DEVELOPMENT OF FATAL BONE MARROW SUPPRESSION DURING D-PENICILLAMINE THERAPY IN THREE PATIENTS WITH RHEUMATOID ARTHRITIS

Abstract

Three patients with advanced rheumatoid arthritis developed fatal pancytopenia in one case and fatal agranulocytosis in the other two, during the course of D-penicillamine therapy. One patient with classical rheumatoid arthritis experienced fatal pancytopenia after four year treatment of 600mg/day of D-penicillamine which had successfully inhibited acute arthritic episodes during that time. Without any abnormal data suggestive of blood crisis in routine peripharal blood analysis, the patient had begun to complain of palpitation and arrhythmia. The later blood count revealed severe anemia (Hb 6.2g/dl)with leukopenia (2100/mm3) and no platelet. Every effort of suporting therapies including transfusions of fresh blood and platelets, injections of high doses of corticosteroid and protection against life-threatening infections seemed to be of no value for improvement of his pancytopenia and for sequential severe infections. He died from asphyxiation in air way bleeding after two months of hospitalization. The other two patients with classical rheumatoid arthritis experienced sudden catastrophes similar to the condition of sepsis with agranulocytosis. Until the attaks of high fever and acute arthritis, they had been treated with 400mg/day or 200_??_300mg/day of D-penicillamine only for one month with no beneficial effect for their arthritis. They were immediately hospitalized and were found to have leukopenia with little evidence of anemia and thrombocytopenia in their peripheral blood. On the second day in the hospital, agranulocytosis was seen without any changes of platelet and erythrocyte counts and was continued till the sixth day when they died from cerebral bleeding and septic shock respectively. Our three patients were characterized to possess advanced arthritic lesions, severe infections at the time of fatal blood disturbance and relatively heavy doses of anti-rheumatic drugs including corticosteroids, gold and non-steroidal anti-inflammatory drugs before the start of D-penicillamine. These suggest that our patients had been already suppressed hemopoiesis in bone marrow presumably due to several causes including rheumatoid arthritis itself and medications other than D-penicillamine. In addition, adrenal insufficiency caused by long use of steroid may play a role in sudden onset of severe infections which may result in further consumption of leukocytes. As known to have direct cytotoxic effect on bone marrow or to trigger the immunological reactions toward elimination of leukocytes and other cells, D-penicillamine may further suppress the bone marrow functions enough to be realized by routine blood analysis. Althouth our data of three patients are not enough to elucidate the mechanism of marrow suppression or leukopenia by D-penicillamine, learning of rare cases with fatal pancytopenia or agranulocytosis during D-penicillamine therapy may be important for revaluation of the drug and also general clinics of patients with rheumatoid arthritis.