Methotrexate and Liver Fibrosis: Is is the drug or the associated conditions?

 Have we overestimated the risk of methotrexate associated fibrosis ?

Methotrexate remains an important treatment option for refractory and tough to treat immune mediated hair loss conditions. Methotrexate is used for advanced alopecia areata in children and adults, as well as for the treatment of a small subset of patients with lichen planopilaris, frontal fibrosing alopecia and lupus.

Methotrexate has a number of potential short term and long term side effects. Many patients do not experience side effects but side effects including changes in blood counts, nausea, cough, lung irritation and liver irritation. An important concern has been the possible development of liver fibrosis, cirrhosis and liver failure in patients who use the drug for prolonged periods of time. MTX-induced liver injury has been recognized since the early 1970s.

It's not clear exactly how common liver fibrosis actually is. Some estimates have suggested that the risk of significant liver fibrosis may be as high as 5 %. Minor degrees of fibrosis may even occur much more commonly than that. However, studies are challenging to interpret and some have been subject to selection bias and have tended to underreport important risk factors like obesity, diabetes and alcohol use. Some studies have linked fibrosis to cumulative use but that has come into question as more and more studies from past are re-examined.

Studying Fibrosis with Methotrexate

It’s a challenging task to study the risk of fibrosis in methotrexate users. This is simply because the medical world rarely performs liver biopsies – which are the true gold standard for quantifying and staging liver fibrosis. The liver biopsy a highly invasive procedure with significant associated risks. These risks include bleeding and hospitalization. For example, 7 out of every 1000 biopsies are associated with significant bleeding (West et al,  2010). The rate of death is 1 in 10,000 - again due to bleeding (Rockey et al 2009).

Surrogates for Measuring Liver Fibrosis

Instead of doing so many liver biopsies, multiple non-invasive markers of liver fibrosis have emerged, including really important two groups of tests. The first is liver stiffness measurements through something known as transient elastography (TE). Transient elastography is a non-invasive technique that uses both ultrasound and low-frequency elastic waves to quantify liver fibrosis. Fibroscan is one example of a device used to perform the TE test.

The second is measurement of the enhanced liver fibrosis (ELF) though 3 blood tests that comprise a biomarker panel. This helps generate an ELF score. The ELF score combines the quantitative measurements of three serological markers, procollagen type III N-terminal peptide (PIIINP), tissue inhibitor of matrix metalloproteinase 1 (TIMP1) and hyaluronic acid (HA). The ELF score has been validated in large cohorts of patients with chronic liver diseases and showed a high accuracy to predict mortality and liver-related clinical outcomes. Some evidence suggests a significant correlation of ELF score of 11.3 and greater with biopsy proven cirrhosis. An ELF greater than 9.8 indicates advanced fibrosis.

Together liver stiffness by transient elastography and ELF score are two of the most validated non-invasive biomarkers of liver fibrosis accessible internationally. These were employed in the following study.

Attalah et al 2023

A new study from 2023 by Attalah and colleagues set out to further evaluate the risk of fibrosis in patients with psoriasis or rheumatoid arthritis who use methotrexate.

From 2014 to 2021, eligible adult patients with  and/or psoriasis were recruited from six different sites in the United Kingdom. The MTX group included patients receiving MTX for more than six months prior to recruitment. The unexposed group included patients who had never received MTX (no-MTX).

At the beginning of the study, all patients had liver stiffness measurement through TE (by a well-known test called Fibroscan), and blood tests were taken for a full serological liver profile and ELF biomarkers. Overall, there were 999 patients were included in the analysis. This included 876 exposed to MTX and 123 unexposed.

Patients in the MTX group were older (p <0.001), predominantly females (p <0.01), and more often diagnosed with RA (p <0.001). In contrast, those in the unexposed (no-MTX) group were more likely to drink alcohol >14 units/week (p <0.001) and have received regular non-steroidal anti-inflammatory drugs (NSAIDs) (p = 0.01) and metformin (p = 0.02). There was no significant difference in ethnicity; most participants were white. The difference in the metabolic risk factors between groups (such as hypertension, BMI, type 2 diabetes, dyslipidemia, and MAFLD) were not statistically significant.

There was no significant difference in liver enzymes or AST/ALT ratio between the groups.  Patients who were unexposed to MTX had higher median liver stiffness than those exposed (p = 0.049).  More patients in the non-MTX group met the cut off for cirrhosis.  Specifically, 11.6% met the cut-off for cirrhosis compared to 5.5 % exposed (p = 0.01.)

Interestingly, in multivariable analyses, neither MTX cumulative dose nor the duration of MTX use had a significant association with liver stiffness measurements.   The strongest independent association with liver stiffness was type 2 diabetes. Patients with diabetes had a threefold increased risk of liver stiffness compared to those who did not have diabetes (adjusted odds ratio [OR] = 3.19; 95% CI 1.95–5.20; p <0.001). Other factors that showed significant association with liver stiffness were age (p = 0.04), male sex (p = 0.02) and high BMI (p <0.001)

Regarding the ELF score and the surrogate blood tests, there was no statistically significant difference in PIIINP, HA or ELF score between exposed and unexposed patients.  2.9% of patients from each group had ELF >11.3 suggesting cirrhosis. However, there was no significant difference between groups.

When MTX duration was used as the independent variable, factors that were associated with elevated ELF were age, BMI and regular NSAIDs.

Summary and Conclusion

As we move into a new era of new immunosuppressants for hair loss, it is critically important that we understand the tools that are already there in the toolbox. Methotrexate is a good example of a medication that is helpful for many autoimmune hair loss issues. It’s widespread use is limited in the hair field due to many issues including 1) true side effects, 2) limited specialists who feel comfortable prescribing this medication as well as 3) patient and prescriber views on the potential side effects.

Fibrosis is a feared complication of methotrexate in the hair loss community. This study suggests that young healthy non-diabetic patients with low BMI are a low risk of developing fibrosis.

This study showed that neither MTX cumulative dose (median 4.8 g) nor duration of exposure (median of 6 years) was associated with liver fibrosis using two non-invasive markers, liver stiffness and ELF score. This data is reassuring to some degree.

Our hair loss patients with diabetes, obesity, advanced age and signifcant alcohol use may not be the best candidates for methotrexate. In this study, diabetes was the most significant independent risk factor associated with elevated liver stiffness, in addition to age, male sex, and BMI. Other studies have suggested that alcohol consumption may also be a risk factor to consider as well (Laharie et al, 2010)

For many years PIIINP has been used to determine the presence of liver fibrosis in those receiving MTX and in 2016 it was implemented as a screening and monitoring test for liver fibrosis by the British Association of Dermatologists. PIIINP is one of the biomarkers for fibrosis released during collagen synthesis; this marker forms one of the three components of the ELF score. While ELF score has been recommended by NICE for the non-invasive detection of advanced fibrosis in NAFLD, PIIINP on its own has been validated for the detection and assessment of non-alcoholic steatohepatitis.

In this study, the authors found ELF scores were similar among patients exposed and unexposed to MTX. In multivariable analyses, the cumulative dose of MTX was associated with an increase in the ELF score. However, in further sensitivity analysis, this association was only apparent in patients with rheumatoid arthritis. It was proposed that the association seen might reflect disease severity and inflammation at joints (rather than liver fibrosis) due to increased collagen turnover in inflammatory arthritis and hence, an increase of PIIINP. Regular use of NSAIDs was the most significant independent risk factor associated with elevated ELF greater than or equal to 9.8 (advanced fibrosis), in addition to age and BMI.

Other important studies point to good news for MTX

Other clinical studied provide reassuring news for MTX and the notion that prolonged MTX exposure does not lead to worse clinical outcomes. A meta-analysis Conway et al of 32 randomised controlled trials of MTX vs. comparator in adults with RA, psoriasis and inflammatory bowel disease indicated that exposure to MTX was not associated with risk of liver failure, cirrhosis, or death (relative risk 0.12; 95% CI 0.01–1.09)

This study is indeed in keeping with recent data in the literature.  A 2022 study in the Journal of Investigative Medicine, titled “Review of existing evidence demonstrates that methotrexate does not cause liver fibrosis” concluded that advanced liver fibrosis and cirrhosis previously attributed to methotrexate are in fact more likely to be caused caused by metabolic liver disease or other chronic liver diseases, but not by methotrexate itself. The authors proposed that studies in the past reporting fibrosis are complicate by confounding factors such as diabetes, obesity, pre-existing chronic liver disease but not methotrexate exposure.

Taken together the authors of the Attalah et al 2023 study propose that the risk of fibrosis may be overestimated. Some of the risk in RA and psoriasis may be due to the inherently higher  risk of metabolic syndrome and NAFLD in these patients.

We need good studies to better understand these risks in our hair loss patients. It is clear that patients with alopecia areata and lichen planopilaris – two conditions where we may consider use of methotrexate – may be at increased risk for metabolic syndrome.

MAIN REFERENCE

Atallah E et al. Risk of liver fibrosis associated with long-term methotrexate therapy may be overestimated. J Hepatol. 2023 Jan 23;S0168-8278(23)00020-X.

ADDITIONAL REFERENCES

Cheema HI et al. Review of existing evidence demonstrates that methotrexate does not cause liver fibrosis. J Investig Med. 2022 Oct;70(7):1452-1460.

Conway R, Low C, Coughlan RJ, O’Donnell MJ, Carey JJ. Risk of liver injury among methotrexate users: a meta-analysis of randomised controlled trials. Semin Arthritis Rheum 2015;45(2):156–162

Laharie D, Seneschal J, Schaeverbeke T, Doutre MS, Longy-Boursier M, Pellegrin JL, et al. Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case-control study. J Hepatol 2010;53(6):1035–1040.

Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009;49:1017-1044.

West J, Card TR. Reduced mortality rates following elective percutaneous liver biopsies. Gastroenterology 2010;139(4):1230–1237.

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