Fatal Cytopenia Induced by Low-Dose Methotrexate in Elderly With Rheumatoid Arthritis. Identification of Risk Factors To the Editor: Methotrexate (MTX) is the disease-modifying anti- rheumatic drug (DMARD) most commonly used in the treatment of a variety of inflammatory rheumatological disorders. In the treatment of rheumatoid arthritis (RA), it is recommended as first-line DMARD by the American College of Rheumatology (ACR), alone or in combina- tion with other DMARDs and biological agents. We report the case of a female patient aged 82, diag- nosed with RA 3 years before. She was treated with MTX with oral doses of 7.5 mg/wk, together with weekly folinic acid. The patient came to the emergency room for lethargy. Physical examination disclosed the follow- ing: temperature 38.4°C, blood pressure 80/50 mm Hg, and heart rate 132 bpm. The laboratory data showed the following: hemoglobin 7.5 g/dL, white blood cells (WBC) 600/mm 3 , neutrophils 200/mm 3 , platelets 4000/mm 3 , creatinine 3.9 mg/dL, and total bilirubin 6.70 mg/dL. Chest computer tomography (CT) revealed diffuse areas of ground-glass opacities and bilateral pleu- ral effusion. Microbiological studies were negative (cul- tures of blood, pleural fluid, sputum, and urine). The patient was admitted to the Intensive Care Unit (ICU) for clinical pulmonary sepsis and severe pancy- topenia. The problem was interpreted as toxicity sec- ondary to MTX. She was treated with broad-spectrum antibiotics, hydration, granulocyte colony-stimulating factor, and IV methylprednisolone. She received trans- fusions of packed red blood cells and platelets. The patient died after 2 days. In patients with RA treated with MTX, the preva- lence of hematologic toxicity is estimated at 3%. The mortality of severe MTX-induced pancytopenia is unknown. We searched in PubMed to identify articles published during the last 11 years (2005–2016) dealing with MTX associated to severe pancytopenia in patients with rheumatic diseases to assess risk factors of poor prognosis. 1–4 We have identified a total of 94 patients in whom pancytopenia due to MTX was reported. The mortality was found to be 25%. After having added the patient described here, we looked for a relationship between pancytopenia and mortality and several variables (Table 1) by a multivariate logistic regression, calculating the odds ratio and 95% confidence intervals. Results show that sepsis was significantly associated to mortality, but the interaction with albumin reached a much more significant relationship (Table 1). The other variables showed only a trend probably because of the small sample size. We conclude that if a relation- ship between mortality and sepsis is to be expected, hypoalbuminemia may be an early and helpful marker in predicting a poor outcome in MTX-induced cytope- nia especially when other critical conditions are present. Antonella Mameli, MD Doris Barcellona, MD Francesco Marongiu, MD AOU Monserrato Department of Internal Medicine and Haemocoagulopathies Monserrato (Cagliari) Monserrato, Italy The authors have no financial or other conflicts of interest to disclose. REFERENCES 1. Preet Singh Y, Aggarwal A, Misra R, et al. Low-dose methotrexate-induced pancytopenia. Clin Rheumatol. 2007;26:84–87. Table 1. Risk factor for mortality in MTX-induced cytopenia. Risk factor Odds ratio 95% CI P Age .65 yrs old 1.42 0.2–7.7 ns MTX dosage .10 mg/wk 2.17 0.6–7.87 ns Sepsis 3.36 1.13–9.98 0.02 Renal failure 1.44 0.4–4.42 ns Low albumin 1.09 0.3–3.3 ns Concomitant drugs (.5) 1.6 0.4–5.47 ns Sepsis and low albumin 7.6 1.7–32.6 0.01 e106 Riley et al American Journal of Therapeutics (2017) 24(1) www.americantherapeutics.com Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.