Biomarkers for methotrexate-induced liver injury: Urinary protein profiling of psoriasis patients

• High cumulative MTX dose in psoriasis patients is associated with hepatic fibrosis.
• Urine proteomics shows a differentiating profile after high cumulative MTX dose.
• Urine of psoriasis patients using MTX contains proteins related to hepatic fibrosis.
• Urinary biomarkers related to fibrosis might be used to monitor MTX hepatotoxicity.

Hepatic fibrosis is an adverse drug reaction of methotrexate (MTX) seen after long-term use in psoriasis patients. Currently, patients are monitored for MTX-induced hepatic fibrosis by performing liver biopsy, which is risky and burdensome for the patient, or by measuring plasma procollagen type III aminopeptide (PIIINP), which is not conclusive. The objective of this study was to identify novel predictive and preferably non-invasive biomarkers to monitor psoriasis patients for MTX-induced hepatic fibrosis.Urine samples were collected from 60 psoriasis patients treated with MTX and divided into two categories: low cumulative dose (<1500 mg MTX) and high cumulative dose (>1500 mg). Urinary proteins were profiled using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and identified using electrospray ionization LTQ. In urine of psoriasis patients with high cumulative MTX dose multiple proteins were identified that are associated with hepatic fibrosis, such as N-cadherin, inter-alpha-trypsin inhibitor heavy chain H4, haptoglobin and serotransferrin. These proteins may be candidate urinary biomarkers to monitor MTX-induced hepatic fibrosis.In conclusion, urinary proteome analysis identified a profile of potentially predictive biomarkers for MTX-induced hepatic fibrosis in psoriasis patients with high cumulative dose of MTX.