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Macrophage Activation Syndrome After Etanercept Treatment To the Editor: Macrophage activation syndrome (MAS), a secondary form of a hemophagocytic lymphohistiocytosis syndrome (HS), involves uncontrolled T cell-induced proliferation and activation of macrophages1. The subsequent cytokine storm and infiltration of tissues by phagocytosing macrophages result in an acute life-threatening disorder2. To date, MAS has been linked to various viral infections [Epstein Barr Virus (EBV), cytomegalovirus (CMV), and parvovirus], autoimmune disorders [rheumatoid arthritis (RA), systemic lupus erythematosus], lymphomas, and leukemias3. Case reports of rheumatoid patients with HS, although limited, have suggested an infective or RA precipitant4,5. Some anecdotal reports describe MAS after treatment with anti-tumor necrosis factor-a (TNF-a) agents6. We describe a patient with RA who may have developed MAS after taking etanercept. A 42-year-old woman with a history of RA presented to hospital with a 2 month history of fever, chills, night sweats, rigors, and a dry cough in August 2005. She had no recent travel or transfusion history and denied any history of headaches, respiratory, gastrointestinal, or genitourinary symptoms. Her medications at the time of admission consisted of prednisone (5–10 mg/day), folic acid, and ketoprofen (100 mg po bid). Immunosuppressive therapy with azathioprine had been discontinued 6 months before due to abnormal liver function tests, and etanercept was discontinued 2 months before because of unexplained fevers. Before this, she had been taking azathioprine for 15 years and etanercept for 2 years. During her 2 month period of fevers, management by her family doctor included a normal chest radiograph and a trial of antibiotics for suspect urinary tract infection. Examination revealed a temperature of 38°C, blood pressure 135/90 mm Hg, heart rate 96 beats/min, respiratory rate 18/min, and oxygen saturation of 99% on room air. Physical examination was significant for hepatosplenomegaly. There were no tender/effused joints, lymphadenopathy, or petechiae present. Her initial laboratory investigations revealed leukopenia (1200/mm3), anemia (hemoglobin 111 g/l), and hepatitis (ALP 218 IU/l, AST 200 IU/l, ALT 57 IU/l, and bilirubin 12 IU/l; ). Routine blood tests, urine, blood, stool, and sputum cultures were negative. A chest radiograph was normal. Viral serology and antigen testing for CMV, parvovirus, EBV, hepatitis B and C were negative. Serum polymerase chain reaction for EBV was negative. Admitting diagnosis was febrile neutropenia and she was given tobramycin and cefazolin. Her fevers lasted only during the initial period of her admission.
She developed progressive liver failure with icterus about 10 days after admission, with increasing international normalized ratio, partial thromboplastin time, and bilirubin levels. Additional laboratory values included C-reactive protein of 243 mg/l, erythrocyte sedimentation rate of 19 mm/h, D-dimers 4690 mg/l, ferritin 56,783 µg/l, and lactate dehydrogenase 4844 IU/l. A bone marrow examination showed several small poorly formed granulomas, as well as focal macrophages exhibiting hemophagocytic activity in the bone marrow (Figure 1). Stains for acid-fast bacillus and fungi were negative as well as immunohistochemistry for CMV and in situ hybridization for EBV. Our patient was diagnosed with MAS and given cyclosporine (5 mg/kg), intravenous immunoglobulin (0.5 mg/kg for 2 days), and dexamethasone (10 mg/m2). Then she developed a gram-negative bacilli septicemia and acute renal failure. She was transferred to the intensive care unit, where all immunosuppressant therapy was discontinued. She developed anasarca and 2 weeks later died of acute respiratory distress syndrome and multiorgan failure considered secondary to sepsis and uncontrolled MAS 6 weeks after admission.
Our patient developed MAS about 2 months after etanercept was discontinued due to her presenting complaint of a fever of unknown origin. The MAS precipitant may have been a preceding infection or pharmacologic agent, such as ketoprofen10. Patients with MAS typically present with a high grade fever, pancytopenia, hepatosplenomegaly, and lymphadenopathy with liver insufficiency. Patients may then develop purpura and mucosal bleeding. Diagnosis of a HS involves 8 criteria of which 5 must be satisfied7. During the course of this case, 6 of these criteria were achieved: the patient experienced a fever of at least 2 weeks, splenomegaly, cytopenia, hypertriglyceridemia (14.66 mmol/l)/ hypofibringenemia (0.2 g/l), macrophage infiltrate within the bone marrow with hemophagocytosis, and finally, hyperferritinemia (56,775 mg/l). Soluble CD25 and natural killer cell activity were not assayed. Evidence derived from studies using pediatric cohorts form the basis of treatment regimens for adult forms of HS8. Immunosuppressive therapy consisting of a course of etoposide, dexamethasone, and cyclosporine is supported by the best available evidence7. Etoposide was contraindicated because of her liver failure. An absence of randomized trials necessitates the use of case reports for insight into the management of MAS in adults. Treatment with immunosuppressants may cause a reduction in mortality in adults where HS was precipitated by an underlying autoimmune process. Patients presenting with an active infection required antibiotic therapy and a reduction in immunosuppressive therapy4. Other treatment modalities used for the treatment of HS include intravenous IgG, with reports of overall response rates of 59% in patients with HS9. However, early diagnosis and initiation of treatment remains critical for effective management of HS3. While MAS is relatively uncommon, our patient serves to heighten awareness of this condition as a potential complication of both RA and, possibly, anti-TNF-a agents used in treatment. CHARANJIT SANDHU, MD, Department of Occupational and Environmental Medicine, St. Michael's Hospital; ALDEN CHESNEY, MD; EUGENIA PILIOTIS, MD; RENA BUCKSTEIN, MD, Department of Hematology; SHARON KOREN, MD, Department of Rheumatology, Sunnybrook Health Science Centre, Toronto, Ontario, Canada. Address reprint requests to Dr. C. Sandhu, St. Michael's Hospital, 4 Shuter, 30 Bond Street, Toronto, Ontario M5B 1W8. E-mail: charanjit.sandhu@utoronto.ca 2. Schneider R, Laxer RM. Systemic onset juvenile rheumatoid arthritis. Baillieres Clin Rheumatol 1998;12:245-71. 3. Emmenegger U, Schaer DJ, Larroche C, Neftel KA. Haemophagocytic syndromes in adults: current concepts and challenges ahead. Swiss Med Wkly 2005;135:299-314. 4. Dhote R, Simon J, Papo T, et al. Reactive hemophagocytic syndrome in adult systemic disease: report of twenty-six cases and literature review. Arthritis Rheum 2003;49:633-9. 5. Reiner AP, Spivak JL. Hematophagic histiocytosis. A report of 23 new patients and a review of the literature. Medicine Baltimore 1988;67:369-88. 6. Ramanan AV, Schneider R. Macrophage activation syndrome following initiation of etanercept in a child with systemic onset juvenile rheumatoid arthritis. J Rheumatol 2003;30:401-3. 7. Henter JI, Tondini C, Pritchard J. Histiocyte disorders. Crit Rev Oncol Hematol 2004;50:157-74. 8. Henter JI, Samuelsson-Horne A, Arico M, et al. Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation. Blood 2002;100:2367-73. 9. Larroche C, Bruneel F, Andre MH, et al. Intravenously administered gamma-globulins in reactive hemophagocytic syndrome. Multicenter study to assess their importance, by the immunoglobulins group of experts of CEDIT of the AP-HP [French]. Ann Med Interne (Paris) 2000;151:533-9. 10. Hadchouel M, Prieur AM, Griscelli C. Acute hemorrhagic, hepatic, and neurologic manifestations in juvenile rheumatoid arthritis: possible relationship to drugs or infection. J Pediatr 1985;106:561-6. |
