A 52-year old female with recently diagnosed rheumatoid arthritis (RA) and chronic kidney disease (baseline creatinine 2.6) was admitted with a 2 week history of fatigue, myalgias, mouth ulcers and a desquamating rash along her lower abdomen. She received a 10-day course of prednisone, fluconazole and amoxicillin from her primary care provider without improvement in her symptoms. The patient presented to the ER and was found to have severe pancytopenia (hemoglobin 6.2 g/dL, WBC 0.7 K/uL, platelets 24 K/uL) requiring blood transfusions.
Three weeks prior to her symptom onset she had been started on 10mg oral methotrexate weekly for rheumatoid arthritis for which she reported correct dosage adherence. Her serum CMV/HSV PCR, Parvovirus titers, ANA, and SPEP were unremarkable. Her methotrexate level was within normal limits. She was started on folic acid and leucovorin for suspected methotrexate toxicity resulting in improvement in all cell line counts along with resolution of her oral ulcers and skin lesions in one week. A diagnosis of severe acute methotrexate toxicity was established. Because of the rapid improvement no bone marrow biopsy was required.
Discussion:
Low-dose methotrexate (up to 25mg per week) is a relatively safe treatment option in patients with RA. The majority of adverse effects (including abnormal liver function tests, gastrointestinal side effects, oral ulcers, headaches and single cell-line cytopenias) are managed in an outpatient basis and rarely require hospitalization for severe acute toxicity. Low-dose methotrexate toxicity requiring hospitalization usually results when patients erroneously take the medication daily as opposed to weekly. It is unusual that severe acute toxicity occurs in patients with close rheumatologic follow up who take the medication as prescribed as illustrated in this case. Risk factors for development of toxicity include acute kidney injury, chronic kidney disease, and low albumin (all of which are relative contraindications that warrant dose-reduction.) In addition, this case also illustrates that methotrexate levels may not be reliable in the diagnosis of methotrexate toxicity and should not delay treatment. Frequent laboratory monitoring is important for patients who take methotrexate.
Conclusions:
Low-dose methotrexate can cause life-threatening severe acute toxicity in patients with rheumatoid arthritis. Although not an absolute contraindication, clinicians must be cautious when using methotrexate in patients with chronic kidney disease. Serum methotrexate levels are not reliable in establishing the diagnosis and treatment should be promptly started if toxicity is suspected. Finally, methotrexate should be taken with folic acid (or leucovorin) given that it prevents and limits toxicity without reducing effectiveness.