Severe methotrexate intoxication in a haemodialysis patient treated for rheumatoid arthritis

Henri Boulanger1, Vincent Launay-Vacher1, Philippe Hierniaux2, Jean-Baptiste Fau1 and Gilbert Deray1

1 Department of Nephrology, Pitie-Salpetriere Hospital, Paris, France 2 Clinique du Plateau, Bezons, France

Sir,

Methotrexate is extensively used in the treatment of neoplastic diseases. It is a folic acid antagonist that inhibits the dihydrofolate reductase involved in the synthesis of puric and pyrimidic bases [1]. Methotrexate is also used at low doses in the treatment of severe rheumatoid arthritis [2] when other therapies remain unsuccessful. In patients with rheumatoid arthritis and normal renal function, the recommended doses of methotrexate are within a range of 5–7.5 mg per week. This dose can be increased by steps of 2–5 mg, up to a maximal dose of 15 mg per week. Methotrexate is primarily cleared by the kidney [3]. Sixty to almost a hundred per cent of the dose is recovered unchanged in the urine. Although toxic accumulation of methotrexate is a potential risk in patients with renal failure, no recommendations are available for the low-dose treatment of rheumatoid arthritis.

Case.

We report the case of a 60-year-old woman treated by intermittent haemodialysis for end-stage renal disease due to diabetic nephropathy and hypertension. She had a severe and painful rheumatoid arthritis that did not improve with corticoids. Methotrexate was then administered at a weekly dose of 5 mg. Four days after the second administration, the patient developed pancytopenia and gastro-intestinal disturbances. Haemoglobin fell to 6.9 g/dl, platelets to 25000/mm3 and white blood cells to 1300/mm3. Polynuclear neutrophils were at 66/mm3. Gastro-intestinal disturbances with diarrhoea were associated with buccal ulcerations. These symptoms were characteristic of methotrexate intoxication [4,5]. The drug was discontinued and the patient was administered calcium folinate. The haemodialysis schedule was not modified and she went on with three 4-h sessions a week on a high-flux membrane without charcoal column. Because of the severity of the pancytopenia, the patient was placed in a sterile room for 1 week. Neither fever nor infection appeared and she completely recovered within 3 weeks.

Comment.

This observation shows that even so-called low doses of methotrexate should be reduced in patients with end-stage renal disease. Since the pharmacokinetics of methotrexate have not been studied in those patients, no dosing recommendations are available as yet. In another patient (personal observation), methotrexate was administered at a weekly dose of 2.5 mg for 3 weeks, without any side effects, and particularly no gastro-intestinal disturbances or haematological abnormalities. We thus suggest that in patients with end-stage renal disease, methotrexate dosage should be reduced to 2.5 mg per week. Any drug adjustment should be based on plasma dosage and clinical and biological tolerance. In patients with drug intoxication, haemodialysis with high-flux membrane with or without charcoal column may help in removing methotrexate. Indeed, haemodialysis clearance of methotrexate has been previously reported to be of 92±10 ml/min [6]. Since our suggestion is based on only one clinical observation, however, more extended experience is clearly needed before making definitive dosage recommendations.

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