title: Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients.
abstract: OBJECTIVE
  Low dose (10-25 mg/week) methotrexate is widely used for the management of systemic inflammatory diseases, and is considered to be relatively safe. Toxicity due to low dose MTX has been reported but is poorly characterized. We describe the clinical features, risk factors, and outcomes of low dose MTX toxicity in a large case series at our center.
  
  
  METHODS
  We conducted a retrospective case series of all adult (>18 years) patients hospitalized at Sheba Medical Center, between 2005 and 2012 for low dose MTX toxicity.
  
  
  RESULTS
  We identified 28 patients (age: 70.4±13.7 years, range: 33-88; 20 (71%) females) hospitalized for low dose MTX toxicity. Indications for MTX therapy included: rheumatoid arthritis (39.2%), psoriasis±arthritis (21.5%), polymyalgia rheumatica (10.8%) and other inflammatory conditions (28.5%). Pancytopenia was the most common manifestation of low dose MTX toxicity detected in 78.5% of the patients. Potential risk factors included acute renal failure, hypoalbuminemia, concurrent use of drugs known to interact with MTX, and dose errors. Serum MTX concentrations (n=20, mean 0.04±0.07 μg/mL range: 0-0.3) did not correlate with the degree of either neutropenia (r=-0.36; p=0.18) or thrombocytopenia (r=0.44; p=0.10). Seven (25%) patients died, all from pancytopenia followed by sepsis. Serum MTX concentrations did not differ between the patients who died from MTX toxicity (n=6; mean: 0.05±0.04 μg/mL) and those who survived the toxicity (n=14 mean 0.04±0.08; p=0.45).
  
  
  CONCLUSIONS
  Low-dose MTX toxicity can be life threatening, mainly due to myelosuppression. There is no rationale for MTX therapeutic drug monitoring in the setting of low-dose toxicity.
authors.affiliation: Department of Medicine A, The Chaim Sheba Medical Center, Ramat-Gan, Israel; Dr. Pinchas Borenstein Talpiot Medical Leadership Program 2013, The Chaim Sheba Medical Center, Ramat-Gan, Israel; Zabludovicz Center for Autoimmune Diseases, The Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler School of Medicine, Ramat-Aviv, Israel. Electronic address: kivitys@gmail.com.
authors.forename: Shaye
authors.initials: S
authors.lastname: Kivity
authors.affiliation: Zabludovicz Center for Autoimmune Diseases, The Chaim Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Zafrir
authors.affiliation: Institute of Clinical Pharmacology & Toxicology, The Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler School of Medicine, Ramat-Aviv, Israel.
authors.forename: Ronen
authors.initials: R
authors.lastname: Loebstein
authors.affiliation: Department of Medicine E, The Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler School of Medicine, Ramat-Aviv, Israel.
authors.forename: Rachel
authors.initials: R
authors.lastname: Pauzner
authors.affiliation: Department of Medicine E, The Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler School of Medicine, Ramat-Aviv, Israel.
authors.forename: Meir
authors.initials: M
authors.lastname: Mouallem
authors.affiliation: Department of Medicine E, The Chaim Sheba Medical Center, Ramat-Gan, Israel; Sackler School of Medicine, Ramat-Aviv, Israel.
authors.forename: Haim
authors.initials: H
authors.lastname: Mayan
mesh_terms: D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D018501:Antirheumatic Agents; D008727:Methotrexate
keywords: Drug toxicity; Methotrexate; Pancytopenia; Psoriasis arthritis; Rheumatoid arthritis