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Methotrexate is one of the most widely prescribed disease-modifying drugs for rheumatoid arthritis. Since it is excreted largely unchanged via the kidney, renal impairment increases the concentration in blood.
A woman of 46 with seropositive rheumatoid arthritis had been treated for 9 years with 10 mg methotrexate and 5 mg folic acid. She took the methotrexate on Fridays. On a Saturday she was admitted to hospital with right lower lobe pneumonia and proved to be in acute renal failure: urea 23.0 mmol/L, creatinine 377 μmol/L, potassium 7.4 mmol/L. On previous routine testing these had been normal. Alanine aminotransferase was raised at 1861 IU/L (previously 7) but liver function tests were otherwise undisturbed. Haemoglobin was 11.1 g/dL, white cell count 29.0×109/L (neutrophils 27.8), platelets 363×109/L, C-reactive protein (CRP) 353 mg/L. She was treated with intravenous fluids, cefuroxime for two days, then cefuroxime plus gentamicin 3 mg/kg. She required invasive ventilation and renal dialysis for a few days. Renal biopsy showed acute tubular necrosis. By day 7 she had improved clinically, the CRP had dropped to 209 mg/L and the alanine aminotransferase was 160 U/L. Nevertheless, the haemoglobin fell to 10.4 g/dL, the white cell count to 0.4×109/L (neutrophils 0.1×109/L) and the platelet count to 27×109/L. The lowest haemoglobin recorded was 7.7 g/dL, platelets 2×109/L. She was treated with calcium folinate 15 mg four times daily for 48 hours, granulocyte-colony stimulating factor (G-CSF) and blood and platelet transfusions. Bone marrow biopsy showed hypocellular marrow. By discharge on day 19 the blood indices, liver function and renal function were normal. Methotrexate was restarted several months later without further incident.
A woman aged 47 with seronegative rheumatoid arthritis had been taking 12.5 mg methotrexate and 5 mg folic acid weekly for 5 years (on Wednesdays). She was admitted on a Wednesday having taken the usual dose of methotrexate; she had had general malaise, cough and drowsiness for 48 hours. Coarse crackles were heard at both lung bases, and despite an essentially normal chest radiograph she was thought to have a lower respiratory tract infection. She proved to be in acute renal failure with urea 11.5 mmol/L and creatinine 281 μmol/L (both of which had been within normal limits on previous routine follow-up). Haemoglobin was 9.7 g/dL, white cell count 30.1×109/L (neutrophilis 28.0×109/L), platelets 272×199/L, CRP 385 mg/L. Liver function was normal. She was treated with intravenous co-amoxiclav and intravenous fluids, and also with inotropes for a short spell. Renal physicians reviewed her regularly but she did not require dialysis. On day 8 she had improved clinically and CRP had dropped to 109 mg/L. However, the haemoglobin had fallen to 10.7 g/dL, the white cell count to 3.2×109/L (neutrophils 1.3×109/L) and the platelet count to 92×109/L. Over the next few days the haemoglobin stabilized and the platelet count gradually improved but the white cell count dropped to a minimum of 2.7×109/L (trough neutrophil count 0.1×109/L). She was given calcium folinate 15 mg four times daily for 4 days. By discharge on day 20 the blood indices had returned to normal apart from the haemoglobin, which remained around 10 g/dL. Methotrexate was subsequently reintroduced.
Both patients had taken their weekly methotrexate shortly before admission but in neither case did the clinicians initially worry about accumulation of the drug when biochemical tests revealed acute renal failure. A possible explanation for the patients’ pancytopenia is sepsis rather than methotrexate toxicity, but the time-course suggests otherwise: marrow suppression became evident only after the symptoms and signs of infection had improved and the CRP had fallen.
Methotrexate is excreted by glomerular filtration and active tubular secretion—hence the known requirement to stop the drug (or not to prescribe it) in patients with renal failure.1–3 In these circumstances, treatment with folinic acid deserves early consideration, especially if blood indices show unexpected declines. Methotrexate acts by inhibiting the formation of reduced folates; folinic acid is a fully reduced folate and can thus reverse the marrow toxicity. Patients taking the drug are already advised to consult a doctor about any symptom suggestive of infection. In our opinion, they should be warned also to stop the drug immediately if such symptoms develop.