overview of methotrexate toxicity a comprehensive literature review

• Find in topic

INTRODUCTION

The broad range of antitumor activity seen with MTX is reflected in the large number of malignant conditions for which MTX is a component of the treatment regimen ( table 1 ). Furthermore, in addition to antiproliferative activity, MTX also has anti-inflammatory and immunomodulating properties, leading to its use in a wide range of doses for a broad range of therapeutic indications across multiple specialties ( table 2 ).

This topic review will cover the clinical use of high-dose MTX for treatment of malignancy, focusing on the prevention and management of toxicity. Intrathecal use of MTX and clinical use of low-dose and intermediate-dose MTX for both malignant and nonmalignant (eg, rheumatologic) conditions are covered elsewhere. (See appropriate topic reviews.)

DEFINITION OF HIGH-DOSE METHOTREXATE

● Most clinicians reserve the term high-dose MTX (HDMTX) for doses ≥500 mg/m 2 , as are used for central nervous system (CNS) prophylaxis in patients with leukemia and high-risk lymphoma, and for the treatment of leptomeningeal metastases, primary CNS lymphoma, and osteosarcoma. These regimens deliver an otherwise lethal dose of MTX in a 4 to 36 hour infusion, and require a two to three day period of multiple leucovorin doses to terminate the toxic effect of MTX (termed leucovorin "rescue"). Successful rescue by leucovorin depends on rapid elimination of MTX by the kidneys, which requires aggressive pretreatment as well as posttreatment hydration and urinary alkalinization. The main toxicities of HDMTX are elevated serum transaminase levels and renal insufficiency, which can delay drug clearance.

To continue reading this article, you must sign in . For more information or to purchase a personal subscription, click below on the option that best describes you:

• Medical Professional
• Resident, Fellow or Student
• Hospital or Institution
• Group Practice
• Patient or Caregiver

Print Options

• Architecture and Design
• Asian and Pacific Studies
• Business and Economics
• Classical and Ancient Near Eastern Studies
• Computer Sciences
• Cultural Studies
• Engineering
• General Interest
• Geosciences
• Industrial Chemistry
• Islamic and Middle Eastern Studies
• Jewish Studies
• Library and Information Science, Book Studies
• Life Sciences
• Linguistics and Semiotics
• Literary Studies
• Materials Sciences
• Mathematics
• Social Sciences
• Sports and Recreation
• Theology and Religion
• Publish your article
• The role of authors
• Promoting your article
• Abstracting & indexing
• Publishing Ethics
• Why publish with De Gruyter
• How to publish with De Gruyter
• Our book series
• Our subject areas
• Your digital product at De Gruyter
• Contribute to our reference works
• Product information
• Tools & resources
• Product Information
• Promotional Materials
• Orders and Inquiries
• FAQ for Library Suppliers and Book Sellers
• Repository Policy
• Free access policy
• Open Access agreements
• Database portals
• For Authors
• Customer service
• People + Culture
• Journal Management
• How to join us
• Working at De Gruyter
• Mission & Vision
• De Gruyter Foundation
• De Gruyter Ebound
• Our Responsibility
• Partner publishers

Your purchase has been completed. Your documents are now available to view.

Methotrexate related cutaneous adverse drug reactions: a systematic literature review

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.

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.

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

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.

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.

Informed consent: Not applicable.

Ethical approval: Not applicable.

Appendix 1: Detailed search strategy used in various databases

Appendix 1a: pubmed search strategy, appendix 1b: scopus search strategy, appendix 1c: embase search strategy.

Appendix 2: Quality assessment

1. Czarnecka-Operacz, M, Sadowska-Przytocka, A. The possibilities and principles of methotrexate treatment of psoriasis–the updated knowledge. Postepy Dermatol Alergol 2014;31:392, https://doi.org/10.5114/pdia.2014.47121 . Search in Google Scholar PubMed PubMed Central

2. Sheagren, JN. Staphylococcus aureus: the persistent pathogen. N Engl J Med 1984;310:1437–42, https://doi.org/10.1056/nejm198405313102206 . Search in Google Scholar PubMed

3. Weinblatt, ME. Methotrexate in rheumatoid arthritis: a quarter century of development. Trans Am Clin Climatol Assoc 2013;124:16. Search in Google Scholar

4. Singh, JA, Saag, KG, Bridges, SLJr, Akl, EA, Bannuru, RR, Sullivan, MC, et al.. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 2016;68:1–26., https://doi.org/10.1002/art.39480 . Search in Google Scholar PubMed

5. Elmets, CA, Korman, NJ, Prater, EF, Wong, EB, Rupani, RN, Kivelevitch, D, et al.. Joint AAD–NPF Guidelines of care for the management and treatment of psoriasis with topical therapy and alternative medicine modalities for psoriasis severity measures. J Am Acad Dermatol 2021;84:432–70, https://doi.org/10.1016/j.jaad.2020.07.087 . Search in Google Scholar PubMed

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;20:5023, https://doi.org/10.3390/ijms20205023 . Search in Google Scholar PubMed PubMed Central

7. Smith, BJ, Cohen, S, Kremer, JM, Winthrop, K, Fahey, S, Genovese, M. American College of Rheumatology updated guideline for the management of rheumatoid arthritis Project Plan 2018:1–35. Available at: https://www.rheumatology.org/Portals/0/Files/Rheumatoid-Arthritis-Guideline-Project-Plan.pdf . Search in Google Scholar

8. Visser, K, van der Heijde, D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: a systematic review of the literature. Ann Rheum Dis 2009;68:1094–9, https://doi.org/10.1136/ard.2008.092668 . Search in Google Scholar PubMed PubMed Central

9. Montaudié, H, Sbidian, E, Paul, C, Maza, A, Gallini, A, Aractingi, S, et al.. Methotrexate in psoriasis: a systematic review of treatment modalities, incidence, risk factors and monitoring of liver toxicity. J Eur Acad Dermatol Venereol 2011;25:12–8, https://doi.org/10.1111/j.1468-3083.2011.03991.x . Search in Google Scholar PubMed

10. Henderson, ES, Adamson, RH, Oliverio, VT. The metabolic fate of tritiated methotrexate: II. Absorption and excretion in man. Cancer Res 1965;25:1018–24. Search in Google Scholar

11. Grim, J, Chládek, J, Martínková, J. Pharmacokinetics and pharmacodynamics of methotrexate in non-neoplastic diseases. Clin Pharmacokinet 2003;42:139–51, https://doi.org/10.2165/00003088-200342020-00003 . Search in Google Scholar PubMed

12. Robey, RB, Block, CA. Adverse effects of low-dose methotrexate. Ann Intern Med 2020;173:166–7, https://doi.org/10.7326/l20-0524 . Search in Google Scholar PubMed

13. Watkins, PB, Seeff, LB. Drug‐induced liver injury: summary of a single topic clinical research conference. Hepatology 2006;43:618–31, https://doi.org/10.1002/hep.21095 . Search in Google Scholar PubMed

14. Taylor, P, Balsa Criado, A, Mongey, AB, Avouac, J, Marotte, H, Mueller, RB. How to get the most from methotrexate (MTX) treatment for your rheumatoid arthritis patient?-MTX in the treat-to-target strategy. J Clin Med 2019;8:515, https://doi.org/10.3390/jcm8040515 . Search in Google Scholar

15. Jeurissen, ME, Boerbooms, AT, Van de Putte, LB. Eruption of nodulosis and vasculitis during methotrexate therapy for rheumatoid arthritis. Clin rheumatol. 1989;8:417–9, https://doi.org/10.1111/j.1365-4632.2009.04256.x . Search in Google Scholar

16. Singal, A, Sonthalia, S, Pandhi, D. Erythema gyratum repens-like eruption occuring in resolving psoriasis during methotrexate therapy. Int J Dermatol . 2010;49:306. https://doi.org/10.1515/jbcpp-2020-0115 . Search in Google Scholar

17. Rashid, M, Kashyap, A, Undela, K. Valproic acid and Stevens‐Johnson syndrome: a systematic review of descriptive studies. Int J Dermatol 2019;58:1014–22, https://doi.org/10.1111/ijd.14411 . Search in Google Scholar

18. Rashid, M, Rajan, AK, Chhabra, M, Kashyap, A. Levetiracetam and cutaneous adverse reactions: a systematic review of descriptive studies. Seizure 2020;75:101–9, https://doi.org/10.1016/j.seizure.2020.01.002 . Search in Google Scholar

19. Howick, J, Chalmers, I, Glasziou, P. The oxford 2011 levels of evidence . Oxford, UK: Oxford Centre for Evidence-Based Medicine; 2011. Available at: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/explanation-of-the-2011-ocebm-levels-of-evidence . Search in Google Scholar

20. Murad, MH, Sultan, S, Haffar, S, Bazerbachi, F. Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med 2018;23:60–3, https://doi.org/10.1136/bmjebm-2017-110853 . Search in Google Scholar

21. Goerttler, E, Kutzner, H, Peter, HH, Requena, L. Methotrexate-induced papular eruption in patients with rheumatic diseases: a distinctive adverse cutaneous reaction produced by methotrexate in patients with collagen vascular diseases. J Am Acad Dermatol 1999;40:702–7, https://doi.org/10.1016/s0190-9622(99)70150-7 . Search in Google Scholar

22. Lewis, HA, Nemer, KM, Chibnall, RJ, Musiek, AC. Methotrexate-induced cutaneous ulceration in 3 nonpsoriatic patients: report of a rare side effect. JAAD Case Rep 2017;3:236–9, https://doi.org/10.1016/j.jdcr.2017.02.002 . Search in Google Scholar

23. Pearce, HP, Wilson, BB. Erosion of psoriatic plaques: an early sign of methotrexate toxicity. J Am Acad Dermatol 1996;35:835–8, https://doi.org/10.1016/s0190-9622(96)90097-3 . Search in Google Scholar

24. Wong, SM, Chong, YT, Thevarajah, S, Baba, R. Methotrexate toxicity presenting as ulcerated psoriatic plaques. Australas J Dermatol 2012;53:81–3, https://doi.org/10.1111/j.1440-0960.2011.00779.x . Search in Google Scholar PubMed

25. Primka, EJIII, Camisa, C. Methotrexate-induced toxic epidermal necrolysis in a patient with psoriasis. J Am Acad Dermatol 1997;36:815–8, https://doi.org/10.1016/s0190-9622(97)70029-x . Search in Google Scholar

26. Salgüero, I, Moreno, C, Aguayo-Leiva, I, Harto, A. Papuloerythroderma of Ofuji associated with chronic lymphatic leukaemia. Eur J Dermatol 2009;19:396–7, https://doi.org/10.1684/ejd.2009.0689 . Search in Google Scholar PubMed

27. Priego-Recio, CM, Camacho-Martinez, FM. Local reaction after subcutaneous injection of methotrexate: uncommon side effect. J Eur Acad Dermatol Venereol . 2014;30:523–4, https://doi.org/10.1111/jdv.12918 . Search in Google Scholar PubMed

28. Borman, P, Bodur, H, Güleç, AT, Ucan, H, Seçkin, Ü, Mocan, G. Atypical methotrexate dermatitis and vasculitis in a patient with ankylosing spondylitis. Rheumatol Int 2000;19:191–3, https://doi.org/10.1007/s002960000047 . Search in Google Scholar PubMed

29. Simonart, TH, Durez, P, Margaux, J, Van Geertruyden, J, Goldschmidt, D, Parent, D. Cutaneous necrotizing vasculitis after low dose methotrexate therapy for rheumatoid arthritis: a possible manifestation of methotrexate hypersensitivity. Clin Rheumatol 1997;16:623–5, https://doi.org/10.1007/bf02247805 . Search in Google Scholar PubMed

30. Mebazaa, A, Kenani, N, Denguezli, M, SCB, Ziadi, S, Sriha, B, et al.. Methotrexate-induced papular eruption following treatment of psoriasis. Ann Pharmacother 2008;42:138–41, https://doi.org/10.1345/aph.1k271 . Search in Google Scholar

31. Behera, B, Kumari, R, Gochhait, D, Thappa, DM. Low dose methotrexate induced asymptomatic keratinocyte dystrophy in a patient of psoriasis vulgaris. J Cutan Pathol 2016;43:1238–41, https://doi.org/10.1111/cup.12810 . Search in Google Scholar PubMed

32. Omoregie, FO, Ukpebor, M, Saheeb, BD. Methotrexate-induced erythema multiforme: a case report and review of the literature. West Afr J Med 2011;30:377–9. Search in Google Scholar

33. Teraki, Y, Izaki, S. Salazosulfapyridine-induced hypersensitivity syndrome triggered by methotrexate. Clin Exp Dermatol 2009;34:e287–8, https://doi.org/10.1111/j.1365-2230.2009.03212.x . Search in Google Scholar PubMed

34. Thami, GP, Kaur, S, Kanwar, AJ. Delayed reactivation of haloperidol induced photosensitive dermatitis by methotrexate. Postgrad Med 2002;78:116–7, https://doi.org/10.1136/pmj.78.916.116 . Search in Google Scholar PubMed PubMed Central

35. Gupta, A, Sardana, K, Bhardwaj, M, Singh, A. Methotrexate cutaneous toxicity following a single dose of 10 mg in a case of chronic plaque psoriasis: a possible idiosyncratic reaction. Indian Dermatol Online J 2018;9:328, https://doi.org/10.4103/idoj.IDOJ_316_17 . Search in Google Scholar PubMed PubMed Central

36. Kurian, A, Haber, R. Methotrexate-induced cutaneous ulcers in a nonpsoriatic patient: case report and review of the literature. J Cutan Med Surg 2011;15:275–9, https://doi.org/10.2310/7750.2011.10078 . Search in Google Scholar PubMed

37. Al-Saffar, F, Ibrahim, S, Patel, P, Jacob, R, Palacio, C, Cury, J. Skin rash in the intensive care unit: Stevens-Johnson syndrome, toxic epidermal necrolysis, or a rare manifestation of a hidden cutaneous malignancy: a case report. Mol Clin Oncol 2016;4:413–5, https://doi.org/10.3892/mco.2015.713 . Search in Google Scholar PubMed PubMed Central

38. Tekur, VK. Methotrexate-induced nonhealing cutaneous ulcers in a nonpsoriatic patient without pancytopenia. Indian Dermatol Online J 2016;7:418, https://doi.org/10.4103/2229-5178.190509 . Search in Google Scholar PubMed PubMed Central

39. Torner, O, Ruber, C, Olive, A, Tena, X. Methotrexate related cutaneous vasculitis. Clin Rheumatol 1997;16:108, https://doi.org/10.1007/bf02238776 . Search in Google Scholar

40. Kazlow, DW, Federgrun, D, Kurtin, S, Lebwohl, MG. Cutaneous ulceration caused by methotrexate. J Am Acad Dermatol 2003;49:197–8, https://doi.org/10.1067/mjd.2003.388 . Search in Google Scholar PubMed

41. Hsu, MC, Chen, CC. Low-dose methotrexate-induced ulcerated psoriatic plaques: a rare case. JAAD Case Rep 2015;1:264–6, https://doi.org/10.1016/j.jdcr.2015.06.003 . Search in Google Scholar PubMed PubMed Central

42. Riquelme-Mc Loughlin, C, Giavedoni, P, Mascaró, JMJr. More than skin deep. Am J Emerg Med 2018;36:1719–e3, https://doi.org/10.1016/j.ajem.2018.05.069 . Search in Google Scholar PubMed

43. Skrek, SV, Timoshchuk, EA, Sidikov, AA, Zaslavsky, DV, Megna, M. Kaposi varicelliform eruption induced by methotrexate in an adult atopic dermatitis patient. Dermatol Ther 2019;32:e12826, https://doi.org/10.1111/dth.12826 . Search in Google Scholar PubMed

44. Borcea, A, Greaves, MW. Methotrexate‐induced exacerbation of urticarial vasculitis: an unusual adverse reaction. Br J Dermatol 2000;143:203–4, https://doi.org/10.1046/j.1365-2133.2000.03624.x . Search in Google Scholar PubMed

45. Arora, S, Abidi, A, Fatima, F, Hasan, R, Rizvi, D, Thadani, A. Methotrexate induced Stevens Johnson syndrome: a rare case report. Era’s J Med Res 2018;5:194–6, https://doi.org/10.24041/ejmr2018.95 . Search in Google Scholar

46. Reed, KM, Sober, AJ. Methotrexate-induced necrolysis. J Am Acad Dermatol 1983;8:677–9, https://doi.org/10.1016/s0190-9622(83)70079-4 . Search in Google Scholar

47. Alaya, Z, Mokni, S, Guerfala, M, Salem, CB, Sriha, B, Nouira, R, et al.. Acute severe cutaneous methotrexate toxicity in a patient with rheumatoid arthritis: report of a rare side effect. Egypt Rheumatol 2018;40:281–4, https://doi.org/10.1016/j.ejr.2017.08.004 . Search in Google Scholar

48. Sako, EY, Famenini, S, Wu, JJ. Bullous drug eruption in a patient with psoriasis after a test dose of methotrexate. J Am Acad Dermatol 2013;69:e264–5, https://doi.org/10.1016/j.jaad.2013.07.012 . Search in Google Scholar

49. Blanes, M, Silvestre, JF, Albares, MP, Pascual, JC, Pastor, N. Erythema multiforme due to methotrexate reproduced with patch test. Contact Dermatitis 2005;52:164–5, https://doi.org/10.1111/j.0105-1873.2005.0548f.x . Search in Google Scholar

50. Rajan, AK, Kashyap, A, Chhabra, M, Rashid, M. Linezolid induced skin reactions in a multi drug resistant infective endocarditis patient: a rare case. Curr Drug Saf 2020;15:222–6, https://doi.org/10.2174/1574886315666200516175053 . Search in Google Scholar

51. Kearsley-Fleet, L, Vicente González, L, Steinke, D, Davies, R, De Cock, D, Baildam, E, et al.. Methotrexate persistence and adverse drug reactions in patients with juvenile idiopathic arthritis. Rheumatology 2019;58:1453–8, https://doi.org/10.1093/rheumatology/kez048 . Search in Google Scholar

52. 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 2020;72:1140–6, https://doi.org/10.1002/acr.23999 . Search in Google Scholar

53. Frikha, R, Jemaa, MB, Frikha, F, Turki, I, Elloumi, M, Keskes, L, et al.. Involvement of C677T MTHFR variant but not A1298C in methotrexate-induced toxicity in acute lymphoblastic leukemia. J Oncol Pharm Pract 2021;27:1382–7, https://doi.org/10.1177/1078155220951898 . Search in Google Scholar

54. McKendry, RJ, Dale, P. Adverse effects of low dose methotrexate therapy in rheumatoid arthritis. J Rheumatol 1993;20:1850–6. Search in Google Scholar

55. Del Campo, M, Kosaki, K, Bennett, FC, Jones, KL. Developmental delay in fetal aminopterin/methotrexate syndrome. Teratology 1999;60:10–2, https://doi.org/10.1002/(sici)1096-9926(199907)60:1<10::aid-tera5>3.0.co;2-h . 10.1002/(SICI)1096-9926(199907)60:1<10::AID-TERA5>3.0.CO;2-H Search in Google Scholar

56. Liu, L, Liu, S, Wang, C, Guan, W, Zhang, Y, Hu, W, et al.. Folate supplementation for methotrexate therapy in patients with rheumatoid arthritis: a systematic review. J Clin Rheumatol 2019;25:197–202, https://doi.org/10.1097/rhu.0000000000000810 . Search in Google Scholar

57. Destiani, DP, Naja, S, Dewi, S, Rahmadi, AR, Sulaiman, SA, Abdulah, R. Efficacy of methotrexate in reducing the risk of bone erosion in patients with rheumatoid arthritis: a systematic review of randomized controlled trials. Osteoporos Int 2020:1–2, https://doi.org/10.1007/s00198-020-05743-z . Search in Google Scholar PubMed

© 2021 Walter de Gruyter GmbH, Berlin/Boston

• X / Twitter

Supplementary Materials

Please login or register with De Gruyter to order this product.

Journal and Issue

Articles in the same issue.

Advertisement

A comprehensive review on methotrexate containing nanoparticles; an appropriate tool for cancer treatment

• Published: 12 September 2022
• Volume 49 , pages 11049–11060, ( 2022 )

Cite this article

• Hanifeh Shariatifar 1 ,
• Fateme Ranjbarian 2 ,
• Fahimeh Hajiahmadi 3 &
• Alireza Farasat   ORCID: orcid.org/0000-0002-4303-1101 4  

720 Accesses

6 Citations

Explore all metrics

For more than seven decades, methotrexate has been used all over the world for treatment of different diseases such as: cancer, autoimmune diseases, and rheumatoid arthritis. Several studies have addressed its formula, efficacy, and delivery methods in recent years. These studies have been focused on the effectiveness of different nanoparticles on drug delivery, delivery of the drug to the target cells, and attenuation of harm to the host cell. Whereas, the main usages of methotrexate are in cancer treatment field, this review provided a brief perspective into using different nanoparticles and their role in the treatment of different cancers .

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (Russian Federation)

Instant access to the full article PDF.

Rent this article via DeepDyve

Institutional subscriptions

Similar content being viewed by others

The Development and Achievement of Polymeric Nanoparticles for Cancer Drug Treatment

Nanoparticles for Anticancer Drug Delivery

Translational nano-medicines: targeted therapeutic delivery for cancer and inflammatory diseases.

Meghna Talekar, Thanh-Huyen Tran & Mansoor Amiji

Rosowsky A, Bader H, Freisheim JHJ (1991) Analogs of methotrexate and aminopterin with gamma-methylene and gamma-cyano substitution of the glutamate side chain: synthesis and in vitro biological activity. J Med Chem 34(1):203–208

Article   CAS   PubMed   Google Scholar  

Choi HK et al (2000) A cost-effectiveness analysis of treatment options for patients with methotrexate-resistant rheumatoid arthritis. Arthritis Rheum 43(10):2316–2327

Hoffmeister RT (1983) Methotrexate therapy in rheumatoid arthritis: 15 years experience. Am J Med 75(6):69–73

Abolmaali SS et al (2013) A review of therapeutic challenges and achievements of methotrexate delivery systems for treatment of cancer and rheumatoid arthritis. Cancer Chemother Pharmacol 71(5):1115–1130

Garg NK et al (2015) Development and characterization of single step self-assembled lipid polymer hybrid nanoparticles for effective delivery of methotrexate. RSC Adv 5(77):62989–62999

Article   CAS   Google Scholar  

Hagner N, Joerger M (2010) Cancer chemotherapy: targeting folic acid synthesis. Cancer Manag Res 2:293–301

CAS   PubMed   PubMed Central   Google Scholar  

Kelemen LE (2006) The role of folate receptor alpha in cancer development, progression and treatment: cause, consequence or innocent bystander? Int J Cancer 119(2):243–250

Balis FM, Savitch JL, Bleyer WAJCR (1983) Pharmacokinetics of oral methotrexate in children. Cancer Res 43(5):2342–2345

CAS   PubMed   Google Scholar  

Xu D et al (2018) Evaluation of methotrexate-conjugated gadolinium(III) for cancer diagnosis and treatment. Drug Des Devel Ther 12:3301–3309

Article   CAS   PubMed   PubMed Central   Google Scholar  

Ferreira M et al (2015) Optimization of nanostructured lipid carriers loaded with methotrexate: a tool for inflammatory and cancer therapy. Int J Pharm 492(1–2):65–72

Khan ZA, Tripathi R, Mishra BJ (2012) Methotrexate: a detailed review on drug delivery and clinical aspects. Expert Opin Drug Deliv 9(2):151–169

Bertino JRJBP, Haematology RC (2009) Cancer research: from folate antagonism to molecular targets. Best Pract Res Clin Haematol 22(4):577–582

Article   PubMed   Google Scholar  

Raghunathan D, Kurady LB, Bhat R (2009) Effect of methotrexate on nor expression in liver of Wistar rats. Iran J Pharmacol Therap 8:11–15

CAS   Google Scholar  

Sramek M, Neradil J, Veselska R (2017) Much more than you expected: the non-DHFR-mediated effects of methotrexate. Biochim Biophys Acta 1861(3):499–503

Yu WJ, Huang DX, Liu S, Sha YL, Gao FH, Liu H (2020) Polymeric nanoscale drug carriers mediate the delivery of methotrexate for developing therapeutic interventions against cancer and rheumatoid arthritis. Front Oncol 10:1734

Article   PubMed   PubMed Central   Google Scholar  

Leveque D (2014) Subcutaneous administration of anticancer agents. Anticancer Res 34(4):1579–1586

Locke KW, Maneval DC, LaBarre MJ (2019) ENHANZE® drug delivery technology: a novel approach to subcutaneous administration using recombinant human hyaluronidase PH20. Drug Deliv 26(1):98–106

Wang J, Li G (2015) Mechanisms of methotrexate resistance in osteosarcoma cell lines and strategies for overcoming this resistance. Oncol Lett 9(2):940–944

Ottaviani G, Jaffe N (2009) The epidemiology of osteosarcoma. Pediatr Adolesc Osteosarcoma 3:13

Google Scholar  

Anninga JK, Gelderblom H, Fiocco M, Kroep JR, Taminiau AH, Hogendoorn PC, Egeler RM (2011) Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer 47(16):2431–2445

Sadykova LR, Ntekim AI, Muyangwa-Semenova M, Rutland CS, Jeyapalan JN, Blatt N, Rizvanov AA (2020) Epidemiology and risk factors of osteosarcoma. Cancer Investig 38(5):259–269

Article   Google Scholar  

Le Deley M-C et al (2007) SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur J Cancer 43(4):752–761

Patiño-García A, Zalacaín M, Marrodán L, San-Julián M, Sierrasesúmaga L (2009) Methotrexate in pediatric osteosarcoma: response and toxicity in relation to genetic polymorphisms and dihydrofolate reductase and reduced folate carrier 1 expression. J Pediatr 154(5):688–693

Wojtuszkiewicz A et al (2015) Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia. J Hematol Oncol 8(1):1–13

Sánchez-del-Campo L, Montenegro MF, Cabezas-Herrera J, Rodríguez-López JN (2009) The critical role of alpha-folate receptor in the resistance of melanoma to methotrexate. Pigment Cell Melanoma Res 22(5):588–600

Sáez-Ayala M et al (2012) Melanoma coordinates general and cell-specific mechanisms to promote methotrexate resistance. Exp Cell Res 318(10):1146–1159

Xie T, Nguyen T, Hupe M, Wei ML (2009) Multidrug resistance decreases with mutations of melanosomal regulatory genes. Cancer Res 69(3):992–999

Remesh A (2012) Toxicities of anticancer drugs and its management. Int J Basic Clin Pharmacol 1(1):2–12

Methotrexate (2005) http://pubchem.ncbi.nlm.nih.gov/

Dastjerd NT et al (2021) Design and characterization of liposomal methotrexate and its effect on BT-474 breast cancer cell line. Med J Islamic Republ Iran 35:1–7

Estlin EJ (2001) Continuing therapy for childhood acute lymphoblastic leukaemia: clinical and cellular pharmacology of methotrexate, 6-mercaptopurine and 6-thioguanine. Cancer Treat Rev 27(6):351–363

Levêque D, Becker G, Toussaint E, Fornecker LM, Paillard C (2017) Clinical pharmacokinetics of methotrexate in oncology. Int J Pharmacokinet 2(2):137–147

Rajšić I et al (2021) The increasing doses of methotrexate pharmacokinetics after intravenous administration in rats: Model selection. Vojnosanit Pregl 78(7):708–715

Friedman B, Cronstein B (2019) Methotrexate mechanism in treatment of rheumatoid arthritis. Jt Bone Spine 86(3):301–307

Dilley S, Huh W, Blechter B, Rositch AF (2021) It’s time to re-evaluate cervical cancer screening after age 65. Gynecol Oncol 162(1):200–202

Prasad A, Kumar A (2018) Utility of Pap smear in detection of cervix cancer in females: a clinical study. Int J Clin Obst Gynaecol 2(3):10–12

Abdalla E et al (2020) Racial differences in 5-year relative survival rates of cervical cancer by stage at diagnosis, between African American (black) and white women, living in the state of Alabama, USA. BMC Cancer 20(1):1–12

Waalkes MP, Rehm S (1994) Cadmium and prostate cancer. J Toxicol Environ Health 43(3):251–269

Khorsand J Prostate Cancer Prevention (PDQ®): Prevention-Health Professional Information [NCI]

Chen FZ, Zhao XK (2013) Prostate cancer: current treatment and prevention strategies. Iran Red Crescent Med J 15(4):279

Brawley OW (2012) Trends in prostate cancer in the United States. J Natl Cancer Inst Monogr 2012(45):152–156

Wu KF et al (2017) H19 mediates methotrexate resistance in colorectal cancer through activating Wnt/beta-catenin pathway. Exp Cell Res 350(2):312–317

Li C et al (2017) TUG1 mediates methotrexate resistance in colorectal cancer via miR-186/CPEB2 axis. Biochem Biophys Res Commun 491(2):552–557

Budithi A et al (2021) Data driven mathematical model of FOLFIRI treatment for colon cancer. Cancers 13(11):2632

Din FU et al (2017) Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. Int J Nanomed 12:7291–7309

Blinman P et al (2010) Adjuvant chemotherapy for early colon cancer: what survival benefits make it worthwhile? Eur J Cancer 46(10):1800–1807

Bialous SA, Sarna L (2017) Lung cancer and tobacco: what is new? Nurs Clin 52(1):53–63

Zhang X et al (2021) Real-world treatment patterns and outcomes in PD-L1-positive non-small cell lung cancer. Immunotherapy 13(18):1521–1533

Wang Z et al (2021) The next generation therapy for lung cancer: taking medicine by inhalation. Nanotechnology 32(39):392002

Birim Ö, Zuydendorp HM, Maat AP, Kappetein AP, Eijkemans MJ, Bogers AJ (2003) Lung resection for non-small-cell lung cancer in patients older than 70: mortality, morbidity, and late survival compared with the general population. Ann Thorac Surg 76(6):1796–1801

Sanli O et al (2017) Bladder cancer. Nat Rev Dis Primers 3:17022

Martínez-Rojo E et al (2021) The role of androgens and androgen receptor in human bladder cancer. Biomolecules 11(4):594

Arai S et al (2015) 261P Tolerability and efficacy of neoadjuvant chemotherapy with three-weekly interval methotrexate, doxorubicin, vinblastine and cisplatin regimen for patients with locally advanced bladder cancer. Ann Oncol 26:71

Saginala K, Barsouk A, Aluru JS, Rawla P, Padala SA, Barsouk A (2020) Epidemiology of bladder cancer. Med Sci 8(1):15

Wei CW et al (2019) Anticancer effects of methotrexate in combination with alphatocopherol and alphatocopherol succinate on triplenegative breast cancer. Oncol Rep 41(3):2060–2066

Wu CW et al (2017) Combined treatment with vitamin C and methotrexate inhibits triple-negative breast cancer cell growth by increasing H 2 O 2 accumulation and activating caspase-3 and p38 pathways. Oncol Rep 37(4):2177–2184

Farasat A, Rahbarizadeh F, Ahmadvand D, Yazdian F (2017) Optimization of an anti-HER2 nanobody expression using the Taguchi method. Prep Biochem Biotechnol 47(8):795–803

Maajani K et al (2019) The global and regional survival rate of women with breast cancer: a systematic review and meta-analysis. Clin Breast Cancer 19(3):165–177

Son G-H, Lee B-J, Cho C-W (2017) Mechanisms of drug release from advanced drug formulations such as polymeric-based drug-delivery systems and lipid nanoparticles. J Pharm Investig 47(4):287–296

Kondiah PPD et al (2018) Nanocomposites for therapeutic application in multiple sclerosis. Woodhead Publishing, Sawston, pp 391–408

Patel G, Misra A (2011) Oral delivery of proteins and peptides. Elsevier, Amsterdam, pp 481–529

Farasat A et al (2019) Effective suppression of tumour cells by oligoclonal HER2-targeted delivery of liposomal doxorubicin. J Liposome Res 29(1):53–65

Nikkhoi SK et al (2018) Liposomal nanoparticle armed with bivalent bispecific single-domain antibodies, novel weapon in HER2 positive cancerous cell lines targeting. Mol Immunol 96:98–109

Hajiahmadi F, Alikhani MY, Shariatifar H, Arabestani MR, Ahmadvand D (2019) The bactericidal effect of lysostaphin coupled with liposomal vancomycin as a dual combating system applied directly on methicillin-resistant Staphylococcus aureus infected skin wounds in mice. Int J Nanomed 14:5943

Hajiahmadi F, Alikhani MY, Shariatifar H, Arabestani MR, Ahmadvand D (2019) The bactericidal effect of liposomal vancomycin as a topical combating system against Methicillin-resistant Staphylococcus aureus skin wound infection in mice. Med J Islamic Repub Iran 33:153

Tavakoli Dastjerd N et al (2021) Design and characterization of liposomal methotrexate and its effect on BT-474 breast cancer cell line. Med J Islamic Repub Iran 35(1):1168–1174

Choi G et al (2016) Anionic clay as the drug delivery vehicle: tumor targeting function of layered double hydroxide-methotrexate nanohybrid in C33A orthotopic cervical cancer model. Int J Nanomed 11:337

Forastiere AA et al (1992) Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: a Southwest Oncology Group study. J Clin Oncol 10(8):1245–1251

Shitole AA et al (2020) LHRH-conjugated PEGylated, poly-lactide-co-glycolide nanocapsules for targeted delivery of combinational chemotherapeutic drugs Docetaxel and Quercetin for prostate cancer. Mater Sci Eng C 114:111035

Costa Lima SA et al (2017) Multifunctional nanospheres for co-delivery of methotrexate and mild hyperthermia to colon cancer cells. Mater Sci Eng C 75:1420–1426

Ajmal M et al (2015) Synthesis, characterization and in vitro evaluation of methotrexate conjugated fluorescent carbon nanoparticles as drug delivery system for human lung cancer targeting. J Photochem Photobiol B 153:111–120

Yang W et al (2018) Selective cell penetrating peptide-functionalized polymersomes mediate efficient and targeted delivery of methotrexate disodium to human lung cancer in vivo. Adv Healthc Mater 7(7):e1701135

Chen J et al (2018) Development of dual-drug-loaded stealth nanocarriers for targeted and synergistic anti-lung cancer efficacy. Drug Deliv 25(1):1932–1942

Guo X et al (2018) Multi-functionalized chitosan nanoparticles for enhanced chemotherapy in lung cancer. Carbohydr Polym 195:311–320

Abdelbary AA, AbouGhaly MH (2015) Design and optimization of topical methotrexate loaded niosomes for enhanced management of psoriasis: application of Box–Behnken design, in-vitro evaluation and in-vivo skin deposition study. Int J Pharm 485(1–2):235–243

Plimack ER et al (2014) Accelerated methotrexate, vinblastine, doxorubicin, and cisplatin is safe, effective, and efficient neoadjuvant treatment for muscle-invasive bladder cancer: results of a multicenter phase II study with molecular correlates of response and toxicity. J Clin Oncol 32(18):1895–1901

International Collaboration of, T et al (2011) International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J Clin Oncol 29(16):2171–2177

Nogueira DR et al (2016) Inclusion of a pH-responsive amino acid-based amphiphile in methotrexate-loaded chitosan nanoparticles as a delivery strategy in cancer therapy. Amino Acids 48(1):157–168

Thapa RK et al (2017) Silver nanoparticle-embedded graphene oxide-methotrexate for targeted cancer treatment. Colloids Surf B 153:95–103

Nosrati H et al (2019) Synthesis, characterization, and kinetic release study of methotrexate loaded mPEG-PCL polymersomes for inhibition of MCF-7 breast cancer cell line. Pharm Dev Technol 24(1):89–98

Davaran S et al (2018) Synthesis and characterization of novel P(HEMA-LA-MADQUAT) micelles for co-delivery of methotrexate and Chrysin in combination cancer chemotherapy. J Biomater Sci Polym Ed 29(11):1265–1286

Ali EMM et al (2018) Methotrexate loaded on magnetite iron nanoparticles coated with chitosan: Biosynthesis, characterization, and impact on human breast cancer MCF-7 cell line. Int J Biol Macromol 120(Pt A):1170–1180

Hess JA, Khasawneh MK (2015) Cancer metabolism and oxidative stress: insights into carcinogenesis and chemotherapy via the non-dihydrofolate reductase effects of methotrexate. BBA Clin 3:152–161

Rai M, Ingle AP, Gaikwad S, Padovani FH, Alves M (2016) The role of nanotechnology in control of human diseases: perspectives in ocular surface diseases. Crit Rev Biotechnol 36(5):777–787

Download references

Acknowledgements

The authors appreciate the Research Council of Qazvin University of Medical Sciences.

Author information

Authors and affiliations.

Health Products Safety Research Center, Qazvin University of Medical Sciences, Qazvin, Iran

Hanifeh Shariatifar

Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran

Fateme Ranjbarian

Department of Medical Imaging Technology (Molecular Imaging), School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran

Fahimeh Hajiahmadi

Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran

Alireza Farasat

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Alireza Farasat .

Ethics declarations

Conflict of interest.

The authors have declared that no conflict of interest exists. (Declaration of interest: none).

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Shariatifar, H., Ranjbarian, F., Hajiahmadi, F. et al. A comprehensive review on methotrexate containing nanoparticles; an appropriate tool for cancer treatment. Mol Biol Rep 49 , 11049–11060 (2022). https://doi.org/10.1007/s11033-022-07782-7

Download citation

Received : 19 November 2021

Accepted : 07 July 2022

Published : 12 September 2022

Issue Date : November 2022

DOI : https://doi.org/10.1007/s11033-022-07782-7

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Methotrexate (MTX)
• Nanoparticles
• Find a journal
• Publish with us
• Track your research

Europe PMC requires Javascript to function effectively.

Either your web browser doesn't support Javascript or it is currently turned off. In the latter case, please turn on Javascript support in your web browser and reload this page.

Search life-sciences literature (43,878,124 articles, preprints and more)

• Available from publisher site using DOI. A subscription may be required. Full text
• Citations & impact
• Similar Articles

Hepatotoxicity of methotrexate in rheumatic diseases.

Author information, affiliations.

Medical Toxicology and Adverse Drug Experience , 01 May 1988 , 3(3): 197-208 https://doi.org/10.1007/bf03259882   PMID: 3041245 

Abstract 

Full text links .

Read article at publisher's site: https://doi.org/10.1007/bf03259882

References 

Articles referenced by this article (79)

The Structure and Synthesis of the Liver L. casei Factor.

Angier RB , Boothe JH , Hutchings BL , Mowat JH , Semb J , Stokstad EL , Subbarow Y , Waller CW , Cosulich DB , Fahrenbach MJ , Hultquist ME , Kuh E , Northey EH , Seeger DR , Sickels JP , Smith JM Jr

Science, (2683):667-669 1946

MED: 17759224

Aponte J, Petrelli M. Hepatic histology following prolonged treatment of rheumatoid arthritis with bolus methotrexate. (Abstract.) Arthritis and Rheumatism 28 (Suppl. 141): S37, 1985

Complications in methotrexate treatment of psoriasis with particular reference to liver fibrosis..

Ashton RE , Millward-Sadler GH , White JE

J Invest Dermatol, (4):229-232 1982

MED: 7130740

Baer AN, Fuchs HA, Avant GA, Said H, Hande KR, et al. Tissue accumulation of methotrexate during methotrexate therapy for rheumatoid and psoriatic arthritis. (Abstract.) Arthritis and Rheumatism 29 (Suppl.): S41, 1986

Methotrexate hepatotoxicity..

Barak AJ , Tuma DJ , Beckenhauer HC

J Am Coll Nutr, (1):93-96 1984

MED: 6201520

Herbal tea induced hepatic veno-occlusive disease: quantification of toxic alkaloid exposure in adults.

Kumana CR , Ng M , Lin HJ , Ko W , Wu PC , Todd D

Gut, (1):101-104 1985

MED: 3965360

Black RL, O’Brien WM, Van Scott EJ, Auerbach R, Eisen AZ, et al. Methotrexate therapy in psoriatic arthritis: double blind study in 21 patients. Journal of the American Medical Association 189: 743–747, 1964

Polyglutamation of methotrexate. is methotrexate a prodrug.

Chabner BA , Allegra CJ , Curt GA , Clendeninn NJ , Baram J , Koizumi S , Drake JC , Jolivet J

J Clin Invest, (3):907-912 1985

MED: 2413074

Clegg DO, Bjorkman DJ, Tolman KG, Hammond EH, Lee RG, et al. Early morphologic evidence of methotrexate toxicity by electron and immunofluorescent microscopy. (Abstract.) Arthritis and Rheumatism 30 (Suppl.): S95, 1987

Cirrhosis associated with methotrexate treatment of psoriasis..

Coe RO , Bull FE

JAMA, (7):1515-1520 1968

MED: 5695945

Citations & impact 

Impact metrics, citations of article over time, alternative metrics.

Smart citations by scite.ai Smart citations by scite.ai include citation statements extracted from the full text of the citing article. The number of the statements may be higher than the number of citations provided by EuropePMC if one paper cites another multiple times or lower if scite has not yet processed some of the citing articles. Explore citation contexts and check if this article has been supported or disputed. https://scite.ai/reports/10.1007/bf03259882

Article citations, overview of methotrexate toxicity: a comprehensive literature review..

Hamed KM , Dighriri IM , Baomar AF , Alharthy BT , Alenazi FE , Alali GH , Alenazy RH , Alhumaidi NT , Alhulayfi DH , Alotaibi YB , Alhumaidan SS , Alhaddad ZA , Humadi AA , Alzahrani SA , Alobaid RH

Cureus , 14(9):e29518, 23 Sep 2022

Cited by: 19 articles | PMID: 36312688 | PMCID: PMC9595261

Synthetic Pharmacotherapy for Systemic Lupus Erythematosus: Potential Mechanisms of Action, Efficacy, and Safety.

Téllez Arévalo AM , Quaye A , Rojas-Rodríguez LC , Poole BD , Baracaldo-Santamaría D , Tellez Freitas CM

Medicina (Kaunas) , 59(1):56, 27 Dec 2022

Cited by: 3 articles | PMID: 36676680 | PMCID: PMC9866503

Methotrexate in sarcoidosis: hematologic and hepatic toxicity encountered in a large cohort over a six year period.

Baughman RP , Cremers JP , Harmon M , Lower EE , Drent M

Sarcoidosis Vasc Diffuse Lung Dis , 37(3):e2020001, 30 Sep 2020

Cited by: 9 articles | PMID: 33264378 | PMCID: PMC7690061

Acute severe hepatitis in adult-onset Still's disease: case report and comprehensive review of a life-threatening manifestation.

Muller R , Briantais A , Faucher B , Borentain P , Nafati C , Blasco V , Gregoire E , Bernit E , Seguier J , Meunier B , Harlé JR , Ebbo M , Schleinitz N

Clin Rheumatol , 40(6):2467-2476, 21 Sep 2020

Cited by: 5 articles | PMID: 32955629

Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease.

Rabinowich L , Shibolet O

Biomed Res Int , 2015:168905, 26 Jul 2015

Cited by: 49 articles | PMID: 26273591 | PMCID: PMC4529891

Similar Articles 

To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

Low incidence of hepatotoxicity associated with long-term, low-dose oral methotrexate in treatment of refractory psoriasis, psoriatic arthritis, and rheumatoid arthritis. An acceptable risk/benefit ratio.

Lanse SB , Arnold GL , Gowans JD , Kaplan MM

Dig Dis Sci , 30(2):104-109, 01 Feb 1985

Cited by: 53 articles | PMID: 3967557

Hepatotoxicity associated with low-dose, long-term methotrexate treatment of rheumatoid arthritis.

Szanto E , Sandstedt B , Kollberg B

Scand J Rheumatol , 16(4):229-234, 01 Jan 1987

Cited by: 6 articles | PMID: 3629206

[Methotrexate, liver and rheumatoid arthritis in tropical areas].

Diouf ML , Diallo S , Mbengue M , Moreira-Diop T

Sante , 11(3):195-200, 01 Jul 2001

Cited by: 6 articles | PMID: 11641084

Massive intrahepatic hemorrhage following routine liver biopsy in a patient with rheumatoid arthritis treated with methotrexate.

Cash JM , Swain M , Di Bisceglie AM , Wilder RL , Crofford LJ

J Rheumatol , 19(9):1466-1468, 01 Sep 1992

Cited by: 2 articles | PMID: 1433018

Longterm methotrexate therapy in rheumatoid arthritis: a review.

J Rheumatol Suppl , 12 Suppl 12:25-28, 01 Dec 1985

Cited by: 4 articles | PMID: 3913773

Europe PMC is part of the ELIXIR infrastructure

• Open access
• Published: 05 March 2024

Methotrexate treatment strategies for rheumatoid arthritis: a scoping review on doses and administration routes

• Esteban Rubio-Romero   ORCID: orcid.org/0000-0001-7402-8880 1 ,
• César Díaz-Torné   ORCID: orcid.org/0000-0001-6275-7699 2 ,
• María José Moreno-Martínez   ORCID: orcid.org/0000-0003-0599-123X 3 &
• Julen De-Luz   ORCID: orcid.org/0000-0002-8620-5888 4  

BMC Rheumatology volume  8 , Article number:  11 ( 2024 ) Cite this article

1270 Accesses

8 Altmetric

Metrics details

To describe the evidence of methotrexate (MTX) initiation strategies in patients with rheumatoid arthritis (RA) and, in the case of non-responders, analyse the efficacy and safety of route and dose optimisation.

We conducted a comprehensive scoping review of randomised controlled trials according to PRISMA Scoping Reviews Checklist and the framework proposed by Arksey and O’Malley. PubMed, EMBASE, and Cochrane were searched without language restriction, and hand searches of relevant articles were examined.

We identified 1,367 potentially eligible studies, of which 12 were selected based on the titles and abstracts and then on the full-length articles. In naïve-MTX patients, a linear dose-response relationship for starting dose was found between 5 mg/m2/week (7.5–10 mg/week) and 10 mg/m2/week (15–22 mg/week), without toxicity correlation. A higher initial dose of MTX (25 mg vs. 15 mg) was more effective, resulting in fewer dose increases due to ineffectiveness and more dose reductions due to higher remission rates. There was also a trend towards increased gastrointestinal toxicity. Comparing different routes of administration of MTX, subcutaneous MTX showed a statistically higher ACR20 response (85%) in comparison with oral MTX (77%) ( p  < 0.05). The clinical efficacy and safety of accelerated and conventional start MTX regimens were comparable between 7.5 and 15 mg with a 2,5 mg dose increase every two weeks. In RA patients who have failed the initial treatment with MTX, the stepwise increase in MTX doses is associated with a higher ACR20 response and sustained remission rate than other strategies. In MTX non-responders, optimisation to SC MTX was associated with improvements in ACR20 and ACR50 rates with similar toxicity between groups. In the early RA patients subgroup, SC MTX showed higher ACR20 response rates than oral MTX, and intensive oral methods have a much higher sustained remission rate, shorter mean time to remission, and better clinical disease activity measures than conventional treatments.

Conclusions

Higher starting doses of MTX and initial subcutaneous MTX made better performance in improving the ACR20 response, although the clinical effectiveness and safety of other MTX start regimens are comparable. This scoping review provides evidence in support of optimising MTX treatment in terms of route and dose prior to concluding that MTX treatment in RA patients has failed.

Peer Review reports

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by pain, inflammation, and potential erosion of the joints. Approximately 0.39 to 1% of the population is affected by RA, making it one of the most prevalent chronic inflammatory diseases [ 1 ]. Unfortunately, the debilitating effects of RA have a long-term impact on patient’s physical and psychological well-being, decreasing their quality of life [ 2 ].

The primary therapeutic goal in RA is to achieve a target of sustained clinical remission or low disease activity (LDA) in each patient [ 3 , 4 ], and this is typically only possible with the help of disease-modifying anti-rheumatic drugs (DMARDs). DMARDs have the potential to prevent or reduce joint damage and preserve joint integrity and function, controlling synovitis and slowing or stopping the radiographic progression [ 5 , 6 ]. Various DMARDs are currently available for the treatment of RA, including conventional synthetic DMARDs (csDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs [ 3 , 4 ].

Among the csDMARDs, methotrexate (MTX; 4-amino-10-methyl folate acid) is currently considered the “anchor drug” for the treatment of RA [ 7 , 8 ]. In fact, it is widely prescribed—for up to 70% of patients with RA [ 9 ]. With a structure similar to that of folate, this agent acts as a competitive inhibitor of multiple folate-dependent enzymes, ultimately leading to the inhibition of DNA and RNA synthesis with an increase of extracellular adenosine. Multiple mechanisms may contribute to MTX’s anti-inflammatory effects, such as purine and pyrimidine synthesis inhibition, nuclear factor-κB translocation, transmethylation reactions, Janus kinase signalling, nitric oxide production, adenosine release, and long non-coding RNA expression [ 10 ]. In the immune system, MTX primarily affects T cells, although it has also been shown to have antiproliferative or anti-inflammatory effects in B cells, monocytes, and dendritic cells [ 11 ]. In patients naïve to DMARDs, MTX is recommended to be part of the first treatment strategy in light of its favourable risk/benefit ratio, acceptable safety profile, and low cost [ 4 ]. It may be used as monotherapy to achieve good control or clinical remission, as well as in combination therapy for patients who require multiple DMARDs or biologic drugs to control the disease [ 12 , 13 ]. Most naïve individuals with early RA begin oral MTX at a dosage range from 7.5 to 30 mg/week, although the optimal dose in each patient will vary because of different disease severity and pharmacokinetic variability [ 14 ]. Nevertheless, although MTX is the first choice for RA treatment, the potential side effects of MTX should not be ignored. Gastrointestinal problems, hepatotoxicity, lung toxicity, haematological toxicity, and renal toxicity are the most prevalent MTX side effects [ 15 ].

In an effort to minimise acute and chronic toxicity associated with MTX, new therapeutic strategies utilising different dosages and routes of administration (oral, subcutaneous, and intramuscular) have been proposed in the literature. Recent guidelines on MTX administration [ 4 , 9 ] have suggested that MTX should be initiated at the highest tolerable dose (at 7.5–15 mg/week [ 16 ]), with a progressive weekly increase of the drug (to about 25 mg once weekly) to the maximal recommended dosage and an early switch to the parenteral route in case of unresponsiveness or evidence of adverse effects, before switching to another drug. However, the optimal starting dose, schedule for dose escalation, and route of administration are uncertain. First, based on the reported literature concerning the use of MTX in different dose regimens, some evidence has shown that in treatments with rapid dose escalation, the next dose increment may not result in clinically significant improvement [ 17 ] but rather increased toxicity. Furthermore, there are no specific recommendations for MTX dosage in patients with early RA since few studies have assessed the efficacy and safety of this agent in particular populations [ 17 ]. Second, regarding the different routes of administration, oral MTX is widely preferred due to patients’ better usability and lower costs [ 18 ]. However, several studies have demonstrated that the subcutaneous (SC) formulation is superior to the oral formulation in terms of discomfort and better usability by both physicians and patients [ 19 , 20 ], as well as in terms of MTX bioavailability, particularly at higher doses [ 21 , 22 , 23 ].

Hence, considerable heterogeneity persists in the prescription of dose and methotrexate regimen for therapy of RA, with a schedule for dose escalation not fully elucidated and routes of administration not well established. Although this may be due in part to the lack of well-studied methotrexate dose-response curves and the differences in endpoints clinicians are aiming for, until now, the available literature has failed to suggest specific strategies for optimising MTX therapy, and there is no current review focusing on which are the optimal dosages and routes of administration for MTX therapy in the clinical setting. Therefore, we conducted a scoping review to describe the efficacy of using different starting doses, the schedule for dose escalation, and routes of administration to optimise the treatment of RA patients with MTX.

The PRISMA extension for Scoping Reviews (PRISMA-ScR) [ 24 ] Checklist and the framework proposed by Arksey and O’Malley [ 25 ] were used to guide this review. The following five steps have been followed in this scoping review: (i) identifying the research question, (ii) identifying relevant studies, (iii) selecting eligible studies, (iv) charting the data, and (v) collating and summarising the results.

Identifying the research question

The main research question was: “What are the efficacy and safety of different therapeutic strategies utilising different dosages and routes of administration of MTX in RA patients?“. The research sub-question was as follows: What are the efficacy and safety of utilising different dosages and routes of administration of MTX in individuals with early RA?

Identifying relevant studies

A primary electronic literature search was conducted in the three major biomedical databases (PubMed, EMBASE, and Cochrane) to identify relevant publications on using different therapeutic strategies with MTX in RA patients. The search strategies were adapted for each database using a combination of free-text terms and medical subject headings (MeSH and Emtree terms). Articles published between database inception to 4th April 2022 were included in the review. In addition to this search with a more global approach aimed at patients with a time from RA diagnosis of any duration, a specific search strategy was developed to identify studies explicitly addressing the efficacy and safety of utilising different dosages and routes of administration in initial treatment with MTX only for patients early RA (disease duration ≤ 2 years). Thus, a total of two searches (one for each research question) were conducted, combining the following main search terms based on inclusion and exclusion criteria: “methotrexate”, “rheumatoid arthritis”, “drug administration routes”, “methotrexate/administration and dosage”, and “randomised controlled trial”. Most of the articles were found using combinations between Boolean operators “AND/OR”, search terms, and synonyms for the keywords.

Further search for any other relevant studies was performed through a hand search of reference lists of the selected and review articles. The searches were restricted to studies in humans, but no language or time restrictions were imposed. The final selected studies from the obtained references were screened by a single reviewer. The complete search strategies are available in Additional File 1 in the supplementary materials.

Study selection

Following the manual removal of duplicates, the titles and abstracts of retrieved articles were screened for relevance. Full texts of retrieved publications were reviewed and marked for inclusion if they met the inclusion criteria. The inclusion criteria were as follows: (1) the study design was a randomised clinical trial (parallel arm and cross-over) published in any format (full paper, conference abstracts) with sufficient data available to estimate outcomes, (2) enrolled adult patients (> 18 years) with RA diagnosis according to validated criteria, irrespective of clinical stage or disease duration; and (3) compared two or more treatment strategies at treatment initiation and later on, by using different dosages or routes of administration, whether or not combined with other drugs. We consider an additional inclusion criterion on RA disease duration (≤ 2 years ) to answer the research sub-question about a specific population (early RA patients) in accordance with prior publications [ 26 ]. Papers were excluded if (1) enrolled pediatric or mixed populations, (2) focused on the use of MTX in combination with other agents or on the splitting dosing strategy (administering the total prescribed dose more frequently and in smaller increments over one week), (3) included a single arm or with any other design (narrative reviews, editorial comments, and letters). Quality appraisal was not performed in accordance with the standard approach to conducting scoping reviews [ 25 , 27 ]. The PRISMA study flow diagram is illustrated in Fig.  1 .

PRISMA flowchart with the main stages of the review process: primary question*. *We combined the reports based on the same research among the selected papers, resulting in 14 references covering 12 original studies

Charting data and reporting the results

A data extraction template was developed to determine which variables to extract for each study. The following data were extracted from full-text publications selected for inclusion in the review: author(s), year of publication, study location, the title of the publication, follow-up (number of patients randomised, follow-up period, frequency of withdrawals), study population (i.e., age, gender, RA duration, baseline severity of RA, baseline functional status, MTX- or other DMARD-exposure), intervention type (i.e., treatment(s) received, dosage and dose schedule), outcome measures and critical results of the publication on the effectiveness and safety of MTX. All data were entered and verified onto a specifically designed ‘data form’ using the database program Excel. The most recent or complete report was used when multiple articles describing the same sample or study were published. We categorised the included studies based on the following three pre-identified themes: (1) initiating MTX therapy, (2) optimising MTX therapy, and (3) optimising MTX therapy in early RA patients, considering different starting doses, dose escalation strategies and routes of administration for each of them. We considered MTX therapy optimisation when the MTX dose or route of administration was modified after a failed first treatment with MTX.

Search results

The initial electronic searches yielded 1,367 potentially eligible papers or abstracts. An additional manual search using the bibliography of select articles identified 48 more records. After excluding 1,327 duplicate references and 1,262 papers or abstracts that did not meet the eligibility criteria, 85 full-text papers were retrieved to confirm their eligibility. Of these, a further 71 articles were excluded. The main reasons for exclusion were related to inadequate study design or intervention. A total of 14 papers that met the inclusion criteria were included in this review. Among selected studies, we combined the reports based on the same research (one conference abstract and one journal article [ 28 , 29 ], and two journal articles [ 30 , 31 ]). Hence, finally, we included 14 references covering 12 original studies.

Characteristics of included studies

Of the 12 trials analysing the efficacy of different MTX treatment strategies, nine sought to determine the optimal MTX dosages, while three studies [ 29 , 30 , 32 ] compared different MTX administration routes. Publication dates ranged from 1989 to 2021, with most studies (9/12, 75%) published since 2000. With the exception of 2 trials reported as conference abstracts [ 32 , 33 ], all publications were journal articles. Except for one study with a cross-over design [ 31 ], all included studies were randomised controlled trials with a parallel longitudinal design. Most studies were conducted in Europe ( n  = 5, 41.7%), followed by Asia ( n  = 4, 33.3%) and America ( n  = 3, 25.0%). The included studies were undertaken in a single centre (including hospitals or clinics), while 4 trials were multicenter studies [ 31 , 34 , 35 , 36 ]. Included studies were grouped into two broad categories that represent (i) the different starting dosages and the plan for dose escalation ( n  = 9) [ 28 , 29 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ] and (ii) the routes of administration for MTX ( n  = 3) [ 30 , 31 , 32 , 34 ]. A sub-analysis of findings that were unique to each category is presented below.

Basal characteristics of patients

The 12 trials included a total of 1,566 participants. In these studies, the number of patients varied widely from 19 [ 38 ] to 384 [ 34 ]. Among included patients, 921 (58.8%) were female, with a mean follow-up of 24.3 (± 13.9) weeks, ranging from 8 to 52 weeks. All included patients fulfilled the revised American College of Rheumatology (ACR) [ 42 ] and/or the 2010 American College of Rheumatology (ACR)/EULAR classification criteria for RA [ 43 ]. The included trials recruited patients with a broad range of time from RA diagnosis (from 2.1 to 14.4 years), with a mean of 5.8 (± 4.8) years. Only two studies [ 28 , 36 ] reported data on body mass index, with a mean of 24.2 (± 0.9) kg/m 2 . The mean Disease Activity Score for 28 joints (DAS28) score was reported by three trials [ 36 , 38 , 39 ] with scores ranging from 4.5 to 5.4 (mean 5.2 [± 0.4]), while only one study [ 40 ] provided data on the basal ACR functional class with a mean of 1.2 (± 1.3). Most subjects (921, 87.2%) were seropositive for rheumatoid factor (RF+), with percentages of RF + participants ranging from 30.4 to 85.0% among included studies. The presence of anti-cyclic citrullinated peptide (anti-CCP) was detected in 13.6% of the individuals comprising the study population. The prevalence of erosive and/or deforming arthropathy on radiographs of the hands, wrists, or feet in patients with advanced disease when this data was reported [ 28 , 36 , 39 ], ranged from 4.5 to 95.6%. According to data from six trials [ 34 , 28 , 36 , 39 , 40 , 41 ], 353 patients (37.1%) had previous treatments with other DMARDs prior to receiving MTX. The most commonly used DMARDs were hydroxychloroquine, chloroquine, or sulfasalazine. Six studies [ 34 , 29 , 36 , 37 , 38 , 39 ] reported a total of 240 patients receiving treatment with concomitant steroids (mainly prednisone), with percentages ranging from 9.0 to 48.1% of the randomised participants. The baseline clinical characteristics of study populations are summarised in Table  1 .

Initiating MTX therapy

Of the 12 included trials, 7 studies [ 34 , 29 , 33 , 36 , 37 , 38 , 41 ] analysed the efficacy of different starting oral MTX strategies. Among them, three [ 29 , 37 , 41 ] compared different initial doses in a total of 337 participants (21.5%), while three trials [ 33 , 36 , 38 ] compared standard versus accelerated regimens for increasing oral MTX dosages on treatment initiation in a total of 312 RA patients (19.9%). Another trial [ 34 ] compared the clinical efficacy and safety of starting SC versus oral administration of MTX at 16 weeks. The main results from included RCT evaluating initial MTX therapy are shown in Table  2 .

The three trials analysing the optimal oral MTX starting dose in patients with RA compared MTX doses ranging from 7.5 mg/week to 35 mg/week. Specifically, these studies compared the following MTX dosages: 5 or 10 mg/m 2 per week [ 37 ]; 15 or 25 mg per week [ 41 ]; and 7.5 mg or 15 mg per week [ 28 ]. The first study [ 37 ] evaluated two oral MTX dosages: 5 mg/m 2 /week (7.5–10 mg/week) and 10 mg/m 2 /week (15–22 mg/week) versus placebo in 52 patients with longstanding active RA who failed other DMARDs (either gold or D-penicillamine). An additional 6 patients, given 20 mg/m 2 MTX (27.5–35 mg/week), contributed to the toxicity but not the efficacy analysis. After 18 weeks, a linear dose-response relationship (placebo vs. 5 mg/m 2 vs. 10 mg/m 2 ) was found for 5 of 11 clinical study variables, including patient pain and global patient scale, global physician scale, joint tenderness count and activity of daily living scale ( p  < 0.05). In other words, increasing doses of MTX resulted in an increased response, and 10 mg/m 2 (15–22 mg/week) produced more significant improvements than 5 mg/m 2 (7.5–10 mg/week) for these outcomes. Regarding safety, despite the apparent dose-to-toxicity relationship, the authors could not find a statistically significant correlation. A second open, prospective 12-month study compared oral MTX beginning doses of 15 mg/week and 25 mg/week in 185 individuals with established RA [ 41 ]. With a few exceptions, medication was started intravenously to maximise the early effect and switched to oral after 3–4 weeks. If the therapeutic efficacy was insufficient after three months on 15 mg/week, the MTX dose was increased to 20 mg/week and, if necessary, 25 mg/week. If, after 6 months, the patient was significantly better and on a steroid dose of no more than 6 mg methylprednisolone per day, the MTX dose was permitted to be reduced in small increments (maximum 5 mg every 3 months) to the lowest effective dose. Due to ineffectiveness, 27% of patients in the 15 mg group and 3% in the 25 mg group increased their dosage. The dose was reduced in 23% and 51% of patients in the 15 and 25 mg groups, respectively, due in part to remission (10% of patients in the 15 and 35% in the 25 mg groups, respectively; p  = 0.0001). In terms of safety, although there was a trend towards increased gastrointestinal toxicity in the higher-dosed group, the percentage of patients who reduced their dose owing to toxicity was 9% in both groups. The 12-month MTX retention rate in the 15 mg group was 74% and 73% in the 25 mg group. According to these studies, the effectiveness is highest with a high initial dose. However, in a third open-label trial [ 29 ], 100 RA patients were randomised to receive oral MTX at a starting dose of 7.5 mg or 15 mg per week, with a dosage increase of 2.5 mg every 2 weeks to a maximum of 25 mg. After 12 weeks, the authors did not find significant differences in efficacy between the 2 starting doses of MTX in terms of mean change in DAS28 ( p  = 0.60), Health Assessment Questionnaire (HAQ) score ( p  = 0.22), tender joint counts, swollen joint counts, erythrocyte sedimentation rate, patient-rated improvement, or adverse effects (transaminitis and cytopenia).

Three trials [ 33 , 36 , 38 ] compared standard versus accelerated regimens for increasing oral MTX concentrations in an effort to determine alternative strategies for initiating MTX administration orally. Patients in the accelerated dosing groups received oral starting doses of 15 mg/week escalated by 5 mg every 2 weeks till a maximum dose of 25 mg once a week [ 36 ]; or escalated up to 0.25 mg/kg/week within 8 weeks after the start of MTX and increased maximum tolerable dose or 16 mg/week until week 12 [ 33 ]; or 25 mg/week maintained until week 16 [ 38 ]. In standard regimen groups, the starting dose of MTX was 15 mg/week, escalated by 5 mg every 2 weeks [ 38 ] or every 4 weeks [ 36 ], or patients were treated with either MTX, tacrolimus, salazosulfapyridine, or bucillamine by the discretion of physicians until week 12 [ 33 ]. The other three trials compared MTX strategies to the fast/conventional approach, exploring intensive schedules [ 35 ], escalating doses of intramuscular (IM) MTX [ 39 ], or using different administration regimens [ 39 ].

Comparing accelerated versus standard regimens for increasing oral MTX dosages, no significant differences at 16 weeks were found for clinical efficacy variables such as DAS28 (-1.8 vs. -2.0, p  = 0.935 [ 38 ], and − 1.3 vs. -1.3, p  = 0.98 [ 36 ]) and HAQ score (-0.8 vs. -0.7, p  = 0.26) [ 36 ] and (-0.8 vs. -0.56, p  = 0.096) [ 33 ] European League Against Rheumatism (EULAR) response (65.2% vs. 61.8%, p  = 0.64) [ 36 ], and DAS28-CRP-based remission (14.6 vs. 13.5, p  = 0.80) [ 36 ]. Similarly, in the longer term (24 and 48 weeks), no significant differences were found between the two groups treated with oral MTX according to simplified disease activity index (SDAI) remission (42% vs. 28%, p  = 0.1), HAQ (0 vs. 0.13, p  = 0.096), and EuroQol-5D (0.78 vs. 0.77, p  = 0.12) scores [ 33 ]. Considering toxicity, although significantly more gastrointestinal AE was found in the fast escalation group over the initial 8 weeks (27%, 40%, p  = 0.048), this difference was not maintained over 16 weeks [ 36 ]. The adverse events during follow-up were generally self-limiting, and no serious adverse events were noted. There were no significant differences between the two groups related to other adverse events (such as cytopenias, transaminitis, or drug discontinuation/dose reduction).

Lastly, the multicenter trial [ 34 ] comparing the clinical efficacy and safety of SC versus oral administration of MTX at week 16 showed that ACR20 response was statistically higher in SC MTX (85%) versus 77% of those receiving oral MTX ( P  < 0.05).

Optimising MTX therapy

MTX increase and reduction dosage strategies.

Four studies [ 34 , 35 , 39 , 40 ] evaluated different strategies for increasing MTX dosages during maintenance treatment in RA patients. The main results from included RCT analysing the optimisation of MTX therapy are shown in Table  3 .

In a multicenter open-label trial [ 35 ], 299 patients with early RA were randomly assigned to either an intensive strategy with oral monthly dosage adjustments in 5 mg increments (based on the clinical response and a computerised decision tree) or a conventional approach with evaluations every 3 months by a physician. In both groups, oral administration of MTX was initiated at 7.5 mg/week, which was increased stepwise by 5 mg/week up to 30 mg/week, according to the clinical response. Individuals with suboptimal responses were switched to SC administration or given add-on cyclosporine therapy. No statistically significant differences in structural damage progression were found between the two strategies. However, the authors found a significantly higher sustained remission rate with the intensive strategy compared to the conventional approach after 1 year (35% vs. 14%, p  < 0.001) and 2 years (50% vs. 35%, p  = 0.03). Additionally, the mean time to sustained remission was about 4 months shorter with the intensive strategy (10.4 months vs. 14.3 months; p  < 0.001). Another study [ 40 ] explored a method for administering oral low-dose MTX in patients with RA in remission. In this trial, 51 RA participants were randomised to continue their weekly regimen with MTX or switch to the every-other-weekly schedule. At 24 weeks, there were no significant statistical differences between the groups regarding joint counts, the Ritchie Articular Index, the HAQ score, the duration of morning stiffness, pain by visual analogue scale (VAS), or patients’ and physicians’ global health assessments ( p value not reported). After 6 months, the incidence of adverse events did not differ statistically between groups, with the exception of a statistically significantly lower laboratory value for aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in the every-other-weekly MTX group (0.041 and 0.006, respectively). Three patients relapsed, 2 taking every-other-weekly MTX, and one taking weekly MTX.

Other authors have proposed new increase dosage strategies using administration routes other than oral. In this sense, in a double-blind trial [ 39 ], 54 RA patients unresponsive to 15 mg of SC MTX were randomised to receive either 15 mg/week IM MTX with placebo dose escalation or escalation of the IM MTX dose up to 45 mg/week. The MTX or placebo dose was escalated every 4 weeks if the DAS28 was > 2.5. In the intervention arm, the dose of MTX was increased to 20 mg, 25 mg, 35 mg, and 45 mg/week consecutively every 4 weeks, while in the placebo arm, patients were administered 15 mg MTX with the addition of carrier solution at an equal volume and in colour identical to that in the intervention arm. After 22 weeks, no differences were found between groups: 1 patient (3.7%) in each group achieved a DAS28 score of < 3.2, and five patients (18.5%) in each group showed an improvement of > 1.2 in the DAS28. In addition, one patient (3.7%) in each group achieved an ACR20 response, although none achieved a good response according to EULAR response criteria. Minor adverse reactions were more frequently reported in the dose escalation group (39 vs. 29), and one patient in each group had a severe adverse reaction.

Finally, a multicenter trial [ 34 ] with 384 MTX- naïve participants was conducted to compare the clinical efficacy and safety of SC versus oral administration of MTX, including dosage adjustment after 16 weeks based on efficacy. Thus, at week 16, patients who did not meet the ACR20 response were switched from 15 mg of oral MTX to 15 mg of SC MTX and from 15 mg of SC MTX to 20 mg of SC MTX. A total of 52 patients (14%) were deemed ACR20 non-responders, and their medications were consequently changed per the protocol. As a result, increasing the dosage of SC MTX from 15 mg to 20 mg was associated with an ACR20 response in an additional 23% of participants.

MTX route of administration switch strategy

Of 12 studies included in our review, two trials [ 32 , 34 ] compared SC MTX versus single-dose treatment with oral MTX; one trial [ 31 ] compared oral versus SC MTX administered via an auto-injector (either into the abdomen or the thigh); and another study [ 39 ] analysed the effects of switching from oral to parenteral MTX. With the exception of one study [ 31 ] in which the authors did not specify whether initial MTX treatment failed, the patients underwent treatment with MTX for at least 3 months before randomisation; all studies included patients who had not responded adequately to initial oral MTX treatment.

The two trials [ 32 , 34 ] comparing SC and oral administration routes in a total of 476 RA patients that had failed previous oral treatment found that, at 24 weeks, the rates were significantly higher in patients treated with 15 mg of SC MTX than with oral MTX for ACR20 (78% vs. 70%, p  < 0.05 [ 34 ]; and 93% vs. 80%, p  = 0.02 [ 32 ]) and ACR50 (89% vs. 72%, p  = 0.03) [ 32 ]. Although one of the two trials showed response rates of ACR70 significantly higher in SC MTX than oral MTX group (41% vs. 33%, p  < 0.05) [ 34 ], the other trial did not find that ACR70 response was significantly higher in the SC MTX group than oral group (11% vs. 9%, p  = 0.72) [ 32 ]. Moreover, the number of swollen joints was lower in the SC group, as was the number of tender joints [ 34 ]. Further exploratory analyses stratified by disease duration showed that switching from 15 mg orally to 15 mg SC MTX when oral MTX in standard dosages was inadequately effective improved the ACR20 response in an additional 30% of patients [ 34 ]. MTX was well tolerated in these studies, and the rate of adverse events was similar in all groups [ 34 ], although the adverse effects incidence was relatively less in SC MTX. The most common side effects of SC and oral MTX were nausea (37% vs. 63%), vomiting (11% vs. 30%), dyspepsia (29% vs. 48%), dizziness (41% vs. 52%), and alopecia (72% vs. 85%), respectively [ 32 ]. Another trial comparing oral versus SC MTX administered via an auto-injector [ 31 ] showed that the mean concentration of MTX 4 h after the dose administration was consistently higher for SC MTX than for oral MTX for all dose levels but most apparent at 15–25 mg doses. Two individuals in SC MTX groups reported significant adverse events in this trial (one case of myocardial infarction with 25 mg MTX into the abdomen and one case of sick sinus syndrome with 15 mg MTX into the thigh), although no dose- or treatment-related patterns were observed. Finally, a trial [ 39 ] examined the safety and efficacy of an alternative strategy consisting of a switch to IM administration of MTX and escalation of the dose beyond conventional doses of 20–25 mg/week up to 45 mg/week. In this study, 64 patients were enrolled and were switched from 15 to 20 mg/week of oral MTX to 15 mg/week IM MTX. After 22 weeks, there was no significant difference between IM MTX and control groups in terms of change in DAS28 (-0.7 ± 1.3 vs. -0.5 ± 1.0, p  < 0.1) or individual components of the ACR core disease activity set, and only 1 patient (3.7%) in each group achieved the primary outcome of a DAS28 < 3.2 (95% CI for the difference between the groups − 15% to + 15%).

Optimising MTX in patients with early rheumatoid arthritis

A second specific systematic search was conducted to identify studies addressing the efficacy and safety of different MTX dosages and administration routes in individuals with early RA (disease duration ≤ 2 years). Of 825 references identified, only three trials [ 33 , 34 , 35 ] (already identified in the broader search) fulfilled the inclusion criteria and compared different MTX regimens, specifically in patients with early RA (Additional file 2 in the Supplementary materials). The main results from included RCT evaluating the optimisation of MTX therapy in patients with early RA are shown in Table  4 .

The three studies recruited 798 individuals with early RA, representing more than half of the total included population (51.0%). Only two of three trials established selection criteria related to the duration of the disease, including limits < 1 year [ 35 ] and ≤ 2 years [ 33 ], while the other trial included mixed populations (early RA and somewhat longer disease duration). In this trial [ 34 ], the mean disease duration ranged from 2.1 to 2.5 months (most patients were a population with early RA); the remaining two trials did not provide information about this data. The mean age was 56.0 years (± 2.5), and 354 patients (51.8%) were female.

Two studies analysed the results of increasing dosage strategies. The results of one of included trials compared rapid escalation and standard MTX therapy in 115 patients with early RA [ 33 ]. One group ( n  = 57) received oral doses of MTX escalated up to 0.25 mg/kg/week within 8 weeks after MTX started and increased maximum tolerable dose or 16 mg/week until week 12. The other group ( n  = 58) was managed using a conventional strategy with either MTX, tacrolimus, salazosulfapyridine, or bucillamine at physicians’ discretion until week 12. The authors found that although the rate of disease remission by SDAI criteria was higher with the rapid strategy after 24 weeks (42% vs. 28%, p  = 0.1), these values were not statistically different between the two groups at week 48. Concerning safety, there were no significant differences between the two groups regarding the incidence of severe adverse events. Another multicenter open-label trial [ 35 ] compared an intensive treatment with oral MTX (according to a strict protocol and a computerised decision program) to conventional therapy with MTX, as described previously in the MTX dosage strategies section. As a result, a significantly higher sustained remission rate was found with the intensive strategy compared to the conventional approach after 1 year (35% vs. 14%, p  < 0.001) and 2 years (50% vs. 35%, p  = 0.03). Additionally, the intensive strategy approach resulted in a statistically significantly shorter mean time to sustained remission (10.4 months vs. 14.3 months; p  < 0.001) and lower median area under the curve (AUC) for the following clinical disease activity parameters compared with the conventional strategy: morning stiffness (17.0 vs. 23.7, p  = 0.009); erythrocyte sedimentation rate (ESR) (17.7 vs. 21.6, p  = 0.007); tender joint count (3.6 vs. 5.5, p  = 0.001); swollen joint count (2.7 vs. 4.7, p  = 0.001); VAS general well-being (19.0 vs. 31.2, p  = 0.001), and VAS pain (12.0 vs. 19.0, p  = 0.001). Although clinical variables (including tender joint count, swollen joint count, VAS general well-being, and VAS pain) improved statistically significantly in the first year in the intensive strategy group, clinical and functional changes from baseline were similar between the two groups at two years. Response rates of ACR50 were significantly higher in the intensive strategy group at 1 year (58% vs. 43%, p  = 0.018), but those differences did not achieve statistical significance at 2 years (46% vs. 45%, p  = 1.00).

In a third trial [ 34 ] comparing the efficacy and safety of SC versus oral administration of MTX, the majority of patients were a population with early RA since the median time between the diagnosis of RA according to the ACR criteria and randomisation into the study was 2.1–2.5 months. In this study, ACR20 response rates over time showed a statistically significant separation between SC and oral therapy beginning as early as week 16 (85% of those receiving SC MTX versus 77% of those receiving oral MTX; p  < 0.05).

The current recommendations for using MTX in RA patients differ on important points and do not universally address all factors linked to its management. The areas of disagreement in this context include the MTX titration (the recommendations range from MTX increments of 2.5-5 mg/week every 2–6 weeks) and the starting route of MTX administration (though most recommendations supported initiating oral MTX) [ 44 ]. This scoping review summarises the available experimental evidence from the literature on the optimal dosage and route of administration of MTX in RA. The included randomised clinical trials serve as evidence for better guiding the starting and optimisation of MTX in patients with RA in daily clinical practice, considering different doses and administration routes.

Concerning the starting dose in MTX- naïve patients, our reviewed data generally showed a linear dose-response relationship for several clinical study variables without a significant dose-to-toxicity correlation. In particular, when comparing starting MTX doses of 7.5 or 15 mg per week, no differences are found in terms of activity disease, laboratory values, or adverse events at 12 weeks. On the other hand, comparing start doses of 15 or 25 mg per week revealed that 25 mg per week is associated with lower rates of dose reduction due in part to remission and the need for a higher dose due to ineffectiveness at 12 months, with no differences in terms of withdrawals due to side-effects between groups. Regarding the dosage increase schedule, in our study, no significant differences were found between accelerated and standard regimens for clinical efficacy and safety outcomes at short (16 weeks) or longer-term (24 and 48 weeks). The intensive strategy has been proposed in patients with early RA to take advantage of the window of opportunity that exists at this stage [ 45 , 46 ]. However, the oral MTX doses in the two studies supporting these findings were greater than 15 mg. In this sense, it should be noted oral MTX absorption is limited by the saturation of the reduced folate carrier 1, a transmembrane transporter that is ubiquitous. This mechanism may become saturated if quantities of 20–25 mg are administered orally, thereby impeding absorption [ 47 ]. This mechanism could therefore explain why no significant differences were observed between the study groups. In addition, two aspects must be taken into account when interpreting these results. First, according to various abstracts presented at recent conferences [ 48 , 49 ], initiating treatment with MTX at higher concentrations is associated with more rapid responses in the short term, which could consequently reduce the accumulation of damage. Second, as hypothesised by the authors, the rapid dose escalation employed by both study groups may have nullified any potential advantage of initiating treatment with a higher dose [ 28 ]. It is essential to assess the effectiveness of increasing the oral MTX dose above 15 mg without switching to the SC route. In MTX- naïve patients, a potential strategy could be to increase the dose of MTX and change to the SC route when doses of 15 mg are exceeded, mainly for reasons of bioavailability, decreased oral efficacy and an increased incidence of gastrointestinal side effects above these doses. In this regard, in the multicenter trial [ 34 ] comparing the clinical efficacy and tolerability of SC versus oral administration of MTX at week 16, the ACR20 response was statistically greater with SC MTX (85%) compared to oral administration (77%; P<0.05).

Concerning the optimisation of MTX dosage after initial treatment failure, the increase in MTX doses was associated with a higher ACR20 response [ 34 ], a higher sustained remission rate for 2 years, and a mean time to sustained remission that was approximately 4 months shorter than other conventional strategies [ 35 ]. The trials comparing SC and oral administration routes after the first failure to MTX revealed that SC MTX is associated with improvements in ACR20 and ACR50 rates at 24 weeks with similar adverse event rates between groups [ 34 ]. Specifically, one of the included trials [ 34 ] demonstrated that switching from 15 mg orally to 15 mg SC resulted in an ACR20 response in an additional 30% of ACR20 non-responders. Unfortunately, none of the included studies compared these results to those obtained by increasing the oral dose of MTX without switching to the SC route. Although oral MTX is widely preferred due to patient preferences and low cost [ 9 ], the greater effectiveness of the parenteral route is consistent with pharmacokinetic findings. In fact, a cross-over study in adult patients with RA showed that at doses more than 25 mg/week, oral bioavailability is 0.64 [0.21–0.96] relative to the SC route [ 47 ]. On the other hand, in RA patients in remission with MTX, no differences have been found for other proposed strategies, such as escalating IM MTX doses or different administration regimens for maintaining RA remission (weekly vs. every-other-week) [ 40 ].

In the subgroup of patients with early RA, compared to the conventional approach, intensive strategy approaches (oral MTX 7.5 mg/week, + 5 mg/month) resulted in a significantly higher sustained remission rate and a shorter mean time to sustained remission after 1 and 2 years, as well as an improvement in clinical disease activity parameters in the first year (but not at 2 years).

Other authors have also reviewed the available literature on the best start dosage and route of administration of MTX in patients with RA as an evidence base for generating clinical practice recommendations [ 23 , 50 , 51 ]. Similar to our results, those studies have pointed out that higher start MTX doses (more than 25 mg/week orally) are associated with larger clinical effects sizes, or the SC administration is more effective than oral administration with no increased adverse effects. However, our results differ slightly from those reported by Visser et al. [ 50 ]. in that fast escalation with 5 mg/month up to 25–30 mg/week was associated with larger clinical effect sizes than slow escalation. In this sense, we did not find significant differences between the two therapeutic strategies. However, these contradictory results may be due to Visser et al. included studies published from 1950 to 2007, so patients enrolled in early studies may differ from those contained in more recent studies. Moreover, the RA patients included in the different monotherapy studies exhibited a degree of heterogeneity concerning the different duration of diseases and differences in the extent of prior MTX failure, and indirect comparisons were also included. On the other side, concerning the safety of MTX and contrary to what has previously been published, we discovered no significant difference in the risk for any adverse effects between different dose regimens or routes of administration for MTX in early RA patients. However, the data on side effects in the included trials was insufficient, and more research is needed to reach a more definitive conclusion.

Our study is, up to our knowledge, the first scoping review describing analysing different starting doses, the schedule for dose escalation, and routes of administration of MTX. In our study, we aimed to find all available experimental evidence on the optimal dosage and route of administration for MTX using a strict methodological search and selection strategy. In contrast to other previous reviews, we focused our search exclusively on randomised controlled trials since this design would potentially yield the highest level of evidence without the bias generally associated with observational studies. Although the published data with this design are scant (which is a contributing factor to the limited quantity of studies retrieved by the search), they constitute the best study design for evaluating the efficacy of interventions [ 52 ]. Furthermore, our analysis was conducted based on a comprehensive search in three major databases– PubMed, EMBASE, and Cochrane Library– and we included six additional trials not included in the previously published systematic reviews and published in the period 2013–2022 with a total of 1,566 subjects. Furthermore, a comprehensive examination of the reference lists of pertinent publications was performed in order to identify any papers that may have been overlooked during the electronic search process. Our results may help to explore further the optimal start doses and route of administration of MTX, contributing to designing future treatment strategies for patients with RA. However, our work has some limitations that should be addressed. Firstly, we included only 12 trials meeting our inclusion criteria due to the lack of other available, despite the fact that MTX is widely used to treat RA in everyday practice. Secondly, we included two trials reported as conference abstracts [ 32 , 33 ]. Although the information presented in conference abstracts is highly variable in reliability, accuracy, and level of detail [ 53 ], we decided to include those trials due to the limited number of randomised control trials published on the current topic. Thirdly, our review provided very little additional information regarding the rate of adverse effects in the compared groups. Considering the limitations mentioned above, we think that future prospective randomised controlled trials may significantly improve our understanding and are required to confirm our findings before any changes to therapy with MTX in everyday clinical practice could be justified. Meanwhile, our results may help to explore further the optimal start doses and route of administration of MTX, contributing to designing future treatment strategies for patients with RA.

In MTX- naïve patients with RA, the oral starting dose demonstrates a linear dose-response relationship for multiple clinical outcomes, but there is no correlation between dose and toxicity. MTX starting doses of 7.5 or 15 mg per week were not significantly different in terms of disease activity, laboratory values, or adverse events. However, starting with doses of 25 mg was associated with a higher dose reduction rate due to an increased remission rate, compared to 15 mg MTX, which showed that the effectiveness might be highest with a high initial dose without differences in withdrawals due to adverse effects. There were no significant differences between accelerated and standard regimens in terms of clinical efficacy and safety, either in the short or long term. Regarding the administration route, SC MTX is associated with higher ACR20 response rates than oral MTX. In RA patients who have failed the initial treatment with MTX, the stepwise increase in MTX doses is associated with a higher ACR20 response, a higher sustained remission rate, and a shorter mean time to sustained remission than other conventional strategies. In these patients, SC MTX is associated with improvements in ACR20 and ACR50 rates, whereas the incidences of adverse events are comparable between groups. In the subgroup of patients with early RA, SC MTX results in higher ACR20 response rates than oral administration, and intensive oral strategies demonstrate a significantly higher sustained remission rate, a shorter mean time to sustained remission, and an improvement in clinical disease activity parameters compared to conventional approaches. Based on our findings, optimising MTX treatment in terms of route and dose prior to concluding that MTX treatment has failed may be an evidence-based therapeutic strategy for MTX in RA patients. However, this approach should always be individually adapted, taking patient characteristics, the level of disease activity, and tolerability. Our results should help to increase uniformity in medical practice and improve the management of patients treated with MTX for RA.

Data availability

All data related to this work are included in the main text or the supplementary materials.

Abbreviations

American College of Rheumatology

Alanine aminotransferase

Aspartate aminotransferase

Area under the curve

Disease Activity Score for 28 joints using 3 variables

Conventional synthetic disease-modifying anti-rheumatic drug

Disease-modifying anti-rheumatic drug

Erythrocyte sedimentation rate

European League Against Rheumatism

Health Assessment Questionnaire

Intramuscular

Low Disease Activity

• Methotrexate
• Rheumatoid arthritis

Rheumatoid factor

Randomized controlled trial

Simplified disease activity index

Subcutaneous

Visual analogue scale

Almutairi K, Nossent J, Preen D, Keen H, Inderjeeth C. The global prevalence of rheumatoid arthritis: a meta-analysis based on a systematic review. Rheumatol Int 2021 [cited 2023 Jan 11];41:863–77. Available from: https://pubmed.ncbi.nlm.nih.gov/33175207/ .

Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA - J Am Med Association. 2018;320:1360–72.

Article   Google Scholar  

Fraenkel L, Bathon JM, England BR, St.Clair EW, Arayssi T, Carandang K et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis and Rheumatology 2021 [cited 2023 Jan 17];73:1108–23. Available from: https://pubmed.ncbi.nlm.nih.gov/34101376/ .

Smolen JS, Landewé RBM, Bergstra SA, Kerschbaumer A, Sepriano A, Aletaha D et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Ann Rheum Dis 2022 [cited 2023 Jan 17];82:3–18. Available from: https://ard.bmj.com/content/82/1/3 .

Schoels M, Knevel R, Aletaha D, Bijlsma JWJ, Breedveld FC, Boumpas DT, et al. Evidence for treating rheumatoid arthritis to target: results of a systematic literature search. Ann Rheum Dis. 2010;69:638–43.

Article   PubMed   Google Scholar  

Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364:263–9.

Pincus T, Yazici Y, Sokka T, Aletaha D, Smolen JS. Methotrexate as the anchor drug for the treatment of early rheumatoid arthritis. Clin Exp Rheumatol. 2003;21:179–85.

Google Scholar  

Giacomelli R, Cipriani P, Matucci Cerinic M, Fulminis A, Barattelli G, Pingiotti E, et al. Combination therapy with cyclosporine and methotrexate in patients with early rheumatoid arthritis soon inhibits TNFα production without decreasing TNFα mRNA levels. An in vivo and in vitro study. Clin Exp Rheumatol. 2002;20:365–72.

CAS   PubMed   Google Scholar  

Cipriani P, Ruscitti P, Carubbi F, Liakouli V, Giacomelli R. Methotrexate in rheumatoid arthritis: Optimizing therapy among different formulations. Current and emerging paradigms. Clin Ther2014 [cited 2023 Mar 14];36:427–35. Available from: https://pubmed.ncbi.nlm.nih.gov/24612941/ .

Cronstein BN, Aune TM. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 2020 [cited 2023 May 16];16:145–54. Available from: https://pubmed.ncbi.nlm.nih.gov/32066940/ .

Yu X, Wang C, Luo J, Zhao X, Wang L, Li X. Combination with methotrexate and cyclophosphamide attenuated maturation of dendritic cells: Inducing treg skewing and Th17 suppression in vivo. Clin Dev Immunol. 2013;2013.

Zhuang Y, Xu Z, Frederick B, de Vries DE, Ford JA, Keen M, et al. Golimumab pharmacokinetics after repeated subcutaneous and intravenous administrations in patients with rheumatoid arthritis and the effect of concomitant methotrexate: an open-label, randomized study. Clin Ther. 2012;34:77–90.

Article   CAS   PubMed   Google Scholar  

Zintzaras E, Dahabreh IJ, Giannouli S, Voulgarelis M, Moutsopoulos HM. Infliximab and methotrexate in the treatment of rheumatoid arthritis: A systematic review and meta-analysis of dosage regimens. Clin Ther 2008 [cited 2023 Mar 13];30:1939–55. Available from: https://pubmed.ncbi.nlm.nih.gov/19108784/ .

Bergstra SA, Allaart CF, Stijnen T, Landewé RBM. Meta-Regression of a Dose-Response Relationship of Methotrexate in Mono- and Combination Therapy in Disease-Modifying Antirheumatic Drug–Naive Early Rheumatoid Arthritis Patients. Arthritis Care Res (Hoboken) 2017 [cited 2023 Mar 14];69:1473–83. Available from: https://pubmed.ncbi.nlm.nih.gov/27992656/ .

Zhang A, Sun H, Wang X. Potentiating therapeutic effects by enhancing synergism based on active constituents from traditional medicine. Phytotherapy Research2014 [cited 2023 Mar 14];28:526–33. Available from: https://pubmed.ncbi.nlm.nih.gov/23913598/ .

Lucas CJ, Dimmitt SB, Martin JH. Optimising low-dose methotrexate for rheumatoid arthritis—A review. Br J Clin Pharmacol. 2019;85:2228–34.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Nair SC, Jacobs JWG, Bakker MF, Jahangier ZN, Bijlsma JWJ, Van Laar JM et al. Determining the lowest optimally effective methotrexate dose for individual RA patients using their dose response relation in a tight control treatment approach. PLoS One 2016 [cited 2023 Mar 14];11:e0148791. Available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148791 .

Tan JM, Reeve E, Fraser L, Proudman SM, Wiese MD. The Barriers and Enablers to the Use of Parenteral Methotrexate in Rheumatoid Arthritis Patients: A Scoping Review. Arthritis Care Res (Hoboken) 2023 [cited 2023 May 30];Available from: https://onlinelibrary.wiley.com/doi/full/ https://doi.org/10.1002/acr.25141 .

Striesow F, Brandt A. Preference, satisfaction and usability of subcutaneously administered methotrexate for rheumatoid arthritis or psoriatic arthritis: Results of a postmarketing surveillance study with a high-concentration formulation. Ther Adv Musculoskelet Dis. 2012;4:3–9. Available from: http://journals.sagepub.com/doi/ https://doi.org/10.1177/1759720X11431004 .

Stamp LK, Barclay ML, O’Donnell JL, Zhang M, Drake J, Frampton C et al. Effects of changing from oral to subcutaneous methotrexate on redblood cell methotrexate polyglutamate concentrations and disease activity in patients with rheumatoid arthritis. Journal of Rheumatology 2011;38:2540–7. Available from: http://www.jrheum.org/lookup/doi/ https://doi.org/10.3899/jrheum.110481 .

Brooks PJ, Spruill WJ, Parish RC, Birchmore DA. Pharmacokinetics of methotrexate administered by intramuscular and subcutaneous injections in patients with rheumatoid arthritis. Arthritis Rheum. 1990;33:91–4.

Visser K, Katchamart W, Loza E, Martinez-Lopez JA, Salliot C, Trudeau J et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: Integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E. Ann Rheum Dis2009 [cited 2023 Mar 13];68:1086–93. Available from: https://ard.bmj.com/content/68/7/1086 .

Mouterde G, Baillet A, Gaujoux-Viala C, Cantagrel A, Wendling D, Le Loët X, et al. Optimizing methotrexate therapy in rheumatoid arthritis: a systematic literature review. Joint Bone Spine. 2011;78:587–92.

Tricco AC, Lillie E, Zarin W, O’Brien KK, Colquhoun H, Levac D, et al. PRISMA Extension for scoping reviews (PRISMA-ScR): Checklist and Explanation. Ann Intern Med. 2018;169:467.

Arksey H, O’Malley L. Scoping studies: towards a methodological framework. Int J Social Res Methodology: Theory Pract. 2005;8:19–32.

van der Woude D, Young A, Jayakumar K, Mertens BJ, Toes REM, van der Heijde D et al. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug–free remission in rheumatoid arthritis: Results from two large early arthritis cohorts. Arthritis Rheum. 2009;60:2262–71. Available from: https://onlinelibrary.wiley.com/doi/ https://doi.org/10.1002/art.24661 .

Levac D, Colquhoun H, O’Brien KK. Scoping studies: advancing the methodology. Implement Sci. 2010;5:69.

Article   PubMed   PubMed Central   Google Scholar  

Dhir V, Singla M, Gupta N, Goel P, Sagar V, Sharma A et al. Randomized controlled trial comparing starting dose of 7.5 mg and 15 mg per week of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2013;72. Available from: https://www.embase.com/search/results?subaction=viewrecord &id=L71332844&from=export.

Dhir V, Singla M, Gupta N, Goyal P, Sagar V, Sharma A, et al. Randomized controlled trial comparing 2 different starting doses of methotrexate in rheumatoid arthritis. Clin Ther. 2014;36:1005–15.

Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ≥ 15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014;73:1549–51.

Schiff MH, Sadowski P. Oral to subcutaneous methotrexate dose-conversion strategy in the treatment of rheumatoid arthritis. Rheumatol Int. 2017;37:213–8.

Islam MS, Haq SA, Islam MN, Azad AK, Islam MA, Barua R, et al. Comparative efficacy of subcutaneous versus oral methotrexate in active rheumatoid arthritis. Mymensingh Med J. 2013;22:483–8.

Tsutsumino M, Sakai R, Kihara M, Amano K, Yoshimi R, Inoo M et al. THU0170 Outcomes of the rapid dose escalation of methotrexate in japanese patients with early rheumatoid arthritis; results from a randomized controlled trial. Ann Rheum Dis. 2017;76:265.3–266. Available from: https://www.embase.com/search/results?subaction=viewrecord &id=L621421109&from=export.

Braun J, Kästner P, Flaxenberg P, Währisch J, Hanke P, Demary W et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: Results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;58:73–81. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18163521 .

Verstappen SMM, Jacobs JWG, Van Der Veen MJ, Heurkens AHM, Schenk Y, Ter Borg EJ, et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer assisted management in early rheumatoid arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis. 2007;66:1443–9.

Jain S, Dhir V, Aggarwal A, Gupta R, Leishangthem B, Naidu S, et al. Comparison of two dose escalation strategies of methotrexate in active rheumatoid arthritis: a multicentre, parallel group, randomised controlled trial. Ann Rheum Dis. 2021;80:1376–84.

Furst DE, Koehnke R, Burmeister LF, Kohler J, Cargill I. Increasing methotrexate effect with increasing dose in the treatment of resistant rheumatoid arthritis. Journal of Rheumatology. 1989;16:313–20. Available from: http://www.ncbi.nlm.nih.gov/pubmed/2724250 .

Hobl EL, Mader RM, Jilma B, Duhm B, Mustak M, Bröll H, et al. A Randomized, Double-Blind, parallel, single-site pilot trial to compare two different starting doses of Methotrexate in Methotrexate-Naïve Adult patients with rheumatoid arthritis. Clin Ther. 2012;34:1195–203.

Lambert CM, Sandhu S, Lochhead A, Hurst NP, McRorie E, Dhillon V. Dose escalation of parenteral methotrexate in active rheumatoid arthritis that has been unresponsive to conventional doses of Methotrexate: a Randomized, Controlled Trial. Arthritis Rheum. 2004;50:364–71.

Luis M, Pacheco-Tena C, Cazarín-Barrientos J, Lino-Pérez L, Goycochea MV, Vázquez-Mellado J et al. Comparison of two schedules for administering oral low-dose methotrexate (weekly versus every-other-week) in patients with rheumatoid arthritis in remission: A twenty-four-week, single-blind, randomized study. Arthritis Rheum. 1999;42:2160–5. Available from: https://onlinelibrary.wiley.com/doi/ https://doi.org/10.1002/1529-0131 (199910)42:10%3C2160::AID-ANR17%3E3.0.CO;2-T.

Schnabel A, Reinhold-Keller E, Willmann V, Gross WL. Tolerability of methotrexate starting with 15 or 25 mg/week for rheumatoid arthritis. Rheumatol Int. 1994;14:33–8.

Arnett FC, Edworthy SM, Bloch DA, Mcshane DJ, Fries JF, Cooper NS, et al. The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988;31:315–24.

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis2010 [cited 2023 Nov 10];69:1580–8. Available from: https://pubmed.ncbi.nlm.nih.gov/20699241/ .

Valerio V, Kwok M, Loewen H, Winkler J, Mody GM, Scuccimarri R, et al. Systematic review of recommendations on the use of methotrexate in rheumatoid arthritis. Clin Rheumatol. 2021;40:1259–71.

Lard LR, Visser H, Speyer I, Vander Horst-Bruinsma IE, Zwinderman AH, Breedveld FC et al. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am J Med 2001 [cited 2023 Mar 28];111:446–51. Available from: https://pubmed.ncbi.nlm.nih.gov/11690569/ .

Nell VPK, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 2004 [cited 2023 Mar 28];43:906–14. Available from: https://pubmed.ncbi.nlm.nih.gov/15113999/ .

Hoekstra M, Haagsma C, Neef C, Proost J, Knuif A, Van De Laar M. Bioavailability of Higher Dose Methotrexate Comparing Oral and Subcutaneous Administration in Patients with Rheumatoid Arthritis. Journal of Rheumatology. 2004;31:645–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15088287 .

Krijbolder DI, Verstappen M, van Dijk BT, Dakkak YJ, Burgers LE, Boer AC et al. Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial. The Lancet 2022 [cited 2023 Jun 2];400:283–94. Available from: https://pubmed.ncbi.nlm.nih.gov/35871815/ .

Communication PÓSTERES.| Reumatología Clínica. [cited 2023 Jun 2];Available from: https://www.reumatologiaclinica.org/en-congresos-xlvi-congreso-nacional-sociedad-espanola-111-sesion-posteres-6095-mecanismo-accion-metotrexato-celulas-del-72474 .

Visser K, Van Der Heijde D. Optimal dosage and route of administration of methotrexate in rheumatoid arthritis: A systematic review of the literature. Ann Rheum Dis. 2009;68:1094–9. Available from: https://ard.bmj.com/lookup/doi/ https://doi.org/10.1136/ard.2008.092668 .

Bujor AM, Janjua S, LaValley MP, Duran J, Braun J, Felson DT. Comparison of oral versus parenteral methotrexate in the treatment of rheumatoid arthritis: a meta-analysis. PLoS ONE. 2019;14:1–11.

Higgins JPT GS, editor. Higgins. Cochrane Handbook for Systematic Reviews of Interventions. Wiley; 2019. Available from: https://onlinelibrary.wiley.com/doi/book/10.1002/9781119536604 .

Li G, Abbade LPF, Nwosu I, Jin Y, Leenus A, Maaz M et al. A scoping review of comparisons between abstracts and full reports in primary biomedical research. BMC Med Res Methodol 2017 [cited 2023 Mar 28];17:1–12. Available from: https://bmcmedresmethodol.biomedcentral.com/articles/ https://doi.org/10.1186/s12874-017-0459-5 .

Download references

Acknowledgements

Not applicable.

This Project was financed by Gebro Pharma, Barcelona, Spain.

Author information

Authors and affiliations.

Department of Rheumatology, Hospital Universitario Virgen del Rocío, Seville, Spain

Esteban Rubio-Romero

Department of Rheumatology, Hospital de la Santa Creu i Sant Pau, Universitat Autonòma de Barcelona, Barcelona, Spain

César Díaz-Torné

Department of Rheumatology, Hospital Rafael Méndez, Lorca, Spain

María José Moreno-Martínez

Gebro Pharma, Barcelona, Spain

Julen De-Luz

You can also search for this author in PubMed   Google Scholar

Contributions

E.R., C.D., M.M., and J.D. declare to have made substantial contributions to the conception, design of the work, the acquisition, analysis, and interpretation of data, to have drafted the work or substantially revised it, and to have approved the submitted version, as well as to have agreed both to be personally accountable for their own contributions and to ensure that questions concerning the accuracy or integrity of any.

Corresponding author

Correspondence to Esteban Rubio-Romero .

Ethics declarations

Ethics approval and consent to participate.

All authors confirm that they have read the journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Accordingly, this work is exempt from IRB review as it synthesises published literature.

Consent for publication

Competing interests.

The authors declare no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Supplementary material 2, rights and permissions.

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Rubio-Romero, E., Díaz-Torné, C., Moreno-Martínez, M.J. et al. Methotrexate treatment strategies for rheumatoid arthritis: a scoping review on doses and administration routes. BMC Rheumatol 8 , 11 (2024). https://doi.org/10.1186/s41927-024-00381-y

Download citation

Received : 03 August 2023

Accepted : 19 February 2024

Published : 05 March 2024

DOI : https://doi.org/10.1186/s41927-024-00381-y

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Anti-rheumatic agents
• Drug therapy
• Clinical protocols

BMC Rheumatology

ISSN: 2520-1026

• Submission enquiries: [email protected]
• General enquiries: [email protected]

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Pan Afr Med J
• PMC10957722

Acute methotrexate toxicity in a patient with psoriasis: a case report

Hind abouzahir.

1 Medico-Legal Institute, Ibn Rochd University Hospital, Casablanca, Morocco,

2 University Hassan II, Faculty of Medicine and Pharmacy, Casablanca, Morocco

Ahmed Belhouss

Hicham benyaich.

Aside from rheumatoid arthritis, methotrexate is also used to treat cancer, psoriasis, and other diseases. Side effects with methotrexate are possible, as they are with any medication. This drug is extremely potent and has the potential to produce serious adverse effects. Those who use this medication need to be tracked often. We provide a case of a patient with psoriasis vulgaris who died due to methotrexate administration without proper dosage verification. A female patient in her forties had a history of psoriasis vulgaris of the lower limbs. Under treatment, she developed acute methotrexate toxicity. This drug was taken as an intramuscular injection per day in an infirmary without checking that the dose regimen prescribed was per week. She developed extensive bullous and pustular lesions associated with digestive signs related to generalized toxiderma. But at that point, she had septic shock, which led to her death a few weeks after the methotrexate injection. The medical responsibilities of the doctor, pharmacist, and nurse were discussed. To conclude, methotrexate is not a killer drug in most cases, but it can be extremely harmful if it's overused. Acute toxicity is a potentially fatal condition, and a deeper understanding of its potential toxicity is still necessary.

Introduction

Methotrexate (MTX) is an antimitotic cytotoxic antagonist of folic acid. It is a cytostatic medication that is utilized as an anticancer agent in the treatment of cancer and other malignancies. It suppresses the immune system and reduces inflammation when taken in low doses [ 1 ]. Psoriasis has been treated with low doses of MTX for more than half a century since it is both an effective and safe medication. The principal form of elimination is through the kidneys, and the rate of this process is determined by both the dosage and the way in which it is taken [ 1 ]. Even at a low therapeutic dose, serious side effects can occur, including hepatic cirrhosis, pulmonary fibrosis, impaired renal function, erythema of the skin, and vasculitis. In order to properly diagnose acute MTX poisoning, this necessitates vigilant monitoring of renal function tests and blood counts, in addition to vigilantly scanning for mucosal sores or ulcerations in the skin. If the guidelines are not followed, there is a risk of severe toxicity, which could possibly result in death [ 2 ]. There are many articles that talk about adverse outcomes from MTX, and even fewer of those don't talk about fatalities that occurred because this medicine is so secure. Here, we report a case of a patient with psoriasis vulgaris who died of an MTX overdose without checking the dose prescribed.

Patient and observation

Patient information: a female patient in her forties who had a medical history of psoriasis vulgaris of the lower limbs for 5 years under regular treatment. She was treated with oral retinoids. She had aggravation of lesions, and then her treatment was switched to MTX (15 mg per week). However, following an error in the dispensing of the prescribed packaging of methotrexate by a pharmacy, the patient received a dose of 15 mg of MTX per day through intramuscular injection in a nursing facility without verifying the prescribed dosage.

Clinical findings and therapeutic interventions: the patient was admitted to the hospital with a fever and extensive bullous and pustular lesions associated with digestive signs related to generalized toxiderma that appeared on the third day after receiving a third intramuscular injection of MTX. Blood tests showed pancytopenia (hemoglobin 10.5 grams, white blood cells 800 cells/mm 3 , and platelet count 100,000 cells/mm 3 ) with normal renal and liver functions.

Follow-up and outcomes: her state evolution was complicated by rectorragia, melena, and dyspnea with persistant fever in a shock septic state. Despite the resuscitation measures, she died a few weeks after the MTX injection due to multiorgan failure.

Autopsy and histopathological findings: a medicolegal autopsy was requested by the prosecutor for suspicion of medical malpractice.

External examination of the corpse found pustular and bullous skin lesions in the thoraco-abdominal, back, and limbs, with impetiginized erosions covering the face. An autopsy revealed moderate sero-hematic pleural effusion and congestion of most organs, without any other specific lesions. Bone marrow samples were taken for histopathology examination, and the results showed cellular hypoplasia without neoplastic changes ( Figure 1 ).

bone marrow hypocellularity after methotrexate injection

Ethical approval/informed consent: this article does not contain any studies with human participants or animals performed by any of the authors. The information was collected and kept confidential during data entry, data analysis, communication, and publication of results. Anonymity was respected and the name of the deceased was not mentioned.

Informed consent statement: informed consent was obtained from the deceased’s family.

Methotrexate has become an important drug in the treatment of numerous chronic pathologies such as rheumatoid arthritis, psoriasis, lupus, Crohn's disease, and other diseases. The side effects of this medication are very serious, mainly affecting the bone marrow, liver, intestines, kidneys, lungs, skin, and blood [ 3 ].

Patients who suffer from severe forms of psoriasis typically receive treatment with methotrexate administered in low doses. It is a preferred option due to its therapeutic value, known side effect profile, and inexpensive cost, and it is typically recommended as a weekly dose. On the other hand, it has the potential to be extremely poisonous and even lethal [ 4 ]. Despite the fact that patients ingesting high dosages are more likely to experience toxicity, every dosing plan has the potential to cause toxicity [ 4 ]. Across the globe, there have been a number of documented deaths linked to the use of methotrexate. Patients have frequently taken methotrexate on a daily basis rather than once every seven days as a result of errors that were committed by the patient, the clinician, or the pharmacist. The most recent deadly incidents in New Zealand were recorded in 2006 and 2012, respectively [ 5 ].

A study of four different Danish registers identified 173 errors, with nearly two-thirds resulting in harm. Serious harm occurred in 15%, and there were 9 deaths (5%). These involved incorrect daily administration (31%), dosing errors (62%), and improper monitoring (9%). Serious outcomes, including deaths, were more common when hospital physicians made mistakes in prescribing involving daily administration rather than weekly administration [ 6 , 7 ]. In our case, taking MTX as a daily dose instead of a per-week dose was the most common cause of acute MTX toxicity. Pneumonitis, which may happen following a single dose of methotrexate, is the most common reason for death resulting from the use of methotrexate. Bone marrow suppression is another cause of mortality with multiple organ failure [ 8 - 10 ], and it occurred in our reported case.

In our case, the pharmacist disregarded the rules by handing over methotrexate without explanation and, moreover, did not comply with the doctor's prescription. Whereas the nurse carried out the MTX injection as a daily dose. Also, she should have contacted the prescribing clinician to check with him on the appropriate dose of this medication when there is doubt. All participants in our case were responsible: the dermatologist because of his prescription, which was lacking instructions with the dose; the pharmacist who didn´t explain the prescription; and the nurse who did not check how many times the prescribed dose should be taken.

However, the appeals court retained the responsibility of the dermatologist, who made a mistake by not writing clear instructions with the dose in his prescription. The court considered that the medical malpractice committed by the doctor made the patient lose her chance of survival. Consequently, the dermatologist was ordered to compensate the family of the deceased by providing financial restitution.

This study serves as a valuable reminder of the importance of recognizing and managing acute methotrexate toxicity in patients with psoriasis. By fostering increased awareness, implementing appropriate monitoring strategies, and tailoring treatment regimens, healthcare providers can mitigate the risk of adverse events and ensure safe and effective therapeutic outcomes for individuals with psoriasis receiving methotrexate therapy.

Cite this article: Hind Abouzahir et al. Acute methotrexate toxicity in a patient with psoriasis: a case report. Pan African Medical Journal. 2024;47(19). 10.11604/pamj.2024.47.19.39012

Competing interests

The authors declare no competing interests.

Authors' contributions

Hind Abouzahir performed autopsy cases of the study, analyzed and interpreted the patient data regarding the autopsy and the histopathology results; Ahmed Belhouss and Hicham Benyaich served as supervisors. All the authors read and approved the final version of this manuscript.