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Severe pancytopenia following etanercept administration in rheumatoid arthritis

Dear Editor, Severe cytopenia, including neutropenia and anemia, are adverse effects that are rarely reported in patients receiving tumor necrosis factor (TNF)-blockers, including etanercept. The mechanism of etanercept-induced pancytopenia has not yet been established and little is known about it. Furthermore, patients with rheumatoid arthritis usually receive concomitant treatment with methotrexate, which can also induce this blood dyscrasia. A 78-year-old woman with rheumatoid arthritis had been receiving treatment with etanercept 50 mg once weekly since July 2011. She had also been taking daily prednisone and weekly methotrexate 20 mg for 7 years. Blood tests were performed before treatment with etanercept: platelets 289 9 10/lL, erythrocytes 3.54 9 10/lL, hematocrit 33.9%, hemoglobin 10.8 g/dL, neutrophils 4.5 9 10/lL, lymphocytes 1.5 9 10/lL and leukocytes 6.30 9 10/lL. The patient started to show clinical symptoms of weakness 1 month after commencing etanercept treatment. Another month later, she presented to the accident and emergency department of our hospital due to a worsening clinical situation. After routine laboratory tests, she was diagnosed with severe pancytopenia: platelets 122 9 10/lL, erythrocytes 2.81 9 10/lL, hematocrit 26.2%, hemoglobin 8.4 g/dL, neutrophils 950/lL, lymphocytes 290/lL and leukocytes 1.41 9 10/lL. The patient was immediately admitted to the Hematology Department and she was given prophylactic antibiotic treatment: piperacillin-tazobactam and targocid. Blood counts improved slightly after her initial treatment was discontinued: platelets 212 9 10/ lL, erythrocytes 3.68 9 10/lL, hematocrit 33.5%, hemoglobin 11.1 g/dL, neutrophils 10.35 9 10/lL, lymphocytes 6.9 9 10/lL and leukocytes 27.84 9 10/lL. Despite this she developed bilateral pneumonia. Four days after hospitalization, the patient was moved to the Intensive Care Unit (ICU). At the time of admission she had an Acute Physiology and Chronic Health Evaluation II (APACHE II) score of 25. The patient developed severe multilobar pneumonia as a complication of the initial immunodeficiency, which in turn led to acute respiratory distress syndrome. The intensive medicine specialists suspected that Aspergillus was the causal agent, but this could not be demonstrated. They used linezolid, piperacillin-tazobactam, azitromycin and fluconazol to treat the respiratory infection. She had no disseminated intravascular coagulation and there was no evidence of Felty′s syndrome. The patient finally died due to multi-organ failure secondary to septic shock of respiratory origin, with hemodynamic, respiratory, renal, hematological and metabolic dysfunction, refractory to medical treatment. Specialists could not identify any definite infection, maybe due to the previous prophylactic therapy. Post-marketing warnings about etanercept that have been issued by regulatory agencies and manufacturers relate to a possible risk of aplastic anemia and pancytopenia. This is also the case for methotrexate, but it is obvious that the chronology of events mean that we can rule out methotrexate as the drug that caused the pancytopenia. However, it can be considered as an exacerbating agent. With regard to the infectious complication, etanercept, methotrexate and prednisone weaken the immune system. Acquired infection could have been a result of the hospital environment and of the pancytopenia itself, together with the weak immune system secondary to immunosuppressive treatment. According to the official causality assessment scale used by the Spanish Pharmacovigilance System, applying the Karch and Lasagna scale, the causality relationship between etanercept and pancytopenia shows a category of ‘probable’. Moreover, using the Adverse Drug Reaction probability scale proposed by Naranjo et al., this case obtains a score of 5, which establishes a probable causality. Neither the drug label nor the Federal Drug Administration advises performing regular blood tests during