Table 3. The effects of methotrexate on liver fibrosis in chronic inflammatory disease patients.

MTX: methotrexate; AST: aspartate aminotransferase; ALT: alanine aminotransferase; RA: rheumatoid arthritis; SWE: shear wave elastography; JIA: juvenile idiopathic arthritis; DMARD: disease-modifying antirheumatic drug; LE: liver enzyme; LB: liver biopsy; BMI: basal metabolic index.

Author and year of publication	Purpose of the study	Number of patients/procedures used	Type of study	Conclusion
Lindsay et al. 2009 [15]	Assessment of liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose MTX therapy	54/liver biopsies	Prospective study	There was no correlation found between MTX dosing, duration, cumulative dose, or disease duration and hepatic fibrosis.
Bafna et al. 2021 [16]	Prevalence of liver fibrosis in rheumatoid arthritis patients on long-term MTX therapy	75/FibroScan	Cross-sectional	Long-term MTX use in RA patients was linked to increased liver stiffness. Obesity and increased waist circumference were common risk factors in patients with liver fibrosis. There was a significant correlation between higher cumulative MTX dose and FibroScan scores.
Kim et al. 2015 [17]	To investigate concerns about liver toxicities, including liver fibrosis, induced by long-term use of MTX in RA patients	185/Real-time shear wave elastography (SWE)	Prospective study	Significant liver fibrosis on SWE was observed in approximately 5% (9 out of 185 MTX-treated RA patients) and was associated with only a high BMI but not with the cumulative MTX dose (4,825 mg), implying that other comorbidities may play a more important role in liver fibrosis.
Park et al. 2010 [18]	To assess the degree of liver fibrosis with transient elastography and noninvasive biochemical methods in rheumatoid arthritis patients treated with methotrexate	177	Prospective study	In rheumatoid arthritis patients treated with a high cumulative dose of methotrexate, significant liver fibrosis is rare and is not accurately detected in patients with abnormal liver enzymes. The kilopascal values and levels of biochemical markers are not related with the cumulative dose of methotrexate but are related with the AST to ALT ratio, AST to platelet ratio index, and haptoglobin level.
Barbero-Villares et al. 2011 [19]	Evaluation of liver fibrosis in methotrexate (MTX)-treated patients by transient elastography	53/FibroScan	Prospective study	No correlation could be observed between liver stiffness and cumulative dose of MTX.
Lahdenne et al. 2002 [20]	Hepatotoxicity in patients with juvenile idiopathic arthritis (JIA) receiving long-term methotrexate therapy	36	Prospective study	Treatment of JIA with MTX at 20-30 mg/m2 in combination with disease-modifying antirheumatic drugs (DMARDs) and corticosteroids may contribute to minor, reversible liver abnormalities.
Laharie et al. 2006 [21]	To evaluate liver fibrosis with FibroScan and non-invasive biochemical methods in Crohn’s disease patients treated with methotrexate	54/FibroScan and liver biopsies	Prospective study	Significant liver fibrosis is rare in Crohn's disease patients treated with a high dose of methotrexate and is not accurately detected with liver enzyme abnormalities.
Laharie et al. 2010 [22]	Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases	518/FibroTest	Case-control study	Severe liver fibrosis is a rare occurrence in MTX patients and is unrelated to the total or cumulative dose.
Visser and van der Heijde 2009 [23]	To systematically review the literature on liver toxicity in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients treated with methotrexate (MTX), as an evidence base for generating clinical practice recommendations for the management of MTX and the indication for a liver biopsy (LB) in case of elevated liver enzymes (LEs)	47	Systematic review	According to this review, LE elevations during MTX therapy are a common but transient problem, that serial abnormal LE tests may be associated with liver pathology, but that cirrhosis/fibrosis caused by MTX is uncommon.
Maybury et al. 2014 [24]	To provide relevant data on methotrexate and liver fibrosis in people with psoriasis	429	Systematic review	According to liver biopsy data, the data report/findings from this paper show an association between MTX use and disease progression.