title: Biomarkers for methotrexate-induced liver injury: urinary protein profiling of psoriasis patients.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Rachel P L
authors.initials: RP
authors.lastname: van Swelm
authors.forename: Coby M M
authors.initials: CM
authors.lastname: Laarakkers
authors.forename: Marisol
authors.initials: M
authors.lastname: Kooijmans-Otero
authors.forename: Elke M G J
authors.initials: EM
authors.lastname: de Jong
authors.forename: Rosalinde
authors.initials: R
authors.lastname: Masereeuw
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Russel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000652:urine*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000652:urine*; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000009:adverse effects* / Q000493:pharmacokinetics; D008875:Middle Aged; D040901:Proteomics / Q000379:methods; D011565:Psoriasis / Q000188:drug therapy* / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D015415:Biomarkers; D008727:Methotrexate
keywords: ALT; Biomarker; ESI; Hepatic fibrosis; ITIH4; MALDI-TOF MS; MTX; Methotrexate; N-cadherin; PASI; PIIINP; RA; alanine aminotransferase; electrospray ionization; inter-alpha-trypsin inhibitor heavy chain H4; matrix-assisted laser desorption/ionization time-of-flight mass spectrometry; methotrexate; procollagen type III aminopeptide; psoriasis area and severity index; rheumathoid arthritis