrexate-induced oral mucositis in patients with rheumatoid arthritis: A case series and literature review. South African Dental Journal, 80(01), 33-41. https://doi.org/10.17159/sadj.v80i01.20071