Team: MTX Myth Busters

Base Article: Di Martino, V., Verhoeven, D.W., Verhoeven, F. et al. Busting the myth of methotrexate chronic hepatotoxicity. Nat Rev Rheumatol 19, 96–110 (2023). 

Authors The Duke Rheumatology Fellowship Program

1. Eric A. Wilson, MD, second year internal medicine resident
2. Courtney Bair, BA, fourth year medical student
3. Benjamin D. Lueck, fourth year medical student
4. Shannon Herndon, MD, first year rheumatology fellow
5. John B. Kellogg, MD, first year rheumatology fellow
6. Mafe Ortiz Kaemena, MD, first year rheumatology fellow
7. Jeffrey Shen, MD, second year rheumatology fellow
8. Nathaniel Harris, MD, PhD, second year rheumatology fellow
9. Sonali Bracken, MD, PhD, third year rheumatology fellow
10. Catherine Sims, MD, Clinical Associate Professor of Medicine
11. Lisa Criscione-Schreiber, MD, MEd, Professor of Medicine
12. David Leverenz, MD, MEd, Program Director

Team Overview

Team ‘MTX Myth Busters’ sets out to dismantle any misconceptions about methotrexate (MTX)-associated chronic hepatotoxicity. In addition to challenging historical evidence that suggests an association between long-term MTX use and the development of hepatic fibrosis, this team also devised a practical protocol to screen and monitor for liver disease in patients treated with MTX.

Our team’s story begins in the 1960s, when cases of MTX-associated liver fibrosis were first reported in patients with psoriasis¹. While reports of this association continued over the next few decades, our team astutely noted that non-alcoholic fatty liver disease (NAFLD) and non-alcoholic hepatic steatosis (NASH), disease processes that were incompletely identified until 2000², have a similar histologic appearance to so-called MTX-induced liver fibrosis³. Thus, given the similar prevalence of steatosis and fibrosis among patients receiving and not receiving MTX^4-5, they postulate that these historical studies documented previously unappreciated NASH, rather than the development of liver fibrosis secondary to chronic MTX exposure. To further drive this point to the basket, they share findings from two meta-analysis^6-7 showing no association between cumulative MTX dose and hepatic fibrosis.

From here, our team turns their attention to the role of non-invasive markers of fibrosis, such as the Fib-4 index, in monitoring patients on MTX. This is particularly enticing in those with underlying NAFLD, where there is a theoretically increased risk of hepatic fibrosis with MTX use. Stay tuned to see whether this and other elements of our team’s proposed hepatotoxicity monitoring protocol are adopted by rheumatologists across the globe!

References

1. Coe, R. O. & Bull, F. E. Cirrhosis associated with methotrexate treatment of psoriasis. JAMA 206, 1515–1520 (1968).
2. Sanyal, A. J. Past, present and future perspectives in nonalcoholic fatty liver disease. Rev. Gastroenterol. Hepatol. 16, 377–386 (2019).
3. Langman, G., Hall, P. M. & Todd, G. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. Gastroenterol. Hepatol. 16, 1395–1401 (2001).

Want to learn more?

See the Q&A on theMednet.org about the following question: What is your approach to monitoring for hepatic fibrosis in chronic methotrexate use?

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