1 Department of Rheumatology, Slotervaart Hospital,
2 Department of Internal Medicine, Slotervaart Hospital,
3 Department of Haematology, Academic Medical Center,
4 Department of Rheumatology, Free University Hospital and
5 Jan van Breemen Institute, Amsterdam, The Netherlands.
SIR, Bone marrow aplasia has been described very rarely as a complication of sulphasalazine therapy [15]. We report a case in which cyclosporin was used successfully to treat sulphasalazine-induced aplastic anaemia.
A 68-yr-old woman with recent-onset rheumatoid arthritis was admitted with pancytopenia. Four months before admission, treatment had been initiated with sulphasalazine, which she had never received before. At that time the erythrocyte sedimentation rate (ESR) was 75 mm/h and the C-reactive protein (CRP) concentration 32.2 mg/l. The haemoglobin concentration was 7.4 mmol/l, the leucocyte count 9.3x109/l and the thrombocyte count 341x109/l. The joint symptoms ameliorated after 8 weeks of sulphasalazine therapy. The patient had an unremarkable history, except for mild hypercholesterolaemia, for which she had used pravastatin for more than 1 yr. Other medications were Naprosyn (naproxen) and omeprazole, initiated several months before sulphasalazine was started. There were no complaints suggestive of haemorrhagic diathesis or infection.
After admission, vital signs were normal, body weight was 65 kg, and on physical examination there were no abnormalities. Laboratory testing revealed severe pancytopenia, with a platelet count of 11x109/l (normal range 150x109/l to 350x109/l), a haemoglobin concentration of 5.4 mmol/l and a leucocyte count of 1.4x109/l, with 3% neutrophils, 4% band forms and 88% lymphocytes.
The ESR was 110 mm/h and the CRP concentration 56 mg/l. The serum creatinine concentration was 58 µmol/l, lactate dehydrogenase 128 U/l, iron 26 µmol/l, bilirubin 14 µmol/l, alkaline phosphatase 89 U/l, aspartate aminotransferase 9 U/l and alanine aminotransferase 12 U/l. The vitamin B12 concentration was 146 pmol/l (normal range 145610 pmol/l) and folic acid 1.7 nmol/l (normal range 610 nmol/l). The direct Coombs test was positive and the haptoglobin concentration was 2.05 g/l (normal range 0.402.00 g/l). There were no autoantibodies against thrombocytes and the thrombopoietin concentration was raised (266 U/ml, normal range 432 U/ml).
Bone marrow examination showed severe aplasia with severe depression of megakaryocytes, myeloid cells and erythroid precursors. Repeated blood, urine and stool cultures showed no growth of pathogens. Serological testing revealed no recent infections with hepatitis A, B or C, parvovirus B19 or EpsteinBarr virus. Chest X-ray, abdominal X-ray and ultrasonic examination revealed no significant abnormalities.
As the results of the physical examination and laboratory tests made infection unlikely, sulphasalazine was considered to be the causal agent of this severe aplastic anaemia. This possibility was strengthened by the gradual decrease in the cell counts in the months before hospital admission. A relationship with pravastatin, omeprazol or Naprosyn treatment was not likely as these had been used for long periods before sulphasalazine. Moreover, aplastic anaemia associated with pravastatin, omeprazol or Naprosyn has not been described before. Although the direct Coombs test was positive, the antibodies detected were non-specific and did not lead to haemolysis, as the haptoglobin, bilirubin and lactate dehydrogenase concentrations were normal and there were no fragmentocytes. We have no clear explanation for the raised CRP concentration and ESR, although the latter could be explained at least partly by the anaemia.
Sulphasalazine was stopped and the patient was treated with repeated erythrocyte and thrombocyte transfusions, and folinic acid and granulocyte colony-stimulating factor were given. There was a gradual recovery of the leucocyte count. However, the haemoglobin concentration and particularly the thrombocyte count remained low (Fig. 1) despite increased numbers of cells of all three lines at the repeated bone marrow examination 5 weeks after admission. Laboratory tests showed no haemolysis. The need for transfusions persisted, and high doses of i.v. corticosteroids did not exert any effect on the thrombocyte count or the haemoglobin concentration. Thus, at day 76 cyclosporin treatment was initiated at a dose of 200 mg/day. After 1 month of treatment the thrombocyte count had increased and 4 months after the initiation of cyclosporin treatment it was around 50x109/l. Cyclosporin had to be stopped at this time because of renal toxicity. Thereafter, the thrombocyte count increased slightly and the creatinine value normalized. The haemoglobin concentration showed a similar pattern (Fig. 1
). No bleeding complications were observed during the entire period. At the last laboratory check (October 1999), the haemoglobin concentration was 7.0 mmol/l, the thrombocyte count 76x109/l and the leucocyte count 8.0x109/l, with normal differentiation. Repeated bone marrow examination (June 1999) showed almost complete normalization of the bone marrow.
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Cyclosporin treatment resulted in sustained (partial) recovery of the thrombocyte count and haemoglobin concentration. As there was a clear time-dependent relationship between the administration of cyclosporin and the recovery of thrombocyte count and haemoglobin concentration, it is unlikely, that this (partial) remission occurred spontaneously [6]. Hence, we suggest cyclosporin as a therapeutic option in (persistent) sulphasalazine-induced aplastic anaemia.
Notes
Correspondence to: M. T. Nurmohamed, Department of Rheumatology, B417, Free University Hospital, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
References