JRSM >
Volume 97, Number 11 >
Pp. 536-537
Rheumatic Diseases Unit, Ninewells Hospital & Medical School, Dundee DD1 9SY, Scotland, UK
E-mail: a.h.strang{at}dundee.ac.uk
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.
CASE HISTORIES
Case 1
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 29.0x109/L
(neutrophils 27.8), platelets 363x109/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
0.4x109/L (neutrophils 0.1x109/L) and the
platelet count to 27x109/L. The lowest haemoglobin recorded
was 7.7 g/dL, platelets 2x109/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.
Case 2
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
30.1x109/L (neutrophilis 28.0x109/L),
platelets 272x199/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 3.2x109/L (neutrophils
1.3x109/L) and the platelet count to
92x109/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 2.7x109/L (trough neutrophil count
0.1x109/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.
COMMENT
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.
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