Optimal timing of liver stiffness assessment in methotrexate-treated rheumatoid arthritis patients

The cumulative methotrexate (MTX) dose threshold for initiating hepatic fibrosis screening in patients with rheumatoid arthritis (RA) remains undefined. This study aimed to identify this threshold and compare the utility of transient elastography versus the Fibrosis‑4 (FIB-4) index as a screening tool.

We conducted a cross-sectional study of consecutive RA patients receiving MTX who had documented normal hepatic evaluation before treatment initiation. All participants underwent clinical assessment, laboratory testing (liver function tests, complete blood count, inflammatory markers), transient elastography (FibroScan; EchoSens, Paris, France), and FIB‑4 index calculation. Receiver operating characteristic (ROC) curve analysis was performed to determine the optimal cumulative MTX dose cutoff for predicting liver fibrosis (defined as a liver stiffness measurement ≥ 6 kPa). Multivariable logistic regression was used to identify independent predictors of liver fibrosis.

We included 73 patients. The median liver stiffness was 4.1 kPa (IQR 3.45-4.95). Nine patients (12.3%) had evidence of liver fibrosis (≥ 6 kPa), of whom four (5.5%) had significant fibrosis (≥ 7.2 kPa). The median FIB‑4 index was 0.87 (IQR 0.61-1.20). Liver stiffness significantly correlated with age (r = 0.236, p = 0.045), cumulative MTX dose (r = 0.297, p = 0.003), MTX treatment duration (r = 0.279, p = 0.006), total bilirubin (r = 0.263, p = 0.025), and direct bilirubin (r = 0.622, p = 0.041). The FIB‑4 index correlated with age (r = 0.613, p  0.001), AST (r = 0.482, p  0.001), and bilirubin levels. A cutoff of 2990  mg cumulative MTX dose can discriminate between patients with normal liver function and those with liver fibrosis (sensitivity 100%, specificity 58%; AUC 0.793). This same cutoff can also discriminate between patients with a normal and those with an abnormal FIB‑4 index, albeit with lower sensitivity (69.5%) and specificity (58%) (AUC 0.587; p = 0.298).

A cumulative MTX dose of approximately 3 g represents a practical screening threshold for initiating liver fibrosis evaluation in RA patients. Transient elastography is superior to the FIB‑4 index for this purpose. Screening should be individualized based on metabolic risk factors, and elevated liver stiffness should prompt etiological investigation rather than automatic MTX discontinuation. Prospective studies are needed to validate these findings and assess long-term outcomes.